VictorJuiz/thesis huggingface dataset:
Molecular Mechanisms and Determinants of Species Sensitivity in Thalidomide Teratogenesis

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.

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
Advisor: Wells, Peter G.
SATB2 is a Modulator of p63(alpha) in Cancer and 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.

Keywords: p63
SATB2
Squamous Cell Carcinoma
Ectoderm Development
Advisor: Kaplan, David
Irwin, Meredith
Randomized Primitives For Linear Algebra and Applications

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.

Keywords: randomized algorithms
linear algebra
Advisor: Mark, Braverman
The Effects of Hip Hop and Rap on Young Women in Academia

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.

Keywords: 0733
0325
Advisor: Dehli, Kari
Development of Bio-based Phenol Formaldehyde Resol Resins Using Mountain Pine Beetle Infested Lodgepole Pine Barks

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.

Keywords: PF resin
Lodgepole pine
Bark
Liquefaction
Extraction
Bio-based bark PF resin
Mountain pine beetle
Advisor: Yan, Ning
Compiler Support for Fine-grain Software-only Checkpointing

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.

Keywords: checkpoinitng
compiler
program analysis
optimization
speculation
parallelism
programming
transactional memory
Advisor: Steffan, J. Gregory
Amza, Cristiana
Relationships between Missing Response and Skill Mastery Profiles of Cognitive Diagnostic Assessment

This study explores the relationship between students’ missing responses on a large-scale assessment and their cognitive skill profiles and characteristics. Data from the 48 multiple-choice items on the 2006 Ontario Secondary School Literacy Test (OSSLT), a high school graduation requirement, were analyzed using the item response theory (IRT) three-parameter logistic model and the Reduced Reparameterized Unified Model, a Cognitive Diagnostic Model. Missing responses were analyzed by item and by student. Item-level analyses examined the relationships among item difficulty, item order, literacy skills targeted by the item, the cognitive skills required by the item, the percent of students not answering the item, and other features of the item. Student-level analyses examined the relationships among students’ missing responses, overall performance, cognitive skill mastery profiles, and characteristics such as gender and home language. Most students answered most items: no item was answered by fewer than 98.8% of the students and 95.5% of students had 0 missing responses, 3.2% had 1 missing response, and only 1.3% had more than 1 missing responses). However, whether students responded to items was related to the student’s characteristics, including gender, whether the student had an individual education plan and language spoken at home, and to the item’s characteristics such as item difficulty and the cognitive skills required to answer the item. Unlike in previous studies of large-scale assessments, the missing response rates were not higher for multiple-choice items appearing later in the timed sections. Instead, the first two items in some sections had higher missing response rates. Examination of the student-level missing response rates, however, showed that when students had high numbers of missing responses, these often represented failures to complete a section of the test. Also, if nonresponse was concentrated in items that required particular skills, the accuracy of the estimates for those skills was lower than for other skills. The results of this study have implications for test designers who seek to improve provincial large-scale assessments, and for teachers who seek to help students improve their cognitive skills and develop test taking strategies.

Keywords: missing response, large-scale assessment, psychometrics, Cognitive Diagnostics Assessment/ Models, Skill Mastery Profiles, and Item Response Theory
Advisor: Childs, Ruth A.
Does Duration of Nicotine Replacement Therapy Use Matter in Quitting Smoking? A Longitudinal Study of Smokers in the General Population

Background and Objectives: Little is known about the impact of nicotine replacement therapy (NRT) use duration on smoking cessation in the general population. This study determines whether duration of NRT use is associated with smoking cessation. Methods: Data were from the Ontario Tobacco Survey longitudinal study of a population-based cohort of baseline smokers who made serious quit attempts during 18 months of follow-up. The association between NRT (any NRT, patches, or gum) use duration and smoking cessation outcomes (short-term abstinence ≥1 month and long-term abstinence ≥12 months) was estimated by Poisson regression, adjusting for all confounding variables. Results: Among the 1,590 eligible smokers, 933 (59%) did not use any NRT, 535 (34%) used NRT <8 weeks, and 112 (8%) used NRT ≥8 weeks at follow-up. The median duration of NRT use was 14 days. A consistent “J” shape of associations between quit aid use duration and smoking cessation outcomes (quit rates) was found. Using any NRT, patches, or gum <8 weeks was generally associated with a lower likelihood of quitting, but using them ≥8 weeks was generally associated with a higher likelihood of quitting, compared to not using them. Only using patches for the recommended duration (≥8 weeks) was associated with a higher likelihood of short-term (relative risk, RR 1.74, 95% confidence interval, CI 1.21-2.50) and long-term (RR 2.62, 95% CI 1.25-5.50) abstinence at the end of 18 months of follow-up, compared to not using patches. Using gum ≥8 weeks was not associated with short- or long-term abstinence at the end of 18 months of follow-up. Conclusions: Using nicotine patches for the recommended duration is associated with successful short- and long-term abstinence in the general population. More efforts are needed to encourage smokers to use nicotine patches for eight or more weeks when attempting to quit.

Keywords: Nicotine replacement therapy (NRT)
Population-based prospective cohort study
Smoking cessation
Advisor: Cohen, Joanna
Investigation of ClpXP Protease Mechanism of Function and its Interaction with the Folding Chaperone Trigger Factor

The major chaperones identified in Escherichia coli that assist in protein folding include trigger factor (TF), DnaK/DnaJ/GrpE and GroEL/GroES systems. The main ATP-dependent proteases are ClpXP, ClpAP, HslUV, Lon, and FtsH. From detailed sequence analysis, we found that tig (gene for TF), clpX, and clpP genes co-localize next to each other in most examined bacteria. We hypothesized that TF and ClpXP are functionally associated. TF is a ribosome-associated folding chaperone whereas ClpXP is a degradation complex. ClpX serves as the regulatory ATPase that recognizes substrates, unfolds and translocates polypeptides into ClpP for degradation. I found that TF physically interacts with ClpX, and that they collaborate to enhance degradation of certain ClpXP substrates. It is estimated that TF enhances the degradation of about 2% of newly synthesized E. coli proteins. One of the ClpXP substrates with degradation enhanced by TF was λO, the λ phage replication protein. Furthermore, TF also enhanced the degradation of ribosome-stalled λO nascent chains. Experiments suggest that TF transfers ribosome-stalled λO to ClpX for degradation by ClpP, demonstrating the existence of co-translational protein degradation in E. coli. To understand ClpXP mechanism, we had previously proposed that the degraded peptides are released from ClpP through transient equatorial side pores. To further understand ClpP dynamics, we determined the structure of ClpP(Ala153Cys) in its oxidized state. The structure shows that each opposing pair of protomers is linked by a disulfide bond. Unexpectedly, this structure resembles the compact structures of Streptococcus pneumoniae, Mycobacterium tuberculosis, and Plasmodium falciparum ClpPs, rather than the extended states seen in previous E. coli ClpP structures. Normal mode analysis of ClpP structures suggested that the iii compact structure is a naturally sampled conformation of WT ClpP. My findings provide insights for understanding ClpP dynamics as well as reveal a novel association between ClpXP protease and TF folding chaperone.

Keywords: chaperones
proteases
cotranslational
ClpP dynamics
Advisor: Houry, Walid A.
Adaptation Techniques for Publish/Subscribe Overlays

Publish/Subscribe (in short pub/sub) allows clients that share common interest communicate in an asynchronous and loosely-coupled fashion. This paradigm is adopted by many distributed event-driven applications such as social networking services, distributed business processes and cyber-physical systems. These applications cannot afford to have the underlying pub/sub substrate perform unreliably, permanently fail or behave arbitrarily as it will cause significant disturbance to stably serving many end-users. Therefore, a research effort on making pub/sub systems resilient against various failures to sustain high quality of service to the clients is imperative. In this thesis, we focus on the overlay of pub/sub brokers that are widely adopted as a popular architecture for large-scale pub/sub systems. Broker overlays can suffer from various issues such as degradation of topology quality, brokers causing transient or permanent benign failures and Byzantine brokers behaving arbitrarily. We aim to make novel research contributions by exploring fundamental techniques that can help the broker overlays maintain functional and non-functional requirements even under the presence of the aforementioned failures and necessary administrative updates. We first build a set of overlay adaptation primitives that re-configure topologies such as shifting links and replicating brokers. These primitives are designed to involve a small local group of brokers in the pub/sub overlays so that the disruption during the execution of large-scale and dynamic changes can be controlled in a fined-grained manner. For the problem of degrading topology quality, automated planning systems are developed to find a sequence of adaptations that would cause minimal disruption to running services. Also, our primitives can be executed on demand to quickly fail-over a crashed broker or off-load congested brokers. In addition, these on-demand primitives can be used to form a group of dynamically replicated brokers that enforce a novel safety measure to prevent Byzantine brokers from sabotaging the pub/sub overlays. Our contributions are evaluated with systematic consideration of various trade-offs between functional and non-functional properties.

Keywords: Publish/subscribe
Overlay networks
Distributed systems
Adaptive systems
Advisor: Jacobsen, Hans-Arno