22689 research outputs found
Sort by
Insights into the diversity of human gene regulation and functional genetic variation
Full text linkGene regulatory networks and functional genetic variation that confers differences in regulation between individuals are major contributors to the development of human traits and disease. In this dissertation, I describe several new resources to facilitate a deeper understanding of the diversity of human functional genetic variation and of the molecular mechanisms by which such variation drives human complex traits. I first describe the development of a large globally diverse human RNA-sequencing resource, which I used to uncover expression- and splicing-associated genetic variation, and to explore the prevalence and nature of functional variation private to populations historically underrepresented in human genetics research. Next, I describe a database of candidate cis-regulatory element (cCRE) annotations derived from a model of epigenetic signatures in the hematopoietic lineage, and verify the enrichment of these cCREs in heritability of human blood-related traits. Finally, I describe the development of the first truly complete human genome by the Telomere-to-Telomere consortium, and I benchmark the utility of this assembly as a reference genome in characterizing human functional genetic variation, particularly in regions of the genome that were previously unresolved. Together, this work provides deeper understanding of the sources of variation in genome function across diverse human populations, while providing valuable resources to facilitate exploration of the molecular mechanisms underlying human traits
Developing A Quantitative Systems Pharmacology Model for Clinical Trial Simulation in Immuno-Oncology
Full text linkWhile the number of clinical trials has increased over the past decades, the success rate of oncology trials remains the lowest among all therapeutic areas. This challenge necessitates the development of computational tools to inform clinical trial design. As a mechanistic modeling approach, quantitative systems pharmacology (QSP) models have been used in new drug applications to determine optimal dosage and predict drug effectiveness in humans. As part of the effort, I developed a modular QSP platform in immuno-oncology (QSP-IO) that describes the cancer-immunity cycle, which allows for simulation of tumor growth under treatments of interest, including immune checkpoint inhibitors (ICIs), small-molecule inhibitors, and chemotherapy. The model has been applied for clinical trial simulation in both retrospective and prospective settings for multiple cancer types. More recently, I generated a virtual patient population with non-small cell lung cancer that statistically matched the immuno-genomic data and agreed with the digital pathology analyses on tumor samples from real patients. With the validated virtual patient population, the QSP model was shown to provide reliable prediction of clinical response to ICIs when compared to clinical analyses. When combined with machine learning approaches, the model also identified predictive biomarkers and proposed cutoffs to select patients who are likely to become responders. Overall, my work aims to demonstrate the robustness of virtual patient generation methods and the application of QSP modeling in model-informed drug development
High-resolution characterization of HIV and extracellular vesicles by STORM-FISHing: combining dSTORM and smFISH
Full text linkOver the last two decades, advancements in optical microscopy have led to the development of a variety of super-resolution microscopy (SRM) methods, each with the capacity to examine subcellular structures at high resolution, including the virions of exogenous viruses such as human immunodeficiency virus (HIV) and host extracellular vesicles (EVs). Accurately identifying and characterizing complete virions within complex biological samples is essential for advancing our understanding of the structural diversity of virions and virus-like particles. However, few approaches take advantage of the detailed structural insights that SRM can offer to characterize free-floating virions and multiple types of molecules associated with them. In this study, we evaluate STORM-FISH, a dual-labeling technique that combines antibody-based HIV protein labeling and smFISH-based HIV RNA labeling with dSTORM for accurate, high-resolution characterization of HIV virions. Using smFISH probes specific to BaL HIV vRNA, we observed high specificity for virion labeling in dSTORM imaging, with minimal levels of binding in control samples (DCL4 plant probes and non-BaL HIV strains). While individual labeling of viral proteins (gp120) alone resulted in considerable non-specific binding to host-derived EVs, the combined use of gp120 antibodies and BaL smFISH probes allowed clear identification of complete BaL HIV virions, as demonstrated by distinct populations of double-positive (BaL smFISH+/gp120+) and triple-positive (BaL smFISH+/gp120+/CD63+) particles. Interestingly, the smFISH probes sometimes localized externally to gp120+ particles, raising questions about the origin of this potential external vRNA. The high-resolution imaging capabilities of STORM-FISH allow for detailed analysis of virion structure, protein localization, and component orientation, facilitating deeper insights into the structural dynamics of HIV. Our results validate STORM-FISH as an effective technique for dual protein/RNA labeling of free-floating virions in dSTORM microscopy and could translate well into furthering virological research and characterization of therapeutic extracellular vesicles or virus-mediated gene delivery systems
SPECIAL AFFECTS: DIGITAL EFFECTS LABOR AND SCIENCE FICTION CINEMA AFTER HOLLYWOOD’S DIGITAL TRANSITION, 2009-2019
No full textStarting in the early 1990s, the U.S. film industry was slowly but radically transformed by the emergence and widespread adoption of digital technologies. Promising reduced production costs and greater creative freedom, digital filmmaking and distribution tools increasingly replaced older analog systems and jobs, heralding a “digital transition” that would affect every level of Hollywood production. Special Affects offers a literary and economic history of the aftermath of this transition. It does so by examining the production and distribution of novel digital filmmaking techniques in science fiction cinema and television in the decade after Avatar.
As one of the genres most closely associated with the rise of the blockbuster, Hollywood science fiction tends to self-referentially draw upon its own history for narrative raw material; in this way, it typifies the industry’s reliance upon nostalgia during the digital turn. I argue that the key to this doubled pastiche lies in a homologous operation at the level of effects, where state-of-the-art film production technologies digitally recreate older practical effects and visual logics—and thus also remediate audience and producer sentiment toward these older artefacts. These “special affects” thus co-produce Hollywood nostalgia. Where film scholarship tends to treat special effects as a symptom or theme of other concerns, and thus risks abstracting effects from their material context, this dissertation follows calls from scholars such as Julie Turnock to foreground the technical, historical, and aesthetic continuities across special effects practice. Special Affects thus emphasizes the stylistic and formal organization of digital special effects in film and television. It examines three key moments in the production and distribution of new effects: from blockbuster filmmaking’s capital-intensive experiments with tools and workflows; to their cheaper and streamlined use in network television; and, finally, the transition to streaming and virtual production with its renewed declarations of a ‘frictionless’ and democratized filmmaking practice. Situating the history of the digital transition within a broader account of capitalist development and crisis, Special Affects shows how, on the one hand, these changes are aesthetically liberating, but, instead of democratizing art, digital cinema developments largely function to decrease capital’s labor costs
A Functional Approach to Cycle Decompositions
Full text linkThis thesis explores developments both from 1960s and more recently regarding functional graphs
and how different types of labelings relate to cycle decompositions. Motivated by Rosa, Abrham,
Kotzig, Häggkvist, and Gnang, it is of great interest to build upon their results and ask if a graph
consisting of cycles of length power of two together with a loop edge admits oriented β labeling.
We will briefly talk about the integrations of previous results, and review some important theorems
that motivates this thesis in the first chapter. Chapter two will be devoted to unfold the theorem
by Kotzig and Abrham, which plays a crucial role connecting the key lemma the thesis is proving
and decomposition of graphs. In chapter three, we will first present some theorems that are not
central to proving the key lemma but extend the key lemma to proving Erdős-Gyárfás Conjecture.
In section 3.2 we will answer the question raised before by extensively using polynomial methods.
Although we believe that the last component of the lemma is true, it is not yet proved. Thus, we
put it in the chapter 4 together with possible directions for future works
Maternal nutrition influences offspring reward behavior and dopamine neurocircuitry
No full textMaternal obesity and overnutrition increases offspring’s risk of overweight and obesity, cardiovascular disease, diabetes, and psychiatric disorders. Increased weight gain, impaired metabolic hormone signaling, increased adiposity, and greater sensitivity to and motivation for palatable food and drugs of abuse are observed in offspring in experiments using a rodent model of maternal overnutrition in which dams are fed a high fat (HF) diet during gestation and lactation. Alterations to dopaminergic neurocircuitry, observed following exposure to a maternal HF diet, may contribute to these metabolic and behavioral outcomes. Here, we use amphetamine to characterize alterations to dopamine neurocircuits in rat offspring exposed to a maternal HF diet during gestation and lactation. We find sex-specific influences of maternal HF diet on locomotor activity and dopamine release in the nucleus accumbens shell in response to amphetamine. HF males exhibit greater increases in locomotor activity relative to offspring exposed to a perinatal standard chow (CHOW) diet than HF females. Conversely, HF females have greater increases in dopamine release than HF males. We also find decreased expression of dopamine transporter in the nucleus accumbens shell of male HF offspring. Next, we use immunohistochemical staining for cFos, a marker of increased neuronal activity, to examine activity of neurons in reward-related brain regions receiving dopaminergic input. Again, we found a sex-specific effect of HF diet on dopamine neurocircuits with HF females exhibiting increased and HF males, decreased or no differences in neuronal activity in the nucleus accumbens and caudate and putamen in response to amphetamine. Finally, we present our findings that HF female offspring maintained on a CHOW diet from weaning to adulthood have a hypolocomotor response to amphetamine relative to CHOW offspring. Exposure to a HF diet for 10 days restores that response to levels observed in CHOW offspring. HF females also consume more calories and have a stronger preference for HF diet than CHOW females during a 10-day food choice experiment. We interpret these findings as evidence of sex-specific alterations to dopaminergic neurocircuits, hypothesizing the involvement of modulation of DAT expression in males and a sex-specific rebalancing of D1- and D2-receptor expressing neurocircuits
A Leninist New Left: The Rise and Decline of the Chilean MIR 1957-1975
No full textThis dissertation examines the rapid development and subsequent decline of the Chilean Movimiento de Izquierda Revolucionaria (MIR) from 1965 to 1975. Among the insurrectionary movements promoting armed struggle in Latin America at the time, the MIR stands out for its success in growing rapidly through grounding its members in the urban and rural masses, and becoming a significant political force during the Salvador Allende government. Although the MIR relentlessly insisted on preparing for armed struggle, it was unprepared for the 1973 coup that overthrew Allende. Why did the MIR succeed in growing so rapidly and why did it ultimately fail to withstand the 1973 coup d’état and its aftermath?
The dissertation draws on a range of sources, including previously unmined documents from the Fundación Miguel Enríquez Archive. Part I reconstructs a narrative account of the MIR leadership’s trajectory from its members’ political initiation in 1957 to the party foundation in 1965, its peak in 1972-1973, and eventual decline following the coup d'état. It focuses on the critical role played by the small group around Miguel Enríquez and Bautista van Schouwen that constituted the MIR’s uncontested leadership. Part II re-analyzes the MIR’s 1969-1973 trajectory from three angles of vision, successively focusing on leadership, organization, and theory.
In contrast to the existing literature, which either tends toward hagiographic treatments of the MIR’s leaders or ignores the leadership entirely and focuses on grassroots mobilizations, I argue that the MIR leaders’ competencies were embedded in the party’s development. More specifically, their competencies were inseparable from the establishment of a democratic centralist organizational structure (1969), an institutionalized leadership (1970), and a political scientific research program (1972). Paradoxically, this focus on political development, coupled with the radicalization of the reform/revolution divide within Allende’s coalition, prevented the MIR from responding effectively to the military coup d’état.
The dissertation underscores the critical importance of small groups, leadership and strategy in building a class-independent party under democratic conditions, and contributes to debates in the fields of political sociology, organizational sociology, and the sociology of revolution
Evaluating the World Health Organization "Stop the Lies" Campaign: A Mixed Methods Proposal for Promoting Anti-Tobacco Advocacy Among Adolescents
Full text linkThe tobacco industry is using its marketing tactics at point-of-sale to market e-cigarette products as harmless and appealing to adolescents. E-cigarette prevalence is increasing among adolescents. The World Health Organization launched the Stop the Lies campaign to create awareness among youth about misinformation spread by the tobacco industry and change attitudes and beliefs about e-cigarettes. This proposed program uses Social Cognitive Theory (SCT) to create positive behavioral change through public health interventions like campaigns and evaluate the changes in attitude and belief about e-cigarettes among adolescents. This program will create awareness among youth with a presentation based on the Stop the Lies campaign and encourage youth advocates to disseminate the #tobaccoexposed materials on social media to influence other youth and their peers to expose the tobacco industry's tactics
MICROSTRUCTURAL EVOLUTION AND REACTION MECHANISMS IN MULTI-PHASE METAL SYSTEMS
Full text linkSelecting materials for high-strength applications typically requires sacrificing other properties to meet mechanical requirements. For applications in extreme environments, such as ships exposed to saltwater corrosion and large loads, polymer-based coatings are applied to protect the substrates, which are typically Ni- and Fe-based and prone to corrosion. However, these coatings are not robust and better solutions are required. We investigate the application of Ti-Cr coatings onto a variety of substrates to develop a procedure to generate a high-quality interface which has corrosion-resistant and mechanically robust phases. This work focuses on understanding the underlying reaction mechanisms and the effect of different alloying elements in generating a fully reacted substrate-coating interface.
The work of this thesis aims to elucidate the phase formation and microstructural evolution of interface reactions in metal systems of increasing complexity, beginning with ternary-type systems of Ni and Fe with Ti-Cr layers. The effect of different alloying elements is investigated using substrates of varying compositions, and the resulting phase evolution is tracked to determine the change in phase solubility and diffusivity. Increasing complexity is added by changing the morphology from high-contact area model bilayers to coated substrates. Two main methods of coating application are investigated; plasma-spraying, which results in a porous solid-solution phase Ti55Cr45, and a binder-sintered coating generated by applying a gel binder-powder mixture, which results in a gel-suspended phase-separated Ti55Cr45 powder as the coating. It was found that the coating-substrate reaction proceeds through a liquid-mediated mechanism, where high contact area allows the diffusion of Ni into the Ti-Cr phase, forming a layered interface and reaching the composition where a Ni-Ti eutectic liquid phase forms. This liquid phase facilitates interdiffusion of Ti, Cr, and Ni to allow fast growth of the reaction region, and to densify the applied coating into a highly dense, fully reacted coating with an interconnected interface with the applied substrate. The overarching theme of this work is studying the impact of different elemental compositions to determine the effect of processing conditions on the properties to expand the ability to tune the microstructural features scales to maximize performance
Evaluating the World Health Organization "Stop the Lies" Campaign: A Mixed Methods Proposal for Promoting Anti-Tobacco Advocacy Among Adolescents
No full textThe tobacco industry is using its marketing tactics at point-of-sale to market e-cigarette products as harmless and appealing to adolescents. E-cigarette prevalence is increasing among adolescents. The World Health Organization launched the Stop the Lies campaign to create awareness among youth about misinformation spread by the tobacco industry and change attitudes and beliefs about e-cigarettes. This proposed program uses Social Cognitive Theory (SCT) to create positive behavioral change through public health interventions like campaigns and evaluate the changes in attitude and belief about e-cigarettes among adolescents. This program will create awareness among youth with a presentation based on the Stop the Lies campaign and encourage youth advocates to disseminate the #tobaccoexposed materials on social media to influence other youth and their peers to expose the tobacco industry's tactics