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Publication Record


Enhanced Ion Transmission Efficiency up to m/ z 24 000 for MALDI Protein Imaging Mass Spectrometry.
Prentice BM, Ryan DJ, Van de Plas R, Caprioli RM, Spraggins JM
(2018) Anal Chem 90: 5090-5099
MeSH Terms: Animals, Apoproteins, Brain, Ions, Kidney, Molecular Weight, Myoglobin, Proteins, Rats, Signal-To-Noise Ratio, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Ubiquitin
Show Abstract · Added March 22, 2018
The molecular identification of species of interest is an important part of an imaging mass spectrometry (IMS) experiment. The high resolution accurate mass capabilities of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) have recently been shown to facilitate the identification of proteins in matrix-assisted laser desorption/ionization (MALDI) IMS. However, these experiments are typically limited to proteins giving rise to ions of relatively low m/ z due to difficulties transmitting and measuring large molecular weight ions of low charge states. Herein we have modified the source gas manifold of a commercial MALDI FT-ICR MS to regulate the gas flow and pressure to maximize the transmission of large m/ z protein ions through the ion funnel region of the instrument. By minimizing the contribution of off-axis gas disruption to ion focusing and maximizing the effective potential wall confining the ions through pressure optimization, the signal-to-noise ratios (S/N) of most protein species were improved by roughly 1 order of magnitude compared to normal source conditions. These modifications enabled the detection of protein standards up to m/ z 24 000 and the detection of proteins from tissue up to m/ z 22 000 with good S/N, roughly doubling the mass range for which high quality protein ion images from rat brain and kidney tissue could be produced. Due to the long time-domain transients (>4 s) required to isotopically resolve high m/ z proteins, we have used these data as part of an FT-ICR IMS-microscopy data-driven image fusion workflow to produce estimated protein images with both high mass and high spatial resolutions.
0 Communities
3 Members
0 Resources
12 MeSH Terms
Poly(glycidol) Coating on Ultrahigh Molecular Weight Polyethylene for Reduced Biofilm Growth.
Lockhart JN, Spoonmore TJ, McCurdy MW, Rogers BR, Guelcher SA, Harth E
(2018) ACS Appl Mater Interfaces 10: 4050-4056
MeSH Terms: Biofilms, Coated Materials, Biocompatible, Molecular Weight, Polyethylenes, Propylene Glycols, Staphylococcus aureus
Show Abstract · Added March 25, 2018
Semibranched poly(glycidol) (PG-OH) and poly(glycidol allylglycidyl ether) (PG-Allyl) coatings were formed on ultrahigh molecular weight polyethylene (UMWPE) in a unique two-step process which included radiation of UHMWPE followed by grafting of PG-OH or PG-Allyl to the surface via free radical cross-linking. Resulting surfaces were extensively characterized by FTIR-ATR, XPS, fluorescent microscopy, and contact goniometry. The performance was evaluated using the most prominent biofilm-forming bacteria Staphylococcus aureus for 24 and 48 h. The PG-Allyl coating demonstrated a 3 log reduction in biofilm growth compared to noncoated control, demonstrating a promising potential to inhibit adherence and colonization of biofilm-forming bacteria that often develop into persistent infections.
0 Communities
1 Members
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6 MeSH Terms
Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients.
Schonhoft JD, Monteiro C, Plate L, Eisele YS, Kelly JM, Boland D, Parker CG, Cravatt BF, Teruya S, Helmke S, Maurer M, Berk J, Sekijima Y, Novais M, Coelho T, Powers ET, Kelly JW
(2017) Sci Transl Med 9:
MeSH Terms: Amyloidosis, Familial, Benzoxazoles, Case-Control Studies, Cross-Linking Reagents, Diazomethane, Genotype, Humans, Ions, Light, Molecular Probes, Molecular Weight, Peptides, Prealbumin, Protein Folding, Protein Multimerization, Protein Structure, Secondary, Proteolysis, Proteomics, Solubility
Show Abstract · Added March 3, 2020
Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure-based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant-mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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1 Members
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MeSH Terms
Simple rules for passive diffusion through the nuclear pore complex.
Timney BL, Raveh B, Mironska R, Trivedi JM, Kim SJ, Russel D, Wente SR, Sali A, Rout MP
(2016) J Cell Biol 215: 57-76
MeSH Terms: Biological Transport, Computer Simulation, Diffusion, Fluorescence Recovery After Photobleaching, Kinetics, Macromolecular Substances, Molecular Weight, Mutation, Nuclear Pore, Nuclear Pore Complex Proteins, Permeability, Protein Domains, Saccharomyces cerevisiae, Substrate Specificity, Thermodynamics, Time Factors
Show Abstract · Added April 14, 2017
Passive macromolecular diffusion through nuclear pore complexes (NPCs) is thought to decrease dramatically beyond a 30-60-kD size threshold. Using thousands of independent time-resolved fluorescence microscopy measurements in vivo, we show that the NPC lacks such a firm size threshold; instead, it forms a soft barrier to passive diffusion that intensifies gradually with increasing molecular mass in both the wild-type and mutant strains with various subsets of phenylalanine-glycine (FG) domains and different levels of baseline passive permeability. Brownian dynamics simulations replicate these findings and indicate that the soft barrier results from the highly dynamic FG repeat domains and the diffusing macromolecules mutually constraining and competing for available volume in the interior of the NPC, setting up entropic repulsion forces. We found that FG domains with exceptionally high net charge and low hydropathy near the cytoplasmic end of the central channel contribute more strongly to obstruction of passive diffusion than to facilitated transport, revealing a compartmentalized functional arrangement within the NPC.
© 2016 Timney et al.
0 Communities
1 Members
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16 MeSH Terms
Preprocessing significantly improves the peptide/protein identification sensitivity of high-resolution isobarically labeled tandem mass spectrometry data.
Sheng Q, Li R, Dai J, Li Q, Su Z, Guo Y, Li C, Shyr Y, Zeng R
(2015) Mol Cell Proteomics 14: 405-17
MeSH Terms: Animals, Databases, Protein, Ions, Isotope Labeling, Molecular Weight, Peptides, Proteins, Rats, Search Engine, Statistics as Topic, Tandem Mass Spectrometry
Show Abstract · Added February 19, 2015
Isobaric labeling techniques coupled with high-resolution mass spectrometry have been widely employed in proteomic workflows requiring relative quantification. For each high-resolution tandem mass spectrum (MS/MS), isobaric labeling techniques can be used not only to quantify the peptide from different samples by reporter ions, but also to identify the peptide it is derived from. Because the ions related to isobaric labeling may act as noise in database searching, the MS/MS spectrum should be preprocessed before peptide or protein identification. In this article, we demonstrate that there are a lot of high-frequency, high-abundance isobaric related ions in the MS/MS spectrum, and removing isobaric related ions combined with deisotoping and deconvolution in MS/MS preprocessing procedures significantly improves the peptide/protein identification sensitivity. The user-friendly software package TurboRaw2MGF (v2.0) has been implemented for converting raw TIC data files to mascot generic format files and can be downloaded for free from https://github.com/shengqh/RCPA.Tools/releases as part of the software suite ProteomicsTools. The data have been deposited to the ProteomeXchange with identifier PXD000994.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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2 Members
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11 MeSH Terms
Immediate recovery of acquired von Willebrand syndrome after left ventricular assist device explantation: implications for heart transplantation.
Davis ME, Haglund NA, Tricarico NM, Matafonov A, Gailani D, Maltais S
(2015) ASAIO J 61: e1-4
MeSH Terms: Heart Transplantation, Heart-Assist Devices, Humans, Male, Middle Aged, Molecular Weight, Myxovirus Resistance Proteins, Postoperative Hemorrhage, Shock, Cardiogenic, von Willebrand Diseases, von Willebrand Factor
Show Abstract · Added January 20, 2015
All patients supported with continuous flow-left ventricular assist devices (CF-LVADs) develop acquired von Willebrand syndrome due to the loss of von Willebrand factor (vWF) high molecular weight (HMW) multimers and this phenomenon has been associated with clinical manifestation of bleeding diatheses. The precise timing of postoperative recovery of HMW multimers and correction of this condition after CF-LVAD explantation and heart transplantation is unknown. We sought to determine the specific timing of HMW multimer recovery by serially quantifying plasma vWF multimer ratios after CF-LVAD explant and orthotopic heart transplantation (OHT) in a patient implanted with a HeartWare ventricular assist device. Using densitometric analysis of multimer patterns, we demonstrated complete recovery of HMW multimers within the first few hours following CF-LVAD explant and OHT. These findings have critical implications in the context of perioperative bleeding diatheses in patients bridged to transplantation with a CF-LVAD.
0 Communities
1 Members
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11 MeSH Terms
JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function.
Monteiro AC, Sumagin R, Rankin CR, Leoni G, Mina MJ, Reiter DM, Stehle T, Dermody TS, Schaefer SA, Hall RA, Nusrat A, Parkos CA
(2013) Mol Biol Cell 24: 2849-60
MeSH Terms: Animals, Capsid Proteins, Cell Adhesion Molecules, Cell Line, Cell Membrane Permeability, Cell Polarity, Cytoskeleton, Down-Regulation, Endocytosis, Epithelial Cells, Guanine Nucleotide Exchange Factors, Humans, Mice, Microfilament Proteins, Models, Biological, Molecular Weight, Nerve Tissue Proteins, Protein Binding, Protein Transport, Receptors, Cell Surface, Tight Junctions, Zonula Occludens-2 Protein, rap1 GTP-Binding Proteins, ras Proteins, rhoA GTP-Binding Protein
Show Abstract · Added December 10, 2013
Intestinal barrier function is regulated by epithelial tight junctions (TJs), structures that control paracellular permeability. Junctional adhesion molecule-A (JAM-A) is a TJ-associated protein that regulates barrier; however, mechanisms linking JAM-A to epithelial permeability are poorly understood. Here we report that JAM-A associates directly with ZO-2 and indirectly with afadin, and this complex, along with PDZ-GEF1, activates the small GTPase Rap2c. Supporting a functional link, small interfering RNA-mediated down-regulation of the foregoing regulatory proteins results in enhanced permeability similar to that observed after JAM-A loss. JAM-A-deficient mice and cultured epithelial cells demonstrate enhanced paracellular permeability to large molecules, revealing a potential role of JAM-A in controlling perijunctional actin cytoskeleton in addition to its previously reported role in regulating claudin proteins and small-molecule permeability. Further experiments suggest that JAM-A does not regulate actin turnover but modulates activity of RhoA and phosphorylation of nonmuscle myosin, both implicated in actomyosin contraction. These results suggest that JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.
0 Communities
1 Members
0 Resources
25 MeSH Terms
A magnetic bead-based method for concentrating DNA from human urine for downstream detection.
Bordelon H, Russ PK, Wright DW, Haselton FR
(2013) PLoS One 8: e68369
MeSH Terms: Adsorption, Base Sequence, Buffers, DNA, Freeze Drying, Humans, Kinetics, Limit of Detection, Magnetics, Microspheres, Molecular Weight, Polymerase Chain Reaction, Reagent Kits, Diagnostic, Silicon Dioxide, Specimen Handling
Show Abstract · Added May 27, 2014
Due to the presence of PCR inhibitors, PCR cannot be used directly on most clinical samples, including human urine, without pre-treatment. A magnetic bead-based strategy is one potential method to collect biomarkers from urine samples and separate the biomarkers from PCR inhibitors. In this report, a 1 mL urine sample was mixed within the bulb of a transfer pipette containing lyophilized nucleic acid-silica adsorption buffer and silica-coated magnetic beads. After mixing, the sample was transferred from the pipette bulb to a small diameter tube, and captured biomarkers were concentrated using magnetic entrainment of beads through pre-arrayed wash solutions separated by small air gaps. Feasibility was tested using synthetic segments of the 140 bp tuberculosis IS6110 DNA sequence spiked into pooled human urine samples. DNA recovery was evaluated by qPCR. Despite the presence of spiked DNA, no DNA was detectable in unextracted urine samples, presumably due to the presence of PCR inhibitors. However, following extraction with the magnetic bead-based method, we found that ∼50% of spiked TB DNA was recovered from human urine containing roughly 5×10(3) to 5×10(8) copies of IS6110 DNA. In addition, the DNA was concentrated approximately ten-fold into water. The final concentration of DNA in the eluate was 5×10(6), 14×10(6), and 8×10(6) copies/µL for 1, 3, and 5 mL urine samples, respectively. Lyophilized and freshly prepared reagents within the transfer pipette produced similar results, suggesting that long-term storage without refrigeration is possible. DNA recovery increased with the length of the spiked DNA segments from 10±0.9% for a 75 bp DNA sequence to 42±4% for a 100 bp segment and 58±9% for a 140 bp segment. The estimated LOD was 77 copies of DNA/µL of urine. The strategy presented here provides a simple means to achieve high nucleic acid recovery from easily obtained urine samples, which does not contain inhibitors of PCR.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Flagellar localization of a Helicobacter pylori autotransporter protein.
Radin JN, Gaddy JA, González-Rivera C, Loh JT, Algood HM, Cover TL
(2013) mBio 4: e00613-12
MeSH Terms: Animals, Bacterial Proteins, Disease Models, Animal, Flagella, Gene Deletion, Gene Expression Regulation, Bacterial, Helicobacter Infections, Helicobacter pylori, Humans, Locomotion, Male, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Molecular Weight, Stomach, Virulence
Show Abstract · Added January 13, 2014
UNLABELLED - Helicobacter pylori contains four genes that are predicted to encode proteins secreted by the autotransporter (type V) pathway. One of these, the pore-forming toxin VacA, has been studied in great detail, but thus far there has been very little investigation of three VacA-like proteins. We show here that all three VacA-like proteins are >250 kDa in mass and localized on the surface of H. pylori. The expression of the three vacA-like genes is upregulated during H. pylori colonization of the mouse stomach compared to H. pylori growth in vitro, and a wild-type H. pylori strain outcompeted each of the three corresponding isogenic mutant strains in its ability to colonize the mouse stomach. One of the VacA-like proteins localizes to a sheath that overlies the flagellar filament and bulb, and therefore, we designate it FaaA (flagella-associated autotransporter A). In comparison to a wild-type H. pylori strain, an isogenic faaA mutant strain exhibits decreased motility, decreased flagellar stability, and an increased proportion of flagella in a nonpolar site. The flagellar localization of FaaA differs markedly from the localization of other known autotransporters, and the current results reveal an important role of FaaA in flagellar localization and motility.
IMPORTANCE - The pathogenesis of most bacterial infections is dependent on the actions of secreted proteins, and proteins secreted by the autotransporter pathway constitute the largest family of secreted proteins in pathogenic Gram-negative bacteria. In this study, we analyzed three autotransporter proteins (VacA-like proteins) produced by Helicobacter pylori, a Gram-negative bacterium that colonizes the human stomach and contributes to the pathogenesis of gastric cancer and peptic ulcer disease. We demonstrate that these three proteins each enhance the capacity of H. pylori to colonize the stomach. Unexpectedly, one of these proteins (FaaA) is localized to a sheath that overlies H. pylori flagella. The absence of FaaA results in decreased H. pylori motility as well as a reduction in flagellar stability and a change in flagellar localization. The atypical localization of FaaA reflects a specialized function of this autotransporter designed to optimize H. pylori colonization of the gastric niche.
1 Communities
3 Members
0 Resources
17 MeSH Terms
Localized in situ hydrogel-mediated protein digestion and extraction technique for on-tissue analysis.
Harris GA, Nicklay JJ, Caprioli RM
(2013) Anal Chem 85: 2717-23
MeSH Terms: Animals, Cerebrum, Chemical Fractionation, Chromatography, Liquid, Hydrogels, Molecular Weight, Proteins, Proteolysis, Rats, Rats, Sprague-Dawley, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tandem Mass Spectrometry
Show Abstract · Added March 7, 2014
A simultaneous on-tissue proteolytic digestion and extraction method is described for the in situ analysis of proteins from spatially distinct areas of a tissue section. The digestion occurs on-tissue within a hydrogel network, and peptides extracted from this gel are identified with liquid chromatography tandem MS (LC-MS/MS). The hydrogels are compatible with solubility agents (e.g., chaotropes and detergents) known to improve enzymatic digestion of proteins. Additionally, digestions and extractions are compatible with imaging mass spectrometry (IMS) experiments. As an example application, an initial IMS experiment was conducted to profile lipid species using a traveling wave ion mobility mass spectrometer. On-tissue MS/MS was also performed on the same tissue section to identify lipid ions that showed spatial differences. Subsequently, the section underwent an on-tissue hydrogel digestion to reveal 96 proteins that colocalized to the rat brain cerebellum. Hematoxylin and eosin (H & E) staining was then performed to provide additional histological information about the tissue structure. This technology provides a versatile workflow that can be used to correlate multiple complementary analytical approaches in the analysis of a single tissue section.
1 Communities
1 Members
0 Resources
12 MeSH Terms