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  • 1.
    Bergman, Hilde-Marlene
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Andersson, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Profiling and quantifying endogenous molecules in single cells using nano-DESI MS2017In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 142, no 19, p. 3639-3647Article in journal (Refereed)
    Abstract [en]

    Molecular profiling of single cells has the potential to significantly advance our understanding of cell function and cellular processes of importance to health and disease. In particular, small molecules with rapid turn-over rates can reveal activated metabolic pathways resulting from an altered chemical environment or cellular events such as differentiation. Consequently, techniques for quantitative metabolite detection acquired in a higher throughput manner are needed to characterize the biological variability between seemingly homogenous cells. Here, we show that nanospray desorption electrospray ionization (nano-DESI) mass spectrometry ( MS) enables sensitive molecular profiling and quantification of endogenous species in single cells in a higher throughput manner. Specifically, we show a large number of detected amino acids and phospholipids, including plasmalogens, readily detected from single cheek cells. Further, by incorporating a phosphatidylcholine ( PC) internal standard into the nano-DESI solvent, we determined the total amount of PC in one cell to be 1.2 pmoles. Finally, we describe a higher throughput approach where molecules in single cells are automatically profiled. These developments in single cell analysis provide a basis for future studies to understand cellular processes related to drug effects, cell differentiation and altered chemical microenvironments.

  • 2.
    Carter, Sarah-Sophia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Atif, Abdul
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Lanekoff, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Tenje, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Mestres, Gemma
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Tailoring the biocompatibility of the elastomer PDMS for on-chip applications2018Conference paper (Refereed)
  • 3.
    Carter, Sarah-Sophia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Atif, Abdul Raouf M.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Lanekoff, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Tenje, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Mestres, Gemma
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Improving the biocompatibility of PDMS by improving its curing time and temperature2018Conference paper (Other academic)
  • 4.
    Duncan, Kyle D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergman, Hilde-Marlene
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lanekoff, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    A pneumatically assisted nanospray desorption electrospray ionization source for increased solvent versatility and enhanced metabolite detection from tissue2017In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 142, no 18, p. 3424-3431Article in journal (Refereed)
    Abstract [en]

    Nanospray desorption electrospray ionization (nano-DESI) has been established as a powerful technique for mass spectrometry imaging (MSI) of biomolecules from tissue samples. The direct liquid extraction of analytes from a surface at ambient pressure negates the need for significant sample preparation or matrix application. Although many recent studies have applied nano-DESI to new and exciting applications, there has not been much work in the development and improvement of the nano-DESI source. Here, we incorporate a nebulizer to replace the self-aspirating secondary capillary in the conventional nano-DESI setup, and characterize the device by use of rat kidney tissue sections. We find that the pneumatically assisted nano-DESI device offers improved sensitivity for metabolite species by 1-3 orders of magnitude through more complete desolvation and reduced ionization suppression. Further, the pneumatically assisted nano-DESI device reduces the dependence on probe-to-surface distance and enables sampling and imaging using pure water as the nano-DESI solvent. This provides exclusive detection and imaging of many highly polar endogenous species. Overall, the developed pneumatically assisted nano-DESI device provides more versatile solvent selection and an increased sensitivity for metabolites, which generates ion images of higher contrast - allowing for more intricate studies of metabolite distribution.

  • 5.
    Duncan, Kyle D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Fang, Ru
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Yuan, Jia
    Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA.
    Chu, Rosalie K.
    Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA.
    Dey, Sudhansu K.
    Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA.
    Burnum-Johnson, Kristin E.
    Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA.
    Lanekoff, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Quantitative Mass Spectrometry Imaging of Prostaglandins as Silver Ion Adducts with Nanospray Desorption Electrospray Ionization2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 12, p. 7246-7252Article in journal (Refereed)
    Abstract [en]

    Prostaglandins (PG) are an important class of lipid biomolecules that are essential in many biological processes, including inflammation and successful pregnancy. Despite a high bioactivity, physiological concentrations are typically low, which makes direct mass spectrometric analysis of endogenous PG species challenging. Consequently, there have not been any studies investigating PG localization to specific morphological regions in tissue sections using mass spectrometry imaging (MSI) techniques. Herein, we show that silver ions, added to the solvent used for nanospray desorption electrospray ionization (nano-DESI) MSI, enhances the ionization of PGs and enables nano-DESI MSI of several species in uterine tissue from day 4 pregnant mice. It was found that detection of [PG + Ag](+) ions increased the sensitivity by similar to 30 times, when compared to [PG - H](-) ions. Further, the addition of isotopically labeled internal standards enabled generation of quantitative ion images for the detected PG species. Increased sensitivity and quantitative MSI enabled the first proof-of-principle results detailing PG localization in mouse uterus tissue sections. These results show that PG species primarily localized to cellular regions of the luminal epithelium and glandular epithelium in uterine tissue. Further, this study provides a unique scaffold for future studies investigating the PG distribution within biological tissue samples.

  • 6.
    Duncan, Kyle D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lanekoff, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Oversampling To Improve Spatial Resolution for Liquid Extraction Mass Spectrometry Imaging2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 4, p. 2451-2455Article in journal (Refereed)
    Abstract [en]

    Liquid extraction mass spectrometry imaging (MSI) experiments provide users with direct analysis of biological surfaces with minimal sample preparation. Until now, much of the effort to increase spatial resolution for MSI with liquid extraction techniques has focused on reducing the size of the sampling area. However, this can be experimentally challenging. Here, we present oversampling as a simple alternative to increase the spatial resolution using nanospray desorption electrospray ionization (nano-DESI) MSI. By imaging partial rat spinal cord tissue sections, two major concerns with oversampling are addressed: whether endogenous molecules are significantly depleted from repeated sampling events and whether analytes are redistributed as a result of oversampling. In depth examination of ion images for representative analytes show that depletion and redistribution do not affect analyte localization in the tissue sample. Nano-DESI MSI experiments using three times oversampling provided higher spatial resolution, allowing the observation of features not visible with undersampling. Although proper care must be taken to ensure that oversampling will work in specific applications, we envision oversampling as a simple approach to increase image quality for liquid extraction MSI techniques.

  • 7. Håkansson, P
    et al.
    Andersson, Ingela
    AstraZeneca R&D Mo¨lndal, Discovery, Mo¨lndal, Sweden.
    Nyström, S
    Löfgren, L
    Amrot, L F
    Li, Hong
    Ontogenetic development and spatial distribution of the ileal apical sodium-dependent bile acid transporter and the ileal lipid-binding protein in apoE knockout and C57BL/6 mice2002In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 37, no 9, p. 1089-1096Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although apoE-/- mice are characterized by hypercholesterolemia, the bile acid enterohepatic circulation, which plays a crucial role in cholesterol homeostasis, has not been examined in these mice. The differences between apoE-/- and C57BL/6 mice in expression of the ileal ASBT and ILBP and in intestinal bile acid absorption were studied.

    METHODS: The intestinal tissues of the fetal, neonatal and post-weaning mice were processed for immunohistochemistry. Body retention and fecal excretion of 75SeHCAT were measured. The bile acid pool size and its composition were analysed by HPLC.

    RESULTS: In apoE-/- and C57BL/6 mice, the bile acid pool size was 75 +/- 13 and 78 +/- 13 micromol/ 100 g body weight, respectively, while the ratio of cholic acid/beta-muricholic acid was 1.8 +/- 0.3 and 1.4 +/- 0.3 (P < 0.05), respectively. The daily body retention of 75SeHCAT was 48% = 1.8% in C57 black mice and 58.4% +/- 2.7% in apoE-/- mice (P < 0.05). In both mouse strains, ASBT expression in the small intestine was found in the near-term fetal and post-weaning mice, while ILBP expression was found in all postnatal mice. In the post-weaning mice, ILBP expression was limited to the distal 25%-30% of the small intestine, while ASBT expression was limited to the distal 18%.

    CONCLUSIONS: The bile acid enterohepatic circulation in apoE-/- mice probably does not differ greatly from that in C57BL/6 mice.

  • 8.
    Lanekoff, Ingela
    et al.
    Physical Sciences Division, Pacific Northwest National Laboratory,Richland, WA 99354, USA .
    Burnum-Johnson, Kristin
    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
    Thomas, Mathew
    Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
    Cha, Jeeyeon
    Division of Reproductive Sciences, The Perinatal Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
    Dey, SudhansuK.
    Division of Reproductive Sciences, The Perinatal Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
    Yang, Pengxiang
    Thermo Fisher Scientific, San Jose, CA 95134, USA.
    Prieto Conaway, MariaC.
    Thermo Fisher Scientific, San Jose, CA 95134, USA.
    Laskin, Julia
    Physical Sciences Division, Pacific Northwest National Laboratory,Richland, WA 99354, USA .
    Three-dimensional imaging of lipids and metabolites in tissues by nanospray desorption electrospray ionization mass spectrometry2015In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 407, no 8, p. 2063-2071Article in journal (Refereed)
  • 9. Lanekoff, Ingela
    et al.
    Burnum-Johnson, Kristin
    Thomas, Mathew
    Short, Joshua
    Carson, James P
    Cha, Jeeyeon
    Dey, Sudhansu K
    Yang, Pengxiang
    Prieto Conaway, Maria C
    Laskin, Julia
    High-speed tandem mass spectrometric in situ imaging by nanospray desorption electrospray ionization mass spectrometry2013In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 85, no 20, p. 9596-9603Article in journal (Refereed)
    Abstract [en]

    Nanospray desorption electrospray ionization (nano-DESI) combined with tandem mass spectrometry (MS/MS), high-resolution mass analysis of the fragment ions (m/Δm = 17 500 at m/z 200), and rapid spectral acquisition enabled simultaneous imaging and identification of a large number of metabolites and lipids from 92 selected m/z windows (±1 Da) with a spatial resolution of better than 150 μm. Mouse uterine sections of implantation sites on day 6 of pregnancy were analyzed in the ambient environment without any sample pretreatment. MS/MS imaging was performed by scanning the sample under the nano-DESI probe at 10 μm/s, while higher-energy collision-induced dissociation (HCD) spectra were acquired for a targeted inclusion list of 92 m/z values at a rate of ∼6.3 spectra/s. Molecular ions and their corresponding fragments, separated by high-resolution mass analysis, were assigned on the basis of accurate mass measurement. Using this approach, we were able to identify and image both abundant and low-abundance isobaric and isomeric species within each m/z window. MS/MS analysis enabled efficient separation and identification of isomeric and isobaric phospholipids that are difficult to separate in full-scan mode. Furthermore, we identified several metabolites associated with early pregnancy and obtained the first 2D images of these molecules.

  • 10. Lanekoff, Ingela
    et al.
    Geydebrekht, Oleg
    Pinchuk, Grigoriy E
    Konopka, Allan E
    Laskin, Julia
    Spatially resolved analysis of glycolipids and metabolites in living Synechococcus sp. PCC 7002 using nanospray desorption electrospray ionization2013In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 138, no 7, p. 1971-1978Article in journal (Refereed)
    Abstract [en]

    Microorganisms release a diversity of organic compounds that couple interspecies metabolism, enable communication, or provide benefits to other microbes. Increased knowledge of microbial metabolite production will contribute to understanding of the dynamic microbial world and can potentially lead to new developments in drug discovery, biofuel production, and clinical research. Nanospray desorption electrospray ionization (nano-DESI) is an ambient ionization technique that enables detailed chemical characterization of molecules from a specific location on a surface without special sample pretreatment. Due to its ambient nature, living bacterial colonies growing on agar plates can be rapidly analyzed without affecting the viability of the colony. In this study we demonstrate for the first time the utility of nano-DESI for spatial profiling of chemical gradients generated by microbial communities on agar plates. We found that despite the high salt content of the agar used in this study (~350 mM), nano-DESI analysis enables detailed characterization of metabolites produced by the Synechococcus sp. PCC 7002 colonies. High resolution mass spectrometry and MS/MS analysis of the living Synechococcus sp. PCC 7002 colonies allowed us to detect metabolites and lipids on the colony and on the surrounding agar, and confirm their identities. High sensitivity of nano-DESI enabled identification of several glycolipids that have not been previously reported by extracting the cells using conventional methods. Spatial profiling demonstrated that a majority of lipids and metabolites were localized on the colony while sucrose and glucosylglycerol, an osmoprotective compound produced by cyanobacteria, were secreted onto agar. Furthermore, we demonstrated that the chemical gradients of sucrose and glucosylglycerol on agar depend on the age of the colony. The methodology presented in this study will facilitate future studies focused on molecular-level characterization of interactions between bacterial colonies.

  • 11. Lanekoff, Ingela
    et al.
    Heath, Brandi S
    Liyu, Andrey
    Thomas, Mathew
    Carson, James P
    Laskin, Julia
    Automated platform for high-resolution tissue imaging using nanospray desorption electrospray ionization mass spectrometry2012In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 84, no 19, p. 8351-8356Article in journal (Refereed)
    Abstract [en]

    An automated platform has been developed for acquisition and visualization of mass spectrometry imaging (MSI) data using nanospray desorption electrospray ionization (nano-DESI). The new system enables robust operation of the nano-DESI imaging source over many hours by precisely controlling the distance between the sample and the nano-DESI probe. This is achieved by mounting the sample holder onto an automated XYZ stage, defining the tilt of the sample plane, and recalculating the vertical position of the stage at each point. This approach is useful for imaging of relatively flat samples such as thin tissue sections. Custom software called MSI QuickView was developed for visualization of large data sets generated in imaging experiments. MSI QuickView enables fast visualization of the imaging data during data acquisition and detailed processing after the entire image is acquired. The performance of the system is demonstrated by imaging rat brain tissue sections. Low background noise enables simultaneous detection of lipids and metabolites in the tissue section. High-resolution mass analysis combined with tandem mass spectometry (MS/MS) experiments enabled identification of the observed species. In addition, the high dynamic range (>2000) of the technique allowed us to generate ion images of low-abundance isobaric lipids. A high-spatial resolution image was acquired over a small region of the tissue section revealing the distribution of an abundant brain metabolite, creatine, on the boundary between the white and gray matter. The observed distribution is consistent with the literature data obtained using magnetic resonance spectroscopy.

  • 12. Lanekoff, Ingela
    et al.
    Karlsson, Roger
    Analysis of intact ladderane phospholipids, originating from viable anammox bacteria, using RP-LC-ESI-MS2010In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 397, no 8, p. 3543-3551Article in journal (Refereed)
    Abstract [en]

    Since the discovery of the anaerobic ammonium oxidizing (anammox) bacteria, many attempts have been made in order to identify these environmentally important bacteria in natural environments. Anammox bacteria contain a unique class of lipids, called ladderane lipids and here we present a novel method to detect viable anammox bacteria in sediments and waste water treatment plants based on the use of a ladderane lipid biomarker. Intact ladderane phosphatidylcholine (PC) lipids are analyzed using reversed-phase liquid chromatography-electrospray ionization-mass spectrometry. Following extraction from the complex sediment matrix, reversed-phase LC is used to separate ladderane PC lipids based on their tail group hydrophobicity as well as their ether or ester link to the glycerol backbone in the sn-2 position. We investigate the presence of intact ladderane lipids in natural sediments displaying anammox activity and illustrate the use of a specific intact membrane forming PC lipid as a biomarker for viable anammox bacterial cells. The presented method can be used to elucidate the whereabouts of viable anammox bacteria, subsequently enabling an estimation of anammox activity. This will greatly increase the knowledge of anammox bacteria and their importance in the global nitrogen cycle.

  • 13. Lanekoff, Ingela
    et al.
    Kurczy, Michael E.
    Adams, Kelly L.
    Malm, Jakob
    Karlsson, Roger
    Sjövall, Peter
    Ewing, Andrew G.
    An in situ fracture device to image lipids in single cells using ToF-SIMS2011In: Surface and Interface Analysis, ISSN 0142-2421, E-ISSN 1096-9918, Vol. 43, no 1-2, p. 257-260Article in journal (Refereed)
    Abstract [en]

    Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) imaging yields molecule-specific images showing the spatial distribution of specific lipids with submicron resolution, making it a potentially powerful method for studying a variety of biological questions in single cells. In order to make possible the analysis of hydrated cells in vacuum, we have designed a device for in situ freeze-fracture of cell samples. PC12 cells are frozen between two silicon shards in a sandwich geometry, and the fracture is conducted under vacuum inside the analysis chamber of the instrument. After freeze-fracture, ToF-SIMS analysis was carried out using a Bi cluster ion source, providing high-resolution images of single cells. We also show that when combining freeze-fracture and cluster SIMS imaging, low abundant biologically important lipids, specifically PE, PC and non-SM PC, can be imaged in single cells. Finally, K+ ion localization was used as a diagnostic to identify fracture planes through the cell for these fractured samples.

  • 14. Lanekoff, Ingela
    et al.
    Kurczy, Michael E
    Hill, Rowland
    Fletcher, John S
    Vickerman, John C
    Winograd, Nick
    Sjövall, Peter
    Ewing, Andrew G
    Time of flight mass spectrometry imaging of samples fractured in situ with a spring-loaded trap system2010In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 82, no 15, p. 6652-9Article in journal (Refereed)
    Abstract [en]

    An in situ freeze fracture device featuring a spring-loaded trap system has been designed and characterized for time of flight secondary ion mass spectrometry (TOF SIMS) analysis of single cells. The device employs the sandwich assembly, which is typically used in freeze fracture TOF SIMS experiments to prepare frozen, hydrated cells for high-resolution SIMS imaging. The addition of the spring-loaded trap system to the sandwich assembly offers two advances to this sample preparation method. First, mechanizing the fracture by adding a spring standardizes each fracture by removing the need to manually remove the top of the sandwich assembly with a cryogenically cooled knife. A second advance is brought about because the top of the sandwich is not discarded after the sandwich assembly has been fractured. This results in two imaging surfaces effectively doubling the sample size and providing the unique ability to image both sections of a cell bifurcated by the fracture. Here, we report TOF SIMS analysis of freeze fractured rat pheochromocytoma (PC12) cells using a Bi cluster ion source. This work exhibits the ability to obtain single cell chemical images with subcellular lateral resolution from cells preserved in an ice matrix. In addition to preserving the cells, the signal from lipid fragment ions rarely identified in single cells are better observed in the freeze-fractured samples for these experiments. Furthermore, using the accepted argument that K(+) signal indicates a cell that has been fractured though the cytoplasm, we have also identified different fracture planes of cells over the surface. Coupling a mechanized freeze fracture device to high-resolution cluster SIMS imaging will provide the sensitivity and resolution as well as the number of trials required to carry out biologically relevant SIMS experiments.

  • 15. Lanekoff, Ingela
    et al.
    Laskin, Julia
    Imaging of lipids and metabolites using nanospray desorption electrospray ionization mass spectrometry.2015In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1203, p. 99-106Article in journal (Refereed)
    Abstract [en]

    Nanospray desorption electrospray ionization (nano-DESI) is an ambient ionization technique that uses localized liquid extraction for mass spectrometry imaging of molecules on surfaces. Nano-DESI enables imaging of ionizable molecules from a sample in its native state without any special sample pretreatment. In this chapter we describe the protocol for nano-DESI imaging of thin tissue sections.

  • 16. Lanekoff, Ingela
    et al.
    Phan, Nhu Tn
    Van Bell, Craig T
    Winograd, Nicholas
    Sjövall, Peter
    Ewing, Andrew G
    Mass spectrometry imaging of freeze-dried membrane phospholipids of dividing Tetrahymena pyriformis2013In: Surface and Interface Analysis, ISSN 0142-2421, E-ISSN 1096-9918, Vol. 45, no 1, p. 211-214Article in journal (Refereed)
    Abstract [en]

    Time of Flight secondary ion mass spectrometry (TOF-SIMS) has been used to explore the distribution of phospholipids in the plasma membrane of Tetrahymena pyriformis during cell division. The dividing cells were freeze dried prior to analysis followed by line scan and region of interest analysis at various stages of cell division. The results showed no signs of phospholipid domain formation at the junction between the dividing cells. Instead the results showed that the sample preparation technique had a great impact on one of the examined phospholipids, namely phosphatidylcholine (PC). Phosphatidylcholine and 2-aminoethylphosphonolipid (2-AEP) have therefore been evaluated in Tetrahymena cells that have been subjected to different sample preparation techniques: freeze drying ex situ, freeze fracture, and freeze fracture with partial or total freeze drying in situ. The result suggests that freeze-drying ex situ causes the celia to collapse and cover the plasma membrane.

  • 17. Lanekoff, Ingela
    et al.
    Sjövall, Peter
    Ewing, Andrew G
    Relative quantification of phospholipid accumulation in the PC12 cell plasma membrane following phospholipid incubation using TOF-SIMS imaging2011In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, no 13, p. 5337-5343Article in journal (Refereed)
    Abstract [en]

    Time of flight secondary ion mass spectrometry (TOF-SIMS) imaging has been used to investigate the incorporation of phospholipids into the plasma membrane of PC12 cells after incubation with phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The incubations were done at concentrations previously shown to change the rate of exocytosis in model cell lines. The use of TOF-SIMS in combination with an in situ freeze fracture device enables the acquisition of ion images from the plasma membrane in single PC12 cells. By incubating cells with deuterated phospholipids and acquiring ion images at high mass resolution, specific deuterated fragment ions were used to monitor the incorporation of lipids into the plasma membrane. The concentration of incorporated phospholipids relative to the original concentration of PC was thus determined. The observed relative amounts of phospholipid accumulation in the membrane range from 0.5 to 2% following 19 h of incubation with PC at 100-300 μM and from 1 to 9% following incubation with PE at the same concentrations. Phospholipid accumulation is therefore shown to be dependent on the concentration in the surrounding media. In combination with previous exocytosis results, the present data suggests that very small changes in the plasma membrane phospholipid concentration are sufficient to produce significant effects on important cellular processes, such as exocytosis in PC12 cells.

  • 18. Lanekoff, Ingela
    et al.
    Stevens, Susan L
    Stenzel-Poore, Mary P
    Laskin, Julia
    Matrix effects in biological mass spectrometry imaging: identification and compensation2014In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 139, no 14, p. 3528-3532Article in journal (Refereed)
    Abstract [en]

    Matrix effects in mass spectrometry imaging (MSI) may affect the observed molecular distribution in chemical and biological systems. In this study, we use mouse brain tissue of a middle cerebral artery occlusion (MCAO) stroke model to examine matrix effects in nanospray desorption electrospray ionization MSI (nano-DESI MSI). This is achieved by normalizing the intensity of the sodium and potassium adducts of endogenous phosphatidylcholine (PC) species to the intensity of the corresponding adduct of the PC standard supplied at a constant rate with the nano-DESI solvent. The use of MCAO model with an ischemic region localized to one hemisphere of the brain enables immediate comparison of matrix effects within one ion image. Furthermore, significant differences in sodium and potassium concentrations in the ischemic region in comparison with the healthy tissue allowed us to distinguish between two types of matrix effects. Specifically, we discuss matrix effects originating from variations in alkali metal concentrations and matrix effects originating from variations in the molecular composition of the tissue. Compensation for both types of matrix effects was achieved by normalizing the signals corresponding to endogenous PC to the signals of the standards. This approach, which does not introduce any complexity in sample preparation, efficiently compensates for signal variations resulting from differences in the local concentrations of sodium and potassium in tissue sections and from the complexity of the extracted analyte mixture derived from local variations in molecular composition.

  • 19. Lanekoff, Ingela
    et al.
    Thomas, Mathew
    Carson, James P
    Smith, Jordan N
    Timchalk, Charles
    Laskin, Julia
    Imaging nicotine in rat brain tissue by use of nanospray desorption electrospray ionization mass spectrometry2013In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 85, no 2, p. 882-889Article in journal (Refereed)
    Abstract [en]

    Imaging mass spectrometry offers simultaneous spatially resolved detection of drugs, drug metabolites, and endogenous substances in a single experiment. This is important when evaluating effects of a drug on a complex organ system such as the brain, where there is a need to understand how regional drug distribution impacts function. Nanospray desorption electrospray ionization, nano-DESI, is a new ambient technique that enables spatially resolved analysis of a variety of samples without special sample pretreatment. This study introduces an experimental approach for accurate spatial mapping of drugs and metabolites in tissue sections by nano-DESI imaging. In this approach, an isotopically labeled standard is added to the nano-DESI solvent to compensate for matrix effects and ion suppression. The analyte image is obtained by normalizing the analyte signal to the signal of the standard in each pixel. We demonstrate that the presence of internal standard enables online quantification of analyte molecules extracted from tissue sections. Ion images are subsequently mapped to the anatomical brain regions in the analyzed section by use of an atlas mesh deformed to match the optical image of the section. Atlas-based registration accounts for the physical variability between animals, which is important for data interpretation. The new approach was used for mapping the distribution of nicotine in rat brain tissue sections following in vivo drug administration. We demonstrate the utility of nano-DESI imaging for sensitive detection of the drug in tissue sections with subfemtomole sensitivity in each pixel of a 27 μm × 150 μm area. Such sensitivity is necessary for spatially resolved detection of low-abundance molecules in complex matrices.

  • 20. Lanekoff, Ingela
    et al.
    Thomas, Mathew
    Laskin, Julia
    Shotgun approach for quantitative imaging of phospholipids using nanospray desorption electrospray ionization mass spectrometry2014In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 86, no 3, p. 1872-80Article in journal (Refereed)
    Abstract [en]

    Mass spectrometry imaging (MSI) has been extensively used for determining spatial distributions of molecules in biological samples, and there is increasing interest in using MSI for quantification. Nanospray desorption electrospray ionization (nano-DESI) is an ambient MSI technique where a solvent is used for localized extraction of molecules followed by nanoelectrospray ionization. Doping the nano-DESI solvent with carefully selected standards enables online quantification during MSI experiments. In this proof-of-principle study, we demonstrate that this quantification approach can be extended to provide shotgun-like quantification of phospholipids in thin brain tissue sections. Specifically, two phosphatidylcholine (PC) standards were added to the nano-DESI solvent for simultaneous imaging and quantification of 22 endogenous PC species observed in nano-DESI MSI. Furthermore, by combining the quantitative data obtained in the individual pixels, we demonstrate quantification of these PC species in seven different regions of a rat brain tissue section.

  • 21.
    Laskin, Julia
    et al.
    Pacific Northwest National Laboratory.
    Lanekoff, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ambient Mass Spectrometry Imaging Using Direct Liquid Extraction Techniques2016In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 1, p. 52-73Article, review/survey (Refereed)
  • 22. Liu, Pengyuan
    et al.
    Lanekoff, Ingela T
    Laskin, Julia
    Dewald, Howard D
    Chen, Hao
    Study of electrochemical reactions using nanospray desorption electrospray ionization mass spectrometry2012In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 84, no 13, p. 5737-5743Article in journal (Refereed)
    Abstract [en]

    The combination of electrochemistry (EC) and mass spectrometry (MS) is a powerful analytical tool for studying mechanisms of redox reactions, identification of products and intermediates, and online derivatization/recognition of analytes. This work reports a new coupling interface for EC/MS by employing nanospray desorption electrospray ionization, a recently developed ambient ionization method. We demonstrate online coupling of nanospray desorption electrospray ionization MS with a traditional electrochemical flow cell, in which the electrolyzed solution emanating from the cell is ionized by nanospray desorption electrospray ionization for MS analysis. Furthermore, we show first coupling of nanospray desorption electrospray ionization MS with an interdigitated array (IDA) electrode enabling chemical analysis of electrolyzed samples directly from electrode surfaces. Because of its inherent sensitivity, nanospray desorption electrospray ionization enables chemical analysis of small volumes and concentrations of sample solution. Specifically, good-quality signal of dopamine and its oxidized form, dopamine o-quinone, was obtained using 10 μL of 1 μM solution of dopamine on the IDA. Oxidation of dopamine, reduction of benzodiazepines, and electrochemical derivatization of thiol groups were used to demonstrate the performance of the technique. Our results show the potential of nanospray desorption electrospray ionization as a novel interface for electrochemical mass spectrometry research.

  • 23. Mossberg, Ann-Kristin
    et al.
    Puchades, Maja
    Halskau, Øyvind
    Baumann, Anne
    Lanekoff, Ingela
    Chao, Yinxia
    Martinez, Aurora
    Svanborg, Catharina
    Karlsson, Roger
    HAMLET interacts with lipid membranes and perturbs their structure and integrity.2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 2, p. e9384-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cell membrane interactions rely on lipid bilayer constituents and molecules inserted within the membrane, including specific receptors. HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded alpha-lactalbumin (HLA) and oleic acid that is internalized by tumor cells, suggesting that interactions with the phospholipid bilayer and/or specific receptors may be essential for the tumoricidal effect. This study examined whether HAMLET interacts with artificial membranes and alters membrane structure.

    METHODOLOGY/PRINCIPAL FINDINGS: We show by surface plasmon resonance that HAMLET binds with high affinity to surface adherent, unilamellar vesicles of lipids with varying acyl chain composition and net charge. Fluorescence imaging revealed that HAMLET accumulates in membranes of vesicles and perturbs their structure, resulting in increased membrane fluidity. Furthermore, HAMLET disrupted membrane integrity at neutral pH and physiological conditions, as shown by fluorophore leakage experiments. These effects did not occur with either native HLA or a constitutively unfolded Cys-Ala HLA mutant (rHLA(all-Ala)). HAMLET also bound to plasma membrane vesicles formed from intact tumor cells, with accumulation in certain membrane areas, but the complex was not internalized by these vesicles or by the synthetic membrane vesicles.

    CONCLUSIONS/SIGNIFICANCE: The results illustrate the difference in membrane affinity between the fatty acid bound and fatty acid free forms of partially unfolded HLA and suggest that HAMLET engages membranes by a mechanism requiring both the protein and the fatty acid. Furthermore, HAMLET binding alters the morphology of the membrane and compromises its integrity, suggesting that membrane perturbation could be an initial step in inducing cell death.

  • 24.
    Nakamachi, Tomoya
    et al.
    Toyama Univ, Grad Sch Sci & Engn, Lab Regulatory Biol, 3190 Gofuku, Toyama, Toyama 9308555, Japan.;Showa Univ, Sch Med, Dept Anat, Shinagawa Ku, Tokyo 1428555, Japan..
    Ohtaki, Hirokazu
    Showa Univ, Sch Med, Dept Anat, Shinagawa Ku, Tokyo 1428555, Japan..
    Seki, Tamotsu
    Showa Univ, Sch Med, Dept Anat, Shinagawa Ku, Tokyo 1428555, Japan..
    Yofu, Sachiko
    Showa Univ, Sch Med, Dept Anat, Shinagawa Ku, Tokyo 1428555, Japan..
    Kagami, Nobuyuki
    Showa Univ, Sch Med, Dept Anat, Shinagawa Ku, Tokyo 1428555, Japan..
    Hashimoto, Hitoshi
    Osaka Univ, Grad Sch Pharmaceut Sci, Lab Mol Neuropharmacol, 1-6 Yamadaoka, Suita, Osaka 5650871, Japan.;Osaka Univ, Grad Sch Pharmaceut Sci, iPS Cell Based Res Project Brain Neuropharmacol &, 1-6 Yamadaoka, Suita, Osaka 5650871, Japan.;Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan.;Kanazawa Univ, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan.;Hamamatsu Univ Sch Med, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan.;Chiba Univ, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan.;Univ Fukui, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan..
    Shintani, Norihito
    Osaka Univ, Grad Sch Pharmaceut Sci, Lab Mol Neuropharmacol, 1-6 Yamadaoka, Suita, Osaka 5650871, Japan..
    Baba, Akemichi
    Hyogo Univ Hlth Sci, Chuo Ku, 1-3-6 Minatojima, Kobe, Hyogo 6508530, Japan..
    Mark, Laszlo
    Univ Pecs, Sch Med, Inst Biochem & Med Chem, Dept Analyt Biochem, Szigeti U 12, H-7624 Pecs, Hungary.;Univ Pecs, Imaging Ctr Life & Mat Sci, Szigeti U 12, H-7624 Pecs, Hungary.;Univ Pecs, Janos Szentagothai Res Ctr, Szigeti U 12, H-7624 Pecs, Hungary.;PTE MTA Human Reprod Res Grp, Szigeti U 12, H-7624 Pecs, Hungary..
    Lanekoff, Ingela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Kiss, Peter
    Univ Pecs, Ctr Neurosci, MTA PTE PACAP Lendulet Res Grp, Dept Anat, Szigeti U 12, H-7624 Pecs, Hungary..
    Farkas, Jozsef
    Showa Univ, Sch Med, Dept Anat, Shinagawa Ku, Tokyo 1428555, Japan.;Univ Pecs, Ctr Neurosci, MTA PTE PACAP Lendulet Res Grp, Dept Anat, Szigeti U 12, H-7624 Pecs, Hungary..
    Reglodi, Dora
    Univ Pecs, Ctr Neurosci, MTA PTE PACAP Lendulet Res Grp, Dept Anat, Szigeti U 12, H-7624 Pecs, Hungary..
    Shioda, Seiji
    Hoshi Univ, Global Res Ctr Innovat Life Sci, Innovat Drug Discovery, Shinagawa Ku, 4-41 Ebara 2 Chome, Tokyo 1428501, Japan..
    PACAP suppresses dry eye signs by stimulating tear secretion2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12034Article in journal (Refereed)
    Abstract [en]

    Dry eye syndrome is caused by a reduction in the volume or quality of tears. Here, we show that pituitary adenylate cyclase-activating polypeptide (PACAP)-null mice develop dry eye-like symptoms such as corneal keratinization and tear reduction. PACAP immunoreactivity is co-localized with a neuronal marker, and PACAP receptor (PAC1-R) immunoreactivity is observed in mouse infraorbital lacrimal gland acinar cells. PACAP eye drops stimulate tear secretion and increase cAMP and phosphorylated (p)-protein kinase A levels in the infraorbital lacrimal glands that could be inhibited by pre-treatment with a PAC1-R antagonist or an adenylate cyclase inhibitor. Moreover, these eye drops suppress corneal keratinization in PACAP-null mice. PACAP eye drops increase aquaporin 5 (AQP5) levels in the membrane and pAQP5 levels in the infraorbital lacrimal glands. AQP5 siRNA treatment of the infraorbital lacrimal gland attenuates PACAP-induced tear secretion. Based on these results, PACAP might be clinically useful to treat dry eye disorder.

  • 25. Piwowar, Alan M
    et al.
    Keskin, Selda
    Delgado, Melissa Ortiz
    Shen, Kan
    Hue, Jonathan J
    Lanekoff, Ingela
    Ewing, Andrew G
    Winograd, Nicholas
    C60-ToF SIMS imaging of frozen hydrated HeLa cells2013In: Surface and Interface Analysis, ISSN 0142-2421, E-ISSN 1096-9918, Vol. 45, no 1, p. 302-304Article in journal (Refereed)
    Abstract [en]

    Sample preparation continues to be a major challenge for secondary ion mass spectrometry studies of biological materials. Maintaining the native hydrated state of the material is important for preserving both chemical and spatial information. Here, we discuss a method which combines a sample wash and dry protocol discussed by Berman et al (1 (1)) followed by plunge freezing in liquid ethane for a frozen-hydrated analysis of mammalian cells (HeLa). This method allows for the removal of the growth media and maintains the hydrated state of the cells so that they can be prepared frozen-hydrated without the need for a freeze-fracture device. The cells, which were grown on silicon, have been successfully re-grown after the cleaning procedure, confirming that a significant portion of the cells remain undamaged during the wash and dry. Results from preliminary SIMS measurements show that is it possible to detect a large variety of bio-molecular signals, including intact lipids from the plasma membrane in the mass range of 700-900 Da from single cells, with little external water interference at the surface.

  • 26. Van Dam, K.K.
    et al.
    Carson, J.
    Corrigan, A.
    Einstein, D.
    Guillen, Z.
    Heath, B.
    Kuprat, A.
    Lanekoff, Ingela
    Lansing, C.
    Laskin, J.
    Li, D.S.
    Liu, Y.
    Marshall, M.
    Miller, E.
    Orr, G.
    da Silva, P.P.
    Ryu, S.
    Szymanski, C.
    Thomas, M.
    Velo and REXAN – Integrated Data Management and High Speed Analysis for Experimental Facilities2012In: Proceeding IEEE International Conference on E-Science 2012, 2012, p. 1-9Conference paper (Other academic)
    Abstract [en]

    The Chemical Imaging Initiative at the Pacific Northwest National Laboratory (PNNL) is creating a `Rapid Experimental Analysis' (REXAN) Framework, based on the concept of reusable component libraries. REXAN allows developers to quickly compose and customize high throughput analysis pipelines for a range of experiments, as well as supporting the creation of multi-modal analysis pipelines. In addition, PNNL has coupled REXAN with its collaborative data management and analysis environment Velo to create an easy to use data management and analysis environments for experimental facilities. This paper will discuss the benefits of Velo and REXAN in the context of three examples: PNNL High Resolution Mass Spectrometry - reducing analysis times from hours to seconds, and enabling the analysis of much larger data samples (100KB to 40GB) at the same time. · ALS X-Ray Tomography - reducing analysis times of combined STXM and EM data collected at the ALS from weeks to minutes, decreasing manual work and increasing data volumes that can be analysed in a single step. · Multi-modal nano-scale analysis of STXM and TEM data - providing a semi automated process for particle detection. The creation of REXAN has significantly shortened the development time for these analysis pipelines. The integration of Velo and REXAN has significantly increased the scientific productivity of the instruments and their users by creating easy to use data management and analysis environments with greatly reduced analysis times and improved analysis capabilities.

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