VictorJuiz/thesis huggingface dataset:
Palladium-catalyzed Methods for Stereoselective Synthesis of 3-(Chloromethylene)Oxindoles using o-Alkynyl Aryl Carbamoyl Chlorides

3-(Chloromethylene)oxindoles are a class of valuable molecules with prominent biological and chemical significance. In light of this, we attempted to develop novel and efficient methods for the synthesis of this scaffold using palladium catalysis. Herein, we report a palladium(0)-catalyzed intramolecular chlorocarbamoylation of alkynes, a highly stereoselective method for the synthesis of (Z)-3-(chloromethylene)oxindoles. This chlorocarbamoylation reaction utilizes carbohalogenation-reactivity to form two new bonds – carbon–carbon and carbon–halogen – in an atom-economical fashion. This novel reactivity is uniquely promoted by the relatively underexplored phosphaadamantane ligands. We also report the complementary method of synthesizing (E)-3-(chloromethylene)oxindole via a palladium(II)-catalyzed cycloisomerization of o-alkynyl aryl carbamoyl chlorides. The combination of these two methods provides convenient access to both geometric isomers of the 3-(chloromethylene)oxindole scaffold.

Keywords: carbohalogenation
domino catalysis
methylene oxindole
palladium catalysis
phosphaadamantane ligands
Advisor: Lautens, Mark
Probing the Role of Astrocytes in Postanesthetic Memory Deficits

Many patients who undergo surgery and general anesthesia suffer from memory impairments for weeks to months afterwards. However, the mechanisms underlying this phenomenon remain poorly understood. We previously showed that postanesthetic memory deficits are associated with a sustained increase in tonic inhibitory conductance in hippocampal neurons. Interestingly, astrocytes offer a new target for studying this disorder due to their interconnectedness with GABAergic signaling and tonic inhibition. Specifically, astrocytes express GABAA receptors, the primary target of anesthetics, as well as secrete numerous soluble factors that regulate memory. This thesis explores the underpinnings of anesthetic-induced enhancement of tonic inhibition in hippocampal neurons with a cell culture model. The results show that activation of astrocytic GABAA receptors is necessary and sufficient to trigger an increase in tonic current, and that the interleukin-1 receptor and p38 MAP kinase subsequently participate in up-regulating GABAA receptor function in neurons. These results bring us closer to understanding, treating and preventing postanesthetic memory deficits.

Keywords: Astrocytes
Electrophysiology
Etomidate
GABA
Hippocampus
Tonic Inhibition
Advisor: Orser, Beverley A
Glucagon Action in the Dorsal Vagal Complex and the Regulation of Glucose Homeostasis during High-protein Feeding

High-protein feeding acutely lowers plasma glucose compared to low-protein feeding, despite a seemingly dichotomous stimulation of circulating glucagon concentration. The physiological function of this postprandial glucagon rise has been largely overlooked. Notably, glucagon has recently been discovered to trigger a negative-feedback system in the brain to reduce glucose production. Here, we tested the hypothesis that glucagon signals in the dorsal vagal complex (DVC) to mediate the glucose-lowering effect of high-protein feeding. First, we found that intra-DVC administration of glucagon suppresses glucose production in vivo. Second, we identified a Gcgr–PKA–Erk1/2–KATP channel signalling mechanism of DVC glucagon action. Third, we demonstrated that disruption of Gcgr signalling in the DVC blunts the ability of high-protein feeding to acutely lower plasma glucose levels compared to low-protein feeding. Collectively, these data revise the traditional view of how high-protein feeding regulates glucose homeostasis and introduce a physiological role of postprandial brain glucagon action.

Keywords: Dorsal Vagal Complex
Glucagon
Glucose Homeostasis
High-protein Feeding
Advisor: Lam, Tony K T
Therapeutically Targeting the Cystic Fibrosis Transmembrane Conductance Regulator in Cerebrovascular Dysfunction associated with Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is a devastating type of stroke consisting of an initial intracranial bleed followed by delayed cerebral ischemia (DCI). Current therapeutic strategies are problematic; primarily aim to reduce the pathologically enhanced cerebrovascular constriction by disrupting cerebral autoregulation. We have identified an inflammatory mechanism that pathologically augments myogenic vasoconstriction: at its core, tumor necrosis factor α (TNFα) downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), thereby augmenting pro-constrictive sphingosine-1-phosphate (S1P) signaling. Knocking-out CFTR in cerebral olfactory arteries and reducing its activity with CFTR(inh)-172 augments myogenic tone. In SAH, correcting CFTR expression with C-18, a CFTR trafficking corrector compound, normalizes tone in addition to reversing neuronal injury at 48 hours and rectifying neurobehavioral function at 24 hours post-surgery. We conclude that CFTR correctors, like C-18, can be used to reduce the clinical impact of SAH-induced cerebral ischemia.

Keywords: Ischemia
Myogenic response
Neuronal injury
Resistance arteries
Sphingosine-1-phosphate
Vascular smooth muscle
Advisor: Bolz, Steffen-Sebastian
Sensitivity and Stability Analysis for Inverse Optimization with Applications in Intensity-modulated Radiation Therapy

Inverse optimization aims to use observed data to understand the dynamics of a system by estimating the parameters of the underlying optimization problem. In this dissertation, we first develop an inverse model and investigate its properties for the cases where single and multiple observed data points are available. Next, we study the sensitivity and stability of the inverse model with respect to changes in the model parameters and perturbations in data. In particular, we illustrate the sensitivity of the inverse model with respect to the type of penalty functions used in the objective. Furthermore, we show that perturbations in the observed data can dramatically alter the outcome of the inverse model. We subsequently generalize our model to improve its stability with respect to perturbations in the input. Finally, we perform extensive simulations on synthetic and Intensity-Modulated Radiation Therapy (IMRT) data to validate the effectiveness of the generalized inverse model.

Keywords: IMRT
Inverse optimization
Sensitivity
Stability
Advisor: Chan, Timothy C.Y.
Glycosyl Methanesulfonates in Regio- and Stereoselective Glycosylations Catalyzed by Borinic Acids

Stoichiometric and catalytic activation of unprotected glycosyl acceptors toward reaction with glycosyl donors represent a growing breadth of methodologies recently developed with the goal of simplifying the synthesis of important carbohydrate targets. Most of these methods rely on glycosyl halides, a class of donor which has been essentially deprecated in recent literature by the advent of more convenient and versatile species. This report describes the development and use of glycosyl methanesulfonates in borinic acid-catalyzed glycosylations of partially protected acceptors. Good to high yields and selectivities for 1,2-trans-linked disaccharides are obtained without the need for a participating group. Studies of glycosylations with variously protected and configured donors and acceptors suggest wide applicability of the method to the preparation of important classes of linkages and protecting group patterns. Finally, mechanistic insights from NMR observation of the intermediate methanesulfonates are reported and discussed to develop a rationale for the observed catalyst-controlled stereoselectivity.

Keywords: Borinic Acid
Carbohydrate
Glycosylation
Regioselective
Stereoselective
Sulfonate
Advisor: Taylor, Mark S
How does Genetic Burden Determine Disease Onset of Systemic Lupus Erythematosus?

Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disease product of the interaction between genetic and environmental factors. Although patients with pediatric-onset SLE (pSLE) and adult-onset SLE (aSLE) differ in disease presentation, activity and outcomes, all studies to date have not found any set of genes specific to pSLE as compared to aSLE. However, some studies found that early-onset SLE patients exhibited higher polygenetic risk scores. The present study included a large, multi-ethnic pSLE and aSLE cohort to identify how non-HLA and HLA genetic risk scores are associated with age of SLE onset. Samples were genotyped using Immunochip, scores were calculated based on validated SLE SNPs, analyzed in the total population and in each ancestry separately. We found that HLA and non-HLA alleles had different associations with SLE onset; the higher the non-HLA score the younger the patient, whereas the higher the HLA scores the older the SLE patient.

Keywords: age of onset
genetic
lupus
risk
scores
SLE
Advisor: Silverman, Earl D
Recovery of Skeletal Muscle Microvascular Myogenic Reactivity After Smooth Muscle Cell-TNF Knockout

Resistance arteries possess an intrinsic ability, termed the myogenic response, which enables them to adapt to changes in blood pressure, allowing for the regulation of total peripheral resistance and thus blood flow. Tumor necrosis factor (TNF) is a master regulator of the myogenic response, as pharmacological inhibition and inducible smooth muscle cell-knockout of TNF specifically abrogated the myogenic response and accordingly lowers blood pressure. Surprisingly, the attenuated myogenic responsiveness following smooth muscle cell TNF knockout completely recovered within 7 days, independent of enhanced transcription of TNF and its receptors. Interestingly, the recovered myogenic response still depended completely on TNF signaling. Furthermore, the recovered myogenic response was much stronger at physiological pressures. This was associated with a significantly higher reliance on Ca2+-independent myogenic signaling. These findings advance the idea of a redundantly organized myogenic response that is required for the essential maintenance of hemodynamic homeostasis.

Keywords: Ca2+ sensitivity
compensation
resistance artery
sphingosine-1-phosphate
tumor necrosis factor
vascular smooth muscle
Advisor: Bolz, Steffen-Sebastian
Dental Sedation and General Anaesthesia in Manitoba: A Survey of Need, Demand, and Perceptions

Background: Dental anxiety is a major reason why patients seek sedation/general anaesthesia (SGA) for dental treatment. Objective: To investigate patients’ reported and perceived dental anxiety and provision of SGA services in Manitoba dental practices. Methods: A paper-based survey was distributed to Manitoba dentists registered to provide intravenous sedation and a sample of their patients. Results: 21 dentists (53% response) and 505 patients participated. Dentists overestimated patients’ dental anxiety (Dental Fear/Avoidance Scale, p = 0.01; Index Dental Anxiety/Fear, p = 0.02), and underestimated patient interest for SGA. Patients also reported a preference for SGA services (ie., 2.5-fold demand for restorations) more often than they received SGA services (ie., 11.1-fold increase for implant surgery.) Conclusion: Dentists overestimate their patients’ anxiety levels but underestimate their interest in SGA services. Use of validated dental anxiety scales would aid in more accurate assessment of patient anxiety, and better alignment with patients SGA needs and demands.

Keywords: Anxiety
Avoidance
Conscious sedation
General anaesthesia
Manitoba
Sedation
Advisor: Dempster, Laura
Perinuclear Tethers License Telomeric DSBs for a Broad Kinesin- and NPC-dependent DNA Repair Process

DNA double-strand breaks (DSBs) are often targeted to nuclear pore complexes (NPCs) for repair. We show that the Kinesin-14 motor protein complex (Cik1-Kar3) cooperates with chromatin remodellers to mediate interactions between subtelomeric DSBs and the Nup84 nuclear pore complex to ensure cell survival via break-induced replication (BIR), an error prone DNA repair process. Insertion of a DNA zip code near the subtelomeric DSB site artificially targets it to NPCs hyperactivating this repair mechanism. Repair of non-telomeric DSBs by BIR depend on Kinesin-14 and Nup84, but not perinuclear telomere tethers. However, we show that Kinesin-14 in general and more specifically its catalytic activity is needed for the targeting and release of DSBs to and from Nup84, respectively. Thus, we uncover roles for kinesin and NPCs in DNA repair by BIR and reveal that perinuclear telomere anchors license subtelomeric DSBs for this error-prone DNA repair mechanism.

Advisor: Mekhail, Karim
The Effects of Multiple Mutualisms in the Tropical Perennial Plant, Turnera

Many species interact with multiple mutualists, yet most studies investigate mutualisms as pairwise interactions between partners, potentially obscuring the benefits of multiple mutualists that interact synergistically or the costs of multiple mutualists that conflict. To examine costs of associating with multiple mutualists, I manipulated floral and extrafloral nectar (EFN) production and found that the two nectars trade off. This trade-off negatively affected ant defense and pollination mutualisms in the field. I then tested if EFN plays a role in seed removal, in addition to defense. Plants with active extrafloral nectaries had increased seed removal, demonstrating a novel role of EFN and an example of ecological pleiotropy. To explore how focal species avoid negative interactions between partners, I measured ant preference for EFN versus floral nectar using baits and a CAFE assay. Ants consumed similar volumes, but recruited more to EFN, suggesting that the rewards are tailored to the specific mutualist.

Keywords: ant-plant interactions
extrafloral nectar
floral nectar
myrmecochory
pollination
trade-off
Advisor: Frederickson, Megan E
The Fibroblast Specific α11β1 Integrin is Important for Postnatal Cardiomyocyte Growth, Alignment and Function

Integrins are transmembrane adhesion and signaling receptors that interact with the extracellular matrix to mediate diverse cellular and developmental processes. Recent work has demonstrated cardiac fibroblasts mediate cardiomyocyte development through integrins. However, the predominant integrins involved and the role of integrins in cardiac development is poorly defined. Thus, we investigated the contribution of the α11β1 integrin (α11), which is expressed by fibroblasts and binds preferentially to type I collagen fibers, in mediating postnatal cardiomyocyte development and function. Utilizing a germline mutation of the α11 gene in mice, we found that deletion resulted in growth and structural abnormalities in cardiomyocyte development and reductions in myocardial collagen, which was associated with impairments in both active and passive diastolic function. These results suggest that the α11 integrin is a key component of the cardiac fibroblast that is required for the normal development of cardiomyocytes and maintenance of cardiac function.

Keywords: Cardiac Development
Extracellular Matrix
Heart Structure and Function
Integrins
Advisor: Connelly, Kim A
Impact of Time of Day Feeding, High Fat Diet, and Exercise on Adult Hippocampal Neurogenesis in Rats

Experiences like education and exercise buffer against age-related cognitive decline; however, the neurological underpinnings of this process are unknown. Adult neurogenesis in the hippocampus, a structure central to learning and memory, is believed to play a role as neurogenesis affects cognition and is a plastic phenomenon capable of being modified by experiences throughout life. Critically, recent evidence shows that early life experiences in rodents cause persistent changes in neurogenesis lasting into old age. Therefore, this thesis explored the effects of experiences including diet and exercise on neurogenesis within the context of a neurogenic reserve (the sustained production of neurons throughout life). Rats on high fat diets had impaired neuronal differentiation, suggestive of a shift towards non-neuronal cell fates. Additionally, extensive early life exercise did not affect neurogenesis in later life nor did it elicit any synergistic effects on running-induced neurogenesis in later life, suggestive of neurogenic homeostatic mechanisms at work.

Advisor: Wojtowicz, Martin
Quadrotor Control in the Presence of Unknown Mass Properties

Quadrotor UAVs are popular due to their mechanical simplicity, as well as their capability to hover and vertically take-off and land. As applications diversify, quadrotors are increasingly required to operate under unknown mass properties, for example as a multirole sensor platform or for package delivery operations. The work presented here consists of the derivation of a generalized quadrotor dynamic model without the typical simplifying assumptions on the first and second moments of mass. The maximum payload capacity of a quadrotor in hover, and the observability of the unknown mass properties are discussed. A brief introduction of L1 adaptive control is provided, and three different L1 adaptive controllers were designed for the Parrot AR.Drone quadrotor. Their tracking and disturbance rejection performance was compared to the baseline nonlinear controller in experiments. Finally, the results of the combination of L1 adaptive control with iterative learning control are presented, showing high performance trajectory tracking under uncertainty.

Keywords: Control Systems
L1 Adaptive Control
Quadrotor Dynamics
Advisor: Schoellig, Angela P
Investigating the use of Reliability-calibrated Partial Factors in Tunnel Design

Variability is prevalent in rock engineering conditions. This renders commonly used deterministic design approaches with empirical factors of safety unsuitable for objectively quantifying safety. Instead, probabilistic reliability based design (RBD) can objectively do so with probabilities of failure. However, due to the unfamiliarity of RBD to practicing engineers, 'partial factors' are calibrated which allow deterministic analyses to achieve designs of predefined probabilities of failure. This dissertation investigates the application of calibrated partial factors in tunnel liner design, and its possible inclusion in a coherent design code format. The dissertation concludes that partial factors calibrated from RBD can be applied in design of tunnel liners. However, due to the lack of data collected in rock engineering, development of a design code cannot be currently undertaken. In addition, it is only realistically feasible for simple tunnel construction and support sequences, suggesting that the application of RBD is best done on case-by-case basis.

Keywords: Limit state design
Probabilistic design
Reliability based design
Tunnel design
Advisor: Harrison, John P.
Identification and Characterization of Novel Anti-phage Compounds using a High Throughput Approach

Bacteriophages play important roles in human health. They encode and spread diverse virulence factors, and have been implicated in regulating microbiome symbiosis. In this thesis, I performed a growth curve-based high throughput screen and identified eleven novel anti-phage compounds that prevent 位 phage-mediated bacterial cell lysis. Six lead compounds were further investigated to elucidate their inhibitory activities against a diverse collection of phages. I found that these compounds showed different phage inhibition profiles, suggesting diverse inhibitory mechanisms. Furthermore, I examined compound effects on individual steps of the 位 infection cycle. I found that Ro 90-7501 inactivates phage particles, dequalinium chloride prevents genome injection, and mitoxantrone blocks an early step of the infection cycle. The phage inhibitors identified here represent powerful new tools for fundamental phage research. Additionally, they can

Advisor: Davidson, Alan R
Excitation of Molecular Systems by Incoherent Light

The excitation of molecular systems by incoherent light is studied primarily using a V-system model in the Partial Secular Bloch-Redfield formalism. First, the dynamical regimes are characterized for a system irradiated by suddenly turned on light and the relevant timescales are defined in terms of system parameters. Then excitation by slowly turned-on light is studied, showing a decay in the magnitude of noise-induced coherences with increasing turn-on times, leading to their disapearance in the very slow turn-on limit relevant to many natural systems.

Keywords: Coherences
Incoherent Light
Open Quantum Systems
Photosynthesis
Quantum Dynamics
Advisor: Brumer, Paul
Shift of Argument Subalgebras and Gelfand-Tsetlin Bases

There is a famous construction of a maximal commutative subalebgra in U(gln) called the Gelfand-Tsetlin algebra, with the special property that its eigenvectors are precisely the Gelfand-Tsetlin basis for gln and each eigenspace has dimension 1. We aim to find a replacement for the Gelfand-Tsetlin subalgebra in types B, C, and D by using shift of argument subalgebras, which are a family of commutative subalgebras in U(g) parametrized by elements of h. We compute generators of shift of argument subalgebras in the cases of so4 and sp4, and in the case of sp4 we also check these generators against the Gelfand-Tsetlin basis of sp4.

Keywords: Gelfand-Tsetlin
Advisor: Kamnitzer, Joel
Reward Processing following Mindfulness-based Cognitive Therapy and Cognitive-behavioral Therapy for Wellbeing

The aim of this study was to examine: (a) treatment-related changes in the reward system following two interventions designed to prevent the recurrence of depression, Mindfulness-Based Cognitive Therapy (MBCT) and Cognitive Behavioral Therapy with Wellbeing focus (CBT-WB); (b) changes following treatment that relate to relapse status at a two-year follow-up. Previously depressed patients were randomly assigned to 8-week MBCT (N=43) or CBT-WB (N=34) and scanned using fMRI while completing a card gambling task before and after treatment. Whole-brain analyses found that an increased neural sensitivity in the reward system following treatment to winning trials (outcome phase) and reduced sensitivity to the anticipation of a win were associated with relapse status. Differences between interventions were found for the anticipatory phases of winning. Overall, these findings suggest that maintenance interventions may derive their therapeutic effects from preserving baseline responses, rather than heightening reward sensitivity to outcome.

Keywords: Cognitive behavioral therapy
Mindfulness
Mindfulness based cognitive therapy
Neuroimaging
Reward
Wellbeing
Advisor: Segal, Zindel
Farb, Norman
Evaluating the Relationship between Ceramides and Depressive Symptoms in Coronary Artery Disease Patients

Depression is highly prevalent in individuals with coronary artery disease (CAD), and increases risk of mortality. Ceramides, a family of sphingolipid species, have been implicated in the pathophysiology of both CAD and depression due to their pro-inflammatory and pro-apoptotic characteristics. This study assessed the relationship between ceramides and depression in a CAD population. Linear regression models were used to assess the association between plasma ceramide concentrations and depressive symptoms, as measured by the Center for Epidemiological Studies Depression Scale (CESD). High performance liquid chromatography coupled electrospray ionization tandem mass spectrometry was used to measure ceramide species. Higher plasma concentrations of the ceramide species C16:0 (β=0.195, p=0.039) and C22:1 (β=0.199, p=0.039) were significantly associated with greater depressive symptoms. Plasma concentrations of C18:0 (β =0.108, p=0.257) and C20:0 (β=0.167, p=0.078) were not significantly associated with depressive symptoms. Findings suggest a potential role of specific ceramides in the pathophysiology of depression in CAD.

Keywords: Ceramides
Coronary Artery Disease
Depression
Depressive Symptoms
Sphingolipids
Advisor: Lanct么t, Krista L