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Recent Submissions

Open Access
Iron Homeostasis and Oxidative Stress Regulation by the PrrF Small RNAs in Pseudomonas Species
(2025) Ouattara, Khady; Oglesby, Amanda G.
Iron is an essential micronutrient for bacterial growth and survival, yet its redox activity promotes the formation of reactive oxygen species (ROS), requiring organisms to tightly regulate iron uptake, utilization, and storage. Pseudomonads provide a rich system for examining these processes, as species within this genus occupy diverse ecological niches but share a strong dependence on iron metabolism. This dissertation investigates iron regulatory mechanisms in Pseudomonas aeruginosa and Pseudomonas fluorescens, with a particular focus on the iron-responsive PrrF small RNAs (sRNAs). These sRNAs are central to maintaining iron homeostasis, but their contributions to oxidative stress responses remain poorly defined. Using the PrrF sRNAs as a molecular probe, I examined how peroxide stress influences their expression and regulatory activity. My work provides new insight into the intersection of iron regulation and oxidative stress protection by demonstrating that hydrogen peroxide alters PrrF-mediated regulation in P. aeruginosa. I further extended this analysis to P. fluorescens, generating the first characterization of PrrF regulation by iron limitation and peroxide stress in a non-pathogenic pseudomonad. These findings reveal both conserved and divergent regulatory features that may reflect each species’ evolutionary adaptation to distinct environments. A major component of this thesis is an investigation of PA4880, a conserved Dps-like protein and PrrF target. In my thesis, I demonstrate that PA4880 expression is regulated by PrrF during iron limitation and this protein is induced by peroxide treatment. Preliminary findings also suggest a potential role for BrnD in biofilm formation, raising new questions about how iron and oxidative stress responses intersect with community-associated growth. Together, this work expands our understanding of iron homeostasis and oxidative stress regulation in the pseudomonads, laying the foundation for future studies exploring how these pathways evolve and contribute to survival across environmental niches.
Embargo
From Cancer Targets to Polysaccharides: Leveraging Molecular Simulation and Machine Learning to Accelerate Drug and Material Discovery
(2025) Romany, Aarion; Shen, Jana
Fundamental to rational drug and material design is a clear understanding of underlying molecular mechanisms. However, these processes are often challeng- ing to probe experimentally. Molecular dynamics simulations and machine learning (ML) offer high temporal and spatial resolution that can complement experimen- tal techniques, providing novel insights to accelerate discovery. This dissertation investigates molecular mechanisms related to kinase inhibition and chitosan/chitin self-assembly, with implications for rational drug and material design. Chapter 1 introduces and discusses the theory behind the methodologies ap- plied throughout the dissertation. Chapter 2 and 3 develop and apply molecular dynamics methods to identify covalently druggable sites in ERK pathway kinases and elucidate the mechanism of action of MEK1 inhibitors. Chapter 2 presents a novel computational protocol for assessing cysteine druggability, integrating continuous constant pH molecular dynamics simulations with pocket analysis. This protocol is prospectively applied to cysteines in MEK and RAF kinases. The analysis suggests that the GK+3 cysteine in RAF kinases and the back-loop cysteine in MEK kinases are druggable, offering promising opportunities for targeted covalent kinase inhibitor design. In Chapter 3 long-timescale MD was applied to investigate the mechanism of action of two MEK1 inhibitors (avutometinib and cobimetinib) in terms of their ability to disrupt RAF-MEK1 heterodimerization. The simulations reveal that cobimetinib disrupts the dimer through ligand-mediated destabilization of the MEK activation loop (A-loop), weakening the interface. In contrast, avutometinib enhances dimer stability via strong hydrogen bonding to the A-loop and a polar head group that forms unique inter-protomer contacts. Chapter 4–6 investigate the self-assembly mechanisms of the second most abundant biopolymer chitin and its derivative chitosan. Chapter 4 applies de novo simulations to elucidate the temperature-dependent mechanism and polymorphism of chitin self-assembly. The analysis reveals that hydrophobic interactions drive increased assembly at elevated temperatures. In chapter 5 a similar approach is used to investigate the influence of acetylation on chitosan self-assembly. The re- sults demonstrate that increasing acetylation reduces solubility, while the pattern subtly alters hydrogen bonding and chain registry. Chapter 6, non-equilibrium MD simulations are then used to study the electric field-induced contraction of chitosan hydrogels, providing mechanistic insights with relevance to the electro-fabrication of chitosan-based functional material. These simulations reveal that the electric field induces dewetting transitions between amphiphilic sheets which underlie the observed contraction behavior. Chapter 7 focuses on a preliminary study toward the development of machine learning models to classify the chemical reactivity of acrylamide-based warheads, using experimentally derived half-lives as training data. Chapter 8 summarizes the conclusions and lessons learned in this dissertation work and suggests future direction of studies.
Open Access
Sex-Specific Effects of Stress and Depression on Nucleus Accumbens Neuron Subtype Transcriptomes and Social Behavior
(2025) Kumar, Gautam; Lobo, Mary Kay
Major depressive disorder (MDD) has been a leading cause of disease burden among neuropsychiatric conditions for the past 30 years. There are significant sex differences in its distribution, symptoms, and treatment outcomes, with women consistently showing higher incidence across geographic, cultural, and socioeconomic groups—suggesting underlying biological factors. Several brain regions implicated in MDD exhibit sexual dimorphism, but the nucleus accumbens (NAc) has received particular attention due to its role in reward circuitry, its sexually dimorphic features in both healthy and disease states, and its altered activity in MDD. The primary neuron type found in the NAc is the medium spiny neuron (MSN), consisting of two major subtypes defined by dopamine receptor expression (D1 or D2) and other molecular signatures. D1-MSN activity is broadly associated with reward, and D2-MSN activity with aversion, though these roles are more nuanced. In this study, we establish baseline sex differences in the transcriptomic profiles of these MSN subtypes to understand potential sources of vulnerability contributing to higher MDD rates in women. We use MSN subtype transcriptomic data from unstressed adult mice, along with NAc tissue from juvenile mice and healthy human patients. We then apply chronic witness defeat stress (CWDS), a highly translatable social defeat paradigm, to female mice to examine transcriptional alterations induced by chronic stress—the strongest predictor of MDD onset. Using differential gene expression (DEG) and weighted gene coexpression network analysis (WGCNA), we characterize transcriptional profiles of high and low social interaction phenotypes defined through the three-chamber social interaction test. Through consensus module analysis, we compare these profiles with data from male mice undergoing chronic social defeat stress (CSDS) and human MDD patients to identify a sex- and MSN subtype–specific gene coexpression module involving the PI3K–Akt–mTOR pathway. Finally, using DeepLabCut-derived social microbehavior variables from video recordings, we perform factor analysis to derive a five-factor structure of sociability and link the sex- and subtype-specific module to latent social factors to identify molecular mechanisms driving sex differences in maladaptive social behavior in MDD.
Embargo
The Untold Story of Burnout Among Inpatient, Hospital-Based Palliative Care Nurse Practitioners
(2025) Zogby, Colleen; McPherson, Mary Lynn
Burnout among palliative care (PC) providers has been extensively documented, yet little is known about the experiences of inpatient, hospital-based PC nurse practitioners (NPs). This dissertation presents a cohesive body of work that explores and conceptualizes burnout among this population. Guided by Lazarus and Folkman’s cognitive appraisal theory (CAT), the study examined how NPs’ appraisals of stress and coping interact with the high-intensity hospital environment of palliative care. The first manuscript, a systematic literature review, examined what is known about burnout among PC providers. Findings revealed that while burnout prevalence among PC providers is concerning across palliative disciplines, few studies focused specifically on NPs or distinguished the inpatient setting from outpatient or hospice contexts. Depersonalization (DP), a core dimension of burnout, emerged as a particularly concerning aspect among clinicians. The second manuscript critically evaluated the psychometric properties of existing burnout instruments, especially those that measure DP. Results demonstrated that no instrument adequately captures the unique experience of burnout among inpatient, hospital-based PC NPs, thereby limiting their utility in guiding intervention research. Together, these manuscripts identified significant knowledge gaps that informed the third manuscript: a qualitative descriptive study exploring the firsthand experiences of inpatient hospital-based PC NPs. Eligible participants were U.S.-based NPs aged 18 years or older, working in inpatient PC for at least one year. Data were collected through audio- and video-recorded semistructured interviews, transcribed verbatim, and analyzed using inductive content analysis. Twenty-one participants were recruited through purposive sampling. All participants practiced in urban hospitals (N = 21), were female (n = 19) and male (n = 2), identified as White (n = 20) or Mexican American (n = 1), and had 1–15 years of inpatient PC NP experience. Findings revealed that burnout is shaped by moral tension, emotional exhaustion, constrained autonomy, systemic and organizational barriers, and late consults that challenge the relational core of PC practice. Sustaining forces included professional role identity, autonomy, team cohesion, and patient connections. Within the context of limited organizational support, participants’ appraisal of their professional commitment underscored their susceptibility to exploitation. The synthesis of findings culminated in the development of the Concentric Ring Model of Stress and Coping, a visual framework illustrating the multilayered and interconnected factors that influence NP well-being.
Open Access
Development of Highly Selective Immunotherapies for the Treatment of Cancer
(2025) Baker, Jillian; Luetkens, Tim
Cancer is currently one of the leading causes of death worldwide with 1 in 6 deaths being cancer related. Conventional therapies such as surgery, radiation and chemotherapy have offered hope for patients and in many cases have resulted in complete tumor remission. Unfortunately, many tumors become resistant to conventional cancer therapies and require more effective targeting to achieve lasting remissions or cures. Immunotherapies, such as monoclonal antibodies and chimeric antigen receptor (CAR) T cells, exert substantial anti-tumor activity and have advanced the field greatly. However, due to their high specificity for a single target antigen, these therapies generally lack tumor selectivity resulting in on-target, off-tumor toxicity against healthy tissues. The central focus of my dissertation is to develop immunotherapies that are highly selective for tumor cells and spare healthy tissues. To prevent on-target, off-tumor toxicities, three separate approaches were taken with different therapies. The first approach focused on the generation of low-affinity CAR constructs using systematic mutagenesis of a parental high-affinity single-chain variable fragment (scFv) to more precisely target CD229 on multiple myeloma cells, while sparing healthy CD229-positive lymphocytes. The second approach focused on restricting the trafficking of LINGO1 CAR T cells through integrin knockout. LINGO1 CAR T cells with restricted trafficking would be able to target LINGO1-positive Ewing sarcoma cells but not LINGO1-positive healthy cells in the brain. The third approach taken to engineer tumor selectivity focused on the development of sweeping antibodies against interleukin 16 (IL-16), an antigen that is soluble, pro-tumorigenic and has minimal physiological function. The significant findings from these three studies are: (1) low-affinity CAR constructs can be generated from a high-affinity CAR construct and spare healthy T cells while maintaining anti-tumor activity. (2) Integrin knockout in activated, primary T cells prevents binding to VCAM1 and trafficking of CAR T cells to the brain. (3) Sweeping antibodies against IL-16 could be generated and clear soluble IL-16 in vitro. Together, these approaches show that selectivity can be engineered into both monoclonal antibodies and CAR T cell therapies to reduce on-target off-tumor toxicity and increase anti-tumor efficacy.