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The evolution of Oskar function in insects
No full textThe emergence of genetic novelty underlies major shifts in the evolution of development. In this thesis, I investigate evolution in primordial germ cell specification in insects, with a particular focus on the gene oskar. As a lineage-restricted, rapidly evolving gene with essential roles not only in the germ line, but also in the developing nervous system of some species, oskar presents a compelling case study of how genetic innovation drives phenotypic evolution. First, I synthesize observational and experimental data on the origin of primordial germ cells to describe how germ cell specification has evolved in insects, and more broadly across panarthropods. I also speculate on how evolution in germ line gene expression and function may drive shifts in the mechanisms of germ cell formation. Next, I specifically investigate evolution in oskar, which has undergone functionally significant sequence divergence over a short evolutionary timescale. I determine how protein-coding sequence differences between oskar orthologs from Drosophila melanogaster and D. virilis prevent the D. virilis ortholog from rescuing D. melanogaster oskar loss-of-function. I identify domains of the D. virilis Oskar protein that differentially impact localization of germ line and patterning determinants and dramatically influence downstream cell fate decisions. By leveraging this natural sequence variation as an evolution-guided mutagenesis strategy, I uncover new insights into the in vivo mechanisms of Oskar function. These experiments also reveal how oskar gene dosage affects germ plasm assembly and germ cell specification, shedding light on how embryos respond to changes not only in gene sequence but also quantity. Finally, I explore the potential co-option of oskar to different tissue contexts. I present preliminary data testing the hypothesis that oskar is expressed in the central nervous system of D. melanogaster, and I describe ongoing efforts to characterize oskar expression and function in other insect species. This broader comparative approach will eventually allow us to reconstruct the trajectory of oskar’s functional evolution across insects. I conclude by outlining promising directions for future research into the evolution of development, particularly through the lens of the genes that both influence and are influenced by these processes.Biology, Molecular and Cellula
Solo in Good Company
No full textSolo in Good Company: A Memoir of Risk, Tenacity, and Building an Architecture Firm while Manifesting a Bountiful Life, recounts the author’s fifty year journey from Wyoming to building a prominent architecture firm in New York City. During this time, the author relied on strong instincts, personal skills, perseverance and tenacity to face harrowing setbacks and ultimately succeed in a male dominated profession. This is a modern-day adventure story about a woman who pushes the envelope, not afraid to put herself on the line. It is an affirmation of an alternative way for a woman born in the early 50s who is determined to live her best life, against all odds. Her stories take the reader from New York City in the late 70s and 80s, describing life on the fringes of the fast lanes of fashion, finance, music and art, to explorations in far flung corners of the world including Africa, India and the Arctic. The thesis describes lessons she learned as a young female corporate executive and explores her connections to the people and places of the world that gave her the confidence necessary to make it on her own.
Solo: on one’s own. In Good Company: with the support of others. Solo and never alone.Extension Studie
Novel mechanisms of gene regulation driving aggressive leukemias
Full text linkAcute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases coopting stem cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, I engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell-like states by directly repressing prodifferentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kb downstream of the myeloid differentiation regulator CEBPA, is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo. In an effort to translate these biological insights into a therapeutic strategy, this work also explored the use of heterobifunctional small molecules and chemically induced proximity to rewire MECOM transcriptional activity. While efficacy was limited, this portion of the study revealed key principles to consider when aiming to therapeutically engineer and reprogram transcription in this manner. In sum, these findings suggest a broadly applicable approach for functionally dissecting oncogenic gene regulatory networks to inform improved therapeutic strategies.Biological and Biomedical Science
How Culture Drove Us Into the Cognitive Niche
Full text linkHow have humans become such outliers in our behavioral flexibility and our rapid learning? How have our brains evolved to learn and reason in evolutionarily novel domains, such as mathematics and number systems, laws and mores, or science and medicine? In this dissertation, combining work in cognitive science and cultural evolution, I seek to answer such questions by building informational-ecological models that show how minds that perform different computational strategies fare under different conditions. In the first chapter, I show, using a simple and general model, that any species that is heavily dependent on social learning to acquire much of its adaptive behavior would evolve to make increasingly accurate generalizations. This in turn demands greater mental capacity to learn abstract concepts and world-models. This model ties the evolution of our brains directly to the fact that our babies can expect to be born into a world where they can learn from other skilled individuals. However, our nature as a cultural species has done more than just making available skilled models to learn from. Culture can shape our informational environments (i.e. informational niche construction) in other ways as well. In chapter two of my dissertation, I show how differences between cultural populations in communication styles, or in how knowledge flows across a population, can alter how information is sampled, in such a way as to explain computationally why different cultural groups develop Analytic or Holistic thought--a major distinction made by cross-cultural psychologists. In the third chapter, I extend this informational-ecological perspective to the physical world of tools and dwellings, and the social world of norms, institutions and organizations, to show how the phenomenon of standardization in cultural products is yet another form of informational-niche construction, with far-reaching consequences that explain a wide range of cross-cultural findings in cognitive psychology, sociology, anthropology and political science. One source of increasing standardization in a cultural system is increased population mobility, and on my final chapter, I present archaeogenetic work showing how an ancient episode of increased mobility has led to the development of just such a standardized suite of bronze weaponry that took on ritual, political and economic significance across Northern Eurasian societies in the Bronze Age.Human Evolutionary Biolog
Learning to Lead Many: Online Algorithms for Bayesian Stackelberg Games
Full text linkA \textit{Stackelberg Game} models a strategic interaction in which a leader takes an action that influences the behavior of the followers. Stackelberg games have been applied in various real-world domains, including security, transportation, computer networks, and supply chains. In many practical settings, the leader often faces uncertainty about key environmental parameters, requiring them to learn and adapt over time. We consider a \textit{Bayesian} Stackelberg Game, where followers have private types unknown to the leader. These types represent the followers' private information. The followers each have one of types, which may be either independent or correlated with other followers. The leader's objective is to learn about the environment (i.e. the distribution over follower types) in order to compute an optimal strategy. We formulate this as an \textit{online learning} problem, where the leader repeatedly plays the Stackelberg Game over rounds, with follower types drawn from an unknown but fixed distribution at each interaction. The leader's goal in this setting is to minimize their \textit{regret}, defined as the cumulative difference between the utility of the optimal fixed strategy and that of the strategy that they choose at each round. This thesis theoretically and empirically analyzes the regret of various learning algorithms for the leader. Under \textit{type feedback}, where the leader observes the followers' types after each round, we design learning algorithms that achieve an \textit{upper bound} of on expected regret. Under \textit{action} feedback, where the leader only observes the followers' actions, we design algorithms with at most regret. Furthermore, we establish a \textit{lower bound} of on the regret of this learning problem.Computer Scienc
Investigating the Mechanisms of Cholesterol 25-Hydroxylase in Promoting Pulmonary Fibrosis
No full textPulmonary fibrosis is a chronic and fatal disease characterized by progressive lung scarring. In many cases, its etiology is not fully understood, and treatment options are limited due to the complexity of profibrotic signaling pathways and the interplay between multiple cell types involved in the pathogenesis. Emerging studies have linked disruptions in lipid metabolism to pulmonary fibrosis, though the underlying mechanisms remain poorly defined, and some studies have reported contradictory findings. Our lab recently identified that cholesterol 25-hydroxlase (CH25H), an enzyme that converts cholesterol to 25-hydroxycholesterol (25-HC), promotes lung fibrosis elicited by diverse exposures including the common aeroallergen Alternaria Alternata and the chemotherapeutic agent bleomycin. To further understand the cellular and molecular mechanism(s) by which this occurs, we assessed the function of 25-HC in murine lung in vivo and in human fibroblasts in vitro. We found that 25-HC upregulates type 1 collagen expression in murine lungs and in human lung fibroblasts, suggesting that it promotes the activation of fibroblasts to myofibroblasts, a pathological cell state that readily remodels and stiffens the extracellular matrix. We showed that 25-HC-induced collagen upregulation in human lung fibroblasts is dependent on RORa activation, and also likely involves LXR and av integrin/FAK activation. Furthermore, CH25H is upregulated in lung fibrobalsts by several pro-fibrotic factors including TGF-β1, bleomycin, and the type 2 inflammatory cytokines IL-4 and IL- 13. Collectively, our findings suggest that CH25H drives pulmonary fibrosis through promoting lung fibroblast activation via the 25-HC/RORa axis. This potentially suggests a novel mechanism through which dysregulated cholesterol metabolism exacerbates pulmonary fibrosis and may offer new therapeutic targets for the disease.Graduate Educatio
Investigating the Assumptions in Current Methods of Observing and Modeling Tropical Vertical Motion Profiles
Full text linkThis thesis investigates tropical vertical motion profiles using both observations and modelling work. Firstly, we investigate if we can use in-situ observations of heavy-water isotopologues in rainfall to understand vertical motion profiles in the tropics. Next, this thesis will also systematically investigate the different methodologies used to parameterize the large-scale tropical circulation in idealized small-domain simulations, and the differences between them, and whether we can assume that these different schemes are interchangeable. Lastly, I also discuss what these different parametrizations can tell us about convective organization in idealized large-domain simulations, and also within the tropics.
Previous work has provided proof-of-concept in using in-situ observations of depletion of heavy-water isotopologues to understand vertical motion profiles in the tropical East Pacific. Using station observational data collected around the time of the OTREC field campaign and after, we show that top-heavy convection results in rainfall that is more depleted in heavy-water isotopologues such as HDO and HO. However, these trends of depletion are not spatially consistent, resulting in rainfall that may be more enriched in one location compared to other locations despite having similar rainfall rate and vertical-motion structure. We verify these results using realistic WRF simulations, and based on our results, we provide another metric to measure top-heaviness, one that is also partially dependent on vertical moisture advection.
Next, we discuss how large-scale vertical motion profiles are parameterized in idealized small-domain models using the WTG framework. Ever since the canonical formulation of the WTG, adjustment schemes utilizing its explicit and implicit forms have become ubiquitous when modelling tropical convection in small-domain simulations. However, despite the prevalence of these schemes in modelling work for tropical climate, they often produce noticeably different vertical motion structures. For example, the original Weak Temperature Gradient formulation of Raymond and Zeng [2005] is known to produce vertical-motion structures that are more top-heavy than the Damped Gravity Wave formulation of Kuang [2008] and Blossey et al. [2009]. We show that the differences observed when using different WTG-adjustment schemes are often more pronounced under more idealized conditions, and can be traced back to how different WTG-adjustment schemes treat the different vertical modes.
Lastly, most past research surrounding small-domain simulations in the WTG framework have focused on the analogues to the wet- and dry-regimes of self-aggregation in large-domain simulations. My work also shows that the WTG framework is potentially able to attain analogues to convectively-coupled waves (CCWs) in small domain simulations. Model runs in large-domain simulations are able to replicate these CCWs regardless of radiative scheme. We note that despite prevalence of convective organization in the form of CCWs across all large-domain simulations we have run, it is still a somewhat overlooked aspect of convective organization, as current work on this field predominantly focuses on self-aggregation of convection.Earth and Planetary Science
Mimi and the Jackalope
No full text“Mimi and the Jackalope” is a midgrade portal fantasy set in West Texas during
the early years of the Operation Iraqi Freedom (OIF) and Operation Enduring Freedom
(OEF) campaigns in the Middle East. In this story, a young girl—Mimi—is raised by her
older half-sister, a veteran of OIF/OEF. Mimi has difficulty understanding the way her
sister’s PTSD manifests and seeks escape by having imaginary adventures in the rugged
environment of West Texas. During one of these adventures, Mimi encounters a mythical
Jackalope that is entirely real. She follows this Jackalope to a world populated by elves,
fairies, dragons, and other fantastic beings. As she explores, she realizes that the citizens
of this world are on the brink of their own war. Mimi ultimately must find a way to
communicate with her older sister in order to protect the fairy world she has come to
love.
“Mimi and the Jackalope” is a portal fantasy, but it is also a war story. It is not a
story about fighting wars, but a story about the human cost of fighting wars. This story
pre-supposes (and argues) that war has a lasting traumatic effect not only on the fighters,
but also on all the friends and relatives of the dead, wounded, and witnesses. Even though
this story deals with mature themes such as war, PTSD, substance dependency, death,
and child neglect, these themes are handled in an age-appropriate way that is suitable for
midgrade readers.Extension Studie
Reptin is Required to Maintain Cardiomyocytes in a Proliferative Diploid State
No full textCardiomyocyte proliferation drives the addition of new myocardium during heart development and regeneration. We previously reported that the ATPase Reptin is a suppressor of cardiomyocyte proliferation in zebrafish as reptin mutant hearts show increased BrdU incorporation at 3 days post fertilization (dpf). In chapter 2, we determine that the ATPase function of Reptin is essential for its ability to repress cardiomyocyte proliferation at 3 dpf before making the paradigm shifting discovery that despite being hyperproliferative at 3 dpf, reptin-/- cardiomyocytes exhibit an anti-proliferative transcriptional profile. We then demonstrate that reptin-/- cardiomyocyte proliferation rates significantly decrease by 5 dpf and that reptin-/- cardiomyocytes accumulate in a polyploid state. The loss of Reptin drives cellular senescence but not an accumulation of DNA damage or apoptosis in cardiomyocytes. Through RNA-sequencing we identify several pathways and cellular processes which are dysregulated in reptin mutants including AP-1, tp53, cbx7a, and midbody/cytokinesis. We investigate the role of these mechanisms and their relationship to Reptin’s ability to regulate cardiomyocyte proliferation. We show that AP-1 signaling plays a role in controlling ventricular area in reptin mutants, but its effects on proliferation in reptin mutant hearts remain unclear. We further demonstrate that tp53 and cbx7a are not major drivers of the later stage cell cycle exit observed in reptin-/- cardiomyocytes. We further observe using human iPSC derived cardiomyocytes that Reptin localizes to the midbody of cytokinetic cardiomyocytes. We show that in mice, like zebrafish, Reptin is required for healthy heart development and the maintenance of cardiomyocyte proliferation. In the mouse, we show that the regulation of cardiomyocyte cell cycle exit by Reptin is cell autonomous and like in zebrafish loss of Reptin does not result in the significant induction of apoptosis. Our work has led to a new model whereby Reptin initially represses cardiomyocyte cell cycle entry in early heart development, but that it is required to maintain cardiomyocytes in a proliferative diploid state over the course of cardiac development. Since the major barrier to heart regeneration is cardiomyocyte cell cycle exit, therapeutic manipulation of Reptin could be used to stimulate renewal of the diseased heart.Biological and Biomedical Science
Tank Imaginaries! Rethinking Water Infrastructure Design in Bengaluru
No full textScattered across Bengaluru is a vast network of manmade lakes (also called “tanks” or keres). Over the last fifty years, this once provisional water infrastructure has been disrupted by rapid urbanization. Under the pretext of conservation, many lakes are currently being restored, however this same narrative is also used to limit access, regulate usage, and diminish holistic spaces. This thesis uses Bengaluru to investigate how water infrastructure can become a central protagonist in the city—an organizing force in fostering new imaginations of public space, civic engagement, and ecological awareness. The first written component skewers current approaches to the tanks, suggesting alternative models of polyfunctional use. The second component presents design scenarios for Bellandur lake at different scales, producing typology toolkits and mechanisms of governance for each. Combined, these are presented as an instrument of advocacy for not just redesigning Bengaluru’s lakes, but critically reimagining urban water infrastructure more broadly.Department of Urban Planning and Desig