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Historical Remedies Versus Current Pathogens : Laboratory Investigation Of The Efficacy Of Traditional Herbal Remedies Against Present-Day Common Causes Of Bacterial Pneumonia, Eibhlin Mccarthy

Theses

Despite the medical advances of recent years, pneumonia is still a common disease in Ireland, accounting for approximately 7% of deaths in this country'. While national databases such as those run by CIDR and SARI ensure that incidences of systemic and notifiable infections such as tuberculosis are recorded, there are currently no available statistics on commonplace respiratory isolates within Ireland. This study analysed the available data on bacterial pathogens isolated from respiratory samples at a 355 bed Irish hospital over a one year period. Seasonal variations and resistance patterns were noted. The most frequently isolated pathogens were Staphylococcus aureus (27%), …

Effects Of Electrical Stimulation And Testosterone In Translational Models Of Peripheral Nerve Injury, Gina Monaco

Dissertations

As functional recovery following peripheral nerve injury is dependent upon successful regeneration and target reconnection, combinatorial treatments that enhance different regeneration events may be required for recovery from severe injuries. The neurotherapeutic effects of electrical stimulation (ES) and gonadal steroids have been demonstrated independently and in combination in extratemporal and intratemporal facial nerve injuries. The goals of the first aim were to develop a reliable intracranial facial nerve crush model and to investigate the therapeutic potential of combining ES with testosterone propionate (TP) in this most proximal injury model. Adult male rats were divided into intracranial sham-operated, intracranial crush, and …

Investigating The Role For Il-21 In Rabies Virus Vaccine-Induced Immunity., Corin L Dorfmeier, Evgeni P Tzvetkov, Anthony Gatt, James P Mcgettigan

Department of Microbiology and Immunology Faculty Papers

Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 55,000 deaths per year globally. A major goal in rabies virus (RABV) research is to develop a single-dose PEP that would simplify vaccination protocols, reduce costs associated with RABV prevention, and save lives. Protection against RABV infections requires virus neutralizing antibodies; however, factors influencing the development of protective RABV-specific B cell responses remain to be elucidated. Here we used a mouse model of IL-21 receptor-deficiency (IL-21R-/-) to characterize the role for IL-21 in RABV …

Comparison Of Heterologous Prime-Boost Strategies Against Human Immunodeficiency Virus Type 1 Gag Using Negative Stranded Rna Viruses., Tessa M Lawrence, Celestine N Wanjalla, Emily A Gomme, Christoph Wirblich, Anthony Gatt, Elena Carnero, Adolfo García-Sastre, Douglas S Lyles, James P Mcgettigan, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

This study analyzed a heterologous prime-boost vaccine approach against HIV-1 using three different antigenically unrelated negative-stranded viruses (NSV) expressing HIV-1 Gag as vaccine vectors: rabies virus (RABV), vesicular stomatitis virus (VSV) and Newcastle disease virus (NDV). We hypothesized that this approach would result in more robust cellular immune responses than those achieved with the use of any of the vaccines alone in a homologous prime-boost regimen. To this end, we primed BALB/c mice with each of the NSV-based vectors. Primed mice were rested for thirty-five days after which we administered a second immunization with the same or heterologous NSV-Gag viruses. …

Evaluation Of Higher Plant Virus Resistance Genes In The Green Alga, Chlorella Variabilis Nc64a, During The Early Phase Of Infection With Paramecium Bursaria Chlorella Virus-1, Janet M. Rowe, David D. Dunigan, Guillaume Blanc, James R. Gurnon, Yuannan Xia, James L. Van Etten

Nebraska Center for Virology: Faculty Publications

With growing industrial interest in algae plus their critical roles in aquatic systems, the need to understand the effects of algal pathogens is increasing. We examined a model algal host–virus system, Chlorella variabilis NC64A and virus, PBCV-1. C. variabilis encodes 375 homologs to genes involved in RNA silencing and in response to virus infection in higher plants. Illumina RNA-Seq data showed that 325 of these homologs were expressed in healthy and early PBCV-1 infected (≤60 min) cells. For each of the RNA silencing genes to which homologs were found, mRNA transcripts were detected in healthy and infected cells. C. variabilis …

‘‘Megavirales’’, A Proposed New Order For Eukaryotic Nucleocytoplasmic Large Dna Viruses, Philippe Colson, Xavier De Lamballerie, Natalya Yutin, Sassan Asgari, Yves Bigot, Dennis K. Bideshi, Xiao-Wen Cheng, Brian A. Federici, James L. Van Etten, Eugene V. Koonin, Bernard La Scola, Didier Raoult

Nebraska Center for Virology: Faculty Publications

The nucleocytoplasmic large DNA viruses (NCLDVs) comprise a monophyletic group of viruses that infect animals and diverse unicellular eukaryotes. The NCLDV group includes the families Poxviridae, Asfarviridae, Iridoviridae, Ascoviridae, Phycodnaviridae, Mimiviridae and the proposed family ‘‘Marseilleviridae’’. The family Mimiviridae includes the largest known viruses, with genomes in excess of one megabase, whereas the genome size in the other NCLDV families varies from 100 to 400 kilobase pairs. Most of the NCLDVs replicate in the cytoplasm of infected cells, within so-called virus factories. The NCLDVs share a common ancient origin, as demonstrated by evolutionary reconstructions that trace approximately 50 genes encoding …

Recent Advances On The Use Of Structural Biology For The Design Of Novel Envelope Immunogens Of Hiv-1, Shi-Hua Xiang

Nebraska Center for Virology: Faculty Publications

Many efforts have been made in the worldwide quest for a prophylactic HIV vaccine to end the AIDS pandemic, but none has yet succeeded. The lessons learned have repeatedly informed us that the traditional or conventional approaches directly using the pathogens or subunits will not be sufficient for an effective HIV/AIDS vaccine. Recent advances in structure-based technology have shown some promise in the quest for a better immunogen in HIV vaccine development. According to the basic binding structural relationship of an antigen and an antibody, structure-based antigen design could bring some hope for the development of an effective vaccine against …

Characterization Of A Serologic Marker Candidate For Development Of A Live-Attenuated Diva Vaccine Against Porcine Reproductive And Respiratory Syndrome Virus, Hiep Vu, Byungjoon Kwon, Marcelo De Lima, Asit K. Pattnaik, Fernando A. Osorio

School of Veterinary and Biomedical Sciences: Faculty Publications

DIVA (differentiating infected from vaccinated animals) vaccines have proven extremely useful for control and eradication of infectious diseases in livestock. We describe here the characterization of a serologic marker epitope, so-called epitope-M201, which can be a potential target for development of a live-attenuated DIVA vaccine against porcine reproductive and respiratory syndrome virus (PRRSV). Epitope-M201 is located at the carboxyl terminus (residues 161-174) of the viral M protein. The epitope is highly immunodominant and well-conserved among type-II PRRSV isolates. Rabbit polyclonal antibodies prepared against this epitope are non-neutralizing; thus, the epitope does not seem to contribute to the protective immunity against …

Influence Of Therapeutic Ceftiofur Treatments Of Feedlot Cattle On Fecal And Hide Prevalences Of Commensal Escherichia Coli Resistant To Expanded-Spectrum Cephalosporins, And Molecular Characterization Of Resistant Isolates, John W. Schmidt, Dee Griffin, Larry A. Kuehn, Dayna M. Brichta-Harhay

School of Veterinary and Biomedical Sciences: Faculty Publications

In the United States, the bla_CMY-2 gene contained within incompatibility type A/C (IncA/C) plasmids is frequently identified in extended-spectrum-cephalosporin-resistant (ESC^r) Escherichia coli strains from both human and cattle sources. Concerns have been raised that therapeutic use of ceftiofur in cattle may increase the prevalence of ESC^r E. coli. We report that herd ESC^r E. coli fecal and hide prevalences throughout the residency of cattle at a feedlot, including during the period of greatest ceftiofur use at the feedlot, were either not significantly different (P≥0.05) or significantly less (Pr E. coli shedding that follows ceftiofur …

Complete Closed Genome Sequences Of Mannheimia Haemolytica Serotypes A1 And A6, Isolated From Cattle, Gregory P. Harhay, Sergey Koren, Adam M. Phillippy, D. Scott Mcvey, Jennifer Kuszak, Michael L. Clawson, Dayna M. Harhay, Michael P. Heaton, Carol G. Chitko-Mckown, Timothy P. L. Smith

School of Veterinary and Biomedical Sciences: Faculty Publications

Mannheimia haemolytica is a respiratory pathogen affecting cattle and related ruminants worldwide. M. haemolytica is commonly associated with bovine respiratory disease complex (BRDC), a polymicrobial multifactorial disease.Wepresent the first two complete closed genome sequences of this species, determined using an automated assembly pipeline requiring no manual finishing.

Deep Sequencing And Genome-Wide Analysis Reveals The Expansion Of Microrna Genes In The Gall Midge Mayetiola Destructor, Chitvan Khajuria, Christie E. Williams, Mustapha El Bouhssini, R. Jeff Whitworth, Stephen Richards, Jeffrey J. Stuart, Ming-Shun Chen

School of Veterinary and Biomedical Sciences: Faculty Publications

Background: MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating post transcriptional gene expression. Gall midges encompass a large group of insects that are of economic importance and also possess fascinating biological traits. The gall midge Mayetiola destructor, commonly known as the Hessian fly, is a destructive pest of wheat and model organism for studying gall midge biology and insect – host plant interactions.

Results: In this study, we systematically analyzed miRNAs from the Hessian fly. Deep-sequencing a Hessian fly larval transcriptome led to the identification of 89 miRNA species that are either identical or very …

Development And Evaluation Of A Replicon Particle Vaccine Expressing The E2 Glycoprotein Of Bovine Viral Diarrhea Virus (Bvdv) In Cattle, John Dustin Loy, Jill Gander, Mark Mogler, Ryan Vander Veen, Julia Ridpath, Delbert Hank Harris, Kurt Kamrud

School of Veterinary and Biomedical Sciences: Faculty Publications

Background: Bovine viral diarrhea virus is one of the most significant and costly viral pathogens of cattle worldwide. Alphavirus-derived replicon particles have been shown to be safe and highly effective vaccine vectors against a variety of human and veterinary pathogens. Replicon particles are non-propagating, DIVA compatible, and can induce both humoral and cell mediated immune responses. This is the first experiment to demonstrate that Alphavirus-based replicon particles can be utilized in a standard prime/boost vaccination strategy in calves against a commercially significant bovine pathogen.

Findings: Replicon particles that express bovine viral diarrhea virus sub-genotype 1b E2 glycoprotein were …

Investigation Of The Protective Effects Of L-Carnitine And L-Arginine On Cardiovascular Changes Induced By Acth And Dexamethasone In Rabbits, Bi̇rkan Topçu, Metehan Uzun

Turkish Journal of Medical Sciences

To determine the protective effects of L-carnitine on cardiovascular changes that may occur in rabbits treated with adrenocorticotropic hormone (ACTH) and dexamethasone (DEX). Materials and methods: Rabbits of equal weight were divided into 7 groups with 6 animals in each. Blood samples were collected from all groups on days 1, 7, and 14, and blood pressure values and ECG monitoring were recorded. Nitric oxide (NO), creatine kinase MB (CK-MB), and troponin I (TnI) levels were determined in blood samples. Heart rate, QT, and corrected QT (QTc) values were calculated from ECG records. Results: The QT and QTc times were prolonged …

Retrospective Evaluation Of 104 Tinea Capitis Cases, Ömer Çalka, Serap Güneş Bi̇lgi̇li̇, Ayşe Serap Karadağ, Sevda Önder

Turkish Journal of Medical Sciences

Tinea capitis is a superficial scalp dermatophyte infection. Tinea capitis is particularly seen during childhood and is not usually seen after puberty. In untreated cases, it can be contagious and can progress to cicatricial alopecia. This study aimed to retrospectively evaluate cases of tinea capitis. Materials and methods: We evaluated 104 tinea capitis patients presenting to our dermatology clinic between 2007 and 2011. Results: Of these patients, 38 (36.5%) were female and 66 (63.5%) were male. The median age was 6.41 ± 3.4 years (range: 1-18 years old). The clinical types appearing in descending order were tinea capitis profunda (88.5%), …

The Phenotypic Expression Of Usp14 Deficiency Is Dependent Upon Genetic Background, Andrea Gail Marshall

All ETDs from UAB

The ubiquitin proteasome system (UPS) plays a critical role in regulating a diversity of cellular processes that are essential to neuronal function, such as synaptic transmission, axon guidance, and neurite outgrowth. Dysfunctions of the UPS are linked with many neurodegenerative disorders, including motor neuron diseases like spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), although it is not known how UPS dysfunction contributes to disease pathology. The proteasome, an approximate 2.5 megadalton protein complex comprised of a 20S core particle and 19S regulatory particle, is the site of ubiquitin-mediated proteolysis in the cell. Recent studies have linked ubiquitin specific …

Cd5 Regulation Of T Helper Cell Differentiation And Cytokine Signaling, Donald J. Mcguire

All ETDs from UAB

CD5 is expressed on T and B1a cells and is an important regulator of cell survival and activation. Engagement of CD5 promotes cell survival through the activation of the serine threonine kinase CK2. Mice with genetic abrogation of CD5 binding to CK2 (CD5∆CK2bd) exhibited reduced severity of experimental autoimmune encephalomyelitis that was associated with increased activation induced cell death. In addition to inhibiting cell death, CD5 activation of CK2 significantly enhances Th17 differentiation. Loss of CD5-CK2 signaling reduces the generation of Th17 cells despite an unexpected increase in pSTAT3 levels. The mechanisms of CD5's enhancement of Th17 differentiation have not …

Identification Of Claudin-1 As An Entry Factor In Dengue Infection And Development Of A High Throughput Screening Assay For Antivirals Against Dengue Virus, Pulin Che

All ETDs from UAB

Dengue virus (DENV) has become a huge public health concern around the world with no vaccine or antivirals available. More than one-third of the world's population is living in areas at risk of infection. To conquer the dengue disease, a better understanding of virus-host interactions and development of the appropriate therapeutic treatments are required. In this dissertation, we first broadly reviewed the factors involved in dengue viral entry and the role of tight junctions as a pathogen target. Second, we developed, optimized and validated a high throughput screening (HTS) assay for anti-dengue virus drug screening. Taking advantage of using live …

Selection And Evolution Of Pneumococci In Response To Conjugate Vaccines, Christina M. Croney

All ETDs from UAB

Pneumococcal conjugate vaccines (PCVs) containing subsets of the >90 capsular polysaccharide antigens have been successful as a means of decreasing invasive and non-invasive pneumococcal disease worldwide. However, this success is limited to the specif-ic capsular serotypes against which PCVs are formulated and studies have reported the increase of nonvaccine serotypes. The 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the United States in 2010 for the prevention of invasive pneumococcal disease (IPD) and otitis media and was released without efficacy data. In this study we set out to 1) determine potential efficacy for invasive and noninvasive pneumococcal disease and 2) …

Neutropenia And Progenitor Cell Mobilization In Ap3-B1 Mutant Pearl Mice, Matthew Vallejo

All ETDs from UAB

Mutations in the AP3-ß1 gene are known to cause Hermansky-Pudlak syndrome type 2 (HPS2) in humans and canine cyclic hematopoiesis (CH) in gray collie dogs. HPS2 patients have severe congenital neutropenia (SCN), and dogs have cyclic neutropenia (CN). The mechanism behind neutropenia is uncertain. Pearl mice have an AP3-ß1 mutation, but whether they actually have neutropenia has not yet been evaluated. This dissertation presents a discussion of the evaluation of neutropenia in pearl mice, hematopoietic progenitor cell mobilization defect in pearl mice and finally an evaluation of methods of dog-to-mouse xenotransplantation to establish a xenotransplant model of the dog hematopoietic …

Glioma-Vasculature Interactions, Stacey Watkins

All ETDs from UAB

Malignant gliomas are highly invasive brain tumors, which lack effective treatment options. To date, the standard therapy includes surgical debulking followed by chemotherapy and radiation. Despite efforts to eradicate the disease, the median patient survival time is only 14 months. In an attempt to discover novel therapies, research has focused on understanding the heterogeneous biological mechanisms employed by these cells. Uniquely, they do not metastasize through the vasculature or lymphatics like other solid cancers but alternatively, glioma cells utilize the abluminal surface of the vasculature to guide invasion and migration throughout the brain. The intimate association between glioma cells and …

Hur Regulation In Central Nervous System Disorders, Crystal G. Wheeler

All ETDs from UAB

In inflammatory diseases of the central nervous system (CNS), astrocytes play a major role in the systemic response to disease by either enhancing or limiting the inflammatory response through secretion of growth factors or cytokines. HuR RNA binding protein regulates many genes involved in inflammation. Inflammatory diseases such as brain tumors, Amylotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), have been linked to HuR, by our laboratory and others. To determine whether astrocytic overexpression of HuR would regulate inflammation in diseases of the CNS, we designed a transgenic mouse in which the HuR gene is overexpressed. In the first study, …

Role Of Gsk3 In The Immunopathogenesis Of Eae, Amber Rowse

All ETDs from UAB

Lithium, a glycogen synthase kinase 3 (GSK3) inhibitor, ameliorates experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS) in different mouse models. However, the mechanism of lithium's attenuation of EAE and the role of GSK3 in these processes are currently unknown. IFN-g producing Th1 cells and IL-17-producing Th17 cells are both effector cells in MS and in EAE models. However, relapsing remitting MS patients segregate into Th1 or Th17 serum cytokine signatures and each is differentially responsive to IFN-ß therapy, a first line therapy for MS. Studies in this dissertation revealed a differential effect of lithium on Th1 …

Role Of Endothelial Mannose Residues In Monocyte Adhesion Under Flow, David Wayne Scott

All ETDs from UAB

Atherosclerosis is a chronic inflammatory disease of the vessel wall and underlying cause of most cardiovascular disease. Much is understood about the nature of atherosclerosis development, including contributions from leukocytes that drive the disease process forward. The general process by which leukocytes are trafficked to sites of atherosclerosis development, and sites of inflammation in general, is understood and relies upon endothelial expressed protein adhesion molecules which serve as ligands for cognate leukocyte receptors. While these adhesion molecules share the post-translation modification of N-glycosylation, relatively little is known as to what functional role these modification plays in: i) interactions of leukocytes …

Epigenetic Markers In The Developing Postnatal Brain, Rebecca Kaye Simmons

All ETDs from UAB

Epigenetic mechanisms provide a critical and plausible mechanism by which genes and the environment can interact and have been implicated in a number of diseases and disorders. In order to better understand how epigenetic mechanisms go awry in a diseased brain we must first understand how epigenetic mechanisms unfold during normal development. The present body of work begins to examine the role of DNA methylation in normal development and how it may contribute to a rodent model of emotion dysfunction. Using a variety of techniques, we evaluated the transcript, protein and functional output levels of DNA methyltransferase1, -3a, and -3b …

Regulation Of Capsule By Cpsa And Global Regulatory Networks In Streptococcus Pneumoniae Type 2, Kanupriya Gupta

All ETDs from UAB

Streptococcus pneumoniae is a major human pathogen that can reside asymptomatically in the nasopharynx before causing invasive disease by entering systemic sites. This involves regulation of colonization and virulence factors including capsule. cps2A, the first gene of the capsule (cps) locus has been proposed to regulate capsule, however its exact role and mechanism is not well understood. A complete deletion of cps2A resulted in enhanced capsule levels, with no alteration in the transcription levels of cps genes. Complementation of Cps2A restored wild type levels of capsule. Expression of the C-terminal tail alone was able to partially complement the deletion strain, …

Potential Roles Of The Immunostimulatory Signals Il-15 And Mica In Oncolytic Hsv-1 Therapy For Malignant Glioma, David Curtis Gaston

All ETDs from UAB

Malignant gliomas are the most frequently diagnosed and the most fatal primary brain tumors. Innovative therapeutic approaches are necessary to combat these devastating cancers, and oncolytic herpes simplex virus type-1 (oHSV) deleted of the γ134.5 neurovirulence gene is a promising adjunctive therapy. The primary mechanism of tumor clearance by oHSV is lytic replication specifically within malignant cells. oHSV also stimulates tumor infiltration of cytotoxic immune effector cells that can participate in tumor clearance. However, cytotoxic immune cells target oHSV as well as tumor, which may limit therapeutic efficacy. Further knowledge regarding the nature of these interactions and how the interactions …

Virus-Induced Inflammation And Central Nervous System Development, Kate Kosmac

All ETDs from UAB

Congenital human cytomegalovirus (HCMV) infection is a complex cause of central nervous system (CNS) disease. Infection with HCMV during pregnancy results in virus transmission across the placenta and infection of the fetus. With a seroconversion rate in pregnant women between 1% and 4%, HCMV is the most frequently transmitted virus from mother to developing child. Each year between 2,000 and 4,000 infants will suffer from long-term neurologic deficits as a result of congenital infection. The well documented CNS sequelae resulting from congenital HCMV infection have described a wide range of damage without a specific set of pathologic markers for disease. …

The Molecular Mechanisms Underlying Cardiac Hypertrophy Due To Volume Overload., Justin Andrew Barnes

All ETDs from UAB

Mitral regurgitation (MR) is a common form of heart disease, but there are no approved medical therapies for MR or other cardiovascular conditions associated with hemodynamic volume overload (VO) and eccentric remodeling. We have previously shown that a standard heart failure treatment, ß-adrenergic system blockade (ß-RB), improves function in animal models of VO and in MR patients without attenuating the adverse eccentric hypertrophy that occurs in conjunction with VO. This paradox highlights how poorly we understand eccentric remodeling of the heart, and a better understanding of the molecular mechanisms at work in VO must be obtained before we can develop …

Adapter Based Strategies For Adenovirus Vector Retargeting To T Lymphocytes, Matthew S. Beatty

All ETDs from UAB

Adenoviruses are the most commonly used gene therapy vector for cancer therapy clinical trials. While adenovirus has shown a great track record in a variety of cancer therapeutics it has not progressed as a vector system for the modification of T lymphocytes. One of the major roadblocks towards utilizing adenovirus for T cell therapy is the lack of coxsackie virus and adenovirus receptor on the cell surface of T cell lineages. Exploitation of alternative receptors has allowed adenovirus vectors to be utilized in a variety of cell types that native adenovirus type 5 cannot infect. Thus, retargeting adenovirus to an …

Epigenetic Regulation Of Kir4.1 In Normal And Pathological States: A Focus On Spinal Cord Injury, Sinifunanya Elvee Nwaobi

All ETDs from UAB

Astrocytes are the most numerous cells in the brain and play a critical role in maintaining homeostatic extracellular potassium ([K+]e). This process is mediated, in part, by a glial-specific, inwardly rectifying potassium channel, Kir4.1. Pharmacological inhibition, knock down, or complete knock out of this channel results in astrocytes with increased membrane resistance, depolarized resting membrane potential, and altered extracellular potassium dynamics. Subsequent to the dysregulation of [K+]e, Kir4.1 knockout (KO) animals suffer from ataxia, seizures, and early postnatal death. Interestingly, Kir4.1 has long been characterized as a seizure susceptibility gene. The importance of Kir4.1 is further underscored by recent studies …