MEDICA@MUSC (Medical University of South Carolina)
Not a member yet
1558 research outputs found
Sort by
Palmitic Acid-Rich Diet Induced Cerebrovascular Tau Pathology Contributes to the Development and Progression of Cognitive Impairment
No full textPalmitic acid (PA) is the most abundant saturated fatty acid in the human body, playing a critical role in multiple metabolic processes. Epidemiological studies unequivocally demonstrate that diets high in saturated fatty acids and elevated levels of palmitic acid are directly associated with diminished cognitive function. PA is sourced both from dietary intake and synthesized through de novo lipogenesis in the liver, and it possesses the remarkable ability to cross the blood-brain barrier. This capability increases the fatty acid pool within the brain, ultimately influencing cognitive health. Importantly, palmitic acid (C16:0) has been linked to severe neurodegenerative processes, most notably to the neuronal hyperphosphorylation and deposition of tau protein. Given that cerebrovascular dysfunction is one of the earliest pathologies detected in dementia, our novel hypothesis is that a PA-rich diet mediates neurovascular dysfunction in part by cerebrovascular tau hyperphosphorylation without neurodegeneration, leading to cognitive impairment. To rigorously test this hypothesis, we implemented a comprehensive approach to evaluate both physiological and cognitive functions over time, supported by lipidomic, transcriptomic, molecular, and biochemical studies. In a preclinical murine model exposed to a novel PA-rich diet, significant cerebrovascular tau phosphorylation (p-tau), neurovascular uncoupling, and behavioral dysfunction were observed as early as twelve weeks. Over time, the behavioral dysfunction progressed into cognitive impairment, coupled with sustained structural and functional cerebrovascular deficits as determined by transmission electron microscopy and Laser Doppler flowmetry. PA-rich diet didn’t promote cerebrovascular p-tau accumulation associated behavioral deficits in a global tau knockout (KO) murine model, underscoring the importance of p-tau accumulation in the cerebrovasculature. Moreover, another transgenic animal harboring the humanized tau has shown accelerated cognitive and neurovascular impairment after being on the same PA-rich diet for 12 weeks. Collectively, using a PA-rich diet in three different mouse models and integrating molecular, biochemical, and functional methodologies, we provide novel evidence that dysregulation of tau protein in the cerebrovasculature leads to structural and functional impairments, which are likely precursors to neurodegeneration
E3 Ubiquitin Ligase UBR5 Promotes Proteasomal Degradation of Oncogenic Substrates in Ovarian Cancer Metastasis
No full textOvarian cancer is the most lethal gynecological cancer and one of the leading causes of cancer-related deaths. In the United States, it is estimated that over 20,000 new cases and over 12,000 deaths will occur in 2025. The high mortality rate can be attributed to both acquired drug resistance and metastasis. The study of metastatic ovarian cancer is necessary to determine novel mechanisms that can be targeted to improve the standard of care for ovarian cancer. We have previously shown that the E3 ubiquitin ligase UBR5 promotes cisplatin resistance in ovarian cancer cells and xenografts. Proteomic screening revealed a novel substrate of UBR5 that has been associated with ovarian cancer progression. In this study, we hypothesize that UBR5 promotes proteasomal degradation of this novel substrate concomitant with an additional oncogene to facilitate ovarian cancer metastasis. To elucidate this mechanism, we performed gene knockout or knockdown in an ovarian cancer metastasis model to assess the effects on cell morphology, proliferation, and gene and protein expression by using imaging, cell viability assay, RT-qPCR, and immunoblotting. Our results demonstrate a novel role of UBR5 in promoting proteasomal degradation of two substrates in ovarian cancer metastasis and suggest a novel gene regulatory mechanism that may contribute to metastasis in ovarian cancer
Mouse Model of Post-Traumatic Stress Disorder Demonstrates Negative Alterations of Cardiac Homeostasis
No full textPost-traumatic stress disorder (PTSD) is a disabling psychological disorder characterized by chronic symptoms of intrusiveness, avoidance, and hyperarousal after a traumatic event. Patients diagnosed with PTSD have a two-times higher risk of experiencing an adverse cardiac event like myocardial infarction or stroke compared to patients without PTSD even after adjustment for confounding factors like diabetes, hypertension, and depression. While there are multiple clinical observations addressing a correlation between PTSD and cardiovascular disease (CVD) outcomes, basic science studies investigating potential mechanisms for the connection between PTSD and CVD are few.
The goal of this study was to define a scoring method using a murine model of cued fear conditioning (inescapable foot shock, IFS) to distinguish the cardiovascular phenotype of a PTSD-like behavioral phenotype. Controls, non-responders (NR), and PTSD-like mice at 2 time points [4-weeks and 8-weeks post-IFS] were compared to evaluate left ventricular structure and function along with physiological changes associated with PTSD-like behavioral symptomology.
At 8-weeks post-IFS, both male and female PTSD-like mice demonstrated prolonged isovolumetric relaxation time, whereas females exhibited additional signs of diastolic impairment, including elevated E/e′ ratio, increased left atrial diameter, and reduced ejection fraction compared to controls. The elevated fibrotic genetic and protein expression observed in female PTSD-like mice is likely contributing to LV stiffening and impaired relaxation in female PTSD-like mice.
Sex-specific immune alterations were also observed. Resident cardiac macrophages increased in male PTSD-like mice at 4-weeks post-IFS and in both sexes by 8-weeks. In contrast, splenic neutrophils were elevated and circulating B- and CD8+ T-cells were reduced exclusively in female PTSD-like mice. Single-cell RNA sequencing of bone marrow revealed enhanced activation of PTSD-like neutrophils, suggesting a potential priming of neutrophils that may promote cardiac pathology.
Collectively, these findings identify possible interconnected immune and fibrotic mechanisms that may underlie PTSD-associated cardiac dysfunction in a sex-dependent manner. This study provides novel mechanistic insight into the cardiovascular consequences of PTSD and establishes a foundation for future investigations aimed at understanding and mitigating CVD risk in trauma-exposed populations
Creating Caregiver Education Resources forCaregivers of Adults with Alzheimer’s and Dementia
No full textThis project addressed the significant issue of caregiver burden experienced by individuals caring for loved ones with Alzheimer\u27s disease and dementia. The purpose of this quality improvement project was to develop simplified and easy-to-understand educational resources for these caregivers, focusing on strategies for managing loved ones, community resources, and physical and emotional wellness. The project aimed to enhance the caregiving experience and reduce caregiver burden by increasing their knowledge of physical and cognitive changes, available resources, and self-care strategies.
The project involved caregivers and staff at a dementia-specific medical-model day memory care program. The primary deliverable was a four-part “Caring for the Caregiver” resource covering caregiver burnout, prevention tips, self-care integration, and long-term self-care planning. These resources included educational information, lists of additional resources, and interactive components. Feedback from caregivers led to the creation of additional support materials.
The project\u27s anticipated impact includes increased caregiver knowledge and improved physical and mental well-being, ultimately benefiting the members receiving care. The resources are available in physical and digital formats at the site, and staff education ensures the project\u27s sustainability
Social-Emotional Activities to Decrease Problematic Behaviors, Ages 3-5
No full textThe purpose of this capstone experience is to implement social-emotional activities into specific classrooms of a local daycare center for preschoolers ages three to five years old that are both easy to implement by the teachers and are well received by the children. The overall goals of this capstone are as follows: To develop social emotional training materials for teachers. To help teachers develop evidence-based strategies to develop social-emotional learning in the classroom. To gain a thorough understanding of the social emotional milestones in children ages three to five and how those behaviors manifest in the classroom to facilitate proficiency of skills in the classroom. To gain a thorough understanding of the typical classroom management techniques and how those may potentially facilitate or hinder social emotional development. To gain self confidence in the ability to effectively collaborate with teachers/staff to create effective and practical solutions to classroom challenges. The social-emotional activities that were instilled into these classrooms were positively received by the teachers and enjoyed by the children from conversations with the teachers. Through those conversations, they included reported days of increased knowledge and actions of sharing, using kinder words, and not hitting others by most of the children. In the beginning, the activities were chosen and trialed to target the most common problematic behaviors. Due to teachers leaving and being replaced, it resulted in changes in their current schedules for a certain number of days and the social-emotional activities were put in the back seat. So, additional activities and resources that cover the same topics of focus have been integrated into their existing schedule to help achieve a consistent implementation of these learning objectives to improve and/or facilitate the social-emotional development of these children
Apical Membrane Dynamics: Insights into Intestinal Homeostasis and Mucosal Injury
No full textThe intestinal epithelium functions as a dynamic barrier, relying on precise apical membrane organization to maintain homeostasis and respond to environmental challenges. While apical trafficking, glycoprotein localization, and microvillar organization are critical for barrier integrity, the molecular mechanisms regulating these processes and their roles in inflammation and mucosal defense remain incompletely understood. This dissertation addresses these gaps in knowledge by investigating Myosin 5b (MYO5B), mucosal defense glycoproteins, and adhesion proteins involved in microvillar organization. I demonstrate that MYO5B plays a key role in colonic barrier function by regulating the mucus layer and limiting susceptibility to inflammation. In a heterozygous MYO5B mouse model, reduced MYO5B expression leads to a thinner mucus layer, increased bacterial permeability, and exacerbated injury in DSS-induced colitis. MYO5B-deficient cells and organoids exhibit heightened proinflammatory responses, suggesting that even partial MYO5B loss predisposes the intestine to inflammation, with implications for inflammatory bowel disease (IBD). Further, I show that MYO5B is critical for the apical trafficking of mucosal defense proteins, MUC13 and DMBT1. MYO5B deficiency in mouse models results in intracellular accumulation of these glycoproteins, which is maintained in vitro in epithelial-only organoid cultures. Additionally, MYO5B-inhibited cells have impaired wound healing in a scratch assay, suggesting that defective glycoprotein trafficking may disrupt epithelial regeneration. Beyond MYO5B, I investigate inflammation-induced changes in apical membrane composition. Clostridioides difficile infection (CDI) upregulates IL-22, promoting the expression of adherent mucins MUC1, MUC4, and MUC13 and altering N-glycosylation in patient samples and mouse models. These findings suggest that IL-22 enhances epithelial defense against CDI by modifying the mucosal surface to resist infection and promote repair. Finally, I investigate the structural adaptations of chemosensory intestinal tuft cells, revealing their enrichment with protocadherins, CDHR2 and CDHR5. Within tuft cells, these adhesion molecules localize to the apical membrane, suggesting a role in organizing microvilli to support sensory and defense functions. Together, these findings illustrate how apical membrane dynamics shape intestinal homeostasis, mucosal defense, and epithelial repair. By elucidating these mechanisms, this dissertation provides new insights into intestinal epithelial regulation and identifies potential therapeutic targets for inflammatory and infectious diseases
A Theoretical Model of Clinical Documentation Burden: Exploratory Factor Analysis Investigating Usability, Effort, and Perceived Burden Among Healthcare Providers
No full textThis study investigates the clinical documentation burden experienced by healthcare providers, focusing on the usability, effort, and perceived value of clinical documentation tasks. The main theory explored in the study is the concept of intrinsic motivation and task value perception, which is linked to professional dissonance and burnout, providing a framework to understand the clinical documentation burden experienced by clinicians. It aims to understand the relationship between these factors and the clinician experience of burden with the goal of developing a comprehensive conceptual framework. To establish an understanding of clinical documentation burden, a scoping literature review was conducted using four electronic databases covering studies from 2014 to 2024. The review was guided by the PRISMA-ScR guidelines and utilized the Covidence software for systematic management. The review identified key factors contributing to documentation burden, including EHR usability issues, regulatory requirements, and payer-driven demands. The analysis discusses how perceived task value significantly influences the burden experienced by clinicians. A newly constructed questionnaire based on a scoping review of the literature was used, incorporating elements from established instruments. Data were collected from a cross-sectional, nonexperimental survey using a convenience sample of healthcare providers. Descriptive and exploratory factor analysis was performed to identify significant findings and develop the Clinical Documentation Burden Model. The analysis revealed three main factors underpinning clinical documentation burden: poor usability, perceived task value, and excessive mental exertion. These factors were significantly correlated with professional dissonance and burnout, underscoring the complex interplay between design challenges, task engagement, and cognitive load. The resulting theoretical model highlights the importance of aligning documentation tasks with provider values to mitigate burden. The study describes the critical impact of documentation burden on healthcare providers and suggests that consideration of psychological factors into documentation processes could alleviate operational strain and reduce professional dissonance and burnout. The developed model provides a framework for future interventions and calls for empirical studies to validate its applicability across diverse healthcare settings
Supporting Elementary Educators through a Nervous System Regulation and Social-Emotional Learning Skills Workshop Intervention: An MUSC Capstone Project
No full textTeachers have a great influence on developing children’s emotional intelligence, regulatory capacity, and occupational engagement. These professionals also happen to report some of the highest rates of stress, mental health challenges (Agyapong, B. et al, 2022), and burnout (Xie, M., et al, 2022). Providing teachers with education and support on nervous system regulation, social-emotional learning skills, and related topics can improve their ability to manage job stress, enhance modeling and interactions with students, and improve their quality of life. This project aimed to enhance knowledge, provide access to resources, and serve to support elementary educators at an inner-city school in nervous system regulation, social-emotional learning, coping skills, emotional processing, burnout, and classroom application. This intervention took place over the course of a 14-week period with a total of four live and recorded presentation sessions. These sessions were paired with discussions and the provision of various supplemental resources to reinforce content. School staff were given access to a virtual hub for these resources as well as a physical binder of its contents. Data and analysis were collected via qualitative and quantitative methods, including surveys, interviews, and observation. Overall, the majority of participants reported that this series improved their stress management, increased their knowledge, and provided them with resources they planned to continue to refer to. All participants also reported that they felt the information they received would improve their ability to model and interact with their students
The Role of Myosin 5b in Intestinal Health and Disease: From Microvilli Assembly to Colorectal Cancer Progression
Get PDFBackground: Myosin Vb (Myo5b) is an essential molecular motor responsible for delivering diverse cargo to the apical membrane of enterocytes. Mutations in Myo5b cause congenital enteropathies, but its broader role in maintaining the integrity of the intestinal brush border under normal physiological conditions and in disease remain unclear. We hypothesize that Myo5b participates in the assembly and maintenance of the intestinal brush border by transporting members of the intermicrovillar adhesion complex (IMAC) and the xenobiotic efflux pump P-glycoprotein (P-gp) to the apical membrane of enterocytes. We further hypothesize that dysregulation of the myosin chaperone protein, UNC45A, and downregulation of Myo5b play critical roles in Colorectal Adenocarcinoma (COAD). Methods: We used multiple murine models, a swine model, and intestinal organoids that lack functional Myo5b to examine IMAC and P-gp trafficking. Human intestinal tissue was used to determine the localization of P-gp and Myo5b in the setting of intestinal diseases. Functional assays to measure P-gp efflux activity were performed in human organoids and colorectal cancer (CRC) cells. To investigate Myo5b and UNC45A dysregulation in COAD, we used multiple human databases and validated findings in human organoids and CRC cells. Results: In Myo5b deficient models, IMAC components and P-gp were mislocalized from the apical membrane to the subapical domain. Similarly, immunofluorescent staining in human inflammatory bowel disease tissue showed decreased levels of Myo5b and P-gp. The efflux activity of P-gp in CRC cells and organoids was significantly reduced by inhibition of Myosin V and its inhibition decreased cell viability when treated with the chemotherapeutic drug doxorubicin. In COAD, we found that Myo5b mRNA and protein levels were reduced compared to nontumor tissue and identified its promoter region to be hypermethylated in human tissue and in CRC cells. Evaluating UNC45A using the same methods revealed reduced UNC45A protein levels in COAD. We identified upregulated UNC45A targeting miRNAs in COAD tissue and in CRC cell lines. Conclusions: These findings not only define new apical trafficking cargoes for Myo5b but demonstrates its role in maintaining the physical and biochemical barrier of the intestine. Targeting Myo5b mediated pathways could provide new therapeutic strategies for intestinal disorders and cancer
The Feasibility of a Telerehabilitation Screening Protocol for Wheelchair Follow-Up in a Rural Clinic: A Pilot Exploration
No full textObjective: This capstone project aimed to determine the feasibility of a telerehabilitation approach to wheelchair follow-up care coordination within the East Carolina University Student Run Clinic (SRC). Methods: A Wheelchair Follow-Up Protocol was developed and piloted with a student clinician. Guided by the AHRQ Care Coordination Measurement Framework, this 9-week feasibility project was completed in 3 steps: (1) resource and process development, (2) student training, (3) implementation and data collection. Quantitative and qualitative pilot data were collected from the student clinician who completed the Wheelchair Follow-Up Protocol to examine the feasibility and acceptability of the protocol. Questions included items relating to time (Reach Time, Screening Time, and Documentation Time) and ease (Ease of Documenting and Ease of Completing). Results: The student clinician rated both Ease of Documenting and Ease of Completing as Easy. The student clinician reported Reach Time as 0-15 minutes (67%) or 15-30 minutes (33%); Screening Time as 16-30 minutes; and Documentation Time as 0-15 minutes. Conclusion: This quality improvement project supports the feasibility of a telerehabilitation approach to wheelchair follow-up care coordination within the East Carolina University SRC. Further iterations of this process aim to expand the reach to the larger healthcare system and identify gaps in wheelchair follow-up services