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Genetic Studies at the Intersection of Alcohol Use and Pain
No full textAlcohol use disorder and pain are complex public health concerns affecting millions of people, and these conditions are often characterized by a bidirectional relationship. People experiencing pain may drink alcohol for its analgesic effects. In turn, excessive consumption of alcohol can lead to conditions that cause pain, leading to an escalating feedback loop of pain and alcohol use. Negating this cycle requires a nuanced understanding of the mechanisms underlying alcohol analgesia, which are presently not fully understood. The Miles and Damaj labs have previously shown that ethanol-induced antinociception is moderately heritable in mice, indicating a genetic component to the trait. Here we identify specific genes and pathways contributing to these analgesic effects by leveraging complementary behavioral genetics and time-dependent brain gene expression studies. We assayed strains from the BXD panel of recombinant inbred mice to highlight genomic loci linked with post-ethanol thermal nociception and ethanol analgesia-like responses, then prioritized positional candidate genes in these regions with a battery of systems genetics approaches. Our results reveal Myo6 as a strong ethanol analgesia candidate gene through combined evidence of our present work, historic BXD gene expression correlations, roles for the gene in ethanol consumption in other rodent models, and significant associations in human GWAS literature. We additionally describe correlations between post-ethanol nociception and the expression of genes implicated in myelination, protein transport, and other biological processes that could be modulating ethanol analgesia. Finally, we investigate transcriptomic profiles of two common pain conditions, alcohol- and chemotherapy- 2 induced peripheral neuropathy, to characterize toxin-specific and overlapping mechanisms of pathophysiology. The work in this dissertation contributes to our understanding of both ethanol as an analgesic and the transcriptomic correlates of two pain conditions, and it prioritizes specific targets for future research into these phenotypes
Devices and Methods for the Efficient Delivery of Surfactant Aerosol Therapy to the Lungs of Infants
No full textThis research project focuses on non- and minimally-invasive pharmaceutical aerosol systems for low- to high-income countries that improve the delivery of dry powder aerosols to the lungs of neonates with an emphasis on surfactant aerosol therapies to treat respiratory distress syndrome (RDS), a significant advancement compared with the current approach of high-risk intubation and lung instillation of high-volume liquid boluses. Several key components and strategies have been combined to achieve this goal: (1) state-of-the-art infant air-jet dry powder inhaler (DPI) technology, (2) engineered spray-dried powder formulations, (3) an excipient enhanced growth (EEG) strategy for regional dose targeting and efficient upper airway transmission, (4) advances in patient interface design, and (5) in vitro methods (such as airway pressure modeling using simulation of pulmonary mechanics (PM), quantification of regional deposition, and aerosol size characterization) to ensure realistic testing conditions and elucidate critical transport dynamics. The first objective required development of the infant air-jet DPI aerosol delivery system (iDP-ADS), which uses a direct-to-infant (D2I) strategy, with a bifurcating dual-prong nasal interface for the administration of a model spray-dried albuterol EEG formulation. Using a co-flow approach with a flexible ergonomic prong design, lung delivery efficiencies of 34% and 45% (based on loaded dose; compared to 0 – 14% with other systems) were achieved in full-term and 34-week gestational age (GA) preterm infant airway models, respectively, with age-appropriate resistance and compliance while maintaining targeted positive end-expiratory pressure (PEEP) between 4 – 6 cm H2O and peak inspiratory pressures (PIPs) below 25 cm H2O. Furthermore, the hygroscopic growth of a novel synthetic lung surfactant EEG (SLS-EEG) powder formulation was assessed using physiologically-realistic thermodynamic conditions, revealing a diameter growth ratio of 1.7 (and mass increase ratio of 5-fold) following particle residence times consistent with a breath cycle and final aerosol mass median aerodynamic diameter of 3.11 µm for enhanced alveolar retention. The second objective resulted in a first-of-its-kind laryngeal mask airway ADS (LMA-ADS) capable of delivering ~22% and ~29% (based on device-loaded dose) of an SLS-EEG powder to the tracheal filter of a preterm infant nose-throat in vitro model with and without PM, respectively, after the development and optimization of a co-flow design. The third objective integrated bubble CPAP into the LMA-ADS for different levels of pressure support: termed open and full pressure assistance. Both configurations, regardless of the level of PEEP, air source (an electromechanical timer for high-resourced settings or a hand actuator for low- and middle-income countries), use of a breath-hold, or device/mass loading combination, produced similar aerosol transmission (~20%) during timing of device actuation with the beginning of inhalation and demonstrated safe operating parameters. In summary, this work contributes multiple platforms for rapid and efficient administration of dry powder surfactant aerosols to the lungs of premature infants in combination with providing critical respiratory ventilation support that maintains lung pressures within targeted ranges
PlzA RNA Chaperone Activity in Borreliella burgdorferi is modulated by c-di-GMP
No full textLyme disease (LD) is the most common arthropod-borne disease in North America and is caused by the spirochete, Borreliella burgdorferi. LD spirochetes are maintained in an enzootic cycle of Ixodes species ticks and a vertebrate reservoir. The secondary messenger molecule c-di-GMP plays a crucial role in adaptive responses during the enzootic cycle. PlzA is the sole c-di-GMP-binding protein identified to date that is encoded by all Borreliella burgdorferi isolates. PlzA has both c-di-GMP-dependent and c-di-GMP-independent functions and is required to complete the enzootic cycle. The full range of PlzA regulatory activities has yet to be fully defined. We determined the atomic structure of the PlzA protein in complex with dimeric c-di-GMP. The structure revealed N- and C-terminal domains that consist of small β-barrel domains (SBB) that we hypothesize mediate RNA chaperone activities, including RNA binding, RNA annealing, displacement, and unwinding. PlzA RNA chaperone activity was demonstrated and found to be regulated by c-di-GMP. C-di-GMP negatively impacted the RNA displacement and RNA-unwinding activities of PlzA. In contrast, its RNA-binding and RNA annealing activities were not affected by the presence or absence of c-di-GMP. Utilizing FRET, we demonstrated that RNA binding to PlzA induces structural rearrangements. The crystal structure also revealed surface-exposed Phe residues within the N-terminal and C-terminal domains of PlzA. We hypothesize that the Phe residues are involved in ligand binding, specifically RNA binding. RNA binding studies showed that the site-directed substitution mutagenesis of specific Phe residues to Ala in the N-terminal and the C-terminal reduced or abolished RNA binding, respectively, when combined with mutations that removed c-di-GMP binding. We also demonstrated that PlzA binds DNA, and that the amino acid residues involved in RNA binding are also involved in DNA binding. The data presented within provides significant insight into the functional activities and functional determinants of PlzA
Swarming Segregation: Leveraging Swarm Intelligence and Regionalization as Instruments for School District Desegregation
No full textEven after Brown led to the South briefly having the most diverse schools in the nation, schools throughout the Northeast have remained the most segregated in the nation for decades. While federal jurisprudence has made compelling desegregation pursuant to the Equal Protection Clause more challenging, New Jersey has a particularly favorable landscape to address severe segregation. With a highly diverse, densely populated public enrollment, favorable state constitutional precedent, and a history of successfully compelling desegregation, New Jersey is fertile ground exploring regional desegregation. Scholars, judges, and even plaintiffs in ongoing litigation (Latino Action Network v. N.J.) have called for New Jersey to regionally consolidate districts to advance desegregation, but research has not yet explored what regionally consolidated districts might look like, or even how to develop those boundaries. In this dissertation, I develop a redistricting heuristic, SegSwarmEP, which novelly employs an Ant Colony Optimization (ACO) to optimize a combinatorially explosive redistricting problem to examine how New Jersey could regionally desegregate school districts across eight counties with the most segregated districts in the state. After assessing existing segregation, I employ SegSwarmEP to form clusters of existing districts, assessing segregation across three remedial maps compared to existing districts and counties. Compared to existing district boundaries, my heuristic was able to generate remedial maps which reduce interdistrict segregation by as much as 95 percent
Re-Member the Time: Informed Engagement Through Embodied Memory Among Queer Black Greek Letter Organization Members
Get PDFThis study examines the reflexivity of queer BGLO members after graduation and how they made meaning of their involvement when considering encounters with past critical incidents. The authors observed how queer-identified members of Black Greek-lettered organizations navigated opportunities for campus engagement in spaces prone to present heteronormative attitudes. The authors explored how queer-identified members of Black Greek-lettered organizations navigated the processes of identity development and meaning making in spaces prone to presenting heteronormative attitudes. This work is salient because it illustrates the development of subcultures within Black counterspaces in the postsecondary sector. These analyses explicate Black queer folx’s capacity to validate aspects of their identity through BGLO involvement
Ramerican Political Science Review (Vol. 9, Feb. 2025 Special Edition)
Get PDFFrance\u27s Strategic Dynamics: Power, Partnerships, and Prospects / Marie Cox -- The Contribution of the United Kingdom to the Security of Europe / Kelly Williams -- Poland: A Pivotal Actor for the Future of European Security / Zack Kloman -- The End of Finlandization / Natasha C. Smith -- A New Age: Turkish Security in a Changing World / Alexandra Pabo
S18, E09: BATFE (Aired 3/7/2025)
Get PDFAughie and Nia explore the history and responsibilities of the Bureau of Alcohol, Tobacco, Firearms, and Explosives.https://scholarscompass.vcu.edu/civil_discourse/1264/thumbnail.jp
Faculty Recital, VCU Jazz Septet
Get PDFFaculty recitalVCU Jazz Faculty SeptetRoy Haynes TributeThursday, February 13, 2025 at 7:30 p.m.Sonia Vlahcevic Concert HallW.E. Singleton Center for the Performing Arts922 Park Avenue | Richmond, Virgini
Wind Chamber Recital
Get PDFWind Chamber RecitalTuesday, April 8, 2025 at 7:00 p.m.Sonia Vlahcevic Concert HallW.E. Singleton Center for the Performing Arts922 Park Avenue | Richmond, Virgini
“It’s a Constant Wear and Tear”: Trans Visibility as Educational Labour in the Neoliberal School
Get PDFAlthough transgender people are increasingly visible in mainstream North America, trans teachers are without adequate resources or protections to support their employment in schools. Legislation in both Canada and the United States that invokes concern about parental rights and “LGBT indoctrination” in schools illustrate the dangerous political landscape facing teachers. In 2023, over 500 anti-LGBT (lesbian, gay, bisexual, and transgender) bills were introduced in state legislatures across the United States (Choi, 2024). Given this context, this paper explores trans education workers’ descriptions of trans visibility in the workplace. Drawing from interviews from the Trans Workers in Schools Project (TWISP), we ask: how do trans education workers describe how visibility related to their gender impacts their work lives? Findings from this study indicate that trans education workers believe being visibly trans in schools creates simultaneous joys and burdens. Trans workers’ descriptions of carrying identity-based burdens have broader implications for minority workers within the political context of neoliberalism. Although many workers are drawn toward providing better representation for students, this often comes with personal burdens that push workers’ capacity and professional limits. Building from scholarship that details the politics of visibility for trans people, this paper complicates the narratives of trans visibility and inclusion in the education system. In doing so, our findings expose some of the operations and mechanics of neoliberalism as they relate to trans workers in schools