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The Effects Of Gspt1 Degradation On Serum Calcium, Parathyroid Hormone, And Fibroblast Growth Factor 23 Concentrations In Human Cereblon Knock-In Mice, Kamran Ghoreishi

Theses and Dissertations

Test article CC-325 is a potent oral cereblon (CRBN) modulator that has shown potent G1 to S phase transition 1 (GSPT1) degradation and anti-tumor activity in pre-clinical models. One of the adverse effects associated with CC-325 was dose dependent hypocalcemia, which was determined to be an on-target toxicity.

To investigate the mechanism of hypocalcemia, we conducted a toxicity study in human cereblon (huCRBN) knock-in (KI) mice with CC-325. The huCRBN KI mice are transgenic mice engineered to express human cereblon that is capable of binding to CRBN and degrading GSPT1. Four groups of mice were treated with vehicle (0 mg/kg), …

Augmenting Guadecitabine To Promote Anticancer Immunity In Murine Breast Cancer, Timothy M. Smith Jr.

Theses and Dissertations

In immune-competent individuals, tumor growth occurs due to a failure of the immune system to recognize and destroy malignant cells. Immune surveillance can be curtailed by the presence of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (Tregs) which both serve to dampen antitumor immunity. These studies utilize a metronomic low-dose therapeutic approach to examine the effects of anticancer drugs against murine breast cancer and the effects on the immune cell compartments. The focus of these studies revolve around the drug guadecitabine (guad), a second-generation DNA methyl-transferase inhibitor (DNMTi). DNMTi’s have been shown to dysregulate the methylation …

Insulin-Induced Serine 22 Phosphorylation Of Retinoid X Receptor Alpha Is Dispensable For Adipogenesis In Brown Adipocytes, Jacob Ardenkjær-Larsen, Kaja Rupar, Goda Sinkevičiūtė, Patricia S.S. Petersen, Julia Villarroel, Morten Lundh, Romain Barrès, Atefeh Rabiee, Brice Emanuelli

School of Pharmacy Faculty Articles

Insulin action initiates a series of phosphorylation events regulating cellular differentiation, growth and metabolism. We have previously discovered, in a mass spectrometry-based phosphoproteomic study, that insulin/IGF-1 signalling induces phosphorylation of retinoid x receptor alpha (RXRα) at S22 in mouse brown pre-adipocytes. Here, we show that insulin induces the phosphorylation of RXRα at S22 in both brown precursor and mature adipocytes through a pathway involving ERK, downstream of IRS-1 and −2. We also found that RXRα S22 phosphorylation is promoted by insulin and upon re-feeding in brown adipose tissue in vivo, and that insulin-stimulated S22 phosphorylation of RXRα is dampened by …

Espad Report 2019: Results From European School Survey Project On Alcohol And Other Drugs, Sabrina Mokinaro, Julian Vincente, Elisa Benedetti, Sonia Cerrai, Emanuala Colasante, Sharon Arpa, Pavla Chomynova, Ludwig Kraus, Karin Monshouwer, Stanislas Spika, Arsaell Mar Arnarsson, Olga Balakireva, Begona Brime Beteta, Elin Kristin Bye, Anina Chileva, Luke Clancy, Zamira Hyseni Duraku, Tatijana Durisic, Olga Ekholm, Zsuzsanna Elekes, Silvia Florescu, Biljana Kilibarda, Anna Kokkevi, Elsa Lavado, Tanja Urdih Lazar, Martina Markelic, Alojz Nociar, Silvana Oncheva, Kirsimarja Raitasalo, Ludmilla Rupsience, Janusz Sieroslawski, Julian Strizek, Lela Sturua, Johan Svensson, Diana Vanaga, Kyriakos Veresies, Sigrid Vorobjov, Pai Weihe, Rodolfo Cotichini, Loredana Fortunato, Katenna Skarupova

Reports

The main purpose of the European School Survey Project on Alcohol and Other Drugs (ESPAD) is to collect comparable data on substance use and other forms of risk behaviour among 15- to 16-year-old students in order to monitor trends within, as well as between, countries. Between 1995 and 2019, seven waves of data collection were conducted across 49 European countries. This report presents selected key results. The full set of data on which the current report is based, including all of the standard tables, is available online (http://www.espad.org). All tables can be downloaded in Excel format and used for further …

Rural Business Development Corporation Annual Report 2020, Department Of Primary Industries And Regional Development, Western Australia

All other publications

I

n accordance with section 63 of the Financial Management Act 2006, we hereby submit for your information and presentation to Parliament, the annual report of the Rural Business Development Corporation for the reporting period ended 30 June 2020.

The annual report has been prepared in accordance with the provisions of the Financial Management Act 2006 and the Rural Business Development Corporation Act 2000.

Digital Media Minor, Technology

Program Revisions/Additions

No abstract provided.

Neuroscience Minor, Biological Sciences

Program Revisions/Additions

No abstract provided.

Computer And Information Technology Major, Technology

Program Revisions/Additions

No abstract provided.

Parent Knowledge Of The Definition Of Fape In Light Of The Endrew Vs. Douglas County School Board Decision, Karin M. Fisher Ph.D., Cassandra B. Willis Ph.D., Barbara E. Ransom J.D.

The Journal of Special Education Apprenticeship

In 2017, the Supreme Court of the United States redefined Free and Appropriate Public Education (FAPE) for students with disabilities (SWD) in Endrew F. v. Douglas County School District. The Court’s new standard for FAPE was more demanding than previous rulings. Parents of SWD are expected to participate in the special education program process and a more robust Individualized Education Program (IEP) should be implemented to ensure sufficient student progress. However, it is unknown how much parents know about the Endrew F. Case and what, if any, impact the case had on IEP meetings since the ruling. To determine knowledge …

Validation Of Ninein As An Ethanol-Related Quantitative Trait Gene: Reassessment, Design, And Functional Validation Of Reference Genes For Qpcr Analysis Of Brain Tissue In Mice, Jessica L. Jurmain

Theses and Dissertations

The increasing use of quantitative real-time polymerase chain reaction (qPCR) as a method for quantifying gene expression has led to an increased demand for standardization of data analysis methods to ensure accurate reporting and robust, reproducible results. The exponential nature of qPCR amplification results in the potential magnification of what are usually very small sources of error. Relative gene expression calculations circumvent this issue by normalizing target gene expression data to within-sample expression of a previously validated, stably expressed reference gene or genes. Multiple studies discussed herein have found that qPCR data are more reliable and reproducible when multiple reference …

The Functional Importance Of Methyl Cpg Binding Domain Proteins 2 And 3 In Regulating Fetal Hemoglobin Expression In Human Adult Erythroid Cells, Alexander Azzo

Theses and Dissertations

Humans undergo two developmental switches in the predominantly expressed β-like globin chain during embryogenesis and fetal development. The first switch from embryonic (ε) to fetal (γ) occurs around week 5 of embryonic development, while the second switch from fetal to adult (β) globin occurs shortly after birth. By adulthood, fetal hemoglobin represents only 1-2% of total hemoglobin in the blood. As sufficiently elevated levels of fetal hemoglobin are beneficial for improving clinical outcomes in sickle cell disease and β-thalassemia, the mechanisms that enforce silencing of fetal hemoglobin expression postnatally are of great clinical significance. The methyl-CpG binding domain protein MBD2 …

Quantification And Modeling Of Bladder Biomechanics Mechanisms Linking Spontaneous Rhythmic Contractions And Dynamic Elasticity To Detrusor Overactivity, Zachary E. Cullingsworth

Theses and Dissertations

Overactive bladder (OAB) is a chronic condition affecting approximately 20% of adults in the United States. Detrusor overactivity (DO) is the presence of non-voiding contractions in the detrusor (bladder) muscle during filling and is present in some individuals with OAB. DO is currently identified visually during a urodynamics (UD) study involving pressure catheters and filling and voiding of the bladder to evaluate function. UD provides limited subtyping of DO, and an incomplete understanding of mechanisms contributing to OAB.

Aim 1 of this study was to develop objective tools to quantify, subgroup and better understand …

A Study On The Mechanism Of Clp290 Restoration Of Kcc2 And Neuroprotection After Traumatic Brain Injury, Ekaterina Stepanova

Theses and Dissertations

The research of this thesis investigated the mechanism of action for the therapeutic compound CLP290, which our laboratory has previously demonstrated to reverse degradation of the protein potassium-chloride co-transporter 2 (KCC2) and restore neuronal function following modeled traumatic brain injury (TBI) in the rat. The loss of membranous KCC2 from the plasma membrane after TBI worsens the excitation/inhibition imbalance common in neurotrauma. Addressed here were the specific aims to: 1) assess that CLP290 treatment restores the functional oligomeric form of KCC2 to the neuronal plasma membrane as necessary to provide chloride homeostasis; 2) investigate the signaling mechanism by which CLP290 …

Disruption Of The Dream Complex Results In Cell Cycle Deregulation, Hayley C. Walston

Theses and Dissertations

The Dimerization Partner, Rb-like, E2F, And MuvB (DREAM) complex was identified in humans due to homology of the genes involved in the D. melanogaster dREAM complex. It assembles during cellular arrest, or G0, to function as a transcriptional repressor of cell cycle genes. It is known that phosphorylation of LIN52 at serine 28 is necessary for the critical DREAM forming interaction between LIN52 and the pocket protein p130. Our laboratory has previously shown that gene editing of LIN52 to replace serine 28 with alanine (S28A) prevents phosphorylation by the kinase DYRK1A and inhibits DREAM formation. Here we have confirmed this …

Accounting For The Uncertainty Due To Chemicals Below The Detection Limit In Mixture Analysis, Paul M. Hargarten

Theses and Dissertations

Humans are exposed to multiple chemicals every day. Epidemiological studies have shown that chemical mixtures are associated with cancers, allergies, neurodevelopmental disorders, and other adverse health effects. To assess these associations, investigators are increasingly using chemical mixture approaches like weighted quantile sum (WQS) regression. In these studies, the research objectives are to determine whether a mixture of correlated chemicals is associated with an adverse health outcome and to identify the important chemicals. However, as experimental equipment measures each exposure to a chemical-specific detection limit, the exposures are unknown between zero and the detection limit. Indeed, the number of exposures below …

Modulation Of K V 7 Channel Deactivation By Pi(4,5)P 2, Carlos A. Villalba-Galea

School of Pharmacy Faculty Articles

The activity of K_V7 channels critically contributes to the regulation of cellular electrical excitability in many cell types. In the central nervous system, the heteromeric K_V7.2/K_V7.3 channel is thought to be the chief molecular entity giving rise to M-currents. These K⁺-currents as so called because they are inhibited by the activation of Gq protein-coupled muscarinic receptors. In general, activation of Gq protein-coupled receptors (GqPCRs) decreases the concentration of the phosphoinositide PI(4,5)P₂ which is required for K_V7 channel activity. It has been recently reported that the deactivation rate of K …

Communicating Punishment, Marah Stith Mcleod

Journal Articles

Does it matter whether convicted offenders understand why they are being punished? In the death penalty context, the Supreme Court has said yes; a prisoner who cannot understand the state's reasons for imposing a death sentence may not be executed. Outside of capital punishment, the answer is still open. This Article begins to fill that gap, focusing on why and how states should help all offenders make sense of their sanctions, whether imposed for retribution, for deterrence, for incapacitation, or for rehabilitation.

Judges today sometimes try to explain sentences to criminal offenders so that they know the purposes of their …

Artificially-Generated Scenes Demonstrate The Importance Of Global Properties During Early Scene Perception, Mavuso Wesley Mzozoyana

Browse all Theses and Dissertations

During scene perception, studies have shown the importance of the global distribution of a scene. Electrophysiological studies have found these global effects concentrated corresponding to the second positive and first negative peaks (P2 and N1, respectively) of the Event-related potential (ERP) during the first 600 ms of scene perception. We sought to understand in Experiment 1, to what extent early responses to scenes were driven by mid-level global information such as the degree of naturalness or openness in a scene image in the absence of specific low-and high-level information (color and semantic object detail). This was done using artificially-generated stimuli …

Optimization Study Of A Combined Wind-Solar Farm For A Specified Demand, Venkat Siddhartha Rama

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At the present time, using wind and solar energy for producing electricity in the United States is becoming cost competitive. According to Lazard’s 2019 [36] levelized cost of energy (LCOE) analysis of a number of energy sources used for producing electricity in the United States, wind and solar are cheaper than natural gas and coal. While capital, maintenance, operation, and fuel costs are included in LCOE numbers, energy source intermittency is not. Intermittency is an important issue with wind and solar energy sources, but not with natural gas or coal energy sources. Combining wind and solar energy sources into one …

Visual Sampling With The Eeg Alpha Oscillation, Kevin Eugene Alexander

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The posterior alpha rhythm, seen in human electroencephalograms (EEG), is posited to originate from cycling inhibitory/excitatory states of visual relay cells in the thalamus, which could result in discrete sampling of visual information. Here, we tested this hypothesis by presenting light flashes at perceptual threshold intensity through closed eyelids to 20 participants during times of spontaneous alpha oscillations. Alpha phase and amplitude were calculated relative to each individual’s retina-to-V1 conduction delay, estimated by the individuals’ C1 visual-evoked potential latency. Our results show that an additional 20.96% of stimuli are observed when afferenting at V1 during an alpha wave trough (272.41°) …

Targeting Oncogenic K-Ras And Monoamine Oxidase B Utilizing Chalcones Bearing The 3,4,5-Trimethoxyphenyl Motif, Cody Fourman

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Oncogenic K-Ras is a driver protein found in specific cancers and was once thought to be “undruggable.” However, recent advances have suggested that mislocalizing K-Ras from the plasma membrane could be a viable strategy to target these cancers. The objective of this project was to identify a lead compound and determine a structure-activity relationship from chalcones bearing the 3,4,5-trimethoxy motif towards oncogenic K-Ras and MAO-B. This was accomplished by keeping the trimethoxy group consistent on one ring while varying the electron-donating or -withdrawing groups on the opposite ring. Previous work showed chalcones of this specific archetype exhibiting indiscriminate MAO inhibition, …

Effects Of Forest Age And Composition On Coleoptera Associated With Fungal Fruiting Bodies In Southwest Ohio, Jeffrey M. Brown

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Mature forests often harbor greater biodiversity than younger woods. As this relationship of forest age to biodiversity has not been examined for all taxa, this study sought to document the diversity of mycophilous beetle communities in deciduous forests of southwest Ohio and understand how they vary in relation to forest age. I surveyed fungus associated beetles using baited traps at eight forested sites in the Dayton, Ohio region. Traps were surveyed three times during 2018 to account for seasonal variation, something that has not been done for this geographic region. Forest age had no significant effect on beetle abundance or …

Alternative Splicing Of Mdm4 In Human Melanomas, Abdullah Salem S. Alatawi

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Melanoma is a potentially lethal type of skin cancer and regarded to be the third most common type of skin cancer. Although melanoma is not as common as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), it is more likely to metastasize than BCC and SCC. Interestingly, the incidence of melanoma continues to go up (expected 2% in 2020), but the deaths continue to decrease (-5.3% in 2020) due to improvements in detection and treatment. The treatment of melanoma depends on several aspects but most importantly the tumor's stage and the location. In the early stages, melanoma can be …

Composition Of Dung Beetle Communities In A Tropical Montane Forest Alters The Rate Of Dung Removal More Than Species Diversity Alone, Elizabeth A. Engle

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Dung beetles provide key ecological functions by degrading and recycling dung. I used experimentally-assembled communities to examine the role of species richness, community biomass, species diversity, species identity, and community composition in dung removal, using Ateuchus chrysopyge, Copris nubilosis, Onothophagus cyanellus, and Dichotomius satanas. I hypothesized: (1) that as species richness, biomass, and diversity increases within a community, dung removal increases; and (2) species are not functionally equivalent, so community composition should influence dung removal rates. As species richness, biomass, and diversity of experimentally-assembled communities increased, the proportion of dung removed also increased. Also, the four species in this study …

Role Of Exercise In Macrophage Polarization Of Perivascular Adipose Tissue And Adipose Tissue Inflammation In Hypertensive Mice Model, Venkata Sai Usha Sri Polaki

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Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. It can lead to severe health complications and increase the risk of heart disease, stroke, and sometimes death. Perivascular adipose tissue (PVAT) is known as the adipose tissue (AT) surrounding all the blood vessels and plays a critical role in the pathogenesis of the vascular disease. In vascular pathologies, PVAT increases in volume and becomes dysfunctional, with altered cellular composition and molecular characteristics. Macrophages have been found to accumulate in PVAT during hypertension, which might be involved …

Exploring The Impact Of Affective Processing On Visual Perception Of Large-Scale Spatial Environments, Auroabah S. Almufleh

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This thesis explores the interaction between emotions and visual perception using large scale spatial environment as the medium of this interaction. Emotion has been documented to have an early effect on scene perception (Olofsson, Nordin, Sequeira, & Polich, 2008). Yet, most popularly-used scene stimuli, such as the IAPS or GAPED stimulus sets often depict salient objects embedded in naturalistic backgrounds, or “events” which contain rich social information, such as human faces or bodies. And thus, while previous studies are instrumental to our understanding of the role that social-emotion plays in visual perception, they do not isolate the effect of emotion …

Stabilization Of Β-Cristobalite In The Sio2-Alpo4-Bpo4 System, Kathryn Doyle

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Fused silica (silica glass) is transparent in the optical and near-infrared and has a low dielectric constant, making it suitable as a window material for radio frequency radiation. However, at high temperatures (>1100C), fused silica will easily creep and lose dimensional stability. Crystallized silica is much more creep resistant than fused silica. Silica crystallizes to many different structures including quartz, tridymite, and α- and β cristobalite. The only cubic polymorph, which is suitable for both optical and radio frequency transmission in polycrystalline form, is β -cristobalite. Unfortunately, this polymorph transforms to α-cristobalite at ~300C, and the volume change during …

Assessment Of In Vivo Muscle Force In The R6/2 Mouse Model Of Huntington's Disease Using Newly Designed Force Rig, Steven Russell Alan Burke

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In this thesis, we develop a system to study in vivo muscle function in a mouse model of Huntington’s disease that allows for the recording of muscle force by stimulating the motor nerves or the muscles directly after a nerve block. This allows us to distinguish between defects in the nerve, such as problems with vesicle release, and primary muscle defects, such as altered intracellular calcium homeostasis. We hypothesize that there are primary defects in R6/2 skeletal muscle that are separate from neurodegeneration or defects in the CNS. In this case, we should see defects in muscle force generation during …

Ultraviolet-B Radiation Induces Release Of Bioactive Microvesicle Particles In Keratinocytes Via Platelet-Activating Factor And Acid Sphingomyelinase, Langni Liu

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Ultraviolet-B (UV-B) radiation is one of the most common environmental factors and is known to induce the production of bioactive agents that cause several diseases including skin cancer. UVB exposure stimulates the production of a phospholipid activator, platelet-activating factor (PAF), and its analogs in keratinocytes that activate the PAF receptor (PAF-R) resulting in acute inflammatory and delayed systematic immunosuppressive effects. However, as UVB only penetrates into the skin epidermal layer, the detailed mechanisms of how UVB exerts systematic effects remains unclear. Previously we found that UVB induces keratinocytes to release large numbers of microvesicle particles (MVPs). These small membrane-bound particles …

Global Identification Of Human Modifier Genes Of Alpha-Synuclein Toxicity, Ishita Haider

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Alpha-synuclein is a small lipid binding protein abundantly expressed in the brain. Lewy body or Lewy-like pathology, primarily composed of misfolded alpha-synuclein, is a pathological feature shared by several neurodegenerative disorders, including Parkinson's disease (PD). Both missense mutations and increased copy numbers of the SNCA gene, encoding the alpha-synuclein protein, have been genetically linked to autosome dominant PD. Other genetic variations affecting the expression of the SNCA gene have been associated with sporadic PD. Although the physiological function of alpha-synuclein is not well understood, its localization to plasma and vesicular membranes at the presynaptic terminals suggests a role in neurotransmission. …