The Get List

TV Producer Brooke Quinn escapes to a remote Alaskan fish camp. There, free from the professional pressure to stay unpregnant, she can pursue her next story. Or so she hopes. In a trade of stories with a fishwife, Brooke learns to salt salmon and what it takes to make it as an Outsider in the Alaskan Bush. A tenuous friendship builds as Brooke learns firsthand about the Alaska Native women gone missing in her fishing village, their names listed in an oilman’s yacht logbook and disguised as deckhands. The dark discovery convinces Brooke to extend her stay, immersing herself in a new language and people. Brooke wagers it all—her reputation, her marriage, her chance to start a family—to get the story that could make or break her career. But landing the logbook traced to the revered CEO of Arc’d, a major oil company celebrated for its green practices, could land her name on his “get list,” the women invited to his yacht who never return. This creative work anchors me both in the culminating mission of my master’s–-publishing a novel—and my craft study: create intimacy with my audience through interiority. By focusing on the “inside voice” of the protagonist, Brooke Quinn, the craft challenge becomes constructing her interior world. The interiority must draw readers into a psychological escape so intoxicating that the emotional weight exchanged between the character and the reader genuinely resonates. To do this, I draw on plot-rich scenes from my professional experience: from covering an oil spill in the Gulf and dark money ties in Arctic Alaska to interviewing the CEO of the much-revered company Rivian ahead of its $5-billion electric car company being built in rural Georgia. As my muse Charlotte Brontë might say, Reader, I’m ready to write!Extension Studie

Characterization of Thymocytes and Splenocytes in Gdf8^Gdf11MD mice

Immunosenescence refers to an age-related decline in immune function, primarily characterized by the gradual degeneration of the thymus, also known as thymic involution. Transforming growth factor-β (TGF-β) signaling is integral to the formation and normal function of the thymus. As a member of the TGF-β superfamily, Growth differentiation factor 11 (GDF11) and its receptors are expressed during thymocyte development. Moreover, GDF11 plays a critical role in the immune system by reducing inflammation through the regulation of specific pathways and immune cell functions. More importantly, GDF11 has been shown to have potential rejuvenating effects on various organs, including the heart and brain. However, its impact on thymic rejuvenation remains unknown. To study the effect of GDF11 on thymic involution, here we utilized the Gdf8^Gdf11MD mice, which have increased levels of circulating GDF11, and analyzed changes in their thymocyte and splenocyte populations. Our results showed that young adult female (4-month-old) and male (3-month-old) Gdf8^Gdf11MD mice exhibited a trend toward accelerated thymic involution compared to controls. Although this difference diminished with age, the reduction in thymic cellularity persisted into late adulthood (8-month-old) in male mutants. Notably, significant changes in the absolute number of multiple thymic subsets were observed in young (3-month-old) and pre-middle-aged (8-month-old) Gdf8^Gdf11MD males, indicating potential alterations in thymocyte development. Using flow cytometry, distinct immune cell subsets within the spleen were analyzed to further explore the effects of accelerated thymic involution on peripheral T cells in mutant mice. We found that, despite a significant increase in spleen weight in 12-month-old female and 8-month-old male mutants, there were no differences in the frequency or absolute number of splenocytes compared to controls. In addition, 4-month-old female Gdf8^Gdf11MD mutants exhibited an increased spleen-to-body weight ratio, accompanied by a decreased proportion but increased number of CD4⁺ central memory T cells (TCM). These findings demonstrate a possible correlation between GDF11 expression levels and thymic involution, highlighting the important role of GDF11 in immunosenescence.Graduate Educatio

Investigating Differential Binding Stabilities of MHC-E Restricted Epitopes in SIV Vaccination

HIV continues to pose a global health challenge and has prompted extensive research into exploring effective vaccine strategies. Previous breakthroughs in simian immunodeficiency virus (SIV) vaccine development using a rhesus CMV vector recombinant for SIV antigen (RhCMV 68-1/SIV) showed unprecedented sterile immune clearance against SIV challenge. Subsequent studies sought to determine the underlying mechanism of protection in this promising prophylactic vaccine strategy. An unconventional, MHC-E-restricted subset of CD8+ T cells was identified and shown to be necessary for protection. However, RhCMV 68-1/SIV vaccine-identified SIV epitopes identified by Hansen et al. lack canonical primary anchor residues, present low or negligible binding to human HLA-E, and thus do not support stable HLA-E/B2M complex formation. This inconsistency raises questions about their role and functionality in RhCMV 68-1/SIV vaccination. We therefore performed a comprehensive and direct comparison of SIV peptide binding to human and rhesus MHC-E. This thesis study aims to evaluate the binding characteristics and stability of RhCMV 68-1/SIV vaccine-identified SIV epitopes in complex with a panel of rhesus macaque and human MHC-E orthologs, specifically Mamu-E*02:04, Mamu-E*02:11, and HLA-E*01:03. The objective is to validate whether these SIV epitopes demonstrate comparable binding to Mamu-E and HLA-E, or if there is enhanced stability for Mamu-E as opposed to HLA-E. If the latter holds true, with Mamu-E exhibiting superior stability in complex with vaccine-identified SIV epitopes, it could explain the mechanism of vaccine efficacy but indicate challenges in translating this vaccine success to human clinical applications. If Mamu-E and HLA-E show similar binding to RhCMV 68-1/SIV vaccine-identified SIV epitopes, then alternative mechanisms of vaccine-mediated protection should be explored. To accomplish these goals, Mamu-E and HLA-E were recombinantly expressed in prokaryotic expression systems and refolded to form MHC-E/B2-microglobulin complexes prior to performing in vitro SIV peptide loading reactions. Thermostability assays using Differential Scanning Fluorimetry were conducted to compare the stability of Mamu-E and HLA-E complexes in the presence of excess SIV peptides. By examining the interactions between the vaccine-identified SIV epitopes and MHC-E molecules, this study aims to clarify the underlying mechanisms of the observed vaccine efficacy thereby facilitating its translation into the human clinic. Our findings reveal that the majority of vaccine-identified SIV epitopes do not stabilize either Mamu-E or HLA-E alleles. Given this weak or insignificant stabilization, it is likely that direct presentation of vaccine-identified SIV epitopes by MHC-E is not the primary mechanism of protection introduced by RhCMV68-1/SIV vaccination.Graduate Educatio

Guarding Against Heedlessness: Time and Temporality Among the Early Ottomans

This dissertation explores the multifaceted nature of early Ottoman temporal culture, arguing against its characterization as a monolithic entity. Temporal culture here refers to the system of practices, beliefs, and attitudes through which Ottomans experienced time in their everyday lives as well as the cosmic sense shaped by religious frameworks. I argue ultimately that Ottoman temporal culture was characterized by a bimodal approach, balancing intersecting frameworks of time. The critical distinction I aim to draw is that bimodal, unlike binary, dichotomy, or duality, implies a more nuanced scenario in which the two parts are not necessarily opposites; there is room for overlap. Chapter One sets the groundwork by challenging the notion of modern time as wholly divorced from natural phenomena, using the regulation of atomic clocks by leap seconds as an example. This contextualizes the history of temporal systems, focusing on variable “temporal hours” and fixed “equal hours.” The chapter argues that the Ottomans employed both systems pragmatically, illustrating that temporal (also known as seasonal) hours—aligned with natural cycles of light and dark—were not less sophisticated than equal hours associated with mechanical clocks. While clocks were present in Ottoman society from the late sixteenth century, their adoption of equal hours cannot solely be attributed to technological determinism. This chapter underscores how temporal practices served diverse societal needs. Chapter Two examines the Ottoman use of multiple calendars, introducing the concept of “calendrical pluralism” to describe the coexistence of systems like the Hijrī, Rūmī, and Folk calendars. Each calendar had distinct origins, purposes, and contexts, reflecting the multicultural and syncretic nature of medieval Anatolian society where such calendrical pluralism could flourish. The Ottoman Rūmī calendar, derived from the Julianized Seleucid Era, was widely used well before its official adoption in 1677 and was influenced by Syriac and Greek traditions. Additionally, the Folk Calendar, linked to agricultural cycles and festivals such as Ḫıḍrellez, exemplifies the integration of Mediterranean seasonal divisions into Ottoman temporal culture. This chapter demonstrates how these calendars operated along various bimodals, such as solar-lunar and seasonal-aseasonal, emphasizing the adaptability and complexity of Ottoman timekeeping. Chapter Three highlights the Hijrī calendar and its development as a purely lunar system. The calendar’s aseasonal nature is interpreted as a spiritual admonition against attachment to the transient, earthly realm, aligning with Islamic eschatological themes. The chapter also analyzes the Qurʾanic absence of the term zamān, often used to denote abstract time, and instead highlights terms like ʿaṣr and dahr, emphasizing the timelessness of the afterlife. Drawing on Sufi teachings, the chapter introduces the figure of the ibn-i vaḳt (son of time), who embodies the spiritual ideal of living in the eternal present. For ordinary believers, however, this ideal was tempered by anxieties about the temporal world and the afterlife, a theme further explored in subsequent chapters. Chapter Four shifts to popular Ottoman literature, examining works by Aḥmed Bīcān and Yazıcıoğlu Meḥmed, who synthesized Sufi mysticism and Hanafī orthodoxy into vernacular texts for recent converts to Islam. Alongside these, the chapter considers melhemes (meteorological prognostication manuals), which combined cosmic prognostication with spiritual comfort, reflecting the shared goal of addressing temporal and eternal anxieties. The figure of Ḫıḍır and the festival of Ḫıḍrellez serve as case studies of Ottoman syncretism, integrating Islamic, Christian, and local traditions into a cohesive temporal-spiritual framework. Finally, Chapter Five explores early Ottoman historiography, particularly historical almanacs embedded in astrological texts. These almanacs, employing a reverse-dating system, linked past events to cosmological patterns, aligning historical narratives with Ottoman state-building ambitions. By situating the empire within a purposeful chronology, these texts echoed the Sufi emphasis on the present as the intersection of the past and future. This chapter demonstrates how state-centered histories paralleled individual spiritual frameworks in providing continuity and meaning. This dissertation does not claim to uncover all Ottoman temporal bimodals but instead highlights how these intersecting frameworks resisted the formation of a unified temporal culture. By examining calendrical, spiritual, meteorological, astrological, and historical traditions, it reveals how Ottoman temporality defied simple categories and instead inhabited multiple bimodal frameworks, offering insights into broader questions of time, culture, and meaning in the premodern world.Middle Eastern Studies Committe

Debugging and Help-seeking with Chatbots in CS1

For many beginner programmers, encountering errors in code can be frustrating and disheartening—leading some to questions their belonging in computer science (CS). In these moments, timely debugging help is essential to sustain motivation and foster learning. While students have traditionally turned to peers or teaching assistants for guidance, many now seek debugging support from conversational Large Language Models (LLMs). These chatbots offer promise in providing immediate help, but their ability to generate full-code solutions raises concerns about learning and over-reliance. As these tools become more prevalent, it is important to understand how they can be used to support student's in their debugging and how students seek-help with chatbots. This dissertation explores how students interact with chatbots in introductory computer science courses (CS1) and opportunities to support debugging. The research is presented in a three-paper format. The first paper examines past debugging interventions before the rise of LLMs, identifying gaps that these tools could potentially address. The second paper presents findings from student interviews about their experiences using a course-integrated chatbot, highlighting how they engage with the debugging assistance throughout the semester and their evolving beliefs about appropriate chatbot use. The third study analyzes naturalistic chat data and survey responses in another CS1 course to investigate how students' goal-orientation and beliefs associate with their help-seeking behaviors. The findings from this dissertation offer insights into designing course chatbots and instructional framing around chatbot use to support students' debugging and learning.Educatio

Mechanism of replisome-mediated parental histone inheritance

Inheritance of histones from parental DNA during DNA replication is important for the maintenance of epigenetic information and chromatin assembly. Decades of studies have demonstrated that parental histones are symmetrically segregated to the two newly synthesized daughter DNA strands. However, the mechanism(s) by which parental histones are inherited in coordination with DNA replication remain unclear. In my Ph.D. thesis, I use an inducible heterochromatin domain in Schizosaccharomyces pombe as a model system to study the requirement of a replisome-associated histone chaperone network for epigenetic maintenance of heterochromatin. Using this system, I demonstrated that several previously reported replisome-associated histone binding proteins and the histone chaperone FACT are required for epigenetic inheritance of heterochromatin. In addition, I discovered that epigenetic maintenance of heterochromatin requires the full fork protection complex consisting of Swi1, Swi3 and Mrc1 proteins. In particular, I showed that the non-essential DNA checkpoint factor Mrc1 is required for epigenetic inheritance through a newly identified conserved histone binding activity. Through collaborations examining the parental histone occupancy at newly synthesized DNA, we discovered that mutations in the Mrc1 histone-binding domain disrupt parental histone transfer to both the leading and lagging DNA strands. Using AlphaFold predictions, I found that the Mrc1 histone-binding domain preferentially locates at the center of the replication fork, suggesting that Mrc1 acts as a parental histone distribution site in the replisome. With additional AlphaFold predictions, I identified multiple histone-binding domains and FACT-binding domains in the replisome. Several subcomplexes containing FACT and histones are predicted to form through these interaction interfaces. Genetic and biochemical experiments further confirmed that these newly identified interaction interfaces are required for heterochromatin maintenance. Collectively, these data led me to propose a model by which parental histones are captured by the FACT complex from the partially disassembled nucleosome induced by the replicative helicase and then inherited through multiple histone transfer intermediate sites at the replication fork. My thesis work provides a mechanistic framework for studying the dynamics of parental histone inheritance at the replication fork. Future studies are needed to validate the presence of all parental histone transfer intermediate sites at the replication fork, determine the order of parental histone movements, and investigate the role of replisome-mediated parental histone inheritance in the development of multicellular organisms.Biological and Biomedical Science

Integrating Mobile Health Technology into Sleep Research and Environmental Epidemiology

Sleep is fundamental to human health. In aspects of both duration and quality, the majority of adults in the United States suffer from suboptimal sleep. During sleep and during wake, through the simultaneous presence of sensory stimuli, neighborhood-level contextual factors, and structural forces that inform our movement through a city, our environments affect our sleep. Sleep is an outcome that individuals experience on a daily basis and environmental exposures are ubiquitous; therefore, interrogations of the relationship between sleep and environment can be highly impactful for advancing public health. Using sleep data collected in the prospective cohort of the Nurses’ Health Study 3, this dissertation explores how mobile health technologies like consumer wearable sleep trackers and smartphone global positioning systems (GPS), as well as exposome-based approaches that aim to capture an individual’s environmental exposures more comprehensively, can increase the depth of insights from sleep research and environmental epidemiology. In Chapter 2, we quantified differences in sleep measurement between a consumer wearable and a research-grade accelerometer in free-living adults. We observed modest differences in measurement of total sleep time, time in bed, and sleep efficiency between the consumer wearable (Fitbit) and research-standard actigraphy. In Chapter 3, we examined the association between daily GPS-derived walkability exposure and consumer wearable-measured sleep. We did not observe an association between walkability and sleep duration or sleep efficiency. In Chapter 4, we investigated the associations of multiple environmental exposures assessed at the residential address, including greenness, light at night, noise, neighborhood socioeconomic status (SES), and walkability, with self-reported sleep duration and quality. We observed consistent associations between higher neighborhood SES and reduced odds of adverse sleep health outcomes. We also observed protective associations for light at night, and harmful associations for noise and greenness. With these three dissertation aims, we examined how measurement tools, study design, and exposure assessment approaches can be improved to advance studies of sleep and the environment. We first demonstrated viability for consumer wearables in epidemiologic studies. Then, we illustrated how they can be embedded into a population-level study alongside smartphone GPS to study an environmental exposure, walkability. Finally, we expanded the range of exposures studied with sleep and identified neighborhood SES as a key environmental contextual factor impacting sleep health in the US. Together, this body of work contributes to our understanding of how modifiable environmental exposures can be leveraged to improve sleep on a population-level.Population Health Science

Elucidating novel chemical and genetic mechanisms of LSD1-HDAC1/2-CoREST complex regulation

Protein complexes have a wide range of functions that can be modulated through both enzymatic activity and protein-protein interactions. In efforts to design small molecule therapeutics that target specific protein functions, molecules with diverse mechanisms of action have been developed. Traditionally, drug design has focused on inhibiting an enzyme’s catalytic activity, either by directly blocking its active site or by designing an allosteric modulator. However, beyond catalytic function, enzymes often serve as scaffolds that mediate interactions with other proteins—interactions that influence the overall function of a protein complex within cells. Discovering new small molecule modalities that selectively target one function of a protein can optimize therapies for various disease indications, while also offering insight into novel mechanisms of protein regulation and disease pathogenesis. In this thesis, I investigate the mechanisms of action of two recently developed small molecule modalities targeting the LSD1-HDAC1/2-CoREST (LHC) complex and uncover how mutations in an E3 ligase substrate adaptor lead to a new mode of LHC complex dysregulation in cells. In Chapter 1, I provide an overview of the LHC complex and key structural studies that have elucidated its fundamental functions and biological roles in cells and human development. I then review its involvement in disease and therapeutic applications, which has driven efforts to identify small molecules that target the complex. Finally, I introduce the concepts of targeted protein degradation—a therapeutic strategy recently applied to targeting the LHC complex—and genomic screening methodologies that we have used to evaluate novel mechanisms of protein regulation. In Chapter 2, I describe our work elucidating the mechanism of action of the small molecule T-448, an LSD1 inhibitor that selectively targets enzymatic activity while preserving LSD1’s interactions with transcription factors. Through mass spectrometry and structure-activity relationship studies with T-448 analogs, we found that T-448 forms a covalent drug-FAD adduct in LSD1’s active site, which subsequently undergoes Grob fragmentation to yield a compact formyl-FAD adduct. This adduct preserves LSD1’s scaffolding function with transcription factors such as GFI1/GFI1B, thereby reducing hematological toxicity and making T-448 a more promising candidate for treating neurological disorders. Additionally, we show that this conversion from drug-FAD to formyl-FAD can serve as a resistance mechanism in AML cells. Using CRISPR suppressor scanning, we previously identified a loop deletion mutation distal to the catalytic site that confers resistance to certain LSD1 inhibitors through this mechanism. Altogether, this work highlights how small molecule design can target specific LSD1 functions and how distal loop mutations can impact drug mechanism of action. In Chapter 3, I detail our investigation into the mechanism of action of another LSD1-targeting molecule, UM171. It was initially identified in a phenotypic screen and later shown to induce degradation of LSD1 and CoREST via the E3 ubiquitin ligase substrate adaptor KBTBD4, however the direct binding partners of UM171 remained unknown. Using fluorescence-based cellular assays and biochemical binding studies, we determined that HDAC1/2 is the direct binding partner of UM171 within the LHC complex. UM171 acts as a molecular glue and increases the affinity between LHC and KBTBD4. We validated this by solving a cryo-EM structure of the KBTBD4-UM171-LHC complex and unexpectedly identified a second molecular glue—inositol hexakisphosphate—at the binding interface. The structure revealed that the KBTBD4 dimer engages a single copy of the HDAC1/2-CoREST complex asymmetrically. Additionally, base editing scanning was performed and confirmed UM171’s binding sites. This was the first study to elucidate the binding mode of a molecular glue that engages a Cullin3 E3 ligase substrate adaptor, revealing the mechanism behind LSD1 and CoREST degradation. In Chapter 4, I move beyond small molecule regulation to explore how mutations can also modulate protein-protein interactions. In medulloblastoma, complex insertion-deletion and substitution mutations have been found in a single loop in the Kelch domain of KBTBD4. In patient-derived xenograft models harboring these mutations, CoREST and LSD1 levels are depleted and knockout of mutant KBTBD4 rescues these protein levels. Through a series of biochemical assays, we also discover that the mutant KBTBD4 have increased binding affinities to LHC. To understand the scope of these gain-of-function mutations, we performed a deep mutational scan of the loop mutated in medulloblastoma. Surprisingly, a wide array of mutations promoted CoREST degradation and further analysis was performed to determine the types of mutations that had the strongest phenotype. Structural studies were performed to determine how these KBTBD4 variants were engaging the LHC substrate and revealed that mutant KBTBD4 mimics the UM171-induced binding mode observed in Chapter 3. This structural insight prompted us to test known HDAC active-site inhibitors as a potential therapeutic strategy to disrupt the mutant KBTBD4-LHC interaction. Through this study, we show that KBTBD4 cancer mutations chemically and functionally mimic UM171 and that deep mutational scanning can identify mutations that drive substrate degradation. We also demonstrate that active-site inhibitors can be repurposed to disrupt pathogenic protein-protein interactions. Overall, this thesis showcases multiple ways to perturb the LHC protein complex, via distinct small molecule modalities and neomorphic mutations that induce novel protein interactions leading to degradation. These studies not only teach us how we can differentially regulate the LHC complex for different therapeutic applications but also serve as an instructive example of how we can use both chemical and genetic methodologies to induce similar phenotypic effects. This work opens the door to applying high-throughput genomics to discover novel modulators for other protein complexes and cellular pathways in various disease contexts.Chemistry and Chemical Biolog

Building Beyond the Standard Model: Tools from Cosmology to Particle Theory

The current landscape of high-energy theory and cosmology suffers from an abundance of theoretical models coupled with a lack of immediate new data to constrain them. This thesis addresses several open questions in early-universe cosmology and beyond-the-Standard-Model (BSM) particle physics, specifically focusing on inflation, dark matter, axions and axion strings, and baryogenesis. Rather than relying solely on forthcoming experimental results, I argue for refining the BSM model space through theoretical consistency checks and cross-examination against multiple existing datasets. For instance, inflationary models often encounter severe naturalness (or $\eta$) problems; applying effective field theory techniques and symmetry considerations helps exclude models that fail these theoretical standards. Similarly, axion models naturally predict distinctive topological defects, such as axion strings, allowing their observational signatures (or lack thereof) to impose valuable constraints. On the observational side, I emphasize that jointly analyzing the Hubble and large-scale structure (LSS) tensions can significantly constrain dark-sector theories. Additionally, I introduce a novel observational probe, analyzing the effect of early universe inhomogeneities generated prior to Big Bang Nucleosynthesis (BBN) on predicted deuterium abundances. This probe rules out baryogenesis scenarios that produce excessive inhomogeneities which are not fully erased by diffusion, and it can potentially constrain regions of parameter space in prominent high energy scale models such as electroweak baryogenesis (EWBG). Together, these theoretical and observational approaches offer robust methods for refining the BSM landscape and demonstrate the critical role particle theorists can play in interpreting cosmological data, even in the absence of new experimental results.Physic

The Future as Warning: Narrative Voice and Literary Form in Modern Dystopian Novels

Since modern dystopian fiction appeared in the wake of the First World War and the Russian Revolution, texts in the genre have warned against the dreadful consequences that could result from current sociopolitical trends and have sought to intervene in the present to prevent the manifestation of nightmarish futures. During this time, Anglophone dystopian novels have frequently eschewed the transparent first- and third-person narrators that dominate both realist literary fiction and genre fiction, instead favoring conspicuous and estranging voices. Putting narrative theory in dialogue with dystopian scholarship, “The Future as Warning” investigates this under-researched phenomenon, exploring the relationship between narratorial form, thematic content, and ideological messaging in dystopian fiction. Analyzing texts by American, British, and Canadian writers, as well as one influential Russian, this dissertation examines four narratorial forms that recur across twentieth- and twenty-first-century dystopian novels: the plural first-person we-voice, narration in an invented future version of English, the diary conceit, and the found-document conceit.Englis