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51.
In order to increase our understanding of the mechanisms of learning and memory in the central nervous system, it is necessary to know the neurotransmitters and neuromodulators used in the specific neuronal circuits under study. Methods have been developed to identify the peptides released from single neurons and neuronal clusters from the common neuronal model Aplysia californica. Specifically, solid-phase extraction (SPE), capillary electrophoresis (CE) and matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) are combined for profiling neuropeptide releasates. A variety of combinations of SPE and CE were coupled off-line with MALDI-TOF-MS to reduce the high physiological salts, to concentrate the analytes, and to reduce the complexity of the mass spectra using separation. With these protocols, peptides and proteins up to 11000 Da were detected in releasates, offering a much wider mass range compared to direct MALDI analysis of the same releasates. A number of expected and unknown neuropeptides, including egg-laying hormone (ELH) and the partially processed delta/gamma-bag cell peptide were observed in the SPE-treated releasates from a single Aplysia-cultured bag cell neuron. However, by adding a CE separation after the SPE step preceding off-line MALDI-TOF-MS detection, the most complete neuropeptide profiles were obtained. 相似文献
52.
Dr. Dong-Kyu Lee Prof. Stanislav S. Rubakhin Prof. Irina Kusmartseva Prof. Clive Wasserfall Prof. Mark A. Atkinson Prof. Jonathan V. Sweedler 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(50):22773-22779
Linking molecular and chemical changes to human disease states depends on the availability of appropriate clinical samples, mostly preserved as formalin-fixed paraffin-embedded (FFPE) specimens stored in tissue banks. Mass spectrometry imaging (MSI) enables the visualization of the spatiotemporal distribution of molecules in biological samples. However, MSI is not effective for imaging FFPE tissues because of the chemical modifications of analytes, including complex crosslinking between nucleophilic moieties. Here we used an MS-compatible inorganic nucleophile, hydroxylamine hydrochloride, to chemically reverse inter- and intra-crosslinks from endogenous molecules. The analyte restoration appears specific for formaldehyde-reactive amino acids. This approach enabled the MSI-assisted localization of pancreatic peptides expressed in the alpha, beta, and gamma cells. Pancreatic islet-like distributions of islet hormones were observed in human FFPE tissues preserved for more than five years, demonstrating that samples from biobanks can effectively be investigated with MSI. 相似文献
53.
Integrated microfluidic structures, comprised of three-dimensional assemblies of microfluidic channels, can effect sequentially-linked analytical operations with mass-limited samples. This three-dimensional operation is enabled by electrically-switchable nanocapillary array membranes with novel transport properties. 相似文献
54.
Kevin R. Tucker Zhen Li Stanislav S. Rubakhin Jonathan V. Sweedler 《Journal of the American Society for Mass Spectrometry》2012,23(11):1931-1938
Neurons often exhibit a complex chemical distribution and topography; therefore, sample preparation protocols that preserve structures ranging from relatively large cell somata to small neurites and growth cones are important factors in secondary ion mass spectrometry (SIMS) imaging studies. Here, SIMS was used to investigate the subcellular localization of lipids and lipophilic species in neurons from Aplysia californica. Using individual neurons cultured on silicon wafers, we compared and optimized several SIMS sampling approaches. After an initial step to remove the high salt culturing media, formaldehyde, paraformaldehyde, and glycerol, and various combinations thereof, were tested for their ability to achieve cell stabilization during and after the removal of extracellular media. These treatments improved the preservation of cellular morphology as visualized with SIMS imaging. For analytes >250?Da, coating the cell surface with a 3.2?nm-thick gold layer increased the ion intensity; multiple analytes previously not observed or observed at low abundance were detected, including intact cholesterol and vitamin E molecular ions. However, once a sample was coated, many of the lower molecular mass (<200?Da) analyte signals were suppressed. The optimum approach depended on the analyte being studied; the approaches evaluated included rinsing with water and cell stabilization with glycerol and 4?% paraformaldehyde. The sample preparation methods described here enhance SIMS imaging of processes of individual cultured neurons over a broad mass range with enhanced image contrast. 相似文献
55.
Romanova EV Roth MJ Rubakhin SS Jakubowski JA Kelley WP Kirk MD Kelleher NL Sweedler JV 《Journal of mass spectrometry : JMS》2006,41(8):1030-1040
The beta-thymosins have been known as actin-sequestering proteins, but now are recognized as molecules with multiple and diverse intracellular and extracellular functions. Two closely related proteins, beta-thymosin(His) and beta-thymosin(Gln), have been de novo sequenced by top-down mass spectrometry in the common neurobiology model, Aplysia californica. As determined by nanoelectrospray quadrupole-enhanced Fourier-Transform mass spectrometry with collisionally activated and electron-capture dissociations, both of these Aplysia beta-thymosins are acetylated and differ by a single residue in the central actin-binding domain. Profiling of individual cells and tissue by matrix-assisted laser desorption/ionization mass spectrometry reveals that these proteins are widely expressed in the Aplysia central nervous system, including in individual identified neurons, neuronal clusters, nerves and connective tissues. Newly identified beta-thymosin(His) and beta-thymosin(Gln) are also detected by mass spectrometry in hemolymph, and in releasates collected from whole ganglia. When applied exogenously, beta-thymosin proteins, purified from nerve cell extract, support the anchoring of neurons, and increase neurite sprouting and total neurite outgrowth in culture. These positive effects on neurite regeneration in cell culture suggest that the beta-thymosin proteins have an extracellular function in the central nervous system of Aplysia californica. 相似文献
56.
Christopher A. Dailey Nicolas Garnier Stanislav S. Rubakhin Jonathan V. Sweedler 《Analytical and bioanalytical chemistry》2013,405(8):2451-2459
Capillary electrophoresis (CE) with laser-induced native fluorescence (LINF) detection offers the ability to characterize low levels of selected analyte classes, depending on the excitation and emission wavelengths used. Here a new automated CE-LINF system that provides deep ultraviolet (DUV) excitation (224 nm) and variable emission wavelength detection was evaluated for the analysis of small molecule tryptophan- and tyrosine-related metabolites. The optimized instrument design includes several features that increase throughput, lower instrument cost and maintenance, and decrease complexity when compared with earlier systems using DUV excitation. Sensitivity is enhanced by using an ellipsoid detection cell to increase the fluorescence collection efficiency. The limits of detection ranged from 4 to 30 nmol/L for serotonin and tyrosine, respectively. The system demonstrated excellent linearity over several orders of magnitude of concentration and intraday precision from 1–11 % relative standard deviation (RSD). The instrument’s performance was validated via tryptophan and serotonin characterization using tissue extracts from the mammalian brain stem, with RSDs of less than 10 % for both metabolites. The flexibility and sensitivity offered by DUV laser excitation and tunable emission enables a broad range of small-volume measurements. 相似文献
57.
Troy J. Comi Elizabeth K. Neumann Thanh D. Do Jonathan V. Sweedler 《Journal of the American Society for Mass Spectrometry》2017,28(9):1919-1928
Image-guided mass spectrometry (MS) profiling provides a facile framework for analyzing samples ranging from single cells to tissue sections. The fundamental workflow utilizes a whole-slide microscopy image to select targets of interest, determine their spatial locations, and subsequently perform MS analysis at those locations. Improving upon prior reported methodology, a software package was developed for working with microscopy images. microMS, for microscopy-guided mass spectrometry, allows the user to select and profile diverse samples using a variety of target patterns and mass analyzers. Written in Python, the program provides an intuitive graphical user interface to simplify image-guided MS for novice users. The class hierarchy of instrument interactions permits integration of new MS systems while retaining the feature-rich image analysis framework. microMS is a versatile platform for performing targeted profiling experiments using a series of mass spectrometers. The flexibility in mass analyzers greatly simplifies serial analyses of the same targets by different instruments. The current capabilities of microMS are presented, and its application for off-line analysis of single cells on three distinct instruments is demonstrated. The software has been made freely available for research purposes. 相似文献
58.
M E Lacey J V Sweedler C K Larive A J Pipe R D Farrant 《Journal of magnetic resonance (San Diego, Calif. : 1997)》2001,153(2):215-222
A capillary NMR flow probe was designed to generate high-resolution (1)H NMR spectra at 600 MHz from the cleaved product of individual 160-microm Tentagel combinatorial chemistry beads. By injecting a dissolved sample sandwiched between an immiscible, perfluorinated organic liquid directly into the probe, NMR spectra of the product cleaved from single beads were acquired in just 1 h of spectrometer time without diffusional dilution. Sample handling efficiency on the single bead scale was comparable to that obtained with a bulk sample. Using the relative intensity of the DMSO-d(5)H versus the analyte signals in a fully relaxed CPMG spectrum, the amount of product cleaved from a single bead was determined to be 540+/-170 pmol in one of the samples. Following the NMR data collection, the samples were examined with electrospray ionization mass spectrometry to provide additional structural information. By coupling with microliter-volume fluidic capabilities, the capillary flow probe described here will enable multidimensional characterization of single solid-phase resin products in an online manner. 相似文献
59.
Aveek N. Chatterjee Donald M. Cannon Enid N. Gatimu Jonathan V. Sweedler Narayana R. Aluru Paul W. Bohn 《Journal of nanoparticle research》2005,7(4-5):507-516
Electrokinetic fluid flow in nanocapillary array (NCA) membranes between vertically separated microfluidic channels offers an attractive alternative to using mechanical action to achieve fluidic communication between different regions of lab-on-a-chip devices. By adjusting the channel diameter, a, and the inverse Debye length, к, and applying the appropriate external potential, the nanochannel arrays, can be made to behave like digital fluidic switches, and the movement of molecules from one side of the array to the other side can be controlled. However, inherent differences in ionic mobility lead to non-equilibrium ion populations on the downstream side, which, in turn, shows up through transient changes in the microchannel conductance. Here we describe coupled calculations and experiments in which the electrical properties of a microfluidic–nanofluidic hybrid architecture are simulated by a combination of a compact model for the bulk electrical properties and iterative self-consistent solutions of the coupled Poisson, Nernst–Planck, and Navier–Stokes equations to recover the detailed ion motion in the nanopores. The transient electrical conductivity in the microchannel, after application of a forward bias pulse to the NCA membrane, is recovered in quantitative detail. The surface charge density of the nanopores and the capacitance of the membrane, which are critical determinants of electrokinetic flow through NCA, fall out of the analysis in a natural way, providing a clear mechanism to determine these critically important parameters. 相似文献
60.
Microfluidic devices are well suited for manipulating and measuring mass limited samples. Here we adapt a microfluidic device containing functionalized surfaces to chemically stimulate a small number of neurons (down to a single neuron), collect the release of neuropeptides, and characterize them using mass spectrometry. As only a small fraction of the peptides present in a neuron are released with physiologically relevant stimulations, the amount of material available for measurement is small, thereby requiring minimal sample loss and high-sensitivity detection. Although a number of detection schemes are used with microfluidic devices, mass spectrometric detection is used here because of its high information content, allowing the characterization of the released peptide complement. Rather than using an on-line approach, off-line analysis is used; after collection of the peptides onto a surface, mass spectrometric imaging interrogates that surface to determine the peptides released from the cell. The overall utility of this scheme is demonstrated using several device formats with measurement of neuropeptides released from Aplysia californica bag cell neurons. 相似文献