Digital Commons Network^™

Sodium Valproate-Induced Hyperemesis In A Patient Post-Bariatric Surgery, Mohammed Alsubhi, Khalid Alharb, Bandar Alrehaili

Saudi Toxicology Journal

Long-term treatment of patients with medications is associated with adverse drug reactions and continues to be a challenge. Sodium valproate is commonly used to treat bipolar disorder and epilepsy. It can induce adverse gastrointestinal effects, and its absorption may vary depending on the excipient used. In this case study, a middle-aged woman with a history of bipolar disorder developed hyperemesis after the use of a generic sodium valproate formulation. The patient had undergone gastric sleeve surgery 3 years ago and lost weight. Using generic formulation of sodium valproate stimulated vomiting 3 years after the patient had been tolerating the branded …

Cholesterol Mass Fingerprinting To Probe Cholesterol-Protein Interactions, Warren Lowther

Electronic Theses and Dissertations

Cryomicroscopy, crystallography and NMR have been considered the “gold standard” of structural biophysics for some time. Recent successes in using these techniques has provided us with a plethora of insight into the architecture of different macromolecules like channels, transporters, and other molecular machines. However, information is often limited to a single allosteric state with the macromolecule in a non-native environment. Additionally, these traditional methods tend to be expensive and labor-intensive, requiring samples that are concentrated and highly purified. Chemical crosslinking coupled with mass spectrometry (CX-MS) has emerged as the ideal accessory for the aforementioned structural tools. In order to address …

Drivers And Mechanisms Of Golgi Fragmentation As A Modulator Of Disease, Amanda Macke

Theses & Dissertations

The Golgi apparatus plays a pivotal role in post-translational modification, trafficking, and secretion of proteins, ensuring proper cellular function. As a result, its fragmentation has been implicated in multiple pathological conditions, including alcohol-induced liver injury and prostate cancer (PCa). Despite its known impact on cellular homeostasis, the molecular mechanisms governing Golgi fragmentation remain to be clarified. Additionally, we have only just begun to understand the vast consequences of Golgi disorganization on disease progression.

This dissertation investigates the drivers and mechanisms of Golgi fragmentation, with a focus on its role as a modulator of disease. Using both in vitro and in …

The Impact Of The Mediterranean Diet On Depression: A Narrative Review, Emma Kate Schaaf

Honors Theses

Background. The Western diet has extensive negative ramifications on physical health and emotional well-being. The Mediterranean diet, widely regarded as one of the healthiest eating patterns in the world, may have the ability to improve psychological conditions. This study aims to examine existing research from randomized control trials (RCTs) on the association between depression prevalence and the Mediterranean diet.

Methods. The following review was conducted using PRISMA guidelines and the Google Scholar and PsycInfo databases. The criteria for inclusion were that studies: 1) were randomized control trials (RCTs) examining the Mediterranean diet; 2) included samples of adults (i.e., > 18 years …

Coxiella Burnetii Manipulation Of Membrane Contact Sites In The Intracellular Niche, Margaret F. Sladek

Theses & Dissertations

Coxiella burnetii is a highly infectious and environmentally persistent bacterium that causes the disease Q Fever. Its intracellular home, the Coxiella-Containing Vacuole (CVV), is formed from fusion of host-derived vesicles and is rich in sterols - yet cholesterol accumulation in the CCV is bacteriolytic. Our lab’s goal is to understand how Coxiella manages intracellular cholesterol levels and survives within the host. One way Coxiella may modulate CCV cholesterol is through membrane contact sites (MCS), areas where molecular complexes bridge two organelles and exchange lipids. This thesis explores how Coxiella uses both a mammalian lipid transfer protein and bacterially-encoded effector …

Impaired Dnajb2 Response To Heat Shock In Fibroblasts From A Neuropathy Patient With Dnajb2/Hsj1 Mutation: Cystamine As A Potential Therapeutic Intervention, Raj K. Pradhan, Nikolas G. Kinney, Brigid K. Jensen, Hristelina Ilieva

Farber Institute for Neuroscience Faculty Papers

Background and Objectives: Neuropathy is a debilitating disorder characterized by peripheral nerve dysfunction and damage to sensory, motor, and autonomic neurons and their axons. While homozygous mutations in DNAJB2/HSJ1 have been linked to early-onset neuropathy, a heterozygous DNAJB2 c.823+6C>T was discovered in an adult patient with severe sensory–motor polyneuropathy. This mutation is predicted to affect both isoforms of the protein. DNAJB2 (HSP40), a key member of the heat shock protein family, plays a critical role in cellular protection and stress, including response to heat shock. DNAJB2 traffics unfolded proteins to another heat shock protein, HSP70, and activates its ATPase …

Impact Of Unconventional Gas Extraction On Tributaries Of Tenmile Creek, Greene County, Pennsylvania: A 12-Year Perspective, Christian L. Beall

Electronic Theses and Dissertations

Much of southwestern Pennsylvania has been central to a rapid increase in development for unconventional natural gas extraction in the past two decades. The continued monitoring of streams over their lifetime as extraction sites is pivotal to understanding the effects of fracking on local waterways and their ability to provide for wildlife and human use. Here, using multiple indices of biotic integrity (IBI), I perform analyses of fish and macroinvertebrate communities as well as water chemistry on two streams, Bates Fork (with shale wells) and Fonner Run (without), as part of a follow-up to work performed there from 2010-2012. Fish …

Household Point-Of-Use Faucet Filters For Lead Removal: Field Performance And User Experiences, Jeannie M. Purchase, Chantaly Villalona, Adrienne Katner, Kelsey Pieper, Marc Edwards

School of Public Health Faculty Publications

Lead certified point of use (POU) faucet filters were field tested in two Louisiana cities in a total of 21 occupied homes during normal use and in two unoccupied homes with very high risk of water lead (Pb) contamination. In an unoccupied home with a 28 m lead service line (LSL) with average lead of 17 μg/L in flushed water, treatment by POU filters generally produced water with < 5 μg/L Pb even when tested to 200% of rated capacity. In the unoccupied home with a disturbed LSL, the water had erratic influent particulate lead of 9-3053 μg/L, and the POUs did not consistently produce water with < 10 μg/L Pb despite very high percentage removals. When testing POUs in occupied homes known to occasionally have lead over 5 μg/L, POUs always reduced lead to < 1 μg/L. In addition, POUs were also effectively removing high levels of iron and manganese present in the water of one city, but this also caused clogging before reaching half of their rated capacity. Laboratory experiments confirmed POU susceptibility to iron clogging.

Student Perceptions Of Supports And Barriers For Transferring Quantitative Reasoning In Introductory Biology Lab Courses, Joelle Prate, Jeremy L. Hsu

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Quantitative reasoning is a critical skill in biology and has been highlighted as a core competency by Vision and Change. Despite its importance, students often struggle to apply mathematical skills in new contexts in biology, a process called transfer of knowledge. However, the supports and barriers that students perceive for this process remain unclear. To explore this further, we interviewed undergraduate students in an introductory biology lab course about how they understand and report the transfer of quantitative skills in these courses. We then applied these themes to the Step Back, Translate, and Extend (SBTE) framework to examine student …

Sirt6 Deficiency Promotes Senescence And Age-Associated Intervertebral Disc Degeneration In Mice, Pranay Ramteke, Bahiyah Watson, Mallory Toci, Victoria Tran, Shira N Johnston, Maria Tsingas, Ruteja Barve, Ramkrishna Mitra, Richard Loeser, John Collins, Makarand Risbud

Department of Orthopaedic Surgery Faculty Papers

Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc (Acan^CreERT2; Sirt6^fl/fl). Histological studies showed a degenerative phenotype in knockout mice …

Depalmitoylation Regulates Metabolism And Mitochondrial Function, Sarah Lilly Speck

Arts & Sciences Graduate Student Theses and Dissertations

Tens of millions of Americans suffer from metabolic disorders, predisposing patients to cardiovascular disease, kidney disease, liver disease, infertility, and cancer. Unfortunately, the etiology of many of these diseases remains a mystery, limiting our ability to identify targets for pharmacologic therapies. Due to the relationship between altered lipid dynamics and metabolic dysfunction, we decided to study the effect of the posttranslational lipid modification, S-palmitoylation, on metabolism. S-palmitoylation is the only known reversible lipid modification for proteins, and this depalmitoylation process is catalyzed by acyl-protein thioesterases including APT1 and APT2. We hypothesized that APT deficiency in various tissues would predispose mammals …

Parental Guidance Suggested: Genetic, Epigenetic, And Environmental Factors Shape Allele-Specific Gene Regulation In Metabolic Traits, Celine Louise St. Pierre

Arts & Sciences Graduate Student Theses and Dissertations

Deciphering the “genotype to phenotype” map is a crucial goal of biology. We will not improve our ability to predict phenotypes from DNA sequences until we better incorporate epigenetic and environmental variation into our models of human health and disease. Genes are typically presumed to express both parental alleles equally, but genetic and epigenetic factors can cause one allele to function differently than the other (e.g. expressed or silenced more). These allele-specific imbalances can alter the final composition of a gene’s transcriptional product and ultimately shape phenotypes. Allele-specific effects have widespread impacts on complex traits, but how environmental signals contribute …

Overconfidence And Financial Risk Tolerance In Older Age, Colleen C Frank, Gary R Mottola, Meiru Chen, Lei Yu, Patricia A Boyle, Gregory R Samanez-Larkin, Kendra L Seaman

Faculty, Staff and Student Publications

Objectives: Excessive financial risk-taking in older age can have harmful consequences as opportunities to recover lost wealth are limited. Understanding financial risk-taking in older age is important for identifying vulnerabilities and developing interventions to empower aging investors to make wise financial choices. In this paper, we explore how overconfidence in financial knowledge affects financial risk-taking among older adults.

Methods: We examine this research question in older adults aged 58-101 (N = 1,242) using data from the Rush Memory and Aging Project (MAP).

Results: After controlling for demographics, overconfidence was associated with self-reported financial risk tolerance such that those who were …

Pan-Cancer Universal Targets For Immunotherapy Resulted From Transposable Elements Activation, Yonghao Liang

Arts & Sciences Graduate Student Theses and Dissertations

Transposable elements (TEs) contribute to nearly half of the human genome yet have been overlooked in genomic medicines due to the stereotypic impression as “junk DNA” and technical challenges. However, studies in the last two decades demonstrated that dysregulation of the epigenome in cancer cells resurrects the cis-regulatory functions of TEs, including the promoter activities. The tumor-specific TE activation events along with the resulting tumor-specific RNA and protein molecules, provide a potential “gold mine” for identifying tumor-specific therapeutic targets for cancer treatments, including immunotherapy. Here, I present a series of works to investigate the potential of providing actionable, pan-cancer, and …

A Subset Of Senescent Myofibroblasts Orchestrates Immunosuppression In Pancreatic Cancer., Jad Belle

Arts & Sciences Graduate Student Theses and Dissertations

Pancreatic Ductal Adenocarcinoma (PDAC) is the most lethal solid malignancy with a 12% 5-year survival rate. Most tumors are detected at metastatic stages that are extremely resistant to therapy. PDAC recalcitrance is driven by a unique tumor microenvironment (TME) comprising dense collagenous fibrosis embedded with an abundance of cancer associated fibroblasts (CAFs) and infiltrating leukocytes. Preclinical studies have indicated that PDAC CAFs can have both pro- and anti-tumorigenic effects. This is likely owed to CAF phenotypic heterogeneity which was recently uncovered by single cell transcriptomics. Three major CAF subpopulations have been identified in mouse and human PDAC thus far: myofibroblastic …

Circuit-Specific Vulnerability In A Mouse Model Of Alzheimer's Disease, Samuel Brunwasser

Arts & Sciences Graduate Student Theses and Dissertations

The relationship between brainwide functional decline and accumulation of pathological protein aggregates in Alzheimer’s disease (AD) is complex and not well understood. A set of highly interconnected cortical regions known as the Default Mode Network (DMN) exhibits selective vulnerability to both functional decline and amyloid beta (Aβ) plaques in early AD. One possibility is that early Aβ accumulation in the DMN drives vulnerability. However, it is unknown whether there is something intrinsic to neuronal projections within the DMN that biases these circuits towards dysfunction. In this dissertation, I describe the development of a multisite in vivo electrophysiology pipeline for chronic …

Disrupting Nrf2-Driven Cancer Biology Through One-Carbon Metabolism Inhibition, Julius Chembo

Arts & Sciences Graduate Student Theses and Dissertations

Cancer remains a leading cause of mortality worldwide, with treatment resistance and recurrence posing major barriers to long-term survival. Despite advancements in targeted therapies, many cancers develop resistance to chemotherapy, radiation, and immunotherapy, significantly limiting their effectiveness. One key driver of therapeutic resistance is nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2), a transcription factor that regulates antioxidant responses and drug detoxification. While NRF2 protects normal cells from oxidative stress, its aberrant activation in cancer promotes tumor progression, metabolic reprogramming, and resistance to standard treatments. Alarmingly, NRF2 hyperactivation is implicated in some of the most aggressive and refractory malignancies, yet no …

Induced Cd8a Identifies Enhanced Human Nk Cell Il-15-Induced Proliferation And Metabolism And Modulates Nk Cell Activation, Celia Cubitt

Arts & Sciences Graduate Student Theses and Dissertations

Natural Killer (NK) cells are cytotoxic innate lymphoid cells that play an important role in the surveillance and elimination of virally-infected and malignantly-transformed cells. These primary effector functions are achieved by producing cytokines and chemokines which activate and recruit additional immune effectors, as well as direct cytotoxic killing via perforin and granzymes. NK cell function is tightly regulated by a balance of germ-line encoded activating, inhibitory, co-stimulatory, and cytokine receptors expressed at the cell surface. Through these activating and inhibitory receptors, NK cells recognize and kill targets without prior sensitization through the loss of self-identifying molecules such as major histocompatibility …

Mechanisms Of Mll-Rearranged Infant Leukemogenesis, Jonny Mendoza-Castrejon

Arts & Sciences Graduate Student Theses and Dissertations

Infant leukemias arise as either B cell acute lymphoblastic leukemia (B-ALL) or acute myeloid leukemia (AML) and are primarily driven by MLL/KMT2A-rearrangements (MLLr). Prior work has shown that MLLr transform fetal/neonatal hematopoietic progenitors more efficiently than adult progenitors. However, the genetics and epidemiology of MLLr leukemias present an important paradox. MLLr arise during late gestation under conditions that would seemingly favor leukemic transformation (i.e., fetal/neonatal progenitors have high proliferation rates and self-renewal). Furthermore, MLLr infant leukemias require very few cooperating mutations for transformation. Yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias …

Expanding The Druggable Proteome By Integrating Deep Learning With Molecular Simulations To Predict Cryptic Pockets, Artur Meller

Arts & Sciences Graduate Student Theses and Dissertations

Of the protein structures deposited in the Protein Data Bank, less than half have pockets suitable for the binding of drugs. Even when proteins contain pockets in their ground state structures (e.g., the nucleotide-binding active site in myosin motors), achieving specificity remains a central challenge in drug design as many protein families share common structural motifs. Cryptic pockets are cavities absent in ligand-free experimental structures that form due to protein fluctuations in solution. They provide a means to specifically target proteins currently considered undruggable. While cryptic pockets are alluring drug targets, it remains difficult to predict which proteins will form …

Oxycodone Self-Administration Modulates Ventral Pallidal Neuron Activity And Plasticity, Jessica Tooley

Arts & Sciences Graduate Student Theses and Dissertations

Opioid use disorder is an urgent public health crisis in the United States. Over 800,000 Americans have died from opioid-related overdoses since 2000. Nearly 30% of people who misuse opioids begin with prescription oral opioids, such as oxycodone, and continue misusing to avoid the immediate aversive state of withdrawal and the persistent dysphoria associated with protracted abstinence from opioids. The persistency of these dysphoric symptoms increases the risk of relapse even after long periods of abstinence. Treatment for opioid use disorder currently consists of pharmacological opioid treatment to reduce withdrawal symptoms and behavioral counseling. However, these strategies have significant real-world …

Parapinopsin: A Photoswitchable Inhibitory Gpcr For Two-Photon Optogenetics, Bobbie J. Brown

Arts & Sciences Graduate Student Theses and Dissertations

The development of optogenetic tools has greatly advanced the capability of researchers to understand the connection between neuronal activity and behavior. Optogenetics makes use of opsins, which are light activated ion-channels, ion pumps, or G-Protein coupled receptor (GPCR-based) proteins used to regulate cellular activity. Coupled with technological advances in genetics and optical physics/microscopy, optogenetics can be used to control specific populations of cells in a time-locked, spatially specific manner. The experiments possible with optogenetics depend largely on the capabilities and limitations of the opsin used; thus, there have been continuous efforts to design and employ new opsins with a variety …

Performance Of Lasso And Ridge Regression For Variable Selection In Genome-Wide Association Studies Of Maize Flowering Time, Dipok Deb

Data Science and Data Mining

Genome-Wide Association Studies (GWAS) are instrumental in identifying genetic variants linked to complex traits, providing valuable insights into trait heritability and biological mechanisms. This study applies GWAS to investigate flowering time in maize, a critical adaptive trait, using a diverse dataset of 5,000 recombinant inbred lines across eight environments. Traditional GWAS methods often encounter challenges in high-dimensional datasets due to the presence of multiple small-effect genetic loci. To address this, we compared two penalized regression methods—LASSO and Ridge regression—to perform variable selection and regression analysis within a GWAS framework. LASSO effectively reduced the number of predictors by selecting the most …

The Role Of The Cgas-Sting Sensing Pathway In Hiv-1 And Sars-Cov-2 Infections, Jenna Eve Eschbach

Arts & Sciences Graduate Student Theses and Dissertations

Human immunodeficiency virus type I (HIV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the causative agents of two unique pandemics. For a successful replication cycle to occur, viruses need to strategically outmaneuver host cell defenses. The innate immune system is the first line of defense against viruses and other pathogens. Host pattern recognition receptors detect viral nucleic acids and initiate signaling cascades that culminate in the expression of interferon (IFN) and transcriptional upregulation of antiviral interferon-stimulated genes (ISGs). This dissertation examines the involvement of the innate immune response during early, post-entry steps of HIV-1 and SARS-CoV-2 infection. During …

Investigating Genetic Regulators Of Crystal Cell Development In Drosophila Melanogaster, Anisa Turaeva, Nyla Walbrook, Andrea Feria, Rebecca Spokony

Publications and Research

In Drosophila melanogaster, hematopoiesis produces three types of blood cells (hemocytes): plasmatocytes, lamellocytes, and crystal cells, all of which provide vital immunological activities. Crystal cells have an especially essential role in melanization, a wound reaction mediated by prophenoloxidase enzymes. This study investigates genetic regulators of crystal cell growth by RNAi-mediated knockdown of five potential genes: ACXA, ACXB, Gp210, CG4390, and Cyp4s3. We used the GAL4/UAS system to selectively silence each gene and quantify crystal cell counts in wandering third instar larvae after heat shock-induced melanization. Our findings indicate that knockdown of ACXA and ACXB resulted in higher crystal cell …

The Role Of Il-33 In Itch, Anna M. Trier

Arts & Sciences Graduate Student Theses and Dissertations

Chronic itch is associated with a broad range of medical conditions, from inflammatory skin diseases to cancer and organ dysfunction, and has a lifetime prevalence of up to 20%. Despite being common and debilitating, the cellular and molecular mechanisms that drive chronic itch are just beginning to be elucidated. Thus, therapeutic options are limited. Recent studies have identified that various pro-inflammatory cytokines can directly activate sensory neurons. This has resulted in mounting interest in the therapeutic potential of inhibiting these neuro-immune interactions. IL-33 is constitutively expressed by epithelial cells, which allows for its rapid release upon tissue damage or stress. …

Understanding Loss Of Beta-Cell Identity And Progression Of Diabetes In Polygenic Mouse Models Of T2dm, Sumitkumar Patel

Arts & Sciences Graduate Student Theses and Dissertations

Type 2 diabetes (T2DM) is caused by the complex interaction of multiple genes and environmental factors. T2DM is characterized by hyperglycemia, insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing β-cells, recent studies indicate that β cell apoptosis rates are relatively low in diabetes. In this dissertation, I investigated β-cell failure in diabetes using KK and KKAy mouse models of polygenic T2DM, which spontaneously develop hyperglycemia, glucose intolerance, glucosuria, impaired insulin secretion and insulin resistance. I found that β-cell failure in KK …

Single-Cell Analysis Of Clonal And Transcriptional Dynamics During Direct Reprogramming, Brent Biddy

Arts & Sciences Graduate Student Theses and Dissertations

Direct lineage reprogramming converts one cell type into another, a process characterized by significant heterogeneity. Single-cell genomic techniques have been instrumental in dissecting this variability, yet they often fail to preserve lineage relationships. Here, I present CellTagging, a sequential, combinatorial indexing method that enables the reconstruction of clonal history and gene expression dynamics at single-cell resolution. This facilitates the construction of multi-level lineage trees, providing insights into cellular reprogramming trajectories. We applied CellTagging to investigate direct lineage reprogramming of mouse embryonic fibroblasts into induced endoderm progenitors. Our analysis revealed two distinct reprogramming trajectories: one leading to successful conversion and another …

Investigating The Roles Of Sox10 And Etv4 In Melanocyte And Melanoma Development, Catherine Marie Newsom-Stewart

Arts & Sciences Graduate Student Theses and Dissertations

The neural crest is a transient, multipotent cell population unique to vertebrates that gives rise to diverse lineages, including craniofacial cartilage, peripheral neurons, glia, and pigment-producing melanocytes. Proper specification and differentiation of neural crest derivatives are orchestrated by tightly regulated gene regulatory networks, and disruption of these developmental programs can lead to congenital disorders and malignancies. Melanocytes, derived from the neural crest, are best known for their role in skin pigmentation but also contribute to homeostasis and specialized functions in the eye, ear, and heart. These cells produce melanin to protect tissues from ultraviolet radiation and oxidative damage, and they …

Characterizing Piezo1 Mechanotransduction In Articular Chondrocytes, Jaquelin Marlen Garcia Castorena

Arts & Sciences Graduate Student Theses and Dissertations

Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 350 million people worldwide. Along with inflammation and pain, a hallmark of OA is the degradation of articular cartilage (AC), an avascular and aneural tissue that coats and facilitates the bending of diarthrodial joints. AC withstands millions of cyclic mechanical loads annually, and chondrocytes, the only resident cells in the tissue, sense these loads through mechanically gated ion channels, including Transient Receptor Potential Vanilloid 4 (TRPV4), PIEZO1 and PIEZO2. PIEZO1 is a highly expressed calcium ion channel in chondrocytes that can be activated through mechanical loading or chemically …