| 1. |
- Lu, Ru-Sen, et al.
(author)
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Detection of Intrinsic Source Structure at similar to 3 Schwarzschild Radii with Millimeter-VLBI Observations of SAGITTARIUS A*
- 2018
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In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 859:1
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Journal article (peer-reviewed)abstract
- We report results from very long baseline interferometric (VLBI) observations of the supermassive black hole in the Galactic center, Sgr A*, at 1.3 mm (230 GHz). The observations were performed in 2013 March using six VLBI stations in Hawaii, California, Arizona, and Chile. Compared to earlier observations, the addition of the APEX telescope in Chile almost doubles the longest baseline length in the array, provides additional uv coverage in the N-S direction, and leads to a spatial resolution of similar to 30 mu as (similar to 3 Schwarzschild radii) for Sgr A*. The source is detected even at the longest baselines with visibility amplitudes of similar to 4%-13% of the total flux density. We argue that such flux densities cannot result from interstellar refractive scattering alone, but indicate the presence of compact intrinsic source structure on scales of similar to 3 Schwarzschild radii. The measured nonzero closure phases rule out point-symmetric emission. We discuss our results in the context of simple geometric models that capture the basic characteristics and brightness distributions of disk-and jet-dominated models and show that both can reproduce the observed data. Common to these models are the brightness asymmetry, the orientation, and characteristic sizes, which are comparable to the expected size of the black hole shadow. Future 1.3 mm VLBI observations with an expanded array and better sensitivity will allow more detailed imaging of the horizon-scale structure and bear the potential for a deep insight into the physical processes at the black hole boundary.
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| 2. |
- Hulme, Heather E., et al.
(author)
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Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection
- 2017
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
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Journal article (peer-reviewed)abstract
- Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169(+) sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4(+) CD25(+) T cells and an increased number of B220(+) CD19(+) B cells. The reduction in CD4(+) CD25(+) T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome.
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| 3. |
- Swales, John G., et al.
(author)
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Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging
- 2018
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In: Analytical Chemistry. - : AMER CHEMICAL SOC. - 0003-2700 .- 1520-6882. ; 90:10, s. 6051-6058
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Journal article (peer-reviewed)abstract
- Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used to support drug-discovery efficacy testing. We evaluate and report on preanalysis-stabilization methods aimed at improving the reproducibility and efficiency of quantitative assessments of endogenous molecules in tissues. Stability experiments demonstrate that optimum stabilization protocols consist of frozen-tissue embedding, post-tissue-sectioning desiccation, and storage at -80 degrees C of tissue sections sealed in vacuum-tight containers. Optimized stabilization protocols are used in combination with qMSI methodology for the absolute quantitation of lactate and glutamate in tumors, incorporating the use of two different stable-isotope-labeled versions of each analyte and spectral-clustering performed on each tissue section using k-means clustering to allow region-specific, pixel-by-pixel quantitation. Region-specific qMSI was used to screen different tumor models and identify a phenotype that has low lactate heterogeneity, which will enable accurate measurements of lactate modulation in future drug-discovery studies. We conclude that using optimized qMSI protocols, it is possible to quantify endogenous metabolites within tumors, and region-specific quantitation can provide valuable insight into tissue heterogeneity and the tumor microenvironment.
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| 4. |
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| 5. |
- Hamm, Gregory R., et al.
(author)
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Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging
- 2020
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In: Journal of Aerosol Medicine. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 33:1, s. 43-53
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Journal article (peer-reviewed)abstract
- Background: For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI).Methods: Salmeterol, salbutamol, and FP were simultaneously delivered by inhaled nebulization to rats. In the same animals, salmeterol-d(3), salbutamol-d(3), and FP-d(3) were delivered by intravenous (IV) injection. Samples of lung tissue were obtained at 2- and 30-minute postdosing, and high-resolution MSI was used to study drug distribution and retention.Results: IV delivery resulted in homogeneous lung distribution for all molecules. In comparison, while inhalation also gave rise to drug presence in the entire lung, there were regional chemotype-dependent areas of higher abundance. At the 30-minute time point, inhaled salmeterol and salbutamol were preferentially retained in bronchiolar tissue, whereas FP was retained in all regions of the lungs.Conclusion: This study clearly demonstrates that inhaled small molecule chemotypes are differentially distributed in lung tissue after inhalation, and that high-resolution MSI can be applied to study these retention patterns.
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| 8. |
- Shariatgorji, Mohammadreza, et al.
(author)
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Bromopyrylium Derivatization Facilitates Identification by Mass Spectrometry Imaging of Monoamine Neurotransmitters and Small Molecule Neuroactive Compounds
- 2020
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In: Journal of the American Society for Mass Spectrometry. - : AMER CHEMICAL SOC. - 1044-0305 .- 1879-1123. ; 31:12, s. 2553-2557
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Journal article (peer-reviewed)abstract
- Mass spectrometry imaging using matrix-assisted laser desorption/ionization and desorption electrospray ionization has recently been employed to investigate the distribution of neurotransmitters, including biogenic amines and amino acids, directly in brain tissue sections. Ionization is facilitated by charge-tagging through pyrylium derivatization of primary amine containing neurotransmitters directly in tissue sections, significantly improving the limit of detection. Since the derivatization adds carbon and hydrogen to the target compounds, the resulting isotopic patterns of the products are not distinctive from those of the nonderivatized species. Here, we describe an approach for chemically modifying the reactive pyrylium ion to introduce the distinct isotopic signature of bromine in mass spectra of chemically derivatized substances in tissue sections. The method enables monoamine compounds to be distinguished directly in tissue sections, facilitating their identification.
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| 9. |
- Shariatgorji, Mohammadreza, et al.
(author)
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Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry
- 2016
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In: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 136, s. 129-138
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Journal article (peer-reviewed)abstract
- With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate,gamma-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.
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| 10. |
- Shariatgorji, Reza, et al.
(author)
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Spatial visualization of comprehensive brain neurotransmitter systems and neuroactive substances by selective in situ chemical derivatization mass spectrometry imaging
- 2021
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In: Nature Protocols. - : Springer Nature. - 1754-2189 .- 1750-2799. ; 16:7, s. 3298-3321
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Journal article (peer-reviewed)abstract
- Molecule-specific techniques such as MALDI and desorption electrospray ionization mass spectrometry imaging enable direct and simultaneous mapping of biomolecules in tissue sections in a single experiment. However, neurotransmitter imaging in the complex environment of biological samples remains challenging. Our covalent charge-tagging approach using on-tissue chemical derivatization of primary and secondary amines and phenolic hydroxyls enables comprehensive mapping of neurotransmitter networks. Here, we present robust and easy-to-use chemical derivatization protocols that facilitate quantitative and simultaneous molecular imaging of complete neurotransmitter systems and drugs in diverse biological tissue sections with high lateral resolution. This is currently not possible with any other imaging technique. The protocol, using fluoromethylpyridinium and pyrylium reagents, describes all steps from tissue preparation (-1 h), chemical derivatization (1-2 h), data collection (timing depends on the number of samples and lateral resolution) and data analysis and interpretation. The specificity of the chemical reaction can also help users identify unknown chemical identities. Our protocol can reveal the cellular locations in which signaling molecules act and thus shed light on the complex responses that occur after the administration of drugs or during the course of a disease.
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