Life Sciences Commons^™

On The Anti-Adipogenic Function Of Collagen Triple Helix Repeat-Containing Protein 1, Matthew E. Siviski

Electronic Theses and Dissertations

Adipogenesis is regulated by the coordinated activity of adipogenic transcription factors, including PPAR-gamma (PPARG) and C/EBP alpha (CEBPA). Thus, dysregulated adipogenesis predisposes adipose tissues to adipocyte hypertrophy and hyperplasia. We have previously reported that mice possessing a homozygous null gene mutation in collagen triple helix repeat-containing protein 1 (CTHRC1) have increased adiposity compared to wildtype mice, supporting the concept that CTHRC1 regulates body composition. Herein, we investigated the anti-adipogenic activity of CTHRC1. Using 3T3-L1 preadipocytes, we showed significantly reduced adipogenic differentiation in the presence of CTHRC1 commensurate to marked suppression of Cebpa and Pparg gene expression. In addition, CTHRC1 increased …

Endothelial Interleukin-17 Receptor D (Il17rd) Promotes Western Diet-Induced Aortic Myeloid Cell Infiltration, Shivangi Pande

Electronic Theses and Dissertations

The Interleukin-17 (IL17) family is a group of cytokines implicated in the etiology of several inflammatory diseases. Interleukin-17 receptor D (IL17RD), also known as Sef (similar expression to fibroblast growth factor), belonging to the family of IL17 receptors, has been shown to modulate IL17A-associated inflammatory phenotypes. The objective of this study was to test the hypothesis that IL17RD promotes endothelial cell activation and consequent monocyte adhesion. We utilized primary human aortic endothelial cells and demonstrated that RNAi targeting of IL17RD suppressed transcript levels by 83% compared to non-targeted controls. Further, RNAi knockdown of IL17RD decreased the adhesion of THP-1 cells …

A Quantitative Visualization Tool For The Assessment Of Mammographic Risky Dense Tissue Types, Margaret R. Mccarthy

Electronic Theses and Dissertations

Breast cancer is the second most occurring cancer type and is ranked fifth in terms of mortality. X-ray mammography is the most common methodology of breast imaging and can show radiographic signs of cancer, such as masses and calcifcations. From these mammograms, radiologists can also assess breast density, which is a known cancer risk factor. However, since not all dense tissue is cancer-prone, we hypothesize that dense tissue can be segregated into healthy vs. risky subtypes. We propose that risky dense tissue is associated with tissue microenvironment disorganization, which can be quantified via a computational characterization of the whole breast …

A Small Molecule Screen On Zebrafish Embryos Identifies Pathways Vital To Hypaxial Muscle Precursor Migration, Teresa Easterbrooks

Electronic Theses and Dissertations

Hypaxial muscles form through long-range migration of muscle precursor cells (MMPs) from the somites. In zebrafish, the MMPs migrate in three compact streams to generate four muscles - the sternohyoideus muscle, homologous to mammalian neck and tongue; the posterior hypaxial muscle; and the two pectoral fin muscles, homologous to mammalian limbs. Several factors, such as Six1/4, are known to promote this migration; however, many aspects of guidance, pathing, and modulation of these streams are still unknown. To fill this gap, we conducted a small-molecule screen. This pharmacological approach allows us to identify molecules that cause pronounced changes in the normal …

The Tricarboxylic Acid Cycle As A Central Regulator Of The Rate Of Aging: Implications For Metabolic Interventions, Jonathan M. Borkum

Psychology Faculty Scholarship

Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high-capacity …

Mitochondria Mediated Outcomes Of Developmental Exposure To Low-Level Chemical Mixtures In Zebrafish Danio Rerio, Remy Babich

Electronic Theses and Dissertations

Exposure to drinking water contaminants has been linked to developmental outcomes in both epidemiological and model organism studies. However, low level mixture effects, on early development has yet to be explored. It is hypothesized that early chemical exposures may increase disease susceptibility later in life. This work aimed to investigate impacts of a variety of chemicals and concentrated on metals arsenic (As), cadmium (Cd), vanadium (V), and lead (Pb) due to their presence in drinking water and known developmental toxicity. To determine the effects of a metal and organic contaminant co-exposure, the ubiquitously used herbicide glyphosate was also explored. The …

Regulation Of Line-1 In Developing Oocytes And The Impact On The Ovarian Reserve, Rose Besen-Mcnally

Electronic Theses and Dissertations

In humans and mice, the ovarian reserve (OR) is established during a lengthy process that starts during early embryogenesis with germ cell specification and culminates in the first weeks after birth when primordial follicles (PF) are formed. OR establishment is an important process which influences the fertile lifespan and fecundity of the individual. Fetal oocyte attrition (FOA) has been identified as a critical developmental event that regulates how many oocytes survive and contribute to the final OR. In addition to FOA, OR size and quality also depend on efficiency of meiotic recombination. Chromosome asynapsis and unrepaired meiotic double-strand breaks (DSB) …

Understanding The Contribution Of Gα To The Yeast Pheromone Response, Cory Johnson

Electronic Theses and Dissertations

G-protein coupled receptors (GPCRs) are the target of approximately 35% of all FDA-approved pharmaceuticals. This is because GPCRs regulate different cellular signals including control of cell polarity. The yeast, Saccharomyces cerevisiae, use a GPCR for mating which induces chemotropic growth and morphogenesis toward a mate. In mammalian cells, signaling downstream of the receptor is primarily conducted by the Gα subunit of the large G-protein. In the yeast pheromone response little is known about Gα’s contribution to signaling and the Gβγ subunit is the primary known contributor. This begs the question, what is the contribution of Gα to the yeast pheromone …

The Cpsa And Psr Proteins Of Streptococcus Agalactiae Provide A United Front To Protect Against The Host Immune System, Atefeh Rajaei

Electronic Theses and Dissertations

Bacteria need suitable and resourceful environments to live and reproduce, including soil, oceans, plants, animals and humans. Streptococci are Gram positive pathogens that have the ability to infect a wide variety of hosts including fish, horses, swine, cattle and humans. Among the many streptococcus species, Streptococcus agalactiae (Group B streptococcus or GBS) is an opportunistic pathogen that has been identified as the leading cause of sepsis and meningitis in neonates, in addition to causing invasive and systemic infections in immunocompromised individuals. To survive inside different host environments, bacteria utilize many virulence factors to combat the host immune response, including the …

The Role Of Foxd1 In Clear Cell Renal Cell Carcinoma, Kyle H. Bond

Electronic Theses and Dissertations

Renal cell carcinoma (RCC) is the 8^th most common cancer in the United States, with the clear cell variant (ccRCC) being the most prevalent. Over 14,000 people die every year to RCC, with rates continuing to increase with an aging general population. Patients suffering from metastatic RCC (mRCC) have extremely poor prognoses, with a 5-year survival of only 11.2%. Current treatment options include resection of primary lesions, tyrosine kinase inhibition (Sunitinib, Pazopanib), mTOR inhibition (Temsirolimus, Everolimus), and immune checkpoint inhibition (Nivolumab, Atezolizumab). Recent attention has been drawn to inhibition of transcription factors like HIF2α (Belzutifan). There is a need …

Computationally Modeling Dynamic Biological Systems, Katherine Jarvis

Electronic Theses and Dissertations

Modeling biological systems furthers our understanding of dynamic relationships and helps us make predictions of the unknown properties of the system. The simple interplay between individual species in a dynamic environment over time can be modeled by equation-based modeling or agent- based modeling (ABM). Equation based modeling describes the change in species quantity using ordinary differential equations (ODE) and is dependent on the quantity of other species in the system as well as a predetermined rates of change. Unfortunately, this method of modeling does not model each individual agent in each species over time so individual dynamics are assumed to …

The Intersection Of Extracellular Signaling And Stress Pathways, Sari Mayhue

Electronic Theses and Dissertations

Cell growth is reliant on the flawless orchestration of cellular signaling and is crucial to evade cancer metastasis. It is important to understand key elements of cellular processes like gene regulation and stress signaling and how they contribute to oncogenesis. Cancer cells prove exceptionally adaptive as they effectively evade cellular stress, thus encouraging a tumor hospitable environment and subsequently cancer metastasis. Protein-folding and cellular homeostasis are essential functions of the endoplasmic reticulum (ER). An overabundance of protein accumulation within the ER jeopardizes cellular homeostasis causing stress. Under ER stress, these functions fail to maintain cellular stability resulting in the activation …

Deciphering The Perpetual Fight Between Virus And Host: Utilizing Bioinformatics To Elucidate The Host's Genetic Mechanisms That Influence Jc Polyomavirus Infection, Michael P. Wilczek

Electronic Theses and Dissertations

JC polyomavirus (JCPyV) is a human-specific pathogen that infects 50-80% of the population, and can cause a deadly, demyelinating disease, known as progressive multifocal leukoencephalopathy (PML). In most of the population, JCPyV persistently infects the kidneys but during immunosuppression, it can reactivate and spread to the central nervous system (CNS), causing PML. In the CNS, JCPyV targets two cell types, astrocytes, and oligodendrocytes. Due to the hallmark pathology of oligodendrocyte lysis observed in disease, oligodendrocytes were thought to be the main cell type involved during JCPyV infection. However, recent evidence suggests that astrocytes are targeted by the virus and act …

Hells And Prdm9 Form A Pioneer Complex To Open Chromatin At Meiotic Recombination Hotspots: A Technological Perspective, Catrina Spruce

Electronic Theses and Dissertations

Chromatin functions as a physical barrier regulating access to DNA, however pioneer factors are able to engage partial recognition motifs present within nucleosomal DNA to initiate access to specific DNA sequences. During spermatogenesis, genomic locations that become recombination hotspots are generally in regions of closed chromatin, or heterochromatin, before meiosis. However, in leptotene and zygotene stages of meiosis, PRDM9 marks nucleosomes at recombination hotspots with H3K4me3 and H3K36me3 and recruits other factors that deposit additional histone marks. Here I focus on the technological approaches by which we discovered that hotspots also transition from closed to open chromatin, dependent on the …

Characterizing Mab Cluster R Prophage Of Pathogen Mycobacterium Abscessus (Mab), Madeline Kimble

Honors College

Mycobacterium abscessus (Mab) is an emerging pathogen that can cause pulmonary, skin and disseminating infections. It is one of the most drug-resistant pathogens and infections typically result in high morbidity and mortality. Understanding mechanisms of antibiotic resistance is critical for developing more effective treatments. Prophage, integrated viral genomes, are known to contribute to bacterial virulence and antibiotic resistance, yet Mab prophages remain largely uncharacterized.My research aims to characterize the diversity of the novel cluster MabR prophage genomes. The Molloy lab has demonstrated that the prophage McProf increases mycobacterial resistance to antibiotics. Using the McProf prophage genome sequence, we probed the …

Infection And Diet-Induced Gut Dysbiosis: Impact On Sleep Quality In Danio Rerio, Benjamin Williams

Honors College

A known bidirectional relationship between intestinal microflora and the central nervous system, coined the gut-brain-axis, has stimulated work on the association between gut dysbiosis and inflammation, and sleep quality. Previous studies in the Hayes Lab have reported that a high fat (HF) diet was correlated with immobile phases, a marker of low motility during sleep found in some neurological disease and sleep duration[1]. Long sleep duration (>1 S.D. above norms for age) is associated with poor sleep quality or sleep fragmentation in participants who are overweight or obese according to body mass index values[2]. The current work utilizes a …

The Impact Of Natural Rubber As A Toughening Agent On The Strength, Degradability, And Toxicity Of An Algae-Based Bioplastic, Megan Driscoll

Honors College

With the growing attention on widespread plastic usage and its impact on the environment and human health, the need for sustainable alternatives to petroleum-based plastics is more important than ever. One of the most promising solutions is bioplastics; however, current bioplastics struggle to compete with the material properties of petroleum- based plastics. Agar is a sustainable algae-derived hydrocolloid polysaccharide that can be used for bioplastics and biofilms. Despite promising characteristics, bioplastics made from agar are brittle. Common additives, such as the plasticizer glycerol, offset brittleness but sacrifice strength in return. This study looks at the impact of natural rubber as …

Live Cell Super-Resolution Microscopy Quanitifies An Interaction Between Influenza Hemagglutinin And Phosphatidylinositol 4,5-Bisphosphate, Jaqulin N. Wallace

Electronic Theses and Dissertations

Influenza virus, colloquially known as the flu, is an acute respiratory disease that infects several millions of individuals each year in the U.S. and kills tens of thousands of those infected. Yearly viral vaccines are widely available, however, due to the virus’s high mutation rate, their efficacy varies greatly. Due to the variability in vaccine efficiency against seasonal influenza, and the potential for even more pathogenic versions of influenza to emerge at any time, there is a high demand for a universal treatment option.

Influenza virus hijacks a variety of host cell components in order to replicate. The glycoprotein hemagglutinin …

Examining The Function Of Protein Acyltransferase Via The Dhhc Domain Of The Paz5 Protein In The Organism Dictyostelium Discoideum, George M. Stuart-Ranchev

Electronic Theses and Dissertations

Protein S-palmitoylation plays a crucial role in many biological systems. S-palmitoylation involves the post-translational attachment of palmitate to a cysteine residue through a reversible thioester linkage. S-Palmitoylation is used to modify both integral and membrane proteins, many of which are involved in intracellular trafficking, membrane localization, and signal transduction pathways. Intracellular palmitoylation is mediated by a family of protein acyltransferases (PATs). PAT mutations are associated with neurological diseases and cancer progression. Proteins in the PAT family are defined by the presence of a 51-amino acid cysteine-rich domain (CRD), which contains a highly conserved aspartate-histidine-histidine-cysteine (DHHC) motif. The …

Triclosan Disrupts Immune Cell Function By Depressing Ca2+ Influx Via Acidification Of The Cytoplasm, Suraj Sangroula

Electronic Theses and Dissertations

Triclosan (TCS) is an antimicrobial agent that was effectively banned by the FDA from hand soaps in 2016, hospital soaps in 2017, and hand sanitizers in 2019; however, TCS can still be found in a few products. At consumer-relevant, non-cytotoxic doses, TCS inhibits the functions of both mitochondria and mast cells, a ubiquitous cell type. Via the store-operated Ca²⁺ entry mechanism utilized by many immune cells, mast cells undergo antigen-stimulated Ca²⁺ influx into the cytosol, for proper function. Previous work showed that TCS inhibits Ca²⁺ dynamics in mast cells, and here we show that TCS also inhibits …

Quantification Of Interactions Between Influenza Hemagglutinin And Host Cell Phosphoinositides By Super-Resolution Microscopy, Matthew T. Parent

Electronic Theses and Dissertations

The influenza viral membrane protein hemagglutinin (HA) forms dense nanoscale clusters on host cell plasma membranes (PM), but the mechanisms that direct HA clustering are not well understood. Previous studies have observed HA associated with actin rich regions of the PM, but there are no known direct interactions between HA and actin. Phosphatidylinositol 4,5-biphosphate (PIP2) is a signaling lipid in the PM which can regulate the actin cytoskeleton, and actin comets initiated by PIP2 are known to be exploited by HA to reach the PM of infected cells. PIP2 is also used by other viruses, such as HIV and Ebola, …

Identifying The Link Between Non-Coding Regulatory Rnas And Phenotypic Severity In A Zebrafish Model Of Gmppb Dystroglycanopathy, Grace Smith

Honors College

Muscular Dystrophy (MD) is characterized by varying severity and time-of-onset by individuals afflicted with the same forms of MD, a phenomenon that is not well understood. MD affects 250,000 individuals in the United States and is characterized by mutations in the dystroglycan complex. gmppb encodes an enzyme that glycosylates dystroglycan, making it functionally active; thus, mutations in gmppb cause dystroglycanopathic MD1 . The zebrafish (Danio rerio) is a powerful vertebrate model for musculoskeletal development and disease. Like human patients, gmppb mutant zebrafish present both mild and severe phenotypes. In order to understand the molecular mechanisms involved, we performed high-throughput RNA …

The Potential For Dickeya Dianthicola To Be Vectored By Two Common Insect Pests Of Potatoes, Jonas K. Insinga

Electronic Theses and Dissertations

Dickeya dianthicola (Samson) causing blackleg and soft rot was first detected in potatoes grown in Maine in 2014. Previous work has suggested that insects, particularly aphids, may be able to vector bacteria in this genus between plants, but no conclusive work has been done to confirm this theory. In order to determine whether insect-mediated transmission is likely to occur in potato fields, two model potato pests common in Maine were used: the Colorado potato beetle (Leptinotarsa decimlineata Say) and the green peach aphids (Myzus persicae Sulzer). Olfactometry and recruitment experiments evaluated if either insect discriminates between infected and …

Cpsa Protein-Protein Interactions In Group B Streptococcus, Ben Tero

Honors College

Group B Streptococcal (GBS) infections pose a great threat to mortality in neonates. Neonates are often exposed to GBS both before, during, and after delivery, which can cause a range of health problems including meningitis, sepsis, or stillbirth. One of the major virulence factors that contributes to the infectivity of the pathogen is the bacterial capsule. The capsule is a polysaccharide matrix surrounding the cell which helps in the evasion of host defenses, and penetration into normally sterile sites like the bloodstream. The highly conserved GBS protein CpsA has been shown to regulate expression of the capsule. The objective of …

Dynamic Regulation Of G-Protein Signaling, William C. Simke

Electronic Theses and Dissertations

G protein-coupled receptors (GPCRs) are involved in numerous signaling processes ranging from neuronal growth to immune cells tracking invaders. GPCR signaling plays a role in many human diseases and thus GPCRs are important drug targets. Yeast respond to mating pheromone using a GPCR signaling system homologous to those used in humans to polarize their cytoskeleton toward the pheromone source. This is accomplished by initializing a MAPK signaling cascade to arrest the cells in mitosis and upregulate expression of chemotropic proteins. Pathway desensitization is accomplished by the Regulator of G-protein Signaling (RGS). RGS abrogates signaling by binding to the active GPCR, …

Cellular And Molecular Mechanisms Of Mapk Signaling During Jc Polyomavirus Infection, Jeanne Dushane

Electronic Theses and Dissertations

As obligate intracellular parasites, viruses must infect a host-cell and requisition cellular machinery for viral replication. JC polyomavirus (JCPyV) is a ubiquitous human pathogen that can cause a lytic infection in glial cells of the central nervous system in immunocompromised individuals. In order to initiate infection however, the virus must alter prototypical cellular processes that promote cellular homeostasis. The main driver of these processes are signaling pathways, the means by which the cell interacts and responds to the extracellular environment. Many signaling cascades are responsible for promoting growth, responding to pathogens, initiating differentiation, or inducing cell death. Through the works …

Genomic And Proteomic Effects Of Red Raspberry (Rubus Idaeus) Consumption On The Perivascular Adipose Tissue Of The Obese Zucker Rat, A Model Of Human Metabolic Syndrome, Jasmine Waite

Honors College

The Metabolic Syndrome (MetS) affects 35% of U.S. adults and is an indicator of early death. While pharmacological treatments have been developed for the majority of MetS risk factors, obesity-induced inflammation remains to be addressed. Dysfunctional adipose tissue is a source of inflammation, and perivascular adipose tissue (PVAT) is critical in its pathogenesis. This study investigates the effects of red raspberry (rubus idaeus) diet-enrichment on inflammation of PVAT. The obese Zucker rat (OZR) model of MetS and the lean Zucker rat (LZR) control (C) model were used. Rats received an eight-week control or whole red raspberry-enriched (WRR) diet …

Determining The Key Residues For Capsule Production In The Gbs Cpsa Protein, Anna Struba

Honors College

Streptococcus agalactiae (GBS) is a common bacterium found commensally in the vaginal mucosa of healthy adults. GBS also causes severe infection in neonates, often leading to meningitis, which can cause lifelong health consequences including impaired hearing and seizures. Infection of newborns mainly arises from a colonized mother, either before birth through ascending infection or during labor. Ascending infection, where the bacteria travel to the fetus from the vaginal mucosa, is especially concerning as it can lead to loss of pregnancy or premature birth. The most common method of neonatal GBS disease prevention is antibiotic prophylaxis during delivery, though this method …

Thermal And Microbial Effects On Brown Macroalgae: Heat Acclimation And The Biodiversity Of The Microbiome, Charlotte Tc Quigley

Electronic Theses and Dissertations

This dissertation examines effects of stress on brown algal biology from a macroscopic scale by examining the whole aquaculture crops, and at a microscopic level by examining the macroalgal microbiome, across the vertical stress gradient of the intertidal zone and across the latitudes of their biogeographic ranges. Thermal stress negatively affected seedstock gametophytes of the kelp Alaria esculenta isolated from northern and southern locations in Maine. However, previous thermal stress had a positive effect on growth of the next-generation sporophytes. Alaria esculenta has potential as a kelp crop in Maine’s sea vegetable aquaculture sector and implementing this protocol may allow …

Molecular Mechanisms Underlying Toxicant Effects On Mast Cell Signaling And Mitochondria, Juyoung Katherine Shim

Electronic Theses and Dissertations

Mast cells contribute to numerous physiological processes and diseases including immunological and neurological roles. Mast cells degranulate, releasing potent mediators, following signaling transduction initiated by receptor crosslinking. Previously, we showed that the environmental toxicant arsenic and the antibacterial agent triclosan inhibit mast cell degranulation; thus, we have investigated the mechanisms underlying their inhibitory action. We have discovered that arsenic targets early steps in the mast cell signaling pathway: it inhibits phosphorylation of early tyrosine kinase Syk and of Syk’s direct substrate PI3K. Arsenic’s tyrosine phosphorylation inhibition causes inhibition of calcium influx into the cytosol, a key event necessary for degranulation. …