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Ultra-High Mass Resolving Power, Mass Accuracy, and Dynamic Range MALDI Mass Spectrometry Imaging by 21-T FT-ICR MS
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  • Andrew P. Bowman
    Andrew P. Bowman
    Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry (IMS), Maastricht University, Universiteitssingel 50, Maastricht 6629ER, The Netherlands
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  • Greg T. Blakney
    Greg T. Blakney
    Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry (IMS), Maastricht University, Universiteitssingel 50, Maastricht 6629ER, The Netherlands
    More by Greg T. Blakney
    Orcidhttp://orcid.org/0000-0002-4205-9866
  • Christopher L. Hendrickson
    Christopher L. Hendrickson
    National High Magnetic Field Laboratory, Florida State University, 1800 East Paul Dirac Drive, Tallahassee, Florida 32310-4005, United States
    Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, Florida 32306, United States
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  • Shane R. Ellis
    Shane R. Ellis
    Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry (IMS), Maastricht University, Universiteitssingel 50, Maastricht 6629ER, The Netherlands
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    Orcidhttp://orcid.org/0000-0002-3326-5991
  • Ron M. A. Heeren*
    Ron M. A. Heeren
    Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry (IMS), Maastricht University, Universiteitssingel 50, Maastricht 6629ER, The Netherlands
    *(R.M.A.H.) Email: [email protected]
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    Orcidhttp://orcid.org/0000-0002-6533-7179
  • Donald F. Smith*
    Donald F. Smith
    National High Magnetic Field Laboratory, Florida State University, 1800 East Paul Dirac Drive, Tallahassee, Florida 32310-4005, United States
    *(D.F.S.) Email: [email protected]
    More by Donald F. Smith
    Orcidhttp://orcid.org/0000-0003-3331-0526
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Analytical Chemistry

Cite this: Anal. Chem. 2020, 92, 4, 3133–3142
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https://doi.org/10.1021/acs.analchem.9b04768
Published January 19, 2020

Copyright © 2020 American Chemical Society. This publication is licensed under CC-BY-NC-ND.

Abstract

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Detailed characterization of complex biological surfaces by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) requires instrumentation that is capable of high mass resolving power, mass accuracy, and dynamic range. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) offers the highest mass spectral performance for MALDI MSI experiments, and often reveals molecular features that are unresolved on lower performance instrumentation. Higher magnetic field strength improves all performance characteristics of FT-ICR; mass resolving power improves linearly, while mass accuracy and dynamic range improve quadratically with magnetic field strength. Here, MALDI MSI at 21T is demonstrated for the first time: mass resolving power in excess of 1 600 000 (at m/z 400), root-mean-square mass measurement accuracy below 100 ppb, and dynamic range per pixel over 500:1 were obtained from the direct analysis of biological tissue sections. Molecular features with m/z differences as small as 1.79 mDa were resolved and identified with high mass accuracy. These features allow for the separation and identification of lipids to the underlying structures of tissues. The unique molecular detail, accuracy, sensitivity, and dynamic range combined in a 21T MALDI FT-ICR MSI experiment enable researchers to visualize molecular structures in complex tissues that have remained hidden until now. The instrument described allows for future innovative, such as high-end studies to unravel the complexity of biological, geological, and engineered organic material surfaces with an unsurpassed detail.

Copyright © 2020 American Chemical Society

Subjects

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Mass spectrometry imaging (MSI) has proven to be a versatile tool, finding applications in a variety of fields including diseased tissue classification, (1−4) bacterial infections and resistance, (5,6) and drug metabolism. (7,8) The main strength of MSI is the ability to simultaneously reveal the spatial distributions of multiple molecules in a single experiment from complex biological materials, typically tissue sections. (9) However, the chemically complex samples typically analyzed bring challenges associated with the mass resolution and unambiguous assignment of the many different molecules detected. Due to this complexity, many signals are often unresolved from isobaric ions, such that generated ion images are not reflective of one unique molecule. This is a major hindrance to the study of the biochemical changes within tissues.
The most popular approach to begin addressing this complexity is the coupling of high mass resolving power and high mass accuracy analyzers with MSI ion sources, most commonly matrix-assisted laser desorption/ionization (MALDI). (10) This combination allows mass resolution of many isobaric ion species and direct assignment of elemental composition, thereby providing insight into the specific identities of the detected molecules. For lipids that are arguably the most widespread analyte class studies with MSI, (11−14) high mass resolving power and accuracy can facilitate true identification of sum-composition formula (i.e., lipid class and the combined number of carbons and double bonds across both fatty acyl chains), when sufficient to allow separation from isobaric interferences. In comparison to other biological molecules, resolving lipid complexity is further complicated by their relatively narrow mass range, with the majority of signals observed between m/z 700–900. (15) Lipids can further be observed as multiple adducts (e.g., addition of H+, Na+, K+, OAc–, Cl–, or loss of H+) that are entangled with isotopes and other isobaric species. This results in a highly complex mass spectra that cannot be resolved with conventional high mass resolving power (e.g., ≤ 150 000 @ m/z 750). (15) Improvements in the achievable mass resolving of MSI technology is needed to unravel the spatial distributions of unique sum-composition lipid species that can have dramatically different biological functions
Fourier transform mass spectrometers; Fourier transform ion cyclotron resonance (FT-ICR) or orbital trapping (i.e., Orbitrap) offer higher mass resolving power and mass accuracy than other types of mass spectrometers (e.g., time-of-flight and ion trap). FT-ICR mass spectrometers provide the highest mass resolving power and mass accuracy of any mass analyzer, with up to parts-per-billion (ppb) mass accuracy, high dynamic range, and mass resolving power values greater than 1 000 000 in routine analyses. (16−18) Mass resolution and sensitivity in FT-ICR instrumentation can also be improved by the use of absorption mode processing, (18,19) although this has not yet been widely exploited for MSI applications. (17) In a proof-of-principle study, absorption mode MALDI FT-ICR MSI on a 9.4 T system provided mass resolving powers in excess of 250 000 for lipid species observed from mouse brain tissue. (18,20) Several studies have shown similar high mass resolution on Orbitrap systems, (21−23) though additional difficulties introduced in imaging systems typically report lower overall mass resolution. (24−26) High mass resolution is necessary to distinguish both nominally isobaric lipids, where common mass differences of less than 10 mDa (15) occur, as well as isotopic interferences, where mass differences less than 3 mDa occur. While many lower field FT-ICR and Orbitrap instruments can distinguish the more common isobaric interferences, they are typically incapable of resolving mass differences less than 3 mDa. (27−29) More recently, desorption-electrospray ionization-MSI using a 7T FT-ICR system combined with absorption mode processing and external acquisition electronics demonstrated resolving powers up to 1 000 000 for lipid species. (17) However, the number of ions had to be reduced to avoid space-charge and peak coalescence effects, which reduced the dynamic range by 2 orders of magnitude, and the m/z range was truncated (m/z 765–832). Higher magnetic field strength mitigates these problems, and enables larger ion populations to be analyzed, for high dynamic range broadband spectra at high mass resolution. The method described for DESI at 7 T helps overcome a key challenge in FT-ICR MSI by increasing the transient length while minimizing acquisition overhead, helping to balance the desired mass resolution with practical acquisition times for experiments that typically involve acquisitions of tens of thousands of spectra. These practical acquisition times are paramount within MALDI imaging, where the use of volatile matrices limits how long any single experiment can be performed before the matrix sublimes from the sample.
Outside of the improvements offered by absorption mode data processing, analysis times can be reduced by increasing the strength of the magnet used for FT-ICR. Mass resolution increases linearly with magnetic field strength, (30) allowing for decreases in transient length without sacrificing resolving power. In the context of typically long MSI acquisition times, this improvement can reduce experimental times by several hours, a significant increase in throughput. Multiple frequency detection promises an increase in mass resolving power that scales linearly with the frequency order multiple. (31) However, to date this technique has not been applied to mass spectrometry imaging, though significant progress has been shown in ESI-based methods, which have reported mass resolving power of more than 10 000 000 in the lipid range. (16,21,32)
The key parameters of FT-ICR that vary with magnetic field strength (dynamic range, mass accuracy, and ion-number induced frequency fluctuations) are especially important in MSI, due to the changes in ion yield depending on tissue type, (33) as well as a lack of control (e.g., via automatic gain control) over the number of ions entering the analyzer cell at each pixel. Further, the rich information available within the lipid range sees an enormous benefit from higher magnetic fields, in part from the biological dynamic range of lipids, but also from the number of nominally isobaric peaks possible in biological tissues. The advantage of increased mass resolution is obvious, but the improvement to mass accuracy and dynamic range can be crucial. High mass accuracy over long analysis times is important to generate highly accurate MSI images, as any drift in mass across an experiment would necessitate either pixel-to-pixel correction for this drift, or wider mass selection windows for image generation to encapsulate the ion as its apparent m/z shifts over time. High-field FT-ICR mass spectrometers offer external mass calibrations of less than 0.2 ppm (ppm), (34) and internal calibration less than 0.1 ppm. (35) High dynamic range is a key performance metric for MSI, given the wide dynamic range of lipid concentrations, (36) and differences in the ionization efficiencies of these biomolecules. Increased dynamic range is important to distinguish low abundance species while still detecting highly abundant lipids without distortion in relative ion abundances. The higher the magnetic field of an FT-ICR, the less susceptible it is to ion-number induced frequency shifts, which can hinder identification of peaks and complicate calibration of data sets, as has been described previously. (37−39)
Within the field of lipidomics, both shotgun and LC-MS based methodologies have achieved mass resolution in the lipid range greater than 100 000 along with sub-ppm mass accuracy, enabling assignment of 200–500 lipids in a single experiment. (40−42) Due to the increased fluctuations in signal intensity inherent to MSI, progress toward such endeavors is slower, success has been shown in a variety of FT based instruments with numerous ionization techniques, including Liquid Extraction Surface Analysis, (43) MALDI, (44) DESI, (17) and LAESI. (20) LAESI was performed on a 21 T FT-ICR mass spectrometer which separated the isotopic fine structure of nominally overlapping metabolites of plant leaves, which improved identification by utilizing multiple peaks per metabolite in the identification process. Additionally, the experimental time frame for the 21 T is significantly reduced compared to other instruments with similar mass resolution, without sacrificing either signal magnitude or mass range, as has been attempted with lower-field instruments. (17,20,35)
In this work, we evaluate for the first time the performance of MALDI MSI combined with 21 T FT-ICR MS for biological tissue imaging, as well as the use of automated annotation to begin exploring the highly complex information available from such experiments. In particular, we demonstrate (i) the combined higher mass resolving power and mass accuracy with the stability of these parameters across long MSI experiments; (ii) increased biochemical information obtained during MALDI MSI facilitated by the high mass resolving power and mass accuracy; (iii) single-pixel dynamic range exceeding 500:1, which enables imaging and identification of very low abundance ions; (iv) automated analytical tools to identify potentially hundreds of lipids utilizing thousands of peaks. Combined, this work demonstrates the high potential of MALDI MSI and 21 T FT-ICR for studying localized biomolecular processes within tissues and their disease-induced alterations.

Methods

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Materials

Methanol (LC-MS grade), ethanol (LC-MS grade), xylene (LC-MS grade), water (LC-MS grade), anhydrous chloroform (≥99.9% purity), and crystalline norharmane (9H-β-carboline) were purchased from Sigma-Aldrich (Zwijndrecht, The Netherlands) and used without further purification. Indium tin oxide (ITO)-coated glass slides were purchased from Delta Technologies (Loveland, CO).

Biological Samples

Healthy rat brain was obtained from Maastricht University in accordance with protocols approved by the Animal Care and Use Committee under Animal Experiment Committee (DEC) number 2016–006 AVD107002016720. Four transverse rat brain segments (12 μm thick) were sectioned with a cryo-microtome at −20 °C and thaw-mounted on ITO-coated glass slides. Some distortion of the tissue sections occurred during the mounting process.

Sample Preparation

Norharmane matrix (7 mg/mL) in CHCl3:MeOH (2:1 v/v) was applied to the tissue with a TM-Sprayer (HTX Technologies, Chapel Hill, NC). Spray conditions were as follows: flow rate, 0.12 mL/min; N2 pressure, 10 psi; N2 temperature, 30 °C; spray-head velocity, 1200 mm/min; track spacing, 3 mm; number of layers, 15; drying time between layers, 30 s.

Instrumentation

All MSI experiments were performed on a hybrid linear ion trap 21 T FT-ICR mass spectrometer at the National High Magnetic Field Laboratory (NHMFL) at Florida State University (Tallahassee, FL). A Velos Pro linear ion trap (Thermo Scientific, San Jose, CA) was combined with NHMFL-designed external linear quadrupole ion trap, quadrupole ion transfer optics, and a novel dynamically harmonized ICR cell, which is operated at 7.5-V trapping potential. (34) Briefly, the cell uses 120° cell segments for ion excitation and detection, for improved excitation electric field, detection sensitivity, and reduced third harmonic signals. (45,46)
The commercial ion source and stacked ring ion guide were replaced with an elevated-pressure MALDI ion source incorporating a dual-ion funnel interface (Spectroglyph LLC, Kennewick, WA) as has been described previously. (47) Voltages within the funnels were 625 kHz, 150 V peak-to-peak (first, high-pressure ion funnel), and 1.2 MHz, 90 V peak-to-peak (second, low-pressure ion funnel). An electric field gradient of ∼10 Vcm–1 was maintained within the dual-funnel system, with a gradient of 100 Vcm–1 between the sample and the funnel inlet. The system was equipped with a Q-switched, frequency-tripled Nd:YLF laser emitting 349 nm light (Explorer One, Spectra Physics, Mountain View, CA). The laser was operated at a repetition rate of 1 kHz and pulse energy of ∼1.2 μJ. Pressure within the ion source was set to 10 mbar in the first ion funnel, and 2 mbar in the second ion funnel. MALDI stage motion was synchronized with ion accumulation using the Velos trigger signal indicating commencement of the ion trap injection event, as previously described. (47) The mass spectrometer was operated with an ion injection time of 250 ms and automatic gain control (AGC) was turned off. A transient duration of 3.1 s was used for ultrahigh mass resolving power analyses, resulting in a total time of 4s per pixel. Spectra were obtained in both positive and negative mode, at 100 μm spatial resolution. Total number of pixels per brain section were approximately 22 000, and 24 h of experimental time. A Predator data station was used for ion excitation and detection. (48)

Data Processing and analysis

Absorption mode mass spectra were generated by phase correction of the time domain transients, (49) and peaks with a signal magnitude greater than 6 times the standard deviation of the baseline root-mean-square (RMS) noise were exported to peak lists. Mass calibration was performed on known lipid species, with a wide range of spectral intensities ([PC 34:1 + K]+, [SM 34:1;2 + H]+, [PE 36:4 13C + H]+, [PC 32:0 + Na]+, [PC 34:1 + H]+, [PC 38:4 + Na]+, and [PC 38:4 + K]+) and the data were converted to imzML format using in-house Matlab routines, msconvert from the ProteoWizard software suite (version 3.0.11537), (50) and imzMLConverter version 1.3. (51) The ALEX123 software package was used for sum-composition lipid identification at a search tolerance of 1 mDa. (41,52) All phospholipid classes were chosen, as were sphingolipids and glycerolipids, with chain-lengths of 14 carbons or greater. Adducts were limited to H+, Na+, and K+, and negative mode was restricted here to simple loss of H+. Images generated are normalized to the total ion current per pixel (TIC).

Results and Discussion

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High Mass Resolving Power

To assess the benefits of performing 21 T MALDI MSI in terms of mass resolving power, we analyzed rat brain sections in both positive and negative ion mode using different transient acquisition times. Figure 1 shows the achieved mass resolving power in the positive-ion mode using 0.76, 1.55, and 3.1 s transients within the m/z range 785.52–785.6. Increasing mass resolution shows increasing spectral complexity, as five peaks are resolved from what first appears to be only two, with two additional peaks within 100 mDa which were sufficiently distinct to be identified at all transient lengths. We annotated the seven peaks within this region as belonging to six different species of lipids: [PE(36:1)+K]+, [PC-O(34:1)+K]+, [PC(34:1)+Na]+, [PC(36:4)+H]+, [PC(34:0)+Na]+, and [PC(36:3)+H]+. Of these, four are the 13C1 isotope: ([PE(36:1)+13C+K]+, [PC-O(34:1)+13C+K]+, [PC(34:0)+13C+Na]+, and [PC(36:3)+13C+H]+), two are the 13C3 isotope ([PC(34:1)+ 13C3+Na]+ and [PC(36:4)+ 13C3+H]+), and the final peak is the 13C18O isotope ([PC(34:1)+ 13C18O+Na]+). These peaks show mass accuracy errors between −50 and 13 parts-per-billion (ppb). Additionally, isotope ratios in the summed average spectra deviate <15% from theoretical in these seven peaks (SI Figure 1), offering additional certainty in that correct sum-composition identification has been made, as well that there are no convoluted peaks being presented as a single peak. Deviation from the expected 2-fold improvement in mass resolving power upon doubling of the transient duration is due to known collisional damping during the detection event. (34) Current work focuses on a solution to limit transmission of the neutral buffer gas in the external accumulation multipole to the ultrahigh vacuum region. Recently, a mass resolving power of ∼600 000 (at m/z 760) for MALDI MSI on a 15 T FT-ICR MS (the highest commercially magnetic field available for FT-ICR) was reported. This value also deviates from the theoretical mass resolving power for a 5.2 s transient (magnitude mode), which is ∼788 000. (53)

Figure 1

Figure 1. Mass resolution and sensitivity improve with longer transient length. Within a 100 mDa mass range, seven different peaks are detected, which belong to six different lipid species. Of these, five are unresolved at 0.77 s. While distinguishable at 1.55 s, all seven peaks are fully resolved only at 3.1 s transient. These seven peaks correspond to the isotopologues of the monoisotopic species, typically the 13C ion, as in (a), (b), (f), and (g). Other species are also present, corresponding to the 13C3 isotopologue, as in (d) and (e). The 18O13C isotopologue of [PC(34:1)+Na]+ is also resolved (c) from the 13C3 isotopologue of the same parent species.

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To further assess the utility of the 21 T, we analyzed the data set for peaks with close neighbors (here defined as <10 mDa). We extracted the 3.1 s transient from a single pixel (number 10 000) as a representative spectrum from each data set. In positive-ion mode, a difference of 0.0024 Da (2.4 mDa) at m/z 810 was present (Figure 2a), representing the difference between Na1H1 versus C2 (the addition of two carbon atoms and three double bonds to the lipid fatty acid chains) which requires a mass resolving power (m/Δm50%) of 337 000 at m/z 810 to resolve. These two ions were well resolved, and lipid identities were assigned [PC(36:1)+Na]+ and [PC(38:4+H)]+ with high confidence (100 ppb, see discussion below). Each species had very different spatial distributions, with the former ([PC(36:1)+Na]+) being relatively evenly distributed (Figure 2b), while the latter ([PC(38:4+H)]+) had higher abundance in the lateral ventricle (Figure 2c). The higher abundance of [PC(38:4)+Na]+ in the ventricles matches with its role as a pro-inflammatory cytokine. (54) Interestingly, such a small mass difference was not uncommon, with a mass difference of 2.4 mDa observed over 190 times in any single pixel spectrum, and more than 1 000 000 times over a single MSI experiment (Figure 2d). Without sufficient mass resolving power, any one of the images of these ∼190 pairs of closely spaced ions could yield incorrect assignments and yield a summed spatial distribution reflective of neither individual species. A variety of other recurrent mass differences can be detected in the single spectra, ranging from 1 to 10 mDa, including isotopic patterns (e.g., 13C2 vs H2 is a difference of 8.94 mDa). The change in 13C2 vs H2 is an important one, as this denotes the possible overlap for species that differ by a single double bond (i.e., as PC(34:1) to PC(34:0)). Single unsaturation changes have been shown to be important in various types of disease states, including cancers (55,56) and multiple sclerosis, (57) and so the ability to resolve such fine mass differences opens the door to studying the precise roles of the subtle changes in lipid structure throughout tissues.

Figure 2

Figure 2. Representative images of close mass differences in negative and positive mode, from a single, scan. Images are total ion current normalized. Positive mode lipid spectra have a significant number of mass differences of 2.4 mDa (a), representing the difference between 12C2 and 23Na1H. 2.4 mDa differences are baseline resolved, and show significantly different distributions within brain tissue (b and c). There are nearly 200 such differences in the averaged spectra, shown in 0.5 mDa bins (d). Similarly, negative mode spectra have 1.79 mDa mass differences (e). These 1.79 mDa differences are resolved to better than full-width half-maximum, differentiated well enough to distinguish them in brain tissue (f and g). The of 1.79 mDa mass difference is relatively uncommon in negative mode, but mass differences of 10 mDa or less occur approximately 500 times in the averaged spectra, shown in 0.25 mDa bins (h).

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Using the same experimental design in the negative-ion mode, additional small mass differences could be resolved. For example, a mass difference of 0.00179 Da (1.79 mDa) at m/z 757.52 was observed at 31 different masses. This corresponds the mass difference of C2N113C1 versus H3O3 (Figure 2e). While less common than the NaH vs C2 mass difference in positive mode, ether-linked phosphatidylethanolamine (PE) and PC lipids can have this difference from the phosphatidylglycerol (PG) class. These peaks were thus identified as phosphatidylethanolamine [PE(O-38:7)+13C–H]− and [PG(34:1)-H]−. This is the smallest mass difference observed in any MSI data set to date. The PE is a 13C-containing nuclide of the monoisotopic PE lipid at m/z 746.51300. PE and PG lipids are synthesized by different biological pathways and have different physiological function. PE lipids are ∼20% of all phospholipids, and are especially abundant in white matter of the cerebellum (Figure 2f). (58) By contrast, PG lipids are associated with ATP-Binding Cassette 3, though what transport function is utilized is unknown. (59) The 1.79 mDa mass difference occurred over 100 000 times in our MSI experiment, with 33 unique pairs detected in the total mass spectrum. As in the positive mode, the 13C2 vs H2 difference occurs regularly, and has many of the same ramifications as discussed above.

Dynamic Range

One of the most problematic complications in MSI is the low relative ionization efficiency from the surface, which combined with the wide range of analyte concentrations, places significant demands on the single scan dynamic range achievable in an MSI experiment. High sensitivity and dynamic range are thus necessary to detect low abundance and/or poorly ionized species without distorting the peak abundances obtained from high intensity signals. Figure 3a shows a single pixel mass spectrum of the lipid m/z range from the positive-ion mode data set (scan no. 10 000), which has a dynamic range of 536:1 (expanded mass range spectrum shown in SI Figure 2). The dynamic range was calculated by dividing the signal magnitude of the base peak by the peak detection threshold of six standard deviations (6σ) above the baseline noise. As typically observed from brain tissue, the [M+K]+ ion of PC(34:1) generated the highest signal magnitude, with a signal-to-noise = 2370:1 (Figure 3b; side lobe artifacts are a result of the absorption mode processing, and current work is focused on their removal). By contrast, rat brain tissue sections prepared from the same original organ and under the same conditions showed a signal-to-noise = 336:1 on a Thermo Orbitrap Elite set at 240 000 resolving power (@ m/z 400) at the Maastricht MultiModal Molecular Imaging Institute (data not shown). Using a peak detection threshold of 6σ above the baseline noise, the lowest intensity signal was observed with a signal-to-noise = 6 and corresponded to the (PE(46:5)+13C2+H)+ (Figure 3c). SI Figure 3 shows the isotopic distribution for PE 46:5, where the 13C2 containing nuclide can be identified at M+2. In addition, SI Figure 4 shows ppm error distributions for the monoisotopic peak, M+1 (13C1), and M+2 (13C2) which show good mass accuracy, despite the low S/N of the M+2 peak. Per pixel, the average dynamic range in positive ion mode was 438:1, with a maximum dynamic range of 2090:1 and a minimum of 60:1 (SI Figure 5). Negative-ion mode spectra had lower signal magnitude than positive mode, limiting the average dynamic range to 214:1, with a maximum of 849:1 and minimum of 30:1 (SI Figure 6).

Figure 3

Figure 3. Single on-tissue mass spectrum illustrates high dynamic range per pixel. Peaks were picked at a threshold of six standard deviations above the baseline noise. Dynamic range in a single average pixel of at 536:1 is demonstrated here at pixel number 10 000, (a). Mass scale expanded segment around most abundant peak [PC 34:1 + K]+ (b). Further, peak at 798.5410 generates a bright image (b). One of the lowest S/N peaks, the 13C2 isotope of [PE 46:5 + H]+ (c) while less clear, still yields informative molecular images, being highlighted especially in the ventricles (images are TIC normalized).

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High Mass Accuracy

FT-ICR MSI at 21 T showed a root-mean-square (rms) mass measurement accuracy of 62.12 ppb (Figure 4a), over 2-fold lower rms mass accuracy achieved on a 9 T instrument, which was limited to an rms of 158 ppb. (60) The center of the distribution is centered near zero, and the low standard deviation indicates low m/z fluctuation during the imaging experiment. SI Figure 7 shows the measured m/z variation for [PC(36:1)+H]+ (m/z = 788.61638, dotted red line indicates the exact m/z) over the imaging experiment, where the maximum m/z deviation is 0.00018, with a standard deviation of 0.00078. Internal calibration was performed using seven tentatively identified lipid masses ([PC(34:1)+K]+, [SM(34:1;2)+H]+, [PE(36:4)+13C+H]+, [PC(32:0)+Na]+, [PC(34:1)+H]+, [PC(38:4)+Na]+, and [PC(38:4)+K]+). After this internal calibration, all scans were summed (in the mass domain), which generated an initial peak list of 2,643 above the 6σ noise limit. This list was then submitted to ALEX123 for identification. We tentatively identify 702 monoistopic lipid peaks in positive-ion mode, which all have mass accuracy values of ±150 ppb (Figure 4b). These 702 lipid peaks correspond to 388 unique lipid IDs, after accounting for three possible cations types, which accounts for 26.9% of the initial peak list. SI Table 1 contains a full list of these lipids. An additional 1400 spectral peaks are as isotopologues (typically 13C and 13C2) of the 702 lipids, which accounts for ∼80% of all peaks. Negative ion mode yielded similar results, where 662 potential monoisotopic lipid peaks (34%) were identified out of an initial peak list of 1927. Due to the lower S/N of the negative mode spectra, only 738 further peaks were identified as isotopes, for a total of ∼72.6% of all peaks identified.

Figure 4

Figure 4. Error histogram and average mass error of tentatively identified lipids after internal calibration. Measured mass error histogram of 139 phosphatidylcholine lipids; the rms error is 61.12 ppb. Bin size = 10 ppb. (a), Lipid identifications by class. A tolerance of ±250 ppb results in 702 potential lipids identified within 150 ppb of their expected mass (b).

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These lipid IDs are supported both by the high mass accuracy (<150 ppb, most <100 ppb) and in the positive mode by the intensity of multiple cations for the same species, relative to one another (Figure 5a). As protonation, sodiation, and potassiation are all potentially available in brain MSI, we examined the potential to confirm our lipid identifications by comparing all three cations. For the most abundant lipid (PC(34:1)), the [M+K] ion has an average ppb error of 16.7, [M + Na] −43.5, and [M + H] 2.2. While these mass errors are low enough individually to be highly confident in their assignment, having all three ions within 60 ppb of one another provides another layer of certainty. Additionally, we can examine the normalized peak intensities of all three ions to one another, in this case showing 100%, 47.9%, and 21.4%, simplified to a ratio of 4.7:2.2:1. While this insight is not necessarily informative on its own, we can compare this ratio to other PCs, with all the PCs above 3% of the base peak showing the same ratio (Figure 5a). Further, PCs that vary in relative intensity down to 0.2% of the base peak have generally similar ratios to PC(34:1), although as the intensities begin to approach the 6σ limit, the ratios begin to deviate and be less similar (Figure 5b). One likely scenario for this discrepancy at low S/N is that as peaks for any given scan drop below the 6σ threshold, the least abundant ions are ignored, leading to sum signal magnitudes in the averaged spectrum that are slightly erroneous. However, as the relative ratios of the three cations are invariable across three orders of magnitude, it improves our certainty that each identification is correct for all lipids within that class. While we observe no alterations to this ratio in the abundant lipid classes, theoretically alterations to this standard ratio could indicate greater abundance of a given lipid within different brain structures (i.e., within the ventricle space rather than within gray or white matter). It is worthwhile to further explore the potentials here, and whether there are observable changes to this ratio between other brain tissues. Additionally, we observe that other lipid classes show similar, though slightly different ratios (SI Figure 8), potentially related to the changes in brain tissue. Negative ionization does not typically have multiple ions of the same species (with deprotonation being the only common method of generating lipid anions unless dopants are added (61,62)); however, between the most abundant phosphatidylserine (PS(40:6)) and the least abundant (PS(34:4)) there is only a change in ppb error of 17.3 despite a change in intensity of more than an order of magnitude (Figure 5c).

Figure 5

Figure 5. Relative abundance of identified lipids by cation and anion for selected classes. In the positive mode, the three major cations (proton, sodium, and potassium) are aligned next to one another, showing the same relative percentages between species, from the most abundant species (PC 34:1) and the other PCs above 3% (a), as well as for the lower abundant species down to the least abundant species with all three cations represented, PC 44:12 (b). The relative ionization rate between K+, H+, and Na+ hold strictly true down to 1.5%, and generally true down to 0.05%. While the dynamic range is lower for negative mode, we see many potential identifications for many lipid classes (c). We further observe a similar ability to identify potential lipids as low as 0.15% of the most abundant peak (PI 38:4), for a range of nearly three orders of magnitude from the summed spectra (d).

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Conclusion

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We have demonstrated the utility of combining MSI workflows with a 21 T FT-ICR mass spectrometer. The high magnetic field, combined with a state-of-the-art ICR cell design provides ultrahigh mass resolving power, ppb mass measurement accuracy, and high sensitivity for molecular imaging studies. This advanced instrumentation will pave the way for better understanding of the molecular structure of many tissue types, as well as clarifying current ambiguities in MSI. The unique capabilities of this instrument have not yet been fully utilized: online tandem mass spectrometry is possible via collision induced dissociation in the linear ion trap, or in the ICR cell via infrared multiphoton dissociation or ultraviolet photo dissociation. Further, the use of harmonic detection cells would further increase the speed of acquisition in these experiments or allow for even higher mass resolving power in a similar time frame. Combined with data-driven MSI acquisition techniques (such as Data-Dependent Acquisition), this instrument promises the most information per unit time of any MSI platform. The estimated number of charges sent to the ICR cell in these experiments is ∼4 × 105, based on the mass spectral calibration parameters. The 21T FT-ICR routinely operates with ion targets of 1–3 × 106, so additional improvement in dynamic range per pixel is expected. Further, we aim to leverage the unique capabilities of this instrument for other biomolecule imaging experiments, such as metabolites, tryptic peptides, and intact proteins.. This instrument will provide valuable insight into the molecular complexity of tissues at an unprecedented mass spectral resolution, allowing for greater insight into the true distribution of all molecules, as well as accelerating the identification of subtle changes hidden within tissues.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.9b04768.

  • Eight additional figures as described in the text and table with a complete list of all tentatively identified lipid species (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Andrew P. Bowman - Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry (IMS), Maastricht University, Universiteitssingel 50, Maastricht 6629ER, The Netherlands
    • Greg T. Blakney - Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry (IMS), Maastricht University, Universiteitssingel 50, Maastricht 6629ER, The Netherlands;  Orcidhttp://orcid.org/0000-0002-4205-9866
    • Christopher L. Hendrickson - National High Magnetic Field Laboratory, Florida State University, 1800 East Paul Dirac Drive, Tallahassee, Florida 32310-4005, United States;  Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, Florida 32306, United States
    • Shane R. Ellis - Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry (IMS), Maastricht University, Universiteitssingel 50, Maastricht 6629ER, The Netherlands;  Orcidhttp://orcid.org/0000-0002-3326-5991
  • Author Contributions

    R.M.A.H. and D.F.S. conceived and coordinated the experiments. A.P.B., C.L.H., S.R.E., R.M.A.H., and D.F.S. designed the experiments. A.P.B., S.R.E., R.M.A.H., and D.F.S. carried out the MSI experiments. A.P.B., G.T.B., S.R.E., and D.F.S., conducted data processing and analysis. G.T.B., C.L.H., and R.M.A.H. provided feedback and quality control of MSI data. A.P.B., S.R.E., and D.F.S. wrote the manuscript, which was edited by all coauthors.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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A portion of this work was performed at the National High Magnetic Field Laboratory ICR User Facility, which is supported by the National Science Foundation Division of Chemistry through DMR-1644779 and the State of Florida. The 21T FT-ICR is available free of charge to all qualified users as part of the NSF High Field FT-ICR Mass Spectrometry User Facility. Part of this work was financially supported through the LINK program of the Dutch province of Limburg. Part of this work was financially supported through the EURLIPIDS program of Euregio.

References

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    Current Opinion in Chemical Biology (2018), 42 (), 138-146CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    Tissues present complex biochem. and morphol. compn. assocd. with their various cell types and physiol. functions. Mass spectrometry (MS) imaging technologies are powerful tools to investigate the mol. information from biol. tissue samples and visualize their complex spatial distributions. Coupling of gas-phase ion mobility spectrometry (IMS) technologies to MS imaging has been increasingly explored to improve performance for biol. tissue imaging. This approach allows improved detection of low abundance ions and sepn. of isobaric mol. species, thus resulting in more accurate detn. of the spatial distribution of mol. ions. In this review, we highlight recent advances in the field focusing on promising applications of these technologies for metabolite, lipid and protein tissue imaging.
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  15. 15
    Bielow, C.; Mastrobuoni, G.; Orioli, M.; Kempa, S. On Mass Ambiguities in High-Resolution Shotgun Lipidomics. Anal. Chem. 2017, 89 (5), 2986– 2994,  DOI: 10.1021/acs.analchem.6b04456
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    15
    On Mass Ambiguities in High-Resolution Shotgun Lipidomics
    Bielow, Chris; Mastrobuoni, Guido; Orioli, Marica; Kempa, Stefan
    Analytical Chemistry (Washington, DC, United States) (2017), 89 (5), 2986-2994CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Mass-spectrometry-based lipidomics aims to identify as many lipid species as possible from complex biol. samples. Due to the large combinatorial search space, unambiguous identification of lipid species is far from trivial. Mass ambiguities are common in direct-injection shotgun expts., where an orthogonal sepn. (e.g., liq. chromatog.) is missing. Using the rich information within available lipid databases, we generated a comprehensive rule set describing mass ambiguities, while taking into consideration the resolving power (and its decay) of different mass analyzers. Importantly, common adduct species and isotopic peaks are accounted for and are shown to play a major role, both for perfect mass overlaps due to identical sum formulas and resolvable mass overlaps. We identified known and hitherto unknown mass ambiguities in high- and ultrahigh resoln. data, while also ranking lipid classes by their propensity to cause ambiguities. On the basis of this new set of ambiguity rules, guidelines and recommendations for experimentalists and software developers of what constitutes a solid lipid identification in both MS and MS/MS were suggested. For researchers new to the field, our results are a compact source of ambiguities which should be accounted for. These new findings also have implications for the selection of internal stds., peaks used for internal mass calibration, optimal choice of instrument resoln., and sample prepn., for example, in regard to adduct ion formation.
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  16. 16
    Shaw, J. B.; Lin, T. Y.; Leach, F. E., 3rd; Tolmachev, A. V.; Tolic, N.; Robinson, E. W.; Koppenaal, D. W.; Pasa-Tolic, L. 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer Greatly Expands Mass Spectrometry Toolbox. J. Am. Soc. Mass Spectrom. 2016, 27 (12), 1929– 1936,  DOI: 10.1007/s13361-016-1507-9
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    16
    21 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer Greatly Expands Mass Spectrometry Toolbox
    Shaw, Jared B.; Lin, Tzu-Yung; Leach, Franklin E., III; Tolmachev, Aleksey V.; Tolic, Nikola; Robinson, Errol W.; Koppenaal, David W.; Pasa-Tolic, Ljiljana
    Journal of the American Society for Mass Spectrometry (2016), 27 (12), 1929-1936CODEN: JAMSEF; ISSN:1044-0305. (Springer)
    We provide the initial performance evaluation of a 21 T Fourier transform ion cyclotron resonance mass spectrometer operating at the Environmental Mol. Sciences Lab. at the Pacific Northwest National Lab. The spectrometer constructed for the 21T system employs a com. dual linear ion trap mass spectrometer coupled to a FTICR spectrometer designed and built inhouse. Performance gains from moving to higher magnetic field strength are exemplified by the measurement of peptide isotopic fine structure, complex natural org. matter mixts., and large proteins. Accurate detn. of isotopic fine structure was demonstrated for doubly charged Substance P with minimal spectral averaging, and 8158 mol. formulas assigned to Suwannee River Fulvic Acid std. with root-mean-square (RMS) error of 10 ppb. We also demonstrated superior performance for intact proteins; namely, broadband isotopic resoln. of the entire charge state distribution of apo-transferrin (78 kDa) and facile isotopic resoln. of monoclonal antibody under a variety of acquisition parameters (e.g., 6 s time-domains with absorption mode processing yielded resoln. of approx. 1 M at m/z = 2700).
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  17. 17
    Kooijman, P. C.; Nagornov, K. O.; Kozhinov, A. N.; Kilgour, D. P. A.; Tsybin, Y. O.; Heeren, R. M. A.; Ellis, S. R. Increased throughput and ultra-high mass resolution in DESI FT-ICR MS imaging through new-generation external data acquisition system and advanced data processing approaches. Sci. Rep. 2019, 9 (1), 8,  DOI: 10.1038/s41598-018-36957-1
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    17
    Increased throughput and ultra-high mass resolution in DESI FT-ICR MS imaging through new-generation external data acquisition system and advanced data processing approaches
    Kooijman Pieter C; Heeren Ron M A; Ellis Shane R; Kooijman Pieter C; Nagornov Konstantin O; Kozhinov Anton N; Tsybin Yury O; Kilgour David P A
    Scientific reports (2019), 9 (1), 8 ISSN:.
    Desorption electrospray ionisation-mass spectrometry imaging (DESI-MSI) is a powerful imaging technique for the analysis of complex surfaces. However, the often highly complex nature of biological samples is particularly challenging for MSI approaches, as options to appropriately address molecular complexity are limited. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) offers superior mass accuracy and mass resolving power, but its moderate throughput inhibits broader application. Here we demonstrate the dramatic gains in mass resolution and/or throughput of DESI-MSI on an FT-ICR MS by developing and implementing a sophisticated data acquisition and data processing pipeline. The presented pipeline integrates, for the first time, parallel ion accumulation and detection, post-processing absorption mode Fourier transform and pixel-by-pixel internal re-calibration. To achieve that, first, we developed and coupled an external high-performance data acquisition system to an FT-ICR MS instrument to record the time-domain signals (transients) in parallel with the instrument's built-in electronics. The recorded transients were then processed by the in-house developed computationally-efficient data processing and data analysis software. Importantly, the described pipeline is shown to be applicable even to extremely large, up to 1 TB, imaging datasets. Overall, this approach provides improved analytical figures of merits such as: (i) enhanced mass resolution at no cost in experimental time; and (ii) up to 4-fold higher throughput while maintaining a constant mass resolution. Using this approach, we not only demonstrate the record 1 million mass resolution for lipid imaging from brain tissue, but explicitly show such mass resolution is required to resolve the complexity of the lipidome.
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  18. 18
    Smith, D. F.; Kilgour, D. P.; Konijnenburg, M.; O’Connor, P. B.; Heeren, R. M. Absorption mode FTICR mass spectrometry imaging. Anal. Chem. 2013, 85 (23), 11180– 4,  DOI: 10.1021/ac403039t
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    18
    Absorption mode FTICR mass spectrometry imaging
    Smith, Donald F.; Kilgour, David P. A.; Konijnenburg, Marco; O'Connor, Peter B.; Heeren, Ron M. A.
    Analytical Chemistry (Washington, DC, United States) (2013), 85 (23), 11180-11184CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Fourier transform ion cyclotron resonance mass spectrometry offers the highest mass resolving power for mol. imaging expts. This high mass resolving power ensures that closely spaced peaks at the same nominal mass are resolved for proper image generation. Typically higher magnetic fields are used to increase mass resolving power. However, a gain in mass resolving power can also be realized by phase correction of the data for absorption mode display. In addn. to mass resolving power, absorption mode offers higher mass accuracy and signal-to-noise ratio over the conventional magnitude mode. Here, the authors present the first use of absorption mode for Fourier transform ion cyclotron resonance mass spectrometry imaging. The Autophaser algorithm is used to phase correct each spectrum (pixel) in the image, and then, these parameters are used by the Chameleon work-flow based data processing software to generate absorption mode Datacubes for image and spectral viewing. Absorption mode reveals new mass and spatial features that are not resolved in magnitude mode and results in improved selected ion image contrast.
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  19. 19
    Qi, Y.; Barrow, M. P.; Li, H.; Meier, J. E.; Van Orden, S. L.; Thompson, C. J.; O’Connor, P. B. Absorption-mode: the next generation of Fourier transform mass spectra. Anal. Chem. 2012, 84 (6), 2923– 9,  DOI: 10.1021/ac3000122
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    19
    Absorption-Mode: The Next Generation of Fourier Transform Mass Spectra
    Qi, Yulin; Barrow, Mark P.; Li, Huilin; Meier, Joseph E.; Van Orden, Steve L.; Thompson, Christopher J.; O'Connor, Peter B.
    Analytical Chemistry (Washington, DC, United States) (2012), 84 (6), 2923-2929CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The Fourier transform spectrum can be presented in the absorption-mode (commonly used in FT-NMR), magnitude-mode (FT-ICR), and power-mode (engineering applications). As is routinely used in FT-NMR, it is known that the absorption-mode display gives a much narrower peak shape which greatly improves the spectrum; recently, the successful soln. of the phase equation allowed broadband phase correction which makes it possible to apply the absorption-mode routinely in FT-ICR. With the empirical evidence provided herein, in addn. to the improvement on resolving power, compared to the conventional magnitude-mode, the new absorption-mode improves the signal-to-noise ratio (S/N) of a spectrum by 1.4-fold and can improve the mass accuracy up to 2-fold with no extra cost in instrumentation. Therefore, it is worthwhile to apply and promote absorption-mode in routine FT-ICR expts.
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  20. 20
    Stopka, S. A.; Samarah, L. Z.; Shaw, J. B.; Liyu, A. V.; Velickovic, D.; Agtuca, B. J.; Kukolj, C.; Koppenaal, D. W.; Stacey, G.; Pasa-Tolic, L.; Anderton, C. R.; Vertes, A. Ambient Metabolic Profiling and Imaging of Biological Samples with Ultrahigh Molecular Resolution Using Laser Ablation Electrospray Ionization 21 T FTICR Mass Spectrometry. Anal. Chem. 2019, 91 (8), 5028– 5035,  DOI: 10.1021/acs.analchem.8b05084
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    20
    Ambient Metabolic Profiling and Imaging of Biological Samples with Ultrahigh Molecular Resolution Using Laser Ablation Electrospray Ionization 21 Tesla FTICR Mass Spectrometry
    Stopka, Sylwia A.; Samarah, Laith Z.; Shaw, Jared B.; Liyu, Andrey V.; Velickovic, Dusan; Agtuca, Beverly J.; Kukolj, Caroline; Koppenaal, David W.; Stacey, Gary; Pasa-Tolic, Ljiljana; Anderton, Christopher R.; Vertes, Akos
    Analytical Chemistry (Washington, DC, United States) (2019), 91 (8), 5028-5035CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Mass spectrometry (MS) is an indispensable anal. tool to capture the array of metabolites within complex biol. systems. However, conventional MS-based metabolomic workflows require extensive sample processing and sepn. resulting in limited throughput and potential alteration of the native mol. states in these systems. Ambient ionization methods, capable of sampling directly from tissues, circumvent some of these issues but require high-performance MS to resolve the mol. complexity within these samples. Here, the authors demonstrate a unique combination of laser ablation electrospray ionization (LAESI) coupled with a 21 T Fourier transform ion cyclotron resonance (21T-FTICR) for direct MS anal. and imaging applications. This anal. platform provides isotopic fine structure information directly from biol. tissues, enabling the rapid assignment of mol. formulas and delivering a higher degree of confidence for mol. identification.
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  21. 21
    Schwudke, D.; Schuhmann, K.; Herzog, R.; Bornstein, S. R.; Shevchenko, A. Shotgun lipidomics on high resolution mass spectrometers. Cold Spring Harbor Perspect. Biol. 2011, 3 (9), a004614  DOI: 10.1101/cshperspect.a004614
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    Hu, C.; Duan, Q.; Han, X. Strategies to Improve/Eliminate the Limitations in Shotgun Lipidomics. Proteomics 2019, e1900070  DOI: 10.1002/pmic.201900070
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    Ryan, E.; Reid, G. E. Chemical Derivatization and Ultrahigh Resolution and Accurate Mass Spectrometry Strategies for “Shotgun” Lipidome Analysis. Acc. Chem. Res. 2016, 49 (9), 1596– 604,  DOI: 10.1021/acs.accounts.6b00030
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    23
    Chemical Derivatization and Ultrahigh Resolution and Accurate Mass Spectrometry Strategies for "Shotgun" Lipidome Analysis
    Ryan, Eileen; Reid, Gavin E.
    Accounts of Chemical Research (2016), 49 (9), 1596-1604CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Lipids play crit. structural and functional roles in the regulation of cellular homeostasis, and it is increasingly recognized that the disruption of lipid metab. and/or signaling is assocd. with the onset and progression of certain metabolically linked diseases. As a result, the field of lipidomics has emerged to comprehensively identify and structurally characterize the diverse range of lipid species within a sample of interest, and to quant. monitor their abundances under different physiol. or pathol. conditions. Mass spectrometry (MS) has become a crit. enabling platform technol. for lipidomic researchers. However, the presence of isobaric (i.e., same nominal mass) and isomeric (i.e., same exact mass) lipids within complex lipid exts. means that MS-based identification and quantification of individual lipid species remains a significant anal. challenge. Ultrahigh resoln. and accurate mass spectrometry (UHRAMS) offers a convenient soln. to the isobaric mass overlap problem, while a range of chromatog. sepn., differential extn., intrasource sepn. and selective ionization methods, or tandem mass spectrometry (MS/MS) strategies, may be used to address some types of isomeric mass lipid overlaps. Alternatively, chem. derivatization strategies represent a more recent approach for the "sepn." of lipids within complex mixts., including for isomeric lipids. In this Account, the authors highlight the key components of a lipidomics workflow developed in the authors' lab., whereby certain lipid classes and/or subclasses, namely aminophospholipids and O-alk-1'-enyl (i.e., plasmalogen) ether-contg. lipids, are shifted in mass following sequential functional group selective chem. derivatization reactions prior to "shotgun" nanoESI-UHRAMS anal., "targeted" tandem mass spectrometry (MS/MS), and automated database searching. This combined derivatization and UHRAMS approach resolves both isobaric mass lipids and certain categories of isomeric mass lipids within crude lipid exts., with no requirement for extensive sample handling prior to anal., with addnl. potential for enhanced ionization efficiencies, improved "mol. level" structural characterization, and "multiplexed" relative quantification. When integrated with a monophasic method for the simultaneous "global" extn. of both highly polar and nonpolar lipids, this workflow has been shown to enable the "sum-compn." level identification and relative quantification of 500-600 individual lipid species across 4 lipid categories and from 36 lipid classes and subclasses, in only 1-2 min data acquisition time and with minimal sample consumption. Thus, while some anal. challenges remain to be addressed, "shotgun" lipidomics workflows encompassing chem. derivatization strategies have particular promise for the anal. of samples with limited availability, but requiring rapid and unbiased assessment of "global" lipid metab.
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  24. 24
    Wildburger, N. C.; Wood, P. L.; Gumin, J.; Lichti, C. F.; Emmett, M. R.; Lang, F. F.; Nilsson, C. L. ESI-MS/MS and MALDI-IMS Localization Reveal Alterations in Phosphatidic Acid, Diacylglycerol, and DHA in Glioma Stem Cell Xenografts. J. Proteome Res. 2015, 14 (6), 2511– 9,  DOI: 10.1021/acs.jproteome.5b00076
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    24
    ESI-MS/MS and MALDI-IMS Localization Reveal Alterations in Phosphatidic Acid, Diacylglycerol, and DHA in Glioma Stem Cell Xenografts
    Wildburger, Norelle C.; Wood, Paul L.; Gumin, Joy; Lichti, Cheryl F.; Emmett, Mark R.; Lang, Frederick F.; Nilsson, Carol L.
    Journal of Proteome Research (2015), 14 (6), 2511-2519CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    Glioblastoma (GBM) is the most common adult primary brain tumor. Despite aggressive multimodal therapy, the survival of patients with GBM remains dismal. However, recent evidence has demonstrated the promise of bone marrow-derived mesenchymal stem cells (BM-hMSCs) as a therapeutic delivery vehicle for anti-glioma agents due to their ability to migrate or home to human gliomas. While several studies have demonstrated the feasibility of harnessing the homing capacity of BM-hMSCs for targeted delivery of cancer therapeutics, it is now also evident, based on clin. relevant glioma stem cell (GSC) models of GBMs, that BM-hMSCs demonstrate variable tropism toward these tumors. In this study, we compared the lipid environment of GSC xenografts that attract BM-hMSCs (N = 9) with those that do not attract (N = 9) to identify lipid modalities that are conducive to homing of BM-hMSC to GBMs. We identified lipids directly from tissue by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) and electrospray ionization-tandem mass spectrometry (ESI-MS/MS) of lipid exts. Several species of signaling lipids, including phosphatidic acid (PA 36:2, PA 40:5, PA 42:5, and PA 42:7) and diacylglycerol (DAG 34:0, DAG 34:1, DAG 36:1, DAG 38:4, DAG 38:6, and DAG 40:6), were lower in attracting xenografts. Mol. lipid images showed that PA (36:2), DAG (40:6), and docosahexaenoic acid (DHA) were decreased within tumor regions of attracting xenografts. Our results provide the first evidence for lipid signaling pathways and lipid-mediated tumor inflammatory responses in the homing of BM-hMSCs to GSC xenografts. Our studies provide new fundamental knowledge on the mol. correlates of the differential homing capacity of BM-hMSCs toward GSC xenografts.
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  25. 25
    Holcapek, M.; Cervena, B.; Cifkova, E.; Lisa, M.; Chagovets, V.; Vostalova, J.; Bancirova, M.; Galuszka, J.; Hill, M. Lipidomic analysis of plasma, erythrocytes and lipoprotein fractions of cardiovascular disease patients using UHPLC/MS, MALDI-MS and multivariate data analysis. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2015, 990, 52– 63,  DOI: 10.1016/j.jchromb.2015.03.010
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    Lipidomic analysis of plasma, erythrocytes and lipoprotein fractions of cardiovascular disease patients using UHPLC/MS, MALDI-MS and multivariate data analysis
    Holcapek, Michal; Cervena, Blanka; Cifkova, Eva; Lisa, Miroslav; Chagovets, Vitaliy; Vostalova, Jitka; Bancirova, Martina; Galuszka, Jan; Hill, Martin
    Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2015), 990 (), 52-63CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
    Differences among lipidomic profiles of healthy volunteers, obese people and three groups of cardiovascular disease (CVD) patients are investigated with the goal to differentiate individual groups based on the multivariate data anal. (MDA) of lipidomic data from plasma, erythrocytes and lipoprotein fractions of more than 50 subjects. Hydrophilic interaction liq. chromatog. on ultrahigh-performance liq. chromatog. (HILIC-UHPLC) column coupled with electrospray ionization mass spectrometry (ESI-MS) is used for the quantitation of four classes of polar lipids (phosphatidylethanolamines, phosphatidylcholines, sphingomyelins and lysophosphatidylcholines), normal-phase UHPLC-atm. pressure chem. ionization MS (NP-UHPLC/APCI-MS) is applied for the quantitation of five classes of nonpolar lipids (cholesteryl esters, triacylglycerols, sterols, 1,3-diacylglycerols and 1,2-diacylglycerols) and the potential of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is tested for the fast screening of all lipids without a chromatog. sepn. Obtained results are processed by unsupervised (principal component anal.) and supervised (orthogonal partial least squares) MDA approaches to highlight the largest differences among individual groups and to identify lipid mols. with the highest impact on the group differentiation.
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    Korte, A. R.; Yandeau-Nelson, M. D.; Nikolau, B. J.; Lee, Y. J. Subcellular-level resolution MALDI-MS imaging of maize leaf metabolites by MALDI-linear ion trap-Orbitrap mass spectrometer. Anal. Bioanal. Chem. 2015, 407 (8), 2301– 9,  DOI: 10.1007/s00216-015-8460-5
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    Subcellular-level resolution MALDI-MS imaging of maize leaf metabolites by MALDI-linear ion trap-Orbitrap mass spectrometer
    Korte, Andrew R.; Yandeau-Nelson, Marna D.; Nikolau, Basil J.; Lee, Young Jin
    Analytical and Bioanalytical Chemistry (2015), 407 (8), 2301-2309CODEN: ABCNBP; ISSN:1618-2642. (Springer)
    A significant limiting factor in achieving high spatial resoln. for matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging is the size of the laser spot at the sample surface. Here, we present modifications to the beam-delivery optics of a com. MALDI-linear ion trap-Orbitrap instrument, incorporating an external Nd:YAG laser, beam-shaping optics, and an aspheric focusing lens, to reduce the min. laser spot size from ∼50 μm for the com. configuration down to ∼9 μm for the modified configuration. This improved system was applied for MALDI-MS imaging of cross sections of juvenile maize leaves at 5-μm spatial resoln. using an oversampling method. A variety of different metabolites including amino acids, glycerolipids, and defense-related compds. were imaged at a spatial resoln. well below the size of a single cell. Such images provide unprecedented insights into the metab. assocd. with the different tissue types of the maize leaf, which is known to asym. distribute the reactions of C4 photosynthesis among the mesophyll and bundle sheath cell types. The metabolite ion images correlate with the optical images that reveal the structures of the different tissues, and previously known and newly revealed asym. metabolic features are obsd.
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    Olsen, J. V.; de Godoy, L. M.; Li, G.; Macek, B.; Mortensen, P.; Pesch, R.; Makarov, A.; Lange, O.; Horning, S.; Mann, M. Parts per million mass accuracy on an Orbitrap mass spectrometer via lock mass injection into a C-trap. Mol. Cell. Proteomics 2005, 4 (12), 2010– 21,  DOI: 10.1074/mcp.T500030-MCP200
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    27
    Parts per million mass accuracy on an orbitrap mass spectrometer via lock mass injection into a C-trap
    Olsen, Jesper V.; de Godoy, Lyris M. F.; Li, Guoqing; Macek, Boris; Mortensen, Peter; Pesch, Reinhold; Makarov, Alexander; Lange, Oliver; Horning, Stevan; Mann, Matthias
    Molecular and Cellular Proteomics (2005), 4 (12), 2010-2021CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology)
    Mass accuracy is a key parameter of mass spectrometric performance. TOF instruments can reach low ppm, and FT-ICR instruments are capable of even greater accuracy provided ion nos. are well controlled. Here the authors demonstrate sub-ppm mass accuracy on a linear ion trap coupled via a radio frequency-only storage trap (C-trap) to the orbitrap mass spectrometer (LTQ Orbitrap). Prior to acquisition of a spectrum, a background ion originating from ambient air is first transferred to the C-trap. Ions forming the MS or MSn spectrum are then added to this species, and all ions are injected into the orbitrap for anal. Real time recalibration on the "lock mass" by corrections of mass shift removes mass error assocd. with calibration of the mass scale. The remaining mass error is mainly due to imperfect peaks caused by weak signals and is addressed by averaging the mass measurement over the LC peak, weighted by signal intensity. For peptide database searches in proteomics, the authors introduce a variable mass tolerance and achieve av. abs. mass deviations of 0.48 ppm (std. deviation 0.38 ppm) and maximal deviations of less than 2 ppm. For tandem mass spectra the authors demonstrate similarly high mass accuracy and discuss its impact on database searching. High and routine mass accuracy in a compact instrument will dramatically improve certainty of peptide and small mol. identification.
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  28. 28
    Makarov, A.; Denisov, E.; Lange, O.; Horning, S. Dynamic range of mass accuracy in LTQ Orbitrap hybrid mass spectrometer. J. Am. Soc. Mass Spectrom. 2006, 17 (7), 977– 982,  DOI: 10.1016/j.jasms.2006.03.006
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    Dynamic Range of Mass Accuracy in LTQ Orbitrap Hybrid Mass Spectrometer
    Makarov, Alexander; Denisov, Eduard; Lange, Oliver; Horning, Stevan
    Journal of the American Society for Mass Spectrometry (2006), 17 (7), 977-982CODEN: JAMSEF; ISSN:1044-0305. (Elsevier Inc.)
    Using a novel orbitrap mass spectrometer, the dynamic range over which accurate masses can be detd. (extent of mass accuracy) were studied for short duration expts. typical for LC/MS. A linear ion trap is used to selectively fill an intermediate ion storage device (C-trap) with ions of interest, following which the ensemble of ions is injected into an orbitrap mass analyzer and analyzed using image current detection and fast Fourier transformation. Using this technique, it is possible to generate ion populations with intraspectrum intensity ranges up to 104. All measurements (including ion accumulation and image current detection) were performed in <1 s at a resolving power of 30,000. 5-Ppm mass accuracy of the orbitrap mass analyzer is reached with >95% probability at a dynamic range of >5000, which is at least an order of magnitude higher than typical values for time-of-flight instruments. Due to the high resolving power of the orbitrap, accurate mass of an ion could be detd. when the signal was reliably distinguished from noise (S/Np-p>2...3).
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  29. 29
    Scigelova, M.; Makarov, A. Orbitrap mass analyzer--overview and applications in proteomics. Proteomics 2006, 6 (Suppl 2), 16– 21,  DOI: 10.1002/pmic.200600528
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    29
    Orbitrap mass analyzer--overview and applications in proteomics
    Scigelova Michaela; Makarov Alexander
    Proteomics (2006), 6 Suppl 2 (), 16-21 ISSN:.
    The orbitrap mass analyzer is proving itself as a useful addition to a proteomics tool box. The key attributes of this analyzer are accurate mass and high resolution similar to those achievable with FT ICR instrumentation. The basic principles underlying these capabilities, and how they translate into benefits in real-life proteomics experiments are discussed. The focus is on reviewing examples of protein identification with bottom-up and top-down approaches, and detection of post-translational modifications.
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    Marshall, A. G.; Hendrickson, C. L.; Jackson, G. S. Fourier transform ion cyclotron resonance mass spectrometry: A primer. Mass Spectrom. Rev. 1998, 17 (1), 1– 35,  DOI: 10.1002/(SICI)1098-2787(1998)17:1<1::AID-MAS1>3.0.CO;2-K
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    Fourier transform ion cyclotron resonance mass spectrometry: a primer
    Marshall, Alan G.; Hendrickson, Christopher L.; Jackson, George S.
    Mass Spectrometry Reviews (1998), 17 (1), 1-35CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
    A review with 149 refs. This review offers an introduction to the principles and generic applications of FT-ICR mass spectrometry, directed to readers with no prior experience with the technique. The authors are able to explain the fundamental FT-ICR phenomena from a simplified theor. treatment of ion behavior in idealized magnetic and elec. fields. The effects of trapping voltage, trap size and shape, and other nonidealities are manifested mainly as perturbations that preserve the idealized ion behavior modified by appropriate numerical correction factors. Topics include: effect of ion mass, charge, magnetic field, and trapping voltage on ion cyclotron frequency; excitation and detection of ICR signals; mass calibration; mass resolving power and mass accuracy; upper mass limit(s); dynamic range; detection limit, strategies for mass and energy selection for MSn; ion axialization, cooling, and remeasurement; and means for guiding externally formed ions into the ion trap. The relation of FT-ICR MS to other types of Fourier transform spectroscopy and to the Paul (quadrupole) ion trap is described. The article concludes with selected applications, an appendix listing accurate fundamental consts. needed for ultrahigh-precision anal., and an annotated list of selected reviews and primary source publications that describe in further detail various FT-ICR MS techniques and applications.
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    Nikolaev, E. N.; Gorshkov, M. V.; Mordehai, A. V.; Talrose, V. L. Ion cyclotron resonance signal-detection at multiples of the cyclotron frequency. Rapid Commun. Mass Spectrom. 1990, 4 (5), 144– 146,  DOI: 10.1002/rcm.1290040503
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    Ion cyclotron resonance signal-detection at multiples of the cyclotron frequency
    Nikolaev, E. N.; Gorshkov, M. V.; Mordehai, A. V.; Talrose, V. L.
    Rapid Communications in Mass Spectrometry (1990), 4 (5), 144-6CODEN: RCMSEF; ISSN:0951-4198.
    A Fourier-transform mass spectrometric technique for detecting ion cyclotron resonance signals at multiple cyclotron frequencies is proposed and initial exptl. results are presented. The technique is readily adapted to existing instruments.
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    Walker, L. R.; Tfaily, M. M.; Shaw, J. B.; Hess, N. J.; Pasa-Tolic, L.; Koppenaal, D. W. Unambiguous identification and discovery of bacterial siderophores by direct injection 21 T Fourier transform ion cyclotron resonance mass spectrometry. Metallomics 2017, 9 (1), 82– 92,  DOI: 10.1039/C6MT00201C
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    Unambiguous identification and discovery of bacterial siderophores by direct injection 21 Tesla Fourier transform ion cyclotron resonance mass spectrometry
    Walker, Lawrence R.; Tfaily, Malak M.; Shaw, Jared B.; Hess, Nancy J.; Pasa-Tolic, Ljiljana; Koppenaal, David W.
    Metallomics (2017), 9 (1), 82-92CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
    Under iron-limiting conditions, bacteria produce low mol. mass Fe(iii) binding mols. known as siderophores to sequester the Fe(iii), along with other elements, increasing their bioavailability. Siderophores are thought to influence iron cycling and biogeochem. in both marine and terrestrial ecosystems and hence the need for rapid, confident characterization of these compds. has increased. In this study, the type of siderophores produced by two marine bacterial species, Synechococcus sp. PCC 7002 and Vibrio cyclitrophicus 1F53, were characterized by use of a newly developed 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FTICR MS) with direct injection electrospray ionization. This technique allowed for the rapid detection of synechobactins from Synechococcus sp. PCC 7002 as well as amphibactins from Vibrio cyclitrophicus 1F53 based on high mass accuracy and resoln. allowing for observation of specific Fe isotopes and isotopic fine structure enabling highly confident identification of these siderophores. When combined with mol. network anal. two new amphibactins were discovered and verified by tandem MS. These results show that high-field FTICR MS is a powerful technique that will greatly improve the ability to rapidly identify and discover metal binding species in the environment.
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    Zimmerman, T. A.; Monroe, E. B.; Tucker, K. R.; Rubakhin, S. S.; Sweedler, J. V. Chapter 13: Imaging of cells and tissues with mass spectrometry: adding chemical information to imaging. Methods Cell Biol. 2008, 89, 361– 90,  DOI: 10.1016/S0091-679X(08)00613-4
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    Imaging of cells and tissues with mass spectrometry: adding chemical information to imaging
    Zimmerman, Tyler A.; Monroe, Eric B.; Tucker, Kevin R.; Rubakhin, Stanislav S.; Sweedler, Jonathan V.
    Methods in Cell Biology (2008), 89 (Biophysical Tools for Biologists, Volume Two), 361-390CODEN: MCBLAG; ISSN:0091-679X. (Elsevier Inc.)
    A review. Techniques that map the distribution of compds. in biol. tissues can be invaluable in addressing a no. of crit. questions in biol. and medicine. One of the newer methods, mass spectrometric imaging, has enabled investigation of spatial localization for a variety of compds. ranging from atomics to proteins. The ability of mass spectrometry to detect and differentiate a large no. of unlabeled compds. makes the approach amenable to the study of complex biol. tissues. This chapter focuses on recent advances in the instrumentation and sample prepn. protocols that make mass spectrometric imaging of biol. samples possible, including strategies for both tissue and single-cell imaging using the following mass spectrometric ionization methods: matrix-assisted laser desorption/ionization, secondary ion, electrospray, and desorption electrospray.
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    Hendrickson, C. L.; Quinn, J. P.; Kaiser, N. K.; Smith, D. F.; Blakney, G. T.; Chen, T.; Marshall, A. G.; Weisbrod, C. R.; Beu, S. C. 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer: A National Resource for Ultrahigh Resolution Mass Analysis. J. Am. Soc. Mass Spectrom. 2015, 26 (9), 1626– 32,  DOI: 10.1007/s13361-015-1182-2
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    21 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer: A National Resource for Ultrahigh Resolution Mass Analysis
    Hendrickson, Christopher L.; Quinn, John P.; Kaiser, Nathan K.; Smith, Donald F.; Blakney, Greg T.; Chen, Tong; Marshall, Alan G.; Weisbrod, Chad R.; Beu, Steven C.
    Journal of the American Society for Mass Spectrometry (2015), 26 (9), 1626-1632CODEN: JAMSEF; ISSN:1044-0305. (Springer)
    We describe the design and initial performance of the first 21 T Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The 21 T magnet is the highest field superconducting magnet ever used for FT-ICR and features high spatial homogeneity, high temporal stability, and negligible liq. helium consumption. The instrument includes a com. dual linear quadrupole trap front end that features high sensitivity, precise control of trapped ion no., and collisional and electron transfer dissocn. A third linear quadrupole trap offers high ion capacity and ejection efficiency, and rf quadrupole ion injection optics deliver ions to a novel dynamically harmonized ICR cell. Mass resolving power of 150,000 (m/Δm50%) is achieved for bovine serum albumin (66 kDa) for a 0.38 s detection period, and greater than 2,000,000 resolving power is achieved for a 12 s detection period. Externally calibrated broadband mass measurement accuracy is typically less than 150 ppb rms, with resolving power greater than 300,000 at m/z 400 for a 0.76 s detection period. Combined anal. of electron transfer and collisional dissocn. spectra results in 68% sequence coverage for carbonic anhydrase. The instrument is part of the NSF High-Field FT-ICR User Facility and is available free of charge to qualified users.
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    Smith, D. F.; Podgorski, D. C.; Rodgers, R. P.; Blakney, G. T.; Hendrickson, C. L. 21 T FT-ICR Mass Spectrometer for Ultrahigh-Resolution Analysis of Complex Organic Mixtures. Anal. Chem. 2018, 90 (3), 2041– 2047,  DOI: 10.1021/acs.analchem.7b04159
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    21 Tesla FT-ICR Mass Spectrometer for Ultrahigh-Resolution Analysis of Complex Organic Mixtures
    Smith, Donald F.; Podgorski, David C.; Rodgers, Ryan P.; Blakney, Greg T.; Hendrickson, Christopher L.
    Analytical Chemistry (Washington, DC, United States) (2018), 90 (3), 2041-2047CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The authors describe complex org. mixt. anal. by 21 T Fourier transform ICR mass spectrometry (FT-ICR MS). Ultrahigh mass-resolving power (m/Δm50% > 2,700,000 at m/z 400) and mass accuracy (80 ppb root-mean-square) enable resoln. and confident identification of tens of thousands of unique elemental compns. The authors demonstrate 2.2-fold higher mass-resolving power, 2.6-fold better mass measurement accuracy, and 1.3-fold more assigned mol. formulas compared to the authors' custom-built, state-of-the-art 9.4 T FT-ICR mass spectrometer for petroleum and dissolved org. matter (DOM) analyses. Anal. of a heavy petroleum distillate exemplifies the need for ultrahigh-performance mass spectrometry (49,040 assigned mol. formulas for 21 T vs. 29,012 for 9.4 T) and extends the identification of previously unresolved Oo, SsOo, and NOo classes. Mass selective ion accumulation (20 Thompson isolation) of an asphalt volcano sample yields 462 resolved mass spectral peaks at m/z 677 and reveals previously unresolved CcHhNnOoSs mass differences at high mass (m/z > 600). Similar performance gains are realized in the anal. of dissolved org. matter, where doubly charged Oo species are resolved from singly charged SOo species, which requires a mass-resolving power >1,400,000 (at m/z 600). This direct comparison reveals the continued need for higher mass-resolving power and better mass accuracy for comprehensive mol. characterization of the most complex org. mixts.
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    Burla, B.; Arita, M.; Arita, M.; Bendt, A. K.; Cazenave-Gassiot, A.; Dennis, E. A.; Ekroos, K.; Han, X.; Ikeda, K.; Liebisch, G.; Lin, M. K.; Loh, T. P.; Meikle, P. J.; Oresic, M.; Quehenberger, O.; Shevchenko, A.; Torta, F.; Wakelam, M. J. O.; Wheelock, C. E.; Wenk, M. R. MS-based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines. J. Lipid Res. 2018, 59 (10), 2001– 2017,  DOI: 10.1194/jlr.S087163
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    MS-based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines
    Burla, Bo; Arita, Makoto; Arita, Masanori; Bendt, Anne K.; Cazenave-Gassiot, Amaury; Dennis, Edward A.; Ekroos, Kim; Han, Xianlin; Ikeda, Kazutaka; Liebisch, Gerhard; Lin, Michelle K.; Loh, Tze Ping; Meikle, Peter J.; Oresic, Matej; Quehenberger, Oswald; Shevchenko, Andrej; Torta, Federico; Wakelam, Michael J. O.; Wheelock, Craig E.; Wenk, Markus R.
    Journal of Lipid Research (2018), 59 (10), 2001-2017CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology)
    Human blood is a self-regenerating lipid-rich biol. fluid that is routinely collected in hospital settings. The inventory of lipid mols. found in blood plasma (plasma lipidome) offers insights into individual metab. and physiol. in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metab.; therefore, plasma lipidomics based on MS is an emerging tool in an array of clin. diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clin. applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quant. MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent labs. as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.
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    Xiang, X.; Grosshans, P. B.; Marshall, A. G. Image charge-induced ion cyclotron orbital frequency shift for orthorhombic and cylindrical FT-ICR ion traps. Int. J. Mass Spectrom. Ion Processes 1993, 125 (1), 33– 43,  DOI: 10.1016/0168-1176(93)80014-6
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    Image charge-induced ion cyclotron orbital frequency shift for orthorhombic and cylindrical FT-ICR ion traps
    Xiang, Xinzhen; Grosshans, Peter B.; Marshall, Alan G.
    International Journal of Mass Spectrometry and Ion Processes (1993), 125 (1), 33-43CODEN: IJMPDN; ISSN:0168-1176.
    A coherently orbiting ion packet induces a distribution of image charge on the ion trap electrodes, the resultant elec. field from the image charge shifts the ICR orbital frequency of the ions in the ion packet. The effect of image charges upon the cyclotron motion of a trapped ion was previously modeled for infinite parallel plate and spherical cavity geometries. In other prior work, an anal. method to solve for the charge induced on any of the electrodes of a Fourier transform ion cyclotron resonance (FT-ICR) ion trap was presented. In this work, the authors report approx. anal. solns. for the frequency shift due to the induced image charges for both finite-size cylindrical and tetragonal traps as a function of ion axial and radial position. For a cubic trap, the mass-independent frequency shift at an ICR orbital radius equal to half the trap radius is ≈10-5 Hz for one ion. Thus, image charge-induced frequency shifts in the ppm range can be expected for typical ICR expts. involving 103-105 ions at low mass-to-charge ratio (60 ≤ m/z ≤ 600), whereas the shift can increase to ≈1 u for 100,000 singly-charged 3000 u ions at 3.0 T. The image charge-induced shift for a cylindrical trap is higher than for a cubic trap of comparable size. Implications for mass calibration are discussed.
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    Wong, R. L.; Amster, I. J. Experimental Evidence for Space-Charge Effects between Ions of the Same Mass-to-Charge in Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry. Int. J. Mass Spectrom. 2007, 265 (2–3), 99– 105,  DOI: 10.1016/j.ijms.2007.01.014
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    Experimental evidence for space-charge effects between ions of the same mass-to-charge in Fourier-transform ion cyclotron resonance mass spectrometry
    Wong, Richard L.; Amster, I. Jonathan
    International Journal of Mass Spectrometry (2007), 265 (2-3), 99-105CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
    It is often stated that ions of the same mass-to-charge do not induce space-charge frequency shifts among themselves in an ICR mass spectrometry measurement. Here, the authors demonstrate space-charge induced frequency shifts for ions of a single mass-to-charge. The monoisotopic at. ion, Cs+, was used for this study. The measured frequency decreases linearly with an increase in the no. of ions, as was reported previously for space-charge effects between ions of different mass-to-charge. The frequency shift between ions of the same m/z value are compared to that induced between ions of different m/z value, and is 7.5 times smaller. Control expts. were performed to ensure that the obsd. space-charge effects are not artifacts of the measurement or of exptl. design. The results can be rationalized by recognizing that the elec. forces between ions in a magnetic field conform to the weak form of the Newton's 3rd law, where the action and reaction forces do not cancel exactly.
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    Savory, J. J.; Kaiser, N. K.; McKenna, A. M.; Xian, F.; Blakney, G. T.; Rodgers, R. P.; Hendrickson, C. L.; Marshall, A. G. Parts-per-billion Fourier transform ion cyclotron resonance mass measurement accuracy with a “walking” calibration equation. Anal. Chem. 2011, 83 (5), 1732– 6,  DOI: 10.1021/ac102943z
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    Parts-Per-Billion Fourier Transform Ion Cyclotron Resonance Mass Measurement Accuracy with a "Walking" Calibration Equation
    Savory, Joshua J.; Kaiser, Nathan K.; McKenna, Amy M.; Xian, Feng; Blakney, Greg T.; Rodgers, Ryan P.; Hendrickson, Christopher L.; Marshall, Alan G.
    Analytical Chemistry (Washington, DC, United States) (2011), 83 (5), 1732-1736CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    ICR frequency, f, is conventionally converted to ion mass-to-charge ratio, m/z (mass calibration) by fitting exptl. data spanning the entire detected m/z range to the relation, m/z = A/f + B/f2, to yield root-mean-square mass error as low as ∼200 ppb for ∼10,000 resolved components of a petroleum crude oil. Anal. of residual error vs. m/z and peak abundance reveals that systematic errors limit mass accuracy and thus the confidence in elemental compn. assignments. Here, the authors present a calibration procedure in which the spectrum is divided into dozens of adjoining segments, and a sep. calibration is applied to each, thereby eliminating systematic error with respect to m/z. Further, incorporation of a 3rd term in the calibration equation that is proportional to the magnitude of each detected peak minimizes systematic error with respect to ion abundance. Finally, absorption-mode data anal. increases mass measurement accuracy only after minimization of systematic errors. The authors are able to increase the no. of assigned peaks by ≤25%, while reducing the root-mean-square mass error by ≤3-fold, for significantly improved confidence in elemental compn. assignment.
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    Schuhmann, K.; Almeida, R.; Baumert, M.; Herzog, R.; Bornstein, S. R.; Shevchenko, A. Shotgun lipidomics on a LTQ Orbitrap mass spectrometer by successive switching between acquisition polarity modes. J. Mass Spectrom. 2012, 47 (1), 96– 104,  DOI: 10.1002/jms.2031
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    Shotgun lipidomics on a LTQ Orbitrap mass spectrometer by successive switching between acquisition polarity modes
    Schuhmann, Kai; Almeida, Reinaldo; Baumert, Mark; Herzog, Ronny; Bornstein, Stefan R.; Shevchenko, Andrej
    Journal of Mass Spectrometry (2012), 47 (1), 96-104CODEN: JMSPFJ; ISSN:1076-5174. (John Wiley & Sons Ltd.)
    Top-down shotgun lipidomics relies on direct infusion of total lipid exts. into a high-resoln. tandem mass spectrometer and implies that individual lipids are recognized by their accurately detd. m/z. Lipid ionization efficiency and detection specificity strongly depend on the acquisition polarity, and therefore it is beneficial to analyze lipid mixts. in both pos. and neg. modes. Hybrid LTQ Orbitrap mass spectrometers are widely applied in top-down lipidomics; however, rapid polarity switching was previously unfeasible because of the severe and immediate degrdn. of mass accuracy. Here, the authors report on a method to rapidly acquire high-resoln. spectra in both polarity modes with sub-ppm mass accuracy and demonstrate that it not only simplifies and accelerates shotgun lipidomics analyses but also improves the lipidome coverage because more lipid classes and more individual species within each class are recognized. In this way, shotgun anal. of total lipid exts. of human blood plasma enabled to quantify 222 species from 15 major lipid classes within 7 min acquisition cycle. Copyright © 2012 John Wiley & Sons, Ltd.
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    Almeida, R.; Pauling, J. K.; Sokol, E.; Hannibal-Bach, H. K.; Ejsing, C. S. Comprehensive lipidome analysis by shotgun lipidomics on a hybrid quadrupole-orbitrap-linear ion trap mass spectrometer. J. Am. Soc. Mass Spectrom. 2015, 26 (1), 133– 48,  DOI: 10.1007/s13361-014-1013-x
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    Comprehensive Lipidome Analysis by Shotgun Lipidomics on a Hybrid Quadrupole-Orbitrap-Linear Ion Trap Mass Spectrometer
    Almeida, Reinaldo; Pauling, Josch Konstantin; Sokol, Elena; Hannibal-Bach, Hans Kristian; Ejsing, Christer S.
    Journal of the American Society for Mass Spectrometry (2015), 26 (1), 133-148CODEN: JAMSEF; ISSN:1044-0305. (Springer)
    Here we report on the application of a novel shotgun lipidomics platform featuring an Orbitrap Fusion mass spectrometer equipped with an automated nanoelectrospray ion source. To assess the performance of the platform for in-depth lipidome anal., we evaluated various instrument parameters, including its high resoln. power unsurpassed by any other contemporary Orbitrap instrumentation, its dynamic quantification range and its efficacy for in-depth structural characterization of mol. lipid species by quadrupole-based higher-energy collisional dissocn. (HCD), and ion trap-based resonant-excitation collision-induced dissocn. (CID). This evaluation demonstrated that FTMS anal. with a resoln. setting of 450,000 allows distinguishing isotopes from different lipid species and features a linear dynamic quantification range of at least four orders of magnitude. Evaluation of fragmentation anal. demonstrated that combined use of HCD and CID yields complementary fragment ions of mol. lipid species. To support global lipidome anal., we designed a method, termed MSALL, featuring high resoln. FTMS anal. for lipid quantification, and FTMS2 anal. using both HCD and CID and ITMS3 anal. utilizing dual CID for in-depth structural characterization of mol. glycerophospholipid species. The performance of the MSALL method was benchmarked in a comparative anal. of mouse cerebellum and hippocampus. This anal. demonstrated extensive lipidome quantification covering 311 lipid species encompassing 20 lipid classes, and identification of 202 distinct mol. glycerophospholipid species when applying a novel high confidence filtering strategy. The work presented here validates the performance of the Orbitrap Fusion mass spectrometer for in-depth lipidome anal.
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    Simons, B.; Kauhanen, D.; Sylvanne, T.; Tarasov, K.; Duchoslav, E.; Ekroos, K. Shotgun Lipidomics by Sequential Precursor Ion Fragmentation on a Hybrid Quadrupole Time-of-Flight Mass Spectrometer. Metabolites 2012, 2 (1), 195– 213,  DOI: 10.3390/metabo2010195
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    Shotgun lipidomics by sequential precursor ion fragmentation on a hybrid quadrupole time-of-flight mass spectrometer
    Simons, Brigitte; Kauhanen, Dimple; Sylvanne, Tuulia; Tarasov, Kirill; Duchoslav, Eva; Ekroos, Kim
    Metabolites (2012), 2 (1), 195-213CODEN: METALU; ISSN:2218-1989. (MDPI AG)
    Shotgun lipidomics has evolved into a myriad of multi-dimensional strategies for mol. lipid characterization, including bioinformatics tools for mass spectrum interpretation and quant. measurements to study systems-lipidomics in complex biol. exts. Taking advantage of spectral mass accuracy, scan speed and sensitivity of improved quadrupole linked time-of-flight mass analyzers, we developed a bias-free global lipid profiling acquisition technique of sequential precursor ion fragmentation called MS/MSALL. This generic information-independent tandem mass spectrometry (MS) technique consists of a Q1 stepped mass isolation window through a set mass range in small increments, fragmenting and recording all product ions and neutral losses. Through the accurate MS and MS/MS information, the mol. lipid species are resolved, including distinction of isobaric and isomeric species, and composed into more precise lipidomic outputs. The method demonstrates good reproducibility and at least 3 orders of dynamic quantification range for isomeric ceramides in human plasma. More than 400 mol. lipids in human plasma were uncovered and quantified in less than 12 min, including acquisitions in both pos. and neg. polarity modes. We anticipate that the performance of sequential precursor ion fragmentation both in quality and throughput will lead to the uncovering of new avenues throughout the biomedical research community, enhance biomarker discovery and provide novel information target discovery programs as it will prospectively shed new insight into affected metabolic and signaling pathways.
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    Velickovic, D.; Chu, R. K.; Carrell, A. A.; Thomas, M.; Pasa-Tolic, L.; Weston, D. J.; Anderton, C. R. Multimodal MSI in Conjunction with Broad Coverage Spatially Resolved MS(2) Increases Confidence in Both Molecular Identification and Localization. Anal. Chem. 2018, 90 (1), 702– 707,  DOI: 10.1021/acs.analchem.7b04319
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    Multimodal MSI in Conjunction with Broad Coverage Spatially Resolved MS2 Increases Confidence in Both Molecular Identification and Localization
    Velickovic, Dusan; Chu, Rosalie K.; Carrell, Alyssa A.; Thomas, Mathew; Pasa-Tolic, Ljiljana; Weston, David J.; Anderton, Christopher R.
    Analytical Chemistry (Washington, DC, United States) (2018), 90 (1), 702-707CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    One crit. aspect of mass spectrometry imaging (MSI) is the need to confidently identify detected analytes. While orthogonal tandem MS (e.g., LC-MS2) expts. from sample exts. can assist in annotating ions, the spatial information about these mols. is lost. Accordingly, this could cause mislead conclusions, esp. in cases where isobaric species exhibit different distributions within a sample. In this Tech. Note, the authors employed a multimodal imaging approach, using matrix assisted laser desorption/ionization (MALDI)-MSI and liq. extn. surface anal. (LESA)-MS2I, to confidently annotate and localize a broad range of metabolites involved in a tripartite symbiosis system of moss, cyanobacteria, and fungus. The authors found that the combination of these two imaging modalities generated very congruent ion images, providing the link between highly accurate structural information offered by LESA and high spatial resoln. attainable by MALDI. These results demonstrate how this combined methodol. could be very useful in differentiating metabolite routes in complex systems.
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  44. 44
    Spraggins, J. M.; Rizzo, D. G.; Moore, J. L.; Rose, K. L.; Hammer, N. D.; Skaar, E. P.; Caprioli, R. M. MALDI FTICR IMS of Intact Proteins: Using Mass Accuracy to Link Protein Images with Proteomics Data. J. Am. Soc. Mass Spectrom. 2015, 26 (6), 974– 85,  DOI: 10.1007/s13361-015-1147-5
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    MALDI FTICR IMS of Intact Proteins: Using Mass Accuracy to Link Protein Images with Proteomics Data
    Spraggins, Jeffrey M.; Rizzo, David G.; Moore, Jessica L.; Rose, Kristie L.; Hammer, Neal D.; Skaar, Eric P.; Caprioli, Richard M.
    Journal of the American Society for Mass Spectrometry (2015), 26 (6), 974-985CODEN: JAMSEF; ISSN:1044-0305. (Springer)
    MALDI imaging mass spectrometry is a highly sensitive and selective tool used to visualize biomols. in tissue. However, identification of detected proteins remains a difficult task. Indirect identification strategies have been limited by insufficient mass accuracy to confidently link ion images to proteomics data. Here, we demonstrate the capabilities of MALDI FTICR MS for imaging intact proteins. MALDI FTICR IMS provides an unprecedented combination of mass resolving power (∼75,000 at m/z 5000) and accuracy (<5ppm) for proteins up to ∼12kDa, enabling identification based on correlation with LC-MS/MS proteomics data. Anal. of rat brain tissue was performed as a proof-of-concept highlighting the capabilities of this approach by imaging and identifying a no. of proteins including N-terminally acetylated thymosin β4 (m/z 4963.502, 0.6ppm) and ATP synthase subunit ε (m/z 5636.074, -2.3ppm). MALDI FTICR IMS was also used to differentiate a series of oxidn. products of S100A8 (m/z 10,164.03, -2.1ppm), a subunit of the heterodimer calprotectin, in kidney tissue from mice infected with Staphylococcus aureus. S100A8 - M37O/C42O3 (m/z 10228.00, -2.6ppm) was found to colocalize with bacterial microcolonies at the center of infectious foci. The ability of MALDI FTICR IMS to distinguish S100A8 modifications is crit. to understanding calprotectin's roll in nutritional immunity.
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  45. 45
    Hendrickson, C. L.; Beu, S. C.; Blakney, G. T.; Kaiser, N. K.; McIntosh, D. G.; Quinn, J. P.; Marshall, A. G. In Optimized cell geometry for Fourier transform ion cyclotron resonance mass spectrometry, Proceedings of the 57th ASMS Conference on Mass Spectrometry and Allied Topics, Philadelphia, PA, May 31 to June 4; Philadelphia, PA, 2009.
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    There is no corresponding record for this reference.
  46. 46
    Chen, T.; Beu, S. C.; Kaiser, N. K.; Hendrickson, C. L. Note: Optimized circuit for excitation and detection with one pair of electrodes for improved Fourier transform ion cyclotron resonance mass spectrometry. Rev. Sci. Instrum. 2014, 85 (6), 066107,  DOI: 10.1063/1.4883179
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    Note: Optimized circuit for excitation and detection with one pair of electrodes for improved Fourier transform ion cyclotron resonance mass spectrometry
    Chen, T.; Beu, S. C.; Kaiser, N. K.; Hendrickson, C. L.
    Review of Scientific Instruments (2014), 85 (6), 066107/1-066107/3CODEN: RSINAK; ISSN:0034-6748. (American Institute of Physics)
    A conventional Fourier transform-Ion Cyclotron Resonance (ICR) detection cell is azimuthally divided into four equal sections. One pair of opposed electrodes is used for ion cyclotron excitation, and the other pair for ion image charge detection. In this work, we demonstrate that an appropriate elec. circuit facilitates excitation and detection on one pair of opposed electrodes. The new scheme can be used to minimize the no. of elec. independent ICR cell electrodes and/or improve the electrode geometry for simultaneously increased ICR signal magnitude and optimal post-excitation radius, which results in higher signal-to-noise ratio and decreased space-charge effects. (c) 2014 American Institute of Physics.
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  47. 47
    Belov, M. E.; Ellis, S. R.; Dilillo, M.; Paine, M. R. L.; Danielson, W. F.; Anderson, G. A.; de Graaf, E. L.; Eijkel, G. B.; Heeren, R. M. A.; McDonnell, L. A. Design and Performance of a Novel Interface for Combined Matrix-Assisted Laser Desorption Ionization at Elevated Pressure and Electrospray Ionization with Orbitrap Mass Spectrometry. Anal. Chem. 2017, 89 (14), 7493– 7501,  DOI: 10.1021/acs.analchem.7b01168
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    47
    Design and Performance of a Novel Interface for Combined Matrix-Assisted Laser Desorption Ionization at Elevated Pressure and Electrospray Ionization with Orbitrap Mass Spectrometry
    Belov, Mikhail E.; Ellis, Shane R.; Dilillo, Marialaura; Paine, Martin R. L.; Danielson, William F.; Anderson, Gordon A.; de Graaf, Erik L.; Eijkel, Gert B.; Heeren, Ron M. A.; McDonnell, Liam A.
    Analytical Chemistry (Washington, DC, United States) (2017), 89 (14), 7493-7501CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Matrix-Assisted Laser Desorption Ionization, MALDI, has been increasingly used in a variety of biomedical applications, including tissue imaging of clin. tissue samples, and in drug discovery and development. These studies strongly depend on the performance of the anal. instrumentation and would drastically benefit from improved sensitivity, reproducibility, and mass/spatial resoln. In this work, we report on a novel combined MALDI/ESI interface, which was coupled to different Orbitrap mass spectrometers (Elite and Q Exactive Plus) and extensively characterized with peptide and protein stds., and in tissue imaging expts. In our approach, MALDI is performed in the elevated pressure regime (5-8 Torr) at a spatial resoln. of 15-30 μm, while ESI-generated ions are injected orthogonally to the interface axis. We have found that introduction of the MALDI-generated ions into an electrodynamic dual-funnel interface results in increased sensitivity characterized by a limit of detection of ∼400 zmol, while providing a mass measurement accuracy of 1 ppm and a mass resolving power of 120 000 in anal. of protein digests. In tissue imaging expts., the MALDI/ESI interface has been employed in expts. with rat brain sections and was shown to be capable of visualizing and spatially characterizing very low abundance analytes sepd. only by 20 mDa. Comparison of imaging data has revealed excellent agreement between the MALDI and histol. images.
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  48. 48
    Blakney, G. T.; Hendrickson, C. L.; Marshall, A. G. Predator data station: A fast data acquisition system for advanced FT-ICR MS experiments. Int. J. Mass Spectrom. 2011, 306 (2–3), 246– 252,  DOI: 10.1016/j.ijms.2011.03.009
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    Predator data station: A fast data acquisition system for advanced FT-ICR MS experiments
    Blakney, Greg T.; Hendrickson, Christopher L.; Marshall, Alan G.
    International Journal of Mass Spectrometry (2011), 306 (2-3), 246-252CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
    Presented is the Predator data station, a control system for FT-ICR mass spectrometers that champions speed and exptl. flexibility while simultaneously providing stability, ease of use, and the ability to integrate more advanced hardware as it becomes available. The Predator is the first FT-ICR MS data station comprised solely of fast PCI, PXI, and yet faster PXI Express-based com. data acquisition hardware. Increased data transfer speed is required because recorded transient data count increases linearly at higher magnetic field (higher measured frequency) with extended transient duration for FT-ICR MS instruments. The application of new cell designs with addnl. compensation voltages, exptl. techniques to increase resoln., and exptl. techniques that minimize/reject variations in ion abundance exemplify the scope of recent Predator data station implementations. When the above techniques are applied simultaneously, the results give rise to sub-30 ppb rms mass error for 5250 assigned peaks in a petroleum FT-ICR mass spectrum. The Predator data station is designed for facile implementation with any FT-ICR MS instrument. The Predator hardware provides 17 analog voltage outputs and 18 digital TTL outputs synchronized to a single timing source. SWIFT, chirp, and single frequency excitation waveforms are generated by a 100 MSample/s arbitrary waveform generator with a min. 32 MB of onboard memory and the potential of terabytes of virtual memory via first in-first out (FIFO) buffering. Transient detection is facilitated by a 2-channel, 100 MSample/s digitizer with a min. of 32 MB of onboard memory per channel. FIFO buffering implementation allows TB transient collection as well. Com. hardware, royalty-free software solns., and com. produced custom printed circuit boards (PCB) for the cell controller ensure open availability. The present data complement numerous extant publications: the Predator data station was the sole data station for the National High Magnetic Field Lab. (NHMFL) 9.4 T FT-ICR MS instrument since July 2004, and several addnl. Predator data stations are in operation elsewhere.
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  49. 49
    Xian, F.; Hendrickson, C. L.; Blakney, G. T.; Beu, S. C.; Marshall, A. G. Automated broadband phase correction of Fourier transform ion cyclotron resonance mass spectra. Anal. Chem. 2010, 82 (21), 8807– 12,  DOI: 10.1021/ac101091w
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    Automated Broadband Phase Correction of Fourier Transform Ion Cyclotron Resonance Mass Spectra
    Xian, Feng; Hendrickson, Christopher L.; Blakney, Greg T.; Beu, Steven C.; Marshall, Alan G.
    Analytical Chemistry (Washington, DC, United States) (2010), 82 (21), 8807-8812CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    It was known for 35 years that phase correction of FTICR data can in principle produce an absorption-mode spectrum with mass resolving power as much as a factor of 2 higher than conventional magnitude-mode display, an improvement otherwise requiring a (much more expensive) increase in magnetic field strength. However, temporally dispersed excitation followed by time-delayed detection results in steep quadratic variation of signal phase with frequency. Here, the authors present a robust, rapid, automated method to enable accurate broadband phase correction for all peaks in the mass spectrum. Low-pass digital filtering effectively eliminates the accompanying baseline roll. Exptl. FTICR absorption-mode mass spectra exhibit at least 40% higher resolving power (and thus an increased no. of resolved peaks) as well as higher mass accuracy relative to magnitude mode spectra, for more complete and more reliable elemental compn. assignments for mixts. as complex as petroleum.
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  50. 50
    Chambers, M. C.; Maclean, B.; Burke, R.; Amodei, D.; Ruderman, D. L.; Neumann, S.; Gatto, L.; Fischer, B.; Pratt, B.; Egertson, J.; Hoff, K.; Kessner, D.; Tasman, N.; Shulman, N.; Frewen, B.; Baker, T. A.; Brusniak, M. Y.; Paulse, C.; Creasy, D.; Flashner, L.; Kani, K.; Moulding, C.; Seymour, S. L.; Nuwaysir, L. M.; Lefebvre, B.; Kuhlmann, F.; Roark, J.; Rainer, P.; Detlev, S.; Hemenway, T.; Huhmer, A.; Langridge, J.; Connolly, B.; Chadick, T.; Holly, K.; Eckels, J.; Deutsch, E. W.; Moritz, R. L.; Katz, J. E.; Agus, D. B.; MacCoss, M.; Tabb, D. L.; Mallick, P. A cross-platform toolkit for mass spectrometry and proteomics. Nat. Biotechnol. 2012, 30 (10), 918– 20,  DOI: 10.1038/nbt.2377
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    A cross-platform toolkit for mass spectrometry and proteomics
    Chambers, Matthew C.; MacLean, Brendan; Burke, Robert; Amodei, Dario; Ruderman, Daniel L.; Neumann, Steffen; Gatto, Laurent; Fischer, Bernd; Pratt, Brian; Egertson, Jarrett; Hoff, Katherine; Kessner, Darren; Tasman, Natalie; Shulman, Nicholas; Frewen, Barbara; Baker, Tahmina A.; Brusniak, Mi-Youn; Paulse, Christopher; Creasy, David; Flashner, Lisa; Kani, Kian; Moulding, Chris; Seymour, Sean L.; Nuwaysir, Lydia M.; Lefebvre, Brent; Kuhlmann, Frank; Roark, Joe; Rainer, Paape; Detlev, Suckau; Hemenway, Tina; Huhmer, Andreas; Langridge, James; Connolly, Brian; Chadick, Trey; Holly, Krisztina; Eckels, Josh; Deutsch, Eric W.; Moritz, Robert L.; Katz, Jonathan E.; Agus, David B.; MacCoss, Michael; Tabb, David L.; Mallick, Parag
    Nature Biotechnology (2012), 30 (10), 918-920CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    Mass spectrometry-based proteomics has become an important component of biol. research. There have been several calls for improvements and standardization of proteomics data anal. frameworks, as well as for an application programming interface for proteomics data access. In response, ProteoWizard Toolkit was developed, a robust set of opensource, software libraries and applications designed to facilitate proteomics research. With version 3.0 of the ProteoWizard Toolkit8, the challenges in the field can be mitigated through open-source, permissively licensed, cross-platform software. The Toolkit has two components: first, a suite of libraries that facilitate the development and comparison of tools for proteomics data anal. and second, a set of tools, developed using these libraries, that performs a wide array of common proteomics analyses. ProteoWizard is built upon a modular framework of many independent libraries grouped in dependency levels.
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  51. 51
    Race, A. M.; Styles, I. B.; Bunch, J. Inclusive sharing of mass spectrometry imaging data requires a converter for all. J. Proteomics 2012, 75 (16), 5111– 2,  DOI: 10.1016/j.jprot.2012.05.035
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    Inclusive sharing of mass spectrometry imaging data requires a converter for all
    Race, Alan M.; Styles, Iain B.; Bunch, Josephine
    Journal of Proteomics (2012), 75 (16), 5111-5112CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)
    With continued efforts towards a single MSI data format, data conversion routines must be made universally available. The benefits of a common imaging format, imzML, are slowly becoming more widely appreciated but the format remains to be used by only a small proportion of imaging groups. Increased awareness amongst researchers and continued support from major MS vendors in providing tools for converting proprietary formats into imzML are likely to result in a rapidly increasing uptake of the format. It is important that this does not lead to the exclusion of researchers using older or unsupported instruments. We describe an open source converter, imzMLConverter, to ensure against this. We propose that proprietary formats should first be converted to mzML using one of the widely available converters, such as msconvert and then use imzMLConverter to convert mzML to imzML. This will allow a wider audience to benefit from the imzML format immediately.This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biol. and Biomedical Research.
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  52. 52
    Husen, P.; Tarasov, K.; Katafiasz, M.; Sokol, E.; Vogt, J.; Baumgart, J.; Nitsch, R.; Ekroos, K.; Ejsing, C. S. Analysis of lipid experiments (ALEX): a software framework for analysis of high-resolution shotgun lipidomics data. PLoS One 2013, 8 (11), e79736  DOI: 10.1371/journal.pone.0079736
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    Analysis of Lipid Experiments (ALEX): a software framework for analysis of high-resolution shotgun lipidomics data
    Husen, Peter; Tarasov, Kirill; Katafiasz, Maciej; Sokol, Elena; Vogt, Johannes; Baumgart, Jan; Nitsch, Robert; Ekroos, Kim; Ejsing, Christer S.
    PLoS One (2013), 8 (11), e79736CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Global lipidomics anal. across large sample sizes produces high-content datasets that require dedicated software tools supporting lipid identification and quantification, efficient data management and lipidome visualization. Here we present a novel software-based platform for streamlined data processing, management and visualization of shotgun lipidomics data acquired using high-resoln. Orbitrap mass spectrometry. The platform features the ALEX framework designed for automated identification and export of lipid species intensity directly from proprietary mass spectral data files, and an auxiliary workflow using database exploration tools for integration of sample information, computation of lipid abundance and lipidome visualization. A key feature of the platform is the organization of lipidomics data in "database table format" which provides the user with an unsurpassed flexibility for rapid lipidome navigation using selected features within the dataset. To demonstrate the efficacy of the platform, we present a comparative neurolipidomics study of cerebellum, hippocampus and somatosensory barrel cortex (S1BF) from wild-type and knockout mice devoid of the putative lipid phosphate phosphatase PRG-1 (plasticity related gene-1). The presented framework is generic, extendable to processing and integration of other lipidomic data structures, can be interfaced with post-processing protocols supporting statistical testing and multivariate anal., and can serve as an avenue for disseminating lipidomics data within the scientific community. The ALEX software is available at online.
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  53. 53
    Spraggins, J. M.; Djambazova, K. V.; Rivera, E. S.; Migas, L. G.; Neumann, E. K.; Fuetterer, A.; Suetering, J.; Goedecke, N.; Ly, A.; Van de Plas, R.; Caprioli, R. M. High-Performance Molecular Imaging with MALDI Trapped Ion-Mobility Time-of-Flight (timsTOF) Mass Spectrometry. Anal. Chem. 2019, 91 (22), 14552– 14560,  DOI: 10.1021/acs.analchem.9b03612
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    High-Performance Molecular Imaging with MALDI Trapped Ion-Mobility Time-of-Flight (timsTOF) Mass Spectrometry
    Spraggins, Jeffrey M.; Djambazova, Katerina V.; Rivera, Emilio S.; Migas, Lukasz G.; Neumann, Elizabeth K.; Fuetterer, Arne; Suetering, Juergen; Goedecke, Niels; Ly, Alice; Van de Plas, Raf; Caprioli, Richard M.
    Analytical Chemistry (Washington, DC, United States) (2019), 91 (22), 14552-14560CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Imaging mass spectrometry (IMS) enables the spatially targeted mol. assessment of biol. tissues at cellular resolns. New developments and technologies are essential for uncovering the mol. drivers of native physiol. function and disease. Instrumentation must maximize spatial resoln., throughput, sensitivity, and specificity, because tissue imaging expts. consist of thousands to millions of pixels. Here, the authors report the development and application of a matrix-assisted laser desorption/ionization (MALDI) trapped ion mobility spectrometry imaging platform. This prototype MALDI timsTOF instrument is capable of 10 μm spatial resolns. and 20 pixels/s throughput mol. imaging. The MALDI source utilizes a Bruker SmartBeam 3-D laser system that can generate a square burn pattern of <10 × 10 μm at the sample surface. General image performance was assessed using murine kidney and brain tissues and demonstrate that high spatial resoln. imaging data can be generated rapidly with mass measurement errors < 5 ppm and ∼40,000 resolving power. Initial TIMS-based imaging expts. were performed on whole body mouse pup tissue demonstrating the sepn. of closely isobaric [PC(32:0)+Na]+ and [PC(34:3)+H]+ (3 mDa mass difference) in the gas-phase. The authors have shown that the MALDI timsTOF platform can maintain reasonable data acquisition rates (>2 pixels/s) while providing the specificity necessary to differentiate components in complex mixts. of lipid adducts. The combination of high spatial resoln. and throughput imaging capabilities with high-performance TIMS sepns. provides a uniquely tunable platform to address many challenges assocd. with advanced mol. imaging applications.
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  54. 54
    Campos, A. M.; Maciel, E.; Moreira, A. S.; Sousa, B.; Melo, T.; Domingues, P.; Curado, L.; Antunes, B.; Domingues, M. R.; Santos, F. Lipidomics of Mesenchymal Stromal Cells: Understanding the Adaptation of Phospholipid Profile in Response to Pro-Inflammatory Cytokines. J. Cell. Physiol. 2016, 231 (5), 1024– 32,  DOI: 10.1002/jcp.25191
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    Lipidomics of Mesenchymal Stromal Cells: Understanding the Adaptation of Phospholipid Profile in Response to Pro-Inflammatory Cytokines
    Campos, Ana Margarida; Maciel, Elisabete; Moreira, Ana S. P.; Sousa, Bebiana; Melo, Tania; Domingues, Pedro; Curado, Liliana; Antunes, Brigida; Domingues, M. Rosario M.; Santos, Francisco
    Journal of Cellular Physiology (2016), 231 (5), 1024-1032CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
    Mesenchymal stromal cells (MSCs) present anti-inflammatory properties and are being used with great success as treatment for inflammatory and autoimmune diseases. In clin. applications MSCs are subjected to a strong pro-inflammatory environment, essential to their immunosuppressive action. Despite the wide clin. use of these cells, how MSCs exert their effect remains unclear. Several lipids are known to be involved in cell's signaling and modulation of cellular functions. The aim of this paper is to examine the variation in lipid profile of MSCs under pro-inflammatory environment, induced by the presence of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), using the most modern lipidomic approach. Major changes in lipid mol. profile of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), lysoPC (LPC), and sphingomyelin (SM) classes were found. No changes were obsd. in the phosphatidylinositol (PI) profile. The levels of PC species with shorter fatty acids (FAs), mainly C16:0, decreased under pro-inflammatory stimuli. The level of PC(40:6) also decreased, which may be correlated with enhanced levels of LPC(18:0), which is known to be an anti-inflammatory LPC, obsd. in MSCs subjected to TNF-α and IFN-γ. Simultaneously, the relative amts. of PC(36:1) and PC(38:4) increased. TNF-α and IFN-γ also enhanced the levels of PE(40:6) and decreased the levels of PE(O-38:6). Higher expression of PS(36:1) and SM(34:0) along with a decrease in PS(38:6) levels were obsd. These results indicate that lipid metab. and signaling are modulated during MSCs activation, which suggests that lipids may be involved in MSCs functional and anti-inflammatory activities. J. Cell. Physiol. 9999: 1-9, 2015. © 2015 Wiley Periodicals, Inc.
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    Guo, S.; Wang, Y.; Zhou, D.; Li, Z. Significantly increased monounsaturated lipids relative to polyunsaturated lipids in six types of cancer microenvironment are observed by mass spectrometry imaging. Sci. Rep. 2015, 4, 5959,  DOI: 10.1038/srep05959
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    Ide, Y.; Waki, M.; Hayasaka, T.; Nishio, T.; Morita, Y.; Tanaka, H.; Sasaki, T.; Koizumi, K.; Matsunuma, R.; Hosokawa, Y.; Ogura, H.; Shiiya, N.; Setou, M. Human breast cancer tissues contain abundant phosphatidylcholine(36ratio1) with high stearoyl-CoA desaturase-1 expression. PLoS One 2013, 8 (4), e61204  DOI: 10.1371/journal.pone.0061204
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    Human breast cancer tissues contain abundant phosphatidylcholine(36:1) with high stearoyl-CoA desaturase-1 expression
    Ide, Yoshimi; Waki, Michihiko; Hayasaka, Takahiro; Nishio, Tomohisa; Morita, Yoshifumi; Tanaka, Hiroki; Sasaki, Takeshi; Koizumi, Kei; Matsunuma, Ryoichi; Hosokawa, Yuko; Ogura, Hiroyuki; Shiiya, Norihiko; Setou, Mitsutoshi
    PLoS One (2013), 8 (4), e61204CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Breast cancer is the leading cause of cancer and mortality in women worldwide. Recent studies have argued that there is a close relationship between lipid synthesis and cancer progression because some enzymes related to lipid synthesis are overexpressed in breast cancer tissues. However, lipid distribution in breast cancer tissues has not been investigated. We aimed to visualize phosphatidylcholines (PCs) and lysoPCs (LPCs) in human breast cancer tissues by performing matrix assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), which is a novel technique that enables the visualization of mols. comprehensively. Twenty-nine breast tissue samples were obtained during surgery and subjected to MALDI-IMS anal. We evaluated the heterogeneity of the distribution of PCs and LPCs on the tissues. Three species [PC(32:1), PC(34:1), and PC(36:1)] of PCs with 1 mono-unsatd. fatty acid chain and 1 satd. fatty acid chain (MUFA-PCs) and one [PC(34:0)] of PCs with 2 satd. fatty acid chains (SFA-PC) were relatively localized in cancerous areas rather than the rest of the sections (named ref. area). In addn., the LPCs did not show any biased distribution. The relative amts. of PC(36:1) compared to PC(36:0) and that of PC(36:1) to LPC(18:0) were significantly higher in the cancerous areas. The protein expression of stearoyl-CoA desaturase-1 (SCD1), which is a synthetic enzyme of MUFA, showed accumulation in the cancerous areas as obsd. by the results of immunohistochem. staining. The ratios were further analyzed considering the differences in expressions of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and Ki67. The ratios of the signal intensity of PC(36:1) to that of PC(36:0) was higher in the lesions with pos. ER expression. The contribution of SCD1 and other enzymes to the formation of the obsd. phospholipid compn. is discussed.
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  57. 57
    Harbige, L. S.; Sharief, M. K. Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis. Br. J. Nutr. 2007, 98 (Suppl 1), S46– 53,  DOI: 10.1017/S0007114507833010
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    Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis
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    The detection of phospholipids (PLs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was demonstrated nearly a decade ago. However, its use as a conventional tool for PL anal. has been hindered by ambiguities in peak assignments caused by spectral overlaps and difficulties in the detection of some PL classes when analytes with pos. charged head groups, such as sphingomyelins (SMs) and phosphatidylcholines (PCs) are present. In this work, either a strong cation-exchange resin or CsCl crystals were added directly to the PL samples to reduce spectral complexity and enhance sensitivity. The quant. exchange resulted in virtually only protonated or Cs+ adducts. To alleviate difficulties in the detection and identification of PL classes with ionization efficiencies lower than those of SMs and PCs, improvements in the sensitivity of neg.-ion mass spectra were sought. For this purpose, several neutral and basic matrixes were tried. Among them, p-nitroaniline (PNA) proved to be an advantageous alternative to the use of 2,5-dihydroxybenzoic acid (DHB), the most commonly used matrix in PL anal. Because of its lower acidity, PNA increased the relative amt. of deprotonated species and improved the sensitivity of neg.-ion mass spectra. It was possible to confirm peak assignments for PL classes that normally give weak signals when DHB is used. Noteworthy is the detection (in both pos. and neg. modes) and conclusive identification of species in natural mixts. of phosphatidylethanolamines (PEs) and PE plasmalogens (PEps). PNA allowed the identification of PEs and PEps even in mixts. contg. SMs and PCs. Although some cations related to PCs and PEs overlapped in pos.-ion spectra, these interferences were eliminated in the neg. mode as only the deprotonated forms of PEs and PEps were detectable and those of SMs and PCs were absent owing to their neutrality.
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    A direct and simple method of coupling matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) to thin-layer chromatography (TLC) for the analysis of phospholipids from egg yolk
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    Although the most important application of matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) is "proteomics," there is growing evidence that this soft ionization method is also useful for phospholipid (PL) anal. Although all PLs are detectable by MALDI-TOF MS, some lipid classes, particularly those with quaternary amines such as phosphatidylcholines (PCs), are more sensitively detected than others, and these suppress the signals of less sensitively detected PLs when complex mixts. are analyzed. Therefore, a sepn. of the total org. ext. into individual lipid classes is necessary. As MALDI uses a solid sample, the direct evaluation of thin-layer chromatog. (TLC) plates is possible. The authors report here on a method of directly coupling MALDI-TOF MS and TLC that can be easily implemented on com. available MALDI-TOF devices. A total ext. of hen egg yolk is used as a simple PL mixt. to demonstrate the capabilities of this method. It will be shown that "clean" spectra without any major contributions from fragmentation products and matrix peaks can be obtained, and that this approach is even sensitive enough to detect the presence of PLs at levels of less than 1% of the total ext.
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Cite this: Anal. Chem. 2020, 92, 4, 3133–3142
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https://doi.org/10.1021/acs.analchem.9b04768
Published January 19, 2020

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  • Abstract

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    Figure 1

    Figure 1. Mass resolution and sensitivity improve with longer transient length. Within a 100 mDa mass range, seven different peaks are detected, which belong to six different lipid species. Of these, five are unresolved at 0.77 s. While distinguishable at 1.55 s, all seven peaks are fully resolved only at 3.1 s transient. These seven peaks correspond to the isotopologues of the monoisotopic species, typically the 13C ion, as in (a), (b), (f), and (g). Other species are also present, corresponding to the 13C3 isotopologue, as in (d) and (e). The 18O13C isotopologue of [PC(34:1)+Na]+ is also resolved (c) from the 13C3 isotopologue of the same parent species.

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    Figure 2

    Figure 2. Representative images of close mass differences in negative and positive mode, from a single, scan. Images are total ion current normalized. Positive mode lipid spectra have a significant number of mass differences of 2.4 mDa (a), representing the difference between 12C2 and 23Na1H. 2.4 mDa differences are baseline resolved, and show significantly different distributions within brain tissue (b and c). There are nearly 200 such differences in the averaged spectra, shown in 0.5 mDa bins (d). Similarly, negative mode spectra have 1.79 mDa mass differences (e). These 1.79 mDa differences are resolved to better than full-width half-maximum, differentiated well enough to distinguish them in brain tissue (f and g). The of 1.79 mDa mass difference is relatively uncommon in negative mode, but mass differences of 10 mDa or less occur approximately 500 times in the averaged spectra, shown in 0.25 mDa bins (h).

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    Figure 3

    Figure 3. Single on-tissue mass spectrum illustrates high dynamic range per pixel. Peaks were picked at a threshold of six standard deviations above the baseline noise. Dynamic range in a single average pixel of at 536:1 is demonstrated here at pixel number 10 000, (a). Mass scale expanded segment around most abundant peak [PC 34:1 + K]+ (b). Further, peak at 798.5410 generates a bright image (b). One of the lowest S/N peaks, the 13C2 isotope of [PE 46:5 + H]+ (c) while less clear, still yields informative molecular images, being highlighted especially in the ventricles (images are TIC normalized).

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    Figure 4

    Figure 4. Error histogram and average mass error of tentatively identified lipids after internal calibration. Measured mass error histogram of 139 phosphatidylcholine lipids; the rms error is 61.12 ppb. Bin size = 10 ppb. (a), Lipid identifications by class. A tolerance of ±250 ppb results in 702 potential lipids identified within 150 ppb of their expected mass (b).

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    Figure 5

    Figure 5. Relative abundance of identified lipids by cation and anion for selected classes. In the positive mode, the three major cations (proton, sodium, and potassium) are aligned next to one another, showing the same relative percentages between species, from the most abundant species (PC 34:1) and the other PCs above 3% (a), as well as for the lower abundant species down to the least abundant species with all three cations represented, PC 44:12 (b). The relative ionization rate between K+, H+, and Na+ hold strictly true down to 1.5%, and generally true down to 0.05%. While the dynamic range is lower for negative mode, we see many potential identifications for many lipid classes (c). We further observe a similar ability to identify potential lipids as low as 0.15% of the most abundant peak (PI 38:4), for a range of nearly three orders of magnitude from the summed spectra (d).

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      Hoefler, B. Christopher; Gorzelnik, Karl V.; Yang, Jane Y.; Hendricks, Nathan; Dorrestein, Pieter C.; Straight, Paul D.
      Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (32), 13082-13087, S13082/1-S13082/12CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Many species of bacteria secrete natural products that inhibit the growth or development of competing species. In turn, competitors may develop or acquire resistance to antagonistic mols. Few studies have investigated the interplay of these countervailing forces in direct competition between two species. The authors have used an imaging mass spectrometry (IMS) approach to track metabolites exchanged between Bacillus subtilis and Streptomyces sp. Mg1 cultured together. Surfactin is a cyclic lipopeptide produced by B. subtilis that inhibits the formation of aerial hyphae by streptomycetes. IMS anal. exposed an addn. of 18 mass units to surfactin in the agar proximal to Streptomyces sp. Mg1 but not other streptomycetes tested. The spatially resolved change in the mass of surfactin indicated hydrolysis of the mol. The authors obsd. that the aerial growth of Streptomyces sp. Mg1 was resistant to inhibition by surfactin, which suggests that hydrolysis was a mechanism of resistance. To identify possible enzymes from Streptomyces sp. Mg1 with surfactin hydrolase activity, they isolated secreted proteins and identified candidates by mass spectrometry. They purified one candidate enzyme that hydrolyzed surfactin in vitro. The authors tested the role of this enzyme in surfactin resistance by deleting the corresponding gene from the S. Mg1 genome. They obsd. that aerial growth by the ΔsfhA mutant strain was now sensitive to surfactin. Thus, the results identify an enzyme that hydrolyzes surfactin and confers resistance to aerial growth inhibition, which demonstrates the effective use of an IMS approach to track natural product modifications during interspecies competition.
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    7. 7
      Schulz, S.; Becker, M.; Groseclose, M. R.; Schadt, S.; Hopf, C. Advanced MALDI mass spectrometry imaging in pharmaceutical research and drug development. Curr. Opin. Biotechnol. 2019, 55, 51– 59,  DOI: 10.1016/j.copbio.2018.08.003
      7
      Advanced MALDI mass spectrometry imaging in pharmaceutical research and drug development
      Schulz, Sandra; Becker, Michael; Groseclose, M. Reid; Schadt, Simone; Hopf, Carsten
      Current Opinion in Biotechnology (2019), 55 (), 51-59CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
      Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) has emerged as a key technol. for label-free bioanal. of the spatial distribution of biomols., pharmaceuticals and other xenobiotics in tissue sections. Recent advances in instrumentation, sample prepn., multimodal workflows, quantification, anal. standardization and 'big data' processing have led to widespread utilization of MALDI MSI in pharmaceutical research. These developments have led to applications of the technol. in drug discovery beyond drug disposition anal., most notably in pharmacodynamic biomarker research and in toxicol.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFWgsLzL&md5=376972a07bcfc4fefea4ac20e6aec68f
    8. 8
      Castellino, S.; Groseclose, M. R.; Wagner, D. MALDI imaging mass spectrometry: bridging biology and chemistry in drug development. Bioanalysis 2011, 3 (21), 2427– 41,  DOI: 10.4155/bio.11.232
      8
      MALDI imaging mass spectrometry: bridging biology and chemistry in drug development
      Castellino, Stephen; Groseclose, M. Reid; Wagner, David
      Bioanalysis (2011), 3 (21), 2427-2441CODEN: BIOAB4; ISSN:1757-6180. (Future Science Ltd.)
      A review. Our understanding of drug tissue distribution impacts a no. of areas in drug development, including: pharmacol., pharmacokinetics, safety, drug-drug interactions, transport and metab. Despite their extensive use, autoradiog. and tissue homogenate LC-MS anal. have limitations in providing a comprehensive assessment of tissue distributions. In the case of autoradiog., it is the inability to distinguish between parent drug and drug metabolites. In LC-MS anal. of tissue homogenate, all tissue localization information is lost. The emerging technique of MALDI imaging mass spectrometry has the capability to distinguish between parent and metabolites while maintaining spatial distribution in tissues. In this article, we will review the MALDI imaging MS methodol. as applied to drug development and provide examples highlighting the impact of this important technique in drug development.
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    9. 9
      Ellis, S. R.; Bruinen, A. L.; Heeren, R. M. A critical evaluation of the current state-of-the-art in quantitative imaging mass spectrometry. Anal. Bioanal. Chem. 2014, 406 (5), 1275– 89,  DOI: 10.1007/s00216-013-7478-9
      9
      A critical evaluation of the current state-of-the-art in quantitative imaging mass spectrometry
      Ellis, Shane R.; Bruinen, Anne L.; Heeren, Ron M. A.
      Analytical and Bioanalytical Chemistry (2014), 406 (5), 1275-1289CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      Mass spectrometry imaging (MSI) has evolved into a valuable tool across many fields of chem., biol., and medicine. However, arguably its greatest disadvantage is the difficulty in acquiring quant. data regarding the surface concn. of the analyte(s) of interest. These difficulties largely arise from the high dependence of the ion signal on the localized chem. and morphol. environment and the difficulties assocd. with calibrating such signals. The development of quant. MSI approaches would correspond to a giant leap forward for the field, particularly for the biomedical and pharmaceutical fields, and is thus a highly active area of current research. In this review, we outline the current progress being made in the development and application of quant. MSI workflows with a focus on biomedical applications. Particular emphasis is placed on the various strategies used for both signal calibration and correcting for various ion suppression effects that are invariably present in any MSI study. In addn., the difficulties in validating quant.-MSI data on a pixel-by-pixel basis are highlighted.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVGgt73K&md5=fd0dee4709f7c80e0f7f040405ff7632
    10. 10
      Taban, I. M.; Altelaar, A. F. M.; Van der Burgt, Y. E. M.; McDonnell, L. A.; Heeren, R. M. A.; Fuchser, J.; Baykut, G. Imaging of peptides in the rat brain using MALDI-FTICR mass spectrometry. J. Am. Soc. Mass Spectrom. 2007, 18 (1), 145– 151,  DOI: 10.1016/j.jasms.2006.09.017
      10
      Imaging of Peptides in the Rat Brain Using MALDI-FTICR Mass Spectrometry
      Taban, Ioana M.; Altelaar, A. F. Maarten; van der Burgt, Yuri E. M.; McDonnell, Liam A.; Heeren, Ron M. A.; Fuchser, Jens; Baykut, Goekhan
      Journal of the American Society for Mass Spectrometry (2007), 18 (1), 145-151CODEN: JAMSEF; ISSN:1044-0305. (Elsevier Inc.)
      Anal. methods are pursued to measure the identity and location of biomols. down to the subcellular (μm) level. Available mass spectrometric imaging methods either compromise localization accuracy or identification accuracy in their anal. of surface biomols. In this study, imaging FTICR-MS is applied for the spatially resolved mass anal. of rat brain tissue with the aim to optimize protein identification by the high mass accuracy and online MS/MS capabilities of the technique. Mass accuracies up to 6 ppm were obtained in the direct MALDI-anal. of the tissue together with a spatial resoln. of 200 μm. The spatial distributions of biomols. differing in mass by less than 0.1 Da could be resolved, and are shown to differ significantly. Online MS/MS anal. of selected ions was demonstrated. A comparison of the FTICR-MS imaging results with stigmatic TOF imaging on the same sample is presented. To reduce the extended measuring times involved, it is recommended to restrict the FTICR-MS analyses to areas of interest as can be preselected by other, faster imaging methods.
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    11. 11
      Bowman, A. P.; Heeren, R. M. A.; Ellis, S. R., Advances in mass spectrometry imaging enabling observation of localised lipid biochemistry within tissues. TrAC, Trends Anal. Chem. 2019. 120 115197 DOI: 10.1016/j.trac.2018.07.012
      There is no corresponding record for this reference.
    12. 12
      Zhao, C.; Xie, P. S.; Yang, T.; Wang, H. L.; Chung, A. C. K.; Cai, Z. W. Identification of glycerophospholipid fatty acid remodeling by using mass spectrometry imaging in bisphenol S induced mouse liver. Chin. Chem. Lett. 2018, 29 (8), 1281– 1283,  DOI: 10.1016/j.cclet.2018.01.034
      12
      Identification of glycerophospholipid fatty acid remodeling by using mass spectrometry imaging in bisphenol S induced mouse liver
      Zhao, Chao; Xie, Peisi; Yang, Ti; Wang, Hailin; Chung, Arthur Chi Kong; Cai, Zongwei
      Chinese Chemical Letters (2018), 29 (8), 1281-1283CODEN: CCLEE7; ISSN:1001-8417. (Elsevier B.V.)
      Bisphenol A (BPA) plays an important role in metabolic disorders. As a major alternative to BPA, it is unclear whether the exposure of bisphenol S (BPS) may result in lipidome disturbance. Using a mouse model, the authors investigated the effects of BPS exposure on metab. and spatial distribution of lipids by using lipidomics anal. and matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry imaging (MSI) in mouse liver tissues. Lipid metabolites displayed significant up-regulation in phosphatidylethanolamines (PE), lysophosphatidylcholines (LPC), lysophosphatidylethanolamines (LPE) and lysophosphatidylserine (LPS) as well as remarkable down-regulation in phosphatidylcholine (PC) and phosphatidylserine (PS) in mouse liver after the exposure at 100μg BPS/kg body wt./day. The obtained results indicated that the lipidome of liver was perturbed significantly in glycerophospholipid (GP) fatty acid remodeling pathway upon the BPS exposure. The authors applied MSI and multivariate statistical anal. to evaluate the abundance variation of lipid markers in BPS-treated liver sections and to compare with the anal. from olive oil-treated liver sections. Differential structural lipids with up-regulated PE (20:1/20:4), LPC (20:4), LPE (20:4), LPS (33:4) and down-regulated PC (20:4/22:6) and PS (18:0/22:6), which were related to GP fatty acid remodeling, changed and co-localized in the liver sections. To explore the cause of variation of lipid abundance, expression of enzymes that regulate biosynthesis and metab. of fatty acid in liver tissues were analyzed. Consistent with the results of liver lipidome and spatial distribution, a decrease in hepatic expression of LPC actransferase 1 (LPCAT1), LPCAT2 and LPS acyltransferase and an increase expression of LPCAT3, LPCAT4, LPE acyltransferase 1 (LPEAT1), LPEAT2 and phospholipase A2 s were obsd. in GP fatty acid remodeling pathway. The authors' results demonstrated that exposure to BPS could induce the GP fatty acid remodeling, which might be useful in toxicity evaluation for bisphenols-induced hepatic diseases.
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    13. 13
      Sugiyama, E.; Yao, I.; Setou, M. Visualization of local phosphatidylcholine synthesis within hippocampal neurons using a compartmentalized culture system and imaging mass spectrometry. Biochem. Biophys. Res. Commun. 2018, 495 (1), 1048– 1054,  DOI: 10.1016/j.bbrc.2017.11.108
      13
      Visualization of local phosphatidylcholine synthesis within hippocampal neurons using a compartmentalized culture system and imaging mass spectrometry
      Sugiyama, Eiji; Yao, Ikuko; Setou, Mitsutoshi
      Biochemical and Biophysical Research Communications (2018), 495 (1), 1048-1054CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
      Neurons extend neurites with an increased synthesis of phosphatidylcholine (PC) that is not only a membrane component but also a functional regulator with specific fatty acid compn. To analyze the local synthesis of the PC mol. species within neurons, we combined a compartmentalized culture system with matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). We obsd. that a newly synthesized PC, which contains exogenously administered palmitic acid-d3, is accumulated at the cell bodies and the tips of the distal neurites. The local accumulation within distal neurites is formed by distinct metabolic activity from cell bodies, suggesting that the local extracellular compn. of free fatty acid can be a key to regulate specific functions of each PC mol. species. We expect our simple method to be a starting point for more sophisticated in vitro anal. methods for unveiling detailed lipid metabs. within neurons.
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    14. 14
      Sans, M.; Feider, C. L.; Eberlin, L. S. Advances in mass spectrometry imaging coupled to ion mobility spectrometry for enhanced imaging of biological tissues. Curr. Opin. Chem. Biol. 2018, 42, 138– 146,  DOI: 10.1016/j.cbpa.2017.12.005
      14
      Advances in mass spectrometry imaging coupled to ion mobility spectrometry for enhanced imaging of biological tissues
      Sans, Marta; Feider, Clara L.; Eberlin, Livia S.
      Current Opinion in Chemical Biology (2018), 42 (), 138-146CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      Tissues present complex biochem. and morphol. compn. assocd. with their various cell types and physiol. functions. Mass spectrometry (MS) imaging technologies are powerful tools to investigate the mol. information from biol. tissue samples and visualize their complex spatial distributions. Coupling of gas-phase ion mobility spectrometry (IMS) technologies to MS imaging has been increasingly explored to improve performance for biol. tissue imaging. This approach allows improved detection of low abundance ions and sepn. of isobaric mol. species, thus resulting in more accurate detn. of the spatial distribution of mol. ions. In this review, we highlight recent advances in the field focusing on promising applications of these technologies for metabolite, lipid and protein tissue imaging.
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    15. 15
      Bielow, C.; Mastrobuoni, G.; Orioli, M.; Kempa, S. On Mass Ambiguities in High-Resolution Shotgun Lipidomics. Anal. Chem. 2017, 89 (5), 2986– 2994,  DOI: 10.1021/acs.analchem.6b04456
      15
      On Mass Ambiguities in High-Resolution Shotgun Lipidomics
      Bielow, Chris; Mastrobuoni, Guido; Orioli, Marica; Kempa, Stefan
      Analytical Chemistry (Washington, DC, United States) (2017), 89 (5), 2986-2994CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Mass-spectrometry-based lipidomics aims to identify as many lipid species as possible from complex biol. samples. Due to the large combinatorial search space, unambiguous identification of lipid species is far from trivial. Mass ambiguities are common in direct-injection shotgun expts., where an orthogonal sepn. (e.g., liq. chromatog.) is missing. Using the rich information within available lipid databases, we generated a comprehensive rule set describing mass ambiguities, while taking into consideration the resolving power (and its decay) of different mass analyzers. Importantly, common adduct species and isotopic peaks are accounted for and are shown to play a major role, both for perfect mass overlaps due to identical sum formulas and resolvable mass overlaps. We identified known and hitherto unknown mass ambiguities in high- and ultrahigh resoln. data, while also ranking lipid classes by their propensity to cause ambiguities. On the basis of this new set of ambiguity rules, guidelines and recommendations for experimentalists and software developers of what constitutes a solid lipid identification in both MS and MS/MS were suggested. For researchers new to the field, our results are a compact source of ambiguities which should be accounted for. These new findings also have implications for the selection of internal stds., peaks used for internal mass calibration, optimal choice of instrument resoln., and sample prepn., for example, in regard to adduct ion formation.
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    16. 16
      Shaw, J. B.; Lin, T. Y.; Leach, F. E., 3rd; Tolmachev, A. V.; Tolic, N.; Robinson, E. W.; Koppenaal, D. W.; Pasa-Tolic, L. 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer Greatly Expands Mass Spectrometry Toolbox. J. Am. Soc. Mass Spectrom. 2016, 27 (12), 1929– 1936,  DOI: 10.1007/s13361-016-1507-9
      16
      21 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer Greatly Expands Mass Spectrometry Toolbox
      Shaw, Jared B.; Lin, Tzu-Yung; Leach, Franklin E., III; Tolmachev, Aleksey V.; Tolic, Nikola; Robinson, Errol W.; Koppenaal, David W.; Pasa-Tolic, Ljiljana
      Journal of the American Society for Mass Spectrometry (2016), 27 (12), 1929-1936CODEN: JAMSEF; ISSN:1044-0305. (Springer)
      We provide the initial performance evaluation of a 21 T Fourier transform ion cyclotron resonance mass spectrometer operating at the Environmental Mol. Sciences Lab. at the Pacific Northwest National Lab. The spectrometer constructed for the 21T system employs a com. dual linear ion trap mass spectrometer coupled to a FTICR spectrometer designed and built inhouse. Performance gains from moving to higher magnetic field strength are exemplified by the measurement of peptide isotopic fine structure, complex natural org. matter mixts., and large proteins. Accurate detn. of isotopic fine structure was demonstrated for doubly charged Substance P with minimal spectral averaging, and 8158 mol. formulas assigned to Suwannee River Fulvic Acid std. with root-mean-square (RMS) error of 10 ppb. We also demonstrated superior performance for intact proteins; namely, broadband isotopic resoln. of the entire charge state distribution of apo-transferrin (78 kDa) and facile isotopic resoln. of monoclonal antibody under a variety of acquisition parameters (e.g., 6 s time-domains with absorption mode processing yielded resoln. of approx. 1 M at m/z = 2700).
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    17. 17
      Kooijman, P. C.; Nagornov, K. O.; Kozhinov, A. N.; Kilgour, D. P. A.; Tsybin, Y. O.; Heeren, R. M. A.; Ellis, S. R. Increased throughput and ultra-high mass resolution in DESI FT-ICR MS imaging through new-generation external data acquisition system and advanced data processing approaches. Sci. Rep. 2019, 9 (1), 8,  DOI: 10.1038/s41598-018-36957-1
      17
      Increased throughput and ultra-high mass resolution in DESI FT-ICR MS imaging through new-generation external data acquisition system and advanced data processing approaches
      Kooijman Pieter C; Heeren Ron M A; Ellis Shane R; Kooijman Pieter C; Nagornov Konstantin O; Kozhinov Anton N; Tsybin Yury O; Kilgour David P A
      Scientific reports (2019), 9 (1), 8 ISSN:.
      Desorption electrospray ionisation-mass spectrometry imaging (DESI-MSI) is a powerful imaging technique for the analysis of complex surfaces. However, the often highly complex nature of biological samples is particularly challenging for MSI approaches, as options to appropriately address molecular complexity are limited. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) offers superior mass accuracy and mass resolving power, but its moderate throughput inhibits broader application. Here we demonstrate the dramatic gains in mass resolution and/or throughput of DESI-MSI on an FT-ICR MS by developing and implementing a sophisticated data acquisition and data processing pipeline. The presented pipeline integrates, for the first time, parallel ion accumulation and detection, post-processing absorption mode Fourier transform and pixel-by-pixel internal re-calibration. To achieve that, first, we developed and coupled an external high-performance data acquisition system to an FT-ICR MS instrument to record the time-domain signals (transients) in parallel with the instrument's built-in electronics. The recorded transients were then processed by the in-house developed computationally-efficient data processing and data analysis software. Importantly, the described pipeline is shown to be applicable even to extremely large, up to 1 TB, imaging datasets. Overall, this approach provides improved analytical figures of merits such as: (i) enhanced mass resolution at no cost in experimental time; and (ii) up to 4-fold higher throughput while maintaining a constant mass resolution. Using this approach, we not only demonstrate the record 1 million mass resolution for lipid imaging from brain tissue, but explicitly show such mass resolution is required to resolve the complexity of the lipidome.
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    18. 18
      Smith, D. F.; Kilgour, D. P.; Konijnenburg, M.; O’Connor, P. B.; Heeren, R. M. Absorption mode FTICR mass spectrometry imaging. Anal. Chem. 2013, 85 (23), 11180– 4,  DOI: 10.1021/ac403039t
      18
      Absorption mode FTICR mass spectrometry imaging
      Smith, Donald F.; Kilgour, David P. A.; Konijnenburg, Marco; O'Connor, Peter B.; Heeren, Ron M. A.
      Analytical Chemistry (Washington, DC, United States) (2013), 85 (23), 11180-11184CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Fourier transform ion cyclotron resonance mass spectrometry offers the highest mass resolving power for mol. imaging expts. This high mass resolving power ensures that closely spaced peaks at the same nominal mass are resolved for proper image generation. Typically higher magnetic fields are used to increase mass resolving power. However, a gain in mass resolving power can also be realized by phase correction of the data for absorption mode display. In addn. to mass resolving power, absorption mode offers higher mass accuracy and signal-to-noise ratio over the conventional magnitude mode. Here, the authors present the first use of absorption mode for Fourier transform ion cyclotron resonance mass spectrometry imaging. The Autophaser algorithm is used to phase correct each spectrum (pixel) in the image, and then, these parameters are used by the Chameleon work-flow based data processing software to generate absorption mode Datacubes for image and spectral viewing. Absorption mode reveals new mass and spatial features that are not resolved in magnitude mode and results in improved selected ion image contrast.
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    19. 19
      Qi, Y.; Barrow, M. P.; Li, H.; Meier, J. E.; Van Orden, S. L.; Thompson, C. J.; O’Connor, P. B. Absorption-mode: the next generation of Fourier transform mass spectra. Anal. Chem. 2012, 84 (6), 2923– 9,  DOI: 10.1021/ac3000122
      19
      Absorption-Mode: The Next Generation of Fourier Transform Mass Spectra
      Qi, Yulin; Barrow, Mark P.; Li, Huilin; Meier, Joseph E.; Van Orden, Steve L.; Thompson, Christopher J.; O'Connor, Peter B.
      Analytical Chemistry (Washington, DC, United States) (2012), 84 (6), 2923-2929CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The Fourier transform spectrum can be presented in the absorption-mode (commonly used in FT-NMR), magnitude-mode (FT-ICR), and power-mode (engineering applications). As is routinely used in FT-NMR, it is known that the absorption-mode display gives a much narrower peak shape which greatly improves the spectrum; recently, the successful soln. of the phase equation allowed broadband phase correction which makes it possible to apply the absorption-mode routinely in FT-ICR. With the empirical evidence provided herein, in addn. to the improvement on resolving power, compared to the conventional magnitude-mode, the new absorption-mode improves the signal-to-noise ratio (S/N) of a spectrum by 1.4-fold and can improve the mass accuracy up to 2-fold with no extra cost in instrumentation. Therefore, it is worthwhile to apply and promote absorption-mode in routine FT-ICR expts.
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    20. 20
      Stopka, S. A.; Samarah, L. Z.; Shaw, J. B.; Liyu, A. V.; Velickovic, D.; Agtuca, B. J.; Kukolj, C.; Koppenaal, D. W.; Stacey, G.; Pasa-Tolic, L.; Anderton, C. R.; Vertes, A. Ambient Metabolic Profiling and Imaging of Biological Samples with Ultrahigh Molecular Resolution Using Laser Ablation Electrospray Ionization 21 T FTICR Mass Spectrometry. Anal. Chem. 2019, 91 (8), 5028– 5035,  DOI: 10.1021/acs.analchem.8b05084
      20
      Ambient Metabolic Profiling and Imaging of Biological Samples with Ultrahigh Molecular Resolution Using Laser Ablation Electrospray Ionization 21 Tesla FTICR Mass Spectrometry
      Stopka, Sylwia A.; Samarah, Laith Z.; Shaw, Jared B.; Liyu, Andrey V.; Velickovic, Dusan; Agtuca, Beverly J.; Kukolj, Caroline; Koppenaal, David W.; Stacey, Gary; Pasa-Tolic, Ljiljana; Anderton, Christopher R.; Vertes, Akos
      Analytical Chemistry (Washington, DC, United States) (2019), 91 (8), 5028-5035CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Mass spectrometry (MS) is an indispensable anal. tool to capture the array of metabolites within complex biol. systems. However, conventional MS-based metabolomic workflows require extensive sample processing and sepn. resulting in limited throughput and potential alteration of the native mol. states in these systems. Ambient ionization methods, capable of sampling directly from tissues, circumvent some of these issues but require high-performance MS to resolve the mol. complexity within these samples. Here, the authors demonstrate a unique combination of laser ablation electrospray ionization (LAESI) coupled with a 21 T Fourier transform ion cyclotron resonance (21T-FTICR) for direct MS anal. and imaging applications. This anal. platform provides isotopic fine structure information directly from biol. tissues, enabling the rapid assignment of mol. formulas and delivering a higher degree of confidence for mol. identification.
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    21. 21
      Schwudke, D.; Schuhmann, K.; Herzog, R.; Bornstein, S. R.; Shevchenko, A. Shotgun lipidomics on high resolution mass spectrometers. Cold Spring Harbor Perspect. Biol. 2011, 3 (9), a004614  DOI: 10.1101/cshperspect.a004614
      There is no corresponding record for this reference.
    22. 22
      Hu, C.; Duan, Q.; Han, X. Strategies to Improve/Eliminate the Limitations in Shotgun Lipidomics. Proteomics 2019, e1900070  DOI: 10.1002/pmic.201900070
      There is no corresponding record for this reference.
    23. 23
      Ryan, E.; Reid, G. E. Chemical Derivatization and Ultrahigh Resolution and Accurate Mass Spectrometry Strategies for “Shotgun” Lipidome Analysis. Acc. Chem. Res. 2016, 49 (9), 1596– 604,  DOI: 10.1021/acs.accounts.6b00030
      23
      Chemical Derivatization and Ultrahigh Resolution and Accurate Mass Spectrometry Strategies for "Shotgun" Lipidome Analysis
      Ryan, Eileen; Reid, Gavin E.
      Accounts of Chemical Research (2016), 49 (9), 1596-1604CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Lipids play crit. structural and functional roles in the regulation of cellular homeostasis, and it is increasingly recognized that the disruption of lipid metab. and/or signaling is assocd. with the onset and progression of certain metabolically linked diseases. As a result, the field of lipidomics has emerged to comprehensively identify and structurally characterize the diverse range of lipid species within a sample of interest, and to quant. monitor their abundances under different physiol. or pathol. conditions. Mass spectrometry (MS) has become a crit. enabling platform technol. for lipidomic researchers. However, the presence of isobaric (i.e., same nominal mass) and isomeric (i.e., same exact mass) lipids within complex lipid exts. means that MS-based identification and quantification of individual lipid species remains a significant anal. challenge. Ultrahigh resoln. and accurate mass spectrometry (UHRAMS) offers a convenient soln. to the isobaric mass overlap problem, while a range of chromatog. sepn., differential extn., intrasource sepn. and selective ionization methods, or tandem mass spectrometry (MS/MS) strategies, may be used to address some types of isomeric mass lipid overlaps. Alternatively, chem. derivatization strategies represent a more recent approach for the "sepn." of lipids within complex mixts., including for isomeric lipids. In this Account, the authors highlight the key components of a lipidomics workflow developed in the authors' lab., whereby certain lipid classes and/or subclasses, namely aminophospholipids and O-alk-1'-enyl (i.e., plasmalogen) ether-contg. lipids, are shifted in mass following sequential functional group selective chem. derivatization reactions prior to "shotgun" nanoESI-UHRAMS anal., "targeted" tandem mass spectrometry (MS/MS), and automated database searching. This combined derivatization and UHRAMS approach resolves both isobaric mass lipids and certain categories of isomeric mass lipids within crude lipid exts., with no requirement for extensive sample handling prior to anal., with addnl. potential for enhanced ionization efficiencies, improved "mol. level" structural characterization, and "multiplexed" relative quantification. When integrated with a monophasic method for the simultaneous "global" extn. of both highly polar and nonpolar lipids, this workflow has been shown to enable the "sum-compn." level identification and relative quantification of 500-600 individual lipid species across 4 lipid categories and from 36 lipid classes and subclasses, in only 1-2 min data acquisition time and with minimal sample consumption. Thus, while some anal. challenges remain to be addressed, "shotgun" lipidomics workflows encompassing chem. derivatization strategies have particular promise for the anal. of samples with limited availability, but requiring rapid and unbiased assessment of "global" lipid metab.
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    24. 24
      Wildburger, N. C.; Wood, P. L.; Gumin, J.; Lichti, C. F.; Emmett, M. R.; Lang, F. F.; Nilsson, C. L. ESI-MS/MS and MALDI-IMS Localization Reveal Alterations in Phosphatidic Acid, Diacylglycerol, and DHA in Glioma Stem Cell Xenografts. J. Proteome Res. 2015, 14 (6), 2511– 9,  DOI: 10.1021/acs.jproteome.5b00076
      24
      ESI-MS/MS and MALDI-IMS Localization Reveal Alterations in Phosphatidic Acid, Diacylglycerol, and DHA in Glioma Stem Cell Xenografts
      Wildburger, Norelle C.; Wood, Paul L.; Gumin, Joy; Lichti, Cheryl F.; Emmett, Mark R.; Lang, Frederick F.; Nilsson, Carol L.
      Journal of Proteome Research (2015), 14 (6), 2511-2519CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
      Glioblastoma (GBM) is the most common adult primary brain tumor. Despite aggressive multimodal therapy, the survival of patients with GBM remains dismal. However, recent evidence has demonstrated the promise of bone marrow-derived mesenchymal stem cells (BM-hMSCs) as a therapeutic delivery vehicle for anti-glioma agents due to their ability to migrate or home to human gliomas. While several studies have demonstrated the feasibility of harnessing the homing capacity of BM-hMSCs for targeted delivery of cancer therapeutics, it is now also evident, based on clin. relevant glioma stem cell (GSC) models of GBMs, that BM-hMSCs demonstrate variable tropism toward these tumors. In this study, we compared the lipid environment of GSC xenografts that attract BM-hMSCs (N = 9) with those that do not attract (N = 9) to identify lipid modalities that are conducive to homing of BM-hMSC to GBMs. We identified lipids directly from tissue by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) and electrospray ionization-tandem mass spectrometry (ESI-MS/MS) of lipid exts. Several species of signaling lipids, including phosphatidic acid (PA 36:2, PA 40:5, PA 42:5, and PA 42:7) and diacylglycerol (DAG 34:0, DAG 34:1, DAG 36:1, DAG 38:4, DAG 38:6, and DAG 40:6), were lower in attracting xenografts. Mol. lipid images showed that PA (36:2), DAG (40:6), and docosahexaenoic acid (DHA) were decreased within tumor regions of attracting xenografts. Our results provide the first evidence for lipid signaling pathways and lipid-mediated tumor inflammatory responses in the homing of BM-hMSCs to GSC xenografts. Our studies provide new fundamental knowledge on the mol. correlates of the differential homing capacity of BM-hMSCs toward GSC xenografts.
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    25. 25
      Holcapek, M.; Cervena, B.; Cifkova, E.; Lisa, M.; Chagovets, V.; Vostalova, J.; Bancirova, M.; Galuszka, J.; Hill, M. Lipidomic analysis of plasma, erythrocytes and lipoprotein fractions of cardiovascular disease patients using UHPLC/MS, MALDI-MS and multivariate data analysis. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2015, 990, 52– 63,  DOI: 10.1016/j.jchromb.2015.03.010
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      Lipidomic analysis of plasma, erythrocytes and lipoprotein fractions of cardiovascular disease patients using UHPLC/MS, MALDI-MS and multivariate data analysis
      Holcapek, Michal; Cervena, Blanka; Cifkova, Eva; Lisa, Miroslav; Chagovets, Vitaliy; Vostalova, Jitka; Bancirova, Martina; Galuszka, Jan; Hill, Martin
      Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2015), 990 (), 52-63CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
      Differences among lipidomic profiles of healthy volunteers, obese people and three groups of cardiovascular disease (CVD) patients are investigated with the goal to differentiate individual groups based on the multivariate data anal. (MDA) of lipidomic data from plasma, erythrocytes and lipoprotein fractions of more than 50 subjects. Hydrophilic interaction liq. chromatog. on ultrahigh-performance liq. chromatog. (HILIC-UHPLC) column coupled with electrospray ionization mass spectrometry (ESI-MS) is used for the quantitation of four classes of polar lipids (phosphatidylethanolamines, phosphatidylcholines, sphingomyelins and lysophosphatidylcholines), normal-phase UHPLC-atm. pressure chem. ionization MS (NP-UHPLC/APCI-MS) is applied for the quantitation of five classes of nonpolar lipids (cholesteryl esters, triacylglycerols, sterols, 1,3-diacylglycerols and 1,2-diacylglycerols) and the potential of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is tested for the fast screening of all lipids without a chromatog. sepn. Obtained results are processed by unsupervised (principal component anal.) and supervised (orthogonal partial least squares) MDA approaches to highlight the largest differences among individual groups and to identify lipid mols. with the highest impact on the group differentiation.
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    26. 26
      Korte, A. R.; Yandeau-Nelson, M. D.; Nikolau, B. J.; Lee, Y. J. Subcellular-level resolution MALDI-MS imaging of maize leaf metabolites by MALDI-linear ion trap-Orbitrap mass spectrometer. Anal. Bioanal. Chem. 2015, 407 (8), 2301– 9,  DOI: 10.1007/s00216-015-8460-5
      26
      Subcellular-level resolution MALDI-MS imaging of maize leaf metabolites by MALDI-linear ion trap-Orbitrap mass spectrometer
      Korte, Andrew R.; Yandeau-Nelson, Marna D.; Nikolau, Basil J.; Lee, Young Jin
      Analytical and Bioanalytical Chemistry (2015), 407 (8), 2301-2309CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      A significant limiting factor in achieving high spatial resoln. for matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging is the size of the laser spot at the sample surface. Here, we present modifications to the beam-delivery optics of a com. MALDI-linear ion trap-Orbitrap instrument, incorporating an external Nd:YAG laser, beam-shaping optics, and an aspheric focusing lens, to reduce the min. laser spot size from ∼50 μm for the com. configuration down to ∼9 μm for the modified configuration. This improved system was applied for MALDI-MS imaging of cross sections of juvenile maize leaves at 5-μm spatial resoln. using an oversampling method. A variety of different metabolites including amino acids, glycerolipids, and defense-related compds. were imaged at a spatial resoln. well below the size of a single cell. Such images provide unprecedented insights into the metab. assocd. with the different tissue types of the maize leaf, which is known to asym. distribute the reactions of C4 photosynthesis among the mesophyll and bundle sheath cell types. The metabolite ion images correlate with the optical images that reveal the structures of the different tissues, and previously known and newly revealed asym. metabolic features are obsd.
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    27. 27
      Olsen, J. V.; de Godoy, L. M.; Li, G.; Macek, B.; Mortensen, P.; Pesch, R.; Makarov, A.; Lange, O.; Horning, S.; Mann, M. Parts per million mass accuracy on an Orbitrap mass spectrometer via lock mass injection into a C-trap. Mol. Cell. Proteomics 2005, 4 (12), 2010– 21,  DOI: 10.1074/mcp.T500030-MCP200
      27
      Parts per million mass accuracy on an orbitrap mass spectrometer via lock mass injection into a C-trap
      Olsen, Jesper V.; de Godoy, Lyris M. F.; Li, Guoqing; Macek, Boris; Mortensen, Peter; Pesch, Reinhold; Makarov, Alexander; Lange, Oliver; Horning, Stevan; Mann, Matthias
      Molecular and Cellular Proteomics (2005), 4 (12), 2010-2021CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology)
      Mass accuracy is a key parameter of mass spectrometric performance. TOF instruments can reach low ppm, and FT-ICR instruments are capable of even greater accuracy provided ion nos. are well controlled. Here the authors demonstrate sub-ppm mass accuracy on a linear ion trap coupled via a radio frequency-only storage trap (C-trap) to the orbitrap mass spectrometer (LTQ Orbitrap). Prior to acquisition of a spectrum, a background ion originating from ambient air is first transferred to the C-trap. Ions forming the MS or MSn spectrum are then added to this species, and all ions are injected into the orbitrap for anal. Real time recalibration on the "lock mass" by corrections of mass shift removes mass error assocd. with calibration of the mass scale. The remaining mass error is mainly due to imperfect peaks caused by weak signals and is addressed by averaging the mass measurement over the LC peak, weighted by signal intensity. For peptide database searches in proteomics, the authors introduce a variable mass tolerance and achieve av. abs. mass deviations of 0.48 ppm (std. deviation 0.38 ppm) and maximal deviations of less than 2 ppm. For tandem mass spectra the authors demonstrate similarly high mass accuracy and discuss its impact on database searching. High and routine mass accuracy in a compact instrument will dramatically improve certainty of peptide and small mol. identification.
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    28. 28
      Makarov, A.; Denisov, E.; Lange, O.; Horning, S. Dynamic range of mass accuracy in LTQ Orbitrap hybrid mass spectrometer. J. Am. Soc. Mass Spectrom. 2006, 17 (7), 977– 982,  DOI: 10.1016/j.jasms.2006.03.006
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      Dynamic Range of Mass Accuracy in LTQ Orbitrap Hybrid Mass Spectrometer
      Makarov, Alexander; Denisov, Eduard; Lange, Oliver; Horning, Stevan
      Journal of the American Society for Mass Spectrometry (2006), 17 (7), 977-982CODEN: JAMSEF; ISSN:1044-0305. (Elsevier Inc.)
      Using a novel orbitrap mass spectrometer, the dynamic range over which accurate masses can be detd. (extent of mass accuracy) were studied for short duration expts. typical for LC/MS. A linear ion trap is used to selectively fill an intermediate ion storage device (C-trap) with ions of interest, following which the ensemble of ions is injected into an orbitrap mass analyzer and analyzed using image current detection and fast Fourier transformation. Using this technique, it is possible to generate ion populations with intraspectrum intensity ranges up to 104. All measurements (including ion accumulation and image current detection) were performed in <1 s at a resolving power of 30,000. 5-Ppm mass accuracy of the orbitrap mass analyzer is reached with >95% probability at a dynamic range of >5000, which is at least an order of magnitude higher than typical values for time-of-flight instruments. Due to the high resolving power of the orbitrap, accurate mass of an ion could be detd. when the signal was reliably distinguished from noise (S/Np-p>2...3).
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    29. 29
      Scigelova, M.; Makarov, A. Orbitrap mass analyzer--overview and applications in proteomics. Proteomics 2006, 6 (Suppl 2), 16– 21,  DOI: 10.1002/pmic.200600528
      29
      Orbitrap mass analyzer--overview and applications in proteomics
      Scigelova Michaela; Makarov Alexander
      Proteomics (2006), 6 Suppl 2 (), 16-21 ISSN:.
      The orbitrap mass analyzer is proving itself as a useful addition to a proteomics tool box. The key attributes of this analyzer are accurate mass and high resolution similar to those achievable with FT ICR instrumentation. The basic principles underlying these capabilities, and how they translate into benefits in real-life proteomics experiments are discussed. The focus is on reviewing examples of protein identification with bottom-up and top-down approaches, and detection of post-translational modifications.
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    30. 30
      Marshall, A. G.; Hendrickson, C. L.; Jackson, G. S. Fourier transform ion cyclotron resonance mass spectrometry: A primer. Mass Spectrom. Rev. 1998, 17 (1), 1– 35,  DOI: 10.1002/(SICI)1098-2787(1998)17:1<1::AID-MAS1>3.0.CO;2-K
      30
      Fourier transform ion cyclotron resonance mass spectrometry: a primer
      Marshall, Alan G.; Hendrickson, Christopher L.; Jackson, George S.
      Mass Spectrometry Reviews (1998), 17 (1), 1-35CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
      A review with 149 refs. This review offers an introduction to the principles and generic applications of FT-ICR mass spectrometry, directed to readers with no prior experience with the technique. The authors are able to explain the fundamental FT-ICR phenomena from a simplified theor. treatment of ion behavior in idealized magnetic and elec. fields. The effects of trapping voltage, trap size and shape, and other nonidealities are manifested mainly as perturbations that preserve the idealized ion behavior modified by appropriate numerical correction factors. Topics include: effect of ion mass, charge, magnetic field, and trapping voltage on ion cyclotron frequency; excitation and detection of ICR signals; mass calibration; mass resolving power and mass accuracy; upper mass limit(s); dynamic range; detection limit, strategies for mass and energy selection for MSn; ion axialization, cooling, and remeasurement; and means for guiding externally formed ions into the ion trap. The relation of FT-ICR MS to other types of Fourier transform spectroscopy and to the Paul (quadrupole) ion trap is described. The article concludes with selected applications, an appendix listing accurate fundamental consts. needed for ultrahigh-precision anal., and an annotated list of selected reviews and primary source publications that describe in further detail various FT-ICR MS techniques and applications.
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    31. 31
      Nikolaev, E. N.; Gorshkov, M. V.; Mordehai, A. V.; Talrose, V. L. Ion cyclotron resonance signal-detection at multiples of the cyclotron frequency. Rapid Commun. Mass Spectrom. 1990, 4 (5), 144– 146,  DOI: 10.1002/rcm.1290040503
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      Ion cyclotron resonance signal-detection at multiples of the cyclotron frequency
      Nikolaev, E. N.; Gorshkov, M. V.; Mordehai, A. V.; Talrose, V. L.
      Rapid Communications in Mass Spectrometry (1990), 4 (5), 144-6CODEN: RCMSEF; ISSN:0951-4198.
      A Fourier-transform mass spectrometric technique for detecting ion cyclotron resonance signals at multiple cyclotron frequencies is proposed and initial exptl. results are presented. The technique is readily adapted to existing instruments.
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    32. 32
      Walker, L. R.; Tfaily, M. M.; Shaw, J. B.; Hess, N. J.; Pasa-Tolic, L.; Koppenaal, D. W. Unambiguous identification and discovery of bacterial siderophores by direct injection 21 T Fourier transform ion cyclotron resonance mass spectrometry. Metallomics 2017, 9 (1), 82– 92,  DOI: 10.1039/C6MT00201C
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      Unambiguous identification and discovery of bacterial siderophores by direct injection 21 Tesla Fourier transform ion cyclotron resonance mass spectrometry
      Walker, Lawrence R.; Tfaily, Malak M.; Shaw, Jared B.; Hess, Nancy J.; Pasa-Tolic, Ljiljana; Koppenaal, David W.
      Metallomics (2017), 9 (1), 82-92CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      Under iron-limiting conditions, bacteria produce low mol. mass Fe(iii) binding mols. known as siderophores to sequester the Fe(iii), along with other elements, increasing their bioavailability. Siderophores are thought to influence iron cycling and biogeochem. in both marine and terrestrial ecosystems and hence the need for rapid, confident characterization of these compds. has increased. In this study, the type of siderophores produced by two marine bacterial species, Synechococcus sp. PCC 7002 and Vibrio cyclitrophicus 1F53, were characterized by use of a newly developed 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FTICR MS) with direct injection electrospray ionization. This technique allowed for the rapid detection of synechobactins from Synechococcus sp. PCC 7002 as well as amphibactins from Vibrio cyclitrophicus 1F53 based on high mass accuracy and resoln. allowing for observation of specific Fe isotopes and isotopic fine structure enabling highly confident identification of these siderophores. When combined with mol. network anal. two new amphibactins were discovered and verified by tandem MS. These results show that high-field FTICR MS is a powerful technique that will greatly improve the ability to rapidly identify and discover metal binding species in the environment.
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    33. 33
      Zimmerman, T. A.; Monroe, E. B.; Tucker, K. R.; Rubakhin, S. S.; Sweedler, J. V. Chapter 13: Imaging of cells and tissues with mass spectrometry: adding chemical information to imaging. Methods Cell Biol. 2008, 89, 361– 90,  DOI: 10.1016/S0091-679X(08)00613-4
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      Imaging of cells and tissues with mass spectrometry: adding chemical information to imaging
      Zimmerman, Tyler A.; Monroe, Eric B.; Tucker, Kevin R.; Rubakhin, Stanislav S.; Sweedler, Jonathan V.
      Methods in Cell Biology (2008), 89 (Biophysical Tools for Biologists, Volume Two), 361-390CODEN: MCBLAG; ISSN:0091-679X. (Elsevier Inc.)
      A review. Techniques that map the distribution of compds. in biol. tissues can be invaluable in addressing a no. of crit. questions in biol. and medicine. One of the newer methods, mass spectrometric imaging, has enabled investigation of spatial localization for a variety of compds. ranging from atomics to proteins. The ability of mass spectrometry to detect and differentiate a large no. of unlabeled compds. makes the approach amenable to the study of complex biol. tissues. This chapter focuses on recent advances in the instrumentation and sample prepn. protocols that make mass spectrometric imaging of biol. samples possible, including strategies for both tissue and single-cell imaging using the following mass spectrometric ionization methods: matrix-assisted laser desorption/ionization, secondary ion, electrospray, and desorption electrospray.
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      Hendrickson, C. L.; Quinn, J. P.; Kaiser, N. K.; Smith, D. F.; Blakney, G. T.; Chen, T.; Marshall, A. G.; Weisbrod, C. R.; Beu, S. C. 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer: A National Resource for Ultrahigh Resolution Mass Analysis. J. Am. Soc. Mass Spectrom. 2015, 26 (9), 1626– 32,  DOI: 10.1007/s13361-015-1182-2
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      21 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer: A National Resource for Ultrahigh Resolution Mass Analysis
      Hendrickson, Christopher L.; Quinn, John P.; Kaiser, Nathan K.; Smith, Donald F.; Blakney, Greg T.; Chen, Tong; Marshall, Alan G.; Weisbrod, Chad R.; Beu, Steven C.
      Journal of the American Society for Mass Spectrometry (2015), 26 (9), 1626-1632CODEN: JAMSEF; ISSN:1044-0305. (Springer)
      We describe the design and initial performance of the first 21 T Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The 21 T magnet is the highest field superconducting magnet ever used for FT-ICR and features high spatial homogeneity, high temporal stability, and negligible liq. helium consumption. The instrument includes a com. dual linear quadrupole trap front end that features high sensitivity, precise control of trapped ion no., and collisional and electron transfer dissocn. A third linear quadrupole trap offers high ion capacity and ejection efficiency, and rf quadrupole ion injection optics deliver ions to a novel dynamically harmonized ICR cell. Mass resolving power of 150,000 (m/Δm50%) is achieved for bovine serum albumin (66 kDa) for a 0.38 s detection period, and greater than 2,000,000 resolving power is achieved for a 12 s detection period. Externally calibrated broadband mass measurement accuracy is typically less than 150 ppb rms, with resolving power greater than 300,000 at m/z 400 for a 0.76 s detection period. Combined anal. of electron transfer and collisional dissocn. spectra results in 68% sequence coverage for carbonic anhydrase. The instrument is part of the NSF High-Field FT-ICR User Facility and is available free of charge to qualified users.
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    35. 35
      Smith, D. F.; Podgorski, D. C.; Rodgers, R. P.; Blakney, G. T.; Hendrickson, C. L. 21 T FT-ICR Mass Spectrometer for Ultrahigh-Resolution Analysis of Complex Organic Mixtures. Anal. Chem. 2018, 90 (3), 2041– 2047,  DOI: 10.1021/acs.analchem.7b04159
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      21 Tesla FT-ICR Mass Spectrometer for Ultrahigh-Resolution Analysis of Complex Organic Mixtures
      Smith, Donald F.; Podgorski, David C.; Rodgers, Ryan P.; Blakney, Greg T.; Hendrickson, Christopher L.
      Analytical Chemistry (Washington, DC, United States) (2018), 90 (3), 2041-2047CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The authors describe complex org. mixt. anal. by 21 T Fourier transform ICR mass spectrometry (FT-ICR MS). Ultrahigh mass-resolving power (m/Δm50% > 2,700,000 at m/z 400) and mass accuracy (80 ppb root-mean-square) enable resoln. and confident identification of tens of thousands of unique elemental compns. The authors demonstrate 2.2-fold higher mass-resolving power, 2.6-fold better mass measurement accuracy, and 1.3-fold more assigned mol. formulas compared to the authors' custom-built, state-of-the-art 9.4 T FT-ICR mass spectrometer for petroleum and dissolved org. matter (DOM) analyses. Anal. of a heavy petroleum distillate exemplifies the need for ultrahigh-performance mass spectrometry (49,040 assigned mol. formulas for 21 T vs. 29,012 for 9.4 T) and extends the identification of previously unresolved Oo, SsOo, and NOo classes. Mass selective ion accumulation (20 Thompson isolation) of an asphalt volcano sample yields 462 resolved mass spectral peaks at m/z 677 and reveals previously unresolved CcHhNnOoSs mass differences at high mass (m/z > 600). Similar performance gains are realized in the anal. of dissolved org. matter, where doubly charged Oo species are resolved from singly charged SOo species, which requires a mass-resolving power >1,400,000 (at m/z 600). This direct comparison reveals the continued need for higher mass-resolving power and better mass accuracy for comprehensive mol. characterization of the most complex org. mixts.
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    36. 36
      Burla, B.; Arita, M.; Arita, M.; Bendt, A. K.; Cazenave-Gassiot, A.; Dennis, E. A.; Ekroos, K.; Han, X.; Ikeda, K.; Liebisch, G.; Lin, M. K.; Loh, T. P.; Meikle, P. J.; Oresic, M.; Quehenberger, O.; Shevchenko, A.; Torta, F.; Wakelam, M. J. O.; Wheelock, C. E.; Wenk, M. R. MS-based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines. J. Lipid Res. 2018, 59 (10), 2001– 2017,  DOI: 10.1194/jlr.S087163
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      MS-based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines
      Burla, Bo; Arita, Makoto; Arita, Masanori; Bendt, Anne K.; Cazenave-Gassiot, Amaury; Dennis, Edward A.; Ekroos, Kim; Han, Xianlin; Ikeda, Kazutaka; Liebisch, Gerhard; Lin, Michelle K.; Loh, Tze Ping; Meikle, Peter J.; Oresic, Matej; Quehenberger, Oswald; Shevchenko, Andrej; Torta, Federico; Wakelam, Michael J. O.; Wheelock, Craig E.; Wenk, Markus R.
      Journal of Lipid Research (2018), 59 (10), 2001-2017CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology)
      Human blood is a self-regenerating lipid-rich biol. fluid that is routinely collected in hospital settings. The inventory of lipid mols. found in blood plasma (plasma lipidome) offers insights into individual metab. and physiol. in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metab.; therefore, plasma lipidomics based on MS is an emerging tool in an array of clin. diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clin. applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quant. MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent labs. as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVegsb3L&md5=55532799766f221aaf9392b2a5e87e55
    37. 37
      Xiang, X.; Grosshans, P. B.; Marshall, A. G. Image charge-induced ion cyclotron orbital frequency shift for orthorhombic and cylindrical FT-ICR ion traps. Int. J. Mass Spectrom. Ion Processes 1993, 125 (1), 33– 43,  DOI: 10.1016/0168-1176(93)80014-6
      37
      Image charge-induced ion cyclotron orbital frequency shift for orthorhombic and cylindrical FT-ICR ion traps
      Xiang, Xinzhen; Grosshans, Peter B.; Marshall, Alan G.
      International Journal of Mass Spectrometry and Ion Processes (1993), 125 (1), 33-43CODEN: IJMPDN; ISSN:0168-1176.
      A coherently orbiting ion packet induces a distribution of image charge on the ion trap electrodes, the resultant elec. field from the image charge shifts the ICR orbital frequency of the ions in the ion packet. The effect of image charges upon the cyclotron motion of a trapped ion was previously modeled for infinite parallel plate and spherical cavity geometries. In other prior work, an anal. method to solve for the charge induced on any of the electrodes of a Fourier transform ion cyclotron resonance (FT-ICR) ion trap was presented. In this work, the authors report approx. anal. solns. for the frequency shift due to the induced image charges for both finite-size cylindrical and tetragonal traps as a function of ion axial and radial position. For a cubic trap, the mass-independent frequency shift at an ICR orbital radius equal to half the trap radius is ≈10-5 Hz for one ion. Thus, image charge-induced frequency shifts in the ppm range can be expected for typical ICR expts. involving 103-105 ions at low mass-to-charge ratio (60 ≤ m/z ≤ 600), whereas the shift can increase to ≈1 u for 100,000 singly-charged 3000 u ions at 3.0 T. The image charge-induced shift for a cylindrical trap is higher than for a cubic trap of comparable size. Implications for mass calibration are discussed.
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    38. 38
      Wong, R. L.; Amster, I. J. Experimental Evidence for Space-Charge Effects between Ions of the Same Mass-to-Charge in Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry. Int. J. Mass Spectrom. 2007, 265 (2–3), 99– 105,  DOI: 10.1016/j.ijms.2007.01.014
      38
      Experimental evidence for space-charge effects between ions of the same mass-to-charge in Fourier-transform ion cyclotron resonance mass spectrometry
      Wong, Richard L.; Amster, I. Jonathan
      International Journal of Mass Spectrometry (2007), 265 (2-3), 99-105CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
      It is often stated that ions of the same mass-to-charge do not induce space-charge frequency shifts among themselves in an ICR mass spectrometry measurement. Here, the authors demonstrate space-charge induced frequency shifts for ions of a single mass-to-charge. The monoisotopic at. ion, Cs+, was used for this study. The measured frequency decreases linearly with an increase in the no. of ions, as was reported previously for space-charge effects between ions of different mass-to-charge. The frequency shift between ions of the same m/z value are compared to that induced between ions of different m/z value, and is 7.5 times smaller. Control expts. were performed to ensure that the obsd. space-charge effects are not artifacts of the measurement or of exptl. design. The results can be rationalized by recognizing that the elec. forces between ions in a magnetic field conform to the weak form of the Newton's 3rd law, where the action and reaction forces do not cancel exactly.
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    39. 39
      Savory, J. J.; Kaiser, N. K.; McKenna, A. M.; Xian, F.; Blakney, G. T.; Rodgers, R. P.; Hendrickson, C. L.; Marshall, A. G. Parts-per-billion Fourier transform ion cyclotron resonance mass measurement accuracy with a “walking” calibration equation. Anal. Chem. 2011, 83 (5), 1732– 6,  DOI: 10.1021/ac102943z
      39
      Parts-Per-Billion Fourier Transform Ion Cyclotron Resonance Mass Measurement Accuracy with a "Walking" Calibration Equation
      Savory, Joshua J.; Kaiser, Nathan K.; McKenna, Amy M.; Xian, Feng; Blakney, Greg T.; Rodgers, Ryan P.; Hendrickson, Christopher L.; Marshall, Alan G.
      Analytical Chemistry (Washington, DC, United States) (2011), 83 (5), 1732-1736CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      ICR frequency, f, is conventionally converted to ion mass-to-charge ratio, m/z (mass calibration) by fitting exptl. data spanning the entire detected m/z range to the relation, m/z = A/f + B/f2, to yield root-mean-square mass error as low as ∼200 ppb for ∼10,000 resolved components of a petroleum crude oil. Anal. of residual error vs. m/z and peak abundance reveals that systematic errors limit mass accuracy and thus the confidence in elemental compn. assignments. Here, the authors present a calibration procedure in which the spectrum is divided into dozens of adjoining segments, and a sep. calibration is applied to each, thereby eliminating systematic error with respect to m/z. Further, incorporation of a 3rd term in the calibration equation that is proportional to the magnitude of each detected peak minimizes systematic error with respect to ion abundance. Finally, absorption-mode data anal. increases mass measurement accuracy only after minimization of systematic errors. The authors are able to increase the no. of assigned peaks by ≤25%, while reducing the root-mean-square mass error by ≤3-fold, for significantly improved confidence in elemental compn. assignment.
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    40. 40
      Schuhmann, K.; Almeida, R.; Baumert, M.; Herzog, R.; Bornstein, S. R.; Shevchenko, A. Shotgun lipidomics on a LTQ Orbitrap mass spectrometer by successive switching between acquisition polarity modes. J. Mass Spectrom. 2012, 47 (1), 96– 104,  DOI: 10.1002/jms.2031
      40
      Shotgun lipidomics on a LTQ Orbitrap mass spectrometer by successive switching between acquisition polarity modes
      Schuhmann, Kai; Almeida, Reinaldo; Baumert, Mark; Herzog, Ronny; Bornstein, Stefan R.; Shevchenko, Andrej
      Journal of Mass Spectrometry (2012), 47 (1), 96-104CODEN: JMSPFJ; ISSN:1076-5174. (John Wiley & Sons Ltd.)
      Top-down shotgun lipidomics relies on direct infusion of total lipid exts. into a high-resoln. tandem mass spectrometer and implies that individual lipids are recognized by their accurately detd. m/z. Lipid ionization efficiency and detection specificity strongly depend on the acquisition polarity, and therefore it is beneficial to analyze lipid mixts. in both pos. and neg. modes. Hybrid LTQ Orbitrap mass spectrometers are widely applied in top-down lipidomics; however, rapid polarity switching was previously unfeasible because of the severe and immediate degrdn. of mass accuracy. Here, the authors report on a method to rapidly acquire high-resoln. spectra in both polarity modes with sub-ppm mass accuracy and demonstrate that it not only simplifies and accelerates shotgun lipidomics analyses but also improves the lipidome coverage because more lipid classes and more individual species within each class are recognized. In this way, shotgun anal. of total lipid exts. of human blood plasma enabled to quantify 222 species from 15 major lipid classes within 7 min acquisition cycle. Copyright © 2012 John Wiley & Sons, Ltd.
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    41. 41
      Almeida, R.; Pauling, J. K.; Sokol, E.; Hannibal-Bach, H. K.; Ejsing, C. S. Comprehensive lipidome analysis by shotgun lipidomics on a hybrid quadrupole-orbitrap-linear ion trap mass spectrometer. J. Am. Soc. Mass Spectrom. 2015, 26 (1), 133– 48,  DOI: 10.1007/s13361-014-1013-x
      41
      Comprehensive Lipidome Analysis by Shotgun Lipidomics on a Hybrid Quadrupole-Orbitrap-Linear Ion Trap Mass Spectrometer
      Almeida, Reinaldo; Pauling, Josch Konstantin; Sokol, Elena; Hannibal-Bach, Hans Kristian; Ejsing, Christer S.
      Journal of the American Society for Mass Spectrometry (2015), 26 (1), 133-148CODEN: JAMSEF; ISSN:1044-0305. (Springer)
      Here we report on the application of a novel shotgun lipidomics platform featuring an Orbitrap Fusion mass spectrometer equipped with an automated nanoelectrospray ion source. To assess the performance of the platform for in-depth lipidome anal., we evaluated various instrument parameters, including its high resoln. power unsurpassed by any other contemporary Orbitrap instrumentation, its dynamic quantification range and its efficacy for in-depth structural characterization of mol. lipid species by quadrupole-based higher-energy collisional dissocn. (HCD), and ion trap-based resonant-excitation collision-induced dissocn. (CID). This evaluation demonstrated that FTMS anal. with a resoln. setting of 450,000 allows distinguishing isotopes from different lipid species and features a linear dynamic quantification range of at least four orders of magnitude. Evaluation of fragmentation anal. demonstrated that combined use of HCD and CID yields complementary fragment ions of mol. lipid species. To support global lipidome anal., we designed a method, termed MSALL, featuring high resoln. FTMS anal. for lipid quantification, and FTMS2 anal. using both HCD and CID and ITMS3 anal. utilizing dual CID for in-depth structural characterization of mol. glycerophospholipid species. The performance of the MSALL method was benchmarked in a comparative anal. of mouse cerebellum and hippocampus. This anal. demonstrated extensive lipidome quantification covering 311 lipid species encompassing 20 lipid classes, and identification of 202 distinct mol. glycerophospholipid species when applying a novel high confidence filtering strategy. The work presented here validates the performance of the Orbitrap Fusion mass spectrometer for in-depth lipidome anal.
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    42. 42
      Simons, B.; Kauhanen, D.; Sylvanne, T.; Tarasov, K.; Duchoslav, E.; Ekroos, K. Shotgun Lipidomics by Sequential Precursor Ion Fragmentation on a Hybrid Quadrupole Time-of-Flight Mass Spectrometer. Metabolites 2012, 2 (1), 195– 213,  DOI: 10.3390/metabo2010195
      42
      Shotgun lipidomics by sequential precursor ion fragmentation on a hybrid quadrupole time-of-flight mass spectrometer
      Simons, Brigitte; Kauhanen, Dimple; Sylvanne, Tuulia; Tarasov, Kirill; Duchoslav, Eva; Ekroos, Kim
      Metabolites (2012), 2 (1), 195-213CODEN: METALU; ISSN:2218-1989. (MDPI AG)
      Shotgun lipidomics has evolved into a myriad of multi-dimensional strategies for mol. lipid characterization, including bioinformatics tools for mass spectrum interpretation and quant. measurements to study systems-lipidomics in complex biol. exts. Taking advantage of spectral mass accuracy, scan speed and sensitivity of improved quadrupole linked time-of-flight mass analyzers, we developed a bias-free global lipid profiling acquisition technique of sequential precursor ion fragmentation called MS/MSALL. This generic information-independent tandem mass spectrometry (MS) technique consists of a Q1 stepped mass isolation window through a set mass range in small increments, fragmenting and recording all product ions and neutral losses. Through the accurate MS and MS/MS information, the mol. lipid species are resolved, including distinction of isobaric and isomeric species, and composed into more precise lipidomic outputs. The method demonstrates good reproducibility and at least 3 orders of dynamic quantification range for isomeric ceramides in human plasma. More than 400 mol. lipids in human plasma were uncovered and quantified in less than 12 min, including acquisitions in both pos. and neg. polarity modes. We anticipate that the performance of sequential precursor ion fragmentation both in quality and throughput will lead to the uncovering of new avenues throughout the biomedical research community, enhance biomarker discovery and provide novel information target discovery programs as it will prospectively shed new insight into affected metabolic and signaling pathways.
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    43. 43
      Velickovic, D.; Chu, R. K.; Carrell, A. A.; Thomas, M.; Pasa-Tolic, L.; Weston, D. J.; Anderton, C. R. Multimodal MSI in Conjunction with Broad Coverage Spatially Resolved MS(2) Increases Confidence in Both Molecular Identification and Localization. Anal. Chem. 2018, 90 (1), 702– 707,  DOI: 10.1021/acs.analchem.7b04319
      43
      Multimodal MSI in Conjunction with Broad Coverage Spatially Resolved MS2 Increases Confidence in Both Molecular Identification and Localization
      Velickovic, Dusan; Chu, Rosalie K.; Carrell, Alyssa A.; Thomas, Mathew; Pasa-Tolic, Ljiljana; Weston, David J.; Anderton, Christopher R.
      Analytical Chemistry (Washington, DC, United States) (2018), 90 (1), 702-707CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      One crit. aspect of mass spectrometry imaging (MSI) is the need to confidently identify detected analytes. While orthogonal tandem MS (e.g., LC-MS2) expts. from sample exts. can assist in annotating ions, the spatial information about these mols. is lost. Accordingly, this could cause mislead conclusions, esp. in cases where isobaric species exhibit different distributions within a sample. In this Tech. Note, the authors employed a multimodal imaging approach, using matrix assisted laser desorption/ionization (MALDI)-MSI and liq. extn. surface anal. (LESA)-MS2I, to confidently annotate and localize a broad range of metabolites involved in a tripartite symbiosis system of moss, cyanobacteria, and fungus. The authors found that the combination of these two imaging modalities generated very congruent ion images, providing the link between highly accurate structural information offered by LESA and high spatial resoln. attainable by MALDI. These results demonstrate how this combined methodol. could be very useful in differentiating metabolite routes in complex systems.
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    44. 44
      Spraggins, J. M.; Rizzo, D. G.; Moore, J. L.; Rose, K. L.; Hammer, N. D.; Skaar, E. P.; Caprioli, R. M. MALDI FTICR IMS of Intact Proteins: Using Mass Accuracy to Link Protein Images with Proteomics Data. J. Am. Soc. Mass Spectrom. 2015, 26 (6), 974– 85,  DOI: 10.1007/s13361-015-1147-5
      44
      MALDI FTICR IMS of Intact Proteins: Using Mass Accuracy to Link Protein Images with Proteomics Data
      Spraggins, Jeffrey M.; Rizzo, David G.; Moore, Jessica L.; Rose, Kristie L.; Hammer, Neal D.; Skaar, Eric P.; Caprioli, Richard M.
      Journal of the American Society for Mass Spectrometry (2015), 26 (6), 974-985CODEN: JAMSEF; ISSN:1044-0305. (Springer)
      MALDI imaging mass spectrometry is a highly sensitive and selective tool used to visualize biomols. in tissue. However, identification of detected proteins remains a difficult task. Indirect identification strategies have been limited by insufficient mass accuracy to confidently link ion images to proteomics data. Here, we demonstrate the capabilities of MALDI FTICR MS for imaging intact proteins. MALDI FTICR IMS provides an unprecedented combination of mass resolving power (∼75,000 at m/z 5000) and accuracy (<5ppm) for proteins up to ∼12kDa, enabling identification based on correlation with LC-MS/MS proteomics data. Anal. of rat brain tissue was performed as a proof-of-concept highlighting the capabilities of this approach by imaging and identifying a no. of proteins including N-terminally acetylated thymosin β4 (m/z 4963.502, 0.6ppm) and ATP synthase subunit ε (m/z 5636.074, -2.3ppm). MALDI FTICR IMS was also used to differentiate a series of oxidn. products of S100A8 (m/z 10,164.03, -2.1ppm), a subunit of the heterodimer calprotectin, in kidney tissue from mice infected with Staphylococcus aureus. S100A8 - M37O/C42O3 (m/z 10228.00, -2.6ppm) was found to colocalize with bacterial microcolonies at the center of infectious foci. The ability of MALDI FTICR IMS to distinguish S100A8 modifications is crit. to understanding calprotectin's roll in nutritional immunity.
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    45. 45
      Hendrickson, C. L.; Beu, S. C.; Blakney, G. T.; Kaiser, N. K.; McIntosh, D. G.; Quinn, J. P.; Marshall, A. G. In Optimized cell geometry for Fourier transform ion cyclotron resonance mass spectrometry, Proceedings of the 57th ASMS Conference on Mass Spectrometry and Allied Topics, Philadelphia, PA, May 31 to June 4; Philadelphia, PA, 2009.
      There is no corresponding record for this reference.
    46. 46
      Chen, T.; Beu, S. C.; Kaiser, N. K.; Hendrickson, C. L. Note: Optimized circuit for excitation and detection with one pair of electrodes for improved Fourier transform ion cyclotron resonance mass spectrometry. Rev. Sci. Instrum. 2014, 85 (6), 066107,  DOI: 10.1063/1.4883179
      46
      Note: Optimized circuit for excitation and detection with one pair of electrodes for improved Fourier transform ion cyclotron resonance mass spectrometry
      Chen, T.; Beu, S. C.; Kaiser, N. K.; Hendrickson, C. L.
      Review of Scientific Instruments (2014), 85 (6), 066107/1-066107/3CODEN: RSINAK; ISSN:0034-6748. (American Institute of Physics)
      A conventional Fourier transform-Ion Cyclotron Resonance (ICR) detection cell is azimuthally divided into four equal sections. One pair of opposed electrodes is used for ion cyclotron excitation, and the other pair for ion image charge detection. In this work, we demonstrate that an appropriate elec. circuit facilitates excitation and detection on one pair of opposed electrodes. The new scheme can be used to minimize the no. of elec. independent ICR cell electrodes and/or improve the electrode geometry for simultaneously increased ICR signal magnitude and optimal post-excitation radius, which results in higher signal-to-noise ratio and decreased space-charge effects. (c) 2014 American Institute of Physics.
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    47. 47
      Belov, M. E.; Ellis, S. R.; Dilillo, M.; Paine, M. R. L.; Danielson, W. F.; Anderson, G. A.; de Graaf, E. L.; Eijkel, G. B.; Heeren, R. M. A.; McDonnell, L. A. Design and Performance of a Novel Interface for Combined Matrix-Assisted Laser Desorption Ionization at Elevated Pressure and Electrospray Ionization with Orbitrap Mass Spectrometry. Anal. Chem. 2017, 89 (14), 7493– 7501,  DOI: 10.1021/acs.analchem.7b01168
      47
      Design and Performance of a Novel Interface for Combined Matrix-Assisted Laser Desorption Ionization at Elevated Pressure and Electrospray Ionization with Orbitrap Mass Spectrometry
      Belov, Mikhail E.; Ellis, Shane R.; Dilillo, Marialaura; Paine, Martin R. L.; Danielson, William F.; Anderson, Gordon A.; de Graaf, Erik L.; Eijkel, Gert B.; Heeren, Ron M. A.; McDonnell, Liam A.
      Analytical Chemistry (Washington, DC, United States) (2017), 89 (14), 7493-7501CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Matrix-Assisted Laser Desorption Ionization, MALDI, has been increasingly used in a variety of biomedical applications, including tissue imaging of clin. tissue samples, and in drug discovery and development. These studies strongly depend on the performance of the anal. instrumentation and would drastically benefit from improved sensitivity, reproducibility, and mass/spatial resoln. In this work, we report on a novel combined MALDI/ESI interface, which was coupled to different Orbitrap mass spectrometers (Elite and Q Exactive Plus) and extensively characterized with peptide and protein stds., and in tissue imaging expts. In our approach, MALDI is performed in the elevated pressure regime (5-8 Torr) at a spatial resoln. of 15-30 μm, while ESI-generated ions are injected orthogonally to the interface axis. We have found that introduction of the MALDI-generated ions into an electrodynamic dual-funnel interface results in increased sensitivity characterized by a limit of detection of ∼400 zmol, while providing a mass measurement accuracy of 1 ppm and a mass resolving power of 120 000 in anal. of protein digests. In tissue imaging expts., the MALDI/ESI interface has been employed in expts. with rat brain sections and was shown to be capable of visualizing and spatially characterizing very low abundance analytes sepd. only by 20 mDa. Comparison of imaging data has revealed excellent agreement between the MALDI and histol. images.
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    48. 48
      Blakney, G. T.; Hendrickson, C. L.; Marshall, A. G. Predator data station: A fast data acquisition system for advanced FT-ICR MS experiments. Int. J. Mass Spectrom. 2011, 306 (2–3), 246– 252,  DOI: 10.1016/j.ijms.2011.03.009
      48
      Predator data station: A fast data acquisition system for advanced FT-ICR MS experiments
      Blakney, Greg T.; Hendrickson, Christopher L.; Marshall, Alan G.
      International Journal of Mass Spectrometry (2011), 306 (2-3), 246-252CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)
      Presented is the Predator data station, a control system for FT-ICR mass spectrometers that champions speed and exptl. flexibility while simultaneously providing stability, ease of use, and the ability to integrate more advanced hardware as it becomes available. The Predator is the first FT-ICR MS data station comprised solely of fast PCI, PXI, and yet faster PXI Express-based com. data acquisition hardware. Increased data transfer speed is required because recorded transient data count increases linearly at higher magnetic field (higher measured frequency) with extended transient duration for FT-ICR MS instruments. The application of new cell designs with addnl. compensation voltages, exptl. techniques to increase resoln., and exptl. techniques that minimize/reject variations in ion abundance exemplify the scope of recent Predator data station implementations. When the above techniques are applied simultaneously, the results give rise to sub-30 ppb rms mass error for 5250 assigned peaks in a petroleum FT-ICR mass spectrum. The Predator data station is designed for facile implementation with any FT-ICR MS instrument. The Predator hardware provides 17 analog voltage outputs and 18 digital TTL outputs synchronized to a single timing source. SWIFT, chirp, and single frequency excitation waveforms are generated by a 100 MSample/s arbitrary waveform generator with a min. 32 MB of onboard memory and the potential of terabytes of virtual memory via first in-first out (FIFO) buffering. Transient detection is facilitated by a 2-channel, 100 MSample/s digitizer with a min. of 32 MB of onboard memory per channel. FIFO buffering implementation allows TB transient collection as well. Com. hardware, royalty-free software solns., and com. produced custom printed circuit boards (PCB) for the cell controller ensure open availability. The present data complement numerous extant publications: the Predator data station was the sole data station for the National High Magnetic Field Lab. (NHMFL) 9.4 T FT-ICR MS instrument since July 2004, and several addnl. Predator data stations are in operation elsewhere.
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    49. 49
      Xian, F.; Hendrickson, C. L.; Blakney, G. T.; Beu, S. C.; Marshall, A. G. Automated broadband phase correction of Fourier transform ion cyclotron resonance mass spectra. Anal. Chem. 2010, 82 (21), 8807– 12,  DOI: 10.1021/ac101091w
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      Automated Broadband Phase Correction of Fourier Transform Ion Cyclotron Resonance Mass Spectra
      Xian, Feng; Hendrickson, Christopher L.; Blakney, Greg T.; Beu, Steven C.; Marshall, Alan G.
      Analytical Chemistry (Washington, DC, United States) (2010), 82 (21), 8807-8812CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      It was known for 35 years that phase correction of FTICR data can in principle produce an absorption-mode spectrum with mass resolving power as much as a factor of 2 higher than conventional magnitude-mode display, an improvement otherwise requiring a (much more expensive) increase in magnetic field strength. However, temporally dispersed excitation followed by time-delayed detection results in steep quadratic variation of signal phase with frequency. Here, the authors present a robust, rapid, automated method to enable accurate broadband phase correction for all peaks in the mass spectrum. Low-pass digital filtering effectively eliminates the accompanying baseline roll. Exptl. FTICR absorption-mode mass spectra exhibit at least 40% higher resolving power (and thus an increased no. of resolved peaks) as well as higher mass accuracy relative to magnitude mode spectra, for more complete and more reliable elemental compn. assignments for mixts. as complex as petroleum.
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    50. 50
      Chambers, M. C.; Maclean, B.; Burke, R.; Amodei, D.; Ruderman, D. L.; Neumann, S.; Gatto, L.; Fischer, B.; Pratt, B.; Egertson, J.; Hoff, K.; Kessner, D.; Tasman, N.; Shulman, N.; Frewen, B.; Baker, T. A.; Brusniak, M. Y.; Paulse, C.; Creasy, D.; Flashner, L.; Kani, K.; Moulding, C.; Seymour, S. L.; Nuwaysir, L. M.; Lefebvre, B.; Kuhlmann, F.; Roark, J.; Rainer, P.; Detlev, S.; Hemenway, T.; Huhmer, A.; Langridge, J.; Connolly, B.; Chadick, T.; Holly, K.; Eckels, J.; Deutsch, E. W.; Moritz, R. L.; Katz, J. E.; Agus, D. B.; MacCoss, M.; Tabb, D. L.; Mallick, P. A cross-platform toolkit for mass spectrometry and proteomics. Nat. Biotechnol. 2012, 30 (10), 918– 20,  DOI: 10.1038/nbt.2377
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      A cross-platform toolkit for mass spectrometry and proteomics
      Chambers, Matthew C.; MacLean, Brendan; Burke, Robert; Amodei, Dario; Ruderman, Daniel L.; Neumann, Steffen; Gatto, Laurent; Fischer, Bernd; Pratt, Brian; Egertson, Jarrett; Hoff, Katherine; Kessner, Darren; Tasman, Natalie; Shulman, Nicholas; Frewen, Barbara; Baker, Tahmina A.; Brusniak, Mi-Youn; Paulse, Christopher; Creasy, David; Flashner, Lisa; Kani, Kian; Moulding, Chris; Seymour, Sean L.; Nuwaysir, Lydia M.; Lefebvre, Brent; Kuhlmann, Frank; Roark, Joe; Rainer, Paape; Detlev, Suckau; Hemenway, Tina; Huhmer, Andreas; Langridge, James; Connolly, Brian; Chadick, Trey; Holly, Krisztina; Eckels, Josh; Deutsch, Eric W.; Moritz, Robert L.; Katz, Jonathan E.; Agus, David B.; MacCoss, Michael; Tabb, David L.; Mallick, Parag
      Nature Biotechnology (2012), 30 (10), 918-920CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      Mass spectrometry-based proteomics has become an important component of biol. research. There have been several calls for improvements and standardization of proteomics data anal. frameworks, as well as for an application programming interface for proteomics data access. In response, ProteoWizard Toolkit was developed, a robust set of opensource, software libraries and applications designed to facilitate proteomics research. With version 3.0 of the ProteoWizard Toolkit8, the challenges in the field can be mitigated through open-source, permissively licensed, cross-platform software. The Toolkit has two components: first, a suite of libraries that facilitate the development and comparison of tools for proteomics data anal. and second, a set of tools, developed using these libraries, that performs a wide array of common proteomics analyses. ProteoWizard is built upon a modular framework of many independent libraries grouped in dependency levels.
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    51. 51
      Race, A. M.; Styles, I. B.; Bunch, J. Inclusive sharing of mass spectrometry imaging data requires a converter for all. J. Proteomics 2012, 75 (16), 5111– 2,  DOI: 10.1016/j.jprot.2012.05.035
      51
      Inclusive sharing of mass spectrometry imaging data requires a converter for all
      Race, Alan M.; Styles, Iain B.; Bunch, Josephine
      Journal of Proteomics (2012), 75 (16), 5111-5112CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)
      With continued efforts towards a single MSI data format, data conversion routines must be made universally available. The benefits of a common imaging format, imzML, are slowly becoming more widely appreciated but the format remains to be used by only a small proportion of imaging groups. Increased awareness amongst researchers and continued support from major MS vendors in providing tools for converting proprietary formats into imzML are likely to result in a rapidly increasing uptake of the format. It is important that this does not lead to the exclusion of researchers using older or unsupported instruments. We describe an open source converter, imzMLConverter, to ensure against this. We propose that proprietary formats should first be converted to mzML using one of the widely available converters, such as msconvert and then use imzMLConverter to convert mzML to imzML. This will allow a wider audience to benefit from the imzML format immediately.This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biol. and Biomedical Research.
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    52. 52
      Husen, P.; Tarasov, K.; Katafiasz, M.; Sokol, E.; Vogt, J.; Baumgart, J.; Nitsch, R.; Ekroos, K.; Ejsing, C. S. Analysis of lipid experiments (ALEX): a software framework for analysis of high-resolution shotgun lipidomics data. PLoS One 2013, 8 (11), e79736  DOI: 10.1371/journal.pone.0079736
      52
      Analysis of Lipid Experiments (ALEX): a software framework for analysis of high-resolution shotgun lipidomics data
      Husen, Peter; Tarasov, Kirill; Katafiasz, Maciej; Sokol, Elena; Vogt, Johannes; Baumgart, Jan; Nitsch, Robert; Ekroos, Kim; Ejsing, Christer S.
      PLoS One (2013), 8 (11), e79736CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Global lipidomics anal. across large sample sizes produces high-content datasets that require dedicated software tools supporting lipid identification and quantification, efficient data management and lipidome visualization. Here we present a novel software-based platform for streamlined data processing, management and visualization of shotgun lipidomics data acquired using high-resoln. Orbitrap mass spectrometry. The platform features the ALEX framework designed for automated identification and export of lipid species intensity directly from proprietary mass spectral data files, and an auxiliary workflow using database exploration tools for integration of sample information, computation of lipid abundance and lipidome visualization. A key feature of the platform is the organization of lipidomics data in "database table format" which provides the user with an unsurpassed flexibility for rapid lipidome navigation using selected features within the dataset. To demonstrate the efficacy of the platform, we present a comparative neurolipidomics study of cerebellum, hippocampus and somatosensory barrel cortex (S1BF) from wild-type and knockout mice devoid of the putative lipid phosphate phosphatase PRG-1 (plasticity related gene-1). The presented framework is generic, extendable to processing and integration of other lipidomic data structures, can be interfaced with post-processing protocols supporting statistical testing and multivariate anal., and can serve as an avenue for disseminating lipidomics data within the scientific community. The ALEX software is available at online.
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    53. 53
      Spraggins, J. M.; Djambazova, K. V.; Rivera, E. S.; Migas, L. G.; Neumann, E. K.; Fuetterer, A.; Suetering, J.; Goedecke, N.; Ly, A.; Van de Plas, R.; Caprioli, R. M. High-Performance Molecular Imaging with MALDI Trapped Ion-Mobility Time-of-Flight (timsTOF) Mass Spectrometry. Anal. Chem. 2019, 91 (22), 14552– 14560,  DOI: 10.1021/acs.analchem.9b03612
      53
      High-Performance Molecular Imaging with MALDI Trapped Ion-Mobility Time-of-Flight (timsTOF) Mass Spectrometry
      Spraggins, Jeffrey M.; Djambazova, Katerina V.; Rivera, Emilio S.; Migas, Lukasz G.; Neumann, Elizabeth K.; Fuetterer, Arne; Suetering, Juergen; Goedecke, Niels; Ly, Alice; Van de Plas, Raf; Caprioli, Richard M.
      Analytical Chemistry (Washington, DC, United States) (2019), 91 (22), 14552-14560CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Imaging mass spectrometry (IMS) enables the spatially targeted mol. assessment of biol. tissues at cellular resolns. New developments and technologies are essential for uncovering the mol. drivers of native physiol. function and disease. Instrumentation must maximize spatial resoln., throughput, sensitivity, and specificity, because tissue imaging expts. consist of thousands to millions of pixels. Here, the authors report the development and application of a matrix-assisted laser desorption/ionization (MALDI) trapped ion mobility spectrometry imaging platform. This prototype MALDI timsTOF instrument is capable of 10 μm spatial resolns. and 20 pixels/s throughput mol. imaging. The MALDI source utilizes a Bruker SmartBeam 3-D laser system that can generate a square burn pattern of <10 × 10 μm at the sample surface. General image performance was assessed using murine kidney and brain tissues and demonstrate that high spatial resoln. imaging data can be generated rapidly with mass measurement errors < 5 ppm and ∼40,000 resolving power. Initial TIMS-based imaging expts. were performed on whole body mouse pup tissue demonstrating the sepn. of closely isobaric [PC(32:0)+Na]+ and [PC(34:3)+H]+ (3 mDa mass difference) in the gas-phase. The authors have shown that the MALDI timsTOF platform can maintain reasonable data acquisition rates (>2 pixels/s) while providing the specificity necessary to differentiate components in complex mixts. of lipid adducts. The combination of high spatial resoln. and throughput imaging capabilities with high-performance TIMS sepns. provides a uniquely tunable platform to address many challenges assocd. with advanced mol. imaging applications.
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    54. 54
      Campos, A. M.; Maciel, E.; Moreira, A. S.; Sousa, B.; Melo, T.; Domingues, P.; Curado, L.; Antunes, B.; Domingues, M. R.; Santos, F. Lipidomics of Mesenchymal Stromal Cells: Understanding the Adaptation of Phospholipid Profile in Response to Pro-Inflammatory Cytokines. J. Cell. Physiol. 2016, 231 (5), 1024– 32,  DOI: 10.1002/jcp.25191
      54
      Lipidomics of Mesenchymal Stromal Cells: Understanding the Adaptation of Phospholipid Profile in Response to Pro-Inflammatory Cytokines
      Campos, Ana Margarida; Maciel, Elisabete; Moreira, Ana S. P.; Sousa, Bebiana; Melo, Tania; Domingues, Pedro; Curado, Liliana; Antunes, Brigida; Domingues, M. Rosario M.; Santos, Francisco
      Journal of Cellular Physiology (2016), 231 (5), 1024-1032CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
      Mesenchymal stromal cells (MSCs) present anti-inflammatory properties and are being used with great success as treatment for inflammatory and autoimmune diseases. In clin. applications MSCs are subjected to a strong pro-inflammatory environment, essential to their immunosuppressive action. Despite the wide clin. use of these cells, how MSCs exert their effect remains unclear. Several lipids are known to be involved in cell's signaling and modulation of cellular functions. The aim of this paper is to examine the variation in lipid profile of MSCs under pro-inflammatory environment, induced by the presence of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), using the most modern lipidomic approach. Major changes in lipid mol. profile of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), lysoPC (LPC), and sphingomyelin (SM) classes were found. No changes were obsd. in the phosphatidylinositol (PI) profile. The levels of PC species with shorter fatty acids (FAs), mainly C16:0, decreased under pro-inflammatory stimuli. The level of PC(40:6) also decreased, which may be correlated with enhanced levels of LPC(18:0), which is known to be an anti-inflammatory LPC, obsd. in MSCs subjected to TNF-α and IFN-γ. Simultaneously, the relative amts. of PC(36:1) and PC(38:4) increased. TNF-α and IFN-γ also enhanced the levels of PE(40:6) and decreased the levels of PE(O-38:6). Higher expression of PS(36:1) and SM(34:0) along with a decrease in PS(38:6) levels were obsd. These results indicate that lipid metab. and signaling are modulated during MSCs activation, which suggests that lipids may be involved in MSCs functional and anti-inflammatory activities. J. Cell. Physiol. 9999: 1-9, 2015. © 2015 Wiley Periodicals, Inc.
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    55. 55
      Guo, S.; Wang, Y.; Zhou, D.; Li, Z. Significantly increased monounsaturated lipids relative to polyunsaturated lipids in six types of cancer microenvironment are observed by mass spectrometry imaging. Sci. Rep. 2015, 4, 5959,  DOI: 10.1038/srep05959
      There is no corresponding record for this reference.
    56. 56
      Ide, Y.; Waki, M.; Hayasaka, T.; Nishio, T.; Morita, Y.; Tanaka, H.; Sasaki, T.; Koizumi, K.; Matsunuma, R.; Hosokawa, Y.; Ogura, H.; Shiiya, N.; Setou, M. Human breast cancer tissues contain abundant phosphatidylcholine(36ratio1) with high stearoyl-CoA desaturase-1 expression. PLoS One 2013, 8 (4), e61204  DOI: 10.1371/journal.pone.0061204
      56
      Human breast cancer tissues contain abundant phosphatidylcholine(36:1) with high stearoyl-CoA desaturase-1 expression
      Ide, Yoshimi; Waki, Michihiko; Hayasaka, Takahiro; Nishio, Tomohisa; Morita, Yoshifumi; Tanaka, Hiroki; Sasaki, Takeshi; Koizumi, Kei; Matsunuma, Ryoichi; Hosokawa, Yuko; Ogura, Hiroyuki; Shiiya, Norihiko; Setou, Mitsutoshi
      PLoS One (2013), 8 (4), e61204CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Breast cancer is the leading cause of cancer and mortality in women worldwide. Recent studies have argued that there is a close relationship between lipid synthesis and cancer progression because some enzymes related to lipid synthesis are overexpressed in breast cancer tissues. However, lipid distribution in breast cancer tissues has not been investigated. We aimed to visualize phosphatidylcholines (PCs) and lysoPCs (LPCs) in human breast cancer tissues by performing matrix assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), which is a novel technique that enables the visualization of mols. comprehensively. Twenty-nine breast tissue samples were obtained during surgery and subjected to MALDI-IMS anal. We evaluated the heterogeneity of the distribution of PCs and LPCs on the tissues. Three species [PC(32:1), PC(34:1), and PC(36:1)] of PCs with 1 mono-unsatd. fatty acid chain and 1 satd. fatty acid chain (MUFA-PCs) and one [PC(34:0)] of PCs with 2 satd. fatty acid chains (SFA-PC) were relatively localized in cancerous areas rather than the rest of the sections (named ref. area). In addn., the LPCs did not show any biased distribution. The relative amts. of PC(36:1) compared to PC(36:0) and that of PC(36:1) to LPC(18:0) were significantly higher in the cancerous areas. The protein expression of stearoyl-CoA desaturase-1 (SCD1), which is a synthetic enzyme of MUFA, showed accumulation in the cancerous areas as obsd. by the results of immunohistochem. staining. The ratios were further analyzed considering the differences in expressions of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and Ki67. The ratios of the signal intensity of PC(36:1) to that of PC(36:0) was higher in the lesions with pos. ER expression. The contribution of SCD1 and other enzymes to the formation of the obsd. phospholipid compn. is discussed.
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    57. 57
      Harbige, L. S.; Sharief, M. K. Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis. Br. J. Nutr. 2007, 98 (Suppl 1), S46– 53,  DOI: 10.1017/S0007114507833010
      57
      Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis
      Harbige, Laurence S.; Sharief, Mohammad K.
      British Journal of Nutrition (2007), 98 (Suppl. 1), S46-S53CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
      A review. Epidemiol., biochem., animal model and clin. trial data described in this overview strongly suggest that polyunsatd. fatty acids, particularly n-6 fatty acids, have a role in the pathogenesis and treatment of multiple sclerosis (MS). Data presented provides further evidence for a disturbance in n-6 fatty acid metab. in MS. Disturbance of n-6 fatty acid metab. and dysregulation of cytokines are shown to be linked and a "proof of concept clin. trial" further supports such a hypothesis. In a randomized double-blind, placebo controlled trial of a high dose and low dose selected GLA (18:3n-6)-rich oil and placebo control, the high dose had a marked clin. effect in relapsing-remitting MS, significantly decreasing the relapse rate and the progression of disease. Lab. findings paralleled clin. changes in the placebo group in that prodn. of mononuclear cell pro-inflammatory cytokines (TNF-α, IL-1β) was increased and anti-inflammatory TGF-β markedly decreased with loss of membrane n-6 fatty acids linoleic (18:2n-6) and arachidonic acids (20:4n-6). In contrast there were no such changes in the high dose group. The improvement in disability (Expanded Disability Status Scale) in the high dose suggests there maybe a beneficial effect on neuronal lipids and neural function in MS. Thus disturbed n-6 fatty acid metab. in MS gives rise to loss of membrane long chain n-6 fatty acids and loss of the anti-inflammatory regulatory cytokine TGF-β, particularly during the relapse phase, as well as loss of these important neural fatty acids for CNS structure and function and consequent long term neurol. deficit in MS.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlGmtr%252FK&md5=b47bca0196f26d59eaf78d1b857e9eb7
    58. 58
      Vance, J. E.; Tasseva, G. Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831 (3), 543– 54,  DOI: 10.1016/j.bbalip.2012.08.016
      58
      Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells
      Vance, Jean E.; Tasseva, Guergana
      Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2013), 1831 (3), 543-554CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
      A review. Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are metabolically related membrane aminophospholipids. In mammalian cells, PS is required for targeting and function of several intracellular signaling proteins. Moreover, PS is asym. distributed in the plasma membrane. Although PS is highly enriched in the cytoplasmic leaflet of plasma membranes, PS exposure on the cell surface initiates blood clotting and removal of apoptotic cells. PS is synthesized in mammalian cells by two distinct PS synthases that exchange serine for choline or ethanolamine in phosphatidylcholine (PC) or PE, resp. Targeted disruption of each PS synthase individually in mice demonstrated that neither enzyme is required for viability whereas elimination of both synthases was embryonic lethal. Thus, mammalian cells require a threshold amt. of PS. PE is synthesized in mammalian cells by four different pathways, the quant. most important of which are the CDP-ethanolamine pathway that produces PE in the ER, and PS decarboxylation that occurs in mitochondria. PS is made in ER membranes and is imported into mitochondria for decarboxylation to PE via a domain of the ER [mitochondria-assocd. membranes (MAM)] that transiently assocs. with mitochondria. Elimination of PS decarboxylase in mice caused mitochondrial defects and embryonic lethality. Global elimination of the CDP-ethanolamine pathway was also incompatible with mouse survival. Thus, PE made by each of these pathways has independent and necessary functions. In mammals PE is a substrate for methylation to PC in the liver, a substrate for anandamide synthesis, and supplies ethanolamine for glycosylphosphatidylinositol anchors of cell-surface signaling proteins. Thus, PS and PE participate in many previously unanticipated facets of mammalian cell biol. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metab.
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    59. 59
      Kim, W. S.; Weickert, C. S.; Garner, B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J. Neurochem. 2008, 104 (5), 1145– 66,  DOI: 10.1111/j.1471-4159.2007.05099.x
      59
      Role of ATP-binding cassette transporters in brain lipid transport and neurological disease
      Kim, Woojin Scott; Weickert, Cynthia Shannon; Garner, Brett
      Journal of Neurochemistry (2008), 104 (5), 1145-1166CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
      A review. The brain is lipid-rich compared to other organs and although previous studies have highlighted the importance of ATP-binding cassette (ABC) transporters in the regulation of lipid transport across membranes in peripheral tissues, very little is known regarding ABC transporter function in the CNS. In this study, we bring together recent literature focusing on potential roles for ABC transporters in brain lipid transport and, where appropriate, identify possible links between ABC transporters, lipid transport and neurol. disease. Of the 48 transcriptionally active ABC transporters in the human genome, we have focused on 13 transporters (ABCA1, ABCA2, ABCA3, ABCA4, ABCA7 and ABCA8; ABCB1 and ABCB4; ABCD1 and ABCD2; ABCG1, ABCG2, and ABCG4) for which there is evidence suggesting they may contribute in some way to brain lipid transport or homeostasis. The transporters are discussed in terms of their location within brain regions and brain cell types and, where possible, in terms of their known functions and established or proposed assocn. with human neurol. diseases. Specific examples of novel treatment strategies for diseases, such as Alzheimer's disease and X-linked adrenoleukodystrophy that are based on modulation of ABC transporter function are discussed and we also examine possible functions for specific ABC transporters in human brain development.
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    60. 60
      Smith, D. F.; Kharchenko, A.; Konijnenburg, M.; Klinkert, I.; Pasa-Tolic, L.; Heeren, R. M. Advanced mass calibration and visualization for FT-ICR mass spectrometry imaging. J. Am. Soc. Mass Spectrom. 2012, 23 (11), 1865– 72,  DOI: 10.1007/s13361-012-0464-1
      60
      Advanced Mass Calibration and Visualization for FT-ICR Mass Spectrometry Imaging
      Smith, Donald F.; Kharchenko, Andriy; Konijnenburg, Marco; Klinkert, Ivo; Pasa-Tolic, Ljiljana; Heeren, Ron M. A.
      Journal of the American Society for Mass Spectrometry (2012), 23 (11), 1865-1872CODEN: JAMSEF; ISSN:1044-0305. (Springer)
      Mass spectrometry imaging by Fourier transform ion cyclotron resonance (FT-ICR) yields hundreds of unique peaks, many of which cannot be resolved by lower performance mass spectrometers. The high mass accuracy and high mass resolving power allow confident identification of small mols. and lipids directly from biol. tissue sections. Here, calibration strategies for FT-ICR MS imaging were investigated. Sub-parts-per-million mass accuracy is demonstrated over an entire tissue section. Ion abundance fluctuations are cor. by addn. of total and relative ion abundances for a root-mean-square error of 0.158 ppm on 16,764 peaks. A new approach for visualization of FT-ICR MS imaging data at high resoln. is presented. The "Mosaic Datacube" provides a flexible means to visualize the entire mass range at a mass spectral bin width of 0.001 Da. The high resoln. Mosaic Datacube resolves spectral features not visible at lower bin widths, while retaining the high mass accuracy from the calibration methods discussed.
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    61. 61
      Estrada, R.; Yappert, M. C. Alternative approaches for the detection of various phospholipid classes by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J. Mass Spectrom. 2004, 39 (4), 412– 22,  DOI: 10.1002/jms.603
      61
      Alternative approaches for the detection of various phospholipid classes by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
      Estrada, Rosendo; Yappert, M. Cecilia
      Journal of Mass Spectrometry (2004), 39 (4), 412-422CODEN: JMSPFJ; ISSN:1076-5174. (John Wiley & Sons Ltd.)
      The detection of phospholipids (PLs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was demonstrated nearly a decade ago. However, its use as a conventional tool for PL anal. has been hindered by ambiguities in peak assignments caused by spectral overlaps and difficulties in the detection of some PL classes when analytes with pos. charged head groups, such as sphingomyelins (SMs) and phosphatidylcholines (PCs) are present. In this work, either a strong cation-exchange resin or CsCl crystals were added directly to the PL samples to reduce spectral complexity and enhance sensitivity. The quant. exchange resulted in virtually only protonated or Cs+ adducts. To alleviate difficulties in the detection and identification of PL classes with ionization efficiencies lower than those of SMs and PCs, improvements in the sensitivity of neg.-ion mass spectra were sought. For this purpose, several neutral and basic matrixes were tried. Among them, p-nitroaniline (PNA) proved to be an advantageous alternative to the use of 2,5-dihydroxybenzoic acid (DHB), the most commonly used matrix in PL anal. Because of its lower acidity, PNA increased the relative amt. of deprotonated species and improved the sensitivity of neg.-ion mass spectra. It was possible to confirm peak assignments for PL classes that normally give weak signals when DHB is used. Noteworthy is the detection (in both pos. and neg. modes) and conclusive identification of species in natural mixts. of phosphatidylethanolamines (PEs) and PE plasmalogens (PEps). PNA allowed the identification of PEs and PEps even in mixts. contg. SMs and PCs. Although some cations related to PCs and PEs overlapped in pos.-ion spectra, these interferences were eliminated in the neg. mode as only the deprotonated forms of PEs and PEps were detectable and those of SMs and PCs were absent owing to their neutrality.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtlKrur8%253D&md5=e87c9ff1214e4151deb5e3f2cdf4c8aa
    62. 62
      Fuchs, B.; Schiller, J.; Suss, R.; Schurenberg, M.; Suckau, D. A direct and simple method of coupling matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) to thin-layer chromatography (TLC) for the analysis of phospholipids from egg yolk. Anal. Bioanal. Chem. 2007, 389 (3), 827– 34,  DOI: 10.1007/s00216-007-1488-4
      62
      A direct and simple method of coupling matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) to thin-layer chromatography (TLC) for the analysis of phospholipids from egg yolk
      Fuchs, Beate; Schiller, Juergen; Suess, Rosmarie; Schuerenberg, Martin; Suckau, Detlev
      Analytical and Bioanalytical Chemistry (2007), 389 (3), 827-834CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      Although the most important application of matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) is "proteomics," there is growing evidence that this soft ionization method is also useful for phospholipid (PL) anal. Although all PLs are detectable by MALDI-TOF MS, some lipid classes, particularly those with quaternary amines such as phosphatidylcholines (PCs), are more sensitively detected than others, and these suppress the signals of less sensitively detected PLs when complex mixts. are analyzed. Therefore, a sepn. of the total org. ext. into individual lipid classes is necessary. As MALDI uses a solid sample, the direct evaluation of thin-layer chromatog. (TLC) plates is possible. The authors report here on a method of directly coupling MALDI-TOF MS and TLC that can be easily implemented on com. available MALDI-TOF devices. A total ext. of hen egg yolk is used as a simple PL mixt. to demonstrate the capabilities of this method. It will be shown that "clean" spectra without any major contributions from fragmentation products and matrix peaks can be obtained, and that this approach is even sensitive enough to detect the presence of PLs at levels of less than 1% of the total ext.
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  • Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.9b04768.

    • Eight additional figures as described in the text and table with a complete list of all tentatively identified lipid species (PDF)


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