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Investigating the Function of MCL-1 During Oligodendrocyte Development
No full textOligodendrocytes are the myelinating cells of the central nervous system. Regulation of the early stages of oligodendrocyte development is critical to the function of the cell. Specifically, myelin sheath formation is an energetically demanding event that requires precision, as alterations may lead to dysmyelination. Fatty acid β-oxidation has been shown to be critical for the function of oligodendrocytes. We previously showed that MCL-1, a well-characterized anti-apoptotic protein, is required for the development of oligodendrocytes in vivo. Further, MCL-1 regulates long-chain fatty acid β-oxidation in cancer cells through its interaction with Acyl-CoA Synthetase Long-Chain Family Member 1 (ACSL1), an enzyme responsible for the conversion of free long-chain fatty acids into fatty acyl-CoA esters. Here, we developed novel tools to investigate the function of MCL-1 during oligodendrogenesis. First, we optimized an in vitro system to isolate human stem cell-derived oligodendrocyte progenitor cells (OPCs) and used a motor neuron-oligodendrocyte co-culture system to investigate early stages of myelination. Secondly, we modified CRISPRoff and sgRNA Sleeping Beauty transposon vectors that depend on tetracycline-controlled transcriptional activation to silence the expression of MCL-1, an embryonic lethal gene, in early development of oligodendrocytes. Lastly, to expand our toolkit and modulate activity of MCL-1 in OPCs, we pharmacologically inhibited MCL-1 and elucidated a non-apoptotic function of the protein at this developmental stage. We demonstrate that the mitochondrial network changes in human oligodendrocyte development resemble those reported in mouse tissue. Our findings also point to MCL-1 as a critical factor essential at the OPC stage for proper oligodendrocyte morphogenesis
Bridging the Gap: Junior Achievement’s Role in Shaping Tennessee’s Workforce
No full textThis mixed-methods study evaluates the impact of Junior Achievement (JA) programming in Tennessee on students’ financial literacy, durable employment skills, and career readiness. Based on the analysis of quantitative and qualitative data, the research underscores JA’s effectiveness in preparing students across diverse geographic contexts for economic and career success. The study acknowledges the need for further disaggregated data, longitudinal tracking, and curricular embeddedness in schools. Findings also support JA’s alignment with statewide workforce development goals and recommend integrating state programming into core educational strategies across regions in the state to cultivate equitable, experiential learning that ultimately benefits the school-to-work pipeline.Peabody College of Education and Human DevelopmentDepartment of Leadership Policy and Organization
Kappa Opioid Receptor Activity Underlies Individual Differences in Motivated Behaviors
No full textSince the discovery of the kappa opioid receptor (KOR) and its endogenous ligand, dynorphin, the KOR system has held the curiosity of basic and clinical researchers across disciplines. Recent advances in technologies for measuring and manipulating KOR activity, along with the development of several clinically viable KOR compounds, have poised the field for breakthrough discoveries and treatments. As paradigms shift, it is paramount that lessons from the prior literature are synthesized and passed forward to inform future studies, thus optimizing the ability to translate understanding of the KOR system into evidenced based pharmacotherapeutics. To this end, we directly assess long-standing hypotheses of the KOR field, namely that it is a negative valence system that drives negative reinforcement and that it is persistently upregulated during long term periods of abstinence after chronic alcohol intake. Through this work, we find discrepancies that undermine the canon that the KOR system solely plays a role in negative affective states. Instead, we find that it is involved in valence-independent behaviors through increased exploration of, and motivation for, novel stimuli. We do find evidence that the system remains upregulated during abstinence, but hypotheses on the mechanism by which this would be maintained (i.e. through differential gene expression) are once again undermined by the empirical results. Rather, we find an experience-dependent relationship between transcription and function that calls into question the interpretation of many foundational works in neurobiology. Despite these complexities and discrepancies in KOR function, we find that individual differences in KOR activity can still be leveraged to optimize therapeutic outcomes in the treatment of alcohol use disorder, highlighting the utility of a precision medicine approach.
By calling into question many long-standing hypotheses on KOR/dynorphin function, we highlight missing links in our understanding and apply these new findings to maximize therapeutic efficacy and inform the next generation of KOR research
MC Study of the Impact of Jet Quenching on Energy Correlators in Heavy Ion Collisions (A JEWEL-based Analysis on ENCs for N = 2 and 3)
No full textIn the framework of QCD, energy correlators (ENCs) in jets offer a sensitive
probe of the quark–gluon plasma (QGP) formed in relativistic heavy-ion collisions. We employ the JEWEL Monte Carlo generator to study QGP-induced modifications to ENCs measured on jets reconstructed with the anti-kt algorithm. We analyze both N = 2 and N = 3 correlators to characterize the medium effects on the reconstructed jet. For N = 2, our simulations reveal pronounced enhancements at both large and small angles, in agreement with CMS data. The small-angle enhancement is attributed to the flavor dependence of the initiating parton combined with jet pT selection biases induced by energy loss. For N = 3, we observe almost all the features of the N = 2 case and find that the E3C distribution with respect to RS is far more sensitive to medium enhancement compared to RL. It is noteworthy that the E3C(ϕ) distribution remains largely unaltered at LHC energies, suggesting that its ϕ profile—predominantly set by the first parton splitting—is robust against QGP effects; however, further simulations indicate that medium modifications become observable at RHIC energies. Additionally, we introduce a new (X, Y) coordinate system to map recoil-induced modifications, showing that the enhancement is concentrated along the isosceles region of the particle-triplet triangle, in contrast to the more equilateral pattern expected from the wake effect.Funding provided through DE-SC0024660.
Computation supported by ACCRE at Vanderbilt.College of Arts and ScienceDepartment of Physics and Astronom
Leveraging Electronic Health Records to Advance the Study of Gene-by-Environment Interactions in Psychiatry
No full textLeveraging real-world clinical biobanks to investigate the relationships between genetic and environmental risk factors for mental illness may help direct clinical screening efforts and evaluate genetic effects across environmental contexts. In this thesis, we focused on sexual trauma (ST) exposure, a known mental health risk factor that can be documented in electronic health records (EHRs). We developed an approach to extract ST documentation from the EHR, identified clinical diagnoses and settings associated with ST, and quantified the contributions of ST and polygenic scores (PGS) to risk for schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD).
First, we conducted a search using relevant keywords and phrases to identify disclosures of ST in the Vanderbilt University Medical Center (VUMC) EHR. In a phenome-wide association study, ST disclosures significantly associated with 465 clinical traits, including 90% of the psychiatric diagnoses tested. Next, we examined the clinical settings of ST documentation, finding that documentation occurred primarily in psychiatry (38.4% of notes), primary care (14.6%), and obstetrics/gynecology (14.5%) settings. Finally, in a meta-analysis across VUMC and Mass General Brigham biobanks, we studied the influence of ST on psychiatric risk in the context of genetics. ST exposure and PGS jointly explained 3.8-8.8% of phenotypic variance across traits (schizophrenia, BD, and MDD) and analysis sites. Further, a PGS-by-ST interaction analysis revealed that schizophrenia and BD PGS were more strongly associated with their respective diagnoses in individuals without ST documentation. These associations were robust to confounding by comorbid psychiatric conditions, substance use disorders, housing instability, and the clinical setting of ST documentation (psychiatry clinics).
Taken together, these studies emphasize the public health impact of ST, illustrate the importance of considering settings of ST documentation, and quantify the interplay between ST and genetics in psychiatric disease. The results of the PGS-by-ST interaction analysis suggest that genetic predisposition to psychiatric illness may be less impactful in the presence of a severe environmental risk factor. More broadly, this work demonstrates that EHR-linked biobanks can be valuable resources for studying interactions between genetics and the environment in psychiatry
Murmuring of Alzheimer Caring: Analyzing Social Dynamics in Online Alzheimer’s Disease and Related Dementias Communities
No full textThis dissertation investigates the social dynamics in online Alzheimer’s disease and related dementias (ADRD) communities. As more caregivers turn to online forums to seek support and share experiences, understanding the patterns of interaction and the roles of different contributors becomes increasingly important. Across five aims, this work examines how topic initiators catalyze engagement, how replies affect community participation, how the emotional and linguistic characteristics of posts influence response behaviors, and how AI-augmented models compare with human caregivers and clinicians in providing support.
Methodologically, this study integrates social computing, natural language processing, and causal inference techniques. It introduces novel metrics to assess community dynamics, evaluates the linguistic and emotional dimensions of caregiving discourse, and tests retrieval-augmented generative models within this context. Results highlight the importance of reciprocal interaction, emotional expression, and readability in sustaining community engagement. Moreover, the findings inform the design of hybrid human-AI systems that may supplement caregiving resources in an emotionally intelligent and context-aware manner.
Together, these findings contribute to our understanding of digital health communities and offer insights for future interventions that bridge data-driven models and compassionate caregiving
Orthopedic Implants Integrating Fluidic Pumps and Smart Sensors
No full textThis thesis presents the development of miniature fluidic pumps and biosensors integrated into smart bone implants for post-operative infection monitoring and on demand drug delivery. First, a modular, magnetically actuated screw-based pump and a lockable flexible magnetic valve are proposed to enable controlled drug release. These components are demonstrated in a dental implant platform, whose structure is optimized to ensure effective drug distribution under varying gap sizes and surface geometries, simulating the progression of peri-implant diseases. Second, to enable closed-loop drug delivery in orthopedic implants, a pH-responsive hydrogel sensor, comprising poly[2-(diisopropylamino)ethyl methacrylate] and poly(ethylene glycol)diacrylate (PDPAEMA-
PEGDA) blocks and paired with an optical readout system, is developed to reliably detect synovial fluid pH changes under physiological conditions. This sensing system is integrated into a knee implant. Modular pumps are coupled with microfluidic channels to enable repeatable, non-invasive biofluid sampling and therapeutic delivery. To optimize implant design, two decoupled control strategies are introduced for spatial configuration of the integrated components. Additionally, remote charging and Bluetooth Low Energy (BLE) modules are embedded to support long-term operation and real-time data transmission. A wearable magnetic actuation system is developed to wirelessly control two pumps within the knee implant for fluid sampling and drug ejection. Closed-loop sensing and therapy for infection detection and treatment in knee implants is demonstrated. The system is further validated in a porcine tibial bone model using X-ray imaging to visualize drug delivery. Mechanical testing confirms that the integration of sensors and pumps does not compromise the implant's structural integrity. Overall, this thesis demonstrates multi-functional smart orthopedic implants capable of real-time biosensing and closed-loop therapy. The proposed platform offers a promising approach for long-term monitoring and autonomous therapeutic intervention in orthopedic applications
User-Centered Design of Clinical Decision Support for Personalized Evidence Based Care
No full textClinical decision support (CDS) can improve patient outcomes by balancing competing goals for standardization and personalization. However, problems with CDS user-interfaces (UIs) hinder widespread adoption. In two studies of CDS systems to guide pneumonia and heart failure management in the emergency department, I apply user-centered design methods to evaluate which UI features influence the usability of CDS. I conclude that design features that meet clinician's needs for interacting with an automating technology, and increased use of high-fidelity simulation during CDS development, may improve CDS usability and adoption
Cognitive Behavioral Immersion for Depression in the Metaverse: Exploring the Feasibility of an ‘A La Carte’ Manualized Group Intervention
No full textBackground: Despite the availability of effective treatments, the rising prevalence of depression is largely driven by barriers to access including cost, stigma, and provider shortages. Cognitive Behavioral Immersion™ (CBI), delivered by lay coaches via an avatar-based metaverse platform (Innerworld), presents one scalable solution. This study evaluated the feasibility of an eight-session CBI for Depression course and compared two delivery models: a sequential weekly "Serialized" format versus a flexible, user-driven "A La Carte" format developed via Community-Based Participatory Research (CBPR).
Methods: A mixed-methods quality improvement pilot study was conducted within the Innerworld platform. Participants were Innerworld users (N=229 with baseline PHQ-9 ≥ 10). Data included quantitative measures (PHQ-9 scores, session attendance logs) and qualitative interviews (N=12) analyzed using an adapted Consensual Qualitative Research method incorporating artificial intelligence (“aiCQR”). Analyses compared engagement patterns and initial symptom trajectories between the Serialized and A La Carte delivery models and explored predictors of symptom change.
Results: Delivering the CBI for Depression course proved feasible, although participants only attended two sessions on average. Participation was associated with modest reductions in depressive symptoms over time, albeit with larger drops for highly engaged users presenting with mild to severe baseline symptoms. Within the initial 56-day period, no significant difference was found in the total number of sessions attended between the Serialized and A La Carte groups. However, significant differences emerged in engagement patterns. Serialized participants largely adhered to the linear sequence, whereas the attendance of A La Carte participants was evenly distributed attendance across all sessions. A La Carte participants utilized sessions over longer periods and attended some sessions repeatedly, aligning with preferences for flexibility. Qualitative data highlighted key mechanisms including psychological safety, anonymity, accessibility of CBT tools, peer support, and the impact of guide interaction.
Conclusion: The CBI for Depression course, delivered by lay coaches in a metaverse environment, is a scalable and feasible approach for depression support that is associated with a modest reduction in symptoms of depression that approaches clinically meaningful levels among mild to severely depressed participants with greater engagement. The flexible A La Carte delivery model may better accommodate user preference for autonomy and on-demand access, although engagement continues to be a problem for many. This novel approach, developed through direct feedback from individuals with lived experience, may confer unique benefits to individuals with depression. These findings present an alternative to conventional "once-per-week" structures and suggest user-centric, flexible models warrant tests of efficacy through randomized controlled trials
Interprofessional Education to Improve Team Performance
No full textSchool of Nursing Doctor of Nursing Practice Program ProjectPURPOSE:
This innovation project tested the effect of interprofessional education (IPE) on clinical team performance and on a specific patient harm indicator, peripheral intravenous infiltration and extravasation (PIVIE) rates in neonates.
METHODS:
In November 2024, five nurses, one physician, one dietitian, one pharmacist and two quality improvement specialists practicing in Nemours Children’s Hospital, Delaware’s NICU collaborated with the project leader to design an educational activity focused on PIVIE prevention. This team’s recommendations for building PIVIE prevention knowledge and increasing interprofessional competencies in the areas of teamwork, role clarity, teamwork and shared values culminated in delivery of six educational sessions. A total of 53 participants that included nurses, providers, pharmacists, dietitians, and students attended the educational sessions. Participants completed pre- and post- tests assessing PIVIE prevention knowledge as well as surveys about changes in their self-assessed interprofessional competencies.
RESULTS:
The project resulted in several positive outcomes, including improvement in interprofessional competencies and a gain in knowledge about PIVIE prevention, with an average pre-test score of 77% and an average post-test score of 89%. Following completion of the interprofessional education sessions, PIVIE rates dropped to zero and were sustained at that level for two consecutive months. Feedback from post-activity evaluations attests to the value of intentionally including multiple disciplines in a shared learning activity. This approach promotes respect for the expertise of others and increases the team’s effectiveness in delivering safe, high-quality care.
IMPLICATIONS FOR PRACTICE:
To promote development of interprofessional competencies, clinicians practicing in high-acuity settings should partner with clinical educators to design IPE activities focused on identified learning needs. As new clinicians are hired, incorporating IPE into orientation curricula is also recommended. High-functioning teams improve organizational culture and drive a focus on patient safety, with the potential to reduce patient harm as well as cost