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Interplay between Airway Smooth Muscle and Airway Epithelium: From Glutamate Metabolism to Epigenetic Reprogramming in Airway Hyperresponsiveness
No full textAsthma is a chronic airway disease affecting 330 million individuals globally, characterized by airway inflammation, hyperresponsiveness (AHR), and remodeling. The complexity of asthma stems from the involvement of various airway cells. Key pathological changes include airway epithelial (AEP) apoptosis/autophagy, goblet cell hyperplasia, airway smooth muscle (ASM) proliferation and contraction, and fibroblast activation. Glutamate (Glu) metabolism is known to regulate redox states in various diseases, but its role in asthma remains underexplored, despite the increased oxidative stress in asthmatic airways.
Recent evidence suggests that epigenetic mechanisms play a significant role in regulating metabolism-related genes, and vice versa. Glu is metabolically converted to α-ketoglutarate (α-KG), which affects the activity levels of α-KG-dependent epigenetic enzymes like Ten-eleven Translocation (TET) and Histone Lysine Demethylase (KDM). While AEP cells are thought to contribute to ASM remodeling and enhanced AHR, the role of Glu metabolism in these processes is unclear. We hypothesize that epithelial-derived Glu metabolism epigenetically modifies ASM functions, driving airway inflammation and remodeling in asthma.
Our study demonstrates that the Glu transporter SLC1A1 is upregulated in asthmatic ASM cells, correlating with elevated intracellular Glu and α-KG levels and increased TET activity. Knockdown of SLC1A1 reversed aberrant phenotypic changes like ASM proliferation and migration, likely through modulating α-KG-dependent TET and KDM4 activity levels and altering DNA hydroxymethylation and histone demethylation at ASM gene promoters.
Additionally, we found that IL-13 induced Glu release in AEP cells cultured under air-liquid interface (ALI) conditions, which stimulated ASM growth and proliferation, and increased global DNA hydroxymethylation. These effects were also reversed by knocking down SLC1A1 in ASM cells. Our study reveals how Glu metabolism contributes to epigenetic regulation of airway structural cell functions and identifies SLC1A1 as a target for reversing asthma exacerbation. These findings advance our understanding of the epigenetic mechanisms underlying airway cell function in asthma, suggesting new directions for therapeutic intervention that may ultimately reduce the global disease burden
Investigating Genetic Determinants of Venous Thromboembolism in African Americans
No full textVenous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, disproportionately affects African Americans, yet the genetic factors contributing to this disparity remain poorly understood. Current research has largely focused on predominantly White popula-tions, leading to the underrepresentation of African Americans in genomic studies. Identifying ge-netic variants that influence VTE risk in African Americans is crucial for developing targeted pre-vention and treatment strategies. To address this gap, I conducted a genome-wide association study (GWAS) of 1,074 VTE cases and 26,743 controls. The study employed logistic regression adjust-ing for age, sex, and principal components of ancestry. Only unrelated individuals were included to reduce potential biases from relatedness. Four genome-wide significant variants were identified: one intergenic variant near AC021193.1 on chromosome 4 and three variants located within the first intron of DCC on chromosome 18. The alternate alleles of these variants were associated with in-creased VTE risk (OR range: 2.86 to 4.27). The association of variants in DCC, a gene involved in tumor suppression that is highly expressed in brain and testis tissues, is intriguing because VTE is more common in individuals with a history of cancer. These findings, if validated, warrant further investigation to explore the functional impact of these variants and their potential role in VTE path-ogenesis. The identification of genetic variants associated with VTE in African Americans could ultimately lead to the development of precision medicine approaches for more effective risk as-sessment, prevention, and treatment strategies tailored to this high-risk population
Successful Development and Implementation of Electronic Audit Tool to Assure Compliance with Infection Control Regulations
No full textCommon patient equipment, including blood glucometers, are of high focus during various regulatory activities in healthcare settings. Point-of-care blood glucometers (“glucometers”) are known to transmit common bloodborne pathogens including Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV). Blood glucometers have complicated and in-depth cleaning standards that are set by the manufacturer. Glucometers are used in various clinical care settings.
For my internship at a large academic medical center, I developed and implemented an electronic audit tool starting June 2024 to track compliance rates with updated cleaning procedures and Joint Commission guidelines for glucometer reprocessing. A two-part comprehensive education plan was developed. Part one included development of a standardized education tool called an SBAR (Situation, Background, Assessment, Response) which was distributed to units at the beginning of June 2024. An SBAR is a one-page quick reference sheet describing a situation and the required education for the topic. Part two was an electronic audit tool that was used to track and show compliance with in-the-moment instances of non-compliance which began mid-June and was tracked through the end of September.
In June 2024, 279 baseline audits were conducted with only 67.0% of glucometers passing inspection. A total of 46.6% of audited nurses correctly described the cleaning process. In July 2024, 348 audits were conducted, 71.1% of glucometers passed inspection, with 68.7% of audited nurses correctly describing the cleaning process. In August 2024, 107 audits were conducted, 86.2% of glucometers passed inspection with 93.1% of audited nurses correctly describing the cleaning process. For the three-month period, the most common non-compliance issue found was blood on the device (50% in June, 52.6% in July).
Electronic audit tools are an innovative way to easily collect, collate, and analyze large amounts of data. We were easily able to demonstrate an improvement in glucometer cleaning compliance post-education during the three-month period for an overall improvement in public health safety within the hospital of interest
Patterns of Breastfeeding Among Individuals with Opioid Use Disorder and Integration of Lactation Support into Perinatal Recovery Programs Across the United States
No full textBackground: Prenatal opioid use continues to increase across the United States with a corresponding incidence of neonatal opioid withdrawal syndrome. Breastfeeding remains one of the only evidence-based practices that can decrease the need for medication in the newborn with proven benefits to individuals with opioid use. Despite these benefits, breastfeeding rates remain low. This dissertation study sought to understand patterns of breastfeeding outcomes among individuals with prenatal opioid use as well as breastfeeding support provided by perinatal recovery programs across the United States.
Methods:
To examine patterns of breastfeeding, the 2019-20 PRAMS Core 8 and Opioid Supplement were analyzed using binary logistic regression for complex sample surveys to model the impact of prenatal opioid use, Social Determinants of Health using race as a proxy for racism, years of maternal education for educational attainment, and enrollment in a supplemental nutrition program as a proxy for socio-economic status on the primary outcomes of breastfeeding initiation and continuation.
An online survey querying perinatal recovery program staff and leaders about their programs’ lactation support services and perceived barriers and facilitators to providing lactation support within the program and affiliated healthcare system(s) was distributed to all known programs across the United States between January and April of 2024. Quantitative data were summarized with descriptive statistics and open-ended survey responses were analyzed using content analysis. Qualitative themes were overlaid on quantitative findings to triangulate findings.
Results:
Among the overall sample using PRAMS data, 7.1 % of participants reported prenatal opioid use. Prenatal opioid use, racism, and educational attainment conferred an increased risk for breastfeeding non-initiation and non-continuation when adjusted for all covariates.
Of the 43 perinatal recovery program personnel who complete the survey, 35 unique programs in 16 states were represented. Four themes were identified: breastfeeding support, provider knowledge, limited breastfeeding feasibility and access to breastfeeding support, and updating and implementing evidence-based policies.
Conclusions:
To increase breastfeeding uptake for individuals with prenatal opioid use, the context of their unique social determinants of health must be taken into account and addressed along with increasing breastfeeding knowledge, support, and evidence-based policies within perinatal recovery programs
A persistent variant telomere sequence in a human pedigree
No full textThe telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. We identified a family with a heterozygous variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant was inherited across at least one generation and one family member is clinically normal despite ~9% of their telomeres converting to the novel sequence. The variant template disrupted telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1 in vitro. Despite these disruptions, the sequence was readily incorporated into cellular chromosomes. While overexpression of the variant telomerase led to decreased cell proliferation and a DNA damage response, heterozygous expression of the variant appeared to be tolerated. Incorporation of a variant sequence prevented POT1-mediated inhibition of telomerase and promoted telomere lengthening, somewhat offsetting the defect in enzyme processivity. These findings demonstrate that the telomere sequence directly influences telomerase activity and identifies a novel mechanism by which telomeres that have incorporated a variant sequence are rapidly lengthened by creating highly extendable telomeres
MULTI-METHOD APPROACHES TO IDENTIFYING REPRODUCIBLE, ROBUST, AND REPLICABLE NEURAL NETWORK RISK MARKERS OF BIPOLAR DISORDER
No full textBipolar Disorder (BD) is a debilitating neuropsychiatric disorder characterized by recurrent alternating episodes of mania/hypomania, depression, mixed states, and psychosis, although it is mania and hypomania that define BD and set it apart from other psychiatric disorders and brain- based diseases. While having a familial history of BD can increase one’s risk by tenfold, there are many individuals that become diagnosed with BD who do not have a genetic predisposition, yet we do not have established methods or biomarkers for identifying these individuals. Neuroimaging can identify objective risk markers for BD by capitalizing on its neural basis to yield neurobiologically-relevant markers that can subsequently inform targets for future treatments. However, for neuroimaging-defined biomarkers of BD to be clinically informative, they must also be reproducible, robust, and replicable, and this dissertation proposes three different methods to derive such markers. We started with a large-scale meta-analysis, synthesizing three decades of functional neuroimaging studies in BD, that sought to determine whether the extant literature provided justification for reproducible and robust markers of BD given substantial clinical and methodological heterogeneity, and this meta-analysis identified robust group-level markers distinguishing adults with BD from controls that were also condition-dependent (Chapter 3). Next, in a cross-sectional analysis of three independent samples of young adults with spectrum-level mania/hypomania and depression, we aimed to determine whether there were objective, reproducible neural markers specific to risk for mania/hypomania (i.e., BD-specific risk) versus risk for depression, and we identified several patterns of neural network connectivity distinguishing, and common to, risk for mania/hypomania and depression that also replicated across samples (Chapter 4). Finally, we aimed to identify neural markers of low versus high risk for BD, defined by trait emotion-related impulsivity i.e., negative and positive urgency (Chapter 5). The neuroimaging findings identified by these three approaches highlight the involvement of four neural networks—the salience, default mode, ventral attention, and central executive networks—and both reinforce long-held consensus views about the neurobiology implicated in BD and BD risk while also expanding this consensus, thereby validating and challenging our broader understanding of the neural mechanisms underlying and predisposing to the starting point of BD
Anxieties and Influences: Italian Cultural Entanglements with the Ottoman Empire, 1400 - 1600
No full textMy dissertation focuses scholarly attention to early modern Southern Italy, linking it more cohesively with prior scholarship that considers Italy within an international context during the early modern period (c.1350-1600). This project focuses on artworks that reveal the cross-cultural interaction and movement between various Italian sites and the Ottoman empire during the early modern period. It aims to highlight the interconnectedness and reliance of Italian city-states on bordering cultures as they crafted their own local artistic identities. By focusing on geographic regions that fall beyond most accounts of Renaissance art, this dissertation builds on recent scholarship that has sought to expand the Italian Renaissance through re-examining both geographic and cultural peripheries. This project places Italian artistic culture directly into dialog with other cultures, though with a different focus than much of the work that has recently examined artistic exchange in the Renaissance. By focusing on understudied Italian sites and broadening the kinds of objects considered within art history, this dissertation expands recent scholarship by integrating sites in Southern Italy historically understudied into the ongoing discourse of “Global Renaissance”. This project argues that cultural forms of the local must be thought of within horizontal, contemporary cultural networks and vertical, sedimented histories, especially as applied to Mediterranean port cities, as prime sites of cultural-contact and migration. Through Archival research in sites often relegated to the margins, like Venetian Dalmatia or Puglia, reveals how integrated these sites were within the cultural networks of the early modern Mediterranean
A change would do you good…or would it? The role of emotion dynamics in adolescent girls’ depressive symptoms
No full textDepressive symptoms increase considerably in adolescence, especially for adolescent girls at risk for depression due to dispositional factors. Affect dynamics, or change in emotional experience over time, may serve as a mutable mechanistic factor for developing prevention and intervention efforts. Two primary affect dynamics constructs have been investigated in association with adolescent depressive symptoms: affective variability and socioaffective flexibility. Affective variability captures adolescent affective experience across multiple contexts in daily life through momentary methods like ecological momentary assessment (EMA), is operationalized using measures like the standard deviation, and is assumed to be broadly maladaptive, reflecting difficulties with reactivity and regulation. Socioaffective flexibility, on the other hand, typically examines affect change throughout the course of lab-based interpersonal interactions, often between an adolescent and caregiver, and is broadly assumed to be adaptive, reflecting the ability to shift emotion states in response to changes in context. To date, these two constructs have not been examined in the same sample, and it is thus unknown to what extent they provide competing versus complementary understanding of the role of affect dynamics in adolescent depression. In a sample of girls ages 11-13 oversampled for risk for the development of depression, this study examined affective variability and socioaffective flexibility in association with adolescent depressive symptoms, both concurrently and longitudinally over an 18-month period. Results from latent growth curve models indicated that modal negative affect, negative affect variability, and positive affect variability were all positively associated with adolescent depressive symptoms at baseline but were not associated with change in depressive symptoms over time. Notably, higher levels of variability in positive affect were typically the result of larger drops from high modal levels of positive affect and were also associated with maternal depressive symptoms. Socioaffective flexibility was not associated with adolescent depressive symptoms. Findings suggest that the putative difficulties with reactivity and regulation captured by affective variability measures are more strongly related to adolescent depressive symptoms – at least at non-clinical levels – than the ability to flexibly move through multiple emotion states with a close caregiver (here, a biological mother)
“I am My CSister’s Keeper” Community Cultural Wealth and persistence among CUNY’s Black, Indigenous, Women of Color (BIWOC) in Computer Science
No full textThere is a purported shortage of employable labor in the tech workforce, yet Black, Indigenous, Women of Color (BIWOC) in urban centers struggle to find and sustain roles in “high-tech.” The tech ecosystem is a CIS-gendered, white male heterosexual space that perpetuates and “ideal worker norm” (Kachchaf et al., 2015), which further excludes BIWOC from roles in tech. Given this social construct, fostering persistence among undergraduates who identify as BIWOC is imperative to disrupt this inequitable structure.
According to Blaney and Stout (2017), persistence is fostered by a few key factors: sense of belonging, self-efficacy, and overall satisfaction with the undergraduate experience, which is inclusive of faculty and coursework. This dissertation in practice (DiP) posits the Community Cultural Wealth (CCW) (Yosso, 2005) framework as a viable tool to enhance these factors for BIWOC in the City University of New York’s (CUNY) Computer Science programs of study.
Employing the tenets of Improvement Science, the “Sister Circles” Methodology (Johnson, 2015) served as an intervention by creating “counterspaces” for undergraduate BIWOC to build their cultural capital. The Transformative Mixed Method was utilized to gather both qualitative and quantitative, or “QuantCrit” (Johnson, 2015) data that acknowledges the value of quantitative data in studies associated with components of Critical Race Theory (Crenshaw et al., 1995). Transformative methods give space for a Black Feminist Thought (P. H. Collins, 1989) lens to be applied to the research process.
The key findings of the study indicate that Community Cultural Wealth is an underutilized, invaluable resource for fostering persistence in CUNY’s BIWOC to persist to careers in high-tec
Combinatorics of Finite Open Covers
No full textGiven any graph or simplicial invariant , we can define an analogous topological invariant and determine its values for a given topological space . These topological invariants are defined by applying the graph or simplicial invariant to the nerves of finite open covers of . In this work, we discuss how to define such topological invariants, and we analyze several topological invariants that correspond to classical graph invariants. We also define and investigate the related notion of forced substructures of a topological space. Lastly, we investigate topological invariants that correspond to a particular class of graph invariants known as minor-monotone invariants