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Mechanisms Of Macrophage Metabolic Activation And Paracrine Wnt Signaling In The Pathogenesis Of Systemic Sclerosis, Emily Ann Morris

Dartmouth College Ph.D Dissertations

Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology. We have previously shown that macrophages (MØs) play a critical role in its pathogenesis; however, the mechanisms driving MØ activation in SSc remain poorly understood. This dissertation investigates the molecular signaling pathways and biochemical mechanisms underlying profibrotic MØ activity in SSc.

First, I identify a novel MØ-specific effect of mycophenolate mofetil (MMF), the standard-of-care treatment for SSc. While MMF is a well characterized lymphostatic, my findings demonstrate that its active metabolite, mycophenolic acid (MPA), is also capable of directly inhibiting myeloid viability and profibrotic MØ activation by suppressing de …

Exploring Oxylipins In Host–Microbe Interactions And Their Impact On Infection And Immunity, Robert J. Neff, Christopher D. Radka

Markey Cancer Center Faculty Publications

Plasma lipids are essential components of biological systems, transported through interactions with proteins to maintain cellular functions. These lipids exist in various forms, such as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, and prenol lipids, derived from dietary intake, adipose tissue, and biosynthesis. While the association between certain fatty acids and cardiovascular diseases has been widely recognized, polyunsaturated fatty acids (PUFAs) exhibit cardioprotective effects, reducing risks of arrhythmias and heart-related mortality. This is due to their role in the production of eicosanoids, which modulate inflammation. Chronic inflammation, particularly in obesity, is significantly influenced by fatty acids, with saturated fatty acids promoting …

Bloom: Behavioral Learning And Outcome Observation In Microbes, Sean Sarwar Haque, Luke Compton Wharton, Ming Lin, Razvan Voicu

Symposium of Student Scholars

Understanding how pathogens respond to physical changes in their environment is crucial for developing effective treatments and preventative measures. Current research often relies on static models or experimental data that either fail to capture the dynamic interactions within cellular environments or are not generalizable to other types of pathogens. This project aims to address this gap by creating a comprehensive cell simulation that models pathogens and their response to chemical, physical, and physiological changes. The proposed solution is a simulation that integrates biological data and computational modeling to replicate the behavior of pathogens in real time as they are affected …

Single Amino Acid Changes Impact The Ability Of Drosophila Melanogaster Cecropins To Inhibit Growth Of Providencia Pathogens, Sarah Smith, Marla Forfar, Christopher Feudale, Lauren Shaffer, Grace Ginder, Marion Duval, Quinn Smith, Moria C. Chambers

Faculty Journal Articles

As antibiotic-resistant bacteria spread worldwide, the need to develop novel antimicrobial agents is urgent. One rich source of potential antimicrobials is the insect immune system, as insects produce a wide range of antimicrobial peptides (AMPs) with diverse sequences and structures. Insects also encounter many bacterial pathogens, some of which are closely related to pathogens of clinical relevance. However, despite interest in AMPs as therapeutics, the relationships between the amino acid sequence, biophysical properties, antimicrobial activity, and specificity are still not generalizable. To improve our understanding of these relationships, we assessed how single amino acid changes in cecropin AMPs produced by …

Optimizing Biofilm Assay Reproducibility And Characterizing The 12-Hydroxystearic Acid On Escherichia Coli, Khilola Khusanova

Theses and Dissertations

Biofilm formation in Escherichia coli plays a critical role in microbial chemical communication and surface-associated persistence. This study investigates the antibiofilm activity of 12-hydroxystearic acid (12-HSA), evaluating its R and S enantiomers as well as a racemic mixture. E. coli BL21, biofilms were grown under standardized laboratory conditions and quantified using the Crystal Violet staining assay. Treatment with 12-HSA resulted in a measurable reduction in biofilm biomass, with differences observed between the individual enantiomers and the mixture. These findings suggest that 12-HSA influences early adhesion and biofilm development, supporting its potential as a small-molecule modulator of bacterial surface behavior. This …

Characterization Of Legionella Pneumophila Effector Protein Ceg10, Emmanuella Ofoka

Masters Theses & Specialist Projects

Legionella pneumophila, the causative agent of Legionnaires' disease, utilizes a Type IV secretion system (T4SS) to transport effector proteins into host cells. This bacterium is said to have over 300 effector proteins. Among these, the Ceg10 effector protein had remained uncharacterized, despite evidence suggesting the importance of bacterial effector proteins in the host-pathogen interaction. This study aimed to perform a structural and functional characterization of Ceg10 through transcriptomic, bioinformatics, and molecular analyses. Transcriptomic profiling of HEK 293T cells expressing Ceg10 revealed significant differential gene expression, with approximately 20 upregulated genes, including leucine-rich repeat, as well as other downregulated genes. …

The Role Of Sodium Butyrate As An Inflammatory Regulator And Its Effect On Long Noncoding Rnas In Neuroinflammation, Angel Covarrubias

Chemistry & Biochemistry Theses - Archive

Inflammation is a crucial homeostatic process that contributes to both the elimination of foreign invaders and tissue repair. Inflammation at sites of tissue injury or infection is initiated by the detection of a harmful stimulus, triggering vital inflammatory immune signaling pathways and a cascade of cytokines and inflammatory mediators. The dysregulation of this process, however, can result in inappropriate inflammatory responses manifesting in tissue damage and compromised cell function. Dysregulation of the inflammatory response is seen frequently in many human diseases such as Diabetes, Cancer, cardiovascular disease, and neurodegenerative diseases.

In the context of the Central Nervous system, inflammation is …

Functional Analysis Of Ligand Binding Domain 2 Of Outer Surface Protein C Of Borreliella Burgdorferi, Gavin Z. Chambers

Theses and Dissertations

Lyme disease, caused by the spirochete Borreliella burgdorferi, is the most common vector-borne infection in North America. A critical determinant of early mammalian infection is outer surface protein C (OspC), a highly variable lipoprotein that is indispensable for spirochete survival but whose precise function remains unresolved. OspC has been proposed to mediate diverse roles, including complement evasion, adhesion, tissue dissemination, and antiphagocytic activity, supporting the view that it is a multifunctional virulence factor. Structural studies have identified two putative ligand-binding domains (LBD1 and LBD2), with LBD2 forming a solvent-exposed crown at the membrane-distal end of the OspC dimer.

To …

Functional Characterization Of Vago In Black Tiger Shrimp Penaeus Monodon Ikk-Nf-Κb Signaling Pathway Against Viral Infection, Zittipong Nanakorn

Chulalongkorn University Theses and Dissertations (Chula ETD)

Cytokines serve as key regulators in innate antiviral defense. In crustaceans, research on cytokine-mediated immunity remains limited. A previous study in Penaeus monodon has demonstrated that PmVago proteins exhibit cytokine-like function by acting through the inhibitor of kappa B kinase-nuclear factor κB (IKK-NF-κB) cascade to defend against white spot syndrome virus (WSSV). In this study, five PmVago isoforms were identified, each showing differential transcriptional responses to pathogen challenges. Among them, PmVago1 and PmVago4 exhibited strong antiviral responses against WSSV infection. RNA interference of PmVago1 and PmVago4 increased shrimp susceptibility to WSSV infection with enhanced viral replication. Their suppression also disrupted …

Rwanda's Natural Remedies: A Fresh Look At The Fight Against Malaria, Leandre Nsabimana Ndisanze

Pomona Senior Theses

Malaria remains one of the most devastating parasitic diseases globally, disproportionately affecting sub-Saharan Africa, where Rwanda continues to face high transmission rates and rising resistance to conventional interventions. Despite decades of control efforts, the emergence of drug-resistant Plasmodium falciparum and insecticide-resistant Anopheles mosquitoes threatens to reverse recent gains. This research responds to the urgent need for sustainable and culturally relevant alternatives by exploring the therapeutic potential of Rwandan traditional medicinal plants. These indigenous remedies, long used by local healers, offer an underexplored reservoir of bioactive compounds that may provide the basis for novel antimalarial drugs.

The central hypothesis of this …

Long-Term Antibacterial Efficacy Of Silver (I) Cyanoximates Against Streptococcus Mutans Ua159 Biofilm Growth, Tiffany A. Rojas

Honors Program Theses

Streptococcus mutans is the primary causative agent of dental caries due to its ability to form resilient multispecies biofilms. These biofilms promote acid production and degradation of the protective layers of the tooth, making biofilm formation a target for novel treatments. Silver(I) cyanoximates are of interest as alternatives to traditional antimicrobials and antibiotics due to the high UV and heat resistivity as well as poor solubility of the cyanoxime ligand paired with the well-established antimicrobial silver ion. Previous research has shown that silver(I) cyanoximates can effectively inhibit S. mutans biofilm formation after 24 hours in vitro. This study aimed to …

Caspases Protect Against Hyperglycemia Induced Necroptosis-Like Cell Death In Brain Endothelial Cells, Aleena S. Mathew

Theses and Dissertations

Acute diabetes characterized by high spikes in blood glucose levels in association with severe hyperglycemia can lead to an increased risk of ischemic stroke in the brain. To better understand high blood glucose levels, hyperglycemia, in the brain we explored its effects on endothelial cells. Endothelial cells line the inner walls of blood vessels and are directly impacted in hyperglycemia. Brain endothelial cells are a major component of the blood brain barrier (BBB) which tightly regulates the brain’s microenvironment. The type of cell death such as apoptosis, caspase dependent, or necroptosis, caspase independent, can exacerbate diabetes associated complications. There is …

Molecular Interactions Between The Shellfish Pathogen Vibrio Coralliilyticus Re22 And The Probiont Phaeobacter Inhibens S4sm, Jessica Coppersmith

Open Access Dissertations

Oyster larvae aquaculture is an important industry, both economically and environmentally, helping to create sustainable food systems by supplying seed oysters to farms, and also to restoration projects aimed at building coastal resilience and improving water quality by rejuvenating wild populations. However, oyster larvae are highly susceptible to rapid mortality events, crashes, which can seriously impact the industry. One source of these crashes in hatchery systems is vibriosis, caused by pathogenic species of Vibrio bacteria that are ubiquitous in temperate coastal waters, and with rising surface water temperatures their prevalence and virulence are increasing. To prevent these larval crashes from …

Bacteria-Engineered Vesicles For Cancer Immunotherapy: From Immunomodulation In Vitro To Anti-Tumor Effects In Melanoma Models, Lan Li

Theses and Dissertations--Chemistry

Bacterial vesicles hold immense potential in various biomedical fields. Among these, outer membrane vesicles (OMVs) produced by Gram-negative bacteria are the most extensively studied. While the exact mechanism of OMV production remains unclear, numerous environmental factors have been shown to influence both their yield and composition. In this study, we investigated the effect of three different antimicrobial families on OMV production by E. coli. Interestingly, antimicrobials within the same family did not provide the same effects on OMV yield, suggesting that OMV production may not directly correlate with the antimicrobial mechanism of action. OMVs have demonstrated tumor-inhibitory activity in multiple …

Science, Physiology, And Nutrition For The Nonscientist, Judi S. Morrill

Open Educational Resources

A wonderful blend of physiology, nutrition, biochemistry, genetics, biology, evolution, chemistry--what we all need to know as informed citizens. A basic knowledge of the life sciences and how our bodies work--to promote our own good health, especially as we're bombarded with misleading advertisements, soundbites, and the like. DNA fingerprinting, calorie requirements, dietary advice, genetic engineering (including gene editing with CRISPR cas9)--all in an easy-to understand book.

Investigating Mono-Driver Versus Multi-Driver Oncogenesis Via Alterations To Cell Signaling Pathways, Abygail Chapdelaine

Open Access Dissertations

The latest edition of Global Cancer Statistics released by the American Cancer Society reported approximately 20 million newly diagnosed cancer cases worldwide in 2022 with 9.7 million deaths. This ranks cancer as the second leading cause of death worldwide. For the majority of cancer patients, the standard treatment approach is chemotherapy and/or radiation therapy, and while this has been successful in some patients, a lack of specificity to cancer cells causes severe side-effects when these agents damage healthy cells. Despite extensive efforts that have gone into developing targeted cancer therapeutics that block functions specific to cancer, they have not been …

Assessment And Health Benefit Of Vitamin C Using A549 Cell, Yetunde Adepoju

College of Graduate Studies: Theses & Dissertations

Vitamin C (ascorbic acid) is a vital micronutrient recognized for its antioxidant capacity and essential bodily functions, such as collagen formation, neurotransmitter activity, and regulation of the immune system. This study explores how vitamin C can protect and potentially heal cells under oxidative stress and inflammation, using A549 cells, a human lung epithelial cell line, as the model system. The cells were exposed to varying concentrations of vitamin C dissolved in water, DMSO, and 5% DMSO. To assess the outcome, cell viability was measured with an MTT assay. In addition, the expression of key genes related to oxidative stress and …

Interactions Of The Sars-Cov-2 Viral Genome 3’-Untranslated Region With Viral And Host Rnas, Caleb Frye, Mihaela Rita Mihailescu

Electronic Theses and Dissertations

This dissertation focuses on the characterization of RNA-RNA interactions within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome and with host microRNAs. As the causative agent of coronavirus disease 2019 (COVID-19), SARS-CoV-2 has evolved rapidly since its appearance. This has warranted prompt characterization of the virus particularly of its single stranded RNA (ssRNA) genome. By using a combination of bioinformatics, biophysics, and/or biological assays, we analyzed the SARS-CoV-2 viral genomic RNA and uncovered interactions of genomic RNA with host RNAs, highlighting an underutilized method of targeting RNA viruses. We showed here that the conserved elements in the viral genomic …

Comparing Multivalent Cross-Linked Sodium Alginate/ Montmorillonite Beads Containing Curcumin Or Cayenne Pepper As Drug Carriers And Their Antimicrobial Resistance, Shionainn Traynor, Shubham Sharma

SURE Journal: Science Undergraduate Research Experience Journal

The aim of the following work was to investigate and compare curcumin and cayenne pepper in microbeads composed of sodium alginate (SA) crosslinked with montmorillonite (MMT) to act as drug carriers and their antimicrobial resistance. The microbeads were prepared through ion-exchange in multivalent solutions of CaCl₂, MgCl₂ and AlCl₃. The microbeads were characterized by Scanning Electron Microscopy (SEM), Energy Dispersive X-ray analysis (EDX) and the time required for intercalation of curcumin and cayenne pepper with MMT. Simulated intestinal fluid (pH 7.3) and gastric fluid (pH 1.2) at 37°C were used for comparison in swelling studies. …

Editorial - Sure Journal Vol 6, Anne M. Friel, Eva Campion, Sinead Loughran

SURE Journal: Science Undergraduate Research Experience Journal

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Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore

Master's Theses

Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor …

Synthesis Of Novel Chromenone Esters For Biochemical Assays, Andrew Dean Helmerich

Undergraduate Honors Thesis Collection

This project details the synthesis of a variety of novel chromenone esters to be used as enzymatic probes. A robust, initial library of 22 chromenone esters was successfully synthesized with differences in chain length, branching, and the incorporation of cyclic and heteroatomic moieties. These new chromenones were fully characterized by 1HNMR, 13CNMR, DEPT HRMS, 19FNMR, and HSQC. The utility of these compounds comes from the fact that they will fluoresce upon cleavage of the ester; thus, this property makes them ideal candidates to be used in the monitoring of enzymatic activity of esterases. Elucidating the enzyme-substrate structure activity relationship (SAR) …

From Resistance To Host Response: An Integrative Study Of C. Difficile Infections, Amber Consul

UNLV Theses, Dissertations, Professional Papers, and Capstones

Clostridioides difficile infection (CDI) is a major healthcare challenge, causing severe gastrointestinal illness and significant mortality. Understanding the mechanisms of antibiotic resistance, epidemiology, and immune response in CDI is critical for developing effective treatments and prevention strategies.

This dissertation encompasses three complementary studies. The first study investigates the genetic mechanisms underlying cephalosporin resistance in C. difficile strain 630 through differential gene expression analysis. The second study provides a descriptive epidemiological analysis of C. difficile ribotypes in a Las Vegas patient population, highlighting differences between healthcare-associated (HA-CDI) and community-associated (CA-CDI) cases. The third study integrates serum analyte profiling and transcriptomic analysis …

Noncontact Diffuse Reflectance Spectroscopy Of Synovial Fluid Samples For Rapid Identification Of Infections, Erin E. Drewke, Robert L. Brand, Caroline G. Geels, Hanna K. Jensen, Kevin Wong, Jarret D. Sanders, Narasimhan Rajaram

Biomedical Engineering Faculty Publications and Presentations

Severe joint infections, such as septic arthritis, require rapid diagnostic testing of the synovial fluid aspirated from joints level so that a surgical team can be assembled quickly. We present a diffuse reflectance spectroscopy (DRS) system for noncontact determination of infection. Using a light-tight syringe holder and fiber optic probe, diffusely reflected light from 475 to 655 nm was acquired from 18 patient samples through the wall of a syringe in a noncontact and sterile manner. We determined the reflectance ratios at two different wavelengths—R ₄₉₀/R ₆₀₀ and R ₅₈₀/R ₆₀₀ and found statistically significant …

Electric Potential Energy Optimized 3d Radial Sampling Trajectories For Mri, Christopher Huynh, Datta Singh Goolaub, Christopher K Macgowan

Faculty, Staff and Students Publications

A novel method for creating “golden” 3D center-out radial MRI sampling trajectories was developed and analyzed. This method, called ELECTRO (ELECTRic potential energy Optimized), uses repulsive forces to minimize electric potential energy. An objective function , the electric potential energies of all subsets of consecutive readouts in a 3D radial trajectory, and its reduced form were minimized using a multi-stage optimization strategy. A metric called normalized mean nearest neighbor angular distance (NMNA) was proposed for describing distributions of points on a sphere. ELECTRO and other relevant golden trajectories were compared in silico using NMNA and point spread function analysis. Consecutive …

Characterization Of Stealth Liposome-Based Nanoparticles Encapsulating Acat1/Soat1 Inhibitor F26: Potential Therapeutics For Niemann-Pick Type C And Other Neurodegenerative Diseases., Junghoon Lee

Dartmouth College Ph.D Dissertations

Cholesterol dysregulation is implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Niemann-Pick type C disease (NPCD). This study focused on evaluating the potent ACAT1 inhibitor, F26, as a therapeutic strategy for NPCD. F26 demonstrated superior ACAT1 inhibition and efficacy compared to the previously studied inhibitor, F12511, both in vitro and in vivo. Notably, F26 exhibited enhanced pharmacokinetic properties, including prolonged duration of action and better brain retention, making it a more promising candidate for treating neurodegenerative diseases.

F26 was encapsulated in a liposome-based nanoparticle system, DSPE-PEG2000 with phosphatidylcholine (PC), for enhancing its …

The Anaerobic Rose Chamber (Arc): Novel Applications For Probing Clostridioides Difficile Dynamics, Tatiana Zvonareva

Chemistry & Biochemistry Theses & Dissertations

Clostridioides difficile infection (CDI) is an urgent public health threat with a high rate of recurrence and limited treatment options. Caused by the anaerobic intestinal pathogen C. difficile, this disease affects up to 500,000 Americans annually. Despite progress in our understanding of CDI pathophysiology, the lack of effective and accessible experimental platforms compatible with obligate anaerobe physiology hinders the advancement of treatment therapy. The application of in vivo models has been indispensable in understanding CDI pathophysiology, probing the complexity of the host response to the microbe, and establishing treatment protocols, and it continues to be essential in preclinical testing. …

Integrated Safety And Efficacy Analyses Of Phase 3 Trials Of A Microbiome Therapeutic For Recurrent Cdi, Colleen S Kraft, Matthew Sims, Michael Silverman, Thomas J Louie, Paul Feuerstadt, Edward S Huang, Sahil Khanna, Charles S Berenson, Elaine E L Wang, Stuart H Cohen, Louis Korman, Christine Lee, Colleen R Kelly, Alberto Odio, Paul P Cook, Bret Lashner, Mayur Ramesh, Princy Kumar, Ananya De, Asli Memisoglu, David A Lombardi, Brooke R Hasson, Barbara H Mcgovern, Lisa Von Moltke, Darrell S Pardi, Ecospor Iii And Ecospor Iv Investigators

Faculty, Staff and Students Publications

INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI.

OBJECTIVE, DESIGN, AND PATIENTS: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities.

METHODS: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest …

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

All ETDs from UAB

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

Retinoblastoma Malignance And Exosome Mechanisms Facilitating Optic Nerve Head Metastatic Niche Formation, Cui Shi

Dissertations, Theses, and Capstone Projects

Retinoblastoma (RB) is a rare pediatric ocular tumor that occurs before five years of age and it is the most common intraocular cancer of childhood with more than 300 children in the United States and 8000 diagnosed globally each year. RB arises from the proliferation of cone photoreceptor precursor cells in the retina as a result of mutations in the RB1 gene. The influence of RB secreted factors on cells in the retinal environment has not been fully elucidated. Cancer cell released exosomes have been shown to transform their microenvironment through transfer of metastasis promoting molecular cargo. Cancer cell extracellular …