Life Sciences Commons^™

Role Of Nuclear Lamins In Oligodendrocyte Lineage Cells, Camila Yattah

Dissertations, Theses, and Capstone Projects

Differentiation of oligodendrocytes from progenitor cells is a highly regulated process characterized by a series of molecular changes, resulting in nuclear and morphological features unique to the mature oligodendrocyte state. Heterochromatin formation starting at the nuclear periphery, as well as increased nuclear rigidity are characteristically observed. The nuclear periphery is characterized by the presence of the nuclear lamina and it has been implicated in higher-order genome organization in cells. Lamins are the protein components of the nuclear lamina, and their expression is dependent upon the cell differentiation stage of the cells. While Lamin B1 (LMNB1) expression is high in progenitors …

Novel Therapeutic Strategies For Alzheimer’S Disease: Prostaglandin D2 Signaling And Its Human Polymorphisms As Well As A Polypharmacological Approach, Charles H. Wallace

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is an age related neurodegenerative disease with pathology that includes amyloid plaques, neurofibrillary tangles and non-resolving neuroinflammation. Non-resolving neuroinflammation lasts the entire course of the disease and has deleterious effects and is often thought to accelerate AD pathology. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) have commonly been used as therapeutics to treat pain, inflammation and vascular. NSAIDs work by altering the cyclooxygenase (COX) mediated biosynthesis of prostaglandins which are lipid mediators that have many physiological functions, for example nociception, inflammation and vasodilation. Epidemiological studies support the notion that NSAIDs could be used to treat AD. Yet, clinical trials using …

Mechanism Of Activation And Regulation Of By-Kinases, A Unique Family Of P-Loop Enzymes, Fatlum Hajredini

Dissertations, Theses, and Capstone Projects

The bacterial tyrosine kinases (BY-kinase) represent a class of membrane-bound enzymes that utilize a cycle of auto-phosphorylation and de-phosphorylation to drive the synthesis and export of exopolysaccharides in both Gram-positive and Gram-negative bacteria. The catalytic domain of BY-kinases utilizes a P-loop nucleoside triphosphatase (NTPase) fold that is commonly used by NTPases and small molecule kinases, being the only protein kinase to do so. In the work presented in this thesis, we aimed to obtain an understanding of the mechanisms of the BY-kinases’ unconventional deployment of P-loop scaffold to phosphorylate on tyrosine. We used the BY-kinase of Escherichia coli (K12) as …

Prenatal Choline Supplementation During Maternal Obesity Alters Offspring Response To Western Diets, Hunter W. Korsmo

Dissertations, Theses, and Capstone Projects

Maternal obesity has led to an increase in adverse offspring developmental outcomes and a greater risk for long-term metabolic diseases. Choline, a semi-essential nutrient, can be incorporated into phosphatidylcholine (PC) as well as sphingomyelin (SM) and donate its labile methyl group for the remethylation of homocysteine after choline is oxidized to betaine. Prenatal choline insufficiency has been related to maternal obesity and metabolic diseases, such as metabolic associated fatty liver disease (MAFLD). Choline may interact with maternal obesity to influence the programming offspring.

Chapter 1 presents an introduction of choline and the various clinical outcomes associated with choline supplementation during …

Conformation Of The U12-U6atac Snrna Complex Of The Minor Spliceosome And Binding By Ntc-Related Protein Rbm22, Joanna Ciavarella

Dissertations, Theses, and Capstone Projects

Splicing of precursor messenger (pre-m)RNA is a critical process in eukaryotes in which the non-coding regions, called introns, are removed and coding regions, or exons, are ligated to form a mature mRNA. This process is catalyzed by the spliceosome, a multi-mega Dalton ribonucleoprotein complex assembled from five small nuclear ribonucleoproteins (snRNP) in the form of small nuclear (sn)RNA-protein complexes (U1, U2, U4, U5 and U6) and >100 proteins. snRNA components catalyze the two transesterification reactions while proteins perform critical roles in assembly and rearrangement. U2 and U6 snRNAs are the only snRNAs directly implicated in catalyzing the splicing of pre-mRNA. …

Determining The Roles Of The Oligomerization And C-Terminal Domains In Mutant P53 Gain-Of-Function Activities, George K. Annor

Dissertations, Theses, and Capstone Projects

The tumor suppressor p53 (TP53) gene is often mutated in cancer, with missense mutations found in the central DNA binding domain, and less often in the oligomerization domain (OD) and C-terminal domain (CTD). The OD and CTD have been found to be critical for the tumor suppressor functionality of wild-type p53 (wtp53). Specific missense mutations in the DNA binding domain have been found to confer new gain-of-function (GOF) activities. Mutations that destabilize tetramer formation, or deletion of key lysine residues within the CTD, downregulate the ability of wtp53 to transactivate (increase the rate of transcription of) its target …

Novel Therapeutic Strategies For Alzheimer’S Disease: Targeting Toll-Like Receptor Signaling And A Multi-Target Approach, Giovanni Oliveros

Dissertations, Theses, and Capstone Projects

Alzheimer’s disease (AD) is multifactorial, and its hallmarks include the formation of amyloid-beta (Ab) plaques and neurofibrillary tau tangles, accompanied by an increase in glial cell activation, culminating in neurodegeneration, chronic neuroinflammation, and cognitive decline in human patients. AD will cost the United States over $300 million this year alone and is projected to cost over $1 trillion by 2050, AD is a serious concern for the aging population, and efforts need to be redirected towards more effective therapeutic intervention strategies. Drugs aimed at halting AD progression have so far proven unsuccessful due to the development of pharmaceuticals that target …

Elucidating Mechanisms Of Biofluorescence And Bioluminescence In Marine Organisms, Andrew M. Guarnaccia

Dissertations, Theses, and Capstone Projects

Biofluorescence and bioluminescence are two methods of light emission that entail separate mechanisms of action but end at the same process: a colorful display that have tremendous ecological and behavioral benefits, whether it be used to communicate with conspecifics, camouflage into a multicolored background, attract unsuspecting prey, or alert others to a predator. In biofluorescence, higher-energy, shorter wavelength light is absorbed then re-emitted as lower-energy, longer-wavelength light. Bioluminescence on the other hand entails a chemical reaction in which a small molecule is oxidized by an enzyme, creating a high-energy intermediate that sheds the excess energy in the form of visible …

Molecular Mechanism Of Rapamycin Resistance In Cancer Cells, Sohag Chakraborty

Dissertations, Theses, and Capstone Projects

The mammalian target of rapamycin (mTOR) acts as the central regulator of multiple cellular processes including cell growth, proliferation, and survival by integrating signals via nutrients, growth factors, hormones, and energy sensing. In cancer cells, the mTOR pathway is highly dysregulated providing survival signals to the cells for their uncontrolled growth. Hence, mTOR has evolved to be a potential therapeutic target for cancer treatment for the past two decades. Application of micro-molar doses of Rapamycin in vitro has been found to successfully inhibit mTOR complex 1 (mTORC1) by blocking the phosphorylation of its downstream substrates- a) ribosomal protein p70 S6 …

Symmetry-Inspired Analysis Of Biological Networks, Ian Leifer

Dissertations, Theses, and Capstone Projects

The description of a complex system like gene regulation of a cell or a brain of an animal in terms of the dynamics of each individual element is an insurmountable task due to the complexity of interactions and the scores of associated parameters. Recent decades brought about the description of these systems that employs network models. In such models the entire system is represented by a graph encapsulating a set of independently functioning objects and their interactions. This creates a level of abstraction that makes the analysis of such large scale system possible. Common practice is to draw conclusions about …

Cdc6 Is Sequentially Regulated By Pp2a-Cdc55, Cdc14, And Sic1 For Origin Licensing In S. Cerevisiae, Jasmin Philip

Dissertations, Theses, and Capstone Projects

Control of DNA replication is critical for progression of the cell cycle and genomic stability. Cyclin-dependent kinases (CDKs) coordinate numerous phosphorylation events to accomplish two biological tasks for all living organisms: DNA replication and cell division. One CDK, Cyclin-Cdc28, is responsible for cell cycle progression in budding yeast. DNA replication requires a stepwise assembly of the pre-replicative complex on DNA, including Orc1-6, Cdc6, Cdt1 and Mcm2-7, during M-G1 phase. Cdc6 contains eight Cdc28 consensus sites, SP or TP motifs. Clb5-Cdc28 phosphorylates Cdc6-T7 to recruit Cks1, the Cdc28 phospho-adaptor, for subsequent multisite phosphorylation during S phase. There are two phospho-degrons at …

Scientific Development Of An Integrated Workflow For Latent Print, Questioned Document, And Dna Processing Of Paper Evidence, Ashley Morgan

Dissertations, Theses, and Capstone Projects

Touch paper evidence could be the source of probative human DNA but recovery is challenging and forensic laboratories instead prioritize processing by the Latent Print and Questioned Document disciplines. Recent advances in DNA collection methods and the increased sensitivity of STR typing kits have improved success rates for DNA testing of paper evidence; but prior to implementing DNA collection, laboratories have to decide in which order to examine paper for the different types of forensic evidence. This thesis developed and tested a multi-discipline workflow for processing paper evidence by DNA, Latent Prints and Questioned Documents experts. Preliminary sampling studies indicated …

Histone Post-Translational Modification Dysregulation Contributes To Toxicity In Amyotrophic Lateral Sclerosis Proteinopathy Models, Seth A. Bennett

Dissertations, Theses, and Capstone Projects

Amyotrophic Lateral Sclerosis (ALS) is the third most common adult onset neurodegenerative disorder worldwide. It is generally characterized by progressive paralysis starting at the limbs ultimately leading to death caused by respiratory failure. There is no cure and current treatments fail to slow the progression of the disease. As such, new treatment options are desperately needed. Epigenetic targets are an attractive possibility because they are reversible. Epigenetics refers to heritable changes in gene expression unrelated to changes in DNA sequence. Histone modifications, a main epigenetic mechanism, occur in many amino acid residues and include phosphorylation, acetylation, methylation as well as …

Eukaryotic Initiation Factor 3 Interactions With Structural Elements Of Barley Yellow Dwarf Virus Untranslated Regions Reveal Details Of A New Cap-Independent Translation Initiation Model, Paul S. Powell

Dissertations, Theses, and Capstone Projects

Barley Yellow Dwarf Virus (BYDV) is a positive strand RNA plant virus that translates without using a 5′ 7-methylguanosine cap or a 3′ poly-adenosine tail, features that are required for canonical mRNA translation. BYDV’s non-canonical translation relies on RNA structures in the 5′ and 3′ untranslated regions (UTRs) to recruit eukaryotic initiation factors (eIFs) and ribosomes. BYDV’s 3′ translation enhancer (BTE) is a cruciform structure capable of recruiting the cap-binding complex eIF4F, the large scaffolding complex eIF3, and the 40S ribosomal subunit. Together eIF3, eIF4F, and BTE influence factor binding and 40S recruitment on the 5′ UTR and play a …

Paddling Along The Voltage Gated Sodium Channel Galaxy With Sea Anemone Toxins: Structural Studies Of The Interaction Between The Paddle Motif From Nav1.5div And Sea Anemone Toxin, Adel K. Hussein

Dissertations, Theses, and Capstone Projects

Voltage gated sodium channels (VGSC) are membrane proteins that serve an important function in the central nervous system (CNS), peripheral nervous system (PNS), and cardiac muscles amongst others. The main function of VGSC is in the propagation of electrical signals by depolarizing excitable cells. Nine mammalian VGSC subtypes have been characterized, Na_V1.1 – Na_V1.9, that are expressed in a tissue specific manner, each with unique gating properties. Numerous diseases have been linked to defects in VGSC including epilepsy, mental retardation, long QT syndrome, and Brugada disease. Furthermore, these channels are one of the primary targets of …

An In Silico Approach To Investigate The Structural And Biochemical Basis Of The Rna Binding Functions Of Nucleolin, Avdar San

Dissertations, Theses, and Capstone Projects

Nucleolin (NCL) is a stress responsive multifunctional nucleolar protein and accounts for 10% of the total nucleolar protein content. NCL belongs to the class of RNA binding proteins (RBPs) that regulate many important cellular processes through their interactions with different RNA molecules. The dysregulation of RBPs and the RNA metabolism pathways they intersect is a known driver of tumorigenesis. NCL regulates ribosome biogenesis, chromatin remodeling, microRNA processing, and gene expression on multiple levels. The RNA-protein interactions of NCL are primarily driven by its four RNA binding domains (RBDs). NCL is known to interact with a growing list of primary-miRNA (pri-miRNA) …

Role Of Metals In Human Immune System: Study Of Metal-Dependent Structural Changes Of S100a12 Protein, Aleksey Aleshintsev

Dissertations, Theses, and Capstone Projects

S100A12 protein belongs to the S100 family of calcium-binding proteins and participates in the innate immune system. Antimicrobial proteins from the S100 family of the proteins (S100A12, S100A8/A9, etc.) are secreted and expressed by neutrophils during microbial infection and perform their antimicrobial activity through metal sequestration. While most S100 proteins function intracellularly, S100A12 is highly expressed and secreted into the extracellular space by neutrophils during infection. Sequestration of Zn²⁺ by S100A12 is aided by the nanomolar zinc binding affinity of the protein at neutral pH conditions, which is further enhanced upon calcium-binding. The Zn²⁺ binding scaffold in S100A12 …

Structural And Biochemical Investigations Of The Initiation Of Dna Replication In Bacteriophage Lambda And Escherichia Coli, Jillian D. Chase

Dissertations, Theses, and Capstone Projects

Faithful transmission of genetic information is requisite for the propagation of all life. DNA replication in each of the three domains of life requires the separation of double stranded DNA (dsDNA) into single stranded DNA (ssDNA) which then serves as a template for genomic duplication of each original DNA strand. Initiation of replication events occurs by tightly regulated processes during which specialized proteins are loaded at a specific locus within the genome, termed the origin of replication, in preparation of bidirectional replication events. A replicative helicase must be loaded or assembled on both strands of DNA at the origin to …

Water-Based Lead Generation, Brian Olson

Dissertations, Theses, and Capstone Projects

Water-based Lead Generation. The opioid epidemic and the SARS-CoV-2 pandemic are current serious challenges whose devastating effects could be assuaged through the development of new drugs. Opioids that are functional painkillers, that are less likely to cause overdose, and small molecule drugs that could inhibit the life cycle of SARS-CoV-2 would be useful. The work herein investigated the use of water molecules for lead generation in drug development against opioid receptors and SARS-CoV-2 viral proteins. In opioid receptor binding sites, purported bridging waters were obtained from crystal waters or from molecular dynamics simulations, as Hydration Site Analysis was used to …