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A Bioinformatics Approach To Understanding The Pathogenesis Of Ectopic Spine Calcification, Fang Chi Wang

Electronic Thesis and Dissertation Repository

This study used mice lacking equilibrative nucleoside transporter 1 (ENT1^-/-) as a preclinical model to study pathogenesis of ectopic spine mineralization in diffuse idiopathic skeletal hyperostosis (DISH). We hypothesized that mineralization of the annulus fibrosus (AF), was driven by dysregulation of cellular processes and pathways associated with apoptosis, S100A9 proteins, the PI3K-Akt pathway, and lipid metabolism. Target pathways and processes were assessed using in situ localization and quantitative analyses. Metabolomic analysis of AF and plasma data was conducted to identify altered metabolites. Results demonstrate increased caspase-3 activity in the AF of ENT1^-/- mice at both timepoints …

Regulation Of Sterile Inflammatory Responses By Mitochondria-Associated Proteins, Meghana Venkatesan

Master's Theses

Inflammation is an important defense mechanism through which cells respond to pathogenic insults and damage/stress signals. Immune cells mediate extracellular inflammatory responses by synthesizing and releasing small proteins called cytokines, which play critical roles in modulating these responses. Specifically, key pro-inflammatory cytokines such as IL-1beta are released upon the assembly and activation of a multi-protein intracellular complex called the inflammasome, the most well-studied of which is the NLRP3 inflammasome. Several proteins have been identified as important regulators of cellular stress responses, including vacuole membrane protein 1 (VMP1). The present research shows that VMP1-depleted cells exhibit exacerbated cellular inflammation and are …

A Comparison Of Diploid And Triploid Eastern Oysters For Aquaculture Production Under Extreme Temperatures And Salinities, Joshua H. Kim

LSU Master's Theses

Off-bottom aquaculture of Eastern oysters (Crassostrea virginica) is a nascent industry that is increasingly supported by the use of triploid oysters, which grow faster than diploids. Despite their growth advantage, elevated triploid mortality compared to diploids under high temperature, low salinity, or a combination of these conditions challenge consistent triploid production. Identifying the environmental thresholds at which differential triploid mortality occurs and predicting its economic impact are important to informing decision-making in oyster aquaculture. The goal of this thesis was to compare the biological and economic performance of diploid and triploid oysters under high temperature and low salinity conditions. …

Investigating The Cellular Mechanisms Of Intracellular Ph Regulation During Exposure To High Co2., Dillon Flowers

Biology Theses

There are at least two different strategies of pH regulation among fish. The first is coupled pH regulation (CPR), where regulation of blood pH facilitates tissue pH regulation; and the second is preferential intracellular pH (pHi) regulation (PPR), where tissue pH remains tightly regulated despite a sustained reduction in blood pH. The cellular and molecular mechanisms underlying the differences in pHi regulation are currently unknown. I investigated the mechanisms of pH regulation in fishes using Rainbow Trout (Oncorhynchus mykiss) and Channel Catfish (Ictalurus punctatus) which use CPR and PPR, respectively. Fish were exposed to elevated CO …

Placental Co-Transcriptional Activator Vestigial-Like 1 (Vgll1) Drives Tumorigenesis Via Increasing Transcription Of Proliferation And Invasion Genes, Heather Sonnemann

Dissertations & Theses (Open Access)

Vestigial-like 1 (VGLL1) is a co-transcriptional activator that binds to TEA domain containing transcription factors (TEADs). Its expression is upregulated in a variety of aggressive cancer types, including pancreatic and basal-like breast cancer, and increased transcription of VGLL1 is strongly correlated with poor prognosis and decreased overall patient survival. In normal tissues, VGLL1 is most highly expressed within placental trophoblast cells, which share the common attributes of rapid cellular proliferation and invasion with tumor cells. The impact of VGLL1 in cancer has not been fully elucidated and no VGLL1-targeted therapy currently exists. The aim of this study was to evaluate …

Elucidating The Roles Of Septin Proteins In Thermotolerance And Cell Wall Integrity In Cryptococcus Neoformans, Stephani S. Martinez Barrera

All Dissertations

Cryptococcus neoformans is a globally distributed fungal pathogen responsible for causing cryptococcal meningitis in immunocompromised individuals. This pathogenic yeast must adapt to changes in temperature upon entering the human host. Septin proteins are conserved filament-forming GTPases that assemble as higher-order complexes at the cell cortex to support cytokinesis and morphogenesis in fungal and animal cells. In C. neoformans, four septin homologs (Cdc3, Cdc10, Cdc11, and Cdc12) assemble at the mother-bud neck, contributing to cytokinesis through poorly understood mechanisms. C. neoformans strains lacking the septins Cdc3 or Cdc12 are viable at 25°C, but fail to proliferate at 37°C, and are …

Early Onset Alzheimer’S Disease Markers In Mouse Hippocampus Unveiled By Single-Cell Transcriptomic Analysis Following Cranial Radiotherapy, Tuba Aksoy

Dissertations & Theses (Open Access)

Cranial radiation therapy plays an integral role in the treatment of brain tumors but can lead to progressive cognitive deficits in survivors by mechanisms that are poorly understood. To develop preventive or mitigative strategies, it is crucial to better understand the underlying pathogenesis of radiation-induced cognitive impairments. The study investigated single-cell transcriptomics and DNA methylation changes as potential drivers of persistent cellular dysfunction after radiation exposure, specifically concentrating on the CA1-3 regions of the hippocampus and the prefrontal cortex due to their role in cognitive functions. Thirteen-week-old mice underwent whole-brain radiation at clinically relevant doses. Following whole-brain radiation, an assessment …

Vesicle-Associated Membrane Proteins In Airway Mucin Secretion, Boxuan Yang

Dissertations & Theses (Open Access)

Mucus plays a vital role in shielding the lungs against harmful substances such as particles, pathogens, and chemicals inhaled from the environment. It captures these harmful elements, and ciliary action helps to expel them from the lungs. Paradoxically, malfunctioning of mucus induces the development of various respiratory illnesses, including asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases. Despite extensive research on controlling mucin production and hydration, the process of secretion is not yet fully comprehended.

Mucin undergoes regulated secretion at two rates: a low baseline rate and a high stimulated rate. Over the past 25 years, …

Wee1 And Cell Size Control In Fission Yeast By The Protein Kinase Cdr2, Rachel Berg-Murante

Dartmouth College Ph.D Dissertations

The mechanisms that govern cell size have long been topics of study in the field of cell biology. In eukaryotic cells this size control is tied to checkpoints, a set threshold of minimum necessary growth linked to cyclin dependent kinase activity regulation. In the fission yeast Schizosaccharomyces pombe, the Cdk1 regulatory network is conserved, and G2/M represents the major size checkpoint. Prior to mitosis, Cdk1 is inhibited by phosphorylation applied by Wee1 during G2 phase. Once S. pombe cells have satisfied the size checkpoint, Cdk1 is activated through dephosphorylation by Cdc25. Wee1 is a dose-dependent regulator of mitotic entry …

Neuroinflammation In Alzheimer’S Disease Mouse Brain Following Repetitive Mild Traumatic Brain Injury, Lujain Almuhanna

Electronic Theses and Dissertations

Traumatic brain injuries (TBIs) are a common form of head injury, with mild TBIs (mTBIs) making up 75-90% of the TBI severity scale. It’s been suggested that repetitive mild TBIs (rmTBIs) may enhance effects of Alzheimer’s Disease (AD). With dementia linking TBI and AD together, we investigated the memory hub of the brain - the hippocampus. Astrocytes and microglia are two glial cells that respond to neuroinflammation and therefore imaged in hippocampal regions of the 3xTg-AD mouse brain. We hypothesized that AD brain pathology (i.e., neuroinflammation) would be accelerated in 3xTg-AD mice following rmTBIs early in life. Analyses revealed that …

Investigating The Regulation Of The Hypothalamic-Pituitary-Interrenal Axis In Atlantic Sturgeon (Acipenser Oxyrinchus) Following An Acute Stressor, Liam Doherty

Undergraduate Theses, Capstones, and Recitals

This study investigated the response to acute stress in Atlantic sturgeon (Acipenser oxyrinchus) and HPI axis regulation of glucocorticoid production during stress by examining the expression of key genes― corticotropin-releasing hormone (crh), corticotropin-releasing hormone receptor (crhr), proopiomelanocortin (pomca/pomcb), melanocortin 2 receptor (mc2r), and steroidogenic acute regulatory protein (star)―that are associated with hypothalamus/pituitary/interrenal (HPI) axis of bony fishes. Additionally, tyrosine hydrogenase (th1 and th2) and phosphoenolpyruvate carboxykinase (pepck), found in catecholamine-producing cells in the head kidney of the sturgeon, were investigated …

Deciphering The Contribution Of Microglia To Neurodegeneration In Friedreich's Ataxia, Sydney N. Gillette

Master's Theses

Friedreich's ataxia (FRDA) is the most prevalent inherited ataxia, affecting one in every 50,000 individuals in the United States. This hereditary condition is caused by an abnormal GAA trinucleotide repeat expansion within the first intron of the frataxin gene resulting in decreased levels of the frataxin protein (FXN). Insufficient cellular frataxin levels results in iron accumulation, increased reactive oxygen species production and mitochondrial dysfunction. Tissues most heavily impacted are those most dependent on oxidative phosphorylation as an energy source and include the nervous system and muscle tissue. This is evident in the clinical phenotype which includes muscle weakness, ataxia, neurodegeneration …

Quantitative Proteomic Strategies To Determine Substrate Specificities Of Phosphoprotein Phosphatases, Hieu Trung Nguyen

Dartmouth College Ph.D Dissertations

Reversible phosphorylation is a crucial regulatory mechanism of cellular signaling pathways. Being the most prevalent post-translational modification (PTM) in the cells, with over 75% of all proteins detected to be phosphorylated, phosphorylation regulates a significant number of important cellular processes that have implications in various diseases. Phosphorylation is carried out by protein kinases, which have been extensively studied. However, the opposite reaction, carried out by protein phosphatases, has lagged significantly, exposing a gap of knowledge that is required to be investigated to delineate the kinase-substrate-phosphatase relationship. Phosphoprotein phosphatase family (PPPs), containing seven members of phospho-Serine (pS) and phospho-Threonine (pT) phosphatases, …

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Cell Cycle Regulator Delays Pilus Production In Caulobacter Crescentus, Eli Johnson

Honors Theses

Caulobacter crescentus is a model bacterium for its unusual life cycle. This cycle features three distinct phases- the stalked stage, pre-divisional or actively dividing stage, and the swarmer stage, characterized by the production of a flagellum and multiple pili. Pili are necessary for cell attachment to surfaces and their reuptake into the cell can help drive the cell cycle forward. The gene that encodes the pilus subunit, pilA, is regulated by four binding sites for the cell cycle regulator CtrA. Previous research has determined that one site induces expression while two of the four sites inhibit expression. It is unknown …

Omani Camels From A Cultural And Genomics Perspective, Al Muatasim Al Zadjali

Electronic Theses and Dissertations

The Dromedarian camel, Camelus dromedarius, is native to the Arabian Peninsula, including the Sultanate of Oman. These camels are used for food, milk, as well as show and racing competitions. Despite their economic and cultural importance research on camels in Oman is limited. The goal of this study was to examine their genomic variation, relationship with camels in other parts of the Arabian Peninsula, and to determine if selective breeding has led to the establishment of distinct breeds in Oman. Information was compiled from multiple sources to produce a comprehensive review on the breeding, management, economic and cultural use, …

Investigating The Antibacterial And Immunomodulatory Effects Of Resolvin D2 On Monocytes And Macrophages, Cristina Maria Padovani

Theses and Dissertations

In the late phase of sepsis, immunosuppression occurs, where the host is unable to clear the pre-existing infection and is susceptible to secondary infections. It is believed that the ideal treatments for sepsis should attenuate immunosuppression so that the host can get back to homeostasis. Specialized Pro-resolving Mediators (SPMs) are endogenously- produced fatty acids that resolve infectious inflammation without being immunosuppressive. We hypothesize that an SPM – Resolvin D2 (RvD2) – can augment exhausted macrophage function during the immunosuppressive phase of sepsis. We developed a two-hit model to establish macrophage exhaustion in vitro, and found that RvD2 increased NF-κB activity, …

Neuroinflammation Levels Measured By Microglial Cell Activation, Emma G. Whitlock, Linda S. Yasui

Honors Capstones

Neuroinflammation is an inflammatory response in the brain that can be caused by different stressors such as diseases and/or external factors such as traumatic brain injuries. It is important to note duration and intensity of neuroinflammation levels when determining the impacts of these stressors to the brain environment. During neuroinflammation, a type of immune cell that becomes activated in the brain is called microglial cells. Microglial cells play a role in progression of the pathophysiological effects from the brain stressor. Studying changes in microglial cell shape provides evidence of the degree of neuroinflammation in the brain. Researchers can quantify neuroinflammation …

Characterizing The Neuronal Signaling Required For Muscle-Specific And Whole Body Enhanced Proteostasis Effects Of Low Mrna Translation, Marissa N. Ruzga

Electronic Theses and Dissertations

In the study of aging, there is a common paradigm that organisms allocate energy between surviving stressful conditions and growth/reproduction (Masoro, 2000). Driving mechanisms that favor the former extend lifespan and protect against cellular stress in different animal systems, including C. elegans. Dietary restriction is one such environmental stressor, which leads to downregulation of the energy-intensive process of mRNA translation (Karol, 2009; Tavernarakis, 2008). When knocked down in adulthood, IFG-1, a component of translation regulation, also protects against cellular stress. Protective effects of low translation appear to be orchestrated by certain tissues in C. elegans, namely neurons and …

Importance Of Specific Nk Cell Subsets For Antitumor Immunity In Hpv+ Cancers, Madison O'Hara

Dissertations & Theses (Open Access)

High-risk type human papillomaviruses (HPV) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing worldwide. Survival rates for patients with locally advanced disease are poor and variable after standard of care (SOC) treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential for improving clinical outcome. The natural killer (NK) cells are a critical component for antitumor innate effector immunity. Among the multitude of activation and inhibitory receptors on immune cells, HLA-DR is recognized as an important activation marker …

Foxo1 Inhibitor, As1842856, Induces Cell Cycle Arrest And Reverses Anticancer Drug-Induced Cytotoxicity In Osteosarcoma Cells, Antanay Hall

Theses (2016-Present)

Forkhead box class O (FOXO)-1 transcription factor controls cell proliferation, apoptosis, oxidative stress, and other cellular activities; FOXO1 has also been implicated in cell cycle regulation. This research project aims to determine the contribution of FOXO1 to cell cycle regulation and response to anticancer drug treatment in osteosarcoma. Osteosarcoma is the most common bone cancer, with most cases occurring in people younger than 30 years old. The study explores the impact of FOXO1 inhibitor AS1842856 on the cytotoxic effects of anticancer drugs in CCHOSD, Hos, and LM7 osteosarcoma (OGS) cell lines. Following chemical inhibition of FOXO1 and anticancer drug treatment, …

Stability Of Dna In Saliva Evidence Collected With Two Different Swabbing Solutions, Kuanwei Lu

Student Theses

As the significance of trace DNA has increased over time, it has become more important to optimize each process to avoid any loss of genetic material. Factors that could negatively affect the quality and quantity of DNA during transport or storage include environmental temperature, the DNA collection devices, the packaging, and possible contamination. This study compared the DNA stability of saliva stain swabs collected by moistening the swab with deionized water or Sample Keeper and stored at room temperature. Sample Keeper (Microread Genetics, Beijing) is a proprietary buffer marketed as a DNA stabilizing agent. We swabbed 110 saliva stains from …

Uncovering Novel Small Regulatory Rna In Protostome, Sweta Khanal

Dissertations

Small RNAs play pivotal roles in post-transcriptional gene regulation across diverse phylum of protostomes. In this study, we investigate the functional significance of atypical miRNAs, mirtron miR-1017 in Drosophila. Through ectopic expression in neuronal cells, we demonstrate that miR-1017 extends lifespan by targeting its host transcript, acetylcholine receptor Dα2, and influencing its splicing. This novel trans-regulatory function suggests a mechanism for mirtron evolution, highlighting the interplay between splicing and post-transcriptional regulation. Additionally, we profile small RNA populations in the polychaete developmental model Capitella teleta, shedding light on the small RNA landscape in annelid worms. Our analysis reveals a rich …

Characterization Of Mitochondrial Morphology In Drosophila: Early Embryogenesis Description Via Confocal Microscopy, Kendall Miller

Biological Sciences Undergraduate Honors Theses

Mitochondria are not static organelles, but instead are dynamic networks that undergo rapid changes in subcellular distribution, organization, and activity in response to external stimuli. Notably, mitochondria can undergo fission and fusion, collectively known as mitochondrial dynamics. Mitochondrial fusion creates assembled networks of mitochondria that are maximally efficient at generating ATP through oxidative phosphorylation. Conversely, mitochondrial fission leads to network fragmentation and a shift towards glycolysis, which is the dominant mode of ATP generation in oxygen-limiting and stressed conditions. While mitochondrial dynamics have been intensively studied in isolated cells under stressful conditions, much less is known about how mitochondria behave …

Atlas-Based Analysis Of The Neural Projections From The Lateral Hypothalamic Area To The Lower Brainstem In The Adult Male Rat, Jessica Valeria Salcido Padilla

Open Access Theses & Dissertations

Within the last decade, the number of diseases associated with dysregulation of the neural circuits responsible for energy balance, glucosensing, and feeding control has increased. One brain region containing these circuits is the lateral hypothalamic area (LHA), which plays an important role in the sleep/wake cycle, energy balance, and motivated behavior. Although the LHA has been termed a â??feeding centerâ??, other regions within the hindbrain are known for the regulation of similar functions including energy balance, glucosensing, and feeding control. While many studies have explored and reported projections from the LHA to the hindbrain, few have further investigated the interconnections …

Sdf-1Α Mediates Primary Tumor Escape In Glioblastoma Through Activation Of Mesenchymal Transitions., Charles T. Froman-Glover

College of Arts & Sciences Senior Honors Theses

Glioblastoma (GBM), a highly aggressive primary brain tumor originating in glial cells, poses a significant challenge due to its rapid growth and invasive nature within healthy brain tissue.

Current treatments involve surgical resection, chemotherapy, and radiation. These treatments alone are not enough to cure this disease, and a better understanding the mechanics of the tumor micro-environment is imperative to furthering the field of cancer research. This research focuses on understanding the tumor microenvironment's impact, specifically investigating the role of stromal cell-derived factor 1 (SDF-1) mechanics on GBM aggressiveness. SDF-1 is known to facilitate disease progression by facilitating chemotaxis toward the …

The Anti-Diabetic Drug Metformin Disrupts Feeding And Sleeping Behaviors In Drosophila Melanogaster., Lucas Fitzgerald

College of Arts & Sciences Senior Honors Theses

Dimethylbiguanide, also known as metformin, is the single most prescribed oral treatment for non-insulin dependent diabetes mellitus, or type 2 diabetes, in Western countries. The primary mechanism of action that metformin acts through is the activation of AMP kinase, an important regulator of energy homeostasis. While the anti-diabetic effects of metformin are well documented, its effects on feeding and sleeping behaviors are not well characterized. Using the model organism Drosophila melanogaster, the mean daily quantity of food consumed was measured and compared between groups treated with several dosages of metformin. Feeding interactions such as meal frequency and length were …

Single Cell Pharmacodynamic Modeling Of Cancer Cell Lines, Arnab Mutsuddy

All Dissertations

Cancer is one of the leading causes of disease related death worldwide. Since the discovery of the genomic origins of cancer, targeted therapy has been developed towards specific mutations implicated for oncogenic transformation. However, current standard-of-care for mapping cancer patients to efficacious drug combination is often inadequate. The pathophysiology of tumor progression relies on the dysregulation of biomolecular pathways of which the topology and the dynamics challenge prognosis. Moreover, the overall genomic instability involved in disease states and the resulting inter-patient as well as intra-tumoral heterogeneity challenge rationalization of therapy and clinical decision-making. It highlights the need for the use …

Simvastatin Induces Autophaghy-Mediated Cell Death In Metastatic Breast Cancer Cells, Jessica Allagoa

Theses (2016-Present)

Breast cancer remains one of the leading causes of cancer deaths among women. Due to the limited effectiveness of current anticancer drugs, ongoing research has extended towards alternative drug categories for potential treatments. Recent findings indicate that statins possess the ability to suppress tumors across various cell types. Traditionally, statins are known as a class of cholesterol-lowering agents and function by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a key enzyme in the mevalonate pathway. However, statins can also suppress cell proliferation and ultimately lead to cell death, which includes Type I apoptosis-induced cell death or Type II autophagy-induced cell death. Autophagy is …

Biophysical Model Of Retraction Motor Neurons And Their Modification By Operant Conditioning, Maria Rasheed

Dissertations & Theses (Open Access)

Operant conditioning (OC) is a form of associative learning in which an animal modifies its behavior based on the consequences that follow that behavior. Despite its ubiquity, the underlying mechanisms of OC are poorly understood. Insights into the mechanisms of OC can be obtained by studying Aplysia feeding behavior as it can be modified by OC. This behavior is mediated by a central pattern generator (CPG) network in the buccal ganglia that contains a relatively small number of neurons. This CPG generates rhythmic motor patterns (BMPs) that move food into the gut by closing a tongue-like structure (i.e., radula) during …