Digital Commons Network^™

Screen For Beneficial Genetic And Chemical Modifiers In Drosophila Models Of Als And Traumatic Brain Injury, Will Bonderer

Biological Sciences Theses and Dissertations

The underlying molecular processes of aberrant protein expression in neurodegeneration are intricate and multifaceted, with ribosome-associated quality control (RQC) emerging as a promising avenue of exploration. Ribosome-associated quality control is integral to cellular function. Its evolutionarily conserved pathway encompasses a network of mechanisms designed to ensure the fidelity of protein synthesis, folding, and degradation within the cells of all eukaryotes. The ribosome, central to protein synthesis, plays a pivotal role in this quality control network, and its malfunction can lead to the accumulation of misfolded or aberrant proteins. In the context of neurodegenerative disorders, this dysfunction can have dire consequences. …

Dissecting The Tissue-Specific Contributions To Seizures, Cardiorespiratory Dysfunction, And Sudden Death In The Kv1.1 Mouse Model Of Epilepsy Using Conditional Knockout Approaches, Kelsey Paulhus

Biological Sciences Theses and Dissertations

Sudden unexpected death in epilepsy (SUDEP), the primary cause of mortality in epilepsy, remains poorly understood. Studies suggest seizures may trigger dangerous signals affecting the heart and lungs leading to collapse and death. The Kv1.1 deficiency mouse model mirrors clinical SUDEP cases, showing spontaneous seizures, cardiorespiratory issues, and premature death. However, this model lacks regional specificity in Kv1.1 deletion, hindering insights into SUDEP’s mechanisms and anatomical substrates.

This dissertation employs three distinct conditional knockout (cKO) techniques to investigate the individual roles for the forebrain, brainstem, and heart in SUDEP related phenotypes. The findings reveal that the forebrain alone can trigger …

Tools For Biomolecular Modeling And Simulation, Xin Yang

Mathematics Theses and Dissertations

Electrostatic interactions play a pivotal role in understanding biomolecular systems, influencing their structural stability and functional dynamics. The Poisson-Boltzmann (PB) equation, a prevalent implicit solvent model that treats the solvent as a continuum while describes the mobile ions using the Boltzmann distribution, has become a standard tool for detailed investigations into biomolecular electrostatics. There are two primary methodologies: grid-based finite difference or finite element methods and body-fitted boundary element methods. This dissertation focuses on developing fast and accurate PB solvers, leveraging both methodologies, to meet diverse scientific needs and overcome various obstacles in the field.

Eco-Interoception: What Plants, Fungi And Protista Have Taught My Body, Sara Riley Dotterer

Art Theses and Dissertations

To me, ecology is the relational, full-body awareness that I am made up of and deeply connected to everything around me; and for better or worse, this is reciprocal. I form ecotones, an ecological transitional zone between two ecosystems, with the world around me. I use this ecotonal lens to blur binaries and dissolve boundaries between me and the world “outside my body.” During my Masters of Fine Arts at Southern Methodist University, I have continuously explored and represented the lives of various more-than-human species outside of my body, including plants, fungi and protista through an ecotonal lens. Although these …

Protein Dynamics In Allostery And Computer-Aided Drug Design, Mayar Mohamed

Chemistry Theses and Dissertations

Molecular dynamics (MD) simulation is a powerful and versatile computational tool, that can be used in a wide range of applications from studying complex biological processes such as allostery to investigating the process of the protein-ligand binding in different computer-aided drug design implementations. In this work, various structural and drug discovery projects were performed by combining the state-of-art techniques molecular dynamics simulations, virtual screening, and binding free energy calculations with the innovative Markov State Model analysis and the machine learning techniques.

In the first project, the role of A’a helix as a key player in the transition between the light …

Roles Of Individual Protein In De Novo Polycomb Protein Recruitment, Piao Ye

Biological Sciences Theses and Dissertations

Polycomb Group (PcG) proteins are evolutionarily conserved epigenetic transcriptional regulators that maintain the transcriptional repression of silenced genes by maintaining heritable chromatin states. PcG proteins first discovered as repressors of Hox genes in Drosophila, later were shown to regulate a wide range of genes. In mammals, PcG proteins are involved in maintaining pluripotent state of stem cells and controlling cell differentiation. Misexpression of PcG protein leads to cancers like lymphoma and melanoma. PcG proteins maintain rather than initiate transcriptional repression, once PcG – mediated repression is established it can be maintained through an unlimited number of cycles. Most studies of …

Dissecting Interactions Across Gene Regulatory Layers In C. Elegans, Morgan Taylor

Biological Sciences Theses and Dissertations

The nematode Caenorhabditis elegans is a powerful tool for studying nervous system genetics. Though relatively simple compared to mammals, C. elegans boasts a remarkably well-conserved neuronal genome and proteome, and its utility in the characterization of neuronal genes has been well-established. However, gene expression is often controlled by complex interactions between multiple genes, and teasing apart the functions of individual genes within such networks remains a challenge. Dissecting these interaction networks is crucial in determining the multifaceted functions of important, conserved regulatory genes. Here we explore interactions between gene regulatory layers in the C. elegans nervous system, employing a synthetic …

Regulation And Function Of The Mec-8/Rbpms Rna Binding Protein In Vivo, Xiaoyu Liang

Biological Sciences Theses and Dissertations

Alternative splicing is a major form of post-transcriptional regulation of gene expression which plays a pivotal role in cell/tissue- specific identity, diversity, and function. The mechanisms of alternative splicing are well studied; however, the functional consequences of the spliced transcripts are relatively less demonstrated. Therefore, many efforts are needed to understand the physiological relevance of alternative splicing. RNA binding proteins are critical regulators of alternative splicing, their malfunction disrupt the normal networks, and further underlies many diseases. To understand how alternative splicing contributes to the physiological functions in the cells or tissues, we explored the regulatory networks of RNA binding …

Activation Of P53-Regulated Pro-Survival Signals And Hypoxia-Independent Mitochondrial Targeting Of Tigar By E6 Oncoproteins Of High-Risk Hpvs, Lacin Yapindi

Biological Sciences Theses and Dissertations

The high-risk human papillomaviruses are small, non-enveloped double-stranded DNA viruses that infect the basal epithelial keratinocytes. The majority of HPV infections are self-limiting and asymptomatic; however, in 2-4% of all infected individuals, persistent infections with high-risk HPVs lead to malignancies, including head-and-neck cancers and anogenital carcinomas, particularly cervical cancers. The HPV life cycle is strongly tied to the normal differentiation process of the epithelial tissue. Upon cell entry, the viral genome is maintained as episomal DNA within the nuclei of HPV-infected basal keratinocytes and amplified to a low copy number as the cells divide. As a part of the self-renewing …

Closed-Loop Brain-Computer Interfaces For Memory Restoration Using Deep Brain Stimulation, David Xiaoliang Wang

Electrical Engineering Theses and Dissertations

The past two decades have witnessed the rapid growth of therapeutic brain-computer interfaces (BCI) targeting a diversity of brain dysfunctions. Among many neurosurgical procedures, deep brain stimulation (DBS) with neuromodulation technique has emerged as a fruitful treatment for neurodegenerative disorders such as epilepsy, Parkinson's disease, post-traumatic amnesia, and Alzheimer's disease, as well as neuropsychiatric disorders such as depression, obsessive-compulsive disorder, and schizophrenia. In parallel to the open-loop neuromodulation strategies for neuromotor disorders, recent investigations have demonstrated the superior performance of closed-loop neuromodulation systems for memory-relevant disorders due to the more sophisticated underlying brain circuitry during cognitive processes. Our efforts are …

Assembly Of The Peripheral Arm Subunits Of Escherichia Coli Complex I And Analysis Of Clinical Mutations, Hind Alkhaldi

Biological Sciences Theses and Dissertations

Respiratory Complex I from E. coli is a proto-type of the mitochondrial enzyme, consisting of a 6-subunit peripheral arm (B-CD-E-F-G-I) and a 7-subunit membrane arm. When subunits E-F-G (N-module), were expressed alone they formed an active complex as determined by co-immunoprecipitation and native gel electrophoresis. When co-expressed with subunits B and CD, only a complex of E-F-G was found. When these five subunits were co-expressed with subunit I and two membrane subunits, A and H, a complex of B-CD-E-F-G-I was membrane-bound, constituting the N- and Q-modules. Assembly of Complex I was also followed by splitting the genes between two plasmids, …

The Roles Of Individual Proteins In De Novo Recruitment Of Pcg Repressive Complexes To Giant, Anni Kum

Biological Sciences Theses and Dissertations

Epigenetic gene regulation is the process by which external factors regulate the genome. This research studies Polycomb Group (PcG) proteins which function as epigenetic agents that work together in complexes to maintain gene silencing for multiple cellular generations. Drosophila melanogaster PcG proteins can be organized into three canonical complexes: Pho-RC, PRC1, and PRC2. Though there are multiple proposed models for the order of recruitment, it is generally accepted that PhoRC, PRC1, and PRC2 interact with each other to stably recruit to a target gene. Since these proteins are highly conserved, this project studies PcG proteins in the model organism, Drosophila …

Making Forests, Making Communities: An Ethnography Of Reforestation In Monteverde, Costa Rica, Megan Brown

Anthropology Theses and Dissertations

Reforestation is not just planting trees in the ground. More than net increase in forest cover, reforestation is a complex political endeavor undertaken by both humans and non-humans and a popular climate change mitigation tactic. However, little research has examined the dynamics between selection of specific reforestation strategies, health, and community resilience, particularly with attention to entanglements between the lives of both human and non-human forest dwellers. This ethnographic work, based on six months of in-person fieldwork and six months of digital ethnography, examines reforestation and forest relations in Costa Rica’s Monte Verde zone, a region which experienced widespread deforestation, …

Biochemical Evaluation Of Drug Inhibition Of Abc Transporters, Maisa Correa De Oliveira

Biological Sciences Theses and Dissertations

Multidrug resistant (MDR) cancers often become resistant to pharmacologically and structurally diverse drugs by overexpressing members of the family of ATP Binding Cassette (ABC) transporters. These membrane pumps protect normal cells by actively exporting a large range of toxins out of the cells. Classic MDR is often correlated with the overexpression of three well-studied mammalian ABC transporters: P-glycoprotein (P-gp), Breast Cancer Resistant Protein (BCRP), and Multidrug Resistant Protein 1 (MRP1).

P-gp is the most studied ABC transporter, and the search for P-gp inhibitors as co-therapeutics to combat MDR has had little success after decades of studies. We previously used high-throughput …

Application Of Artificial Intelligence And Machine Learning In Chemistry, Niraj Verma

Chemistry Theses and Dissertations

In the last four years, I have been exposed to various topics in scientific research under the supervision of Dr. Kraka in the CATCO group. Numerous involved chemistry projects were undertaken to gain an understanding of the basic laws of nature involving vibrational spectroscopy, molecular acidity, and catalysts based on transition metals for halogen chemistry. The insights from computational chemistry were then applied to model and predict various complicated problems in chemistry via artificial intelligence. With the help of classical artificial intelligence, the non-covalent interactions governing the properties of proteins and water properties were analyzed. Significant improvements were made in …

Bayesian Statistical Modeling Of Metagenomics Sequencing Data, Shuang Jiang

Statistical Science Theses and Dissertations

Microbiome count data are high-dimensional and usually suffer from uneven sampling depth, over-dispersion, and zero-inflation. In this thesis, we develop specialized analytical models for analyzing such count data. In Chapter 2, I develop a bi-level Bayesian hierarchical framework for microbiome differential abundance analysis. The bottom level is a multivariate count-generating process that links the observed counts to their latent normalized abundances. The top level is a mixture of Gaussian distributions with a feature selection scheme for differential abundance analysis. A simulation study on both simulated and synthetic data is conducted. A colorectal cancer case study demonstrates that a resulting diagnostic …

Dynamic Mechanisms Of Multidrug Resistance In Human Cancers And Gram Negative Pathogens, Lauren Ammerman

Biological Sciences Theses and Dissertations

This dissertation focuses upon dynamic agents of multidrug resistance (MDR). We used a combination of in silico and in vitro techniques to investigate two membrane transporters that confer MDR – P-glycoprotein, which confers MDR in human cancers, and MtrD, which confers MDR in Neisseria gonorrhoeae. Inhibitors targeting both proteins have tremendous potential for use as co-therapeutics in the treatment of multidrug resistant cancers, or of multidrug resistant infections. However, previously identified inhibitors of P-gp have failed clinical trials due to off-target effects and associated toxicities. Furthermore, the molecular mechanism of antibiotic transport by MtrD is poorly understood, and this dearth …

Mechanistic Studies Of Drug-Like Inhibitors Of P-Glycoprotein Using Atpase Assays, Electron Spin Resonance Spectroscopy And Cancer Cell Models, Gang Chen

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) in cancer and other diseases is frequently associated with transmembrane efflux proteins, one of which is P-glycoprotein (P-gp). Over-expression of P-gp in cancer cells increases the efflux of therapeutic drugs rendering them ineffective. In order to re-sensitize multidrug resistant cancers to chemotherapy, we have found potential inhibitors of P-gp by in silico screening methods, and several of these inhibitors were shown to successfully overcome MDR in the drug resistant DU145TXR prostate cancer cell line. The best of the identified hit compounds were further investigated with regard to the mechanism of inhibition using ATPase activity assays and electron …

Rela/P65 Blocks Histone Deacetylase-3 Neurotoxicity And Protects Neurons Against Neuronal Death Induced By Polyq-Expanded Huntingtin And Ataxin-1 In A P65 Phospho S276 Dependent Manner, Yiyu Zhang

Biological Sciences Theses and Dissertations

Neurodegenerative diseases have a large negative impact to human society. Symptoms of neurodegenerative diseases includes memory loss, impaired recognition, motor dysfunction due to dysregulated neuronal loss in different brain regions. However, the neurobiological basis of these brain diseases is not fully understood and there are no cures or effective treatments. Polyglutamine (Poly-Q) disorders is a class of neurodegenerative diseases that are caused by polyglutamine expansion within the protein coding regions of specific genes. Huntington’s disease (HD), Spinal Cerebellar Ataxia Type 1 (SCA1) and Spinal Cerebellar Ataxia Type 3 (SCA3) are three common diseases among Poly-Q disorders. To better understand the …

Peroxiredoxin 6 And Inflammation In Alzheimer's Disease, Jared Ferrell-Penniman

Biological Sciences Theses and Dissertations

Alzheimer’s disease (AD) is known for its debilitating symptoms and poor prognosis. However, despite intense research into neurodegenerative diseases, there are few therapies targeted at the underlying mechanisms of the disease. Oxidative stress (OS) and inflammation are cellular phenomena thought to be key to the progression of the disease. Critically, peroxiredoxin 6 (Prx6), an antioxidant protein with multiple functions, has been identified from mammalian studies as a potential regulator of both OS and inflammation that may have a specific effect on AD. This project seeks to elucidate the role of Prx6 in AD as well as the underlying mechanisms. Drosophila …

Recruitment Of Polycomb-Group Proteins At Giant In Drosophila Embryos, Elnaz Ghotbi Ravandi

Biological Sciences Theses and Dissertations

Polycomb Group (PcG) proteins are evolutionarily conserved epigenetic transcriptional regulators that maintain the transcriptional repression of silenced genes. PcG mediated silencing is divided into two phases: initiation and maintenance. During the initiation phase, PcG proteins initially recognize and bind to their target genes. Once PcG proteins are recruited to their target genes, they can maintain transcriptional repression through an unlimited number of cell cycles. Most studies on PcG proteins have been focused on the maintenance phase of PcG silencing, and the molecular mechanisms by which PcG proteins are initially recruited to their target genes remained unknown. Two models have been …

Investigation Of The Electrode Polarization Effect For Biosensor Applications, Anil Koklu

Mechanical Engineering Research Theses and Dissertations

My research focuses on electrokinetic transport. Particularly, in this dissertation, we focus on fabrication and testing of micro electrodes with nanostructured surfaces to minimize the electrode polarization (EP) effects for biosensor applications. In the first study, electrochemical deposition of gold nanoparticles on to planar gold electrodes was used to generate rough surfaces. Dendritic nanostructures that reduced EP up to two orders of magnitude was obtained by optimizing the deposition conditions. These structures also enhanced dielectrophoresis (DEP) response of our bio-chips, making them usable in physiological buffers. In further studies we discovered a universal scaling of EP in the frequency domain, …

Parallel Multipole Expansion Algorithms And Their Biology Applications, Jiahui Chen

Mathematics Theses and Dissertations

N-body pairwise interactions are ubiquitous in scientific areas such as astrophysics, fluids mechanics, electrical engineering, molecular biology, etc. Computing these interactions using direct sum of an O(N) cost is expensive, whereas multipole expansion methods, such as the fast multipole method (FMM) or treecode, can reduce the cost to O(N) or O(N log N). This thesis focuses on developing numerical algorithms of Cartesian FMM and treecode, as well as using these algorithms to directly or implicitly solve biological problems involving pairwise interactions. This thesis consists of the following topics. 1) A cyclic parallel scheme is developed to handle the load balancing …

Htlv-1 Latency-Maintenance Factor P30ii Modulates Tax-Induced Nf-Kappa B Signaling Through A P53-Regulated Mechanism, Aditi Malu

Biological Sciences Theses and Dissertations

The human T-cell leukemia virus type-1 (HTLV-1) infects CD4+ T-cells and is the etiological agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and often-fatal lymphoproliferative neoplastic disease. The major transactivator protein, Tax, drives proviral gene expression and replication and plays a key role during the early-stage immortalization of T-cells by HTLV-1. Tax has also been shown to regulate many host cellular signaling pathways, including CREB/ATF, SRF, and NFκB. Another accessory viral protein p30_II acts as a latency-maintenance factor and negatively regulates proviral gene expression and replication. The p30^II protein counters Tax-dependent gene expression at the transcriptional and posttranscriptional …

Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Overexpression of ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two well-studied drug transporters which are associated with MDR. These two transporters also act as a major functional unit of the blood brain barrier to protect the brain from xenobiotics and toxins. Lack of clinically approved P-gp and BCRP inhibitors renders chemotherapy treatments of many MDR cancers ineffective and obstructs drug uptake into the brain.

Using computational methods, we have identified new compounds that inhibit P-gp (Brewer et al., Mol. Pharmacol. 2014). Several of …

Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Overexpression of ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two well-studied drug transporters which are associated with MDR. These two transporters also act as a major functional unit of the blood brain barrier to protect the brain from xenobiotics and toxins. Lack of clinically approved P-gp and BCRP inhibitors renders chemotherapy treatments of many MDR cancers ineffective and obstructs drug uptake into the brain.

Using computational methods, we have identified new compounds that inhibit P-gp (Brewer et al., Mol. Pharmacol. 2014). Several of …

Design And Synthesis Of Circadian Clock Modulators And The Study Of Lov Domain Protein Lkp2 In Arabidosis Thaliana And Brassica Rapa, Aditi Nagar

Chemistry Theses and Dissertations

Circadian rhythms are self-autonomous endogenous clocks synchronized with the rotation of the Earth. With the Earth’s rotation and revolution on its axis, the internal clock undergoes oscillation in the period of ~24 hour and governs day to day activities in most organisms. In humans, it regulates the day to day physiological activities. Today’s modern lifestyle has an impact on health: shift work, jet lag, and irregular eating habits contribute to the misalignment of the endogenous circadian oscillator, thereby, increasing the risk of many metabolic disorders including diabetes, irregular blood pressure, sleep disorders, obesity, depression, and cancer. The primary goal of …

Thermoregulatory Dysfunction In Multiple Sclerosis, Dustin R. Allen

Applied Physiology and Wellness Theses and Dissertations

Multiple sclerosis (MS) is a progressive neurological disease of the central nervous system (CNS) affecting an estimated 2.3 million people worldwide. Marked by lesions in the brain and spinal cord, MS leads to conduction abnormalities in the CNS. Evidence suggests ~60% of individuals with MS experience temporary worsening of their symptoms upon exposure to heat. Adding complexity, observational evidence suggests these individuals exhibit reduced thermoregulatory responses in upon increases in core temperature. Consequently, these individuals face a vicious cycle of heat sensitivity and thermoregulatory dysfunction, substantially impacting their quality of life. With this in mind, our lab is dedicated to …

Structural And Functional Characterization Of Plant And Fungal Lov Proteins, Jameela Lokhandwala

Chemistry Theses and Dissertations

The plant blue light photoreceptor proteins Flavin binding Kelch F-box protein-1 (FKF1) and LOV Kelch protein-2 (LKP2) play an important role in maintaining circadian rhythmicity and photo-periodic flowering responses. These proteins along with light sensitive Light Oxygen Voltage (LOV) domain contain F-box and Kelch repeat domains. Therefore, these proteins control blue light mediated degradation of various protein targets to regulate circadian rhythmicity, growth, and photo-periodic flowering. Blue-light excitation of these proteins leads to formation of a cysteinyl-flavin adduct, which then decays depending upon various factors. Therefore, spectral studies were conducted to measure the kinetics of light–dark recovery. Size Exclusion Chromatography …