Dissertations / Theses: 'High resolution mass spectrometry (HRMS)'

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Kamleh, Muhammad Anas. "The combination of hydrophilic interaction liquid chromatography and high resolution mass spectrometry (HILIC-HRMS) : optimisation and application in pharmaceutical analysis." Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=22731.

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The development of analytical technology over the last few decades has opened the door to new and intriguing fields of research, allowing investigations at a level of quality not achieved before. Chromatography and mass spectrometry have undergone a revolution of advances in the last four decades with extensive developments in new stationary phases and new developments in ionisation and ion separation techniques. The work in this thesis investigated the application of two of these advances, hydrophilic interaction liquid chromatography (HILIC) and Fourier transformation mass spectrometry (FTMS) for the analysis of complex biological samples. This thesis focuses on the development of metabolic profiling methods which have applications in disease diagnosis, personalized healthcare and drug discovery. The complex nature of the type of samples is discussed and data simulation was used to show the importance of a separation step before detection, even with high resolution mass spectromet ers. HILIC was compared to more traditional reversed phase stationary phases and found to be more suitable for the research questions in this thesis. Several commercially available chromatographic columns share the HILIC retention mechanism but differ in their chemistry. Four of these columns were compared using injections of 140 authentic standards and they were evaluated according to the retention range for the standards, peak width, isomer separation and background signal level generated in the mass spectrometer. The most "fit for purpose" column was then selected and further tested with different organic modifiers and mobile phase additives. The final method was tested for repeatability and reproducibility of retention time. The selected analytical method was then applied to the analysis of the metabolome of two biological systems i.e. Drosophila melanogaster and Trypanosoma brucei. This demonstrated the ability of this method to rapidly profile and extract biological information from the tested systems. The complex output of the analytical methods needed data processing tools, and for this purpose a computer programme was written and is described and tested in the work reported in this thesis. The in-house built code was compared with a commercially available and an academic software package and the pros and cons of each of these tools are discussed within this thesis.

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Chaker, Jade. "Développements analytiques pour la caractérisation non-ciblée et par profilage de suspects de l’exposome chimique dans le plasma et le sérum humain par LC-ESI-HRMS : optimisation et implémentation d’un workflow haut débit pour l’identification de nouveaux biomarqueurs d’exposition dans le plasma et le sérum sanguins." Electronic Thesis or Diss., Rennes, École des hautes études en santé publique, 2022. http://www.theses.fr/2022HESP0002.

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L’exposition chronique à des mélanges complexes de contaminants chimiques (xénobiotiques) est suspectée de contribuer à la survenue de certaines maladies chroniques. Encouragées par le développement de la spectrométrie de masse à haute résolution (SMHR) et l’émergence du concept d’exposome, des méthodes analytiques non-ciblées commencent à voir le jour pour caractériser l’exposition humaine aux xénobiotiques sans a priori. Ces méthodes innovantes pourraient ainsi permettre un changement d’échelle pour identifier de nouveaux facteurs de risque chimiques dans des études épidémiologiques. Ces approches présentent néanmoins plusieurs verrous, en lien, entre autres, avec la présence des contaminants à l’état de trace dans des matrices biologiques. Une optimisation de chaque étape analytique (préparation d’échantillon) et bio-informatique (prétraitement des données, annotation) est donc indispensable pour surmonter ces limites. L’objectif principal de ce travail est d’implémenter un workflow non-ciblé applicable aux études épidémiologiques pour apporter une solution opérationnelle à la caractérisation de l’exposome chimique interne à large échelle. Les développements effectués ont permis de proposer un workflow de préparation d’échantillon simple à mettre en œuvre et s’appuyant sur deux méthodes complémentaires pour élargir significativement l’espace chimique visible (jusqu’à 80% de marqueurs spécifiques à une méthode). L’optimisation de logiciels de prétraitement des données, réalisée pour la première fois dans un contexte exposomique, a permis de démontrer la nécessité d’ajuster certains paramètres pour assurer la détection des xénobiotiques à l’état de trace. Le développement d’un logiciel pour automatiser les approches de profilage de suspects avec des prédicteurs MS1, ainsi que le développement d’indices de confiance a permis de prioriser les marqueurs pertinents pour la curation manuelle. Une application à large échelle sur 125 échantillons de sérum de la cohorte Pélagie a permis de démontrer la robustesse et la sensibilité de ce nouveau workflow, ainsi que d’enrichir l’exposome chimique documenté avec la mise en évidence de nouveaux biomarqueurs d’exposition
Chronic exposure to complex mixtures of chemical contaminants (xenobiotics) is suspected to contribute to the onset of chronic diseases. The technological advances high-resolution mass spectrometry (HRMS), as well as the concept of exposome, have set the stage for the development of new non-targeted methods to characterize human exposure to xenobiotics without a priori. These innovative approaches may therefore allow changing scale to identify chemical risk factors in epidemiological studies. However, non-targeted approaches are still subject to a number of barriers, partly linked to the presence of these xenobiotics at trace levels in biological matrices. An optimization of every analytical (i.e. sample preparation) and bioinformatical (i.e. data processing, annotation) step of the workflow is thus required. The main objective of this work is to implement an HRMS-based non-targeted workflow applicable to epidemiological studies, to provide an operational solution to characterize the internal chemical exposome at a large scale. The undertaken developments allowed proposing a simple sample preparation workflow based on two complementary methods to expand the visible chemical space (up to 80% of features specific to one method). The optimization of various data processing tools, performed for the first time in an exposomics context, allowed demonstrating the necessity to adjust key parameters to accurately detect xenobiotics. Moreover, the development of a software to automatize suspect screening approaches using MS1 predictors, and of algorithms to compute confidence indices, allowed efficiently prioritizing features for manual curation. A large-scale application of this optimized workflow on 125 serum samples from the Pélagie cohort allowed demonstrating the robustness and sensitivity of this new workflow, and enriching the documented chemical exposome with the uncovering of new biomarkers of exposure

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Planinc, Ana. "Detection of changes in n-glycosylation profiles of therapeutic glycoproteins using LC-MS." Doctoral thesis, Universite Libre de Bruxelles, 2016. https://dipot.ulb.ac.be/dspace/bitstream/2013/241427/4/Table.pdf.

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Biopharmaceuticals are becoming one of the most promising drugs on the market mainly due to their successful treatment of a vast array of serious diseases, such as cancers, immune disorders, and infections. Structurally, biopharmaceuticals are proteins and it is important to mention that more than 60 % of biopharmaceuticals are glycosylated. Glycosylation is one of the most common posttranslational modifications. It is also the most demanding and the most complex posttranslational modification. The research showed that glycosylation can significantly impact on the safety, efficiency, and quality of the therapeutic glycoproteins. In the first part of the introduction of the present thesis, the development of the therapeutic glycoproteins and their classification were reviewed. Glycosylation process and nomenclature were also discussed. The second part of the introduction revealed current issues in the field of the production and the characterization of the therapeutic glycoproteins. In the context of the doctoral thesis, we introduced new approach, namely hydrophilic interaction liquid chromatography coupled to a high-resolution mass spectrometer (HILIC-HR-MS) combined with Principal Component Analysis (PCA) and classification through Soft Independent Modelling by Class Analogy (SIMCA) data treatment. Accordingly, N-glycans were first enzymatically released using peptide-N-glycosidase F (PNGase F) and reduced using sodium borohydride. Then those N-glycans were separated by HILIC and detected by HR-MS. PCA and SIMCA simplified interpretation of the MS data collected in the huge tables. PCA was applied to test whether it is possible to visualize N-glycosylation differences between samples and to help identifying within which N-glycans changes occurred. SIMCA, which is a more complex data analysis technique, was applied to build and validate a classification models. SIMCA was also applied to verify whether it is possible to use built models to classify real samples. Described approach enabled us to detect small changes in N-glycosylation of the therapeutic glycoproteins (a change of only 1% in relative glycan abundance). It was applied to assess changes in N-glycosylation of therapeutic glycoproteins. Accordingly, we tested N-glycosylation consistency between batches of infliximab, trastuzumab, and bevacizumab and monitored the N-glycosylation of bevacizumab over storage time in plastic syringes.Furthermore, we worked on the faster sample preparation technique, where online-solid-phase extraction (SPE)-LC was combined to the previously mentioned HILIC-MS-PCA/SIMCA method. Online-SPE-LC allowed us to faster the sample preparation in terms of avoiding time-consuming cleaning steps.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished

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Cece, Esra Nurten 1984. "Metabolite identification in drug discovery : from data to information and from information to knowledge." Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/403648.

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Drug metabolism studies provide the opportunity to enhance metabolic properties of new drugs. The overall aims of the drug metabolism studies are to (1.) optimize pharmacokinetic properties of the drug candidates, (2.) characterize the polymorphic enzyme contribution to clearance, and (3.) support the selection of safe drugs with respect to bioactivation potentials. The ultimate goal in drug metabolism assays in early drug discovery is to translate analytical data to build final knowledge. By contribution of this translation, metabolism scientists can rationalize how structures of new drug compounds could be changed and how metabolic pathways could be better understood. Analytical techniques, such as High Resolution Mass Spectrometry (HRMS), have progressed and now it is possible to generate large datasets through High Throughput Screening (HTS) assays in drug metabolism laboratories. However, the transformation of these data into information and information into knowledge is insufficient. In-depth data inspection is necessary to support the generation of high quality results which are consistent across experiments. For this purpose, innovative software solutions can be utilized to process analytical data. In this respect, by applying standardized and fully automated data evaluation tools, it is possible to (1.) enable comprehensive data analysis, (2.) accelerate structure-based information handling, (3.) eliminate human error and finally (4.) improve chemical features of lead molecules in terms of biotransformation properties. This thesis research aimed to use a novel automated workflow within HRMS to identify the drug metabolites and their structures. Final results confirmed that this new workflow can be used to translate HRMS data into information, which is required for building useful and ultimate knowledge in drug metabolism.
Los estudios de metabolismo de fármacos ofrecen la oportunidad de mejorar las propiedades metabólicas de nuevos fármacos. Los objetivos generales de los estudios de metabolismo de fármacos son: (1.) optimizar las propiedades farmacocinéticas de los fármacos candidatos, (2.) caracterizar la contribución de las enzimas polimórficas a la elimicación y (3.) apoyar la selección de fármacos seguros con respecto a los potenciales bioactivación. El objetivo final en los ensayos de metabolismo de fármacos es traducir los datos analíticos para construir conocimiento final. Mediante la aportación de esta traducción, los científicos que trabajan en metabolismo pueden racionalizar cómo las estructuras de los nuevos compuestos de fármacos podrían ser cambiadas y cómo las vías metabólicas podrían ser mejor entendidaa. Las técnicas analíticas, como la espectrometría de masas de alta resolución (HRMS), han progresado y ahora es posible generar grandes volúmenes de datos a través de ensayos masivos (HTS) en laboratorios de metabolismo de fármacos. Sin embargo, la transformación de estos datos a información y la información a conocimiento es insuficiente. Es necesario un estudio en profundidad de los datos para ayudar a la generación de resultados de alta calidad que sean consistentes con los experimentos. Para este propósito, las soluciones innovadoras de software pueden ser utilizados con el objetivo de procesar los datos analíticos. A este respecto, mediante la aplicación de datos estandarizados y totalmente automatizados herramientas de evaluación, es posible (1.) permitir el análisis de datos completos, (2.) acelerar el manejo de información basada en la estructura, (3.) eliminar el error humano y finalmente (4.) mejorar las características químicas de las moléculas en términos de sus propiedades metabólicas. La investigación de esta tesis tuvo el objetivo que utilizar una novedoso y automatizado “sistema de trabajo” dentro HRMS para identificar los metabolitos de compuestos así como sus estructuras. Los resultados finales se confirmaron que se pueden utilizar herramientas de software para convertir los datos en información de HRMS, necesario para la construcción del conocimiento útil en el metabolismo de fármacos

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Schuhmann, Kai. "Shotgun lipidomics of metabolic disorders by high resolution mass spectrometry." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-101305.

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The characterization of lipids is performed by mass spectrometry based on structure specific fragments or by accurate mass measurements of intact precursor ions. The latter method, termed ’top-down lipidomics’, is due to its robustness, simplicity and speed a valuable tool for medical research to elucidate the molecular background of lipid metabolic disorders. The current thesis aims to improve the established lipidomics methods. Therefore, a new top-down lipidomics method was introduced that increased the analysis throughput, lipidome coverage and accuracy of quantification, compared to previous approaches, by rapid successive acquisition of high resolution Fourier transform mass spectra in positive and negative ion modes. Furthermore, the characterization of molecular lipid species by utilizing high energy collisional dissociation was achieved on Orbitrap instruments. The mass accuracy of acquired MS/MS spectra increased the confidence in identification for unusual very-long chain polyunsaturated phosphatidylcholine species and a new lipid class, the maradolipids. Beyond that, effort was made to enhance the accuracy and comparability of MS/MS based bottom-up lipidomics data. In this respect, lipids with varying degree of unsaturation were analyzed and revealed discrete fragmentation properties. The technical refined lipidomics methods allowed insight into the lipid composition of lipoproteins and changes of the blood plasma induced by apheresis. Lipidomics screening of blood plasma uncovered an altered lipid pattern in consequence of impaired glucose metabolism and type 2 diabetes. The lipidomics characterization of islet allowed their quality assessment.

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Albratty, Mohammed Mofareh. "Metabonomic analysis of Drosophila mutants using high resolution mass spectrometry." Thesis, University of Strathclyde, 2013. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18695.

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The availability of fully sequenced genomes of model organisms such as Drosophila and their subsequent annotation has afforded opportunities for reverse genetics in a complex model organism. Metabonomics used as an aid to functional genomics can be used to understand the functions of genes in living systems. Thus metabonomics has been employed to study Drosophila samples extracted from whole animals at different developmental stages or in response to external stimuli or genetic mutation. With unmatched mass resolution, accuracy, and detection sensitivity, linear ion trap - Fourier Transform Orbitrap Mass Spectrometry (LTQ-Orbitrap-MS) has the potential for high throughput metabonomic analysis. Five different but linked studies are reported in this work. A global metabolic profiling method based on electrospray ionisation mass spectrometry was developed for Drosophila melanogaster metabolites. The method involved optimizing the extraction of Drosophila metabolites followed by analysi s using liquid chromatography coupled with high-resolution mass spectrometry. The effect of extraction conditions and storage were studied, thus 750-800 metabolites were putatively identified in order to obtain the metabolite profiles of Drosophila reference strains and mutants. Metabolic studies were carried out to elucidate gene functions using established protocols. The online resource FlyAtlas.org provides detailed microarray-based expression data for the tissues and life-stages of Drosophila. Since downstream genes, such as urate oxidase are tubule-specific, an Orbitrap technology has been used to elucidate tissue specific metabolomes. Additionally, genetic interventions using designed RNA interference were also made and validated by qPCR and metabonomics. The method produced a new opportunity for metabonomics use in validating gene expressions. The xanthine oxidase inhibitor allopurinol was used to phenocopy the rosy mutation which caused the levels of xanthine and hypoxanthine to rise while the levels of uric acid fell. In addition, many unexpected metabolic changes followed this treatment with effects on the pentose phosphate pathway and tryptophan metabolism being the most marked. The yellow (y) gene was first discovered in Drosophila, but occurs in many insect species and in some bacteria. The y protein is similar to the major royal jelly proteins produced by bees. Metabolomic profiling was carried out on Oregon R (OR) and y Drosophila larvae at the third instar. There were numerous metabolic differences between the metabolic profiles of OR and y. Phenylalanine, tyrosine and DOPA were all elevated in y, as might be expected since the mutation blocks melanin biosynthesis. In addition, there were other metabolic effects including marked effects on to lysine metabolism. The white mutation of Drosophila, which affects ABC transporters, was studied with regards to its effect on pigment biosynthesis in Drosophila. In addition to the expected effects on pigme nts there were interesting male/female differences possibly related to the presence of the white gene in the X chromosome. In addition the effect of salt stess on wild type and white flies was studied. Overall, LTQ-Orbitrap-MS proved suitable for metabonomic analysis of both wild-type and mutant Drosophila and had potential in the analysis of metabolomes of single tissues. The possibility of using Orbitrap-based metabonomics in combination with Drosphila for drug testing is discussed and is a goal for the future.

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Gellein, Kristin. "High resolution inductively coupled plasma mass spectrometry: Some applications in biomedicine." Doctoral thesis, Norwegian University of Science and Technology, Department of Chemistry, 2008. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-2233.

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Even though trace elements are present at minute amounts in the human body, they have a considerable impact on human health, either as essential elements in biochemical functions indispensable for life, or on the contrary, interfering with vital processes. Knowledge of the optimal concentrations of trace elements in the human body is therefore of great importance. Since the first systematic determinations of trace elements in human body fluids started in the 1940s there has been an incredible development in analytical instrumentation. The objective of this thesis is to demonstrate successful applications of HR-ICP-MS (high resolution inductively coupled plasma mass spectrometry) in biomedicine.

Research on trace elements in humans is challenging because of very low levels and many different types of matrices. The first important issue regarding trace element analysis is sampling and sample storage. It is essential to control all possible sources of contamination and other factors that can influence the concentrations. Preservation of biological samples is often required, and effects of the frequently used preservation and storage of biological tissue in formalin have been examined in this work. The concentrations of 20 trace elements were determined in formalin where brain samples had been stored at different time intervals ranging from few weeks to several years. The results show that storage of biological tissue in formalin may result in losses of trace elements from the tissue to the formalin, and that the leakage is time-dependent. This emphasizes the importance of controlling all steps from sample collection to analysis.

With its low detection limits, high resolution and multielement capability, HR-ICP-MS offers a considerable potential for further understanding the role of trace elements in biological material. These features were used to develop a method to study protein-bound metals in cerebrospinal fluid (CSF). CSF samples from eight healthy persons were separated by size exclusion HPLC and the resulting fractions were analyzed using HR-ICPMS. The major challenge in this work was the very low concentrations as only 100 μl CSF was injected to the column resulting in 35 fractions of 0.75 ml. It was possible to determine more than 10 elements of clinical interest in the CSF fractions and the method provides an opportunity to study MT and other metal binding proteins in CSF.

Further, the potential to study exposure and intake of trace elements by HRICP- MS was explored by analyzing hair strands of five occupationally unexposed subjects. The trace element profiles of single hair strands were determined by analyzing 1 cm long segments. The challenge in this study was again the extremely small sample size, as the samples had an average weight of 0.05 mg. It was possible however to obtain results for 12 elements in these minute samples and valuable information about intake and exposure for Hg, Se and Sr was obtained.

HR-ICP-MS has the potential to be an excellent tool for obtaining information about disease development and progress. A rare and relatively unexplored neurodegenerative disease (Skogholt’s disease) was studied. The trace element concentrations in whole blood, plasma and CSF were determined in Skogholt patients, multiple sclerosis patients and controls. Increased levels of Cu, Fe, Zn, Se and S in CSF were found in CSF from Skogholt patients. These increased levels were not reflected in blood, and it is quite obvious that the increased levels are not caused by increased environmental exposure. The results suggest that the increased levels of these elements in CSF are due to a leakage of metal binding proteins from blood to the CSF.

Trace elements have been implicated in the development of Parkinson’s disease (PD), and a study was performed on trace elements in serum from Parkinson patients collected in 1995-97, 4-12 years before they were diagnosed with the disease. New samples from more than half of these patients were collected in 2007. No significant differences were found between preclinical levels and controls, except for a lower level of Hg in the patient group. However, when trace element serum levels in patients from before and after they were diagnosed were compared, significant differences for several elements were found. This suggests that trace element imbalances found in PD patients may be a result of disease development rather than a causal factor.

HR-ICP-MS offers a considerable potential for further understanding the role of trace elements in humans. Biological material is often available for analysis only in small amounts. HR-ICP-MS gives the opportunity of simultaneous quantification of many trace elements even in very small samples and with very low detection limits. This promotes new research in the field of trace elements in biological material. HR-ICP-MS also reduces the time and cost per analysis and broadens the amount of information available from a single specimen.

Paper II,III and V are reprinted with kind permission from Elsevier, sciencedirect.com

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Klapa, Maria I. "High resolution metabolic flux determination using stable isotopes and mass spectrometry." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/8203.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2001.
Page 313 blank.
Includes bibliographical references.
Cellular physiology is a combination of many different functions that have to be accurately probed individually and then precisely correlated to each other, in order to reveal the language used by the cell to communicate changes from the environment to gene expression and vice versa. Genes are transcribed to proteins, which catalyze metabolic pathways, whose activity may in return affect gene expression. DNA microarrays allowed the measurement of the full gene expression profile under a particular set of environmental conditions and genetic backgrounds. To understand, however, the correlation between gene expression and the actual metabolic state of the cell, the latter needs to be also determined with high accuracy. This requires that a comprehensive set of variables is defined to describe metabolic activity and reliable methodologies are developed for the accurate determination of such variables. Defining flux as the rate at which material is processed through a metabolic pathway, the fluxes of a metabolic bioreaction network can be employed to provide an overall measure of metabolic activity. A complete and accurate flux map is the phenotypic equivalent of the gene expression profile. In addition, metabolic fluxes, and especially their changes in response to genetic or environmental perturbations, provide insightful information about the distribution of kinetic and regulatory controls in metabolism.
(cont.) In this context, my Ph.D. thesis focused in the development of methods for high-resolution metabolic flux determination using stable isotopes, mass spectrometry and bioreaction network analysis. Metabolic fluxes cannot be measured directly, but they are rather estimated from measurements of extracellular metabolite consumption and production rates along with data of isotopic-tracer distribution at various network metabolites after the introduction of labeled substrates. This indirect estimation is possible because the unknown fluxes are mapped into the measurements through mass and isotopomer balances. I applied observability analysis techniques into metabolic systems to determine which is the maximum resolution of the in vivo metabolic flux network that can be obtained from potential or provided experimental data. My research focused primarily in examining whether mass spectrometric measurements can be used as sensors of the metabolic fluxes. An experimental protocol for the acquisition of mass spectrometric measuremets of biomass hydrolysates using GC-(ion-trap) MS was developed. Finally, the developed computational and experimental methodology for flux quantification was applied in the elucidation of lysine biosynthesis flux network of Corynebacterium glutamicum under glucose limitation.
by Maria Ioanni Klapa.
Ph.D.

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Rummel, Julia Diane Laney. "Direct Analysis in Real Time ionization for high-resolution mass spectrometry." [Gainesville, Fla.] : University of Florida, 2009. http://purl.fcla.edu/fcla/etd/UFE0041066.

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Raptakis, Emmanuel N. "High resolution, high sensitivity tandem mass spectrometry of macromolecules using time-of-flight techniques." Thesis, University of Warwick, 1996. http://wrap.warwick.ac.uk/110843/.

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The first of the three parts of this study involves the construction of a large scale time-of-flight mass spectrometer. A large aluminium-alloy vacuum chamber was designed and manufactured. Ion trajectory modelling was carried out for defining the optimum ion optical configuration of the matrix-assisted laser desorption/ionisation (MALDI) ion source that was designed and constructed. A floating ion detector assembly was designed and installed. MALDI mass spectrometry experiments were performed with biomolecules and polymer samples. The second part of this work involves the design and construction of a MALDI ion source in the collision cell area of a four-sector tandem mass spectrometer. The apparatus makes use of an array detector installed as the detector of the second double-focusing mass analyser of this instrument. High resolution and sensitivity mass spectra of high mass biomolecules and polymer samples were acquired. Resolution in excess of 3500 full-width at half maximum (FWHM) has been observed. The third part of this work describes the theoretical considerations, the design the construction and the performance of a prototype magnetic sector/time-of- flight tandem mass spectrometer with an ideal time-focusing ion mirror as the second mass analyser (Mag-TOF). The method followed in order to overcome the inherent incompatibilities of the two mass-analysis stages is discussed. The theoretical description of the ideal time-focusing reflectron is presented, together with analysis of the time-aberrations of the delivery ion optics and the TOF part of the instrument, and their influence to resolution and sensitivity. Initial experiments have been performed to prove the feasibility of the operational principle of this prototype instrument. High resolution (approximately 3000, FWHM) tandem mass spectra of peptides are presented. The instrument also achieved high levels of sensitivity.

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Bristow, Anthony Walter Thomas. "Laser desorption and high resolution studies in quadrupole ion trap mass spectrometry." Thesis, Nottingham Trent University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336973.

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Li, Huilin. "Studies of protein post-translational modifications using high resolution tandem mass spectrometry." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/54993/.

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Electron capture dissociation (ECD) is a powerful and superior tandem mass spectrometry (MS) fragmentation technique in the study of protein post-translational modifications (PTMs) due to its unique features of preserving labile modifications and providing more detailed sequence information, which has been used to study protein platination and disulfide linked proteins. Cisplatin was found cross-linking multiple methionine (Met) pairs on calmodulin (CaM). The cross–linking of cisplatin to apo–CaM or Ca–CaM can inhibit the ability of CaM to recognize its target proteins as proved by a melittin binding assay. To further establish MS strategies to quickly assign the platinum-modification sites, a series of peptides with potential cisplatin binding sites were reacted with cisplatin and then analyzed by ECD. Radical-mediated side chain losses from the charge-reduced M+Pt species (such as CH3S• or CH3SH from Met, SH• from Cys, CO2 from Glu or Asp, and NH2• from amine groups) were found to be characteristic indicators for rapid and unambiguous localization of the Pt-modification sites on certain amino acid residues. Furthermore, the potential of cisplatin as a protein crosslinking reagent was further explored and demonstrated on other peptides and proteins. Many of the inherent features of cisplatin make it an interesting cross-linking reagent, such as targeting new protein functional groups (thioether and imidazole groups), its unique isotopic pattern, its inherent positive charges, its potential of binding to different functional groups, etc. However, it was found that the distance constraints obtained from NMR structures of CaM are inconsistent with the measured distance constraints by cross–linking. Therefore, a newly developed flexibility simulation method was applied to explore whether the flexibility motions of CaM might contribute to the observed Pt-crosslinking on CaM. The flexibility analysis showed that the structural flexibility of CaM is key to cisplatin crosslinking CaM. ECD mechanism of disulfide bonds is still under debate. To further explore the ECD mechanism of sulfur– containing species, a series of disulfide (S–S), sulfur–selenium (S–Se), and diselenide (Se–Se) bond–containing peptides was studied by ECD. The results demonstrate that the radical has higher tendency to stay at selenium rather than sulfur after cleavage of Se–S bonds by ECD and suggest that direct electron capture at Se–Se and C–Se bonds is the main process during ECD of inter–chain diselenide peptides. Last but not least, a new active ion ECD (AI-ECD) method, named Shots-ECD, was developed and applied to improve Top-down ECD backbone fragmentation efficiency of disulfide-rich proteins. The results show that the Shots–ECD approach can not only cleave multiple disulfide bonds but also significantly improve the backbone cleavage efficiency. This strategy is fast, efficient, and with no need of chemical reduction of samples and instrument modification, and therefore can be a powerful approach to improve top-down ECD efficiency of not only disulfide bonded proteins but all proteins by Fourier transform ion cyclotron mass spectrometry (FTICR MS).

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Kim, Hyun Sik. "High performance fourier transform mass spectrometry : soft ionization methods and resolution enhancement /." The Ohio State University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487859879937953.

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Castro, Waleska. "Elemental Analysis of Biological Matrices by Laser Ablation High Resolution Inductively Coupled Plasma Mass Spectrometry (LA-HR-ICP-MS) and High Resolution Inductively Coupled Plasma Mass Spectrometry (HR-ICP-MS)." FIU Digital Commons, 2008. http://digitalcommons.fiu.edu/etd/185.

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The need for elemental analysis of biological matrices such as bone, teeth, and plant matter for sourcing purposes has emerged within the forensic and geochemical laboratories. Trace elemental analyses for the comparison of aterials such as glass by inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS has been shown to offer a high degree of discrimination between different manufacturing sources. Unit resolution ICP-MS instruments may suffer from some polyatomic interferences including 40Ar16O+, 40Ar16O1H+, and 40Ca16O+ that affect iron measurement at trace levels. Iron is an important element in the analysis of glass and also of interest for the analysis of several biological matrices. A comparison of the nalytical performance of two different ICP-MS systems for iron analysis in glass for determining the method detection limits (MDLs), accuracy, and precision of the measurement is presented. Acid digestion and laser ablation methods are also compared. Iron polyatomic interferences were reduced or resolved by using dynamic reaction cell and high resolution ICP-MS. MDLs as low as 0.03 ìg g-1 and 0.14 ìg g-1 for laser ablation and solution based analyses respectively were achieved. The use of helium as a carrier gas demonstrated improvement in the detection limits of both iron isotopes (56Fe and 57Fe) in medium resolution for the HR-ICP-MS and with a dynamic reaction cell (DRC) coupled to a quadrupole ICP-MS system. The development and application of robust analytical methods for the quantification of trace elements in biological matrices has lead to a better understanding of the potential utility of these measurements in forensic chemical analyses. Standard reference materials (SRMs) were used in the development of an analytical method using HR-ICP-MS and LA-HR-ICP-MS that was subsequently applied on the analysis of real samples. Bone, teeth and ashed marijuana samples were analyzed with the developed method. Elemental analysis of bone samples from 12 different individuals provided discrimination between individuals, when femur and humerus bones were considered separately. Discrimination of 14 teeth samples based on elemental composition was achieved with the exception of one case where samples from the same individual were not associated with each other. The discrimination of 49 different ashed plant (cannabis)samples was achieved using the developed method.

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Tang, Yue tang. "Non-Integer Root Transformations for Preprocessing Nano-Electrospray Ionization High Resolution Mass Spectra for the Classification of Cannabis." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1534221170873289.

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Smart, K. E. "High resolution secondary ion mass spectrometry analysis of trace metals in biological materials." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442655.

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Albassam, Osamah M. "Using high resolution mass spectrometry to profile impurities in drugs from different sources." Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=28666.

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Impurities in active pharmaceutical ingredients (APIs) include volatile and involatile organic compounds and inorganic anions and cations. The impurities in an API are acquired during the manufacturing process and may arise from impurities in reagents, side reactions and may, as in the case of ionic impurities associate with the molecule during purification processes. Impurity levels have to be controlled to conform to pharmacopoeial requirements; although this is less apparent in the case of organic and inorganic counterions. In the work reported in this thesis four applications of impurity profiling in APIs and API intermediates were investigated. In chapter 3 the removal of impurities in lipoic acid prior to crystallisation was investigated using high resolution mass spectrometry in combination with chemometric modelling of the data. Several impurities of lipoic acid were characterised by using MSn and the success of the purification process in removing impurities was verified. In chapter 4 the organic impurities in chlorpheniramine maleate were investigated using high resolution mass spectrometry in combination with chemometric modelling of the data. Several new impurities of chlorpheniramine maleate were characterised by using MSn and it was demonstrated that it was possible to distinguish between different manufacturers’ batches of chlorpheniramine maleate according to their impurity profiles by using high resolution mass spectrometry data in combination with chemometric modelling. In chapter 5 the anionic impurities in different pharmaceutical bases were investigated by using capillary ion chromatography. The different pharmaceutical bases contained a wide range of trace ions as well as the main counter-anion. Aside from the anions being present as impurities they might have an impact of processing procedures such as crystallisation. In chapter 6 a range of techniques including nuclear magnetic resonance spectroscopy, high resolution LC-MSn, headspace gas chromatography mass spectrometry, anion and cation chromatography were applied to the analysis of 6-aminopenicillanic acid (6-APA) samples, provided by GSK, which had of low to high clarity values. It was not possible to find any direct association between clarity readings and the various impurity profiles although a number of new impurities in 6-APA were characterised.

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Aboulmagd, Khodier Sarah. "Analysis of Lipids in Kidney Tissue Using High Resolution MALDI Mass Spectrometry Imaging." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19443.

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Massenspektrometrisches Imaging (MSI) ist unverzichtbar für die Untersuchung der räumlichen Verteilung von Molekülen in einer Vielzahl von biologischen Proben. Seit seiner Einführung hat sich MALDI zu einer dominierenden Bildgebungsmethode entwickelt, die sich als nützlich erwiesen hat, um die Komplexität von Lipidstrukturen in biologischen Geweben zu bestimmen. Einerseits ist die Rolle von Cisplatin bei der Behandlung von menschlichen malignen Erkrankungen gut etabliert, jedoch ist Nephrotoxizität eine limitierende Nebenwirkung, die Veränderungen des renalen Lipidprofils beinhaltet. Dies führte zu der Motivation, die Lipidzusammensetzung des Nierengewebes in mit Cisplatin behandelten Ratten zu untersuchen, um die involvierten Lipid-Signalwege aufzuklären. Es wurde eine Methode zur Kartierung der Lipidzusammensetzung in Nierenschnitten unter Verwendung von MALDI MSI entwickelt. Die Verteilung von Nierenlipiden in Cisplatin-behandelten Proben zeigte deutliche Unterschiede in Bezug auf die Kontrollgruppen. Darüber hinaus wurde die Beurteilung der Ionenbilder von Lipiden in Cisplatin-behandelten Nieren meist als qualitative Aspekte betrachtet. Relative quantitative Vergleiche wurden durch den variablen Einfluss von experimentellen und instrumentellen Bedingungen begrenzt. Daher bestand die Notwendigkeit, ein Normalisierungsverfahren zu entwickeln, das einen Vergleich der Lipidintensität verschiedener Proben ermöglicht. Das Verfahren verwendete einen Tintenstrahldrucker, um eine Mischung der MALDI-Matrix und der internen internen Lipid-Metall-Standards aufzubringen. Unter Verwendung von ICP-MS erlaubte der interne Metallstandard, die Konsistenz der Matrix und der internen Standards zu bestätigen. Die Anwendung der Methode zur Normalisierung von Ionenintensitäten von Nierenlipiden zeigte eine ausgezeichnete Bildkorrektur und ermöglichte einen relativen quantitativen Vergleich von Lipidbildern in Cisplatin-behandelten Proben.
Mass spectrometry imaging is indispensable for studying the spatial distribution of molecules within a diverse range of biological samples. Since its introduction, MALDI has become a dominant imaging method, which proved useful to sort out the complexity of lipid structures in biological tissues. The role of cisplatin in the treatment of human malignancies is well-established. However, nephrotoxicity is a limiting side effect that involves an acute injury of the proximal tubule and alterations in the renal lipid profile. This evolved the motivation to study the spatial distribution of lipids in the kidney tissue of cisplatin-treated rats to shed light on the lipid signaling pathways involved. A method for mapping of lipid distributions in kidney sections using MALDI-LTQ-Orbitrap was developed, utilizing the high performance of orbitrap detection. The distribution of kidney lipids in cisplatin-treated samples revealed clear differences with respect to control group, which could be correlated to the proximal tubule injury. The findings highlight the usefulness of MALDI MSI as complementary tool for clinical diagnostics. Furthermore, assessment of the ion images of lipids in cisplatin-treated kidney mostly considered qualitative aspects. Relative quantitative comparisons were limited by the variable influence of experimental and instrumental conditions. Hence, the necessity developed to establish a normalization method allowing comparison of lipid intensity in MALDI imaging measurements of different samples. The method employed an inkjet printer to apply a mixture of the MALDI matrix and dual lipid-metal internal standards. Using ICP-MS, the metal internal standard allowed to confirm the consistency of the matrix and internal standards application. Applying the method to normalize ion intensities of kidney lipids demonstrated excellent image correction and successfully enabled relative quantitative comparison of lipid images in control and cisplatin-treated samples.

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Verkh, Yaroslav. "Characterization of dissolved organic matter in wastewater using liquid chromatography-high resolution mass spectrometry." Doctoral thesis, Universitat de Girona, 2019. http://hdl.handle.net/10803/667411.

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Individual hazardous chemicals and substance mixtures with synergistic toxicity ef-fects occur in the dissolved organic matter (DOM) of wastewater and negatively im-pact human health. Yet a large number of chemicals and their treatment by-products in wastewater makes the tracking of individual compounds nearly impossible and de-mands new analytical strategies. The thesis describes the development and evaluation of non-targeted and suspect anal-ysis methods aimed at the transformation of DOM and micro-contaminants of interest during wastewater treatment using liquid chromatography-high-resolution mass spec-trometry (LC-HRMS) data. On one hand, a non-targeted method to track transformations of DOM in a multiphase wastewater treatment using LC-HRMS data was developed. LC-MS signals were ex-tracted, aligned, and had their isotopologues clustered and elemental composition pre-dicted using open license software MZmine 2 in a way that conceptually prioritized the detection of anthropogenic compounds
El destino de los microcontaminantes en el tratamiento de aguas residuales ha ido ga-nando atención debido al impacto ecológico y toxicológico de estas sustancias en la salud humana. Adicionalmente a los productos químicos peligrosos individuales, las mezclas de sustancias como las que ocurren en la materia orgánica disuelta (MOD) en las aguas residuales, pueden producir efectos de toxicidad sinérgicos. Sin embargo, el gran número de compuestos naturales y antropogénicos, así como sus productos de transformación de tratamiento (PTs) provocan que el seguimiento de los compuestos individuales sea casi imposible, exigiendo nuevas estrategias para realizar un segui-miento eficaz de transformaciones MOD. Esta tesis describe un método desarrollado y probado para rastrear transformaciones de MOD en aguas residuales, utilizando un análisis no dirigido de cromatografía de líquidos y espectrometría de masas de alta resolución (LC-MS). Potencialmente, el análisis prioriza la detección de compuestos antropogénicos

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Myton, David Michael. "Development and Applications of High Resolution Kinetic Atmospheric Pressure Ionization Mass Spectrometry in Atmospheric Chemistry." PDXScholar, 1991. https://pdxscholar.library.pdx.edu/open_access_etds/1209.

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Much important work has been done to understand reaction pathways and identify products, yields, and reaction rates for atmospheric oxidation processes. Non-methane hydrocarbons (NMHCs) are the most significant of the organic compounds present in the atmosphere from a chemical perspective and are released into the atmosphere from both natural and anthropogenic sources. The oxidation of these hydrocarbons by hydroxyl radical HO generates products that may themselves be toxic, that play a major role in the formation of photochemical smog, and that to a lesser extent contribute to the formation of acid precipitation. NMHCs have chemical reactivities many times that of methane, the most abundant HC in the atmosphere. However, the atmospheric oxidation processes of less than 50% of atmospheric NMHCs are known. A new experimental technique is needed that can provide insight into atmospheric oxidation products, reaction intermediates, and the relative importance of secondary reaction pathways that follow the initial attack of HO upon a hydrocarbon. The technique should operate at atmospheric pressure to better represent natural reaction processes and conditions, and provide a rapid and direct measure of product identities and yields. In this study we will describe the development and application of a technique that we believe meets these requirements, a technique we call High Resolution Kinetic Atmospheric Pressure Ionization Mass Spectrometry (HRKAPIMS). We begin with the use of atmospheric pressure ionization mass spectrometry in studies of atmospheric oxidation processes. We first describe a potential pitfall in the use of APIMS for the analysis of smog chamber experiments, a common APIMS application, discussing methods to eliminate interference reactions that would otherwise make interpretation difficult. A new experimental approach to the use of APIMS for the analysis of oxidation processes is next described and its use demonstrated. The oxidation of toluene by API source-generated HO produces oxidation products that are protonated and detected by the mass spectrometer. With this approach, we observe all the products found in a variety of previous studies employing a large array of experimental setups and analytical instrumentation. This is significant because our experiments are carried out in a far simpler experimental environment. Toluene is chosen for these experiments because it is an important constituent in polluted urban atmospheres with a complex oxidation mechanism that remains poorly understood. We describe the development of HRKAPIMS, a powerful new approach that allows the simultaneous detection of stable products along with free radical intermediates. The use of nitric oxide to affect product yields is demonstrated, giving valuable insights into reaction kinetics and mechanisms. We also address the theoretical aspects of HRKAPIMS, describing semiempirical calculations to estimate gas-phase basicities for a wide variety of compounds and discuss the errors implicit in this approach. The use of gas-phase basicities is discussed in terms of mass spectrometric analysis and analyte response. Kinetic and thermodynamic modeling is used to address the issues of APIMS and HRKAPIMS sensitivity and response and gain insights into the conditions necessary for linear response and quantitative detection of analytes.

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Pervukhin, Anton. "Molecular formula identification using high resolution mass spectrometry algorithms and applications in metabolomics and proteomics /." kostenfrei, 2009. http://d-nb.info/1001408578/34.

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Moore, Katie Louise. "High resolution secondary ion mass spectrometry analysis of trace elements in cereal grain and roots." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:ab4f4a19-baca-48a7-af54-b9c5d87f3b7a.

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This thesis presents information on the subcellular localisation of two important trace elements, selenium and arsenic, in wheat, rice and rice roots for what is believed to be the first time. The general aim of this work was to illustrate the potential of using physical science techniques to solve biological problems. High resolution secondary ion mass spectrometry was undertaken using the CAMECA NanoSIMS50 with a sensitivity down to ppm concentrations and a lateral resolution of less than 100 nm. Selenium in wheat grain was found to be distributed across both the bran layer and the endosperm region with Se-rich hotspots found in the aleurone cells and a higher intensity of Se in the subaleurone region. Arsenic in rice grain was found in two key regions. In grains with high As and high dimethylarsinic acid (DMA) content, As was predominantly localised to the subaleurone region yet in lower concentration, hydroponically grown As(III)-treated grains the As was only localised to the aleurone layer near the ovular vascular trace (OVT). A combined NanoSIMS and S-XRF experiment revealed As hotspots near the OVT. A combination of high pressure freezing, high resolution secondary ion mass spectrometry and TEM was used to localise As in the roots of rice plants revealing a contrasting subcellular distribution of As and Si in the roots even though arsenite and silicic acid are transported across the plasma membranes by the same transporters. Fe plaque forms only on the root epidermis and was shown to be a strong sink for As. Colocalisation of S with As in the vacuoles of the endodermis, pericycle and xylem parenchyma supports the notion that As is stored as arsenite-phytochelatin complexes in the roots while Si is localised in the endodermis cell walls and is not strongly affected by the Lsi2 mutation.

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Wang, Kai [Verfasser]. "Chemical characterization of organic aerosol from Chinese cities using high resolution mass spectrometry / Kai Wang." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1201829089/34.

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Mathieson, Jennifer Sharon. "Probing the self assembly, reactivity and structure of supramolecular architectures using high resolution mass spectrometry." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2693/.

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Electrospray (ESI-MS) and cryospray mass spectrometry (CSI-MS) techniques were developed to analyse and investigate the self-assembly, reactivity and structure of supramolecular architectures. Using ESI-MS, the complexation reactions of the ligand cis,trans-1,3,5-tris(pyridine-2-carboxaldimino)cyclohexane (ttop) with divalent first row transition metal salts to form complexes with nuclearities 1,2 and 4 were followed. In-situ mass spectrometry was also utilised to show the stepwise formation of the ligand-metal complexes. Mass spectrometry has been used to identify the reactive species in the catalytic oxidation of conventionally hard to activate C-H and C=C moieties. The identity of the reactive species under catalytic conditions has been postulated as Fe(V)=O but direct observation of this species has not been possible before. Using cryospray mass spectrometry, the Fe(V)=O reactive intermediate within the synthetic [FeV(O)(OH)(PyMe2tacn)]+ (PyMe2tacn = 1-(2’-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane) complex at -40 ºC and its reaction with an olefin was observed. Oxygen atom transfer from H2O2 / H2O was followed through Fe(V)=O to the products with isotopic labelling, and the reactivity was probed as a function of temperature. Mass spectrometry has been used as both a qualitative and quantitative tool to deduce the stoichiometry of an anion receptor and the corresponding anion. Job plots of mass spectrometry data have been compared to the conventional 1H NMR job plot data to give corresponding results therefore providing evidence of the use of mass spectrometry as a quantitative and qualitative analytical tool. Mass spectrometry has been used to follow the formation of heterometallic complexes and provide evidence of their building block in solution. The formation of the complexes has been followed using time-resolved mass spectrometry experiments and the building blocks analysed.

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Jiang, Haibo. "Exploiting stable isotope imaging with high resolution secondary ion mass spectrometry for applications in biology." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:15456362-6022-41e1-b78d-1127d6d172b0.

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This thesis presents applications of high resolution secondary ion mass spectrometry (NanoSIMS) analysis for stable isotope imaging in biological samples. These projects were designed to explore the potential applications of NanoSIMS analysis, and to develop protocols and novel methodologies to visualize and quantify biological processes. Working with collaborators in the UK and USA, I have applied NanoSIMS analysis to study 3 research areas, including molecule interactions, single cell metabolisms and lipid imaging in tissues. Antimicrobial peptides (AMPs) play important role in the immune system, and understanding how AMPs interact with cell membranes can provide useful information to design new therapies to control infection. The pore structures and dynamics of the interaction of AMPs with membranes has been visualized for the first time and confirmed with combined AFM and NanoSIMS analysis. A correlative backscattered electron (BSE) imaging and NanoSIMS analysis methodology has been developed to study glutamine metabolism in single cancer cells. This method enables us to measure the chemical information in specific organelles in these cells and can be widely applied to study metabolisms and to trace the uptake of labelled molecules in biological matrices. Quantitative analysis on the effects of hypoxic conditions and the PYGL gene were studied. Applying correlative BSE and NanoSIMS analysis, I also studied lipid uptake mechanisms in various mouse tissues, including brown adipose tissue, heart, intestines, liver and skeletal muscle, mainly focused on a recently discovered protein, GPIHBP1, and its function in the lipid uptake process. TRL margination was proved to depend on the GPIBP1-LPL complex, and 3 stages of lipid transport from capillary lumen to lipid droplets was also visualized by combined BSE and NanoSIMS analysis.

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Wang, Mingda. "New and improved ion traps for high resolution Fourier transform ion cyclotron resonance mass spectrometry /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487681788254101.

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Kawashima, Masahiro. "High-resolution imaging mass spectrometry reveals detailed spatial distribution of phosphatidylinositols in human breast cancer." Kyoto University, 2014. http://hdl.handle.net/2433/188666.

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Seither, Joshua Zolton. "Application of High Resolution Mass Spectrometry for the Screening and Confirmation of Novel Psychoactive Substances." FIU Digital Commons, 2018. https://digitalcommons.fiu.edu/etd/3823.

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There has been an emergence of novel psychoactive substances (NPS) in forensic casework globally. Although the reported prevalence of these compounds has been relatively low in comparison to traditional drugs of abuse, published case studies suggest that some NPS have significant pharmacological effects that may cause severe impairment and/or death. Because of these effects, it is important that toxicology laboratories have the capability of identifying these compounds to complete a comprehensive toxicological analysis for human performance and post-mortem investigations. Recently, mass spectrometry has gained favor over traditional screening assays such as immunoassays for the identification of NPS in biological specimens. This trend is mainly a result of the fact that mass spectrometry provides the required sensitivity and selectivity for a broader range of analytes. High resolution tandem mass spectrometry has been suggested for analysis of NPS, as this technique further increases selectivity by increasing mass accuracy and providing MS/MS spectral data. The main goal of the present study was to investigate the applicability of using high resolution mass spectrometry to screen for and confirm a large number of novel psychoactive substances. The present study consisted of three main tasks, which included 1) the creation of a large high resolution MS/MS spectral library and database, 2) the development of a solid phase extraction (SPE) method and acquisition methods, and 3) a collision induced dissociation (CID) study of regioisomeric NPS compounds. The MS/MS spectral library created contains spectral data for 252 NPS. In addition, 875 NPS entities were included in the compound database. The library and database can be used by toxicology laboratories to aid in the identification of NPS in casework using MS/MS spectral data and full scan MS data, respectively. The analytical method developed used SPE and high resolution mass spectrometry (HRMS). The HRMS method demonstrated limits of detection ranging from 0.5- 5 ng/mL for NPS from various structural drug classes. The CID experiments demonstrated that relative ion abundance alone could be used to differentiate some sets of regioisomers. The present work can aid toxicology laboratories in the identification of NPS and demonstrates the applicability of HRMS for their screening and confirmation.

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Ofori, Hayford. "Characterisation of sandalwood essential oils using high performance thin-layer chromatography and high resolution gas chromatography mass spectrometry." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2020. https://ro.ecu.edu.au/theses/2326.

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Sandalwood essential oil is extensively used in perfumes, cosmetics, and pharmaceuticals. The unique woody aroma of sandalwood essential oil is produced by (Z)-α-santalol and (Z)-β-santalol and these two compounds influence the oil quality. Variation in sesquiterpene composition and oil yield have been observed both within and across Santalum species. Gas Chromatography-Mass Spectrometry (GC-MS) is a technique commonly used to identify and quantify sesquiterpene compounds in sandalwood essential oils. High Performance Thin-Layer Chromatography (HPTLC) has yet to be fully explored as an alternative to GC-MS in authenticating sandalwood essential oils of different species. In this study, sandalwood essential oils were characterised using HPTLC and high resolution GC-MS. The potential of HPTLC to identify differences in sandalwood essential oils of Santalum album, Santalum spicatum, Santalum austrocaledonicum, Santalum paniculatum, Santalum lanceolatum and a natural substitute for sandalwood, Osyris lanceolata, was explored. Variation was observed in the profile of bands and peak intensity profiles of the essential oils with some bands being unique to the individual species. The potential of HPTLC fingerprinting as a quality control tool in identifying differences in sandalwood essential oils was demonstrated (Study I). Study I was limited to a maximum of five oils for each species studied. The natural variability was likely not captured for such a small sample size. The potential of HPTLC to generate a sandalwood profile that better represents Santalum album, Santalum spicatum, Santalum austrocaledonicum and Santalum paniculatum was explored. Santalum spicatum could confidently be distinguished from other species with a distinctive pink band at RF 0.71 and unique peak intensities at RF 0.28, 0.45 and 0.47. Santalum album and Santalum paniculatum could easily be distinguished from each other with distinctive peak intensities at RF 0.51 and 0.17 respectively. The intense peak at RF 0.09 displayed by Santalum austrocaledonicum distinguished it from Santalum album, and Santalum paniculatum but not Santalum spicatum (Study II). An ultrasonication extraction method was optimised for extraction of essential oil from Western Australia sandalwood (Santalum spicatum) using n-hexane, isopropanol, and n-hexane/isopropanol (50:50, v/v) for different extraction times. Oil yield was moderately influenced by solvent, particle size and extraction time. Extracting for 30 minutes with particle size 250µm-500µm using n-hexane gave the highest oil yield and santalol content. The santalol content achieved in Santalum spicatum extract was influenced by particle size and solvent (Study III). The optimised method in Study III was moderately modified and successively applied to extract oil from 340 milled heartwoods of Santalum spicatum. GC-MS analysis was performed on oil extracts. Variation in sesquiterpene composition of 340 heartwood oil extracts of Santalum spicatum sampled from 19 locations across five regions in Western Australia was explored. Variation was observed in sesquiterpene composition, and oil yield both across and within all five regions. Heartwood oil extracts from trees in the north obtained higher oil yield and santalol content when compared to oil extracts from trees in the south. Interestingly, one oil extract of S. spicatum met the ISO specification of 90% combined α-santalol and β-santalol in Santalum album, obtaining 67.47% α-santalol and 22.92% β-santalol (Study IV).

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Huang, Fan. "APPLICATION OF HIGH-RESOLUTION ACCURATE MASS (HRAM) MASS SPECTROMETRY FOR ANALYSIS OF LIGNIN MODEL COMPOUNDS AND THE POST-PRETREATMENT PRODUCTS." UKnowledge, 2017. http://uknowledge.uky.edu/chemistry_etds/74.

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Lignin, one of main components in the woody cell walls, is a complex heterogeneous biopolymer, which provides structural support and transportation of water in plants. It is highly recalcitrant to degradation (both chemically and environmentally) and protects cellulose from being degraded/hydrolyzed. Due to the structural complexity of native lignin, complete characterization and elucidation of lignin’s structure remains very challenging. The overarching goal of this work is to develop mass spectrometry based analytical methods to contribute to a better understanding of lignin structures. This dissertation will focus on the development and application of High-Resolution Accurate-Mass (HRAM) Mass Spectrometry (MS) as main analytical technique for studying lignin model compounds, including understanding the ionization behavior, studying corresponding fragmentation patterns and extracting structural information for structural elucidation eventually. Analytical methods were also developed to study the post-pretreatment products of the synthetic trimeric model compound using High-Performance Liquid Chromatography (HPLC) coupled with High-Resolution Accurate Mass (HRAM) Mass Spectrometry (MS). The first project of this dissertation focuses on mass spectral the characterization of lignin models from the in vitro oxidative coupling reactions. Three specific trimeric compounds were isolated and their ionization behaviors were investigated using HRAMMS via electrospray ionization (ESI). The reaction parameters of the in vitro oxidative coupling reaction were critical in alternating the linkage profiles of resulting dehydrogenation polymers (DHPs). Reaction parameters were tuned to obtain desired DHP linkages profile. Upon the isolation of three different trimeric compounds, a systematic comparison of ionization efficiency of three trimeric compounds was carried out using ESI-HRAM-MS under different ionization conditions. The second project was aimed to design a synthetic route for a lignin model compound that will be a good representation for native lignin during the pretreatment process. The model compound of interest has not been obtained previously through chemical synthesis. Due to the reactivity of cinnamyl alcohol, which contains the unsaturated side chain, this new synthesis strategy was developed based on the known aldol-type reaction route. A versatile synthesis procedure for preparation of β-O-4 oligomeric compounds was designed and implemented to include the most important functional groups (phenolic alcohol, aryl glycerol β-aryl ether bond and unsaturated side chain) in the resulting model compound. This new synthesis route also allowed incorporation of different monolignols. In the third project, Fenton chemistry was applied to a synthetic lignin model compound. Due to the non-specificity in the post pretreatment product profile, nontargeted analytical strategy was developed and applied to study the post-pretreatment products of the model compound using HPLC-HRMS. The results from this dissertation showed a significant difference in ionization behavior between three structurally different model compounds and indicated that primary structures of lignin compounds can largely affect corresponding electrospray ionization properties as well as fragmentation pattern. The work in this dissertation provides analytical techniques for non-targeted analysis of complex lignin samples and an insightful understanding of Fenton’s reaction pretreatment upon lignin model compound.

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Aiken, Allison Carol. "Quantitative chemical analysis of ambient organic aerosols using high-resolution time-of-flight aerosol mass spectrometry." Connect to online resource, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3337069.

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32

Pereira, Kelly Louise. "Investigation of high resolution mass spectrometry to study the formation and evolution of secondary organic aerosol." Thesis, University of York, 2014. http://etheses.whiterose.ac.uk/8285/.

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Secondary organic aerosol (SOA) is well known to have adverse effects on climate, air quality and human health. However, the dynamic mechanisms occurring during SOA formation and ageing are poorly understood. In this study, a number of new instrumental methods based on liquid chromatography coupled to mass spectrometry were developed and validated to study the complex mechanisms controlling SOA formation and ageing. The method was tested on methyl chavicol, an oxygenated biogenic volatile organic compound that was recently identified as the main floral emission from an oil palm plantation in Malaysian Borneo. The photo-oxidation of methyl chavicol was investigated at the European Photoreactor. The SOA yield was determined to range between 19 - 31% depending on initial precursor (VOC:NOx) mixing ratios. In total, 79 SOA compounds were observed and the structures of 10 compounds have been identified. The use of a time resolved aerosol collection method followed by offline mass spectrometry allowed the temporal evolution of individual compounds in the particulate phase to be observed. The majority of the observed initial SOA composition consisted of substituted nitrophenols. The photo-oxidation of two other aromatic systems (toluene and 4-methyl catechol) were also investigated. The photo-oxidation of toluene also resulted in the formation of substituted nitrophenols during initial aerosol growth. However, based on the volatility of these species and the amount of absorptive mass present, these compounds would not be expected to be in the aerosol phase. One possible explanation for this observation, is the formation of gas-phase clusters; suggesting that the presence of the nitro-group on the aromatic ring may be responsible for new particle formation. However, the structure of the nitrophenols were found to be critically important; highlighting the importance of studying SOA formation and evolution at a molecular level.

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Hertzog, Jasmine. "High resolution mass spectrometry for molecular characterization of bio-oils produced by pyrolysis of lignocellulosic biomass." Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0180/document.

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Les produits de la pyrolyse de la biomasse lignocellulosique présentent un potentiel important dans le cadre des ressources renouvelables. Cependant, leur utilisation directe est réduite en raison de leur importante complexité et de leur teneur élevée en oxygène. Il est nécessaire de leur faire subir des traitements de désoxygénation et/ou de craquage. Afin de déterminer quels sont les traitements les mieux adaptés, il est indispensable de connaitre aussi précisément que possible leur composition. Les travaux menés dans le cadre de cette thèse portent sur la mise en place de méthodologies d’analyse robustes pour obtenir la description la plus exhaustive possible des bio-huiles. Pour cela, la spectrométrie de masse à résonance cyclotronique d’ions à transformée de Fourier (FT-ICR MS) a été employée en couplage avec différentes sources d’ionisation. L’électronébulisation (ESI), dans des conditions contrôlées d’ionisation, permet d’observer plus particulièrement les composés dérivés de la cellulose et de l’hémicellulose ainsi que des lipides et des dérivés de la lignine. La photoionisation à pression atmosphérique (APPI) et la désorption-ionisation par laser (LDI) sont plus spécifiques des espèces relatives à la lignine. Celles qui sont alors observées sont plus insaturées qu’en ESI. La complémentarité des différentes techniques d’analyse a été établie et a permis la description détaillée de bio-huiles. Cette méthodologie a été appliquée à des bio-huiles avant et après traitement de désoxygénation/cracking sur zéolithes. L’analyse par ESI FT-ICR MS a mis en évidence la sélectivité de ces catalyseurs envers les dérivés cellulosiques alors que l’étude par APPI et LDI a permis de déterminer la nature des composés obtenus après traitement catalytique. Ceux-ci présentent une diminution de la teneur en oxygène et résultent, pour une partie d’entre eux, du craquage catalytique sur les composés de la bio-huile originelle
The products of lignocellulosic biomass pyrolysis are potential sources of renewable materials such as bio-fuels, biochars, and chemicals. However, their ready-to-use capacity is limited by their high chemical complexity and their high oxygen content. Therefore, they have to be upgraded by different treatments such as deoxygenation and/or cracking. In order to assess the most suited upgrading process, it is necessary to obtain an extensive composition description of the raw pyrolysis products. The works carried out during this PhD thesis are dealing with the development of though analytical methods to reach the most detailed composition description of bio-oils. This study was performed by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) using different ionization sources. The electrospray ionization (ESI), in controlled-conditions, ensures to ionize the cellulose and the hemicellulose derived compounds as well as the lipids and the lignin derivatives. The atmospheric pressure photoionisation (APPI) and the laser desorption/ionization (LDI) allow specifically to detect more unsaturated pyrolytic lignin species. The combination of the different results ensures to obtain an extensive bio-oil description. The established methodology was applied to raw and upgraded (catalytic deoxygenation/cracking treatment on different zeolites) bio-oils. The ESI FT-ICR MS measurements evidenced the selectivity of the used catalysts on sugaric compounds whereas the APPI and LDI highlighted the nature of the resulting compounds which are less oxygenated and produced, for a part of them, by catalytic cracking

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Nambiar, Shabarinath. "Unravelling the Lipidome of Idiopathic Pulmonary Fibrosis and its Spatial Distribution using High Resolution Mass Spectrometry." Thesis, Nambiar, Shabarinath (2018) Unravelling the Lipidome of Idiopathic Pulmonary Fibrosis and its Spatial Distribution using High Resolution Mass Spectrometry. PhD thesis, Murdoch University, 2018. https://researchrepository.murdoch.edu.au/id/eprint/43984/.

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Chronic lung diseases are complex, progressive disorders with increasing incidence and mortality. Chronic obstructive pulmonary disease (COPD), asthma and pulmonary fibrosis are examples of chronic lung conditions that can significantly impact the quality of life. Minimally-invasive diagnostic methods that eliminate bronchoscopic and surgical biopsy from patients are ideal; metabolomics therefore holds considerable promise for the discovery of biomarkers that can aid diagnosis and treatment with greater sensitivity, specificity and precision. The main aim of this project was to employ ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-QTOF) high resolution mass spectrometry (HRMS) and matrix-assisted laser desorption ionisation (MALDI) mass spectral imaging (MSI) together with multivariate statistics-based metabolomics to identify and characterize potential lipid biomarkers of idiopathic pulmonary fibrosis (IPF). This dissertation consists of the following studies: (1) literature review of metabolomics in chronic lung diseases; (2) application of HRMS for untargeted metabolic profiling of chronic lung disease including COPD and IPF; (3) investigation of a novel data-independent acquisition (DIA) approach to augment untargeted approaches for lipid biomarker identification; (4) development of a novel matrix application technique to improve MALDI-MSI acquisitions of tissue sections whilst maintaining spatial localisation of endogenous metabolites; and (5) exploiting potassium adduct formation to resolve the spatial distribution of lipids in fibrotic tissues. A total of 65 clinical plasma samples (from 20 healthy control subjects, 21 COPD and 24 IPF patients) were profiled using UHPLC-QTOF-MS. A fundamental challenge in using HRMS for untargeted profiling of complex, chronic lung diseases is the heterogeneity of the human samples. Various contaminations present in fibrotic tissues or adjacent non-fibrotic constituents can confound characterization and encumber the discovery of reliable biomarkers. The results of this study revealed significant correlation between COPD and IPF clinical phenotypes and plasma metabolite profiles. The unbiased metabolomics workflow and deconvolution pipeline provided end-to-end analysis from peak picking and annotation through to metabolite identification. Subsequently, the ability of the UPLC-QTOF-MS method to discriminate between lipid species was enhanced by the application of a DIA method to distinguish between “stable versus progressor” IPF patients. This DIA method is known as SONAR and uses a wide, continuously sliding precursor window for fragmentation, thereby allowing correlation of precursor and fragment ions. SONAR lipid data were processed using Progenesis QI and searched against LIPID MAPS for structural elucidation and metabolite confirmation. The lipids identified were found to be intermediates of key metabolic pathways such as the glycolytic/TCA cycle, mitochondrial-beta oxidation and lipid metabolism and hold considerable promise as biomarkers of disease. The matrix deposition step in MALDI-MSI is crucial for simultaneous extraction of metabolites from tissue sections as well as maintaining the spatial dimensionality of the endogenous metabolites. A novel, efficient and cost-effective preparative method referred to as the “freeze-spot” method was developed using wheat seed sections to demonstrate extraction efficiency and reliability, whilst maintaining the spatial resolution of the acquired MALDI-MSI images. The technique was also found to be simple and robust, forming fine matrix crystals that enabled efficient ionisation of surface metabolites, further eliminating the need for sophisticated matrix application approaches. In the final study, 10 healthy and 10 fibrotic tissues were compared using MALDI-MSI. The MSI technique developed uses potassium adduct formation to improve spatial resolution and dimensionality of lipid species such as triglycerides (TG), ceramides, sphingolipids and glycerophospholipids. The results of this study showed changes in lipid composition of IPF tissues compared to healthy controls. This study identified lysophosphatidylcholine (LysoPC), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) as potential lipid biomarkers of the disease and requires further study as targets of intervention and treatment. Both SONAR and MSI successfully identified similar classes of lipids (TG, PE, LysoPC and PC) which may play a role in the pathophysiology of the IPF lipidome. This project highlighted the complementarity of HRMS and MSI based metabolomics for the characterization of unique lipid features in fibrotic tissue and plasma samples. The study also demonstrated the discriminative power of the unbiased DIA approach for the identification of lipids via fragment ion patterns that were indicative of specific lipid classes. In addition, the application of chemometric principal component analysis (PCA) and orthogonal partial least-squares to latent structures-direct analysis (OPLS-DA) proved useful for the identification of statistically significant lipids. This statistical approach allowed for the assessment of covariance and correlation between lipids and the modelled lung diseases, and further illustrated lipid compositional changes in chronic lung diseases. Taken together, the experimental work presented in this thesis show the large potential for mass spectrometry-based metabolomics as a tool for discovery. The specificity of the novel methods outlined will be highly beneficial for compound identification and further confirmation of disease biomarkers.

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Wink, Carina S. D. Verfasser], and Hans H. [Akademischer Betreuer] [Maurer. "1,2-diphenylethylamine designer drugs metabolism studies and toxicological analysis using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry coupled to low and high resolution-mass spectrometry / Carina S. D. Wink. Betreuer: Hans H. Maurer." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2016. http://d-nb.info/1104733323/34.

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Sievers-Engler, Adrian [Verfasser], and Michael [Akademischer Betreuer] Lämmerhofer. "High resolution quadrupole time of flight mass spectrometry in pharmaceutical bioanalysis / Adrian Sievers-Engler ; Betreuer: Michael Lämmerhofer." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1207831417/34.

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Blackburn, John William Teasdale. "High-resolution Fourier transform ion cyclotron resonance mass spectrometry and nuclear magnetic resonance spectroscopy of humic substances." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31149.

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Humic substances (HS) are described as a complex mixture of organic molecules formed by incomplete decomposition of plant, animal and microbial matter. They are found in soil, water and air and have many environmental roles, e.g. water retention and metal ion binding in soil. Despite their importance, the molecular composition of HS is poorly understood. This is mostly because of an inability to separate individual molecules from these complex mixtures and then characterise them by standard analytical methods such as NMR and MS. In order improve the understanding of these important mixtures I have studied them using a high-resolution analytical method, Fourier transform ion-cyclotron resonance mass spectrometry (FTICR MS). Initial efforts focussed on testing the, fast, automated data analysis of the large data sets produced. Two pieces of software were compared and the reliability of the formulae assigned by these was critically evaluated. This confident formula assignment was then applied to study the consequences of different ionisation and instrumental parameters on the mass spectra obtained. The use of laser desorption/ionisation (LDI) without the need to employ a matrix required in matrix assisted laser desorption/ionisation (MALDI) was explored. A comparison of LDI and electrospray ionisation (ESI) FTICR MS of natural organic matter samples showed that these methods ionise complementary sets of compounds. The LDI ionised compounds were characterised as aromatics or condensed aromatics and compounds belonging to lower oxygen classes (maximum number at O8), while ESI ionised higher oxygen classes (maximum number at O16) with a vast majority of compounds classified as aliphatic based on their modified aromaticity index. MALDI and LDI spectra produced very similar data with over 90% matching formulas implying that fragmentation is not caused by LDI, as taught previously. My work showed that to maximize the coverage by FTICR MS of the molecular space occupied by these complex mixtures, multiple ionization methods must be used. As a particularly convenient and readily deployable ionization technique, LDI should be included in standard analytical protocols for FTICR MS analysis of NOM. I have explored different parameters and experimental settings to obtain a fuller coverage of the molecular space of NOM, this showed that different experimental conditions enhance peak intensities in different m/z regions of the FTICR MS spectra and that information can be obtained outside of the narrow 200-700 m/z window. To gain chemical and structural information about humic substances beyond what is currently known, experiments aimed to label HS using different isotopes and at specific sites were developed and tested. Two methylation reactions were of particular interest. A methylation that selectively targeted carboxylic acid groups and incorporated deuterium in the form of CD3 groups. An international standard, Suwannee River fulvic acid, was methylated and analysed by high-resolution mass spectrometry in order to gain information on the number and distribution carboxylic acid groups. This proved challenging due to the reactivity of the unknown molecules being difficult to determine in advance. Additionally, the peak separation being reduced to as low as 1.5 mDa pushed the instrument resolution and assignment confidence to their limits. The second methylation method explored used 13CH3I, a nonselective agent reacting with any labile proton, particularly attaching 13CH3 groups to carboxylic, phenolic and alcoholic OH groups. I prepared a methylated sample of fulvic acid from a Red Moss raised bog (Balerno, near Edinburgh) ready for analyses by high field NMR. This investigation yielded structures of a number of phenolic compounds for the first time by NMR.

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Murch, Sarah Louise. "The role of liquid chromatography-high resolution mass spectrometry in the diagnosis and treatment of substance misuse." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-liquid-chromatographyhigh-resolution-mass-spectrometry-in-the-diagnosis-and-treatment-of-substance-misuse(e155a5b7-6155-4416-9516-6ea54e048a3b).html.

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Substance misuse remains problematic with current concerns being the rise in acute poisoning deaths, particularly opioid-associated, and the ever-widening range of drugs available. Strategies for tackling opioid addiction and opioid related-deaths include researching alternative routes of therapeutic agent administration. Initial urine screening for substance misuse has traditionally employed immunoassays, with confirmation of specific analytes by chromatographic methods. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) offers untargeted analysis without compromising selectivity, and enables users to ascertain putative elemental compositions of an analyte, retrospectively interrogate data, and to incorporate novel analytes easily. These features enable screening and confirmation of drugs in a single method, and may be advantageous for detecting novel psychoactive substances (NPS). This thesis aims to investigate the role of LC-HRMS in drug analysis in the clinical setting. A simple system was developed that is capable of detecting a wide range of commonly-encountered drugs and metabolites. Non-selective sample preparation was used to enable detection of as many compounds as possible, but significant matrix effects were observed. Additional information regarding selected NPS was ascertained through retrospective identification of mephedrone metabolites in patient urines, and through later incorporation of ethylphenidate, methylphenidate, and ritalinic acid, into the method. A separate quantitative LC-HRMS method was developed to facilitate pharmacokinetic studies of naloxone and naltrexone administered through alternative routes. The method was also applied to urine samples, with naloxone-3-glucuronide identified as a potential marker to differentiate between Subutex and Suboxone use. LC-HRMS has advantages in drug detection, particularly in regard to NPS, and in method development. However, application in the clinical setting is restricted by requirements for high throughput, timely results, and operation to accepted ‘cutoff’ values that introduce awkward compromises in system operation. LC-HRMS may have greater application in the forensic setting where more time is available for the analysis of a single sample.

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Rocha, Cláudia Manuela Mesquita da. "Metabolic signature of lung cancer: a metabolomic study of human tissues and biofluids." Doctoral thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/13957.

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Doutoramento em Química
This thesis reports the application of metabolomics to human tissues and biofluids (blood plasma and urine) to unveil the metabolic signature of primary lung cancer. In Chapter 1, a brief introduction on lung cancer epidemiology and pathogenesis, together with a review of the main metabolic dysregulations known to be associated with cancer, is presented. The metabolomics approach is also described, addressing the analytical and statistical methods employed, as well as the current state of the art on its application to clinical lung cancer studies. Chapter 2 provides the experimental details of this work, in regard to the subjects enrolled, sample collection and analysis, and data processing. In Chapter 3, the metabolic characterization of intact lung tissues (from 56 patients) by proton High Resolution Magic Angle Spinning (HRMAS) Nuclear Magnetic Resonance (NMR) spectroscopy is described. After careful assessment of acquisition conditions and thorough spectral assignment (over 50 metabolites identified), the metabolic profiles of tumour and adjacent control tissues were compared through multivariate analysis. The two tissue classes could be discriminated with 97% accuracy, with 13 metabolites significantly accounting for this discrimination: glucose and acetate (depleted in tumours), together with lactate, alanine, glutamate, GSH, taurine, creatine, phosphocholine, glycerophosphocholine, phosphoethanolamine, uracil nucleotides and peptides (increased in tumours). Some of these variations corroborated typical features of cancer metabolism (e.g., upregulated glycolysis and glutaminolysis), while others suggested less known pathways (e.g., antioxidant protection, protein degradation) to play important roles. Another major and novel finding described in this chapter was the dependence of this metabolic signature on tumour histological subtype. While main alterations in adenocarcinomas (AdC) related to phospholipid and protein metabolisms, squamous cell carcinomas (SqCC) were found to have stronger glycolytic and glutaminolytic profiles, making it possible to build a valid classification model to discriminate these two subtypes. Chapter 4 reports the NMR metabolomic study of blood plasma from over 100 patients and near 100 healthy controls, the multivariate model built having afforded a classification rate of 87%. The two groups were found to differ significantly in the levels of lactate, pyruvate, acetoacetate, LDL+VLDL lipoproteins and glycoproteins (increased in patients), together with glutamine, histidine, valine, methanol, HDL lipoproteins and two unassigned compounds (decreased in patients). Interestingly, these variations were detected from initial disease stages and the magnitude of some of them depended on the histological type, although not allowing AdC vs. SqCC discrimination. Moreover, it is shown in this chapter that age mismatch between control and cancer groups could not be ruled out as a possible confounding factor, and exploratory external validation afforded a classification rate of 85%. The NMR profiling of urine from lung cancer patients and healthy controls is presented in Chapter 5. Compared to plasma, the classification model built with urinary profiles resulted in a superior classification rate (97%). After careful assessment of possible bias from gender, age and smoking habits, a set of 19 metabolites was proposed to be cancer-related (out of which 3 were unknowns and 6 were partially identified as N-acetylated metabolites). As for plasma, these variations were detected regardless of disease stage and showed some dependency on histological subtype, the AdC vs. SqCC model built showing modest predictive power. In addition, preliminary external validation of the urine-based classification model afforded 100% sensitivity and 90% specificity, which are exciting results in terms of potential for future clinical application. Chapter 6 describes the analysis of urine from a subset of patients by a different profiling technique, namely, Ultra-Performance Liquid Chromatography coupled to Mass Spectrometry (UPLC-MS). Although the identification of discriminant metabolites was very limited, multivariate models showed high classification rate and predictive power, thus reinforcing the value of urine in the context of lung cancer diagnosis. Finally, the main conclusions of this thesis are presented in Chapter 7, highlighting the potential of integrated metabolomics of tissues and biofluids to improve current understanding of lung cancer altered metabolism and to reveal new marker profiles with diagnostic value.
A presente tese reporta a aplicação da metabolómica ao estudo de tecidos e biofluidos humanos (plasma sanguíneo e urina), com o intuito de caracterizar a assinatura metabólica do cancro pulmonar primário. No Capítulo 1, apresenta-se uma breve introdução sobre a epidemiologia e a patogénese deste tipo de cancro, bem como um sumário das principais alterações metabólicas tipicamente associadas ao cancro em geral. Descreve-se ainda a abordagem metabolómica, nomeadamente os métodos analíticos e estatísticos utilizados, assim como o estado da arte da sua aplicação em estudos clínicos do cancro do pulmão. No Capítulo 2, apresentam-se os detalhes experimentais deste trabalho, no que diz respeito ao grupo de indivíduos envolvidos, à colheita e análise das amostras e ao posterior tratamento dos dados. O Capítulo 3 descreve a caracterização metabólica de tecidos do pulmão (de 56 doentes) por espetroscopia de Ressonância Magnética Nuclear (RMN) de alta resolução com rotação no ângulo mágico. Após a otimização cuidada das condições de aquisição e a identificação detalhada dos sinais espetrais (mais de 50 metabolitos identificados), os perfis metabólicos dos tumores e dos tecidos adjacentes não envolvidos (controlos) foram comparados por análise multivariada, tendo sido discriminados com uma exatidão de 97%. Os metabolitos que mais significativamente contribuíram para esta diferenciação foram: glucose e acetato (diminuídos nos tumores), lactato, alanina, glutamato, GSH, taurina, creatina, fosfocolina, glicerofosfocolina, fosfoetanolamina, nucleótidos de uracilo e péptidos (aumentados nos tumores). Algumas destas variações corroboraram alterações típicas do metabolismo do cancro (e.g., glicólise e glutaminólise aumentadas), enquanto outras sugeriram novas pistas sobre a possível relevância de processos como a proteção antioxidante e a degradação proteica. Um outro resultado novo e importante descrito neste capítulo foi a dependência da assinatura metabólica em relação ao tipo histológico do tumor. Enquanto as principais alterações observadas nos adenocarcinomas (AdC) se relacionaram com o metabolismo fosfolipídico e proteico, os carcinomas de células escamosas (SqCC) apresentaram perfis glicolíticos e glutaminolíticos mais pronunciados, sendo possível construir um modelo válido para a discriminação destes subtipos. No Capítulo 4, apresenta-se o estudo metabolómico por RMN de plasma sanguíneo de mais de 100 doentes e quase 100 controlos saudáveis, do qual resultou um modelo multivariado com uma taxa de classificação de 87%. A distinção entre os grupos foi feita essencialmente com base nos níveis de lactato, piruvato, acetoacetato, lipoproteínas LDL+VLDL e glicoproteínas (aumentados nos doentes), juntamente com os níveis de glutamina, histidina, valina, metanol, lipoproteínas HDL e dois compostos não identificados (diminuídos nos doentes). Estas variações foram detetadas desde os estádios iniciais da doença e a magnitude de algumas delas dependeu do tipo histológico, embora não permitindo discriminar AdC de SqCC. Para além disso, mostra-se neste capítulo que o desequilíbrio dos grupos controlo e cancro em termos da idade dos indivíduos poderá ter alguma influência nos resultados, e apresenta-se uma tentativa exploratória de validação externa, que resultou numa taxa de classificação de 85%. O estudo por RMN do perfil metabólico da urina dos doentes com cancro do pulmão e dos controlos é apresentado no Capítulo 5. Comparativamente ao plasma, o modelo construído com os perfis urinários apresentou uma taxa de classificação superior (97%). Após uma avaliação cuidada da possível influência do género, idade e hábitos tabágicos, um conjunto de 19 metabolitos foi proposto como estando relacionado com a doença (incluindo 3 compostos desconhecidos e 6 parcialmente identificados como metabolitos N-acetilados). Tal como no caso do plasma, estas variações foram detetadas em doentes no estádio inicial e mostraram alguma dependência em relação ao tipo histológico, obtendo-se um modelo válido para a discriminação AdC vs. SqCC, ainda que com um poder preditivo modesto. Para além disso, o teste preliminar de validação externa revelou 100% de sensibilidade e 90% de especificidade, o que é um resultado bastante promissor em termos da potencial utilização dos perfis urinários em aplicações clínicas futuras. No Capitulo 6, descreve-se a caracterização dos perfis metabólicos da urina (de um subgrupo de indivíduos) por cromatografia líquida de ultra-eficiência acoplada a espetrometria de massa (UPLC-MS). Embora não avançando muito na identificação estrutural de possíveis marcadores, este estudo reforçou o valor diagnóstico da urina, já que os modelos multivariados resultantes apresentaram taxa de classificação e poder preditivo elevados. Finalmente, no Capítulo 7, apresentam-se as principais conclusões deste trabalho, realçando o contributo da metabolómica integrada de tecidos e biofluidos para a compreensão do metabolismo alterado do cancro do pulmão e para a deteção de novos perfis marcadores com valor diagnóstico.

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Linscheid, Michael [Gutachter], and Michael [Gutachter] Weller. "Analysis of Lipids in Kidney Tissue Using High Resolution MALDI Mass Spectrometry Imaging / Gutachter: Michael Linscheid, Michael Weller." Berlin : Humboldt-Universität zu Berlin, 2018. http://d-nb.info/1185578609/34.

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Alonezi, Sanad M. Z. "Metabolomic profiling of the effects of melittin and cisplatin on ovarian cancer cells using high resolution mass spectrometry." Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=28650.

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Over the last few years, metabolomics has come to play an increasingly important part in many fields of research, notably medical studies. However, there is a dearth of research on metabolomics in the area of ovarian cancer and the increase in anti-cancer (platinum) drug resistance. Thus further studies on the modes of anticancer action and the mechanisms of resistance of ovarian cancer cells at the metabolome level are needed. The aim of this study was to characterise the metabolic profiles of two human ovarian cancer cell lines, A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant), in response to their exposure to melittin, cisplatin and melittin-cisplatin combination therapy. It has been suggested that melittin may have potential as an anti-cancer therapy; combining cisplatin and melittin may increase response and tolerability in cancer treatment, as well as reducing drug resistance. The A2780 and A2780CR cell lines were treated with sub-lethal doses of melittin, cisplatin and melittin-cisplatin combination therapy for 24 hours before extraction and global metabolite analysis of cell lysates by LC-MS using a HPLC system. Phenotype MicroArray™ experiments were also applied in order to test carbon substrate utilisation or sensitivity in both cell lines after exposure to melittin and cisplatin. Data extraction was carried out with MZmine 2.10 with metabolite searching against an in-house database. The data were analysed using univariate and multivariate methods. The changes induced by melittin in the cisplatin-sensitive cells mainly resulted in reduced levels of amino acids in the proline/glutamine/arginine pathway, as well as to decreased levels of carnitines, polyamines, ATP and NAD+. It was necessary to evaluate the effect of a melittin on lipid activities of ovarian cancer cell lines. In order to do so, an LC coupled to an Orbitrap Exactive mass spectrometer using an ACE silica gel column was employed. The two cell lines had distinct lipid compositions, with the A2780CR cells having lower levels of several ether lipids than the A2780 cells. The changes induced by melittin in both cell lines mainly led to a decrease the level of PC and PE. Lipids were significantly altered in both A2780 and A2780CR cells. The observed effect was much more marked in the cisplatin-sensitive cells, suggesting that the sensitive cells undergo much more extensive membrane re-modelling in responsexviito melittin in comparison with the resistant cells. Regarding the metabolic effects of cisplatin on A2780 cells, these mainly resulted decreased levels of acetylcarnitine, phosphocreatine, arginine, proline and glutathione disulfide, as well as to increased levels of tryptophan and methionine. A number of metabolites were differently affected between the A2780 and A2780CR cells following cisplatin treatment, with A2780CR cells presenting increased levels of lysine, and decreased levels of N-acetyl-glutamate, oxoglutarate and 2-oxobutanoate compared to sensitive cells. However, when the combination treatment was applied, there were significant changes in both cell lines, mainly resulting in a reduction of levels of citrate cycle, oxidative phosphorylation, purine, pyrimidine and arginine/proline pathways. The combination of melittin with cisplatin has a synergistic effect when targeting these pathways. The melittin-cisplatin combination had stronger effect on A2780 cell lines than it had on those of A2780CR.Overall, this study suggests that melittin may have some potential as an adjuvant therapy in cancer treatment. A global metabolomics approach can be a useful tool for evaluating the pharmacological effects of anti-cancer compounds or synergetic sensitisers using mass spectrometry.

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Leppla, Denis [Verfasser]. "Comprehensive Study of Secondary Organic Aerosol Particles from the Amazon Rainforest by High-Resolution Mass Spectrometry / Denis Leppla." Mainz : Universitätsbibliothek der Johannes Gutenberg-Universität Mainz, 2021. http://d-nb.info/1232912743/34.

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Sarkate, Pradeep Samadhan. "Quantitative Analysis for Measuring Lower Levels of Fusarium Mycotoxins in Wheat and Barley Using High-Resolution Mass Spectrometry." Thesis, North Dakota State University, 2020. https://hdl.handle.net/10365/31882.

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This project involved the application of Quadrupole Time of Flight (QTOF) technology in quantitating the low concentrations of multiple Fusarium mycotoxins in barley and wheat, also focused on simplified sample extraction protocols such as ‘dilute and shoot.’ Ground samples of wheat and barley were extracted with acetonitrile-water-acetic acid solution (70:29:1 v/v/v). The quantitation was performed using a post spiking matrix-matched calibration curve approach. The method was linear over the range of 1.56 – 100 μg/kg for the toxins deoxynivalenol (DON), deoxynivalenol-3-glucoside (D3G), 3-acetyl deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), diacetoxyscirpenol (DAS), fusarenon-X (FUS-X), nivalenol (NIV), Neosolaniol (NEO), T2, and HT2 toxin. Zearalenone (ZEA). The recovery of the 11 mycotoxins in wheat and barley matrices at two levels were within 60 - 130.1%, and the relative standard deviation (RSD) of the replicate sample assay fell within 5 to 40%. Overall, this method was successfully validated for all the Fusarium toxins.

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Gilchrist, Elizabeth Sarah. "Ion chromatography and ion chromatography-high resolution mass spectrometry technologies for the analysis of low-order explosive residues." Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/ion-chromatography-and-ion-chromatographyhigh-resolution-mass-spectrometry-technologies-for-the-analysis-of-loworder-explosive-residues(8b6c406d-97f2-4fe3-9739-0decc5ef26d3).html.

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The development of chromatographic methods for the detection of low molecular weight organic acids and inorganic anions found in low-order explosive residues are presented. The work is divided into six sections. Firstly, Chapter 1 provides a background on low-order explosives and fingermarks. Existing methods for the analysis of these sample types, focussing on ion chromatography (IC) and mass spectrometry (MS) technologies, are reviewed. Gaps in knowledge are highlighted and the aims and objectives of the thesis presented and justified towards addressing these challenges. Chapter 2 applies an anion exchange chromatographic method for the analysis of gunshot residue. This micro-bore scale method utilises a hydroxide gradient with suppressed conductivity detection. A study on external contamination, such as from environmental matrices and collection devices, is presented suggesting that direct extraction of the residues is more advantageous for the analysis of these residues on small items. Analytical performance characteristics for linearity, repeatability and limits of detection are also presented and discussed. Chapter 3 extends the performance limits of IC by investigating the use of capillary-scale IC technology for the detection of low-order explosive residues for the first time, including gunshot residues and black powder substitutes, in biological matrices such as sweat and human latent fingermarks. A comparison to the micro-bore method in Chapter 2 is made, with a focus on the measured increase in absolute sensitivity at the lower limits. In a brief study, a capillary-scale organic polymer monolithic resin (IonSwift MAX-100) was also investigated in terms of backpressure and efficiency. Chapter 4 presents the selectivity offered by alternative anion exchange resins with the addition of organic solvents to the eluent, specifically methanol and acetonitrile. The combined effect of temperature and organic solvent-containing eluents on IC selectivity is also presented for the first time and discussed regarding their use as variables in IC method development. Analytical performance characteristics for linearity, repeatability and limits of quantification are presented. Chapter 5 combines the organic solvent and temperature-enhanced IC method developed in Chapter 4 with high resolution mass spectrometry (HRMS) detection which enabled simplified coupling of these two technologies. The method was applied to the forensic detection of low-order explosives in fingermarks for the first time, offering confirmatory analysis of several forensically important species at pg amounts. Analytical performance characteristics for linearity, repeatability and limits of quantification are once again presented and compared to the published literature. Chapter 6 presents results collected by capillary electrophoresis and Raman spectroscopy as alternative/complementary techniques to IC. These techniques are applied to the detection of explosive residues in biological matrices, and their relative merits are discussed. The development of several IC-based technologies enabled the successful interrogation of small anions in low-order explosives within fingermarks at fg-ng amounts for the first time, offering the potential to link identity with criminal activity. In particular, the development of a solvent enhanced-IC method with simplified coupling to HRMS shows considerable benefit not just for forensic purposes, but for IC applications in a number of alternative fields.

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Kosmata, M. "Elastische Rückstoßatomspektrometrie leichter Elemente mit Subnanometer-Tiefenauflösung." Helmholtz-Zentrum Dresden-Rossendorf, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:d120-qucosa-85381.

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In der vorliegenden Arbeit wird erstmals das QQDS-Magnetspektrometer für die höchstauflösende Ionenstrahlanalytik leichter Elemente am Helmholtz-Zentrum Dresden-Rossendorf umfassend vorgestellt. Zusätzlich werden sowohl alle auf die Analytik Einfluss nehmenden Parameter untersucht als auch Methoden und Modelle vorgestellt, wie deren Einfluss vermieden oder rechnerisch kompensiert werden kann. Die Schwerpunkte dieser Arbeit gliedern sich in fünf Bereiche. Der Erste ist der Aufbau und die Inbetriebnahme des QQDS-Magnetspektrometers, der zugehörige Streukammer mit allen Peripheriegeräten und des eigens für die höchstauflösende elastische Rückstoßanalyse entwickelten Detektors. Sowohl das umgebaute Spektrometer als auch der im Rahmen dieser Arbeit gebaute Detektor wurden speziell an experimentelle Bedingungen für die höchstauflösende Ionenstrahlanalytik leichter Elemente angepasst und erstmalig auf einen routinemäßigen Einsatz hin getestet. Der Detektor besteht aus zwei Komponenten. Zum einen befindet sich am hinteren Ende des Detektors eine Bragg-Ionisationskammer, die zur Teilchenidentifikation genutzt wird. Zum anderen dient ein Proportionalzähler, der eine Hochwiderstandsanode besitzt und direkt hinter dem Eintrittsfenster montiert ist, zur Teilchenpositionsbestimmung im Detektor. Die folgenden zwei Schwerpunkte beinhalten grundlegende Untersuchungen zur Ionen-Festkörper-Wechselwirkung. Durch die Verwendung eines Magnetspektrometers ist die Messung der Ladungszustandsverteilung der herausgestreuten Teilchen direkt nach einem binären Stoß sowohl möglich als auch für die Analyse notwendig. Aus diesem Grund werden zum einen die Ladungszustände gemessen und zum anderen mit existierenden Modellen verglichen. Außerdem wird ein eigens entwickeltes Modell vorgestellt und erstmals im Rahmen dieser Arbeit angewendet, welches den ladungszustandsabhängigen Energieverlust bei der Tiefenprofilierung berücksichtigt. Es wird gezeigt, dass ohne die Anwendung dieses Modells die Tiefenprofile nicht mit den quantitativen Messungen mittels konventioneller Ionenstrahlanalytikmethoden und mit der Dickenmessung mittels Transmissionselektronenmikroskopie übereinstimmen, und damit falsche Werte liefern würden. Der zweite für die Thematik wesentliche Aspekt der Ionen-Festkörper-Wechselwirkung, sind die Probenschäden und -modifikationen, die während einer Schwerionenbestrahlung auftreten. Dabei wird gezeigt, dass bei den hier verwendeten Energien sowohl elektronisches Sputtern als auch elektronisch verursachtes Grenzflächendurchmischen eintreten. Das elektronische Sputtern kann durch geeignete Strahlparameter für die meisten Proben ausreichend minimiert werden. Dagegen ist der Einfluss der Grenzflächendurchmischung meist signifikant, so dass dieser analysiert und in der Auswertung berücksichtigt werden muss. Schlussfolgernd aus diesen Untersuchungen ergibt sich für die höchstauflösende Ionenstrahlanalytik leichter Elemente am Rossendorfer 5-MV Tandembeschleuniger, dass die geeignetsten Primärionen Chlor mit einer Energie von 20 MeV sind. In Einzelfällen, wie zum Beispiel der Analyse von Bor, muss die Energie jedoch auf 6,5 MeV reduziert werden, um das elektronische Sputtern bei der notwendigen Fluenz unterhalb der Nachweisgrenze zu halten. Der vierte Schwerpunkt ist die Untersuchung von sowohl qualitativen als auch quantitativen Einflüssen bestimmter Probeneigenschaften, wie beispielsweise Oberflächenrauheit, auf die Form des gemessenen Energiespektrums beziehungsweise auf das analysierte Tiefenprofil. Die Kenntnis der Rauheit einer Probe an der Oberfläche und an den Grenzflächen ist für die Analytik unabdingbar. Als Resultat der genannten Betrachtungen werden die Einflüsse von Probeneigenschaften und Ionen-Festkörper-Wechselwirkungen auf die Energie- beziehungsweise Tiefenauflösung des Gesamtsystems beschrieben, berechnet und mit der konventionellen Ionenstrahlanalytik verglichen. Die Möglichkeiten der höchstauflösenden Ionenstrahlanalytik werden zudem mit den von anderen Gruppen veröffentlichten Komplementärmethoden gegenübergestellt. Der fünfte und letzte Schwerpunkt ist die Analytik leichter Elemente in ultradünnen Schichten unter Berücksichtigung aller in dieser Arbeit vorgestellten Modelle, wie die Reduzierung des Einflusses von Strahlschäden oder die Quantifizierung der Elemente im dynamischen Ladungszustandsnichtgleichgewicht. Es wird die Tiefenprofilierung von Mehrschichtsystemen, bestehend aus SiO2-Si3N4Ox-SiO2 auf Silizium, von Ultra-Shallow-Junction Bor-Implantationsprofilen und von ultradünnen Oxidschichten, wie zum Beispiel High-k-Materialien, demonstriert.

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MacIntyre, Lynsey. "Application of matrix-assisted laser desorption/ionisation (MALDI) imaging mass spectrometry and high resolution Fourier transform mass spectrometry for profiling pharmaceuticals and biomarkers in a variety of biological samples." Thesis, University of Strathclyde, 2011. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=15488.

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Goto, Takayuki. "The Expression Profile of Phosphatidylinositol in High Spatial Resolution Imaging Mass Spectrometry as a Potential Biomarker for Prostate Cancer." Kyoto University, 2016. http://hdl.handle.net/2433/215378.

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GUILBOT, Kelly. "Determination of dioxins in Cretaceous strata from the South of Sweden. : Can the environmental anthropogenic pollutant dioxin be of natural origin ?" Thesis, Örebro universitet, Institutionen för naturvetenskap och teknik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-25916.

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Eleven sediment samples from different geological layers and four fossils from the South of Sweden were collected and estimated to be 80 million years old (approximately late of Cretaceous period). The samples were analyzed for polychlorinated dibenzo-p dioxins (PCDD/Fs) to investigate whether these samples are likely to contain dioxins from a natural formation. For over thirty years, the scientific community has discussed the possibility of a natural formation of dioxins. Several hypothesis have been put forward, but often rejected by the evidence of a source of anthropogenic pollution in the samples. In order to answer this issue, two types of analyses have been performed : high resolution gas chromatography-high resolution mass spectrometry (HRGC/HRMS) and elemental analyzer-isotopic ratio mass spectrometry (EA-IRMS). HRGC/HRMS provides information about the source of dioxins comparing the distribution of all PCDD/Fs to experimental isotopic patterns from past publications. δ13C of organic carbon gives information about the nature of carbon present in soils and can be helpful to trace paleoclimates.

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Lippert, Wayne [Verfasser]. "Further development and application of a mobile multiple-reflection time-of-flight mass spectrometer for analytical high-resolution tandem mass spectrometry / Wayne Lippert." Gießen : Universitätsbibliothek, 2016. http://d-nb.info/1114053686/34.

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Tworek, Luiza. "Development of a liquid chromatography - high resolution mass spectrometry method for multi-component screening of synthetic cannabinoids in blood." Thesis, Örebro universitet, Institutionen för hälsovetenskaper, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-50803.

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Dissertations / Theses on the topic 'High resolution mass spectrometry (HRMS)'

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