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PubMed2004

An optimized CZE method for analysis of mono- and oligomeric aldose mixtures.

An optimized capillary electrophoresis (CZE) method to analyze complex mixtures of aldoses was developed. The approach allows simultaneous quantitative analysis of all four isomeric aldopentoses, eight aldohexoses, as well as xylo- and cellooligosaccharides up to the tetraoses. UV tagging with 4-aminobenzoic acid ethyl ester (ABEE) in combination with reductive amination was used as pre-column derivatization. With optimum baseline separation and short run times, the method is very robust, and especially suited to follow reaction and isomerization kinetics of monosaccharides.

Aldehydes↗
PubMedDate not supplied

[A possible approach to the analysis of protease mixtures].

A problem of quantitative assay of proteases in complex mixtures is solved by using a set of peptide substrates with detectable (chromogenic or fluorogenic) groups (DGs). Quantitation of separate DGs released in reaction of enzyme mixture with a set of substrates is carried out in chromatographic analysis of reaction products. Reaction of peptide derivatives of aminonaphthalene sulfamides with a mixture of thrombin and proteases from viper venom shows the amounts of produced DGs to be proportional to the amounts of both thrombin and venom proteases, confirming the validity of proposed approach. There are cases of mutual influence of some components in proteases mixtures as illustrated by inhibition of trypsin activity in presence of viper venom; one determines enzyme activities in this specific mixture rather than their amounts.

Animals↗
PubMed2005

Multidimensional separation of peptides for effective proteomic analysis.

Current solution based proteomic analysis methods are generally based on enzymatic digestion of a protein mixture followed by separation using multidimensional liquid chromatography and/or electrophoresis where peptide identification is typically accomplished by tandem mass spectrometry (MS/MS). It is generally accepted that no single chromatographic or electrophoretic procedure is capable of resolving the complex mixture of peptides that results from a global proteolytic digest of a proteome. Therefore, combining two or more orthogonal (multimodal) separation procedures dramatically improves the overall resolution and results in a larger number of peptides being identified from complex proteome digests. Separation of a proteome digest is a particularly challenging analytical problem due to the large number of peptides and the wide concentration dynamic range. While it has been demonstrated that increasing the number of dimensions of separation prior to MS analysis increases the number of peptides that may be identified, a balance between the time invested and the overall results obtained must be carefully considered. This manuscript provides a review of two- and three-dimensional peptide separation strategies combined with MS for the analysis of complex peptide mixtures.

Chromatography, Liquid↗
PubMed2001

Gas-phase separations of complex tryptic peptide mixtures.

High-resolution ion mobility and time-of-flight mass spectrometry techniques have been used to analyze complex mixtures of peptides generated from tryptic digestion of fourteen common proteins (albumin, bovine, dog, horse, pig, and sheep; aldolase, rabbit; beta-casein, bovine; cytochrome c, horse; beta-lactoglobulin, bovine; myoglobin, horse; hemoglobin, human, pig, rabbit, and sheep). In this approach, ions are separated based on differences in mobilities in helium in a drift tube and on differences in their mass-to-charge ratios in a mass spectrometer. From data recorded for fourteen individual proteins (over a m/z range of 405 to 1,000), we observe 428 peaks, of which 205 are assigned to fragments that are expected from tryptic digestion. In a separate analysis, the fourteen mixtures have been combined and analyzed as one system. In the single dataset, we resolve 260 features and are able to assign 168 peaks to unique peptide sequences. Many other unresolved features are observed. Methods for assigning peptides based on the use of m/z information and existing mobilities or mobilities that are predicted by use of intrinsic size parameters are described.

Amino Acid Sequence↗
PubMed1996

Capillary electrophoretic examination of underivatized oligosaccharide mixtures released from immunoglobulin G antibodies and CTLA4Ig fusion protein.

A procedure is presented for the separation of underivatized oligosaccharides by capillary electrophoresis (CE) with a phytic acid-borate buffer system. The presence of the phytic acid ion-pairing agent greatly increases resolution between oligosaccharides in the complex mixtures studied, which was demonstrated by the separation of oligosaccharides originating from various immunoglobulin G antibodies and CTLA4Ig, a biologic fusion protein. The conditions also resolve neutral oligosaccharides, usually a major CE limitation. High-performance anion-exchange chromatography with pulsed amperometric detection, a standard technique for oligosaccharide and sugar analysis, is used as a reference method to analyze some of the complex oligosaccharide mixtures.

Abatacept↗
PubMed1999

Biomonitoring of human genotoxicity induced by complex occupational exposures.

Sensitivity, specificity and correlations among several biomarkers for monitoring occupational exposure to complex mixtures of genotoxic agents were assessed in occupational environments in Hungarian study populations. The studies have been focused on DNA adduct formation, urinary metabolites, mutations and micronuclei induced by exposures to complex organic mixtures. In two Hungarian aluminium plants, increased DNA adduct and 1-hydroxypyrene (1-OH-PY) levels were observed in workers as compared to controls. However, no association between the biomarker levels was evident on an individual basis. In Hungarian garage mechanics, DNA adduct determinations did not show increased genotoxic exposure as compared to the controls. However, ambient air measurements, significantly enhanced 1-OH-PY levels, and slightly enhanced frequency of micronuclei indicated increased polycyclic aromatic hydrocarbon (PAH) exposure in the garages, as compared to the general environment. In a Hungarian vulcanizing plant, DNA adduct determinations and 1-OH-PY did not show significantly elevated exposure levels as compared to controls. The glycophorin A (GPA) somatic mutation assay was also negative for this occupational exposure. The results support previous observations of a lack of correlation between DNA adducts detectable by 32P-postlabelling and those measured by the PAH-DNA immunoassay in the same DNA sample. These studies also demonstrate a lack of close correlation between levels of DNA adducts and urinary 1-OH-PY in the same individual.

Air Pollutants, Occupational↗
PubMed2004

Proteomics to diagnose human tumors and provide prognostic information.

Proteomics is a rapidly emerging scientific discipline that holds great promise in identifying novel diagnostic and prognostic biomarkers for human cancer. Technologic improvements have made it possible to profile and compare the protein composition within defined populations of cells. Laser capture microdissection is a tool for procuring pure populations of cells from human tissue sections to be used for downstream proteomic analysis. Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) has been used traditionally to separate complex mixtures of proteins. Improvements in this technology have greatly enhanced resolution and sensitivity providing a more reproducible and comprehensive survey. Image analysis software and robotic instrumentation have been developed to facilitate comparisons of complex protein expression patterns and isolation of differentially expressed proteins spots. Differential in-gel electrophoresis (DIGE) facilitates protein expression by labeling different populations of proteins with fluorescent dyes. Isotope-coded affinity tagging (ICAT) uses mass spectroscopy for protein separation and different isotope tags for distinguishing populations of proteins. Although in the past proteomics has been primarily used for discovery, significant efforts are being made to develop proteomic technologies into clinical tools. Reverse-phase protein arrays offer a robust new method of quantitatively assessing expression levels and the activation status of a panel of proteins. Surface-enhanced laser-desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy rapidly assesses complex protein mixtures in tissue or serum. Combined with artificial intelligence-based pattern recognition algorithms, this emerging technology can generate highly accurate diagnostic information. It is likely that mass spectroscopy-based serum proteomics will evolve into useful clinical tools for the detection and treatment of human cancers.

Early Diagnosis↗
PubMed2004

Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens.

We have evaluated whether mixtures of estrogens, present in the mix at doses that are individually inactive in the immature rat uterotrophic assay, can give a uterotrophic response. Seven chemicals were evaluated: nonylphenol, bisphenol A (BPA), methoxychlor, genistein (GEN), estradiol, diethylstilbestrol, and ethinyl estradiol. Dose responses in the uterotrophic assay were constructed for each chemical. The first series of experiments involved evaluating binary mixtures of BPA and GEN at dose levels that gave moderate uterotrophic responses when tested individually. The mixtures generally showed an intermediate or reduced uterotrophic effect compared with when the components of the mixture were tested alone at the dose used in the mixture. The next series of experiments used a multicomponent (complex) mixture of all seven chemicals evaluated at doses that gave either weakly positive or inactive uterotrophic responses when tested individually in the assay. Doses that were nominally equi-uterotrophic ranged over approximately six orders of magnitude for the seven chemicals. Doses of agents that gave a weak uterotrophic response when tested individually gave a marginally enhanced positive response in the assay when tested combined as a mixture. Doses of agents that gave a negative uterotrophic response when tested individually gave a positive response when tested as a mixture. These data indicate that a variety of different estrogen receptor (ER) agonists, present individually at subeffective doses, can act simultaneously to evoke an ER-regulated response. However, translating these findings into the process of environmental hazard assessment will be difficult. The simple addition of the observed, or predicted, activities for the components of a mixture is confirmed here to be inappropriate and to overestimate the actual effect induced by the mixture. Equally, isobole analysis is only suitable for two- or three-component mixtures, and concentration addition requires access to dose-response data and EC50 values (concentration giving 50% of the maximum response) for the individual components of the mixture--requirements that will rarely be fulfilled for complex environmental samples. Given these uncertainties, we conclude that it may be most expedient to select and bioassay whole environmental mixtures of potential concern.

Animals↗
PubMed2001

Effects of hypochlorous acid on unsaturated phosphatidylcholines.

Effects of hypochlorous acid and of the myeloperoxidase-hydrogen peroxide-chloride system on mono- and polyunsaturated phosphatidylcholines were analyzed by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Chlorohydrins and glycols were detected as main products according to the characteristic shift of molecular masses. Mainly mono-chlorohydrins result upon the incubation of HOCl/(-)OCl with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, whereas only traces of mono-glycols were detected. 1-Palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine yielded a complex mixture of products. Mono-chlorohydrins and glycols dominated only at short incubation, while bis-chlorohydrins as well as products containing one chlorohydrin and one glycol moiety appeared after longer incubation. Similarly, a complex product mixture resulted upon incubation of 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine with hypochlorous acid. Additionally, tris-chlorohydrins, products with two chlorohydrin and one glycol moiety, as well as lysophosphatidylcholines and fragmentation products of the arachidonoyl side chain were detectable. Mono-chlorohydrins of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine were detected after the incubation of the latter phospholipid with the myeloperoxidase-hydrogen peroxide-chloride system at pH 6.0. These chlorohydrins were not observed in the absence of chloride, hydrogen peroxide, or myeloperoxidase as well as in the presence of methionine, taurine, or sodium azide. Thus, mono-chlorohydrins in 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine produced by hypochlorous acid from the myeloperoxidase-hydrogen peroxide-chloride system can also be detected by means of MALDI-TOF MS.

Chlorides↗
PubMed2004

0,2An cross-ring cleavage as a general diagnostic tool for glycan assignment in glycoconjugate mixtures.

In contrast to proteomics significantly less efficient analytical tools are presently available for high throughput glycomics using mass spectrometry. In this article, a strategy to use the (0,2)A(n) ring cleavage ion at the reducing end of free glycans as a diagnostic ion for assignment of free glycans, in presence of glycopeptides containing similar glycosylation patterns, is presented for rapid distinction in complex mixtures by mass spectrometry. The MS to MS/MS automatic switching, already previously introduced for the on-line LC-MS and CE-MS analysis, is shown in this contribution to be highly functional to obtain diagnostic fragmentation patterns of free glycan precursors in rapid screening of highly complex glycoconjugate mixtures obtained from clinical samples, namely from the urine of patients suffering from congenital disorders of glycosylation. Congenital disorders of glycosylation (CDG) are inherited metabolic diseases based on defects in the glycosylation pathways of glycoconjugates. The urine of CDG patients was reported to contain O-glycans and glycosylated amino acids at concentrations two to three orders of magnitude higher in comparison with the healthy control, characterized by a high degree of heterogeneity concerning the type, number, and values of molecular ions. Using the (0,2)A(n) ring cleavage ion approach by tandem MS, it was possible to sort out free glycans and get them assigned.

Glycopeptides↗
PubMed2005

Complex formation in alkyldimethylamine oxide/sodium palmitate/water mixtures.

The complex formation between nonionic alkyldimethylamine oxide (CnDMAO, n=14, 16, and 18) and sodium palmitate (NaPa) in the solid phase of CnDMAO/NaPa mixtures and the dependence of the interaction parameter beta of the regular solution theory (RST) on the mixed micelle composition of C16DMAO/NaPa mixtures were investigated. The dissolution temperature showed a maximum at a NaPa mole fraction X(Pa)(*) of 0.3-0.4 for C16DMAO/NaPa and 0.2 for C18DMAO/NaPa. The compositions of the complexes suggested by X(Pa)(*) are C16DMAO: NaPa=3:2 or 2:1 and C18DMAO:NaPa=4:1. The composition X(Pa)(*) depended on the chain length of the amine oxides. The maximum was not observed in the case of the C14DMAO/NaPa/water system. In the range 0.7< or =X(Pa)< or =1.0, dissolution temperature depression was observed with decreasing X(Pa). The dissolution temperature depression was analyzed by taking into account the nonideal behavior in the mixed micelles and the counterion binding on the mixed micelle surface. The negative beta values were obtained for all three mixed systems. It was shown that the counterion activity remained practically constant in the range of 0.7< or =X(Pa)< or =1.0. The cmc values of C16DMAO/NaPa mixtures were determined by pyrene fluorescence measurement. For C16DMAO/NaPa mixtures, the dependence of the RST interaction parameter beta on the mixed micelle composition X(Pa) was determined for a wide range (0.2< or =X(Pa) < or =0.9). In the range 0.2< or =X(Pa)< or =0.5, the beta values were obtained from an analysis of cmc based on the RST. In the range 0.7< or=X(Pa)< or=0.9, the beta values were obtained from an analysis of the dissolution temperature depression. From the analysis of the micelle composition dependence of the beta values, a short-range attractive interaction between the headgroup of C16DMAO and palmitate anion is suggested.

Journal Article↗
PubMed2005

Electrospray tandem mass spectrometry of underivatised acetylated xylo-oligosaccharides.

Acetylated neutral (Xyl(n)Ac(m)) and acidic xylo-oligosaccharides (Xyl(n)Ac(m)MeGlcA, and Xyl(n)Ac(m)MeGlcAHex) obtained by partial acid hydrolysis of Eucalyptus globulus wood glucuronoxylans and fractionated by preparative ligand exchange/size-exclusion chromatography were identified by electrospray ionisation mass spectrometry (ESI-MS). Low molecular weight acetylated xylo-oligosaccharides were studied by ESI-tandem mass spectrometry (MS/MS). All the acetylated xylo-oligosaccharides showed an abundant ion due to the neutral loss of 60 Da (CH(3)CO(2)H) in the MS/MS spectra. The presence of diacetylated xylo-oligosaccharides was confirmed by the ions formed by loss of two molecules of acetic acid. Furthermore, characteristic [Xyl(res)Ac(2)+Na](+) and [XylAc(2)+Na](+) ions, and ions due to loss of XylAc(2), indicate that both acetyl groups are located in the same Xyl residue. On the other hand, losses of Xyl(res)Ac and XylAc are also observed as well as [Xyl(res)Ac+Na](+) and [XylAc+Na](+) , indicating the location of both acetyl groups in different Xyl residues, in some cases even in adjacent xyloses. The MS/MS spectra of triacetylated xylo-oligosaccharides were complex due to the presence of different isobaric xylo-oligosaccharides containing the acetyl groups at different locations in the xylo-oligosaccharide backbone. In the MS/MS spectra of acidic xylo-oligosaccharides, the ion at m/z 387, [Xyl(res)AcMeGlcA+Na](+), indicates that the acetyl groups are preferentially linked to Xyl substituted with MeGlcA. However, acidic xylo-oligosaccharides with the acetyl and 4-O-methylglucuronic acid groups in different Xyl residues were also identified. In neutral and in acidic xylo-oligosaccharides several possible locations of the acetyl groups were identified, namely at terminal positions. In summary, ESI-MS/MS is shown to be a powerful tool for the characterisation of acetylated patterns in complex mixtures of oligosaccharides.

Acetylation↗
PubMed1981

Tandem mass spectrometry in trace toxicant analysis.

Mass spectrometers coupled in series offer a promising technique for quantitative analysis of trace constituents in complex mixtures. Despite the relatively high cost and complexity of such instruments, this technique appears to be particularly promising in terms of the sensitivity, specificity, and speed of analysis for targeted compounds in body fluids, foods and other biological mixtures.

Body Fluids↗
PubMed1996

A practical ion trap mass spectrometer for the analysis of peptides by matrix-assisted laser desorption/ionization.

The present paper describes the performance of a newly configured matrix-assisted laser desorption/ionization quadrupole ion trap mass spectrometer (MALDI-ITMS), designed for biological applications that require the determination of the primary structures of proteins, e.g., the rapid identification of proteins and the elucidation of posttranslational modifications. The strategy used for solving problems of this type involves enzymatic digestion of the protein, followed by MALDI ion trap mass spectrometric analysis of the components of the resulting complex mixture of peptide ions. The new instrument is demonstrated to be a highly practical tool for analyzing proteins. In particular, mixtures containing as many as 30 peptide components can be rapidly and sensitively analyzed without prior chromatographic separation of the components. Informative tandem mass spectra can be obtained from the peptide components with m/z values up to 3500. A single subpicomole sample loading of a complex peptide mixture is more than sufficient for a complete set of experiments that includes both low- and high-resolution molecular mass determinations as well as a complete MS/MS study of the various components present in the sample. Extensive use is made of improved methods for trapping, isolating, fragmenting, and detecting ions in the ITMS (details are to be provided in two future papers).

Amino Acid Sequence↗
PubMed2002

Identification and relative quantitation of protein mixtures by enzymatic digestion followed by capillary reversed-phase liquid chromatography-tandem mass spectrometry.

In this report, we describe an approach for identification and relative quantitation of individual proteins within mixtures using LC/MS/MS analysis of protein digests. First, the proteins are automatically identified by correlating the tandem mass spectra with peptide sequences from a database. Then, peak areas of identified peptides from one protein are added together to define the total reconstructed peak area of the protein digest. The total reconstructed peak area is further normalized to the peak area of an internal standard protein digest present in the mixture at a constant level. The method was illustrated using digested mixtures of five standard proteins as follows. One protein was gradually diluted while the other four components were present in the mixtures at constant level. This study revealed that relative peak area of the variable protein increased linearly (trend line R2 = 0.9978) with increasing amount from 10 to 1000 fmol, while relative peak areas of four constant proteins remained approximately the same (within 20% relative standard deviation). To further evaluate the applicability of this method for the quantitation of proteins from complex mixtures, human plasma protein digest was spiked with 200 and 400 fmol of myoglobin digest. Total peak area of myoglobin peptides was normalized to the total peak area of apolipoprotein A-I peptides from human plasma, which played the role of an internal standard. The myoglobin/apolipoprotein A-I peak area ratio was 2 times larger for the human plasma digest spiked with a double amount of myoglobin. After several repetitions, the error of the relative peak area measurements remained below 11%, suggesting that the method described here can be used for relative concentration measurements of proteins in the complex biological mixtures. In the presented method, chemical derivatization steps are not needed to create an internal standard, as in isotope-coded affinity tag or similar methods.

Amino Acid Sequence↗
PubMedDate not supplied

Is there a rational method to purify proteins? From expert systems to proteomics.

The purification of recombinant proteins for therapeutic or analytical applications requires the use of several chromatographic steps in order to achieve a high level of purity. A range of techniques is available such as anion and cation exchange chromatography, which can be carried out at different pHs, and hence used at different steps, hydrophobic interaction chromatography, gel filtration and affinity chromatography. Evidently when confronted with a complex mixture of partially unknown proteins or a clarified cell extract there are many different routes one can take in order to choose the minimum and most efficient number of purification steps to achieve a desired level of purity (e.g. 98, 99.5 or 99.9%). In this review we will show how an initial "proteomic" characterization of the complex initial mixture of target protein and protein contaminants can be used to select the most efficient chromatographic separation steps in order to achieve a maximum level of purity with a minimum number of steps. The chosen methodology was implemented in a computer based expert system. The first algorithm developed was used to select the most efficient purification method to separate a protein from its contaminants based on the physicochemical properties of the protein product and the protein contaminants. The second algorithm developed was used to predict the number and concentration of contaminants after each separation as well as protein product purity. The successful application of the expert system approach, based on an initial proteomic characterization, to the practical cases of protein mixtures and clarified fermentation supernatant is presented and discussed. The purification strategy proposed was experimentally tested and validated with a mixture of four proteins and the experimental validation was also carried out with an "unknown" supernatant of Bacillus subtilis producing a recombinant beta-1,3-glucanase. The system was robust to errors <10% which is the range that can be found in the experimental determination of the properties in the database of product and contaminants. On the other hand, the system was sensitive both to larger variations (>20%) in the properties of the contaminant database and the protein product and to variations in one protein property (e.g. hydrophobicity).

Animals↗
PubMed2000

Mixtures and interactions.

Drinking water can be considered as a complex mixture that consists of tens, hundreds or thousands of chemicals of which the composition is qualitatively and quantitatively not fully known. From a public health point of view it is most relevant to answer the question of whether chemicals in drinking water interact in a way that results in an increased overall response as compared to the sum of the responses to the individual chemicals in the mixture, or indeed in an effect that is simply a summation of the expected effects of the individual chemicals. Present methods for risk assessment of mixtures rely heavily on some form of additivity model, unless data are adequate for a direct risk assessment of the mixture of concern in its entirety. The "dose-addition" concept ("simple similar action") is the most common approach to risk assessment of mixtures and it is applicable over the whole range of exposure levels from low non-toxic to toxic levels when all chemicals in the mixture act in a similar way. However, in toxicity studies at environmentally relevant exposure scenarios the mixtures that meet such conditions are the exception rather than the rule. In that case the "effect addition" model has to be followed assuming "independent joint action". For these compounds now experimental data have indicated that the results at low exposure levels are probably difficult to predict based on response additivity found at higher dose levels. Thus, although the additivity models are mathematically simple, they require assumptions about the mechanisms of action and the high-to-low dose extrapolation. Therefore, theoretical considerations in risk assessment of chemical mixtures should be verified by simple case studies. Up till now, the number of environmentally relevant mixtures to which a direct risk assessment has been devoted is limited. Even if toxicity data on individual compounds are available, we are still facing the immense problem of extrapolation of findings obtained at relatively high exposure concentration in laboratory animals to man being exposed to (much) lower concentrations. Therefore the prioritization of compounds for further research and the extrapolation to low doses should be considered as key issues in the assessment of possible health risks from exposure to chemical mixtures such as drinking water.

Drug Interactions↗
PubMed1997

Polyvalent vaccines in fish: the interactive effects of multiple antigens.

Fermentation and cell-grown products commonly used as fish vaccines present a relatively crude mixture of antigenic and other immunologically active components to the immune system. The specific antigenic make-up and the potential protective immunogenicity of this mixture is dependent upon the strain of the pathogen, production parameters, inactivation methods, down-stream processing, product formulation, storage conditions and the delivery method under which the final product is applied. In the past ten years, commercial vaccine products for fish have more often consisted of mixtures of multiple products, including two, three, four and five vaccines. Such mixtures present an even more extensive and complex array of antigens to the immune system. Considering the fact that not all antigens stimulate a protective immune response, that antigens vary in their immuno-dominance relative to each other and that the immune system of fish has a defined and limited capacity to respond to individual antigenic substances, it becomes increasingly difficult to formulate these complex mixtures into safe and effective commercial products. The clonal capacity of fish to respond to multiple antigens may depend on a variety of factors including host species and age, water temperature, route of administration and temporal considerations. There is growing evidence that antigenic as well as non-antigenic components of vaccines can interact synergistically or antagonistically and that they can stimulate, cross-react with, inhibit or even suppress the immune response to specific antigens. This paper reviews current knowledge about the interactive effects of antigenic components of fish vaccines and gives specific examples of how these interactions might affect the formulation and performance of multivalent products. This paper also considers the potential basis for these interactive effects and discusses technical approaches that take advantage of this knowledge for the development of new multivalent products.

Animals↗