Medicine and Health Sciences Commons^™

A Mechanism Linking Id2-Tgfβ Crosstalk To Reversible Adaptive Plasticity In Neuroblastoma, Lina Chakrabarti, Bi-Dar Wang, Norman H. Lee, Anthony D. Sandler

Pharmacology and Physiology Faculty Publications

The ability of high-risk neuroblastoma to survive unfavorable growth conditions and multimodal therapy has produced an elusive childhood cancer with remarkably poor prognosis. A novel phenomenon enabling neuroblastoma to survive selection pressure is its capacity for reversible adaptive plasticity. This plasticity allows cells to transition between highly proliferative anchorage dependent (AD) and slow growing, anoikis-resistant anchorage independent (AI) phenotypes. Both phenotypes are present in established mouse and human tumors. The differential gene expression profile of the two cellular phenotypes in the mouse Neuro2a cell line delineated pathways of proliferation in AD cells or tyrosine kinase activation/ apoptosis inhibition in AI …

Septins Of Platyhelminths: Identification, Phylogeny, Expression And Localization Among Developmental Stages Of Schistosoma Mansoni, Ana E. Zeraik, Gabriel Rinaldi, Victoria H. Mann, Anastas Popratiloff, Ana P.U. Araujo, Ricardo Demarco, Paul J. Brindley

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Septins are a family of eukaryotic GTP binding proteins conserved from yeasts to humans. Originally identified in mutants of budding yeast, septins participate in diverse cellular functions including cytokinesis, organization of actin networks, cell polarity, vesicle trafficking and many others. Septins assemble into heteroligomers to form filaments and rings. Here, four septins of Schistosoma mansoni are described, which appear to be conserved within the phylum Platyhelminthes. These orthologues were related to the SEPT5, SEPT10 and SEPT7 septins of humans, and hence we have termed the schistosome septins SmSEPT5, SmSEPT10, SmSEPT7.1 and SmSEPT7.2. Septin transcripts were detected throughout the developmental cycle …

Auditory Stimuli Mimicking Ambient Sounds Drive Temporal "Delta Brushes" In Premature Infants, Mathilde Chipaux, Matthew Colonnese, Audrey Mauguen, Laure Fellous, Mostafa Mokhtari, Oscar Lezcano, Mathieu Milh, Olivier Dulac, Catherine Chiron, Rustem Khazipov, Anna Kaminska

Pharmacology and Physiology Faculty Publications

In the premature infant, somatosensory and visual stimuli trigger an immature electroencephalographic (EEG) pattern, “delta-brushes,” in the corresponding sensory cortical areas. Whether auditory stimuli evoke delta-brushes in the premature auditory cortex has not been reported. Here, responses to auditory stimuli were studied in 46 premature infants without neurologic risk aged 31 to 38 postmenstrual weeks (PMW) during routine EEG recording. Stimuli consisted of either low-volume technogenic “clicks” near the background noise level of the neonatal care unit, or a human voice at conversational sound level. Stimuli were administrated pseudo-randomly during quiet and active sleep. In another protocol, the cortical response …

The Minimum M3-M4 Loop Length Of Neurotransmitter-Activated Pentameric Receptors Is Critical For The Structural Integrity Of Cytoplasmic Portals, Daniel T. Baptista-Hon, Tarek Z. Deeb, Jeremy J. Lambert, John A. Peters, Tim G. Hales

Pharmacology and Physiology Faculty Publications

The 5-HT₃A receptor homology model, based on the partial structure of the nicotinic acetylcholine receptor from Torpedo marmorata, reveals an asymmetric ion channel with five portals framed by adjacent helical amphipathic (HA) stretches within the 114-residue loop between the M3 and M4 membrane-spanning domains. The positive charge of Arg-436, located within the HA stretch, is a rate-limiting determinant of single channel conductance (γ). Further analysis reveals that positive charge and volume of residue 436 are determinants of 5-HT₃A receptor inward rectification, exposing an additional role for portals. A structurally unresolved stretch of 85 residues constitutes …

Blood Neutrophil Counts In Hiv-Infected Patients With Pulmonary Tuberculosis: Association With Sputum Mycobacterial Load, Andrew D. Kerkhoff, Robin Y. Wood, David M. Lowe, Monica Vogt, Stephen D. Lawn

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Increasing evidence suggests that neutrophils play a role in the host response toMycobacterium tuberculosis. We determined whether neutrophil counts in peripheral blood are associated with tuberculosis (TB) and with mycobacterial load in sputum in HIV-infected patients.

Methodology/Principal Findings

Adults enrolling in an antiretroviral treatment (ART) clinic in a Cape Town township were screened for TB regardless of symptoms. Paired sputum samples were examined using liquid culture, fluorescence microscopy, and the Xpert MTB/RIF assay. Absolute neutrophil counts (ANC) were measured in blood samples. Of 602 HIV-infected patients screened, 523 produced one or more sputum samples and had complete …

The Proportions Of People Living With Hiv In Low And Middle-Income Countries Who Test Tuberculin Skin Test Positive Using Either A 5 Mm Or A 10 Mm Cut-Off: A Systematic Review, Andrew D. Kerkhoff, Ankur Gupta, Taraz Samandari, Stephen D. Lawn

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Exosomes Derived From Hiv-1-Infected Cells Contain Trans-Activation Response Element Rna., Aarthi Narayanan, Sergey Iordanskiy, Ravi Das, Rachel Van Duyne, Steven Santos, Elizabeth Jaworski, Irene Guendel, Gavin Sampey, Elizabeth Dalby, Maria Iglesias-Ussel, Anastas Popratiloff, Ramin Hakami, Kylene Kehn-Hall, Mary Young, Caroline Subra, Caroline Gilbert, Charles Bailey, Fabio Romerio, Fatah Kashanchi

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Exosomes are nano-sized vesicles produced by healthy and virus-infected cells. Exosomes derived from infected cells have been shown to contain viral microRNAs (miRNAs). HIV-1 encodes its own miRNAs that regulate viral and host gene expression. The most abundant HIV-1-derived miRNA, first reported by us and later by others using deep sequencing, is the trans-activation response element (TAR) miRNA. In this study, we demonstrate the presence of TAR RNA in exosomes from cell culture supernatants of HIV-1-infected cells and patient sera. TAR miRNA was not in Ago2 complexes outside the exosomes but enclosed within the exosomes. We detected the host miRNA …

Spatially Explicit Modeling Of Schistosomiasis Risk In Eastern China Based On A Synthesis Of Epidemiological, Environmental, And Intermediate Host Genetic Data, Matthias Schrader, Torsten Hauffe, Zhijie Zhang, George M. Davis, Fred Jopp, Justin V. Remais, Thomas Wilke

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Schistosomiasis japonica is a major parasitic disease threatening millions of people in China. Though overall prevalence was greatly reduced during the second half of the past century, continued persistence in some areas and cases of re-emergence in others remain major concerns. As many regions in China are approaching disease elimination, obtaining quantitative data on Schistosoma japonicum parasites is increasingly difficult. This study examines the distribution of schistosomiasis in eastern China, taking advantage of the fact that the single intermediate host serves as a major transmission bottleneck. Epidemiological, population-genetic and high-resolution ecological data are combined to construct a predictive model capable …

Microproteinuria During Opisthorchis Viverrini Infection: A Biomarker For Advanced Renal And Hepatobiliary Pathologies From Chronic Opisthorchiasis, Prasert Saichua, Paiboon Sithithaworn, Amar R. Jariwala, David J. Diemert, Jiraporn Sithithaworn, Banchob Sripa, Thewarach Laha, Eimorn Mairiang, Chawalit Pairojkul, Maria V. Periago, Narong Khuntikeo, Jason Mulvenna, Jeffrey M. Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Approximately 680 million people are at risk of infection with Opisthorchis viverrini (OV) andClonorchis sinensis, with an estimated 10 million infected with OV in Southeast Asia alone. While opisthorchiasis is associated with hepatobiliary pathologies, such as advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA), animal models of OV infection show that immune-complex glomerulonephritis is an important renal pathology that develops simultaneously with hepatobiliary pathologies. A cardinal sign of immune-complex glomerulonephritis is the urinary excretion of immunoglobulin G (IgG) (microproteinuria). In community-based studies in OV endemic areas along the Chi River in northeastern Thailand, we observed that over half of …

Vbp15, A Glucocorticoid Analogue, Is Effective At Reducing Allergic Lung Inflammation In Mice, Jesse M. Damsker, Blythe C. Dillingham, Mary C. Rose, Molly A. Balsley, Christopher R. Heier, Alan M. Watson, Erik J. Stemmy, Rosalyn A. Jurjus, Tony Huynh, Kathleen Tatem, Kitipong Uaesoontrachoon, Dana M. Berry, Angela S. Benton, Robert J. Freishtat, Eric P. Hoffman, John M. Mccall, Heather Gordish-Dressman, Stephanie L. Constant, Erica K.M. Reeves, Kanneboyina Nagaraju

Pharmacology and Physiology Faculty Publications

Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel …

Vaccination With Human Hookworm Vaccine "Necator Americanus Aspartic Protease-1 M74" Generates Neutralizing Antibodies And A Potent Immune Response In Balb/C Mice, Amar R. Jariwala, Xi Chen, Mark S. Pearson, Brian Keegan, Jill B. Brelsford, Jordan L. Plieskatt, Alex Loukas, Bin Zhan, Peter J. Hotez, Jeffrey M. Bethony

Microbiology, Immunology, and Tropical Medicine Posters and Presentations

Backgound: Human Hookworm Infection, a neglected tropical disease infects more than 600 million people around the world. Hookworms ingest hemoglobin containing erythrocytes and Necator americanus Aspartic Protease-1 wild type (Na-APR-1wt) a hemoglobinase cleaves hemoglobin to form Heme and Globin. Globin is further digested by other gut enzymes and the nutritional end products are absorbed by the hookworm’s gut wall. Also, Heme which is toxic to hookworm is detoxified by the Necator americanus Glutathione Transferase-1 (Na-GST-1) a detoxification enzyme secreted by the gut of the hookworm. Necator americanus Aspartic Protease-1 M74 (Na-APR-1 M74) is the …

Break Out: Urogenital Schistosomiasis And Schistosoma Haematobium Infection In The Post-Genomic Era, Paul J. Brindley, Peter J. Hotez

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Association Between The Luteinizing Hormone/Chorionic Gonadotropin Receptor (Lhcgr) Rs4073366 Polymorphism And Ovarian Hyperstimulation Syndrome During Controlled Ovarian Hyperstimulation, Travis J. O'Brien, Mariah M. Kalmin, Arthur F. Harralson, Adam M. Clark, Ian Gindoff, Samuel J. Simmens, David Frankfurter, Paul Gindoff

Pharmacology and Physiology Faculty Publications

Background

The aim of this study was to determine the relationship between a purported luteinizing hormone/chorionic gonadotropin (LHCGR) high function polymorphism (rs4539842/insLQ) and outcome to controlled ovarian hyperstimulation (COH).

Methods

This was a prospective study of 172 patients undergoing COH at the Fertility and IVF Center at GWU. DNA was isolated from blood samples and a region encompassing the insLQ polymorphism was sequenced. We also investigated a polymorphism (rs4073366 G > C) that was 142 bp frominsLQ. The association of the insLQ and rs4073366 alleles and outcome to COH (number of mature follicles, …

Androgen Receptor-Target Genes In African American Prostate Cancer Disparities, Bi-Dar Wang, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas W. Jarrett, Harold A. Frazier, Steven R. Patierno, Norman H. Lee

Pharmacology and Physiology Faculty Publications

The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter …

Effects Of Treatment On Ige Responses Against Parasite Allergen-Like Proteins And Immunit To Reinfection In Childhood Schistosome And Hookworm Coinfections, Angela Pinot De Moira, Frances M. Jones, Shona Wilson, Edridah Tukahebwa, Colin M. Fitzsimmons, Joseph K. Mwatha, Jeffrey M. Bethony, Narcis B. Kabatereine, David W. Dunne

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Naturally occurring human immunity to both schistosomiasis and hookworm infection has been associated with IgE responses against parasite allergen-like proteins. Since the two helminths frequently coinfect the same individuals, there is growing advocacy for their concurrent treatment. However, both helminths are known to exert strong immunomodulatory effects; therefore, coinfected individuals could have immune responses different from those characteristically seen in monoinfected individuals. In this study, we measured changes in IgE, IgG1, and IgG4 responses to schistosome and hookworm antigens, including the allergen-like proteins Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1), SmTAL2, and Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2), following concurrent …

Htlv Tax: A Fascinating Multifunctional Co-Regulator Of Viral And Cellular Pathways, Robert Currer, Rachel Van Duyne, Elizabeth Jaworski, Irene Guendel, Gavin Sampey, Ravi Das, Aarthi Narayanan, Fatah Kashanchi

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Human T-cell lymphotropic virus type 1 (HTLV-1) has been identified as the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus infects between 15 and 20 million people worldwide of which approximately 2–5% develop ATL. The past 35 years of research have yielded significant insight into the pathogenesis of HTLV-1, including the molecular characterization of Tax, the viral transactivator, and oncoprotein. In spite of these efforts, the mechanisms of oncogenesis of this pleiotropic protein remain to be fully elucidated. In this review, we illustrate the multiple oncogenic roles of Tax by summarizing a recent …

Transcriptional Responses Of In Vivo Praziquantel Exposure In Schistosomes Identifies A Functional Role For Calcium Signalling Pathway Member Camkii, Hong You, Donald P. Mcmanus, Wei Hu, Michael J. Smout, Paul J. Brindley, Geoffrey N. Gobert

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Treatment for clinical schistosomiasis has relied centrally on the broad spectrum anthelmintic praziquantel; however, there is limited information on its mode of action or the molecular response of the parasite. This paper presents a transcriptional and functional approach to defining the molecular responses of schistosomes to praziquantel. Differential gene expression in Schistosoma japonicum was investigated by transcriptome-wide microarray analysis of adult worms perfused from infected mice after 0.5 to 24 hours after oral administration of sub-lethal doses of praziquantel. Genes up-regulated initially in male parasites were associated with “Tegument/Muscle Repair” and “Lipid/Ion Regulation” functions and were followed by “Drug Resistance” …

Thrombospondin-1 Signaling Through Cd47 Inhibits Self-Renewal By Regulating C-Myc And Other Stem Cell Transcription Factors, Sukhbir Kaur, David R. Soto-Pantoja, Erica V. Stein, Chengyu Liu, Abdel G. Elkahloun, Michael L. Pendrak, Alina Nicolae, Satya P. Singh, Zuqin Nie, David Levens, Jeffrey S. Isenberg, David D. Roberts

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. c-Myc, Klf4, Oct4, and Sox2 expression is elevated in CD47-null endothelial cells, in several tissues of CD47- and thrombospondin-1-null mice, and in a human T cell line lacking CD47. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells and in vivo, …

Cd56negcd16+ Nk Cells Are Activated Mature Nk Cells With Impaired Effector Function During Hiv-1 Infection, Jeffrey M. Milush, Sandra López-Vergès, Vanessa A. York, Steven G. Deeks, Jeffrey N. Martin, Frederick M. Hecht, Lewis L. Lanier, Douglas F. Nixon

Microbiology, Immunology, and Tropical Medicine Faculty Publications

BACKGROUND: A subset of CD3(neg)CD56(neg)CD16⁺ Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations.

RESULTS: Using CD7 as an additional NK cell marker, we found that CD3(neg)CD56(neg)CD16⁺ cells are a heterogeneous population comprised of CD7⁺ NK cells and CD7(neg) non-classical myeloid cells. CD7⁺CD56(neg)CD16⁺ NK cells are significantly expanded in HIV-1 infection. CD7⁺CD56(neg)CD16⁺ NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to …

The Expanding Genomic Landscape Of Autism: Discovering The 'Forest' Beyond The 'Trees', Valerie Wailin Hu

Biochemistry and Molecular Medicine Faculty Publications

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication, and restricted, repetitive behaviors. Because ASDs are among the most heritable of neuropsychiatric disorders, much of autism research has focused on the search for genetic variants in protein-coding genes (i.e., the "trees"). However, no single gene can account for more than 1% of the cases of ASD. Yet, genome-wide association studies have often identified statistically significant associations of genetic variations in regions of DNA that do not code for proteins (i.e., intergenic regions). There is increasing evidence that such noncoding regions are actively …