VictorJuiz/thesis huggingface dataset:
Studying Myotonic Dystrophy Pathogenesis using Engineered Patient Derived Fibroblasts
Keywords:  Department of Biology
Myotonic dystrophy
Genetic Engineering
Gene targeting
CRISPRS
TALENs
CTG Repeat Expansion
DMPK
Thesis

Myotonic dystrophy type 1 (DM1), a neuromuscular degenerative disorder, is
characterized by a CTG repeat expansion (>100 CTGs) in the 3’ untranslated region of the
Dystrophia myotonica protein kinase (DMPK) gene. The leading hypothesis regarding DM1
pathology is that this expansion leads to the sequestration of splicing factors, which is
responsible for aberrant splicing events in insulin receptor gene (INSR), Cardiac troponin T
(Tnnt2), and DMPK itself, resulting in severe muscular degeneration at the clinical level.
However, studying genetic diseases such as DM1 has historically been complicated by the
inherent genetic bias between cells from different sources, a complication that can now be
removed by using gene targeting technologies. The purpose of this research is to generate a
genetically unbiased model to study myotonic dystrophy’s pathology by targeting the expanded
CTG repeat in the DMPK locus in patient-derived fibroblasts. A set of engineered nucleases,
transcription activator-like effector nucleases (TALENS) and RNA-guided nucleases
(CRISPRs), were constructed to target the CTG expansion. To repair the CTG expansion, donor
DNA with arms of homology to the DMPK gene and a normal number of CTG repeats were
introduced to serve as a template for correction via homologous recombination. By correcting
this expanded CTG repeat through gene targeting, aberrant alternative splicing events caused by
the sequestering of splicing factors at the expanded repeat can be further studied by analyzing the
mRNA isoforms of genes known to be affected by the expanded repeat, such as INSR, Tnnt2,
and DMPK. Creating this genetically unbiased model of DM can provide insight into what other
genes are involved in the pathology of the disease, providing an invaluable tool in developing
potential therapeutics for this disease.
Supply chain management through cascading [electronic resource]
Keywords: Management Science and Engineering.

Supply chain disruptions affect companies across all industries. For highly specific products, such as semiconductors, contingency planning is necessary in advance. This is aggravated by supply chain invisibility as a result of a multi-tier supply chain structure. In this research, we identify how supply chain performance can be improved in the presence of disruption risk and limited visibility. By analyzing stylized supply chain models, we identify possible reasons for the particular inefficiencies observed in semiconductor supply chains. We investigate the optimal capacity decisions of different players in a supply chain and the effects of multiple emergency sources. We then explore what type of contracts can be used to coordinate multi-tier supply chains. Further, we introduce the concept of incentive cascading and analyze whether cascading can be used to coordinate multi-tier supply chains.
Surrogate modeling and active subspaces for efficient optimization of supersonic aircraft [electronic resource]
Keywords: Aeronautics and Astronautics.

This dissertation presents approaches for surrogate based optimization of supersonic vehicles analyzed with high fidelity flow simulations. It integrates several developments in surrogate modeling to enable a robust regression procedure in the presence of sparse data and inaccurate gradients. A series of hyperparameter constraints are developed which encourage the learning process to generate a physically representative fit of the data. It identifies the existence of subspaces based on linear combinations of inputs called "active subspaces" that reasonably model the behavior of objectives within aerospace design problems such as lift coefficient, drag coefficient and an equivalent area functional. Coherent physical features were found across several design problems for both two and three dimensional geometries. This dissertation further proposes an approach for adaptive refinement by conditioning the traditional expected improvement sampling criterion to avoid exploration of the design bounds. To begin work on applying active subspaces to optimization, inverse maps were developed to enable the linking of separate active subspaces for objectives and constraints, enabling surrogate based optimization in high dimension. Several design problems are explored, and it is shown that surrogate based optimization in active subspaces could enable the optimization of problems otherwise intractable via gradient based optimization alone.
Synthetic biochemical production of medicinal natural products in yeast [electronic resource]
Keywords: Chemistry.

Natural products, organic molecules made by Nature, are the principal source of and inspiration for pharmaceuticals. Because of their complex regio- and stereo-chemistry, many natural products are most economically made by cultivating the producer. Plant natural products from opium poppy, which include morphine and codeine, are produced in this way. Agricultural supply of drugs and drug precursors from opium poppy is an annual process with a large demand on land, subject to high variability due to weather, pests, soil conditions, and natural variation, and requiring intensive mechanical and chemical processing for product isolation. Therefore, there is a need for alternative processes to provide opiates with greater supply stability and less resource use. Heterologous microbial biosynthesis has been used successfully to make plant natural products, most notably the sesquiterpene artemisinic acid, and could provide a more stable supply of opiates due to greater process control and shorter batch times. The objective of this research was to design and build yeast strains to biosynthesize two classes of plant natural products found in opium poppy, morphinan and protoberberine alkaloids, using a synthetic biology framework. One challenge to implementing these pathways is the decrease in titers observed with increasing pathway length, which must be tackled with strain engineering efforts. Another challenge was that a key enzyme in morphine biosynthesis was not yet discovered. Both target classes of alkaloids were successfully accessed. Using metabolic engineering approaches, we optimized a yeast strain to convert a commercially available substrate to protoberberine alkaloids. This strain provided a 70-fold increase in titer relative to its predecessor. We developed yeast strains to convert either sugar or a commercially available substrate to morphinan alkaloids, which required the discovery of a novel epimerase from opium poppy. We co-discovered this missing enzyme and demonstrated its activity in the context of our engineered yeast strain. Rational protein engineering of a plant cytochrome P450 enzyme increased product titers. The engineered yeast strains are able to biosynthesize the morphinan alkaloid thebaine and the opiate-derived semi-synthetic drug hydrocodone de novo at proof-of-principle levels. Further protein and strain engineering will lead to improved strains for microbial biosynthesis of opium poppy alkaloids and their congeners.
Systematic discovery of human gene function and principles of modular organization through phylogenetic profiling [electronic resource]
Keywords: Chemical and Systems Biology.

A significant fraction of human genes remain functionally uncharacterized despite major advances in perturbation and mapping techniques. The correlated gain and loss of orthologous genes across species, reflecting a shared evolutionary history, can be used to infer novel functional interactions in a technique known as phylogenetic profiling. Advances in sequencing technology and plummeting costs have enabled the sequencing of hundreds of eukaryotic genomes, hugely increasing the potential utility of phylogenetic profiling in providing systematic functional predictions for the human genome. However, genome-wide profiling has been hindered by challenges in orthology assignment caused by the large number of human genes related to each other through duplication events and the lack of robust scalable methods to assess the degree of coevolution. I overcame these challenges in automatically profiling over 30,000 groups of homologous human genes (orthogroups) representing the entire protein-coding genome across 177 eukaryotic species. By generating a full pairwise orthogroup phylogenetic co-occurrence matrix, I derived unbiased genome-wide predictions of functional modules and identified topological constraints on evolutionary modularity, with metabolic genes and physical protein complexes more likely to coevolve than signaling and transcriptional networks. Importantly, the algorithm predicts functions for hundreds of poorly characterized genes. To demonstrate its utility in guiding experimental gene function discovery, I validated two subsets of candidates experimentally for their predicted link to the actin-nucleating WASH complex and cilia/basal body function.
System-level effects of soft errors [electronic resource]
Keywords: Electrical Engineering.

Radiation-induced transient errors (soft errors) are a major reliability concern for digital systems in advanced silicon CMOS technologies. Soft errors create unexpected changes in signal values during system operation, mostly in on-chip memories and flip-flops, resulting in undetected data corruption or expensive downtimes. This dissertation focuses on soft errors in flip-flops because design techniques to protect flip-flops are generally expensive. To protect on-chip memories, coding techniques are routinely used. Error injection simulations are widely used for characterizing system-level effects of soft errors in a given design. These techniques generally inject single-bit errors into randomly-chosen locations (flip-flops, software-visible registers and memories) during randomly-chosen clock cycles. Flip-flop-level error injections suffer from slow Register-Transfer-Level (RTL) simulations. High-level error injections, that inject errors into software-visible registers or memories, are generally fast. Unfortunately, very little literature exists on the accuracies of high-level error injection techniques. We demonstrate that existing high-level error injections can be highly inaccurate by over an order of magnitude, and present detailed error propagation analysis to quantitatively explain the causes of such inaccuracies. For fast, yet accurate, error injection simulations, we present a new mixed-mode simulation platform that combines simulators at two different abstraction levels. This platform achieves 20,000× speedup over RTL-only simulation for an industrial multi-core chip consisting of approximately half-a-billion transistors. This platform targets soft errors in uncore components (e.g., memory subsystem, I/O controllers) that occupy significant portions of the overall chip area. Using this platform, we demonstrate, for the first time, that flip-flop soft errors in uncore components can significantly impact system-level reliability. We also demonstrate that recovery from uncore soft errors can be challenging for traditional system-level checkpointing techniques. A new replay technique overcomes these challenges for uncore components belonging to the memory subsystem.
Table-Top THz Pulses via Large-Area Photoconductive Antennas
Keywords:  Department of Physics
THz pulses
THz emitter
molecular orientation
photoconductive switch
antenna array
water spectroscopy
Thesis

THz pulses have a variety of applications in atomic and molecular physics. As molecular probes, they are broadband excitation pulses to study dynamics on a unique time scale. This time scale (on the order of picoseconds) is associated with the "THz gap," or the regime in the electromagnetic spectrum previously difficult to create due to the gap between electronic frequencies and optical frequencies. Given this technological gap, THz pulses pose many engineering challenges for table-top generation. Photoconductive switches offer an elegant solution to this challenge. They take advantage of the time scale associated with charge carrier dynamics in certain semiconductor materials to generate radiation in the THz regime. These devices are triggered by laser pulses, and the majority of their radiative energy is stored in a bias field applied to the semiconductor material itself. Their power is also derived from the area of semiconductor that is triggered. Hence, these devices are easily scalable from a theoretical point of view. We have developed a large-area array of photoconductive antennas for generating high-field, broadband THz pulses in such applications. The device is a 50 cm^2 patterned array of interdigitated leads on GaAs driven by a 50 fs pulse of IR light. We also report improvements for fabrication and experimental setup using the antenna array.
Tackling radio polarization data of high energy pulsars [electronic resource]
Keywords: Applied Physics.

The focus of this thesis is on understanding the pulsar magnetosphere particularly with the exploitation of radio polarization. The rotating vector model (the standard pulsar polarization model) can be modified to estimate emission altitude. However, more realistic treatment of relativistic and sweep-back effects show that such augmentations break down relatively quickly. This break-down is quantified and fitting functions are provided that preserve accuracy to higher altitude. The rotating vector model has proven particularly poor for modeling energetic pulsars. We remedy this by including the effects of orthogonal mode jumps, multiple emission altitudes, open zone growth via y-point lowering, and interstellar scattering. A large number of discrepancies can be understood while retaining the geometric picture. The model is systematically applied to six Fermi-detected pulsars (PSR J0023+0923, PSR J1024−0719, PSR J1744−1134, PSR J1057−5226, PSR J1420−6048, and PSR J2124−3358). Several other examples of utilizing polarization modeling to understand pulsar geometry and emission characteristics are also presented. Finally, a bidirectional emission model is applied to the polarization data of PSR J1057−5226 and PSR J1705−1906. Overall, we push the limit of what can be learned from a geometrically based model and emphasize the importance of tying such models to data.
The teacher labor market in Brazil [electronic resource]
Keywords: Education.

This dissertation explores the significance of the bargaining power of the players involved in the wage decisions for teachers in Brazil, namely the teacher unions and the municipal governments. The dissertation is divided in two parts, which together form a broad analysis of the labor market for public school teachers in Brazil and the underlying institutional factors that have determined its functioning in the past twenty years. This research indicates that the bargaining power of municipal governments and teacher unions plays an essential role in setting wages. Moreover, the results suggest that the bargaining power is more important to the wage levels than the available budget of the municipalities, and that market power is driven by the lack of alternative job opportunities to the teachers. The first paper analyzes the degree of monopsony power held by municipal public employers in teacher hiring. It shows evidence of very low elasticities for the teachers' labor supply curve (of 0.11 - 0.36, depending on the model specifications), suggesting that the market power held by municipal governments allows them to enjoy rents that are, in absence of other players to counterbalance their action, as large as 275% - 901% of the teachers wage value. It also indicates that the proportion of female teachers increase the power that municipalities have to set wages, given the relatively lower elasticity of women's supply curve. The second paper examines the actual behavior of governments in teacher hiring and uses two models -- the Monopoly-Monopsony and the Insider-Outsider -- as possible interpretations of the results. I use the FUNDEF funding reform in Brazil that has redistributed funds across municipal and state systems within each Brazilian state to identify the wage-setting decisions. It shows evidence that municipalities that benefitted from the redistribution were more likely to increase teacher salaries (by an average of 3.9%), while municipalities relatively harmed by the redistribution tended to increase the number of teachers (by 8.8%) and to decrease salaries (by -4.4%). Surprisingly, the analyses of the value transferred to the municipalities reveal that receiving more funds for education does not necessarily translate to higher teacher salaries, suggesting that the bargaining power of the municipal governments and teacher unions matter more to wage determination than the amount of funds the school systems have. This dissertation provides evidence, in the context of Brazil, that policies focused on raising across-the-board wages can be desirable as a counterforce to the market power held by municipal governments. Moreover, it suggests that federal policies focused on changing the bargaining power of the municipalities would be more effective in influencing wage levels than the amount of grants given to local governments.
Temperature-compensated silicon MEMS resonators with high quality factors and low motional impedances [electronic resource]
Keywords: Mechanical Engineering.

Microelectromechanical systems (MEMS) have become ubiquitous today, existing alongside electronics in many products and fabricated using standard semiconductor fabrication techniques. The focus of this work is on furthering the performance of silicon resonators for frequency / time references, based on the epi-seal encapsulation process that has been demonstrated to be crucial for the stability of MEMS. Temperature-compensation via heavy doping is investigated and the temperature dependence of the elastic constants of silicon is extracted for several doping types and concentrations. The values are shown to be able to predict the frequency-temperature dependence of various resonators operating in the linear regime. Also addressed is the relatively large motional impedance of capacitive resonators (typically ~100 kΩ) in the epi-seal process. The motional impedance can be significantly decreased by having narrower capacitive gaps, and two methods compatible with the epi-seal process are demonstrated: the first by adding a selective epitaxial deposition step to the epi-seal process, and the other by designing movable electrodes that can pull-in closer to the resonator. Furthermore, high quality factor Lamé mode resonators are demonstrated here with f × Q products of 2 × 1013 Hz, in conjunction with first-order temperature compensation and low second-order temperature dependences. Lastly, charge-biasing is presented as a viable alternative to voltage-biasing for lower power consumption: charges introduced on the resonator body within the epi-seal cavity via mechanical switches show no signs of leakage even after a year. All these features can co-exist simultaneously on the same resonator with the demonstrated epi-seal stability, providing a pathway for further enhancing the performance of MEMS resonators.
The Backup Plan: Visualizing Disappearing Groundwater Resources on the US-Mexico Border
Keywords: groundwater
conflict
treaty
Center for International Security and Cooperation
Thesis

The absence of groundwater treaties is a global trend despite the fact that groundwater crosses the majority of international boundaries. Why have property rights over groundwater failed to evolve from the national level to the international level? Given the broad scope of the question, this thesis narrows its geographic focus and asks: What explains the absence of a groundwater treaty for the US-Mexico border?
Visibility is the obvious difference between groundwater and other resources such as surface water which are regulated by treaties. As a result, current research on groundwater treaties assumes the role of visibility and moves on to look at other issues such as institutional dynamics.1 This is a mistake. This thesis argues that visibility does not play the traditional role it is assumed to have. Its customary role is one that creates ambiguity. For example, negotiators cannot act due to underground data gaps.
This reveals a critical misunderstanding. These explanations look at groundwater as a singular resource rather than through its relationship with surface water. Within the larger system, groundwater is the dependable resource – it is the backup plan. It lets people know that even in times of a drought they will have water. Groundwater serves as the lack of ambiguity. It lowers the perception of scarcity and with it incentives to manage use.
To test this argument, this thesis tracks three periods of rapid change in the visibility of groundwater and the reaction in the Mexicali and Imperial Valleys. These three periods are: the completion of the lining of the All American Canal in April 2010, the 7.2 Sierra El Mayor Cucapah Earthquake in April 2010, and Minute 319 in November 2012. Interviews and written accounts provide an understanding of how visibility, specifically its rate of change, impacted bilateral action on groundwater.
This thesis looks not only at the perception of groundwater’s dependability, but also at what will happen when it is no longer dependable. An analysis of n-level datasets on surface water conflict and cooperation illuminates the role of groundwater in reducing conflict and the implications of its absence.
These findings provide a novel understanding of the roadblocks to a groundwater treaty, and the implications of inaction.
The C1ql3 gene affects emotional memory
Keywords:  Department of Biology
Biology
Neuroscience
Behavior
Thesis

The complement component 1, q subcomponent-like 3 (C1ql3) gene is expressed in neurons in important brain regions such as the hippocampus, the basolateral amygdala and the insular cortex, which are known to regulate spatial memory, emotional memory, and interoception, respectively. Interoception is the brain’s awareness of bodily states, and it is important for mammals to feel the rewarding effects of a drug like cocaine. Preliminary cocaine conditioned place preference experiments on C1ql3 mutant mice showed that C1ql3 may have a role in drug reward behavior. Based on the literature and preliminary data, we hypothesized that C1QL3 has a role in regulating the interoception necessary for such drug-associated conditioning. In order to test our hypothesis, adult mice with conditional alleles for C1ql3 were intracranially injected with either control viruses or viruses expressing Cre recombinase to knock out C1ql3 expression in the insular cortex. Incidentally, the virus also diffused into the amygdala, removing C1ql3 expression in a region known as the basolateral amygdala. After recovery, several behavior assays were performed on the mice to understand the nature of the cocaine CPP phenotype. The virus-injected conditional mutant mice showed normal drug-associated conditioning, yet they exhibited emotional memory deficits, suggesting that our original hypothesis needed refinement. A thorough behavioral characterization of the mutant mice demonstrated that, rather than specifically affecting drug-associated conditioning through alterations in interoception, C1QL3 has a more general role in regulating short-term emotional memory, which is most likely due to its expression in the amygdala. The lack of CPP phenotype after virus targeting to the insular cortex is likely due to the only partial inactivation of the basolateral amygdala. Further research is required to definitively demonstrate that C1QL3 expressed in the basolateral amygdala is required for mice to form memory associations between contexts and emotional salient stimuli.