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Untargeted Molecular Discovery in Primary Metabolism: Collision Cross Section as a Molecular Descriptor in Ion Mobility-Mass Spectrometry.
Nichols CM, Dodds JN, Rose BS, Picache JA, Morris CB, Codreanu SG, May JC, Sherrod SD, McLean JA
(2018) Anal Chem 90: 14484-14492
MeSH Terms: Carbohydrates, Chromatography, High Pressure Liquid, Humans, Ion Mobility Spectrometry, Isomerism, Mass Spectrometry, Metabolomics
Show Abstract · Added December 17, 2018
In this work, we established a collision cross section (CCS) library of primary metabolites based on analytical standards in the Mass Spectrometry Metabolite Library of Standards (MSMLS) using a commercially available ion mobility-mass spectrometer (IM-MS). From the 554 unique compounds in the MSMLS plate library, we obtained a total of 1246 CCS measurements over a wide range of biochemical classes and adduct types. Resulting data analysis demonstrated that the curated CCS library provides broad molecular coverage of metabolic pathways and highlights intrinsic mass-mobility relationships for specific metabolite superclasses. The separation and characterization of isomeric metabolites were assessed, and all molecular species contained within the plate library, including isomers, were critically evaluated to determine the analytical separation efficiency in both the mass ( m/ z) and mobility (CCS/ΔCCS) dimension required for untargeted metabolomic analyses. To further demonstrate the analytical utility of CCS as an additional molecular descriptor, a well-characterized biological sample of human plasma serum (NIST SRM 1950) was examined by LC-IM-MS and used to provide a detailed isomeric analysis of carbohydrate constituents by ion mobility.
1 Communities
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7 MeSH Terms
Low bone toughness in the TallyHO model of juvenile type 2 diabetes does not worsen with age.
Creecy A, Uppuganti S, Unal M, Clay Bunn R, Voziyan P, Nyman JS
(2018) Bone 110: 204-214
MeSH Terms: Aging, Animals, Arginine, Bone Density, Chromatography, High Pressure Liquid, Diabetes Mellitus, Type 2, Femur, Fractures, Bone, Lysine, Male, Mice, Spectrum Analysis, Raman, X-Ray Microtomography
Show Abstract · Added February 19, 2018
Fracture risk increases as type 2 diabetes (T2D) progresses. With the rising incidence of T2D, in particular early-onset T2D, a representative pre-clinical model is needed to study mechanisms for treating or preventing diabetic bone disease. Towards that goal, we hypothesized that fracture resistance of bone from diabetic TallyHO mice decreases as the duration of diabetes increases. Femurs and lumbar vertebrae were harvested from male, TallyHO mice and male, non-diabetic SWR/J mice at 16weeks (n≥12 per strain) and 34weeks (n≥13 per strain) of age. As is characteristic of this model of juvenile T2D, the TallyHO mice were obese and hyperglycemic at an early age (5weeks and 10weeks of age, respectively). The femur mid-shaft of TallyHO mice had higher tissue mineral density and larger cortical area, as determined by micro-computed tomography, compared to the femur mid-shaft of SWR/J mice, irrespective of age. As such, the diabetic rodent bone was structurally stronger than the non-diabetic rodent bone, but the higher peak force endured by the diaphysis during three-point (3pt) bending was not independent of the difference in body weight. Upon accounting for the structure of the femur diaphysis, the estimated toughness at 16weeks and 34weeks was lower for the diabetic mice than for non-diabetic controls, but neither toughness nor estimated material strength and resistance to crack growth (3pt bending of contralateral notched femur) decreased as the duration of hyperglycemia increased. With respect to trabecular bone, there were no differences in the compressive strength of the L6 vertebral strength between diabetic and non-diabetic mice at both ages despite a lower trabecular bone volume for the TallyHO than for the SWR/J mice at 34weeks. Amide I sub-peak ratios as determined by Raman Spectroscopy analysis of the femur diaphysis suggested a difference in collagen structure between diabetic and non-diabetic mice, although there was not a significant difference in matrix pentosidine between the groups. Overall, the fracture resistance of bone in the TallyHO model of T2D did not progressively decrease with increasing duration of hyperglycemia. However, given the variability in hyperglycemia in this model, there were correlations between blood glucose levels and certain structural properties including peak force.
Copyright © 2018 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Dynamics of Zebrafish Heart Regeneration Using an HPLC-ESI-MS/MS Approach.
Ma D, Tu C, Sheng Q, Yang Y, Kan Z, Guo Y, Shyr Y, Scott IC, Lou X
(2018) J Proteome Res 17: 1300-1308
MeSH Terms: Animals, Chromatography, High Pressure Liquid, Fish Proteins, Gene Ontology, Heart Injuries, Heart Ventricles, Metabolic Networks and Pathways, Molecular Sequence Annotation, Myocardium, Proteomics, Real-Time Polymerase Chain Reaction, Regeneration, Spectrometry, Mass, Electrospray Ionization, Tumor Suppressor Protein p53, Zebrafish
Show Abstract · Added April 3, 2018
Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. To characterize protein dynamics during heart regeneration, we employed an HPLC-ESI-MS/MS (mass spectrometry) approach. Myocardium tissues were taken from sham-operated fish and ventricle-resected sample at three different time points (2, 7, and 14 days); dynamics of protein expression were analyzed by an ion-current-based quantitative platform. More than 2000 protein groups were quantified in all 16 experiments. Two hundred and nine heart-regeneration-related protein groups were quantified and clustered into six time-course patterns. Functional analysis indicated that multiple molecular function and metabolic pathways were involved in heart regeneration. Interestingly, Ingenuity Pathway Analysis revealed that P53 signaling was inhibited during the heart regeneration, which was further verified by real-time quantitative polymerase chain reaction (Q-PCR). In summary, we applied systematic proteomics analysis on regenerating zebrafish heart, uncovered the dynamics of regenerative genes expression and regulatory pathways, and provided invaluable insight into design regenerative-based strategies in human hearts.
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15 MeSH Terms
Enhanced Spatially Resolved Proteomics Using On-Tissue Hydrogel-Mediated Protein Digestion.
Rizzo DG, Prentice BM, Moore JL, Norris JL, Caprioli RM
(2017) Anal Chem 89: 2948-2955
MeSH Terms: Acrylic Resins, Animals, Cerebellum, Chromatography, High Pressure Liquid, Hydrogels, Liver, Proteins, Proteolysis, Rats, Tandem Mass Spectrometry, Trypsin
Show Abstract · Added March 10, 2017
The identification of proteins from tissue specimens is a challenging area of biological research. Many current techniques for identification forfeit some level of spatial information during the sample preparation process. Recently, hydrogel technologies have been developed that perform spatially localized protein extraction and digestion prior to downstream proteomic analysis. Regiospecific protein identifications acquired using this approach have thus far been limited to 1-2 mm diameter areas. The need to target smaller populations of cells with this technology necessitates the production of smaller diameter hydrogels. Herein, we demonstrate hydrogel fabrication processes that allow hydrogel applications down to a diameter of ∼260 μm, approximately 1/15 of the area of previous approaches. Parameters such as the percent polyacrylamide used in hydrogel construction as well as the concentration of trypsin with which the hydrogel is loaded are investigated to maximize the number of protein identifications from subsequent liquid chromatography tandem MS (LC-MS/MS) analysis of hydrogel extracts. An 18% polyacrylamide concentration is shown to provide for a more rigid polymer network than the conventional 7.5% polyacrylamide concentration and supports the fabrication of individual hydrogels using the small punch biopsies. Over 600 protein identifications are still achieved at the smallest hydrogel diameters of 260 μm. The utility of these small hydrogels is demonstrated through the analysis of sub regions of a rat cerebellum tissue section. While over 900 protein identifications are made from each hydrogel, approximately 20% of the proteins identified are unique to each of the two regions, highlighting the importance of targeting tissue subtypes to accurately characterize tissue biology. These newly improved methods to the hydrogel process will allow researchers to target smaller biological features for robust spatially localized proteomic analyses.
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11 MeSH Terms
Quantitative Analysis and Discovery of Lysine and Arginine Modifications.
Galligan JJ, Kingsley PJ, Wauchope OR, Mitchener MM, Camarillo JM, Wepy JA, Harris PS, Fritz KS, Marnett LJ
(2017) Anal Chem 89: 1299-1306
MeSH Terms: Arginine, Chromatography, High Pressure Liquid, HEK293 Cells, Histones, Humans, Hydrolysis, Jumonji Domain-Containing Histone Demethylases, Lysine, Peptides, Protein Processing, Post-Translational, Recombinant Proteins, Tandem Mass Spectrometry
Show Abstract · Added April 22, 2018
Post-translational modifications (PTMs) affect protein function, localization, and stability, yet very little is known about the ratios of these modifications. Here, we describe a novel method to quantitate and assess the relative stoichiometry of Lys and Arg modifications (QuARKMod) in complex biological settings. We demonstrate the versatility of this platform in monitoring recombinant protein modification of peptide substrates, PTMs of individual histones, and the relative abundance of these PTMs as a function of subcellular location. Lastly, we describe a product ion scanning technique that offers the potential to discover unexpected and possibly novel Lys and Arg modifications. In summary, this approach yields accurate quantitation and discovery of protein PTMs in complex biological systems without the requirement of high mass accuracy instrumentation.
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12 MeSH Terms
Absolute Quantification of Rifampicin by MALDI Imaging Mass Spectrometry Using Multiple TOF/TOF Events in a Single Laser Shot.
Prentice BM, Chumbley CW, Caprioli RM
(2017) J Am Soc Mass Spectrom 28: 136-144
MeSH Terms: Animals, Antibiotics, Antitubercular, Chromatography, High Pressure Liquid, Humans, Lasers, Liver, Rabbits, Rifampin, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tandem Mass Spectrometry
Show Abstract · Added April 17, 2017
Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) allows for the visualization of molecular distributions within tissue sections. While providing excellent molecular specificity and spatial information, absolute quantification by MALDI IMS remains challenging. Especially in the low molecular weight region of the spectrum, analysis is complicated by matrix interferences and ionization suppression. Though tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity and improve sensitivity by eliminating chemical noise, typical MALDI MS/MS modalities only scan for a single MS/MS event per laser shot. Herein, we describe TOF/TOF instrumentation that enables multiple fragmentation events to be performed in a single laser shot, allowing the intensity of the analyte to be referenced to the intensity of the internal standard in each laser shot while maintaining the benefits of MS/MS. This approach is illustrated by the quantitative analyses of rifampicin (RIF), an antibiotic used to treat tuberculosis, in pooled human plasma using rifapentine (RPT) as an internal standard. The results show greater than 4-fold improvements in relative standard deviation as well as improved coefficients of determination (R) and accuracy (>93% quality controls, <9% relative errors). This technology is used as an imaging modality to measure absolute RIF concentrations in liver tissue from an animal dosed in vivo. Each microspot in the quantitative image measures the local RIF concentration in the tissue section, providing absolute pixel-to-pixel quantification from different tissue microenvironments. The average concentration determined by IMS is in agreement with the concentration determined by HPLC-MS/MS, showing a percent difference of 10.6%. Graphical Abstract ᅟ.
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10 MeSH Terms
Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension.
Itani HA, Dikalova AE, McMaster WG, Nazarewicz RR, Bikineyeva AT, Harrison DG, Dikalov SI
(2016) Hypertension 67: 1218-27
MeSH Terms: Analysis of Variance, Angiotensin II, Animals, Biomarkers, Cells, Cultured, Chromatography, High Pressure Liquid, Cyclophilins, Disease Models, Animal, Endothelium, Vascular, Hypertension, Lactones, Male, Mice, Mice, Inbred C57BL, Mitochondria, Oxidative Stress, Random Allocation, Spiro Compounds, Superoxides, Vasodilation
Show Abstract · Added April 26, 2016
Vascular superoxide (O˙2 (-)) and inflammation contribute to hypertension. The mitochondria are an important source of O˙2 (-); however, the regulation of mitochondrial O˙2 (-) and the antihypertensive potential of targeting the mitochondria remain poorly defined. Angiotensin II and inflammatory cytokines, such as interleukin 17A and tumor necrosis factor-α (TNFα) significantly contribute to hypertension. We hypothesized that angiotensin II and cytokines co-operatively induce cyclophilin D (CypD)-dependent mitochondrial O˙2 (-) production in hypertension. We tested whether CypD inhibition attenuates endothelial oxidative stress and reduces hypertension. CypD depletion in CypD(-/-) mice prevents overproduction of mitochondrial O˙2 (-) in angiotensin II-infused mice, attenuates hypertension by 20 mm Hg, and improves vascular relaxation compared with wild-type C57Bl/6J mice. Treatment of hypertensive mice with the specific CypD inhibitor Sanglifehrin A reduces blood pressure by 28 mm Hg, inhibits production of mitochondrial O˙2 (-) by 40%, and improves vascular relaxation. Angiotensin II-induced hypertension was associated with CypD redox activation by S-glutathionylation, and expression of the mitochondria-targeted H2O2 scavenger, catalase, abolished CypD S-glutathionylation, prevented stimulation mitochondrial O˙2 (-), and attenuated hypertension. The functional role of cytokine-angiotensin II interplay was confirmed by co-operative stimulation of mitochondrial O˙2 (-) by 3-fold in cultured endothelial cells and impairment of aortic relaxation incubated with combination of angiotensin II, interleukin 17A, and tumor necrosis factor-α which was prevented by CypD depletion or expression of mitochondria-targeted SOD2 and catalase. These data support a novel role of CypD in hypertension and demonstrate that targeting CypD decreases mitochondrial O˙2 (-), improves vascular relaxation, and reduces hypertension.
© 2016 American Heart Association, Inc.
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20 MeSH Terms
Absolute Quantitative MALDI Imaging Mass Spectrometry: A Case of Rifampicin in Liver Tissues.
Chumbley CW, Reyzer ML, Allen JL, Marriner GA, Via LE, Barry CE, Caprioli RM
(2016) Anal Chem 88: 2392-8
MeSH Terms: Animals, Chromatography, High Pressure Liquid, Liver, Rats, Rifampin, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added February 22, 2016
Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) elucidates molecular distributions in thin tissue sections. Absolute pixel-to-pixel quantitation has remained a challenge, primarily lacking validation of the appropriate analytical methods. In the present work, isotopically labeled internal standards are applied to tissue sections to maximize quantitative reproducibility and yield accurate quantitative results. We have developed a tissue model for rifampicin (RIF), an antibiotic used to treat tuberculosis, and have tested different methods of applying an isotopically labeled internal standard for MALDI IMS analysis. The application of the standard and subsequently the matrix onto tissue sections resulted in quantitation that was not statistically significantly different from results obtained using HPLC-MS/MS of tissue extracts. Quantitative IMS experiments were performed on liver tissue from an animal dosed in vivo. Each microspot in the quantitative images measures the local concentration of RIF in the thin tissue section. Lower concentrations were detected from the blood vessels and around the portal tracts. The quantitative values obtained from these measurements were comparable (>90% similarity) to HPLC-MS/MS results obtained from extracts of the same tissue.
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6 MeSH Terms
MID Max: LC-MS/MS Method for Measuring the Precursor and Product Mass Isotopomer Distributions of Metabolic Intermediates and Cofactors for Metabolic Flux Analysis Applications.
McCloskey D, Young JD, Xu S, Palsson BO, Feist AM
(2016) Anal Chem 88: 1362-70
MeSH Terms: Adenosine Triphosphate, Carbohydrate Metabolism, Chromatography, High Pressure Liquid, Escherichia coli, Isotope Labeling, Metabolic Flux Analysis, Molecular Structure, Tandem Mass Spectrometry
Show Abstract · Added March 31, 2016
The analytical challenges to acquire accurate isotopic data of intracellular metabolic intermediates for stationary, nonstationary, and dynamic metabolic flux analysis (MFA) are numerous. This work presents MID Max, a novel LC-MS/MS workflow, acquisition, and isotopomer deconvolution method for MFA that takes advantage of additional scan types that maximizes the number of mass isotopomer distributions (MIDs) that can be acquired in a given experiment. The analytical method was found to measure the MIDs of 97 metabolites, corresponding to 74 unique metabolite-fragment pairs (32 precursor spectra and 42 product spectra) with accuracy and precision. The compounds measured included metabolic intermediates in central carbohydrate metabolism and cofactors of peripheral metabolism (e.g., ATP). Using only a subset of the acquired MIDs, the method was found to improve the precision of flux estimations and number of resolved exchange fluxes for wild-type E. coli compared to traditional methods and previously published data sets.
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8 MeSH Terms
Analysis of the Phosphoinositide Composition of Subcellular Membrane Fractions.
Sarkes DA, Rameh LE
(2016) Methods Mol Biol 1376: 213-27
MeSH Terms: Cell Fractionation, Cell Membrane, Chromatography, High Pressure Liquid, Phosphatidylinositols, Staining and Labeling, Subcellular Fractions, Tritium
Show Abstract · Added November 26, 2018
Phosphoinositides play critical roles in the transduction of extracellular signals through the plasma membrane and also in endomembrane events important for vesicle trafficking and organelle function (Di Paolo and De Camilli, Nature 443(7112):651-657, 2006). The response triggered by these lipids is heavily dependent on the microenvironment in which they are found. HPLC analysis of labeled phosphoinositides allows quantification of the levels of each phosphoinositide species relative to their precursor, phosphatidylinositol. When combined with subcellular fractionation techniques, this strategy allows measurement of the relative phosphoinositide composition of each membrane fraction or organelle and determination of the microenvironment in which each species is enriched. Here, we describe the steps to separate and quantify total or localized phosphoinositides from cultured cells.
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MeSH Terms