VictorJuiz/thesis huggingface dataset:
Structural phase changes and strain engineering in two-dimensional materials [electronic resource]
Keywords: Applied Physics.

Two-dimensional (2D) materials are a family of crystals that are only a few atomic layers thick. The discovery of 2D materials has triggered increasing research efforts, motivated by their unique properties, such as ultra-low thickness, high mechanical strength and high flexibility. In the first part of this dissertation, I show that electrostatic gating can induce structural semiconductor-to-semimetal phase changes in 2D materials. Dynamic control of conductivity and optical properties via atomic structure changes is of technological importance in information storage. Energy consumption considerations provide a driving force towards employing thin materials in devices. Monolayer transition metal dichalcogenides (TMDs) are nearly atomically thin materials that can exist in multiple crystal structures, each with distinct electrical properties. By developing new density functional-based methods, I discover that electrostatic gating device configurations have the potential to drive structural semiconductor-to-semimetal phase transitions in some monolayer TMDs. I show that semiconductor-to-semimetal phase transition in monolayer MoTe2 can be driven by a gate voltage of several volts with an appropriate choice of dielectric. I find that the transition gate voltage can be reduced arbitrarily by alloying, for example, for MoxW(1-x)Te2 monolayers. My findings identify a new physical mechanism nonexistent in bulk materials to dynamically control structural phase transitions in 2D materials, enabling potential applications in phase-change electronic devices. Next, I discuss low energy consumption phase change memory that utilizes electrostatically induced structural phase changes in 2D materials. I compare electrostatically driven phase transition with thermally induced phase transition from an energy perspective. I discover that electrostatically driven phase transition is much more energy efficient and does not necessarily generate heat dissipation into its surroundings, which is unavoidable and the most significant part of energy consumption in thermally driven phase transition. In the last part of this work, I describe strain engineering in 2D materials using lithographically or otherwise patterned adatom adsorption. I discover that the monolayer strain results from a competition between the in-plane elasticity and out-of-plane relaxation deformations. I find that some adsorption patterns have the potential to produce strains of as large as 5\%, larger than the strains applied using a substrate approach.
Structure-based engineering of immunomodulatory agents for the treatment of cancer [electronic resource]
Keywords: Structural Biology.

Immune-based therapies for cancer are powerful, lasting, and generally less toxic than most other cancer treatment paradigms. Consequently, the development of new immunotherapeutic agents and the study of the interplay between tumors and the immune system have emerged as central lines of research for this nascent field of medicine. Here, I describe my efforts to improve an existing cancer immunotherapy (Interleukin-2), to study an experimental immunotherapeutic agent (Interleukin-15), and to generate novel protein therapeutics against an emerging target of cancer immune evasion (CD47). These studies highlight a structure- and mechanism-based approach to protein engineering in the development of next-generation cancer immunotherapies.
Studies of unconventional superconductivity [electronic resource]
Keywords: Physics.

The physics of unconventional superconductors has been studied for decades but is still not well understood. The present thesis consists of two parts, each intended to shed light on some aspects of this long-standing problem. In the first part, I discuss, based on the Hubbard model in the weak-coupling limit, how the repulsion between electrons gives rise to Cooper pairing. I present simple rules that connect the features of the band structure to those of the gap function, as well as detailed numerical results for various model systems. In the second part, I focus on symmetry constraints on light reflection; a precise understanding of this issue is essential for identifying broken symmetries in various unconventional superconductors from polar Kerr effect measurements. Using a Green's function approach, I prove that the Onsager symmetry of the nonlocal electromagnetic response function implies the absence of the polar Kerr effect in backscattering.
Studies towards the total synthesis of bryostatin 3 [electronic resource]
Keywords: Chemistry.

The bryostatins, first isolated by Petit et al. from the marine bryozoan Bugula neritina, are a family of 21 macrolides with potent antineoplastic, immunopotentiating, synaptogenesis-inducing and latent HIV-modulating activity. Beneficial effects as a post-stroke treatment and for restoring the blood brain barrier after traumatic blast injuries have also been reported. While the exact mechanism of action remains an ongoing area of research, it has become clear that bryostatins act as agonists of protein kinase C with low nanomolar affinities for their target. Within the bryostatins bryostatin 3 stands out as the most complex member of this family of natural products. While the majority of bryostatins share a common macrocyclic backbone with three tetrahydropyran rings bryostatin 3 features an additional butenolide ring fused to the C-ring. Our retrosynthetic plan for bryostatin 3 disconnects the target into three fragments of similar complexity and we were able to elaborate these fragments to a protected version of bryostatin 3. This direct precursor to the natural product was synthesized in 22 steps (longest linear, 31 total). The only previous total synthesis of bryostatin 3 was accomplished in 43 steps (longest linear, 89 total).
A study of environmental contributions to the growth and function of the gentle touch receptor neurons in Caenorhabditis elegans [electronic resource]
Keywords: Molecular and Cellular Physiology.

Eukaryotic organisms use sensory systems to receive information about the world in which they live. They convert environmental stimuli into signals, usually electrical, which can then be processed and translated into pro survival behavior. A key capability for many of these organisms is the ability to sense direct mechanical stimulation, or mechanosensation. Mechanosensory systems consist of the core transduction machinery and the surrounding cellular environment that houses and supports that machinery. In this work, I discuss three studies in which I examined the contribution of the cellular environment to the development and function of the gentle touch mechanosensory system in the nematode Caenorhabditis elegans. In the first study, we show that alterations of the lipid environment in the touch receptor neurons impairs their function. In the second, we demonstrate that the roles of various tubulin isotypes in the touch receptor neurons is context dependent. Finally, in the third study I explore the contribution of the mechanical environment surrounding the TRNs to their length. Taken together, these three studies demonstrate that mechanosensation relies on the interplay between the core transduction machinery and the environmental context in which it acts.
Sub nano kelvin thermometry and temperature stabilization using resonant cavity thermometry [electronic resource]
Keywords: Mechanical Engineering.

This thesis describes a general purpose high resolution thermometer based on measuring the resonant frequency of an optical cavity with high coefficient of expansion. It is capable of operating at an arbitrary temperature near room temperature and we have demonstrated an exceptionally low noise figure of 6.6 nK/rtHz at 1Hz. The thermometer has a continuous dynamic range of 0.74 K and an estimated total dynamic range of > 400 K. We evaluate its performance by observing the beat note between the cavity resonance and a reference frequency derived from an ultra low expansion coefficient glass cavity operating near its expansion coefficient null. A hyperfine line feature at a10 transition in iodine near 532 nm is used to calibrate both optical cavities. The temperature sensitivity of the device estimated from its expansion coefficient was found to agree with thermistor measurements to within measurement uncertainty. The device shows a steady drift when compared with the thermistor over many hours. After removing this drift, the resulting calibrated signal is used as an error signal for thermal control, and 7.6 nK stability is achieved with 1 s integration time. When averaged over longer time spans the device shows improved noise performance reaching 200 pK temperature stability at 10,000 s integration time. We describe its construction and performance and mention some modifications to improve its utility.
A sub-nyquist ultrasound imager with subarray beamforming [electronic resource]
Keywords: Electrical Engineering.

Ultrasound is a popular imaging modality today. In the medical community, it is commonly used for a wide variety of applications, including early-stage cancer detection and gallstone detection. When compared to other imaging methods such as X-ray or MRI, ultrasound is safe, fast, noninvasive, and low-cost. Traditional ultrasound imagers suffer from high data rates between their sensors and their digital processing back end. This seemingly fundamental data rate is caused both by the use of many analog-to-digital converters (ADCs), each of which samples at a rate corresponding to a traditional interpretation of the Shannon-Nyquist sampling theorem. These data rates can often exceed 4 GB/s (128 sensor elements with 12 bit sampling at 20 MS/s). These data rates hold back the development of fully integrated imagers with high transducer element counts, such as 2D imaging arrays. In a departure from traditional imager design, I sample received ultrasound signals at rates below their physical bandwidth, leveraging compressive sensing (CS) techniques for digital reconstruction. These techniques allow us to reduce data rate on a per-ADC basis. I additionally introduce a mixer-based subarray beamforming technique which exploits the narrowband nature of the receiver to reduce the required number of data converters. Reducing the number of digitizers results in a multiplicative reduction in aggregate data rate. These techniques are demonstrated with a 32- channel ultrasound receiver in a PCB-based hardware implementation which reduces aggregate data rates by a factor of 50 times when compared to a conventional ultrasound topology. There exists a tradeoff between the accuracy of the reconstructed image and the fraction of the bandwidth sampled; we evaluate this tradeoff using experimental data.
Subversive Style in Wartime Los Angeles: Explaining the Zoot Suit Riots
Keywords:  Center for International Security and Cooperation
Zoot Suit Riots
Center for International Security and Cooperation
Stanford University
racial deprivation theory
ethnic competition theory
segregation
race riots
Mexican-American
military
World War II
Thesis

The Zoot Suit Riots happened in Los Angeles during the summer of 1943, consisting of about one week of fighting between the local zoot-suiters—a mainly Mexican-American group of young people—and servicemen training at the Naval Reserve Armory Center. The first chapter of this paper demonstrates that two existing theories of racial violence—ethnic competition theory and deprivation theory—are not able to adequately explain why wartime Los Angeles erupted into violence upon racial lines, thus demonstrating the need for further study. The second chapter provides a comparison between San Diego and Los Angeles and highlights important infrastructural differences that allowed San Diego—a city with similar demographic characteristics and military intrusion into local Mexican-American neighborhoods—to avoid racial violence. The third and last substantive chapter delves a little bit further into the local context of Los Angeles and the Chavez Ravine neighborhood in particular in order to understand the aspects of zoot-suiters—rather than simply Mexican-Americans—and servicemen—rather than the whites of Los Angeles—that made them antagonistic towards each other.
Successful pre-meiotic anther development is required for male fertility in Zea mays L [electronic resource]
Keywords: Biology.

Anthers, the male reproductive organ of angiosperms, are critical for the fertility and production of pollen. In this thesis I show that collection of anthers of specific developmental stages is possible for a maize tassel of a known size, making the other studies in later chapters possible. The studies detailed in the following chapters focus on the pre-meiotic events required to convert a group of meristematic cells into a complex organ with both meiotically-competent and somatic cell types. Establishment of the somatic niche happens through a series of periclinal patterning divisions, establishing a layered organ of somatic cell types with a column of germinal cells at the center of this somatic niche. Each of the somatic cell types of the anther has a distinct cell fate and morphological appearance. Errors in the periclinal divisions responsible for the patterning of these layers are present in nearly half of identified pre-meiotic male sterile mutants. Using a new approach to mutant phenotype classification, I quantified phenotypes from confocal images and show that not only do somatic defects vary in the number of extra periclinal divisions produced, but also that even minor defects in somatic identity are sufficient to cause male sterility. Furthermore, when looking deeper into these defects using transcriptome and proteome analyses, I detected large and dynamic changes both across anther development as cell types mature and between individual cell types collected using laser capture microdissection. These changes at the transcript level were not tightly correlated with protein changes at the same developmental stage, perhaps hinting at levels of post-transcriptional regulation in the anther that remain unexplored. Clear differences in transcriptomes were observed when male-sterile mutants were compared with their fertile siblings, even in cases where morphological defects were comparatively minor, highlighting, again, that even relatively minor defects in somatic cell specification can result in complete male sterility in maize anthers.
SUFU and SMO mutations in Hedgehog signaling drive resistance pathways in basal cell carcinoma
Keywords:  Department of Biology
Biology
Basal Cell Carcinoma
Suppressor of Fused
Smoothened
Thesis

The Hedgehog pathway, involved in regulating cellular growth and proliferation, has been implicated in the development of many cancers including basal cell carcinoma (BCC). BCC can be treated with vismodegib to inhibit Hedgehog signaling, but many tumors acquire resistance to this drug. The majority of BCCs are known to arise from mutations in Patched, the receptor for the Hedgehog pathway. However, a secondary driver mutation in another Hedgehog protein is generally required for oncogenesis. Given the exposure of the skin to environmental stressors, these tumors develop high mutational loads. This high mutation rate creates a range of functional consequences whose contribution to the growing cancer remain unknown; some mutations help drive tumor development, while others cause neutral or deleterious effects. This study reveals secondary driver mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway, and Smoothened (SMO), the major activator of the Hedgehog pathway. We sequenced both tumor and normal skin samples from patients with early sporadic and drug-resistant BCCs. This resulted in the discovery of novel mutations in SUFU and SMO, which were functionally investigated to determine whether they help drive BCC formation and serve as drivers for vismodegib resistance development. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they act as driver mutations for BCC development. SMO variants were mostly neutral or deleterious, supporting a model in which tumors “roll the genetic dice” to generate as many mutations as possible to increase their chances of resistance development. Our results from functional characterization of these mutations further clarifies tumor progression, better specifies SUFU’s role in Hedgehog signaling, and presents novel ways in which BCCs can arise and evolve. This information is invaluable for understanding the mechanisms of tumor development in Hedgehog-driven cancers and provides new avenues for drug targets and personalized medicine.
Sustainable engineering of biopolymer composites [electronic resource] : end-of-life degradation mechanisms
Keywords: Civil and Environmental Engineering.

Biodegradable plastics and composites have the potential to replace traditional plastics and their composites in a variety of applications, thereby enabling sustainable material and energy life-cycles. The envisioned material life-cycle that is investigated here, is a microbially produced class of bioplastics, poly(hydoxyalkanoates) (PHAs), which can be anaerobically degraded at the end of their serviceable life into a methane-rich feedstock. By recovering methane produced from controlled anaerobic digestion (AD) of this bioplastic and its composites at end-of-life, these materials can be engineered to create a sustainable and industrially viable material cycle. The application primarily addressed in this work is biodegradable wood-plastic composites (WPCs), bio-WPCs, that can be used in large-volume applications, such as the construction industry. This work is also applicable to bioplastic applications, such as containers and packaging. Widespread adoption of these and other bioplastic-natural fiber composites has the potential to reduce greenhouse gas emissions, the consumption of fossil fuels as a material feedstock, and the accumulation of plastic in the environment and in landfills. In order understand and engineer this material cycle, one must understand the biogas production properties, such as rate and quantity, in the end-of-life anaerobic degradation process. This work investigates relationship between processing, properties, and biodegradation of biodegradable polymers (bioplastics) and biocomposites by (i) evaluating kinetic models to for bioplastic degradation and methane recovery, (ii) developing a methodology that can be used to predict and model methane generation from bioplastics and biocomposites, and (iii) investigating the anaerobic degradation mechanisms of these materials in simulated anaerobic landfills or AD facilities. The results from this work can be used as inputs to life-cycle assessments of material end-of-life, to help optimize biocomposite materials properties, and design future resource recovery centers targeted for biopolymer and biocomposite degradation, methane collection, and biopolymer production.
The symmetric power and etale realisation functors commute [electronic resource]
Keywords: Mathematics.

We show that under mild hypotheses on a proper algebraic space X, the functors of taking its symmetric powers and its etale realisation commute up to weak equivalence. We conclude an effective version of the Dold-Thom theorem for the etale site and discuss the stabilisation results for the natural morphisms of etale homotopy groups π_k Sym^n X → π_k Sym^{n+1} X in the context of the Weil conjectures.
Synthetic optobiology [electronic resource] : engineering of photodissociable proteins and application to optical control of biology
Keywords: Bioengineering.

If protein activities can be controlled with light, the exquisite spatial and temporal control possible would enable more precise understanding of how proteins function within signaling pathways and control cell behaviors. Previously described approaches either relied on protein relocalization to indirectly regulate protein activity, or required extensive screening and optimization. Thus, these methods have been successfully used to control only a few proteins, and a generalizable way to control protein activities has not yet been achieved. We describe the discovery and engineering of the first synthetic light-controlled protein-protein interaction, and the use of this interaction to develop a generalizable design for constructing light-inducible proteins. We used this design, termed "Fluorescent Light-inducible Proteins", or "FLiPs", to successfully control four protein classes with light: guanine nucleotide exchange factor, protease, kinase and Cas9. Using our engineered light-controllable kinases, we discovered a previously undetected feedback mechanism in the Raf-MEK-ERK cascade, demonstrated the potential of photoswitchable kinases in drug development, and proved the efficacy of these light-controllable domains in vivo. Our results demonstrate that engineered photodissociable proteins enable a general method for spatiotemporal investigation of protein function in cells and animals.
Systematic mapping of the voltage-gated sodium channel outer pore using modified saxitoxins [electronic resource]
Keywords: Chemistry.

Modulation of action potentials in electrically excitable cells is controlled by tight regulation of ion channel expression and distribution. Voltage-gated sodium channels (NaVs) represent one such class of obligatory membrane proteins, comprised of nine mammalian isoforms (NaV1.1--NaV1.9) differentially expressed in excitable tissues. Our ambition to understand the role of individual NaV subtypes in neuronal signaling motivates development of isoform-selective small molecule modulators of NaV function. The paralytic shellfish poison saxitoxin (STX) has historically been used as a critical tool for interrogating NaV structure and function and, as a result, represents an excellent template for creating such probes. However, given the marked sequence similarity between members of this protein family, designing NaV selective agents requires a comprehensive understanding of channel structure. Accordingly, we endeavored to gain insight into the three-dimensional architecture of the outer vestibule of NaV (Site 1) through a systematic structure-activity relationship (SAR) study employing saxitoxin, synthetically modified saxitoxins, and protein mutagenesis. The preparation and electrophysiological characterization of natural and non-natural STX analogues modified at six positions (N7, N9, C10, C11, C13, and N21) is described. A single synthetic route adapted from a previously disclosed strategy toward gonyautoxin-3 facilitates access to the bis-guanidinium core of STX and enables late-stage introduction of substituent groups. Mutant cycle analysis, a systematic method for mapping non-covalent ligand-receptor interactions, has been conducted with modified saxitoxins and point mutant NaVs. These studies have culminated in a revised toxin-receptor binding model, which is consistent with the large body of SAR data described in Chapters 3 and 4. During the course of this work, an acetylated variant of STX was identified with unprecedented affinity for human NaV1.7 (hNaV1.7), a channel subtype that has been implicated in pain perception. We have leveraged bis-guanidinium toxin analogues modified at positions C10/C13, C11, and C12 in supplemental studies aimed to examine a possible two-state toxin binding model. Although a two-state model cannot be completely discounted at this time, the large majority of results with STX-based probes and mutant NaVs support our revised one-state binding model. Insight gained from mutant cycle analysis has been used to rationally develop a cysteine mutant NaV that is irreversibly inhibited by nanomolar concentrations of a STX-maleimide conjugate. These findings provide a proof-of-concept for engineering NaV-mutant specific covalent inhibitors around the Site 1 locus. Future efforts to design selective, non-covalent NaV inhibitors should also be facilitated with the availability of our proposed STX-NaV binding model.