VictorJuiz/thesis huggingface dataset:
Synthesis of Caseinolytic Protease Agonists Towards the Synthesis of the Natural Acyldepsipeptides
Keywords: Chemistry
Medicinal chemistry
ClpP
depsipeptide
antibiotic
caseinolytic protease
ACP
Activators of Self-Compartmentalizing Proteases

Caseinolytic protease (ClpP) is a cylindrical protease forming the core of protein degradation machinery in eubacteria. ClpP is tightly regulated and is non-functional without a member of the Clp-ATPases. A new class of antibiotics, termed ADEPs, bind to ClpP and allow for activation without the Clp-ATPases; leading to cell death. A more efficient synthetic route to the ADEPs utilizing solid-phase peptide synthesis was investigated. A linear peptide was synthesized, however attempts to close the depsipeptidic macrocycle via macrolactonization failed. Further attempts of assembling a branched depsipeptide for ring closure via a macrolactamization resulted in products that were not stable to cleavage conditions. A group of molecules termed Activators of Self-Compartmentalizing Proteases (ACP) were identified through a screen for activity towards ClpP. Compound ACP1 was synthesized along with twelve analogs and their activity towards ClpP evaluated. The project resulted in a compound with a higher activity than its natural product counterpart.
New Synthetic Strategies, Spectral and Molecular Recognition Studies on Verdazyl-Derived [n]-Paracyclophanes
Keywords: Verdazyl
Cyclophane

Verdazyl radicals are a unique class of stable radicals that have found uses as reporter molecules in biological systems, substrates for molecular-based magnets and mediators in living radical polymerizations. Over the past few years, our laboratory has pioneered the use of verdazyl radicals as substrates in 1,3-dipolar cycloaddition reactions to provide unique small molecule five-membered ring systems containing structural features commonly found in therapeutic agents. As an extension to this work we became interested in seeing whether this chemistry could be applied to the synthesis of macrocyclic scaffolds, in particular cyclophanes. Cyclophanes have been attractive synthetic targets for organic chemists because of their unique structural properties, conformational behaviours and molecular recognition capabilities. Presented in this thesis is the successful demonstration of the extension of the verdazyl chemistry to novel [n]-paracyclophanes. The structural features and conformational biases of these molecules as evidenced by 1H-NMR and X-ray crystallography are highlighted along with molecular recognition studies.
Leaf Area Index, Carbon Cycling Dynamics and Ecosystem Resilience in Mountain Pine Beetle Affected Areas of British Columbia from 1999 to 2008
Keywords: Insect disturbance
Boreal Ecosystem Productivity Simulator
Biophysical parameter mapping
Spatially explicit, process-oriented ecosystem modelling
TRAC
LAI-2000

The affect on leaf area index (LAI) and net ecosystem production (NEP) of the mountain pine beetle (Dendroctonus ponderosae) (MPB) outbreak in British Columbia affecting lodgepole pine (Pinus contorta var. latifolia) forests was examined from 1999 to 2008. The process-based carbon (C) cycle model – Boreal Ecosystem Productivity Simulator (BEPS) with remotely sensed LAI inputs was used to produce annual NEP maps, which were validated using field measurements. The annual NEP ranged from 2.43 to -8.03 MtC between 1999 and 2008, with sink to source conversion in 2000. The inter-annual variability for both LAI and NEP displayed initial decreases followed by a steadily increasing trend from 2006 to 2008 with NEP returning to near C neutrality in 2008 (-1.84 MtC). The resistance of LAI and NEP to MPB attack was attributed to ecosystem resilience in the form of secondary overstory growth and increased production of non-attacked host trees.
Regulation of Cell Polarity by Septin 7
Keywords: septins
cell polarity

Septins are a group of filament forming proteins that act as scaffolds and diffusion barriers that regulate various cellular functions, such as cytokinesis. Recently, evidence was obtained in our laboratory that septins may also regulate mammalian cell polarity through their interaction with Par3, an important metazoan polarity regulator. In this thesis I sought to examine whether septins regulated the polarization of migrating cells through their interaction with Par3 as well as how this interaction occurred. I demonstrated that the C terminus of Sept7 was capable of binding to Par3 in vitro. Sept7 was also able to colocalize with Par3, but an interaction between the two proteins could not be detected by immunoprecipitation. Migration assays used to examine the significance of Sept7 in polarization showed a small decrease in polarization after Sept7 depletion. This suggests that septins may play a non-essential role in regulating the polarization of migrating cells.
System-level Structural Reliability of Bridges
Keywords: Bridge engineering
Robustness
Reliability analysis
Redundancy
Two-girder and two-web bridges

The purpose of this thesis is to demonstrate that two-girder or two-web structural systems can be employed to design efficient bridges with an adequate level of redundancy. The issue of redundancy in two-girder bridges is a constraint for the bridge designers in North America who want to take advantage of efficiency in this type of structural system. Therefore, behavior of two-girder or two-web structural systems after failure of one main load-carrying component is evaluated to validate their safety. A procedure is developed to perform system-level reliability analysis of bridges. This procedure is applied to two bridge concepts, a twin steel girder with composite deck slab and a concrete double-T girder with unbonded external tendons. The results show that twin steel girder bridges can be designed to fulfill the requirements of a redundant structure and the double-T girder with external unbonded tendons can be employed to develop a robust structural system.
Iroquois Homeobox 3 is an Essential Transcription Factor in the Maintenance of Proper Electrical Propagation and Development of the Ventricular Conduction System
Keywords: ventricular conduction system
transcription factor
development
gap junction

The specialized myocytes of the ventricular conduction system (VCS) coordinate ventricular contraction and are critical for efficient pumping by the heart. Impaired VCS conduction is characteristic of inherited forms of cardiac conduction disorders. Here we show that the Iroquois homeobox 3 (Irx3) transcription factor is preferentially expressed in the developing and mature VCS. Loss of Irx3 in mice results in slowed VCS conduction and prolonged QRS duration with right bundle branch block, caused by reduction (42%) in VCS-specific connexin 40 (Cx40) expression and VCS fiber hypoplasia, absent in littermate controls. Therefore, we show that the role of Irx3 in the heart is two-fold, whereby Irx3 (1) indirectly regulates Cx40 gene expression, by repressing a repressor of Cx40 transcript, and (2) controls VCS maturation, possibly in an Nkx2-5-dependent manner. To our knowledge, this is the first report of a role for Irx3 in regulating the development and function of the VCS.
SLIT/ROBO Signaling in Monocyte Chemotaxis and Function: A Role in Vascular Inflammation
Keywords: slit2
monocyte

Vascular inflammation and associated leukocyte influx is a hallmark in the pathogenesis of atherosclerosis. In both animal models and human subjects, inhibiting monocyte recruitment is beneficial in preventing atherosclerosis and its clinical manifestations. The trafficking signals that recruit cells to areas of inflammation are provided by small secreted proteins called chemokines. Chemokines play a major role in the pathogenesis of inflammation, and redundancy among the chemokine signaling pathways means that blocking one pathway could result in another assuming its function. Therefore, we aim to block a cell’s response to a range of chemokine-induced directional migration signals. Slit2 treatment inhibits monocyte migration in vitro using transwell migration assays, and in vivo, using a murine peritonitis model of inflammatory cell influx. This inhibition is shown to be dose- and time- dependent. Furthermore, Slit2 inhibits monocyte adhesion to activated endothelial cell monolayers. These data may suggest a therapeutic role for Slit2 in atherosclerosis.
White Matter Damage and Inflammation in Rat Models of Ischemic and Hemorrhagic Stroke
Keywords: Stroke
Inflammation
White matter

Cerebral ischemia and intracerebral hemorrhage (ICH) are both characterized by a prolonged inflammatory response and secondary injury phase, yet the spatial/temporal relationships between inflammation and white matter (WM) damage were largely unknown. Thus, I quantified the development of WM damage and inflammation over 7 days after ischemia, and 14 days after ICH. Following ischemia, myelin and axons were progressively damaged, and myelin damage coincided with neutrophil infiltration. Activated microglia/macrophages increased dramatically in the lesion core and edge, and selectively infiltrated damaged WM tracts while surrounding undamaged ones. To investigate the involvement of neutrophils in WM damage and inflammation after ICH, rats were rendered neutropenic before performing ICH. Neutrophil depletion reduced peri-hematomal axonal damage, BBB breakdown, and MMP-9 production at early times, and lessened microglia/macrophage and astrocyte responses at later times. Activated microglia/macrophages infiltrated peri-hematomal WM tracts, correlating with myelin fragmentation and axonal loss, and this was reduced with neutrophil depletion.
Folate Absorption across the Colon: Caplet Study
Keywords: folate
caplet
colon

The purpose of this study was to determine the absorption of [13C]5-formyltetrahydrofolic acid across the human colon with an intact microflora. Bioavailability was determined after administration of a pH-dependent acrylic co-polymer coated barium sulphate caplet containing 855 nmol and measuring the plasma appearance of [13C5]5-methyltetrahydrofolic acid compared to an intravenous injection of the same compound (214 nmol). Blood samples serially collected after both test doses were analyzed by microbiological assay and tandem mass spectrometry to determine total folates and ratio of labeled to unlabeled folates, respectively. Caplet disintegration in the colon was quantitatively assessed by fluoroscopic imaging for six of nine subjects. The plasma [13C5]5-methyltetrahydrofolic acid appearance rate was 4 + 0.9 nmol/h (intravenous) and 0.35 + 0.02 nmol/h (caplet). Mean apparent absorption across the colon was 35%. These findings suggest that physiological doses of natural folate are absorbed across the human colon in the presence of an undisturbed microbiota.
Phospho-proteomic Analysis of Neuroblastoma Tumor Initiating Cell Signaling Pathways: Identification of Src Family and B Cell Receptor Signaling as Novel Drug Targets
Keywords: Neuroblastoma
Phospho-proteomics

Neuroblastoma (NB) is the most common extra-cranial solid tumor in children. Recently discovered neuroblastoma tumor-initiating cells (NB-TICs) have many properties of cancer stem cells and form tumors with as few as 10 cells. To elucidate the signaling pathways driving NB- TIC survival and proliferation, we surveyed the phospho-tyrosine containing subset of the NB- TIC proteome. Over 300 phosphorylated proteins were identified, including 21 tyrosine kinases of which several belong to the Src kinase family. Using bioinformatics tools, several hematopoietic signaling pathways were identified, including the B cell receptor (BCR) pathway. Further proteomic approaches substantiated molecular hematopoietic features in NB-TICs. Inhibitors of BCR proximal kinases SYK and SFKs were cytotoxic to NB-TICs. Clinically utilized inhibitors of SFKs induce apoptosis in NB-TICs. Targeting hematopoietic survival pathways in NB-TICs from the bone marrow, which have thus far not been predicted to play a role in this neural malignancy, may provide new drug therapies for NB.
Detection of the BCR-ABL Leukemia Gene Fusion using Chip-based Electrochemical Assay
Keywords: biosensor
CML
diagnostics

Ability to diagnose cancer before it progresses into advanced stages is highly desirable for the best treatment outcome. A sensitive test to analyze complex samples for specific cancer biomarkers would provide with important prognostic information and help to select the best treatment regimen. A highly robust, ultra sensitive and cost-effective electronic chip platform was used to detect nucleic acid biomarkers in heterogeneous biological samples without any amplification or purification. Chronic myelogenous leukemia (CML) was chosen as a model disease due to its hallmark genetic abnormality. This disease state therefore has an ideal market to test the detection of the fusion transcripts in complex samples, such as blood. It was shown that the CML-related fusion can be detected from unpurified cell lysates and as low as 10 cells were needed for detection. Finally, patient samples were analyzed using the assay and the fusion transcripts were accurately identified in all of them.
Transition to Seizure in the CA3 Hippocampal Network: Predominant Preictal GABAergic Potentials, followed by Predominant Ictal Glutamatergic Potentials
Keywords: epilepsy
hippocampus
GABA
glutamate

The mechanisms underlying the transition to seizure are still unresolved. Proposed mechanisms include excitatory GABAergic drive, loss of interneuron-mediated inhibition, and glutamatergic input potentiation. The objective of this thesis was to investigate the relative contributions of synchronized glutamatergic and GABAergic inputs and their functional roles during ictogenesis in the epileptic neonatal (postnatal days 6-12) mouse hippocampus, induced with 0.25mM Mg2+/5mM K+ perfusion. Simultaneous field and whole-cell patch-clamp recordings were obtained from CA3 stratum-oriens interneurons and pyramidal cells. The antagonists for GABAA and glutamate receptors abolished the preictal and ictal discharges, respectively, suggesting that the preictal state is mediated by the coherent discharges of GABAergic inhibitory interneurons, whereas the recurrent excitatory inputs are required for ictogenesis. Synaptic charge transfers underlying the synchronized discharges showed a dynamic change in the balance between the inputs: GABAergic currents markedly diminished by ictal onset whereas glutamatergic currents dominated at ictal onset and throughout the ictus.
New Generation of Programmable Neuroprostheses - Switched Mode Power Supply Functional Electrical Stimulator
Keywords: Functional Electrical Stimulator
Switched Mode Power Supply
Neuroprostheses
Functional Electrical Stimulation
FES
Neuroprosthesis
Switch-mode power supply
SMPS

Functional electrical stimulation (FES) devices have direct applications in the realm of rehabilitation engineering, physiotherapy, occupational therapy and medicine for research, diagnostic and therapeutic purposes. This thesis presents a novel electrical stimulator for use in a FES system. The stimulator produces regulated current pulses using two switched mode power supplies (SMPS) in series. The first power stage - a flyback converter - steps up the supply voltage using primary side digital control. The second power stage is a buck converter with output current hysteretic control. An output switched capacitor circuit shapes the current pulses. All pulse variables are programmable and various pulses can be formed for virtually any FES application. Compared to previous FES devices, the pulses generated here are sharper, have faster rise time and the amplitude and temporal characteristics are more tightly regulated. A single channel prototype system is implemented and experimental results are shown.
Nutrient Cycling and Water Pollution in Lake Zapotlan, Mexico
Keywords: Water Quality
Mexico

Lake Zapotlán is a small (1100 ha) endorheic lake in western Mexico that is internationally recognized by RAMSAR. It receives point source pollution from partially treated sewage from two surrounding cities, as well as non-point sources, including urban runoff, agricultural runoff, erosion and consequent deposition of sediment as a result of deforestation surrounding the Lake. The purpose of this study was to determine the severity of pollution in the Lake through measurement of nutrient and bacteria levels and assess for potential human health and ecological risks in Lake Zapotlán. Results found that nutrient levels have increased since 1994 and that they are high enough to cause eutrophication problems. Partially treated wastewater contributes over 30 tonnes of phosphorus to the Lake each year. E. coli levels were extremely high and could pose a health risk to those participating in recreational activities on the Lake.
The Effects of Alkaline Peroxide Treatment on Physical and Structural Properties of Low Consistency Refined Paper
Keywords: mechanical pulp
alkaline peroxide
low consistency
chemical treatment

Physical property data was used to test two hypotheses pertaining to the impact of a chemical pre-treatment on the qualities of low consistency refined pulp. The first objective was to determine whether the addition of a chemical treatment would effectively accelerate the refining process when compared to a regular pulp. This involved the measurement of the physical property data and how it changed with increased refining energy. The second objective was to determine how the chemical treatment affected fibre development during refining, and whether its implementation could result in enhancement of inter-fibre bondability. Theoretical models for the physical properties of paper were used to study the fibre-to-fibre bonding properties of the tested paper samples. Additionally, SEM images were obtained to study the deferences in morphology of the tested pulp samples.
Comparison of Different Strategies for the Management of Febrile Neutropenia in Children - A Cost-utility Analysis
Keywords: pediatric oncology
febrile neutropenia

Introduction: There is uncertainty whether low-risk febrile neutropenia (FN) episodes in children with cancer are best managed in the inpatient or outpatient setting. Methods: A cost-utility model was created to compare four different treatment strategies for low-risk FN in pediatric cancer patients. Outcome measures were quality-adjusted FN episodes (QAFNE), costs (Canadian dollar), and incremental cost-effectiveness ratios (ICER). Results: The most cost-effective strategy was outpatient treatment with intravenous antibiotics. It was cost saving ($2,732 versus $2,757) and more effective (0.66 QAFNE versus 0.55 QAFNE) as compared to outpatient treatment with oral antibiotics. An early discharge strategy after 48 hours in hospital was slightly more effective but significantly more expensive than outpatient treatment with intravenous antibiotics resulting in an unacceptably high ICER of more than $130,000 per QAFNE. Inpatient care was the least cost-effective strategy. Conclusions: Outpatient strategies for treatment of low-risk FN in children are more cost-effective than traditional inpatient care.
A Systematic Review of Teleradiology for Remote Neurosurgical Evaluation of Patients in Facilities without Neurosurgery Specialists
Keywords: Teleradiology
Neurosurgery
Radiology
Remote
Consulation
GRADE
Transfer
Systematic Review

Background: Teleradiology is currently being explored to enhance services for patients seeking emergency neurosurgical diagnoses in Ontario, Canada. Design: Systematic review of literature and cost-consequence analysis. Data sources: Medline, Embase, Cochrane, and Database of Abstracts of Reviews of Effects. Methods: Studies published between 1950 and 2008 describing remote consultations for neurosurgical assessments were retrieved. Two reviewers selected studies through multi-staged content screening and extracted data. Results 12 of 3765 studies met the inclusion criteria: two were randomized controlled trials and ten were case series. Teleradiology [88% (207/236)] and video-conferencing [89% (213/239] consultations produced higher diagnostic accuracy than telephone consultations [64% (150/235), p<0.001]. Savings varied by location and were based on avoided costs for ground and air transportation and hospitalization. Conclusions: There is limited evidence of clinical benefit of teleradiology. Savings associated with reduction in patient transfer rates depend on transportation mode and may be attenuated by higher operational costs.
Reform in Tibet as a Social Movement
Keywords: Reform
Social Movement
Tibet
Education

Reform as a social process is underresearched in the case of Tibet. This study addresses this gap using Social Movement Theory, which sees social change as a complex process involving various Tibetan social groups and external reformers, the Communist Party of China (CPC). This approach was applied by comparing recruitment and mobilization efforts of several key internal and external reform movements in 20th century Tibetan history. Findings include that internal reform failures can be explained by their narrow social and geographic basis and limited mass appeal. Moreover, initial CPC reforms succeeded through recruitment and mobilization across Tibetan regions and social groupings. Subsequent reforms failed due to decreased attention to recruitment and mass mobilization of Tibetans. A major implication of the study is that understanding social reform in today’s Tibet requires a SM Theory approach, which currently is lacking among scholars of the Tibetan question and political representatives of both sides.
Characterizing the Role of a Novel F-actin Binding Protein in IRS1/PI3K Signaling and Glucose Uptake
Keywords: type 2 diabetes
insulin resistance

Studies show that insulin induced activation and assembly of insulin receptor substrate-1 (IRS1) and phosphatidylinositol-3-kinase (PI3K), within remodelled actin structures is critical for GLUT4 translocation to the cell surface in muscle cells. This study identifies the F-actin binding protein, nexilin, as a novel IRS1 binding partner. Insulin stimulates nexilin to dissociate from IRS1 and interact with actin. Nexilin knockdown has no effect on insulin-stimulated IRS1 tyrosine phosphorylation, but does enhance insulin-stimulated IRS1-PI3K interaction, increasing PIP3 formation, PKB activation and glucose uptake. This study also shows that nexilin overexpression may have an inhibitory effect on PKB phosphorylation and glucose uptake in adipocytes. These findings suggest nexilin is a negative regulator of IRS1 action on PI3K and insulin-stimulated dissociation of IRS1-nexilin allows the formation of IRS1-PI3K complexes in cytoskeletal-membrane compartments. Nexilin also specifically associates with the PH domain of IRS1, and not IRS2, suggesting a mechanism for signaling specificity of these isoforms.
Electroless Copper Deposition: A Sustainable Approach
Keywords: copper plating

A sustainable electroless copper coating process was developed for plating automotive fasteners shaped from AISI 9255 low carbon, high silicon steel. The objective was to minimize the ionic and organic species present in each step of the plating process. A sulfuric acid solution inhibited with quinine was defined to clean the steel prior to plating. The corrosivity of the solution was examined through electrochemical and weight loss measurements to evaluate the efficiency of the cleaning process at high temperatures and high acid concentrations. An electroless copper coating process was then developed using a simple copper sulfate chemistry inhibited with quinine to extend the possible operating window. Finally, benzotriazole was evaluated as a possible anti-oxidant coating. Accelerated thioacetamide corrosion tests were used to evaluate the corrosion inhibition of benzotriazole on copper coatings.