Digital Commons Network^™

A Study On The Hormonal Regulation And Novel Role Of Na+ Leak Channel, Non-Selective (Nalcn) In Human Myometrial Smooth Muscle Cells, Chinwendu Amazu

Arts & Sciences Electronic Theses and Dissertations

During pregnancy, the uterus transitions from a quiescent state to an excitable, highly contractile state to deliver the fetus. Two important contributors essential for this transition are progesterone (P4) and estrogen (E2), which promote quiescence or contraction, respectively, by acting on the myometrial smooth muscle cells (MSMCs). While these hormones regulate uterine contractions, it is unclear how they affect electrical activity of MSMCs, which underlies uterine contractile activity. Our lab recently identified Na+ leak channel, non-selective (NALCN) as a component of the leak current in human MSMCs and showed that mice lacking NALCN in the uterus have dysfunctional labor. In …

Genetic Effects Mediated Through Epistatic Networks Onto Metabolic Traits, Juan Francisco Macias-Velasco

Arts & Sciences Electronic Theses and Dissertations

Predicting variation in complex traits from DNA sequence is a major public health goal, but our understanding of the genotype-to-phenotype relationship is incomplete. It will remain so unless we can adequately integrate genetic, epigenetic, and environmental information into a systems level framework. In a step towards that goal, quantitative trait mapping studies have attempted to account for environmental factors such as sex and diet, and epigenetic factors such as allelic parent-of-origin effects. Several studies used an advanced intercross of the LG/J and SM/J inbred mouse strains to unravel the genetic architecture of multiple metabolic traits. These studies found that parent-of-origin …

Identification Of Multi-Tissue Protein Quantitative Trait Loci And Causal Inference Of Protein Effects In Neurological And Other Complex Human Diseases Via Mendelian Randomization, Chengran Yang

Arts & Sciences Electronic Theses and Dissertations

Alzheimer disease (AD) is the most common neurodegenerative disease, affecting 6.2 million people mostly aged 65 years or older in the United States as of early 2021. AD has been widely studied and characterized worldwide, but there is still no effective treatment or cure. Even the latest FDA-approved treatment, Aducanumab, cannot stop decline or improve cognition. To develop a truly effective treatments, researchers keep discovering genetic and molecular mechanisms underlying the disease. Protein biomarkers are keys to bridge the mechanisms to disease. Here, I first used a high-throughput proteomic dataset from three tissues (CSF, plasma, and brain) with array-based genotype …

Mass Spectrometry-Based Protein Footprinting: High-Throughput Maldi Platform And Large Protein Complexes Of Baf, Ruidong Jiang

Arts & Sciences Electronic Theses and Dissertations

Human’s advances in understanding biological processes rely heavily on the breakthroughs in biophysical tools. Mass spectrometry (MS)-based protein footprinting, which interrogates protein structures by measuring protein solvent assessable surface area (SASA), has grown rapidly in the last decade, successful in providing valuable data for numerous protein systems. This thesis focuses mainly on this technology.We set out to push the boundary of MS-based protein footprinting further into the new areas, preparing it for potential future applications including large-scale experiments that require high-throughput analysis the structure of large, complicated protein complexes. This thesis devotes five chapters to the method development of MS-based …

On Arousal And The Internal Regulation Of Brain Function: Theory And Evidence Across Modalities And Species, Ryan Raut

Arts & Sciences Electronic Theses and Dissertations

The brain is an organ. It is subject to the same physiological regulatory processes that engage the rest of the body’s organs, sculpted over hundreds of millions of years to sustain life so effectively. The central message of this thesis is that the holistic functioning of the brain, rather than operating at some level above or independent from these systemic regulatory processes, is deeply related to them. In short, as our limited attention spans might suggest: brain function is internally regulated. I propose that this internal regulation is a primary function of intrinsic brain activity. Chapter 2 provides a theoretical …

Regulatory Effects Of The E. Coli Recbcd Nuclease Domain On Dna Unwinding Kinetics, Nicole Fazio

Arts & Sciences Electronic Theses and Dissertations

I have examined the effects of deleting the nuclease domain of the E. coli helicase RecBCD on the rates of ATP-independent DNA melting, single stranded (ss) DNA translocation, and double stranded (ds) DNA unwinding by RecBCD. The canonical role of the nuclease domain is DNA degradation, but the removal of this domain showed unexpected effects on other RecBCD activities including DNA binding, melting, and unwinding. This thesis presents a mechanistic study of DNA unwinding by RecBCD and a RecBCD variant with the nuclease domain deleted (RecBΔnucCD). I examined the rates of ssDNA translocation and dsDNA unwinding by RecBCD and RecBΔnucCD …

Influence Of Focal Activity On Macroscale Brain Dynamics In Health And Disease, Zachary Pollack Rosenthal

Arts & Sciences Electronic Theses and Dissertations

Macroscopic recordings of brain activity (e.g. fMRI, EEG) are a sensitive biomarker of the neural networks supporting neurocognitive function. However, it remains largely unclear what mechanisms mediate changes in macroscale networks after focal brain injuries like stroke, seizure, and TBI. Recently, optical neuroimaging in animal models has emerged as a powerful tool to begin addressing these questions. Using widefield imaging of cortical calcium dynamics in mice, this dissertation investigates the mechanisms by which focal disruptions in activity alter brain-wide functional dynamics. In two chapters, I demonstrate 1) that focal sensory stimulation elicits state-dependent, global slow waves propagating from primary somatosensory …

Examining Individual Differences In Forgetting From Long-Term Memory, Christopher Lee Zerr

Arts & Sciences Electronic Theses and Dissertations

Forgetting reflects the decreased likelihood of memory retrieval over time. With a few exceptions, although the mean likelihood of retrieval (or retention) across experimental conditions may differ markedly, rates of forgetting across those conditions do not differ. Similarly, although groups (e.g., young and old adults) may differ in the amount retained at a given point in time, the rates of forgetting tend not to differ across groups. In contrast, recent work suggests that individual differences in rates of forgetting may emerge when more sensitive statistical analyses are used on person-level performance. Some person-level variables purported to influence forgetting rate include …

Regional Reprogramming And The Small Intestine: Analysis And Modeling Of Adaptive Regeneration Of The Epithelium, Sarah Elizabeth Waye

Arts & Sciences Electronic Theses and Dissertations

The small intestine in homeostasis is capable of regular regeneration, but in cases of massive injury like Short Bowel Syndrome, the innate human response often fails to fully compensate for the loss of nutrient absorptive surface area that accompanies bowel resection. Murine models display an active compensatory reaction deemed “adaptation” in which the surface area of the bowel is increased to accommodate nutrient absorptive needs. This observation has highlighted several gaps in knowledge regarding bowel adaptation. Firstly, what occurs on a molecular level in murine models during adaptation? Secondly, how can the findings in mice be applied to humans in …

Human Plcg2 Haploinsufficiency Results In A Novel Immunodeficiency, Joshua Brandon Alinger

Arts & Sciences Electronic Theses and Dissertations

NK cells are critical for the recognition and lysis of herpesvirus-infected cells. Patients with NK cell immunodeficiency may suffer from unusually severe and/or recurrent herpesvirus infections; however, the genetic cause is frequently unknown. PLCG2 encodes a signaling protein in NK cell and B cell receptor signaling, in which dominant-negative or gain-of-function mutations may cause cold urticaria, antibody deficiency, or autoinflammation. However, loss-of-function mutations and PLCG2 haploinsufficiency have never been reported in human disease. We examined 2 families with autosomal dominant NK cell immunodeficiency with dual high-dimensional techniques, mass cytometry and whole-exome sequencing, to identify the cause of disease. We identified …

Process Information And Creative Mindsets: An Examination Of Their Role In The Evaluation Of Creativity, Brendon Michael Cummiskey

Arts & Sciences Electronic Theses and Dissertations

Evaluating creativity is a key role for any organization interested in innovation and how that evaluation occurs has been a focal point of researchers. Although creativity scholars have made strides in understanding creativity evaluations, questions remain about the role that process information plays in the evaluation. While most creativity research involves some type of outcome, such as an idea or product, the evaluators often have no description of the creator’s work process or any understanding of the idea or product’s creation. In this dissertation, I build upon the existing evaluation literature and critically examine how process information may influence the …

The Effects Of Molecular Chaperone Modulation On Protein Folding, Prion Formation, And Prion Propagation In Saccharomyces Cerevisiae, Leeran Blythe Dublin Ryan

Arts & Sciences Electronic Theses and Dissertations

Proper and efficient protein folding is vital for cell survival. Many factors affect protein folding fidelity and prion formation, including molecular chaperone availability and activity. Research has shown that modulating chaperone availability and function can affect protein misfolding and aggregation, as well as de novo prion formation and propagation. However, the factors involved and underlying mechanisms influencing prion formation and protein folding are largely unknown. The following work aims to elucidate these areas. The Nascent Polypeptide-Associated Complex (NAC) is the first point of chaperone contact for nascent polypeptides. Previous work has shown that disruption of the NAC leads to improved …

Slo2.1 Channels: A New Molecular Mechanism To Regulate Uterine Excitability, Juan Jose Ferreira

Arts & Sciences Electronic Theses and Dissertations

At the end of pregnancy, the uterus transitions from a non-contractile state to a highly contractile state. Two processes primarily drive this transition. First, from the 28th week of pregnancy until labor, the resting membrane potential of uterine (myometrial) smooth muscle cells (MSMCs) gradually becomes more positive (depolarizes) (Parkington et al. 1999). Second, at the end of pregnancy, MSMCs express more oxytocin receptors and become more sensitive to oxytocin (Kimura et al. 1996). However, the detailed mechanisms by which these processes occur have not been determined. My central hypothesis was that the Na+-activated K+ channel SLO2.1 plays a key role …

Quantitative Characterization Of Microbial Ecologies In Dysbiosis And Infection, Eric Keen

Arts & Sciences Electronic Theses and Dissertations

In 1973, Theodosius Dobzhansky famously wrote that nothing in biology makes sense except in the light of evolution. Today, nearly 50 years later, little in microbiology – or in biology, for that matter – makes sense except in the light of genomics. Microbial genomics populates the field with innumerable testable hypotheses for evaluation in vitro and in vivo, allows us to monitor microbial populations in real time and at a massive scale, and underpins our approach to entire domains of microbiology, including microbial evolution. In this Thesis, I present three studies from my graduate research united by their common theme …

Material Difficulty And Individual Difference Factors Moderate The Eyewitness Confidence-Accuracy Relationship, Wenbo Lin

Arts & Sciences Electronic Theses and Dissertations

Recent studies have shown that eyewitness confidence is positively associated with high identification (ID) accuracy, but some eyewitness researchers have expressed concerns regarding the reliability of this confidence-accuracy relationship in applied settings (e.g., are there circumstances or moderator variables that make this relationship less reliable?). For the present study, we considered two types of moderator variables: material difficulty (i.e., the difficulty level associated with different sets of eyewitness stimuli) and individual difference factors such as face recognition ability. Experiment 1 examined whether these moderator variables significantly impair the confidence-accuracy relationship and Experiment 2 examined whether these same moderator variables equally …

Developments In Proteomics, Trans-Splicing Technology And Endogenous Transcript Manipulation, Justin Alexander Melendez

Arts & Sciences Electronic Theses and Dissertations

Technological innovation drives scientific discovery, unlocks new avenues of research, and allows us to ask questions in ways that were previously unavailable. With each technological advance, our ability to perturb and explore biological systems has grown in ways previously unimagined. The theme of my thesis is the development of new technologies in biology. To this end, I have worked on three technologies that contribute to the areas of protein sequencing, RNA barcoding for trans-splicing and single-cell applications, and a new method for transcriptional knockdown.

In my first project, digital analysis of proteins by end sequencing (DAPES), we set out to …

Computational Methods For Analysis Of Data For Conformational And Phase Equilibria Of Disordered Proteins, Jared Michael M Lalmansingh

Arts & Sciences Electronic Theses and Dissertations

Intrinsically disordered proteins and regions (IDPs / IDRs) are a class of proteins with diverse conformational heterogeneity that do not fold into a tertiary structure due to the lack of a native structural state. Consequently, disordered proteins are remarkably flexible and exhibit multivalent properties that enable them to adopt myriad functional roles within the cell such as: signaling transduction, transcription, enzymatic catalysis, translation, and many more. Due to their multivalency, some IDPs undergo monomeric and heterotypic interactions which can drive phase separation. Such IDPs can form membraneless organelles with specific regulatory roles within the cell which include, but are not …

Deconvolving Genomic Regulatory Heterogeneity With Self-Reporting Transposons, Arnav Moudgil

Arts & Sciences Electronic Theses and Dissertations

A cell’s identity is a function of the genes expressed in that cell, which are in turn regulated by transcription factors. Over the last decade, single-cell RNA sequencing (RNA-seq) has emerged as a powerful class of techniques to characterize cellular diversity in heterogeneous tissues. These methods barcode transcripts by their cell-of-origin and assign them to specific genes. The resulting high-dimensional data are further processed to reveal clusters of cells sharing transcriptional states. Annotating these clusters, based on either known or discovered marker genes, offers a glimpse into the dynamic composition of an organ or biological process. While single-cell RNA-seq excels …

Weedy Rice As A Model System For The Study Of Microevolutionary Interactions In Agricultural Contexts, Marshall Jon Wedger

Arts & Sciences Electronic Theses and Dissertations

Just under one-half of the global population relies on cultivated rice (Oryza sativa) astheir primary source of calories, making the optimization of rice agriculture immensely important. One of the primary constraints to rice agriculture is the de-domesticated (feral) form of rice known as ‘weedy rice’ that aggressively competes for space, soil nutrients, and light. Heavy infestation can reduce crop yields by as much as 80%. As a closely-related weedy descendant of cultivated rice, chemical control is difficult in rice fields, and physical weeding is labor intensive, time consuming, and largely ineffective due to early life-stage mimicry of the crop.

Weedy …

Cancer Epigenome Reprogramming, Jennifer Ann Karlow

Arts & Sciences Electronic Theses and Dissertations

The identification of recurrent genetic mutations in cancer and their functionalcharacterization has provided a strong foundation for our understanding of tumorigenesis. The more recent observation of recurrent and specific epigenetic changes also present in cancer has widened this view, now establishing cancer as a disease of both genetic and epigenetic misregulation. Enhancers, genomic regions primarily responsible for tissue-specific gene expression, have been shown to be frequent targets of both genetic and epigenetic abnormalities. The observation that DNA methylation within regulatory regions has traditionally correlated with reduced gene expression, coupled with the known role of enhancers in regulating tissuespecific gene expression, …

Evaluating Recognition Memory Models From An Individual Differences Perspective, Kyle Gramer Featherston

Arts & Sciences Electronic Theses and Dissertations

Although recognition memory models have been thoroughly compared in various recognition memory paradigms, the relative reliability and validity of their parameters have not been thoroughly assessed using an individual differences approach. In two studies, I evaluated three models: the dual-process signal detection (DPSD) model, the continuous dual process (CDP) model, and the unequal variance signal detection (UVSD) model. In Study 1, participants performed a remember-know procedure that also included confidence ratings. When model parameters were estimated twice in the same individual, both key parameters from the DPSD model were reliable within an individual, whereas the CDP version of familiarity was …

Dissecting The Molecular Mechanism Of Familial Cardiomyopathies, Sarah Ruth Clippinger Schulte

Arts & Sciences Electronic Theses and Dissertations

Familial cardiomyopathies, including hypertrophic (HCM), restrictive (RCM) and dilated cardiomyopathy (DCM), are the leading cause of sudden cardiac death in young people. These diseases, which are characterized by altered cardiac contractility and remodeling of the heart, can lead to heart failure. These diseases are primarily caused by point mutations in sarcomeric proteins that generate or regulate heart contraction, such as troponin T. In the heart, the troponin complex together with tropomyosin lie along the actin filament and regulate myosin’s ability to bind actin and produce force. Here I show how mutations in troponin T affect contractility at the molecular level …

Probing New Physics Beyond The Standard Model Via New Neutrino Interactions, Garv Chauhan

Arts & Sciences Electronic Theses and Dissertations

The Standard Model (SM) of Particle Physics provides a self-consistent quantum field theoretic framework to explain three of the four known fundamental forces (electromagnetic, weak, strong) along with classifying all known elementary particles. Since its conception in the 1960s, the SM has been one of the most tested theories of physics and has withstood all experimental batterings. In spite of these successes, there are compelling indications, both experimental and theoretical, that require us to expand our understanding of the nature beyond the SM (BSM). Arguably the most glaring indication of BSM physics is the observation of neutrino oscillations, which implies …

The Potential Of Mental Health Policy Implementation: Methods And Applications, Meagan Renee Pilar

Arts & Sciences Electronic Theses and Dissertations

Mental illness affects roughly 20% of the world in some capacity and can be debilitating. Though a large emphasis has historically been placed on individual-level interventions (e.g., therapy or medication), mental health policies present an opportunity to intervene on a large scale, with the potential to enhance impact and equity. This dissertation contributes to the mental health policy research literature in three main ways—(1) exploring factors affecting policymakers’ overall support of mental health policies; (2) assessing the use and quality of quantitative and qualitative methods within this field; and (3) exploring implementation determinants and outcomes, as well as strategies used …

Iron And Manganese Oxidation By Oxyhalogen Species: Implications For Paleoenvironmental Reconstruction On Mars, Kaushik Mitra

Arts & Sciences Electronic Theses and Dissertations

As the nearest planetary neighbor with potential earlier habitable conditions, Mars is replete with minerals that hold clues to its past chemistry and evolution of the aqueous systems. Oxidized iron (Fe) and manganese (Mn) minerals on Mars are geochemical markers of such environments in which they formed and record past pH, redox conditions, and intensity of water-rock interaction. Fe and Mn oxides can therefore be used to reconstruct past Martian environmental conditions from settings where aqueous fluids were active. Various processes that form Fe and Mn oxide minerals on Mars have been previously proposed, including chemical oxidation using molecular oxygen …

Deep Multi-Omics Investigations Elucidate Novel Oncogenesis Paradigms, Therapeutic Targets, And Mechanisms Of Treatment Resistance In Cancer, Daniel Cui Zhou

Arts & Sciences Electronic Theses and Dissertations

No abstract provided.

Defining The Epigenetic And Transcriptional Regulatory Mechanisms By Which Hrsv Ns1 Alters Host Transcriptional Response, Nina Rose Beri

Arts & Sciences Electronic Theses and Dissertations

No abstract provided.

Paleo-Environmental Pollution Of The Bronze Production During The Shang Period At Anyang, Henan Province, China, Yi-Ling Lin

Arts & Sciences Electronic Theses and Dissertations

Paleo-environmental pollution is invested in both identifying anthropogenic activities and evaluating the environmental condition and its impact on humans to understand human-environment relationships and the human experience of the past. This project first investigates the environmental and health consequences of bronze production during the Shang period at Anyang. As a contribution to the growing scholarship in paleo-environmental and archaeological studies, this dissertation uses Shang bronze production in Anyang as a case study into how paleo- environmental pollution study can inform us about the on environmental and health conditions of lives in the Bronze Age China. Through geochemical analysis (ICP-MS, ICP-OES) …

Causal Function And Bias Correlation Of The Orbitofrontal Cortex In Economic Choices, Shi Weikang

Arts & Sciences Electronic Theses and Dissertations

Economic choices entail two mental processes, value calculation and value comparison (Niehans, 1990). Studies in the last twenty years have shown that neurons in the orbitofrontal cortex (OFC) could support both processes. Namely, in the studies in which monkeys chose between two juice options with various amounts, three functional cell groups had been found in the OFC: offer value cells encode the value of individual juices, chosen juice cells encode the choice in a binary way and chosen value cells encode the value of the chosen juice (Padoa-Schioppa and Assad, 2006). These results suggest a decision circuit within OFC with …

Petrology, Geochemistry, And Experimental Studies Of Mafic Enclaves And Amphibole At Shiveluch Volcano, Kamchatka, Andrea Elizabeth Goltz

Arts & Sciences Electronic Theses and Dissertations

This thesis connects mineralogical, chemical, and physical observables in quenched mafic inclusions from Shiveluch Volcano in Kamchatka and high pressure and temperature experiments to elucidate the water content of primitive magmas at Shiveluch, the timing of magmatic recharge events relative to eruption, and the petrogenetic history of andesites erupted at Shiveluch. Using the petrology of basaltic andesite mafic inclusions erupted from Shiveluch, in Chapter 2, the water content of primitive magmas at Shiveluch is found to be 8-10 wt%, which is two to three times higher than the global average determined by other methods, and the temperature of primitive magmas …