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Engineered Transcription Activator-Like Effector Dimer Proteins Confer Dna Loop-Dependent Gene Repression Comparable To Lac Repressor, Nicole A. Becker, Justin P. Peters, Elizabeth Lewis, Camden L. Daby, Karl Clark, L. James Maher

Faculty Publications

Natural prokaryotic gene repression systems often exploit DNA looping to increase the local concentration of gene repressor proteins at a regulated promoter via contributions from repressor proteins bound at distant sites. Using principles from the Escherichia coli lac operon we design analogous repression systems based on target sequence-programmable Transcription Activator-Like Effector dimer (TALED) proteins. Such engineered switches may be valuable for synthetic biology and therapeutic applications. Previous TALEDs with inducible non-covalent dimerization showed detectable, but limited, DNA loop-based repression due to the repressor protein dimerization equilibrium. Here, we show robust DNA loop-dependent bacterial promoter repression by covalent TALEDs and verify …

Chimes: September 9, 2024, Calvin University

Chimes

Football is here! by Dillion Baumchen

Library construction nears completion by Ethan Meyers

Restructured church fair sees record attendance by Graham Kort

Here's what to know about Synod 2024 by Grace Buller and Nolan Cowan

Engineering department adds new aerospace concentration by EJ Emesiabumchi

Q&A with SAO Director, Jack Droppers on upcoming events by Natasha Jayaputra

Oral Administration Of Alpha-Cyclodextrin Corrects Diabetes Induced Retinopathy And Bone Marrow Pathology By Modulation Of The Gut-Retina Axis., Yvonne Adu-Agyeiwaah

All ETDs from UAB

Diabetic retinopathy represents a common complication of diabetes, exerting a significant financial burden globally across nations, particularly impacting the working-age population and thereby affecting productivity. Extensive investigations have unveiled its multifaceted etiology, implicating a convergence of diverse causative factors. Notably, seminal studies such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study have underscored the pivotal role of cholesterol dysregulation and dyslipidemia in the pathogenesis of diabetic retinopathy. This dysregulation stems from an imbalance characterized by heightened cholesterol production coupled with deficient cholesterol efflux or removal mechanisms. Liver X receptors (LXRs), ligand-activated nuclear receptors function in transcriptional …

Experiences Of Discrimination And Stress In People With And Without Hiv: Associations With Experimental Pain Sensitivity And Substance Use, Joanna Hobson

All ETDs from UAB

People living with HIV (PLWH) are at an increased risk for experiencing not only discrimination, but the adverse health outcomes that are related to discrimination. Specifically, studies have identified direct relationships between HIV, discrimination and substance use, pain, poor sleep (e.g. insomnia symptoms) and depression. Thus, this study aimed to elucidate the relationships between discrimination, stress, experimental pain sensitivity, mood and substance abuse. We used various questionnaires to measure mood and health behavior. Lastly, participants underwent a series of pain experiments to measure group differences in experimental pain sensitivity. We found group differences in cortisol levels (p = .031) and …

Non-Invasive Pet Imaging Probes For Immune Activation And Fibrosis In Cancer And Pulmonary Fibrosis, Yujun Zhang

All ETDs from UAB

Immune activation plays an important role in the development and treatment of tumor and fibrotic diseases. Granzyme B is a serine protease granzymes secreted by cytotoxic T cells or natural killer (NK) cells, which induces target cell apoptosis. Measuring granzyme B level is a way to quantify immune activation non-invasively. [68Ga]-NOTA-GZP PET imaging was applied in 4T1 breast cancer mouse model and LLC non-small cell lung cancer mouse model after treated with combination of 12 Gy irradiation and dual checkpoint inhibitors. There was a tumor growth and metastasis inhibition in the combination treatment group. The uptake of [68Ga]-NOTA-GZP on day …

Multi-Omics Analysis Of Nf1 Deficiency In Various Cell Types Implicates Roles Outside Of Ras For Cells And Their Microenvironment, Christian Xavier Fay

All ETDs from UAB

Neurofibromatosis type 1 is an autosomal dominant disease in which many patients develop the hallmark feature, neurofibromas, benign tumors that develop along the peripheral nerves. Currently there is no known cure for NF1, and more than 3000 germline pathogenic variants (PVs) in NF1 have been observed. The neurofibromin gene encodes the 320kDa NF1 protein which has multiple predicted functions. Its most under-stood molecular role is in binding GTP-Ras and stimulating Ras-GTPase to cleave GTP to GDP and inactivate Ras signaling. In fact, the only FDA-approved therapeutic is the MEK inhibitor selumetinib which acts downstream of Ras. NF1 also has Ras …

Unraveling The Lymphatic Landscape In The Normal And Injured Kidney, Gelare Ghajar-Rahimi

All ETDs from UAB

The lymphatic vascular system, tasked with managing interstitial fluid homeostasis, clearing cellular debris, and trafficking immune cells, is a promising yet largely untapped area for therapeutic intervention in kidney diseases. Clinically, kidney biopsies of patients with acute kidney injury (AKI) and chronic kidney disease (CKD) show evidence of injury-associated lymphangiogenesis. Recent pre-clinical studies have established that manipulation of the lymphangiogenic response greatly impacts the pathophysiology of serval kidney diseases. However, conflicting results in the literature, unresolved knowledge gaps, and technical challenges hinder the development of lymphatic-modifying therapeutics. Here, we interrogate the long-term effects of ischemia-reperfusion and aging in AKI and …

Biomedical Informatic Analysis Of Critical Care Outcomes & Chronic Sequelae Of Sars-Cov-2 Infection, Michael John Patton

All ETDs from UAB

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19), resulted in an unprecedented loss of life over the past 4 years and has left an indelible mark on nearly every facet of medical care. Unlike pandemics of the 20th century or earlier, global adoption of electronic medical records (EMR) in the decade prior to the COVID-19 pandemic provided the bedrock for real-time healthcare innovation guided by biomedical informatics research. Mirroring the needs of healthcare providers, early informatics studies focused on identifying biomarkers and risk factors for severe presentations of COVID-19 and their …

Factors Associated With Early Onset Anal Cancer And Facilitators And Barriers To Screening Among Men Living With Hiv And Their Providers In The Deep South: A Mixed Methods Investigation, Anna Junkins

All ETDs from UAB

For my dissertation work, I aimed to 1) determine the occurrence of early onset (diagnosis at <50 years) anal cancer and the impact of HIV infection and other risk factors, and 2) utilize a mixed methods research approach to identify and explain factors associated with screening among men living with HIV (MLHIV) and their providers. In Aim 1, I used logistic regression to estimate the odds of early onset cancer by sociodemographic and clinical characteristics among anal cancer patients in the Alabama cancer registry from 2012-2018. Among 519 patients, 17.7% were diagnosed at <50 years. Male sex, Black race, and HIV infection were associated with younger age at diagnosis. Black patients had a 4-fold increased odds of early onset anal cancer compared to White patients and disproportionately lived in areas with higher social vulnerability. In Aim 2, I used logistic regression to estimate the odds of anal cancer screening by sociodemographic and sexual risk characteristics among MLHIV using retrospective survey data from 1917 Clinic in 2018. Among 1,114 men, 52% had received an anal pap within one year of completing the survey. Men who were screened were more likely to have multiple sexual partners. Heterosexual men had lower odds and men who reported unprotected anal sex had higher odds of screening. Older Black men were less likely to be screened. In Aim 3, I used thematic analyses to identify themes related to health beliefs, barriers and facilitators, and perceived and evaluated need of screening using in-depth interviews among MLHIV and their providers. Benefits of screening among MLHIV were early detection and awareness about one’s body. Suggestions for overcoming barriers to screening among providers included screening guidelines, patient education, inclusion of screening into routine care, and self-collection. Among men that were aware of HPV-associated cancers, there was perceived risk and desire to receive HPV vaccination. Individuals who are male, Black, or living with HIV may be at increased risk of developing anal cancer younger. Among MLHIV, improving education about HPV-associated cancer, and offering self-collected screening as part of routine care could facilitate screening in the South.

Spatiotemporal Characterization Of The Immune Response In Acute Kidney Injury And Pig-To-Human Kidney Xenotransplantation, Matthew David Cheung

All ETDs from UAB

The kidney is an intricate organ responsible for filtering our blood, maintaining bone health, regulating blood pressure, and numerous other vital functions. Acute kidney injury (AKI) is a temporary loss of kidney function, affecting up to 20% of hospitalized and 60% of critically ill patients. Despite the high mortality rate and frequency of occurrence, targeted therapies to treat AKI have not been successfully developed. Unresolved AKI confers an increased risk for the development of chronic kidney disease (CKD) and ultimately end-stage kidney disease (ESKD). Although dialysis can sustain life for individuals with ESKD, transplantation is the only definitive cure. With …

Cross-Sectional Retrospective Study To Determine The Prevalence Of Periodontal Bone Loss As A Function Of Age In The Predoctoral Clinic Patient Population, Lincoln Nguyen

All ETDs from UAB

Age has a significant effect on the body’s ability fight off disease, recover, and maintain collagen structures, and it has been observed that older adults have a higher prevalence of periodontal diseases. Studies have shown that age is a risk factor for alveolar bone loss. However, there is a lack of research done looking at if this is a linear progression or if there is a specific age that susceptibility increases. The aim of this study is to investigate (1) changes in radiographic bone loss in varying age groups in the University of Alabama patient population and (2) to evaluate …

Elucidating The Role Of Glut3 In Glioblastoma Invasion And The Tumor Microenvironment, Sarah Elizabeth Williford

All ETDs from UAB

GBM is characterized by aggressive growth and therapy resistance, with a median survival of 14 months despite treatment. Brain tumor initiating cells (BTICs), as a subset of stem-like GBM cells known for their invasiveness, therapy resistance, and immune evasion. BTICs have increased GLUT3 expression, which is correlated with poor patient prognosis. This study identifies a novel role of GLUT3 in GBM invasion, distinct from its canonical function in glucose uptake and glycolysis, as well as a mechanism by which GLUT3 contained in exosomes promotes monocyte migration. Our data show that blocking phosphorylation of GLUT3 at T492, abolishes its pro-invasive phenotype, …

Uncovering The Contribution Of Desmoplakin Isoforms To Desmosome Structure And Function, Krishna Patel

All ETDs from UAB

UNCOVERING THE CONTRIBUTION OF DESMOPLAKIN ISOFORMS TO DESMOSOME STRUCTURE AND FUNCTION KRISHNA PATEL MULTIDISCIPLINARY BIOMEDICAL SCIENCE ABSTRACT Desmosomes are cell-cell junctions that maintain the integrity of tissues that experience significant mechanical stress, such as the skin and heart. Desmosomal plaque proteins are connected to the intermediate filaments by desmoplakin (DP), and genetic variants in DP are associated with several skin and heart pathologies, including erythrokeratodermia and arrhythmogenic cardiomyopathy. DP contains three domains: an N-terminal plakin head, a central rod, and an intermediate filament-binding C-terminal tail. Furthermore, DP has three splice isoforms (DPI, DPIa, and DPII) that differ only in the …

Computational Approaches To Identify Circular Rnas In Parkinson's Disease, Lisa Shrestha

All ETDs from UAB

Parkinson’s Disease (PD) is the second most common neurodegenerative disease, affecting approximately a million individuals in the United States. Despite its high prevalence, PD is generally diagnosed at a progressed stage after the manifestation of characteristic motor symptoms (bradykinesia, tremor, rigidity, etc.). Hence, it is imperative to understand the underlying molecular mechanisms involved in the progression of PD at an early stage. Several non-coding RNAs have emerged as important regulators in several key cellular processes, among which circular RNAs' role has not been studied well enough. Here, we explore the changes in the expression of circRNAs with respect to the …

Biochemical Characterization Of Rna Polymerases Across The Domains Of Life, Stephanie Lois Cooper

All ETDs from UAB

RNA polymerases perform the essential function of RNA synthesis from a DNA template. This process, known as transcription, is critical for all living species and a key point for regulation of gene expression. The function of RNA polymerases allow species from all domains of life to not only survive, but also respond to environmental changes such as heat and nutrient deprivation. In biological taxonomy, the highest classification is domain. The three domains are Eukarya, Bacteria, and Archaea. The domain Eukarya contains all eukaryotic organisms, ranging from yeast, to plants, to metazoans. Bacteria and Archaea are both prokaryotic domains, the species …

Drug Resistance Mechanisms Of Trichomonas Vaginalis, Keonte Graves

All ETDs from UAB

Trichomonas vaginalis is a facultative anaerobic parasitic protozoan and the main causative agent of the most common non-viral sexually transmitted infection, trichomoniasis. Trichomoniasis affects both men and women but is more commonly observed in women. The majority of infections are asymptomatic, but those with symptomatic infections often experience malodorous and discolored vaginal discharge, pruritis, dysuria, and/or dyspareunia. T. vaginalis infections have been associated with multiple adverse health outcomes including an increased risk of acquiring HIV and other STIs, infertility, adverse birth outcomes, and cervical cancer. The only current FDA-approved treatments come from the 5-nitroimidazole class of drugs (metronidazole, tinidazole, and …

Investigating Molecular Mechanisms Behind Neuronotypic Gba1 Mutations In Lewy Body Dementias, Casey Mahoney-Crane

All ETDs from UAB

Nonmotor deficits are present in nearly all Parkinson’s disease (PD) patients, with ~80% of these patients developing dementia. Importantly, expression of the severe GBA1 L444P heterozygous mutation increases the risk for Parkinson’s disease devel-opment by 5.43 times compared to mild mutation carriers. Currently, many PD treat-ments predominately focus motor symptoms, while treatments for nonmotor symptoms, such as visual-spatial difficulties and dementia, focus on symptom management and continue to remain elusive. Therefore, understanding the molecular mechanisms behind these nonmotor symptoms is essential for the development of effective therapeutics leading to slower disease progression. The work presented in this dissertation sought to …

Health Systems' Adaptations To "Disruptive Primary Care Models", Jolynn R. Suko

All ETDs from UAB

Since the 1990s, hospitals and health systems have built primary care networks to establish market share and ensure sustainability. At this same time, the under?performance of the U.S. primary care system in terms of quality, service, and access has been widely documented. Value-based payment models have emerged. These trends created opportunities for new primary care market entrants. These market entrants may erode the primary care base of established health systems. This study examined how health systems may be adapting to a subset of new, disruptive primary care market entrants or disruptive primary care models. This study included disruptive primary care …

Individualized Cellular Response To Influenza-A Infection, Abel Lopez

All ETDs from UAB

Influenza A Virus (IAV) presents a significant threat to global health, causing millions of severe cases and substantial mortality annually. This study uses single-cell RNA sequencing to investigate the individualized cellular response to IAV infection in human bronchial epithelial cells (HBECs). We employed air-liquid interface (ALI) cultures to model the respiratory epithelium and differentiated HBECs into basal, ciliated, secretory (goblet/club), and rare cell types (Ionocytes). Following IAV infection, we analyzed transcriptional changes across these cell types, focusing on differential gene expression and pathway activation. Our results highlight the variability in IAV infection and the distinct cellular responses. Ciliated cells, the …

The Effects Of Acute Beetroot Juice Intake On Glycemic And Blood Pressure Responses When Controlling For Medication In Individuals With Type 2 Diabetes, Andrew Tyler

All ETDs from UAB

The prevalence of cardiometabolic diseases has continued to rise within the United. Physical activity and poor dietary choices are two factors that are known to contribute to the rise in cardiometabolic diseases. Thus, it is critical to identify strategies that may mitigate the negative impact from these behaviors. Several recent studies have shown that consumption of dietary inorganic nitrate (diNO3) may improve vascular health and glucose regulation in animal models and some human studies. However, the improvements in glucose regulation have yet to be corroborated in humans with type 2 diabetes (T2D). Thus, the purpose of this study was to …

Prenatally-Derived Macrophages Regulate Choroidal Health And Are Depleted In Age-Related Macular Degeneration, Seth Daniel Fortmann

All ETDs from UAB

The ocular choroid is the pigmented vascular bed that lies immediately deep to the retinal pigmented epithelium (RPE). The principal function of the choroid is to supply the photoreceptors with oxygen and nutrients and to remove waste products from the outer retina. In age-related macular degeneration (AMD), the choroid is dysfunctional as evidenced by hallmark histopathological findings including accumulation of extracellular lipid and vasodegeneration of the choriocapillaris. How and why the choroid fails in AMD remains incompletely understood. To this end, much attention has been paid to the RPE and endothelium but less is known about the contributions of other …

Sleep And Stigma: Novel Factors In The Relationship Between Weight Status And Cognitive Function?, Lindsay M. Stager

All ETDs from UAB

U.S. obesity rates are rising. Impaired cognitive function (CF) negatively correlates with obesity and may impact food consumption. However, the mechanisms of action demand assessment. This study aimed to identify adiposity-based differences in adolescent CF and food consumption and determine the roles of sleep and stigma within these relationships. Adolescents completed questionnaires including the Behavior Rating Inventory of Executive Function and Brief Version of the Stigmatizing Situations Inventory assessing weight stigma. Actigraphy and food diaries assessed typical sleep duration and food consumption. Participants then completed two sleep conditions in a randomized order: adequate (AS; >8 hours asleep) and restricted (RS; <5 hours asleep) sleep. Each condition was preceded by a 2-night washout period (9 hours in bed per night) and followed by a morning lab visit involving a cognitive battery and self-serve breakfast. Adolescents with healthy weight (HW) demonstrated greater performance-based episodic memory compared to adolescents with overweight/obesity (OWOB), but self-reported poorer inhibition, self-monitoring, and planning/organizing. Findings were similar in models using total body fat percent (TBF%) as a predictor, and stigma did not mediate these relationships. Adiposity did not relate to typical self-reported food consumption. RS predicted poorer performance-based global cognition, fluid cognition, and cognitive flexibility for adolescents with OWOB and improved cognitive flexibility among adolescents with HW. Adolescents with OWOB also had poorer attention compared to adolescents with HW following RS, while there were no group differences following AS. Findings were similar in models using TBF% as a predictor. However, adolescents with TBF% elevated above 42, also had poorer processing speed following RS, and the relationship between sleep and attention did not vary based on TBF%. RS also predicted decreased consumption of total calories, calories from processed foods, and fat for both BMI groups. This study increases understanding of the relationships among weight, CF, and food consumption, and the roles of sleep and stigma within these relationships. Adolescents with OWOB were more vulnerable to the negative cognitive effects of RS and RS predicted decreased consumption of calories and fat. Promotion of improved sleep hygiene and duration may be critical for the cognitive health of adolescents with OWOB.

Elucidating The Nanoscale Architecture Of The Desmosome, William F. Dean

All ETDs from UAB

Desmosomes are intercellular anchoring junctions that are crucial for maintaining the mechanical integrity of tissues routinely subjected to large forces, such as epithelia and cardiac muscle. Adhesion in desmosomes is mediated by a specialized class of transmembrane glycoproteins known as the desmosomal cadherins (DCs). Defects in desmosomal adhesion are associated with severe disease of the heart and skin and are frequently linked to mutations in the DCs. It is therefore important to understand the relationship between DC architecture and desmosome function. Accordingly, several groups have attempted to elucidate DC architecture—primarily using electron tomography (ET). However, ET studies of the desmosome …

Pubertal Timing In Relation To Epigenetic Aging And Mortality Risk In Young Adulthood, Marlon Goering

All ETDs from UAB

Early pubertal timing is associated with adverse health outcomes in adulthood, which may be mediated by DNA methylation-based epigenetic changes associated with accelerated aging and mortality risk. However, only few studies examined links between pubertal timing and epigenetic aging and these focused mainly on females, relied on retrospective reports of single pubertal events, and did not examine protective factors and underlying mechanisms. Thus, this dissertation examined two distinct dimensions of pubertal timing (i.e., phenotypical pubertal timing relative to age and self-perceived pubertal timing relative to peers) in relation to subsequent epigenetic aging and mortality risk in adulthood together with sex …

The T Cell Response In A Mouse Model Of Multiple System Atrophy, Nicole Jane Corbin-Stein

All ETDs from UAB

Multiple System Atrophy (MSA) is a fatal and rare demyelinating synucleinopathy, characterized by the accumulation of alpha-synuclein (α-syn) in glial cytoplasmic inclusions (GCIs) within oligodendrocytes. This condition is marked by neuroinflammation, demyelination, and neurodegeneration in areas showing GCI pathology, involving antigen presentation by myeloid cells and infiltration of CD4+ and CD8+ T cells. Despite strong evidence of neuroinflammation in post-mortem MSA tissue, the specific mechanisms driving the disease pathogenesis remain elusive. In prior research using the Olig001-SYN mouse model, which involves the modified AAV vector, it was shown that depleting CD4+ T cells can reduce neuroinflammation and demyelination. Notably, this …

Testicular Phenotypes Of Rdhe Dko Mice, Aja Slay

All ETDs from UAB

The bioactive form of vitamin A, all-trans-retinoic acid (RA), plays a critical role in cell differentiation, metabolism, and cellular proliferation by regulating gene transcription. RA signaling is critical during embryogenesis to ensure proper development and during adulthood for tissue maintenance. Disruption of the RA signaling pathway induced by vitamin A deficiency and genetic defects in vitamin A metabolizing enzymes results in embryonic malformations. Previous studies implicate the short-chain dehydrogenase/reductase (SDR) family members as important in RA synthesis. Among the SDR family are retinol dehydrogenase epidermal 2 (RDHE2) and RDHE2-similar (RDHE2S)- collectively RDHE. To gain insight into how RDHE influences the …

Hope In Hyperbaric Medicine: A New Approach To Treat Neurological Injury, Lucas Andrew Lowe

All ETDs from UAB

Hyperbaric oxygen therapy (HBOT) has emerged as a promising adjunctive treatment approach for various neurological diseases. This literature review explores the role of HBOT in the treatment of spinal cord injuries. The review discusses the mechanisms of action by which HBOT exerts its effects on neural tissues, such as oxygen delivery, anti-inflammatory actions and neuroprotection. The analysis also highlights the findings from cellular biology, animal studies and clinical trials, offering insights into the potential benefits of HBOT in improving neurological injury outcomes and enhancing patients' quality of life. Furthermore, it addresses the safety considerations and guidelines for the application of …

Investigation On The Epigenetic Mechanisms Modified By Dietary Phytochemicals In Inhibiting Mammary Cancer, Mohammad Mijanur Rahman

All ETDs from UAB

Breast cancer (BC) is global burden for the health of women. It is the most commonly diagnosed cancer in women and the second leading cause of cancer mortality among women in the United States. One in every eight women in the USA has a chance of developing invasive BC in her lifetime. The limitations of the available therapeutics for BC treatment have brought the dietary prevention of BC to the attention of the scientific community as a safe, natural, and easy to implement therapeutic strategy. In this regard, our laboratory with many other laboratories have demonstrated the anti-BC effect of …

Use Of Molecular Dynamics Simulations To Characterize Structural Interactions Of Protein And Drug In Antiviral Drug Discovery, Caitlin Joan Smith

All ETDs from UAB

Since 2019, the novel coronavirus SARS-CoV-2 the etiological cause of the COVID-19 pandemic has led researchers and physicians to look for effective antiviral treatments as interventions in mitigating COVID-19 disease. The severity of the disease and the limitations of current treatments have led to antiviral drug research beyond currently approved antiviral drugs. Many antivirals exist and are currently approved by the Food and Drug Administration (FDA) for other viral illnesses, yet currently only remdesivir and nirmatrelvir/ritonivir are approved for COVID-19 (October 2020, May 2023, respectively), while molnupiravir is still under emergency FDA use authorization [1, 2, 3]. Here, we have …

Promoting Endogenous Cardiomyocyte Proliferation In Large Mammal Hearts Via Cell Transfer Therapy Or Apical Resection: Understanding The Underlying Mechanism, Yuhua Wei

All ETDs from UAB

Cardiovascular diseases are the leading causes of global death. Due to the limit regenerative capacities of adult mammalian cardiomyocytes (CMs), myocardium is repaired with non-contractile fibrotic scar after a myocardial infarction (MI). Various strategies, including apical resection (AR) and cardiac cell therapy, are being explored to promote heart regeneration after MI. This dissertation research aimed to identify proliferating pig CM population after AR and understand the underlying mechanism of human induced pluripotent stem cells (hiPSCs) derived CMs (hiPSC-CMs) implantation for regenerating the pig hearts after MI. Our previous study showed that AR prolonged the heart regeneration window to postnatal day-28 …