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Developing Oligonucleotide Combinations for Neurological Disorders
No full textOligonucleotides are short nucleic acid polymers that have emerged as a novel class of therapeutics, showing clinical success in the past decade due to advances in chemistry. However, their broader clinical application remains limited by delivery challenges, restricted tissue distribution, and lack of polypharmacology. While many are addressing delivery and distribution, few have explored how different oligonucleotides work in combination or how to design single oligonucleotides that act on multiple targets. This is especially relevant for neurological disorders, most of which are polygenic.In the first part of this dissertation, I investigated how single-stranded antisense oligonucleotides (ASOs) with different mechanisms act in tandem. Using ASOs that upregulate SCN1A mRNA, I demonstrated synergistic mRNA upregulation. This is clinically significant, as SCN1A deficiency causes Dravet Syndrome (DS), a severe childhood epilepsy. Upregulating SCN1A is a promising treatment for DS.In the second part, I explored combinations of small interfering RNAs (siRNAs) to reduce amyloid beta (Aβ) and phosphorylated tau (p-tau)—hallmarks of Alzheimer’s Disease (AD). This led to the discovery of key effects involving mTOR signaling and the development of a siRNA combination targeting APP and MAPT to reduce both Aβ and p-tau.Lastly, I developed a novel method to chemically link two oligonucleotides into a single, multi-targeting molecule. Altogether, my dissertation lays the groundwork for designing next-generation, multi-targeting oligonucleotide therapeutics.</p
The Effects of Intersecting Identity and Social Determinants of Health on Afro-Latina Maternal Morbidity and Infant Birth Outcomes in Florida
No full textLatinos are often treated as a homogeneous group in health research, overlooking the diverse racial identities within this population. Afro-Latinas and their infants face heightened risk for adverse outcomes due to intersecting marginalized identities. Guided by Intersectionality Theory, this dissertation examines maternal morbidities (gestational diabetes, hypertensive disorders in pregnancy) and adverse infant outcomes (preterm birth, small- and large-for-gestational-age) among Afro-Latina mothers and their infants in Florida. It also assesses the impact of social determinants of health (SDoH), particularly neighborhood deprivation and prenatal care adequacy. Presented in a three-manuscript format, the dissertation includes: (1) a systematic review on Afro-Latina maternal and infant outcomes, (2) a population-based analysis of Florida Vital Statistics data from 2004–2022 across racial/ethnic groups (N=4,009,855), and (3) a focused analysis of Hispanic mother-infant dyads in 2022 (N=25,899). Logistic regression models estimated associations between racial/ethnic identity, health outcomes, and SDoH indicators (Area Deprivation Index, Adequacy of Prenatal Care Utilization). Findings revealed Afro-Latina mothers had unique risk profiles, more aligned with Black non-Hispanic than White Hispanic mothers. Hypertensive disorders were a consistent disparity, persisting after adjustment for SDoH. Iinfants of Afro-Latinas had lower odds of preterm birth and SGA than those of White non-Hispanic mothers. These results highlight how race, ethnicity, and structural inequities interact to influence outcomes. This work underscores the need for disaggregated data, inclusive methods, and intersectional public health approaches to improve maternal-child health equity among Afro-Latinas. </p
The Effect of Music-Based Mindfulness on Attention and Anxiety in East Asian International Students Experiencing Acculturative Stress
No full textEast Asian international students face unique challenges related to acculturative stress while studying in the U.S., yet they often underutilize mental health services. Music-based mindfulness—combining mindfulness techniques with the therapeutic features of music—may offer an accessible intervention by using music as an engaging auditory stimulus to support attention regulation and reduce anxiety.This study investigated the short-term effects of music-based mindfulness on anxiety and attention in East Asian international students experiencing acculturative stress. Sixty participants were randomly assigned to either a 20-minute music-based mindfulness session (incorporating Western music and instruments) or a 20-minute mindfulness psychoeducation session. Acculturative stress and trait anxiety were measured pre-session; state anxiety and state attention were assessed pre- and post-session using self-reports and a task-based attention test.Results indicated significant reductions in state anxiety for both groups, with the music-based mindfulness group showing a larger effect size. Self-reported attention improved in the experimental group with a significant effect, while the control group showed no change. Both groups improved on task-based attention, possibly due to practice effects. No significant between-group differences were found, though qualitative feedback suggested music-based mindfulness was more engaging and relaxing.Findings highlight the potential of music-based mindfulness to support present-moment awareness and reduce anxiety through rhythmic and continuous auditory cues. This study contributes to the understanding the role of music in mindfulness and suggests implications for culturally responsive mental health support in higher education. Future research should explore long-term effects and optimize musical elements for therapeutic impact.</p
Multifunctional Magnetoelectric Nanoparticles for Cancer Theranostics and Neurological Applications
No full textThis dissertation explores the synthesis, properties, and biomedical applications of magnetoelectric nanoparticles (MENPs) with a focus on their potential in cancer therapy and neurological stimulation. MENPs, characterized by their ability to convert magnetic fields into localized electric fields, offer promising non-invasive alternatives for therapeutic interventions in oncology and neuroscience. The research begins with a detailed examination of the fundamental requirements for MENPs in biomedical applications, including biocompatibility, magnetic properties, and targeted delivery, that need to be addressed. A detailed synthesis method for producing highly efficient MENPs is presented, demonstrating their functionality in theranostic applications, particularly for treating solid tumors like pancreatic cancer.MENPs, when combined with magnetic fields, have shown potential to induce localized tumor ablation, paving the way for minimally invasive cancer treatments. Furthermore, the particles were found to be effective when used as a tumor specific contrast agent in MRI.In addition to their cancer applications, MENPs are also investigated for their role in neurological interventions, particularly in stimulating movement in vivo. By acting as nanoelectrodes on neuronal membranes, MENPs can wirelessly control neural activity, offering a breakthrough for brain-machine interfaces (BMIs), neuroprosthetics, and other potential therapeutics. The research highlights the ability of MENPs to induce specific motor responses without the need for implanted electrodes, demonstrating their potential for non-invasive neuromodulation.The dissertation concludes by discussing future directions, emphasizing the steps required for clinical translation of MENP-based cancer therapies and the further development of MENPs as a brain-machine interface tool. The findings underscore MENPs' transformative potential in modern medicine, offering new paradigms for treating both neurological disorders and cancer
LanModulin as a Biomarker-Targeting Platform for Precision Imaging
No full textBiomarkers play a critical role in modern medicine, guiding disease detection, monitoring, and treatment decisions. Protein biomarkers offer dynamic insights into physiological and pathological processes, making them invaluable tools for diagnostic imaging. This dissertation explores the development of a novel biomarker-targeting platform by integrating LanModulin (LanM), a high-affinity lanthanide-binding protein, with a HER2-specific Designed Ankyrin Repeat Protein (DARPin). By leveraging the molecular specificity of HER2-targeting DARPins and the unique lanthanide-binding properties of LanM, this work aims to enhance the stability and precision of imaging agents for HER2+ breast cancer. Through the design, expression, and characterization of this fusion protein, this research establishes a framework for the use of LanM as a lanthanide carrier in bioimaging, highlighting its potential to advance biomedical applications that rely on lanthanide-based diagnostics and imaging techniques.</p
Suicidal Ideation and Attempt Among Trans Women and Femmes at the Intersection of HIV Risk and Marginalization Stress
No full textSuicide represents a public health priority, and trans and gender diverse persons and persons living with HIV continue to face disparities in suicidal ideation and attempts. Approximately 1 in 2 trans women and femmes report a prior attempt, and 1 in 2 are living with HIV. The gender minority stress model, which posits that repeated exposure to marginalization results in chronic stress may explain suicide disparities, but prior work has not examined suicide risk at the intersection of both minority stress and HIV in this high priority population. Trans women and femmes living with or at risk for HIV acquisition completed a cross-sectional psychosocial assessment including measures of gender minority stress and suicide risk. Stochastic search variable selection was used to identify data-driven minority stress predictors of suicidal ideation and attempt. Linear and negative binomial regressions were used to examine direct and indirect associations of minority stress factors with suicidal ideation and attempt. Differences in minority stress and suicide risk by HIV status were explored. Rejection, rejection sensitivity, and nondisclosure were identified as potential predictors of suicidal ideation, and rejection sensitivity was identified as a potential predictor for suicide attempt. Higher rejection, higher rejection sensitivity, and lower nondisclosure predicted higher suicidal ideation severity. Rejection indirectly increased ideation severity via rejection sensitivity, and decreased suicidal ideation severity via nondisclosure. Rejection sensitivity did not predict the presence or severity of suicide attempt history. There were no differences in minority stress or suicide risk by HIV status. Rejection-based pathways appeared important to consider in the context of HIV in this population. Assessments of and interventions for suicide may be more responsive to the needs of trans women and femmes impacted by HIV risk when they consider the effects of compounded stigma on rejection.</p
Investigate the Role of ROS and RNS in Axon Degeneration
No full textFollowing injury, sensory neuron terminals rapidly degenerate before initiating regeneration. While reactive oxygen species (ROS) are known to promote axon regeneration through epidermal mechanisms, their role in axon degeneration remains unclear. A hallmark of neurodegenerative diseases is the formation of mitochondrial ROS (mitoROS), but whether mitoROS contribute to injury-induced axon degeneration was unknown.Here, I demonstrate that mitochondrial superoxide in cutaneous sensory neurons drives axon degeneration following fin amputation. Further analysis showed that reactive nitrogen species (RNS), specifically peroxynitrite, are formed by superoxide and contribute to axonal destruction. I identified putative nitration and nitrosylation sites at conserved residues in NMNAT, a key regulator of SARM1-driven axon degeneration. Modulation of ROS/RNS with the ROS scavenger NADPH significantly reduced amputation-induced sensory axon degeneration while enhancing the regeneration of cutaneous axons. Furthermore, NADPH co-administration mitigated axon degeneration under pathological conditions induced by paclitaxel, suggesting that oxidative stress-induced axon degeneration extends beyond injury models and may underlie broader neurotoxic mechanisms.To further investigate the role of ROS in paclitaxel-induced axon degeneration, I examined the expression and function of the ROS-producing enzyme Nox1 in the presence and absence of paclitaxel. Paclitaxel treatment induced a nuclear translocation of Nox1 in epidermal keratinocytes, leading to increased nuclear ROS formation and upregulation of mmp13 transcription. Sensory axon degeneration was prevented in cyba-/- mutants, which impair Nox1 activity, confirming a role for Nox-induced ROS in paclitaxel neurotoxicity. These findings suggest that ROS contribute to axon degeneration through distinct mechanisms: extrinsically via keratinocyte-mediated Nox1 signaling in paclitaxel-induced pathology and intrinsically through mitochondrial superoxide in acute injury-induced degeneration.</p
Engineering Fluidic Platforms for Optimizing Retinal Organoids and Eye Transplants
No full textIn-vitro culture systems generally apply homogeneous stimuli and rely on intercellular signaling to guide growth of tissues. However, to derive complex tissue structures such as the human retina, a gradation of certain stimuli is required. The inner retina resides in a hypoxic environment (2% O2) adjacent to the vitreous cavity. From there, oxygenation levels rapidly increase towards the outer retina (18% O2) at the choroid. We developed a retinal organoid chip allowing the maturation of inner and outer retinal cell phenotypes. The chip is assembled from a micro-milled acrylic slide, a gas-permeable film, a cover glass, and double-sided adhesives. The 55 culture wells, connected by a singular channel, each hold one retinal organoid. A sodium sulfite solution provides the chip with an oxygen leaching channel and a push/pull syringe pump creates a 50 µL/hour continuous flow of culture medium though the bioreactor. Retinal organoids are placed in the wells exposed to the oxygen gradient for the duration of 20 weeks. The gas diffusion throughout the culture medium resulted in an oxygen concentration gradient along the z-axis. Retinal organoids are successfully differentiated and present both inner and outer retinal cell phenotypes. This open-well retinal organoid chip is easily accessible for downstream analysis, establishes a steep oxygen gradient and allows high-throughput retinal organoid culture. It will help retinal organoids mature into the complex structure to use them for disease modeling and drug testing. Furthermore, the culture system contains a holder setup to facilitate the use of microfluidics during culture and allows transport to a microscope for live imaging. Continuous culture medium flow provides a stable environment without changes in pH due to waste secretion of organoids. In addition to retinal organoid culture, this bioreactor can also be used for other applications that benefit from an oxygen concentration gradient.</p
Fluid Dynamics of Ciliated Marine Invertebrate Larvae Under Confinement
No full textCilia and ciliary-driven flows are ubiquitous in biological systems ranging from unicellular organisms like Paramecium to higher animals like humans. Here, we investigate the ciliary-driven flow fields generated by marine invertebrate larvae of sea star and sea urchin. Understanding the physics of ciliary-driven flows in these larvae are important for a variety of reasons. First, the flow regime belongs to low-to intermediate Reynolds numbers (0.1 to 1), where the fluid dynamics is not yet fully understood, hence this study would help to bridge the gap. Second, dysfunction in ciliary motility may lead to chronic diseases, so understanding ciliary-driven flows can help diagnosis and develop therapies.This thesis is focused on addressing an important aspect of ciliary-driven flows: the effects of confinement on the flows generated by microorganisms. We study sea star and sea urchin larvae with simple to complex geometries and quantify their flow fields by systematically varying the confinement height. We demonstrate that the number of vortices around these larvae change with the confinement strength. Moreover other flow parameters such as vortex size, velocity and rate of decay of velocity depends upon the confinement strength. In addition, the different types of larvae studied under confinement reveal that the flow field also depends upon the larval body plan and local morphology. Further, we showed that the results are in good agreement with a low Reynolds number based theoretical model based on superposition of Stokelets.Finally, we applied our techniques to quantify the flow fields generated by chemically treated sea urchin larvae, and Xenopus tadpoles with a specific ciliary motor protein knockdown. Our findings are broadly applicable to understanding and quantifying fluid flows generated by a wide range of ciliated organisms with complex body plans and morphologies from micrometer to millimeter scales
Navigating Caregiving Challenges: An Intersectional and Mixed-Methods Analysis of Resilience among Family Cancer Caregivers
No full textFramed by the Communication Theory of Resilience (CTR) and intersectionality framework, this explanatory sequential mixed-methods study examined how family cancer caregivers with diverse identities experience and enact communicative resilience. In Phase 1, a U.S.-based online survey (N = 240) assessed caregivers’ resilience and posttraumatic growth (PTG), producing four profiles: Vulnerable Reflectors (high PTG-low resilience), Survival Seekers (low PTG-high resilience), Adaptive Strivers (high PTG-high resilience), and At-Risk Strugglers (low PTG-low resilience). In Phase 2, twenty semi-structured interviews were conducted across these profiles to explore resilience triggers, resilience processes, and coping strategies.Findings revealed five common resilience triggers that intersected across gender, race/ethnicity, and socioeconomic status, often emerging simultaneously rather than sequentially. While some communicative processes stabilized caregivers, others created additional strain when structural resources were lacking. Notably, resilience and PTG followed divergent patterns. High PTG was often rooted in meaning-making through relational talk, whereas high resilience centered on routine-based coping. Based on these findings, we propose the concept of resilience-switching—the fluid movement between anticipatory and reactive caregiving responses—as a micro-temporal mechanism within the resilience construct. This concept refines CTR by emphasizing temporal flexibility and structural constraints in communicative adaptation.Together, the results suggest that resilience is not a uniform process but one shaped by identity, context, and communicative access. The study offers theoretical contributions to CTR and practical guidance for tailoring intervention tools for diverse family cancer caregivers.</p