VictorJuiz/thesis huggingface dataset:
Genome-wide CRISPR Screens to Uncover Novel Therapeutic Targets in Wnt-β-catenin Driven Gastrointestinal Cancers
Keywords: Colorectal cancer
CRISPR
FZD5
Pancreatic cancer
RNF43
Wnt

Gastrointestinal tract cancers are some of the deadliest cancers and novel therapeutic options are needed. One hallmark of gastrointestinal cancers is the frequent mutation of tumour suppressor genes resulting in constitutive activation of the Wnt-β-catenin signalling pathway. Wnt-β-catenin signalling is a positive regulator of stem cell self-renewal in normal tissues, but cancer cells may take advantage of it to promote their proliferation and survival. Despite frequent cancer cell reliance on Wnt-β-catenin signalling, no clinical therapeutics currently exist that target it. CRISPR/Cas9 gene editing technology has recently allowed for genome-wide loss- of-function screens in vertebrate cells and may therefore be used to identify novel genetic vulnerabilities in human cancer cells. Genome-wide CRISPR screens were completed in RNF43 mutant pancreatic ductal adenocarcinoma (PDAC) cells lines, which rely on Wnt-β- catenin autocrine signaling for their proliferation. These screens revealed a single Frizzled receptor gene out of ten paralogs, FZD5, to be essential for the proliferation of each RNF43 mutant PDAC line. We generated a synthetic human monoclonal antibody specific to FZD5, and found it effective in reducing the growth of RNF43 mutant pancreatic cancers in vitro and in orthotopic xenograft models. We next identified the homeobox transcription factor CDX2 as a context-dependent fitness gene and Wnt-β-catenin transcriptional target in RNF43 mutant pancreatic cancer cells. CDX2 is uniquely overexpressed in Wnt-FZD5 dependent PDAC cells and transcriptome analysis revealed it may drive an intestinal metaplasia phenotype, and may be a suitable biomarker for Wnt-FZD5 dependency. To further identify novel therapeutic targets we completed synthetic-lethal interaction CRISPR screens in cells in which we engineered APC mutations. APC loss of function mutations cause Wnt-β-catenin pathway activation and occur in 80% of colorectal cancers. As a surrogate model for APC mutant colorectal cancer we engineered APC mutant PDAC cell lines to compare with their parental APC wild-type cell lines. Isogenic CRISPR screens comparing these cell lines identified many synthetic-lethal genes, most notably the Aryl Hydrocarbon Receptor (AHR), as a potential druggable vulnerability. Together this work demonstrates the power of genome-wide CRISPR screens for assessing signalling pathways in cancers, and may lead directly to the development of novel targeted therapeutics.
The Chiarelli Doctrine: Immigration Exceptionalism and the Canadian Charter of Rights and Freedoms
Keywords: Charter
Constitutional Law
Human Rights
Immigration
Refugee

Since the 19th century, American courts have relied on the “plenary power doctrine” to hold that federal immigration law is immune from constitutional challenge. Despite no such rule in Canada, this paper argues that a similar doctrine has silently crept into Canadian constitutional law. With its roots in the Supreme Court of Canada’s 1992 decision in Chiarelli, Canadian courts have set out a doctrine of evasion and technicality that has rendered many of the Charter rights of immigrants and refugees to be effectively non-justiciable. Without explanation, laws that detain, uproot, exile, separate families, and return people to persecution have been exempted from normal standards of justice. This paper charts the emergence of the “Chiarelli doctrine”, critiques its incoherence, and explores why judges have so steadfastly refused to engage with the human rights claims of non-citizens. It concludes with a simple proposal to bring these doctrines of exception to an end.
On the Margins of Experience: Rubbish in the Works of Miron Białoszewski and Tadeusz Różewicz
Keywords: antirealism
epistemology
Różewicz, Tadeusz
Polish literature
realism
Białoszewski, Miron

Placeholder Text - Focusing on the philosophical dimension of these works, I argue that they express two epistemological models of the relationship between human cognitive practices and an objective reality. This relationship is discussed in my dissertation in terms of the link between the conceptual and the extra-conceptual, and it is developed in the texts of the two authors in the context of but also as a response to a constructivist understanding of human cognition. I argue that by linking the conceptual and the extra-conceptual, the models offered by Białoszewski and Różewicz seek to escape the confines of epistemological constructivism. The key element in these attempts is the notion of rubbish. Understood as a cognitive category and used as a metaphor for all unassimilable elements that disrupt the pattern-making tendencies of human cognition, rubbish, I argue, simultaneously subverts and maintains the stability of the conceptual order into which it does not fit. This double nature of rubbish links the conceptual and the extra-conceptual in the epistemological models presented in Białoszewski’s and Różewicz’s texts. My study demonstrates that although Białoszewski’s and Różewicz’s models exemplify contemporary antirealist tendencies in philosophy, the contributions of these two authors to the philosophical debate concerning the limits of human cognition do not consist solely in rejecting a traditionally understood realism. Rather, they offer reassessments of the antirealist framework and propose a uniquely non-essentialist understanding of the world.
The Teacher's Role in Orchestrating a Knowledge Community and Inquiry Classroom
Keywords: K-12 science
Knowledge Community and Inquiry
learning sciences
pedagogy for competencies
science education
teacher's role

This design-based study examined the teacher’s role in orchestrating a secondary science curriculum designed according to the pedagogical model known as Knowledge Community and Inquiry (KCI -- Slotta, 2013). In KCI, students collaboratively construct a community knowledge base that is both the product of, and a resource for scaffold inquiry activities. These inquiry activities are designed to address content expectations and other learning goals, and also accommodate the community’s “voice”. Central to KCI is the emphasis on procedural scripting (Fischer et al., 2013; Raes et al., 2012) that guides students through a productive sequence of activities and helps ensure that the curriculum addresses mandated content expectations. This study introduces a new 12th grade health science curriculum known as “Mission to Mars” together with a design analysis that evaluates the fit to KCI. The curriculum was then implemented in a pilot study for which an orchestration analysis revealed four fundamental roles of the teacher. In response to the pilot study, the curriculum was revised, then implemented again, with a second orchestration analysis producing a more refined description of the role of the teacher at various points throughout the curriculum. A formalism of orchestration graphs (Dillenbourg, 2015) was introduced as one element of the orchestration analysis to represent the locus of activities on individual, group or community levels, and the role of the teacher during any given period. The fundamental roles revealed during the first iteration of the curriculum provided a basis for the more nuanced analysis of the second iteration. The teacher in this study was also the researcher, which allowed a valuable lens for pinpointing teaching decisions, priorities and forms of interaction with students. Because of this dual role, the teacher-researcher was able to provide an introspective source of insight and information, allowing greater depth and nuance to the analysis. This role of researcher-practitioner is discussed, including a critical comparison with the related category of action research.
Rereading Identity Cards: The Early Anticolonial Poetics of Mahmoud Darwish and their Hebrew Afterlives
Keywords: Arabic Literature
Hebrew Literature
Israel
Mahmoud Darwish
Palestine
Translation

Abstract In 1964, Mahmoud Darwish, the late national Palestinian poet, published his canonical poem "Identity Card". The poem, constructing an essentialized Arab identity, has since enjoyed a prolific afterlife in both modern Arabic poetry, and Israeli literary discourse. Although it had become an instant 'hit' with Arab crowds, Darwish himself disavowed it at a later stage, refusing to read it for its essentialist perception of identity. Widely reviewed by scholars, the poem has still been scarcely read in its original context, as the closing poem of Darwish's first ever published collection, Olive Leaves (1964). Unlike the essentialist poetics of "Identity Card", the reading of the Olive Leaves poems reveals a complex poetic subjectivity embedded in a network of intertextual references. These in turn engage in a vital dialogue with the anti-colonial moment and poetic innovations prevailing in modern Arabic poetics from the 1950's and on. Through the rereading of the collection's poems and the exploration of Darwish's own theory of poetics, I venture to re-accord these early poetics their deserved place within modern Arabic poetry, echoing Darwish's own assertion that Palestinian poetry, "is neither rival nor an alternative to modern Arabic poetry, it is an integral part of it, a creek within the creeks of the great river". The dissertation then proceeds to explore the Hebrew afterlife of "Identity Card", focusing on two realms: Translation and Mizrahi poetry. Through various public debates and several of the poem's mistranslations, I explore the difficulties of 'digesting' the poem and the manner in which Darwish's presence evokes an ambivalent sense of anxiety, forcing Hebrew culture to face its haunting colonial past and presence. For Mizrahi poetics, on the other hand, Darwish offers a powerful model of self-assertion, opening up a new poetic space where a Mizrahi poetics of deconstruction takes place. This new space is mainly explored through the close reading of Sami Shalom-Chetrit's poem: "A Mural With no Wall: A Qasida for Mahmoud Darwish".
Understanding Short-term Labor Supply Decisions
Keywords: Discrete Choice
Flexibility
Gig Economy
Labor Supply
Reference Dependence
Taxi

In this thesis, I study the short-term labor supply decisions of workers involved in flexible work arrangements. In the first chapter, I develop and estimate the first dynamic model of within-day labor supply. The model includes several factors that influence the decision to take breaks: fatigue, opportunity costs, preferences across hours of the day, and random utility shocks. I estimate the model using high-frequency data covering millions of taxi trips in New York City during an entire year. The estimated parameters indicate that the fixed costs of taking a break are high, suggesting that a policy aimed at increasing the availability of taxi parking spaces could reduce the aggregate level of fatigue. In Chapter 2, I use the previously developed model to quantify the value of flexibility and evaluate the effect of a 'mandatory breaks' policy. This chapter proposes a novel methodological approach to deal with unobserved heterogeneity: I estimate the model separately for each driver. My results show that flexibility is valued highly with the average driver in my sample requiring a 23 percent increase in revenue to accept a counterfactual fixed work schedule. I then study the effects of a realistic 'mandatory breaks' policy and show that such a policy would substantially increase the frequency of breaks but would reduce labor supply between 6 and 9 percent. Chapter 3 presents empirical evidence indicating that the daily labor supply elasticity of workers is large and negative in response to small windfall gains, contrary to the prediction of the standard neoclassical model. In the main specification, I identify windfall gains using tips received by drivers and find that the drivers respond to these shocks by decreasing their labor supply substantially. I also find that these shocks do not affect future labor supply, indicating that standard neoclassical income effects cannot explain this result. In contrast, a positive shock to average hourly earnings causes drivers' labor supply to increase, consistent with the neoclassical model. My findings suggest that increasing the wage and reducing the income earned through tips or bonuses could increase labor supply in a cost-neutral way.
Mapping interstellar plasma structures in space and time through global interferometry of pulsars
Keywords: global interferometry
pulsars
radio astronomy
scintillation

Pulsar scintillation has traditionally been used to investigate the statistical properties of small- scale density structure in the ionized interstellar medium. Scintillation, variation of the observed flux density with time and frequency due to the interference of scattered emission, is commonly considered to arise from a distributed scattering process in the interstellar medium, but over the last two decades evidence has accumulated that the scintillation of many pulsars is dominated by a single intervening thin screen. The simplicity of this scattering system can be exploited in global interferometric observations to create a three-dimensional map of the scattered flux that includes the distance of the plasma lens. In this thesis, I introduce two techniques for this reconstruction: The first can be applied to autocorrelations from coordinated global observations of single screen systems, eliminating the need for correlating baseband data. The second requires correlated visibilities but can be applied to systems with multiple scattering screens. These techniques provide more precise ways to measure the distance to and velocity of the intervening scattering screens. I apply the first of these techniques to multi-epoch observations of PSR B0834+06, where we find strong evidence that the lens profiles of the compact substructures in the screen are asymmetric. This is unexpected for turbulent density fluctuations, but consistent with the corrugated plasma sheet model for scintillation arcs, presented in this thesis. In this model, the scattered images are expected to move very slightly, but in a predictable manner, within the scattering screen as the pulsar moves behind it. We find that a more precise measurement of the distance to the screen is needed to detect this motion, and in future will apply the second technique for measuring this distance to these observations. The techniques presented in this thesis when applied to multi-epoch and wide-bandwidth observations will provide key constraints on predictive scintillation models, which, when finessed, will enable removing scintillation, a source of noise that is of growing importance as wide-bandwidth timing campaigns become commonplace, from pulsar observations.
The Neural Bases of Cognitive Conflict in Musicians with Absolute and Relative Pitch
Keywords: Absolute Pitch
EEG
Executive Function
Information Conflict
Neural Plasticity
Relative Pitch

Musicians have considerable experience naming pitch-classes with verbal (e.g., Doh, Ré, Mi, etc.) and semiotic tags (e.g., musical notation, etc.), which can become automatic. Such experience may facilitate auditory processing even when there is conflicting information. However, there is a special instance (e.g., absolute pitch) where a strong association between perceived pitch and verbal label could be detrimental when conflicting information not usually detectable by the general population is perceived (i.e., conflicting verbal encodings). To better understand how neuronal systems tune to perceptual inputs and hone conscious control over abstract associational structures (e.g., language, music, etc.), we measured scalp-recorded event-related potentials while non-musicians and musicians with absolute or relative pitch performed three different auditory Stroop tasks. In separate blocks of trials, participants were presented with congruent or incongruent auditory words from English language (standard auditory Stroop), Romanic solemnization or German keycode lexicons (the latter two versions require some knowledge of music notation). Musicians with absolute pitch were more accurate when responding to incongruent English words than musicians with relative pitch as well as non-musicians who showed significantly lowered accuracy for incongruent compared to congruent conditions for this task unlike the absolute pitch group. Relative to congruent stimuli, incongruent trials generated an increased negativity that peaked between 325 and 525 ms after sound onset (N450) over the central scalp area. This modulation is considered to be a neural index of inhibitory executive control processing and conflict resolution and was larger in the auditory word Stroop than in the other two versions of the Stroop task. This neural index was also larger in non-musicians than musicians with absolute or relative pitch. In musicians, the reduced modulation associated with processing cognitive conflict may reflect more efficient processing. Only musicians with absolute pitch showed significant congruity effects in both N450 and P600 modulations when stimuli were presented as Germanic keycodes (i.e., C or G). This suggests that absolute pitch possessors may process alpha-numeric encodings as word forms with a semantic and syntactic value, unlike their relative pitch possessing counterparts and non-musically trained individuals.
Pan-Cancer Analysis of Non-Coding Driver Mutations
Keywords: Cancer Driver
Cancer Genomics
RNA Splicing
Software

Cancers are caused by genomic alterations known as drivers. As drivers have broad applications in precision oncology, their discovery has become one of the central motivations for cancer genomics. At present, the majority of drivers have been found in the ~2% protein-coding regions. Despite an intensive search for non-coding cancer drivers, however, only a few have been discovered to date. Here I describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify drivers within cancer whole genomes. Using 1,373 genomic features, DriverPower's background model explains up to 93% of the regional variance in mutation rates across multiple tumour types. By incorporating functional impact scores, I further increase the accuracy of driver discovery. Comparing to six published methods, DriverPower has the highest F1-score for both coding and non-coding driver discovery. Applied to 2,583 cancer genomes from public sources, DriverPower identifies 217 coding and 95 non-coding driver candidates in well-defined genomic regions, including novel candidates like the SGK1 splice site, GPR126 enhancer and ALB promoter. To test whether the surprisingly low number of non-coding drivers is related to missing drivers in poorly-defined genomic regions, I investigate non-coding spliceosomal RNAs since protein-coding splicing factors are frequently mutated in cancer. Indeed, I found a highly recurrent A>C somatic mutation at the third base of U1 spliceosomal RNA across several tumour types. This mutation changes the preferential A-U base-pairing between U1 and 5′ splice site to C-G base-pairing, thereby creating novel splice junctions and altering the splice pattern of multiple genes, including known cancer drivers. Clinically, the A>C mutation is associated with alcohol abuse in hepatocellular carcinoma and the aggressive subtype of chronic lymphocytic leukaemia (CLL). The mutation also confers an adverse prognosis to CLL patients independently. This finding demonstrates the first non-coding driver in spliceosomal RNAs, reveals a novel mechanism of aberrant splicing in cancer and may represent a new target for treatment. Together, my research indicates that non-coding mutations play crucial roles in cancer, and future studies should focus on completing the cancer driver catalog and using it for precision oncology.
Towards Fluorescence Resonance Energy Transfer Based Detection of Nucleic Acid Hybridization using Intrinsically Labeled Fluorescent Oligonucleotide Probes as Acceptors and Quantum Dots as Donors
Keywords: DNA
FRET
Hybridization
Intercalation
Quantum Dots

The work described herein explored solution-phase and solid-phase transduction of nucleic acid hybridization using intrinsically labeled oligonucleotide probes immobilized on the surface of quantum dots (QD). Multiple copies of a derivative of thiazole orange, an intercalating dye known to form non-emissive dimers, were conjugated to single-stranded oligonucleotide probes. Dimerization resulted in formation of H-aggregates where excitonic interactions led to suppression of fluorescence. The hybridization of the oligonucleotide probe with complementary target resulted in enhancement of fluorescence emission as the dimers dissociated and the dyes preferentially intercalated with the duplex. Detection of oligonucleotide targets using this configuration eliminated the need for labeling the target strands, and fluorescence intensity was proportional of the extent of hybridization. The dye molecules were excited using Fӧrester Resonance Energy Transfer (FRET) from QD donors, which resulted in improved selectivity and allowed for ratiometric detection. The dependence of the ratiometric signal on the type of linkage used to conjugate the dyes to the probe, the location of the dye along the length of the probe, and the distance between adjacent dye molecules were investigated. The limit of detection for 34mer and 90mer targets was found to be identical and similar to analogous QD-FRET using labeled oligonucleotide target. The detection system could discriminate a one base pair mismatch (1BPM) target and was functional without substantial compromise of the signal in goat serum. The 1BPM was found to reduce background signal, indicating that the structure of the mismatch affected the environment of the intercalating dyes. The paper-based solid-phase substrates provided several advantages to this transduction scheme. QD-probe conjugates were immobilized in sufficient density on the paper matrix to provide for multiple-donor-multiple-acceptor interactions that resulted in a 40-fold enhancement of acceptor emission compared to the solution-based assay. The paper-based assay provided for reduction of the time needed for sample preparation and data acquisition, demonstrated that transduction was possible in a complex matrix (goat serum) without compromise of the performance observed in buffer solution, and that oligonucleotides generated from standard PCR amplification could be detected.