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Thinking Beyond Association Tests: Using Mathematical Models to Identify Genes Influencing Exceptional Longevity
Get PDFThe main goal in the genetic study of trait biology is to identify genetic factors, such as variants and genes, that causally influence traits and to understand the downstream mechanisms through which they exert their effects. This dissertation improves our understanding of trait biology by building on widely applied omics-wide association studies (omics-WAS), such as GWAS and TWAS, and proposing methods that (1) combine association statistics from multiple omics modalities and (2) systematically incorporate prior knowledge from biological networks and functional annotations with omics-WAS summary statistics. First, we apply meta-analysis to integrate gene-level p-values from GWAS, TWAS, and rare-variant analyses to identify novel and replicable genes associated with cardiovascular risk in the Long Life Family Study (LLFS) cohort. This approach improves statistical power, reduces confounding effects in individual omics-WAS, and prioritizes gene-trait relationships supported by multiple omics-WAS. Second, we develop FISHNET (FInding Significant Hits in NETworks), which incorporates gene interaction networks and functional annotations to identify genes that do not meet genome-wide significance thresholds but replicate nonetheless. Third, we reconstruct transcription factor (TF) network maps to identify direct and functional TF-target gene relationships in a tissue-specific context. By integrating high- throughput omics datasets that capture different aspects of TF-target gene regulation, these network maps provide insights into TF-TG relationships that may mediate variant/gene-trait associations in omics-WAS. Together, these three approaches advance the interpretation of statistical associations from individual omics-WAS, contributing to a deeper understanding of trait biology
Advancing Precision Treatment of Multiple Myeloma with Single-Cell and Spatial Immune Profiling
No full textMultiple myeloma (MM) is a highly refractory hematologic malignancy for which targeted immunotherapy and stem cell transplant have shown great promise. Two key challenges in advancing treatment lie in identifying broadly representative tumor markers and understanding the how post-transplant bone marrow (BM) immune repopulation influences treatment outcomes. Recent technological developments in single-cell RNA-sequencing (RNA-seq) and probe-based spatial transcriptomic assays now allow us to perform deep molecular characterization, interrogating cellular heterogeneity and interaction at unprecedented granularity. My dissertation leverages these platforms to uncover therapeutic targets and enhance our understanding of transplant-induced bone marrow remodeling. First, I utilize scRNA-seq to analyze BM aspirates from MM patients, applying a high-throughput, unbiased pipeline to identify candidate MM marker genes, including novel markers not yet under clinical investigation and previously characterized as potential therapeutic targets. These findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry, confirming the ability of single-cell technologies to accurately capture marker expression despite sample size and sequencing depth limitations. Next, I focus on understanding how BM dysregulation impacts MM treatment outcomes, particularly after autologous stem cell transplantation (ASCT). We conducted scRNA-seq on post-transplant BM aspirates, alongside samples from newly diagnosed MM patients and healthy controls, revealing immune features linked to MM pathogenesis and transplant response. These included dysregulated NFκB signaling in MM plasma cells and naive B cells, increased T cell exhaustion, and altered myeloid signatures associated with tumor burden and survival outcomes. Using probe-based spatial transcriptomics, we further mapped the BM microenvironment, observing compartmentalization of lymphocyte- and progenitor-rich regions and disruption of early B cell developmental niches, which correlated with treatment outcomes. This study underscores the importance of the BM milieu in post-transplant responses and provides new insights into how spatial and immune dysregulation contribute to treatment resistance in MM. Together, these findings demonstrate the power of single-cell and spatial transcriptomics in uncovering new therapeutic targets and elucidating the complex BM microenvironment in MM, offering promising avenues for enhancing precision medicine in MM treatment
X-ray Polarization of Accreting Stellar-Mass Black Holes through Accretion States
No full textIn recent years, X-ray polarization has opened up a new window into our understanding of astrophysical sources. Among them are accreting stellar-mass black holes, which play a key role in testing the behavior of matter in extreme gravitational environments. These sources can be observed in different states of the accretion cycle, predominantly in the soft and hard states. Every state is dominated by a combination of thermal disk, coronal, or reflected emission—each type containing different information about the environment around the black hole that can be understood through polarization. Polarimeters such as the Imaging X-ray Polarimetry Explorer and XL-Calibur allow us to probe the inner X-ray emitting parts of the system to study the black hole’s accretion flow. In this work, we model recent polarization observations of black holes in X-ray binaries, paying special attention to multiple observations of a source in different accretion states. We conduct timing, spectral, polarimetric, and spectropolarimetric analyses to study black hole mass accretion rate, ionization, disk temperature, and corona properties through the polarization of their different emission mechanisms
Exploring the Structure, Dynamics, and Pharmacology of Opioid Receptors
No full textThe opioid receptor family is comprised of four G protein-coupled receptors, mu (MOR), kappa (KOR), delta (DOR), and nociceptin (NOP), which are involved in many physiological processes including pain, emotion, and digestion, making them important targets for drug development. MOR has commonly been used as an effective target for pain therapies. However, MOR-based therapeutics are associated with negative side effects, including addiction and respiratory depression, limiting their use in chronic pain treatments. Other receptors in the opioid family, particularly DOR, pose as potential alternative for chronic pain treatment. However, despite extensive research, the molecular mechanisms behind ligand binding, receptor activation, and transducer signaling remain poorly understood. To better understand DOR, we used cryo-electron microscopy (cryo-EM) and pharmacological assays to investigate processes underlying ligand pharmacology, aiding in the development of the next generation of DOR-based therapeutics. We used cryo-EM to solve structures of various ligands, including peptides, small molecule agonists, and antagonists, bound to DOR. These structures, together with pharmacological assays, provided insights into key residues responsible for DOR selectivity, a hydrophobic pocket relevant for receptor activation, and distinct residue conformations in peptide vs small molecule binding. Using insights from structure, we then developed the first selective DOR partial agonist using a bitopic approach, engaging two distinct pockets in the receptor. The reduced receptor activity of partial agonists allowed us to develop a ligand with analgesia and minimized side effects. Because our pharmacological experiments rely on ensemble measurements, which limit spatiotemporal resolution, we conducted single-molecule fluorescence resonance energy transfer (smFRET) experiments to study discrete measurements and gain deeper insights into receptor dynamics. smFRET experiments showed that, even in the presence of DOR full agonists and G proteins, the fully active-state DOR only occupied 60% of states, which is in contrast to the nearly 100% population observed at MOR. We have also extended the smFRET studies to KOR and observed a higher population of fully active state than DOR but a lesser extent than MOR. These data suggest that opioid receptors have intrinsically differing coupling efficiency with G proteins which could contribute to their effectiveness in pain modulation. Together, the results from this study provide a deeper understanding of opioid receptor function and lay out a framework for developing partial agonists with safer therapeutic profiles
The Making of the Mental and Material Map of the Pacific Ocean in Early America, 1740-1819
No full textHow did early Americans make sense of the vast oceanic space between Asia and the Americas? In this dissertation, I address this question by examining how Americans conceptualized the spaces now called “the Pacific Ocean” through print culture, correspondence, lived experiences, and foreign policies from the mid-eighteenth and early nineteenth centuries. I argue that Americans did not comprehend the Pacific as a single geographical space, but as multiple disjointed spaces connected by networks of trade, knowledge systems, and geopolitical interests. To recover the origin and development of their ideas, I focus on the role of cartographers, sailors, traders, merchants, newspaper editors, and politicians in the production of knowledge about distant spaces and unfamiliar cultures, as well as Americans’ relationship to them. The many images and debates regarding the Pacific would complicate how Americans understood the North American mainland and shape the extent and limitations of American expansionism and imperialism throughout the nineteenth century. This dissertation develops three closely related arguments. First, I argue that Americans relied on existing systems of knowledge to comprehend the Pacific. Americans actively embraced their European peers\u27 intellectual traditions and cultural practices, especially that of their British predecessors. They consulted charts and journals produced by European explorers, embraced ideas of civilization promoted by British evangelicals, and turned to transatlantic communication networks for Pacific news. Second, the Pacific that emerged as a result was fragmented and uncertain. Americans did not cover the spaces between Asia and the Americas evenly but focused on specific trading posts, enclaves, and corridors, connecting them through commercial networks of sea lanes. As these sites were also claimed and contested by European empires and Indigenous peoples, Americans\u27 relationships with them were unstable and subject to broader political, cultural, and social changes at a given time. Lastly, I am arguing for a corrective to the historiography of U.S. empire, which situates the Pacific in the history of the American West after 1840. Long before the United States claimed parts of the Pacific coast through diplomatic negotiations and establishing settlements, Americans were already in the Pacific and thinking about the Pacific. By focusing on their various imperial practices before the arrival of empire, this research probes the complicated relationship between imperialism and empire in the history of the early republic
The Search for Correlated Topology in Quantum Materials
No full textTopological quantum materials have sparked intense research due to their robust physical properties and technological promise. While non-interacting topological phases are well understood, the topic becomes more complex when strong correlations are introduced --- often rendering conventional theoretical tools insufficient. Faced with a growing number of candidate materials and powerful experimental toolkit enabled by university and national laboratory collaboration, a critical question emerges: which materials warrant intensive study, and when do strong correlations demand a departure from standard approaches? My dissertation address this challenge by developing an experimentally driven strategy for identifying and characterizing correlated topological materials. Focusing on uranium-based single crystals, this work combines machine learning technologies --- including Random Forest classification and Bayesian optimization --- with electron transport probes, such as inverted resistance measurements for detecting surface states and quantum oscillation measurements to resolve the electronic structure. These tools are deployed not only to understand emergent topological behavior in 5-electron systems, but also define a framework for selecting high-impact materials that advance our knowledge of correlated topology
Emergence and Evolution of Antibiotic Resistance in the Built Environment
No full textMicrobes are everywhere. They live inside and on top of our bodies; they live in the natural environment as well as the environments we build for ourselves. Our interactions with those habitats affects those microbes, and negative perturbations to those habitats can promote selection for harmful bacteria. Perhaps the most serious risk we face is the increase in prevalence of antibiotic-resistant bacteria. Since the introduction of antibiotics in the mid-20th century, resistance in agricultural and clinical settings has increased, leading to an increase in morbidity and mortality of bacterial infections. Understanding the genomic context, time scale, and evolutionary trajectory of antibiotic resistance is crucial for predicting and mitigating their spread. In this work, I take a genomic approach to understanding antibiotic resistance through surveillance of existing threats in the environment, and future threats that may not be captured by current surveillance efforts. The emergence of antibiotic resistance is a global phenomenon, and perhaps most troublesome in low-income and middle-income countries (LMICs). It is estimated that per-capital burden from antibiotic-resistant infections is highest in LMICs, but surveillance networks are not as complete as they are in high-income countries. To address this gap, I first examined the genotypic mechanisms of carbapenem resistance in Pseudomonas aeruginosa clinical isolates recovered from three hospitals in Pakistan. My genotypic and phenotypic analyses revealed that resistance to carbapenems – a critical tool in treating P. aeruginosa infection – was common. I found that these properties were present in both globally-disseminated and novel sequence types. Although phylogenomic background was correlated with overall antibiotic resistance gene (ARG) content, there was no correlation with the presence of high-risk carbapenemases. I next found that presence of multiple resistance mechanisms in the same genomes was associated with significantly higher resistance phenotype, suggesting that there is a selective benefit to acquiring redundant ARGs. Hospitals are a critical environment for surveilling resident microbes. Pathogens from patients or healthcare workers can contaminate surfaces and transmit to a vulnerable patient. I next examined the contamination of hospital intensive care unit (ICU) sinks, a surface that has been linked to clinical outbreaks, to understand the time scales and dynamics of surface contamination. I recovered over 100 unique species and novel genomospecies and found that some taxa established long-term contamination across multiple ICU rooms, while others were more transient. I also found that bacteria recovered from ICU rooms were enriched in ARGs compared to non- hospital rooms. This ARG richness was maintained both by persistence of specific ARG-rich lineages as well as mobilizable resistance-conferring plasmids which were observed across multiple unrelated hosts. Finally, I examine the evolution of a specific mechanism of tetracycline resistance – the tetracycline destructases (TDases). TDases are a family of flavoenzymes capable of selectively inactivating tetracyclines. Although they have a common function, they display a wide sequence diversity. To better understand the sequence-structure-function relationships of TDases I performed a deep mutational scan on tet(X7), a particularly active enzyme that has been identified in a clinical pathogen. I find a correlation between enzyme activity and residues that are critical for cofactor binding. I also find sites distal to the cofactor or substrate binding site which appear to mediate degradation, suggesting that there is complex allosteric effects that we do not fully understand. When comparing activity towards different substrates, I find that multiple residues proximal to the substrate binding site mediate high activity towards tigecycline. Taken together, these effects imply that tet(X7) has evolved a larger binding pocket to accommodate more diverse substrates compared to its evolutionary relatives
Oriented Matroid Circuit Polytopes
Get PDFMatroids give rise to several natural constructions of polytopes. Inspired by this, we examine polytopes that arise from the signed circuits of an oriented matroid. We give the dimensions of these polytopes arising from graphical oriented matroids and their duals. Moreover, we consider polytopes constructed from cocircuits of oriented matroids generated by the positive roots in any type A root system. We give an explicit description of their face structure and determine the Ehrhart series. We also study an action of the symmetric group on these polytopes, giving a full description the subpolytopes fixed by each permutation. These type A polytopes are graphic zonotopes, are polar duals of symmetric edge polytopes, and also make an appearance in Stapledon’s paper introducing Equivariant Ehrhart Theory
Understanding the Behavioral Health of Children in Child Protective Services: Prevalence, Community Context, and System Involvement Using Administrative Data
Get PDFThis dissertation investigates the behavioral health of children involved in the U.S. child welfare system through a three-paper approach. Amid rising concerns over youth mental health, suicide rates, and ADHD diagnoses, this study explores how these issues manifest among children reported for maltreatment – a population at elevated risk and often underserved. Paper 1 estimates the prevalence of behavioral health problems using national administrative datasets (NCANDS and AFCARS), providing insight into trends over time and disparities by age, race/ethnicity, sex, geographic context (urban vs. rural), and system involvement (CPS investigation vs. foster care). Paper 2 leverages county-level data to examine contextual factors on adolescent behavioral health. It describes how the prevalence of behavioral health concerns differs across racial and ethnic groups of children and geographic contexts, and explores how local socioeconomic conditions may be associated with the identification of these concerns. Paper 3 analyzes the associations between behavioral health concerns, prior maltreatment history, and system involvement, and examines whether behavioral health concerns are linked to report substantiation and foster care involvement. Stratified by developmental stage, the study offers nuanced insights into the trajectories of children experiencing maltreatment. Together, these papers provide evidence on the behavioral health of children in CPS at both the individual and county levels, aiming to inform policy and improve services for this vulnerable population. Findings contribute to both scientific literature and practice efforts addressing disparities in child behavioral health
Innovation and Advocacy in Perinatal Harm Reduction by Birth Workers and Perinatal Workforce Providers: A Qualitative Study Utilizing Narrative Inquiry
No full textBackground: The criminalization and stigmatization of perinatal substance use has created a public health crisis, isolating birthing people away from vital healthcare and social supports and separating families (Bach & Terplan, 2023a; Earnshaw et al., 2024; Kavattur et al., 2023; Merritt, 2020; Ocen, 2017). During the perinatal period, up to approximately 10% of birthing people in the United States self-report past-month use of illicit substances and/or alcohol (McCance-Katz, 2020; Rodriguez & Smith, 2019), however only approximately 60% of birthing people who use substances report being able to access any MOUD during the perinatal period (Jarlenski et al., 2021). The birth professionals who work with birthing people who use substances can influence health, social, and familial outcomes, becoming facilitators or barriers to obtaining care (Barnett et al., 2021; Puccio, 2023). Significance: This dissertation presents the perspectives of perinatal harm reduction birth professionals who work with birthing people who use substances. The perspectives and applications highlighted in this dissertation can be used as a model for more widespread implementation of perinatal harm reduction as a values-based and liberatory movement. Methods: This dissertation was done through two methods: 1) phenomenological qualitative research utilizing semi-structured interviews and thematic analysis and 2) narrative inquiry. The analysis for the first two papers in this dissertation uses data from 16 semi-structured phenomenological interviews with birth workers, peer navigators, and perinatal workforce providers. The first paper also combines multiple participants into four case studies to examine the application of PHR. In anthology format, the third paper uses co-created narratives from seven of the 16 original participants. Findings: This research aims to define perinatal harm reduction, informed by the birth professionals who practice it. After establishing a working definition and identifying the motivations and values necessary for the birth professionals, this research examines four settings in which the birth professionals apply PHR. In the second paper, the birth professionals discuss the barriers to implementing perinatal harm reduction and the opportunities for transforming the birth system. In the anthology, seven narratives are connected to Emergent Strategy frameworks to illustrate how the birth professionals view their roles as advocates and create an archive of perinatal harm reduction narratives. Future Implications: This research aims to create a cohesive foundation for the nascent area of perinatal harm reduction research. The liberatory and abolitionist frameworks that inform this work can and should influence the widespread implementation of perinatal harm reduction. This research establishes perinatal harm reduction as a values-based and justice-oriented care movement based on the radical love of birthing people who use substances. It calls for transformational shifts in how the birthing professions interact with birthing people who use substances and how these birth professionals resist systems of oppression, including those at play in the family regulation system, white supremacy, and punitive anti-drug policy