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GADOLINIUM-BASED CONTRAST AGENT (GBCA) DISTRIBUTION IN THE CSF AFTER CISTERNAL AND VENTRICULAR INJECTIONS IN A LARGE ANIMAL MODEL OF HYDROCEPHALUS
Get PDFCerebrospinal fluid (CSF) circulation plays a critical role in the clearance of metabolic waste products from the brain. Dysfunctional CSF dynamics are implicated in various neurological conditions, including hydrocephalus. While recent discoveries of the glymphatic system in rodents have revolutionized the understanding of brain clearance mechanisms, interspecies differences remain inadequately explored. Given recent interests in the glymphatic system and the clinical relevance of Gadolinium-based contrast agents (GBCA) deposition, studying GBCA distribution in canine CSF provides valuable insights into potential clinical applications and pathological alterations of CSF dynamics.
This study utilized an optimized T2-weighted turbo-spin-echo (TSE) MRI sequence to evaluate GBCA distribution after cisternal and ventricular injections in six dogs. For one of the animals, an additional experiment was performed to compare GBCA dynamics before and after induction of obstructive hydrocephalus. A total of 34 anatomical regions of interest (ROIs) were analyzed to quantify temporal and spatial variations in MRI signal intensities following GBCA administration.
Both cisternal and ventricular injections resulted in a decrease in MR signal intensity post-injection, indicative of GBCA distribution within the CSF spaces. For ventricular injections, significant signal reduction predominantly occurred in regions adjacent to the ventricles. In contrast, cisternal injections demonstrated a more widespread pattern of signal reduction across multiple brain regions over time. In the induced obstructive hydrocephalus model, the recovery of signal intensity to baseline levels was notably faster compared to the pre-hydrocephalus state, suggesting altered CSF circulation dynamics under pathological conditions.
Our findings highlight distinct spatial-temporal patterns of GBCA distribution following cisternal and ventricular injections, and demonstrate the impact of pathological states such as obstructive hydrocephalus on CSF dynamics. This work underscores the importance of utilizing large animal models to better understand glymphatic function and contrast agent pharmacokinetics, offering insights that may inform future clinical imaging and diagnostic strategies
Bridging Perception and Performance: Generating, Calibrating, and Evaluating Multimodal Sensory Stimuli
No full textHuman sensorimotor control is inherently multimodal: our actions are shaped not by one sense alone, but by the integration of various sensory channels. Yet most motor rehabilitation tools and experiments still rely on single-modality feedback, overlooking the richness of our perceptual systems. This thesis investigates how multimodal sensory cues can be perceptually calibrated and effectively integrated to augment motor performance and inform the design of more intuitive human-machine interfaces.
We begin by establishing a principled method for calibrating different sensory modalities. Through a cross-modal matching paradigm, we demonstrate how visual and haptic stimuli can be perceptually equalized within individuals in motor control tasks. We further introduce a reduced-order protocol that significantly shortens experimental time – reducing duration by over 80% – while preserving perceptual mapping accuracy, offering a step toward practical clinical implementation.
Building on this perceptual framework, we evaluate how visual, haptic, and combined (visual + haptic) feedback affect motor performance in a virtual precision grip task. We assess objective metrics like success rate and force regulation, alongside subjective measures of workload. Our results reveal that multimodal feedback is not universally beneficial: while some participants leveraged combined cues to enhance performance, others relied on a single dominant modality, particularly vision. Even when perceptually balanced, multimodal cues may offer limited advantages if not aligned with task demands or the individual's inherent integration methods.
Lastly, to enable multimodal tactile feedback in wearables, we introduce “pneumatactors” – soft pneumatic actuators that deliver both transient and continuous haptic stimuli. Unlike traditional devices, pneumatactors independently target both fast- and slow-adapting mechanoreceptors at the same skin location, enabling more naturalistic tactile feedback. We characterize their mechanical behavior and actuation dynamics, laying the groundwork for applications in human-robot interaction.
Together, these studies offer a cohesive framework spanning perception, performance, and hardware. In addition to practical tools for multimodal rehabilitation, this thesis offers conceptual insight: more sensory stimuli are not inherently better for motor learning; rather, the true benefits depend on how humans perceive and integrate these cues. We suggest that bridging perception and performance – through frameworks centered on perceptual alignment – is essential for transforming multimodal feedback into meaningful, functional improvement
INVESTIGATING Β-1,4-GALACTOSYLTRANSFERASE V KNOCKOUT IN HCT116 CELLS VIA CRISPR-CAS9: INSIGHTS INTO CELL PROLIFERATION AND CANCER PROGRESSION
No full textβ-1,4-Galactosyltransferase-V(GALT-V) is a glycosyltransferase enzyme involved in the synthesis of glycosphingolipids and glycoproteins, both of which are essential for regulating cell adhesion, signaling, and proliferation. Recent studies have identified GALT-V as significantly overexpressed at both the gene and protein levels as much as 6.5-fold increase in colorectal cancer (CRC) tissues compared to adjunct normal tissue suggesting it may play a role in tumor progression and metastasis. To evaluate its functional role, we performed CRISPR-Cas9-mediated knockout of GALT-V in HCT116 cells using high and low efficiency single guide RNAs (sgRNAs). GALT-V protein levels were reduced by 3.25 fold in the high-efficiency KO and 1.27 fold in the low-efficiency KO compared to untreated placebo cells as measured by ELISA. At the transcriptional level, qPCR revealed a 12-fold and 5.28-fold reduction in mRNA expression in high and low-efficiency KOs respectively. In addition, expression of key CRC-associated genes including Kirsten rat sarcoma viral oncogene homolog (KRAS), adenomatous polyposis coli (APC), and programmed death-ligand 1 (PD-L1) were analyzed following GALT-V knockout to assess downstream molecular effects. The high-efficiency guide resulted in a significant decrease in the mRNA levels of all three genes. Interestingly, the low-efficiency guide showed a greater reduction in APC mRNA levels compared to the high-efficiency knockout. This may be due to increased off-target effects from the low-efficiency guide, potentially leading to deletions in other regions of the genome. Additionally, cell viability and proliferation were measured using MTT assays, confluency tracking, immunofluorescence, and thymidine incorporation analysis—all of which showed significantly reduced GALT-V expression in the high-efficiency knockout cells. Both mRNA and protein levels of PD-L1 were reduced following GALT-V knockout, suggesting a potential role for GALT-V in regulating PD-L1 through n linked glycosylation affecting the stabilization of the protein. This study demonstrates that GALT-V promotes CRC cell survival and proliferation, potentially through modulation of KRAS and PD-L1. The downregulation of PD-L1 following GALT-V KO suggests there could be a mechanistic link between GALT-V mediated glycosylation and immune evasion in CRC. These findings highlight GALT-V as a promising molecular target for therapeutic intervention in colorectal cancer
Neural Image Processing and Imaging Platform Optimization for Two-Photon Fiberscope Imaging in Freely Moving Rodents
No full textHead-mounted two-photon (2P) imaging enables high-resolution recordings in freely behaving rodents, but rotational resistance and payload weight can still constrain natural movement and confound neural data. To address these issues, we developed a proactive optoelectrical commutator (pOEC) that senses and compensates for tether torque in real time, allowing unrestricted head rotation. Experiments show that the pOEC preserves natural movement and reveals distinct motor cortex activity compared to tether-restricted conditions. To further reduce burden, we introduced a buoyancy-assisted method using helium balloons to offset up to 7 g of head-mounted weight. Combined, these solutions provide a lightweight, rotation-free platform for functional neuroimaging under near-natural behavioral conditions
Robust Planning and Coordination under Uncertainty for Aerial Manipulation and Multi-Robot Teams
No full textRobotic system planning combines information from various sources, including information about the environment, dynamical models for the robotic system, and sensor models and measurements. This information allows the robotic system to autonomously reason about the world and develop a sequence of actions to achieve a goal. Uncertainty is inherent in each of the sources of information that form a robotic system's internal and world models. Thus, robust approaches for operating in complex real-world environments under uncertainty are necessary for robots to be deployed in real operational scenarios. In this dissertation, I investigated methods for planning and coordination under various forms of uncertainty to enable more reliable operation of robots. To advance the utilization of robots in a broad spectrum of scenarios, I developed general algorithms that can be applied across the field of robotics. I demonstrate these algorithms and methods in two application spaces in particular: aerial manipulation, where an aerial vehicle manipulates objects in its environment, and multi-robot teaming, where a group of robots coordinate to accomplish a common goal. In particular, I present an iterative algorithm for identification of dynamical model parameters in the presence of unmodeled dynamics, such as the imbalance caused by grasping an object with unknown mass. I then explore high-precision prehensile aerial manipulation in the form of pick-and-place experiments with visual object pose estimation, visual odometry, and motion planning computed onboard a small form factor vehicle. For non-prehensile aerial manipulation, I introduce a generalized deep reinforcement learning pipeline for learning robust robot control policies when contact dynamics with the environment are unknown. Finally, I present a compact mixed-integer programming algorithm for multi-robot team coordination and planning on dynamic topological graphs, including an embedding for planning under environmental uncertainty with a heterogeneous team. These algorithms and methods enable efficient and effective planning in the presence of various forms of uncertainty in estimation, perception, and the environment. Through extensive experimental results in simulation and hardware, I demonstrate the robustness of the proposed approaches to achieve prehensile and non-prehensile aerial manipulation and multi-robot team coordination under uncertainty
Emergency Medicine Service Encounters for Obstetric Patients in North Carolina: The Impact of Rurality, Patient Demographics, and the COVID-19 Pandemic on Transport Times and Volumes
Get PDFEmergency medical services (EMS) are a vital component of the health service continuum, but they are often overlooked as an entry point for patients accessing care. Obstetric encounters are rare compared to other types of EMS activations (cardiac, trauma), but for patients who rely on EMS clinicians during an obstetric emergency, they can be life-saving. This thesis attempts to fill in gaps in existing EMS research to focus specifically on obstetric emergencies in the prehospital setting.
This study focused exclusively on EMS encounters in the state of North Carolina from January 2021 through December 2022 (research aims one and two) and January 2021 through March 2023 (research aim three). The first aim of the thesis was to examine variations in encounter times for obstetric patients according to the rurality of the incident location. The second aim of the thesis was to examine variations in encounter times based on patient demographics including age and race. Finally, the third aim sought to examine variations in encounter times and volumes of encounters as affected by the COVID-19 pandemic. For all three aims, several components of the activation times were examined in addition to the total encounter time: initial activation, response time, scene time, and transport time.
The study identified statistically significant variations in activation times for obstetric emergencies based on the rurality of the patient incident, patient race, and patient age group. The study also identified small but significant variations in encounter times and volumes in relation to volumes of COVID-19 deaths from January 2021 to March 2023
How to Determine Nonwoven Material Durability: Addressing Challenges in Abrasion Testing to Improve Methodologies and Interpretation of Results
No full textRating abrasive resistance of low basis weight nonwoven materials has been challenging with
the existing standards and methodologies. The structure and compositions of nonwovens
was investigated to gain insight on the web structure present in these materials. The web
structure determines the elasticity of a material and is disrupted when it is abraded. This
indicates that abrasion affects the elasticity of a material. The existing mass relationship
to abrasion was investigated and the correlation between Young’s modulus and Martindale
abrasion cycles was statistically determined to be stronger along with having less variance in
the data. Thus, a new method of rating these materials has been developed in which the
Young’s modulus of a material is determined after certain intervals of Martindale abrasion
cycles to construct a cubic model. The resistance to abrasion can be determined using the
developed models and is generally applicable to low basis weight nonwovens
REMOTE PATIENT MONITORING AND SELF-ADMINISTERED PULSE OXIMETRY TO IMPROVE COVID-19 OUTCOMES IN TEGUCIGALPA AND COMAYAGÜELA, HONDURAS: IMPACT, ACCEPTABILITY, AND IMPLEMENTATION FIDELITY
No full textIntroduction: The COVID-19 pandemic strained healthcare systems, creating an urgent need for approaches to discharge and remotely monitor stable, but high-risk patients. In collaboration with the Honduran Secretariat of Health, we conducted a trial evaluating remote patient monitoring with versus without self-administered pulse oximetry. The study assessed clinical impact, acceptability, appropriateness, and implementation outcomes.
Methods: This dissertation contains three manuscripts informed by the Comprehensive Framework for Implementation Research. The first manuscript presents the results of a pragmatic, randomized trial that examined intervention impact on morbidity and mortality among non-hospitalized COVID-19 patients. The second manuscript investigates intervention acceptability and appropriateness from participant and healthcare provider perspectives, grounded in Sekhon et al’s healthcare acceptability framework and Proctor et al’s approach to appropriateness. Guided by Carroll et al’s fidelity framework, the third manuscript examines the influence of implementation strategies, quality of delivery, and participant responsiveness on adherence.
Results: Between March 30, 2022 and January 24, 2023, we enrolled 1,821 COVID-19 positive patients. Vaccination coverage was high with nearly 99% reporting at least one COVID-19 vaccine dose. Adding pulse oximetry increased referrals for clinical evaluation (OR 1.60 [95% CI 1.09 – 2.46], p = 0.018) but not hospitalizations (OR 1.55 [95% CI 0.55 – 4.37], p = 0.401). Adverse outcomes were rare (one death, two ICU admissions, no mechanical ventilation), preventing assessment of mortality.
Acceptability assessments revealed high participant satisfaction, with 94.9% willing to participate again. While participants reported successfully using and understanding pulse oximeters, some healthcare staff expressed concerns about participant comprehension and intervention appropriateness given competing priorities. Participants and providers reported a positive impact on mental health during isolation.
The intervention achieved high implementation fidelity: 97.9% coverage of eligible patients and 97.7% completion of daily monitoring calls. Success was enabled by implementation strategies including culturally-adapted materials, tailored communication strategies, and multi-disciplinary team engagement.
Conclusion: We found that adding pulse oximetry to remote patient monitoring increased care referrals, though low adverse events prevented assessment of clinical impact. The interventions achieved high implementation fidelity and acceptability among participants. These findings suggest potential for leveraging remote monitoring technology to expand healthcare access and identify urgent care needs across emergency and non-emergency settings
EXPLORING COREST INHIBITOR, CORIN, AS A NOVEL STRATEGY FOR TARGETED THERAPY IN RHABDOID TUMORS
Get PDFMalignant rhabdoid tumors (MRTs) are aggressive pediatric malignancies characterized by inactivation of SMARCB1 or SMARCA4, leading to epigenetic dysregulation and poor clinical outcomes. Current therapies yield limited efficacy, highlighting an urgent need for novel treatment strategies. This study investigates the therapeutic potential of corin, a dual inhibitor of LSD1 and HDAC1/2, which disrupts the CoREST corepressor complex—a key epigenetic regulator implicated in maintaining the undifferentiated and proliferative state of MRTs.
Using MRT cell lines (A204, G401, RLM) and a mouse flank tumor model, we demonstrate that Corin remodels chromatin by increasing histone modifications associated with gene activation (H3K4me1, H3K9ac), thereby reactivating silenced differentiation and tumor suppressor genes. Functional assays reveal that Corin significantly reduces cell proliferation, induces apoptosis, and downregulates stemness-associated proteins such as LIN28A/B. Additionally, Corin upregulates neuronal differentiation markers including L1CAM, indicating a shift toward a less malignant phenotype. In vivo, Corin treatment resulted in enhanced chromatin accessibility and increased apoptosis within tumor tissues, supporting its mechanistic activity beyond in vitro settings.
Our findings provide compelling evidence that targeting the CoREST complex with Corin offers a promising epigenetic therapy for MRTs. By modulating chromatin accessibility and altering key oncogenic processes, Corin holds potential for clinical development in the treatment of these otherwise intractable tumors
DEVELOPING A CELLULAR MODEL FOR HEAT SHOCK PROTEIN RESEARCH
No full textHeat shock proteins (HSPs) are essential for maintaining proteostasis, particularly under conditions of cellular stress. As a type I HSP40 co-chaperone, DNAJA2 interacts with HSP70 to regulate client protein folding, trafficking, and degradation. However, the specific role of DNAJA2 in coordinating stress responses remains incompletely understood. To build a foundational model for future functional studies, I generated a DNAJA2 knockout (KO) in human retinal pigment epithelial (RPE-1) cells using CRISPR-Cas9. Three single-guide RNAs (sgRNAs) targeting exon regions of DNAJA2 were designed and cloned into a PX330-based plasmid. After transfection and antibiotic selection, bulk and single-cell clones were screened via Sanger sequencing. Two independent clones, sg3-1 and sg3-2, were confirmed to harbor a clean 1 bp insertion, introducing a frameshift and premature stop codon. While I did not conduct downstream phenotypic assays in this study, this KO model holds strong potential for dissecting co-chaperone-specific functions under proteotoxic stress, including roles in stress granule assembly, client protein regulation, and neurodegeneration-related aggregation. Given RPE-1 cells’ near-diploid genome and high amenability to gene editing and synchronization, this model provides a robust and physiologically relevant platform for studying HSP networks. In summary, this work establishes a validated DNAJA2 KO cell line as a clean, versatile tool to probe the dynamics of protein quality control. This system will be critical for advancing our understanding of HSP40 functions in proteostasis