VictorJuiz/thesis huggingface dataset:
New Synthetic Applications of Rhodium-Catalyzed Carbon-Carbon and Carbon-Heteroatom Bond Forming Reactions

This thesis is divided into four chapters that describe the new development in rhodium-catalyzed addition reactions and asymmetric ring opening (ARO) reactions of strained alkenes. Chapter 1 describes a regioselective Rh(I)-catalyzed addition reaction of arylboronic acids to unactivated alkenes - protected allylic amines and allyl sulfones. These formal hydroarylation processes have significantly advanced the substrate scope. Comprehensive studies were carried out to optimize the reaction conditions and a wide range of arylboronic acids were employed. The reaction was found to be linear-selective and a mechanism based on functional group- directing effects has been proposed. Chapter 2 discloses the discovery of Rh(I)-catalyzed addition of arylboronic acids to (benzyl- /arylsulfonyl)acetonitriles. Novel β-sulfonylvinylamine products were formed in a stereoselective fashion (Z-alkene). Upon hydrolysis, β-keto sulfones were obtained with a broad scope of aryl and sulfonyl substituents. These (Z)-β-sulfonylvinylamines were useful synthons in the synthesis of unsymmetrical polysubstituted pyridines via 1-aza-allyl anion intermediates as well as 1,4- benzothiazine derivatives via intramolecular cyclization. Chapter 3 reports the use of two new nucleophiles in Rh(I)-catalyzed ARO of oxabicyclic alkenes - water and triethylamine trihydrofluoride. In the water-induced ARO, an unprecedented domino ARO/isomerization process was discovered which led to the formation of 2-hydroxy-1- tetralones. By modifying the reaction conditions, trans-1,2-diols can be obtained in excellent enantioselectivity. Using triethylamine trihydrofluoride as a nucleophile, an aliphatic C-F bond was constructed enantioselectively in the ring-opening process which provided fluorinated building blocks containing both allylic fluoride and fluorohydrin units. Finally, Chapter 4 details the development of a one-pot synthesis of a chiral dihydrobenzofuran framework using Rh-catalyzed asymmetric ring opening and Pd-catalyzed C-O coupling. The product can be obtained in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an indicator.

Keywords: organic chemistry
transition metal
organic synthesis
heterocycle
rhodium
asymmetric catalysis
regioselective
stereoselective
Advisor: Lautens, Mark
Post-translational Regulations of FUSCA3 in Arabidopsis thaliana

Seed formation consists of two major stages: embryo pattern formation and maturation. During seed maturation, the embryo accumulates storage material, acquires desiccation tolerance, and enters a stage of dormancy. Genetic analyses have identified several master regulators that orchestrate late embryogenesis, including the B3-domain transcription factor FUSCA3 (FUS3). In Arabidopsis, FUS3 has been shown to be a central regulator of hormonal pathways; it positively regulates late embryogenesis by increasing abscisic acid (ABA) level while repressing gibberellin (GA) synthesis. In turn, FUS3 protein level is positively and negatively regulated by ABA and GA, respectively. However, the mechanism of how this regulation occurs has not been well characterized. In this study, FUS3 has been shown to be an unstable protein rapidly degraded by the proteasome through a PEST instablility motif. To further characterize the mechanisms involved in FUS3 homeostasis, FUS3-interacting proteins were identified. The SnRK1 kinase AKIN10 was shown to interact with and phosphorylate FUS3 at its N-terminus. Furthermore, overexpression of AKIN10 delays FUS3 degradation, suggesting AKIN10 positively regulates FUS3 protein accumulation. Overexpression of AKIN10 delays developmental phase transitions, and causes defects in lateral organ development. These defects were partially rescued by the loss-of-function fus3-3 mutation, suggesting FUS3 and AKIN10 genetically interact to regulate these developmental processes. SnRK1/AMPK/Snf1 kinases are regulators of energetic stress responses. Overexpression studies suggest both FUS3 and AKIN10 positively regulate ABA signaling, but differ in sugar responses during germination; AKIN10 mediates glucose sensitivity, while FUS3 regulates osmotic stress responses. Overexpression of AKIN10 and FUS3 results in glucose and osmotic stress hypersensitivities, respectively, both of which are partially dependent on de novo ABA synthesis. Thus, FUS3 and AKIN10 act in overlapping pathways and combine different environmental signals to generate a common ABA-dependent response. In summary, novel mechanisms that regulate FUS3 homeostasis and function were identified. A model explaining the interaction between FUS3 and AKIN10 during embryonic and vegetative development, and the function of these two central developmental regulators in hormonal and stress signaling pathways is discussed.

Keywords: Development
Protein-protein interaction
Phosphorylation
Phase transition
Plant hormone
Protein degradation
Advisor: Gazzarrini, Sonia
Write the Book of Your Heart: Career, Passion and Publishing in the Romance Writing Community

This dissertation explores how a solitary writer becomes a social writer, entering into the industrial and community relations of mass publishing. A significant part of this transformation is managed through writing organizations which mediate between the corporate world and individual writers. Despite being one of the most prolific and commercially successful book-markets in a time when both publishing and reading are perceived to be under threat, romance fiction, because of its gendered and classed status, is often neglected by the academy and patronized in the media. Researched through observation of the largest romance writers groups in Canada, which I call City Romance Writers, this dissertation explores how writers’ associations help shape would-be writers into players in the professional market, negotiating the boundaries between professional and amateur, local and global, creative and market-driven. It explores how romance writers organize to manage risk and uncertainty in the publishing industry and how they make claims to legitimacy and authority in the public sphere. Finally, it examines how structures of gender, race and class shape the communities romance writers form and the claims they make. I argue that romance writers’ discourses and practices surrounding writing and publication are a revealing terrain for the exploration of contemporary issues of media production, flexible labour, gender and community. In part because of the particular characteristics of romance writing itself, these themes are also underpinned by the constant presence of love, as a discourse, an activity and a story. While revealing the importance of affective discourses of passion and love in mobilizing writers to embrace their own flexibility, this dissertation also argues that writers’ affective relationship with their writing is not fully contained by capitalism.

Keywords: romance fiction
gender
flexible labour
women writers
linguistic anthropology
creativity
Canadian writers
work
Advisor: Barker, Joshua
Bamford, Sandra
Efficient Machine Learning with High Order and Combinatorial Structures

The overaching goal in this thesis is to develop the representational frameworks, the inference algorithms, and the learning methods necessary for the accurate modeling of domains that exhibit complex and non-local dependency structures. There are three parts to this thesis. In the first part, we develop a toolbox of high order potentials (HOPs) that are useful for defining interactions and constraints that would be inefficient or otherwise difficult to use within the standard graphical modeling framework. For each potential, we develop associated algorithms so that the type of interaction can be used efficiently in a variety of settings. We further show that this HOP toolbox is useful not only for defining models, but also for defining loss functions. In the second part, we look at the similarities and differences between special-purpose and general-purpose inference algorithms, with the aim of learning from the special-purpose algorithms so that we can build better general-purpose algorithms. Specifically, we show how to cast a popular special-purpose algorithm (graph cuts) in terms of the degrees of freedom available to a popular general-purpose algorithm (max-product belief propagation). After, we look at how to take the lessons learned and build a better general-purpose algorithm. Finally, we develop a class of model that allows for the discrete optimization algorithms studied in the previous sections (as well as other discrete optimization algorithms) to be used as the centerpoint of probabilistic models. This allows us to build probabilistic models that have fast exact inference procedures in domains where the standard probabilistic formulation would lead to intractability.

Keywords: Machine Learning
Advisor: Zemel, Richard S.
Neto1 and Neto2 are Auxiliary Subunits of Synaptic Kainate Receptors

Neto1 and Neto2 are CUB domain-containing transmembrane proteins that are expressed in the mammalian brain. Previous studies showed that Neto1 is a NMDAR-associated protein with important roles in synaptic plasticity and learning/memory (Ng et al., 2009). To establish the functions of Neto2, I first searched for its binding partners. Using yeast two-hybrid analysis, GST pull-down and co-immunoprecipitation studies, I found that Neto2 can bind to the PDZ domain-containing protein GRIP. In the brain, GRIP regulates the synaptic trafficking and stability of AMPA and kainate receptors (KARs) (Hirbec et al., 2003). To determine whether Neto2 is required for the synaptic expression of KARs and/or AMPARs, I examined whether Neto2 was associated with these receptors at the postsynaptic membrane. Coimmunoprecipitation studies showed that while Neto2 is a component of postsynaptic KAR protein complexes, it is not associated with AMPARs. In the cerebellum, Neto2-null mice showed a 44% (n=3;p<0.01) decrease in the abundance of postsynaptic KARs with no change in the level of total KARs, thus suggesting a specific deficit in KAR synaptic localization. Unexpectedly, loss of Neto2 had no effect on the abundance of hippocampal KARs (n=3; p>0.05), or on neurotransmission by them (n=12; p>0.05). To determine whether this normal KAR function might be due to compensation by Neto1, which also interacts with KARs, I examined KAR abundance in Neto1-null, and Neto1/2-double null hippocampus. Loss of Neto1 resulted in a 53% decrease in postsynaptic levels of GluK2-KARs (n=3;p<0.01). However, in double null animals, the reduction was indistinguishable from Neto1 single null mice, suggesting that Neto2 is not involved in the postsynaptic localization of hippocampal KARs. In Neto1-null mice, KAR-mediated currents showed smaller amplitude (61% of wild-type;n=14;p<0.01), and faster decay kinetics (40% of wild-type;n=14;p<0.001). Together, these findings establish both Neto1 and Neto2 as auxiliary proteins of native KARs: Neto1 regulates the synaptic abundance and kinetics of KARs in the hippocampus, while Neto2 mediates the synaptic localization of cerebellar KARs. Additionally, the results presented here, in conjunction with previous findings, reveal a unique ability of Neto1 in controlling synaptic transmission by serving as an auxiliary protein for two different classes of ionotropic glutamate receptors.

Keywords: glutamate receptors
auxiliary proteins
Advisor: McInnes, Roderick
The French Wh Interrogative System: Est-ce que, Clefting?

This thesis revisits the variation inherent to the French wh interrogative system. In La[urentien]F[rench], there are many ways to ask wh questions, all of which are said to have the same general interpretation. By looking at different types of data, historical as well as contemporary, this thesis puts forward three main findings/proposals: i. the high degree of variation is due to the use of wh est-ce que, which appeared in Old French as an interrogative cleft (Rouquier 2003); ii. between Old and Modern French, wh est-ce que has gone through a typical cycle of grammaticalisation (as described by Roberts & Roussou 2003, van Gelderen 2008a, b), while the free relative of the Old French cleft remained unchanged; iii. today’s LaF wh system is dominated by the wh est-ce que and variants (over 98 percent of use – Elsig 2009), which lack traditional wh movement. It is proposed that wh est-ce que and variants appear in a construction containing an atrophied clefted CP adjoined to a main clause containing a wh operator, whereas the variant traditionally called wh in situ is generated in a structure in which the wh element is interpreted and spelled-out in the position of Merge. In addition to its theoretical contribution, this thesis helps to bring together theoretical and applied linguistics, since it makes use of different types of data, both historical and synchronic (oral and written corpora, experimental studies and grammaticality judgements). Moreover, the conclusions raise important questions about the realities of diglossia in the French diaspora: wh interrogative variants are divided according to fundamental structural differences; some have wh movement (high, formal register) and others do not (vernacular and neutral register). Finally, this thesis also contributes to the theories of oralité (Gadet 1992), since it sheds light on a complex system of variants found exclusively in vernacular speech.

Keywords: Canadian French
Syntax
Historical Linguistics
Wh- Interrogatives
Variation
Diglossia
Advisor: Roberge, Yves
Training Recurrent Neural Networks

Recurrent Neural Networks (RNNs) are powerful sequence models that were believed to be difficult to train, and as a result they were rarely used in machine learning applications. This thesis presents methods that overcome the difficulty of training RNNs, and applications of RNNs to challenging problems. We first describe a new probabilistic sequence model that combines Restricted Boltzmann Machines and RNNs. The new model is more powerful than similar models while being less difficult to train. Next, we present a new variant of the Hessian-free (HF) optimizer and show that it can train RNNs on tasks that have extreme long-range temporal dependencies, which were previously considered to be impossibly hard. We then apply HF to character-level language modelling and get excellent results. We also apply HF to optimal control and obtain RNN control laws that can successfully operate under conditions of delayed feedback and unknown disturbances. Finally, we describe a random parameter initialization scheme that allows gradient descent with momentum to train RNNs on problems with long-term dependencies. This directly contradicts widespread beliefs about the inability of first-order methods to do so, and suggests that previous attempts at training RNNs failed partly due to flaws in the random initialization.

Keywords: Recurrent Neural Networks
Optimization
Advisor: Hinton, Geoffrey
The Value of Branding in Two-sided Platforms

This thesis studies the value of branding in the smartphone market. Measuring brand value with data available at product level potentially entails computational and econometric challenges due to data constraints. These issues motivate the three studies of the thesis. Chapter 2 studies the smartphone market to understand how operating system platform providers can grow one of the most important intangible assets, i.e., brand value, by leveraging the indirect network between two user groups in a two-sided platform. The main finding is that iPhone achieved the greatest brand value growth by opening its platform to the participation of third-party developers, thereby indirectly connecting the consumers and the developers via its app store effectively. Without the open app store, I find that iPhone would have lost its brand value by becoming a two-sided platform. Hence these findings provide an important lesson that open platform strategy is vital to the success of building platform brands. Chapter 3 solves a computational challenge in structural estimation of aggregate demand. I develop a computationally efficient MCMC algorithm for the GMM estimation framework developed by Berry, Levinsohn and Pakes (1995) and Gowrisankaran and Rysman (forthcoming). I combine the MCMC method with the classical approach by transforming the GMM into a Laplace type estimation framework, therefore avoiding the need to formulate a likelihood model. The proposed algorithm solves the two fixed point problems, i.e., the market share inversion and the dynamic programming, incrementally with MCMC iteration. Hence the proposed approach achieves computational efficiency without compromising the advantages of the conventional GMM approach. Chapter 4 reviews recently developed econometric methods to control for endogeneity bias when the random slope coefficient is correlated with treatment variables. I examine how standard instrumental variables and control function approaches can solve the slope endogeneity problem under two general frameworks commonly used in the literature.

Keywords: brand
two-sided platform
mcmc
laplace
demand estimation
slope endogeneity
random coefficient
dynamic
Advisor: Goldfarb, Avi
Essays on Money, Business Cycles and Household Formation

This dissertation consists of three independent essays in Macroeconomics. The ﬁrst essay studies whether efficiency can be improved by introducing government-issued illiquid bonds to an economy where money is the only asset and essential. In contrast with perfectly liquid bonds, illiquid bonds can increase societal welfare in two ways: First, allocating consumption goods among heterogeneous agents more efficiently; second, stimulating consumption and output level by loosening the liquidity constraints of households. More importantly, since societal welfare is elevated persistently when the inﬂation rates range from a level slightly above Friedman Rule to an upper bound, this essay provides an insight into the essentiality of illiquid bonds. The second essay provides a novel propagation mechanism of productivity shocks to explain an empirical fact: The response curve of output to a positive productivity shock reaches its peak up to eight quarters after the shock. Using a micro-founded monetary search model and focusing on agents’ decisions on establishing long-term trading relationships in the goods market, I show that when a positive shock takes place in the economy, marginal agents break down previous trading relationships and explore better matching opportunities. As a result, shortly after the shock, the average productivity level of transactions increases, but the total number of transactions decreases. The calibrated model shows that the latter effect dominates, resulting a slightly decrease of aggregate output after a positive productivity shock. The search friction, together with the monetary channel, gives rise to a delayed output response at the aggregate level. The third essay develops a general equilibrium theory of household formation – i.e., marriage – following Coase’s theory of ﬁrm formation. Individuals in the model consume both market-and home-produced commodities, and home production is facilitated through marriage. Market frictions, including taxation, search and bargaining problems, increase marriage rates when home and market goods are substitutes. In particular, inﬂation, as a tax on market activity, makes household production and hence marriage more attractive, as long as singles use cash more than married individuals, which is supported by data. The prediction that inﬂation and other taxes affect household formation is also supported by evidence.

Keywords: Illiquid Bonds
Societal Welfare
Search Model
Money
Delayed Output Response
Productivity Shocks
Marriage
Money
Markets
Households
Business Cycles
Advisor: Shi, Shouyong
Atomic Force Microscopic, Electron Spectroscopic Imaging and Molecular Simulation Investigations of the Assembly and Structures of Collagen Constructs

Collagen is one of the major protein constituents in mammals and is present in all tissues and organs with the exceptions of keratin tissues such as hair and nails. Collagen monomers self-aggregate into a number of structures. In order to understand the physical bases for the structural polymorphism observed in collagen, a good starting point is one of the simplest collagen aggregates, segmental long spacing (SLS) collagen. Although SLS collagen formation induced by the presence of adenosine 5’-triphosphate is widely known, effects of other triphosphates, on the other hand, are much less studied. By varying the pH, it is discovered that all the nucleoside 5’-triphophsates, as well as inorganic triphosphate, are able to induce SLS formation over certain pH ranges. Adenosine 5’-diphosphate and para-nitrophenylphosphate cannot induce SLS formation at any pH. Based on the pH ranges at which SLS collagen can be formed, it is concluded the triphosphate functionality, with one negative charge per phosphate group, is primarily responsible for the formation of SLS collagen. Since inorganic triphosphate is able to induce SLS collagen formation, the presence of the nucleoside is optional for the assembly process; however if present, the assembly process prefers the nucleosides carrying acidic protons. Using electron spectroscopic imaging (ESI) technique, it is found phosphorus, present only in nucleotides but not in polypeptides, is localized in certain regions of SLS collagen, forming a unique banding pattern transverse the long axis of the SLS collagen. Nitrogen mapping indicates the localization of phosphorus is not due to accumulation of materials. The phosphorus banding pattern demonstrates an excellent consistency across SLS collagen assembled from both bovine and recombinant human collagen monomers. Results from molecular simulation are consistent with the experimental results. All threephosphate groups seem to be involved in the assembly process to some degree. In the last chapter of the thesis, a reliable protocol to synthesis native type collagen fibers is introduced.

Keywords: collagen
Atomic Force Microscopy
Molecular Simulation
Electron Spectroscopic Imaging
segmental long spacing collagen
native collagen
Advisor: Goh, M. Cynthia
Organizing Cellular Heterogeneity in High-grade Serous Cancer

High-grade serous ovarian cancer (HG-SOC) is the most lethal gynecologic malignancy. Although most respond to initial therapy, the vast majority of patients eventually recur and die of their disease. Understanding intra-tumor cellular heterogeneity and inter-patient variability is necessary to effectively cure HG-SOC. The work described in this thesis should help to speed the progress of ovarian cancer research in several ways. First, I generated a robust xenograft model that recapitulates the cellular heterogeneity of HG-SOC. In addition, I performed gene expression profiling on a subset of xenografts and showed that they recapitulate the inter-patient diversity of this disease. Second, I applied this model to pre-clinical testing of a folate-targeted imaging agent and showed that it can identify metastatic studding by PET/CT and fluorescence imaging. Using my xenograft model, I investigated the properties of tumor-initiating cells (TIC) and demonstrated that TIC in HG-SOC are rare. Furthermore, although CD133 marks most TIC, heterogeneity in the phenotype is observed within individual tumors and between different patients. Finally, I used a transformative technology, CyTOF, to develop a novel pipeline for prioritization of candidate TIC markers, as well as for characterization of cellular heterogeneity in primary HG-SOC samples.

Keywords: Ovarian Cancer
Cancer Stem Cell
CyTOF
CD133
Advisor: Neel, Benjamin