VictorJuiz/thesis huggingface dataset:
Empirical assessment of practices and bias across diverse research domains

Research today is expensive, time consuming, and low yield. Much work has been done to describe research practices and quantify biases that may contribute to this. However, new ways of conducting research are constantly being proposed. Potential biases may not be as well characterized for these new fields. I aimed to describe the prevalence of practices and potential for biases in three relatively new and fast-growing fields. Specifically, these included: comparative oncology trials in domestic dogs, E-values for sensitivity analysis in observational studies, and machine learning diagnostic tools. Primary research articles were systematically retrieved from literature databases. Data regarding research methodology, reporting, and study results were extracted. In addition to field-specific findings, conserved trends were observed across multiple fields, including a reluctance to report experimental details, a tendency for facile automation in methods and interpretation, and an opportunity to learn from adjacent fields. The present study identifies pitfalls that threaten the validity, generalizability, and clinical value of these three fields of research and provides recommendations for improvement

Keywords: Epidemiology and Population Health.
Advisor: Ioannidis John
Goodman Steven R. 
Grimes Kevin
Sainani Kristin
Enabling gaze-contingent accommodation in presbyopia correction and near-eye displays

Humans rely on several different depth cues to navigate the world around them. Among the most important cues are accommodation (refocus) and vergence (inward and outward rotation). Though accommodation and vergence are neurally linked processes, there are situations in which they fall out of synchrony; specifically, we address two seemingly unrelated issues: presbyopia and virtual and augmented reality (VR/AR). In the former, the crystalline lens within the eye itself loses the ability to accommodate due to it stiffening as a function of age. This stiffening defines presbyopia and occurs in all humans, with diagnosis typically in their late 40s. In the latter case of VR/AR, a viewer is forced to fix their accommodation to the single plane of a display while the display's stereoscopic image encourages their eyes to verge to arbitrary distances to achieve a sense of three dimensionality. In both cases, the viewer is no longer able to accommodate naturally. Traditionally, presbyopia and VR/AR optics have been static, making it difficult to approximate the abilities of the once pliable crystalline lens—inherently trading off acuity, field of view, or stereoacuity in exchange. On the other hand, a more dynamic, gaze-contingent solution requires focus-tunable lenses and eye trackers to properly mimic the accommodation reflex. We built and evaluated gaze-contingent optical systems for use in presbyopia correction and VR/AR, with our solutions outperforming traditional ones on both quantitative and qualitative measures

Keywords: Electrical Engineering.
Advisor: Wetzstein Gordon 
Horowitz Mark (Mark Alan)
Norcia Anthony Matthew
End-user programming of virtual assistant skills and graphical user interfaces

Virtual assistants give end-users the capability to access their devices and web data using hundreds of thousands of predefined skills. Nonetheless, there is still a long-tail of personal digital tasks that people want to automate. This dissertation explores how end-users can define useful personalized skills without learning any formal programming languages. We empower an end user to create a web-based skill by demonstrating their skill in a web browser using natural language, their mouse, and keyboard. Our tool is the first program-by-demonstration system that produces programs with control constructs. The system gives the user an easy-to-learn multimodal interface and generates code in a formal programming language which supports parameterization, function invocation, conditionals, and iterative execution. We show that a virtual assistant skill can greatly benefit from having a graphical interface as users can monitor multiple queries simultaneously, re-run skills easily, and adjust settings using multiple modes of interaction. We developed a system that automatically translates a user's voice command into a reusable skill with a graphical user interface. Unlike the formulaic interfaces generated by previous work, we generate interfaces that are interesting and diverse by using a novel template-based approach. To improve the aesthetics of graphical user interfaces we use a technique called style transfer. We show that the previous formulation of style transfer cannot retain structure in an image, which causes the output result to lack definition and legibility, and renders restyled interfaces not usable. Our purely neural solution captures structure by the uncentered cross-covariance between features across different layers of a convolutional neural network. By minimizing the squared error in the structure between the style and output images, our technology retains structure while generating results with texture in the background, shadow and contrast in the borders, consistency of design across edges, and an overall cohesiveness to the design. In summary, our system enables end-users to create web-based skills with automatically generated graphical user interfaces

Advisor: Lam Monica S.
Boneh Dan
Wang Ge
Engineered biomaterials for therapeutic optimization of cardiovascular interventions

Ischemic heart disease continues to represent the leading cause of death worldwide, annually accounting for 10 million deaths globally and 1 in 7 deaths in the United States. Current treatment of severe coronary disease and acute myocardial infarction typically relies on reperfusion therapies, including fibrinolytic therapy, percutaneous coronary intervention, and coronary artery bypass grafting. These methods, while successful at restoring macrovascular blood flow after infarction, inadequately address residual microvascular perfusion deficits resulting in cardiomyocyte death, downstream ventricular remodeling, progression to heart failure, and early mortality. Additionally, following myocardial infarction and/or a cardiac operation, patients can develop Dressler's syndrome, or post-cardiac injury syndrome, where inflammation and scarring form cardiac adhesions resulting in increased risks during secondary cardiac operations. This dissertation discusses several projects related to ischemic heart disease and its multiple sequelae. This work demonstrates improved human mesenchymal stem cell (hMSC) culture techniques by culturing hMSCs on chemically oxidized polystyrene substrates. This technology could be utilized in cell therapy applications where timely access to high quantities of hMSCs is difficult due to cell culture constraints. This thesis also examines the use of a photosynthetic oxygen delivery system that rescues the myocardium following acute ischemia. Finally, the use of a dynamically crosslinked polymer-nanoparticle (PNP) hydrogel adhesion barrier is explored for the prevention of cardiac post-operative adhesions or post-cardiac injury syndrome. The PNP hydrogel adhesion barrier significantly reduced adhesions in both rodent and ovine models of cardiac adhesions. These results are expanded to post-operative peritoneal adhesions and result in a significant reduction in peritoneal adhesions following abdominal surgery

Keywords: Bioengineering.
Advisor: Woo Joseph
Appel Eric (Eric Andrew) 
Cochran Jennifer R.
Engineered CRISPR/dCas9 systems to dynamically control transcription and chromatin organization

The discovery and development of CRISPR/Cas9 technologies have revolutionized the ways in which fundamental cellular processes like gene function and chromatin organization can be studied. Transcriptional regulators based on nuclease-deficient Cas9 (dCas9) allow fine-tuned expression control of virtually any gene in the genome, providing new ways to control cell fate and to identify the genetic drivers of cellular phenotypes. An ever-expanding array of dCas9-based chromatin modifying proteins offers the ability to directly probe the causal role of individual features of chromatin toward regulating nearby and distant regions of the genome. In this dissertation, I present two sets of engineered dCas9-based systems for the dynamic regulation of gene expression and heterochromatin formation, respectively. First, I build and characterize a set of dCas9 transcriptional activators and repressors whose activities are controlled by chemical and light inducers. From a screen of chemical- and light-inducible dimerization systems, I identify two potent chemical inducers that mediate efficient and reversible gene activation and repression in mammalian cells. Different inducer systems can be paired with orthogonal dCas9 transcriptional regulators to independently control expression of different genes within the same cell. Furthermore, using this platform, I devise Boolean AND, OR, NAND, and NOR dCas9 logic processors and a diametric regulator that activates gene expression with one inducer and represses with another. This modular dCas9 platform provides a robust approach for enacting complex transcriptional programs in mammalian cells suitable for controlling directed differentiation and building synthetic gene circuits. Second, I adapt the chemically-inducible dCas9 platform for the conversion of chromatin states across tens of kilobases of genomic DNA, an approach I name CRISPR-Engineered Chromatin Organization (EChO). I show that CRISPR-EChO can be used to recruit heterochromatin components, in particular human Heterochromatin Protein 1α (HP1α), in high numbers to genomic targets on different chromosomes to form discrete structures visible by confocal microscopy. Synthetically tethered HP1α causes the bound genomic region to form novel contacts with other regions of heterochromatin and to reversibly compact into a condensed state. The condensed state induces transcriptional repression across a 600 kilobase genomic region and exhibits delayed disassembly kinetics. These findings collectively support an HP1α polymer model for the regulation of heterochromatin organization and function within the nucleus. Together, these two bodies of work represent divergent applications of dCas9 technology for mammalian synthetic biology that operate at different genomic scales and highlight the distinct advantages of dynamic and targeted control of nuclear processes for studying biological questions

Advisor: Qi Lei (Professor of Bioengineering) 
Bhutani Nidhi
Porteus Matthew H.
Wysocka Joanna
Engineering alternative splicing devices for mammalian synthetic biology

From the approximately 20,000 genes embedded in DNA genomes to the functional proteins they encode for, much of the functional diversity of mammals can be attributed to alternative splicing, a pre-messenger RNA processing mechanism that produces multiple proteins from a single gene through careful arrangement of exons into a final transcript. While synthetic biology harnesses natural sequences refined by genetic evolution to build new functions from modular DNA components in engineered biological systems, few systems have leveraged alternative splicing as a precision tool for genetic control in mammalian systems. Combining the evolved mechanisms of splicing regulation with the ability to produce multiple, distinct proteins from a single gene, alternative splicing in synthetic genetic devices expands our capacity to control mammalian systems for medical, industrial, and biological discovery platforms. We have developed a class of mutually exclusive alternative splicing devices that can express two distinct isoforms based on which one of two internal exons is included in the final RNA molecule. In our efforts to engineer these devices for novel functions to control biological systems, we expanded the functional outputs of our alternative splicing devices using modular protein domains and fluorescent proteins, in addition to updating previous design considerations that limited our initial efforts, such as size and sequence constraints. Our ability to regulate outcomes from alternative splicing devices is important for their use as genetic transcriptional tools for mammalian synthetic biology. We modify our intron framework to support the production of both isoforms at various ratios based on mutations and truncations to consensus elements responsible for alterna- tive splicing. We explored synthetic approaches to controlling isoforms, such as the CRISPR-Cas13 RNA-targeting system and the MS2 protein aptamer, that allowed us to shift splicing patterns in a dynamic fashion. Our strategy to controlling isoform outcomes and protein functionality replicates how evolution evolved RNA splicing for a synthetic alternative splicing device. We present the design, construction, regulation, and versatility of alternative splicing devices. Their unique ability to compress genetic information combined with transcriptional regulation tools, both naturally encoded and artificially introduced, advances the novel mechanism we can harness to engineer biology

Keywords: Bioengineering.
Advisor: Smolke Christina D.
Qi Lei (Professor of Bioengineering) 
Swartz James R.
Engineering and imaging nonlocal spin dynamics in an optical cavity

Photon-mediated interactions between atoms coupled to an optical cavity are a powerful tool for engineering entangled states and many-body Hamiltonians. These applications motivate the construction of an optical cavity enabling coherent nonlocal spin interactions, with transverse optical access for high-resolution imaging and addressing of atomic sub-ensembles. Using this apparatus, we implement a nonlocal Heisenberg Hamiltonian, where the relative strength and sign of spin-exchange and Ising couplings are controllable parameters. This tunability enables the demonstration of an interaction-induced protection of spin coherence against single-atom dephasing terms. The optical access afforded by a near-concentric cavity facilitates local control and imaging of the magnetization for Hamiltonian tomography and spatially resolved detection of the spin coherence. Imaging also allows for the first observation of cavity-mediated spin mixing in a spin-1 system, a new mechanism for generating correlated atom pairs. Whereas the single-mode cavity most naturally mediates all-to-all couplings, I will also discuss progress in generalizing to control the distance-dependence of the interactions, with prospects in engineering the spatial structure of entanglement. I furthermore propose and analyze two specific protocols in quantum control enabled by strong and tunable atom-light interactions. I first introduce a protocol that enables entanglement-enhanced measurements near the Heisenberg limit while reducing technical requirements on detection. This is accomplished via an interaction-enhanced readout that relies on reversing the sign of global Ising interactions. Dispersive atom-light interactions also enable heralded schemes, in which a high-fidelity pure state is produced upon probabilistic detection of a single photon. In this context, I show how a time-shaped single-photon pulse can ``paint'' an arbitrary superposition of coherent spin states while avoiding infidelities due to finite cavity linewidth

Keywords: Physics.
Advisor: Schleier-Smith Monika
Hollberg Leo (Leo William)
Safavi-Naeini Amir H.
An engineering approach to uncover interactions between bacteriophages, bacteria and mammalian cells

The hypothesis driving my thesis is that a major role that bacterial viruses (bacteriophages) may play in the body is to collaborate with the host immune environment to clear a bacterial infection. To probe this question, the existing techniques that can be applied to study bacteria:bacteriophage interactions such as viral particle-based plaque assays are limited to measurements at single points in time and for a bulk population of bacteria and viruses. A relevant experimental model for observing phage-immune interactions will be tripartite: the simultaneous observation of bacteriophages within host bacteria phagocytosed by immune cells. In this thesis, I present three projects that probe how bacteriophages influence the success of bacterial infections of immune cells. In the first, I develop a new method to multiplex the engineering of fluorescent life-cycle reporters into the lysogenic lambda phage. These reporter phages are used to create engineered E. coli lysogens which are infected into macrophages and tracked with live-cell imaging to study prophage induction at the single-cell level. Next, I demonstrate for the first time that prophages induce from phagocytosed E. coli in 20% of the infected macrophages. Furthermore, through a dual bacterial strain infection strategy, I show that the bacteriophages released from one strain of E. coli are functional and can kill other E. coli within the same macrophages. These prophage induction events occur in phagocytosed E. coli at a 26-fold higher frequency than basal levels, suggesting that a factor in the macrophage environment actively triggers the induction process. Finally, through the use of bacterial single gene knockouts, I demonstrate that the PhoP pathway, which responds to outer membrane stress from magnesium limitation, acidic pH and antimicrobial peptides, is involved in the induction process. I identify the mammalian-produced antimicrobial peptide, mCramp1, to be a novel inducer of bacterial prophage induction mediated by PhoP. This thesis suggests several possible new mechanisms by which bacteriophages function to assist the bacterial-killing activity of macrophages

Keywords: Bioengineering.
Advisor: Covert Markus 
Endy Andrew D. 
Huang Kerwyn Casey
Engineering disruption : development of rapid acting anti-IgE therapeutic agents

Allergic diseases are a significant source of human morbidity and mortality. The human antibody isotype IgE plays a central role in the pathogenesis of allergic disease by mediating antigen dependent signals through the high affinity IgE receptor (FcεRI) expressed on the surface of mast cells and basophils. Upon allergen encounter, IgE:FcεRI complexes at the cell surface are crosslinked, driving mast cell/basophil activation and degranulation. This activation event drives a spectrum of allergic events ranging from local hypersensitivity reactions to systemic anaphylaxis and death. Omalizumab, an anti-IgE monoclonal antibody, blocks interactions between IgE and FcεRI and has validated IgE as a therapeutic target in multiple allergic diseases. Unlike many antibody isotypes, IgE binds FcεRI with high affinity (KD < 1nM). The slow dissociation of IgE from the high affinity receptor limits the potential of strictly competitive anti-IgE agents, and these agents cannot be employed in acute allergic settings. Therefore, our group and others have begun to investigate novel anti-IgE agents that can target preformed IgE:FcεRI complexes and accelerate the dissociation of IgE from these complexes on cells without activating them. These disruptive anti-IgE agents hold the promise of completely desensitizing an individual to allergens in minutes to hours. The work presented in this thesis defines key structural parameters of potent disruptive anti-IgE agents, develops a framework to enhance the disruptive activities via directed evolution, and captures the intermediate structure of IgE receptor disruption by an antibody. Finally, using directed evolution and structure guided design, we are able to push the therapeutic limits of disruptive agents and interrupt ongoing systemic allergic reaction in vivo

Advisor: Jardetzky Theodore
Blish Catherine
Galli Stephen J.
Nadeau Kari
Engineering heterologous hosts for the production and study of fungal lignin-degrading enzymes

Lignin is the second-most abundant biopolymer on Earth and has significant potential as a renewable source for commodity chemicals yet remains vastly underutilized. The lack of an established route to lignin deconstruction means that the primary value of industrial lignin by-products is heat and electricity by incineration. Molecular decomposition of lignin would yield derivatives with economic value in chemical and material applications typically reliant on petroleum. Biological catabolism of lignin by wood-decaying basidiomycete fungi is widespread in nature and presents scalable and renewable means of its deconstruction under mild conditions. However, basidiomycete fungi remain genetically intractable and challenging to cultivate rapidly, limiting their utility in the industrial production of lignin-degrading enzymes. Efficient heterologous production of basidiomycete lignin-degrading enzymes has also proven elusive, hampering efforts toward engineering a biochemical route to the valorization of lignin. In this dissertation, I present efforts aimed at overcoming this major obstacle in the field of lignin degradation. I demonstrate that, despite extensive optimization, the model yeast host Saccharomyces cerevisiae is unable to produce most of the lignin-degrading enzymes tested, especially the main agents of fungal lignin degradation, heme peroxidases. In contrast, the model plant host Nicotiana benthamiana natively produces heme peroxidases for cell wall biogenesis, and I found that this host is well-suited for heterologous production of fungal lignin-degrading peroxidases as well as the majority of lignin-degrading enzymes tested. This approach enabled assay of these enzymes in different combinations on a model lignin dimer, revealing different modes of action. Finally, I describe identification of two null mutants of S. cerevisiae that exhibit increased secretion of multiple fungal lignin-degrading peroxidases. This work represents a significant advance in the development of a biochemical route to lignin valorization, with implications for the understanding of biological lignin degradation as well as of factors required for successful production of proteins in heterologous hosts

Keywords: Chemical Engineering.
Advisor: Sattely Elizabeth
Khosla Chaitan
Smolke Christina D.