CA2488584A1 - Methods, mixtures, kits and compositions pertaining to analyte determination - Google Patents

Methods, mixtures, kits and compositions pertaining to analyte determination Download PDF

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CA2488584A1
CA2488584A1 CA002488584A CA2488584A CA2488584A1 CA 2488584 A1 CA2488584 A1 CA 2488584A1 CA 002488584 A CA002488584 A CA 002488584A CA 2488584 A CA2488584 A CA 2488584A CA 2488584 A1 CA2488584 A1 CA 2488584A1
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Darryl J. C. Pappin
Michael Bartlet-Jones
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DH Technologies Development Pte Ltd
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    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6842—Proteomic analysis of subsets of protein mixtures with reduced complexity, e.g. membrane proteins, phosphoproteins, organelle proteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

This invention pertains to methods, mixtures, kits and/or compositions for the determination of analytes by mass analysis using unique labeling reagents or sets of unique labeling reagents. The labeling reagents can be isomeric or isobaric and can be used to produce mixtures suitable for multiplex analysis of the labeled analytes.

Claims (182)

We Claim:
1. A method comprising:
a) reacting two or more samples, each sample comprising one or more reactive analytes, with a different labeling reagent of a set of labeling reagents to thereby produce two or more differentially labeled samples each comprising one or more labeled analytes wherein the different labeling reagents of the set each comprise the formula:
RP-X-LK-Y-RG
or a salt thereof, wherein;
i) RG is a reactive group that is a nucleophile or an electrophile and that is capable of reacting with one or more of the reactive analytes of the sample;
ii) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each reagent of the set;
iii) LK is a linker moiety that links the reactive group and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set;
iv) X is a bond between an atom of the reporter and an atom of the linker;
v) Y is a bond between an atom of the linker and an atom of the reactive group, wherein, once the labeling reagent is reacted with the reactive analyte, bond Y links the linker to the analyte; and vi) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and b) mixing two or more of the differentially labeled samples, or a portion thereof, and optionally one or more calibration standards to thereby produce a sample mixture;
wherein RP:
i) has a gross mass of less than 250 daltons; and/or ii) does not substantially sub-fragment under conditions of dissociative energy applied to cause fragmentation of at least a portion of both bonds X
and Y of a labeled analyte in a mass spectrometer; and/or iii) is not a polymer or is not a biological polymer.
2. A method comprising:
a) reacting two or more samples, each sample comprising one or more reactive analytes, with a different labeling reagent of a set of labeling reagents to thereby produce two or more differentially labeled samples each comprising one or more labeled analytes wherein the different labeling reagents of the set each comprise the formula:
or a salt thereof, wherein;
RP-X-LK-Y-RG
i) RG is a reactive group that is a nucleophile or an electrophile and that is capable of reacting with one or more of the reactive analytes of the sample;
ii) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each reagent of the set;
iii) LK is a linker moiety that links the reactive group and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set;
iv) X is a bond between an atom of the reporter and an atom of the linker;
v) Y is a bond between an atom of the linker and an atom of the reactive group, wherein, once the labeling reagent is reacted with the reactive analyte, bond Y links the linker to the analyte; and vi) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and b) mixing two or more of the differentially labeled samples, or a portion thereof, and optionally one or more calibration standards to thereby produce a sample mixture;
wherein the linker LK undergoes neutral loss under conditions of applied dissociative energy that causes the fragmentation of both bonds X and Y in a mass spectrometer.
3. A method comprising:
a) reacting two or more samples, each sample comprising one or more reactive analytes, with a different labeling reagent of a set of labeling reagents to thereby produce two or more differentially labeled samples each comprising one or more labeled analytes wherein the different labeling reagents of the set each comprise the formula:
RP-X-LK-Y-RG

or a salt thereof, wherein;
i) RG is a reactive group that is a nucleophile or an electrophile and that is capable of reacting with one or more of the reactive analytes of the sample;
ii) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each reagent of the set;
iii) LK is a linker moiety that links the reactive group and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set;
iv) X is a bond between an atom of the reporter and an atom of the linker;
v) Y is a bond between an atom of the linker and an atom of the reactive group, wherein, once the labeling reagent is reacted with the reactive analyte, bond Y links the linker to the analyte; and vi) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and b) mixing two or more of the differentially labeled samples, or a portion thereof, and optionally one or more calibration standards to thereby produce a sample mixture;
wherein, under conditions of dissociative energy applied in a mass spectrometer, the fragmentation of one of bonds X or Y induces the fragmentation of the other of bonds X
or Y.
4. A method comprising:
a) reacting two or more samples, each sample comprising one or more reactive analytes, with a different labeling reagent of a set of labeling reagents to thereby produce two or more differentially labeled samples each comprising one or more labeled analytes wherein the different labeling reagents of the set each comprise the formula:
or a salt thereof, wherein;
RP-X-LIC-Y-RG
i) RG is a reactive group that is a nucleophile or an electrophile and that is capable of reacting with one or more of the reactive analytes of the sample;
ii) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each reagent of the set;

iii) LK is a linker moiety that links the reactive group and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set;
iv) X is a bond between an atom of the reporter and an atom of the linker;
v) Y is a bond between an atom of the linker and an atom of the reactive group, wherein, once the labeling reagent is reacted with the reactive analyte, bond Y links the linker to the analyte; and vi) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and b) mixing two or more of the differentially labeled samples, or a portion thereof, and optionally one or more calibration standards to thereby produce a sample mixture;
wherein:
i) under conditions of dissociative energy applied in a mass spectrometer, bond X is less prone to fragmentation as compared with bond Y; and/or ii) under conditions of dissociative energy applied in a mass spectrometer, bond X is less prone to fragmentation as compared with the peptide bond of a Z-pro amino acid dimer or Z-asp amino acid dimer, wherein Z is any natural amino acid, pro is proline and asp is aspartic acid.
5. A method comprising:
a) reacting two or more samples, each sample comprising one or more reactive analytes, with a different labeling reagent of a set of labeling reagents to thereby produce two or more differentially labeled samples each comprising one or more labeled analytes wherein the different labeling reagents of the set each comprise the formula:
RP-X-LK-Y-RG
or a salt thereof wherein;
i) RG is a reactive group that is an electrophile and that is capable of reacting with one or more of the reactive analytes of the sample;
ii) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each reagent of the set;
iii) LK is a linker moiety that links the reactive group and the reporter group, wherein:

a) the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set; and b) the linker comprises at least one heavy atom isotope and has the formula:
wherein R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
iv) X is a bond between an atom of the reporter and an atom of the linker;
v) Y is a bond between an atom of the linker and an atom of the reactive group, wherein, once the labeling reagent is reacted with the reactive analyte, bond Y links the linker to the analyte; and b) mixing two or more of the differentially labeled samples, or a portion thereof, and optionally one or more calibration standards to thereby produce a sample mixture.
6. The method of any one of claims 1 to 5, further comprising:
c) performing a first mass spectrometric analysis on the sample mixture, or a fraction thereof;
d) treating selected ions of labeled analytes from the first mass spectrometric analysis to dissociative energy levels to thereby form ionized reporter moieties and ionized daughter fragment ions of at least some of the selected ions; and e) performing a second mass analysis of the selected ions, the ionized reporter moieties and the daughter fragment ions, or a fraction thereof.
7. The method of claim 6, further comprising:
f) determining the gross mass and relative amount of each reporter moiety in the second mass analysis and the gross mass of the daughter fragment ions.
8. The method of claim 7, further comprising repeating steps (d) through (f) one or more times on selected ions of labeled analytes at a different selected mass to charge ratio.
9. The method of claim 8, further comprising repeating steps (a) through (f) one or more times, each time with a different fraction of the sample mixture.
10. The method of any one of claims 1 to 5, wherein the two or more samples are the products of an enzymatic digestion reaction.
11. The method of claim 10, wherein the two or more samples are products of a proteolytic digestion reaction.
12. The method of claim 11, wherein the proteolytic enzyme is trypsin, papain, pepsin, ArgC, LysC, V8 protease, AspN, pronase, chymotrypsin or carboxypeptidease C.
13. The method of any one of claims 1 to 5, wherein each sample is a crude or processed cell lysate, a body fluid, a tissue extract or a cell extract.
14. The method of any one of claims 1 to 5, wherein each sample is a fraction from a separations process.
15. The method of claim 14, wherein the separations process is a chromatographic separation or an electrophoretic separation.
16. The method of claim 13, wherein the body fluid is blood, urine, spinal fluid, cerebral fluid, amniotic fluid, lymph fluid or a fluid from a glandular secretion.
17. The method of any one of claims 1 to 5, wherein the one or more analytes are proteins, nucleic acid molecules, carbohydrates, lipids, steroids or small molecules of less than 1500 daltons.
18. The method of any one of claims 1 to 5, wherein the one or more of the analytes are peptides.
19. The method of claim 18, wherein the peptides are formed by digestion of at least one protein.
20. The method of claim 19, wherein the peptides are formed by digestion of the total protein component of a crude cell lysate.
21. The method of any one of claims 1 to 5, wherein the reactive group of each reagent of the set is prepared in-situ for reaction with the reactive analytes.
22. The method of claim 21, wherein the reactive group of the each reagent of the set is a carboxylic acid group that has been activated with a water-soluble carbodiimide.
23. The method of claim 22, wherein the water-soluble carbodiimide is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).
24. The method of any one of claims 1 to 5, wherein the reactive group of each reagent of the set is an amine reactive active ester group.
25. The method of claim 24, wherein the active ester is a N-hydroxysuccinimidyl ester, a N-hydroxysulfosuccinimidyl ester, a pentafluorophenyl ester, a 2-nitrophenyl ester, a 4-nitrophenyl ester, a 2,4-dinitrophenylester or a 2,4-dihalophenyl ester.
26. The method of any one of claims 1 to 4, wherein the reactive group of each reagent of the set is a thiol reactive electrophilic group.
27. The method of claim 26, wherein the thiol reactive group is selected from the group consisting of; malemide, alkyl halide, aryl halide and .alpha.-halo-acyl.
28. The method of any one of claims 1 to 4, wherein the reactive group of each reagent of the set is a hydroxyl reactive electrophilic group.
29. The method of any one of claims 1 to 4, wherein the reactive group of each reagent is a nucleophile selected from the group consisting of an, amine group, a hydroxyl group or a thiol group.
30. The method of any one of claims 1 to 5, wherein the reporter is a substituted or unsubstituted morpholine, piperidine or piperazine compound, or a salt thereof.
31. The method of any one of claims 1 to 5 wherein the reporter is a carboxylic acid, sulfonic acid or phosphoric acid group containing compound, or a salt thereof.
32. The method of any one of claims 1 to 5, wherein the reporter moiety does not substantially sub-fragment under conditions used to determine the analyte.
33. The method of any one of claims 2 to 5, wherein the reporter moiety is not a biological polymer.
34. The method of any one of claims 2 to 5, wherein the reporter moiety is not a polymer.
35. The method of any one of claims 1 to 5, wherein the linker is a carbonyl or thiocarbonyl group.
36. The method of any one of claims 1 to 4, wherein the linker is a polymer or biopolymer moiety.
37. The method of claim 36, wherein the polymeric moiety can sub-fragment.
33. The method of any one of claims 1 to 5, wherein the one or more differentially labeled analytes each comprise an isomeric label that identifies the sample from which it originated.
39. The method of any one of claims 1 to 5, wherein the one or more differentially labeled analytes each comprise an isobaric label that identifies the sample from which it originated.
40. The method of claim 39, wherein the label of each isobarically labeled analyte is a 5, 6 or 7 membered heterocyclic ring comprising a ring nitrogen atom that is N-alkylated with a substituted or unsubstituted acetic acid moiety to which the analyte is linked through the carbonyl carbon of the N-alkyl acetic acid moiety, wherein each different label comprises one or more heavy atom isotopes.
41. The method of claim 40, wherein the isobarically labeled analytes in the sample mixture each comprise the formula:
wherein;
a) Z is O, S, NH or NR1;
b) each J is the same or different and is H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine or iodine;
c) W is an atom or group that is located ortho, meta or para to the ring nitrogen and is NH, N-R1, N-R2, P-R1, P-R2, O or S;
d) each carbon of the heterocyclic ring has the formula CJ2;
e) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
and f) R2 is an amino alkyl, hydroxy alkyl, thio alkyl group or a cleavable linker that cleavably links the reagent to a solid support wherein the amino alkyl, hydroxy alkyl or thio alkyl group comprises one to eight carbon atoms, which may optionally contain a heteroatom or a substituted or unsubstituted aryl group, and wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
42. The method of claim 40, wherein the isobarically labeled analytes are peptides.
43. The method of claim 41, wherein the sample mixture comprises one or more isobarically labeled analytes of the formula:

44. The method of claim 41, wherein the sample mixture comprises one or more isobarically labeled analytes of the formula:
45. The method of claim 41, wherein the sample mixture comprises one or more isobarically labeled analytes of the formula:

wherein each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
46. The method of claim 41, wherein the sample mixture comprises one or more isobarically labeled analytes of the formula:
wherein:
a) G' is an amino alkyl, hydroxy alkyl or thio alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
b) each carbon of the heterocyclic ring has the formula CJ2, wherein each J is the same or different and is selected from the group consisting of: H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine; and c) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
47. The method of claim 39, wherein the isobarically labeled analytes in the sample mixture each comprise the formula:
wherein:
a) Z is O,S,NH or NR1;
b) each J is the same or different and is selected from the group consisting of: H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine;
c) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
48. The method of claim 47, wherein the isobarically labeled analytes are peptides.
49. The method of claim 47, wherein the sample mixture comprises one or more isobarically labeled analytes of the formula:

wherein each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
50. The method of any of claims 1 to 5, wherein each different labeling reagent of the set is support bound and is linked to the support through a cleavable linker such that each different sample is reacted with a support carrying a different labeling reagent; and the method further comprises, before performing step (b);
i) optionally washing the resin to remove components of the sample that do not react with the reactive group of the labeling reagent; and ii) cleaving the cleavable linker to thereby collect the two or more differentially labeled samples, each sample comprising one or more labeled analytes wherein the labeled analytes associated with a particular sample are identifiable and/or quantifiable by the unique reporter linked thereto.
51. The method of claim 50, wherein each different labeling reagent of the set is a solid support of the formula:
E-F-RP-X-LK-Y-RG
wherein;

i) RG is a reactive group that is a nucleophile or an electrophile and that is capable of reacting with one or more of the reactive analytes of the samples;
ii) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each reagent of the set;
iii) LK is a linker moiety that links the reactive group and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set;
iv) X is a bond between an atom of the reporter and an atom of the linker;
v) Y is a bond between an atom of the linker and an atom of the reactive group, wherein, once the labeling reagent is reacted with the reactive analyte, bond Y links the linker to the analyte;
vi) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels;
vii) E is a solid support; and viii) F is a cleavable linker linked to the solid support and cleavably linked to the reporter.
52. The method of claim 51, wherein the set of labeling reagents comprises one or more of the following support bound labeling reagents:
wherein:
i) RG is a reactive group that is a nucleophile or an electrophile and that is capable of reacting with one or more of the reactive analytes of the samples;
ii) E is a solid support;

iii) F is a cleavable linker linked to the solid support and cleavably linked to the reporter;
iv) G is an amino alkyl, hydroxy alkyl or thio alkyl group, cleavably linked to the cleavable linker wherein the amino alkyl, hydroxy alkyl or thio alkyl group comprises one to eight carbon atoms, which may optionally contain a heteroatom or a substituted or unsubstituted aryl group, and wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
v) each carbon of the heterocyclic ring has the formula CJ2, wherein each J is the same or different and is selected from the group consisting of H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine; and vi) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
53. The method of claim 50, wherein the support is composed of polystyrene, polyethylene, polypropylene, polyfluoroethylene, polyethyleneoxy, polyacrylamide, glass, silica, controlled-pore-glass (CPG), or reverse-phase silica.
54. The method of claim 50, wherein the solid support is in the form of beads, spheres, particles, granules, a gel, a membrane or a surface.
55. The method of any of claims 1 to 5, further comprising:
c) digesting each sample with at least one enzyme to partially, or fully, degrade components of the sample prior to performing step (a).
56. The method of claim 55, wherein the enzyme is a proteolytic enzyme.
57. The method of claim 56, wherein the proteolytic enzyme is trypsin, papain, pepsin, ArgC, LysC, V8 protease, AspN, pronase, chymotrypsin or carboxypeptidease C.
58. The method of any of claims 1 to 5, wherein the method further comprises:
c) separating the sample mixture.
59. The method of claim 58, wherein the separation is performed by chromatography.
60. The method of claim 59, wherein the chromatographic separation method is normal phase chromatography, reversed-phase chromatography, ion-exchange chromatography, size exclusion chromatography or affinity chromatography.
61. The method of claim 58, wherein the separation is performed electrophoretically.
62. The method of claim 61, wherein the electrophoretic separation is a 1D
electrophoretic separation, a 2D electrophoretic separation or a capillary electrophoretic separation.
63. The method of any of claims 1 to 5, wherein the method further comprises:
c) digesting each sample with at least one enzyme to partially, or fully, degrade components of the sample prior to performing step (a); and d) separating the sample mixture.
64. The method of claim 63, wherein the enzyme is a proteolytic enzyme.
65. The method of claim 64, wherein the proteolytic enzyme is trypsin, papain, pepsin, chymotrypsin or carboxypeptidease C.
66. The method of claim 63, wherein the separation is performed by chromatography.
67. The method of claim 66, wherein the chromatographic separation method is normal phase chromatography, reversed-phase chromatography, ion-exchange chromatography, size exclusion chromatography or affinity chromatography.
68. The method of claim 63, wherein the separation is an electrophoretic separation.
69. The method of claim 68, wherein the electrophoretic separation is a 1D
electrophoretic separation, a 2D electrophoretic separation or a capillary electrophoretic separation.
70. The method of claim 7, wherein the identity of the labeled analyte associated with the selected mass to charge ratio is determined by analysis of the daughter fragment ions.
71. The method of claim 70, wherein the relative amount of each reporter in the second mass analysis is determined with respect to the other reporters.
72. The method of claim 71, wherein the relative amount of each reporter associated with the identified analyte is correlated with the amount of each sample added to form the sample mixture to thereby determine the relative amount of the analyte in each of two or more of the samples combined to form the mixture.
73. The method of claim 72, wherein:
(i) the sample mixture comprises a known amount of a calibration standard for the identified analyte and the absolute amount of each reporter is determined with reference to the amount of reporter associated with the calibration standard;
and (ii) the absolute amount of the identified analyte in each different sample of the sample mixture is determined with reference to the amount of each reporter.
74. The method of claim 72, further comprising repeating steps (d) through (f), on selected ions of labeled analytes at a different selected mass to charge ratio, one or more times to thereby identify and/or determine the relative amount of one or more other analytes in each of two or more of the samples combined to form the sample mixture.
75. The method of claim 73, further comprising repeating steps (d) through (f), on selected ions of labeled analytes at a different selected mass to charge ratio, one or more times to thereby identify and/or determine the absolute amount of one or more other analytes in each of two or more of the samples combined to form the sample mixture.
76. The method of claim 72, wherein the analytes are peptides and the identity and relative amount of one or more proteins in each of two or more of the samples combined to form the sample mixture is determined based upon the identify and relative amount of the one or more peptides in each of two or more of the samples combined to form the sample mixture.
77. The method of claim 73, wherein the analytes are peptides and the identity and relative amount of one or more proteins in each of two or more of the samples combined to form the sample mixture is determined based upon the identity and absolute amount of the one or more peptides in each of two or more of the samples combined to form the sample mixture.
78. The method of claim 7, further comprising:
g) digesting each sample with at least one enzyme to partially, or fully, degrade components of the sample prior to performing step (a); and h) separating the sample mixture prior to performing step (c).
79. The method of claim 78, wherein the enzyme is a proteolytic enzyme.
80. The method of claim 79, wherein the proteolytic enzyme is trypsin, papain, pepsin, chymotrypsin or carboxypeptidease C.
81. The method of claim 78, wherein the separation is performed by chromatography.
82. The method of claim 81, wherein the chromatographic separation method is normal phase chromatography, reversed-phase chromatography, ion-exchange chromatography, size exclusion chromatography or affinity chromatography.
83. The method of claim 78, wherein the separation is an electrophoretic separation.
84. The method of claim 83, wherein the electrophoretic separation is a 1D
electrophoretic separation, a 2D electrophoretic separation or a capillary electrophoretic separation.
85. The method of claim 78, wherein the identity of the labeled analyte associated with the selected mass to charge ratio is determined by analysis of the daughter fragment ions.
86. The method of claim 85, wherein the relative amount of each reporter in the second mass analysis is determined with respect to the other reporters.
87. The method of claim 86, wherein the relative amount of each reporter associated with the identified analyte is correlated with the amount of each sample added to form the sample mixture to thereby determine the relative amount of the analyte in each of two or more of the samples combined to form the mixture.
88. The method of claim 87, wherein:
(i) the sample mixture comprises a known amount of a calibration standard for the identified analyte and the absolute amount of each reporter is determined with reference to the amount of reporter associated with the calibration standard;
and (ii) the absolute amount of the identified analyte in each different sample of the sample mixture is determined with reference to the amount of each reporter.
89. The method of claim 87, further comprising repeating steps (d) through (f), on selected ions of labeled analytes at a different selected mass to charge ratio, one or more times to thereby identify and/or determine the relative amount of one or more other analytes in each of two or more of the samples combined to form the sample mixture.
90. The method of claim 88, further comprising repeating steps (d) through (f), on selected ions of labeled analytes at a different selected mass to charge ratio, one or more times to thereby identify and/or determine the absolute amount of one or more other analytes in each of two or more of the samples combined to form the sample mixture.
91. The method of claim 87, wherein the analytes are peptides and the identity and relative amount of one or more proteins in each of two or more of the samples combined to form the sample mixture is determined based upon the identity and relative amount of the one or more peptides in each of two or more of the samples combined to form the sample mixture.
92. The method of claim 88, wherein the analytes are peptides and the identity and relative amount of one or more proteins in each of two or more of the samples combined to form the sample mixture is determined based upon the identity and absolute amount of the one or more peptides in each of two or more of the samples combined to form the sample mixture.
93. A mixture comprising at least two labeled analytes, wherein each of the two labeled analytes originates from a different sample combined to form the mixture and each comprises the formula:
RP-X-LK-Y-Analyte or a salt thereof, wherein;
a) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each sample;
b) LK is a linker moiety that links the analyte and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the different reporters such that the aggregate gross mass of the reporter and linker combination is the same for each labeled analyte;
c) X is a bond between an atom of the reporter and an atom of the linker;
d) Y is a bond between an atom of the linker and an atom of the analyte; and e) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and wherein RP:
i) has a gross mass of less than 250 daltons; and/or ii) does not substantially sub-fragment under conditions of dissociative energy applied to cause fragmentation of at least a portion of both bonds X
and Y of a labeled analyte in a mass spectrometer; and/or iii) is not a polymer or is not a biological polymer.
94. A mixture comprising at least two labeled analytes, wherein each of the two labeled analytes originates from a different sample combined to form the mixture and each comprises the formula:
RP-X-LK-Y-Analyte or a salt thereof, wherein;
a) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each sample;
b) LK is a linker moiety that links the analyte and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the different reporters such that the aggregate gross mass of the reporter and linker combination is the same for each labeled analyte;
c) X is a bond between an atom of the reporter and an atom of the linker;
d) Y is a bond between an atom of the linker and an atom of the analyte; and e) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and wherein the linker LK undergoes neutral loss under conditions of applied dissociative energy that causes the fragmentation of both bonds X and Y in a mass spectrometer.
95. A mixture comprising at least two labeled analytes, wherein each of the two labeled analytes originates from a different sample combined to form the mixture and each comprises the formula:
RP-X-LK-Y-Analyte or a salt thereof, wherein;

a) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each sample;
b) LK is a linker moiety that links the analyte and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the different reporters such that the aggregate gross mass of the reporter and linker combination is the same for each labeled analyte;
c) X is a bond between an atom of the reporter and an atom of the linker;
d) Y is a bond between an atom of the linker and an atom of the analyte; and e) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and wherein, under conditions of dissociative energy applied in a mass spectrometer, the fragmentation of one of bonds X or Y induces the fragmentation of the other of bonds X
or Y.
96. A mixture comprising at least two labeled analytes, wherein each of the two labeled analytes originates from a different sample combined to form the mixture and each comprises the formula:
RP-X-LK-Y-Analyte or a salt thereof, wherein;
a) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each sample;
b) LK is a linker moiety that links the analyte and the reporter group, wherein the mass of the linker compensates for the difference in gross mass between the different reporters such that the aggregate gross mass of the reporter and linker combination is the same for each labeled analyte;
c) X is a bond between an atom of the reporter and an atom of the linker;
d) Y is a bond between an atom of the linker and an atom of the analyte; and e) bonds X and Y fragment in at least a portion of the labeled analytes when subjected to dissociative energy levels; and wherein:
i) under conditions of dissociative energy applied in a mass spectrometer, bond X is less prone to fragmentation as compared with bond Y; and/or ii) under conditions of dissociative energy applied in a mass spectrometer, bond X is less prone to fragmentation as compared with the peptide bond of a Z-pro amino acid dimer or Z-asp amino acid dimer, wherein Z is any natural amino acid, pro is proline and asp is aspartic acid.
97. A mixture comprising at least two labeled analytes, wherein each of the two labeled analytes originates from a different sample combined to form the mixture and each comprises the formula:
RP-X-LK-Y-Analyte or a salt thereof wherein;
a) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each sample;
b) LK is a linker moiety that links the reactive group and the reporter group, wherein:
i) the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set; and ii) the linker comprises at least one heavy atom isotope and has the formula:
wherein R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and / or fluorine atoms;
c) X is a bond between an atom of the reporter and an atom of the linker;
d) Y is a bond between an atom of the linker and an atom of the analyte.
98. The mixture of any one of claims 93 to 97, wherein one or more of the analytes are peptides.
99. The mixture of any one of claims 93 to 97, wherein one or more of the analytes are proteins.
100. The mixture of any one of claims 93 to 97, wherein one or more of the analytes are nucleic acid molecules.
101. The mixture of any one of claims 93 to 97, wherein the reporter is a substituted or unsubstituted morpholine, piperidine or piperazine compound, or a salt thereof.
102. The mixture of any one of claims 93 to 97, wherein the reporter is a carboxylic acid, sulfonic acid or phosphoric acid group containing compound, or a salt thereof.
103. The mixture of any one of claims 93 to 97, wherein the linker is a carbonyl or thiocarbonyl group.
104. The mixture of any one of claims 93 to 97, wherein the at least two labeled analytes each comprise an isomeric label.
105. The mixture of any one of claims 93 to 97, wherein the at least two labeled analytes each comprise an isobaric label.
106. The mixture of claim 105, wherein the at least two labeled analytes each comprise an isobaric label that is a 5, 6 or 7 membered heterocyclic ring comprising a ring nitrogen atom that is N-alkylated with a substituted or unsubstituted acetic acid moiety to which the analyte is linked through the carbonyl carbon of the N-alkyl acetic acid moiety, wherein each different label comprises one or more heavy atom isotopes.
107. The mixture of claim 106, wherein each of the at least two isobarically labeled analytes in the mixture comprise the formula:
wherein;
a) Z is O, S, NH or NR1;
b) each J is the same or different and is H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine or iodine;
c) W is an atom or group that is located ortho, meta or para to the ring nitrogen and is NH, N-R1, N-R2, P-R1, P-R2, O or S;
d) each carbon of the heterocyclic ring has the formula CJ2;
e) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
and f) R2 is an amino alkyl, hydroxy alkyl, thio alkyl group or a cleavable linker that cleavably links the reagent to a solid support wherein the amino alkyl, hydroxy alkyl or thio alkyl group comprises one to eight carbon atoms, which may optionally contain a heteroatom or a substituted or unsubstituted aryl group, and wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
108. The mixture of claim 107, wherein the mixture comprises one or more isobarically labeled analytes of the formula:
109. The mixture of claim 107, wherein the mixture comprises one or more isobarically labeled analytes of the formula:
110. The mixture of claim 107, wherein the mixture comprises one or more isobarically labeled analytes of the formula:

wherein:
a) G' is an amino alkyl, hydroxy alkyl or thio alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
b) each carbon of the heterocyclic ring has the formula CJ2, wherein each J is the same or different and is selected from the group consisting of: H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine; and c) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
111. The mixture of claim 105, wherein the mixture comprises one or more isobarically labeled analytes of the formula:
wherein:
a) Z is O, S, NH or NR1;

b) each J is the same or different and is selected from the group consisting of: H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine;
c) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
112. The mixture of any of claims 93 to 97, further comprising one or more calibration standards.
113. An active ester compound that is a 5, 6 or 7 membered heterocyclic ring comprising a ring nitrogen atom that is N-alkylated with a substituted or unsubstituted acetic acid moiety to which the alcohol moiety of the active ester is linked through the carbonyl carbon of the N-alkyl acetic acid moiety, wherein the compound is isotopically enriched with one or more heavy atom isotopes.
114. The compound of claim 113, wherein the compound is isotopically enriched with three or more heavy atom isotopes.
115. The compound of claim 113, wherein the heterocyclic ring is substituted with one or more substituents.
116. The compound of claim 115, wherein the one or more substituents are alkyl, alkoxy or aryl groups.
117. The compound of claim 116, wherein the one or more substituents are protected or unprotected amine groups, hydroxyl groups or thiol groups.
118. The compound of claim 113, wherein the heterocyclic ring is aliphatic.
119. The compound of claim 113, wherein the heterocyclic ring is aromatic.
120. The compound of claim 113, wherein the heterocyclic ring comprises one or more additional nitrogen, oxygen or sulfur atoms.
121. The compound of claim 113, wherein active ester is an N-hydroxysuccinimide ester.
122. The compound of claim 113, wherein the compound is a salt.
123. The compound of claim 113, wherein the compound is a mono-TFA salt, a mono-HCl salt, a bis-TFA salt or a bis-HCl salt.
124. The compound of claim 113, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
125. The compound of claim 113, wherein each incorporated heavy atom isotope is present in at least 93 percent isotopic purity.
126. The compound of claim 113, wherein each incorporated heavy atom isotope is present in at least 96 percent isotopic purity.
127. An N-substituted morpholine acetic acid active ester compound of the formula:
or a salt thereof, wherein;
LG is the leaving group of an active ester;
X is O or S;
each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms; and wherein the N-substituted morpholine acetic acid active ester is isotopically enriched with one or more heavy atom isotopes.
128. The compound of claim 127, wherein the N-substituted morpholine acetic acid active ester is isotopically enriched with three or more heavy atom isotopes.
129. The compound of claim 127, wherein LG is:
and wherein X is O or S.
130. The compound of claim 127, wherein LG is N-hydroxysuccinimide.
131. The compound of claim 127, wherein each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
132. The compound of claim 127, wherein each Z is independently hydrogen, methyl or methoxy.
133. The compound of claim 127, wherein X is 16O or 18O.
134. The compound of claim 127, wherein the nitrogen atom of the morpholine ring is 14N or 15N.
135. The compound of claim 127, of the formula:
wherein;
each C* is independently 12C or 13C;
LG is the leaving group of an active ester;
X is O or S; and each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms.
136. The compound of claim 127, wherein the compound is a mono-TFA salt or a mono-HCl salt.
137. The compound of claim 127, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
138. The compound of claim 127, wherein each incorporated heavy atom isotope is present in at least 93 percent or isotopic purity.
139. The compound of claim 127, wherein each incorporated heavy atom isotope is present in at least 96 percent or isotopic purity.
140. An N-substituted piperidine acetic acid active ester compound of the formula:
or a salt thereof, wherein;
LG is the leaving group of an active ester;

X is O or S;
each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms; and wherein the N-substituted piperidine acetic acid active ester is isotopically enriched with one or more heavy atom isotopes.
141. The compound of claim 140, wherein the N-substituted piperidine acetic acid active ester is isotopically enriched with three or more heavy atom isotopes.
142. The compound of claim 140, wherein LG is:
and wherein X is O or S.
143. The compound of claim 140, wherein LG is N-hydroxysuccinimide.
144. The compound of claim 140, wherein each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
145. The compound of claim 140, wherein each Z is independently hydrogen, methyl or methoxy.
146. The compound of claim 140, wherein X is 16O or 18O.
147. The compound of claim 140, wherein the nitrogen atom of the piperidine ring is 14N or 15N.
148. The compound of claim 140, of the formula:

wherein;
each C* is independently 12C or 13C;
LG is the leaving group of an active ester;
X is O or S; and each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms.
149. The compound of claim 140, wherein the compound is a mono-TFA salt or a mono-HCl salt.
150. The compound of claim 140, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
151. The compound of claim 140, wherein each incorporated heavy atom isotope is present in at least 93 percent or isotopic purity.
152. The compound of claim 140, wherein each incorporated heavy atom isotope is present in at least 96 percent or isotopic purity.
153. An N-substituted piperazine acetic acid active ester compound of the formula:
or a salt thereof, wherein;
LG is the leaving group of an active ester;
X is O or S;
Pg is an amine-protecting group;
each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms; and wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with one or more heavy atom isotopes.
154 The compound of claim 153, wherein the N-substituted piperazine acetic acid active ester is isotopically enriched with three or more heavy atom isotopes
155. The compound of claim 153, wherein LG is:

and wherein X is O or S.
156. The compound of claim 153, wherein LG is N-hydroxysuccinimide.
157. The compound of claim 153, wherein each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
158. The compound of claim 153, wherein each Z is independently hydrogen, methyl or methoxy.
159. The compound of claim 153, wherein X is 16O or 18O.
160. The compound of claim 153, wherein each nitrogen atom of the piperazine ring is 14N or 15N.
161. The compound of claim 153, of the formula:

wherein, each C* is independently 12C or 13C;
LG is the leaving group of an active ester;

X is O or S;

Pg is an amine protecting group; and each Z is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, an amino acid side chain or a straight chain or branched C1-C6 alkyl group that may optionally contain a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups each independently comprise linked hydrogen, deuterium or fluorine atoms.
162. The compound of claim 153, wherein the compound is a mono-TFA salt, a mono-HCl salt, a bis-TFA salt or a bis-HCl salt
163. The compound of claim 153, wherein each incorporated heavy atom isotope is present in at least 80 percent isotopic purity.
164. The compound of claim 153, wherein each incorporated heavy atom isotope is present in at least 93 percent or isotopic purity.
165. The compound of claim 153, wherein each incorporated heavy atom isotope is present in at least 96 percent or isotopic purity.
166. A kit comprising:
a) a set of two or more reagents suitable for the labeling of analytes, each reagent of the set comprising the formula:

RP-X-LK-Y-RG

or a salt thereof wherein;
i) RG is a reactive group that is an electrophile and that is capable of reacting with one or more of the reactive analytes of the sample;
ii) RP is a reporter moiety that comprises a fixed charge or that is ionizable, wherein the gross mass of each reporter is different for each reagent of the set;
iii) LK is a linker moiety that links the reactive group and the reporter group, wherein:
a) the mass of the linker compensates for the difference in gross mass between the reporters for the different labeling reagents of the set such that the aggregate gross mass of the reporter and linker combination is the same for each reagent of the set; and b) the linker comprises at least one heavy atom isotope and has the formula:

wherein R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
iv) X is a bond between an atom of the reporter and an atom of the linker;
v) Y is a bond between an atom of the linker and an atom of the reactive group, wherein, once the labeling reagent is reacted with the reactive analyte, bond Y links the linker to the analyte; and b) one or more reagents, containers, enzymes, buffers or instructions.
167. The kit of claim 166, wherein the kit comprises a proteolytic enzyme.
168. The kit of claim 166, wherein the reactive group of each reagent of the set is an active ester.
169. The kit of claim 168, wherein the alcohol moiety of the active ester is a group of the formula:

wherein X is O or S.
170. The kit of claim 168, wherein the active ester is an N-hydroxysuccinimide ester.
171. The kit of claim 166, wherein the reporter is a substituted or unsubstituted morpholine, piperidine or piperazine.
172. The kit of claim 166, wherein the reporter comprises a carboxylic acid, sulfonic acid or phosphoric acid group.
173. The kit of claim 166, wherein the linker is a carbonyl or thiocarbonyl group.
174. The kit of claim 166, wherein each reagent of the set is independently linked to a solid support through a cleavable linker.
175. The kit of claim 166, wherein all reagents of the set are isomeric.
176. The kit of claim 166, wherein all reagents of the set are isobaric.
177. The kit of claim 176, wherein all reagents of the set comprise the formula:

wherein;
a) RG is a reactive group that is an electrophile;
b) Z is O, S, NH or NR1;
c) each J is the same or different and is selected from the group consisting of: H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine;
d) W is an atom or group that is located ortho, meta or para to the ring nitrogen and is selected from the group consisting of: NH, N-R2, P-R2, O or S; and e) each carbon of the heterocyclic ring has the formula CJ2;
f) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen deuterium and/or fluorine atoms; and g) R2 is an amino alkyl, hydroxy alkyl, thio alkyl group or a cleavable linker that cleavably links the reagent to a solid support wherein the amino alkyl, hydroxy alkyl or thio alkyl group comprises one to eight carbon atoms, which may optionally contain a heteroatom or a substituted or unsubstituted aryl group, and wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
178. The kit of claim 177, wherein the set comprises one or more of the following four reagents:

wherein RG is the reactive group.
179. The kit of claim 177, wherein the set comprises one or more of the following four reagents:

wherein RG is the reactive group.
180. The kit of claim 177, wherein the set comprises one or more of the following four support bound reagents:

wherein:
a) RG is the reactive group;

b) E is a solid support;
c) F is a cleavable linker linked to the solid support;
d) G is an amino alkyl, hydroxy alkyl or thio alkyl group, cleavably linked to the cleavable linker wherein the amino alkyl, hydroxy alkyl or thio alkyl group comprises one to eight carbon atoms, which may optionally contain a heteroatom or a substituted or unsubstituted aryl group, and wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms;
e) each carbon of the heterocyclic ring has the formula CJ2; and wherein each J is the same or different and is selected from the group consisting of: H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine; and f) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen, deuterium and/or fluorine atoms.
181. The kit of claim 176, wherein all reagents of the set comprise the formula:

wherein:
a) RG is a reactive group that is a nucleophile or electrophile;
b) Z is O, S, NH or NR1;
c) each J is the same or different and is selected from the group consisting of: H, deuterium (D), R1, OR1, SR1, NHR1, N(R1)2, fluorine, chlorine, bromine and iodine; and d) each R1 is the same or different and is an alkyl group comprising one to eight carbon atoms which may optionally contain a heteroatom or a substituted or unsubstituted aryl group wherein the carbon atoms of the alkyl and aryl groups independently comprise linked hydrogen deuterium and/or fluorine atoms.
182. The kit of claim 181, wherein the set comprises one or more of the following four wherein RG is the reactive group.
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Families Citing this family (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3267700A (en) * 1999-03-18 2000-10-09 602531 British Columbia Ltd. Data entry for personal computing devices
JP2003527087A (en) * 1999-08-13 2003-09-16 イェール・ユニバーシティ Binary coded array tags
AU2001259586A1 (en) * 2000-05-05 2001-11-20 Agilix Corporation Highly multiplexed reporter carrier systems
US6835545B2 (en) 2000-05-08 2004-12-28 President And Fellows Of Harvard College Methods, products and treatments for diabetes
WO2002014867A2 (en) * 2000-08-11 2002-02-21 Agilix Corporation Ultra-sensitive detection systems
ATE515702T1 (en) * 2003-01-30 2011-07-15 Life Technologies Corp METHODS, MIXTURES, KITS AND COMPOSITIONS FOR ANALYTE DETERMINATION
GB0306756D0 (en) * 2003-03-24 2003-04-30 Xzillion Gmbh & Co Kg Mass labels
CA2542941C (en) * 2003-11-26 2013-02-12 Applera Corporation Analysis of mass spectral data in the quiet zones and label selection therefor
EP1916527A1 (en) * 2003-11-26 2008-04-30 Applera Corporation Analysis of mass spectral data in the quiet zones
US20050148087A1 (en) 2004-01-05 2005-07-07 Applera Corporation Isobarically labeled analytes and fragment ions derived therefrom
US20050148771A1 (en) * 2004-01-05 2005-07-07 Applera Corporation. Active esters of N-substituted piperazine acetic acids, including isotopically enriched versions thereof
US20050147985A1 (en) * 2004-01-05 2005-07-07 Applera Corporation Mixtures of isobarically labeled analytes and fragments ions derived therefrom
JP4832312B2 (en) * 2004-01-05 2011-12-07 ディーエイチ テクノロジーズ デベロップメント プライベート リミテッド Labeling reagent, labeled analyte, and fragment ions derived therefrom, including a mixture of labeling reagent and labeled analyte, and methods for their analysis
EP1623234B1 (en) 2004-03-01 2007-06-06 Applera Corporation Determination of analyte characteristics based upon binding properties
US20080206737A1 (en) * 2004-05-19 2008-08-28 Hunter Christie L Expression quantification using mass spectrometry
US20070054345A1 (en) 2004-05-19 2007-03-08 Hunter Christie L Expression quantification using mass spectrometry
JP2007538262A (en) * 2004-05-19 2007-12-27 アプレラ コーポレイション Quantifying expression using mass spectrometry
US8027791B2 (en) * 2004-06-23 2011-09-27 Medtronic, Inc. Self-improving classification system
US8335652B2 (en) * 2004-06-23 2012-12-18 Yougene Corp. Self-improving identification method
US20050287574A1 (en) * 2004-06-23 2005-12-29 Medtronic, Inc. Genetic diagnostic method for SCD risk stratification
CA2572754A1 (en) * 2004-07-12 2006-02-16 Applera Corporation Mass tags for quantitative analyses
US20070048752A1 (en) * 2004-07-12 2007-03-01 Applera Corporation Mass tags for quantitative analyses
AU2005307808B2 (en) * 2004-11-15 2011-03-10 University Of North Dakota A method for single oxygen atom incorporation into digested peptides using peptidases
US7833725B2 (en) 2005-01-06 2010-11-16 President And Fellows Of Harvard College Mass spectrometric methods and products
AU2006210551A1 (en) * 2005-02-03 2006-08-10 Perkinelmer Las, Inc. Ultra-sensitive detection systems using multidimension signals
US20060183238A1 (en) * 2005-02-09 2006-08-17 Applera Corporation Amine-containing compound analysis methods
US20070037286A1 (en) * 2005-02-09 2007-02-15 Subhasish Purkayastha Thyroxine-containing compound analysis methods
DE102005015005A1 (en) * 2005-04-01 2006-10-05 Qiagen Gmbh Process for treating a sample containing biomolecules
JP2009508118A (en) 2005-09-15 2009-02-26 アルク−アベッロ エイ／エス Quantification method of allergen
WO2007078229A1 (en) * 2006-01-05 2007-07-12 Ge Healthcare Bio-Sciences Ab Kit and method for mass labelling
US8975404B2 (en) 2006-01-24 2015-03-10 Dh Technologies Development Pte. Ltd. Labeling reagents for analyte determination and methods and compounds used in making the same
US20070185346A1 (en) * 2006-02-03 2007-08-09 Vaidya Niteen A Kit for automated resolving agent selection and method thereof
US7982070B2 (en) 2006-03-21 2011-07-19 Wisconsin Alumni Research Foundation Ionizable isotopic labeling reagents for relative quantification by mass spectrometry
JP5413836B2 (en) * 2006-05-26 2014-02-12 ディーエイチ テクノロジーズ デベロップメント プライベート リミテッド Tagging reagents for hydroxylated compounds and methods thereof
US8362242B2 (en) * 2006-06-30 2013-01-29 Dh Technologies Development Pte. Ltd. Analyte determination utilizing mass tagging reagents comprising a non-encoded detectable label
US8580534B2 (en) * 2006-06-30 2013-11-12 The University Of North Dakota Method for incorporation of two oxygen atoms into digested peptides using peptidases
US7906341B2 (en) * 2006-06-30 2011-03-15 Dh Technologies Development Pte, Ltd. Methods, mixtures, kits and compositions pertaining to analyte determination
EP1918714A1 (en) * 2006-11-02 2008-05-07 Koninklijke Philips Electronics N.V. Compounds and methods for double labelling of polypeptides to allow multiplexing in mass spectrometric analysis
EP1921081A1 (en) 2006-11-06 2008-05-14 Koninklijke Philips Electronics N.V. Use of arylboronic acids in protein labelling
US7951608B2 (en) * 2007-05-04 2011-05-31 Perkinelmer Health Sciences, Inc. Detecting succinylacetone
WO2009003188A2 (en) * 2007-06-27 2008-12-31 Cedars-Sinai Medical Center N-terminal specific chemical labeling for proteomics applications
US20090028791A1 (en) * 2007-07-25 2009-01-29 Balatoni Julius A Dichloroacetate Analogs as Imaging Agents
US7820964B2 (en) * 2007-08-06 2010-10-26 Metabolic Analyses, Inc Method for generation and use of stable isotope patterns in mass spectral data
US7982180B2 (en) * 2007-09-10 2011-07-19 Dh Technologies Development Pte. Ltd. Methods and systems for analysis and correction of mass spectrometer data
US8604692B2 (en) 2007-11-06 2013-12-10 Translational Therapeutics, Inc. Mass spectrometry assay for eIF4E and eIF4E regulon activity
WO2009061904A2 (en) 2007-11-06 2009-05-14 Translational Therapeutics, Inc. MASS SPECTROMETRY ASSAY FOR eIF4E AND eIF4E REGULON ACTIVITY
US20090131276A1 (en) * 2007-11-14 2009-05-21 Medtronic, Inc. Diagnostic kits and methods for scd or sca therapy selection
US20110143956A1 (en) * 2007-11-14 2011-06-16 Medtronic, Inc. Diagnostic Kits and Methods for SCD or SCA Therapy Selection
EP2108957A1 (en) * 2008-04-07 2009-10-14 Koninklijke Philips Electronics N.V. Compounds and methods for the labelling and affinity-selection of proteins
GB0809488D0 (en) 2008-05-23 2008-07-02 Electrophoretics Ltd Mass spectrometric analysis
WO2010104981A2 (en) 2009-03-10 2010-09-16 University Of Maryland Biotechnology Institute Deuterium isobaric tag reagents for quantitative analysis
US8592216B2 (en) 2009-04-15 2013-11-26 Wisconsin Alumni Research Foundation Labeling peptides with tertiary amines and other basic functional groups for improved mass spectrometric analysis
WO2010132546A2 (en) * 2009-05-12 2010-11-18 Medtronic, Inc. Sca risk stratification by predicting patient response to anti-arrhythmics
CA2762277C (en) 2009-05-31 2018-08-14 Dh Technologies Development Pte. Ltd. Specific analysis of ketone and aldehyde analytes using reagent compounds, labeling strategies, and mass spectrometry workflow
GB0916881D0 (en) 2009-09-25 2009-11-11 Electrophoretics Ltd Mass labels
CA2784495A1 (en) * 2009-12-15 2011-06-23 Dh Technologies Development Pte. Ltd. Analysis of amino acids and amine-containing compounds using tagging reagents and lc-ms workflow
WO2011088423A2 (en) * 2010-01-15 2011-07-21 California Institute Of Technology Isobaric tags for analyte detection and quantification
JP5730908B2 (en) * 2010-01-25 2015-06-10 ディーエイチ テクノロジーズ デベロップメント プライベート リミテッド Quantitative analysis of vitamin D3, vitamin D2, and their metabolites
US8455818B2 (en) 2010-04-14 2013-06-04 Wisconsin Alumni Research Foundation Mass spectrometry data acquisition mode for obtaining more reliable protein quantitation
WO2011146521A2 (en) * 2010-05-17 2011-11-24 The Uab Research Foundation A general mass spectrometry assay using continuously eluting co-fractionating reporters of mass spectrometry detection efficiency
US8835361B2 (en) * 2010-06-01 2014-09-16 The Curators Of The University Of Missouri High-throughput quantitation of crop seed proteins
WO2012027555A2 (en) 2010-08-25 2012-03-01 President And Fellows Of Harvard College Glycated cd59 peptides, their preparation, and uses thereof
DE102011053684B4 (en) 2010-09-17 2019-03-28 Wisconsin Alumni Research Foundation Method for carrying out jet impact activated dissociation in the already existing ion injection path of a mass spectrometer
JP5711948B2 (en) * 2010-12-02 2015-05-07 良雄 林 Solid phase supported SH group selective labeling reagent
JP5454462B2 (en) * 2010-12-22 2014-03-26 株式会社島津製作所 Chromatograph mass spectrometer
US8492163B2 (en) 2011-01-31 2013-07-23 Dh Technologies Development Pte. Ltd. Methods, mixtures, kits and compositions pertaining to analyte determination
BR112013020274A2 (en) 2011-02-10 2016-11-22 Harvard College post-translationally modified protein substitutes and uses thereof
DE102012102875B4 (en) 2011-04-04 2024-04-18 Wisconsin Alumni Research Foundation Precursor selection with an artificial intelligence algorithm increases coverage and reproducibility of proteomic samples
US9388132B2 (en) 2011-09-15 2016-07-12 Wisconsin Alumni Research Foundation Isobaric tandem mass tags for quantitative proteomics and peptidomics
EP2807482B1 (en) * 2012-01-20 2018-03-14 DH Technologies Development Pte. Ltd. Analysis of estradiol and analytes with phenolic oh using labeling chemistry and lc-msms workflow
US9029086B2 (en) * 2012-01-26 2015-05-12 Masood Kamali Moghaddam Detection of single and multimodal analytes
JP6272834B2 (en) 2012-05-18 2018-01-31 ディーエイチ テクノロジーズ デベロップメント プライベート リミテッド Analysis of a panel of cerebral tendon xanthoma biomarkers using site-specific induction and LC / MS / MS workflow
WO2014013051A1 (en) 2012-07-19 2014-01-23 Institut National De La Sante Et De La Recherche Medicale (Inserm) Method of predicting or diagnosing an hepatic encephalopathy in patients with cirrhosis treated with transjugular intra-hepatic porto-systemic shunt (tips)
US9366678B2 (en) 2012-10-25 2016-06-14 Wisconsin Alumni Research Foundation Neutron encoded mass tags for analyte quantification
GB201410523D0 (en) * 2014-06-12 2014-07-30 Electrophoretics Ltd Mass labels
US20170089915A1 (en) * 2015-09-30 2017-03-30 Agilent Technologies, Inc. Methods of analyte derivatization and enhanced soft ionization
GB201521903D0 (en) * 2015-12-11 2016-01-27 Electrophoretics Ltd Isorbaric mass labels
WO2018003652A1 (en) * 2016-06-29 2018-01-04 株式会社 日立ハイテクノロジーズ Compound for use in enzymatic reaction and mass spectrometry method
CN110383071B (en) * 2017-01-31 2023-10-03 豪夫迈·罗氏有限公司 Reagents for mass spectrometry
CN111512411A (en) * 2017-11-14 2020-08-07 马克思普朗克科学促进会 Use of isobaric tags in mass spectrometry
JP2021532118A (en) 2018-07-24 2021-11-25 エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft Reagents for mass spectrometry
CN112449636A (en) 2018-07-24 2021-03-05 豪夫迈·罗氏有限公司 Reagent for mass spectrometry
CN112492882A (en) * 2018-07-24 2021-03-12 豪夫迈·罗氏有限公司 Reagent for mass spectrometry
CN112146967A (en) * 2019-06-28 2020-12-29 Fei 公司 System and method for preparing and delivering biological samples for charged particle analysis
EP3910341A1 (en) * 2020-05-13 2021-11-17 PreOmics GmbH Sample preparation for mass spectrometry

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3860581A (en) * 1972-12-27 1975-01-14 American Home Prod Preparation of 1,4-benzodiazepines
AU5940186A (en) 1985-07-05 1987-01-08 Institut Fur Pflanzenschutzforschung 2, 6 - dimethyl - morpholine quartenary compounds
US4761415A (en) 1986-08-28 1988-08-02 Smithkline Beckman Corporation Dopamine-β-hydroxylase inhibitors
JPH01125357A (en) 1987-11-06 1989-05-17 Dainippon Pharmaceut Co Ltd Tripeptide derivative
US5800992A (en) * 1989-06-07 1998-09-01 Fodor; Stephen P.A. Method of detecting nucleic acids
US5087815A (en) * 1989-11-08 1992-02-11 Schultz J Albert High resolution mass spectrometry of recoiled ions for isotopic and trace elemental analysis
US5252296A (en) * 1990-05-15 1993-10-12 Chiron Corporation Method and apparatus for biopolymer synthesis
DK51092D0 (en) * 1991-05-24 1992-04-15 Ole Buchardt OLIGONUCLEOTIDE ANALOGUE DESCRIBED BY PEN, MONOMERIC SYNTHONES AND PROCEDURES FOR PREPARING THEREOF, AND APPLICATIONS THEREOF
JPH07507394A (en) 1992-05-29 1995-08-10 ザ ロックフェラー ユニバーシティ Methods and materials for peptide sequencing using a mass spectrometer
GB9300883D0 (en) 1993-01-18 1993-03-10 Pfizer Ltd Antiparasitic agents
AU7247896A (en) 1995-09-29 1997-04-17 Scripps Research Institute, The Protein signature analysis
US6027890A (en) * 1996-01-23 2000-02-22 Rapigene, Inc. Methods and compositions for enhancing sensitivity in the analysis of biological-based assays
US6312893B1 (en) 1996-01-23 2001-11-06 Qiagen Genomics, Inc. Methods and compositions for determining the sequence of nucleic acid molecules
US6613508B1 (en) * 1996-01-23 2003-09-02 Qiagen Genomics, Inc. Methods and compositions for analyzing nucleic acid molecules utilizing sizing techniques
WO1997037953A1 (en) 1996-04-08 1997-10-16 Glaxo Group Ltd. Mass-based encoding and qualitative analysis of combinatorial libraries
US5780232A (en) * 1996-05-28 1998-07-14 Atom Sciences, Inc. DNA sequencing, mapping, and diagnostic processes using hybridization and stable isotope labels of DNA
US6329180B1 (en) * 1996-09-13 2001-12-11 Alex M. Garvin Genetic analysis using peptide tagged in-vitro synthesized proteins
GB9620769D0 (en) 1996-10-04 1996-11-20 Brax Genomics Ltd Nucleic acid sequencing
AU4549997A (en) 1996-10-04 1998-05-05 Dako A/S Novel probes for the detection of mycobacteria
JP2001524808A (en) 1996-12-10 2001-12-04 ジーントレイス・システムズ・インコーポレイテッド Releasable non-volatile mass labeling molecules
CN100434531C (en) 1997-01-15 2008-11-19 X齐里昂有限两合公司 Mass label linked hybridisation probes
ES2205437T3 (en) 1997-01-23 2004-05-01 XZILLION GMBH & CO.KG PROCEDURE THAT ALLOWS CHARACTERIZING POLYPEPTIDES.
EP1002128A1 (en) 1997-07-11 2000-05-24 Brax Genomics Limited Characterising nucleic acids
ATE240408T1 (en) 1997-07-22 2003-05-15 Qiagen Genomics Inc METHOD AND COMPOUNDS FOR ANALYZING NUCLEIC ACIDS BY MASS SPECTROMETRY
GB9718921D0 (en) 1997-09-05 1997-11-12 Brax Genomics Ltd Catalytically generated mass labels
WO1999014362A1 (en) 1997-09-15 1999-03-25 Brax Group Limited Characterising nucleic acid by mass spectrometry
GB9823646D0 (en) * 1997-12-19 1998-12-23 Brax Genomics Ltd Compounds for mass spectrometry
US6326479B1 (en) * 1998-01-27 2001-12-04 Boston Probes, Inc. Synthetic polymers and methods, kits or compositions for modulating the solubility of same
US6428956B1 (en) * 1998-03-02 2002-08-06 Isis Pharmaceuticals, Inc. Mass spectrometric methods for biomolecular screening
US6361942B1 (en) * 1998-03-24 2002-03-26 Boston Probes, Inc. Method, kits and compositions pertaining to detection complexes
AU3775099A (en) * 1998-04-29 1999-11-16 Boston Probes, Inc. Methods, kits and compositions for detecting and quantitating target sequences
DE69912444T3 (en) 1998-08-25 2010-05-06 University Of Washington, Seattle FAST QUANTITATIVE ANALYSIS OF PROTEINS OR PROTEIN FUNCTIONS IN COMPLEX MIXTURES
US6270976B1 (en) * 1998-09-15 2001-08-07 Brax Group Limited Characterizing nucleic acid by mass spectrometry
GB9821669D0 (en) 1998-10-05 1998-12-02 Glaxo Group Ltd Chemical constructs and their uses
US6319476B1 (en) * 1999-03-02 2001-11-20 Perseptive Biosystems, Inc. Microfluidic connector
US6403309B1 (en) * 1999-03-19 2002-06-11 Valigen (Us), Inc. Methods for detection of nucleic acid polymorphisms using peptide-labeled oligonucleotides and antibody arrays
US6629040B1 (en) * 1999-03-19 2003-09-30 University Of Washington Isotope distribution encoded tags for protein identification
JP2003527087A (en) * 1999-08-13 2003-09-16 イェール・ユニバーシティ Binary coded array tags
US6472156B1 (en) * 1999-08-30 2002-10-29 The University Of Utah Homogeneous multiplex hybridization analysis by color and Tm
GB0006141D0 (en) * 2000-03-14 2000-05-03 Brax Group Ltd Mass labels
AUPQ664300A0 (en) * 2000-04-03 2000-05-04 Proteome Systems Ltd Macromolecule detection
AU2001259586A1 (en) 2000-05-05 2001-11-20 Agilix Corporation Highly multiplexed reporter carrier systems
WO2002014867A2 (en) 2000-08-11 2002-02-21 Agilix Corporation Ultra-sensitive detection systems
US6905879B2 (en) * 2000-10-23 2005-06-14 Genetics Institute, Inc. Isotope-coded ionization-enhancing reagents (ICIER) for high-throughput protein identification and quantitation using matrix-assisted laser desorption ionization mass spectrometry
US20020090652A1 (en) * 2000-12-22 2002-07-11 Fu Emil Wei-Ming Inverse labeling method for the rapid identification of marker/target proteins
US7045296B2 (en) 2001-05-08 2006-05-16 Applera Corporation Process for analyzing protein samples
GB0115581D0 (en) 2001-06-26 2001-08-15 Glaxo Group Ltd Method of mass spectometry
GB0116143D0 (en) * 2001-07-02 2001-08-22 Amersham Pharm Biotech Uk Ltd Chemical capture reagent
PT1425586E (en) 2001-09-14 2007-12-31 Electrophoretics Ltd Mass labels
CA2466328A1 (en) 2001-11-09 2003-05-15 Bayer Healthcare Ag Isotopically coded affinity markers 3
ATE358275T1 (en) * 2001-11-16 2007-04-15 Randox Lab Ltd METHOD AND KIT FOR DETECTING OR QUANTIFYING METABOLITES OF FENTANYL AND METABOLITES OF FENTANYL ANALOGUE
GB0130845D0 (en) 2001-12-22 2002-02-06 James Peter Analysis
ES2319634T3 (en) 2002-03-11 2009-05-11 Caprotec Bioanalytics Gmbh COMPOUNDS AND METHODS TO ANALYZE THE PROTEOM.
US20060089807A1 (en) 2002-03-11 2006-04-27 Thermo Finnigan, Llc Identifying peptide modifications
AU2003259029A1 (en) 2002-06-04 2003-12-19 The Institute For Systems Biology Methods for high throughput and quantitative proteome analysis
US7473535B2 (en) 2002-08-20 2009-01-06 The Institute For Systems Biology Chemical reagents and methods for detection and quantification of proteins in complex mixtures
US7425451B2 (en) * 2002-12-13 2008-09-16 Agilent Technologies, Inc. Triazine derivatives as universal peptide isotope tag reagents (U-PIT)
ATE515702T1 (en) * 2003-01-30 2011-07-15 Life Technologies Corp METHODS, MIXTURES, KITS AND COMPOSITIONS FOR ANALYTE DETERMINATION
GB0306756D0 (en) 2003-03-24 2003-04-30 Xzillion Gmbh & Co Kg Mass labels
US20050148087A1 (en) * 2004-01-05 2005-07-07 Applera Corporation Isobarically labeled analytes and fragment ions derived therefrom
US20050148771A1 (en) * 2004-01-05 2005-07-07 Applera Corporation. Active esters of N-substituted piperazine acetic acids, including isotopically enriched versions thereof
US20050147985A1 (en) * 2004-01-05 2005-07-07 Applera Corporation Mixtures of isobarically labeled analytes and fragments ions derived therefrom
US20050147982A1 (en) * 2004-01-05 2005-07-07 Applera Corporation Mixtures of isobarically labeled analytes and fragments ions derived therefrom
US7355045B2 (en) * 2004-01-05 2008-04-08 Applera Corporation Isotopically enriched N-substituted piperazine acetic acids and methods for the preparation thereof
CA2572754A1 (en) * 2004-07-12 2006-02-16 Applera Corporation Mass tags for quantitative analyses

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