The Investigation of Isomers using Differential Mobility Spectrometry and Ultraviolet Photodissociation Spectroscopy

The analysis of complex mixtures in mass spectrometry (MS) is often complicated by the presence of isomers exhibiting the same mass-to-charge ratios. Tandem MS can simplify isomer analysis and enable ion characterization based on their fragmentation patterns. While mass spectrometry dominates the analysis of samples in various fields, it is often paired with orthogonal separation methods to allow for the analysis of complex mixtures. This workflow improves sample throughput for analysis by minimizing time-consuming steps involving sample preparations and modifications required to create distinct fragmentation patterns. The studies detailed in this thesis investigate differential mobility spectrometry (DMS) as a tool for separating and characterizing isomeric species prior to MS. Often used as a prefilter to mass spectrometry, DMS is a variant of ion mobility spectrometry (IMS) that employs an asymmetric electric field to separate ions based on their differential mobility using alternating regions of high- and low-field strength. The resolving power of DMS can be enhanced by the introduction of polar neutral molecules into the gas phase to induce intermolecular interactions with the ions. The resulting gas-phase clusters and dynamic processes taking place in the DMS are dependent on the physicochemical properties of the analytes. With isomers, subtle differences in their properties can be leveraged to induce large differences in the ion behaviour in the DMS. In turn, the DMS behavior of ions can be reverse traced to probe the physicochemical properties of the analytes in the gas phase. In this thesis, different isomeric species are investigated, separated, and characterized using DMS-MS. Thorough investigations are conducted to understand the gas-phase behaviour of ion clusters in the DMS, and computational studies are conducted concurrently to rationalize the observations made. We also probed the electronic structure of DMS-isolated compounds with ultraviolet photodissociation (UVPD) spectroscopy, as while DMS helps separate isomers prior to MS, UVPD can be used to distinguish isomers that are otherwise indistinguishable by tandem MS. The instrumental setup is employed in the study of functional isomers, prototropic isomers and conformers, along with positional isomers. In this thesis, isomers that were challenging to distinguish by MS techniques alone were separated using DMS. Five main cannabinoid isomers are separated by seeding the carrier gas of the DMS with polar solvent vapor. In the case of these ions, it was determined that the composition of the electrospray ionization (ESI) solvent and the polar solvent vapor influenced the survival of ESI-formed adducts. Next, positional isomers, nortriptyline and protriptyline were used to assess the use of DMS-MS coupled with UVPD in the characterization of isomers that present the same fragment ions. UVPD analysis yielded stark differences in their photodissociation efficiencies. Lastly, prototropic isomers of Rivaroxaban—a drug molecule—formed during the ESI process were preserved in the DMS and characterized via UVPD. The coupling of DMS and UVPD to MS provided additional tools in the separation, quantification, and characterization of isomers. The distinct uses of DMS in the analysis of various isomers are highlighted. Identification and characterization were made easier with the ability to probe the interaction potentials of the isomers with solvent modifiers in the DMS and the ability to probe their electronic structures via UVPD

Diversity and Context in Health Ethics: The Case for Rural Health

This review maintains that the book, Rethinking Rural Health Ethics, is essential reading for rural health providers, rural health policy makers, and rural health ethicists because it uncovers the fundamental inadequacies of the traditional, urban-centric health ethics framework with respect to the rural health setting and formulates the basis for a more viable and distinctive rural health ethics. This review further maintains that this book possesses far-reaching, robust implications on the importance of incorporating diversity and context into ethical deliberations within the broader field of health ethics and in all levels of ethical analysis (i.e., micro, meso, and macro), thus serving as a resonating and sage influence for health ethicists in all fields

An evaluation of a brief school-based intervention based on cognitive behaviour therapy to raise pupils' self-esteem amd emotional well-being

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Diversity and Context in Health Ethics: The Case for Rural Health

This review maintains that the book, Rethinking Rural Health Ethics, is essential reading for rural health providers, rural health policy makers, and rural health ethicists because it uncovers the fundamental inadequacies of the traditional, urban-centric health ethics framework with respect to the rural health setting and formulates the basis for a more viable and distinctive rural health ethics. This review further maintains that this book possesses far-reaching, robust implications on the importance of incorporating diversity and context into ethical deliberations within the broader field of health ethics and in all levels of ethical analysis (i.e., micro, meso, and macro), thus serving as a resonating and sage influence for health ethicists in all fields

Diversity and Context in Health Ethics: The Case for Rural Health

This review maintains that the book, Rethinking Rural Health Ethics, is essential reading for rural health providers, rural health policy makers, and rural health ethicists because it uncovers the fundamental inadequacies of the traditional, urban-centric health ethics framework with respect to the rural health setting and formulates the basis for a more viable and distinctive rural health ethics. This review further maintains that this book possesses far-reaching, robust implications on the importance of incorporating diversity and context into ethical deliberations within the broader field of health ethics and in all levels of ethical analysis (i.e., micro, meso, and macro), thus serving as a resonating and sage influence for health ethicists in all fields.Ce compte rendu soutient que le livre Repenser l’éthique de la santé rurale est une lecture essentielle pour les fournisseurs de soins de santé en milieu rural, les décideurs en matière de santé rurale et les éthiciens en santé rurale, parce qu’il révèle les inadéquations fondamentales du cadre traditionnel en éthique de la santé, centré sur les milieux urbains, avec la santé en milieu rural, et formule les bases pour une éthique plus viable et distinctive en santé rurale. Ce compte rendu soutient, en outre, que ce livre a des implications profondes et solides sur l’importance d’incorporer la diversité et le contexte dans les délibérations éthiques à l’intérieur du domaine plus large qu’est l’éthique de la santé, et ce à tous les niveaux de l’analyse éthique (c.-à-d. micro, méso et macro), servant ainsi d’influence résonante et judicieuse pour les éthiciens de la santé de tous domaines

Endothelial nitric oxide synthase reduces crescentic and necrotic glomerular lesions, reactive oxygen production, and MCP1 production in murine lupus nephritis.

Systemic lupus erythematosus, in both animal models and in humans, is characterized by autoantibody production followed by immune complex deposition in target tissues. Ensuing target organ damage is modulated by reactive intermediates, including reactive nitrogen and oxygen species, through as of now incompletely understood mechanisms. Endothelial nitric oxide synthase is known to impact vascular reactivity; however its impact on reactive intermediate production and inflammatory renal disease is less well defined. In this study, we assessed the impact of endothelial nitric oxide synthase (eNOS) on disease in lupus prone MRL/lpr mice. Mice lacking eNOS developed earlier more severe disease with decreased survival. eNOS deficient mice died sooner and developed significantly more glomerular crescents, necrosis, inflammatory infiltrates and vasculitis, indicating a role for eNOS in modulating these renal lesions. Immune complex deposition was similar between groups, indicating the impact of eNOS is distal to antibody/complement glomerular deposition. Urinary nitric oxide production was decreased in the eNOS deficient mice, while proteinuria was increased. Urinary monocyte chemotactic protein-1 was also increased in the knockout mice. CD4+ T cells from MRL/lpr mice demonstrated mitochondrial hyperpolarization, increased nitric oxide and superoxide production and increased calcium flux compared to B6 control mice. Deficiency of eNOS resulted in decreased nitric oxide and mitochondrial calcium levels but had no effect on mitochondrial hyperpolarization. Renal cortices from MRL/lpr mice that are eNOS deficient demonstrated increased superoxide production, which was blocked by both nitric oxide synthase and NADPH oxidase inhibitors. These studies thus demonstrate a key role for eNOS in modulating renal disease in lupus prone MRL/lpr mice. The impact appears to be mediated by effects on superoxide production in the kidney, impacting downstream mediators such as monocyte chemotactic protein-1. These results suggest that modulation of eNOS may be a novel therapeutic approach to treating lupus nephritis