This paper proposes new iterative methods for the efficient computation of the smallest eigenvalue of the symmetric nonlinear matrix eigenvalue problems of large order with a monotone dependence on the spectral parameter. Monotone nonlinear eigenvalue problems for differential equations have important applications in mechanics and physics. The discretization of these eigenvalue problems leads to ill-conditioned nonlinear eigenvalue problems with very large sparse matrices monotone depending on the spectral parameter. To compute the smallest eigenvalue of large matrix nonlinear eigenvalue problem, we suggest preconditioned iterative methods: preconditioned simple iteration method, preconditioned steepest descent method, and preconditioned conjugate gradient method. These methods use only matrix-vector multiplications, preconditioner-vector multiplications, linear operations with vectors and inner products of vectors. We investigate the convergence and derive grid-independent error estimates of these methods for computing eigenvalues. Numerical experiments demonstrate practical effectiveness of the proposed methods for a class of mechanical problems.

Polyketide secondary metabolites constitute a structurally-diverse and clinically-important family of natural products. The wide range of biological activities represented by these substrates have contributed to therapeutic agents with annual sales exceeding $20B USD. Large multi-domain proteins called polyketide synthases (PKSs) use simple building blocks to generate highly-oxygenated and stereochemically-rich frameworks with astonishing selectivity. These substrates often feature rigidifying biases imposed by macrocyclic lactones and substituted heterocycles, which can impact their bioactive conformation. The work of this dissertation combines synthetic chemistry and biochemistry to investigate chemoenzymatic production of macrocyclic polyketide natural products. Research focused on validating a transannular oxa-conjugate addition strategy to assembly 2,6-cis-tetrahydropyran (THP) ring systems, as demonstrated by synthesis of the macrocyclic core to neopeltolide. Ultimately, we wish to apply this chemistry to de novo PKS pathways for rapid, reliable, and sustainable production of THP-bearing products like neopeltolide, and toward building SAR libraries. Additionally, a second study probed the specificity of the macrolactonizing thioesterase (TE) domain from the 6-deoxyerythronolide B (DEBS) biosynthetic pathway. This pathway is the paradigm for type-I PKS systems, and is responsible for producing the macrolide core of erythromycin. Our on-going research evaluates the limits of promiscuity within this specific catalytic domain, to characterize the structural elements required to accurately predict macrolactonization. The long-term goal of this study is to assess the potential applicability of DEBS TE as a generalized cyclization biocatalyst for combinatorial biochemistry and chemoenzymatic research.

A parallel realisation of the Conjugate Gradient Method with Schur-Complement preconditioning, based on a domain decomposition approach, is described in detail. Special kinds of solvers for the resulting interiour and coupling systems are presented. A large range of numerical results is used to demonstrate the properties and behaviour of this solvers in practical situations.

This paper concerns the solution of plate bending problems in domains composed of rectangles. Domain decomposition (DD) is the basic tool used for both the parallelization of the conjugate gradient method and the construction of efficient parallel preconditioners. A so-called Dirich- let DD preconditioner for systems of linear equations arising from the fi- nite element approximation by non-conforming Adini elements is derived. It is based on the non-overlapping DD, a multilevel preconditioner for the Schur-complement and a fast, almost direct solution method for the Dirichlet problem in rectangular domains based on fast Fourier transform. Making use of Xu's theory of the auxiliary space method we construct an optimal preconditioner for plate problems discretized by conforming Bogner-Fox-Schmidt rectangles. Results of numerical experiments carried out on a multiprocessor sys- tem are given. For the test problems considered the number of iterations is bounded independent of the mesh sizes and independent of the number of subdomains. The resulting parallel preconditioned conjugate gradient method requiresO(h^-2 ln h^-1 ln epsilon^-11) arithmetical operations per processor in order to solve the finite element equations with the relative accuracy epsilon.

High resolution imaging of wide fields has been a prerogative of space telescopes for decades. Multi-conjugate adaptive optics (MCAO) is a key technology for the future of ground-based astronomy, especially as we approach the era of ELTs, where the large apertures will provide diffraction limits that will significantly surpass even the James Webb Space Telescope. NFIRAOS will be the first light MCAO system for the Thirty Meter Telescope and to support its development I have worked on HeNOS, its test bench integrated in Victoria at NRC Herzberg. I have aligned the optics, tested the electronic hardware, calibrated the subsystems (cameras, deformable mirrors, light sources, etc.) and characterized the system parameters. Development and support for future MCAO instruments also involves data analysis, a critical process in delivering the expected performance of any scientific instrument. To develop a strategy for optimal stellar photometry with MCAO, I have observed the Galactic globular cluster NGC 1851 with GeMS, the MCAO system on the 8-meter Gemini South telescope. From near-infrared images of this target in two bands, I have found the optimal parameters to employ in the profile-fitting photometry and calibration. As testimony to the precision of the results, I have obtained the deepest near-infrared photometry of a crowded field from the ground and used it to determine the age of the cluster with a method recently proposed that exploits the bend in the lower main sequence. The precise color-magnitude diagram also allows us to clearly observe the double subgiant branch for the first time from the ground, caused by the multiple stellar populations in the cluster. As the only facility MCAO system, GeMS is an important instrument that serves to illuminate the challenges of obtaining accurate photometry using such a system. By coupling the knowledge acquired from an instrument already on-sky with experiments in the lab on a prototype of a future system, I have addressed new challenges in photometry and astrometry, like the promising technique of point spread function reconstruction. This thesis informs the development of appropriate data processing techniques and observing strategies to ensure the ELTs deliver their full scientific promise over extended fields of view. / Graduate

La plupart des médicaments développés pour les maladies du SNC n’atteignent pas leur cible en raison des propriétés uniques de la BHE, nécessitant la mise en place de stratégies de délivrance comme l'utilisation d'un processus physiologique, le RMT. Des peptides ciblant le LDLR (exprimé à la BHE et impliqué dans ces processus) ont été développés. Les objectifs de cette thèse ont été de caractériser le trafic intracellulaire et la capacité de transport de différentes formes de ces peptides dans différents modèles in vitro y compris dans un modèle de BHE.Les résultats obtenus dans une lignée cellulaire surexprimant le LDLR tagué GFP par imagerie en fluorescence montrent que les différentes formes de ces peptides lient le LDLR à la membrane plasmique d’où ils sont internalisés et adressés aux lysosomes sans interférer avec l’endocytose des LDL. Ils permettent l’adressage aux lysosomes de petites molécules (fluorochrome) et de protéines qui leur sont fusionnées, ces résultats indiquent qu’ils pourraient être utilisés pour cibler des molécules thérapeutiques aux lysosomes de cellules exprimant les LDLR. Dans le modèle in vitro de BHE, les peptides sont internalisés via le LDLR à partir du pôle apical et suivent un transport intracellulaire similaire aux LDL, étant déroutés de la voie de dégradation vers les lysosomes pour être transportés jusqu’au compartiment abluminal comme précédemment décrit pour le LDL et la transferrine. Ces données indiquent donc que les peptides ciblant le LDLR sont des candidats vecteurs intéressants pour compléter/améliorer le panel de peptide/anticorps existant et permettre le ciblage et le transport de molécules thérapeutiques à travers la BHE. / Many drugs are ineffective in treating CNS diseases due in part to unique properties of the BBB, requiring the establishment of delivery strategies such as the use of a physiological process, as the RMT. Peptides targeting the LDLR (expressed in the BBB and involved in these processes) have been developed. The objectives of this thesis were to characterize the intracellular traffic and transport capacity of different shapes of these peptides in various in vitro models including a model of BBB.The results obtained in a cell line overexpressing the LDLR tagged GFP by fluorescence imaging shows that the various forms of these peptides bind plasma membrane LDLR, where they are internalized and sent to lysosomes without interfering with LDL endocytosis. They allow lysosomal targeting of small molecules (fluorochrome) and proteins that are fused to them. These results indicate that it might be used to target therapeutic compounds to cells expressing LDLR lysosomes. In the in vitro BBB model, the peptides are internalized via the LDLR from the apical pole and follow a similar intracellular transport than LDL, being diverted from the lysosomal degradation pathway to be transported to the abluminal compartment as previously described for LDL and transferrin. These data indicate that the LDLR-targeting peptides seems useful vectors candidates to complete/improve the existing peptide/antibodies panel and allow the targeting and the transport of therapeutic molecules through the BBB.

The main objective of this Master Thesis project is the development of a new methodology to perform Computational Fluid Dynamics (CFD) conjugate heat transfer simulations for internal combustion engines, at the Fluid and Combustion Simulations Department (NMGD) at Scania CV AB, Södertalje, Sweden. This new method allows to overcome the drawbacks identified in the former methodology, providing the ability to use the more advanced polyhedral mesh type to generate good quality grids in complex geometries like water cooling jackets, and integrating all the different components of the engine cylinder in one unique multi-material mesh. In the method developed, these advantages can be used while optimizing the process to perform the simulations, and obtaining improved accuracy in the temperature field of engine components surrounding the water cooling jacket when compared to the experimental data from Scania CV AB tests rigs. The present work exposes the limitations encountered within the former methodology and presents a theoretical background to explain the physics involved, describing the computational tools and procedures to solve these complex fluid and thermal problems in a practical and cost-effective way, by the use of CFD.A mesh sensitivity analysis performed during this study reveals that a mesh with low y+ values, close to 1 in the water cooling jacket, is needed to obtain an accurate temperature distribution along the cylinder head, as well as to accurately identify boiling regions in the coolant domain. Another advantage of the proposed methodology is that it provides new capabilities like the implementation of thermal contact resistance in periodical contact regions of the engine components, improving the accuracy of the results in terms of temperature profiles of parts like valves, seats and guides. The results from this project are satisfactory, providing a reliable new methodology for multi-material thermal simulations, improving the efficiency of the work to be performed in the NMGD department, with a better use of the available engineering and computational resources, simplifying all the stages of multi-material projects, from the geometry preparation and meshing, to the post-processing tasks.

This thesis aimed to elucidate the demographic characteristics associated with elevated or reduced rates of pneumococcal conjugate 13 (PCV13) vaccination. A retrospective cohort study was performed using the Truven Health MarketScan® Database. Three cohorts were created corresponding to populations for which the CDC recommends PCV13 vaccination. Cohort 1: children < 36 months of age. Cohort 2: adults 19-64 years of age with high infection risk. Cohort 3: adults > 65 years of age. Odds of having a PCV13 claim were calculated for each cohort. For Cohort 1, 78% out of a total of 353,214 subjects had a sufficient number of PCV13 doses to meet CDC recommendations. For Cohort 2, 3.7% out of a total of 673,157 subjects had a PCV13 claim. For Cohort 3, 18% of 1,262,531 subjects had a PCV13 claim. Odds of vaccination were generally lower in younger subjects, those with fewer outpatient claims, and those with residence in the Northeast and South regions. In Cohort 2, odds were reduced in subjects with generalized malignancy. Gender and urban residence were poor predictors of vaccination status. By understanding the demographic factors associated with lower rates of vaccination, clinicians may more effectively direct their efforts to increase pneumococcal vaccination coverage.

Previously, we proposed and experimentally demonstrated enhanced recording speeds by using a resonant optical cavity to semi-passively increase the reference beam power while recording image bearing holograms. In addition to enhancing the reference beam power the cavity supports the orthogonal reference beam families of its eigenmodes, which can be used as a degree of freedom to multiplex data pages and increase storage densities for volume Holographic Data Storage Systems (HDSS). While keeping the increased recording speed of a cavity enhanced reference arm, image bearing holograms are multiplexed by orthogonal phase code multiplexing via Hermite-Gaussian eigenmodes in a Fe: LiNbO3 medium with a 532 nm laser at two Bragg angles for expedited recording of four multiplexed holograms. We experimentally confirmed write rates are enhanced by an average factor of 1.1, and page crosstalk is about 2.5%. This hybrid multiplexing opens up a pathway to increase storage density while minimizing modifications to current angular multiplexing HDSS.

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