@article{tu_garrard_said_muddiman_2021, title={In situ detection of fatty acid C=C positional isomers by coupling on-tissue mCPBA epoxidation with infrared matrix-assisted laser desorption electrospray ionization mass spectrometry}, volume={35}, ISSN={["1097-0231"]}, DOI={10.1002/rcm.9119}, abstractNote={RationaleUnsaturated fatty acids (UFAs) play vital roles in regulating cellular functions. In‐depth structural characterization of UFAs such as localizing carbon–carbon double bonds is fundamentally important but poses considerable challenges in mass spectrometry (MS) given that the most widely accessible ion activation method, low‐energy collision‐induced dissociation (CID), primarily generates uninformative fragments (e.g., neutral loss of CO2) that are not suggestive of the double‐bond positions.}, number={13}, journal={RAPID COMMUNICATIONS IN MASS SPECTROMETRY}, author={Tu, Anqi and Garrard, Kenneth P. and Said, Neveen and Muddiman, David C.}, year={2021}, month={Jul} }
 @article{tu_said_muddiman_2021, title={Spatially resolved metabolomic characterization of muscle invasive bladder cancer by mass spectrometry imaging}, volume={17}, ISSN={["1573-3890"]}, DOI={10.1007/s11306-021-01819-x}, abstractNote={Muscle invasive bladder cancer (MIBC) is an advanced stage of bladder cancer which poses a severe threat to life. Cancer development is usually accompanied by remarkable alterations in cell metabolism, and hence deep insights into MIBC at the metabolomic level can facilitate the understanding of the biochemical mechanisms involved in the cancer development and progression.In this proof-of-concept study, the optimal cutting temperature (OCT)-embedded MIBC samples were first washed with pure water to remove the polymer compounds which could cause severe signal suppression during mass spectrometry. Further, the tissue sections were analyzed by infrared matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI), providing an overview on the spatially resolved metabolomic profiles.The MSI data enabled the discrimination between not only the cancerous and normal tissues, but also the subregions within a tissue section associated with different disease states. Using t-Distributed Stochastic Neighbor Embedding (t-SNE), the hyperdimensional MSI data was mapped into a two-dimensional space to visualize the spectral similarity, providing evidence that metabolomic alterations might have occurred outside the histopathological tumor border. Least absolute shrinkage and selection operator (LASSO) was further employed to classify sample pathology in a pixel-wise manner, yielding excellent prediction sensitivity and specificity up to 96% based on the statistically characteristic spectral features.The results demonstrate great promise of IR-MALDESI MSI to identify molecular changes derived from cancer and unveil tumor heterogeneity, which can potentially promote the discovery of clinically relevant biomarkers and allow for applications in precision medicine.}, number={8}, journal={METABOLOMICS}, author={Tu, Anqi and Said, Neveen and Muddiman, David C.}, year={2021}, month={Aug} }
 @article{xi_tu_muddiman_2020, title={Lipidomic profiling of single mammalian cells by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI)}, volume={412}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-020-02961-6}, abstractNote={To better understand cell-to-cell heterogeneity, advanced analytical tools are in a growing demand for elucidating chemical compositions of each cell within a population. However, the progress of single-cell chemical analysis has been restrained by the limitations of small cell volumes and minute cellular concentrations. Here, we present a rapid and sensitive method for investigating the lipid profiles of isolated single cells using infrared matrix-assisted laser desorption electrospray ionization mass spectrometry (IR-MALDESI-MS). In this work, HeLa cells were dispersed onto a glass slide, and the cellular contents were ionized by IR-MALDESI and measured using a Q-Exactive HF-X mass spectrometer. Importantly, this approach does not require extraction and/or enrichment of analytes prior to MS analysis. Using this approach, 45 distinct lipid species, predominantly phospholipids, were detected and putatively annotated from the single HeLa cells. The proof-of-concept study demonstrates the feasibility and efficacy of IR-MALDESI-MS for rapid lipidomic profiling of single cells, which provides an important basis for future work on differentiation between normal and diseased cells at various developmental states, which can offer new insights into cellular metabolic pathways and pathological processes. Although not yet accomplished, we believe this approach can be readily used as an assessment tool to compare the number of identified species during source evolution and method optimization (intra-laboratory), and also disclose the complementary nature of different direct analytical approaches for the coverage of different types of endogenous analytes (inter-laboratory).Graphical abstract.}, number={29}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Xi, Ying and Tu, Anqi and Muddiman, David C.}, year={2020}, month={Nov}, pages={8211–8222} }
 @article{lakeh_tu_muddiman_abdollahi_2019, title={Discriminating normal regions within cancerous hen ovarian tissue using multivariate hyperspectral image analysis}, volume={33}, ISSN={["1097-0231"]}, DOI={10.1002/rcm.8362}, abstractNote={RationaleIdentification of subregions under different pathological conditions on cancerous tissue is of great significance for understanding cancer progression and metastasis. Infrared matrix‐assisted laser desorption electrospray ionization mass spectrometry (IR‐MALDESI‐MS) can be potentially used for diagnostic purposes since it can monitor spatial distribution and abundance of metabolites and lipids in biological tissues. However, the large size and high dimensionality of hyperspectral data make analysis and interpretation challenging. To overcome these barriers, multivariate methods were applied to IR‐MALDESI data for the first time, aiming at efficiently resolving mass spectral images, from which these results were then used to identify normal regions within cancerous tissue.}, number={4}, journal={RAPID COMMUNICATIONS IN MASS SPECTROMETRY}, author={Lakeh, Mahsa Akbari and Tu, Anqi and Muddiman, David C. and Abdollahi, Hamid}, year={2019}, month={Feb}, pages={381–391} }
 @article{tu_muddiman_2019, title={Internal Energy Deposition in Infrared Matrix-Assisted Laser Desorption Electrospray Ionization With and Without the Use of Ice as a Matrix}, volume={30}, ISSN={["1879-1123"]}, DOI={10.1007/s13361-019-02323-2}, abstractNote={The internal energy deposited into analytes during the ionization process largely influences the extent of fragmentation, thus the appearance of the resulting mass spectrum. The internal energy distributions of a series of para-substituted benzyl pyridinium cations in liquid and solid-state generated by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) were measured using the survival yield method, of which results were subsequently compared with conventional electrospray ionization (ESI). The comparable mean internal energy values (e.g., 1.8–1.9 eV at a collision energy of 15 eV) and peak widths obtained with IR-MALDESI and ESI support that IR-MALDESI are essentially a soft ionization technique where analytes do not gain considerable internal energy during the laser-induced desorption process and/or lose energy during uptake into charged electrospray droplets. An unusual fragment ion, protonated pyridine, was only found for solid IR-MALDESI at relatively high collision energies, which is presumably resulted from direct ionization of the pre-charged analytes in form of salts. Analysis of tissue with an ice layer consistently yielded ion populations with higher internal energy than its counterpart without an ice layer, likely due to a substantially enhanced number of IR absorbers with ice. Further measurements with holo-myoglobin show that IR-MALDESI-MS retains the noncovalently bound heme-protein complexes under both native-like and denaturing conditions, while complete loss of the heme group occurred in denaturing ESI-MS, showing that the softness of IR-MALDESI is equivalent or superior to ESI for biomolecules.}, number={11}, journal={JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY}, author={Tu, Anqi and Muddiman, David C.}, year={2019}, month={Nov}, pages={2380–2391} }
 @article{tu_muddiman_2019, title={Systematic evaluation of repeatability of IR-MALDESI-MS and normalization strategies for correcting the analytical variation and improving image quality}, volume={411}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-019-01953-5}, abstractNote={Mass spectrometry imaging is a powerful tool widely used in biological, clinical, and forensic research, but its often poor repeatability limits its application for quantitative and large-scale analysis. A systematic evaluation of infrared matrix-assisted laser desorption electrospray ionization mass spectrometry (IR-MALDESI-MS) repeatability in absolute ion abundances during short- and long-term experiments was carried out on liver slices from the same rat with minimal biological variability to be expected. Results of median %RSDs ranging from 14 to 45, pooled %RMADs ranging from 11 to 33, and Pearson correlation coefficients ranging from 0.83 to 1.00 demonstrated an acceptable repeatability of IR-MALDESI-MS. Normalization is commonly applied for the purpose of accounting for analytical variability of spectra generated from different runs so as to reveal real biological differences. Nine data normalization strategies were performed on the rat liver data sets to examine their effects on reducing analytical variation, and further on a hen ovary data set containing more morphological features for the investigation of their impact on ion images. Results demonstrated that the majority of normalization approaches benefit data quality to some extent, and local normalization methods significantly outperform their global counterparts, resulting in a reduction of median %RSD up to 22. Local median normalization was found to be promisingly robust for both homogeneous and heterogeneous samples.}, number={22}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Tu, Anqi and Muddiman, David C.}, year={2019}, month={Sep}, pages={5729–5743} }