Medicine and Health Sciences Commons^™

The Role Of Bone Sialoprotein In Periodontal Tissue Development And Bone Repair, Yohannes Soenjaya

Electronic Thesis and Dissertation Repository

Bone development and repair involve complex processes that include interaction between cells and their surrounding matrix. In the body, bone sialoprotein (BSP) expression is up-regulated at the onset of mineralization. BSP is a multifunctional acidic phosphoprotein with collagen-binding, hydroxyapatite nucleating, and integrin recognition (RGD sequence, which is important for cell-attachment and signaling) regions. Mice lacking BSP expression (Bsp^-/-), exhibit a bone phenotype with reductions in bone mineral density, bone length, osteoclast activation, and impaired bone healing. This thesis examined the role of BSP in tooth development and also its potential use as a therapeutic reagent for bone …

Serotonergic System And Gait: Dorsal Raphe Nucleus As A Control System For Gait, Nahal Farhani

Electronic Thesis and Dissertation Repository

In advanced stages of Parkinson Disease (PD), gait and postural abnormalities emerge. These symptoms are not prominent at early stages of PD despite significant dopaminergic neuronal loss. Gait abnormalities are largely not responsive to levodopa. Therefore, other types of neurons might be responsible for gait abnormalities of the PD.

Since the reticulospinal tract (RET) is mainly implicated in the control of axial muscles, the degeneration of this pathway or populations of neurons controlling this pathway might be responsible for axial symptoms. However, there is limited data about the neurons controlling the RET. Our aim in this study is to delineate …

Evidence For Using Immunosuppressive Treatments When Treating Idiopathic Non-Infectious Uveitis: A Systematic Review And Meta-Analysis, Hargurinder Singh

Electronic Thesis and Dissertation Repository

Idiopathic non-infectious uveitis is the spontaneous inflammation of the eye, which can lead to blindness if not treated correctly. Due to long-term side effects of corticosteroids, 4 classes of off-label immunosuppressive treatments are sometimes used (alkylating agents, inhibitors of T-lymphocyte signalling, antimetabolites and biological modifiers). We conducted a systematic review and meta-analysis to assess the effectiveness of different treatment classes on uveitis patients with similar characteristics. Results of the systematic review concurred with the conclusions from the meta-analysis, which found that all immunosuppressive treatments improved patient vision, with a statistically significant change in logMAR of -0.11 (95% CI of -0.152 …

Declining Incidence Of Stroke And Dementia: Coincidence Or Prevention Opportunity?, Luciano A. Sposato, Moira K. Kapral, Jiming Fang, Sudeep S. Gill, Daniel G. Hackam, Lauren E. Cipriano, Vladimir Hachinski

Anatomy and Cell Biology Publications

No abstract provided.

Dexamethasone Regulates Gene Expression Induced By The Mechanosensitive P2x7 Receptor In Osteoblasts, Meena Na

Electronic Thesis and Dissertation Repository

Orthodontic tooth movement involves activation of osteoblasts and osteoclasts in response to mechanical forces. Extracellular nucleotides, released in response to mechanical stimuli, signal through P2 receptors in osteoblasts. P2X7 receptors are ATP-gated cation channels implicated in mechanotransduction in bone. Corticosteroids such as dexamethasone exhibit anti-inflammatory effects and their chronic use has been linked to serious side-effects such as osteoporosis. We investigated gene expression following P2X7 receptor activation with benzoylbenzoyl-ATP (P2X7 receptor agonist) in osteoblast precursor cells in the presence or absence of dexamethasone. We hypothesized that dexamethasone inhibits the ability of ATP to stimulate the expression of anabolic (bone forming) …

Cytochrome P450 3a4 Expression And Regulation In Non-Alcoholic Fatty Liver Disease, Sarah J. Woolsey

Electronic Thesis and Dissertation Repository

Non-alcoholic fatty liver disease (NAFLD) is defined as lipid accumulation within hepatocytes (steatosis) in the absence of excess alcohol consumption. It is the most common liver disease in the western world, affecting one third of the general adult population with particularly high prevalence in obesity and type 2 diabetes. NAFLD is a disease continuum originating with simple hepatic steatosis that can progress to non-alcoholic steatohepatitis (NASH) with fibrosis and potentially cirrhosis, which places patients at risk for hepatocellular carcinoma. Unfortunately, there are not yet specific pharmacologic agents to treat NAFLD and so its management involves treatment of comorbidities, but there …

The Transient Receptor Potential Melastatin 2 (Trpm2) Channel Contributes To Beta-Amyloid Oligomer-Related Neurotoxicity And Memory Impairment, Valeriy G. Ostapchenko, Megan Chen, Monica S. Guzman, Yu-Feng Xie, Natalie Lavine, Jue Fan, Flavio H. Beraldo, Amanda C. Martyn, Jillian C. Belrose, Yasuo Mori, John F. Macdonald, Vania F. Prado, Marco A. M. Prado, Michael F. Jackson

Anatomy and Cell Biology Publications

In Alzheimer's disease, accumulation of soluble oligomers of beta-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca2+-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with beta-amyloid oligomers. Aged APP/PS1 Alzheimer's mouse model showed increased levels of …

Hyperactivity And Attention Deficits In Mice With Decreased Levels Of Stress-Inducible Phosphoprotein 1 (Stip1), Flavio H. Beraldo, Anu Thomas, Benjamin Kolisnyk, Pedro H. Hirata, Xavier De Jaeger, Amanda C. Martyn, Jue Fan, Daniela F. Goncalves, Matthew F. Cowan, Talal Masood, Vilma R.. Martins, Robert Gros, Vania F. Prado, Marco A. M. Prado

Anatomy and Cell Biology Publications

Stress-inducible phosphoprotein I (STIP1, STI1 or HOP) is a cochaperone intermediating Hsp70/Hsp90 exchange of client proteins, but it can also be secreted to trigger prion protein-mediated neuronal signaling. Some mothers of children with autism spectrum disorders (ASD) present antibodies against certain brain proteins, including antibodies against STIP1. Maternal antibodies can cross the fetus blood-brain barrier during pregnancy, suggesting the possibility that they can interfere with STIP1 levels and, presumably, functions. However, it is currently unknown whether abnormal levels of STIP1 have any impact in ASD-related behavior. Here, we used mice with reduced (50%) or increased STIP1 levels (fivefold) to test …

Deep Brain Stimulation And Its Effects On Parkinson Disease Spatiotemporal Gait Parameters., Greydon Gilmore

Electronic Thesis and Dissertation Repository

Subthalamic (STN) deep brain stimulation (DBS) alleviates common appendicular PD symptoms, such as: tremor, rigidity and bradykinesia. However, the effect STN-DBS has on modulating axial gait features has not been properly quantified objectively. The purpose of the present thesis was to investigate the role STN-DBS plays in modulating specific gait features such as pace, asymmetry, variability, rhythm and postural control. It is hypothesized that axial gait function is regulated predominantly by non-dopaminergic control systems. In the acute immediate post-operative phase a surgical effect, named the microlesion effect (MLE), is thought to produce a transient improvement of appendicular and axial symptoms. …

Feasibility Of Using Arterial Spin Labeling For Detecting Longitudinal Changes In Cerebral Blood Flow, Tracy Ssali

Electronic Thesis and Dissertation Repository

The ability of the perfusion MRI technique, arterial spin labeling (ASL), to quantify cerebral blood flow (CBF) makes it attractive for longitudinal studies of changes in brain function, such as those related to chronic pain. However, ASL's poor spatial resolution makes image alignment between sessions difficult, leading to increased variance and greater Type-I errors. In addition, variability due to differences in basal blood flow between sessions and confounding effects such as the arterial transit time (ATT) have the potential to reduce reproducibility over time. The focus of this thesis is to investigate the ability of ASL to detect long-term changes …

Hyperpolarized 129xe Magnetic Resonance Imaging Of Radiation-Induced Lung Injury, Ozkan Doganay

Electronic Thesis and Dissertation Repository

Lung cancer is the largest contributor to cancer-related mortality worldwide. Only 20% of stage III non-small cell lung cancer patients survive after 5-years post radiation therapy (RT). Although RT is an important treatment modality for lung cancer, it is limited by Radiation-Induced Lung Injury (RILI). RILI develops in two phases: (i) the early phase (days-weeks) referred to radiation pneumonitis (RP), and (ii) the late phase (months). There is a strong interest in early detection of RP using imaging to improve outcomes of RT for lung cancer. This thesis describes a promising approach based on ¹²⁹Xe gas as a contrast …

The Effects Of Fatigue On The Reactive Agility Test: Looking At The Difference Between Normal Game Play And The Hurry-Up Offense In Football Game Simulations, Kristine E. Walker

Electronic Thesis and Dissertation Repository

Purpose: The purpose of this study was to assess the effects of fatigue on performance of the Reactive Agility Test (RAT) by University Football players. This test assesses the athlete’s ability to change direction in response to a visual stimulus, somewhat like responding to the actions of an opponent in a game. Two fatiguing conditions were compared, simulations of normal game play and hurry-up offense in football. Methods: Following a warm-up and baseline RAT testing the athletes performed 10 high intensity, sprints on a specialized treadmill, with a 1:5 work to rest ratio to simulate regular game pace. This was …

Expert And Crowd-Sourced Validation Of An Individualized Sleep Spindle Detection Method Employing Complex Demodulation And Individualized Normalization, Laura B. Ray, Stephane Sockeel, Melissa Soon, Arnaud Bore, Ayako Myhr, Bobby Stojanoski, Rhodri Cusack, Adrian M. Owen, Julien Doyon, Stuart M. Fogel

Anatomy and Cell Biology Publications

A spindle detection method was developed that: (1) extracts the signal of interest (i.e., spindle-related phasic changes in sigma) relative to ongoing "background" sigma activity using complex demodulation, (2) accounts for variations of spindle characteristics across the night, scalp derivations and between individuals, and (3) employs a minimum number of sometimes arbitrary, user-defined parameters. Complex demodulation was used to extract instantaneous power in the spindle band. To account for intra- and inter individual differences, the signal was z-score transformed using a 60 s sliding window, per channel, over the course of the recording. Spindle events were detected with a z-score …

Evidence For Differential Viral Oncolytic Efficacy In An In Vitro Model Of Epithelial Ovarian Cancer Metastasis, Jessica G. Tong, Yudith R. Valdes, John W. Barrett, John C. Bell, David Stojdl, Grant Mcfadden, J. Andrea Mccart, Gabriel E. Dimattia, Trevor G. Shepherd

Anatomy and Cell Biology Publications

Epithelial ovarian cancer is unique among most carcinomas in that metastasis occurs by direct dissemination of malignant cells traversing throughout the intraperitoneal fluid. Accordingly, we test new therapeutic strategies using an in vitro three-dimensional spheroid suspension culture model that mimics key steps of this metastatic process. In the present study, we sought to uncover the differential oncolytic efficacy among three different viruses—Myxoma virus, double-deleted vaccinia virus, and Maraba virus—using three ovarian cancer cell lines in our metastasis model system. Herein, we demonstrate that Maraba virus effectively infects, replicates, and kills epithelial ovarian cancer (EOC) cells in proliferating adherent cells and …

A Unified Framework For The Prioritization Of Variants Of Uncertain Significance In Hereditary Breast And Ovarian Cancer Patients, Natasha G. Caminsky

Electronic Thesis and Dissertation Repository

A significant proportion of hereditary breast and ovarian cancer (HBOC) patients receive uninformative genetic testing results, an issue exacerbated by the overwhelming quantity of variants of uncertain significance identified. This thesis describes a framework where, aside from protein coding changes, information theory (IT)-based sequence analysis identifies and prioritizes pathogenic variants occurring within sequence elements predicted to be recognized by proteins involved in mRNA splicing, transcription, and untranslated region binding and structure. To support the utilization of IT analysis, we established IT-based variant interpretation accuracy by performing a comprehensive review of mutations altering mRNA splicing in rare and common diseases.

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Degrees Of Damage: Quantifying Male Vs. Female Exercise-Induced Muscle Damage Through Magnetization Transfer Ratios, Nicholai Michael Clausius Crawford

Electronic Thesis and Dissertation Repository

No direct, quantitative, and non-invasive markers presently exist to assess exercise-induced muscle damage (EIMD). However, magnetization transfer ratios (MTR), an emerging measurement quantified via magnetic resonance imagery, provide more direct indication of muscle integrity following EIMD. This study compares and correlates the temporal pattern of the MTR to alternative indirect markers of EIMD in male vs. female populations, and subsequently establishes whether there are sex differences in biochemical activity during recovery. The antioxidant properties of estrogen hypothetically minimize muscle trauma, maintain membrane stability, and limit swelling resulting in heightened tissue integrity and resilience to EIMD. Six males and three females …

Characterization Of The Atsr/Atst Global Regulatory Pathway In Burkholderia Ceocepacia, Maryam Khodai-Kalaki

Electronic Thesis and Dissertation Repository

Phosphorylation cascades governed by two-component signal transduction systems provide key signalling mechanisms in bacteria, simple eukaryotes and higher plants, allowing them to translate signals into adaptive responses. These regulatory pathways consist of a transmembrane sensor protein that responds to an environmental cue leading to autophosphorylation, followed by the transfer of the phosphate to a cytoplasmic response regulator. Here, I study AtsR, a membrane-bound hybrid sensor kinase of Burkholderia cenocepacia, that negatively regulates quorum sensing related virulence factors such as biofilm, type 6-secretion and protease secretion. B. cenocepacia is a Gram-negative opportunistic pathogen which causes severe, chronic respiratory infections in …

Deletion Of Panx3 Prevents The Development Of Surgically Induced Osteoarthritis, Paxton M. Moon, Silvia Penuela, Kevin Barr, Sami Khan, Christopher L. Pin, Ian Welch, Mukundan Attur, Steven B. Abramson, Dale W. Laird, Frank Beier

Anatomy and Cell Biology Publications

© 2015, Springer-Verlag Berlin Heidelberg. Abstract: Osteoarthritis (OA) is a highly prevalent, disabling joint disease with no existing therapies to slow or halt its progression. Cartilage degeneration hallmarks OA pathogenesis, and pannexin 3 (Panx3), a member of a novel family of channel proteins, is upregulated during this process. The function of Panx3 remains poorly understood, but we consistently observed a strong increase in Panx3 immunostaining in OA lesions in both mice and humans. Here, we developed and characterized the first global and conditional Panx3 knockout mice to investigate the role of Panx3 in OA. Interestingly, global Panx3 deletion produced no …

The Application Of The Ultrafine Technology In Improving The Biocompatibility And Osteo-Inductivity Of Dental Implants, Nicholas Y. Hou

Electronic Thesis and Dissertation Repository

Dental implants are very effective medical devices. However, although stable, the conventional titanium implants are not very bioactive which in some instances could reduce their efficacy. This thesis described the research progress of using polymeric ultrafine-particles with bioactive additives to enrich the surface of titanium substrate, thereby increasing the biocompatibility and osteo-inductivity of the biomaterial. During this doctoral project, three different types of polymers were examined, initially the conventional polyester, and later the novel epoxy as well as the epoxy/polyester hybrid polymers. Physical characterizations confirmed that all of the coating powders were ultrafine particles, and homogeneous surfaces were constructed from …

Non-Invasive Determination Of Pre-Clinical Markers Of Cardiovascular Diseases In Low Birth Weight And Maternal Western Diet Guinea Pig Offspring Exposed To A Postnatal Western Diet, Jacky Chiu

Electronic Thesis and Dissertation Repository

Low birth weight (LBW), and maternal Western Diet (WD) consumption have both been independently implicated to increase the risk of developing cardiovascular diseases (CVDs) in later life. These fetal programmed risks are also believed to exacerbate the effects of a postnatal WD pattern. Therefore, resulting in the development of pre-clinical markers of CVDs, such as insulin resistance (IR), coronary circulation disruptions. This thesis aimed to elucidate the roles of sub-optimal in utero growth through placental insufficiency, or chronic maternal WD consumption, and postnatal WD consumption on the long-term programming of CVDs in a guinea pig model. Early pre-clinical markers of …

Characterization Of The Nicotine-Induced Endoplasmic Reticulum Stress Response In The Rat Placenta In Vivo And In Vitro, Michael Ka Chun Wong

Electronic Thesis and Dissertation Repository

Nicotine exposure during pregnancy leads to adverse health outcomes, including compromised placental development. Although the molecular mechanisms remain elusive, recent studies identified that endoplasmic reticulum (ER) stress may underlie poor placentation. Therefore, we were interested in investigating the effects of nicotine exposure on the ER stress response in the placenta. A well-established maternal nicotine exposure rat model and Rcho-1 trophoblast giant cell model were utilized to address the research questions. Maternal nicotine exposure in vivo led to elevated ER stress in association with impaired disulfide bond formation and hypoxia. Nicotine exposure in vitro further differentiated that ER stress may be …

Analyzing A-Series Gangliosides In Neurons Following Exposure To Glutamate, Dae Hee Park

Electronic Thesis and Dissertation Repository

Neurons within different brain regions have varying levels of vulnerability to external stress and therefore respond differently to injury. A potential reason to explain this may lie within a key lipid class of the cell’s plasma membrane called gangliosides. These glycosphingolipid species have been shown to play various roles in the maintenance of neuronal viability. The purpose of this study is to use electrospray ionization mass spectrometry (ESI-MS) technique and immunohistochemistry to evaluate the temporal changes in the expression profiles of various ganglioside species during the course of neurodegeneration in rat primary cortical neurons exposed to glutamate toxicity. Primary embryonic …

The Effect Of A Multiple Modality Mind-Motor Exercise Intervention On Single And Dual-Task Gait, Balance, And Executive Function, In Community Dwelling Older Adults With A Subjective Cognitive Complaint: A Randomized Controlled Trial., John P. Bocti

Electronic Thesis and Dissertation Repository

Cognitive decline disorders are becoming increasingly prevalent, with older adults at increased risk. Combined exercise has been recently explored as an intervention to help to prevent the decline, however cognitive activation in combination with physical activity has yet to be explored. Therefore, the purpose of the study is to determine the effects of multiple modality exercise programs in combination with a mind-motor task and their effects on mobility and cognitive variables. A total of (n=89) older adults (55+ yrs), with subjective cognitive complaints participated in a multiple modality exercise class, three days a week over six months, with the intervention …

Investigation Of Pancreatic Β-Cell Insulin Receptor Regulation Of Β-Cell Growth, Function, And Survival Via A Temporal Conditional Knockout, Liangyi Zhou

Electronic Thesis and Dissertation Repository

The expression of insulin receptor (IR) in β-cells suggests an autocrine role for insulin signalling in β-cell function and regulation. Studies have demonstrated that β-cell Ir knockout (βIrKO) mice develop age-dependent glucose intolerance. We investigated the temporal role of β-cell IR signaling in pre- and postnatal islet development and function, and under high-fat diet stress, using a tamoxifen-inducible Cre-recombinase Ir knockout mouse model.

Prenatal βIrKO mice exhibited increased mean islet area, β-cell area, and islet area percentage. Additionally, there was upregulation of insulin-like growth factor-2 levels, increased Akt activity, and increased proliferation in islets. Postnatally-induced βIrKO mice did not exhibit …

Beclin-1 Expression Is Retained In High-Grade Serous Ovarian Cancer Yet Is Not Essential For Autophagy Induction In Vitro, Rohann J.M. Correa, Yudith R. Valdes, Trevor G. Shepherd, Gabriel E. Dimattia

Anatomy and Cell Biology Publications

Background: Autophagy is a conserved cellular self-digestion mechanism that can either suppress or promote cancer in a context-dependent manner. In ovarian cancer, prevalent mono-allelic deletion of BECN1 (a canonical autophagy-inducer) suggests that autophagy is impaired to promote carcinogenesis and that Beclin-1 is a haploinsufficient tumor suppressor. Nonetheless, autophagy is known to be readily inducible in ovarian cancer cells. We sought to clarify whether Beclin-1 expression is in fact disrupted in ovarian cancer and whether this impacts autophagy regulation.

Methods: BECN1 expression levels were assessed using The Cancer Genome Atlas (TCGA) datasets from 398 ovarian high-grade serous cystadenocarcinomas (HGSC) and protein …

Whole-Retina Reduced Electrophysiological Activity In Mice Bearing Retina-Specific Deletion Of Vesicular Acetylcholine Transporter, Jake Bedore, Amanda C. Martyn, Anson K. C. Li, Eric A. Dolinar, Ian S. Mcdonald, Stuart G. Coupland, Vania F. Prado, Marco A. Prado, Kathleen A. Hill

Anatomy and Cell Biology Publications

Background: Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT) in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina. Methods & Results A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina-targeted (embryonic day …

Quantifying The Effects Of Systematic Stn-Dbs Programming On Rest And Postural Tremor In Idiopathic Parkinson Disease Patients, Kristina Ognjanovic

Electronic Thesis and Dissertation Repository

Parkinson’s disease (PD) is a complex neurodegenerative disorder that encompasses both motor and non-motor symptoms. These symptoms and their severity are typically assessed by scale based measures in a clinical setting. Scale- based assessments of PD patients undergoing bilateral subthalamic nucleus deep brain stimulation surgery (STN-DBS) such as the Unified Parkinson Disease Rating Scale (UPDRS) are commonly used in a clinical setting to assess symptom severity and progression. However, the subjective nature of these and other clinical scales call into question both the sensitivity and accuracy of patient assessment over time. An objective quantification of rest and postural tremor of …

The Role Of Bone Sialoprotein In The Tendon-Bone Insertion, Ryan M. Marinovich

Electronic Thesis and Dissertation Repository

Tendons and ligaments insert into bone through a transitional tissue termed the enthesis which is susceptible to injury and difficult to repair. Entheses contain a region of calcified fibrocartilage (CFC), however mineral-associated proteins in this tissue remain poorly characterized. Bone sialoprotein (BSP) is a phosphoprotein associated with mineralizing tissues. In these studies BSP was identified in the CFC of entheses by immunohistochemistry. Analysis of the entheses of Bsp^-/- mice indicate abnormalities in the CFC. Compared to controls, the CFC of the quadriceps tendon enthesis is 28% and 41 % longer in 15 week and 14 month old Bsp^{-/- …}

The Ctcf Chromatin Organizer Is Required For Hindlimb Development, Katherine L. Rabicki

Electronic Thesis and Dissertation Repository

Mutations in chromatin organizer CTCF were identified in patients with intellectual disability and skeletal defects. Previous studies demonstrated that depletion of CTCF in murine limb mesenchyme results in apoptosis in the forelimb. The role of CTCF in the hindlimb, however, is unknown. My objective was to investigate effects of CTCF deletion on chondrogenesis and skeletal development in the hindlimb. In vitro wild-type micromass cultures demonstrate that chondrocyte gene expression is delayed in the hindlimb when compared to forelimbs. Embryonic Ctcf^Fl/Fl;Prx1Cre mice were investigated, and qRT-PCR and histology were performed on limb buds and long bones. Results show that …

Contribution Of The Dorsolateral Prefrontal Cortex To Attentional And Mnemonic Processes In Visual Search, Brandon Belbeck

Electronic Thesis and Dissertation Repository

A key characteristic of selective visual attention is that it may be deployed on the basis of our knowledge or goals of the task at hand. Here, we used cryogenic deactivation to investigate the contribution of the dorsolateral PFC to cognitive flexibility and working memory, as well as their relation to the deployment of attention. Macaque monkeys performed visual search tasks requiring them to foveate a target in an array of stimuli. These included a feature search, a constant-target conjunction search, a variable-target search and variable-target with delay search task, with each being more cognitively demanding than the last. Bilateral …