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Testing and Characterization of Selective Trans-Acting Hammerhead Ribozymes that Cleave Two Disease-Causing Mutant Transcripts of the PABPN1 Gene
Get PDFRibozymes are RNA molecules with catalytic functions. These molecules can catalyze a self-cleaving reaction or bind to a target RNA molecule and cleave it. These properties make ribozymes perfect candidates for RNA therapeutics. Hammerhead ribozymes are a well-studied family of ribozymes and can be used to cleave specific mRNA molecules. These synthetically generated ribozymes can then regulate gene expression within cells. Normal PABPN1 protein has 10 alanine (GCG codon) repeats in its structure. Oculopharyngeal Muscular Dystrophy (OPMD), a hereditary disease with no cure, is caused by mutations that result in an increase in the number of GCG repeats in PABPN1 gene. The mutant proteins translated from genes that contain these repeat expansions are believed to be the disease-causing agents, hence targeting the expression of these proteins on the mRNA level is an attractive strategy using RNA therapeutics in OPMD treatment. To generate these RNA molecules, an evolutionary algorithm (Tri-Cleaver) was used to design ribozymes to be tested against two mutants of PABPN1 transcripts. Twenty-nine ribozymes that were designed using this algorithm were tested in human cells (HEK293) to investigate their effect on PABPN1 mutant transcripts with 13 and 17 alanine codon (GCG) repeats. These ribozymes were tested for 1) their efficiency to bind and cleave PABPN1 mRNA with 13 and 17 GCG repeats and 2) their selectivity for the mutant transcripts of PABPN1 gene. The results not only show the successful use of an evolutionary algorithm in designing trans-cleaving ribozymes that can selectively target repeat expansions, but also provide useful data to improve the algorithm’s later designs
Examining the molecular consequences of disrupted clock-gene expression in the mouse striatum
Get PDFMost organisms possess biological pacemakers that generate daily oscillations ranging from molecular processes to rhythms in physiology and behavior. In mammals, this system is composed of a master clock, located in the Suprachiasmatic Nucleus (SCN), and several peripheral clocks found in various tissues and brain regions. Previously, it has been identified that genome-wide or tissue-specific disruptions of circadian clock-genes such as Bmal1 are associated with mood disorders. Particularly in the striatum, a brain region that is vital in the motor and reward systems. Interestingly, the exact underlying molecular mechanisms are not well understood. In this study, gene expression of the receptors corresponding to GABAergic, Dopaminergic and Glutamatergic signalling in the dorsal striatum of adult Male and Female mice with a conditional knockout of Bmal1 (ie: KO – knockout vs. WT- Wild Type) were evaluated at two different time points (ZT2 and ZT14) in order to determine the effect of a clock manipulation on the expression of DRD2, MAOA, A2a, GABBR1, and GAD67. The gene expression of these candidate targets was studied to gain a deeper understanding of the mechanism through which Bmal1 is linked to mood disorders and elucidate a clearer role on the influence of clock-controlled genes with relation to GABAergic, Glutamatergic, and Dopaminergic receptors. Evidence has suggested that disrupted clock function dysregulates cell signalling which contributes to the development of behavioral phenotypes associated with mood disorders. However, the etiology remains unclear. Therefore, this experiment allowed us to further examine the underlying molecular pathways associated with behavioral phenotypes observed in striatal-dependent clock gene knockout mice. Results indicated no significant differences in gene expression were observed in the candidates following gene deletion. Interestingly, different mis-regulation trends were observed in the targets, suggesting Bmal1 may play a role in the dysregulation of the candidates selected
Ce que nous avons perdu/What We Have Lost: Conceptualisation d’une installation immersive sur la notion de la perte de mémoire individuelle à travers la matérialité du livre.
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Ce que nous avons perdu/What we have lost: Conceptualisation d’une installation immersive sur la notion de la perte de mémoire individuelle à travers la matérialité du livre.
Jeanne Garneau-Lévesque
Dans le contexte du vieillissement de la population et de l’augmentation de l’espérance de vie des aînées, les maladies neurodégénératives, telles que la maladie d’Alzheimer, sont de plus en plus diagnostiquées. La maladie d’Alzheimer s’attaque particulièrement à la mémoire et aux fonctions vitales de la personne. Une maladie redoutable et irréversible que les scientifiques connaissent encore très peu. Ces derniers en sont encore à étudier la progression de cette maladie et ignorent encore comment la guérir. Cela étant dit, la maladie d’Alzheimer souvent incomprise fait subir de graves préjudices aux personnes atteintes. À la lumière de cette problématique, cette
recherche-création pose la question suivante : comment conscientiser le public en général à cette maladie afin de susciter chez ceux-ci de l’empathie ? Les objectifs de la recherche sont de réaliser une expérience immersive sur les stades de la maladie d’Alzheimer. Concrètement, pour y parvenir,
la recherche a privilégié la métaphore du livre « détruit » évoquant la perte de la mémoire. De plus, c’est à l’aide d’un genre particulier, « l’installation vidéographique et sonore », qu’il a été permis de mettre en oeuvre et de concrétiser ce projet
Staying in Touch: Mothers’ and Infants’ Dyadic Touching Behaviours Across Time, Context, and Risk Status
Get PDFTouch is the basis of infants’ social, emotional, and cognitive development. Yet, it remains largely understudied in developmental research. A series of three studies were designed to expand our limited knowledge of parents’ and infants’ touching behaviours, including the synchrony of maternal-infant touch, across various types of parent-child interactions over time.
Study 1 utilized an extensive longitudinal design whereby healthy mother-infant dyads (N=12) were observed at 1-, 3-, 5-, 7-, and 9-months postpartum and within two normative interaction contexts (face-to-face; floor play). Study 2 implemented a longitudinal research design whereby typically developing newborns, mothers, and fathers (N=22) were observed immediately after birth and following the physiological stress of labor/delivery, and again 3- months later, following the social stress of maternal emotional unavailability via the Still-Face procedure (SF; Tronick et al., 1978). Study 3 used a cross-sectional research design examining mother-infant dyads (N=41) with high vs. low risk of maternal depressive symptomatology during instances of infant crying within the context of the SF and Separation (SP; Field et al., 1986) procedures at 4-months postpartum.
Overall, results revealed that touch is a pervasive and extensive communicative modality for both infants and parents, including those at-risk, within normative and perturbed contexts, starting from birth and across the first 9-months of life. Study 1 demonstrated that during typical/playful mother-infant interactions from 1- to 9-months postpartum, dyads initially displayed behavioural matching and later transitioned toward synchronous patterns entailing the parallel use of complementary types of touch. Study 2 revealed that mothers and infants displayed an inverse pattern of tactile synchrony (coordinated, converse changes in touch) from the immediate postpartum period to the reunion period of the SF procedure 3-months later. In Study 3, mothers and infants displayed a positive pattern of tactile synchrony (coordinated, analogous changes in touch) within the context of infant crying at 4-months postpartum. However, dyads in the high depression group displayed significantly less affectionate touch. Among other findings, results from all three studies underscored the soothing and regulatory functions of touch. Findings meaningfully contribute to our knowledge of early parent-infant dynamics and support a direction toward comprehensive examinations of touch across infancy
Control-oriented modelling and Model Predictive Control for air-based Building-Integrated Photovoltaic/Thermal systems
Get PDFThis thesis presents a methodology for the development of a grey-box control-oriented model for air-based open-loop Building Integrated Photovoltaic/Thermal (BIPV/T) systems with the scope to apply Model Predictive Control (MPC) to the air flow within the BIPV/T channel to achieve optimal BIPV/T – HVAC integration. The Varennes library, the first institutional net-zero energy building (NZEB) in Canada and one of a handful of buildings worldwide hosting a full-scale fully operational BIPV/T system, is used as an archetype for this work. The methodology presented can optimize the design of air-based BIPV/T systems or be applied to commissioned systems facilitating the broader realization of net-zero energy buildings.
BIPV/T systems combine the concept of BIPV and thermal collectors producing simultaneously electricity and heat by passing a fluid underneath their surface. The waste heat can be used for various thermal applications, however a key factor for broader BIPV/T realization is optimal control of these systems to maximize the amount of useful heat. As the available heat recovered from the BIPV/T is closely related to the respective weather conditions and the applied flow rate, optimally controlling the fan speed within the BIPV/T channel can significantly improve their performance.
Both a transient and steady-state model are developed and compared. The developed BIPV/T models are calibrated and validated using experimental and real weather data. The development of the MPC strategy for the commissioned BIPV/T system covering 1/6 of the south-facing roof at the Varennes library is presented. In one studied design variation of the existing archetype, the BIPV/T system is considered to simultaneously send heat to an Energy Recovery Ventilator (ERV) and an air-to-water heat pump (HP) while the opportunity to provide excess heat to adjacent buildings is explored, facilitating in the development of net-zero energy neighborhoods. Finally, the benefits of covering additional area of the Library’s south-facing roof with BIPV/T are examined to facilitate production of useful heat for other buildings in the community.
Through this work the essential parameters an engineer should have measurements for when applying MPC to a commissioned BIPV/T system are identified. This can prove extremely useful during the design stages as to where sensors should be placed and the relative importance of each measurement.
Through MPC, the fan speed is effectively adjusted simultaneously providing heat to the HP and ERV while adequately cooling the PV panels. The COP of the solar heated air-to-water heat pump showed a maximum increase of 32% for a mild sunny day. The BIPV/T that would cover the whole roof was able to produce up to 1.17 kWh/m2 (of roof area) of heat for a mild sunny day and provide 85.5% of this amount to adjacent buildings. Specifically, for a day-care center located near the library the consumed energy related to ventilation could be decreased by up to 36.8% with the heat provided from Library BIPV/T system
Investigating the Use of Transformer Based Embeddings for Multilingual Discourse Connective Identification
Get PDFIn this thesis, we report on our experiments toward multilingual discourse connective (or DC) identification and show how language-specific BERT models seem to be sufficient even with little task-specific training data and do not require any additional handcrafted features to achieve strong results. Although some languages are under-resourced and do not have large annotated discourse connective corpora. To address this, we developed a methodology to induce large synthetic discourse annotated corpora using a parallel word aligned corpus. We evaluated our models in 3 languages: English, Turkish, and Mandarin Chinese; and applied our induction methodology on English-Turkish and English-Chinese. All our models were evaluated in the context of the recent DISRPT 2021 Task 2 shared task. Results show that the F-measure achieved by our simple approach (93.12%, 94.42%, 87.47% for English, Turkish and Chinese) are near or at state-of-the-art for the 3 languages while being simple and not requiring any handcrafted features
Untangling Bilingualism: Using Code-Switching to Understand Bilingual Language Development
Get PDFSwitching between two languages, or code-switching, is common in bilingual communities. However, little is known about the code-switching young bilinguals hear in their daily lives and how they process it. This dissertation investigated these two aspects of code-switching and proposed new models for defining bilingualism.
Bilingualism is difficult to define and model. In Chapter 2, I proposed that bilingualism researchers can integrate psychometric models, such as the factor mixture model and the grade-of-membership model, which incorporate both categorical and continuous properties. Such models can unify traditional approaches of defining bilingual groups with newer views of bilingualism as a continuous variable. These models will allow researchers to address a variety of research questions, advance theory, and lead to a deeper understanding of bilingualism.
In Chapter 3, I analyzed French–English parents’ code-switching in day-long at-home audio recordings, provided when their infant was 10 and 18 months old. Code-switching was relatively infrequent: an average of 7 times per hour (6 times/1,000 words) at 10 months, increasing to 28 times per hour (18 times/1,000 words) at 18 months. Parents code-switched more between sentences than within a sentence, and this pattern became more pronounced when infants were 18 months. Parents appeared to code-switch most frequently to bolster their infant’s understanding and teach vocabulary, suggesting that code-switching may support successful bilingual language development.
In Chapter 4, I investigated how bilingual children process code-switching, examining how 3-year-old bilinguals process sentences with code-switches at an uninformative determiner-adjective pair before the target noun (e.g., “Can you see el buen [sp. the good] duck?) compared to single-language sentences (e.g., “Can you see the good duck?”). Children were unexpectedly accurate at identifying the target noun in both sentence types, contrasting with previous findings that code-switching leads to processing difficulties. Surprisingly, exploratory results suggested that code-switching may have boosted comprehension for certain children.
In sum, this dissertation has illustrated how code-switching may support bilinguals’ language development. I discovered that parents code-switch to support their child’s learning and showed that children do not always have difficulty processing code-switching. Bilingualism is a multi-faceted phenomenon, and nuanced research is needed to capture this variability
Hodge-Tate decomposition for p-adic abelian varieties with good reduction
Get PDFThe goal of this thesis project is to study the Cp-semilinear representation given by the p-Tate module of an abelian variety X over a local field K, following Fontaine’s paper “Formes différentielles et modules de Tate des variétés abéliennes sur les corps locaux”.
The main aim is to prove the Hodge-Tate decomposition for Tp(X)⊗Cp in terms of the Lie algebra of X and Xv. Thus, in the first chapter we compute the continuous cohomology groups of Cp(n) with respect to the absolute Galois group of K.
In the second chapter, Fontaine’s work analyse the module of Kähler differentials Ω of the extension using an integration of invariant differentials along elements of the Tate module of a Zp-module Γ.
Finally, in the third chapter we prove Tate-Raynaud theorem using the identification Vp(Ω) = Cp(1) and then we derive the Hodge-Tate decomposition
Vorticity-Based Polynomial Adaptation for Unsteady Flows
Get PDFAerospace applications, including but not limited to the aerodynamics of slats and flaps, the aeroacoustics of complete landing gear configurations, and the performance prediction of air brakes, spoilers, fans, and turbines, benefit from high-fidelity scale resolving approaches such as direct numerical simulation and large eddy simulation. These approaches are shown to be accurate in complex unsteady flow regimes where current industry-standard Reynolds-averaged Navier-Stokes methods often fail. For example, recent research has demonstrated that direct numerical simulation can be utilized for analysis of complete jet engine low-pressure turbine cascades at their designed operating condition. High-order unstructured spatial discretizations such as flux reconstruction are particularly appealing for large eddy simulation of unsteady turbulent flows as they are capable of resolving the flow more efficiently; however, their computational cost remains relatively high, preventing their industrial use. Therefore, given the inherent computational cost of high-order methods, it is crucial to deploy strategies to minimize the overall computational cost of large eddy simulation while attaining comparable accuracy. A practical approach is to limit the use of high-order elements to regions where higher resolution is required for an accurate discrete approximation of the solution, reducing the total number of degrees of freedom. This can be achieved by locally increasing or decreasing the solution polynomial degree to adjust resolution and order of accuracy to achieve an accurate and cost-efficient simulation, a practice called polynomial adaptation or p-adaptation. Large eddy simulation can also benefit from the computational power of state-of-the-art hardware architectures by taking advantage of parallel computing, which can achieve a significant speed-up by decomposing the domain and solving the problem concurrently. Parallel computing also provides a larger memory capacity and higher bandwidth, resulting in better performance. However, combining polynomial adaptation with a massively parallel computation can cause overhead because p-adaptation tends to change the degree of solution polynomials locally, leaving the computational domain unbalanced. To maintain parallel efficiency, dynamic load balancing techniques have been exploited. The current work introduces a novel dynamically load-balanced polynomial adaptation method for simulations of unsteady flows in the vicinity of complex geometries using the flux reconstruction scheme. This approach is applied to both two-dimensional and three-dimensional studies, while for the latter, we make use of implicit large eddy simulation, which relies on the dissipation error of the numerical scheme to act as a subgrid-scale model to dissipate the kinetic energy from the smallest turbulent scales in the flow.
We verify the utility of our dynamically load-balanced adaptation approach when applied to the arbitrary Lagrangian-Eulerian form of the compressible Navier–Stokes equations for a range of applications on moving and deforming domains. Specifically, we verify the arbitrary Lagrangian-Eulerian and dynamic load balancing implementation by performing simulations of an Euler vortex, and then illustrate the accuracy and efficiency of the adaptation routine by performing simulations of flow over an oscillating circular cylinder with two different flow settings, dynamic stall of a 2D NACA 0012 airfoil undergoing heaving and pitching motions, and flow over a vertical axis wind turbine composed of two NACA 0012 airfoils. We further illustrate the accuracy and efficiency of the routine when applied to transitional and turbulent flows by performing simulations of a shallow dynamic stall of a 3D SD 7003 airfoil undergoing heaving and pitching motions and transitional flow over a 3D circular cylinder. Results demonstrate that the dynamically load-balanced adaptation algorithm can track regions of interest, such as vortices and boundary layers, and yields a significant speed-up when applied to parallel simulations. We also demonstrate the scalability of the algorithm and the capability of dynamic load balancing technique to distribute uniform computational load among processors
Design and Implementation of Integrated Smart Home Energy Management Systems for Clusters of Buildings
Get PDFTo ensure the balance between power generation and demand at the peak hours, power utilities need to keep additional power generation capacity on standby which usually causes higher operational cost. This will result in variations in hourly to seasonal electricity prices. With a focus on the physical layer integration, we developed a methodology which includes a prototype of a cluster of smart homes with energy management systems (SHEMS) to study and harvest the flexibility in the demand side in the residential building sector by monitoring and controlling the loads at appliances level. For this goal, we developed and fabricated the electronic circuit of five custom-designed smart plugs (DC, MQTT based) and integrated a vendor-based smart plug (AC) to the system. The devices were equally allocated to three home hubs. As opposed to a standalone SHEMS, this methodology is applied at a cluster scale: through awareness of the electricity consumption of all houses, under certain assumptions optimized load patterns can be generated not only to decrease consumers’ electricity bills, but also to meet the grid’s constraints. We crafted 3 scenarios as showcases of the methodology performance, with two electricity price plans and different load configurations. The results show both smart plug types were successful in measuring the loads and communication with other layers resulting in decreased electricity cost. Additionally, using a hybrid cloud-fog based architecture, a function was designed for saving the smart plugs records during cloud service or internet disconnection to enable later synchronization of the local and cloud database