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Development of Microscopy Ambient Ionization Top-down Mass Spectrometry /


There is an immense cellular and molecular heterogeneity in biological system. For example, during the embryonic development, the progenitor cells could differentiate into varieties type of cell due to the gradient of chemical stimulus. Once the cell fate is determined, the metabolomics and proteomic features of the cell will subsequently alter. Knowing the details of the molecular interplays between cellular and chemical heterogeneities is crucial in the understanding of the complex biological system. Mass spectrometry, provides a way of label-free strategy to obtain the chemical information. In the recent decades, considerable amounts of new ionization methods were developed for the use of mass spectrometric analysis on biological system. Among those methods, those so-called "soft ionization" techniques, such as matrix-assisted laser desorption (MALDI) and electrospray ionization (ESI), have been greatly utilized for biomedical studies. However, some technical limitations currently hinder the application to the more general biology society. First, the spatial mass spectrometric measurement is solely based on passive imaging processes. In this regard, a real-time chemical investigation guided by the histological measurement, e.g. optical microscopy, is difficult. Second, high sensitive instruments that allow detection of full molecular weight range, e.g. covering small metabolites, lipids, and proteins, are rare and hardly used for imaging. Third, ionization methods for surface analysis are challenging for soft biological samples, e.g. bacterial colonies, at their native states. My thesis work is the development of mass spectrometry-based tools that are less limited by the abovementioned aspects and to extend the potential use of mass spectrometry. In Chapter 1, I will briefly review the current progress of the development on ambient ionization techniques as well as the emergence of their applications to biological system. Chapter 2 describes how I interfaced an inverted fluorescence microscope with an ambient ionization source (nanoDESI) so that the molecular information was obtained via the guidance of microscope directly on glass slides. Endogenous molecules as large as hemoglobin could be characterized without immunostaining. This is for the first time that proteins on ex vivo tissue sections could be identified using ambient mass spectrometry. Using this platform we found unique molecular patterns that only express at certain embryonic stages. In Chapter 3 a new ways of microbial metabolomics are introduced using a different surface flow-probe. Chapter 4 we further applied the microscope-mass spectrometry interface to study bats with white-nose syndrome. Key molecules that may be causal to the devastating disease are found. Lastly, Chapter 5 put forth a future direction how tools described in the thesis can be extended to cancer pathology

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