VictorJuiz/thesis huggingface dataset:
Modeling Cardiomyopathy of Duchenne Muscular Dystrophy in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Keywords:  Department of Biology
Stanford University Department of Biology
Duchenne muscular dystrophy
Human induced pluripotent stem cell-derived cardiomyocyte
Tamoxifen
Traction force microscopy
Single sarcomere dynamics
Biomechanics
Bioengineering
Text
Thesis

Duchenne muscular dystrophy (DMD) is a lethal, genetic myopathy caused by mutations in the dystrophin gene that lead to loss of muscle function and culminate in early adulthood death due to cardiorespiratory failure. While treatment options for the respiratory effects of DMD have improved, there remain limited treatment options for DMD cardiomyopathy. In addition, researchers lack an understanding of the biophysical disease mechanisms underlying the cardiac dysfunction in DMD patients. The development of new therapeutics and research on this mechanism have been hampered by the lack of an appropriate animal or cell model for the cardiac phenotypes of DMD. In the last several years, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a potent means of investigating both treatments for and the underlying mechanisms of DMD cardiomyopathy. Accordingly, I used a hiPSC-CM platform to investigate the effects of Tamoxifen, a selective estrogen receptor modulator that alleviates DMD symptoms in skeletal muscle. Treatment with Tamoxifen decreased beating rate, increased beating velocity, and prolonged cellular functional longevity of DMD hiPSC-CMs. These findings suggest Tamoxifen can counteract the tachycardia, the decreased left ventricular ejection fraction, and the loss of cardiomyocyte function observed in DMD patients. In addition, in this thesis, I describe a novel computational analysis system that uses traction force microscopy and live-cell cytoskeletal staining imaging to provide a holistic understanding of cardiomyocyte contraction. Upon applying this system to DMD hiPSC CMs, I found that dystrophin mutations impair cardiomyocyte function principally by reducing cytoskeletal contraction. This research demonstrates the effectiveness of a bioengineered hiPSC-CM platform to model the cardiac phenotypes of DMD. Additionally, it highlights the potential of Tamoxifen, a novel therapeutic in overcoming arrythmia, and provides new insights into the understanding of the biophysical mechanisms that drive DMD cardiomyopathy, informing future therapeutic development.
Modeling Vaccination as a Diffusion Process: The Effect of the Johnson & Johnson Pause on Vaccine Hesitancy
Keywords:  Department of Economics
COVID-19
Technology diffusion
Vaccine hesitancy
Johnson & Johnson
Food and Drug Administration
Text
Thesis

On Tuesday, April 13th, 2021, the U.S. Food and Drug Administration (FDA) paused the administration of the Johnson & Johnson COVID-19 vaccine to investigate six cases of blood clots. Though the pause only lasted ten days, survey data suggests that it may have precipitated the major subsequent decline in vaccination rates. I use data on weekly vaccinations to verify this link empirically. Drawing from the literature on the diffusion of new technologies, I develop a structural model of the vaccine rollout in the United States to estimate counterfactual vaccination rates and quantify the effect of the pause. I find that the pause led to a significant decrease in weekly vaccinations on the order of 1.2 million first doses per week, resulting in 11 million fewer Americans receiving the vaccine by mid-June. The reduction is consistent across all manufacturers, suggesting a spillover of vaccine perceptions onto the mRNA vaccines. This reduction in vaccinations could have resulted in as many as 47,000 additional cases and 500 additional deaths due to COVID-19 from infections occurring during the nine-week period following the pause. This is orders of magnitude larger than the likely number of averted blood clot deaths.
Modular and programmable molecular sensors for cell types and states
Keywords: Bioengineering.

Human synthetic biology promises to deliver smart therapies for complex conditions like cancer, as well as tools for basic biology by rewiring existing pathways or creating new ones. Engineered human cells could one day sense the state of their micro- and macro environments using synthetic receptors and other sensors, make decisions based on that information using molecular computation circuits, and map those decisions to biological responses, like removing diseased cells or reprogramming healthy cells to fight disease. While modular computation and effector systems have been created with components sourced from the human genome, available sensors are lacking in modifiability, or are sourced from non-human genomes with potent immunogenicity. In this thesis I describe and demonstrate architectures for robust and modular genetically encoded humanized sensors for the intracellular transcriptional state as well as for intra- and extracellular proteins
Modularization of multifunctional energy storage composites (MESC)
Keywords: Aeronautics and Astronautics.

Electric vehicles are growing in popularity thanks in large part to the cheapening of Li-ion batteries, but the energy density of batteries still pales in comparison to their gasoline counterpart. Furthermore, the levels of protection required to integrate these volatile batteries into safe transports of human life further reduce the energy efficiency on the system level. In the worst case, these structural safety containers for the battery pack have shown to take up nearly 50\% of the entire system weight. Thus, it is just as important to \textit{optimize the integration of the batteries} as it is to improve the cell level chemistry safety and energy density. In this investigation, an innovative method was proposed based on the previously developed Multifunctional Energy Storage Composites (MESC) technique to create structural batteries using pouch cells to simultaneously reduce weight, improve reliability, and increase yield of scaling from cell to module. The proposed method involves reinforcing battery cells using the through thickness reinforcing rivets to integrate the live pouch cell into the structure. If a live pouch cell can be created with pre-existing holes, the through thickness reinforcing rivets can be added after individual cell quality control, resulting in a much higher yield process in scaling from cell to module. After the methodology of adding holes to pouch cells is thoroughly investigated and proven, several MESC pouch cells (MESC-p) were fabricated and characterized by a series of electrical and mechanical tests to prove the viability as an efficient structural battery integration scheme. The design envelope was explored through parametric studies, suggesting the pathway towards optimal pack design. A case study of a prototype design for an electric automotive is discussed and fabricated at a 1/90 scale. A theoretical design to replace the chassis of a 2018 Nissan Leaf is presented to showcase the potential for 40\% range improvement when using MESC-p
Modulating myoblast differentiation with RNA controllers
Keywords: Bioengineering.

RNA synthetic biology utilizes the key roles of RNA in cellular information transmission and regulation to design and build new biological systems. Engineered RNA devices have been applied to many spheres of biotechnology and human health. One area of human health particularly suited to RNA device applications is regenerative medicine and tissue engineering. Skeletal muscle offers a convenient model system to test RNA device activity through the regenerative capacity of muscle mediated by muscle stem cells and their myoblast progeny. Here, I present my work to design, build, and test RNA devices for the modulation of myoblast differentiation in skeletal muscle. I first discuss the history and current state of synthetic biology, the set of possibilities regenerative medicine offers as an application space, and the latest applications of synthetic biology to mammalian cell fate decisions. Next, I review the field of engineered RNA devices and highlight the ongoing application of RNA devices as well as advances in the development of new RNA aptamers and new mechanisms of cell control using RNA. I then introduce my thesis project where I applied ribozyme-based RNA devices to myoblast differentiation and demonstrated ligand-responsive inhibition of differentiation marker transcript levels as well as inhibition of the downstream fusion of myoblasts into differentiated myotubes. Finally, I offer reflections on my project and suggestions for the design of future RNA-based regulatory systems
Mohala Nā Pua Kahiki: An Exploration of the Kanaka ʻŌiwi Past in Diaspora
Keywords: Hawaii
Indigenous peoples
Pacific Islanders
diaspora studies
Text
Thesis

This thesis is a twofold project - at once, Mōhala Nā Pua Kahiki is the cultivation of a research methodology centering Kanaka Maoli epistemology and ontology and the application of this methodology to understand the Kanaka Maoli diaspora in California through a multidisciplinary lens. Firstly, this thesis investigates personal contradictions in the discipline of history that conflict with Kanaka Maoli epistemes of relationship and multiplicity. From there, using the Hawaiian ethnolinguistic orientation to time, where ka wā mua (the time before) is the past and ka wā hope (the time behind) is the future, a philosophical foundation for research is constructed that allows researchers to apply to the past the same theories of knowledge used to produce beliefs about the natural world. This thesis constructs a methodology using foundations of research proffered by Hawaiian scholars in history, Hawaiian studies, ecology, and culture studies that incorporates methods from a number of disciplines and sets forth principles using Hawaiian cultural values. By exploring a personal relationship in relation to research subjects, kilo mua serves to allow Hawaiians to procure and articulate a stronger proximity to Hawaiianness through the attainment of ʻike about the past. The second component of this thesis is an application of kilo mua to the Hawaiian diaspora. Three research sites, dubbed wāhi, which combines the Hawaiian words for time and place, are explored: a traditional moʻolelo called “Ka Ipumakani a Laamaomao”, a brief study of William Heath Mahi Davis, and ethnographic interviews conducted with diaspora Hawaiians. Through these wāhi, the Hawaiian cultural motifs of moʻokūʻauhau (genealogy), kuleana (responsibility), and ʻike (knowledge) are explored reflexively both in regards to the wāhi as well as the author’s personal journey, which is investigated through autoethnographic asides that bookend each chapter.
Molecular ecology and biogeochemical activity of nitrifying archaea and bacteria across spatial and temporal scales in the nitrogen-rich San Francisco Bay
Keywords: Earth System Science.

San Francisco Bay (SFB) is a large and heavily nitrogen-polluted estuary on the west coast of the United States. The community dynamics of nitrogen-cycling microorganisms, especially the bacteria and archaea responsible for nitrification (the oxidation of ammonia to nitrite and then nitrate), are particularly relevant in the ammonia-rich waters of SFB. Despite the critical role of pelagic nitrifiers in transforming ammonia within SFB waters, they have received little attention. In this dissertation, I explore the ecology of pelagic microorganisms in the water column using several time series of microbial data and further focus on the distribution and activity of nitrifying guilds. I investigate the general structure of the bacterial and archaeal community in San Francisco Bay using a two-year monthly time series in conjunction with water quality data, documenting a bloom of ammonia-oxidizing archaea (AOA) associated with nitrite accumulation in South SFB. I then use metagenomic data to uncover dynamics of two dominant ammonia-oxidizing archaea lineages in SFB, including the bloom AOA in South SFB. I generate nitrification rate and microbial data, including metagenomes and metatranscriptomes, over a 1-year time series with targeted sampling over the course of an AOA bloom in autumn of 2018. I analyze both microbial time series datasets together to assess the AOA bloom organism over time (2012 to 2019). I also explore the 50-year timeseries of water quality data available for SFB, primarily focusing on the most recent 9 complete years of data (2012-2020) because of more consistent nitrite measurements. Overall, this dissertation characterizes a previously unknown and recurring massive AOA-bloom in SFB, delving into which AOA lineage blooms, the activity of AOA and other microbes during the bloom, and the conditions conducive to recurring and massive blooms
Molecular mechanisms underlying the genetic architecture of complex traits
Keywords: Genetics.

This thesis focuses on using genetics to better connect complex trait associations to the molecular and cellular processes they affect. Rather than performing top-down post-genome wide association studies (post-GWAS), which has become increasingly popular in recent years as a way to dissect the factors contributing to individual risk loci, we focus here on bottom-up post-GWAS: can we use traits for which the molecular processes governing their concentrations are already well understood, and identify variants affecting them which then might lead to disease or other downstream effects? I hope that you believe this is possible, and useful, in reading these selected works which compose my dissertation
Molecular tools for capturing transient cellular events
Keywords: Biology.

Transient cellular events, including their activity profile (e.g. calcium activity in neurons), their dynamic genetic background (e.g. transcriptome signature) or protein-protein interactions (PPIs) underlie important biological processes. Tools that enable the identification and labeling of cells based on these transient events are fundamental in studying and manipulating cellular behavior. In chapter 1 of this thesis, I discuss a new dual-purpose real-time calcium indicator and transcriptional calcium integrator called LuCID. LuCID's calcium-dependent split luciferase component provides real-time bioluminescence readout of calcium dynamics in cells, while its GI/FKF1 split GAL4 component converts calcium-generated bioluminescence into stable gene expression. I show that LuCID's modular design enables it to read out other cellular events such as protein-protein interactions. In chapter 2, I outline my efforts to develop a RNA detector for deploying CRISPR in a cell-type specific manner and, in Chapter 3, I outline my efforts towards developing a plate-based assay for using proximity-labeling technology to capture PPIs for high-throughput drug screens
Molecular-level material designs for realistic lithium batteries
Keywords: Chemistry.

Lithium (Li)-ion batteries have become the pivot of modern energy storage due to their predominant role in powering consumer electronics and electric vehicles. However, with mature manufacturing and production, the energy density of current Li-ion batteries is reaching the theoretical limit. Substantial efforts in both academia and industry are being made to invent next-generation battery chemistries, such as near-future trending Li-ion electrodes including silicon (Si) based anodes, high-voltage LiNi0.5Mn1.5O4 (LNMO) cathode, layered Li-rich Mn-based oxide (LLMO) cathodes, etc. and far-future high-energy Li metal batteries. For near-future Li-ion chemistries such as Si based anodes, LNMO and LLMO cathodes, the existing electrolyte technologies are far from satisfaction. Therefore, liquid electrolyte engineering becomes a pragmatic and imperative approach, and calls for rational design and in-depth understanding of new electrolytes. Li metal battery is a technology existed and commercialized before Li-ion counterpart but forsaken due to safety issues. The kernel, Li metal anodes, endows batteries with high specific energy; however, this is accomplished at the expense of reduced cycle life and increased safety hazards due to the extremely high reactivity and volume fluctuation of Li metal anodes. Therefore, continuous developments of Li metal batteries are demanded to meet the requirements of practical applications. In Chapter 1, background will be provided on current status and recent research efforts of next-generation Li-ion and Li metal batteries. In Chapter 2 and 3, material design artificial solid-electrolyte interphase for protecting Li metal anodes will be discussed. In Chapters 4 and 5, liquid electrolyte engineering and iterative tuning of molecular structure will be elaborated. In Chapter 6, fine tuning of carbonate electrolytes will be demonstrated in the trending Li-ion batteries for near-future practical applications. In Chapter 7, summary and promising directions of future battery developments will be outlooked
The moral republic : corruption in colonial and postcolonial India, c. 1830-1974
Keywords: History.

This dissertation is a political history of modern India. Using the lens of corruption, it examines the critical transformations that occurred in the subcontinent across the nineteenth and twentieth century India. I investigate the use of corruption in the institutional and popular context to chronicle the changing notions of public and private, trust, and solidarity. British colonialism presented corruption as provisional and anomalous. Postcolonial India reformulated corruption as a problem inherent to the logic of necessary modernization. Exploring the imperial and the independent state of India through episodes of dysfunction and misconduct, my chapters are organized chronologically. My first chapter explores the administrative reforms introduced in 1833 to explore how the East India Company's production of the vocabulary and rhetoric of corruption as serendipitous pathology was a deliberate tactic of legitimizing imperialism. I then move to examine the imperial attitudes towards Indians through a particularly flagrant example of colonial corruption in 1888. While the norms of professionalization advocated distance, ironically, they also resulted in heavy dependence on lower Indian functionaries. For these 'native' officers, corruption was often a path to gain masculine authority and assert indigenous control. My third chapter explores the discourse on corruption in early independent India (1947-1960) through institutional and popular cultures. Studying the Constituent Assembly debates between the various members of the Constituent Assembly, this chapter reflects on some of the original and formative tensions that undergirded Indian democracy. It also examines the popular distrust that was formative to the Indian democracy. My fourth chapter follows the complex trajectories of the anticorruption movement in 1974-1975 to examine the regional, national, and international resistance to corruption as it occurred at the time. Corruption, in this study, becomes a site where different kinds of radical as well as disciplinary political energies are crystallized. Drawing from hitherto unexamined literature in English as well as other Indian languages, my dissertation acknowledges the need to study the narratives around and about corruption to understand the complex careers of nationalism, morality, and sovereignty in the subcontinent
More sample efficient and robust reinforcement learning with domain knowledge
Keywords: Electrical Engineering.

Reinforcement Learning has achieved great success on environments with good simulators (for example, Atari, Starcraft, Go, and various robotic tasks). In these settings, agents were able to achieve performance on par with or exceeding human performance. However, the application of reinforcement learning to real world human-facing applications has been limited due to various issues such as large sample complexity. This dissertation proposes methods that work towards addressing these issues by utilizing domain knowledge and structure. Domain knowledge was the main component of the first class of successful AI systems, expert-rule based systems. However, due to many challenges, including the large amount of expensive expert time required, the research community has shifted towards data-driven methods that learn automatically. This dissertation presents methods that aim to combine the benefits of expert-based systems with the strengths of reinforcement learning. These methods can have better performance, achieving better sample efficiency or more robust performance, with only minimal burden on the experts. This dissertation proposes multiple novel methods for leveraging different types of domain knowledge in multiple different reinforcement learning settings. It will introduce methods for incorporating expert domain knowledge and heuristics to speed online reinforcement learning; for incorporating repeated structure in procedure/imitation learning; for incorporating anticipated domain distribution shift for batch contextual bandit settings; and for incorporating a curriculum graph to create better personalized adaptive progressions in a real world educational webgame. We empirically evaluate our methods in simulators designed with real-world data, such as recommendation systems and educational activities sequencing. We additionally test one of our methods in a real world Korean language learning webgame. For all our methods, we demonstrate that we can achieve faster or more robust performance. This shows promise for reinforcement learning methods to be helpful in human-facing applications