VictorJuiz/thesis huggingface dataset:
Simultaneous analysis and design in PDE-constrained optimization [electronic resource]

New methods for solving certain types of PDE-constrained optimization problems are presented in this thesis. The approach taken is to augment state-of-the-art PDE methods. The PDE variables and the optimization variables are solved for simultaneously. This impacts the PDE method by changing the core from solving a system of nonlinear equations to that of finding a nonlinear saddle point. This in turn alters the character of the linear equations that are solved at each iteration. In the problem we address, the objective function has to match a given target state. Both volume and boundary controls are considered in order to match the target. Regularization is added to the objective function to aid stability and to facilitate computing the solution of the linear systems that arise within the algorithm. Solving such linear systems has been the focus of much research, with many methods being proposed. How to do this simultaneously and efficiently for the specific systems that arise in the PDE-constrained optimization problems of interest is the main focus of our work. The new methods have been implemented by modifying the cutting-edge software AERO-S. Numerical results are presented for a variety of problems including a flapping wing, a robotic control problem, and a thermal control problem.

Advisor: Murray Walter primary advisor. Thesis advisor
Farhat Charbel advisor. Thesis advisor
Pavone Marco
Saunders Michael
Single-cell deep profiling of immune signaling and drug responses in normal and malignant human hematopoiesis [electronic resource]

The human hematopoietic system is a complex mixture of morphologically and functionally distinct cell types. Using high-dimensional single-cell cytometry, functional behaviors in a wide number of cell types can be monitored simultaneously ("deep profiling"), enabling new insights into the structure and relationships of the overall system. Presented in this dissertation are several incremental technical and informatic steps that contributed to this holistic approach to single-cell biology. Using 30-parameter mass cytometry, deep profiling was used to recover the developmental continuum of healthy bone marrow and create a detailed map of the atypical functionally related cell types in a case of oligoclonal pediatric acute myeloid leukemia. These examples demonstrate the utility of a single-cell deep profiling paradigm in attaining an informative snapshot of healthy and malignant human hematopoiesis.

Keywords: Microbiology and Immunology
Advisor: Nolan Garry P. primary advisor. Thesis advisor
Davis Mark M. advisor. Thesis advisor
Levy Ronald
Sarnow P. (Peter) advisor. Thesis advisor
Single-cell gene expression analysis in C. elegans [electronic resource]

Complex organisms contain many individual cells that express unique sets of genes. Unraveling the full complexity of organisms requires an understanding of the unique gene expression signatures of individual cells. Obtaining these cellular signatures enables a deeper understanding of the underlying biological processes, including development and aging. Model organisms, such as C. elegans, are ideal platforms for single-cell studies, offering true single-cell resolution. In the nematode, C. elegans, each of its 959 somatic cells are uniquely identifiable in every individual. Through high-resolution 3D imaging of in-situ fluorescent reporters, expression levels can be observed in all 959 cells. The key to making this powerful system a viable source of discovery through large-scale, high-resolution gene expression analysis requires automation of the annotation process. This dissertation describes computational approaches to identifying single-cells to obtain high-resolution gene expression levels in adult C. elegans. These approaches include an image processing pipeline enabling both manual and automatic annotation of images. For the latter, I describe a set of automatic annotation methods developed for single-cell identification in 3D confocal images of adult C. elegans utilizing machine learning approaches. These approaches automatically assign a set of labels to cells based on (1) cell-lineage, (2) tissue type or (3) the anatomical region occupied within the worm. Finally, this dissertation describes the types of biological insights researchers can gain from such high-resolution data. In particular, it develops a novel gene expression analysis method that combines the known cell lineage and expression levels of 96 genes in 363 single-cells in the first larval stage of C. elegans. Together, these methods provide C. elegans researchers with a powerful toolkit for performing single-cell gene expression analysis of worms. This work enables studies in the field of development and, for the first time, aging at the single-cell resolution using automated annotation approaches in the adult worm.

Advisor: Batzoglou Serafim primary advisor. Thesis advisor
Kim Stuart
Paik David advisor. Thesis advisor
Single-molecule fluorescence and super-resolution imaging of Huntington's disease protein aggregates [electronic resource]

Single-molecule, super-resolution fluorescence microscopy is a powerful technique for studying biological systems because it reveals details beyond the optical diffraction limit (on the 20-100 nm scale) such as structural and conformational heterogeneity. Further, single-molecule imaging measures distributions of behaviors directly through the interrogation of many individual molecules and reports on the nanoscale environment of molecules. Sub-diffraction imaging adds increased resolution to the advantages of fluorescence imaging over the techniques of atomic force microscopy and electron microscopy for studying biological structures, which include imaging of large fields of view in aqueous environments, specific identification of protein(s) of interest by fluorescent labeling, low perturbation of the system, and the ability to image living systems in near real-time (limited by the time required for super-resolution sequential imaging). This dissertation describes the application of single-molecule and super-resolution fluorescence imaging to studying the huntingtin (Htt) protein aggregates that are a hallmark of Huntington's disease and that have been implicated in the pathogenesis of the disease. The intricate nanostructures formed by fibrillar Htt aggregates in vitro and the sub-diffraction widths of individual fibers mark the amyloids as important targets for high-resolution optical imaging. The characterization of Htt aggregate species is critical for understanding the mechanism of Huntington's disease and identifying potential therapies. Following an introduction to single-molecule, super-resolution imaging and Huntington's disease in Chapter 1, Chapter 2 describes the single-molecule methods, experimental techniques, Htt protein sample preparations, and data analysis performed in this dissertation. Chapter 3 discusses the development of super-resolution imaging of Htt protein aggregates and the validation of the images by atomic force microscopy. Chapter 4 continues the study of Htt by one- and two-color super-resolution with imaging of Htt protein aggregates over time from the initial protein monomers to the large aggregate assemblies of amyloid fibers. In Chapter 5, I detail our progress to-date in studying the earliest stages of Htt aggregation using zero-mode waveguide technology. Chapter 6 concludes the dissertation with a discussion of the results from additional projects comprising the effect of chaperonin proteins on Htt aggregation, extension of super-resolution Htt imaging to three dimensions, and cellular imaging of Htt aggregates. The future directions for these exciting projects are summarized with the expectation that research efforts directed in these areas will contribute to our understanding of Htt aggregation and Huntington's disease.

Keywords: Chemistry
Advisor: Moerner W. E. (William Esco)
Boxer Steven G. (Steven George)
Pande Vijay advisor. Thesis advisor
Single-molecule studies of RNA conformations and cotranscriptional folding in adenine riboswitches [electronic resource]

RNA--a ubiquitous and versatile type of biopolymer that is critically involved in many of life's molecular processes--is produced sequentially in single-stranded form during transcription by RNA polymerase and has the propensity to fold back on itself into interesting structures of functional import. In nature, riboswitches are elegant examples of structured RNA that adopt alternate conformations in response to ligand binding and thereby affect gene expression. We have been able to probe riboswitch conformations in novel detail using single-molecule optical-trapping techniques. These experimental approaches supply a unique perspective on folding since the ability to apply force provides an effective handle on the real-time state of individual RNA molecules and a means of modulating that state. In this dissertation, I focus on three studies that explore adenine riboswitch conformations and mechanisms. Specifically, in the first, we dissect the folding landscape of the aptamer (ligand-binding domain) of an adenine riboswitch. Extending this endeavor to full riboswitch sequences, we probe the interplay of a riboswitch aptamer with its downstream expression platform (which executes the switch's regulatory role), and develop methods to do so both during and after transcription. The second study takes full advantage of the latter ability: In a complete adenine riboswitch controlling transcription, we directly observe cotranscriptional folding of the nascent RNA in which the adopted conformation dictates whether or not to terminate transcription. Finally, in a different adenine riboswitch controlling translation, we investigate switch conformational changes and identify a series of competing structural elements that kinetically trap the riboswitch conformation, implying that the initial, cotranscriptional fold of the riboswitch may determine its gene regulatory state. These efforts enhance our understanding of folding architectures in riboswitches, specifically, and in RNA, more broadly. They further highlight the importance of cotranscriptional folding, providing a novel window into the nascent development of RNA conformations.

Advisor: Block Steven
Greenleaf William James advisor. Thesis advisor
Spudich James A.
Single-molecule studies on transcriptional elongation in prokaryotes and eukaryotes [electronic resource]

Transcription, the process of copying genetic information stored in DNA into RNA, is fundamental to life. It is carried out by an extraordinary nano-machine called RNA polymerase (RNAP). Transcriptional elongation, during which RNAP moves along the DNA, adding one nucleotide at a time to the RNA transcript, is highly dynamic and regulated. The motion of RNAP is discontinuous and interrupted by pauses that play an essential role in gene regulation. Fundamental questions regarding the mechanisms of elongation and its modulation by transcription factors, however, remain unclear. In this dissertation, I focus on using high-resolution, optical trapping techniques to study the mechanisms of transcriptional elongation by both prokaryotic and eukaryotic RNA polymerases at the single-molecule level. First, I describe the studies on how the motion of single E.coli RNAP molecules is modulated by two universally conserved, essential transcription factors (NusA and NusG). From individual transcriptional elongation records, the rates of entering pause states, the pause state lifetimes, and the pause-free elongation speeds can all be extracted. By studying the effects of NusA (and NusG) on these kinetic rates as a function of the applied load, we were able to develop a quantitative kinetic scheme for elongation and pausing. This model not only explains the functions of NusA/NusG, but also provides insight into the mechanism of transcriptional pausing, which had previously been controversial. Second, a novel optical-trapping assay capable of directly probing elongation by individual eukaryotic RNA polymerase II (RNAPII) molecules will be described. We find that the RNAPII trigger loop, an evolutionarily conserved protein subdomain, not only affects each of the three main phases of elongation, namely: substrate binding, translocation, and catalysis; but also plays a critical role in controlling the fidelity of transcription. Our data also support a Brownian ratchet model for elongation which incorporates a secondary nucleotide binding site.

Keywords: Applied Physics
Advisor: Block Steven
Chang Howard
Kornberg Roger D.
Size-expanded ribonucleic acids (xRNAs) [electronic resource] : a novel component in siRNAs for investigating the steric restrictions of RISC in RNAi

This thesis project describes the synthesis and use of size-expanded ribonucleic acids (xRNAs) as unnatural components in small interfering RNAs (siRNAs), which serve as a novel set of steric probes for investigating and identifying size restrictions that exist in the active site of the RNA-induced silencing complex (RISC), a critical protein complex in the RNA interference (RNAi) mechanism. xRNAs are analogous to natural RNAs, in which they retain canonical Watson Crick base-pairing groups, except their nucleobases are expanded linearly by 2.4 Å via benzo-fusion. In this report, the synthesis of the entire set of four xRNA nucleosides and their photophysical properties are described. Two of the xRNA nucleosides (i.e. rxA and rxU) are then converted to their corresponding phosphoramidites for use in automated RNA synthesis to synthesize various sets of xRNA-substituted siRNA strands for biophysical and biological studies. RNAi activity studies in HeLa cells using a firefly/Renilla luciferase dual reporter assay showed that xRNA substitutions in the antisense strand displayed poor RNAi activity in the middle of the sequence (positions 7-14) but were generally well tolerated near the 5'- and 3'-ends. Most significantly, single xRNA substitutions at the 3'-end showed RNAi activity that was more potent than that of unmodified siRNAs. Thermal denaturation studies revealed small changes in melting temperature (+1.4 to --5.0 °C); xRNA substitutions in the middle were found to be more thermodynamically destabilizing whereas the ends were shown to be stabilizing. Serum stability studies showed that xRNA-containing siRNAs have longer half-lives in human serum than unmodified siRNAs. Finally, xRNA-substituted siRNA strands and duplexes showed interesting position-dependent fluorescent properties, while CD spectroscopy experiments revealed that xRNA-substituted siRNAs does not greatly distort the native A-form helical structure of the duplexes. Taken together, the data demonstrate the utility of xRNA nucleobases as size-expanded mechanistic probes for RNAi research.

Keywords: Chemistry
Advisor: Kool Eric T. primary advisor. Thesis advisor
Khosla Chaitan
Wandless Thomas advisor. Thesis advisor
Small changes big impact, ligand influence on dioxygen, semiquinone, and phenoxyl radical copper complexes [electronic resource]

Reductive activation of dioxygen by copper to generate potent oxidants for multi- electron organic transformations is exploited extensively in biological systems. This thesis focuses on two types of multi-electron oxidants: Cu2O2 complexes and copper complexes with redox-active ligands. The goal of this work is to identify the influence of nitrogen containing ancillary ligands on properties of dioxygen, semiquinone and phenoxyl radical complexes of copper. This work is aimed primarily at synthetic chemists interested in rational design of ligands for creating bio-inspired oxidants and oxidation catalysts. Chapter 1 of this thesis reports the identification of a Density Functional Theory (DFT) protocol for deriving structure-property relationships in Cu2O2 complexes. Chapter 2 of this thesis applies towards modeling electronic spectra, the DFT protocols that were validated in Chapter 1 for modeling thermodynamics. Chapter 3 of this thesis describes the properties and reactivity of Cu2O2 complex generated from a new hybrid permethylated-amine-guanidine ligand based on a 1,3- propanediamine backbone (2L). Chapter 4 of this thesis describes the characterization of an intermediate (C) that is observed in both phenol hydroxylation and catechol oxidation with the SP core supported by N1, N2-di-t-butylethane-1,2-diamine (DBED). Chapter 5 of this thesis describes the influence of sulfanyl substituents on the optical and redox properties of copper-bonded phenoxyls.

Keywords: Chemistry
Advisor: Stack T. (T. Daniel P.)
Boxer Steven G. (Steven George)
Solomon Edward I. advisor. Thesis advisor
Small-sample behavior of importance sampling estimators [electronic resource]

This thesis studies the small sample behavior of importance sampling estimators under an importance measure that is not necessarily optimal. We first study the asymptotic behavior of IS estimators for sums of random variables when the sample size increases exponentially. We next propose logarithmic relative accuracy as a new measure for estimator accruacy. Finally, we extend the result to the importance sampling estiamtors for slow Markov random walks.

Keywords: Electrical Engineering
Advisor: Glynn Peter W. primary advisor. Thesis advisor
Bambos Nicholas advisor. Thesis advisor
Giesecke Kay advisor. Thesis advisor
Soft limits and color-kinematic dualities in perturbative quantum gravity [electronic resource]

This thesis is a study of the perturbative behavior of quantum gravity through explicit tree- and loop-level supergravity calculations. First, I discuss how using universal soft limits could allow us to reconstruct tree-level amplitudes. Second, I obtain loop-level results in non-maximal (N < 8) supergravity using the double-copy prescription for generating gravity amplitudes from gauge-theory amplitudes, which follows from the recently discovered Bern-Carrasco-Johansson (BCJ) duality in gauge theory. I combine N = 0,1,2 super-Yang-Mills (sYM) amplitudes with N = 4 sYM amplitudes to obtain N = 4,5,6 supergravity amplitudes. I show how the double-copy prescription reproduces known one-loop amplitudes, which correspond to the first explicit demonstration of the validity of the double-copy prescription in non-maximal supergravity. I then present and discuss new amplitudes at two loops in N = 4,5,6 supergravity.

Keywords: Physics
Advisor: Dixon Lance
Kallosh Renata advisor. Thesis advisor
Peskin Michael Edward
Software tools to facilitate research programming [electronic resource]

Research programming is a type of programming activity where the goal is to write computer programs to obtain insights from data. Millions of professionals in fields ranging from science, engineering, business, finance, public policy, and journalism, as well as numerous students and computer hobbyists, all perform research programming on a daily basis. My thesis is that by understanding the unique challenges faced during research programming, it becomes possible to apply techniques from dynamic program analysis, mixed-initiative recommendation systems, and OS-level tracing to make research programmers more productive. This dissertation characterizes the research programming process, describes typical challenges faced by research programmers, and presents five software tools that I have developed to address some key challenges. 1.) Proactive Wrangler is an interactive graphical tool that helps research programmers reformat and clean data prior to analysis. 2.) IncPy is a Python interpreter that speeds up the data analysis scripting cycle and helps programmers manage code and data dependencies. 3.) SlopPy is a Python interpreter that automatically makes existing scripts error-tolerant, thereby also speeding up the data analysis scripting cycle. 4.) Burrito is a Linux-based system that helps programmers organize, annotate, and recall past insights about their experiments. 5.) CDE is a software packaging tool that makes it easy to deploy, archive, and share research code. Taken together, these five tools enable research programmers to iterate and potentially discover insights faster by offloading the burdens of data management and provenance to the computer.

Advisor: Engler Dawson R. primary advisor. Thesis advisor
Heer Jeffrey Michael advisor. Thesis advisor
Seltzer Margo advisor. Thesis advisor
Solid state cavity quantum electrodynamics with quantum dots coupled to photonic crystal cavities [electronic resource]

Quantum dots (QDs) coupled to optical cavities constitute a scalable, robust, on-chip, semiconductor platform for probing fundamental cavity quantum electrodynamics. Very strong interaction between light and matter can be achieved in this system as a result of the eld localization inside sub-cubic wavelength volumes leading to vacuum Rabi frequencies in the range of 10s of GHz. Such strong light-matter interaction produces an optical nonlinearity that is present even at single-photon level and is tunable at a very fast time-scale. This enables one to go beyond fundamental cavity quantum electrodynamics (CQED) studies and to employ such e ects for building practical information processing devices. My PhD work has focused on both fundamental physics of the coupled QD-nanocavity system, as well as on several proof-of-principle devices for low-power optical information processing based on this platform. We have demonstrated the e ects of photon blockade and photon-induced tunneling, which con rm the quantum nature of the coupled dot-cavity system. Using these e ects and the photon correlation measurements of light transmitted through the dot-cavity system, we identify the rst and second order energy manifolds of the Jaynes-Cummings ladder describing the strong coupling between the quantum dot and the cavity eld, and propose a new way to generate multi-Fock states with high purity. In addition, the interaction of the quantum dot with its semiconductor environment gives rise to novel phenomena unique to a solid state cavity QED system, namely phonon-mediated o -resonant dot-cavity coupling. We have employed this effect to perform cavity-assisted resonant quantum dot spectroscopy, which allows us to resolve frequency features far below the limit of a conventional spectrometer. Finally, the applications of such a coupled dot-cavity system in optical information processing including ultrafast, low power all-optical switching and electro-optic modulation are explored. With the light-matter interactions controlled at the most fundamental level, the nano-photonic devices we implemented on this platform operate at extremely low control powers and could achieve switching speeds potentially exceeding 10 GHz.

Keywords: Electrical Engineering
Advisor: Vuckovic Jelena primary advisor. Thesis advisor
Mabuchi Hideo advisor. Thesis advisor
Miller D. A. B. advisor. Thesis advisor
Some analyses of markov chains by the coupling method [electronic resource]

This thesis is concerned with the non-asymptotic convergence rates of various Markov chains, and consists of two main sections. In the first section, I investigate the properties of random birth and death chains with fixed stationary distributions. The main results include a proof of the fact that random birth and death chains are in some sense less likely to exhibit cutoff than a certain natural family of birth and death chains, and conversely a proof that several natural families of random birth and death chains do exhibit cutoff. In the second section, I find accurate bounds for the convergence of Gibbs samplers on continuous state spaces. This includes a resolution of Aldous' conjecture on the mixing time of a sampler on the unit simplex, a generalization of work by Randall and Winkler on a related Gibbs sampler associated to a graph, and improvements on existing bounds on the convergence rates of Kac's walk on the sphere and a Gibbs sampler on narrow matrices with fixed row and column sums.

Keywords: Mathematics
Advisor: Diaconis Persi primary advisor. Thesis advisor
Dembo Amir advisor. Thesis advisor
Soundararajan Kannan