Publications by authors named "Jeremy Post"

10 Publications

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Mass Spectrometric Imaging of Ceramide Biomarkers Tracks Therapeutic Response in Traumatic Brain Injury.

ACS Chem Neurosci 2017 10 14;8(10):2266-2274. Epub 2017 Aug 14.

Structural Biology Unit, Integrative Neuroscience Branch, NIH/NIDA-IRP , Baltimore, Maryland 21224, United States.

Traumatic brain injury (TBI) is a serious public health problem and the leading cause of death in children and young adults. It also contributes to a substantial number of cases of permanent disability. As lipids make up over 50% of the brain mass and play a key role in both membrane structure and cell signaling, their profile is of particular interest. In this study, we show that advanced mass spectrometry imaging (MSI) has sufficient technical accuracy and reproducibility to demonstrate the anatomical distribution of 50 μm diameter microdomains that show changes in brain ceramide levels in a rat model of controlled cortical impact (CCI) 3 days post injury with and without treatment. Adult male Sprague-Dawley rats received one strike and were euthanized 3 days post trauma. Brain MS images showed increase in ceramides in CCI animals compared to control as well as significant reduction in ceramides in CCI treated animals, demonstrating therapeutic effect of a peptide agonist. The data also suggests the presence of diffuse changes outside of the injured area. These results shed light on the extent of biochemical and structural changes in the brain after traumatic brain injury and could help to evaluate the efficacy of treatments.
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http://dx.doi.org/10.1021/acschemneuro.7b00189DOI Listing
October 2017

Mass spectrometry imaging of rat brain lipid profile changes over time following traumatic brain injury.

J Neurosci Methods 2016 10 10;272:19-32. Epub 2016 Feb 10.

Structural Biology Unit, Integrative Neuroscience Branch, NIH/NIDA-IRP, Baltimore, MD 21224, United States. Electronic address:

Background: Mild traumatic brain injury (TBI) is a common public health issue that may contribute to chronic degenerative disorders. Membrane lipids play a key role in tissue responses to injury, both as cell signals and as components of membrane structure and cell signaling. This study demonstrates the ability of high resolution mass spectrometry imaging (MSI) to assess sequences of responses of lipid species in a rat controlled cortical impact model for concussion.

New Method: A matrix of implanted silver nanoparticles was implanted superficially in brain sections for matrix-assisted laser desorption (MALDI) imaging of 50μm diameter microdomains across unfixed cryostat sections of rat brain. Ion-mobility time-of-flight MS was used to analyze and map changes over time in brain lipid composition in a rats after Controlled Cortical Impact (CCI) TBI.

Results: Brain MS images showed changes in sphingolipids near the CCI site, including increased ceramides and decreased sphingomyelins, accompanied by changes in glycerophospholipids and cholesterol derivatives. The kinetics differed for each lipid class; for example ceramides increased as early as 1 day after the injury whereas other lipids changes occurred between 3 and 7 days post injury.

Comparison With Existing Method(s): Silver nanoparticles MALDI matrix is a sensitive new tool for revealing previously undetectable cellular injury response and remodeling in neural, glial and vascular structure of the brain.

Conclusions: Lipid biochemical and structural changes after TBI could help highlighting molecules that can be used to determine the severity of such injuries as well as to evaluate the efficacy of potential treatments.
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http://dx.doi.org/10.1016/j.jneumeth.2016.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577232PMC
October 2016

Gangliosides and ceramides change in a mouse model of blast induced traumatic brain injury.

ACS Chem Neurosci 2013 Apr 17;4(4):594-600. Epub 2013 Jan 17.

Structural Biology Unit, NIDA IRP, National Institutes of Health, Baltimore, MD 21224, USA.

Explosive detonations generate atmospheric pressure changes that produce nonpenetrating blast induced "mild" traumatic brain injury (bTBI). The structural basis for mild bTBI has been extremely controversial. The present study applies matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging to track the distribution of gangliosides in mouse brain tissue that were exposed to very low level of explosive detonations (2.5-5.5 psi peak overpressure). We observed major increases of the ganglioside GM2 in the hippocampus, thalamus, and hypothalamus after a single blast exposure. Moreover, these changes were accompanied by depletion of ceramides. No neurological or brain structural signs of injury could be inferred using standard light microscopic techniques. The first source of variability is generated by the Latency between blast and tissue sampling (peak intensity of the blast wave). These findings suggest that subtle molecular changes in intracellular membranes and plasmalemma compartments may be biomarkers for biological responses to mild bTBI. This is also the first report of a GM2 increase in the brains of mature mice from a nongenetic etiology.
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http://dx.doi.org/10.1021/cn300216hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629744PMC
April 2013

Analysis of native biological surfaces using a 100 kV massive gold cluster source.

Anal Chem 2011 Nov 18;83(22):8448-53. Epub 2011 Oct 18.

Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States.

In the present work, the advantages of a new, 100 kV platform equipped with a massive gold cluster source for the analysis of native biological surfaces are shown. Inspection of the molecular ion emission as a function of projectile size demonstrates a secondary ion yield increase of ~100× for 520 keV Au(400)(4+) as compared to 130 keV Au(3)(1+) and 43 keV C(60). In particular, yields of tens of percent of molecular ions per projectile impact for the most abundant components can be observed with the 520 keV Au(400)(4+) probe. A comparison between 520 keV Au(400)(4+) time-of-flight-secondary ion mass spectrometry (TOF-SIMS) and matrix assisted laser desorption ionization-mass spectrometry (MALDI-MS) data showed a similar pattern and similar relative intensities of lipid components across a rat brain sagittal section. The abundant secondary ion yield of analyte-specific ions makes 520 keV Au(400)(4+) projectiles an attractive probe for submicrometer molecular mapping of native surfaces.
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http://dx.doi.org/10.1021/ac201481rDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236644PMC
November 2011

A Minimalist Approach to MALDI Imaging of Glycerophospholipids and Sphingolipids in Rat Brain Sections.

Int J Mass Spectrom 2008 Dec;278(2-3):143-149

NIDA IRP, NIH.

Matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) is a powerful tool that has allowed researchers to directly probe tissue molecular structure and drug content with minimal manipulations, while maintaining anatomical integrity. In the present work glycerophospholipids and sphingolipids images were acquired from 16 µm thick coronal rat brain sections using MALDI-MS. Images of phosphatidylinositol 38:4 (PI 38:4), suifatide 24:1 (ST 24:1), and hydroxyl sulfatide 24:1 (ST 24:1 (OH)) were acquired in negative ion mode, while the images of phosphatidylcholine 34:1 (PC 34:1), potassiated phosphatidylcholines 32:0 (PC32:0 + K(+)) and 36:1 (PC 36:1 +K(+)) were acquired in positive ion mode. The images of PI 38:4 and PC 36:1+K(+) show the preferential distribution of these two lipids in gray matter; and the images of two sulfatides and PC 32:0+K(+) show their preferential distribution in white matter. In addition, the gray cortical band and its adjacent anatomical structures were also identified by contrasting their lipid makeup. The resulting images were compared to lipid images acquired by secondary ion mass spectrometry (SIMS). The suitability of TLC sprayers, Collison Nebulizer, and artistic airbrush were also evaluated as means for matrix deposition.
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http://dx.doi.org/10.1016/j.ijms.2008.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614269PMC
December 2008

Astaxanthin reduces ischemic brain injury in adult rats.

FASEB J 2009 Jun 13;23(6):1958-68. Epub 2009 Feb 13.

National Institute on Drug Abuse, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.

Astaxanthin (ATX) is a dietary carotenoid of crustaceans and fish that contributes to their coloration. Dietary ATX is important for development and survival of salmonids and crustaceans and has been shown to reduce cardiac ischemic injury in rodents. The purpose of this study was to examine whether ATX can protect against ischemic injury in the mammalian brain. Adult rats were injected intracerebroventricularly with ATX or vehicle prior to a 60-min middle cerebral artery occlusion (MCAo). ATX was present in the infarction area at 70-75 min after onset of MCAo. Treatment with ATX, compared to vehicle, increased locomotor activity in stroke rats and reduced cerebral infarction at 2 d after MCAo. To evaluate the protective mechanisms of ATX against stroke, brain tissues were assayed for free radical damage, apoptosis, and excitoxicity. ATX antagonized ischemia-mediated loss of aconitase activity and reduced glutamate release, lipid peroxidation, translocation of cytochrome c, and TUNEL labeling in the ischemic cortex. ATX did not alter physiological parameters, such as body temperature, brain temperature, cerebral blood flow, blood gases, blood pressure, and pH. Collectively, our data suggest that ATX can reduce ischemia-related injury in brain tissue through the inhibition of oxidative stress, reduction of glutamate release, and antiapoptosis. ATX may be clinically useful for patients vulnerable or prone to ischemic events.
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http://dx.doi.org/10.1096/fj.08-123281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698661PMC
June 2009

A study of phospholipids by ion mobility TOFMS.

J Am Soc Mass Spectrom 2008 Nov 16;19(11):1655-62. Epub 2008 Jul 16.

National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, Maryland 21224, USA.

Combining matrix-assisted laser desorption/ionization (MALDI) mass spectrometry with ion mobility (IM) results in the fast sorting of biomolecules in complex mixtures along trend lines. In this two-dimensional (2D) analysis of biological families, lipids, peptides, and nucleotides are separated from each other by differences in their ion mobility drift times in a timescale of hundreds of microseconds. Molecular ions of similar chemical type fall along trend lines when plotted in 2D plots of ion mobility drift time as a function of m/z. In this study, MALDI-IM MS is used to analyze species from all of the major phospholipid classes. Complex samples, including tissue extracts and sections, were probed to demonstrate the effects that radyl chain length, degree of unsaturation, and class/head group have upon an ion's cross section in the gas phase. We illustrate how these changes can be used to identify individual lipid species in complex mixtures, as well as the effects of cationization on ion cross section and ionization efficiency.
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http://dx.doi.org/10.1016/j.jasms.2008.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630282PMC
November 2008

MALDI-ion mobility-TOFMS imaging of lipids in rat brain tissue.

J Mass Spectrom 2007 Aug;42(8):1093-8

NIDA IRP, NIH, Baltimore, MD 21224, USA.

While maintaining anatomical integrity, matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) has allowed researchers to directly probe tissue, map the distribution of analytes and elucidate molecular structure with minimal preparation. MALDI-ion mobility (IM)-orthogonal time-of-flight mass spectrometry (oTOFMS) provides an advantage by initially separating different classes of biomolecules such as lipids, peptides, and nucleotides by their IM drift times prior to mass analysis. In the present work the distribution of phosphatidlycholine and cerebroside species was mapped from 16 microm thick coronal rat brain sections using MALDI-IM-oTOFMS. Furthermore, the use of gold nanoparticles as a matrix enables detection of cerebrosides, which although highly concentrated in brain tissue, are not easily observed as positive ions because of intense signals from lipids such as phosphatidlycholines and sphingomyelins.
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http://dx.doi.org/10.1002/jms.1245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953759PMC
August 2007

Molecular basis for the specificity of p27 toward cyclin-dependent kinases that regulate cell division.

J Mol Biol 2005 Jun 26;349(4):764-73. Epub 2005 Apr 26.

Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

The cyclin-dependent kinase inhibitors (CKIs) bind to and directly regulate the catalytic activity of cyclin-dependent kinase (Cdk)/cyclin complexes involved in cell cycle control and do not regulate other, closely related Cdks. We showed previously that the CKI, p27, binds to Cdk2/cyclin A though a sequential mechanism that involves folding-on-binding. The first step in the kinetic mechanism is interaction of a small, highly dynamic domain of p27 (domain 1) with the cyclin subunit of the Cdk2/cyclin A complex, followed by much slower binding of a more lengthy and less flexible domain (domain 2) to Cdk2. The second step requires folding of domain 2 into the kinase inhibitory conformation. Rapid binding of p27 domain 1 to cyclin A tethers the inhibitor to the binary Cdk2/cyclin A complex, which reduces the entropic barrier associated with slow binding of domain 2 to the catalytic subunit. We show here that p27/cyclin interactions are an important determinant of p27 specificity towards cell cycle Cdks. We used surface plasmon resonance, limited proteolysis, mass spectrometry, and NMR spectroscopy to study the interaction of p27 with Cdk2/cyclin A, and with another Cdk complex, Cdk5/p25, that is involved in neurodegeneration. Importantly, Cdk5/p35 (the parent complex of Cdk5/p25) is not regulated by p27 in neurons. Our results show that p27 binds to Cdk5 and Cdk2 with similar, slow kinetics. However, p27 fails to interact with p25 within the Cdk5/p25 complex, which we believe prevents formation of a kinetically trapped, inhibited p27/Cdk5/p25 complex in vivo. The helical topology of p25 is very similar to that of cyclin A. However, p25 lacks the MRAIL sequence in one helix that, in the cell cycle cyclins, mediates specific interactions with domain 1 of p21 and p27. Our results strongly suggest that p21 and p27, related Cdk inhibitors, select their cell cycle regulatory Cdk targets by binding specifically to the cyclin subunit of these Cdk/cyclin complexes as a first step in a sequential, folding-on-binding mechanism.
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http://dx.doi.org/10.1016/j.jmb.2005.04.019DOI Listing
June 2005