Publications by authors named "Donald F Smith"

67 Publications

Hydrocarbons to carboxyl-rich alicyclic molecules: A continuum model to describe biodegradation of petroleum-derived dissolved organic matter in contaminated groundwater plumes.

J Hazard Mater 2021 01 19;402:123998. Epub 2020 Sep 19.

Department of Earth, Ocean and Atmospheric Science, Florida State University, Tallahassee, FL, USA; National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL 32310, USA.

Relationships between dissolved organic matter (DOM) reactivity and chemical composition in a groundwater plume containing petroleum-derived DOM (DOM) were examined by quantitative and qualitative measurements to determine the source and chemical composition of the compounds that persist downgradient. Samples were collected from a transect down the core of the plume in the direction of groundwater flow. An exponential decrease in dissolved organic carbon concentration resulting from biodegradation along the transect correlated with a continuous shift in fluorescent DOM from shorter to longer wavelengths. Moreover, ultrahigh resolution mass spectrometry showed a shift from low molecular weight (MW) aliphatic, reduced compounds to high MW, unsaturated (alicyclic/aromatic), high oxygen compounds that are consistent with carboxyl-rich alicyclic molecules. The degree of condensed aromaticity increased downgradient, indicating that compounds with larger, conjugated aromatic core structures were less susceptible to biodegradation. Nuclear magnetic resonance spectroscopy showed a decrease in alkyl (particularly methyl) and an increase in aromatic/olefinic structural motifs. Collectively, data obtained from the combination of these complementary analytical techniques indicated that changes in the DOM composition of a groundwater plume are gradual, as relatively low molecular weight (MW), reduced, aliphatic compounds from the oil source were selectively degraded and high MW, alicyclic/aromatic, oxidized compounds persisted.
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http://dx.doi.org/10.1016/j.jhazmat.2020.123998DOI Listing
January 2021

Barium ion adduct mass spectrometry to identify carboxylic acid photoproducts from crude oil-water systems under solar irradiation.

Environ Sci Process Impacts 2020 Dec;22(12):2313-2321

Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA.

Petroleum derived dissolved organic matter (DOMHC) samples were successfully cationized with barium, revealing many [M-H + Ba]+ peaks in both dark and simulated sunlight treatments. The DOMHC samples generated after light exposure exhibited a greater number of [M-H + Ba]+ peaks compared to the dark control. Multiple [M-H + Ba]+ peaks were investigated in the irradiated DOMHC using low resolution MS/MS in order to confirm the presence of diagnostic fragment ions, m/z 139, 155 and 196 in each treatment. Due to the high complexity of the bariated DOMHC mixture, Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS/MS) was employed to obtain molecular level information for both irradiated and dark treatments. The irradiated DOMHC treatments had more bariated oxygenated species over a wide range of H/C and O/C when compared to the dark controls. Doubly bariated species were also observed in DOMHC, which provides evidence that photochemistry transforms DOMHC to even more complex mixtures with multiple oxygenations per molecule. This study provides evidence that barium adduct mass spectrometry can be successfully applied to DOMHC screening for the presence of COOHs, both in dark samples and solar irradiated samples. Furthermore, direct evidence and molecular composition of aqueous phase crude oil photoproducts is provided by this technique.
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http://dx.doi.org/10.1039/d0em00390eDOI Listing
December 2020

Ultrahigh Resolution Ion Isolation by Stored Waveform Inverse Fourier Transform 21 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometry.

Anal Chem 2020 02 3;92(4):3213-3219. Epub 2020 Feb 3.

National High Magnetic Field Laboratory , Florida State University , 1800 East Paul Dirac Drive , Tallahassee , Florida 32310 , United States.

Stored waveform inverse Fourier transform (SWIFT) is a versatile method to generate complex isolation/ejection waveforms for precursor isolation prior to tandem mass spectrometry experiments. Here, we report ultrahigh resolving power ion isolation by SWIFT on a 21 T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Individual histone proteoforms are isolated (0.6 / isolation window) with near 100% efficiency using a 52 ms SWIFT isolation, followed by in-cell fragmentation by ultraviolet photodissociation (UVPD). Ion isolation resolving power of 175 000 (/Δ) is demonstrated by isolation of individual peaks at a spacing of 0.0034 Da at / 597 from a complex mixture of Canadian bitumen. An individual / ion, which corresponds to a single elemental composition, from a complex mixture is isolated and fragmented by infrared multiphoton dissociation (IRMPD). Theoretical and experimental considerations that limit achievable ion isolation resolving power are discussed.
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http://dx.doi.org/10.1021/acs.analchem.9b04954DOI Listing
February 2020

Ultra-High Mass Resolving Power, Mass Accuracy, and Dynamic Range MALDI Mass Spectrometry Imaging by 21-T FT-ICR MS.

Anal Chem 2020 02 3;92(4):3133-3142. Epub 2020 Feb 3.

National High Magnetic Field Laboratory , Florida State University , 1800 East Paul Dirac Drive , Tallahassee , Florida 32310-4005 , United States.

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 / 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 / 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.
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http://dx.doi.org/10.1021/acs.analchem.9b04768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031845PMC
February 2020

Correction to: Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate.

J Am Soc Mass Spectrom 2018 06;29(6):1230

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Pharmacy Hall North Room 623, 20 N. Pine St, Baltimore, MD, 21201, USA.

In the preceding article "Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate" by Oyler et al., an error in the J5 E. coli LPS chemical structure (Figs. 2 and 4) was introduced and propagated into the final revision.
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http://dx.doi.org/10.1007/s13361-018-1960-8DOI Listing
June 2018

Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate.

J Am Soc Mass Spectrom 2018 06 20;29(6):1221-1229. Epub 2018 Feb 20.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Pharmacy Hall North Room 623, 20 N. Pine St, Baltimore, MD, 21201, USA.

Recent advances in lipopolysaccharide (LPS) biology have led to its use in drug discovery pipelines, including vaccine and vaccine adjuvant discovery. Desirable characteristics for LPS vaccine candidates include both the ability to produce a specific antibody titer in patients and a minimal host inflammatory response directed by the innate immune system. However, in-depth chemical characterization of most LPS extracts has not been performed; hence, biological activities of these extracts are unpredictable. Additionally, the most widely adopted workflow for LPS structure elucidation includes nonspecific chemical decomposition steps before analyses, making structures inferred and not necessarily biologically relevant. In this work, several different mass spectrometry workflows that have not been previously explored were employed to show proof-of-principle for top down LPS primary structure elucidation, specifically for a rough-type mutant (J5) E. coli-derived LPS component of a vaccine candidate. First, ion mobility filtered precursor ions were subjected to collision induced dissociation (CID) to define differences in native J5 LPS v. chemically detoxified J5 LPS (dLPS). Next, ultra-high mass resolving power, accurate mass spectrometry was employed for unequivocal precursor and product ion empirical formulae generation. Finally, MS analyses in an ion trap instrument showed that previous knowledge about dissociation of LPS components can be used to reconstruct and sequence LPS in a top down fashion. A structural rationale is also explained for differential inflammatory dose-response curves, in vitro, when HEK-Blue hTLR4 cells were administered increasing concentrations of native J5 LPS v. dLPS, which will be useful in future drug discovery efforts. Graphical Abstract ᅟ.
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http://dx.doi.org/10.1007/s13361-018-1897-yDOI Listing
June 2018

21 Tesla FT-ICR Mass Spectrometer for Ultrahigh-Resolution Analysis of Complex Organic Mixtures.

Anal Chem 2018 02 5;90(3):2041-2047. Epub 2018 Jan 5.

National High Magnetic Field Laboratory, Florida State University , 1800 East Paul Dirac Drive, Tallahassee, Florida 32310, United States.

We describe complex organic mixture analysis by 21 tesla (T) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Ultrahigh mass-resolving power (m/Δm > 2 700 000 at m/z 400) and mass accuracy (80 ppb rms) enable resolution and confident identification of tens of thousands of unique elemental compositions. We demonstrate 2.2-fold higher mass-resolving power, 2.6-fold better mass measurement accuracy, and 1.3-fold more assigned molecular formulas compared to our custom-built, state-of-the-art 9.4 T FT-ICR mass spectrometer for petroleum and dissolved organic matter (DOM) analyses. Analysis of a heavy petroleum distillate exemplifies the need for ultrahigh-performance mass spectrometry (49 040 assigned molecular formulas for 21 T versus 29 012 for 9.4 T) and extends the identification of previously unresolved O, SO, and NO 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 CHNOS mass differences at high mass (m/z > 600). Similar performance gains are realized in the analysis of dissolved organic matter, where doubly charged O species are resolved from singly charged SO species, which requires a mass-resolving power greater than 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 molecular characterization of the most complex organic mixtures.
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http://dx.doi.org/10.1021/acs.analchem.7b04159DOI Listing
February 2018

Combining Time-of-Flight Secondary Ion Mass Spectrometry Imaging Mass Spectrometry and CARS Microspectroscopy Reveals Lipid Patterns Reminiscent of Gene Expression Patterns in the Wing Imaginal Disc of Drosophila melanogaster.

Anal Chem 2017 09 29;89(18):9664-9670. Epub 2017 Aug 29.

FOM-Institute AMOLF , Science Park 104, 1098 XG Amsterdam, The Netherlands.

Using label-free ToF-SIMS imaging mass spectrometry, we generated a map of small molecules differentially expressed in the Drosophila wing imaginal disc. The distributions of these moieties were in line with gene expression patterns observed during wing imaginal disc development. Combining ToF-SIMS imaging and coherent anti-Stokes Raman spectroscopy (CARS) microspectroscopy allowed us to locally identify acylglycerols as the main constituents of the pattern differentiating the future body wall tissue from the wing blade tissue. The findings presented herein clearly demonstrate that lipid localization patterns are strongly correlated with a developmental gene expression. From this correlation, we hypothesize that lipids play a so far unrecognized role in organ development.
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http://dx.doi.org/10.1021/acs.analchem.7b00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607455PMC
September 2017

Identification and Characterization of Human Proteoforms by Top-Down LC-21 Tesla FT-ICR Mass Spectrometry.

J Proteome Res 2017 02 12;16(2):1087-1096. Epub 2016 Dec 12.

Ion Cyclotron Resonance Program, National High Magnetic Field Laboratory , Tallahassee, Florida 32310, United States.

Successful high-throughput characterization of intact proteins from complex biological samples by mass spectrometry requires instrumentation capable of high mass resolving power, mass accuracy, sensitivity, and spectral acquisition rate. These limitations often necessitate the performance of hundreds of LC-MS/MS experiments to obtain reasonable coverage of the targeted proteome, which is still typically limited to molecular weights below 30 kDa. The National High Magnetic Field Laboratory (NHMFL) recently installed a 21 T FT-ICR mass spectrometer, which is part of the NHMFL FT-ICR User Facility and available to all qualified users. Here we demonstrate top-down LC-21 T FT-ICR MS/MS of intact proteins derived from human colorectal cancer cell lysate. We identified a combined total of 684 unique protein entries observed as 3238 unique proteoforms at a 1% false discovery rate, based on rapid, data-dependent acquisition of collision-induced and electron-transfer dissociation tandem mass spectra from just 40 LC-MS/MS experiments. Our identifications included 372 proteoforms with molecular weights over 30 kDa detected at isotopic resolution, which substantially extends the accessible mass range for high-throughput top-down LC-MS/MS.
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http://dx.doi.org/10.1021/acs.jproteome.6b00696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353847PMC
February 2017

Changing the Face of Veterinary Medicine: Research and Clinical Developments at AAVMC Institutions.

J Vet Med Educ 2015 ;42(5):441-58

This paper provides a 50-year overview of research and clinical advances in AAVMC member colleges in four representative fields of veterinary medicine: oncology, vaccine development, production medicine, and public health. Though emphasis is on the progress since the mid-1960s, the salient background and associated personnel in each field are also identified to the extent that their description informs more recent events. Advances in board certification and post-graduate clinical and research educational opportunities are also described.
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http://dx.doi.org/10.3138/jvme.0515-082RDOI Listing
February 2016

21 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer: A National Resource for Ultrahigh Resolution Mass Analysis.

J Am Soc Mass Spectrom 2015 Sep 20;26(9):1626-32. Epub 2015 Jun 20.

National High Magnetic Field Laboratory, Florida State University, 1800 East Paul Dirac Drive, Tallahassee, FL, 32310, USA,

We describe the design and initial performance of the first 21 tesla Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The 21 tesla magnet is the highest field superconducting magnet ever used for FT-ICR and features high spatial homogeneity, high temporal stability, and negligible liquid helium consumption. The instrument includes a commercial dual linear quadrupole trap front end that features high sensitivity, precise control of trapped ion number, and collisional and electron transfer dissociation. 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/Δm(50%)) 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 analysis of electron transfer and collisional dissociation 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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http://dx.doi.org/10.1007/s13361-015-1182-2DOI Listing
September 2015

Mass spectrometry imaging of biological tissue: an approach for multicenter studies.

Anal Bioanal Chem 2015 Mar 10;407(8):2329-35. Epub 2015 Jan 10.

Institute of Inorganic and Analytical Chemistry, Justus Liebig University, Schubertstrasse 60, Bldg. 16, 35392, Giessen, Germany,

Mass spectrometry imaging has become a popular tool for probing the chemical complexity of biological surfaces. This led to the development of a wide range of instrumentation and preparation protocols. It is thus desirable to evaluate and compare the data output from different methodologies and mass spectrometers. Here, we present an approach for the comparison of mass spectrometry imaging data from different laboratories (often referred to as multicenter studies). This is exemplified by the analysis of mouse brain sections in five laboratories in Europe and the USA. The instrumentation includes matrix-assisted laser desorption/ionization (MALDI)-time-of-flight (TOF), MALDI-QTOF, MALDI-Fourier transform ion cyclotron resonance (FTICR), atmospheric-pressure (AP)-MALDI-Orbitrap, and cluster TOF-secondary ion mass spectrometry (SIMS). Experimental parameters such as measurement speed, imaging bin width, and mass spectrometric parameters are discussed. All datasets were converted to the standard data format imzML and displayed in a common open-source software with identical parameters for visualization, which facilitates direct comparison of MS images. The imzML conversion also allowed exchange of fully functional MS imaging datasets between the different laboratories. The experiments ranged from overview measurements of the full mouse brain to detailed analysis of smaller features (depending on spatial resolution settings), but common histological features such as the corpus callosum were visible in all measurements. High spatial resolution measurements of AP-MALDI-Orbitrap and TOF-SIMS showed comparable structures in the low-micrometer range. We discuss general considerations for planning and performing multicenter studies in mass spectrometry imaging. This includes details on the selection, distribution, and preparation of tissue samples as well as on data handling. Such multicenter studies in combination with ongoing activities for reporting guidelines, a common data format (imzML) and a public data repository can contribute to more reliability and transparency of MS imaging studies.
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http://dx.doi.org/10.1007/s00216-014-8410-7DOI Listing
March 2015

Distributed computing strategies for processing of FT-ICR MS imaging datasets for continuous mode data visualization.

Anal Bioanal Chem 2015 Mar 2;407(8):2321-7. Epub 2014 Oct 2.

FOM Institute AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands,

High-resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging enables the spatial mapping and identification of biomolecules from complex surfaces. The need for long time-domain transients, and thus large raw file sizes, results in a large amount of raw data ("big data") that must be processed efficiently and rapidly. This can be compounded by large-area imaging and/or high spatial resolution imaging. For FT-ICR, data processing and data reduction must not compromise the high mass resolution afforded by the mass spectrometer. The continuous mode "Mosaic Datacube" approach allows high mass resolution visualization (0.001 Da) of mass spectrometry imaging data, but requires additional processing as compared to feature-based processing. We describe the use of distributed computing for processing of FT-ICR MS imaging datasets with generation of continuous mode Mosaic Datacubes for high mass resolution visualization. An eight-fold improvement in processing time is demonstrated using a Dutch nationally available cloud service.
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http://dx.doi.org/10.1007/s00216-014-8210-0DOI Listing
March 2015

Systematic review of an emerging trend in china: resting-state functional connectivity in major depressive disorder.

Authors:
Donald F Smith

J Neuropsychiatry Clin Neurosci 2015 ;27(2):104-11

From the Translational Neuropsychiatry Unit, Psychiatric Hospital of Aarhus University, Institute of Clinical Medicine, Risskov, Denmark.

Major depressive disorder continues to challenge medical and psychological resources worldwide. A marked surge has occurred recently in China in neuroimaging studies of major depressive disorder. Those studies represent an emerging trend in neuropsychiatry in that such research has previously been extremely rare in China. The present article provides a systematic review of reports published in English by research institutes in China on resting-state functional connectivity studied by MRI in depressed subjects and healthy control subjects. Particular attention is given to whether the information may advance effective diagnosis and treatment options for patients with major depressive disorder.
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http://dx.doi.org/10.1176/appi.neuropsych.13110343DOI Listing
January 2016

Exploratory meta-analysis on deep brain stimulation in treatment-resistant depression.

Authors:
Donald F Smith

Acta Neuropsychiatr 2014 Dec 18;26(6):382-4. Epub 2014 Sep 18.

Institute for Clinical Medicine,Translational Neuropsychiatry Unit,Psychiatric Hospital of Aarhus University,Risskov,Denmark.

Objective: Deep brain stimulation is currently an experimental treatment for major depressive disorder. Information is lacking, however, on how sham responding may affect efficacy. This article applies exploratory meta-analysis to address that topic.

Methods: Data on benefits of deep brain electrical stimulation come from a recent review. Stimulated brain regions included subgenual cingulate, capsular interna, nucleus accumbens, and medial forebrain bundle. Expert opinion plus random number software was used to generate hypothetical values for sham responding.

Results: An effect size of 1.71 (95% CI: 1.47-1.96) was obtained for deep brain stimulation versus sham treatment in patients suffering from long-term treatment-resistant depression.

Conclusion: Preliminary findings on deep brain electrical stimulation suggest that the procedure may be 71% more effective than sham treatment. Expressing these findings as patients-needed-to-treat, deep brain electrical stimulation is required by 2.9 patients with long-term treatment-resistant depression in order for one of them to benefit.
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http://dx.doi.org/10.1017/neu.2014.22DOI Listing
December 2014

Experimental investigation of the 2D ion beam profile generated by an ESI octopole-QMS system.

J Am Soc Mass Spectrom 2014 Oct 12;25(10):1780-7. Epub 2014 Aug 12.

FOM Institute AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands.

In this paper, we have employed an ion imaging approach to investigate the behavior of ions exiting from a quadrupole mass spectrometer (QMS) system that employs a radio frequency octopole ion guide before the QMS. An in-vacuum active pixel detector (Timepix) is employed at the exit of the QMS to image the ion patterns. The detector assembly simultaneously records the ion impact position and number of ions per pixel in every measurement frame. The transmission characteristics of the ion beam exiting the QMS are studied using this imaging detector under different operating conditions. Experimental results confirm that the ion spatial distribution exiting the QMS is heavily influenced by ion injection conditions. Furthermore, ion images from Timepix measurements of protein standards demonstrate the capability to enhance the quality of the mass spectral information and provide a detailed insight in the spatial distribution of different charge states (and hence different m/z) ions exiting the QMS.
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http://dx.doi.org/10.1007/s13361-014-0958-0DOI Listing
October 2014

Secondary ion mass spectrometry imaging of Dictyostelium discoideum aggregation streams.

PLoS One 2014 9;9(6):e99319. Epub 2014 Jun 9.

Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, United States of America.

High resolution imaging mass spectrometry could become a valuable tool for cell and developmental biology, but both, high spatial and mass spectral resolution are needed to enable this. In this report, we employed Bi3 bombardment time-of-flight (Bi3 ToF-SIMS) and C60 bombardment Fourier transform ion cyclotron resonance secondary ion mass spectrometry (C60 FTICR-SIMS) to image Dictyostelium discoideum aggregation streams. Nearly 300 lipid species were identified from the aggregation streams. High resolution mass spectrometry imaging (FTICR-SIMS) enabled the generation of multiple molecular ion maps at the nominal mass level and provided good coverage for fatty acyls, prenol lipids, and sterol lipids. The comparison of Bi3 ToF-SIMS and C60 FTICR-SIMS suggested that while the first provides fast, high spatial resolution molecular ion images, the chemical complexity of biological samples warrants the use of high resolution analyzers for accurate ion identification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099319PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049834PMC
October 2015

PET brain imaging of neuropeptide Y2 receptors using N-11C-methyl-JNJ-31020028 in pigs.

J Nucl Med 2014 Apr 10;55(4):635-9. Epub 2014 Mar 10.

Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark.

Unlabelled: Neuropeptide Y2 (NPY2) receptors are implicated in diverse brain disorders, but no suitable PET radiotracers are currently available for studying NPY2 receptors in the living brain. We developed a novel positron-emitting radioligand based on the NPY2 receptor antagonist JNJ-31020028 (N-(4-(4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl)-3-fluorophenyl)-2-pyridin-3-ylbenzamide) and used the radiotracer for PET brain imaging in pigs.

Methods: In vitro receptor autoradiography studies were performed to establish the anatomic distribution of NPY2 receptors in the pig brain. In vivo, baseline 90-min PET recordings of N-(11)C-methyl-JNJ-31020028 were conducted in anesthetized Yorkshire x Landrace pigs, concurrent with arterial blood sampling. Postchallenge scans were conducted after injection of unlabeled JNJ-31020028 as a pharmacologic intervention. Cyclosporine A was used to enhance levels of the PET radiotracer in the brain. The PET images were manually coregistered to a MR imaging atlas of the pig brain. Maps of the N-(11)C-methyl-JNJ-31020028 volume of distribution in the brain were prepared, and regional binding potentials of NPY2 receptors toward the radioligand were calculated using the simplified reference tissue method.

Results: In autoradiography studies, N-(11)C-methyl-JNJ-31020028 receptor binding sites were observed primarily in the hippocampus and were inhibited by unlabeled JNJ-31020028. In PET studies, N-(11)C-methyl-JNJ-31020028 was metabolized slowly in the bloodstream, with 25% of the (11)C-labeled parent compound remaining 30 min after injection. PET imaging showed baseline binding potentials of 0.64 ± 0.07 in the thalamus, 0.55 ± 0.02 in the caudate, and 0.49 ± 0.03 in the hippocampus. Graphical reference region analyses demonstrated that N-(11)C-methyl-JNJ-31020028 binding was reversible; infusion of unlabeled JNJ-31020028 markedly displaced the PET radioligand from binding sites in the hippocampus, thalamus, caudate nucleus, and cerebellum but not in the corpus callosum, which served as reference region for nonspecific binding.

Conclusion: N-(11)C-methyl-JNJ-31020028 has several suitable properties for PET neuroimaging of NPY2 receptors. First, it is metabolized slowly in the bloodstream of pigs. Second, using cyclosporine, the target-to-background ratio of N-(11)C-methyl-JNJ-31020028 is sufficient for estimating pharmacokinetic parameters. Third, N-(11)C-methyl-JNJ-31020028 binds reversibly and competitively to cerebral sites known to contain relatively high numbers of NPY2 receptors, such as the hippocampus, thalamus, caudate nucleus, and cerebellum. Fourth, white matter such as corpus callosum, known to contain negligible numbers of NPY2 receptors, can serve as a reference region for estimating binding potentials in brain regions. To our knowledge, there is no other radioligand with these favorable properties and with this specificity for NPY2 receptors, which makes N-(11)C-methyl-JNJ-31020028 the first candidate radioligand for PET investigations of NPY2 receptors in the living brain.
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http://dx.doi.org/10.2967/jnumed.113.125351DOI Listing
April 2014

Top-down mass spectrometry imaging of intact proteins by laser ablation ESI FT-ICR MS.

Proteomics 2014 May 12;14(10):1283-9. Epub 2014 Feb 12.

FOM Institute AMOLF, Amsterdam, The Netherlands.

Laser ablation ESI (LAESI) is a recent development in MS imaging. It has been shown that lipids and small metabolites can be imaged in various samples such as plant material, tissue sections or bacterial colonies without any sample pretreatment. Further, LAESI has been shown to produce multiply charged protein ions from liquids or solid surfaces. This presents a means to address one of the biggest challenges in MS imaging; the identification of proteins directly from biological tissue surfaces. Such identification is hindered by the lack of multiply charged proteins in common MALDI ion sources and the difficulty of performing tandem MS on such large, singly charged ions. We present here top-down identification of intact proteins from tissue with a LAESI ion source combined with a hybrid ion-trap FT-ICR mass spectrometer. The performance of the system was first tested with a standard protein with electron capture dissociation and infrared multiphoton dissociation fragmentation to prove the viability of LAESI FT-ICR for top-down proteomics. Finally, the imaging of a tissue section was performed, where a number of intact proteins were measured and the hemoglobin α chain was identified directly from tissue using CID and infrared multiphoton dissociation fragmentation.
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http://dx.doi.org/10.1002/pmic.201300306DOI Listing
May 2014

MALDI mass spectrometry imaging in microscope mode with infrared lasers: bypassing the diffraction limits.

Anal Chem 2014 Jan 10;86(1):321-5. Epub 2013 Dec 10.

FOM Institute AMOLF , Science Park 104, 1098 XG Amsterdam, The Netherlands.

This letter demonstrates the use of infrared matrix-assisted laser desorption/ionization coupled with microscope mode mass spectrometry imaging. It is aimed to explore the use of intrinsic water in tissue as a matrix for imaging at spatial resolutions below the diffraction limit of the employed IR optics. Stigmatic ion optics with a magnification factor of ~70 were used to project the spatial distribution of produced ions onto a detector while separating ions with different mass-to-charge ratios using a time-of-flight mass spectrometer. A pixelated detector was used to simultaneously record arrival time and impact position. A previously described dried-droplet sample system of 2,5-dihydroxybenzoic acid (DHB) and 5 peptides covered by a copper grid for defined surface structure was used to benchmark the light- and ion-optical setup for spatial resolution and mass spectrometric performance. A spatial resolving power of 9.8 μm, well below the optical limit of diffraction (14 μm for the given setup), was established. After, frozen cryo-sections from a biological model system were measured by exploiting the endogenous water content as a matrix. Principal component analysis enabled a clear distinction between distinct tissue regions identified by both light microscopy and MS imaging.
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http://dx.doi.org/10.1021/ac403421vDOI Listing
January 2014

Cluster secondary ion mass spectrometry microscope mode mass spectrometry imaging.

Rapid Commun Mass Spectrom 2013 Dec;27(24):2745-50

FOM Institute AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands.

Rationale: Microscope mode imaging for secondary ion mass spectrometry is a technique with the promise of simultaneous high spatial resolution and high-speed imaging of biomolecules from complex surfaces. Technological developments such as new position-sensitive detectors, in combination with polyatomic primary ion sources, are required to exploit the full potential of microscope mode mass spectrometry imaging, i.e. to efficiently push the limits of ultra-high spatial resolution, sample throughput and sensitivity.

Methods: In this work, a C60 primary source was combined with a commercial mass microscope for microscope mode secondary ion mass spectrometry imaging. The detector setup is a pixelated detector from the Medipix/Timepix family with high-voltage post-acceleration capabilities. The system's mass spectral and imaging performance is tested with various benchmark samples and thin tissue sections.

Results: The high secondary ion yield (with respect to 'traditional' monatomic primary ion sources) of the C60 primary ion source and the increased sensitivity of the high voltage detector setup improve microscope mode secondary ion mass spectrometry imaging. The analysis time and the signal-to-noise ratio are improved compared with other microscope mode imaging systems, all at high spatial resolution.

Conclusions: We have demonstrated the unique capabilities of a C60 ion microscope with a Timepix detector for high spatial resolution microscope mode secondary ion mass spectrometry imaging.
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http://dx.doi.org/10.1002/rcm.6719DOI Listing
December 2013

Absorption mode FTICR mass spectrometry imaging.

Anal Chem 2013 Dec 14;85(23):11180-4. Epub 2013 Nov 14.

FOM Institute AMOLF , Science Park 104, Amsterdam, North Holland, 1098 XG The Netherlands.

Fourier transform ion cyclotron resonance mass spectrometry offers the highest mass resolving power for molecular imaging experiments. 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 addition to mass resolving power, absorption mode offers higher mass accuracy and signal-to-noise ratio over the conventional magnitude mode. Here, we 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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http://dx.doi.org/10.1021/ac403039tDOI Listing
December 2013

Enhanced detection of high-mass proteins by using an active pixel detector.

Angew Chem Int Ed Engl 2013 Oct 3;52(43):11261-4. Epub 2013 Sep 3.

Biomolecular Imaging Mass Spectrometry, FOM Institute AMOLF, Science Park 104, 1098 XG Amsterdam (The Netherlands).

Flying high: Application of an active pixel detector with high charge sensitivity to a linear time-of-flight mass spectrometer results in enhanced detection of high-mass proteins (such as Immunoglobulin G; IgG) using a conventional microchannel plate detection system. This technique thus provides a means to extend the mass range of such detectors as well as allowing direct visualization of mass-dependent ion-focusing phenomena.
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http://dx.doi.org/10.1002/anie.201305501DOI Listing
October 2013

Quest for biomarkers of treatment-resistant depression: shifting the paradigm toward risk.

Authors:
Donald F Smith

Front Psychiatry 2013 18;4:57. Epub 2013 Jun 18.

Translational Neuropsychiatry Unit, Psychiatric Hospital of Aarhus University , Risskov , Denmark.

The search for potential biomarkers of psychiatric disorders is a central topic in biological psychiatry. This review concerns published studies on potential biomarkers of treatment-resistant depression (TRD). The search for biomarkers of TRD in the bloodstream has focused on cytokines and steroids as well as brain-derived neurotropic factor. Additional approaches to identifying biomarkers of TRD have dealt with cerebrospinal fluid analysis, magnetic resonance imaging, and positron emission tomography. Some studies have also investigated potential genetic and epigenetic factors in TRD. Most studies have, however, used a post hoc experimental design that failed to determine the association between biomarkers and the initial risk of TRD. Particular attention in future studies should be on shifting the experimental paradigm toward procedures that can determine the risk for developing treatment resistance in untreated depressed individuals.
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http://dx.doi.org/10.3389/fpsyt.2013.00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684787PMC
June 2013

High mass accuracy and high mass resolving power FT-ICR secondary ion mass spectrometry for biological tissue imaging.

Anal Bioanal Chem 2013 Jul 19;405(18):6069-76. Epub 2013 May 19.

FOM Institute AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands.

Biological tissue imaging by secondary ion mass spectrometry has seen rapid development with the commercial availability of polyatomic primary ion sources. Endogenous lipids and other small bio-molecules can now be routinely mapped on the sub-micrometer scale. Such experiments are typically performed on time-of-flight mass spectrometers for high sensitivity and high repetition rate imaging. However, such mass analyzers lack the mass resolving power to ensure separation of isobaric ions and the mass accuracy for elemental formula assignment based on exact mass measurement. We have recently reported a secondary ion mass spectrometer with the combination of a C60 primary ion gun with a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) for high mass resolving power, high mass measurement accuracy, and tandem mass spectrometry capabilities. In this work, high specificity and high sensitivity secondary ion FT-ICR MS was applied to chemical imaging of biological tissue. An entire rat brain tissue was measured with 150 μm spatial resolution (75 μm primary ion spot size) with mass resolving power (m/Δm(50%)) of 67,500 (at m/z 750) and root-mean-square measurement accuracy less than two parts-per-million for intact phospholipids, small molecules and fragments. For the first time, ultra-high mass resolving power SIMS has been demonstrated, with m/Δm(50%) > 3,000,000. Higher spatial resolution capabilities of the platform were tested at a spatial resolution of 20 μm. The results represent order of magnitude improvements in mass resolving power and mass measurement accuracy for SIMS imaging and the promise of the platform for ultra-high mass resolving power and high spatial resolution imaging.
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http://dx.doi.org/10.1007/s00216-013-7048-1DOI Listing
July 2013

A MASSive laboratory tour. An interactive mass spectrometry outreach activity for children.

J Am Soc Mass Spectrom 2013 Jul 17;24(7):979-82. Epub 2013 May 17.

FOM-Institute AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands.

It is imperative to fascinate young children at an early stage in their education for the analytical sciences. The exposure of the public to mass spectrometry presently increases rapidly through the common media. Outreach activities can take advantage of this exposure and employ mass spectrometry as an exquisite example of an analytical science in which children can be fascinated. The presented teaching modules introduce children to mass spectrometry and give them the opportunity to experience a modern research laboratory. The modules are highly adaptable and can be applied to young children from the age of 6 to 14 y. In an interactive tour, the students explore three major scientific concepts related to mass spectrometry; the building blocks of matter, charged particle manipulation by electrostatic fields, and analyte identification by mass analysis. Also, the students carry out a mass spectrometry experiment and learn to interpret the resulting mass spectra. The multistage, inquiry-based tour contains flexible methods, which teach the students current-day research techniques and possible applications to real research topics. Besides the scientific concepts, laboratory safety and hygiene are stressed and the students are enthused for the analytical sciences by participating in "hands-on" work. The presented modules have repeatedly been successfully employed during laboratory open days. They are also found to be extremely suitable for (early) high school science classes during laboratory visit-focused field trips.
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http://dx.doi.org/10.1007/s13361-013-0663-4DOI Listing
July 2013

Lessons of history in veterinary medicine.

Authors:
Donald F Smith

J Vet Med Educ 2013 ;40(1):2-11

College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

The future of veterinary medicine is best understood in the context of history. What began as a profession rooted in urban centers in proximity to horses, physicians, and medical schools, was transformed into a land grant-based agricultural profession with the arrival of the internal combustion engine in the early twentieth century. Most of the United States' current veterinary colleges are still located in towns or small cities in the middle section of the country, outside the largest metropolitan areas where most veterinarians practice companion-animal medicine. Throughout veterinarian history, substantial numbers of US students have been educated in foreign colleges and this continues today, creating an even greater geographic imbalance between the veterinary educational process and US population centers and major medical schools. Three themes deserve special attention as we celebrate the profession's 150th anniversary. We must first move beyond the land-grant culture and develop a more geographically balanced approach to establishing new veterinary colleges that are also in closer association with schools of medicine and public health. We must also facilitate more opportunities for women leadership in organized veterinary medicine, in practice ownership, in academia, and in the corporate structures that educate, hire, and interface with veterinarians. Finally, we need to expand our understanding of One Health to include the concept of zooeyia (the role of animals in promoting human health), as well as continue to emphasize veterinarians' special roles in the control and management of zoonotic diseases and in advancing comparative medicine in the age of the genome.
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http://dx.doi.org/10.3138/jvme.1112.04DOI Listing
June 2013

Molecular Neurobiology of Depression: PET Findings on the Elusive Correlation with Symptom Severity.

Front Psychiatry 2013 4;4. Epub 2013 Mar 4.

Center for Psychiatric Research, Psychiatric Hospital of Aarhus University Risskov, Denmark.

Molecular mechanisms in the brain are assumed to cause the symptoms and severity of neuropsychiatric disorders. This review concerns the elusive nature of relationships between the severity of depressive disorders and neuromolecular processes studied by positron emission tomography (PET). Recent PET studies of human depression have focused on serotonergic, dopaminergic, muscarinic, nicotinic, and GABAergic receptors, as well as central processes dependent on monoamine oxidase, phosphodiesterase type 4, amyloid plaques, neurofibrillar tangles, and P-glycoprotein. We find that reliable causal links between neuromolecular mechanisms and relief from depressive disorders have yet to be convincingly demonstrated. This situation may contribute to the currently limited use of PET for exploring the neuropathways that are currently viewed as being responsible for beneficial effects of antidepressant treatment regimes.
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http://dx.doi.org/10.3389/fpsyt.2013.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586775PMC
March 2013

Microscope mode secondary ion mass spectrometry imaging with a Timepix detector.

Rev Sci Instrum 2013 Jan;84(1):013704

FOM Institute AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands.

In-vacuum active pixel detectors enable high sensitivity, highly parallel time- and space-resolved detection of ions from complex surfaces. For the first time, a Timepix detector assembly was combined with a secondary ion mass spectrometer for microscope mode secondary ion mass spectrometry (SIMS) imaging. Time resolved images from various benchmark samples demonstrate the imaging capabilities of the detector system. The main advantages of the active pixel detector are the higher signal-to-noise ratio and parallel acquisition of arrival time and position. Microscope mode SIMS imaging of biomolecules is demonstrated from tissue sections with the Timepix detector.
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http://dx.doi.org/10.1063/1.4772396DOI Listing
January 2013

Anaesthesia for positron emission tomography scanning of animal brains.

Lab Anim 2013 Jan 24;47(1):12-8. Epub 2013 Jan 24.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospitals, Nørrebrogade 44, 10G, DK-8000 Aarhus C, Denmark.

Positron emission tomography (PET) provides a means of studying physiological and pharmacological processes as they occur in the living brain. Mice, rats, dogs, cats, pigs and non-human primates are often used in studies using PET. They are commonly anaesthetized with ketamine, propofol or isoflurane in order to prevent them from moving during the imaging procedure. The use of anaesthesia in PET studies suffers, however, from the drawback of possibly altering central neuromolecular mechanisms. As a result, PET findings obtained in anaesthetized animals may fail to correctly represent normal properties of the awake brain. Here, we review findings of PET studies carried out either in both awake and anaesthetized animals or in animals given at least two different anaesthetics. Such studies provide a means of estimating the extent to which anaesthesia affects the outcome of PET neuroimaging in animals. While no final conclusion can be drawn concerning the 'best' general anaesthetic for PET neuroimaging in laboratory animals, such studies provide findings that can enhance an understanding of neurobiological mechanisms in the living brain.
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http://dx.doi.org/10.1258/la.2012.011173DOI Listing
January 2013