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Differential Mechanisms Of Intestinal Inflammation Drive Pathogenesis Of Diabetic Retinopathy In Type 1 And Type 2 Diabetes, Jason Levi Floyd Jan 2023

Differential Mechanisms Of Intestinal Inflammation Drive Pathogenesis Of Diabetic Retinopathy In Type 1 And Type 2 Diabetes, Jason Levi Floyd

All ETDs from UAB

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and, along with diabetic macular edema (DME), accounts for the greatest source of vision-threatening eye disease in the working-age community. DR is caused by weakening of the retinal vasculature, the blood-retinal barrier (BRB), by high levels of blood glucose (hyperglycemia), exacerbations of oxidative stress, and systemic inflammatory factors. Many of these inflammatory factors are metabolic by-products and cell membrane constituents of the gut microbiota, the resident community of microbial species which inhabit the lumen of the gastrointestinal tract. These factors are collectively termed gut microbial antigens (GMAs). In diabetes, …


Biochemical Characterization Of Rna Polymerases I, Ii, And Iii And Its Therapeutic Implications, Ruth Qian Jacobs Jan 2023

Biochemical Characterization Of Rna Polymerases I, Ii, And Iii And Its Therapeutic Implications, Ruth Qian Jacobs

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In contrast to Bacteria and Archaea that express a single DNA-dependent RNA polymerase (RNAP), eukaryotes express at least three structurally distinct, nuclear, DNA-dependent RNA polymerases (Pols I, II, and III) that are responsible for synthesizing all the genome-encoded RNA required by the cell. Despite the discovery of the Pols over 50 years ago, there remains a knowledge gap concerning their enzymatic properties. Over the course of evolution, we know that Pols I, II, and III have diverged in structure and function. They share a 10-subunit core and are each responsible for transcribing unique genetic loci. What remains to be understood …


Chronic Hiv Infection Influences The Immune Response To Sars-Cov-2, Skye Opsteen Jan 2023

Chronic Hiv Infection Influences The Immune Response To Sars-Cov-2, Skye Opsteen

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused global morbidity and mortality since late 2019. Many infections result in self-limited disease and recovery in 1-2 weeks. However, a subset of individuals experience more severe illness, associated with hospitalization, ventilation, and potential mortality. HIV infection is a proposed risk factor for more severe illness due to people living with HIV (PLWH) experiencing chronic immune activation and inflammation despite effective antiretroviral therapy. While there is supporting evidence showing worsened clinical outcomes in PLWH experiencing acute COVID-19, the immune response driving these outcomes is less explored. We analyzed markers of immune activation …


Uncovering The Role Of Spt5 In Rna Polymerase I Transcription Through Targeted Protein Degradation Via The Auxin Inducible Degron System In Saccharomyces Cerevisiae, Nathan Bellis Jan 2023

Uncovering The Role Of Spt5 In Rna Polymerase I Transcription Through Targeted Protein Degradation Via The Auxin Inducible Degron System In Saccharomyces Cerevisiae, Nathan Bellis

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RNA Polymerases are the molecular machines responsible for the synthesis of RNA from the DNA template. The presence of these machines is an absolute requirement for the function and replication of all cellular organisms. In eukaryotic organisms, there are a minimum of three RNA polymerases (Pols I, II, II). Despite shared subunits and homology, these three protein complexes are functionally distinct, with many unique sub-units and additional trans-acting factors. Pol I is responsible for the synthesis of three of the four ribosomal RNA species which is the first and rate limiting step of ribosome biogenesis. Pol I synthesizes the majority …


Interactions Between Pseudomonas Aeruginosa And The Oral Commensal Streptococcus Salivarius, Sara Noelle Stoner Jan 2023

Interactions Between Pseudomonas Aeruginosa And The Oral Commensal Streptococcus Salivarius, Sara Noelle Stoner

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The cystic fibrosis airway is a polymicrobial environment often dominated by opportunistic pathogens such as Pseudomonas aeruginosa, a leading cause of lung function decline and mortality in persons with CF. Commensal streptococcal colonization has been associated with stable CF lung function in multiple studies. However, few studies have examined interactions between P. aeruginosa and commensals as well as their impact on P. aeruginosa airway infections. In the first half of this work, we studied interactions between P. aeruginosa and the oral commensal Streptococcus salivarius within a biofilm setting. We found that S. salivarius biofilm formation is promoted by the non-mucoid …


Investigating The P53 Tumor-Suppressive Network And The Dynamics/Mechanism Of P53 Loss Of Heterozygosity, Jun Wang Jan 2023

Investigating The P53 Tumor-Suppressive Network And The Dynamics/Mechanism Of P53 Loss Of Heterozygosity, Jun Wang

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Tumor suppressor gene TP53 is the most frequently mutated gene across human cancers (~50%). Patients with Li-Fraumeni syndrome (LFS) who carry germline p53 mutations exhibit a diverse spectrum of childhood- and adult-onset malignancies. Despite over 40 years of dedicated studies to understand the role of p53 in tumor prevention, there are still many unanswered questions regarding the underlying mechanisms of p53. Previous studies have supported the notion that p53 exerts its tumor-suppressive function through its transcriptional activities. Therefore, strategies to enhance p53’s functions in tumor suppression via manipulating of downstream target gene activities in cancers show promising. To better investigate …


A Tale Of Two Waves: The Role Of Genomic Enhancers In Regulating Transcriptional And Epigenetic Responses To Neuronal Activitiy, Robert A. Phillips Iii Jan 2023

A Tale Of Two Waves: The Role Of Genomic Enhancers In Regulating Transcriptional And Epigenetic Responses To Neuronal Activitiy, Robert A. Phillips Iii

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The mesolimbic dopamine (DA) pathway, which consists of dopaminergic neurons that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), is heavily implicated in drug addiction. Exposure to drugs of abuse results in increases in extracellular concentrations of DA in the NAc, which in turn activates an immediate early gene (IEG) expression program that primarily consists of activity-dependent transcription factors, such as the AP1 subunits Fos and JunB. IEGs engage a set of temporally and functionally distinct genes, termed the late response gene (LRG) expression program. While gene expression changes are critical for drug-dependent adaptations, two major …


Expression Of St6gal1 Imparts Stem-Like Cell Behaviors, Thereby Promoting Neoplasia, Sejal Sanjay Shinde Jan 2023

Expression Of St6gal1 Imparts Stem-Like Cell Behaviors, Thereby Promoting Neoplasia, Sejal Sanjay Shinde

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Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival of ~10%. Recent studies in the US population suggest PDAC as the fourth leading cause of cancer-related deaths in 2022. ST6 β-galactoside α2,6-sialyltransferase (ST6GAL1) is a glycosyltransferase which is known to be upregulated in cancer. It acts as a master regulator of a cell by being the predominant sialyltransferase catalyzing the addition of a bulky negatively charged sialic acid to the galactose sugar in an α2,6-linkage. Due to this, the sialic acid changes the structure and function of cell surface receptor proteins and regulates signal …


Plasticity Characteristics Of Cxcr5+ Cd4+ T Memory Cells And Cxcr5- Non-Tfh Memory Cells, Ching-En Lee Jan 2023

Plasticity Characteristics Of Cxcr5+ Cd4+ T Memory Cells And Cxcr5- Non-Tfh Memory Cells, Ching-En Lee

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iv ability to differentiate into CXCR5- and CXCR5+ effector cells between the CCR7- and CCR7+ CXCR5+ CD4+ T memory cells, between WT and μMT CXCR5+ CD4+ T memory cells, as well as between Bcl6- and Bcl6+ CXCR5- non-Tfh memory cells. This finding did not support the hypothesis that the heterogeneous characteristics within CXCR5- non-Tfh memory cells and CXCR5+ CD4+ T memory cells significantly affect their abilities to differentiate into CXCR5- and CXCR5+ effector cells during recall responses.


Understanding Molecular Mechanisms Of Glioblastoama Resistance To Design Novel Combinatorial Therapies, Amber B. Jones Jan 2023

Understanding Molecular Mechanisms Of Glioblastoama Resistance To Design Novel Combinatorial Therapies, Amber B. Jones

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Treatment options for the universally lethal brain tumor, glioblastoma (GBM), are severely limited and often unsuccessful in fully eradicating the disease. Extremely aggressive in nature, GBM cells often implore suppressive mechanisms to evade therapeutic detection which aids in the dismal 15-month median survival rate. Facilitating disease severity and more importantly, disease recurrence, are the immunosuppressive and chemoresistant phenotypes of GBM cells. Specifically, the DNA alkylating agent, temozolomide (TMZ) possesses lymphodepleting properties shunting robust immune cell infiltration into an immunologically cold tumor microenvironment. Additionally, through inherent or acquired mechanisms, GBM tumors commonly become resistant to the DNA damaging effects of TMZ …


Unveiling The Molecular Features Of Cancer Health Differences Through Multi-Omics Data Analysis, Fengyuan Huang Jan 2023

Unveiling The Molecular Features Of Cancer Health Differences Through Multi-Omics Data Analysis, Fengyuan Huang

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Understanding the molecular features underlying cancer health differences is crucial for developing effective therapeutic strategies. Multi-omics data analysis, integrating various molecular layers such as genomics, transcriptomics, epigenomics, proteomics, and metabolomics, provides a comprehensive approach to characterize the molecular landscape of cancer differences. By integrating diverse omics data, researchers can identify genetic variations, gene expression patterns, epigenetic modifications, and protein alterations that contribute to differences in cancer progression, and treatment response. These molecular features can serve as potential biomarkers for predicting patient outcomes and guiding personalized treatment strategies. Furthermore, multi-omics data analysis enables the identification of molecular subtypes specific to different …


Spatial/Temporal Zonation, Diversification, And Evolutionary Conservation Of Kidney Resident Macrophage Subpopulations In Mice And Humans After Kidney Injury, Elise Nicole Erman Jan 2023

Spatial/Temporal Zonation, Diversification, And Evolutionary Conservation Of Kidney Resident Macrophage Subpopulations In Mice And Humans After Kidney Injury, Elise Nicole Erman

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In the United States, acute kidney injury (AKI) affects nearly 20% of all intensive care unit patients. Additionally, over a third of Americans aged 50 or older suffer from stage 3 chronic kidney disease (CKD) or higher. AKI and CKD are encompassing terms for many etiologies and pathological processes that affect different regions of the kidney but converge at tissue inflammation and fibrosis. Macrophages perform vital homeostatic functions and can initiate or ameliorate inflammation and fibrosis. As the largest component of the kidney immune system, kidney resident macrophages (KRMs) have been implicated in both disease propagation and mitigation, yet the …


Application Of Machine Learning And Network Approaches To Prioritize Safe And Efficacious Drug Repurposing Candidates, Jennifer L. Fisher Jan 2023

Application Of Machine Learning And Network Approaches To Prioritize Safe And Efficacious Drug Repurposing Candidates, Jennifer L. Fisher

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Only ten percent of drugs in clinical trials are ultimately approved by the Food and Drug Administration (FDA). With many diseases and disorders needing therapeutic options, computational drug repurposing methodologies are great alternatives to some drug discovery methods due to quicker FDA approval and lower cost. We sought to gain insights to improve the identification of drug repurposing candidates that will be safe and effective to increase the success of computational drug repurposing approaches. In regards to identifying safe drug candidates, pharmacovigilance studies of adverse event case reports identified that women are more likely to experience an adverse event, and …


Impact Of Streptococcus Parasanguinis-Generated Reactive Nitrogen Species On Pseudomonas Aeruginosa Virulence And The Host Response, Joshua J. Baty Jan 2023

Impact Of Streptococcus Parasanguinis-Generated Reactive Nitrogen Species On Pseudomonas Aeruginosa Virulence And The Host Response, Joshua J. Baty

All ETDs from UAB

Streptococcus parasanguinis is an oral commensal bacterium that produces hydrogen peroxide. Hydrogen peroxide can react with endogenous molecules such as nitrite to form reactive nitrogen intermediates (RNI). These S. parasanguinis-mediated RNI have been shown to inhibit oral pathogens such as Streptococcus mutans, Enterococcus faecalis, and Aggregatibacter actinomycetemcomitans. As such, S. parasanguinis plays a protective role in the oral microbial ecosystem by antagonizing and preventing colonization by oral pathogens. In addition to being an important organism for the health of the oral cavity, S. parasanguinis has also been associated with improved outcomes for people with cystic fibrosis. There are two explanations …


Sialylation Of Epidermal Growth Factor Receptor By The Sialyltransferase St6gal1 Modulates Receptor Activity And Downstream Signaling, Katherine Ankenbauer Jan 2023

Sialylation Of Epidermal Growth Factor Receptor By The Sialyltransferase St6gal1 Modulates Receptor Activity And Downstream Signaling, Katherine Ankenbauer

All ETDs from UAB

During the process of malignant transformation, cells have striking changes in their cell surface glycosylation. One of these changes is an enrichment for α2,6 sialic acid which is added by the sialyltransferase, ST6GAL1. ST6GAL1 is upregulated in numerous malignancies and acts by adding an α2,6 sialic acid onto receptors bound for the plasma membrane. This sialic acid, in turn, modulates the activity of the receptor by regulating conformation, clustering, and cell surface retention. The work presented in this dissertation focuses on how ST6GAL1-mediated sialylation of a specific cell surface receptor, epidermal growth factor receptor (EGFR), regulates many of its properties. …


Epigenetic Aberrations In Systemic Sclerosis And Systemic Lupus Erythematosus, Peter C. Allen Jan 2023

Epigenetic Aberrations In Systemic Sclerosis And Systemic Lupus Erythematosus, Peter C. Allen

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Autoimmune diseases are a classification of more than eighty diseases where the immune system recognizes a self-antigen and mistakenly attacks the body’s own tissue, inducing inflammation a nd p otentially l eading t o d amage. Autoimmune diseases disproportionately affect women and develop at any age depending on the disease. The prevalence of some autoimmune diseases is increased in minority populations. Despite this, research into higher-risk populations is lacking. This highlights the need to contribute research into understanding autoimmune disease pathogenesis in diverse studies to understand why disease is more severe in these populations. We analyzed transcriptomes and methylomes of …


Pharmacologic Proteasome Activators Ameliorate Alzheimer's-Like Pathology In Ad Fly Models, Mehar Bano Jan 2023

Pharmacologic Proteasome Activators Ameliorate Alzheimer's-Like Pathology In Ad Fly Models, Mehar Bano

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The proteasome is a large multi-subunit protease responsible for the degradation and removal of oxidized, misfolded, and polyubiquitinated proteins. The proteasome plays a critical role in nervous system processes. This includes the maintenance of cellular homeostasis in neurons (1). It also includes synaptic efficacy and plasticity as well as protein turnover, presynaptic vesicle transport, and neuronal protesostasis. Proteasome function is impaired as a consequence of aging, which is aggravated by conditions like Alzheimer's Disease and Related-Dementias (AD, ADRD) (2). According to earlier work from our lab the proteasome is critical to how quickly AD progresses. In Drosophila, human cells, and …


Neutrophil Heterogeneity And Alternative Granulopoiesis In Chronic Inflammatory Conditions, Ashley N. Connelly Jan 2023

Neutrophil Heterogeneity And Alternative Granulopoiesis In Chronic Inflammatory Conditions, Ashley N. Connelly

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Neutrophils, the most abundant type of circulating leukocyte, represent a heterogeneous population with distinct roles in immune regulation and disease pathogenesis. A major obstacle to our understanding of neutrophil biology is that neutrophils are readily activated during preparation. The lack of standardized methodology for neutrophil characterization makes the comparison of results across studies challenging. Here we provide a careful comparison of eight characterization methods and present a novel, optimized protocol for the characterization of whole blood neutrophils minimizing activationinduced phenotypic alterations during processing. Despite successful virological control, HIV-1-infected individuals maintain an increased risk of life-threatening comorbidities including liver, cardiovascular, and …


Characterizing A Unique Oprm1 Expressing Neuronal Population In The Rat Nucleus Accumbens, Emma Andraka Jan 2023

Characterizing A Unique Oprm1 Expressing Neuronal Population In The Rat Nucleus Accumbens, Emma Andraka

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Opioid-related overdose deaths have increased drastically in the past three decades, and especially since the beginning of the COVID-19 pandemic, due to the addictive, analgesic, and euphoric properties of the drugs. To produce these effects, opioids bind to the mu opioid receptor (MOR) in GABAergic neurons. The MOR is encoded by the Oprm1 gene and is expressed in multiple brain regions that regulate reward and motivation, such as the nucleus accumbens (NAc). Previous studies of Oprm1 knockdown in medium spiny neurons (MSNs) of the mouse NAc have shown that these neuronal populations are involved in reinforcing reward-context pairing as well …


Investigating The Effects Of Immune Checkpoint Inhibition And Combined Treatment With Evofosfamide On The Tumor Microenvironment Through Hypoxia Imaging, Kaytlyn Carter Mcneal Jan 2023

Investigating The Effects Of Immune Checkpoint Inhibition And Combined Treatment With Evofosfamide On The Tumor Microenvironment Through Hypoxia Imaging, Kaytlyn Carter Mcneal

All ETDs from UAB

Colorectal cancer (CRC) is a prevalent and deadly cancer worldwide. While immunotherapy, particularly immune checkpoint inhibition, shows promise in various cancers, its efficacy in CRC and other tumor types is limited. Hypoxia, characterized by inadequate tissue oxygenation, critically drives cancer progression, promoting tumor growth, metastasis, chemotherapy resistance, and poor prognosis. Evofosfamide, a hypoxia-activating prodrug, is being evaluated in clinical trials for combined use with checkpoint blockade as a potential therapeutic strategy. This study investigates the impact of hypoxia on immune checkpoint inhibition, evofosfamide, and combination therapy, while utilizing non-invasive molecular imaging to develop analytical methods for quantifying and characterizing tumor …


The Effects Of Cannabidiol On Brain Temperature In Treatment-Resistant Epilepsy, Ayushe A. Sharma Jan 2023

The Effects Of Cannabidiol On Brain Temperature In Treatment-Resistant Epilepsy, Ayushe A. Sharma

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Epilepsy affects over 70 million people worldwide with a global incidence of 2.4 million new cases per year. In many of these patients, neuroinflammation (NI) is a key pathological contributor to focal seizure generation and maintenance. Sustained NI degrades the blood–brain barrier, leads to neuronal death, and ultimately decreases seizure threshold. Finding ways to image and treat NI is especially important for the >30% of patients with treatment-resistant epilepsy (TRE) who cannot achieve seizure freedom with standard antiseizure medications. Cannabidiol (CBD) effectively reduces seizure frequency and severity in many TRE patients, although its antiepileptic effects remain poorly understood. Atypically high …


Cis-Regulatory Elements: Relevance For Alzheimer's Disease, Brianne Brazell Rogers Jan 2023

Cis-Regulatory Elements: Relevance For Alzheimer's Disease, Brianne Brazell Rogers

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Alzheimer’s disease (AD) is the most common neurodegenerative disease, currently affecting more than six million Americans with limited treatment options. Identifying genetics contributors to neurodegenerative diseases has contributed critical insights into potential disease mechanisms. The majority of disease-associated genetic variants are located in non-coding regions, likely in regulatory elements, and affect the expression of target genes whose function contributes to neurodegeneration. Here, I performed a case-control study utilizing nuclei from dorsolateral prefrontal cortex postmortem tissue to correlate chromatin accessibility with gene expression and nominate 40,831 AD-specific candidate cis-regulatory elements. Additionally, work in this dissertation nominates ZEB1 and MAFB as candidate …


Applying Pet Imaging To Cancer Immunotherapy To Improve Clinical Outcomes, Kirsten M. Reeves Jan 2022

Applying Pet Imaging To Cancer Immunotherapy To Improve Clinical Outcomes, Kirsten M. Reeves

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The use of biomarkers has significantly enhanced patient outcome by improving diagnosis, personalizing therapy, and monitoring therapeutic response yet most cancers remain non-responsive. Thus, there is a need to better understand the underlying biological mechanisms and tumor microenvironment to enhance therapeutic efficacy. Molecular imaging, including magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) are used to assess response during oncology therapy. Molecular imaging can also provide a noninvasive approach to accurately quantify biomarkers correlated with the tumor microenvironment, including glucose metabolism and hypoxia. 18F-Fluoromisonidazole (18F-FMISO) hypoxia targeted cellular uptake has been shown to correlate with negative …


Regulation Of Stromal Cells Through Inflammatory Signalling, Victoria Matkins Jan 2022

Regulation Of Stromal Cells Through Inflammatory Signalling, Victoria Matkins

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The bone marrow is a complex organization of hematopoietic and nonhematopoietic cells that form niches to maintain systemic homeostasis during stress and disease. Stromal cells are non-hematopoietic cells first proposed in 1978 in the bone marrow to be essential for hematopoietic stem cells (HSC). Since then, mesenchymal stromal cells (MSC) have been shown to be critical for the HSC self-renewal, retention, and differentiation through chemokines, cytokines, and adhesion molecules. However, like HSCs, MSCs are multipotent progenitors that differentiate into osteoblasts, adipocytes, and chondrocytes to from tissues of the skeletal, endocrine, and connective systems. These multipotent progenitors are tightly regulated in …


Il-22 Mediated Host Defense During Attaching-Effacing Pathogen Infection, Baiyi Cai Jan 2022

Il-22 Mediated Host Defense During Attaching-Effacing Pathogen Infection, Baiyi Cai

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Intestinal infections are a cause of morbidity and mortality worldwide and remain a public threat. Interleukin (IL)-22 is central to host immune responses in the intestine during infection and inflammation. IL-22 can be produced by both innate and adaptive immune cells, yet their relative contributions to host protection remain unclear. Here we demonstrated the specific role and mechanism for IL-22 from innate and adaptive sources to protect the host. Using the Citrobacter rodentium (C.r) model, we found that IL-22 from innate cell, protect the host during early infection. IL-22 induces epithelial production of polymorphonuclear neutrophils (PMN) recruiting chemokine CXCL1, CXCL2 …


The Requirement Of Transcriptional Lim Complex Co-Regulators For Pancreatic Endocrine Cell Development And Function, Eliana Davi Toren Jan 2022

The Requirement Of Transcriptional Lim Complex Co-Regulators For Pancreatic Endocrine Cell Development And Function, Eliana Davi Toren

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The prevalence and tremendous impact of diabetes mellitus has made glucose regulation of the insulin-producing -cell and surrounding pancreatic islet of Langerhans a center of public and research interests alike. A comprehensive understanding of these hormone-producing cells begins with their developmental origins. What are the genetic cues and participants in the tightly orchestrated process of their formation? Investigating the earliest determinants of islet-cell fate not only allows us to deeply understand mature - and islet-cell function, but also produces a data-driven template for how these cells can be reproduced in future stem-cell based diabetes therapies. LIM transcriptional complexes are indispensable …


Molecular Imaging Of Cancer For Detection And Monitoring Of Response To Combination Therapy, Tiara S. Napier Jan 2022

Molecular Imaging Of Cancer For Detection And Monitoring Of Response To Combination Therapy, Tiara S. Napier

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Imaging is a primary component of cancer care and aids in diagnosing, response assessment, and monitoring. Molecular imaging techniques provide visualization of unique tumor biology that can be used to personalize treatment. Key features of an effective biomarker are sensitivity, specificity, and ability to provide clinical value beyond that of other types of information already available at the time of diagnosis. For particularly heterogeneous cancer subtypes, such as glioblastoma (GBM) and triple negative breast cancer (TNBC), reliable biomarkers can be challenging to identify and there are few tar-getable receptors for therapy. Our findings demonstrate that quantifying tumor EGFR (panitumumab-IRDye800CW), granzyme …


Study Of The Effects Of Contusion Spinal Cord Injury And Optogenetic Stimulation On Lower Urinary Tract Function, Salvador A. Lopez Jan 2022

Study Of The Effects Of Contusion Spinal Cord Injury And Optogenetic Stimulation On Lower Urinary Tract Function, Salvador A. Lopez

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Lower urinary tract (LUT) dysfunction is a detrimental ailment that negatively affects a person’s independence, health, and overall quality of life. More specifically, LUT dysfunction as a result of spinal cord injury (SCI) is seen in more than 17,000 cases per year and of those cases, <20% are discharged from care with normal micturition1. Initially, after SCI, there is an acute period of spinal shock when the urinary bladder is flaccid and underactive, while the external urethral sphincter (EUS) that constricts the bladder outlet quickly becomes tonically active. In days to weeks after injury, spinallymediated, reflex bladder contractions re-emerge2-4. Numerous studies have examined aspects of LUT function using various models of SCI, primarily utilizing complete transection injuries. This set of studies first examined the effect of moderate to severe midthoracic contusion SCI on LUT function by examining cystometrogram (CMG) and EUS recordings, bladder/spinal cord morphology, sensory innervation of bladder tissue, and spinal neuronal activation in female mice. This model of SCI produced significant changes in normal bladder function as well as altered bladder morphology, including a robust loss of bladder afferent nerve fibers necessary for micturition. Inhibition of histone deacetylase 6 (HDAC6) has been shown to prevent the loss of sensory nerve fibers in mouse hind paw tissue5, thus HDAC6 inhibition was examined as a possible strategy to prevent the observed loss of sensory nerve fibers in bladder tissue post-SCI. iv Mice were treated using intraperitoneal injections of inhibiting compounds ACY-1083 (10 mg/kg) or Tubacin (5 mg/kg). Treatment resulted in significant improvements in CMG measures and sensory innervation of the bladder wall. Finally, optogenetic stimulation was examined using an adenoassociated virus containing cre-recombinase for cre-dependent expression of channelrhodopsin (ChR2) in both spinal intact and SCI mice. The ability to spare afferent axons in bladder tissue post-SCI through HDAC6 inhibition allowed ChR2 expression in sensory nerve fibers. Direct photostimulation of the bladder using various parameters of duration (1, 2, 5, 10 sec continuous stimulation) and power (0.1mW/mm2, 0.95mW/mm2, 6.50mW/mm2) resulted in the ability to control bladder contractions in both spinal intact (SI) and SCI animals, allowing for on-demand voiding post-injury.


Cell Type-Specific Diurnal Variation In Hippocampus Physiology, Lacy Kathryn Goode Jan 2022

Cell Type-Specific Diurnal Variation In Hippocampus Physiology, Lacy Kathryn Goode

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Circadian rhythms are biological processes that cycle across 24 hours. Driven endogenously by widely expressed and highly conserved clock genes that compose the circadian molecular clock, circadian rhythms are exhibited in numerous facets of physiology across nearly every tissue throughout the body. Diurnal rhythms in cognition, long-term potentiation (LTP), and the expression of clock genes in hippocampus subfields support a role for circadian regulation of hippocampus physiology. However, little is known regarding the circadian molecular clock and diurnal rhythms in neurophysiology at the cellular level. Here, we characterized diurnal differences in spatial memory, LTP, excitability of and synaptic transmission onto …


Synergy Between Stenotrophomonas Maltophilia And Pseudomonas Aeruginosa During Polymicrobial Airway Infections, Melissa Skye Mcdaniel Jan 2022

Synergy Between Stenotrophomonas Maltophilia And Pseudomonas Aeruginosa During Polymicrobial Airway Infections, Melissa Skye Mcdaniel

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Stenotrophomonas maltophilia is a Gram-negative bacillus that can act as an opportunistic pathogen in patients with respiratory diseases, including cystic fibrosis (CF) and ventilator-associated pneumonia. Infection with S. maltophilia is associated with worse lung function, but it remains unclear if this organism contributes directly to lung function decline. Lung infections are often polymicrobial, and S. maltophilia can be isolated from the lung with the key pulmonary pathogen Pseudomonas aeruginosa. In the first half of this work, we investigated the pathogenicity of S. maltophilia alone and during polymicrobial infection with P. aeruginosa. We used respiratory infections in mice to assess persistence …