VictorJuiz/thesis huggingface dataset:
A Novel Lipid-based Nanotechnology Platform For Biomedical Imaging And Breast Cancer Chemotherapy
Keywords: Nanotechnology
Breast Cancer
Multidrug Resistance
MRI Thermometry
In Vivo Fluorescence Imaging
Integrin Receptor Targeting

A novel, lipid-based platform nanotechnology has been designed to overcome limitations of in vivo fluorescent imaging, multidrug resistance (MDR) phenotypes hindering breast cancer chemotherapy, and shortcomings of magnetic resonance imaging (MRI) thermometry. Using this platform, three nanoparticle systems have been developed: QD-SLN (quantum dot-loaded solid lipid nanoparticles), DMsPLN (doxorubicin and mitomycin C co-loaded polymer-lipid hybrid nanoparticles), and HLN (hydrogel-lipid hybrid nanoparticles). Stealth, near-infrared emitting QD-SLN were developed for deep tissue fluorescence imaging, which were capable of extending the depth of penetration beyond 2 cm, with near complete probe clearance and good tolerability in vivo. The QD-SLN was used to evaluate the biodistribution of non-targeted SLN and actively targeted RGD-conjugated SLN. Non-targeted SLN accumulated in breast tumors and evaded liver uptake. The RGD-SLN showed prolonged retention in breast tumor neovasculature at the cost of lesser tumor accumulation due to enhanced liver uptake. With this information, a long circulating, non-targeted DMsPLN with a synergistic cancer chemotherapeutic combination of doxorubicin and mitomycin C was formulated to overcome MDR, enhancing breast cancer chemotherapy. Extensive tumor cell uptake and perinuclear trafficking of DMsPLN overcame the MDR phenotype of breast tumor cells in vitro. The DMsPLN provided the most efficacious chemotherapy reported in literature against aggressive mouse mammary tumors in vivo with significant reduction in whole animal and cardiotoxicity as compared to clinically applied liposomal doxorubicin. In establishing our tumor models, the impact of Matrigel™ on the tumor microenvironment was investigated, demonstrating altered tumor vascular and lymphatic anatomy and physiology, and significantly impacting nanomedicines assessment in mouse models of cancer. In all in vivo studies, tumors were established without use of Matrigel™. To guide thermotherapy of solid tumors, a novel HLN was formulated for use in MRI thermometry, presenting the first contrast agent capable of indicating a tunable, absolute two-point temperature window. In using specific limitations of therapeutic and imaging modalities to inform rational nanoparticle design, this lipid-based platform nanotechnology has extended the application of fluorescence imaging in vivo, enhanced the utility of nanoparticulate chemotherapeutics against breast cancer independent of MDR status, and provided novel functionality for MRI thermometry.
Role of Hypoxia-inducible Factor in Kidney Cancer
Keywords: Kidney Cancer
Hypoxia-inducible Factor

Cellular adaptation to conditions of stress is critical to the survival of all organisms. In mammalian cells, reduced oxygen availability, or hypoxia, triggers a myriad of alterations within molecular pathways aimed at ensuring sustained viability and functionality of vital organs. The master regulator of the hypoxic response is the heterodimeric HIF transcription factor, composed of an oxygen-labile HIFalpha subunit and a constitutively expressed and stable HIFbeta(ARNT) subunit. While experiments in mice have demonstrated the indispensability of HIF1alpha/HIF2alpha, unchecked hyperactivation of HIF is associated with pathological complications, such as the development of clear-cell renal cell carcinoma (ccRCC), the most common form of kidney cancer. In particular, overexpression of HIF2alpha has been intimately linked to ccRCC molecular pathogenesis. Here, we report that HIF2alpha overexpression leads to Akt-mediated hyperactivation of Hdm2, resulting in decreased activity of p53 and increased resistance to apoptosis. Significantly, we show that restoration of p53 activity via inhibition of Hdm2 reverses chemoresistance of otherwise refractory ccRCC cells. We also demonstrate that the picornavirus EMCV (Encephalomyocarditis virus) efficiently destroys ccRCC tumour cells in an NF-kappaB- and HIFalpha-dependent manner both in vitro and in a mouse xenograft model. This work provides pre-clinical evidence for the potential use of EMCV in an oncolytic virus-based approach to the treatment of advanced ccRCC. In addition, using a cell biology-based approach we reveal that inhibition of the DNA methyltransferase DNMT1 leads to enhanced HIF promoter-binding affinity and transactivation activity in a manner that is independent of changes in HIFalpha protein levels. This study uncovers a novel HIF regulatory mechanism in mammalian cells. In summary, the work presented here provides insight into the molecular mechanisms governing HIF activity and the effects of HIF on the molecular pathogenesis of ccRCC. Our findings have the potential to provide new therapeutic avenues for the treatment of kidney cancer.
Plants and Peoples: French and Indigenous Botanical Knowledges in Colonial North America, 1600 – 1760
Keywords: Environment
Botany
Colonialism
Colonial Science
Indigenous Knowledge, Traditional Ecological Knowledge
Atlantic World
Jesuits
Natural History
New France
French North America

As North American plants took root in Parisian botanical gardens and regularly appeared in scientific texts in the seventeenth and eighteenth centuries, they retained their connections to networks of ecological and cultural exchange in colonial North America. In this dissertation I study the history of French botany and natural history as it became an Atlantic enterprise during this time, analyzing the production of knowledge about North American flora and the place of this knowledge in larger processes of colonialism and imperial expansion in the French Atlantic World. I focus particular attention on recovering the role of aboriginal peoples in the production of knowledge about colonial environments on both sides of the Atlantic. Rather than integrating aboriginal collectors, chefs and healers into traditional histories of western science, I integrate familiar histories of science into larger histories of cultural contact in an Atlantic World with multiple centres of knowledge production and exchange. This dissertation develops two closely related arguments. First, I argue that French encounters with American environments and Native cultures were inseparable. Jesuit missionaries, for example, called both a plant and a native culture “wild rice,” conflating descriptions of local ecological and morphological features of the Great Lakes plant with accounts of indigenous cultural and moral attributes. Second, “Plants and Peoples” also analyzes the process by which the Paris-based Académie Royale des Sciences expanded its reach into North America and argues that French colonial naturalists drew on a vibrant conversation between diverse colonial and indigenous communities. Yet indigenous participation and the knowledges they provided were progressively effaced over the course of the seventeenth and eighteenth centuries. This research therefore presents both a new understanding of the history of early modern and enlightenment botany and a lens through which to revisit and enrich familiar histories of cultural exchange in colonial North America.
The War on Autism: On Normative Violence and the Cultural Production of Autism Advocacy
Keywords: autism
advocacy
biopolitics
disability studies
critical race theory
violence
normativity
war
governmentality
representation

This dissertation brings together a variety of interpretive theoretical perspectives born of the fields of disability studies, critical race theory, cultural studies and queer and feminist studies to analyze the social significance and productive effects of cultural representations of autism. Specifically, this work addresses contemporary enactments of autism advocacy as found in the mass media, education literature and policy as well as in fundraising campaigns. In response to a global/izing economy that privileges the fast, efficient exchange of information and knowledge, I attend to how autism appears in the field of autism advocacy as an abbreviation; its multiple meaning distilled down to a series of ‘red flags’ in awareness campaigns, bulleted ‘facts’ in information pamphlets, statistics in policy reports. I analyze the relationships between these fragmentary enactments of autism and trace their continuities so as to make legible an underlying logic: a powerful and ubiquitous logic that casts autism as a pathological threat to normative life, and advocacy as that which must eliminate this threat, thus, limiting the role of the ‘good’ autism advocate to one positioned ‘against’ autism. This dissertation shows how dominant, contemporary discourses of autism advocacy that narrate autism as some ‘thing’ to be ‘fought’, ‘combated’, or ‘warred against’ function to shape ‘life’ as conditional and cast autism as (one of) its condition(s). As autism is discursively and ideologically made separate from the vital category of life itself, and as bodies and minds of living people are relentlessly divided up into vital and non-vital parts, individual and collective life ‘with’ (the condition of) autism becomes life that is conceptualized as ‘almost living’ or ‘mostly dead’. I demonstrate how such an understanding of the conditionality of life is a necessary pre-condition for normative acts of violence – violence enacted in the name of securing the norm and violence that is normalized as necessary.
Molecular Mechanisms and Determinants of Species Sensitivity in Thalidomide Teratogenesis
Keywords: thalidomide
birth defects (teratogenesis)
hydrolysis products
rabbit embryo culture
mouse embryo culture
limb embryopathies
fluorothalidomide
thalidomide analogs
reactive oxygen species
free radical reactive intermediates
oxidative DNA damage
8-oxoguanine glycosylase 1 (Ogg1)
DNA repair
prostaglandin H synthase (PHS)
xenobiotic bioactivation

The expanding therapeutic use of thalidomide (TD) remains limited by its species-specific teratogenicity in humans and rabbits, but not rodents. The R and S isomers of TD may be selectively responsible for its respective therapeutic and teratogenic effects, but rapid in vivo racemization makes this impossible to confirm. Fluorothalidomide (FTD), a fluorinated TD analogue with stable, non-racemizing isomers, may serve as a model compound for determining stereoselective effects. In vivo, FTD was undetectable in plasma, suggesting rapid breakdown, as confirmed in vitro, where FTD hydrolyzed up to 22-fold faster than TD. Unlike TD, FTD in pregnant rabbits and mice was highly toxic and lethal to both dams and fetuses. In rabbit embryo culture, FTD initiated optic (eye) vesicle and hindbrain but not classic limb bud embryopathies. Chemical instability, potent general toxicity and absence of limb bud embryopathies make FTD an unsuitable stereoselective model for TD teratogenesis. TD teratogenesis may involve its bioactivation by embryonic prostaglandin H synthases (PHSs) to a free radical intermediate that increases embryopathic reactive oxygen species (ROS) formation. However, the teratogenic potential of rapidly formed TD hydrolysis products and the determinants of species-specific teratogenesis are unclear. For some teratogens, mouse strains that are resistant in vivo are susceptible in embryo culture, suggesting maternal and/or placental determinants of risk. However, TD and two hydrolysis products, 2-phthalimidoglutaramic acid (PGMA) and 2-phthalimidoglutaraic acid (PGA), were non-embryopathic in CD-1 mouse embryo culture. Also, mice deficient in oxoguanine glycosylase 1 (OGG1), which repairs oxidatively damaged DNA, were resistant to TD embryopathies in culture and in vivo. Therefore, murine resistance to TD teratogenesis is dependent on embryonic factors, rather than maternal/placental determinants or increased DNA repair. In contrast, rabbit embryos exposed in culture to TD, PGMA and PGA exhibited head/brain, otic (ear) vesicle and classic limb bud embryopathies, validating the first mammalian embryo culture model for TD teratogenesis and providing the first evidence of a teratogenic role for TD hydrolysis products. Pretreatment with eicosatetraynoic acid (ETYA), a dual PHS/lipoxygenase inhibitor, or phenylbutylnitrone (PBN), a free radical spin trapping agent, completely blocked TD, PGMA and PGA-initiated embryopathies, implicating a PHS-dependent, ROS-mediated embryopathic mechanism.
SATB2 is a Modulator of p63(alpha) in Cancer and Development
Keywords: p63
SATB2
Squamous Cell Carcinoma
Ectoderm Development

p63(alpha) belongs to the p53-family of proteins and has full-length (TA) as well as truncated ((delta)N) p63(alpha) isoforms. Previous studies have shown that TA and (delta)Np63(alpha) play multiple roles in cancer and development. In cancer, (delta)Np63(alpha)-mediated transcriptional repression promotes oncogenesis while transactivation by TAp63(alpha) is critical during development. Despite their importance, little is known regarding how TA or (delta)Np63(alpha) is regulated and factors influencing the function of p63(alpha) have yet to be identified. Here, I identify Special AT-rich Binding Protein 2 (SATB2) as a protein that forms a complex with and modulates the function of p63(alpha). SATB2 is detected in multiple head and neck squamous cell carcinoma (HNSCC) cell lines that also show overexpression of (delta)Np63(alpha). Histological analysis on tumor specimens revealed that SATB2 is predominantly expressed in advanced-stage HNSCC cancers. SATB2 increases DNA-binding capabilities of (delta)Np63(alpha), augmenting (delta)Np63(alpha) repression of apoptotic gene expression. Knockdown of SATB2 in HNSCC cells sensitizes cancer cells towards chemotherapy- and radiation-induced apoptosis. These results indicate that SATB2 functions as a co-factor and promotes the transrepression function of (delta)Np63(alpha) in HNSCC. In addition to examining the role of SATB2 in HNSCC, I also investigated the effect of SATB2 on the ability of TAp63(alpha) to induce gene expression. In particular, perp has been shown to be a critical downstream target of p63 during development. ChIP analysis revealed that while SATB2 increases TAp63(alpha)-binding to apoptotic gene promoters, SATB2 decreases TAp63(alpha) localization on the perp promoter and inhibits p63(alpha)-mediated perp induction. SATB2 more readily interacts with human disease-associated p63(alpha) mutations that are found in the SAM domain, further inhibiting transcriptional properties of these mutants. Together, my results suggest that SATB2 is an important modulator of p63(alpha) in cancer and development.
Randomized Primitives For Linear Algebra and Applications
Keywords: randomized algorithms
linear algebra

The present thesis focuses on the design and analysis of randomized algorithms for accelerating several linear algebraic tasks. In particular, we develop simple, efficient, randomized algorithms for a plethora of fundamental linear algebraic tasks and we also demonstrate their usefulness and applicability to matrix computations and graph theoretic problems. The thesis can be divided into three parts. The first part concentrates on the development of randomized linear algebraic primitives, the second part demonstrates the application of such primitives to matrix computations, and the last part discusses the application of such primitives to graph problems. First, we present randomized approximation algorithms for the problems of matrix multiplication, orthogonal projection, vector orthonormalization and principal angles computation (a.k.a. canonical correlation analysis). Second, utilizing the tools developed in the first part, we present randomized and provable accurate approximation algorithms for the problems of linear regression and element-wise matrix sparsification. Moreover, we present an efficient deterministic algorithm for selecting a small subset of vectors that are in isotropic position. Finally, we exploit well-known interactions between linear algebra and spectral graph theory to develop and analyze graph algorithms. In particular, we present a near-optimal time deterministic construction of expanding Cayley graphs, an efficient deterministic algorithm for graph sparsification and a randomized distributed Laplacian solver that operates under the gossip model of computation.
The Effects of Hip Hop and Rap on Young Women in Academia
Keywords: 0733
0325

This thesis investigates the rise of the cultures and music of hip-hop and rap in the West and its effects on its female listeners and fans, especially those in academia. The thesis consists of two parts. First I conducted a content analysis of 95 lyrics from the book, Hip-Hop & Rap: Complete Lyrics for 175 Songs (Spence, 2003). The songs I analyzed were performed by male artists whose lyrics repeated misogynist and sexist messages. Second, I conducted a focus group with young female university students who self-identify as fans of hip-hop and/or rap music. In consultation with my former thesis supervisor, I selected women enrolled in interdisciplinary programmes focused on gender and race because they are equipped with an academic understanding of the potential damage or negative effects of anti-female or negative political messaging in popular music. My study suggests that the impact of hip-hop and rap music on young women is both positive and negative, creating an overarching feeling of complexity for some young female listeners who enjoy music that is infused with some lyrical messages they revile. The attraction to hip-hop and rap music and cultures by young women in academia seems to be largely contingent upon an appreciation of the aesthetics of the genre and music, including its rhythmic flow, melodic structure and the general appeal of the artists. Therefore, even when the messaging comes across as antagonizing or antithetical to the well-being of the young female academic listener, her enjoyment of the music remains intact. By organizing a discussion group and candid dialogue between young academic women who are self-described hip-hop and/or rap fans, I was able to obtain an intimate understanding of their personal struggle between this appealing musical aesthetic and the sometimes-violent messages of hip-hop and rap.
Development of Bio-based Phenol Formaldehyde Resol Resins Using Mountain Pine Beetle Infested Lodgepole Pine Barks
Keywords: PF resin
Lodgepole pine
Bark
Liquefaction
Extraction
Bio-based bark PF resin
Mountain pine beetle

Phenol formaldehyde (PF) resol resins have long been used widely as wood adhesives due to their excellent bonding performance, water resistance and durability. With the growing concern for fossil fuel depletion and climate change, there is a strong interest in exploring renewable biomass materials as substitutes for petroleum-based feedstock. Bark, rich in phenolic compounds, has demonstrated potential to partially substitute phenol in synthesizing bio-based PF resins. In this study, acid-catalyzed phenol liquefaction and alkaline extraction were used to convert mountain pine beetle (MPB; Dendroctonus ponderosae) infested lodgepole pine (Pinus contorta) barks to phenol substitutes, liquefied bark and bark extractives. Two types of bio-based phenol formaldehyde (PF) resol resins, namely liquefied bark-PF resin and bark extractive-PF resins, were then synthesized and characterized. It was found that acid-catalyzed phenol liquefaction and alkaline extraction were effective conversion methods to obtain phenol substitute with the maximum yield of 85% and 68%, respectively. The bio-based PF resol resins had higher molecular weights, higher polydispersity indices, shorter gel times, and faster curing rates than the lab synthesized control PF resin without the bark components. Based on the lap-shear tests, the bio-based PF resol resins exhibited comparable wet and dry bonding strength to lab PF resin and commercial PF resin. The post-curing thermal stability of the bio-based PF resins was similar to the lab control PF resin. The liquid-state 13C nuclear magnetic resonance (NMR) study revealed significant influences on the resin structures by the inclusion of the bark components. Methylene ether bridges, which were absent in the lab PF resin, were found in the bio-based PF resins. The bark components favored the formation of para-ortho methylene linkages in the bio-based bark extractive-PF resins. The liquefied bark-PF resin showed a higher ratio of para-para/ortho-para methylene link (-CH2-), a higher unsubstituted/substituted hydrogen (-H/-CH2OH) ratio and a higher methylol/methylene (-CH2OH/-CH2-) ratio than the bark extractive-PF resin. Both tannin components of bark alkaline extractives and phenolated barks contributed to the acceleration of the curing rate of the bio-based resins. This research demonstrated the promise of the bio-based PF resins containing either bark alkaline extractives or liquefied barks as environmentally friendly alternatives to PF adhesives derived solely from fossil fuel based phenol and proposed a novel higher value-added application of the largely available barks from the mountain pine beetle-infested lodgepole pine trees.
Compiler Support for Fine-grain Software-only Checkpointing
Keywords: checkpoinitng
compiler
program analysis
optimization
speculation
parallelism
programming
transactional memory

Checkpointing support allows program execution to roll-back to an earlier program point, discarding any modifications made since that point. Existing software-based checkpointing methods are mainly libraries that snapshot all of working-memory, and hence have prohibitive overhead for many potential applications. In this thesis we present a light-weight, fine-grain checkpointing framework implemented entirely in software through compiler transformations and optimizations. A programmer can specify arbitrary checkpoint regions via a simple API, and the compiler automatically transforms the code to implement the checkpoint at the granularity of individual stores, optimizing to remove redundancy. We explore three application areas for this support. First, we investigate its application to debugging, in particular by providing the ability to rewind to an arbitrarily-placed point in a buggy program’s execution. A study using BugBench applications shows that our compiler-based approach is more than 100X less overhead than full-process checkpointing. Second, we demonstrate that compiler-based checkpointing support can be leveraged to free the programmer from manually implementing and maintaining software rollback mechanisms when coding a backtracking algorithm, with runtime overhead of only 15% compared to the manual implementation. Finally, we utilize the efficient software-only checkpointing to support overlapping execution with delinquent loads through the demonstrations both control-speculation and data-speculation transformations. We further propose a theoretical speculative timing model and confirm its prediction effectiveness with real-machine workload.