1,720,965 research outputs found
Interactive hyperspectral approach for exploring and interpreting DESI-MS images of cancerous and normal tissue sections
Get PDFDesorption electrospray ionization (DESI) is an ambient mass spectrometry (MS) technique that can be operated in an imaging mode. It is known to provide valuable information on disease state and grade based on lipid profiles in tissue sections. Comprehensive exploration of the spatial and chemical information contained in 2D MS images requires further development of methods for data treatment and interpretation in conjunction with multivariate analysis. In this study, we employ an interactive hyperspectral approach and principal component analysis (PCA) to interpret the chemical and spatial information obtained from MS imaging of human bladder, kidney, germ cell and prostate cancer and adjacent normal tissues. This multivariate strategy facilitated distinction between tumor and normal tissue by correlating the lipid information with pathological evaluation of the same samples. Some common lipid ions, such as those of m/z 885.5 and m/z 788.5, nominally PI(18:0/20:4) and PS(18:0/18:1), as well as ions of free fatty acids and their dimers, appeared to be highly discriminating across different types of human cancers, while other ions, such as those of m/z 465.5 (cholesterol sulfate) for prostate cancer tissue and m/z 795.5 (seminolipid 16:0/16:0) for germ tissue, appeared to be extremely selective for the type of tissue analyzed. These data confirm that lipid profiles can reflect not only the disease/health state of tissue but also are characteristic of tissue type. The manual interactive strategy presented here is particularly useful to visualize the information contained in hyperspectral images by automatically connecting regions of PCA score space to pixels of the 2D physical object. The procedures developed in the study consider all the spectral variables and their inter-correlations, and guide subsequent investigations of the mass spectra and single ion images to allow one to maximize characterization between different regions of any DESI-MS image
Development of mass spectrometric methods for catalytic studies
No full textInstrumental and experimental mass spectrometric methods have been developed which are applicable to catalyst preparation and characterization. The analytical performance of a multiplexed four channel mass spectrometer has been characterized. Four samples can be analyzed simultaneously, in both MS and MSn modes. This instrument could be used to monitor gas-phase products within a catalytic chamber. A new ionization method, atmospheric pressure thermal desorption ionization (APTDI), has been applied to inorganic compounds. The mass spectra of salen-containing complexes are very simple, containing protonated monomers, dimers and trimers. When solid phase mixtures are analyzed via APTDI, protonated mixed-metal clusters are generated, which demonstrate interesting fragmentation to form radical monomers upon collision-induced dissociation, an unseen phenomenon with the pure clusters. This ionization method may be useful for generating small metal-containing clusters for catalyst surface preparation via soft landing. Lastly, a new soft landing instrument has been constructed and characterized. An ion funnel provides high current, while a bent ion guide discriminates between ions and neutrals. Both the square quadrupole and an elongated RIT can be operated in a novel RF/DC mode to provide maximum throughput to the landing surface. Currents up to 1 nA have been collected at the landing surface. Peptides, dyes and inorganic complexes have been landed on gold surfaces and self-assembled monolayers. Subsequent nanosprayed rinses have demonstrated an overall efficiency of ∼0.2-0.4% from solution to surface. Additional analyses of landed surfaces via desorption electrospray ionization and x-ray photoelectron spectroscopy have demonstrated successful landing. This instrument is intended for preparation of catalytic surfaces via soft landing
Generation, Manipulation, and Detection of Charged Droplets and Ions in the Open Air
Get PDFThis dissertation describes the development of methodologies for characterizing the physical properties of electrosprayed droplets and ions as they exist in the open air. Two novel ways of generating electrospray plumes were developed using voltage induction. Also described is a novel way to measure the sizes of electrosprayed droplets smaller than the diffraction limit of light using super resolution fluorescence microscopy. Studies performed in parallel to the sizing experiments describe an unconventional way of using ablative ions generated by corona discharges to probe chemical reactions occurring inside the inlets of mass spectrometers. Also described is the ability to direct and separate ions in the open air using plastic electrodes
Screening For Cancer by Ambient Ionization Mass Spectrometry
No full textThis dissertation summarizes two separate studies which evaluated whether desorption electrospray ionization (DESI) and TS-MS (TS) mass spectrometry (MS) distinguished cancer from normal tissue for different cancers in different organ systems in different animal species, human and canine. The canine bladder study evaluated whether DESI-MS and TS-MS distinguished InvUC from normal and InvUC in high risk breeds from InvUC in low risk breeds. The study concluded DESI-MS and TS-MS each facilitated differentiation of transitional cell carcinoma (InvUC) from normal canine bladder epithelial tissue using, among other ions, m/z 281.5 (FA 18:1; oleic acid) and m/z 563.5 (oleic acid dimer). PCA-LDA resulted in accuracy rates of 96% for DESI-MS imaging and 93% for TS-MS of InvUC versus normal tissue, and 88% for DESI-MS of InvUC in high risk versus low risk breeds. The human oral cavity study evaluated whether DESI-MS facilitated differentiation of tongue conventional squamous cell carcinoma (“CSCC”) and normal tongue epithelial tissue in three sample groups: fresh frozen banked, and two separate surgical sample groups (Indiana University School of Medicine and University of California – Davis). Each study concluded DESI-MS facilitated differentiation of CSCC from normal oral cavity tissue. In the fresh frozen banked tissue study, PCA-LDA resulted in accuracy rates of 95% for DESI-MS imaging of CSCC versus normal and 93% for DESI-MS imaging of CSCC, adjacent normal and normal. This dissertation suggests that DESI-MS and TS-MS may be useful as either screening or case-finding methods for distinguishing cancer from normal epithelial tissue. Furthermore, DESI-MS may be useful in understanding InvUC development with breed risk and oleic acid dimerization used to uncover novel InvUC lipid metabolism mechanisms. TS-MS may be useful for the rapid differentiation of cancer in a surgical setting or clinical appointment
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Miniaturization of the ion trap mass spectrometer
No full textThe development of miniature ion trap mass spectrometers has been an active area, fueled by the promising analytical capabilities and the convenience of fast in situ analysis with portable instruments. The objective is to miniaturize mass spectrometers in weight, size, and power consumption while retaining the advantages and analytical capabilities of mass spectrometry at the same time. The thesis focuses on the instrumentation of miniature ion trap mass spectrometers, including ionization, ion transfer, mass analyzer, ion detection and related vacuum and electronic techniques. The work presented represents recent progress achieved in miniature ion trap mass spectrometers. The development of two miniature mass spectrometers, a 10 kg Mini 10 mass spectrometer with electron impact ionization source, developed in 2005 and a 5 kg Mini 11 mass spectrometer with multiple ionization sources, developed in 2008, is introduced. The momentum and reasons driving the development from the Mini 10 to the Mini 11 are depicted, and the technical details of key components are discussed. Special focus is given to a glow discharge electron impact ionization source, which is an ideal substitute for the filament electron source used in the electron impact ionization, and a discontinuous atmospheric pressure interface, which enables the implementation of atmospheric pressure ionization sources in miniature ion trap mass spectrometers with limited pumping capabilities
Novel analytical and preparative mass spectrometric methodologies in reaction monitoring and acceleration
No full textThis dissertation explores two roles of limited volume solutions formed by dropcasting or by spray-based ionization processes in mass spectrometry, 1) as microcontainers to allow monitoring of bulk reactions or 2) as microreactors in which to accelerate reactions. Droplets derived from the bulk reaction phase can be used to monitor the reactions. An inductive electrospray mass spectrometry (iESI-MS)-based reaction monitoring system was built to use charged droplets emitted in the electric field of a pulsed DC potential to track chemical reactions in real time, including air and moisture-sensitive and heterogeneous reactions. Highly concentrated solutions can be monitored for long periods without the spray emitter clogging. Sheath gas assists in nebulization and a sample splitter reduces the delay time and minimizes contamination of the instrument. We applied this system in both a mechanistic study of Negishi cross-coupling of 3-bromoquinoline with diethylzinc and in Pd/C-catalyzed hydrogenolysis of 3,4-dimethoxy-benzaldehyde, as well as in process control of the synthetic route to an active pharmaceutical ingredient (API). The MS reaction monitoring system was further enhanced by an on-line quantitation device which allows the introduction of internal standards accurately without affecting the reaction or later product separation. It also allows dilution of aliquots of the reaction solution to different extents, so that the concentration of each analyte falls within the linear dynamic range (LDR), and it thus can be easily quantified. The reaction of L-arginine with N-(Cbz-isopropyl-aminoacyl)-benzotriazole to yield dipeptide Cbz-L-Val-L-Arg was successfully quantified using this system while its reaction kinetics were explored also. Droplets formed by paper spray MS were also used to evaluate enzyme activity by following the product formation of an enzymatic reaction. A simple MS protocol was developed for evaluation of enzymatic activity using few reagents and without sample pretreatment or derivatization reactions (which is commonly used in other methods). In contrast to their role as simple microcontainers, droplets have been found a new role in reaction acceleration compared to the bulk phase. Droplets formed by dropcasting/spray-based ionization mass spectrometry can act as microreactors in which the reactions run much faster than those in the bulk solution. Droplet reaction acceleration also extends to thin film reactions as was performed in the reactive paper spray experiment which represents an alternative version of limited-volume reactors. The Katritzky reaction between a pyrylium salt and mono- or di-amines, including substituted anilines, is an example that was investigated by reactive paper spray. The increase in rate of product formation is attributed to solvent evaporation which increases reagent concentrations, to changes the pH and to enhanced intermolecular interactions at the interface. Droplet acceleration is promising for preparative scale synthesis on a short timescale. It might open a new dimension in the field of synthetic organic chemistry
Development of desorption electrospray ionization mass spectrometry (DESI-MS) for applications in imaging and quantitation
No full textFurther development of the ambient mass spectrometry ionization method desorption electrospray ionization (DESI) is presented with a focus on applications in imaging and quantitation. The second chapter is of a more fundamental nature and describes the DESI analysis of polar lipids. Three novel imaging applications are presented in the third chapter using DESI-MS. First, the chemical imaging of latent fingerprints is presented, in which both the shape and the chemical content of blotted fingerprints are determined. Second, imaging of lipids, including polar lipids, cholesterol, and cholesteryl esters, from atherosclerotic plaques is demonstrated. Finally, tissue imaging using a high mass-to-charge resolution and accuracy mass spectrometer is described. In the final chapter, various aspects of the use of DESI-MS for quantitation are explored. Basic method development is addressed in the first section, while the second extends the analysis to high throughput analysis
Theoretical and statistical solutions to problems in physical mass spectrometry
No full textThe advent of ambient ionization mass spectrometry in the past decade has revolutionized the way direct analysis is performed. DESI mass spectrometry was the first of these techniques to be introduced, in 2004. Since that time an explosion in the number of ambient ionization techniques has occurred, a testament to the utility of performing analysis with mass spectrometry in open and native environments. The first part of this thesis develops a basic hydrodynamic theory of DESI via the methods of diffuse-interface capturing multiphase fluid dynamics. Results from these simulations confirm that a momentum-transfer event on a wetted surface is sufficient to replicate known progeny droplet properties. This is true even without incorporating the influence of electrostatics. The second part of this thesis develops a multivariate statistical method for unsupervised analysis of DESI in the imaging mode. This work is motivated by the need for a simple visualization method for morphological and chemical variation on a sample surface, as well as enabling a non-expert end-user to rapidly identify the state of an interrogated region of sample without a priori knowledge of the sample or complex, systematic analysis of full mass spectra. An approach based on the development of a uniform coordinate system for a given tissue type and disease state is developed via principal component analysis. It is shown that this method gives excellent agreement with false-color ion images of known biomarkers and histological stains. The final section of this thesis concerns the statistical and quantum mechanical treatment of serine clustering in the gas phase. These clusters are produced by a variety of atmospheric ionization methods, including sublimation/APCI, ESI, ESSI and SSI. They have been implicated in one possible mechanism leading to the origin of homochirality, as certain clusters exhibit remarkable chiral selectivity. A “structural landscape” is developed over a range of relevant cluster sizes, enantiomeric compositions, and ionizing charge states. Structures discovered via an approach based on basin-hopping molecular dynamics are used for further DFT-based optimization and analysis. It is shown that the behavior and stability of these systems is due to major structural rearrangements as a function of size and charge. The experimentally observed chiral selectivity may be understood in part by the unique network of hydrogen bonds facilitated by the serine hydroxyl side chain
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