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ACCESSING THE LARGEST ANGULAR SCALE CMB POLARIZATION FROM THE GROUND WITH POLARIZATION MODULATION
Get PDFObservations of the Cosmic Microwave Background (CMB) polarization have the potential
to advance our understanding of the fundamental physics of the Universe. Polarization
measurements on large angular scales have the power to constrain the optical depth to
reionization and the potential to discover the inflationary tensor-to-scalar ratio. To these
ends, the Cosmology Large Angular Scale Surveyor (CLASS) is a telescope array which
observes the CMB polarization on the largest angular scales from the Atacama Desert in
Chile. To enable the observational stability necessary for these measurements from the
ground, CLASS employs novel Variable-delay Polarization Modulators (VPMs), which
utilize a wire grid in front of a movable mirror to encode the incident polarization signal
at a frequency above those of common atmospheric and instrumental noise sources. This
thesis details the assembly, characterization, and polarization modulation principles of
the CLASS VPMs. We demonstrate the improvement in low-frequency noise performance
afforded by the VPMs in data from all four CLASS observing bands
NOVEL CAS9-BASED STRATEGIES TO VISUALIZE GENETIC ABNORMALITIES AND STUDY DNA DOUBLE STRAND BREAK REPAIR
No full textGenome maintenance is a cornerstone of biological function and longevity, underpinning nearly every aspect of human physiology and disease. The genome is maintained by a network of processes including DNA replication, gene regulation, damage repair, chromatin folding, epigenetics, and meiotic gene segregation, among others. These systems work collaboratively to protect the integrity of our genetic blueprint across generations. To study the biophysical drivers of genome maintenance, tools are needed that can measure spatial and temporal features in the 4-dimensional context of the nuclear environment.
The first chapter of this doctoral work covers the development and utilization of genome oligopaint with local denaturation fluorescence in situ hybridization (GOLD FISH), a novel genome labeling methodology leveraging CRISPR Cas9 as a site-specific loader for a super-processive engineered helicase. We utilize this system to visualize repetitive genomic targets and non-repetitive genes in cell culture as well as gene duplications in human breast cancer tissue. We then modify GOLD FISH to visualize single nucleotide variants (SNVs) and identify cells harboring a point mutation causing the accelerated aging disease, Hutchinson’s-Gilford Progeria Syndrome.
In the following chapter we apply this technology to study DNA repair. DNA double-strand breaks (DSBs) are one of the most genotoxic DNA lesions, driving a range of pathological defects from cancers to immunodeficiencies. To combat genomic instability caused by DSBs, evolution has outfitted cells with an intricate protein network dedicated to the rapid and accurate repair of these lesions. In the second chapter of this work, we utilize the inducible Cas9 system, very fast CRISPR (vfCRISPR), to enable rapid and synchronized break induction. When combined with site-specific labeling via GOLD FISH, this system greatly expands our capability to spatiotemporally characterize cellular responses to DSB at specific genomic coordinates, providing mechanistic insights that were previously unobtainable. We present methodological advances that allow for vfCRISPR and GOLD FISH detection of previously intractable proteins γH2AX and BRCA1, and demonstrate the potential to measure damage kinetics at a predetermined non-repetitive genomic locus.
Overall, this work expands our biophysical toolbox, providing new avenues for disease diagnosis to deepen our understanding of the pathological consequences of genome dysregulation
Genetic Diagnosis, Bodies, and Envisioned Family: Assemblage Perspectives on Reproductive Planning Within Inborn Errors of Immunity
No full textIncompletely penetrant and variably expressive conditions expand our understanding of living with a disease-causing genetic variant and potentially complicate patients’ reproductive and family planning processes. The experience of living with a heritable condition, or experiential knowledge, can itself inform reproductive decisions. However, accounts of experiential knowledge and reproductive planning fail to adequately describe the uncertainties experienced by people living with incompletely penetrant and variably expressive conditions. To address this gap, we conducted a qualitative, cross-sectional study that used assemblage theory to render the impacts of experiential knowledge on reproductive planning more visible for individuals living with Inborn Errors of Immunity (IEI) that exhibit incomplete penetrance and variable expressivity. By emphasizing the distribution of agency and action across systems, processes, and relationships, assemblage theory invites novel ways of understanding the role of experiential knowledge on reproductive planning.
Eligible participants were between ages 18 and 48, with a diagnosis of either GATA2 deficiency, PIK3CD gain-of-function disorder, or CTLA4 deficiency. Using an abductive thematic approach, attention was paid to the people, ideas, and non-human objects embedded within participants’ accounts of disease experience and reproductive planning. This analysis presents three key findings, namely that: 1) genetic diagnosis invited renegotiation and revision of illness in family context; 2) the body was understood as an uncertain resource from which to plan reproductive futures, including consideration of artificial reproductive technologies (ART), and 3) participants reconciled conflicts between experiential knowledge and their reproductive hopes through considering “hypothetical children”. By provoking renegotiation, uncertainty, and imagination in reproductive planning, these objects illustrate how disease experience can be conceptualized as an assemblage of human and non-human objects
QUANTIFYING RESPONSES TO SPATIAL GRADIENTS OF STIMULI IN BIOLOGICAL AND SYNTHETIC SYSTEMS USING MICROFLUIDICS
Get PDFThis interdisciplinary research merges microfluidics and synthetic biology to address a need for understanding how biological cells and synthetic systems like hydrogels perceive and react to multifaceted environmental cues, such as molecular gradients and electric fields. By leveraging microfluidic platforms and automated systems, my work offers nuanced control over spatial and temporal stimuli. These microfluidic techniques also serve as a powerful tool to quantify responses to gradients, allowing for precise investigations into cellular behaviors. This makes it possible to do things such as intricately mapping intracellular calcium ion dynamics, contributing to our understanding of complex biological phenomena such as electrotaxis. Additionally, this work explores the complexities inherent in assembling multicellular networks, introducing the concept of a broadcast range to define the scope of intercellular communication, and offers a roadmap for enhancing intercellular signaling mechanisms. By isolating cells within multicellular networks to specific broadcast ranges, we can minimize the number of signals used in individual networks, thus reducing crosstalk and simplifying intercellular communication through the reduction of component complexity. In the synthetic biology sector, my research utilizes DNA-functionalized hydrogels—designed through automated processes that allow meticulous control over size, placement, structure, and functionalization— capable of detecting and reacting to small molecules and undergoing structural and fluorescent changes upon exposure to specific stimuli. My work here employs microfluidic H-channel designs and innovative hydrogel fabrication techniques to create stable, long-term linear chemical gradients, enhancing our ability to investigate system responses to gradients of stimuli. One novel aspect is the use of sender-receiver genelets, serving as localized, switchable nodes in transcriptional networks that facilitate signaling within and between synthetic hydrogel constructs. These sender-receiver genelets implemented in synthetic hydrogel cells offer a promising avenue for soft robotics and smart materials, where specific, localized communication is vital, and pave the way for complex intercellular signaling within synthetic systems. Overall, my research offers an interdisciplinary exploration into designing systems—both biological and synthetic—capable of sensing and interacting with their environment. This seminal work expands on existing knowledge and scientific understanding, particularly in the fields of cellular communication, sensing, and intelligent soft materials
Molecular Basis for DNA Repair and RNA Homeostasis Functions of SAMHD1
Get PDFSterile Alpha Motif and Histidine-Aspartate domain-containing protein 1 (SAMHD1) is the major negative regulator of dNTP pools in human cells through its unique deoxynucleoside triphosphate triphosphohydrolase activity. This activity constitutes a restriction mechanism against retroviral replication in terminally differentiated cells, as well as a resistance mechanism against nucleoside analogue chemotherapies in some leukemias. SAMHD1 is also one of five gene products associated with Aicardi-Goutieres Syndrome (AGS), an autoimmune disorder characterized by chronic type I interferon signaling. Recent work has shown that SAMHD1-associated AGS pathology arises from its DNA repair functions at double stranded breaks (DSBs), stalled replication forks (RFs), R-loops, and telomeres, as well as a putative function in cellular RNA homeostasis. In the absence of functional SAMHD1, self-derived DNA and RNA structures accumulate and activate the viral nucleic acid sensors cGAS and MDA5, inducing the interferon response associated with AGS. The aim of this dissertation is to determine the molecular basis for these newly discovered functions of SAMHD1. In the first investigation, a mechanism for how CDK2-mediated phosphorylation enables the DNA repair functions of SAMHD1 is established. This modification destabilizes the SAMHD1 tetramer and allows single-stranded DNA (ssDNA) to invade the tetramer interface, inactivating dNTPase activity. These effects are predicted to enable site-directed disassembly of SAMHD1 tetramers at stalled RFs and DSBs. In the second investigation, a comprehensive biochemical characterization of nucleic acid binding by SAMHD1 is reported. This work reveals that SAMHD1 binds specifically to guanine bases in ssDNA and ssRNA by repurposing a GTP binding site. Like GTP binding, guanine base binding to this site allosterically modulates the oligomeric state of SAMHD1, producing dimeric and tetrameric species. TEM micrographs demonstrate that these oligomers form “beads on a string” structures on long RNA molecules that disrupt secondary structure. Implications of these findings with respect to the biological functions of SAMHD1 in DNA repair and RNA homeostasis are discussed
UNDERSTANDING THE RELATIONSHIP BETWEEN INTIMATE PARTNER VIOLENCE AND GOING AGAINST THE NORM IN LOW- AND MIDDLE-INCOME COUNTRIES: WHAT ARE THE IMPLICATIONS OF BEING ON THE VANGUARD OF WOMEN'S ECONOMIC PARTICIPATION?
Get PDFBackground: Women’s economic empowerment (WEE) is postulated to reduce intimate partner violence (IPV), yet the results are mixed across low- and middle- income countries (LMICs). Few studies have explored how broader layers of the social ecology inform WEE-IPV relationships at the individual-level. This dissertation 1) constructs an index capturing the extent to which a woman is going against the community norm on women's economic participation, the “vanguard WEE" index, 2) examines associations of the vanguard WEE index with IPV, and 3) tests moderation of the vanguard WEE and IPV relationship by the Women, Business and Law Index (WBL), a validated national-level index capturing WEE-promoting legislation.
Methods: Dissertation analyses were secondary analyses of cross-sectional data from the Demographic and Health Surveys (DHS). The analytic sample for constructing the vanguard WEE index was 440,836 women across 49 LMICs. The analytic sample for IPV analysis was a sub-sample of 189,414 partnered women across 44 LMICs. Multilevel mixed effects models with both random intercepts and random slopes were used to achieve study aims.
Results: The vanguard WEE index (mean: 1.1, SD: 1.2) was a count of women’s individual WEE items, while living in a community with item prevalence 35% and <=65% and in the bottom two-thirds of the community-level distribution within the region. The index was validated through association with increased gender financial discrimination (p<0.001). As compared to women with no vanguard WEE items, women with at least one vanguard WEE item had increased probability of past-year physical IPV (marginal effect 0.01; 95% CI: 0.01, 0.02), past-year sexual IPV (marginal effect 0.01; 95% CI: 0.01, 0.01), and current partner control (marginal effect 0.02; 95% CI: 0.01, 0.03). The WBL index interacted significantly with vanguard WEE on past-year physical IPV (B 0.05, 95% CI 0.02, 0.08), but not on past-year sexual IPV or current partner control.
Conclusions: Dissertation results provide evidence of increased IPV among women going against the economic norm. Given the risk of potential backlash against economic gain, especially where WEE is not normative, WEE operations should incorporate rigorous and locally informed safeguarding systems to monitor and mitigate harmful spousal backlash
Efficiency and Market Power in Electricity Markets with Inelastic Demand, Energy Storage, and Hybrid Energy Resources
Get PDFThis thesis studies electricity markets and analyzes market mechanisms - operation rules for participants in achieving supply-demand balance, to understand how competition between resources, e.g., conventional generators, inelastic loads, and new market participants, such as energy storage and hybrid resources, affects market efficiency.
We first consider the participation of conventional resources in a two-stage market, i.e., day-ahead and real-time settlement. Although designed to allocate resources efficiently and prevent speculation, price manipulation by strategic participants can undermine these goals. To address price manipulation, some markets have proposed system-level market power mitigation (MPM) policies, which substitute noncompetitive bids with default bids based on estimated generation costs. Using equilibrium analysis, we illustrate that such a policy in the day-ahead stage is more robust to price manipulations than in real-time, which may lead to non-equilibrium solutions. Despite being inelastic, loads can shift their allocation between the two stages to manipulate prices and reduce their payments. Further, heterogeneity in cost coefficients, estimation of dispatch cost in excess, and demand uncertainty tend to benefit generators. Together, system-level MPM policies can have unintended consequences when implemented without accounting for the conflicting interests of participants.
We then study how integrating energy storage affects market efficiency. Our analysis indicates that the existing participation mechanism, where energy storage bids power in a market, may diminish market benefits due to its unique operational characteristics, e.g., the operating cost depends on charge-discharge cycles, unlike conventional generators. We propose a novel market mechanism based on an energy-cycling function that maps cycle depth to per-cycle prices. An equilibrium analysis illustrates the efficient competitive equilibrium that aligns with the social planner problem, i.e., net surplus maximization. However, at the Nash equilibrium, storage incurs reductions in profit relative to the competitive equilibrium due to price manipulation by strategic generators.
Finally, we study the participation of hybrid resources combining energy storage and renewable energy sources. We use the New York zonal model as an example of a large-scale electricity market to benchmark the performance of the following two types of market models. We consider (i) a granular model, where the market operator manages the operation of constituent energy storage, and (ii) an integrated model, where the owner manages the storage operation. Our analysis shows that granular models lead to lower operating costs but add computational complexity, which may not be desirable from the operator's perspective. Though less computationally intensive, integrated models result in more intervals violating the physical limits of constituent energy storage
Evaluation of Flashlight360 in Temple ISD
Get PDFThis mixed-methods evaluation studied the impact of Flashlight360 in Temple ISD, a small city school district in Texas serving approximately 8,600 students. The target population was Grades 1-12 emergent bilingual students. Correlational analyses showed significant positive associations between TELPAS composite levels and Speaking and Writing subscale scores for program students in the 2022-23 school year. These associations were generally weaker, though still positive, in 2023-24
CURIOUS EXCURSIONS
No full textCuriosity is a curious word. It comes from the Latin cura, which means “care.” Prior to the 17th century, being “curious” meant taking care to do things properly. The definition only shifted to mean inquisitive around the time of the scientific revolution. In the 19th century, as amateur collectors crammed their “curiosity cabinets” full of interesting oddities from around the world, the word took on a second meaning: a polite way to call something bizarre. It is a roundabout etymological evolution, but it makes sense. When you care about things, you want to understand them, which means asking a lot of questions. The more questions I ask about the world, the more I learn how weird and wonderful it is — and how much more I want to know. I am on a perpetual, peripatetic expedition, where every discovery reveals new paths to explore. This thesis is a collection of intellectual curiosities gathered along the way
CITIZENS UNITED V. FEC, THE FOSSIL FUEL INDUSTRY, AND THE RISE OF ENVIRONMENTAL PLUTOCRACY
Get PDFThe purpose of this paper is to detail the impacts of the Citizens United v. FEC Supreme Court Decision on environmental governance, but on a larger scale, it is the framing of the negative consequences of unrestricted money in politics, using environmental governance as a single example. Because the focus of this paper will be on the impact of this decision on environmental governance, the source of the political contributions discussed throughout the study will be solely from the fossil fuel industry, as it benefits the most from the influence of environmental governance and is the largest contributor to the sector.
The Citizens United v. FEC decision, by enabling unlimited political contributions, elevated financial resources to the most dominant form of political influence. This political influence is used by the fossil industry to fund campaigns for candidates that will serve their interests, influence public perception through coordinated campaign advertisements and media driven narratives, and stall bureaucratic processes that limit regulatory power. These three mechanisms allow the fossil fuel industry to achieve corporate and regulatory capture, transforming environmental governance into a plutocratic system that prioritizes corporate interests over public and ecological welfare