VictorJuiz/thesis huggingface dataset:
A supply-impacting synthesis of clinical lead bryostatin 1 and the design, synthesis and evaluation of novel protein kinase C modulators as preclinical leads

Protein kinase C (PKC) modulators are currently in clinical or preclinical development for a wide range of diseases that represent major causes of mortality and morbidity worldwide. For example, the marine natural product bryostatin 1, a lead PKC modulator, is in clinical trials for HIV/AIDS eradication and Alzheimer's treatment, with a trial for its use in small molecule-enhanced CAR-T cell therapy slated for the near future. Preclinically, bryostatin 1 has been evaluated for its use in treating fragile X syndrome, multiple sclerosis, ischemic stroke and Charcot-Marie-Tooth disease, among others. Other highly active PKC modulating natural products under clinical or preclinical evaluation include the tigliane natural product prostratin and several ingenane natural products. While nature has provided bioactive compounds that, conveniently, offer solutions to hugely important problems of global health and wellness, these compounds and methods of obtaining them are by no means optimal for clinical use. Many of these natural products are extremely scarce and require one to process staggering quantities of host organism to access even milligram quantities of the natural product. This is well illustrated in the case of bryostatin 1, where 14 tons of its host organism -- a coastal marine sponge -- were processed to access only 18 grams of the natural product. Additionally, while these natural products are excellent clinical leads, nature has not optimized them for use in human medicine. These compounds can have narrow therapeutic windows, undesired on- and off-target toxicities, poor metabolic stability and problematic solubility properties. The work presented herein focuses on solving both problems presented above through design, synthesis and evaluation of natural product leads and derivatives thereof. This document should provide a clear example of the influence that synthetic chemistry can have in supporting and driving forward clinical research on some of the most challenging problems in human healthcare to-date.

Keywords: Chemistry.
Advisor: Wender Paul A. 
Burns Noah
Du Bois Justin
The surprising power of little data

Despite the rapid growth of the size of our datasets, the inherent complexity of the problems we are solving is also growing, if not at an even faster rate. This prompts the question of how to infer the most information from the available data. This thesis discusses several examples that reveal a surprising ability to extract accurate information from modest amounts of data. The first setting that we discuss considers data provided by a large number of heterogeneous individuals, and we show that the empirical distribution of the data can be significantly "de-noised". The second setting considers estimating the covariance spectrum of a high-dimensional distribution, in the sublinear sample regime where the empirical distribution of the data is misleading. The final setting focuses on estimating "learnability": given too little data to learn an accurate prediction model, we can accurately estimate the value of collecting more data. Specifically, for some natural model classes, we can estimate the performance of the best model in the class, given too little data to find any model in the class that would achieve good prediction error. We extend our techniques for estimating learnability to the more general stochastic optimization problems, including the contextual bandit setting. In most of these settings, our algorithms are provably information-theoretically optimal, highly practical, and empirically evaluated by real-world datasets.

Advisor: Valiant Gregory 
Charikar Moses 
Reingold Omer
Surviving in China’s Sharing Bike Business: A Five Forces Analysis of Hellobike’s Strategies

Although named the “sharing bike” in China, the Internet bike rental industry does not belong to the classic sharing economy. But the misplaced name did not hinder the industry in becoming one of the most sought-after investing fields since 2014. Though countless entrepreneurs and investors tried to ride this wave, only a few found success. Given fierce competition in the industry, Hellobike, a late-coming, small Internet bike rental bike company, grew rapidly in 2018, while massive industry giants collapsed. Even when ofo and Mobike, the once leading competitors in the industry, struggled to sustain their business, Hellobike fostered the most potential to continue developing. Therefore, the critical question for this thesis is why did Hellobike survive while many other companies failed, especially when compared against the two Internet bike rental companies: ofo and Mobike? Based on Porter’s Five Forces Model, this thesis will analyze the causes of Hellobike’s success from five different perspectives, disclosing its strategies to survive fierce Internet bike rental competition and achieve strong, positive growth.

Keywords:  Stanford Global Studies
Stanford Global Studies
East Asian Studies
Chinese business
sharing economy
Internet bike rental
Five Forces
competition strategy
Thesis
Advisor: Dasher Richard
Synthesis and Use of Solvatochromic Dyes to Label the Mycobacterial Cell Wall

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and is one of the top ten causes of death worldwide. Current diagnostic methods available in low resource settings take days to weeks to perform or suffer from poor sensitivity. Previously, members of the Bertozzi group attached a solvatochromic fluorophore, 4-N,N-dimethylamino-1,8-naphthalimide (DMN), to the sugar trehalose (Tre) for incorporation into the mycomembrane, a hydrophobic layer of the cell envelope formed by trehalose glycolipids unique to Mtb and closely related organisms. Solvatochromic dyes shift in color or intensity based on the electronic properties of the surrounding solvent; DMN is fluorescent in hydrophobic but not hydrophilic environments. Thus, DMN-Tre does not label bacterial species that lack trehalose glycolipids because the dye fluoresces strongly in the mycomembrane but not in the surrounding solution. For this honors research study, we synthesized and characterized new solvatochromic trehalose probes (3HC-2-Tre and 3HC-3-Tre) that improve upon the properties of DMN-Tre. We performed in vitro labeling studies of mycobacteria to determine specificity and found that 3HC-2-Tre and 3HC-3-Tre can be used at concentrations 10x lower than DMN-Tre, are much brighter with less background fluorescence, and, in the case of 3HC-3-Tre, can label bacteria within 1 minute without requiring a wash step. 3HC-2-Tre is highly selective for bacterial species with a mycomembrane. Pre-labeled mycobacteria injected into zebrafish are readily detected by microscopy. These probes have the potential for use in TB diagnostics and the study of the effect of drug treatment on cell wall dynamics.

Keywords:  Department of Biology
Biology
chemistry
diagnostics
tuberculosis
Thesis
Advisor: Carolyn Bertozzi
Judith Frydman
Synthesis of polycyclic conjugated hydrocarbons containing cyclobutadienoids and investigation of their antiaromaticity

Polycyclic conjugated hydrocarbons (PCHs) containing four-membered cyclobutadienoids (CBDs) are of great fundamental and technical interest due to the antiaromaticity brought by CBD circuits. Synthetic accessibility of such molecules, however, has been challenging and limited in scope, thus hampering the exploration and understanding of such systems. In this thesis, a versatile and efficient synthetic strategy was developed to access a large variety of CBD-containing PCHs with variable carbon structures, electronics, and topologies via catalytic arene-(oxa)norbornene annulation (CANAL) from readily accessible aryl bromides and oxanorbornenes (oNBEs). This new synthetic capability opens a myriad of opportunities for systematic investigation into CBD antiaromaticity as well as the potential applications of CBD-PCHs. With this facile method, we proposed and synthesized a series of unprecedented [3]naphthylene regioisomers, and found the regioconnectivity of [3]naphthylenes strongly affects the degree of local antiaromaticity and aromaticity for the fused CBD and naphthalenoid, respectively. Further, the C-C bond activation of CBD units was demonstrated with unsubstituted V-shaped [3]naphthylene to yield helical structures. In addition, we designed and efficiently synthesized a novel CBD-containing acene analogues, dinaphthobenzo-[1,2:4,5]dicyclobutadiene (DNBDCs), with strong antiaromaticity of the CBD units. This design also features orthogonally tunable electronic properties and molecular packing, which resulted in good device performance in organic field effect transistors.

Keywords: Chemistry.
Advisor: Xia Yan
Kool Eric T. 
Trost Barry M.
Synthetic studies on the bis-guanidinium toxins 11-saxitoxinethanoic acid and zetekitoxin AB

Zetekitoxin AB (ZTX) is a potent neurotoxin isolated from the endangered Panamanian golden frog, Atelopus zeteki. The tricyclic, bis-guanidinium core of ZTX is common to other toxins such as (+)-saxitoxin (STX) and 11-saxitoxinethanoic acid (11-SEA), but ZTX and 11-SEA are the only known congeners with a C11-alkyl substituent. An unusual guanidinium N, O-acetal and a bridging macrolactam structure composed of a 3,4-disubstituted isoxazolidine render ZTX considerably more complex than all other members in this family of natural products. Efforts to synthesize ZTX and 11-SEA from a common hydroxyketone intermediate were undertaken. A tricyclic core bearing a C11-ketone moiety was accessed through a previously described route utilizing a C11-silylated pyrrole. The development of chemistry to elaborate the hydroxyketone culminated in the successful total synthesis of 11-SEA. Key steps in the preparation of this toxin include an oxidative annulation of an N-guanidyl pyrrole to form a five-membered cyclic guanidine and a base-catalyzed redox isomerization reaction. The challenges in applying the hydroxyketone intermediate towards the synthesis of ZTX have resulted in the design and implementation of a new synthetic route towards this complex natural product. The use of a formylpyrrole starting material enables the selective installation of an iodide at the desired C11 position. A diastereoselective Mannich cyclization reaction installs the requisite C13 carboxylic acid and generates a key bicyclic intermediate; from this material, the tricyclic guanidinium core is formed through oxidative dearomatization of the pyrrole ring. The identification of cross-coupling conditions to install a suitable heterocyclic group at C11, followed by macrolactam formation with the C13 carboxylic acid should ultimately lead to the assembly of ZTX.

Keywords: Chemistry.
Advisor: Du Bois Justin 
Burns Noah
Wender Paul A.
System modeling, optimization, and analysis of spreading basins receiving stormwater and recycled water for enhanced water resilience

Increasing pressures on existing water systems are leading urban water managers to explore new options for enhancing water supply resilience. In this context, more cities are considering infrastructure systems that use stormwater and recycled water to augment groundwater recharge through spreading basins (groundwater recharge ponds). These systems may represent cost-effective opportunities to enhance and diversify water supplies. However, technical questions remain about 1) how these systems can be made affordable—a primary barrier commonly cited for both recycled water and managed aquifer recharge projects, and 2) the effect of regulatory constraints on the design of the water recycling process. To address this need, this dissertation developed a specialized system model for identifying optimal infrastructure systems that deliver advanced treated recycled water to existing stormwater spreading basins. The resulting systems simultaneously minimize infrastructure life cycle costs and maximize groundwater recharge while satisfying engineering and regulatory constraints. Applying this model to case studies of Los Angeles, CA, this dissertation demonstrates the trade-offs of different system designs with respect to cost, energy use, and total organic carbon, a regulated water quality parameter for groundwater recharge with recycled water. For example, compared to existing conservative planning approaches, more flexible planning approaches that account for the greater dynamic availability of stormwater can reduce system costs by 5--20%. In addition, compared to the membrane-based treatment train predominantly used to produce recycled water for potable reuse, ozone-based and hybrid treatment can reduce system costs up to 35%. In sum, this modeling framework can inform water plans and potentially improve the resilience of urban water infrastructure.

Advisor: Luthy Richard G. 
Gorelick Steven M. 
Mitch William A.
A systematic framework to analyze the design space of DNN accelerators

Deep neural networks (DNNs) have been widely used to solve many modern machine intelligence problems. However, their outstanding accuracy comes at the cost of high computation complexity which limits their speed on conventional CPUs. This difficulty has encouraged researchers to create efficient DNN accelerators. Interestingly these designs use a variety of approaches, and have not converged over time. While each design states the advantages of its approach, without a comprehensive understanding of the global space, it is difficult to understand which design choices really matter. To address this issue, this thesis shows how the space of DNN hardware accelerators can be represented as scheduling choices, including computation orders, storage orders, etc. Different DNN micro-architectures and mappings represent specific choices of loop order and hardware parallelism for computing the seven nested loops of DNNs. This observation enables one to create a formal taxonomy of all existing dense DNN accelerators, and systematically analyze the design space, including dataflow choice. The loop transformations needed to create these hardware variants can be precisely and concisely represented by Halide's scheduling language. By modifying the Halide compiler to generate hardware, we create a system that can fairly compare these prior DNN accelerators, and show that many different dataflows yield similar energy efficiency with good performance. As long as properly choosing the memory sizes to accommodate the efficient blocking strategy, it can ensure that most data references stay on-chip with good locality and the function units have high resource utilization. Thus, the hardware dataflow choices become less critical, but how resources are allocated, especially in the memory system, has a large impact on energy and performance. By optimizing hardware resource allocation while keeping throughput constant, we achieve up to 4.2X energy improvement for Convolutional Neural Networks (CNNs), 1.6X and 1.8X improvement for Long Short-Term Memories (LSTMs) and multi-layer perceptrons (MLPs), respectively

Keywords: Electrical Engineering.
Advisor: Horowitz Mark (Mark Alan) 
Fatahalian Kayvon 
Kozyrakis Christoforos
Systematic identification of regulators of oxidative stress reveals non-canonical roles for peroxisomal import and the pentose phosphate pathway

Reactive oxygen species play critical roles in metabolism and disease, yet a comprehensive analysis of cellular response to oxidative stress is lacking. To systematically identify genetic factors that control this response, we conducted genome-wide Cas9/CRISPR and shRNA screens. We find that, paradoxically, disrupting the pentose phosphate pathway (PPP) at the level of phosphogluconate dehydrogenase (PGD) protects cells against ROS. This dramatically alters metabolites in the PPP, consistent with rewiring of upper glycolysis to promote antioxidant production. In addition, we found that disruption of the peroxisomal import pathway unexpectedly increases resistance to oxidative stress by altering the intracellular localization of canonical ROS scavenger, catalase. In addition to these counterintuitive findings, these results reveal a detailed picture of diverse pathways that control oxidative stress response, which range from components of the TCA cycle and DNA repair machineries to iron transport, trafficking and metabolism. Together, these studies provide new insights into the roles of the peroxisomal matrix import pathway and the pentose phosphate pathway in redox biology, and represent a rich resource for understanding the cellular response to oxidative stress.

Advisor: Bassik Michael 
Dixon Scott James
Jackson Peter K. (Peter Kent) 
Pfeffer Suzanne
Tales of wit and enlightenment : laughter and humor in Northern Song (960-1127) China

This dissertation examines notions of play, wit, and cognate concepts that are broadly pertaining to laughter and humor in premodern China. The Northern Song (960-1127) period witnessed significant enrichment to Chinese literati culture brought by scholar-officials' adoption of laughter and humor in their writings. This dissertation aims to disambiguate the popularity of laughter and humor in the Northern Song literati culture by revealing two important factors. The first factor is the rise of miscellany writing (biji, shihua, and other anecdotal genres) as a new mode of literary expression. The second factor is that Buddhism, through the Chan movement, was more deeply integrated into Chinese society. This dissertation demonstrates how laughter and humor played important roles in negotiating literati's identities, precipitating intellectual breakthroughs, and reconciliating conflicting stances. I focus on two important topics—Chinese literary criticism and literati-Buddhist interaction—in which representations of laughter help define the Northern Song achievements in synthesizing torrents of socio-political and religious changes. The dialectic of laughter emerged in these contexts as an overarching theme: caught between contradicting ideas of elegance and vulgarity, subversion and reverence, friendship and enmity, literati recurrently resorted to laughter to harmonize their dilemmatic stances in their attitudes towards literary writing, associations with Buddhist monks, and social interactions with their bureaucratic peers.

Keywords: East Asian Languages and Cultures.
Advisor: Egan Ronald
Kieschnick John
Zhou Yiqun
Taming nicotine : big tobacco's quest to hide and harness addiction

Nicotine remains America's deadliest drug. By compelling smokers to reach for cigarettes day after day, it causes 480,000 deaths per year in the United States alone. And yet, nicotine is peculiar drug. Smoking a cigarette for pleasure or to stave off withdrawal is, at the end of the day, an off-label use of a powerful natural insecticide. How did this toxic and seductive alkaloid become America's drug of choice? Taming Nicotine: Big Tobacco's Quest to Hide and Harness Addiction draws on millions of formerly secret tobacco industry documents to argue that cigarette makers played a crucial role in 20th century American drug policy and addiction research. These secret documents show that nicotine has led two mutually reinforcing lives: in the first, hidden away in industry laboratories, it was a molecular entity, whose addictiveness industry scientists sought to understand in order to hook new generations of smokers. But nicotine also has had a second, more public, life as a carefully manipulated cultural object. Deploying an army of consultants, cigarette makers claimed that nicotine should not be considered a drug, because it didn't produce intoxication, and that smoking was a free choice (rather than an addiction) because smokers aren't "junkies." In combination, these efforts produced an unprecedented public health crisis that was predicated on both selling nicotine while keeping its addictive power hidden. This remains an unfinished history: even today nicotine has not relinquished its dual nature between the botany of murder and the neurochemistry of desire.

Keywords: History.
Advisor: Proctor Robert
El Ghaoui Laurent 
Mullaney Thomas S. (Thomas Shawn) 
Olivarius Kathryn Meyer McAllister
Target-based genome mining of natural products and heterologous expression in Escherichia coli : choosing and accessing the natural world's menu of potential antibiotics

Expanding genomic databases show that many microorganisms harbor polyketide synthase (PKS) gene clusters, many of which encode natural products with valuable antibacterial properties. However, identifying and accessing novel and useful PKS activities remain challenging, as many host organisms are uncultivable or do not express PKS genes in laboratory conditions, and from sequence data alone it is difficult to ascertain which gene clusters are the most promising. Here I present efforts to address these challenges. We first aimed to improve Escherichia coli as a heterologous host for production of polyketides originating from other bacteria. We studied 13 homologs of propionyl-CoA carboxylase (PCC), an essential enzyme for many PKS gene clusters. We built 13 strains of E. coli, each harboring a different PCC homolog. We observed variability in polyketide production amongst the 13 strains and identified optimal PCC homologs. Next, we leveraged commercial gene synthesis and a recently developed large DNA assembly pipeline to synthesize DNA encoding four PKS gene clusters, ranging in length from 30-40 kB and expressed them in recombinant E. coli strains. Untargeted metabolomics revealed cluster-specific compound production in two of the four strains. Follow-up experiments suggested that these compounds resulted from activity of the tailoring genes in the cluster, not the core PKS genes, and could represent modified endogenous metabolites in E. coli. This result illustrates a need for larger datasets of heterologous expression of PKSs in E. coli to more rapidly identify gene clusters resulting in novel and cluster-specific molecules. To identify PKS genes encoding clinically relevant antibiotics, we developed an automated method to identify and catalog clusters that harbor potential self-resistance genes. These genes, which are modified targets of the produced compounds, provide the cluster-harboring microorganisms a defense against the antibiotics produced by the clusters. We mined all National Center for Biotechnology Information (NCBI) nucleotide databases for known and putative antibacterial target genes from manually curated lists. With this approach, we generated a non-redundant catalog of PKS clusters harboring putative self-resistance genes. This method can be used to prioritize gene clusters producing compounds with new mechanisms of action, as well as to identify putative novel antibacterial targets.

Keywords: Biochemistry.
Advisor: Davis Ronald W. (Ronald Wayne)
Khosla Chaitan
Kim Peter
Krasnow Mark
Teaching in a post-truth era : supporting students to reason about online information

Although young people increasingly rely on the Internet as a source of information, the web's growing complexity has outpaced educational efforts. When asked to evaluate digital content, students often make judgements based on perceived usefulness, appearance, or relevance, or they outsource responsibility for judging reliability to something they assume does a better job—a search engine algorithm. Furthermore, disparities in technological access and learning experiences threaten to expand and determine who has opportunities to learn to evaluate online information. The articles in this dissertation outline the beginnings of an educational response. Taken together, they investigate how students reason about online information (and how schools may, purposefully or not, contribute to students' strategies), characterize skilled practice, and probe how core content area teachers might help students learn to evaluate digital content.

Keywords: Education.
Advisor: Wineburg Samuel S. 
Callan Eamonn 
Kahne Joseph