VictorJuiz/thesis huggingface dataset:
Electroresponsive conducting nanoparticles for drug delivery [electronic resource]

Conducting polymers are organic polymers that can change their shape and size in response to an external electric stimulus. These polymers are promising for developing programmable, adjustable, spatially and temporally controllable drug delivery systems (DDSs). Drug release is evoked by application of weak voltages or currents. However, several limitations including (i) low drug loading, (ii) incompatibility with electroactive drugs, and (iii) difficulty of scale up have made thin conducting films refractory to clinical development. To overcome these difficulties, we have utilized nanoparticles of conducting polypyrrole (PPy NPs) to design a versatile DDS capable of releasing a variety of both small and large molecule therapeutics. As examples, we have shown facile release of fluorescein, a hydrophilic model compound, piroxicam, a hydrophobic small molecule used in the management of chronic arthritic pain, methotrexate, an anti-cancer drug, and insulin, a hydrophilic polypeptide used in the treatment of diabetes. The use of nanoparticles allows easy scale up and substantially increased drug loading, estimated to be as high as 51 wt%. Moreover, by modifying the synthesis and incorporating metallic elements into the polymer scaffold, it is possible to release drugs at voltages as low as - 0.05 V vs Ag/AgCl, almost an order of magnitude lower than typically used voltages for thin films. This widens the window of operating voltage and allows PPy NPs to be used in the delivery of redox sensitive drugs. Moreover, we have demonstrated that PPy NPs can be used as a generalized pH-sensitive drug delivery system, capable of releasing any charged drug preferentially at the pH range of interest. They can be tuned to release drugs at both acidic and basic pH by varying the acidity, the charge of the drug, as well as by adding small amounts of charged amphiphiles. These PPy NPs may be delivered locally by immobilizing them in a hydrogel or coupling them to an implantable chip. We have performed proof-of-principle studies demonstrating that the drug release can be triggered wirelessly. Our results demonstrate the potential of using conducting polymer nanoparticles to treat long lasting conditions such as chronic pain, diabetes and cancer by developing externally controlled, programmable implants.

Keywords: Chemistry.
Advisor: Zare Richard N. primary advisor. Thesis advisor
Cegelski Lynette advisor. Thesis advisor
Fayer Michael D. advisor. Thesis advisor
Elites, institutions and economic development [electronic resource]

This dissertation asks about the consequences of economic and institutional change for the composition of the political elite in three papers. I do so using a core original dataset on the characteristics of Members of Parliament in Britain spanning almost four centuries compiled using web-scraping and natural language processing. The first paper considers the effects of the Industrial Revolution in Britain for electoral competition, and turnover in economic interests and families who hold power. Leveraging subnational variation over time within Britain and an exogenous instrument for the timing and location of industrial activity, I find that industrial activity did increase competition and lead to increased elite circulation. The second paper studies the consequences of the 16th and 17th century expansion of Atlantic trade in Britain for the composition of the political elite. Using detailed data on aggregate expansion in ocean trade, I compare constituencies more or less affected by this expansion by virtue of their connection to transportation networks and manufacturing centers. I find that places with more intense experience of commercial expansion saw more electoral competition and increased entry of commercial elites to politics, but no such turnover in the families that held political power. In the third paper, I investigate the extent to which political elites were able to persist across the revolutionary institutional changes of the 17th century in Britain that saw the Crown and Parliament vie for political supremacy. I code families based on their revealed preferences for the supremacy of one national institutional over the other, finding that institutional change did disrupt the ability of elites to persist when that change was not favorable to their faction. Beyond questions of political representation, this dissertation speaks to the large literature on institutional persistence and change by studying the micro-processes at work during key historical moments considered to have shifted the balance of either economic or political power.

Keywords: Political Science.
Advisor: Haber Stephen H.
Abramitzky Ran advisor. Thesis advisor
Rodden Jonathan advisor. Thesis advisor
Scheve Kenneth F. advisor. Thesis advisor
Elucidating Casein Kinase 2 Regulation of MYC in Medulloblastoma

Medulloblastomas are a malignant (WHO grade IV) brain tumor that comprise the majority of pediatric brain tumors. They are classified into four molecular subgroups each highlighted by amplification of a certain oncogenic pathway. Group 3 medulloblastomas are characterized by MYC amplification and have the worst prognoses of the subgroups, with a dismal overall survival (OS) rate of less than 50% and debilitating toxic side effects for those that survive current modes of therapy. A potential novel therapeutic target for medulloblastomas is casein kinase 2 (CK2), a tetrameric enzyme implicated in MYC regulation. Here, I investigated the role of CK2 activity in the expression of c-myc and one of its phosphorylated forms at serine-62 (p-c-myc). I demonstrated that while CK2 activity and expression did not seem to have a significant effect upon the overall expression of c-myc and p-c-myc, CK2 inhibition exhibited a significant decrease in nuclear c-myc and p-c-myc, suggesting that CK2 can regulate c-myc activity by controlling its localization to the nucleus. This is an important discovery, as c-myc is a transcription factor and requires localization to the nucleus for proper function. The data generated here suggest a crucial relationship between two established oncogenic proteins and help identify CK2 as a promising therapeutic target to more effectively treat a particularly harmful and as-of-yet uncured pediatric brain cancer.

Keywords:  Department of Biology
Biology
cancer
medulloblastoma
CK2
c-myc
Thesis
Advisor: Li Gordon
Shen Kang
Elucidating the Role of N17 in Huntingtin Oligomerization and Aggregation

Huntington’s Disease (HD) arises through pathogenic aggregation of Huntingtin (Htt) protein, causing the formation of fibrillar beta-sheet amyloid aggregates, which can create a toxic environment by disturbing cellular transport, altering mitochondrial function, and undermining transcription regulation [1-4]. Pathogenic aggregation of Htt is mediated by the first 17 residues of Htt exon 1 (N17), which act as an “on” switch for this aggregation [2,5,6]. While a significant amount of research has focused on Htt aggregates, less work has focused on soluble Htt oligomers. This is partly due to the fact that these oligomers are heterogeneous and transient in nature. However, recent research has shown that these oligomers may be the cytotoxic species present in HD [7]. Interestingly, these oligomers also appear to form in an N17-dependent manner [Shen et al., in preparation]. However, the mechanism by which N17 promotes formation of these toxic oligomers, and therefore pathogenesis, remains unclear. The following research utilizes a model protein with slower aggregation kinetics, mutagenesis experiments, and various biochemical assays to elucidate the properties and formation of these oligomers.
We find that our protein (HttQ17) serves as an informative model system for pathogenic Htt, based on aggregation and oligomerization in each system. Surprisingly, HttQ17 oligomers do not seed further HttQ51 aggregation, implying that these species may be interacting with each other in unexpected ways. Experiments with the HttQ17 system further confirm the importance of N17 in the formation of Htt oligomers as Htt lacking this N-terminal sequence (HttQ17△N17) is unable to oligomerize to the same extent as HttQ17. Furthermore, altering the polarity of residues within this motif alters formation of oligomers and aggregates.

Keywords:  Department of Biology
Huntington's Disease
Stanford
Biology
Huntingtin
Aggregation
Oligomerization
Thesis
Advisor: Frydman Judith
Jaroz Daniel
Shen Koning
Emancipation and exclusion [electronic resource] : the politics of slavery and colonization, 1787-1865

For much of the United States' first one-hundred years, a significant and diverse array of politicians argued that the nation's black population should be removed. The most commonly recommended resettlement destination was west Africa, specifically the colony of Liberia, established by colonization advocates and black American emigrants in the early 1820s. Other recommended destinations were Haiti, locations in Central and South America, and unsettled territory in the western part of North America. Although we, in the present, might expect that the cohort of politicians who promoted this idea had limited influence, the roster included many of the nation's most prominent statesmen: Thomas Jefferson, James Madison, Henry Clay, Francis Scott Key, Daniel Webster, and Abraham Lincoln. These individuals, along with allies from nearly every state and territory, repeatedly asked Congress to support the cause of racial separation. My dissertation asks two fundamental questions. First, why was colonization so strongly and persistently advocated by federal politicians during the fifty years prior to slavery's abolition by the Thirteenth Amendment? Second, if colonization had such strong and persistent support, why did Congress pass so few colonization-related bills during this period, and why, in the end, was colonization not part of the final moment of abolition?.

Keywords: History.
Advisor: Campbell James T.
Hobbs Allyson Vanessa advisor. Thesis advisor
White Richard
Emergent phenomena in three systems [electronic resource] : two-component droplets, synthetic ecosystems, and elastomeric focusing

This thesis covers projects on three different systems where interactions within each system lead to behaviors that aren't readily evident from the individual parts. The first project involves the behavior of two-component liquids. Certain mixtures do not spread on clean glass as their individual components do, but instead form droplets which display unusual properties such as self-attraction, chasing, and absence of contact line pinning. I discuss the physical phenomena underlying these effects and show several examples of devices that can be created with this understanding. The second project involves a synthetic microbial community I created by genetic barcoding. Community members interact by competing with each other for shared nutrients, and with experiments and modeling I investigate the limits of treating each member equally in the context of neutral theories debated in ecology. The last project leverages interactions between different materials to obtain greatly amplified displacements due to thermal expansion. I exploit this effect to create a new type of microfluidic valve that can be actuated with electricity or light.

Keywords: Bioengineering.
Advisor: Quake Stephen Ronald primary advisor. Thesis advisor
Prakash Manu advisor. Thesis advisor
Riedel-Kruse Hans
Employing Near-Peer Mentorship to Promote Wellness: The Perceived Impact on Urban Indigenous Youth Mentees and Indigenous College Student Mentors

This study examines the perceived impact of a “near-peer” mentorship program on the well-being of Indigenous adolescents in San Francisco and their Indigenous college student mentors at Stanford University. As previous research has focused primarily on “near-peer” mentorship in the context of medical education, little is known about how this form of mentorship can be used in youth programs. Furthermore, few studies use an Indigenous model of well-being to evaluate the effectiveness of Indigenous youth programs. The current study utilizes a qualitative research design to investigate the perceived impact of this form of mentorship between individuals in high school and college, on the participants’ well-being. Data were collected using grounded, semi-structured in-person interviews and a final sample population of 6 adolescent mentees, and 5 undergraduate mentors, all of whom self-identified as Indigenous, were analyzed. Thematic analysis revealed that Indigenous adolescent mentees perceived the program to positively impact their well-being in three of the quadrants of Cross’ (1997) model of Indigenous wellness: context, mind, and body, and failed to address the spirit quadrant. Indigenous college students that served as mentors for the Native Mentorship in Public Health’s “near-peer” mentorship program perceived the program to impact their well-being in three of the quadrants of Cross’ (1997) model of Indigenous wellness: mind, body, and spirit. However, unlike the mentees, the perceived impact in the mind and spirit quadrant for the mentors was negative, and the context quadrant was not addressed. With greater support for mentors within the context quadrant, the near-peer mentorship model discussed in this paper could serve as a successful approach to promoting comprehensive well-being amongst Indigenous college and high school students.

Keywords: “near-peer”
mentorship
Indigenous adolescents
Indigenous college students
well-being
qualitative research
Indigenous wellness
youth program
Graduate School of Education
Thesis
Endothelial deletion of INO80 disrupts coronary angiogenesis and causes congenital heart disease phenotypes

Organ size control is a vital developmental process that remains poorly understood. One example is the mammalian heart where the determinants that support ventricle wall expansion are not fully characterized. Defects in this developmental process directly contribute to congenital heart defects. For example, left ventricular non-compaction (LVNC) is a congenital heart defect in humans occurring when the compact myocardial layer does not expand properly during development, thus severely compromising heart muscle function. LVNC often requires heart transplantation, and if left untreated can result in heart failure. Despite its clinical significance, the mechanisms underlying LVNC are poorly understood. However, mutations in chromatin regulators have been found to be associated with several congenital heart defects, likely due to their important roles in regulating developmental gene expression programs. Interestingly, while the INO80 chromatin remodeler has demonstrated roles in genome stability, disease pathogenesis, and embryonic stem cell identity, there are currently no published studies detailing its function in mouse development. Our research demonstrates that the INO80 chromatin remodeler is required for proper cardiac development. Specifically, LVNC-like phenotypes arise when INO80 is deleted from the endothelial cells that line blood vessels, which correlated with defective coronary vascularization. Deletion of Ino80 individually in the two major coronary progenitors also resulted in non-compaction phenotypes. Mechanistically, loss of endothelial Ino80 resulted in increased E2F-mediated gene expression and proliferation potential, which suggests angiogenesis requires proliferation and that this process is critical in organ size control. Finally, our data suggests that providing two sources of blood vessels accelerates heart wall expansion and suppresses cardiac disease phenotypes.

Keywords: Biology.
Advisor: Morrison Ashby J.
Bergmann Dominique 
Crabtree Gerald R. 
Red-Horse Kristy
End-to-end seismic risk analysis framework for the identification of infrastructure network retrofits [electronic resource]

Lifeline infrastructure network functionality is key for community operation and safety, especially after natural disasters, such as earthquakes. Thus, this dissertation discusses seismic risk analysis of distributed lifeline infrastructure networks and mitigation strategies informed by this risk analysis to limit the impacts of future earthquakes. First, this thesis proposes an end-to-end framework that encompasses seismic hazard characterization, network performance estimation, and network component retrofit selection. This thesis proceeds to analyze and propose methods within each of these modules to maximize fidelity while maintaining computational palatability for application to large complex networks. A comparative analysis of techniques for the simulation of ground motion amplitude fields is performed to determine the optimal method. The results designate Circulant Embedding to be a computationally superior method and identify trade-offs in terms of computational efficiency and applicability with other techniques. Then, risk informed heuristics for network component retrofit selection are proposed and evaluated against existing methods. The findings demonstrate that the proposed risk informed metrics combined with existing heuristics---specifically, the Tempered Pipe Participation Factor combined with the Risk Achievement Worth---yield superior retrofit selection, indicating the value of the integration of risk analysis to pipe importance estimation. Finally, statistical learning techniques are applied to the estimation of network performance, and their potential to be a computationally efficient supplement or replacement of physics based models is evaluated. This work identifies a strategy that may adequately estimate network performance at a fraction of the computational expense compared to full physical models. Ultimately, this dissertation contributes to the large body of research regarding the reliability of lifeline infrastructure networks exposed to natural hazards. The framework established here provides a foundation for risk informed mitigation strategies for real life complex networks in pursuit of resilient communities.

Advisor: Baker Jack W. primary advisor. Thesis advisor
Deierlein Gregory G. (Gregory Gerard)
Kiremidjian Anne S. (Anne Setian) advisor. Thesis advisor
Engineered protein hydrogels to study neural niche interactions [electronic resource]

The native extracellular matrix (ECM) provides both biophysical and biochemical cues that modulate cellular behaviors, including maintenance of homeostasis and tissue repair following injury. Carefully controlled ECM mimics can permit detailed studies of cell-niche interactions, providing design criteria for engineering solutions to various medical challenges. This dissertation begins with a review of the microenvironmental properties known to regulate stem cell behavior and discusses how these properties can be controlled in hydrogel-based systems. The next chapters present strategies to introduce bio-orthogonal crosslinking chemistries into engineered protein hydrogels while retaining independent control over matrix mechanics and biochemistry. An engineered protein hydrogel system was then used to determine optimal matrix properties for expansion of neural progenitor cells (NPCs). A family of hydrogels with varied matrix stiffness, proteolytic degradability, and adhesive ligand concentration was screened for conditions that maintained NPC stem cell function, or "stemness." Strikingly, stemness maintenance was only correlated with matrix degradability. Matrix degradation and remodeling was required for cadherin-mediated cell-cell contact, which in turn modulated stemness through activation of β-catenin signaling. These results were validated in two other hydrogel systems capable of chemical and physical matrix remodeling. Finally, the dissertation ends with a study exploring the interplay among cell-matrix interactions, cell-cell contact, and soluble factor signaling in a model of peripheral nerve injury. Collectively, the results presented herein demonstrate the power of carefully controlled ECM mimics to identify key regulators of cellular behavior.

Keywords: Bioengineering.
Advisor: Heilshorn Sarah primary advisor. Thesis advisor
Plant Giles advisor. Thesis advisor
Yang Fan (Bioengineering researcher and teacher) advisor. Thesis advisor
Engineered-protein based hydrogels for drug delivery and tissue engineering [electronic resource]

This thesis focuses on studying the structure and properties of engineered elastin-like protein (ELP) based hydrogels, and developing strategies to control the material structure and property for different applications in drug delivery and tissue engineering. Rational control of hydrogel 'bead-string' microstructure was demonstrated to achieve the codelivery and sequential release of hydrophilic and hydrophobic drugs; optical transparency of ELP gels was significantly improved by designing hybrid hydrogels for 3D cell encapsulation; adaptable hydrogel was developed for the use as injectable carriers for both stem cell transplantation and long-term gene therapy; hybrid hydrogels with decoupled matrix parameters were utilized to study the cell-matrix interactions and tissue formation. The achievements presented in this work provide insights for the design of novel biomimetic matrices.

Keywords: Materials Science and Engineering.
Advisor: Heilshorn Sarah primary advisor. Thesis advisor
Melosh Nicholas A. advisor. Thesis advisor
Yang Fan (Bioengineering researcher and teacher) advisor. Thesis advisor
Engineering Bidirectional Regulation of Endogenous Genes

An active field of research within bioengineering is the control of gene expression using small molecules, given the broad impact such a tool would have. A reversible, tunable method for gene expression regulation that does not require frequent intervention or maintenance is optimal for this strategy. Current systems, such as CRISPR/Cas9, are capable of transcriptional activation and repression, but are activated by small molecules not currently in clinical use. Here, we describe a synthetic architecture for a set of transcription factors that allows an endogenous gene to be either repressed or activated through the choice of drug. This work was adapted from the small molecule activated shutoff (SMASh) tag, a self-cleaving protein tag derived from the Hepatitis C virus NS3/NS4a protease. Two sets of mutations were introduced to the NS3 protease to create two protein tags, each inhibited by a different drug. We demonstrate chemical control over the transcription of the secreted protein vascular endothelial growth factor (VEGF) in human cell lines. VEGF is commonly overexpressed in cancers and therapeutically desirable in some applications, so control over its secretion is clinically relevant. This new tool offers the opportunity to study downstream effects of gene suppression or constitutive activation in research contexts. In addition, its dose-dependent and bidirectional nature represents the first step toward a new tool in the gene therapy arsenal to tightly regulate protein levels within either implanted therapeutic cells or afflicted cells over a broad dynamic range.

Keywords:  Department of Biology
biology
NS3
SMASh
bioengineering
transcription
regulation
endogenous
genes
chemical
Thesis
Advisor: Lin Michael
Dixon Scott