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TestSeqs.txt
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In a genome-wide association study (GWAS) to identify genetic variants influencing LDL-C in an isolated population from Kosrae, we observed associations for SNPs in the gene encoding HMG-CoA reductase (HMG-CoA reductase). [('PMC2764366', 'A01000', 183, 200, 'HMG-CoA reductase'), ('PMC2764366', 'A01000', 202, 219, 'HMG-CoA reductase')] ['In', 'a', 'genome', '-', 'wide', 'association', 'study', '(', 'GW', '##AS', ')', 'to', 'identify', 'genetic', 'variants', 'influencing', 'LDL', '-', 'C', 'in', 'an', 'isolated', 'population', 'from', 'Kos', '##ra', '##e', ',', 'we', 'observed', 'associations', 'for', 'SNPs', 'in', 'the', 'gene', 'encoding', 'HM', '##G', '-', 'Co', '##A', 'reductase', '(', 'HM', '##G', '-', 'Co', '##A', 'reductase', ')', '.'] [0, 3, 5, 11, 12, 17, 29, 35, 36, 38, 40, 42, 45, 54, 62, 71, 83, 86, 87, 89, 92, 95, 104, 115, 120, 123, 125, 126, 128, 131, 140, 153, 157, 162, 165, 169, 174, 183, 185, 186, 187, 189, 191, 201, 202, 204, 205, 206, 208, 210, 219, 220] [2, 4, 11, 12, 16, 28, 34, 36, 38, 40, 41, 44, 53, 61, 70, 82, 86, 87, 88, 91, 94, 103, 114, 119, 123, 125, 126, 127, 130, 139, 152, 156, 161, 164, 168, 173, 182, 185, 186, 187, 189, 190, 200, 202, 204, 205, 206, 208, 209, 219, 220, 221] ['In', 'a', 'genome', '-', 'wide', 'association', 'study', '(', 'GWAS', ')', 'to', 'identify', 'genetic', 'variants', 'influencing', 'LDL-C', 'in', 'an', 'isolated', 'population', 'from', 'Kosrae', ',', 'we', 'observed', 'associations', 'for', 'SNPs', 'in', 'the', 'gene', 'encoding', 'HMG-CoA', 'reductase', '(', 'HMG-CoA', 'reductase', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
We followed up the association results and identified a functional SNP in intron13 (rs3846662), which was in linkage disequilibrium with the SNPs of genome-wide significance and affected alternative splicing of HMG-CoA reductase mRNA. [('PMC2764366', 'A01002', 211, 228, 'HMG-CoA reductase')] ['We', 'followed', 'up', 'the', 'association', 'results', 'and', 'identified', 'a', 'functional', 'SNP', 'in', 'intron', '##13', '(', 'rs', '##38', '##46', '##66', '##2', ')', ',', 'which', 'was', 'in', 'linkage', 'dise', '##quilibrium', 'with', 'the', 'SNPs', 'of', 'genome', '-', 'wide', 'significance', 'and', 'affected', 'alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', '.'] [0, 3, 12, 15, 19, 31, 39, 43, 54, 56, 67, 71, 74, 80, 83, 84, 86, 88, 90, 92, 93, 94, 96, 102, 106, 109, 117, 121, 132, 137, 141, 146, 149, 155, 156, 161, 174, 178, 187, 199, 208, 211, 213, 214, 215, 217, 219, 229, 233] [2, 11, 14, 18, 30, 38, 42, 53, 55, 66, 70, 73, 80, 82, 84, 86, 88, 90, 92, 93, 94, 95, 101, 105, 108, 116, 121, 131, 136, 140, 145, 148, 155, 156, 160, 173, 177, 186, 198, 207, 210, 213, 214, 215, 217, 218, 228, 233, 234] ['We', 'followed', 'up', 'the', 'association', 'results', 'and', 'identified', 'a', 'functional', 'SNP', 'in', 'intron13', '(', 'rs3846662', ')', ',', 'which', 'was', 'in', 'linkage', 'disequilibrium', 'with', 'the', 'SNPs', 'of', 'genome', '-', 'wide', 'significance', 'and', 'affected', 'alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'mRNA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
In vitro studies in human lymphoblastoid cells demonstrated that homozygosity for the rs3846662 minor allele was associated with up to 2.2-fold lower expression of alternatively spliced HMG-CoA reductase mRNA lacking exon13 and minigene transfection assays confirmed that allele status at rs3846662 directly modulated alternative splicing of HMG-CoA reductase exon13 (42.9±3.9 vs. 63.7±1.0 %Δexon13/total HMGCR mRNA, p=0.02). [('PMC2764366', 'A01003', 186, 203, 'HMG-CoA reductase'), ('PMC2764366', 'A01003', 342, 359, 'HMG-CoA reductase')] ['In', 'vitro', 'studies', 'in', 'human', 'lymph', '##oblast', '##oid', 'cells', 'demonstrated', 'that', 'hom', '##ozyg', '##osity', 'for', 'the', 'rs', '##38', '##46', '##66', '##2', 'minor', 'allele', 'was', 'associated', 'with', 'up', 'to', '2', '.', '2', '-', 'fold', 'lower', 'expression', 'of', 'alternatively', 'splice', '##d', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'lacking', 'exon', '##13', 'and', 'mini', '##gene', 'transfection', 'assays', 'confirmed', 'that', 'allele', 'status', 'at', 'rs', '##38', '##46', '##66', '##2', 'directly', 'modulated', 'alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'exon', '##13', '(', '42', '.', '9', '##±', '##3', '.', '9', 'vs', '.', '63', '.', '7', '##±1', '.', '0', '%', 'Δ', '##ex', '##on', '##13', '/', 'total', 'HM', '##GC', '##R', 'mRNA', ',', 'p', '=', '0', '.', '02', ')', '.'] [0, 3, 9, 17, 20, 26, 31, 37, 41, 47, 60, 65, 68, 72, 78, 82, 86, 88, 90, 92, 94, 96, 102, 109, 113, 124, 129, 132, 135, 136, 137, 138, 139, 144, 150, 161, 164, 178, 184, 186, 188, 189, 190, 192, 194, 204, 209, 217, 221, 224, 228, 232, 237, 250, 257, 267, 272, 279, 286, 289, 291, 293, 295, 297, 299, 308, 318, 330, 339, 342, 344, 345, 346, 348, 350, 360, 364, 367, 368, 370, 371, 372, 373, 374, 375, 377, 379, 381, 383, 384, 385, 387, 388, 390, 391, 392, 394, 396, 398, 399, 405, 407, 409, 411, 415, 417, 418, 419, 420, 421, 423, 424] [2, 8, 16, 19, 25, 31, 37, 40, 46, 59, 64, 68, 72, 77, 81, 85, 88, 90, 92, 94, 95, 101, 108, 112, 123, 128, 131, 134, 136, 137, 138, 139, 143, 149, 160, 163, 177, 184, 185, 188, 189, 190, 192, 193, 203, 208, 216, 221, 223, 227, 232, 236, 249, 256, 266, 271, 278, 285, 288, 291, 293, 295, 297, 298, 307, 317, 329, 338, 341, 344, 345, 346, 348, 349, 359, 364, 366, 368, 370, 371, 372, 373, 374, 375, 376, 379, 380, 383, 384, 385, 387, 388, 389, 391, 392, 394, 396, 398, 399, 404, 407, 409, 410, 415, 416, 418, 419, 420, 421, 423, 424, 425] ['In', 'vitro', 'studies', 'in', 'human', 'lymphoblastoid', 'cells', 'demonstrated', 'that', 'homozygosity', 'for', 'the', 'rs3846662', 'minor', 'allele', 'was', 'associated', 'with', 'up', 'to', '2.2-fold', 'lower', 'expression', 'of', 'alternatively', 'spliced', 'HMG-CoA', 'reductase', 'mRNA', 'lacking', 'exon13', 'and', 'minigene', 'transfection', 'assays', 'confirmed', 'that', 'allele', 'status', 'at', 'rs3846662', 'directly', 'modulated', 'alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'exon13', '(', '42.9±3.9', 'vs', '.', '63.7±1.0', '%Δexon13', '/', 'total', 'HMGCR', 'mRNA', ',', 'p=0.02', ')', '.'] [1, 1, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 2, 5, 1, 1, 1, 2, 1, 2, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 5, 1, 2, 1, 7, 1, 1, 6, 5, 1, 1, 3, 1, 1, 5, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Further, the alternative splice variant could not restore HMG-CoA reductase activity when expressed in HMG-CoA reductase deficient UT-2 cells. [('PMC2764366', 'A01004', 58, 75, 'HMG-CoA reductase'), ('PMC2764366', 'A01004', 103, 120, 'HMG-CoA reductase')] ['Further', ',', 'the', 'alternative', 'splice', 'variant', 'could', 'not', 'restore', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'activity', 'when', 'expressed', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'deficient', 'UT', '-', '2', 'cells', '.'] [0, 7, 9, 13, 25, 32, 40, 46, 50, 58, 60, 61, 62, 64, 66, 76, 85, 90, 100, 103, 105, 106, 107, 109, 111, 121, 131, 133, 134, 136, 141] [7, 8, 12, 24, 31, 39, 45, 49, 57, 60, 61, 62, 64, 65, 75, 84, 89, 99, 102, 105, 106, 107, 109, 110, 120, 130, 133, 134, 135, 141, 142] ['Further', ',', 'the', 'alternative', 'splice', 'variant', 'could', 'not', 'restore', 'HMG-CoA', 'reductase', 'activity', 'when', 'expressed', 'in', 'HMG-CoA', 'reductase', 'deficient', 'UT-2', 'cells', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
We identified variants in HMG-CoA reductase that are associated with LDL-C across populations and affect alternative splicing of HMG-CoA reductase exon13. [('PMC2764366', 'A02000', 26, 43, 'HMG-CoA reductase'), ('PMC2764366', 'A02000', 129, 146, 'HMG-CoA reductase')] ['We', 'identified', 'variants', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'that', 'are', 'associated', 'with', 'LDL', '-', 'C', 'across', 'populations', 'and', 'affect', 'alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'exon', '##13', '.'] [0, 3, 14, 23, 26, 28, 29, 30, 32, 34, 44, 49, 53, 64, 69, 72, 73, 75, 82, 94, 98, 105, 117, 126, 129, 131, 132, 133, 135, 137, 147, 151, 153] [2, 13, 22, 25, 28, 29, 30, 32, 33, 43, 48, 52, 63, 68, 72, 73, 74, 81, 93, 97, 104, 116, 125, 128, 131, 132, 133, 135, 136, 146, 151, 153, 154] ['We', 'identified', 'variants', 'in', 'HMG-CoA', 'reductase', 'that', 'are', 'associated', 'with', 'LDL-C', 'across', 'populations', 'and', 'affect', 'alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'exon13', '.'] [1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 5, 1, 2, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O']
We identified variants in the HMG-CoA reductase gene that were among our top hits for LDL-C in a GWAS in a population from the Island of Kosrae. [('PMC2764366', 'D00000', 30, 47, 'HMG-CoA reductase')] ['We', 'identified', 'variants', 'in', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'gene', 'that', 'were', 'among', 'our', 'top', 'hits', 'for', 'LDL', '-', 'C', 'in', 'a', 'GW', '##AS', 'in', 'a', 'population', 'from', 'the', 'Island', 'of', 'Kos', '##ra', '##e', '.'] [0, 3, 14, 23, 26, 30, 32, 33, 34, 36, 38, 48, 53, 58, 63, 69, 73, 77, 82, 86, 89, 90, 92, 95, 97, 99, 102, 105, 107, 118, 123, 127, 134, 137, 140, 142, 143] [2, 13, 22, 25, 29, 32, 33, 34, 36, 37, 47, 52, 57, 62, 68, 72, 76, 81, 85, 89, 90, 91, 94, 96, 99, 101, 104, 106, 117, 122, 126, 133, 136, 140, 142, 143, 144] ['We', 'identified', 'variants', 'in', 'the', 'HMG-CoA', 'reductase', 'gene', 'that', 'were', 'among', 'our', 'top', 'hits', 'for', 'LDL-C', 'in', 'a', 'GWAS', 'in', 'a', 'population', 'from', 'the', 'Island', 'of', 'Kosrae', '.'] [1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We then conducted in vitro studies to follow-up the association signals and to identify a functional variant at the HMG-CoA reductase locus. [('PMC2764366', 'D00001', 116, 133, 'HMG-CoA reductase')] ['We', 'then', 'conducted', 'in', 'vitro', 'studies', 'to', 'follow', '-', 'up', 'the', 'association', 'signals', 'and', 'to', 'identify', 'a', 'functional', 'variant', 'at', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', '.'] [0, 3, 8, 18, 21, 27, 35, 38, 44, 45, 48, 52, 64, 72, 76, 79, 88, 90, 101, 109, 112, 116, 118, 119, 120, 122, 124, 134, 139] [2, 7, 17, 20, 26, 34, 37, 44, 45, 47, 51, 63, 71, 75, 78, 87, 89, 100, 108, 111, 115, 118, 119, 120, 122, 123, 133, 139, 140] ['We', 'then', 'conducted', 'in', 'vitro', 'studies', 'to', 'follow', '-', 'up', 'the', 'association', 'signals', 'and', 'to', 'identify', 'a', 'functional', 'variant', 'at', 'the', 'HMG-CoA', 'reductase', 'locus', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
We present evidence that a common intronic SNP (rs384662) that is in linkage disequilibrium with the variants typed in the genome scan modulates alternative splicing of HMG-CoA reductase mRNA. [('PMC2764366', 'D00002', 169, 186, 'HMG-CoA reductase')] ['We', 'present', 'evidence', 'that', 'a', 'common', 'intron', '##ic', 'SNP', '(', 'rs', '##38', '##46', '##62', ')', 'that', 'is', 'in', 'linkage', 'dise', '##quilibrium', 'with', 'the', 'variants', 'typed', 'in', 'the', 'genome', 'scan', 'modulates', 'alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', '.'] [0, 3, 11, 20, 25, 27, 34, 40, 43, 47, 48, 50, 52, 54, 56, 58, 63, 66, 69, 77, 81, 92, 97, 101, 110, 116, 119, 123, 130, 135, 145, 157, 166, 169, 171, 172, 173, 175, 177, 187, 191] [2, 10, 19, 24, 26, 33, 40, 42, 46, 48, 50, 52, 54, 56, 57, 62, 65, 68, 76, 81, 91, 96, 100, 109, 115, 118, 122, 129, 134, 144, 156, 165, 168, 171, 172, 173, 175, 176, 186, 191, 192] ['We', 'present', 'evidence', 'that', 'a', 'common', 'intronic', 'SNP', '(', 'rs384662', ')', 'that', 'is', 'in', 'linkage', 'disequilibrium', 'with', 'the', 'variants', 'typed', 'in', 'the', 'genome', 'scan', 'modulates', 'alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'mRNA', '.'] [1, 1, 1, 1, 1, 1, 2, 1, 1, 4, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
The resulting splice variant could not restore enzyme activity when expressed in HMG-CoA reductase deficient UT-2 cells. [('PMC2764366', 'D00003', 81, 98, 'HMG-CoA reductase')] ['The', 'resulting', 'splice', 'variant', 'could', 'not', 'restore', 'enzyme', 'activity', 'when', 'expressed', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'deficient', 'UT', '-', '2', 'cells', '.'] [0, 4, 14, 21, 29, 35, 39, 47, 54, 63, 68, 78, 81, 83, 84, 85, 87, 89, 99, 109, 111, 112, 114, 119] [3, 13, 20, 28, 34, 38, 46, 53, 62, 67, 77, 80, 83, 84, 85, 87, 88, 98, 108, 111, 112, 113, 119, 120] ['The', 'resulting', 'splice', 'variant', 'could', 'not', 'restore', 'enzyme', 'activity', 'when', 'expressed', 'in', 'HMG-CoA', 'reductase', 'deficient', 'UT-2', 'cells', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
HMG-CoA reductase is a key enzyme in cholesterol homeostasis and catalyzes the rate limiting step in cholesterol biosynthesis 21. [('PMC2764366', 'D01000', 0, 17, 'HMG-CoA reductase')] ['HM', '##G', '-', 'Co', '##A', 'reductase', 'is', 'a', 'key', 'enzyme', 'in', 'cholesterol', 'homeostasis', 'and', 'cataly', '##zes', 'the', 'rate', 'limiting', 'step', 'in', 'cholesterol', 'biosynthesis', '21', '.'] [0, 2, 3, 4, 6, 8, 18, 21, 23, 27, 34, 37, 49, 61, 65, 71, 75, 79, 84, 93, 98, 101, 113, 126, 128] [2, 3, 4, 6, 7, 17, 20, 22, 26, 33, 36, 48, 60, 64, 71, 74, 78, 83, 92, 97, 100, 112, 125, 128, 129] ['HMG-CoA', 'reductase', 'is', 'a', 'key', 'enzyme', 'in', 'cholesterol', 'homeostasis', 'and', 'catalyzes', 'the', 'rate', 'limiting', 'step', 'in', 'cholesterol', 'biosynthesis', '21', '.'] [5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In contrast to other well known determinants of cholesterol homeostasis, e.g. LDL-receptor or Apolipoprotein E, associations between variants in HMG-CoA reductase and LDL-C have only recently emerged in the context of GWAS. [('PMC2764366', 'D01001', 145, 162, 'HMG-CoA reductase')] ['In', 'contrast', 'to', 'other', 'well', 'known', 'determinants', 'of', 'cholesterol', 'homeostasis', ',', 'e', '.', 'g', '.', 'LDL', '-', 'receptor', 'or', 'Ap', '##olip', '##oprotein', 'E', ',', 'associations', 'between', 'variants', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'and', 'LDL', '-', 'C', 'have', 'only', 'recently', 'emerged', 'in', 'the', 'context', 'of', 'GW', '##AS', '.'] [0, 3, 12, 15, 21, 26, 32, 45, 48, 60, 71, 73, 74, 75, 76, 78, 81, 82, 91, 94, 96, 100, 109, 110, 112, 125, 133, 142, 145, 147, 148, 149, 151, 153, 163, 167, 170, 171, 173, 178, 183, 192, 200, 203, 207, 215, 218, 220, 222] [2, 11, 14, 20, 25, 31, 44, 47, 59, 71, 72, 74, 75, 76, 77, 81, 82, 90, 93, 96, 100, 108, 110, 111, 124, 132, 141, 144, 147, 148, 149, 151, 152, 162, 166, 170, 171, 172, 177, 182, 191, 199, 202, 206, 214, 217, 220, 222, 223] ['In', 'contrast', 'to', 'other', 'well', 'known', 'determinants', 'of', 'cholesterol', 'homeostasis', ',', 'e.g', '.', 'LDL-receptor', 'or', 'Apolipoprotein', 'E', ',', 'associations', 'between', 'variants', 'in', 'HMG-CoA', 'reductase', 'and', 'LDL-C', 'have', 'only', 'recently', 'emerged', 'in', 'the', 'context', 'of', 'GWAS', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
As in the Kosrae study, the initial results of the DGI GWAS in 2758 Caucasians supported associations between SNPs in HMG-CoA reductase and LDL-C, but did not meet the statistical threshold of genome-wide significance by themselves (best associated SNP rs12654264: p=4.09×10−4) 13. [('PMC2764366', 'D01002', 118, 135, 'HMG-CoA reductase')] ['As', 'in', 'the', 'Kos', '##ra', '##e', 'study', ',', 'the', 'initial', 'results', 'of', 'the', 'DG', '##I', 'GW', '##AS', 'in', '275', '##8', 'Caucasian', '##s', 'supported', 'associations', 'between', 'SNPs', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'and', 'LDL', '-', 'C', ',', 'but', 'did', 'not', 'meet', 'the', 'statistical', 'threshold', 'of', 'genome', '-', 'wide', 'significance', 'by', 'themselves', '(', 'best', 'associated', 'SNP', 'rs', '##126', '##54', '##26', '##4', ':', 'p', '=', '4', '.', '09', '##×10', '##−4', ')', '13', '.'] [0, 3, 6, 10, 13, 15, 17, 22, 24, 28, 36, 44, 47, 51, 53, 55, 57, 60, 63, 66, 68, 77, 79, 89, 102, 110, 115, 118, 120, 121, 122, 124, 126, 136, 140, 143, 144, 145, 147, 151, 155, 159, 164, 168, 180, 190, 193, 199, 200, 205, 218, 221, 232, 233, 238, 249, 253, 255, 258, 260, 262, 263, 265, 266, 267, 268, 269, 271, 274, 276, 278, 280] [2, 5, 9, 13, 15, 16, 22, 23, 27, 35, 43, 46, 50, 53, 54, 57, 59, 62, 66, 67, 77, 78, 88, 101, 109, 114, 117, 120, 121, 122, 124, 125, 135, 139, 143, 144, 145, 146, 150, 154, 158, 163, 167, 179, 189, 192, 199, 200, 204, 217, 220, 231, 233, 237, 248, 252, 255, 258, 260, 262, 263, 264, 266, 267, 268, 269, 271, 274, 276, 277, 280, 281] ['As', 'in', 'the', 'Kosrae', 'study', ',', 'the', 'initial', 'results', 'of', 'the', 'DGI', 'GWAS', 'in', '2758', 'Caucasians', 'supported', 'associations', 'between', 'SNPs', 'in', 'HMG-CoA', 'reductase', 'and', 'LDL-C', ',', 'but', 'did', 'not', 'meet', 'the', 'statistical', 'threshold', 'of', 'genome', '-', 'wide', 'significance', 'by', 'themselves', '(', 'best', 'associated', 'SNP', 'rs12654264', ':', 'p=4.09×10−4', ')', '13', '.'] [1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 2, 2, 1, 2, 2, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 7, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In this study, genome-wide significance was clearly established for HMG-CoA reductase SNP rs12654264 after validation in three additional Caucasian cohorts, resulting in a combined p-value of 1×10−20 in a total of ~18000 subjects 13. [('PMC2764366', 'D01003', 68, 85, 'HMG-CoA reductase')] ['In', 'this', 'study', ',', 'genome', '-', 'wide', 'significance', 'was', 'clearly', 'established', 'for', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'SNP', 'rs', '##126', '##54', '##26', '##4', 'after', 'validation', 'in', 'three', 'additional', 'Caucasian', 'cohorts', ',', 'resulting', 'in', 'a', 'combined', 'p', '-', 'value', 'of', '1', '##×10', '##−2', '##0', 'in', 'a', 'total', 'of', '~', '180', '##00', 'subjects', '13', '.'] [0, 3, 8, 13, 15, 21, 22, 27, 40, 44, 52, 64, 68, 70, 71, 72, 74, 76, 86, 90, 92, 95, 97, 99, 101, 107, 118, 121, 127, 138, 148, 155, 157, 167, 170, 172, 181, 182, 183, 189, 192, 193, 196, 198, 200, 203, 205, 211, 214, 215, 218, 221, 230, 232] [2, 7, 13, 14, 21, 22, 26, 39, 43, 51, 63, 67, 70, 71, 72, 74, 75, 85, 89, 92, 95, 97, 99, 100, 106, 117, 120, 126, 137, 147, 155, 156, 166, 169, 171, 180, 182, 183, 188, 191, 193, 196, 198, 199, 202, 204, 210, 213, 215, 218, 220, 229, 232, 233] ['In', 'this', 'study', ',', 'genome', '-', 'wide', 'significance', 'was', 'clearly', 'established', 'for', 'HMG-CoA', 'reductase', 'SNP', 'rs12654264', 'after', 'validation', 'in', 'three', 'additional', 'Caucasian', 'cohorts', ',', 'resulting', 'in', 'a', 'combined', 'p-value', 'of', '1×10−20', 'in', 'a', 'total', 'of', '~18000', 'subjects', '13', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 4, 1, 1, 1, 1, 3, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
However in a separate study, the associations between SNPs in HMG-CoA reductase and LDL-C that were observed in the DGI study were not strengthened by a meta analysis approach, consisting of the DGI and two other Caucasian GWAS (best associated SNP rs3846663: p=2.79×10−4 ) 12. [('PMC2764366', 'D01004', 62, 79, 'HMG-CoA reductase')] ['However', 'in', 'a', 'separate', 'study', ',', 'the', 'associations', 'between', 'SNPs', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'and', 'LDL', '-', 'C', 'that', 'were', 'observed', 'in', 'the', 'DG', '##I', 'study', 'were', 'not', 'strengthened', 'by', 'a', 'meta', 'analysis', 'approach', ',', 'consisting', 'of', 'the', 'DG', '##I', 'and', 'two', 'other', 'Caucasian', 'GW', '##AS', '(', 'best', 'associated', 'SNP', 'rs', '##38', '##46', '##66', '##3', ':', 'p', '=', '2', '.', '79', '##×10', '##−4', ')', '12', '.'] [0, 8, 11, 13, 22, 27, 29, 33, 46, 54, 59, 62, 64, 65, 66, 68, 70, 80, 84, 87, 88, 90, 95, 100, 109, 112, 116, 118, 120, 126, 131, 135, 148, 151, 153, 158, 167, 175, 177, 188, 191, 195, 197, 199, 203, 207, 213, 223, 225, 228, 229, 234, 245, 249, 251, 253, 255, 257, 258, 260, 261, 262, 263, 264, 266, 269, 272, 274, 276] [7, 10, 12, 21, 27, 28, 32, 45, 53, 58, 61, 64, 65, 66, 68, 69, 79, 83, 87, 88, 89, 94, 99, 108, 111, 115, 118, 119, 125, 130, 134, 147, 150, 152, 157, 166, 175, 176, 187, 190, 194, 197, 198, 202, 206, 212, 222, 225, 227, 229, 233, 244, 248, 251, 253, 255, 257, 258, 259, 261, 262, 263, 264, 266, 269, 271, 273, 276, 277] ['However', 'in', 'a', 'separate', 'study', ',', 'the', 'associations', 'between', 'SNPs', 'in', 'HMG-CoA', 'reductase', 'and', 'LDL-C', 'that', 'were', 'observed', 'in', 'the', 'DGI', 'study', 'were', 'not', 'strengthened', 'by', 'a', 'meta', 'analysis', 'approach', ',', 'consisting', 'of', 'the', 'DGI', 'and', 'two', 'other', 'Caucasian', 'GWAS', '(', 'best', 'associated', 'SNP', 'rs3846663', ':', 'p=2.79×10−4', ')', '12', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 2, 1, 1, 1, 1, 5, 1, 7, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Combining the association results from the Kosrae and DGI studies revealed three variants in LD (r2>0.81) with genome-wide significance at the HMG-CoA reductase locus, including the two SNPs mentioned above (rs12654264, rs3846663) and SNP rs7703051. [('PMC2764366', 'D01006', 143, 160, 'HMG-CoA reductase')] ['Combining', 'the', 'association', 'results', 'from', 'the', 'Kos', '##ra', '##e', 'and', 'DG', '##I', 'studies', 'revealed', 'three', 'variants', 'in', 'LD', '(', 'r', '##2', '>', '0', '.', '81', ')', 'with', 'genome', '-', 'wide', 'significance', 'at', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', ',', 'including', 'the', 'two', 'SNPs', 'mentioned', 'above', '(', 'rs', '##126', '##54', '##26', '##4', ',', 'rs', '##38', '##46', '##66', '##3', ')', 'and', 'SNP', 'rs', '##77', '##03', '##05', '##1', '.'] [0, 10, 14, 26, 34, 39, 43, 46, 48, 50, 54, 56, 58, 66, 75, 81, 90, 93, 96, 97, 98, 99, 100, 101, 102, 104, 106, 111, 117, 118, 123, 136, 139, 143, 145, 146, 147, 149, 151, 161, 166, 168, 178, 182, 186, 191, 201, 207, 208, 210, 213, 215, 217, 218, 220, 222, 224, 226, 228, 229, 231, 235, 239, 241, 243, 245, 247, 248] [9, 13, 25, 33, 38, 42, 46, 48, 49, 53, 56, 57, 65, 74, 80, 89, 92, 95, 97, 98, 99, 100, 101, 102, 104, 105, 110, 117, 118, 122, 135, 138, 142, 145, 146, 147, 149, 150, 160, 166, 167, 177, 181, 185, 190, 200, 206, 208, 210, 213, 215, 217, 218, 219, 222, 224, 226, 228, 229, 230, 234, 238, 241, 243, 245, 247, 248, 249] ['Combining', 'the', 'association', 'results', 'from', 'the', 'Kosrae', 'and', 'DGI', 'studies', 'revealed', 'three', 'variants', 'in', 'LD', '(', 'r2', '>', '0.81', ')', 'with', 'genome', '-', 'wide', 'significance', 'at', 'the', 'HMG-CoA', 'reductase', 'locus', ',', 'including', 'the', 'two', 'SNPs', 'mentioned', 'above', '(', 'rs12654264', ',', 'rs3846663', ')', 'and', 'SNP', 'rs7703051', '.'] [1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 5, 1, 1, 1, 5, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Our data obtained in the Kosrae isolate thereby adds important evidence about the generalizibility of genetic associations at the HMG-CoA reductase locus, demonstrating that these associations also extend to other ancestries. [('PMC2764366', 'D01007', 130, 147, 'HMG-CoA reductase')] ['Our', 'data', 'obtained', 'in', 'the', 'Kos', '##ra', '##e', 'isolate', 'thereby', 'adds', 'important', 'evidence', 'about', 'the', 'general', '##izi', '##bility', 'of', 'genetic', 'associations', 'at', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', ',', 'demonstrating', 'that', 'these', 'associations', 'also', 'extend', 'to', 'other', 'ancest', '##ries', '.'] [0, 4, 9, 18, 21, 25, 28, 30, 32, 40, 48, 53, 63, 72, 78, 82, 89, 92, 99, 102, 110, 123, 126, 130, 132, 133, 134, 136, 138, 148, 153, 155, 169, 174, 180, 193, 198, 205, 208, 214, 220, 224] [3, 8, 17, 20, 24, 28, 30, 31, 39, 47, 52, 62, 71, 77, 81, 89, 92, 98, 101, 109, 122, 125, 129, 132, 133, 134, 136, 137, 147, 153, 154, 168, 173, 179, 192, 197, 204, 207, 213, 220, 224, 225] ['Our', 'data', 'obtained', 'in', 'the', 'Kosrae', 'isolate', 'thereby', 'adds', 'important', 'evidence', 'about', 'the', 'generalizibility', 'of', 'genetic', 'associations', 'at', 'the', 'HMG-CoA', 'reductase', 'locus', ',', 'demonstrating', 'that', 'these', 'associations', 'also', 'extend', 'to', 'other', 'ancestries', '.'] [1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Interestingly, two pharmacogenetic studies investigating if genetic variants in HMG-CoA reductase influence response to statin therapy demonstrated that common SNP haplotypes in HMG-CoA reductase contribute to variation in statin response 24, 25. [('PMC2764366', 'D01008', 80, 97, 'HMG-CoA reductase'), ('PMC2764366', 'D01008', 178, 195, 'HMG-CoA reductase')] ['Interestingly', ',', 'two', 'pharmac', '##ogenetic', 'studies', 'investigating', 'if', 'genetic', 'variants', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'influence', 'response', 'to', 'statin', 'therapy', 'demonstrated', 'that', 'common', 'SNP', 'haplotypes', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'contribute', 'to', 'variation', 'in', 'statin', 'response', '24', ',', '25', '.'] [0, 13, 15, 19, 26, 35, 43, 57, 60, 68, 77, 80, 82, 83, 84, 86, 88, 98, 108, 117, 120, 127, 135, 148, 153, 160, 164, 175, 178, 180, 181, 182, 184, 186, 196, 207, 210, 220, 223, 230, 239, 241, 243, 245] [13, 14, 18, 26, 34, 42, 56, 59, 67, 76, 79, 82, 83, 84, 86, 87, 97, 107, 116, 119, 126, 134, 147, 152, 159, 163, 174, 177, 180, 181, 182, 184, 185, 195, 206, 209, 219, 222, 229, 238, 241, 242, 245, 246] ['Interestingly', ',', 'two', 'pharmacogenetic', 'studies', 'investigating', 'if', 'genetic', 'variants', 'in', 'HMG-CoA', 'reductase', 'influence', 'response', 'to', 'statin', 'therapy', 'demonstrated', 'that', 'common', 'SNP', 'haplotypes', 'in', 'HMG-CoA', 'reductase', 'contribute', 'to', 'variation', 'in', 'statin', 'response', '24', ',', '25', '.'] [1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
A major aspect of our study was to follow-up the findings from the GWAS and to identify the putative functional variant at the HMG-CoA reductase locus. [('PMC2764366', 'D02000', 127, 144, 'HMG-CoA reductase')] ['A', 'major', 'aspect', 'of', 'our', 'study', 'was', 'to', 'follow', '-', 'up', 'the', 'findings', 'from', 'the', 'GW', '##AS', 'and', 'to', 'identify', 'the', 'putative', 'functional', 'variant', 'at', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', '.'] [0, 2, 8, 15, 18, 22, 28, 32, 35, 41, 42, 45, 49, 58, 63, 67, 69, 72, 76, 79, 88, 92, 101, 112, 120, 123, 127, 129, 130, 131, 133, 135, 145, 150] [1, 7, 14, 17, 21, 27, 31, 34, 41, 42, 44, 48, 57, 62, 66, 69, 71, 75, 78, 87, 91, 100, 111, 119, 122, 126, 129, 130, 131, 133, 134, 144, 150, 151] ['A', 'major', 'aspect', 'of', 'our', 'study', 'was', 'to', 'follow', '-', 'up', 'the', 'findings', 'from', 'the', 'GWAS', 'and', 'to', 'identify', 'the', 'putative', 'functional', 'variant', 'at', 'the', 'HMG-CoA', 'reductase', 'locus', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
Our efforts were facilitated by a near complete inventory (99%) of all common (>5% minor allele frequency) regional sequence variations, resulting from resequencing of the complete HMG-CoA reductase locus in 23 Caucasians 19. [('PMC2764366', 'D02002', 181, 198, 'HMG-CoA reductase')] ['Our', 'efforts', 'were', 'facilitated', 'by', 'a', 'near', 'complete', 'inventory', '(', '99', '%', ')', 'of', 'all', 'common', '(', '>', '5', '%', 'minor', 'allele', 'frequency', ')', 'regional', 'sequence', 'variations', ',', 'resulting', 'from', 'res', '##equ', '##encing', 'of', 'the', 'complete', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', 'in', '23', 'Caucasian', '##s', '19', '.'] [0, 4, 12, 17, 29, 32, 34, 39, 48, 58, 59, 61, 62, 64, 67, 71, 78, 79, 80, 81, 83, 89, 96, 105, 107, 116, 125, 135, 137, 147, 152, 155, 158, 165, 168, 172, 181, 183, 184, 185, 187, 189, 199, 205, 208, 211, 220, 222, 224] [3, 11, 16, 28, 31, 33, 38, 47, 57, 59, 61, 62, 63, 66, 70, 77, 79, 80, 81, 82, 88, 95, 105, 106, 115, 124, 135, 136, 146, 151, 155, 158, 164, 167, 171, 180, 183, 184, 185, 187, 188, 198, 204, 207, 210, 220, 221, 224, 225] ['Our', 'efforts', 'were', 'facilitated', 'by', 'a', 'near', 'complete', 'inventory', '(', '99%', ')', 'of', 'all', 'common', '(', '>', '5%', 'minor', 'allele', 'frequency', ')', 'regional', 'sequence', 'variations', ',', 'resulting', 'from', 'resequencing', 'of', 'the', 'complete', 'HMG-CoA', 'reductase', 'locus', 'in', '23', 'Caucasians', '19', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 5, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Since the only known common coding SNP in HMG-CoA reductase (rs5908, I638V) is not in LD with any of the genotyped SNPs, we consider it to be unlikely that this variant is responsible for the association signal. [('PMC2764366', 'D02003', 42, 59, 'HMG-CoA reductase')] ['Since', 'the', 'only', 'known', 'common', 'coding', 'SNP', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', '(', 'rs', '##59', '##08', ',', 'I', '##63', '##8', '##V', ')', 'is', 'not', 'in', 'LD', 'with', 'any', 'of', 'the', 'genotype', '##d', 'SNPs', ',', 'we', 'consider', 'it', 'to', 'be', 'unlikely', 'that', 'this', 'variant', 'is', 'responsible', 'for', 'the', 'association', 'signal', '.'] [0, 6, 10, 15, 21, 28, 35, 39, 42, 44, 45, 46, 48, 50, 60, 61, 63, 65, 67, 69, 70, 72, 73, 74, 76, 79, 83, 86, 89, 94, 98, 101, 105, 113, 115, 119, 121, 124, 133, 136, 139, 142, 151, 156, 161, 169, 172, 184, 188, 192, 204, 210] [5, 9, 14, 20, 27, 34, 38, 41, 44, 45, 46, 48, 49, 59, 61, 63, 65, 67, 68, 70, 72, 73, 74, 75, 78, 82, 85, 88, 93, 97, 100, 104, 113, 114, 119, 120, 123, 132, 135, 138, 141, 150, 155, 160, 168, 171, 183, 187, 191, 203, 210, 211] ['Since', 'the', 'only', 'known', 'common', 'coding', 'SNP', 'in', 'HMG-CoA', 'reductase', '(', 'rs5908', ',', 'I638V', ')', 'is', 'not', 'in', 'LD', 'with', 'any', 'of', 'the', 'genotyped', 'SNPs', ',', 'we', 'consider', 'it', 'to', 'be', 'unlikely', 'that', 'this', 'variant', 'is', 'responsible', 'for', 'the', 'association', 'signal', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Likewise, since we did not detect significant differences in total HMG-CoA reductase mRNA expression, we consider it to be unlikely that the causal SNP is located in a regulatory element affecting HMG-CoA reductase transcription. [('PMC2764366', 'D02004', 67, 84, 'HMG-CoA reductase'), ('PMC2764366', 'D02004', 197, 214, 'HMG-CoA reductase')] ['Likewise', ',', 'since', 'we', 'did', 'not', 'detect', 'significant', 'differences', 'in', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'expression', ',', 'we', 'consider', 'it', 'to', 'be', 'unlikely', 'that', 'the', 'causal', 'SNP', 'is', 'located', 'in', 'a', 'regulatory', 'element', 'affecting', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'transcription', '.'] [0, 8, 10, 16, 19, 23, 27, 34, 46, 58, 61, 67, 69, 70, 71, 73, 75, 85, 90, 100, 102, 105, 114, 117, 120, 123, 132, 137, 141, 148, 152, 155, 163, 166, 168, 179, 187, 197, 199, 200, 201, 203, 205, 215, 228] [8, 9, 15, 18, 22, 26, 33, 45, 57, 60, 66, 69, 70, 71, 73, 74, 84, 89, 100, 101, 104, 113, 116, 119, 122, 131, 136, 140, 147, 151, 154, 162, 165, 167, 178, 186, 196, 199, 200, 201, 203, 204, 214, 228, 229] ['Likewise', ',', 'since', 'we', 'did', 'not', 'detect', 'significant', 'differences', 'in', 'total', 'HMG-CoA', 'reductase', 'mRNA', 'expression', ',', 'we', 'consider', 'it', 'to', 'be', 'unlikely', 'that', 'the', 'causal', 'SNP', 'is', 'located', 'in', 'a', 'regulatory', 'element', 'affecting', 'HMG-CoA', 'reductase', 'transcription', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
On the other hand, we provide mutually supportive evidence that a common intronic variant (rs3846662) in LD with the genotyped variants is functional and alters the efficiency of HMG-CoA reductase exon13 alternative splicing: We could demonstrate that (1.) expression levels of alternatively spliced Δexon13 HMG-CoA reductase mRNA were significantly lower in lymphoblastoid cells from homozygotes for the rs3846662 minor allele and (2.) allele status at rs3846662 directly modulated alternative splicing of HMGCR mRNA in minigene constructs. [('PMC2764366', 'D02005', 179, 196, 'HMG-CoA reductase'), ('PMC2764366', 'D02005', 308, 325, 'HMG-CoA reductase')] ['On', 'the', 'other', 'hand', ',', 'we', 'provide', 'mutually', 'supportive', 'evidence', 'that', 'a', 'common', 'intron', '##ic', 'variant', '(', 'rs', '##38', '##46', '##66', '##2', ')', 'in', 'LD', 'with', 'the', 'genotype', '##d', 'variants', 'is', 'functional', 'and', 'alters', 'the', 'efficiency', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'exon', '##13', 'alternative', 'splicing', ':', 'We', 'could', 'demonstrate', 'that', '(', '1', '.', ')', 'expression', 'levels', 'of', 'alternatively', 'splice', '##d', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'were', 'significantly', 'lower', 'in', 'lymph', '##oblast', '##oid', 'cells', 'from', 'hom', '##ozyg', '##otes', 'for', 'the', 'rs', '##38', '##46', '##66', '##2', 'minor', 'allele', 'and', '(', '2', '.', ')', 'allele', 'status', 'at', 'rs', '##38', '##46', '##66', '##2', 'directly', 'modulated', 'alternative', 'splicing', 'of', 'HM', '##GC', '##R', 'mRNA', 'in', 'mini', '##gene', 'constructs', '.'] [0, 3, 7, 13, 17, 19, 22, 30, 39, 50, 59, 64, 66, 73, 79, 82, 90, 91, 93, 95, 97, 99, 100, 102, 105, 108, 113, 117, 125, 127, 136, 139, 150, 154, 161, 165, 176, 179, 181, 182, 183, 185, 187, 197, 201, 204, 216, 224, 226, 229, 235, 247, 252, 253, 254, 255, 257, 268, 275, 278, 292, 298, 300, 301, 303, 305, 308, 310, 311, 312, 314, 316, 326, 331, 336, 350, 356, 359, 364, 370, 374, 380, 385, 388, 392, 397, 401, 405, 407, 409, 411, 413, 415, 421, 428, 432, 433, 434, 435, 437, 444, 451, 454, 456, 458, 460, 462, 464, 473, 483, 495, 504, 507, 509, 511, 513, 518, 521, 525, 530, 540] [2, 6, 12, 17, 18, 21, 29, 38, 49, 58, 63, 65, 72, 79, 81, 89, 91, 93, 95, 97, 99, 100, 101, 104, 107, 112, 116, 125, 126, 135, 138, 149, 153, 160, 164, 175, 178, 181, 182, 183, 185, 186, 196, 201, 203, 215, 224, 225, 228, 234, 246, 251, 253, 254, 255, 256, 267, 274, 277, 291, 298, 299, 301, 303, 305, 307, 310, 311, 312, 314, 315, 325, 330, 335, 349, 355, 358, 364, 370, 373, 379, 384, 388, 392, 396, 400, 404, 407, 409, 411, 413, 414, 420, 427, 431, 433, 434, 435, 436, 443, 450, 453, 456, 458, 460, 462, 463, 472, 482, 494, 503, 506, 509, 511, 512, 517, 520, 525, 529, 540, 541] ['On', 'the', 'other', 'hand', ',', 'we', 'provide', 'mutually', 'supportive', 'evidence', 'that', 'a', 'common', 'intronic', 'variant', '(', 'rs3846662', ')', 'in', 'LD', 'with', 'the', 'genotyped', 'variants', 'is', 'functional', 'and', 'alters', 'the', 'efficiency', 'of', 'HMG-CoA', 'reductase', 'exon13', 'alternative', 'splicing', ':', 'We', 'could', 'demonstrate', 'that', '(', '1', '.', ')', 'expression', 'levels', 'of', 'alternatively', 'spliced', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'were', 'significantly', 'lower', 'in', 'lymphoblastoid', 'cells', 'from', 'homozygotes', 'for', 'the', 'rs3846662', 'minor', 'allele', 'and', '(', '2', '.', ')', 'allele', 'status', 'at', 'rs3846662', 'directly', 'modulated', 'alternative', 'splicing', 'of', 'HMGCR', 'mRNA', 'in', 'minigene', 'constructs', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 5, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 4, 5, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Further, alternative splicing of HMG-CoA reductase appeared to be regulated and was present in vivo, as we could detect Δexon13 HMG-CoA reductase mRNA in all eleven human tissues that we studied. [('PMC2764366', 'D02006', 33, 50, 'HMG-CoA reductase'), ('PMC2764366', 'D02006', 128, 145, 'HMG-CoA reductase')] ['Further', ',', 'alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'appeared', 'to', 'be', 'regulated', 'and', 'was', 'present', 'in', 'vivo', ',', 'as', 'we', 'could', 'detect', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'in', 'all', 'eleven', 'human', 'tissues', 'that', 'we', 'studied', '.'] [0, 7, 9, 21, 30, 33, 35, 36, 37, 39, 41, 51, 60, 63, 66, 76, 80, 84, 92, 95, 99, 101, 104, 107, 113, 120, 121, 123, 125, 128, 130, 131, 132, 134, 136, 146, 151, 154, 158, 165, 171, 179, 184, 187, 194] [7, 8, 20, 29, 32, 35, 36, 37, 39, 40, 50, 59, 62, 65, 75, 79, 83, 91, 94, 99, 100, 103, 106, 112, 119, 121, 123, 125, 127, 130, 131, 132, 134, 135, 145, 150, 153, 157, 164, 170, 178, 183, 186, 194, 195] ['Further', ',', 'alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'appeared', 'to', 'be', 'regulated', 'and', 'was', 'present', 'in', 'vivo', ',', 'as', 'we', 'could', 'detect', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'in', 'all', 'eleven', 'human', 'tissues', 'that', 'we', 'studied', '.'] [1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
HMG-CoA reductase mRNA lacking exon13 was described in a survey of alternative pre-mRNA splicing by Johnson et al 20, however its function and the underlying mechanisms remain unknown. [('PMC2764366', 'D03000', 0, 17, 'HMG-CoA reductase')] ['HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'lacking', 'exon', '##13', 'was', 'described', 'in', 'a', 'survey', 'of', 'alternative', 'pre', '-', 'mRNA', 'splicing', 'by', 'Johnson', 'et', 'al', '20', ',', 'however', 'its', 'function', 'and', 'the', 'underlying', 'mechanisms', 'remain', 'unknown', '.'] [0, 2, 3, 4, 6, 8, 18, 23, 31, 35, 38, 42, 52, 55, 57, 64, 67, 79, 82, 83, 88, 97, 100, 108, 111, 114, 116, 118, 126, 130, 139, 143, 147, 158, 169, 176, 183] [2, 3, 4, 6, 7, 17, 22, 30, 35, 37, 41, 51, 54, 56, 63, 66, 78, 82, 83, 87, 96, 99, 107, 110, 113, 116, 117, 125, 129, 138, 142, 146, 157, 168, 175, 183, 184] ['HMG-CoA', 'reductase', 'mRNA', 'lacking', 'exon13', 'was', 'described', 'in', 'a', 'survey', 'of', 'alternative', 'pre-mRNA', 'splicing', 'by', 'Johnson', 'et', 'al', '20', ',', 'however', 'its', 'function', 'and', 'the', 'underlying', 'mechanisms', 'remain', 'unknown', '.'] [5, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The most likely explanation for the observed differences in HMG-CoA reductase mRNA splicing between major and minor allele homozygotes at rs3846662 is that this SNP is located in a binding motif for a splice auxiliary protein and allele status changes the binding affinity of this protein. [('PMC2764366', 'D03002', 60, 77, 'HMG-CoA reductase')] ['The', 'most', 'likely', 'explanation', 'for', 'the', 'observed', 'differences', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'splicing', 'between', 'major', 'and', 'minor', 'allele', 'hom', '##ozyg', '##otes', 'at', 'rs', '##38', '##46', '##66', '##2', 'is', 'that', 'this', 'SNP', 'is', 'located', 'in', 'a', 'binding', 'motif', 'for', 'a', 'splice', 'auxiliary', 'protein', 'and', 'allele', 'status', 'changes', 'the', 'binding', 'affinity', 'of', 'this', 'protein', '.'] [0, 4, 9, 16, 28, 32, 36, 45, 57, 60, 62, 63, 64, 66, 68, 78, 83, 92, 100, 106, 110, 116, 123, 126, 130, 135, 138, 140, 142, 144, 146, 148, 151, 156, 161, 165, 168, 176, 179, 181, 189, 195, 199, 201, 208, 218, 226, 230, 237, 244, 252, 256, 264, 273, 276, 281, 288] [3, 8, 15, 27, 31, 35, 44, 56, 59, 62, 63, 64, 66, 67, 77, 82, 91, 99, 105, 109, 115, 122, 126, 130, 134, 137, 140, 142, 144, 146, 147, 150, 155, 160, 164, 167, 175, 178, 180, 188, 194, 198, 200, 207, 217, 225, 229, 236, 243, 251, 255, 263, 272, 275, 280, 288, 289] ['The', 'most', 'likely', 'explanation', 'for', 'the', 'observed', 'differences', 'in', 'HMG-CoA', 'reductase', 'mRNA', 'splicing', 'between', 'major', 'and', 'minor', 'allele', 'homozygotes', 'at', 'rs3846662', 'is', 'that', 'this', 'SNP', 'is', 'located', 'in', 'a', 'binding', 'motif', 'for', 'a', 'splice', 'auxiliary', 'protein', 'and', 'allele', 'status', 'changes', 'the', 'binding', 'affinity', 'of', 'this', 'protein', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Homozygosity for the major allele at rs3846662 increased the proportion of HMG-CoA reductase mRNA lacking exon13. [('PMC2764366', 'D03003', 75, 92, 'HMG-CoA reductase')] ['Hom', '##ozyg', '##osity', 'for', 'the', 'major', 'allele', 'at', 'rs', '##38', '##46', '##66', '##2', 'increased', 'the', 'proportion', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'lacking', 'exon', '##13', '.'] [0, 3, 7, 13, 17, 21, 27, 34, 37, 39, 41, 43, 45, 47, 57, 61, 72, 75, 77, 78, 79, 81, 83, 93, 98, 106, 110, 112] [3, 7, 12, 16, 20, 26, 33, 36, 39, 41, 43, 45, 46, 56, 60, 71, 74, 77, 78, 79, 81, 82, 92, 97, 105, 110, 112, 113] ['Homozygosity', 'for', 'the', 'major', 'allele', 'at', 'rs3846662', 'increased', 'the', 'proportion', 'of', 'HMG-CoA', 'reductase', 'mRNA', 'lacking', 'exon13', '.'] [3, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 5, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O']
When we stably expressed both HMG-CoA reductase variants in CHO cells deficient of endogenous HMG-CoA reductase activity, the Δexon13 variant appeared to be non-functional and was not able to restore cell growth in the absence of mevalonate. [('PMC2764366', 'D03005', 30, 47, 'HMG-CoA reductase'), ('PMC2764366', 'D03005', 94, 111, 'HMG-CoA reductase')] ['When', 'we', 'stably', 'expressed', 'both', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'variants', 'in', 'CHO', 'cells', 'deficient', 'of', 'endogenous', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'activity', ',', 'the', 'Δ', '##ex', '##on', '##13', 'variant', 'appeared', 'to', 'be', 'non', '-', 'functional', 'and', 'was', 'not', 'able', 'to', 'restore', 'cell', 'growth', 'in', 'the', 'absence', 'of', 'me', '##val', '##onate', '.'] [0, 5, 8, 15, 25, 30, 32, 33, 34, 36, 38, 48, 57, 60, 64, 70, 80, 83, 94, 96, 97, 98, 100, 102, 112, 120, 122, 126, 127, 129, 131, 134, 142, 151, 154, 157, 160, 161, 172, 176, 180, 184, 189, 192, 200, 205, 212, 215, 219, 227, 230, 232, 235, 240] [4, 7, 14, 24, 29, 32, 33, 34, 36, 37, 47, 56, 59, 63, 69, 79, 82, 93, 96, 97, 98, 100, 101, 111, 120, 121, 125, 127, 129, 131, 133, 141, 150, 153, 156, 160, 161, 171, 175, 179, 183, 188, 191, 199, 204, 211, 214, 218, 226, 229, 232, 235, 240, 241] ['When', 'we', 'stably', 'expressed', 'both', 'HMG-CoA', 'reductase', 'variants', 'in', 'CHO', 'cells', 'deficient', 'of', 'endogenous', 'HMG-CoA', 'reductase', 'activity', ',', 'the', 'Δexon13', 'variant', 'appeared', 'to', 'be', 'non', '-', 'functional', 'and', 'was', 'not', 'able', 'to', 'restore', 'cell', 'growth', 'in', 'the', 'absence', 'of', 'mevalonate', '.'] [1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Thus, deletion of exon13 could potentially impact the stability of the enzyme, since experiments in which monomeric soluble proteins were fused to the HMG-CoA reductase membrane domains illustrated that the protein was degraded faster when it was smaller than tetrameric 30. [('PMC2764366', 'D03008', 151, 168, 'HMG-CoA reductase')] ['Thus', ',', 'deletion', 'of', 'exon', '##13', 'could', 'potentially', 'impact', 'the', 'stability', 'of', 'the', 'enzyme', ',', 'since', 'experiments', 'in', 'which', 'monomeric', 'soluble', 'proteins', 'were', 'fused', 'to', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'membrane', 'domains', 'illustrated', 'that', 'the', 'protein', 'was', 'degraded', 'faster', 'when', 'it', 'was', 'smaller', 'than', 'tetra', '##mer', '##ic', '30', '.'] [0, 4, 6, 15, 18, 22, 25, 31, 43, 50, 54, 64, 67, 71, 77, 79, 85, 97, 100, 106, 116, 124, 133, 138, 144, 147, 151, 153, 154, 155, 157, 159, 169, 178, 186, 198, 203, 207, 215, 219, 228, 235, 240, 243, 247, 255, 260, 265, 268, 271, 273] [4, 5, 14, 17, 22, 24, 30, 42, 49, 53, 63, 66, 70, 77, 78, 84, 96, 99, 105, 115, 123, 132, 137, 143, 146, 150, 153, 154, 155, 157, 158, 168, 177, 185, 197, 202, 206, 214, 218, 227, 234, 239, 242, 246, 254, 259, 265, 268, 270, 273, 274] ['Thus', ',', 'deletion', 'of', 'exon13', 'could', 'potentially', 'impact', 'the', 'stability', 'of', 'the', 'enzyme', ',', 'since', 'experiments', 'in', 'which', 'monomeric', 'soluble', 'proteins', 'were', 'fused', 'to', 'the', 'HMG-CoA', 'reductase', 'membrane', 'domains', 'illustrated', 'that', 'the', 'protein', 'was', 'degraded', 'faster', 'when', 'it', 'was', 'smaller', 'than', 'tetrameric', '30', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Therefore, alternative splicing of HMG-CoA reductase appears to result in altered enzymatic activity and could also lead to more rapid degradation of the protein. [('PMC2764366', 'D03010', 35, 52, 'HMG-CoA reductase')] ['Therefore', ',', 'alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'appears', 'to', 'result', 'in', 'altered', 'enzymatic', 'activity', 'and', 'could', 'also', 'lead', 'to', 'more', 'rapid', 'degradation', 'of', 'the', 'protein', '.'] [0, 9, 11, 23, 32, 35, 37, 38, 39, 41, 43, 53, 61, 64, 71, 74, 82, 92, 101, 105, 111, 116, 121, 124, 129, 135, 147, 150, 154, 161] [9, 10, 22, 31, 34, 37, 38, 39, 41, 42, 52, 60, 63, 70, 73, 81, 91, 100, 104, 110, 115, 120, 123, 128, 134, 146, 149, 153, 161, 162] ['Therefore', ',', 'alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'appears', 'to', 'result', 'in', 'altered', 'enzymatic', 'activity', 'and', 'could', 'also', 'lead', 'to', 'more', 'rapid', 'degradation', 'of', 'the', 'protein', '.'] [1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
A decrease in HMG-CoA reductase activity would lead to lower cellular cholesterol synthesis and subsequently a counter-regulatory increase of cholesterol uptake from the plasma via the LDL-receptor pathway to maintain intracellular cholesterol homeostasis. [('PMC2764366', 'D03011', 14, 31, 'HMG-CoA reductase')] ['A', 'decrease', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'activity', 'would', 'lead', 'to', 'lower', 'cellular', 'cholesterol', 'synthesis', 'and', 'subsequently', 'a', 'counter', '-', 'regulatory', 'increase', 'of', 'cholesterol', 'uptake', 'from', 'the', 'plasma', 'via', 'the', 'LDL', '-', 'receptor', 'pathway', 'to', 'maintain', 'intracellular', 'cholesterol', 'homeostasis', '.'] [0, 2, 11, 14, 16, 17, 18, 20, 22, 32, 41, 47, 52, 55, 61, 70, 82, 92, 96, 109, 111, 118, 119, 130, 139, 142, 154, 161, 166, 170, 177, 181, 185, 188, 189, 198, 206, 209, 218, 232, 244, 255] [1, 10, 13, 16, 17, 18, 20, 21, 31, 40, 46, 51, 54, 60, 69, 81, 91, 95, 108, 110, 118, 119, 129, 138, 141, 153, 160, 165, 169, 176, 180, 184, 188, 189, 197, 205, 208, 217, 231, 243, 255, 256] ['A', 'decrease', 'in', 'HMG-CoA', 'reductase', 'activity', 'would', 'lead', 'to', 'lower', 'cellular', 'cholesterol', 'synthesis', 'and', 'subsequently', 'a', 'counter', '-', 'regulatory', 'increase', 'of', 'cholesterol', 'uptake', 'from', 'the', 'plasma', 'via', 'the', 'LDL-receptor', 'pathway', 'to', 'maintain', 'intracellular', 'cholesterol', 'homeostasis', '.'] [1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In accordance with this hypothesis the allele at rs3846662 that was causing higher levels of Δexon13 HMG-CoA reductase mRNA in our in vitro studies was sharing a haplotype with the alleles that were associated with lower LDL-C in the genome-wide association studies. [('PMC2764366', 'D03012', 101, 118, 'HMG-CoA reductase')] ['In', 'accordance', 'with', 'this', 'hypothesis', 'the', 'allele', 'at', 'rs', '##38', '##46', '##66', '##2', 'that', 'was', 'causing', 'higher', 'levels', 'of', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'in', 'our', 'in', 'vitro', 'studies', 'was', 'sharing', 'a', 'haplotype', 'with', 'the', 'alleles', 'that', 'were', 'associated', 'with', 'lower', 'LDL', '-', 'C', 'in', 'the', 'genome', '-', 'wide', 'association', 'studies', '.'] [0, 3, 14, 19, 24, 35, 39, 46, 49, 51, 53, 55, 57, 59, 64, 68, 76, 83, 90, 93, 94, 96, 98, 101, 103, 104, 105, 107, 109, 119, 124, 127, 131, 134, 140, 148, 152, 160, 162, 172, 177, 181, 189, 194, 199, 210, 215, 221, 224, 225, 227, 230, 234, 240, 241, 246, 258, 265] [2, 13, 18, 23, 34, 38, 45, 48, 51, 53, 55, 57, 58, 63, 67, 75, 82, 89, 92, 94, 96, 98, 100, 103, 104, 105, 107, 108, 118, 123, 126, 130, 133, 139, 147, 151, 159, 161, 171, 176, 180, 188, 193, 198, 209, 214, 220, 224, 225, 226, 229, 233, 240, 241, 245, 257, 265, 266] ['In', 'accordance', 'with', 'this', 'hypothesis', 'the', 'allele', 'at', 'rs3846662', 'that', 'was', 'causing', 'higher', 'levels', 'of', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'in', 'our', 'in', 'vitro', 'studies', 'was', 'sharing', 'a', 'haplotype', 'with', 'the', 'alleles', 'that', 'were', 'associated', 'with', 'lower', 'LDL-C', 'in', 'the', 'genome', '-', 'wide', 'association', 'studies', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
HMG-CoA reductase activity is subject to multivalent control on transcriptional and post-transcriptional levels and alternative splicing may be an additional regulatory mechanism. [('PMC2764366', 'D03013', 0, 17, 'HMG-CoA reductase')] ['HM', '##G', '-', 'Co', '##A', 'reductase', 'activity', 'is', 'subject', 'to', 'multiv', '##alen', '##t', 'control', 'on', 'transcriptional', 'and', 'post', '-', 'transcriptional', 'levels', 'and', 'alternative', 'splicing', 'may', 'be', 'an', 'additional', 'regulatory', 'mechanism', '.'] [0, 2, 3, 4, 6, 8, 18, 27, 30, 38, 41, 47, 51, 53, 61, 64, 80, 84, 88, 89, 105, 112, 116, 128, 137, 141, 144, 147, 158, 169, 178] [2, 3, 4, 6, 7, 17, 26, 29, 37, 40, 47, 51, 52, 60, 63, 79, 83, 88, 89, 104, 111, 115, 127, 136, 140, 143, 146, 157, 168, 178, 179] ['HMG-CoA', 'reductase', 'activity', 'is', 'subject', 'to', 'multivalent', 'control', 'on', 'transcriptional', 'and', 'post', '-', 'transcriptional', 'levels', 'and', 'alternative', 'splicing', 'may', 'be', 'an', 'additional', 'regulatory', 'mechanism', '.'] [5, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Modulation of alternatively spliced HMG-CoA reductase mRNA levels could be of pharmacologic interest with regard to response to statin therapy or as target for antisense-mediated exon skipping. [('PMC2764366', 'D04000', 36, 53, 'HMG-CoA reductase')] ['Mod', '##ulation', 'of', 'alternatively', 'splice', '##d', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'levels', 'could', 'be', 'of', 'pharmac', '##ologic', 'interest', 'with', 'regard', 'to', 'response', 'to', 'statin', 'therapy', 'or', 'as', 'target', 'for', 'antisense', '-', 'mediated', 'exon', 'sk', '##ipping', '.'] [0, 3, 11, 14, 28, 34, 36, 38, 39, 40, 42, 44, 54, 59, 66, 72, 75, 78, 85, 92, 101, 106, 113, 116, 125, 128, 135, 143, 146, 149, 156, 160, 169, 170, 179, 184, 186, 192] [3, 10, 13, 27, 34, 35, 38, 39, 40, 42, 43, 53, 58, 65, 71, 74, 77, 85, 91, 100, 105, 112, 115, 124, 127, 134, 142, 145, 148, 155, 159, 169, 170, 178, 183, 186, 192, 193] ['Modulation', 'of', 'alternatively', 'spliced', 'HMG-CoA', 'reductase', 'mRNA', 'levels', 'could', 'be', 'of', 'pharmacologic', 'interest', 'with', 'regard', 'to', 'response', 'to', 'statin', 'therapy', 'or', 'as', 'target', 'for', 'antisense', '-', 'mediated', 'exon', 'skipping', '.'] [2, 1, 1, 2, 5, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Therefore, identification of specific factors that regulate HMG-CoA reductase alternative splicing and elucidating the underlying mechanism may lead to a better understanding of its impact on regulating cellular cholesterol homeostasis and plasma cholesterol levels. [('PMC2764366', 'D05000', 60, 77, 'HMG-CoA reductase')] ['Therefore', ',', 'identification', 'of', 'specific', 'factors', 'that', 'regulate', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'alternative', 'splicing', 'and', 'elucid', '##ating', 'the', 'underlying', 'mechanism', 'may', 'lead', 'to', 'a', 'better', 'understanding', 'of', 'its', 'impact', 'on', 'regulating', 'cellular', 'cholesterol', 'homeostasis', 'and', 'plasma', 'cholesterol', 'levels', '.'] [0, 9, 11, 26, 29, 38, 46, 51, 60, 62, 63, 64, 66, 68, 78, 90, 99, 103, 109, 115, 119, 130, 140, 144, 149, 152, 154, 161, 175, 178, 182, 189, 192, 203, 212, 224, 236, 240, 247, 259, 265] [9, 10, 25, 28, 37, 45, 50, 59, 62, 63, 64, 66, 67, 77, 89, 98, 102, 109, 114, 118, 129, 139, 143, 148, 151, 153, 160, 174, 177, 181, 188, 191, 202, 211, 223, 235, 239, 246, 258, 265, 266] ['Therefore', ',', 'identification', 'of', 'specific', 'factors', 'that', 'regulate', 'HMG-CoA', 'reductase', 'alternative', 'splicing', 'and', 'elucidating', 'the', 'underlying', 'mechanism', 'may', 'lead', 'to', 'a', 'better', 'understanding', 'of', 'its', 'impact', 'on', 'regulating', 'cellular', 'cholesterol', 'homeostasis', 'and', 'plasma', 'cholesterol', 'levels', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Mutant clone of Chinese hamster ovary cells lacking 3-hydroxy-3 -methylglutaryl coenzyme A reductase. [('PMC2764366', 'F15002', 52, 100, '3-hydroxy-3 -methylglutaryl coenzyme A reductase')] ['Mut', '##ant', 'clone', 'of', 'Chinese', 'hams', '##ter', 'ovary', 'cells', 'lacking', '3', '-', 'hydroxy', '-', '3', '-', 'methyl', '##glut', '##aryl', 'coe', '##n', '##zyme', 'A', 'reductase', '.'] [0, 3, 7, 13, 16, 24, 28, 32, 38, 44, 52, 53, 54, 61, 62, 64, 65, 71, 75, 80, 83, 84, 89, 91, 100] [3, 6, 12, 15, 23, 28, 31, 37, 43, 51, 53, 54, 61, 62, 63, 65, 71, 75, 79, 83, 84, 88, 90, 100, 101] ['Mutant', 'clone', 'of', 'Chinese', 'hamster', 'ovary', 'cells', 'lacking', '3-hydroxy-3', '-', 'methylglutaryl', 'coenzyme', 'A', 'reductase', '.'] [2, 1, 1, 1, 2, 1, 1, 1, 5, 1, 3, 3, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O']
Uptake of lipoprotein-X and its effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase and chylomicron remnant removal in human fibroblasts, lymphocytes, and in the rat. [('PMC2764366', 'F16002', 42, 89, '3-hydroxy-3-methylglutaryl coenzyme A reductase')] ['Up', '##take', 'of', 'lipoprotein', '-', 'X', 'and', 'its', 'effect', 'on', '3', '-', 'hydroxy', '-', '3', '-', 'methyl', '##glut', '##aryl', 'coe', '##n', '##zyme', 'A', 'reductase', 'and', 'ch', '##yl', '##omic', '##ron', 'remn', '##ant', 'removal', 'in', 'human', 'fibroblasts', ',', 'lymphocytes', ',', 'and', 'in', 'the', 'rat', '.'] [0, 2, 7, 10, 21, 22, 24, 28, 32, 39, 42, 43, 44, 51, 52, 53, 54, 60, 64, 69, 72, 73, 78, 80, 90, 94, 96, 98, 102, 106, 110, 114, 122, 125, 131, 142, 144, 155, 157, 161, 164, 168, 171] [2, 6, 9, 21, 22, 23, 27, 31, 38, 41, 43, 44, 51, 52, 53, 54, 60, 64, 68, 72, 73, 77, 79, 89, 93, 96, 98, 102, 105, 110, 113, 121, 124, 130, 142, 143, 155, 156, 160, 163, 167, 171, 172] ['Uptake', 'of', 'lipoprotein-X', 'and', 'its', 'effect', 'on', '3-hydroxy-3-methylglutaryl', 'coenzyme', 'A', 'reductase', 'and', 'chylomicron', 'remnant', 'removal', 'in', 'human', 'fibroblasts', ',', 'lymphocytes', ',', 'and', 'in', 'the', 'rat', '.'] [2, 1, 3, 1, 1, 1, 1, 9, 3, 1, 1, 1, 4, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Improved methods for the solubilization and assay of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase. [('PMC2764366', 'F17002', 53, 108, 'hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase')] ['Improved', 'methods', 'for', 'the', 'solub', '##ilization', 'and', 'assay', 'of', 'hepatic', '3', '-', 'hydroxy', '-', '3', '-', 'methyl', '##glut', '##aryl', 'coe', '##n', '##zyme', 'A', 'reductase', '.'] [0, 9, 17, 21, 25, 30, 40, 44, 50, 53, 61, 62, 63, 70, 71, 72, 73, 79, 83, 88, 91, 92, 97, 99, 108] [8, 16, 20, 24, 30, 39, 43, 49, 52, 60, 62, 63, 70, 71, 72, 73, 79, 83, 87, 91, 92, 96, 98, 108, 109] ['Improved', 'methods', 'for', 'the', 'solubilization', 'and', 'assay', 'of', 'hepatic', '3-hydroxy-3-methylglutaryl', 'coenzyme', 'A', 'reductase', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 9, 3, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O']
Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. [('PMC2764366', 'F24002', 17, 65, '3-hydroxyl-3-methylglutaryl coenzyme a reductase')] ['Variation', 'in', 'the', '3', '-', 'hydroxyl', '-', '3', '-', 'methyl', '##glut', '##aryl', 'coe', '##n', '##zyme', 'a', 'reductase', 'gene', 'is', 'associated', 'with', 'racial', 'differences', 'in', 'low', '-', 'density', 'lipoprotein', 'cholesterol', 'response', 'to', 'sim', '##vastatin', 'treatment', '.'] [0, 10, 13, 17, 18, 19, 27, 28, 29, 30, 36, 40, 45, 48, 49, 54, 56, 66, 71, 74, 85, 90, 97, 109, 112, 115, 116, 124, 136, 148, 157, 160, 163, 172, 181] [9, 12, 16, 18, 19, 27, 28, 29, 30, 36, 40, 44, 48, 49, 53, 55, 65, 70, 73, 84, 89, 96, 108, 111, 115, 116, 123, 135, 147, 156, 159, 163, 171, 181, 182] ['Variation', 'in', 'the', '3-hydroxyl-3-methylglutaryl', 'coenzyme', 'a', 'reductase', 'gene', 'is', 'associated', 'with', 'racial', 'differences', 'in', 'low', '-', 'density', 'lipoprotein', 'cholesterol', 'response', 'to', 'simvastatin', 'treatment', '.'] [1, 1, 1, 9, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and the esterification of cholesterol in human long term lymphoid cell lines. [('PMC2764366', 'F25002', 14, 61, '3-hydroxy-3-methylglutaryl coenzyme A reductase')] ['Regulation', 'of', '3', '-', 'hydroxy', '-', '3', '-', 'methyl', '##glut', '##aryl', 'coe', '##n', '##zyme', 'A', 'reductase', 'activity', 'and', 'the', 'ester', '##ification', 'of', 'cholesterol', 'in', 'human', 'long', 'term', 'lymphoid', 'cell', 'lines', '.'] [0, 11, 14, 15, 16, 23, 24, 25, 26, 32, 36, 41, 44, 45, 50, 52, 62, 71, 75, 79, 84, 94, 97, 109, 112, 118, 123, 128, 137, 142, 147] [10, 13, 15, 16, 23, 24, 25, 26, 32, 36, 40, 44, 45, 49, 51, 61, 70, 74, 78, 84, 93, 96, 108, 111, 117, 122, 127, 136, 141, 147, 148] ['Regulation', 'of', '3-hydroxy-3-methylglutaryl', 'coenzyme', 'A', 'reductase', 'activity', 'and', 'the', 'esterification', 'of', 'cholesterol', 'in', 'human', 'long', 'term', 'lymphoid', 'cell', 'lines', '.'] [1, 1, 9, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J. Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. [('PMC2764366', 'F28001', 104, 121, 'HMG-CoA reductase')] ['Is', '##t', '##van', 'ES', ',', 'Pal', '##nit', '##kar', 'M', ',', 'Buch', '##ana', '##n', 'SK', ',', 'De', '##isen', '##hof', '##er', 'J', '.', 'Crystal', 'structure', 'of', 'the', 'catalytic', 'portion', 'of', 'human', 'HM', '##G', '-', 'Co', '##A', 'reductase', ':', 'insights', 'into', 'regulation', 'of', 'activity', 'and', 'catalysis', '.'] [0, 2, 3, 7, 9, 11, 14, 17, 21, 22, 24, 28, 31, 33, 35, 37, 39, 43, 46, 49, 50, 52, 60, 70, 73, 77, 87, 95, 98, 104, 106, 107, 108, 110, 112, 121, 123, 132, 137, 148, 151, 160, 164, 173] [2, 3, 6, 9, 10, 14, 17, 20, 22, 23, 28, 31, 32, 35, 36, 39, 43, 46, 48, 50, 51, 59, 69, 72, 76, 86, 94, 97, 103, 106, 107, 108, 110, 111, 121, 122, 131, 136, 147, 150, 159, 163, 173, 174] ['Istvan', 'ES', ',', 'Palnitkar', 'M', ',', 'Buchanan', 'SK', ',', 'Deisenhofer', 'J', '.', 'Crystal', 'structure', 'of', 'the', 'catalytic', 'portion', 'of', 'human', 'HMG-CoA', 'reductase', ':', 'insights', 'into', 'regulation', 'of', 'activity', 'and', 'catalysis', '.'] [3, 1, 1, 3, 1, 1, 3, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Oligomerization state influences the degradation rate of 3-hydroxy-3-methylglutaryl-CoA reductase. [('PMC2764366', 'F29002', 57, 97, '3-hydroxy-3-methylglutaryl-CoA reductase')] ['Olig', '##omer', '##ization', 'state', 'influences', 'the', 'degradation', 'rate', 'of', '3', '-', 'hydroxy', '-', '3', '-', 'methyl', '##glut', '##aryl', '-', 'Co', '##A', 'reductase', '.'] [0, 4, 8, 16, 22, 33, 37, 49, 54, 57, 58, 59, 66, 67, 68, 69, 75, 79, 83, 84, 86, 88, 97] [4, 8, 15, 21, 32, 36, 48, 53, 56, 58, 59, 66, 67, 68, 69, 75, 79, 83, 84, 86, 87, 97, 98] ['Oligomerization', 'state', 'influences', 'the', 'degradation', 'rate', 'of', '3-hydroxy-3-methylglutaryl-CoA', 'reductase', '.'] [3, 1, 1, 1, 1, 1, 1, 12, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O']
The second best hits for LDL-C were SNPs that mapped to the HMG-CoA reductase (HMG-CoA reductase) gene, the rate-limiting enzyme in cholesterol biosynthesis and the target of LDL-C lowering statin drugs. [('PMC2764366', 'I02003', 60, 77, 'HMG-CoA reductase'), ('PMC2764366', 'I02003', 79, 96, 'HMG-CoA reductase')] ['The', 'second', 'best', 'hits', 'for', 'LDL', '-', 'C', 'were', 'SNPs', 'that', 'mapped', 'to', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', '(', 'HM', '##G', '-', 'Co', '##A', 'reductase', ')', 'gene', ',', 'the', 'rate', '-', 'limiting', 'enzyme', 'in', 'cholesterol', 'biosynthesis', 'and', 'the', 'target', 'of', 'LDL', '-', 'C', 'lowering', 'statin', 'drugs', '.'] [0, 4, 11, 16, 21, 25, 28, 29, 31, 36, 41, 46, 53, 56, 60, 62, 63, 64, 66, 68, 78, 79, 81, 82, 83, 85, 87, 96, 98, 102, 104, 108, 112, 113, 122, 129, 132, 144, 157, 161, 165, 172, 175, 178, 179, 181, 190, 197, 202] [3, 10, 15, 20, 24, 28, 29, 30, 35, 40, 45, 52, 55, 59, 62, 63, 64, 66, 67, 77, 79, 81, 82, 83, 85, 86, 96, 97, 102, 103, 107, 112, 113, 121, 128, 131, 143, 156, 160, 164, 171, 174, 178, 179, 180, 189, 196, 202, 203] ['The', 'second', 'best', 'hits', 'for', 'LDL-C', 'were', 'SNPs', 'that', 'mapped', 'to', 'the', 'HMG-CoA', 'reductase', '(', 'HMG-CoA', 'reductase', ')', 'gene', ',', 'the', 'rate', '-', 'limiting', 'enzyme', 'in', 'cholesterol', 'biosynthesis', 'and', 'the', 'target', 'of', 'LDL-C', 'lowering', 'statin', 'drugs', '.'] [1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 5, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
During the preparation of this manuscript, four GWAS for LDL-C in Caucasian cohorts were published 10–13 and one of them 13 included an association between the same SNPs in HMG-CoA reductase and plasma LDL-C in Caucasians. [('PMC2764366', 'I02004', 173, 190, 'HMG-CoA reductase')] ['During', 'the', 'preparation', 'of', 'this', 'manuscript', ',', 'four', 'GW', '##AS', 'for', 'LDL', '-', 'C', 'in', 'Caucasian', 'cohorts', 'were', 'published', '10', '–', '13', 'and', 'one', 'of', 'them', '13', 'included', 'an', 'association', 'between', 'the', 'same', 'SNPs', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'and', 'plasma', 'LDL', '-', 'C', 'in', 'Caucasian', '##s', '.'] [0, 7, 11, 23, 26, 31, 41, 43, 48, 50, 53, 57, 60, 61, 63, 66, 76, 84, 89, 99, 101, 102, 105, 109, 113, 116, 121, 124, 133, 136, 148, 156, 160, 165, 170, 173, 175, 176, 177, 179, 181, 191, 195, 202, 205, 206, 208, 211, 220, 221] [6, 10, 22, 25, 30, 41, 42, 47, 50, 52, 56, 60, 61, 62, 65, 75, 83, 88, 98, 101, 102, 104, 108, 112, 115, 120, 123, 132, 135, 147, 155, 159, 164, 169, 172, 175, 176, 177, 179, 180, 190, 194, 201, 205, 206, 207, 210, 220, 221, 222] ['During', 'the', 'preparation', 'of', 'this', 'manuscript', ',', 'four', 'GWAS', 'for', 'LDL-C', 'in', 'Caucasian', 'cohorts', 'were', 'published', '10–', '13', 'and', 'one', 'of', 'them', '13', 'included', 'an', 'association', 'between', 'the', 'same', 'SNPs', 'in', 'HMG-CoA', 'reductase', 'and', 'plasma', 'LDL-C', 'in', 'Caucasians', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 3, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In this manuscript, we report associations of SNPs in HMG-CoA reductase with LDL-C in Kosraens that, in combination with similar findings from studies in Caucasians, indicate that the same genetic variants at HMG-CoA reductase contribute to differences in LDL-C across populations. [('PMC2764366', 'I04000', 54, 71, 'HMG-CoA reductase'), ('PMC2764366', 'I04000', 209, 226, 'HMG-CoA reductase')] ['In', 'this', 'manuscript', ',', 'we', 'report', 'associations', 'of', 'SNPs', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'with', 'LDL', '-', 'C', 'in', 'Kos', '##ra', '##ens', 'that', ',', 'in', 'combination', 'with', 'similar', 'findings', 'from', 'studies', 'in', 'Caucasian', '##s', ',', 'indicate', 'that', 'the', 'same', 'genetic', 'variants', 'at', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'contribute', 'to', 'differences', 'in', 'LDL', '-', 'C', 'across', 'populations', '.'] [0, 3, 8, 18, 20, 23, 30, 43, 46, 51, 54, 56, 57, 58, 60, 62, 72, 77, 80, 81, 83, 86, 89, 91, 95, 99, 101, 104, 116, 121, 129, 138, 143, 151, 154, 163, 164, 166, 175, 180, 184, 189, 197, 206, 209, 211, 212, 213, 215, 217, 227, 238, 241, 253, 256, 259, 260, 262, 269, 280] [2, 7, 18, 19, 22, 29, 42, 45, 50, 53, 56, 57, 58, 60, 61, 71, 76, 80, 81, 82, 85, 89, 91, 94, 99, 100, 103, 115, 120, 128, 137, 142, 150, 153, 163, 164, 165, 174, 179, 183, 188, 196, 205, 208, 211, 212, 213, 215, 216, 226, 237, 240, 252, 255, 259, 260, 261, 268, 280, 281] ['In', 'this', 'manuscript', ',', 'we', 'report', 'associations', 'of', 'SNPs', 'in', 'HMG-CoA', 'reductase', 'with', 'LDL-C', 'in', 'Kosraens', 'that', ',', 'in', 'combination', 'with', 'similar', 'findings', 'from', 'studies', 'in', 'Caucasians', ',', 'indicate', 'that', 'the', 'same', 'genetic', 'variants', 'at', 'HMG-CoA', 'reductase', 'contribute', 'to', 'differences', 'in', 'LDL-C', 'across', 'populations', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 3, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To follow-up the association signal, we have implemented a hypothesis driven strategy and performed in vitro studies to identify a functional variant in intron13 of HMG-CoA reductase that affects alternative splicing of exon13. [('PMC2764366', 'I04001', 165, 182, 'HMG-CoA reductase')] ['To', 'follow', '-', 'up', 'the', 'association', 'signal', ',', 'we', 'have', 'implemented', 'a', 'hypothesis', 'driven', 'strategy', 'and', 'performed', 'in', 'vitro', 'studies', 'to', 'identify', 'a', 'functional', 'variant', 'in', 'intron', '##13', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'that', 'affects', 'alternative', 'splicing', 'of', 'exon', '##13', '.'] [0, 3, 9, 10, 13, 17, 29, 35, 37, 40, 45, 57, 59, 70, 77, 86, 90, 100, 103, 109, 117, 120, 129, 131, 142, 150, 153, 159, 162, 165, 167, 168, 169, 171, 173, 183, 188, 196, 208, 217, 220, 224, 226] [2, 9, 10, 12, 16, 28, 35, 36, 39, 44, 56, 58, 69, 76, 85, 89, 99, 102, 108, 116, 119, 128, 130, 141, 149, 152, 159, 161, 164, 167, 168, 169, 171, 172, 182, 187, 195, 207, 216, 219, 224, 226, 227] ['To', 'follow', '-', 'up', 'the', 'association', 'signal', ',', 'we', 'have', 'implemented', 'a', 'hypothesis', 'driven', 'strategy', 'and', 'performed', 'in', 'vitro', 'studies', 'to', 'identify', 'a', 'functional', 'variant', 'in', 'intron13', 'of', 'HMG-CoA', 'reductase', 'that', 'affects', 'alternative', 'splicing', 'of', 'exon13', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
For HMG-CoA reductase mRNA expression studies cells were seeded at a density of 250 000 cells/ml medium. [('PMC2764366', 'M03002', 4, 21, 'HMG-CoA reductase')] ['For', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'expression', 'studies', 'cells', 'were', 'seeded', 'at', 'a', 'density', 'of', '250', '000', 'cells', '/', 'ml', 'medium', '.'] [0, 4, 6, 7, 8, 10, 12, 22, 27, 38, 46, 52, 57, 64, 67, 69, 77, 80, 84, 88, 93, 94, 97, 103] [3, 6, 7, 8, 10, 11, 21, 26, 37, 45, 51, 56, 63, 66, 68, 76, 79, 83, 87, 93, 94, 96, 103, 104] ['For', 'HMG-CoA', 'reductase', 'mRNA', 'expression', 'studies', 'cells', 'were', 'seeded', 'at', 'a', 'density', 'of', '250', '000', 'cells', '/', 'ml', 'medium', '.'] [1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Russell DeBose-Boyd and Michael Brown, UT Southwestern Medical Center) are mutant chinese hamster ovary (CHO) cells that lack HMG-CoA reductase and require mevalonate for growth. [('PMC2764366', 'M04001', 126, 143, 'HMG-CoA reductase')] ['Russell', 'De', '##Bo', '##se', '-', 'Boy', '##d', 'and', 'Michael', 'Brown', ',', 'UT', 'South', '##western', 'Medical', 'Center', ')', 'are', 'mutant', 'chi', '##nes', '##e', 'hams', '##ter', 'ovary', '(', 'CHO', ')', 'cells', 'that', 'lack', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'and', 'require', 'me', '##val', '##onate', 'for', 'growth', '.'] [0, 8, 10, 12, 14, 15, 18, 20, 24, 32, 37, 39, 42, 47, 55, 63, 69, 71, 75, 82, 85, 88, 90, 94, 98, 104, 105, 108, 110, 116, 121, 126, 128, 129, 130, 132, 134, 144, 148, 156, 158, 161, 167, 171, 177] [7, 10, 12, 14, 15, 18, 19, 23, 31, 37, 38, 41, 47, 54, 62, 69, 70, 74, 81, 85, 88, 89, 94, 97, 103, 105, 108, 109, 115, 120, 125, 128, 129, 130, 132, 133, 143, 147, 155, 158, 161, 166, 170, 177, 178] ['Russell', 'DeBose-Boyd', 'and', 'Michael', 'Brown', ',', 'UT', 'Southwestern', 'Medical', 'Center', ')', 'are', 'mutant', 'chinese', 'hamster', 'ovary', '(', 'CHO', ')', 'cells', 'that', 'lack', 'HMG-CoA', 'reductase', 'and', 'require', 'mevalonate', 'for', 'growth', '.'] [1, 6, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 3, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Specific primers and probes for full-length HMG-CoA reductase, Δexon13 HMG-CoA reductase and β-actin mRNA were selected to span exon junctions to avoid co-amplification of genomic DNA. [('PMC2764366', 'M05002', 44, 61, 'HMG-CoA reductase'), ('PMC2764366', 'M05002', 71, 88, 'HMG-CoA reductase')] ['Specific', 'primers', 'and', 'probes', 'for', 'full', '-', 'length', 'HM', '##G', '-', 'Co', '##A', 'reductase', ',', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'and', 'β', '-', 'actin', 'mRNA', 'were', 'selected', 'to', 'span', 'exon', 'junctions', 'to', 'avoid', 'co', '-', 'amplification', 'of', 'genomic', 'DNA', '.'] [0, 9, 17, 21, 28, 32, 36, 37, 44, 46, 47, 48, 50, 52, 61, 63, 64, 66, 68, 71, 73, 74, 75, 77, 79, 89, 93, 94, 95, 101, 106, 111, 120, 123, 128, 133, 143, 146, 152, 154, 155, 169, 172, 180, 183] [8, 16, 20, 27, 31, 36, 37, 43, 46, 47, 48, 50, 51, 61, 62, 64, 66, 68, 70, 73, 74, 75, 77, 78, 88, 92, 94, 95, 100, 105, 110, 119, 122, 127, 132, 142, 145, 151, 154, 155, 168, 171, 179, 183, 184] ['Specific', 'primers', 'and', 'probes', 'for', 'full', '-', 'length', 'HMG-CoA', 'reductase', ',', 'Δexon13', 'HMG-CoA', 'reductase', 'and', 'β-actin', 'mRNA', 'were', 'selected', 'to', 'span', 'exon', 'junctions', 'to', 'avoid', 'co', '-', 'amplification', 'of', 'genomic', 'DNA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 4, 5, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Minigenes were used to assess the influence of SNP rs3846662 on alternative splicing of HMG-CoA reductase exon13. [('PMC2764366', 'M06000', 88, 105, 'HMG-CoA reductase')] ['Mini', '##genes', 'were', 'used', 'to', 'assess', 'the', 'influence', 'of', 'SNP', 'rs', '##38', '##46', '##66', '##2', 'on', 'alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'exon', '##13', '.'] [0, 4, 10, 15, 20, 23, 30, 34, 44, 47, 51, 53, 55, 57, 59, 61, 64, 76, 85, 88, 90, 91, 92, 94, 96, 106, 110, 112] [4, 9, 14, 19, 22, 29, 33, 43, 46, 50, 53, 55, 57, 59, 60, 63, 75, 84, 87, 90, 91, 92, 94, 95, 105, 110, 112, 113] ['Minigenes', 'were', 'used', 'to', 'assess', 'the', 'influence', 'of', 'SNP', 'rs3846662', 'on', 'alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'exon13', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 5, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O']
HEK293 cells were transfected with HMG-CoA reductase pSPL3 minigenes (A, G and A→G) and empty pSPL3 vector (negative control) using FuGene6 reagent (Roche Applied Bioscience). [('PMC2764366', 'M07000', 35, 52, 'HMG-CoA reductase')] ['HEK', '##293', 'cells', 'were', 'transfected', 'with', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'p', '##SP', '##L', '##3', 'mini', '##genes', '(', 'A', ',', 'G', 'and', 'A', '##→', '##G', ')', 'and', 'empty', 'p', '##SP', '##L', '##3', 'vector', '(', 'negative', 'control', ')', 'using', 'Fu', '##Gene', '##6', 'reagent', '(', 'Roche', 'Applied', 'Bios', '##cience', ')', '.'] [0, 3, 7, 13, 18, 30, 35, 37, 38, 39, 41, 43, 53, 54, 56, 57, 59, 63, 69, 70, 71, 73, 75, 79, 80, 81, 82, 84, 88, 94, 95, 97, 98, 100, 107, 108, 117, 124, 126, 132, 134, 138, 140, 148, 149, 155, 163, 167, 173, 174] [3, 6, 12, 17, 29, 34, 37, 38, 39, 41, 42, 52, 54, 56, 57, 58, 63, 68, 70, 71, 72, 74, 78, 80, 81, 82, 83, 87, 93, 95, 97, 98, 99, 106, 108, 116, 124, 125, 131, 134, 138, 139, 147, 149, 154, 162, 167, 173, 174, 175] ['HEK293', 'cells', 'were', 'transfected', 'with', 'HMG-CoA', 'reductase', 'pSPL3', 'minigenes', '(', 'A', ',', 'G', 'and', 'A→G', ')', 'and', 'empty', 'pSPL3', 'vector', '(', 'negative', 'control', ')', 'using', 'FuGene6', 'reagent', '(', 'Roche', 'Applied', 'Bioscience', ')', '.'] [2, 1, 1, 1, 1, 5, 1, 4, 2, 1, 1, 1, 1, 1, 3, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
After 24h, RNA was isolated and reverse transcribed using the SA2 Primer (5’-ATCTCAGTGGTATTTGTGAGC-3’), corresponding to a transcribed exonic sequence in the pSPL3 vector and thus allowing analysis of only vector-specific HMG-CoA reductase transcripts. [('PMC2764366', 'M07001', 222, 239, 'HMG-CoA reductase')] ['After', '24', '##h', ',', 'RNA', 'was', 'isolated', 'and', 'reverse', 'transcribed', 'using', 'the', 'SA', '##2', 'Primer', '(', '5', '’', '-', 'AT', '##CTC', '##AGT', '##GG', '##TA', '##TT', '##TG', '##TG', '##AG', '##C', '-', '3', '’', ')', ',', 'corresponding', 'to', 'a', 'transcribed', 'exon', '##ic', 'sequence', 'in', 'the', 'p', '##SP', '##L', '##3', 'vector', 'and', 'thus', 'allowing', 'analysis', 'of', 'only', 'vector', '-', 'specific', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'transcripts', '.'] [0, 6, 8, 9, 11, 15, 19, 28, 32, 40, 52, 58, 62, 64, 66, 73, 74, 75, 76, 77, 79, 82, 85, 87, 89, 91, 93, 95, 97, 98, 99, 100, 101, 102, 104, 118, 121, 123, 135, 139, 142, 151, 154, 158, 159, 161, 162, 164, 171, 175, 180, 189, 198, 201, 206, 212, 213, 222, 224, 225, 226, 228, 230, 240, 251] [5, 8, 9, 10, 14, 18, 27, 31, 39, 51, 57, 61, 64, 65, 72, 74, 75, 76, 77, 79, 82, 85, 87, 89, 91, 93, 95, 97, 98, 99, 100, 101, 102, 103, 117, 120, 122, 134, 139, 141, 150, 153, 157, 159, 161, 162, 163, 170, 174, 179, 188, 197, 200, 205, 212, 213, 221, 224, 225, 226, 228, 229, 239, 251, 252] ['After', '24h', ',', 'RNA', 'was', 'isolated', 'and', 'reverse', 'transcribed', 'using', 'the', 'SA2', 'Primer', '(', '5’-ATCTCAGTGGTATTTGTGAGC-3', '’', ')', ',', 'corresponding', 'to', 'a', 'transcribed', 'exonic', 'sequence', 'in', 'the', 'pSPL3', 'vector', 'and', 'thus', 'allowing', 'analysis', 'of', 'only', 'vector', '-', 'specific', 'HMG-CoA', 'reductase', 'transcripts', '.'] [1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 15, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
HMG-CoA reductase splicing pattern was analyzed by Real-Time PCR as described above. [('PMC2764366', 'M07002', 0, 17, 'HMG-CoA reductase')] ['HM', '##G', '-', 'Co', '##A', 'reductase', 'splicing', 'pattern', 'was', 'analyzed', 'by', 'Real', '-', 'Time', 'PCR', 'as', 'described', 'above', '.'] [0, 2, 3, 4, 6, 8, 18, 27, 35, 39, 48, 51, 55, 56, 61, 65, 68, 78, 83] [2, 3, 4, 6, 7, 17, 26, 34, 38, 47, 50, 55, 56, 60, 64, 67, 77, 83, 84] ['HMG-CoA', 'reductase', 'splicing', 'pattern', 'was', 'analyzed', 'by', 'Real-Time', 'PCR', 'as', 'described', 'above', '.'] [5, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The open reading frames of HMG-CoA reductase full-length and Δexon13 mRNA were PCR amplified and cloned into the pcDNA3.1 expression vector (Invitrogen). [('PMC2764366', 'M08000', 27, 44, 'HMG-CoA reductase')] ['The', 'open', 'reading', 'frames', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'full', '-', 'length', 'and', 'Δ', '##ex', '##on', '##13', 'mRNA', 'were', 'PCR', 'amplified', 'and', 'cloned', 'into', 'the', 'pc', '##DNA', '##3', '.', '1', 'expression', 'vector', '(', 'Invitrogen', ')', '.'] [0, 4, 9, 17, 24, 27, 29, 30, 31, 33, 35, 45, 49, 50, 57, 61, 62, 64, 66, 69, 74, 79, 83, 93, 97, 104, 109, 113, 115, 118, 119, 120, 122, 133, 140, 141, 151, 152] [3, 8, 16, 23, 26, 29, 30, 31, 33, 34, 44, 49, 50, 56, 60, 62, 64, 66, 68, 73, 78, 82, 92, 96, 103, 108, 112, 115, 118, 119, 120, 121, 132, 139, 141, 151, 152, 153] ['The', 'open', 'reading', 'frames', 'of', 'HMG-CoA', 'reductase', 'full', '-', 'length', 'and', 'Δexon13', 'mRNA', 'were', 'PCR', 'amplified', 'and', 'cloned', 'into', 'the', 'pcDNA3.1', 'expression', 'vector', '(', 'Invitrogen', ')', '.'] [1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
UT-2 cells with stable expression of human full-length (UT-2+FL) or Δexon13 HMG-CoA reductase (UT-2+ex13) were generated by G418 selection of FuGene6 transfected UT-2cells. [('PMC2764366', 'M08001', 76, 93, 'HMG-CoA reductase')] ['UT', '-', '2', 'cells', 'with', 'stable', 'expression', 'of', 'human', 'full', '-', 'length', '(', 'UT', '-', '2', '+', 'FL', ')', 'or', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', '(', 'UT', '-', '2', '+', 'ex', '##13', ')', 'were', 'generated', 'by', 'G', '##41', '##8', 'selection', 'of', 'Fu', '##Gene', '##6', 'transfected', 'UT', '-', '2', '##cells', '.'] [0, 2, 3, 5, 11, 16, 23, 34, 37, 43, 47, 48, 55, 56, 58, 59, 60, 61, 63, 65, 68, 69, 71, 73, 76, 78, 79, 80, 82, 84, 94, 95, 97, 98, 99, 100, 102, 104, 106, 111, 121, 124, 125, 127, 129, 139, 142, 144, 148, 150, 162, 164, 165, 166, 171] [2, 3, 4, 10, 15, 22, 33, 36, 42, 47, 48, 54, 56, 58, 59, 60, 61, 63, 64, 67, 69, 71, 73, 75, 78, 79, 80, 82, 83, 93, 95, 97, 98, 99, 100, 102, 104, 105, 110, 120, 123, 125, 127, 128, 138, 141, 144, 148, 149, 161, 164, 165, 166, 171, 172] ['UT-2', 'cells', 'with', 'stable', 'expression', 'of', 'human', 'full', '-', 'length', '(', 'UT-2', '+', 'FL', ')', 'or', 'Δexon13', 'HMG-CoA', 'reductase', '(', 'UT-2', '+', 'ex13', ')', 'were', 'generated', 'by', 'G418', 'selection', 'of', 'FuGene6', 'transfected', 'UT-2cells', '.'] [3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 4, 5, 1, 1, 3, 1, 2, 1, 1, 1, 1, 3, 1, 1, 3, 1, 4, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
HMG-CoA reductase activity was measured in detergent solubilized cell extracts as described 17 except that mevalonolactone was separated by ion exchange chromatography 18. [('PMC2764366', 'M09001', 0, 17, 'HMG-CoA reductase')] ['HM', '##G', '-', 'Co', '##A', 'reductase', 'activity', 'was', 'measured', 'in', 'detergent', 'solub', '##ilized', 'cell', 'extracts', 'as', 'described', '17', 'except', 'that', 'me', '##val', '##ono', '##lact', '##one', 'was', 'separated', 'by', 'ion', 'exchange', 'chromatography', '18', '.'] [0, 2, 3, 4, 6, 8, 18, 27, 31, 40, 43, 53, 58, 65, 70, 79, 82, 92, 95, 102, 107, 109, 112, 115, 119, 123, 127, 137, 140, 144, 153, 168, 170] [2, 3, 4, 6, 7, 17, 26, 30, 39, 42, 52, 58, 64, 69, 78, 81, 91, 94, 101, 106, 109, 112, 115, 119, 122, 126, 136, 139, 143, 152, 167, 170, 171] ['HMG-CoA', 'reductase', 'activity', 'was', 'measured', 'in', 'detergent', 'solubilized', 'cell', 'extracts', 'as', 'described', '17', 'except', 'that', 'mevalonolactone', 'was', 'separated', 'by', 'ion', 'exchange', 'chromatography', '18', '.'] [5, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The second best locus for LDL-C mapped to a region on chromosome 5q13 containing the HMG-CoA reductase gene (Table1). [('PMC2764366', 'R00003', 85, 102, 'HMG-CoA reductase')] ['The', 'second', 'best', 'locus', 'for', 'LDL', '-', 'C', 'mapped', 'to', 'a', 'region', 'on', 'chromosome', '5', '##q', '##13', 'containing', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'gene', '(', 'Table', '##1', ')', '.'] [0, 4, 11, 16, 22, 26, 29, 30, 32, 39, 42, 44, 51, 54, 65, 66, 67, 70, 81, 85, 87, 88, 89, 91, 93, 103, 108, 109, 114, 115, 116] [3, 10, 15, 21, 25, 29, 30, 31, 38, 41, 43, 50, 53, 64, 66, 67, 69, 80, 84, 87, 88, 89, 91, 92, 102, 107, 109, 114, 115, 116, 117] ['The', 'second', 'best', 'locus', 'for', 'LDL-C', 'mapped', 'to', 'a', 'region', 'on', 'chromosome', '5q13', 'containing', 'the', 'HMG-CoA', 'reductase', 'gene', '(', 'Table1', ')', '.'] [1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 3, 1, 1, 5, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
This gene encodes HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis and thus represents an interesting candidate gene with high plausibility. [('PMC2764366', 'R00004', 18, 35, 'HMG-CoA reductase')] ['This', 'gene', 'encodes', 'HM', '##G', '-', 'Co', '##A', 'reductase', ',', 'the', 'rate', '-', 'limiting', 'enzyme', 'in', 'cholesterol', 'biosynthesis', 'and', 'thus', 'represents', 'an', 'interesting', 'candidate', 'gene', 'with', 'high', 'plaus', '##ibility', '.'] [0, 5, 10, 18, 20, 21, 22, 24, 26, 35, 37, 41, 45, 46, 55, 62, 65, 77, 90, 94, 99, 110, 113, 125, 135, 140, 145, 150, 155, 162] [4, 9, 17, 20, 21, 22, 24, 25, 35, 36, 40, 45, 46, 54, 61, 64, 76, 89, 93, 98, 109, 112, 124, 134, 139, 144, 149, 155, 162, 163] ['This', 'gene', 'encodes', 'HMG-CoA', 'reductase', ',', 'the', 'rate', '-', 'limiting', 'enzyme', 'in', 'cholesterol', 'biosynthesis', 'and', 'thus', 'represents', 'an', 'interesting', 'candidate', 'gene', 'with', 'high', 'plausibility', '.'] [1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Combining p-values across both studies, we validated multiple SNPs at the HMG-CoA reductase locus, three of which surpassed a genome-wide significance of p<5 ×10−8 (rs7703051, rs12654264 and rs3846663) (Table 1 and supplemental Fig.II). [('PMC2764366', 'R02000', 74, 91, 'HMG-CoA reductase')] ['Combining', 'p', '-', 'values', 'across', 'both', 'studies', ',', 'we', 'validated', 'multiple', 'SNPs', 'at', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', ',', 'three', 'of', 'which', 'sur', '##pass', '##ed', 'a', 'genome', '-', 'wide', 'significance', 'of', 'p', '<', '5', '×', '##10', '##−', '##8', '(', 'rs', '##77', '##03', '##05', '##1', ',', 'rs', '##126', '##54', '##26', '##4', 'and', 'rs', '##38', '##46', '##66', '##3', ')', '(', 'Table', '1', 'and', 'supplemental', 'Fig', '.', 'II', ')', '.'] [0, 10, 11, 12, 19, 26, 31, 38, 40, 43, 53, 62, 67, 70, 74, 76, 77, 78, 80, 82, 92, 97, 99, 105, 108, 114, 117, 121, 124, 126, 132, 133, 138, 151, 154, 155, 156, 158, 159, 161, 162, 164, 165, 167, 169, 171, 173, 174, 176, 178, 181, 183, 185, 187, 191, 193, 195, 197, 199, 200, 202, 203, 209, 211, 215, 228, 231, 232, 234, 235] [9, 11, 12, 18, 25, 30, 38, 39, 42, 52, 61, 66, 69, 73, 76, 77, 78, 80, 81, 91, 97, 98, 104, 107, 113, 117, 121, 123, 125, 132, 133, 137, 150, 153, 155, 156, 157, 159, 161, 162, 163, 165, 167, 169, 171, 173, 174, 175, 178, 181, 183, 185, 186, 190, 193, 195, 197, 199, 200, 201, 203, 208, 210, 214, 227, 231, 232, 234, 235, 236] ['Combining', 'p-values', 'across', 'both', 'studies', ',', 'we', 'validated', 'multiple', 'SNPs', 'at', 'the', 'HMG-CoA', 'reductase', 'locus', ',', 'three', 'of', 'which', 'surpassed', 'a', 'genome', '-', 'wide', 'significance', 'of', 'p', '<', '5', '×10−8', '(', 'rs7703051', ',', 'rs12654264', 'and', 'rs3846663', ')', '(', 'Table', '1', 'and', 'supplemental', 'Fig.II', ')', '.'] [1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 5, 1, 5, 1, 5, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
A regional association plot for the combined results showed a peak of association signal over a 47 kb region containing the HMG-CoA reductase gene (Fig.II). [('PMC2764366', 'R02001', 124, 141, 'HMG-CoA reductase')] ['A', 'regional', 'association', 'plot', 'for', 'the', 'combined', 'results', 'showed', 'a', 'peak', 'of', 'association', 'signal', 'over', 'a', '47', 'kb', 'region', 'containing', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'gene', '(', 'Fig', '.', 'II', ')', '.'] [0, 2, 11, 23, 28, 32, 36, 45, 53, 60, 62, 67, 70, 82, 89, 94, 96, 99, 102, 109, 120, 124, 126, 127, 128, 130, 132, 142, 147, 148, 151, 152, 154, 155] [1, 10, 22, 27, 31, 35, 44, 52, 59, 61, 66, 69, 81, 88, 93, 95, 98, 101, 108, 119, 123, 126, 127, 128, 130, 131, 141, 146, 148, 151, 152, 154, 155, 156] ['A', 'regional', 'association', 'plot', 'for', 'the', 'combined', 'results', 'showed', 'a', 'peak', 'of', 'association', 'signal', 'over', 'a', '47', 'kb', 'region', 'containing', 'the', 'HMG-CoA', 'reductase', 'gene', '(', 'Fig.II', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We also combined the p-values of the association analysis results for plasma total cholesterol from the Kosrae and DGI studies and found genome-wide significance for the same three SNPs at the HMG-CoA reductase locus (supplemental Table I). [('PMC2764366', 'R03000', 193, 210, 'HMG-CoA reductase')] ['We', 'also', 'combined', 'the', 'p', '-', 'values', 'of', 'the', 'association', 'analysis', 'results', 'for', 'plasma', 'total', 'cholesterol', 'from', 'the', 'Kos', '##ra', '##e', 'and', 'DG', '##I', 'studies', 'and', 'found', 'genome', '-', 'wide', 'significance', 'for', 'the', 'same', 'three', 'SNPs', 'at', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', '(', 'supplemental', 'Table', 'I', ')', '.'] [0, 3, 8, 17, 21, 22, 23, 30, 33, 37, 49, 58, 66, 70, 77, 83, 95, 100, 104, 107, 109, 111, 115, 117, 119, 127, 131, 137, 143, 144, 149, 162, 166, 170, 175, 181, 186, 189, 193, 195, 196, 197, 199, 201, 211, 217, 218, 231, 237, 238, 239] [2, 7, 16, 20, 22, 23, 29, 32, 36, 48, 57, 65, 69, 76, 82, 94, 99, 103, 107, 109, 110, 114, 117, 118, 126, 130, 136, 143, 144, 148, 161, 165, 169, 174, 180, 185, 188, 192, 195, 196, 197, 199, 200, 210, 216, 218, 230, 236, 238, 239, 240] ['We', 'also', 'combined', 'the', 'p-values', 'of', 'the', 'association', 'analysis', 'results', 'for', 'plasma', 'total', 'cholesterol', 'from', 'the', 'Kosrae', 'and', 'DGI', 'studies', 'and', 'found', 'genome', '-', 'wide', 'significance', 'for', 'the', 'same', 'three', 'SNPs', 'at', 'the', 'HMG-CoA', 'reductase', 'locus', '(', 'supplemental', 'Table', 'I', ')', '.'] [1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To follow-up the association results, we next aimed to discover functional variants at the HMG-CoA reductase locus and study their molecular mode of action. [('PMC2764366', 'R04000', 91, 108, 'HMG-CoA reductase')] ['To', 'follow', '-', 'up', 'the', 'association', 'results', ',', 'we', 'next', 'aimed', 'to', 'discover', 'functional', 'variants', 'at', 'the', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'locus', 'and', 'study', 'their', 'molecular', 'mode', 'of', 'action', '.'] [0, 3, 9, 10, 13, 17, 29, 36, 38, 41, 46, 52, 55, 64, 75, 84, 87, 91, 93, 94, 95, 97, 99, 109, 115, 119, 125, 131, 141, 146, 149, 155] [2, 9, 10, 12, 16, 28, 36, 37, 40, 45, 51, 54, 63, 74, 83, 86, 90, 93, 94, 95, 97, 98, 108, 114, 118, 124, 130, 140, 145, 148, 155, 156] ['To', 'follow', '-', 'up', 'the', 'association', 'results', ',', 'we', 'next', 'aimed', 'to', 'discover', 'functional', 'variants', 'at', 'the', 'HMG-CoA', 'reductase', 'locus', 'and', 'study', 'their', 'molecular', 'mode', 'of', 'action', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We used existing resequencing data of the region containing the entire HMG-CoA reductase gene from 23 Caucasians - estimated to have >99% power to detect variants with a minor allele frequency of >5% 19- to identify candidate functional SNPs. [('PMC2764366', 'R04001', 71, 88, 'HMG-CoA reductase')] ['We', 'used', 'existing', 'res', '##equ', '##encing', 'data', 'of', 'the', 'region', 'containing', 'the', 'entire', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'gene', 'from', '23', 'Caucasian', '##s', '-', 'estimated', 'to', 'have', '>', '99', '%', 'power', 'to', 'detect', 'variants', 'with', 'a', 'minor', 'allele', 'frequency', 'of', '>', '5', '%', '19', '-', 'to', 'identify', 'candidate', 'functional', 'SNPs', '.'] [0, 3, 8, 17, 20, 23, 30, 35, 38, 42, 49, 60, 64, 71, 73, 74, 75, 77, 79, 89, 94, 99, 102, 111, 113, 115, 125, 128, 133, 134, 136, 138, 144, 147, 154, 163, 168, 170, 176, 183, 193, 196, 197, 198, 200, 202, 204, 207, 216, 226, 237, 241] [2, 7, 16, 20, 23, 29, 34, 37, 41, 48, 59, 63, 70, 73, 74, 75, 77, 78, 88, 93, 98, 101, 111, 112, 114, 124, 127, 132, 134, 136, 137, 143, 146, 153, 162, 167, 169, 175, 182, 192, 195, 197, 198, 199, 202, 203, 206, 215, 225, 236, 241, 242] ['We', 'used', 'existing', 'resequencing', 'data', 'of', 'the', 'region', 'containing', 'the', 'entire', 'HMG-CoA', 'reductase', 'gene', 'from', '23', 'Caucasians', '-', 'estimated', 'to', 'have', '>', '99%', 'power', 'to', 'detect', 'variants', 'with', 'a', 'minor', 'allele', 'frequency', 'of', '>', '5%', '19-', 'to', 'identify', 'candidate', 'functional', 'SNPs', '.'] [1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Under our hypothesis driven model we focused on SNPs that would have strong potential for changing HMG-CoA reductase function or levels. [('PMC2764366', 'R04002', 99, 116, 'HMG-CoA reductase')] ['Under', 'our', 'hypothesis', 'driven', 'model', 'we', 'focused', 'on', 'SNPs', 'that', 'would', 'have', 'strong', 'potential', 'for', 'changing', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'function', 'or', 'levels', '.'] [0, 6, 10, 21, 28, 34, 37, 45, 48, 53, 58, 64, 69, 76, 86, 90, 99, 101, 102, 103, 105, 107, 117, 126, 129, 135] [5, 9, 20, 27, 33, 36, 44, 47, 52, 57, 63, 68, 75, 85, 89, 98, 101, 102, 103, 105, 106, 116, 125, 128, 135, 136] ['Under', 'our', 'hypothesis', 'driven', 'model', 'we', 'focused', 'on', 'SNPs', 'that', 'would', 'have', 'strong', 'potential', 'for', 'changing', 'HMG-CoA', 'reductase', 'function', 'or', 'levels', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O']
The lack of LD (r2≤0.02) between these SNPs and the only known non-synonymous SNP in HMG-CoA reductase, rs5908 (I638V) in exon15, suggested that the association was not due to this protein coding mutation (Fig.1). [('PMC2764366', 'R05001', 85, 102, 'HMG-CoA reductase')] ['The', 'lack', 'of', 'LD', '(', 'r', '##2', '##≤', '##0', '.', '02', ')', 'between', 'these', 'SNPs', 'and', 'the', 'only', 'known', 'non', '-', 'syn', '##onymous', 'SNP', 'in', 'HM', '##G', '-', 'Co', '##A', 'reductase', ',', 'rs', '##59', '##08', '(', 'I', '##63', '##8', '##V', ')', 'in', 'exon', '##15', ',', 'suggested', 'that', 'the', 'association', 'was', 'not', 'due', 'to', 'this', 'protein', 'coding', 'mutation', '(', 'Fig', '.', '1', ')', '.'] [0, 4, 9, 12, 15, 16, 17, 18, 19, 20, 21, 23, 25, 33, 39, 44, 48, 52, 57, 63, 66, 67, 70, 78, 82, 85, 87, 88, 89, 91, 93, 102, 104, 106, 108, 111, 112, 113, 115, 116, 117, 119, 122, 126, 128, 130, 140, 145, 149, 161, 165, 169, 173, 176, 181, 189, 196, 205, 206, 209, 210, 211, 212] [3, 8, 11, 14, 16, 17, 18, 19, 20, 21, 23, 24, 32, 38, 43, 47, 51, 56, 62, 66, 67, 70, 77, 81, 84, 87, 88, 89, 91, 92, 102, 103, 106, 108, 110, 112, 113, 115, 116, 117, 118, 121, 126, 128, 129, 139, 144, 148, 160, 164, 168, 172, 175, 180, 188, 195, 204, 206, 209, 210, 211, 212, 213] ['The', 'lack', 'of', 'LD', '(', 'r2≤0.02', ')', 'between', 'these', 'SNPs', 'and', 'the', 'only', 'known', 'non', '-', 'synonymous', 'SNP', 'in', 'HMG-CoA', 'reductase', ',', 'rs5908', '(', 'I638V', ')', 'in', 'exon15', ',', 'suggested', 'that', 'the', 'association', 'was', 'not', 'due', 'to', 'this', 'protein', 'coding', 'mutation', '(', 'Fig.1', ')', '.'] [1, 1, 1, 1, 1, 6, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 5, 1, 1, 3, 1, 4, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Since the existence of a second HMG-CoA reductase mRNA transcript resulting from alternative splicing had been reported in humans 20, we looked for SNPs in the vicinity of exon-intron borders. [('PMC2764366', 'R05002', 32, 49, 'HMG-CoA reductase')] ['Since', 'the', 'existence', 'of', 'a', 'second', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'transcript', 'resulting', 'from', 'alternative', 'splicing', 'had', 'been', 'reported', 'in', 'humans', '20', ',', 'we', 'looked', 'for', 'SNPs', 'in', 'the', 'vicinity', 'of', 'exon', '-', 'intron', 'borders', '.'] [0, 6, 10, 20, 23, 25, 32, 34, 35, 36, 38, 40, 50, 55, 66, 76, 81, 93, 102, 106, 111, 120, 123, 130, 132, 134, 137, 144, 148, 153, 156, 160, 169, 172, 176, 177, 184, 191] [5, 9, 19, 22, 24, 31, 34, 35, 36, 38, 39, 49, 54, 65, 75, 80, 92, 101, 105, 110, 119, 122, 129, 132, 133, 136, 143, 147, 152, 155, 159, 168, 171, 176, 177, 183, 191, 192] ['Since', 'the', 'existence', 'of', 'a', 'second', 'HMG-CoA', 'reductase', 'mRNA', 'transcript', 'resulting', 'from', 'alternative', 'splicing', 'had', 'been', 'reported', 'in', 'humans', '20', ',', 'we', 'looked', 'for', 'SNPs', 'in', 'the', 'vicinity', 'of', 'exon', '-', 'intron', 'borders', '.'] [1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To analyze whether rs3846662 was associated with HMG-CoA reductase splicing efficiency we obtained lymphoblastoid cell lines (LCLs) from Caucasian CEU individuals of the HapMap collection, who were either homozygous for the major (rs3846662/AA) or minor allele (rs3846662/GG). [('PMC2764366', 'R06000', 49, 66, 'HMG-CoA reductase')] ['To', 'analyze', 'whether', 'rs', '##38', '##46', '##66', '##2', 'was', 'associated', 'with', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'splicing', 'efficiency', 'we', 'obtained', 'lymph', '##oblast', '##oid', 'cell', 'lines', '(', 'LC', '##Ls', ')', 'from', 'Caucasian', 'CE', '##U', 'individuals', 'of', 'the', 'Ha', '##p', '##Map', 'collection', ',', 'who', 'were', 'either', 'homozygous', 'for', 'the', 'major', '(', 'rs', '##38', '##46', '##66', '##2', '/', 'AA', ')', 'or', 'minor', 'allele', '(', 'rs', '##38', '##46', '##66', '##2', '/', 'GG', ')', '.'] [0, 3, 11, 19, 21, 23, 25, 27, 29, 33, 44, 49, 51, 52, 53, 55, 57, 67, 76, 87, 90, 99, 104, 110, 114, 119, 125, 126, 128, 130, 132, 137, 147, 149, 151, 163, 166, 170, 172, 173, 177, 187, 189, 193, 198, 205, 216, 220, 224, 230, 231, 233, 235, 237, 239, 240, 241, 243, 245, 248, 254, 261, 262, 264, 266, 268, 270, 271, 272, 274, 275] [2, 10, 18, 21, 23, 25, 27, 28, 32, 43, 48, 51, 52, 53, 55, 56, 66, 75, 86, 89, 98, 104, 110, 113, 118, 124, 126, 128, 130, 131, 136, 146, 149, 150, 162, 165, 169, 172, 173, 176, 187, 188, 192, 197, 204, 215, 219, 223, 229, 231, 233, 235, 237, 239, 240, 241, 243, 244, 247, 253, 260, 262, 264, 266, 268, 270, 271, 272, 274, 275, 276] ['To', 'analyze', 'whether', 'rs3846662', 'was', 'associated', 'with', 'HMG-CoA', 'reductase', 'splicing', 'efficiency', 'we', 'obtained', 'lymphoblastoid', 'cell', 'lines', '(', 'LCLs', ')', 'from', 'Caucasian', 'CEU', 'individuals', 'of', 'the', 'HapMap', 'collection', ',', 'who', 'were', 'either', 'homozygous', 'for', 'the', 'major', '(', 'rs3846662', '/', 'AA', ')', 'or', 'minor', 'allele', '(', 'rs3846662', '/', 'GG', ')', '.'] [1, 1, 1, 5, 1, 1, 1, 5, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We first analyzed if total HMG-CoA reductase mRNA expression differed between both groups. [('PMC2764366', 'R06003', 27, 44, 'HMG-CoA reductase')] ['We', 'first', 'analyzed', 'if', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'expression', 'differed', 'between', 'both', 'groups', '.'] [0, 3, 9, 18, 21, 27, 29, 30, 31, 33, 35, 45, 50, 61, 70, 78, 83, 89] [2, 8, 17, 20, 26, 29, 30, 31, 33, 34, 44, 49, 60, 69, 77, 82, 89, 90] ['We', 'first', 'analyzed', 'if', 'total', 'HMG-CoA', 'reductase', 'mRNA', 'expression', 'differed', 'between', 'both', 'groups', '.'] [1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
As shown in Fig.2A, we did not detect significant differences in total HMG-CoA reductase mRNA levels between the two groups at any time point, indicating that total HMG-CoA reductase mRNA expression is not influenced by allele status at these SNPs. [('PMC2764366', 'R06004', 71, 88, 'HMG-CoA reductase'), ('PMC2764366', 'R06004', 165, 182, 'HMG-CoA reductase')] ['As', 'shown', 'in', 'Fig', '.', '2', '##A', ',', 'we', 'did', 'not', 'detect', 'significant', 'differences', 'in', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'levels', 'between', 'the', 'two', 'groups', 'at', 'any', 'time', 'point', ',', 'indicating', 'that', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'expression', 'is', 'not', 'influenced', 'by', 'allele', 'status', 'at', 'these', 'SNPs', '.'] [0, 3, 9, 12, 15, 16, 17, 18, 20, 23, 27, 31, 38, 50, 62, 65, 71, 73, 74, 75, 77, 79, 89, 94, 101, 109, 113, 117, 124, 127, 131, 136, 141, 143, 154, 159, 165, 167, 168, 169, 171, 173, 183, 188, 199, 202, 206, 217, 220, 227, 234, 237, 243, 247] [2, 8, 11, 15, 16, 17, 18, 19, 22, 26, 30, 37, 49, 61, 64, 70, 73, 74, 75, 77, 78, 88, 93, 100, 108, 112, 116, 123, 126, 130, 135, 141, 142, 153, 158, 164, 167, 168, 169, 171, 172, 182, 187, 198, 201, 205, 216, 219, 226, 233, 236, 242, 247, 248] ['As', 'shown', 'in', 'Fig.2A', ',', 'we', 'did', 'not', 'detect', 'significant', 'differences', 'in', 'total', 'HMG-CoA', 'reductase', 'mRNA', 'levels', 'between', 'the', 'two', 'groups', 'at', 'any', 'time', 'point', ',', 'indicating', 'that', 'total', 'HMG-CoA', 'reductase', 'mRNA', 'expression', 'is', 'not', 'influenced', 'by', 'allele', 'status', 'at', 'these', 'SNPs', '.'] [1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We went on to determine the amounts of full-length and alternatively spliced HMG-CoA reductase (Δexon13) mRNA separately. [('PMC2764366', 'R07000', 77, 94, 'HMG-CoA reductase')] ['We', 'went', 'on', 'to', 'determine', 'the', 'amounts', 'of', 'full', '-', 'length', 'and', 'alternatively', 'splice', '##d', 'HM', '##G', '-', 'Co', '##A', 'reductase', '(', 'Δ', '##ex', '##on', '##13', ')', 'mRNA', 'separately', '.'] [0, 3, 8, 11, 14, 24, 28, 36, 39, 43, 44, 51, 55, 69, 75, 77, 79, 80, 81, 83, 85, 95, 96, 97, 99, 101, 103, 105, 110, 120] [2, 7, 10, 13, 23, 27, 35, 38, 43, 44, 50, 54, 68, 75, 76, 79, 80, 81, 83, 84, 94, 96, 97, 99, 101, 103, 104, 109, 120, 121] ['We', 'went', 'on', 'to', 'determine', 'the', 'amounts', 'of', 'full', '-', 'length', 'and', 'alternatively', 'spliced', 'HMG-CoA', 'reductase', '(', 'Δexon13', ')', 'mRNA', 'separately', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 5, 1, 1, 4, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Δexon13 HMG-CoA reductase mRNA was detectable in all samples and showed significant variation along the time course (Fig.2B). [('PMC2764366', 'R07001', 8, 25, 'HMG-CoA reductase')] ['Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'was', 'detectable', 'in', 'all', 'samples', 'and', 'showed', 'significant', 'variation', 'along', 'the', 'time', 'course', '(', 'Fig', '.', '2', '##B', ')', '.'] [0, 1, 3, 5, 8, 10, 11, 12, 14, 16, 26, 31, 35, 46, 49, 53, 61, 65, 72, 84, 94, 100, 104, 109, 116, 117, 120, 121, 122, 123, 124] [1, 3, 5, 7, 10, 11, 12, 14, 15, 25, 30, 34, 45, 48, 52, 60, 64, 71, 83, 93, 99, 103, 108, 115, 117, 120, 121, 122, 123, 124, 125] ['Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'was', 'detectable', 'in', 'all', 'samples', 'and', 'showed', 'significant', 'variation', 'along', 'the', 'time', 'course', '(', 'Fig.2B', ')', '.'] [4, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We observed a distinct decrease in the percentage of Δexon13 HMG-CoA reductase mRNA in both genotype groups over the first 10h. [('PMC2764366', 'R07002', 61, 78, 'HMG-CoA reductase')] ['We', 'observed', 'a', 'distinct', 'decrease', 'in', 'the', 'percentage', 'of', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'in', 'both', 'genotype', 'groups', 'over', 'the', 'first', '10', '##h', '.'] [0, 3, 12, 14, 23, 32, 35, 39, 50, 53, 54, 56, 58, 61, 63, 64, 65, 67, 69, 79, 84, 87, 92, 101, 108, 113, 117, 123, 125, 126] [2, 11, 13, 22, 31, 34, 38, 49, 52, 54, 56, 58, 60, 63, 64, 65, 67, 68, 78, 83, 86, 91, 100, 107, 112, 116, 122, 125, 126, 127] ['We', 'observed', 'a', 'distinct', 'decrease', 'in', 'the', 'percentage', 'of', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'in', 'both', 'genotype', 'groups', 'over', 'the', 'first', '10h', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
However, the decrease in percentage of Δexon13 HMG-CoA reductase mRNA was significantly less pronounced in LCLs from homozygotes for the rs3846662 major allele. [('PMC2764366', 'R07003', 47, 64, 'HMG-CoA reductase')] ['However', ',', 'the', 'decrease', 'in', 'percentage', 'of', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'was', 'significantly', 'less', 'pronounced', 'in', 'LC', '##Ls', 'from', 'hom', '##ozyg', '##otes', 'for', 'the', 'rs', '##38', '##46', '##66', '##2', 'major', 'allele', '.'] [0, 7, 9, 13, 22, 25, 36, 39, 40, 42, 44, 47, 49, 50, 51, 53, 55, 65, 70, 74, 88, 93, 104, 107, 109, 112, 117, 120, 124, 129, 133, 137, 139, 141, 143, 145, 147, 153, 159] [7, 8, 12, 21, 24, 35, 38, 40, 42, 44, 46, 49, 50, 51, 53, 54, 64, 69, 73, 87, 92, 103, 106, 109, 111, 116, 120, 124, 128, 132, 136, 139, 141, 143, 145, 146, 152, 159, 160] ['However', ',', 'the', 'decrease', 'in', 'percentage', 'of', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'was', 'significantly', 'less', 'pronounced', 'in', 'LCLs', 'from', 'homozygotes', 'for', 'the', 'rs3846662', 'major', 'allele', '.'] [1, 1, 1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 5, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Hence, the percentage of Δexon13 HMG-CoA reductase mRNA per total HMG-CoA reductase mRNA was significantly higher in homozygotes for the major allele as compared to homozygotes for the minor allele at 10h, 24h and 48h (10h: 23.0±7.6 vs. 10.4±3.4, 24h: 23.1±7.9 vs. 11.6±3.8, 48h: 27.1±9.4 vs. 15.7±9.1, % Δexon13/total HMGCR mRNA, major vs. minor allele, Fig.2B). [('PMC2764366', 'R07004', 33, 50, 'HMG-CoA reductase'), ('PMC2764366', 'R07004', 66, 83, 'HMG-CoA reductase')] ['Hence', ',', 'the', 'percentage', 'of', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'per', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'was', 'significantly', 'higher', 'in', 'hom', '##ozyg', '##otes', 'for', 'the', 'major', 'allele', 'as', 'compared', 'to', 'hom', '##ozyg', '##otes', 'for', 'the', 'minor', 'allele', 'at', '10', '##h', ',', '24', '##h', 'and', '48', '##h', '(', '10', '##h', ':', '23', '.', '0', '##±', '##7', '.', '6', 'vs', '.', '10', '.', '4', '##±', '##3', '.', '4', ',', '24', '##h', ':', '23', '.', '1', '##±', '##7', '.', '9', 'vs', '.', '11', '.', '6', '##±', '##3', '.', '8', ',', '48', '##h', ':', '27', '.', '1', '##±', '##9', '.', '4', 'vs', '.', '15', '.', '7', '##±', '##9', '.', '1', ',', '%', 'Δ', '##ex', '##on', '##13', '/', 'total', 'HM', '##GC', '##R', 'mRNA', ',', 'major', 'vs', '.', 'minor', 'allele', ',', 'Fig', '.', '2', '##B', ')', '.'] [0, 5, 7, 11, 22, 25, 26, 28, 30, 33, 35, 36, 37, 39, 41, 51, 56, 60, 66, 68, 69, 70, 72, 74, 84, 89, 93, 107, 114, 117, 120, 124, 129, 133, 137, 143, 150, 153, 162, 165, 168, 172, 177, 181, 185, 191, 198, 201, 203, 204, 206, 208, 210, 214, 216, 218, 219, 221, 222, 224, 226, 227, 228, 229, 230, 231, 233, 235, 237, 239, 240, 241, 242, 243, 244, 245, 247, 249, 250, 252, 254, 255, 256, 257, 258, 259, 261, 263, 265, 267, 268, 269, 270, 271, 272, 273, 275, 277, 278, 280, 282, 283, 284, 285, 286, 287, 289, 291, 293, 295, 296, 297, 298, 299, 300, 301, 303, 305, 306, 308, 310, 312, 313, 319, 321, 323, 325, 329, 331, 337, 339, 341, 347, 353, 355, 358, 359, 360, 361, 362] [5, 6, 10, 21, 24, 26, 28, 30, 32, 35, 36, 37, 39, 40, 50, 55, 59, 65, 68, 69, 70, 72, 73, 83, 88, 92, 106, 113, 116, 120, 124, 128, 132, 136, 142, 149, 152, 161, 164, 168, 172, 176, 180, 184, 190, 197, 200, 203, 204, 205, 208, 209, 213, 216, 217, 219, 221, 222, 223, 226, 227, 228, 229, 230, 231, 232, 235, 236, 239, 240, 241, 242, 243, 244, 245, 246, 249, 250, 251, 254, 255, 256, 257, 258, 259, 260, 263, 264, 267, 268, 269, 270, 271, 272, 273, 274, 277, 278, 279, 282, 283, 284, 285, 286, 287, 288, 291, 292, 295, 296, 297, 298, 299, 300, 301, 302, 304, 306, 308, 310, 312, 313, 318, 321, 323, 324, 329, 330, 336, 339, 340, 346, 353, 354, 358, 359, 360, 361, 362, 363] ['Hence', ',', 'the', 'percentage', 'of', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'per', 'total', 'HMG-CoA', 'reductase', 'mRNA', 'was', 'significantly', 'higher', 'in', 'homozygotes', 'for', 'the', 'major', 'allele', 'as', 'compared', 'to', 'homozygotes', 'for', 'the', 'minor', 'allele', 'at', '10h', ',', '24h', 'and', '48h', '(', '10h', ':', '23.0±7.6', 'vs', '.', '10.4±3.4', ',', '24h', ':', '23.1±7.9', 'vs', '.', '11.6±3.8', ',', '48h', ':', '27.1±9.4', 'vs', '.', '15.7±9.1', ',', '%', 'Δexon13', '/', 'total', 'HMGCR', 'mRNA', ',', 'major', 'vs', '.', 'minor', 'allele', ',', 'Fig.2B', ')', '.'] [1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 2, 1, 2, 1, 2, 1, 2, 1, 7, 1, 1, 7, 1, 2, 1, 7, 1, 1, 7, 1, 2, 1, 7, 1, 1, 7, 1, 1, 4, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We next quantified the expression levels of both HMG-CoA reductase transcripts in vivo, using cDNA samples from various human tissues. [('PMC2764366', 'R09000', 49, 66, 'HMG-CoA reductase')] ['We', 'next', 'quantified', 'the', 'expression', 'levels', 'of', 'both', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'transcripts', 'in', 'vivo', ',', 'using', 'cDNA', 'samples', 'from', 'various', 'human', 'tissues', '.'] [0, 3, 8, 19, 23, 34, 41, 44, 49, 51, 52, 53, 55, 57, 67, 79, 82, 86, 88, 94, 99, 107, 112, 120, 126, 133] [2, 7, 18, 22, 33, 40, 43, 48, 51, 52, 53, 55, 56, 66, 78, 81, 86, 87, 93, 98, 106, 111, 119, 125, 133, 134] ['We', 'next', 'quantified', 'the', 'expression', 'levels', 'of', 'both', 'HMG-CoA', 'reductase', 'transcripts', 'in', 'vivo', ',', 'using', 'cDNA', 'samples', 'from', 'various', 'human', 'tissues', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The percentage of Δexon13 HMG-CoA reductase mRNA per total HMG-CoA reductase mRNA varied between 7 and 18%, with the exception of peripheral blood leukocytes. [('PMC2764366', 'R09002', 26, 43, 'HMG-CoA reductase'), ('PMC2764366', 'R09002', 59, 76, 'HMG-CoA reductase')] ['The', 'percentage', 'of', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'per', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'varied', 'between', '7', 'and', '18', '%', ',', 'with', 'the', 'exception', 'of', 'peripheral', 'blood', 'leukocytes', '.'] [0, 4, 15, 18, 19, 21, 23, 26, 28, 29, 30, 32, 34, 44, 49, 53, 59, 61, 62, 63, 65, 67, 77, 82, 89, 97, 99, 103, 105, 106, 108, 113, 117, 127, 130, 141, 147, 157] [3, 14, 17, 19, 21, 23, 25, 28, 29, 30, 32, 33, 43, 48, 52, 58, 61, 62, 63, 65, 66, 76, 81, 88, 96, 98, 102, 105, 106, 107, 112, 116, 126, 129, 140, 146, 157, 158] ['The', 'percentage', 'of', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'per', 'total', 'HMG-CoA', 'reductase', 'mRNA', 'varied', 'between', '7', 'and', '18%', ',', 'with', 'the', 'exception', 'of', 'peripheral', 'blood', 'leukocytes', '.'] [1, 1, 1, 4, 5, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In peripheral blood leukocytes, Δexon13 HMG-CoA reductase mRNA accounted for 79% of total HMG-CoA reductase mRNA transcripts (Fig.3). [('PMC2764366', 'R09003', 40, 57, 'HMG-CoA reductase'), ('PMC2764366', 'R09003', 90, 107, 'HMG-CoA reductase')] ['In', 'peripheral', 'blood', 'leukocytes', ',', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'accounted', 'for', '79', '%', 'of', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'transcripts', '(', 'Fig', '.', '3', ')', '.'] [0, 3, 14, 20, 30, 32, 33, 35, 37, 40, 42, 43, 44, 46, 48, 58, 63, 73, 77, 79, 81, 84, 90, 92, 93, 94, 96, 98, 108, 113, 125, 126, 129, 130, 131, 132] [2, 13, 19, 30, 31, 33, 35, 37, 39, 42, 43, 44, 46, 47, 57, 62, 72, 76, 79, 80, 83, 89, 92, 93, 94, 96, 97, 107, 112, 124, 126, 129, 130, 131, 132, 133] ['In', 'peripheral', 'blood', 'leukocytes', ',', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'accounted', 'for', '79%', 'of', 'total', 'HMG-CoA', 'reductase', 'mRNA', 'transcripts', '(', 'Fig.3', ')', '.'] [1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 2, 1, 1, 5, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Our studies in LCLs demonstrated that the amount of Δexon13 HMG-CoA reductase mRNA was associated with allele status at SNP rs3846662. [('PMC2764366', 'R10000', 60, 77, 'HMG-CoA reductase')] ['Our', 'studies', 'in', 'LC', '##Ls', 'demonstrated', 'that', 'the', 'amount', 'of', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'was', 'associated', 'with', 'allele', 'status', 'at', 'SNP', 'rs', '##38', '##46', '##66', '##2', '.'] [0, 4, 12, 15, 17, 20, 33, 38, 42, 49, 52, 53, 55, 57, 60, 62, 63, 64, 66, 68, 78, 83, 87, 98, 103, 110, 117, 120, 124, 126, 128, 130, 132, 133] [3, 11, 14, 17, 19, 32, 37, 41, 48, 51, 53, 55, 57, 59, 62, 63, 64, 66, 67, 77, 82, 86, 97, 102, 109, 116, 119, 123, 126, 128, 130, 132, 133, 134] ['Our', 'studies', 'in', 'LCLs', 'demonstrated', 'that', 'the', 'amount', 'of', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'was', 'associated', 'with', 'allele', 'status', 'at', 'SNP', 'rs3846662', '.'] [1, 1, 1, 2, 1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We created exon-trapping vectors containing the genomic DNA sequence of HMG-CoA reductase from intron12 to intron14 of rs3846662/AA (major allele) and rs3846662/GG (minor allele) individuals, respectively and transfected them into HEK293 cells. [('PMC2764366', 'R10002', 72, 89, 'HMG-CoA reductase')] ['We', 'created', 'exon', '-', 'trapping', 'vectors', 'containing', 'the', 'genomic', 'DNA', 'sequence', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'from', 'intron', '##12', 'to', 'intron', '##14', 'of', 'rs', '##38', '##46', '##66', '##2', '/', 'AA', '(', 'major', 'allele', ')', 'and', 'rs', '##38', '##46', '##66', '##2', '/', 'GG', '(', 'minor', 'allele', ')', 'individuals', ',', 'respectively', 'and', 'transfected', 'them', 'into', 'HEK', '##293', 'cells', '.'] [0, 3, 11, 15, 16, 25, 33, 44, 48, 56, 60, 69, 72, 74, 75, 76, 78, 80, 90, 95, 101, 104, 107, 113, 116, 119, 121, 123, 125, 127, 128, 129, 132, 133, 139, 145, 147, 151, 153, 155, 157, 159, 160, 161, 164, 165, 171, 177, 179, 190, 192, 205, 209, 221, 226, 231, 234, 238, 243] [2, 10, 15, 16, 24, 32, 43, 47, 55, 59, 68, 71, 74, 75, 76, 78, 79, 89, 94, 101, 103, 106, 113, 115, 118, 121, 123, 125, 127, 128, 129, 131, 133, 138, 145, 146, 150, 153, 155, 157, 159, 160, 161, 163, 165, 170, 177, 178, 190, 191, 204, 208, 220, 225, 230, 234, 237, 243, 244] ['We', 'created', 'exon', '-', 'trapping', 'vectors', 'containing', 'the', 'genomic', 'DNA', 'sequence', 'of', 'HMG-CoA', 'reductase', 'from', 'intron12', 'to', 'intron14', 'of', 'rs3846662', '/', 'AA', '(', 'major', 'allele', ')', 'and', 'rs3846662', '/', 'GG', '(', 'minor', 'allele', ')', 'individuals', ',', 'respectively', 'and', 'transfected', 'them', 'into', 'HEK293', 'cells', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 2, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In accordance with our previous results in human LCLs, we found significantly lower levels for Δexon13 HMG-CoA reductase mRNA in cells transfected with the minor allele minigene (rs3846662/G) as compared to cells transfected with the major allele minigene (rs3846662/A) (Fig.4). [('PMC2764366', 'R11000', 103, 120, 'HMG-CoA reductase')] ['In', 'accordance', 'with', 'our', 'previous', 'results', 'in', 'human', 'LC', '##Ls', ',', 'we', 'found', 'significantly', 'lower', 'levels', 'for', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'in', 'cells', 'transfected', 'with', 'the', 'minor', 'allele', 'mini', '##gene', '(', 'rs', '##38', '##46', '##66', '##2', '/', 'G', ')', 'as', 'compared', 'to', 'cells', 'transfected', 'with', 'the', 'major', 'allele', 'mini', '##gene', '(', 'rs', '##38', '##46', '##66', '##2', '/', 'A', ')', '(', 'Fig', '.', '4', ')', '.'] [0, 3, 14, 19, 23, 32, 40, 43, 49, 51, 53, 55, 58, 64, 78, 84, 91, 95, 96, 98, 100, 103, 105, 106, 107, 109, 111, 121, 126, 129, 135, 147, 152, 156, 162, 169, 173, 178, 179, 181, 183, 185, 187, 188, 189, 190, 192, 195, 204, 207, 213, 225, 230, 234, 240, 247, 251, 256, 257, 259, 261, 263, 265, 266, 267, 268, 270, 271, 274, 275, 276, 277] [2, 13, 18, 22, 31, 39, 42, 48, 51, 53, 54, 57, 63, 77, 83, 90, 94, 96, 98, 100, 102, 105, 106, 107, 109, 110, 120, 125, 128, 134, 146, 151, 155, 161, 168, 173, 177, 179, 181, 183, 185, 187, 188, 189, 190, 191, 194, 203, 206, 212, 224, 229, 233, 239, 246, 251, 255, 257, 259, 261, 263, 265, 266, 267, 268, 269, 271, 274, 275, 276, 277, 278] ['In', 'accordance', 'with', 'our', 'previous', 'results', 'in', 'human', 'LCLs', ',', 'we', 'found', 'significantly', 'lower', 'levels', 'for', 'Δexon13', 'HMG-CoA', 'reductase', 'mRNA', 'in', 'cells', 'transfected', 'with', 'the', 'minor', 'allele', 'minigene', '(', 'rs3846662', '/', 'G', ')', 'as', 'compared', 'to', 'cells', 'transfected', 'with', 'the', 'major', 'allele', 'minigene', '(', 'rs3846662', '/', 'A', ')', '(', 'Fig.4', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The difference in exon13 splicing efficiency between the two minigenes was 20.8% (42.9±3.9 vs. 63.7±1.0 %Δexon13 HMG-CoA reductase mRNA/total HMG-CoA reductase mRNA, p=0.02). [('PMC2764366', 'R11001', 113, 130, 'HMG-CoA reductase'), ('PMC2764366', 'R11001', 142, 159, 'HMG-CoA reductase')] ['The', 'difference', 'in', 'exon', '##13', 'splicing', 'efficiency', 'between', 'the', 'two', 'mini', '##genes', 'was', '20', '.', '8', '%', '(', '42', '.', '9', '##±', '##3', '.', '9', 'vs', '.', '63', '.', '7', '##±1', '.', '0', '%', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', '/', 'total', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', ',', 'p', '=', '0', '.', '02', ')', '.'] [0, 4, 15, 18, 22, 25, 34, 45, 53, 57, 61, 65, 71, 75, 77, 78, 79, 81, 82, 84, 85, 86, 87, 88, 89, 91, 93, 95, 97, 98, 99, 101, 102, 104, 105, 106, 108, 110, 113, 115, 116, 117, 119, 121, 131, 135, 136, 142, 144, 145, 146, 148, 150, 160, 164, 166, 167, 168, 169, 170, 172, 173] [3, 14, 17, 22, 24, 33, 44, 52, 56, 60, 65, 70, 74, 77, 78, 79, 80, 82, 84, 85, 86, 87, 88, 89, 90, 93, 94, 97, 98, 99, 101, 102, 103, 105, 106, 108, 110, 112, 115, 116, 117, 119, 120, 130, 135, 136, 141, 144, 145, 146, 148, 149, 159, 164, 165, 167, 168, 169, 170, 172, 173, 174] ['The', 'difference', 'in', 'exon13', 'splicing', 'efficiency', 'between', 'the', 'two', 'minigenes', 'was', '20.8%', '(', '42.9±3.9', 'vs', '.', '63.7±1.0', '%Δexon13', 'HMG-CoA', 'reductase', 'mRNA', '/', 'total', 'HMG-CoA', 'reductase', 'mRNA', ',', 'p=0.02', ')', '.'] [1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 4, 1, 7, 1, 1, 6, 5, 5, 1, 1, 1, 1, 5, 1, 1, 1, 5, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
This difference in splicing efficiency was abolished when we transfected a construct in which we had used site directed mutagenesis to convert rs3846662/A to the minor G allele (Fig.4), further corroborating that allelic variants at rs3846662 directly modulate the efficiency of HMG-CoA reductase exon13 splicing. [('PMC2764366', 'R11002', 279, 296, 'HMG-CoA reductase')] ['This', 'difference', 'in', 'splicing', 'efficiency', 'was', 'abolished', 'when', 'we', 'transfected', 'a', 'construct', 'in', 'which', 'we', 'had', 'used', 'site', 'directed', 'mutagenesis', 'to', 'convert', 'rs', '##38', '##46', '##66', '##2', '/', 'A', 'to', 'the', 'minor', 'G', 'allele', '(', 'Fig', '.', '4', ')', ',', 'further', 'corrobor', '##ating', 'that', 'allelic', 'variants', 'at', 'rs', '##38', '##46', '##66', '##2', 'directly', 'modulate', 'the', 'efficiency', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'exon', '##13', 'splicing', '.'] [0, 5, 16, 19, 28, 39, 43, 53, 58, 61, 73, 75, 85, 88, 94, 97, 101, 106, 111, 120, 132, 135, 143, 145, 147, 149, 151, 152, 153, 155, 158, 162, 168, 170, 177, 178, 181, 182, 183, 184, 186, 194, 202, 208, 213, 221, 230, 233, 235, 237, 239, 241, 243, 252, 261, 265, 276, 279, 281, 282, 283, 285, 287, 297, 301, 304, 312] [4, 15, 18, 27, 38, 42, 52, 57, 60, 72, 74, 84, 87, 93, 96, 100, 105, 110, 119, 131, 134, 142, 145, 147, 149, 151, 152, 153, 154, 157, 161, 167, 169, 176, 178, 181, 182, 183, 184, 185, 193, 202, 207, 212, 220, 229, 232, 235, 237, 239, 241, 242, 251, 260, 264, 275, 278, 281, 282, 283, 285, 286, 296, 301, 303, 312, 313] ['This', 'difference', 'in', 'splicing', 'efficiency', 'was', 'abolished', 'when', 'we', 'transfected', 'a', 'construct', 'in', 'which', 'we', 'had', 'used', 'site', 'directed', 'mutagenesis', 'to', 'convert', 'rs3846662', '/', 'A', 'to', 'the', 'minor', 'G', 'allele', '(', 'Fig.4', ')', ',', 'further', 'corroborating', 'that', 'allelic', 'variants', 'at', 'rs3846662', 'directly', 'modulate', 'the', 'efficiency', 'of', 'HMG-CoA', 'reductase', 'exon13', 'splicing', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 5, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O']
Alternative splicing of HMG-CoA reductase mRNA leads to an in-frame deletion of 53 amino acids in the catalytic domain of the protein. [('PMC2764366', 'R12000', 24, 41, 'HMG-CoA reductase')] ['Alternative', 'splicing', 'of', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'mRNA', 'leads', 'to', 'an', 'in', '-', 'frame', 'deletion', 'of', '53', 'amino', 'acids', 'in', 'the', 'catalytic', 'domain', 'of', 'the', 'protein', '.'] [0, 12, 21, 24, 26, 27, 28, 30, 32, 42, 47, 53, 56, 59, 61, 62, 68, 77, 80, 83, 89, 95, 98, 102, 112, 119, 122, 126, 133] [11, 20, 23, 26, 27, 28, 30, 31, 41, 46, 52, 55, 58, 61, 62, 67, 76, 79, 82, 88, 94, 97, 101, 111, 118, 121, 125, 133, 134] ['Alternative', 'splicing', 'of', 'HMG-CoA', 'reductase', 'mRNA', 'leads', 'to', 'an', 'in', '-', 'frame', 'deletion', 'of', '53', 'amino', 'acids', 'in', 'the', 'catalytic', 'domain', 'of', 'the', 'protein', '.'] [1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To investigate the effect of this deletion on enzyme activity, we stably expressed human full-length (UT-2+FL) and Δexon13 (UT-2+ex13) HMG-CoA reductase variants at comparable levels in UT-2 cells (Fig.5A), a CHO cell-line that lacks HMG-CoA reductase activity and requires exogenous mevalonate for growth 16. [('PMC2764366', 'R12001', 135, 152, 'HMG-CoA reductase'), ('PMC2764366', 'R12001', 234, 251, 'HMG-CoA reductase')] ['To', 'investigate', 'the', 'effect', 'of', 'this', 'deletion', 'on', 'enzyme', 'activity', ',', 'we', 'stably', 'expressed', 'human', 'full', '-', 'length', '(', 'UT', '-', '2', '+', 'FL', ')', 'and', 'Δ', '##ex', '##on', '##13', '(', 'UT', '-', '2', '+', 'ex', '##13', ')', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'variants', 'at', 'comparable', 'levels', 'in', 'UT', '-', '2', 'cells', '(', 'Fig', '.', '5', '##A', ')', ',', 'a', 'CHO', 'cell', '-', 'line', 'that', 'lacks', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'activity', 'and', 'requires', 'exogenous', 'me', '##val', '##onate', 'for', 'growth', '16', '.'] [0, 3, 15, 19, 26, 29, 34, 43, 46, 53, 61, 63, 66, 73, 83, 89, 93, 94, 101, 102, 104, 105, 106, 107, 109, 111, 115, 116, 118, 120, 123, 124, 126, 127, 128, 129, 131, 133, 135, 137, 138, 139, 141, 143, 153, 162, 165, 176, 183, 186, 188, 189, 191, 197, 198, 201, 202, 203, 204, 205, 207, 209, 213, 217, 218, 223, 228, 234, 236, 237, 238, 240, 242, 252, 261, 265, 274, 284, 286, 289, 295, 299, 306, 308] [2, 14, 18, 25, 28, 33, 42, 45, 52, 61, 62, 65, 72, 82, 88, 93, 94, 100, 102, 104, 105, 106, 107, 109, 110, 114, 116, 118, 120, 122, 124, 126, 127, 128, 129, 131, 133, 134, 137, 138, 139, 141, 142, 152, 161, 164, 175, 182, 185, 188, 189, 190, 196, 198, 201, 202, 203, 204, 205, 206, 208, 212, 217, 218, 222, 227, 233, 236, 237, 238, 240, 241, 251, 260, 264, 273, 283, 286, 289, 294, 298, 305, 308, 309] ['To', 'investigate', 'the', 'effect', 'of', 'this', 'deletion', 'on', 'enzyme', 'activity', ',', 'we', 'stably', 'expressed', 'human', 'full', '-', 'length', '(', 'UT-2', '+', 'FL', ')', 'and', 'Δexon13', '(', 'UT-2', '+', 'ex13', ')', 'HMG-CoA', 'reductase', 'variants', 'at', 'comparable', 'levels', 'in', 'UT-2', 'cells', '(', 'Fig.5A', ')', ',', 'a', 'CHO', 'cell', '-', 'line', 'that', 'lacks', 'HMG-CoA', 'reductase', 'activity', 'and', 'requires', 'exogenous', 'mevalonate', 'for', 'growth', '16', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 4, 1, 3, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1, 3, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
UT-2+FL cells displayed 51% HMG-CoA reductase enzyme activity of wild-type CHO cells, whereas UT-2+ex13 cells lacked enzyme activity and were indistinguishable from control UT-2 cells (Fig.5B). [('PMC2764366', 'R12002', 28, 45, 'HMG-CoA reductase')] ['UT', '-', '2', '+', 'FL', 'cells', 'displayed', '51', '%', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'enzyme', 'activity', 'of', 'wild', '-', 'type', 'CHO', 'cells', ',', 'whereas', 'UT', '-', '2', '+', 'ex', '##13', 'cells', 'lacked', 'enzyme', 'activity', 'and', 'were', 'indistinguish', '##able', 'from', 'control', 'UT', '-', '2', 'cells', '(', 'Fig', '.', '5', '##B', ')', '.'] [0, 2, 3, 4, 5, 8, 14, 24, 26, 28, 30, 31, 32, 34, 36, 46, 53, 62, 65, 69, 70, 75, 79, 84, 86, 94, 96, 97, 98, 99, 101, 104, 110, 117, 124, 133, 137, 142, 155, 160, 165, 173, 175, 176, 178, 184, 185, 188, 189, 190, 191, 192] [2, 3, 4, 5, 7, 13, 23, 26, 27, 30, 31, 32, 34, 35, 45, 52, 61, 64, 69, 70, 74, 78, 84, 85, 93, 96, 97, 98, 99, 101, 103, 109, 116, 123, 132, 136, 141, 155, 159, 164, 172, 175, 176, 177, 183, 185, 188, 189, 190, 191, 192, 193] ['UT-2', '+', 'FL', 'cells', 'displayed', '51%', 'HMG-CoA', 'reductase', 'enzyme', 'activity', 'of', 'wild', '-', 'type', 'CHO', 'cells', ',', 'whereas', 'UT-2', '+', 'ex13', 'cells', 'lacked', 'enzyme', 'activity', 'and', 'were', 'indistinguishable', 'from', 'control', 'UT-2', 'cells', '(', 'Fig.5B', ')', '.'] [3, 1, 1, 1, 1, 2, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 3, 1, 1, 4, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Further, UT-2+FL cells grew in the absence of mevalonate, whereas UT-2+ex13 and parental UT-2 cells died without mevalonate supplementation (Fig.5C), suggesting that the Δexon13 HMG-CoA reductase variant is unable to restore enzyme activity in these cells. [('PMC2764366', 'R12003', 178, 195, 'HMG-CoA reductase')] ['Further', ',', 'UT', '-', '2', '+', 'FL', 'cells', 'grew', 'in', 'the', 'absence', 'of', 'me', '##val', '##onate', ',', 'whereas', 'UT', '-', '2', '+', 'ex', '##13', 'and', 'parental', 'UT', '-', '2', 'cells', 'died', 'without', 'me', '##val', '##onate', 'supplementation', '(', 'Fig', '.', '5', '##C', ')', ',', 'suggesting', 'that', 'the', 'Δ', '##ex', '##on', '##13', 'HM', '##G', '-', 'Co', '##A', 'reductase', 'variant', 'is', 'unable', 'to', 'restore', 'enzyme', 'activity', 'in', 'these', 'cells', '.'] [0, 7, 9, 11, 12, 13, 14, 17, 23, 28, 31, 35, 43, 46, 48, 51, 56, 58, 66, 68, 69, 70, 71, 73, 76, 80, 89, 91, 92, 94, 100, 105, 113, 115, 118, 124, 140, 141, 144, 145, 146, 147, 148, 150, 161, 166, 170, 171, 173, 175, 178, 180, 181, 182, 184, 186, 196, 204, 207, 214, 217, 225, 232, 241, 244, 250, 255] [7, 8, 11, 12, 13, 14, 16, 22, 27, 30, 34, 42, 45, 48, 51, 56, 57, 65, 68, 69, 70, 71, 73, 75, 79, 88, 91, 92, 93, 99, 104, 112, 115, 118, 123, 139, 141, 144, 145, 146, 147, 148, 149, 160, 165, 169, 171, 173, 175, 177, 180, 181, 182, 184, 185, 195, 203, 206, 213, 216, 224, 231, 240, 243, 249, 255, 256] ['Further', ',', 'UT-2', '+', 'FL', 'cells', 'grew', 'in', 'the', 'absence', 'of', 'mevalonate', ',', 'whereas', 'UT-2', '+', 'ex13', 'and', 'parental', 'UT-2', 'cells', 'died', 'without', 'mevalonate', 'supplementation', '(', 'Fig.5C', ')', ',', 'suggesting', 'that', 'the', 'Δexon13', 'HMG-CoA', 'reductase', 'variant', 'is', 'unable', 'to', 'restore', 'enzyme', 'activity', 'in', 'these', 'cells', '.'] [1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 2, 1, 1, 3, 1, 1, 1, 3, 1, 1, 4, 1, 1, 1, 1, 1, 4, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
A generic primer that recognizes the ligated adapter sequence was used to amplify the ligation products in a polymerase chain reaction. [('PMC2900891', 'M04004', 109, 119, 'polymerase')] ['A', 'generic', 'primer', 'that', 'recognizes', 'the', 'ligated', 'adapt', '##er', 'sequence', 'was', 'used', 'to', 'amplify', 'the', 'ligation', 'products', 'in', 'a', 'polymerase', 'chain', 'reaction', '.'] [0, 2, 10, 17, 22, 33, 37, 45, 50, 53, 62, 66, 71, 74, 82, 86, 95, 104, 107, 109, 120, 126, 134] [1, 9, 16, 21, 32, 36, 44, 50, 52, 61, 65, 70, 73, 81, 85, 94, 103, 106, 108, 119, 125, 134, 135] ['A', 'generic', 'primer', 'that', 'recognizes', 'the', 'ligated', 'adapter', 'sequence', 'was', 'used', 'to', 'amplify', 'the', 'ligation', 'products', 'in', 'a', 'polymerase', 'chain', 'reaction', '.'] [1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O']
Ninety micrograms of purified DNA was fragmented with DNaseI and visualized on a 4% agarose gel. [('PMC2900891', 'M04007', 54, 60, 'DNaseI')] ['Nine', '##ty', 'micro', '##grams', 'of', 'purified', 'DNA', 'was', 'fragmented', 'with', 'DNase', '##I', 'and', 'visualized', 'on', 'a', '4', '%', 'agarose', 'gel', '.'] [0, 4, 7, 12, 18, 21, 30, 34, 38, 49, 54, 59, 61, 65, 76, 79, 81, 82, 84, 92, 95] [4, 6, 12, 17, 20, 29, 33, 37, 48, 53, 59, 60, 64, 75, 78, 80, 82, 83, 91, 95, 96] ['Ninety', 'micrograms', 'of', 'purified', 'DNA', 'was', 'fragmented', 'with', 'DNaseI', 'and', 'visualized', 'on', 'a', '4%', 'agarose', 'gel', '.'] [2, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The top signal of association for BMI was observed for SNP rs7001819 (P = 1.53 × 10−7), and the nearest gene is FDFT1 (farnesyl-diphosphate farnesyltransferase 1). [('PMC2900891', 'R00000', 119, 161, 'farnesyl-diphosphate farnesyltransferase 1')] ['The', 'top', 'signal', 'of', 'association', 'for', 'BMI', 'was', 'observed', 'for', 'SNP', 'rs', '##700', '##18', '##19', '(', 'P', '=', '1', '.', '53', '×', '10−', '##7', ')', ',', 'and', 'the', 'nearest', 'gene', 'is', 'FD', '##FT', '##1', '(', 'far', '##nes', '##yl', '-', 'diph', '##osphate', 'far', '##nes', '##yl', '##transferase', '1', ')', '.'] [0, 4, 8, 15, 18, 30, 34, 38, 42, 51, 55, 59, 61, 64, 66, 69, 70, 72, 74, 75, 76, 79, 81, 84, 85, 86, 88, 92, 96, 104, 109, 112, 114, 116, 118, 119, 122, 125, 127, 128, 132, 140, 143, 146, 148, 160, 161, 162] [3, 7, 14, 17, 29, 33, 37, 41, 50, 54, 58, 61, 64, 66, 68, 70, 71, 73, 75, 76, 78, 80, 84, 85, 86, 87, 91, 95, 103, 108, 111, 114, 116, 117, 119, 122, 125, 127, 128, 132, 139, 143, 146, 148, 159, 161, 162, 163] ['The', 'top', 'signal', 'of', 'association', 'for', 'BMI', 'was', 'observed', 'for', 'SNP', 'rs7001819', '(', 'P', '=', '1.53', '×', '10−7', ')', ',', 'and', 'the', 'nearest', 'gene', 'is', 'FDFT1', '(', 'farnesyl', '-', 'diphosphate', 'farnesyltransferase', '1', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 2, 4, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. [('PMC2923020', 'F21002', 18, 38, 'phosphodiesterase 4D')] ['The', 'gene', 'encoding', 'phospho', '##die', '##ster', '##ase', '4', '##D', 'confers', 'risk', 'of', 'ischemic', 'stroke', '.'] [0, 4, 9, 18, 25, 28, 32, 36, 37, 39, 47, 52, 55, 64, 70] [3, 8, 17, 25, 28, 32, 35, 37, 38, 46, 51, 54, 63, 70, 71] ['The', 'gene', 'encoding', 'phosphodiesterase', '4D', 'confers', 'risk', 'of', 'ischemic', 'stroke', '.'] [1, 1, 1, 4, 2, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
PCR products were checked for quality and yield by agarose gel electrophoresis and the remainder of the PCR products were treated with 3 units of shrimp alkaline phosphatase and 2 units of exonuclease I. SNaPshot analysis was performed using an Applied Biosystems SNaPshot Multiplex Kit. [('PMC2923020', 'M07003', 153, 173, 'alkaline phosphatase'), ('PMC2923020', 'M07003', 189, 202, 'exonuclease I')] ['PCR', 'products', 'were', 'checked', 'for', 'quality', 'and', 'yield', 'by', 'agarose', 'gel', 'electrophoresis', 'and', 'the', 'remainder', 'of', 'the', 'PCR', 'products', 'were', 'treated', 'with', '3', 'units', 'of', 'shr', '##imp', 'alkaline', 'phosphatase', 'and', '2', 'units', 'of', 'exon', '##ucle', '##ase', 'I', '.', 'SN', '##a', '##Ps', '##hot', 'analysis', 'was', 'performed', 'using', 'an', 'Applied', 'Biosystems', 'SN', '##a', '##Ps', '##hot', 'Multiple', '##x', 'Kit', '.'] [0, 4, 13, 18, 26, 30, 38, 42, 48, 51, 59, 63, 79, 83, 87, 97, 100, 104, 108, 117, 122, 130, 135, 137, 143, 146, 149, 153, 162, 174, 178, 180, 186, 189, 193, 197, 201, 202, 204, 206, 207, 209, 213, 222, 226, 236, 242, 245, 253, 264, 266, 267, 269, 273, 281, 283, 286] [3, 12, 17, 25, 29, 37, 41, 47, 50, 58, 62, 78, 82, 86, 96, 99, 103, 107, 116, 121, 129, 134, 136, 142, 145, 149, 152, 161, 173, 177, 179, 185, 188, 193, 197, 200, 202, 203, 206, 207, 209, 212, 221, 225, 235, 241, 244, 252, 263, 266, 267, 269, 272, 281, 282, 286, 287] ['PCR', 'products', 'were', 'checked', 'for', 'quality', 'and', 'yield', 'by', 'agarose', 'gel', 'electrophoresis', 'and', 'the', 'remainder', 'of', 'the', 'PCR', 'products', 'were', 'treated', 'with', '3', 'units', 'of', 'shrimp', 'alkaline', 'phosphatase', 'and', '2', 'units', 'of', 'exonuclease', 'I', '.', 'SNaPshot', 'analysis', 'was', 'performed', 'using', 'an', 'Applied', 'Biosystems', 'SNaPshot', 'Multiplex', 'Kit', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 4, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Extension reactions consisted of 35 cycles of denaturation at 95 °C for 10 s followed by annealing and extension at 58.5 °C for 40 s. Labeled extension products were treated with shrimp alkaline phosphatase (1 unit per sample), diluted 1 in 10, and 1 μl of the diluted product mixed with 9.8 μl of highly deionized (HiDi) formamide and 0.2 μl of Genescan-120 LIZ size standard. [('PMC2923020', 'M07005', 186, 206, 'alkaline phosphatase')] ['Extension', 'reactions', 'consisted', 'of', '35', 'cycles', 'of', 'denaturation', 'at', '95', '°', '##C', 'for', '10', 's', 'followed', 'by', 'annealing', 'and', 'extension', 'at', '58', '.', '5', '°', '##C', 'for', '40', 's', '.', 'Label', '##ed', 'extension', 'products', 'were', 'treated', 'with', 'shr', '##imp', 'alkaline', 'phosphatase', '(', '1', 'unit', 'per', 'sample', ')', ',', 'diluted', '1', 'in', '10', ',', 'and', '1', 'μ', '##l', 'of', 'the', 'diluted', 'product', 'mixed', 'with', '9', '.', '8', 'μ', '##l', 'of', 'highly', 'deionized', '(', 'Hi', '##Di', ')', 'form', '##amide', 'and', '0', '.', '2', 'μ', '##l', 'of', 'Genes', '##can', '-', '120', 'LI', '##Z', 'size', 'standard', '.'] [0, 10, 20, 30, 33, 36, 43, 46, 59, 62, 65, 66, 68, 72, 75, 77, 86, 89, 99, 103, 113, 116, 118, 119, 121, 122, 124, 128, 131, 132, 134, 139, 142, 152, 161, 166, 174, 179, 182, 186, 195, 207, 208, 210, 215, 219, 225, 226, 228, 236, 238, 241, 243, 245, 249, 251, 252, 254, 257, 261, 269, 277, 283, 288, 289, 290, 292, 293, 295, 298, 305, 315, 316, 318, 320, 322, 326, 332, 336, 337, 338, 340, 341, 343, 346, 351, 354, 355, 359, 361, 363, 368, 376] [9, 19, 29, 32, 35, 42, 45, 58, 61, 64, 66, 67, 71, 74, 76, 85, 88, 98, 102, 112, 115, 118, 119, 120, 122, 123, 127, 130, 132, 133, 139, 141, 151, 160, 165, 173, 178, 182, 185, 194, 206, 208, 209, 214, 218, 225, 226, 227, 235, 237, 240, 243, 244, 248, 250, 252, 253, 256, 260, 268, 276, 282, 287, 289, 290, 291, 293, 294, 297, 304, 314, 316, 318, 320, 321, 326, 331, 335, 337, 338, 339, 341, 342, 345, 351, 354, 355, 358, 361, 362, 367, 376, 377] ['Extension', 'reactions', 'consisted', 'of', '35', 'cycles', 'of', 'denaturation', 'at', '95', '°C', 'for', '10', 's', 'followed', 'by', 'annealing', 'and', 'extension', 'at', '58.5', '°C', 'for', '40', 's', '.', 'Labeled', 'extension', 'products', 'were', 'treated', 'with', 'shrimp', 'alkaline', 'phosphatase', '(', '1', 'unit', 'per', 'sample', ')', ',', 'diluted', '1', 'in', '10', ',', 'and', '1', 'μl', 'of', 'the', 'diluted', 'product', 'mixed', 'with', '9.8', 'μl', 'of', 'highly', 'deionized', '(', 'HiDi', ')', 'formamide', 'and', '0.2', 'μl', 'of', 'Genescan-120', 'LIZ', 'size', 'standard', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 2, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 2, 1, 1, 1, 1, 2, 1, 2, 1, 3, 2, 1, 4, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs with expression in COS-1 cells. [('PMC2928134', 'F02002', 37, 64, 'UDP-glucuronosyltransferase')] ['Cl', '##oning', 'of', 'two', 'human', 'liver', 'bilirubin', 'UDP', '-', 'gluc', '##uron', '##osyl', '##transferase', 'cDNA', '##s', 'with', 'expression', 'in', 'COS', '-', '1', 'cells', '.'] [0, 2, 8, 11, 15, 21, 27, 37, 40, 41, 45, 49, 53, 65, 69, 71, 76, 87, 90, 93, 94, 96, 101] [2, 7, 10, 14, 20, 26, 36, 40, 41, 45, 49, 53, 64, 69, 70, 75, 86, 89, 93, 94, 95, 101, 102] ['Cloning', 'of', 'two', 'human', 'liver', 'bilirubin', 'UDP-glucuronosyltransferase', 'cDNAs', 'with', 'expression', 'in', 'COS-1', 'cells', '.'] [2, 1, 1, 1, 1, 1, 6, 2, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Sorich M.J., Miners J.O., McKinnon R.A., Smith P.A. Multiple pharmacophores for the investigation of human UDP-glucuronosyltransferase isoform substrate selectivity. [('PMC2928134', 'F05001', 107, 134, 'UDP-glucuronosyltransferase')] ['Sor', '##ich', 'M', '.', 'J', '.', ',', 'Min', '##ers', 'J', '.', 'O', '.', ',', 'McK', '##inn', '##on', 'R', '.', 'A', '.', ',', 'Smith', 'P', '.', 'A', '.', 'Multiple', 'pharmac', '##ophores', 'for', 'the', 'investigation', 'of', 'human', 'UDP', '-', 'gluc', '##uron', '##osyl', '##transferase', 'isoform', 'substrate', 'selectivity', '.'] [0, 3, 7, 8, 9, 10, 11, 13, 16, 20, 21, 22, 23, 24, 26, 29, 32, 35, 36, 37, 38, 39, 41, 47, 48, 49, 50, 52, 61, 68, 76, 80, 84, 98, 101, 107, 110, 111, 115, 119, 123, 135, 143, 153, 164] [3, 6, 8, 9, 10, 11, 12, 16, 19, 21, 22, 23, 24, 25, 29, 32, 34, 36, 37, 38, 39, 40, 46, 48, 49, 50, 51, 60, 68, 75, 79, 83, 97, 100, 106, 110, 111, 115, 119, 123, 134, 142, 152, 164, 165] ['Sorich', 'M.J', '.', ',', 'Miners', 'J.O', '.', ',', 'McKinnon', 'R.A', '.', ',', 'Smith', 'P.A', '.', 'Multiple', 'pharmacophores', 'for', 'the', 'investigation', 'of', 'human', 'UDP-glucuronosyltransferase', 'isoform', 'substrate', 'selectivity', '.'] [2, 3, 1, 1, 2, 3, 1, 1, 3, 3, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 6, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O']
The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. [('PMC2928134', 'F07002', 4, 27, 'UDP glycosyltransferase')] ['The', 'UDP', 'glycos', '##yl', '##transferase', 'gene', 'superfamily', ':', 'recommended', 'nom', '##enclature', 'update', 'based', 'on', 'evolutionary', 'divergence', '.'] [0, 4, 8, 14, 16, 28, 33, 44, 46, 58, 61, 71, 78, 84, 87, 100, 110] [3, 7, 14, 16, 27, 32, 44, 45, 57, 61, 70, 77, 83, 86, 99, 110, 111] ['The', 'UDP', 'glycosyltransferase', 'gene', 'superfamily', ':', 'recommended', 'nomenclature', 'update', 'based', 'on', 'evolutionary', 'divergence', '.'] [1, 1, 3, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1] ['O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. [('PMC2928134', 'F09002', 47, 86, 'bilirubin UDP-glucuronosyltransferase 1')] "['The', 'genetic', 'basis', 'of', 'the', 'reduced', 'expression', 'of', 'bilirubin', 'UDP', '-', 'gluc', '##uron', '##osyl', '##transferase', '1', 'in', 'Gilbert', ""'"", 's', 'syndrome', '.']" [0, 4, 12, 18, 21, 25, 33, 44, 47, 57, 60, 61, 65, 69, 73, 85, 87, 90, 97, 98, 100, 108] [3, 11, 17, 20, 24, 32, 43, 46, 56, 60, 61, 65, 69, 73, 84, 86, 89, 97, 98, 99, 108, 109] "['The', 'genetic', 'basis', 'of', 'the', 'reduced', 'expression', 'of', 'bilirubin', 'UDP-glucuronosyltransferase', '1', 'in', ""Gilbert's"", 'syndrome', '.']" [1, 1, 1, 1, 1, 1, 1, 1, 1, 6, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
Maruo Y., Wada S., Yamamoto K., Sato H., Yamano T., Shimada M. A case of anorexia nervosa with hyperbilirubinaemia in a patient homozygous for a mutation in the bilirubin UDP-glucuronosyltransferase gene. [('PMC2928134', 'F10001', 161, 198, 'bilirubin UDP-glucuronosyltransferase')] ['Mar', '##uo', 'Y', '.', ',', 'Wa', '##da', 'S', '.', ',', 'Yam', '##amoto', 'K', '.', ',', 'Sato', 'H', '.', ',', 'Yam', '##ano', 'T', '.', ',', 'Shim', '##ada', 'M', '.', 'A', 'case', 'of', 'an', '##ore', '##xia', 'nerv', '##osa', 'with', 'hyper', '##bil', '##irubin', '##aemia', 'in', 'a', 'patient', 'homozygous', 'for', 'a', 'mutation', 'in', 'the', 'bilirubin', 'UDP', '-', 'gluc', '##uron', '##osyl', '##transferase', 'gene', '.'] [0, 3, 6, 7, 8, 10, 12, 15, 16, 17, 19, 22, 28, 29, 30, 32, 37, 38, 39, 41, 44, 48, 49, 50, 52, 56, 60, 61, 63, 65, 70, 73, 75, 78, 82, 86, 90, 95, 100, 103, 109, 115, 118, 120, 128, 139, 143, 145, 154, 157, 161, 171, 174, 175, 179, 183, 187, 199, 203] [3, 5, 7, 8, 9, 12, 14, 16, 17, 18, 22, 27, 29, 30, 31, 36, 38, 39, 40, 44, 47, 49, 50, 51, 56, 59, 61, 62, 64, 69, 72, 75, 78, 81, 86, 89, 94, 100, 103, 109, 114, 117, 119, 127, 138, 142, 144, 153, 156, 160, 170, 174, 175, 179, 183, 187, 198, 203, 204] ['Maruo', 'Y', '.', ',', 'Wada', 'S', '.', ',', 'Yamamoto', 'K', '.', ',', 'Sato', 'H', '.', ',', 'Yamano', 'T', '.', ',', 'Shimada', 'M', '.', 'A', 'case', 'of', 'anorexia', 'nervosa', 'with', 'hyperbilirubinaemia', 'in', 'a', 'patient', 'homozygous', 'for', 'a', 'mutation', 'in', 'the', 'bilirubin', 'UDP-glucuronosyltransferase', 'gene', '.'] [2, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 3, 2, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 6, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
Heme, which is primarily derived from the hemoglobin of red blood cells, is converted to biliverdin by heme oxygenases and is then reduced to bilirubin (1). [('PMC2928134', 'I00001', 103, 118, 'heme oxygenases')] ['Hem', '##e', ',', 'which', 'is', 'primarily', 'derived', 'from', 'the', 'hemoglobin', 'of', 'red', 'blood', 'cells', ',', 'is', 'converted', 'to', 'bil', '##iver', '##din', 'by', 'heme', 'oxygen', '##ases', 'and', 'is', 'then', 'reduced', 'to', 'bilirubin', '(', '1', ')', '.'] [0, 3, 4, 6, 12, 15, 25, 33, 38, 42, 53, 56, 60, 66, 71, 73, 76, 86, 89, 92, 96, 100, 103, 108, 114, 119, 123, 126, 131, 139, 142, 152, 153, 154, 155] [3, 4, 5, 11, 14, 24, 32, 37, 41, 52, 55, 59, 65, 71, 72, 75, 85, 88, 92, 96, 99, 102, 107, 114, 118, 122, 125, 130, 138, 141, 151, 153, 154, 155, 156] ['Heme', ',', 'which', 'is', 'primarily', 'derived', 'from', 'the', 'hemoglobin', 'of', 'red', 'blood', 'cells', ',', 'is', 'converted', 'to', 'biliverdin', 'by', 'heme', 'oxygenases', 'and', 'is', 'then', 'reduced', 'to', 'bilirubin', '(', '1', ')', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Bilirubin is taken into the liver by the solute carrier organic anion transporter family (2) and is glucuronidated by UDP-glycosyltransferase in hepatocytes (3). [('PMC2928134', 'I00002', 118, 141, 'UDP-glycosyltransferase')] ['Bil', '##irubin', 'is', 'taken', 'into', 'the', 'liver', 'by', 'the', 'solute', 'carrier', 'organic', 'anion', 'transporter', 'family', '(', '2', ')', 'and', 'is', 'gluc', '##uron', '##idated', 'by', 'UDP', '-', 'glycos', '##yl', '##transferase', 'in', 'hepatocytes', '(', '3', ')', '.'] [0, 3, 10, 13, 19, 24, 28, 34, 37, 41, 48, 56, 64, 70, 82, 89, 90, 91, 93, 97, 100, 104, 108, 115, 118, 121, 122, 128, 130, 142, 145, 157, 158, 159, 160] [3, 9, 12, 18, 23, 27, 33, 36, 40, 47, 55, 63, 69, 81, 88, 90, 91, 92, 96, 99, 104, 108, 114, 117, 121, 122, 128, 130, 141, 144, 156, 158, 159, 160, 161] ['Bilirubin', 'is', 'taken', 'into', 'the', 'liver', 'by', 'the', 'solute', 'carrier', 'organic', 'anion', 'transporter', 'family', '(', '2', ')', 'and', 'is', 'glucuronidated', 'by', 'UDP-glycosyltransferase', 'in', 'hepatocytes', '(', '3', ')', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 5, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
The UDP-glycosyltransferase 1 family, polypeptide A1 (UGT1A1) and solute carrier organic anion transporter family enzymes SLCO1B1 and SLCO1B3 are responsible for glucuronidation and cellular uptake of bilirubin, respectively, and play an important role in regulating the bilirubin levels (5–7). [('PMC2928134', 'I01000', 4, 29, 'UDP-glycosyltransferase 1')] ['The', 'UDP', '-', 'glycos', '##yl', '##transferase', '1', 'family', ',', 'polypeptide', 'A', '##1', '(', 'U', '##GT', '##1', '##A', '##1', ')', 'and', 'solute', 'carrier', 'organic', 'anion', 'transporter', 'family', 'enzymes', 'SLC', '##O', '##1', '##B', '##1', 'and', 'SLC', '##O', '##1', '##B', '##3', 'are', 'responsible', 'for', 'gluc', '##uron', '##idation', 'and', 'cellular', 'uptake', 'of', 'bilirubin', ',', 'respectively', ',', 'and', 'play', 'an', 'important', 'role', 'in', 'regulating', 'the', 'bilirubin', 'levels', '(', '5', '–', '7', ')', '.'] [0, 4, 7, 8, 14, 16, 28, 30, 36, 38, 50, 51, 53, 54, 55, 57, 58, 59, 60, 62, 66, 73, 81, 89, 95, 107, 114, 122, 125, 126, 127, 128, 130, 134, 137, 138, 139, 140, 142, 146, 158, 162, 166, 170, 178, 182, 191, 198, 201, 210, 212, 224, 226, 230, 235, 238, 248, 253, 256, 267, 271, 281, 288, 289, 290, 291, 292, 293] [3, 7, 8, 14, 16, 27, 29, 36, 37, 49, 51, 52, 54, 55, 57, 58, 59, 60, 61, 65, 72, 80, 88, 94, 106, 113, 121, 125, 126, 127, 128, 129, 133, 137, 138, 139, 140, 141, 145, 157, 161, 166, 170, 177, 181, 190, 197, 200, 210, 211, 224, 225, 229, 234, 237, 247, 252, 255, 266, 270, 280, 287, 289, 290, 291, 292, 293, 294] ['The', 'UDP-glycosyltransferase', '1', 'family', ',', 'polypeptide', 'A1', '(', 'UGT1A1', ')', 'and', 'solute', 'carrier', 'organic', 'anion', 'transporter', 'family', 'enzymes', 'SLCO1B1', 'and', 'SLCO1B3', 'are', 'responsible', 'for', 'glucuronidation', 'and', 'cellular', 'uptake', 'of', 'bilirubin', ',', 'respectively', ',', 'and', 'play', 'an', 'important', 'role', 'in', 'regulating', 'the', 'bilirubin', 'levels', '(', '5–', '7', ')', '.'] [1, 5, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 5, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1] ['O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The genetics of alcohol metabolism: Role of alcohol dehydrogenase and aldehyde dehydrogenase variants. [('PMC3084048', 'F09002', 44, 65, 'alcohol dehydrogenase'), ('PMC3084048', 'F09002', 70, 92, 'aldehyde dehydrogenase')] ['The', 'genetics', 'of', 'alcohol', 'metabolism', ':', 'Role', 'of', 'alcohol', 'dehydrogenase', 'and', 'ald', '##eh', '##yd', '##e', 'dehydrogenase', 'variants', '.'] [0, 4, 13, 16, 24, 34, 36, 41, 44, 52, 66, 70, 73, 75, 77, 79, 93, 101] [3, 12, 15, 23, 34, 35, 40, 43, 51, 65, 69, 73, 75, 77, 78, 92, 101, 102] ['The', 'genetics', 'of', 'alcohol', 'metabolism', ':', 'Role', 'of', 'alcohol', 'dehydrogenase', 'and', 'aldehyde', 'dehydrogenase', 'variants', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O']
Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors. [('PMC3084048', 'F32002', 26, 32, 'kinase')] ['Ha', '##pp', '##y', '##hour', ',', 'a', 'Ste', '##20', 'family', 'kinase', ',', 'implic', '##ates', 'EGFR', 'signaling', 'in', 'ethanol', '-', 'induced', 'behaviors', '.'] [0, 2, 4, 5, 9, 11, 13, 16, 19, 26, 32, 34, 40, 45, 50, 60, 63, 70, 71, 79, 88] [2, 4, 5, 9, 10, 12, 16, 18, 25, 32, 33, 40, 44, 49, 59, 62, 70, 71, 78, 88, 89] ['Happyhour', ',', 'a', 'Ste20', 'family', 'kinase', ',', 'implicates', 'EGFR', 'signaling', 'in', 'ethanol', '-', 'induced', 'behaviors', '.'] [4, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In contrast to alcohol addiction, which has been investigated in numerous genetic studies (5), including recent genome-wide association studies (GWAS) analyses (7–9), few genes regulating alcohol consumption in humans have been described—with the notable exception of alcohol dehydrogenase (3, 5, 10). [('PMC3084048', 'I00006', 268, 289, 'alcohol dehydrogenase')] ['In', 'contrast', 'to', 'alcohol', 'addiction', ',', 'which', 'has', 'been', 'investigated', 'in', 'numerous', 'genetic', 'studies', '(', '5', ')', ',', 'including', 'recent', 'genome', '-', 'wide', 'association', 'studies', '(', 'GW', '##AS', ')', 'analyses', '(', '7', '–', '9', ')', ',', 'few', 'genes', 'regulating', 'alcohol', 'consumption', 'in', 'humans', 'have', 'been', 'described', '—', 'with', 'the', 'notable', 'exception', 'of', 'alcohol', 'dehydrogenase', '(', '3', ',', '5', ',', '10', ')', '.'] [0, 3, 12, 15, 23, 32, 34, 40, 44, 49, 62, 65, 74, 82, 90, 91, 92, 93, 95, 105, 112, 118, 119, 124, 136, 144, 145, 147, 149, 151, 160, 161, 162, 163, 164, 165, 167, 171, 177, 188, 196, 208, 211, 218, 223, 228, 237, 238, 243, 247, 255, 265, 268, 276, 290, 291, 292, 294, 295, 297, 299, 300] [2, 11, 14, 22, 32, 33, 39, 43, 48, 61, 64, 73, 81, 89, 91, 92, 93, 94, 104, 111, 118, 119, 123, 135, 143, 145, 147, 149, 150, 159, 161, 162, 163, 164, 165, 166, 170, 176, 187, 195, 207, 210, 217, 222, 227, 237, 238, 242, 246, 254, 264, 267, 275, 289, 291, 292, 293, 295, 296, 299, 300, 301] ['In', 'contrast', 'to', 'alcohol', 'addiction', ',', 'which', 'has', 'been', 'investigated', 'in', 'numerous', 'genetic', 'studies', '(', '5', ')', ',', 'including', 'recent', 'genome', '-', 'wide', 'association', 'studies', '(', 'GWAS', ')', 'analyses', '(', '7–', '9', ')', ',', 'few', 'genes', 'regulating', 'alcohol', 'consumption', 'in', 'humans', 'have', 'been', 'described', '—', 'with', 'the', 'notable', 'exception', 'of', 'alcohol', 'dehydrogenase', '(', '3', ',', '5', ',', '10', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Before cDNA synthesis, the RNA samples were prepared using the RNeasy Mini Kit (Qiagen) and treated with RQ1 RNase-free DNase (Promega) following the manufacturer's instructions to ensure no DNA contamination. [('PMC3084048', 'M06001', 109, 114, 'RNase'), ('PMC3084048', 'M06001', 120, 125, 'DNase')] "['Before', 'cDNA', 'synthesis', ',', 'the', 'RNA', 'samples', 'were', 'prepared', 'using', 'the', 'RN', '##ea', '##sy', 'Mini', 'Kit', '(', 'Qi', '##agen', ')', 'and', 'treated', 'with', 'RQ', '##1', 'RNase', '-', 'free', 'DNase', '(', 'Prom', '##eg', '##a', ')', 'following', 'the', 'manufacturer', ""'"", 's', 'instructions', 'to', 'ensure', 'no', 'DNA', 'contamination', '.']" [0, 7, 12, 21, 23, 27, 31, 39, 44, 53, 59, 63, 65, 67, 70, 75, 79, 80, 82, 86, 88, 92, 100, 105, 107, 109, 114, 115, 120, 126, 127, 131, 133, 134, 136, 146, 150, 162, 163, 165, 178, 181, 188, 191, 195, 208] [6, 11, 21, 22, 26, 30, 38, 43, 52, 58, 62, 65, 67, 69, 74, 78, 80, 82, 86, 87, 91, 99, 104, 107, 108, 114, 115, 119, 125, 127, 131, 133, 134, 135, 145, 149, 162, 163, 164, 177, 180, 187, 190, 194, 208, 209] "['Before', 'cDNA', 'synthesis', ',', 'the', 'RNA', 'samples', 'were', 'prepared', 'using', 'the', 'RNeasy', 'Mini', 'Kit', '(', 'Qiagen', ')', 'and', 'treated', 'with', 'RQ1', 'RNase', '-', 'free', 'DNase', '(', 'Promega', ')', 'following', 'the', ""manufacturer's"", 'instructions', 'to', 'ensure', 'no', 'DNA', 'contamination', '.']" [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Initial PCR amplification was performed using HotStar Taq DNA polymerase (Qiagen) in a total volume of 12 μL containing 0.25 μM both forward and reverse primer and 24 ng genomic DNA. [('PMC3084048', 'M07001', 54, 72, 'Taq DNA polymerase')] ['Initial', 'PCR', 'amplification', 'was', 'performed', 'using', 'Hot', '##St', '##ar', 'Taq', 'DNA', 'polymerase', '(', 'Qi', '##agen', ')', 'in', 'a', 'total', 'volume', 'of', '12', 'μ', '##L', 'containing', '0', '.', '25', 'μ', '##M', 'both', 'forward', 'and', 'reverse', 'primer', 'and', '24', 'ng', 'genomic', 'DNA', '.'] [0, 8, 12, 26, 30, 40, 46, 49, 51, 54, 58, 62, 73, 74, 76, 80, 82, 85, 87, 93, 100, 103, 106, 107, 109, 120, 121, 122, 125, 126, 128, 133, 141, 145, 153, 160, 164, 167, 170, 178, 181] [7, 11, 25, 29, 39, 45, 49, 51, 53, 57, 61, 72, 74, 76, 80, 81, 84, 86, 92, 99, 102, 105, 107, 108, 119, 121, 122, 124, 126, 127, 132, 140, 144, 152, 159, 163, 166, 169, 177, 181, 182] ['Initial', 'PCR', 'amplification', 'was', 'performed', 'using', 'HotStar', 'Taq', 'DNA', 'polymerase', '(', 'Qiagen', ')', 'in', 'a', 'total', 'volume', 'of', '12', 'μL', 'containing', '0.25', 'μM', 'both', 'forward', 'and', 'reverse', 'primer', 'and', '24', 'ng', 'genomic', 'DNA', '.'] [1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Primers used were forward: 5′-AAACTCAAAACCCACTCCTGAA-3′ and reverse: 5′-CAGTATACATAAACATTGGAAAAGAGG-3′. Amplified samples were incubated with 1 U shrimp alkaline phosphatase (USB) and 2 U exonuclease I (New England Biolabs) for 1 h at 37 °C followed by 15 min at 85 °C. [('PMC3084048', 'M07003', 153, 173, 'alkaline phosphatase'), ('PMC3084048', 'M07003', 188, 201, 'exonuclease I')] ['Primer', '##s', 'used', 'were', 'forward', ':', '5', '′', '-', 'AAA', '##CTC', '##AAA', '##ACC', '##CAC', '##TC', '##CTG', '##AA', '-', '3', '′', 'and', 'reverse', ':', '5', '′', '-', 'CAG', '##TA', '##TA', '##CAT', '##AAA', '##CAT', '##TG', '##GAA', '##AA', '##GA', '##GG', '-', '3', '′', '.', 'Ampl', '##ified', 'samples', 'were', 'incubated', 'with', '1', 'U', 'shr', '##imp', 'alkaline', 'phosphatase', '(', 'US', '##B', ')', 'and', '2', 'U', 'exon', '##ucle', '##ase', 'I', '(', 'New', 'England', 'Biol', '##abs', ')', 'for', '1', 'h', 'at', '37', '°', '##C', 'followed', 'by', '15', 'min', 'at', '85', '°', '##C', '.'] [0, 6, 8, 13, 18, 25, 27, 28, 29, 30, 33, 36, 39, 42, 45, 47, 50, 52, 53, 54, 56, 60, 67, 69, 70, 71, 72, 75, 77, 79, 82, 85, 88, 90, 93, 95, 97, 99, 100, 101, 102, 104, 108, 114, 122, 127, 137, 142, 144, 146, 149, 153, 162, 174, 175, 177, 178, 180, 184, 186, 188, 192, 196, 200, 202, 203, 207, 215, 219, 222, 224, 228, 230, 232, 235, 238, 239, 241, 250, 253, 256, 260, 263, 266, 267, 268] [6, 7, 12, 17, 25, 26, 28, 29, 30, 33, 36, 39, 42, 45, 47, 50, 52, 53, 54, 55, 59, 67, 68, 70, 71, 72, 75, 77, 79, 82, 85, 88, 90, 93, 95, 97, 99, 100, 101, 102, 103, 108, 113, 121, 126, 136, 141, 143, 145, 149, 152, 161, 173, 175, 177, 178, 179, 183, 185, 187, 192, 196, 199, 201, 203, 206, 214, 219, 222, 223, 227, 229, 231, 234, 237, 239, 240, 249, 252, 255, 259, 262, 265, 267, 268, 269] ['Primers', 'used', 'were', 'forward', ':', '5′-AAACTCAAAACCCACTCCTGAA-3′', 'and', 'reverse', ':', '5′-CAGTATACATAAACATTGGAAAAGAGG-3′', '.', 'Amplified', 'samples', 'were', 'incubated', 'with', '1', 'U', 'shrimp', 'alkaline', 'phosphatase', '(', 'USB', ')', 'and', '2', 'U', 'exonuclease', 'I', '(', 'New', 'England', 'Biolabs', ')', 'for', '1', 'h', 'at', '37', '°C', 'followed', 'by', '15', 'min', 'at', '85', '°C', '.'] [2, 1, 1, 1, 1, 14, 1, 1, 1, 17, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 3, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
After single-base extension, reaction products were incubated with 1 U shrimp alkaline phosphatase for 1 h at 37 °C followed by 15 min at 85 °C. [('PMC3084048', 'M07005', 78, 98, 'alkaline phosphatase')] ['After', 'single', '-', 'base', 'extension', ',', 'reaction', 'products', 'were', 'incubated', 'with', '1', 'U', 'shr', '##imp', 'alkaline', 'phosphatase', 'for', '1', 'h', 'at', '37', '°', '##C', 'followed', 'by', '15', 'min', 'at', '85', '°', '##C', '.'] [0, 6, 12, 13, 18, 27, 29, 38, 47, 52, 62, 67, 69, 71, 74, 78, 87, 99, 103, 105, 107, 110, 113, 114, 116, 125, 128, 131, 135, 138, 141, 142, 143] [5, 12, 13, 17, 27, 28, 37, 46, 51, 61, 66, 68, 70, 74, 77, 86, 98, 102, 104, 106, 109, 112, 114, 115, 124, 127, 130, 134, 137, 140, 142, 143, 144] ['After', 'single', '-', 'base', 'extension', ',', 'reaction', 'products', 'were', 'incubated', 'with', '1', 'U', 'shrimp', 'alkaline', 'phosphatase', 'for', '1', 'h', 'at', '37', '°C', 'followed', 'by', '15', 'min', 'at', '85', '°C', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
This identified SNPs in or near Ras protein-specific guanine nucleotide-releasing factor 2 (RASGRF2), OTU domain-containing protein 3 (OTUD3), chromodomain protein on Y chromosome-like (CDYL), syndecan-binding protein 2 (SDCBP2), neuropilin- and tolloid-like 1 (NETO1), and carboxypeptidase A6 (CPA6) (Tables 1 and and2,2, Fig. [('PMC3084048', 'R00006', 274, 293, 'carboxypeptidase A6')] ['This', 'identified', 'SNPs', 'in', 'or', 'near', 'Ras', 'protein', '-', 'specific', 'guan', '##ine', 'nucleotide', '-', 'releasing', 'factor', '2', '(', 'RAS', '##GR', '##F', '##2', ')', ',', 'OT', '##U', 'domain', '-', 'containing', 'protein', '3', '(', 'OT', '##UD', '##3', ')', ',', 'chrom', '##od', '##omain', 'protein', 'on', 'Y', 'chromosome', '-', 'like', '(', 'CD', '##Y', '##L', ')', ',', 'synd', '##ecan', '-', 'binding', 'protein', '2', '(', 'SD', '##CB', '##P', '##2', ')', ',', 'neurop', '##ilin', '-', 'and', 'to', '##ll', '##oid', '-', 'like', '1', '(', 'NET', '##O', '##1', ')', ',', 'and', 'carb', '##oxyp', '##epti', '##dase', 'A', '##6', '(', 'CP', '##A', '##6', ')', '(', 'Tables', '1', 'and', 'and', '##2', ',', '2', ',', 'Fig', '.'] [0, 5, 16, 21, 24, 27, 32, 36, 43, 44, 53, 57, 61, 71, 72, 82, 89, 91, 92, 95, 97, 98, 99, 100, 102, 104, 106, 112, 113, 124, 132, 134, 135, 137, 139, 140, 141, 143, 148, 150, 156, 164, 167, 169, 179, 180, 185, 186, 188, 189, 190, 191, 193, 197, 201, 202, 210, 218, 220, 221, 223, 225, 226, 227, 228, 230, 236, 240, 242, 246, 248, 250, 253, 254, 259, 261, 262, 265, 266, 267, 268, 270, 274, 278, 282, 286, 291, 292, 294, 295, 297, 298, 299, 301, 302, 309, 311, 316, 319, 320, 321, 322, 324, 327] [4, 15, 20, 23, 26, 31, 35, 43, 44, 52, 57, 60, 71, 72, 81, 88, 90, 92, 95, 97, 98, 99, 100, 101, 104, 105, 112, 113, 123, 131, 133, 135, 137, 139, 140, 141, 142, 148, 150, 155, 163, 166, 168, 179, 180, 184, 186, 188, 189, 190, 191, 192, 197, 201, 202, 209, 217, 219, 221, 223, 225, 226, 227, 228, 229, 236, 240, 241, 245, 248, 250, 253, 254, 258, 260, 262, 265, 266, 267, 268, 269, 273, 278, 282, 286, 290, 292, 293, 295, 297, 298, 299, 300, 302, 308, 310, 314, 319, 320, 321, 322, 323, 327, 328] ['This', 'identified', 'SNPs', 'in', 'or', 'near', 'Ras', 'protein', '-', 'specific', 'guanine', 'nucleotide', '-', 'releasing', 'factor', '2', '(', 'RASGRF2', ')', ',', 'OTU', 'domain', '-', 'containing', 'protein', '3', '(', 'OTUD3', ')', ',', 'chromodomain', 'protein', 'on', 'Y', 'chromosome', '-', 'like', '(', 'CDYL', ')', ',', 'syndecan', '-', 'binding', 'protein', '2', '(', 'SDCBP2', ')', ',', 'neuropilin-', 'and', 'tolloid', '-', 'like', '1', '(', 'NETO1', ')', ',', 'and', 'carboxypeptidase', 'A6', '(', 'CPA6', ')', '(', 'Tables', '1', 'and', '\u200band2', ',', '2', ',', 'Fig', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 4, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 4, 1, 1, 3, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 4, 2, 1, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
SNPs rs7590720 and rs1344694 downstream of the peroxisomal trans-2-enoyl-CoA reductase (peroxisomal trans-2-enoyl-CoA reductase) gene have previously been reported to attain genome-wide significance in alcohol dependence (9). [('PMC3084048', 'R04000', 47, 86, 'peroxisomal trans-2-enoyl-CoA reductase'), ('PMC3084048', 'R04000', 88, 127, 'peroxisomal trans-2-enoyl-CoA reductase')] ['SNPs', 'rs', '##75', '##90', '##72', '##0', 'and', 'rs', '##134', '##46', '##94', 'downstream', 'of', 'the', 'peroxis', '##omal', 'trans', '-', '2', '-', 'en', '##oyl', '-', 'Co', '##A', 'reductase', '(', 'peroxis', '##omal', 'trans', '-', '2', '-', 'en', '##oyl', '-', 'Co', '##A', 'reductase', ')', 'gene', 'have', 'previously', 'been', 'reported', 'to', 'attain', 'genome', '-', 'wide', 'significance', 'in', 'alcohol', 'dependence', '(', '9', ')', '.'] [0, 5, 7, 9, 11, 13, 15, 19, 21, 24, 26, 29, 40, 43, 47, 54, 59, 64, 65, 66, 67, 69, 72, 73, 75, 77, 87, 88, 95, 100, 105, 106, 107, 108, 110, 113, 114, 116, 118, 127, 129, 134, 139, 150, 155, 164, 167, 174, 180, 181, 186, 199, 202, 210, 221, 222, 223, 224] [4, 7, 9, 11, 13, 14, 18, 21, 24, 26, 28, 39, 42, 46, 54, 58, 64, 65, 66, 67, 69, 72, 73, 75, 76, 86, 88, 95, 99, 105, 106, 107, 108, 110, 113, 114, 116, 117, 127, 128, 133, 138, 149, 154, 163, 166, 173, 180, 181, 185, 198, 201, 209, 220, 222, 223, 224, 225] ['SNPs', 'rs7590720', 'and', 'rs1344694', 'downstream', 'of', 'the', 'peroxisomal', 'trans-2-enoyl-CoA', 'reductase', '(', 'peroxisomal', 'trans-2-enoyl-CoA', 'reductase', ')', 'gene', 'have', 'previously', 'been', 'reported', 'to', 'attain', 'genome', '-', 'wide', 'significance', 'in', 'alcohol', 'dependence', '(', '9', ')', '.'] [1, 5, 1, 4, 1, 1, 1, 2, 9, 1, 1, 2, 9, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
By the same logic, reduced levels of protein kinase C alpha (e.g., PRKCA gene product) have been linked to an altered amyloid precursor protein secretion in fibroblasts from AD patients (Benussi et al., 1998). [('PMC3319015', 'D04009', 37, 59, 'protein kinase C alpha')] ['By', 'the', 'same', 'logic', ',', 'reduced', 'levels', 'of', 'protein', 'kinase', 'C', 'alpha', '(', 'e', '.', 'g', '.', ',', 'PR', '##K', '##CA', 'gene', 'product', ')', 'have', 'been', 'linked', 'to', 'an', 'altered', 'amyloid', 'precursor', 'protein', 'secretion', 'in', 'fibroblasts', 'from', 'AD', 'patients', '(', 'Ben', '##uss', '##i', 'et', 'al', '.', ',', '1998', ')', '.'] [0, 3, 7, 12, 17, 19, 27, 34, 37, 45, 52, 54, 60, 61, 62, 63, 64, 65, 67, 69, 70, 73, 78, 85, 87, 92, 97, 104, 107, 110, 118, 126, 136, 144, 154, 157, 169, 174, 177, 186, 187, 190, 193, 195, 198, 200, 201, 203, 207, 208] [2, 6, 11, 17, 18, 26, 33, 36, 44, 51, 53, 59, 61, 62, 63, 64, 65, 66, 69, 70, 72, 77, 85, 86, 91, 96, 103, 106, 109, 117, 125, 135, 143, 153, 156, 168, 173, 176, 185, 187, 190, 193, 194, 197, 200, 201, 202, 207, 208, 209] ['By', 'the', 'same', 'logic', ',', 'reduced', 'levels', 'of', 'protein', 'kinase', 'C', 'alpha', '(', 'e.g', '.', ',', 'PRKCA', 'gene', 'product', ')', 'have', 'been', 'linked', 'to', 'an', 'altered', 'amyloid', 'precursor', 'protein', 'secretion', 'in', 'fibroblasts', 'from', 'AD', 'patients', '(', 'Benussi', 'et', 'al', '.', ',', '1998', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Specific role for protein kinase C alpha in the constitutive and regulated secretion of amyloid precursor protein in human skin fibroblasts. [('PMC3319015', 'F05001', 18, 40, 'protein kinase C alpha')] ['Specific', 'role', 'for', 'protein', 'kinase', 'C', 'alpha', 'in', 'the', 'constitutive', 'and', 'regulated', 'secretion', 'of', 'amyloid', 'precursor', 'protein', 'in', 'human', 'skin', 'fibroblasts', '.'] [0, 9, 14, 18, 26, 33, 35, 41, 44, 48, 61, 65, 75, 85, 88, 96, 106, 114, 117, 123, 128, 139] [8, 13, 17, 25, 32, 34, 40, 43, 47, 60, 64, 74, 84, 87, 95, 105, 113, 116, 122, 127, 139, 140] ['Specific', 'role', 'for', 'protein', 'kinase', 'C', 'alpha', 'in', 'the', 'constitutive', 'and', 'regulated', 'secretion', 'of', 'amyloid', 'precursor', 'protein', 'in', 'human', 'skin', 'fibroblasts', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We identified 13 novel biliary bacteria based on WMS sequencing, as well as genes encoding putative proteins related to gallstone formation and bile resistance (e.g., β-glucuronidase and multidrug efflux pumps). [('PMC4667190', 'A00006', 167, 182, 'β-glucuronidase')] ['We', 'identified', '13', 'novel', 'biliary', 'bacteria', 'based', 'on', 'WM', '##S', 'sequencing', ',', 'as', 'well', 'as', 'genes', 'encoding', 'putative', 'proteins', 'related', 'to', 'gall', '##stone', 'formation', 'and', 'bile', 'resistance', '(', 'e', '.', 'g', '.', ',', 'β', '-', 'gluc', '##uron', '##idase', 'and', 'multi', '##drug', 'efflux', 'pumps', ')', '.'] [0, 3, 14, 17, 23, 31, 40, 46, 49, 51, 53, 63, 65, 68, 73, 76, 82, 91, 100, 109, 117, 120, 124, 130, 140, 144, 149, 160, 161, 162, 163, 164, 165, 167, 168, 169, 173, 177, 183, 187, 192, 197, 204, 209, 210] [2, 13, 16, 22, 30, 39, 45, 48, 51, 52, 63, 64, 67, 72, 75, 81, 90, 99, 108, 116, 119, 124, 129, 139, 143, 148, 159, 161, 162, 163, 164, 165, 166, 168, 169, 173, 177, 182, 186, 192, 196, 203, 209, 210, 211] ['We', 'identified', '13', 'novel', 'biliary', 'bacteria', 'based', 'on', 'WMS', 'sequencing', ',', 'as', 'well', 'as', 'genes', 'encoding', 'putative', 'proteins', 'related', 'to', 'gallstone', 'formation', 'and', 'bile', 'resistance', '(', 'e.g', '.', ',', 'β-glucuronidase', 'and', 'multidrug', 'efflux', 'pumps', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 3, 1, 1, 5, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
As this study is the first to apply WMS sequencing to bile samples, we paid special attention to genes encoding bacterial proteins involved in gallstone formation (e.g., β-glucuronidase, phospholipase and urease), which were identified by metagenomic assembly, metabolic reconstruction and/or KEGG GENOME annotation. [('PMC4667190', 'D04002', 170, 185, 'β-glucuronidase'), ('PMC4667190', 'D04002', 187, 200, 'phospholipase'), ('PMC4667190', 'D04002', 205, 211, 'urease')] ['As', 'this', 'study', 'is', 'the', 'first', 'to', 'apply', 'WM', '##S', 'sequencing', 'to', 'bile', 'samples', ',', 'we', 'paid', 'special', 'attention', 'to', 'genes', 'encoding', 'bacterial', 'proteins', 'involved', 'in', 'gall', '##stone', 'formation', '(', 'e', '.', 'g', '.', ',', 'β', '-', 'gluc', '##uron', '##idase', ',', 'phospholip', '##ase', 'and', 'urea', '##se', ')', ',', 'which', 'were', 'identified', 'by', 'meta', '##gen', '##omic', 'assembly', ',', 'metabolic', 'reconstruction', 'and', '/', 'or', 'KE', '##GG', 'GEN', '##OM', '##E', 'annotation', '.'] [0, 3, 8, 14, 17, 21, 27, 30, 36, 38, 40, 51, 54, 59, 66, 68, 71, 76, 84, 94, 97, 103, 112, 122, 131, 140, 143, 147, 153, 163, 164, 165, 166, 167, 168, 170, 171, 172, 176, 180, 185, 187, 197, 201, 205, 209, 211, 212, 214, 220, 225, 236, 239, 243, 246, 251, 259, 261, 271, 286, 289, 290, 293, 295, 298, 301, 303, 305, 315] [2, 7, 13, 16, 20, 26, 29, 35, 38, 39, 50, 53, 58, 66, 67, 70, 75, 83, 93, 96, 102, 111, 121, 130, 139, 142, 147, 152, 162, 164, 165, 166, 167, 168, 169, 171, 172, 176, 180, 185, 186, 197, 200, 204, 209, 211, 212, 213, 219, 224, 235, 238, 243, 246, 250, 259, 260, 270, 285, 289, 290, 292, 295, 297, 301, 303, 304, 315, 316] ['As', 'this', 'study', 'is', 'the', 'first', 'to', 'apply', 'WMS', 'sequencing', 'to', 'bile', 'samples', ',', 'we', 'paid', 'special', 'attention', 'to', 'genes', 'encoding', 'bacterial', 'proteins', 'involved', 'in', 'gallstone', 'formation', '(', 'e.g', '.', ',', 'β-glucuronidase', ',', 'phospholipase', 'and', 'urease', ')', ',', 'which', 'were', 'identified', 'by', 'metagenomic', 'assembly', ',', 'metabolic', 'reconstruction', 'and', '/', 'or', 'KEGG', 'GENOME', 'annotation', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 3, 1, 1, 5, 1, 2, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 2, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'B', 'E', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Compared to HMP stool samples, patient bile samples were enriched in pathways related to glutathione metabolism and genes related to oxidative stress resistance (i.e., glutathione reductase). [('PMC4667190', 'D05003', 168, 189, 'glutathione reductase')] ['Compared', 'to', 'HM', '##P', 'stool', 'samples', ',', 'patient', 'bile', 'samples', 'were', 'enriched', 'in', 'pathways', 'related', 'to', 'glutathione', 'metabolism', 'and', 'genes', 'related', 'to', 'oxidative', 'stress', 'resistance', '(', 'i', '.', 'e', '.', ',', 'glutathione', 'reductase', ')', '.'] [0, 9, 12, 14, 16, 22, 29, 31, 39, 44, 52, 57, 66, 69, 78, 86, 89, 101, 112, 116, 122, 130, 133, 143, 150, 161, 162, 163, 164, 165, 166, 168, 180, 189, 190] [8, 11, 14, 15, 21, 29, 30, 38, 43, 51, 56, 65, 68, 77, 85, 88, 100, 111, 115, 121, 129, 132, 142, 149, 160, 162, 163, 164, 165, 166, 167, 179, 189, 190, 191] ['Compared', 'to', 'HMP', 'stool', 'samples', ',', 'patient', 'bile', 'samples', 'were', 'enriched', 'in', 'pathways', 'related', 'to', 'glutathione', 'metabolism', 'and', 'genes', 'related', 'to', 'oxidative', 'stress', 'resistance', '(', 'i.e', '.', ',', 'glutathione', 'reductase', ')', '.'] [1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O']
Another enriched gene, the putative iron-dependent peroxidase, is also involved in the oxidative stress response. [('PMC4667190', 'D05004', 36, 61, 'iron-dependent peroxidase')] ['Another', 'enriched', 'gene', ',', 'the', 'putative', 'iron', '-', 'dependent', 'peroxidase', ',', 'is', 'also', 'involved', 'in', 'the', 'oxidative', 'stress', 'response', '.'] [0, 8, 17, 21, 23, 27, 36, 40, 41, 51, 61, 63, 66, 71, 80, 83, 87, 97, 104, 112] [7, 16, 21, 22, 26, 35, 40, 41, 50, 61, 62, 65, 70, 79, 82, 86, 96, 103, 112, 113] ['Another', 'enriched', 'gene', ',', 'the', 'putative', 'iron', '-', 'dependent', 'peroxidase', ',', 'is', 'also', 'involved', 'in', 'the', 'oxidative', 'stress', 'response', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Maki T.Pathogenesis of calcium bilirubinate gallstone: role of E. coli, beta-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. [('PMC4667190', 'F03000', 72, 90, 'beta-glucuronidase')] ['Mak', '##i', 'T', '.', 'Path', '##ogenesis', 'of', 'calcium', 'bilirubin', '##ate', 'gall', '##stone', ':', 'role', 'of', 'E', '.', 'coli', ',', 'beta', '-', 'gluc', '##uron', '##idase', 'and', 'coagulation', 'by', 'inorganic', 'ions', ',', 'poly', '##electro', '##ly', '##tes', 'and', 'ag', '##itation', '.'] [0, 3, 5, 6, 7, 11, 20, 23, 31, 40, 44, 48, 53, 55, 60, 63, 64, 66, 70, 72, 76, 77, 81, 85, 91, 95, 107, 110, 120, 124, 126, 130, 137, 139, 143, 147, 149, 156] [3, 4, 6, 7, 11, 19, 22, 30, 40, 43, 48, 53, 54, 59, 62, 64, 65, 70, 71, 76, 77, 81, 85, 90, 94, 106, 109, 119, 124, 125, 130, 137, 139, 142, 146, 149, 156, 157] ['Maki', 'T.Pathogenesis', 'of', 'calcium', 'bilirubinate', 'gallstone', ':', 'role', 'of', 'E', '.', 'coli', ',', 'beta', '-', 'glucuronidase', 'and', 'coagulation', 'by', 'inorganic', 'ions', ',', 'polyelectrolytes', 'and', 'agitation', '.'] [2, 4, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 4, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Rôças I. N. & Siqueira J. F.Identification of bacteria enduring endodontic treatment procedures by a combined Reverse Transcriptase–Polymerase Chain reaction and Reverse-Capture Checkerboard approach. [('PMC4667190', 'F21000', 118, 131, 'Transcriptase'), ('PMC4667190', 'F21000', 132, 142, 'Polymerase')] ['R', '##ô', '##ça', '##s', 'I', '.', 'N', '.', '&', 'Si', '##que', '##ira', 'J', '.', 'F', '.', 'Identification', 'of', 'bacteria', 'end', '##uring', 'end', '##odontic', 'treatment', 'procedures', 'by', 'a', 'combined', 'Reverse', 'Trans', '##cript', '##ase', '–', 'Polymer', '##ase', 'Chain', 'reaction', 'and', 'Reverse', '-', 'Cap', '##ture', 'Check', '##er', '##board', 'approach', '.'] [0, 1, 2, 4, 6, 7, 9, 10, 12, 14, 16, 19, 23, 24, 26, 27, 28, 43, 46, 55, 58, 64, 67, 75, 85, 96, 99, 101, 110, 118, 123, 128, 131, 132, 139, 143, 149, 158, 162, 169, 170, 173, 178, 183, 185, 191, 199] [1, 2, 4, 5, 7, 8, 10, 11, 13, 16, 19, 22, 24, 25, 27, 28, 42, 45, 54, 58, 63, 67, 74, 84, 95, 98, 100, 109, 117, 123, 128, 131, 132, 139, 142, 148, 157, 161, 169, 170, 173, 177, 183, 185, 190, 199, 200] ['Rôças', 'I', '.', 'N', '.', '&', 'Siqueira', 'J', '.', 'F.Identification', 'of', 'bacteria', 'enduring', 'endodontic', 'treatment', 'procedures', 'by', 'a', 'combined', 'Reverse', 'Transcriptase', '–', 'Polymerase', 'Chain', 'reaction', 'and', 'Reverse-Capture', 'Checkerboard', 'approach', '.'] [4, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 1, 4, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Pattinson N. & Willis K.Effect of phospholipase C on cholesterol solubilization in model bile. [('PMC4667190', 'F36000', 34, 49, 'phospholipase C')] ['Pat', '##tin', '##son', 'N', '.', '&', 'Willi', '##s', 'K', '.', 'Effect', 'of', 'phospholip', '##ase', 'C', 'on', 'cholesterol', 'solub', '##ilization', 'in', 'model', 'bile', '.'] [0, 3, 6, 10, 11, 13, 15, 20, 22, 23, 24, 31, 34, 44, 48, 50, 53, 65, 70, 80, 83, 89, 93] [3, 6, 9, 11, 12, 14, 20, 21, 23, 24, 30, 33, 44, 47, 49, 52, 64, 70, 79, 82, 88, 93, 94] ['Pattinson', 'N', '.', '&', 'Willis', 'K.Effect', 'of', 'phospholipase', 'C', 'on', 'cholesterol', 'solubilization', 'in', 'model', 'bile', '.'] [3, 1, 1, 1, 2, 3, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Belzer C., Kusters J., Kuipers E. & Van Vliet A.Urease induced calcium precipitation by Helicobacter species may initiate gallstone formation. [('PMC4667190', 'F37000', 48, 54, 'Urease')] ['Bel', '##zer', 'C', '.', ',', 'Ku', '##ster', '##s', 'J', '.', ',', 'Ku', '##ipe', '##rs', 'E', '.', '&', 'Van', 'V', '##lie', '##t', 'A', '.', 'Ur', '##ea', '##se', 'induced', 'calcium', 'precipitation', 'by', 'Helic', '##obacter', 'species', 'may', 'initiate', 'gall', '##stone', 'formation', '.'] [0, 3, 7, 8, 9, 11, 13, 17, 19, 20, 21, 23, 25, 28, 31, 32, 34, 36, 40, 41, 44, 46, 47, 48, 50, 52, 55, 63, 71, 85, 88, 93, 101, 109, 113, 122, 126, 132, 141] [3, 6, 8, 9, 10, 13, 17, 18, 20, 21, 22, 25, 28, 30, 32, 33, 35, 39, 41, 44, 45, 47, 48, 50, 52, 54, 62, 70, 84, 87, 93, 100, 108, 112, 121, 126, 131, 141, 142] ['Belzer', 'C', '.', ',', 'Kusters', 'J', '.', ',', 'Kuipers', 'E', '.', '&', 'Van', 'Vliet', 'A.Urease', 'induced', 'calcium', 'precipitation', 'by', 'Helicobacter', 'species', 'may', 'initiate', 'gallstone', 'formation', '.'] [2, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 1, 3, 5, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Stewart L., Ponce R., Oesterk A. L., Griffiss J. M. & Way L. W.Pigment gallstone pathogenesis: slime production by biliary bacteria is more important than beta-glucuronidase production. [('PMC4667190', 'F40000', 155, 173, 'beta-glucuronidase')] ['Stewart', 'L', '.', ',', 'Pon', '##ce', 'R', '.', ',', 'O', '##ester', '##k', 'A', '.', 'L', '.', ',', 'Griff', '##iss', 'J', '.', 'M', '.', '&', 'Way', 'L', '.', 'W', '.', 'Pig', '##ment', 'gall', '##stone', 'pathogenesis', ':', 'sl', '##ime', 'production', 'by', 'biliary', 'bacteria', 'is', 'more', 'important', 'than', 'beta', '-', 'gluc', '##uron', '##idase', 'production', '.'] [0, 8, 9, 10, 12, 15, 18, 19, 20, 22, 23, 28, 30, 31, 33, 34, 35, 37, 42, 46, 47, 49, 50, 52, 54, 58, 59, 61, 62, 63, 66, 71, 75, 81, 93, 95, 97, 101, 112, 115, 123, 132, 135, 140, 150, 155, 159, 160, 164, 168, 174, 184] [7, 9, 10, 11, 15, 17, 19, 20, 21, 23, 28, 29, 31, 32, 34, 35, 36, 42, 45, 47, 48, 50, 51, 53, 57, 59, 60, 62, 63, 66, 70, 75, 80, 93, 94, 97, 100, 111, 114, 122, 131, 134, 139, 149, 154, 159, 160, 164, 168, 173, 184, 185] ['Stewart', 'L', '.', ',', 'Ponce', 'R', '.', ',', 'Oesterk', 'A', '.', 'L', '.', ',', 'Griffiss', 'J', '.', 'M', '.', '&', 'Way', 'L', '.', 'W.Pigment', 'gallstone', 'pathogenesis', ':', 'slime', 'production', 'by', 'biliary', 'bacteria', 'is', 'more', 'important', 'than', 'beta', '-', 'glucuronidase', 'production', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 4, 2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O']
Many bacteria, such as Escherichia coli, Klebsiella pneumoniae, Enterococcus faecium, Enterobacter cloacae and Pseudomonas aeruginosa, have been identified in bile or gallstone samples through cultivation or polymerase chain reaction (PCR). [('PMC4667190', 'I01002', 208, 218, 'polymerase')] ['Many', 'bacteria', ',', 'such', 'as', 'Escherichia', 'coli', ',', 'Kle', '##bs', '##iel', '##la', 'pneumoniae', ',', 'Enter', '##ococcus', 'fa', '##ec', '##ium', ',', 'Enter', '##obacter', 'cl', '##oa', '##ca', '##e', 'and', 'Pseudomonas', 'aeruginosa', ',', 'have', 'been', 'identified', 'in', 'bile', 'or', 'gall', '##stone', 'samples', 'through', 'cultivation', 'or', 'polymerase', 'chain', 'reaction', '(', 'PCR', ')', '.'] [0, 5, 13, 15, 20, 23, 35, 39, 41, 44, 46, 49, 52, 62, 64, 69, 77, 79, 81, 84, 86, 91, 99, 101, 103, 105, 107, 111, 123, 133, 135, 140, 145, 156, 159, 164, 167, 171, 177, 185, 193, 205, 208, 219, 225, 234, 235, 238, 239] [4, 13, 14, 19, 22, 34, 39, 40, 44, 46, 49, 51, 62, 63, 69, 76, 79, 81, 84, 85, 91, 98, 101, 103, 105, 106, 110, 122, 133, 134, 139, 144, 155, 158, 163, 166, 171, 176, 184, 192, 204, 207, 218, 224, 233, 235, 238, 239, 240] ['Many', 'bacteria', ',', 'such', 'as', 'Escherichia', 'coli', ',', 'Klebsiella', 'pneumoniae', ',', 'Enterococcus', 'faecium', ',', 'Enterobacter', 'cloacae', 'and', 'Pseudomonas', 'aeruginosa', ',', 'have', 'been', 'identified', 'in', 'bile', 'or', 'gallstone', 'samples', 'through', 'cultivation', 'or', 'polymerase', 'chain', 'reaction', '(', 'PCR', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 2, 3, 1, 2, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O']
Bacterially produced β-glucuronidase was suggested to be associated with the formation of pigment gallstones4,10. [('PMC4667190', 'I01003', 21, 36, 'β-glucuronidase')] ['Bacterial', '##ly', 'produced', 'β', '-', 'gluc', '##uron', '##idase', 'was', 'suggested', 'to', 'be', 'associated', 'with', 'the', 'formation', 'of', 'pigment', 'gall', '##stone', '##s', '##4', ',', '10', '.'] [0, 9, 12, 21, 22, 23, 27, 31, 37, 41, 51, 54, 57, 68, 73, 77, 87, 90, 98, 102, 107, 108, 109, 110, 112] [9, 11, 20, 22, 23, 27, 31, 36, 40, 50, 53, 56, 67, 72, 76, 86, 89, 97, 102, 107, 108, 109, 110, 112, 113] ['Bacterially', 'produced', 'β-glucuronidase', 'was', 'suggested', 'to', 'be', 'associated', 'with', 'the', 'formation', 'of', 'pigment', 'gallstones4', ',', '10', '.'] [2, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Other bacterial products, such as phospholipase and slime, might also participate in gallstone formation6. [('PMC4667190', 'I01004', 34, 47, 'phospholipase')] ['Other', 'bacterial', 'products', ',', 'such', 'as', 'phospholip', '##ase', 'and', 'sl', '##ime', ',', 'might', 'also', 'participate', 'in', 'gall', '##stone', 'formation', '##6', '.'] [0, 6, 16, 24, 26, 31, 34, 44, 48, 52, 54, 57, 59, 65, 70, 82, 85, 89, 95, 104, 105] [5, 15, 24, 25, 30, 33, 44, 47, 51, 54, 57, 58, 64, 69, 81, 84, 89, 94, 104, 105, 106] ['Other', 'bacterial', 'products', ',', 'such', 'as', 'phospholipase', 'and', 'slime', ',', 'might', 'also', 'participate', 'in', 'gallstone', 'formation6', '.'] [1, 1, 1, 1, 1, 1, 2, 1, 2, 1, 1, 1, 1, 1, 2, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Previous studies have demonstrated potential associations of gallstone formation with bacterial products β-glucuronidase, phospholipase and urease6,7,36,37,38,39. [('PMC4667190', 'R09001', 105, 120, 'β-glucuronidase'), ('PMC4667190', 'R09001', 122, 135, 'phospholipase'), ('PMC4667190', 'R09001', 140, 146, 'urease')] ['Previous', 'studies', 'have', 'demonstrated', 'potential', 'associations', 'of', 'gall', '##stone', 'formation', 'with', 'bacterial', 'products', 'β', '-', 'gluc', '##uron', '##idase', ',', 'phospholip', '##ase', 'and', 'urea', '##se', '##6', ',', '7', ',', '36', ',', '37', ',', '38', ',', '39', '.'] [0, 9, 17, 22, 35, 45, 58, 61, 65, 71, 81, 86, 96, 105, 106, 107, 111, 115, 120, 122, 132, 136, 140, 144, 146, 147, 148, 149, 150, 152, 153, 155, 156, 158, 159, 161] [8, 16, 21, 34, 44, 57, 60, 65, 70, 80, 85, 95, 104, 106, 107, 111, 115, 120, 121, 132, 135, 139, 144, 146, 147, 148, 149, 150, 152, 153, 155, 156, 158, 159, 161, 162] ['Previous', 'studies', 'have', 'demonstrated', 'potential', 'associations', 'of', 'gallstone', 'formation', 'with', 'bacterial', 'products', 'β-glucuronidase', ',', 'phospholipase', 'and', 'urease6', ',', '7', ',', '36', ',', '37', ',', '38', ',', '39', '.'] [1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 5, 1, 2, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'B', 'E', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
β-glucuronidase and phospholipase hydrolyse biliary bilirubin and phosphatidylcholine, respectively, leading to precipitation of calcium bilirubinate and calcium palmitate and thereby facilitating pigment solid formation6. [('PMC4667190', 'R10000', 0, 15, 'β-glucuronidase'), ('PMC4667190', 'R10000', 20, 33, 'phospholipase')] ['β', '-', 'gluc', '##uron', '##idase', 'and', 'phospholip', '##ase', 'hydroly', '##se', 'biliary', 'bilirubin', 'and', 'phosphatidyl', '##choline', ',', 'respectively', ',', 'leading', 'to', 'precipitation', 'of', 'calcium', 'bilirubin', '##ate', 'and', 'calcium', 'palm', '##itate', 'and', 'thereby', 'facilitating', 'pigment', 'solid', 'formation', '##6', '.'] [0, 1, 2, 6, 10, 16, 20, 30, 34, 41, 44, 52, 62, 66, 78, 85, 87, 99, 101, 109, 112, 126, 129, 137, 146, 150, 154, 162, 166, 172, 176, 184, 197, 205, 211, 220, 221] [1, 2, 6, 10, 15, 19, 30, 33, 41, 43, 51, 61, 65, 78, 85, 86, 99, 100, 108, 111, 125, 128, 136, 146, 149, 153, 161, 166, 171, 175, 183, 196, 204, 210, 220, 221, 222] ['β-glucuronidase', 'and', 'phospholipase', 'hydrolyse', 'biliary', 'bilirubin', 'and', 'phosphatidylcholine', ',', 'respectively', ',', 'leading', 'to', 'precipitation', 'of', 'calcium', 'bilirubinate', 'and', 'calcium', 'palmitate', 'and', 'thereby', 'facilitating', 'pigment', 'solid', 'formation6', '.'] [5, 1, 2, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1] ['B', 'I', 'I', 'I', 'E', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Seven and ten individuals had samples containing ≥3 species harbouring genes uidA (encoding β-glucuronidase) and pldA (encoding phospholipase A1), respectively (Fig. 4a; Supplementary Table S5). [('PMC4667190', 'R10001', 92, 107, 'β-glucuronidase'), ('PMC4667190', 'R10001', 128, 144, 'phospholipase A1')] ['Seven', 'and', 'ten', 'individuals', 'had', 'samples', 'containing', '≥', '3', 'species', 'harb', '##ouri', '##ng', 'genes', 'ui', '##d', '##A', '(', 'encoding', 'β', '-', 'gluc', '##uron', '##idase', ')', 'and', 'pl', '##d', '##A', '(', 'encoding', 'phospholip', '##ase', 'A', '##1', ')', ',', 'respectively', '(', 'Fig', '.', '4', '##a', ';', 'Supplementary', 'Table', 'S', '##5', ')', '.'] [0, 6, 10, 14, 26, 30, 38, 49, 50, 52, 60, 64, 68, 71, 77, 79, 80, 82, 83, 92, 93, 94, 98, 102, 107, 109, 113, 115, 116, 118, 119, 128, 138, 142, 143, 144, 145, 147, 160, 161, 164, 166, 167, 168, 170, 184, 190, 191, 192, 193] [5, 9, 13, 25, 29, 37, 48, 50, 51, 59, 64, 68, 70, 76, 79, 80, 81, 83, 91, 93, 94, 98, 102, 107, 108, 112, 115, 116, 117, 119, 127, 138, 141, 143, 144, 145, 146, 159, 161, 164, 165, 167, 168, 169, 183, 189, 191, 192, 193, 194] ['Seven', 'and', 'ten', 'individuals', 'had', 'samples', 'containing', '≥', '3', 'species', 'harbouring', 'genes', 'uidA', '(', 'encoding', 'β-glucuronidase', ')', 'and', 'pldA', '(', 'encoding', 'phospholipase', 'A1', ')', ',', 'respectively', '(', 'Fig', '.', '4a', ';', 'Supplementary', 'Table', 'S5', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 5, 1, 1, 3, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
As the species numbers were correlated with bacterial WMS sequencing read ratios (Fig. 1a), failure to identify genes encoding β-glucuronidase or phospholipase might be due to issues related to DNA extraction or sequencing. [('PMC4667190', 'R10003', 127, 142, 'β-glucuronidase'), ('PMC4667190', 'R10003', 146, 159, 'phospholipase')] ['As', 'the', 'species', 'numbers', 'were', 'correlated', 'with', 'bacterial', 'WM', '##S', 'sequencing', 'read', 'ratios', '(', 'Fig', '.', '1', '##a', ')', ',', 'failure', 'to', 'identify', 'genes', 'encoding', 'β', '-', 'gluc', '##uron', '##idase', 'or', 'phospholip', '##ase', 'might', 'be', 'due', 'to', 'issues', 'related', 'to', 'DNA', 'extraction', 'or', 'sequencing', '.'] [0, 3, 7, 15, 23, 28, 39, 44, 54, 56, 58, 69, 74, 81, 82, 85, 87, 88, 89, 90, 92, 100, 103, 112, 118, 127, 128, 129, 133, 137, 143, 146, 156, 160, 166, 169, 173, 176, 183, 191, 194, 198, 209, 212, 222] [2, 6, 14, 22, 27, 38, 43, 53, 56, 57, 68, 73, 80, 82, 85, 86, 88, 89, 90, 91, 99, 102, 111, 117, 126, 128, 129, 133, 137, 142, 145, 156, 159, 165, 168, 172, 175, 182, 190, 193, 197, 208, 211, 222, 223] ['As', 'the', 'species', 'numbers', 'were', 'correlated', 'with', 'bacterial', 'WMS', 'sequencing', 'read', 'ratios', '(', 'Fig', '.', '1a', ')', ',', 'failure', 'to', 'identify', 'genes', 'encoding', 'β-glucuronidase', 'or', 'phospholipase', 'might', 'be', 'due', 'to', 'issues', 'related', 'to', 'DNA', 'extraction', 'or', 'sequencing', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 5, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
For most individuals, the gene predictions did not identify the gene plcC encoding phospholipase C, which promotes cholesterol nucleation in human gallbladder bile37. [('PMC4667190', 'R10004', 83, 98, 'phospholipase C')] ['For', 'most', 'individuals', ',', 'the', 'gene', 'predictions', 'did', 'not', 'identify', 'the', 'gene', 'pl', '##c', '##C', 'encoding', 'phospholip', '##ase', 'C', ',', 'which', 'promotes', 'cholesterol', 'nucleation', 'in', 'human', 'gall', '##bladder', 'bile', '##37', '.'] [0, 4, 9, 20, 22, 26, 31, 43, 47, 51, 60, 64, 69, 71, 72, 74, 83, 93, 97, 98, 100, 106, 115, 127, 138, 141, 147, 151, 159, 163, 165] [3, 8, 20, 21, 25, 30, 42, 46, 50, 59, 63, 68, 71, 72, 73, 82, 93, 96, 98, 99, 105, 114, 126, 137, 140, 146, 151, 158, 163, 165, 166] ['For', 'most', 'individuals', ',', 'the', 'gene', 'predictions', 'did', 'not', 'identify', 'the', 'gene', 'plcC', 'encoding', 'phospholipase', 'C', ',', 'which', 'promotes', 'cholesterol', 'nucleation', 'in', 'human', 'gallbladder', 'bile37', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 2, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Helicobacter-produced urease was reported to promote calcium precipitation, which might initiate gallstone formation38. [('PMC4667190', 'R10005', 22, 28, 'urease')] ['Helic', '##obacter', '-', 'produced', 'urea', '##se', 'was', 'reported', 'to', 'promote', 'calcium', 'precipitation', ',', 'which', 'might', 'initiate', 'gall', '##stone', 'formation', '##38', '.'] [0, 5, 12, 13, 22, 26, 29, 33, 42, 45, 53, 61, 74, 76, 82, 88, 97, 101, 107, 116, 118] [5, 12, 13, 21, 26, 28, 32, 41, 44, 52, 60, 74, 75, 81, 87, 96, 101, 106, 116, 118, 119] ['Helicobacter', '-', 'produced', 'urease', 'was', 'reported', 'to', 'promote', 'calcium', 'precipitation', ',', 'which', 'might', 'initiate', 'gallstone', 'formation38', '.'] [2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 2, 1] ['O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Although the genes encoding urease were prevalent in the bile samples, Helicobacter spp. were not found among the urease-containing bacteria. [('PMC4667190', 'R10006', 28, 34, 'urease'), ('PMC4667190', 'R10006', 114, 120, 'urease')] ['Although', 'the', 'genes', 'encoding', 'urea', '##se', 'were', 'prevalent', 'in', 'the', 'bile', 'samples', ',', 'Helic', '##obacter', 'spp', '.', 'were', 'not', 'found', 'among', 'the', 'urea', '##se', '-', 'containing', 'bacteria', '.'] [0, 9, 13, 19, 28, 32, 35, 40, 50, 53, 57, 62, 69, 71, 76, 84, 87, 89, 94, 98, 104, 110, 114, 118, 120, 121, 132, 140] [8, 12, 18, 27, 32, 34, 39, 49, 52, 56, 61, 69, 70, 76, 83, 87, 88, 93, 97, 103, 109, 113, 118, 120, 121, 131, 140, 141] ['Although', 'the', 'genes', 'encoding', 'urease', 'were', 'prevalent', 'in', 'the', 'bile', 'samples', ',', 'Helicobacter', 'spp', '.', 'were', 'not', 'found', 'among', 'the', 'urease', '-', 'containing', 'bacteria', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O']
Within bile microbial communities in this study, we found 13 species with the gene encoding bile salt hydrolase (bsh) and 30 species with genes encoding efflux pump proteins (acrA, n = 29; acrB, n = 29; emrA, n = 23; emrB, n = 23; tolC, n = 22). [('PMC4667190', 'R11002', 92, 111, 'bile salt hydrolase')] ['Within', 'bile', 'microbial', 'communities', 'in', 'this', 'study', ',', 'we', 'found', '13', 'species', 'with', 'the', 'gene', 'encoding', 'bile', 'salt', 'hydro', '##las', '##e', '(', 'bs', '##h', ')', 'and', '30', 'species', 'with', 'genes', 'encoding', 'efflux', 'pump', 'proteins', '(', 'acr', '##A', ',', 'n', '=', '29', ';', 'acr', '##B', ',', 'n', '=', '29', ';', 'em', '##r', '##A', ',', 'n', '=', '23', ';', 'em', '##r', '##B', ',', 'n', '=', '23', ';', 'to', '##l', '##C', ',', 'n', '=', '22', ')', '.'] [0, 7, 12, 22, 34, 37, 42, 47, 49, 52, 58, 61, 69, 74, 78, 83, 92, 97, 102, 107, 110, 112, 113, 115, 116, 118, 122, 125, 133, 138, 144, 153, 160, 165, 174, 175, 178, 179, 181, 183, 185, 187, 189, 192, 193, 195, 197, 199, 201, 203, 205, 206, 207, 209, 211, 213, 215, 217, 219, 220, 221, 223, 225, 227, 229, 231, 233, 234, 235, 237, 239, 241, 243, 244] [6, 11, 21, 33, 36, 41, 47, 48, 51, 57, 60, 68, 73, 77, 82, 91, 96, 101, 107, 110, 111, 113, 115, 116, 117, 121, 124, 132, 137, 143, 152, 159, 164, 173, 175, 178, 179, 180, 182, 184, 187, 188, 192, 193, 194, 196, 198, 201, 202, 205, 206, 207, 208, 210, 212, 215, 216, 219, 220, 221, 222, 224, 226, 229, 230, 233, 234, 235, 236, 238, 240, 243, 244, 245] ['Within', 'bile', 'microbial', 'communities', 'in', 'this', 'study', ',', 'we', 'found', '13', 'species', 'with', 'the', 'gene', 'encoding', 'bile', 'salt', 'hydrolase', '(', 'bsh', ')', 'and', '30', 'species', 'with', 'genes', 'encoding', 'efflux', 'pump', 'proteins', '(', 'acrA', ',', 'n', '=', '29', ';', 'acrB', ',', 'n', '=', '29', ';', 'emrA', ',', 'n', '=', '23', ';', 'emrB', ',', 'n', '=', '23', ';', 'tolC', ',', 'n', '=', '22', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Upon investigating KEGG orthologues associated with resistance to oxidative stress (Supplementary Table S9), we observed an enrichment of glutathione reductase (NADPH, K00383, adjusted P < 2.1 × 10−4) and putative iron-dependent peroxidase (K07223, adjusted P < 0.042), consistent with the pathway analysis results. [('PMC4667190', 'R14002', 138, 159, 'glutathione reductase'), ('PMC4667190', 'R14002', 214, 239, 'iron-dependent peroxidase')] ['Upon', 'investigating', 'KE', '##GG', 'ortholog', '##ues', 'associated', 'with', 'resistance', 'to', 'oxidative', 'stress', '(', 'Supplementary', 'Table', 'S', '##9', ')', ',', 'we', 'observed', 'an', 'enrichment', 'of', 'glutathione', 'reductase', '(', 'NADPH', ',', 'K', '##003', '##83', ',', 'adjusted', 'P', '<', '2', '.', '1', '×', '10−', '##4', ')', 'and', 'putative', 'iron', '-', 'dependent', 'peroxidase', '(', 'K', '##07', '##22', '##3', ',', 'adjusted', 'P', '<', '0', '.', '04', '##2', ')', ',', 'consistent', 'with', 'the', 'pathway', 'analysis', 'results', '.'] [0, 5, 19, 21, 24, 32, 36, 47, 52, 63, 66, 76, 83, 84, 98, 104, 105, 106, 107, 109, 112, 121, 124, 135, 138, 150, 160, 161, 166, 168, 169, 172, 174, 176, 185, 187, 189, 190, 191, 193, 195, 198, 199, 201, 205, 214, 218, 219, 229, 240, 241, 242, 244, 246, 247, 249, 258, 260, 262, 263, 264, 266, 267, 268, 270, 281, 286, 290, 298, 307, 314] [4, 18, 21, 23, 32, 35, 46, 51, 62, 65, 75, 82, 84, 97, 103, 105, 106, 107, 108, 111, 120, 123, 134, 137, 149, 159, 161, 166, 167, 169, 172, 174, 175, 184, 186, 188, 190, 191, 192, 194, 198, 199, 200, 204, 213, 218, 219, 228, 239, 241, 242, 244, 246, 247, 248, 257, 259, 261, 263, 264, 266, 267, 268, 269, 280, 285, 289, 297, 306, 314, 315] ['Upon', 'investigating', 'KEGG', 'orthologues', 'associated', 'with', 'resistance', 'to', 'oxidative', 'stress', '(', 'Supplementary', 'Table', 'S9', ')', ',', 'we', 'observed', 'an', 'enrichment', 'of', 'glutathione', 'reductase', '(', 'NADPH', ',', 'K00383', ',', 'adjusted', 'P', '<', '2.1', '×', '10−4', ')', 'and', 'putative', 'iron', '-', 'dependent', 'peroxidase', '(', 'K07223', ',', 'adjusted', 'P', '<', '0.042', ')', ',', 'consistent', 'with', 'the', 'pathway', 'analysis', 'results', '.'] [1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Glycolysis/gluconeogenesis, propanoate metabolism, ascorbate/aldarate metabolism, ABC transporter and phosphotransferase system pathways were also enriched (all adjusted P < 4 × 10−5). [('PMC4667190', 'R14004', 102, 120, 'phosphotransferase')] ['Gly', '##col', '##ysis', '/', 'gluc', '##one', '##ogenesis', ',', 'prop', '##ano', '##ate', 'metabolism', ',', 'ascorb', '##ate', '/', 'ald', '##ara', '##te', 'metabolism', ',', 'ABC', 'transporter', 'and', 'phospho', '##transferase', 'system', 'pathways', 'were', 'also', 'enriched', '(', 'all', 'adjusted', 'P', '<', '4', '×', '10−', '##5', ')', '.'] [0, 3, 6, 10, 11, 15, 18, 26, 28, 32, 35, 39, 49, 51, 57, 60, 61, 64, 67, 70, 80, 82, 86, 98, 102, 109, 121, 128, 137, 142, 147, 156, 157, 161, 170, 172, 174, 176, 178, 181, 182, 183] [3, 6, 10, 11, 15, 18, 26, 27, 32, 35, 38, 49, 50, 57, 60, 61, 64, 67, 69, 80, 81, 85, 97, 101, 109, 120, 127, 136, 141, 146, 155, 157, 160, 169, 171, 173, 175, 177, 181, 182, 183, 184] ['Glycolysis', '/', 'gluconeogenesis', ',', 'propanoate', 'metabolism', ',', 'ascorbate', '/', 'aldarate', 'metabolism', ',', 'ABC', 'transporter', 'and', 'phosphotransferase', 'system', 'pathways', 'were', 'also', 'enriched', '(', 'all', 'adjusted', 'P', '<', '4', '×', '10−5', ')', '.'] [3, 1, 3, 1, 3, 1, 1, 2, 1, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Validation studies revealed cyclophilin A, annexin A2, and aldolase A mRNA and protein expression levels were significantly higher in cancer regions than in non-cancer regions. [('PMC5097088', 'A00005', 59, 69, 'aldolase A')] ['Validation', 'studies', 'revealed', 'cyclo', '##ph', '##ilin', 'A', ',', 'anne', '##xin', 'A', '##2', ',', 'and', 'ald', '##olas', '##e', 'A', 'mRNA', 'and', 'protein', 'expression', 'levels', 'were', 'significantly', 'higher', 'in', 'cancer', 'regions', 'than', 'in', 'non', '-', 'cancer', 'regions', '.'] [0, 11, 19, 28, 33, 35, 40, 41, 43, 47, 51, 52, 53, 55, 59, 62, 66, 68, 70, 75, 79, 87, 98, 105, 110, 124, 131, 134, 141, 149, 154, 157, 160, 161, 168, 175] [10, 18, 27, 33, 35, 39, 41, 42, 47, 50, 52, 53, 54, 58, 62, 66, 67, 69, 74, 78, 86, 97, 104, 109, 123, 130, 133, 140, 148, 153, 156, 160, 161, 167, 175, 176] ['Validation', 'studies', 'revealed', 'cyclophilin', 'A', ',', 'annexin', 'A2', ',', 'and', 'aldolase', 'A', 'mRNA', 'and', 'protein', 'expression', 'levels', 'were', 'significantly', 'higher', 'in', 'cancer', 'regions', 'than', 'in', 'non', '-', 'cancer', 'regions', '.'] [1, 1, 1, 3, 1, 1, 2, 2, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Moreover, an in vitro study showed that secretion of aldolase A into the culture medium was clearly suppressed in CRC cells compared to normal colon epithelium. [('PMC5097088', 'A00006', 53, 63, 'aldolase A')] ['Moreover', ',', 'an', 'in', 'vitro', 'study', 'showed', 'that', 'secretion', 'of', 'ald', '##olas', '##e', 'A', 'into', 'the', 'culture', 'medium', 'was', 'clearly', 'suppressed', 'in', 'CRC', 'cells', 'compared', 'to', 'normal', 'colon', 'epithelium', '.'] [0, 8, 10, 13, 16, 22, 28, 35, 40, 50, 53, 56, 60, 62, 64, 69, 73, 81, 88, 92, 100, 111, 114, 118, 124, 133, 136, 143, 149, 159] [8, 9, 12, 15, 21, 27, 34, 39, 49, 52, 56, 60, 61, 63, 68, 72, 80, 87, 91, 99, 110, 113, 117, 123, 132, 135, 142, 148, 159, 160] ['Moreover', ',', 'an', 'in', 'vitro', 'study', 'showed', 'that', 'secretion', 'of', 'aldolase', 'A', 'into', 'the', 'culture', 'medium', 'was', 'clearly', 'suppressed', 'in', 'CRC', 'cells', 'compared', 'to', 'normal', 'colon', 'epithelium', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
These findings suggest that decreased aldolase A in blood may be a novel biomarker for the early detection of CRC. [('PMC5097088', 'A00007', 38, 48, 'aldolase A')] ['These', 'findings', 'suggest', 'that', 'decreased', 'ald', '##olas', '##e', 'A', 'in', 'blood', 'may', 'be', 'a', 'novel', 'biomarker', 'for', 'the', 'early', 'detection', 'of', 'CRC', '.'] [0, 6, 15, 23, 28, 38, 41, 45, 47, 49, 52, 58, 62, 65, 67, 73, 83, 87, 91, 97, 107, 110, 113] [5, 14, 22, 27, 37, 41, 45, 46, 48, 51, 57, 61, 64, 66, 72, 82, 86, 90, 96, 106, 109, 113, 114] ['These', 'findings', 'suggest', 'that', 'decreased', 'aldolase', 'A', 'in', 'blood', 'may', 'be', 'a', 'novel', 'biomarker', 'for', 'the', 'early', 'detection', 'of', 'CRC', '.'] [1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
These criteria led us to select aldolase A, cyclophilin A, and annexin A2 as candidates. [('PMC5097088', 'D01002', 32, 42, 'aldolase A')] ['These', 'criteria', 'led', 'us', 'to', 'select', 'ald', '##olas', '##e', 'A', ',', 'cyclo', '##ph', '##ilin', 'A', ',', 'and', 'anne', '##xin', 'A', '##2', 'as', 'candidates', '.'] [0, 6, 15, 19, 22, 25, 32, 35, 39, 41, 42, 44, 49, 51, 56, 57, 59, 63, 67, 71, 72, 74, 77, 87] [5, 14, 18, 21, 24, 31, 35, 39, 40, 42, 43, 49, 51, 55, 57, 58, 62, 67, 70, 72, 73, 76, 87, 88] ['These', 'criteria', 'led', 'us', 'to', 'select', 'aldolase', 'A', ',', 'cyclophilin', 'A', ',', 'and', 'annexin', 'A2', 'as', 'candidates', '.'] [1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 2, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Although mRNA and protein expression of aldolase A were detected in all tested cell lines (Fig. (Fig.7a7a and d), aldolase A protein was not detected in the culture medium of the three CRC cell lines, while it was clearly detected in the culture medium of normal colon epithelial cells (Fig. (Fig.7e).7e). [('PMC5097088', 'D03000', 40, 50, 'aldolase A'), ('PMC5097088', 'D03000', 115, 125, 'aldolase A')] ['Although', 'mRNA', 'and', 'protein', 'expression', 'of', 'ald', '##olas', '##e', 'A', 'were', 'detected', 'in', 'all', 'tested', 'cell', 'lines', '(', 'Fig', '.', '(', 'Fig', '.', '7', '##a', '##7', '##a', 'and', 'd', ')', ',', 'ald', '##olas', '##e', 'A', 'protein', 'was', 'not', 'detected', 'in', 'the', 'culture', 'medium', 'of', 'the', 'three', 'CRC', 'cell', 'lines', ',', 'while', 'it', 'was', 'clearly', 'detected', 'in', 'the', 'culture', 'medium', 'of', 'normal', 'colon', 'epithelial', 'cells', '(', 'Fig', '.', '(', 'Fig', '.', '7', '##e', ')', '.', '7', '##e', ')', '.'] [0, 9, 14, 18, 26, 37, 40, 43, 47, 49, 51, 56, 65, 68, 72, 79, 84, 90, 91, 94, 97, 98, 101, 102, 103, 104, 105, 107, 111, 112, 113, 115, 118, 122, 124, 126, 134, 138, 142, 151, 154, 158, 166, 173, 176, 180, 186, 190, 195, 200, 202, 208, 211, 215, 223, 232, 235, 239, 247, 254, 257, 264, 270, 281, 287, 288, 291, 294, 295, 298, 299, 300, 301, 302, 303, 304, 305, 306] [8, 13, 17, 25, 36, 39, 43, 47, 48, 50, 55, 64, 67, 71, 78, 83, 89, 91, 94, 95, 98, 101, 102, 103, 104, 105, 106, 110, 112, 113, 114, 118, 122, 123, 125, 133, 137, 141, 150, 153, 157, 165, 172, 175, 179, 185, 189, 194, 200, 201, 207, 210, 214, 222, 231, 234, 238, 246, 253, 256, 263, 269, 280, 286, 288, 291, 292, 295, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307] ['Although', 'mRNA', 'and', 'protein', 'expression', 'of', 'aldolase', 'A', 'were', 'detected', 'in', 'all', 'tested', 'cell', 'lines', '(', 'Fig', '.', '\u200b(Fig.7a7a', 'and', 'd', ')', ',', 'aldolase', 'A', 'protein', 'was', 'not', 'detected', 'in', 'the', 'culture', 'medium', 'of', 'the', 'three', 'CRC', 'cell', 'lines', ',', 'while', 'it', 'was', 'clearly', 'detected', 'in', 'the', 'culture', 'medium', 'of', 'normal', 'colon', 'epithelial', 'cells', '(', 'Fig', '.', '\u200b(Fig.7e).7e', ')', '.'] [1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 7, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Moreover, aldolase A was detected in normal human serum (Fig. [('PMC5097088', 'D03001', 10, 20, 'aldolase A')] ['Moreover', ',', 'ald', '##olas', '##e', 'A', 'was', 'detected', 'in', 'normal', 'human', 'serum', '(', 'Fig', '.'] [0, 8, 10, 13, 17, 19, 21, 25, 34, 37, 44, 50, 56, 57, 60] [8, 9, 13, 17, 18, 20, 24, 33, 36, 43, 49, 55, 57, 60, 61] ['Moreover', ',', 'aldolase', 'A', 'was', 'detected', 'in', 'normal', 'human', 'serum', '(', 'Fig', '.'] [1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
These results suggest that secretion of aldolase A may be suppressed by dysfunction of aldolase A due to accumulated genetic mutations during the carcinogenesis process of CRC. [('PMC5097088', 'D03003', 40, 50, 'aldolase A'), ('PMC5097088', 'D03003', 87, 97, 'aldolase A')] ['These', 'results', 'suggest', 'that', 'secretion', 'of', 'ald', '##olas', '##e', 'A', 'may', 'be', 'suppressed', 'by', 'dysfunction', 'of', 'ald', '##olas', '##e', 'A', 'due', 'to', 'accumulated', 'genetic', 'mutations', 'during', 'the', 'carcinogenesis', 'process', 'of', 'CRC', '.'] [0, 6, 14, 22, 27, 37, 40, 43, 47, 49, 51, 55, 58, 69, 72, 84, 87, 90, 94, 96, 98, 102, 105, 117, 125, 135, 142, 146, 161, 169, 172, 175] [5, 13, 21, 26, 36, 39, 43, 47, 48, 50, 54, 57, 68, 71, 83, 86, 90, 94, 95, 97, 101, 104, 116, 124, 134, 141, 145, 160, 168, 171, 175, 176] ['These', 'results', 'suggest', 'that', 'secretion', 'of', 'aldolase', 'A', 'may', 'be', 'suppressed', 'by', 'dysfunction', 'of', 'aldolase', 'A', 'due', 'to', 'accumulated', 'genetic', 'mutations', 'during', 'the', 'carcinogenesis', 'process', 'of', 'CRC', '.'] [1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Therefore, decreased aldolase A levels in blood may be useful as a biomarker for the early diagnosis of CRC. [('PMC5097088', 'D03004', 21, 31, 'aldolase A')] ['Therefore', ',', 'decreased', 'ald', '##olas', '##e', 'A', 'levels', 'in', 'blood', 'may', 'be', 'useful', 'as', 'a', 'biomarker', 'for', 'the', 'early', 'diagnosis', 'of', 'CRC', '.'] [0, 9, 11, 21, 24, 28, 30, 32, 39, 42, 48, 52, 55, 62, 65, 67, 77, 81, 85, 91, 101, 104, 107] [9, 10, 20, 24, 28, 29, 31, 38, 41, 47, 51, 54, 61, 64, 66, 76, 80, 84, 90, 100, 103, 107, 108] ['Therefore', ',', 'decreased', 'aldolase', 'A', 'levels', 'in', 'blood', 'may', 'be', 'useful', 'as', 'a', 'biomarker', 'for', 'the', 'early', 'diagnosis', 'of', 'CRC', '.'] [1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Aldolase A is a glycolytic enzyme and contributes to various cellular functions related to muscle maintenance, cell shape and mobility regulation, striated muscle contraction, actin filament organization, and ATP biosynthesis [30–40]. [('PMC5097088', 'D04000', 0, 10, 'Aldolase A')] ['Al', '##do', '##las', '##e', 'A', 'is', 'a', 'glycol', '##ytic', 'enzyme', 'and', 'contributes', 'to', 'various', 'cellular', 'functions', 'related', 'to', 'muscle', 'maintenance', ',', 'cell', 'shape', 'and', 'mobility', 'regulation', ',', 'stri', '##ated', 'muscle', 'contraction', ',', 'actin', 'filament', 'organization', ',', 'and', 'ATP', 'biosynthesis', '[', '30', '–', '40', ']', '.'] [0, 2, 4, 7, 9, 11, 14, 16, 22, 27, 34, 38, 50, 53, 61, 70, 80, 88, 91, 98, 109, 111, 116, 122, 126, 135, 145, 147, 151, 156, 163, 174, 176, 182, 191, 203, 205, 209, 213, 226, 227, 229, 230, 232, 233] [2, 4, 7, 8, 10, 13, 15, 22, 26, 33, 37, 49, 52, 60, 69, 79, 87, 90, 97, 109, 110, 115, 121, 125, 134, 145, 146, 151, 155, 162, 174, 175, 181, 190, 203, 204, 208, 212, 225, 227, 229, 230, 232, 233, 234] ['Aldolase', 'A', 'is', 'a', 'glycolytic', 'enzyme', 'and', 'contributes', 'to', 'various', 'cellular', 'functions', 'related', 'to', 'muscle', 'maintenance', ',', 'cell', 'shape', 'and', 'mobility', 'regulation', ',', 'striated', 'muscle', 'contraction', ',', 'actin', 'filament', 'organization', ',', 'and', 'ATP', 'biosynthesis', '[', '30–', '40', ']', '.'] [4, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1] ['B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
There are several reports of elevated expression of aldolase A in the serum of patients with malignant tumors, such as those with lung and renal cancer [41, 42]. [('PMC5097088', 'D04001', 52, 62, 'aldolase A')] ['There', 'are', 'several', 'reports', 'of', 'elevated', 'expression', 'of', 'ald', '##olas', '##e', 'A', 'in', 'the', 'serum', 'of', 'patients', 'with', 'malignant', 'tumors', ',', 'such', 'as', 'those', 'with', 'lung', 'and', 'renal', 'cancer', '[', '41', ',', '42', ']', '.'] [0, 6, 10, 18, 26, 29, 38, 49, 52, 55, 59, 61, 63, 66, 70, 76, 79, 88, 93, 103, 109, 111, 116, 119, 125, 130, 135, 139, 145, 152, 153, 155, 157, 159, 160] [5, 9, 17, 25, 28, 37, 48, 51, 55, 59, 60, 62, 65, 69, 75, 78, 87, 92, 102, 109, 110, 115, 118, 124, 129, 134, 138, 144, 151, 153, 155, 156, 159, 160, 161] ['There', 'are', 'several', 'reports', 'of', 'elevated', 'expression', 'of', 'aldolase', 'A', 'in', 'the', 'serum', 'of', 'patients', 'with', 'malignant', 'tumors', ',', 'such', 'as', 'those', 'with', 'lung', 'and', 'renal', 'cancer', '[', '41', ',', '42', ']', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
However, the expression kinetics and functions of aldolase A in CRC are not well understood. [('PMC5097088', 'D04002', 50, 60, 'aldolase A')] ['However', ',', 'the', 'expression', 'kinetics', 'and', 'functions', 'of', 'ald', '##olas', '##e', 'A', 'in', 'CRC', 'are', 'not', 'well', 'understood', '.'] [0, 7, 9, 13, 24, 33, 37, 47, 50, 53, 57, 59, 61, 64, 68, 72, 76, 81, 91] [7, 8, 12, 23, 32, 36, 46, 49, 53, 57, 58, 60, 63, 67, 71, 75, 80, 91, 92] ['However', ',', 'the', 'expression', 'kinetics', 'and', 'functions', 'of', 'aldolase', 'A', 'in', 'CRC', 'are', 'not', 'well', 'understood', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To our knowledge, this is the first report of decreased secretion of aldolase A in CRC. [('PMC5097088', 'D04003', 69, 79, 'aldolase A')] ['To', 'our', 'knowledge', ',', 'this', 'is', 'the', 'first', 'report', 'of', 'decreased', 'secretion', 'of', 'ald', '##olas', '##e', 'A', 'in', 'CRC', '.'] [0, 3, 7, 16, 18, 23, 26, 30, 36, 43, 46, 56, 66, 69, 72, 76, 78, 80, 83, 86] [2, 6, 16, 17, 22, 25, 29, 35, 42, 45, 55, 65, 68, 72, 76, 77, 79, 82, 86, 87] ['To', 'our', 'knowledge', ',', 'this', 'is', 'the', 'first', 'report', 'of', 'decreased', 'secretion', 'of', 'aldolase', 'A', 'in', 'CRC', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O']
Thus, further studies are necessary to clarify the decrease in aldolase A levels in the blood of CRC patients in order to determine if this protein can be used as an early detection biomarker for CRC. [('PMC5097088', 'D04004', 63, 73, 'aldolase A')] ['Thus', ',', 'further', 'studies', 'are', 'necessary', 'to', 'clarify', 'the', 'decrease', 'in', 'ald', '##olas', '##e', 'A', 'levels', 'in', 'the', 'blood', 'of', 'CRC', 'patients', 'in', 'order', 'to', 'determine', 'if', 'this', 'protein', 'can', 'be', 'used', 'as', 'an', 'early', 'detection', 'biomarker', 'for', 'CRC', '.'] [0, 4, 6, 14, 22, 26, 36, 39, 47, 51, 60, 63, 66, 70, 72, 74, 81, 84, 88, 94, 97, 101, 110, 113, 119, 122, 132, 135, 140, 148, 152, 155, 160, 163, 166, 172, 182, 192, 196, 199] [4, 5, 13, 21, 25, 35, 38, 46, 50, 59, 62, 66, 70, 71, 73, 80, 83, 87, 93, 96, 100, 109, 112, 118, 121, 131, 134, 139, 147, 151, 154, 159, 162, 165, 171, 181, 191, 195, 199, 200] ['Thus', ',', 'further', 'studies', 'are', 'necessary', 'to', 'clarify', 'the', 'decrease', 'in', 'aldolase', 'A', 'levels', 'in', 'the', 'blood', 'of', 'CRC', 'patients', 'in', 'order', 'to', 'determine', 'if', 'this', 'protein', 'can', 'be', 'used', 'as', 'an', 'early', 'detection', 'biomarker', 'for', 'CRC', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Kusakabe T, Motoki K, Hori K. Mode of interactions of human aldolase isozymes with cytoskeletons. [('PMC5097088', 'F29001', 60, 68, 'aldolase')] ['Ku', '##sa', '##ka', '##be', 'T', ',', 'Mot', '##ok', '##i', 'K', ',', 'Hor', '##i', 'K', '.', 'Mode', 'of', 'interactions', 'of', 'human', 'ald', '##olas', '##e', 'iso', '##zymes', 'with', 'cytoskeleton', '##s', '.'] [0, 2, 4, 6, 9, 10, 12, 15, 17, 19, 20, 22, 25, 27, 28, 30, 35, 38, 51, 54, 60, 63, 67, 69, 72, 78, 83, 95, 96] [2, 4, 6, 8, 10, 11, 15, 17, 18, 20, 21, 25, 26, 28, 29, 34, 37, 50, 53, 59, 63, 67, 68, 72, 77, 82, 95, 96, 97] ['Kusakabe', 'T', ',', 'Motoki', 'K', ',', 'Hori', 'K', '.', 'Mode', 'of', 'interactions', 'of', 'human', 'aldolase', 'isozymes', 'with', 'cytoskeletons', '.'] [4, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 2, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
Enzyme kinetic evidence of active-site involvement in the interaction between aldolase and muscle myofibrils. [('PMC5097088', 'F30002', 78, 86, 'aldolase')] ['Enzyme', 'kinetic', 'evidence', 'of', 'active', '-', 'site', 'involvement', 'in', 'the', 'interaction', 'between', 'ald', '##olas', '##e', 'and', 'muscle', 'my', '##ofib', '##ril', '##s', '.'] [0, 7, 15, 24, 27, 33, 34, 39, 51, 54, 58, 70, 78, 81, 85, 87, 91, 98, 100, 104, 107, 108] [6, 14, 23, 26, 33, 34, 38, 50, 53, 57, 69, 77, 81, 85, 86, 90, 97, 100, 104, 107, 108, 109] ['Enzyme', 'kinetic', 'evidence', 'of', 'active', '-', 'site', 'involvement', 'in', 'the', 'interaction', 'between', 'aldolase', 'and', 'muscle', 'myofibrils', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 4, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Carr D, Knull H. Aldolase-tubulin interactions: removal of tubulin C-terminals impairs interactions. [('PMC5097088', 'F31001', 17, 25, 'Aldolase')] ['Carr', 'D', ',', 'Kn', '##ull', 'H', '.', 'Al', '##do', '##las', '##e', '-', 'tubulin', 'interactions', ':', 'removal', 'of', 'tubulin', 'C', '-', 'terminals', 'impairs', 'interactions', '.'] [0, 5, 6, 8, 10, 14, 15, 17, 19, 21, 24, 25, 26, 34, 46, 48, 56, 59, 67, 68, 69, 79, 87, 99] [4, 6, 7, 10, 13, 15, 16, 19, 21, 24, 25, 26, 33, 46, 47, 55, 58, 66, 68, 69, 78, 86, 99, 100] ['Carr', 'D', ',', 'Knull', 'H', '.', 'Aldolase', '-', 'tubulin', 'interactions', ':', 'removal', 'of', 'tubulin', 'C-', 'terminals', 'impairs', 'interactions', '.'] [1, 1, 1, 2, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
St-Jean M, Izard T, Sygusch J. A hydrophobic pocket in the active site of glycolytic aldolase mediates interactions with Wiskott-Aldrich syndrome protein. [('PMC5097088', 'F32001', 85, 93, 'aldolase')] ['St', '-', 'Jean', 'M', ',', 'Iz', '##ard', 'T', ',', 'Sy', '##gu', '##sch', 'J', '.', 'A', 'hydrophobic', 'pocket', 'in', 'the', 'active', 'site', 'of', 'glycol', '##ytic', 'ald', '##olas', '##e', 'mediates', 'interactions', 'with', 'Wi', '##sk', '##ott', '-', 'Aldr', '##ich', 'syndrome', 'protein', '.'] [0, 2, 3, 8, 9, 11, 13, 17, 18, 20, 22, 24, 28, 29, 31, 33, 45, 52, 55, 59, 66, 71, 74, 80, 85, 88, 92, 94, 103, 116, 121, 123, 125, 128, 129, 133, 137, 146, 153] [2, 3, 7, 9, 10, 13, 16, 18, 19, 22, 24, 27, 29, 30, 32, 44, 51, 54, 58, 65, 70, 73, 80, 84, 88, 92, 93, 102, 115, 120, 123, 125, 128, 129, 133, 136, 145, 153, 154] ['St-Jean', 'M', ',', 'Izard', 'T', ',', 'Sygusch', 'J', '.', 'A', 'hydrophobic', 'pocket', 'in', 'the', 'active', 'site', 'of', 'glycolytic', 'aldolase', 'mediates', 'interactions', 'with', 'Wiskott-Aldrich', 'syndrome', 'protein', '.'] [3, 1, 1, 2, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 3, 1, 1, 1, 6, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Tochio T, Tanaka H, Nakata S, Hosoya H. Fructose-1,6-bisphosphate aldolase a is involved in HaCaT cell migration by inducing lamellipodia formation. [('PMC5097088', 'F38001', 40, 76, 'Fructose-1,6-bisphosphate aldolase a')] ['To', '##chi', '##o', 'T', ',', 'Tanaka', 'H', ',', 'Nak', '##ata', 'S', ',', 'Hos', '##oya', 'H', '.', 'Fr', '##uctose', '-', '1', ',', '6', '-', 'bis', '##phosphate', 'ald', '##olas', '##e', 'a', 'is', 'involved', 'in', 'Ha', '##Ca', '##T', 'cell', 'migration', 'by', 'inducing', 'lam', '##elli', '##po', '##di', '##a', 'formation', '.'] [0, 2, 5, 7, 8, 10, 17, 18, 20, 23, 27, 28, 30, 33, 37, 38, 40, 42, 48, 49, 50, 51, 52, 53, 56, 66, 69, 73, 75, 77, 80, 89, 92, 94, 96, 98, 103, 113, 116, 125, 128, 132, 134, 136, 138, 147] [2, 5, 6, 8, 9, 16, 18, 19, 23, 26, 28, 29, 33, 36, 38, 39, 42, 48, 49, 50, 51, 52, 53, 56, 65, 69, 73, 74, 76, 79, 88, 91, 94, 96, 97, 102, 112, 115, 124, 128, 132, 134, 136, 137, 147, 148] ['Tochio', 'T', ',', 'Tanaka', 'H', ',', 'Nakata', 'S', ',', 'Hosoya', 'H', '.', 'Fructose-1,6-bisphosphate', 'aldolase', 'a', 'is', 'involved', 'in', 'HaCaT', 'cell', 'migration', 'by', 'inducing', 'lamellipodia', 'formation', '.'] [3, 1, 1, 1, 1, 1, 2, 1, 1, 2, 1, 1, 9, 3, 1, 1, 1, 1, 3, 1, 1, 1, 1, 5, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Interaction between aldolase and vacuolar H + −ATPase: evidence for direct coupling of glycolysis to the ATP-hydrolyzing proton pump. [('PMC5097088', 'F39002', 20, 28, 'aldolase'), ('PMC5097088', 'F39002', 47, 53, 'ATPase')] ['Interaction', 'between', 'ald', '##olas', '##e', 'and', 'vacu', '##olar', 'H', '+', '−', '##ATPase', ':', 'evidence', 'for', 'direct', 'coupling', 'of', 'glycolysis', 'to', 'the', 'ATP', '-', 'hydroly', '##zing', 'proton', 'pump', '.'] [0, 12, 20, 23, 27, 29, 33, 37, 42, 44, 46, 47, 53, 55, 64, 68, 75, 84, 87, 98, 101, 105, 108, 109, 116, 121, 128, 132] [11, 19, 23, 27, 28, 32, 37, 41, 43, 45, 47, 53, 54, 63, 67, 74, 83, 86, 97, 100, 104, 108, 109, 116, 120, 127, 132, 133] ['Interaction', 'between', 'aldolase', 'and', 'vacuolar', 'H', '+', '−ATPase', ':', 'evidence', 'for', 'direct', 'coupling', 'of', 'glycolysis', 'to', 'the', 'ATP-hydrolyzing', 'proton', 'pump', '.'] [1, 1, 3, 1, 2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1] ['O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'B', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Asaka M, Kimura T, Meguro T, Kato M, Kudo M, Miyazaki T, Alpert E. Alteration of aldolase isozymes in serum and tissues of patients with cancer and other diseases. [('PMC5097088', 'F40001', 81, 89, 'aldolase')] ['As', '##aka', 'M', ',', 'Kim', '##ura', 'T', ',', 'Me', '##gu', '##ro', 'T', ',', 'Kat', '##o', 'M', ',', 'Ku', '##do', 'M', ',', 'Miy', '##aza', '##ki', 'T', ',', 'Al', '##pert', 'E', '.', 'Alter', '##ation', 'of', 'ald', '##olas', '##e', 'iso', '##zymes', 'in', 'serum', 'and', 'tissues', 'of', 'patients', 'with', 'cancer', 'and', 'other', 'diseases', '.'] [0, 2, 6, 7, 9, 12, 16, 17, 19, 21, 23, 26, 27, 29, 32, 34, 35, 37, 39, 42, 43, 45, 48, 51, 54, 55, 57, 59, 64, 65, 67, 72, 78, 81, 84, 88, 90, 93, 99, 102, 108, 112, 120, 123, 132, 137, 144, 148, 154, 162] [2, 5, 7, 8, 12, 15, 17, 18, 21, 23, 25, 27, 28, 32, 33, 35, 36, 39, 41, 43, 44, 48, 51, 53, 55, 56, 59, 63, 65, 66, 72, 77, 80, 84, 88, 89, 93, 98, 101, 107, 111, 119, 122, 131, 136, 143, 147, 153, 162, 163] ['Asaka', 'M', ',', 'Kimura', 'T', ',', 'Meguro', 'T', ',', 'Kato', 'M', ',', 'Kudo', 'M', ',', 'Miyazaki', 'T', ',', 'Alpert', 'E', '.', 'Alteration', 'of', 'aldolase', 'isozymes', 'in', 'serum', 'and', 'tissues', 'of', 'patients', 'with', 'cancer', 'and', 'other', 'diseases', '.'] [2, 1, 1, 2, 1, 1, 3, 1, 1, 2, 1, 1, 2, 1, 1, 3, 1, 1, 2, 1, 1, 2, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Takashi M, Zhu Y, Nakano Y, Miyake K, Kato K. Elevated levels of serum aldolase a in patients with renal cell carcinoma. [('PMC5097088', 'F41001', 71, 81, 'aldolase a')] ['Tak', '##ashi', 'M', ',', 'Zhu', 'Y', ',', 'Nak', '##ano', 'Y', ',', 'Miy', '##ake', 'K', ',', 'Kat', '##o', 'K', '.', 'Ele', '##vated', 'levels', 'of', 'serum', 'ald', '##olas', '##e', 'a', 'in', 'patients', 'with', 'renal', 'cell', 'carcinoma', '.'] [0, 3, 8, 9, 11, 15, 16, 18, 21, 25, 26, 28, 31, 35, 36, 38, 41, 43, 44, 46, 49, 55, 62, 65, 71, 74, 78, 80, 82, 85, 94, 99, 105, 110, 119] [3, 7, 9, 10, 14, 16, 17, 21, 24, 26, 27, 31, 34, 36, 37, 41, 42, 44, 45, 49, 54, 61, 64, 70, 74, 78, 79, 81, 84, 93, 98, 104, 109, 119, 120] ['Takashi', 'M', ',', 'Zhu', 'Y', ',', 'Nakano', 'Y', ',', 'Miyake', 'K', ',', 'Kato', 'K', '.', 'Elevated', 'levels', 'of', 'serum', 'aldolase', 'a', 'in', 'patients', 'with', 'renal', 'cell', 'carcinoma', '.'] [2, 1, 1, 1, 1, 1, 2, 1, 1, 2, 1, 1, 2, 1, 1, 2, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We identified aldolase A as a candidate protein with potential as a novel biomarker for early detection of CRC. [('PMC5097088', 'I02001', 14, 24, 'aldolase A')] ['We', 'identified', 'ald', '##olas', '##e', 'A', 'as', 'a', 'candidate', 'protein', 'with', 'potential', 'as', 'a', 'novel', 'biomarker', 'for', 'early', 'detection', 'of', 'CRC', '.'] [0, 3, 14, 17, 21, 23, 25, 28, 30, 40, 48, 53, 63, 66, 68, 74, 84, 88, 94, 104, 107, 110] [2, 13, 17, 21, 22, 24, 27, 29, 39, 47, 52, 62, 65, 67, 73, 83, 87, 93, 103, 106, 110, 111] ['We', 'identified', 'aldolase', 'A', 'as', 'a', 'candidate', 'protein', 'with', 'potential', 'as', 'a', 'novel', 'biomarker', 'for', 'early', 'detection', 'of', 'CRC', '.'] [1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To measure expression of aldolase A, cyclophilin A, and annexin A2 mRNA, quantitative reverse transcription PCR (qRT-PCR) was performed with the 7500 system (Applied Biosystems, Foster City, CA, USA). [('PMC5097088', 'M08003', 25, 35, 'aldolase A')] ['To', 'measure', 'expression', 'of', 'ald', '##olas', '##e', 'A', ',', 'cyclo', '##ph', '##ilin', 'A', ',', 'and', 'anne', '##xin', 'A', '##2', 'mRNA', ',', 'quantitative', 'reverse', 'transcription', 'PCR', '(', 'qRT', '-', 'PCR', ')', 'was', 'performed', 'with', 'the', '750', '##0', 'system', '(', 'Applied', 'Biosystems', ',', 'Foster', 'City', ',', 'CA', ',', 'USA', ')', '.'] [0, 3, 11, 22, 25, 28, 32, 34, 35, 37, 42, 44, 49, 50, 52, 56, 60, 64, 65, 67, 71, 73, 86, 94, 108, 112, 113, 116, 117, 120, 122, 126, 136, 141, 145, 148, 150, 157, 158, 166, 176, 178, 185, 189, 191, 193, 195, 198, 199] [2, 10, 21, 24, 28, 32, 33, 35, 36, 42, 44, 48, 50, 51, 55, 60, 63, 65, 66, 71, 72, 85, 93, 107, 111, 113, 116, 117, 120, 121, 125, 135, 140, 144, 148, 149, 156, 158, 165, 176, 177, 184, 189, 190, 193, 194, 198, 199, 200] ['To', 'measure', 'expression', 'of', 'aldolase', 'A', ',', 'cyclophilin', 'A', ',', 'and', 'annexin', 'A2', 'mRNA', ',', 'quantitative', 'reverse', 'transcription', 'PCR', '(', 'qRT-PCR', ')', 'was', 'performed', 'with', 'the', '7500', 'system', '(', 'Applied', 'Biosystems', ',', 'Foster', 'City', ',', 'CA', ',', 'USA', ')', '.'] [1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Primers and TaqMan probes for aldolase A (Hs00765620_m1), cyclophilin A (Hs04194521_s1), annexin A2 (Hs00743063_s1), and 18S rRNA (Hs03928990_g1) were used with the TaqMan Gene Expression Assay. [('PMC5097088', 'M08004', 30, 40, 'aldolase A')] ['Primer', '##s', 'and', 'Taq', '##Man', 'probes', 'for', 'ald', '##olas', '##e', 'A', '(', 'Hs', '##007', '##65', '##62', '##0', '_', 'm', '##1', ')', ',', 'cyclo', '##ph', '##ilin', 'A', '(', 'Hs', '##04', '##19', '##45', '##21', '_', 's', '##1', ')', ',', 'anne', '##xin', 'A', '##2', '(', 'Hs', '##007', '##43', '##06', '##3', '_', 's', '##1', ')', ',', 'and', '18', '##S', 'rRNA', '(', 'Hs', '##03', '##92', '##89', '##90', '_', 'g', '##1', ')', 'were', 'used', 'with', 'the', 'Taq', '##Man', 'Gene', 'Expression', 'Assay', '.'] [0, 6, 8, 12, 15, 19, 26, 30, 33, 37, 39, 41, 42, 44, 47, 49, 51, 52, 53, 54, 55, 56, 58, 63, 65, 70, 72, 73, 75, 77, 79, 81, 83, 84, 85, 86, 87, 89, 93, 97, 98, 100, 101, 103, 106, 108, 110, 111, 112, 113, 114, 115, 117, 121, 123, 125, 130, 131, 133, 135, 137, 139, 141, 142, 143, 144, 146, 151, 156, 161, 165, 168, 172, 177, 188, 193] [6, 7, 11, 15, 18, 25, 29, 33, 37, 38, 40, 42, 44, 47, 49, 51, 52, 53, 54, 55, 56, 57, 63, 65, 69, 71, 73, 75, 77, 79, 81, 83, 84, 85, 86, 87, 88, 93, 96, 98, 99, 101, 103, 106, 108, 110, 111, 112, 113, 114, 115, 116, 120, 123, 124, 129, 131, 133, 135, 137, 139, 141, 142, 143, 144, 145, 150, 155, 160, 164, 168, 171, 176, 187, 193, 194] ['Primers', 'and', 'TaqMan', 'probes', 'for', 'aldolase', 'A', '(', 'Hs00765620_m1', ')', ',', 'cyclophilin', 'A', '(', 'Hs04194521_s1', ')', ',', 'annexin', 'A2', '(', 'Hs00743063_s1', ')', ',', 'and', '18S', 'rRNA', '(', 'Hs03928990_g1', ')', 'were', 'used', 'with', 'the', 'TaqMan', 'Gene', 'Expression', 'Assay', '.'] [2, 1, 2, 1, 1, 3, 1, 1, 8, 1, 1, 3, 1, 1, 8, 1, 1, 2, 2, 1, 8, 1, 1, 1, 2, 1, 1, 8, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Paraffin-embedded tissue sections (3 μm) were subjected to immunostaining using a Histofine Simple Stain MAX-PO (R) kit (Nichirei, Tokyo, Japan) for identifying aldolase A, annexin A2, and cyclophilin A. After deparaffinization, sections were pretreated in an autoclave at 121 °C for 15 min in 10 mM citrate buffer (pH 6.0) for cyclophilin A. Endogenous peroxidase activity was blocked by incubation for 30 min with 0.3 % hydrogen peroxide in methanol. [('PMC5097088', 'M09002', 161, 171, 'aldolase A'), ('PMC5097088', 'M09002', 354, 364, 'peroxidase')] ['Par', '##affin', '-', 'embedded', 'tissue', 'sections', '(', '3', 'μ', '##m', ')', 'were', 'subjected', 'to', 'immunostaining', 'using', 'a', 'Hist', '##of', '##ine', 'Simple', 'Sta', '##in', 'MAX', '-', 'PO', '(', 'R', ')', 'kit', '(', 'Nich', '##ire', '##i', ',', 'Tokyo', ',', 'Japan', ')', 'for', 'identifying', 'ald', '##olas', '##e', 'A', ',', 'anne', '##xin', 'A', '##2', ',', 'and', 'cyclo', '##ph', '##ilin', 'A', '.', 'After', 'depar', '##affin', '##ization', ',', 'sections', 'were', 'pretreated', 'in', 'an', 'auto', '##cl', '##ave', 'at', '121', '°', '##C', 'for', '15', 'min', 'in', '10', 'mM', 'citrate', 'buffer', '(', 'pH', '6', '.', '0', ')', 'for', 'cyclo', '##ph', '##ilin', 'A', '.', 'End', '##ogenous', 'peroxidase', 'activity', 'was', 'blocked', 'by', 'incubation', 'for', '30', 'min', 'with', '0', '.', '3', '%', 'hydrogen', 'peroxide', 'in', 'methanol', '.'] [0, 3, 8, 9, 18, 25, 34, 35, 37, 38, 39, 41, 46, 56, 59, 74, 80, 82, 86, 88, 92, 99, 102, 105, 108, 109, 112, 113, 114, 116, 120, 121, 125, 128, 129, 131, 136, 138, 143, 145, 149, 161, 164, 168, 170, 171, 173, 177, 181, 182, 183, 185, 189, 194, 196, 201, 202, 204, 210, 215, 220, 227, 229, 238, 243, 254, 257, 260, 264, 266, 270, 273, 277, 278, 280, 284, 287, 291, 294, 297, 300, 308, 315, 316, 319, 320, 321, 322, 324, 328, 333, 335, 340, 341, 343, 346, 354, 365, 374, 378, 386, 389, 400, 404, 407, 411, 416, 417, 418, 420, 422, 431, 440, 443, 451] [3, 8, 9, 17, 24, 33, 35, 36, 38, 39, 40, 45, 55, 58, 73, 79, 81, 86, 88, 91, 98, 102, 104, 108, 109, 111, 113, 114, 115, 119, 121, 125, 128, 129, 130, 136, 137, 143, 144, 148, 160, 164, 168, 169, 171, 172, 177, 180, 182, 183, 184, 188, 194, 196, 200, 202, 203, 209, 215, 220, 227, 228, 237, 242, 253, 256, 259, 264, 266, 269, 272, 276, 278, 279, 283, 286, 290, 293, 296, 299, 307, 314, 316, 318, 320, 321, 322, 323, 327, 333, 335, 339, 341, 342, 346, 353, 364, 373, 377, 385, 388, 399, 403, 406, 410, 415, 417, 418, 419, 421, 430, 439, 442, 451, 452] ['Paraffin', '-', 'embedded', 'tissue', 'sections', '(', '3', 'μm', ')', 'were', 'subjected', 'to', 'immunostaining', 'using', 'a', 'Histofine', 'Simple', 'Stain', 'MAX-PO', '(', 'R', ')', 'kit', '(', 'Nichirei', ',', 'Tokyo', ',', 'Japan', ')', 'for', 'identifying', 'aldolase', 'A', ',', 'annexin', 'A2', ',', 'and', 'cyclophilin', 'A', '.', 'After', 'deparaffinization', ',', 'sections', 'were', 'pretreated', 'in', 'an', 'autoclave', 'at', '121', '°C', 'for', '15', 'min', 'in', '10', 'mM', 'citrate', 'buffer', '(', 'pH', '6.0', ')', 'for', 'cyclophilin', 'A', '.', 'Endogenous', 'peroxidase', 'activity', 'was', 'blocked', 'by', 'incubation', 'for', '30', 'min', 'with', '0.3', '%', 'hydrogen', 'peroxide', 'in', 'methanol', '.'] [2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 2, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 2, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Tissue sections were then incubated with the anti-ALDOA antibody (1:150 dilution; Atlas Antibodies, Stockholm, Sweden) for aldolase A, anti-cyclophilin A antibody (1:150 dilution; Novus Biologicals, Littleton, CO, USA), or anti-annexin A2 antibody (1:400 dilution; Cell Signaling Technology, Inc., Danvers, MA, USA) in phosphate-buffered saline containing 1 % bovine serum albumin for 16 h at 4 °C. [('PMC5097088', 'M09003', 123, 133, 'aldolase A')] ['Tissue', 'sections', 'were', 'then', 'incubated', 'with', 'the', 'anti', '-', 'AL', '##DO', '##A', 'antibody', '(', '1', ':', '150', 'dilution', ';', 'Atl', '##as', 'Antibodies', ',', 'Stockholm', ',', 'Sweden', ')', 'for', 'ald', '##olas', '##e', 'A', ',', 'anti', '-', 'cyclo', '##ph', '##ilin', 'A', 'antibody', '(', '1', ':', '150', 'dilution', ';', 'Nov', '##us', 'Biological', '##s', ',', 'Little', '##ton', ',', 'CO', ',', 'USA', ')', ',', 'or', 'anti', '-', 'anne', '##xin', 'A', '##2', 'antibody', '(', '1', ':', '400', 'dilution', ';', 'Cell', 'Signaling', 'Technology', ',', 'Inc', '.', ',', 'Dan', '##vers', ',', 'MA', ',', 'USA', ')', 'in', 'phosphate', '-', 'buffered', 'saline', 'containing', '1', '%', 'bovine', 'serum', 'albumin', 'for', '16', 'h', 'at', '4', '°', '##C', '.'] [0, 7, 16, 21, 26, 36, 41, 45, 49, 50, 52, 54, 56, 65, 66, 67, 68, 72, 80, 82, 85, 88, 98, 100, 109, 111, 117, 119, 123, 126, 130, 132, 133, 135, 139, 140, 145, 147, 152, 154, 163, 164, 165, 166, 170, 178, 180, 183, 186, 196, 197, 199, 205, 208, 210, 212, 214, 217, 218, 220, 223, 227, 228, 232, 236, 237, 239, 248, 249, 250, 251, 255, 263, 265, 270, 280, 290, 292, 295, 296, 298, 301, 305, 307, 309, 311, 314, 316, 319, 328, 329, 338, 345, 356, 358, 360, 367, 373, 381, 385, 388, 390, 393, 395, 396, 397] [6, 15, 20, 25, 35, 40, 44, 49, 50, 52, 54, 55, 64, 66, 67, 68, 71, 80, 81, 85, 87, 98, 99, 109, 110, 117, 118, 122, 126, 130, 131, 133, 134, 139, 140, 145, 147, 151, 153, 162, 164, 165, 166, 169, 178, 179, 183, 185, 196, 197, 198, 205, 208, 209, 212, 213, 217, 218, 219, 222, 227, 228, 232, 235, 237, 238, 247, 249, 250, 251, 254, 263, 264, 269, 279, 290, 291, 295, 296, 297, 301, 305, 306, 309, 310, 314, 315, 318, 328, 329, 337, 344, 355, 357, 359, 366, 372, 380, 384, 387, 389, 392, 394, 396, 397, 398] ['Tissue', 'sections', 'were', 'then', 'incubated', 'with', 'the', 'anti-ALDOA', 'antibody', '(', '1', ':', '150', 'dilution', ';', 'Atlas', 'Antibodies', ',', 'Stockholm', ',', 'Sweden', ')', 'for', 'aldolase', 'A', ',', 'anti-', 'cyclophilin', 'A', 'antibody', '(', '1', ':', '150', 'dilution', ';', 'Novus', 'Biologicals', ',', 'Littleton', ',', 'CO', ',', 'USA', ')', ',', 'or', 'anti-', 'annexin', 'A2', 'antibody', '(', '1', ':', '400', 'dilution', ';', 'Cell', 'Signaling', 'Technology', ',', 'Inc', '.', ',', 'Danvers', ',', 'MA', ',', 'USA', ')', 'in', 'phosphate', '-', 'buffered', 'saline', 'containing', '1', '%', 'bovine', 'serum', 'albumin', 'for', '16', 'h', 'at', '4', '°C', '.'] [1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 3, 1, 1, 1, 1, 1, 1, 1, 1, 2, 2, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 2, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Membranes were incubated with an anti-annexin A2 rabbit monoclonal antibody, anti-aldolase A rabbit monoclonal antibody, or anti-cyclophilin A antibody (Cell Signaling Technology Inc., Beverly, MA, USA) at 4 °C overnight. [('PMC5097088', 'M12002', 82, 92, 'aldolase A')] ['Membrane', '##s', 'were', 'incubated', 'with', 'an', 'anti', '-', 'anne', '##xin', 'A', '##2', 'rabbit', 'monoclonal', 'antibody', ',', 'anti', '-', 'ald', '##olas', '##e', 'A', 'rabbit', 'monoclonal', 'antibody', ',', 'or', 'anti', '-', 'cyclo', '##ph', '##ilin', 'A', 'antibody', '(', 'Cell', 'Signaling', 'Technology', 'Inc', '.', ',', 'Be', '##ver', '##ly', ',', 'MA', ',', 'USA', ')', 'at', '4', '°', '##C', 'overnight', '.'] [0, 8, 10, 15, 25, 30, 33, 37, 38, 42, 46, 47, 49, 56, 67, 75, 77, 81, 82, 85, 89, 91, 93, 100, 111, 119, 121, 124, 128, 129, 134, 136, 141, 143, 152, 153, 158, 168, 179, 182, 183, 185, 187, 190, 192, 194, 196, 198, 201, 203, 206, 208, 209, 211, 220] [8, 9, 14, 24, 29, 32, 37, 38, 42, 45, 47, 48, 55, 66, 75, 76, 81, 82, 85, 89, 90, 92, 99, 110, 119, 120, 123, 128, 129, 134, 136, 140, 142, 151, 153, 157, 167, 178, 182, 183, 184, 187, 190, 192, 193, 196, 197, 201, 202, 205, 207, 209, 210, 220, 221] ['Membranes', 'were', 'incubated', 'with', 'an', 'anti-', 'annexin', 'A2', 'rabbit', 'monoclonal', 'antibody', ',', 'anti-', 'aldolase', 'A', 'rabbit', 'monoclonal', 'antibody', ',', 'or', 'anti-', 'cyclophilin', 'A', 'antibody', '(', 'Cell', 'Signaling', 'Technology', 'Inc', '.', ',', 'Beverly', ',', 'MA', ',', 'USA', ')', 'at', '4', '°C', 'overnight', '.'] [2, 1, 1, 1, 1, 2, 2, 2, 1, 1, 1, 1, 2, 3, 1, 1, 1, 1, 1, 1, 2, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Fructose-bisphosphate aldolase A (aldolase A), peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), and annexin A2 were upregulated in cancer regions (Table (Table3)3) and consequently selected as candidate diagnostic biomarkers. [('PMC5097088', 'R04000', 0, 32, 'Fructose-bisphosphate aldolase A'), ('PMC5097088', 'R04000', 34, 44, 'aldolase A'), ('PMC5097088', 'R04000', 47, 84, 'peptidyl-prolyl cis-trans isomerase A')] ['Fr', '##uctose', '-', 'bis', '##phosphate', 'ald', '##olas', '##e', 'A', '(', 'ald', '##olas', '##e', 'A', ')', ',', 'pepti', '##dy', '##l', '-', 'prol', '##yl', 'cis', '-', 'trans', 'isomer', '##ase', 'A', '(', 'also', 'known', 'as', 'cyclo', '##ph', '##ilin', 'A', ')', ',', 'and', 'anne', '##xin', 'A', '##2', 'were', 'upregulated', 'in', 'cancer', 'regions', '(', 'Table', '(', 'Table', '##3', ')', '3', ')', 'and', 'consequently', 'selected', 'as', 'candidate', 'diagnostic', 'biomarkers', '.'] [0, 2, 8, 9, 12, 22, 25, 29, 31, 33, 34, 37, 41, 43, 44, 45, 47, 52, 54, 55, 56, 60, 63, 66, 67, 73, 79, 83, 85, 86, 91, 97, 100, 105, 107, 112, 113, 114, 116, 120, 124, 128, 129, 131, 136, 148, 151, 158, 166, 167, 174, 175, 180, 181, 182, 183, 185, 189, 202, 211, 214, 224, 235, 245] [2, 8, 9, 12, 21, 25, 29, 30, 32, 34, 37, 41, 42, 44, 45, 46, 52, 54, 55, 56, 60, 62, 66, 67, 72, 79, 82, 84, 86, 90, 96, 99, 105, 107, 111, 113, 114, 115, 119, 124, 127, 129, 130, 135, 147, 150, 157, 165, 167, 172, 175, 180, 181, 182, 183, 184, 188, 201, 210, 213, 223, 234, 245, 246] ['Fructose', '-', 'bisphosphate', 'aldolase', 'A', '(', 'aldolase', 'A', ')', ',', 'peptidyl', '-', 'prolyl', 'cis-', 'trans', 'isomerase', 'A', '(', 'also', 'known', 'as', 'cyclophilin', 'A', ')', ',', 'and', 'annexin', 'A2', 'were', 'upregulated', 'in', 'cancer', 'regions', '(', 'Table', '\u200b(Table3)3', ')', 'and', 'consequently', 'selected', 'as', 'candidate', 'diagnostic', 'biomarkers', '.'] [2, 1, 2, 3, 1, 1, 3, 1, 1, 1, 3, 1, 2, 2, 1, 2, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'E', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Aldolase A was not detected in the culture medium of the three CRC cell lines, but it was detected in normal colon epithelial cells (Fig. (Fig.7e,7e, upper panel). [('PMC5097088', 'R06003', 0, 10, 'Aldolase A')] ['Al', '##do', '##las', '##e', 'A', 'was', 'not', 'detected', 'in', 'the', 'culture', 'medium', 'of', 'the', 'three', 'CRC', 'cell', 'lines', ',', 'but', 'it', 'was', 'detected', 'in', 'normal', 'colon', 'epithelial', 'cells', '(', 'Fig', '.', '(', 'Fig', '.', '7', '##e', ',', '7', '##e', ',', 'upper', 'panel', ')', '.'] [0, 2, 4, 7, 9, 11, 15, 19, 28, 31, 35, 43, 50, 53, 57, 63, 67, 72, 77, 79, 83, 86, 90, 99, 102, 109, 115, 126, 132, 133, 136, 139, 140, 143, 144, 145, 146, 147, 148, 149, 151, 157, 162, 163] [2, 4, 7, 8, 10, 14, 18, 27, 30, 34, 42, 49, 52, 56, 62, 66, 71, 77, 78, 82, 85, 89, 98, 101, 108, 114, 125, 131, 133, 136, 137, 140, 143, 144, 145, 146, 147, 148, 149, 150, 156, 162, 163, 164] ['Aldolase', 'A', 'was', 'not', 'detected', 'in', 'the', 'culture', 'medium', 'of', 'the', 'three', 'CRC', 'cell', 'lines', ',', 'but', 'it', 'was', 'detected', 'in', 'normal', 'colon', 'epithelial', 'cells', '(', 'Fig', '.', '\u200b(Fig.7e,7e', ',', 'upper', 'panel', ')', '.'] [4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 8, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Finally, we detected aldolase A in normal human serum and confirmed that the level depended on the loaded serum volume (Fig. (Fig.7f,7f, lane 1–3). [('PMC5097088', 'R06006', 21, 31, 'aldolase A')] ['Finally', ',', 'we', 'detected', 'ald', '##olas', '##e', 'A', 'in', 'normal', 'human', 'serum', 'and', 'confirmed', 'that', 'the', 'level', 'depended', 'on', 'the', 'loaded', 'serum', 'volume', '(', 'Fig', '.', '(', 'Fig', '.', '7', '##f', ',', '7', '##f', ',', 'lane', '1', '–', '3', ')', '.'] [0, 7, 9, 12, 21, 24, 28, 30, 32, 35, 42, 48, 54, 58, 68, 73, 77, 83, 92, 95, 99, 106, 112, 119, 120, 123, 126, 127, 130, 131, 132, 133, 134, 135, 136, 138, 143, 144, 145, 146, 147] [7, 8, 11, 20, 24, 28, 29, 31, 34, 41, 47, 53, 57, 67, 72, 76, 82, 91, 94, 98, 105, 111, 118, 120, 123, 124, 127, 130, 131, 132, 133, 134, 135, 136, 137, 142, 144, 145, 146, 147, 148] ['Finally', ',', 'we', 'detected', 'aldolase', 'A', 'in', 'normal', 'human', 'serum', 'and', 'confirmed', 'that', 'the', 'level', 'depended', 'on', 'the', 'loaded', 'serum', 'volume', '(', 'Fig', '.', '\u200b(Fig.7f,7f', ',', 'lane', '1–', '3', ')', '.'] [1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 8, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. [('PMC6396534', 'F02002', 14, 33, 'catalase-peroxidase')] ['Myc', '##obacterial', 'catalase', '-', 'peroxidase', 'is', 'a', 'tissue', 'antigen', 'and', 'target', 'of', 'the', 'adaptive', 'immune', 'response', 'in', 'systemic', 'sarc', '##oid', '##osis', '.'] [0, 3, 14, 22, 23, 34, 37, 39, 46, 54, 58, 65, 68, 72, 81, 88, 97, 100, 109, 113, 116, 120] [3, 13, 22, 23, 33, 36, 38, 45, 53, 57, 64, 67, 71, 80, 87, 96, 99, 108, 113, 116, 120, 121] ['Mycobacterial', 'catalase', '-', 'peroxidase', 'is', 'a', 'tissue', 'antigen', 'and', 'target', 'of', 'the', 'adaptive', 'immune', 'response', 'in', 'systemic', 'sarcoidosis', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1] ['O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. [('PMC6396534', 'F03002', 34, 53, 'catalase-peroxidase')] ['T', 'cell', 'responses', 'to', 'myc', '##obacterial', 'catalase', '-', 'peroxidase', 'profile', 'a', 'pathogenic', 'antigen', 'in', 'systemic', 'sarc', '##oid', '##osis', '.'] [0, 2, 7, 17, 20, 23, 34, 42, 43, 54, 62, 64, 75, 83, 86, 95, 99, 102, 106] [1, 6, 16, 19, 23, 33, 42, 43, 53, 61, 63, 74, 82, 85, 94, 99, 102, 106, 107] ['T', 'cell', 'responses', 'to', 'mycobacterial', 'catalase', '-', 'peroxidase', 'profile', 'a', 'pathogenic', 'antigen', 'in', 'systemic', 'sarcoidosis', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
PrimerProspector: de novo design and taxonomic analysis of barcoded polymerase chain reaction primers. [('PMC6428700', 'F66001', 68, 78, 'polymerase')] ['Primer', '##Pro', '##spec', '##tor', ':', 'de', 'novo', 'design', 'and', 'taxonomic', 'analysis', 'of', 'bar', '##coded', 'polymerase', 'chain', 'reaction', 'primers', '.'] [0, 6, 9, 13, 16, 18, 21, 26, 33, 37, 47, 56, 59, 62, 68, 79, 85, 94, 101] [6, 9, 13, 16, 17, 20, 25, 32, 36, 46, 55, 58, 62, 67, 78, 84, 93, 101, 102] ['PrimerProspector', ':', 'de', 'novo', 'design', 'and', 'taxonomic', 'analysis', 'of', 'barcoded', 'polymerase', 'chain', 'reaction', 'primers', '.'] [4, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O']
Wang W.; Zhuang X.; Liu W.; Dong L.; Sun H.; Du G.; Ye L.Determinationof kynurnine and tryptophan, biomarkersof indoleamine 2,3-dioxygenase by LC–MS/MS in plasma and tumor. [('PMC6503468', 'F41000', 112, 139, 'indoleamine 2,3-dioxygenase')] ['Wang', 'W', '.', ';', 'Zhu', '##ang', 'X', '.', ';', 'Liu', 'W', '.', ';', 'Dong', 'L', '.', ';', 'Sun', 'H', '.', ';', 'Du', 'G', '.', ';', 'Ye', 'L', '.', 'Determination', '##of', 'k', '##yn', '##urn', '##ine', 'and', 'tryptophan', ',', 'biomarkers', '##of', 'ind', '##ole', '##amine', '2', ',', '3', '-', 'di', '##oxygenase', 'by', 'LC', '–', 'MS', '/', 'MS', 'in', 'plasma', 'and', 'tumor', '.'] [0, 5, 6, 7, 9, 12, 16, 17, 18, 20, 24, 25, 26, 28, 33, 34, 35, 37, 41, 42, 43, 45, 48, 49, 50, 52, 55, 56, 57, 70, 73, 74, 76, 79, 83, 87, 97, 99, 109, 112, 115, 118, 124, 125, 126, 127, 128, 130, 140, 143, 145, 146, 148, 149, 152, 155, 162, 166, 171] [4, 6, 7, 8, 12, 15, 17, 18, 19, 23, 25, 26, 27, 32, 34, 35, 36, 40, 42, 43, 44, 47, 49, 50, 51, 54, 56, 57, 70, 72, 74, 76, 79, 82, 86, 97, 98, 109, 111, 115, 118, 123, 125, 126, 127, 128, 130, 139, 142, 145, 146, 148, 149, 151, 154, 161, 165, 171, 172] ['Wang', 'W', '.', ';', 'Zhuang', 'X', '.', ';', 'Liu', 'W', '.', ';', 'Dong', 'L', '.', ';', 'Sun', 'H', '.', ';', 'Du', 'G', '.', ';', 'Ye', 'L.Determinationof', 'kynurnine', 'and', 'tryptophan', ',', 'biomarkersof', 'indoleamine', '2', ',', '3-dioxygenase', 'by', 'LC', '–', 'MS', '/', 'MS', 'in', 'plasma', 'and', 'tumor', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 1, 1, 1, 2, 3, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Rescigno A.; Sanjust E.; Soddu G.; Rinaldi A. C.; Sollai F.; Curreli N.; Rinaldi A.Effect of 3-hydroxyanthranilicacidon mushroom tyrosinase activity. [('PMC6503468', 'F55000', 93, 139, '3-hydroxyanthranilicacidon mushroom tyrosinase')] ['Res', '##ci', '##gn', '##o', 'A', '.', ';', 'San', '##ju', '##st', 'E', '.', ';', 'So', '##dd', '##u', 'G', '.', ';', 'Ri', '##nal', '##di', 'A', '.', 'C', '.', ';', 'Sol', '##la', '##i', 'F', '.', ';', 'Curr', '##eli', 'N', '.', ';', 'Ri', '##nal', '##di', 'A', '.', 'Effect', 'of', '3', '-', 'hydroxy', '##anth', '##ran', '##ilic', '##acid', '##on', 'mus', '##hr', '##oo', '##m', 'ty', '##ros', '##inase', 'activity', '.'] [0, 3, 5, 7, 9, 10, 11, 13, 16, 18, 21, 22, 23, 25, 27, 29, 31, 32, 33, 35, 37, 40, 43, 44, 46, 47, 48, 50, 53, 55, 57, 58, 59, 61, 65, 69, 70, 71, 73, 75, 78, 81, 82, 83, 90, 93, 94, 95, 102, 106, 109, 113, 117, 120, 123, 125, 127, 129, 131, 134, 140, 148] [3, 5, 7, 8, 10, 11, 12, 16, 18, 20, 22, 23, 24, 27, 29, 30, 32, 33, 34, 37, 40, 42, 44, 45, 47, 48, 49, 53, 55, 56, 58, 59, 60, 65, 68, 70, 71, 72, 75, 78, 80, 82, 83, 89, 92, 94, 95, 102, 106, 109, 113, 117, 119, 123, 125, 127, 128, 131, 134, 139, 148, 149] ['Rescigno', 'A', '.', ';', 'Sanjust', 'E', '.', ';', 'Soddu', 'G', '.', ';', 'Rinaldi', 'A', '.', 'C', '.', ';', 'Sollai', 'F', '.', ';', 'Curreli', 'N', '.', ';', 'Rinaldi', 'A.Effect', 'of', '3-hydroxyanthranilicacidon', 'mushroom', 'tyrosinase', 'activity', '.'] [4, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 3, 3, 1, 8, 4, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O']
The majority of available tryptophan ismetabolized in mammaliansystems through the kynurenine pathway via the tryptophan 2,3-dioxygenase(TDO) or indoleamine 2,3-dioxygenase (indoleamine 2,3-dioxygenase) enzymes (Figure S1). [('PMC6503468', 'I02000', 112, 138, 'yptophan 2,3-dioxygenase(T'), ('PMC6503468', 'I02000', 148, 175, 'oleamine 2,3-dioxygenase (i'), ('PMC6503468', 'I02000', 177, 204, 'oleamine 2,3-dioxygenase) e')] ['The', 'majority', 'of', 'available', 'tryptophan', 'is', '##met', '##abol', '##ized', 'in', 'mammalian', '##systems', 'through', 'the', 'k', '##yn', '##uren', '##ine', 'pathway', 'via', 'the', 'tryptophan', '2', ',', '3', '-', 'di', '##oxygenase', '(', 'TD', '##O', ')', 'or', 'ind', '##ole', '##amine', '2', ',', '3', '-', 'di', '##oxygenase', '(', 'ind', '##ole', '##amine', '2', ',', '3', '-', 'di', '##oxygenase', ')', 'enzymes', '(', 'Figure', 'S', '##1', ')', '.'] [0, 4, 13, 16, 26, 37, 39, 42, 46, 51, 54, 63, 71, 79, 83, 84, 86, 90, 94, 102, 106, 110, 121, 122, 123, 124, 125, 127, 136, 137, 139, 140, 142, 145, 148, 151, 157, 158, 159, 160, 161, 163, 173, 174, 177, 180, 186, 187, 188, 189, 190, 192, 201, 203, 211, 212, 219, 220, 221, 222] [3, 12, 15, 25, 36, 39, 42, 46, 50, 53, 63, 70, 78, 82, 84, 86, 90, 93, 101, 105, 109, 120, 122, 123, 124, 125, 127, 136, 137, 139, 140, 141, 144, 148, 151, 156, 158, 159, 160, 161, 163, 172, 174, 177, 180, 185, 187, 188, 189, 190, 192, 201, 202, 210, 212, 218, 220, 221, 222, 223] ['The', 'majority', 'of', 'available', 'tryptophan', 'ismetabolized', 'in', 'mammaliansystems', 'through', 'the', 'kynurenine', 'pathway', 'via', 'the', 'tryptophan', '2', ',', '3-dioxygenase(TDO)', 'or', 'indoleamine', '2', ',', '3-dioxygenase', '(', 'indoleamine', '2', ',', '3-dioxygenase', ')', 'enzymes', '(', 'Figure', 'S1', ')', '.'] [1, 1, 1, 1, 1, 4, 1, 2, 1, 1, 4, 1, 1, 1, 1, 1, 1, 8, 1, 3, 1, 1, 4, 1, 3, 1, 1, 4, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
Pyruvate dehydrogenase kinase (pyruvate dehydrogenase kinase) is a Ser/Thr kinase that inactivates mitochondrial pyruvate dehydrogenase and serves a key role in aerobic glycolysis, which is a hallmark of cancer cells. [('PMC6507336', 'A00000', 0, 29, 'Pyruvate dehydrogenase kinase'), ('PMC6507336', 'A00000', 31, 60, 'pyruvate dehydrogenase kinase'), ('PMC6507336', 'A00000', 67, 81, 'Ser/Thr kinase'), ('PMC6507336', 'A00000', 99, 135, 'mitochondrial pyruvate dehydrogenase')] ['Pyr', '##uvate', 'dehydrogenase', 'kinase', '(', 'pyruvate', 'dehydrogenase', 'kinase', ')', 'is', 'a', 'Ser', '/', 'Thr', 'kinase', 'that', 'in', '##activ', '##ates', 'mitochondrial', 'pyruvate', 'dehydrogenase', 'and', 'serves', 'a', 'key', 'role', 'in', 'aerobic', 'glycolysis', ',', 'which', 'is', 'a', 'hallmark', 'of', 'cancer', 'cells', '.'] [0, 3, 9, 23, 30, 31, 40, 54, 60, 62, 65, 67, 70, 71, 75, 82, 87, 89, 94, 99, 113, 122, 136, 140, 147, 149, 153, 158, 161, 169, 179, 181, 187, 190, 192, 201, 204, 211, 216] [3, 8, 22, 29, 31, 39, 53, 60, 61, 64, 66, 70, 71, 74, 81, 86, 89, 94, 98, 112, 121, 135, 139, 146, 148, 152, 157, 160, 168, 179, 180, 186, 189, 191, 200, 203, 210, 216, 217] ['Pyruvate', 'dehydrogenase', 'kinase', '(', 'pyruvate', 'dehydrogenase', 'kinase', ')', 'is', 'a', 'Ser', '/', 'Thr', 'kinase', 'that', 'inactivates', 'mitochondrial', 'pyruvate', 'dehydrogenase', 'and', 'serves', 'a', 'key', 'role', 'in', 'aerobic', 'glycolysis', ',', 'which', 'is', 'a', 'hallmark', 'of', 'cancer', 'cells', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'E', 'B', 'B', 'I', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The present study determined the pyruvate dehydrogenase kinase expression in cholangiocarcinoma (CCA) tissues and sera to evaluate their applicability as a biomarker for CCA. [('PMC6507336', 'A00001', 33, 62, 'pyruvate dehydrogenase kinase')] ['The', 'present', 'study', 'determined', 'the', 'pyruvate', 'dehydrogenase', 'kinase', 'expression', 'in', 'chol', '##angi', '##ocarcinoma', '(', 'CCA', ')', 'tissues', 'and', 'sera', 'to', 'evaluate', 'their', 'applicability', 'as', 'a', 'biomarker', 'for', 'CCA', '.'] [0, 4, 12, 18, 29, 33, 42, 56, 63, 74, 77, 81, 85, 96, 97, 100, 102, 110, 114, 119, 122, 131, 137, 151, 154, 156, 166, 170, 173] [3, 11, 17, 28, 32, 41, 55, 62, 73, 76, 81, 85, 95, 97, 100, 101, 109, 113, 118, 121, 130, 136, 150, 153, 155, 165, 169, 173, 174] ['The', 'present', 'study', 'determined', 'the', 'pyruvate', 'dehydrogenase', 'kinase', 'expression', 'in', 'cholangiocarcinoma', '(', 'CCA', ')', 'tissues', 'and', 'sera', 'to', 'evaluate', 'their', 'applicability', 'as', 'a', 'biomarker', 'for', 'CCA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Using proteomic analysis, pyruvate dehydrogenase kinase was revealed to be the most overexpressed mitochondrial protein in CCA tissues. [('PMC6507336', 'A00002', 26, 55, 'pyruvate dehydrogenase kinase')] ['Using', 'proteomic', 'analysis', ',', 'pyruvate', 'dehydrogenase', 'kinase', 'was', 'revealed', 'to', 'be', 'the', 'most', 'overexpressed', 'mitochondrial', 'protein', 'in', 'CCA', 'tissues', '.'] [0, 6, 16, 24, 26, 35, 49, 56, 60, 69, 72, 75, 79, 84, 98, 112, 120, 123, 127, 134] [5, 15, 24, 25, 34, 48, 55, 59, 68, 71, 74, 78, 83, 97, 111, 119, 122, 126, 134, 135] ['Using', 'proteomic', 'analysis', ',', 'pyruvate', 'dehydrogenase', 'kinase', 'was', 'revealed', 'to', 'be', 'the', 'most', 'overexpressed', 'mitochondrial', 'protein', 'in', 'CCA', 'tissues', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Then, the expression of pyruvate dehydrogenase kinase isoforms in CCA tissues was examined in 15 CCA cases by immunohistochemistry. [('PMC6507336', 'A00003', 24, 53, 'pyruvate dehydrogenase kinase')] ['Then', ',', 'the', 'expression', 'of', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'in', 'CCA', 'tissues', 'was', 'examined', 'in', '15', 'CCA', 'cases', 'by', 'immunohist', '##ochemistry', '.'] [0, 4, 6, 10, 21, 24, 33, 47, 54, 63, 66, 70, 78, 82, 91, 94, 97, 101, 107, 110, 120, 130] [4, 5, 9, 20, 23, 32, 46, 53, 62, 65, 69, 77, 81, 90, 93, 96, 100, 106, 109, 120, 130, 131] ['Then', ',', 'the', 'expression', 'of', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'in', 'CCA', 'tissues', 'was', 'examined', 'in', '15', 'CCA', 'cases', 'by', 'immunohistochemistry', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We studied the expression of all pyruvate dehydrogenase kinase isoforms and found that PDK1, PDK2 and PDK3, but not PDK4, were significantly overexpressed in 15 CCA tissues. [('PMC6507336', 'D00005', 33, 62, 'pyruvate dehydrogenase kinase')] ['We', 'studied', 'the', 'expression', 'of', 'all', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'and', 'found', 'that', 'PD', '##K', '##1', ',', 'PD', '##K', '##2', 'and', 'PD', '##K', '##3', ',', 'but', 'not', 'PD', '##K', '##4', ',', 'were', 'significantly', 'overexpressed', 'in', '15', 'CCA', 'tissues', '.'] [0, 3, 11, 15, 26, 29, 33, 42, 56, 63, 72, 76, 82, 87, 89, 90, 91, 93, 95, 96, 98, 102, 104, 105, 106, 108, 112, 116, 118, 119, 120, 122, 127, 141, 155, 158, 161, 165, 172] [2, 10, 14, 25, 28, 32, 41, 55, 62, 71, 75, 81, 86, 89, 90, 91, 92, 95, 96, 97, 101, 104, 105, 106, 107, 111, 115, 118, 119, 120, 121, 126, 140, 154, 157, 160, 164, 172, 173] ['We', 'studied', 'the', 'expression', 'of', 'all', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'and', 'found', 'that', 'PDK1', ',', 'PDK2', 'and', 'PDK3', ',', 'but', 'not', 'PDK4', ',', 'were', 'significantly', 'overexpressed', 'in', '15', 'CCA', 'tissues', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 3, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
PDK3 inhibits pyruvate dehydrogenase activity via phosphorylation of the E1 subunit of pyruvate dehydrogenase E1 component subunit α, somatic form, mitochondrial, and thereby regulates glucose metabolism and aerobic glycolysis in cancer. [('PMC6507336', 'D00009', 14, 36, 'pyruvate dehydrogenase'), ('PMC6507336', 'D00009', 87, 112, 'pyruvate dehydrogenase E1')] ['PD', '##K', '##3', 'inhibits', 'pyruvate', 'dehydrogenase', 'activity', 'via', 'phosphorylation', 'of', 'the', 'E', '##1', 'subunit', 'of', 'pyruvate', 'dehydrogenase', 'E', '##1', 'component', 'subunit', 'α', ',', 'somatic', 'form', ',', 'mitochondrial', ',', 'and', 'thereby', 'regulates', 'glucose', 'metabolism', 'and', 'aerobic', 'glycolysis', 'in', 'cancer', '.'] [0, 2, 3, 5, 14, 23, 37, 46, 50, 66, 69, 73, 74, 76, 84, 87, 96, 110, 111, 113, 123, 131, 132, 134, 142, 146, 148, 161, 163, 167, 175, 185, 193, 204, 208, 216, 227, 230, 236] [2, 3, 4, 13, 22, 36, 45, 49, 65, 68, 72, 74, 75, 83, 86, 95, 109, 111, 112, 122, 130, 132, 133, 141, 146, 147, 161, 162, 166, 174, 184, 192, 203, 207, 215, 226, 229, 236, 237] ['PDK3', 'inhibits', 'pyruvate', 'dehydrogenase', 'activity', 'via', 'phosphorylation', 'of', 'the', 'E1', 'subunit', 'of', 'pyruvate', 'dehydrogenase', 'E1', 'component', 'subunit', 'α', ',', 'somatic', 'form', ',', 'mitochondrial', ',', 'and', 'thereby', 'regulates', 'glucose', 'metabolism', 'and', 'aerobic', 'glycolysis', 'in', 'cancer', '.'] [3, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We also studied the serum pyruvate dehydrogenase kinase levels in normal controls, and patients with BBD and CCA. [('PMC6507336', 'D01000', 26, 55, 'pyruvate dehydrogenase kinase')] ['We', 'also', 'studied', 'the', 'serum', 'pyruvate', 'dehydrogenase', 'kinase', 'levels', 'in', 'normal', 'controls', ',', 'and', 'patients', 'with', 'BB', '##D', 'and', 'CCA', '.'] [0, 3, 8, 16, 20, 26, 35, 49, 56, 63, 66, 73, 81, 83, 87, 96, 101, 103, 105, 109, 112] [2, 7, 15, 19, 25, 34, 48, 55, 62, 65, 72, 81, 82, 86, 95, 100, 103, 104, 108, 112, 113] ['We', 'also', 'studied', 'the', 'serum', 'pyruvate', 'dehydrogenase', 'kinase', 'levels', 'in', 'normal', 'controls', ',', 'and', 'patients', 'with', 'BBD', 'and', 'CCA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Until now, the pyruvate dehydrogenase kinase level in the serum or plasma has not been determined in healthy controls and patients with diseases. [('PMC6507336', 'D01001', 15, 44, 'pyruvate dehydrogenase kinase')] ['Until', 'now', ',', 'the', 'pyruvate', 'dehydrogenase', 'kinase', 'level', 'in', 'the', 'serum', 'or', 'plasma', 'has', 'not', 'been', 'determined', 'in', 'healthy', 'controls', 'and', 'patients', 'with', 'diseases', '.'] [0, 6, 9, 11, 15, 24, 38, 45, 51, 54, 58, 64, 67, 74, 78, 82, 87, 98, 101, 109, 118, 122, 131, 136, 144] [5, 9, 10, 14, 23, 37, 44, 50, 53, 57, 63, 66, 73, 77, 81, 86, 97, 100, 108, 117, 121, 130, 135, 144, 145] ['Until', 'now', ',', 'the', 'pyruvate', 'dehydrogenase', 'kinase', 'level', 'in', 'the', 'serum', 'or', 'plasma', 'has', 'not', 'been', 'determined', 'in', 'healthy', 'controls', 'and', 'patients', 'with', 'diseases', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
As pyruvate dehydrogenase kinase is a mitochondrial protein, it was surprising that PDK1, 2 and 3 were detected in the sera, especially in the sera of patients with CCA. [('PMC6507336', 'D01002', 3, 32, 'pyruvate dehydrogenase kinase')] ['As', 'pyruvate', 'dehydrogenase', 'kinase', 'is', 'a', 'mitochondrial', 'protein', ',', 'it', 'was', 'surprising', 'that', 'PD', '##K', '##1', ',', '2', 'and', '3', 'were', 'detected', 'in', 'the', 'sera', ',', 'especially', 'in', 'the', 'sera', 'of', 'patients', 'with', 'CCA', '.'] [0, 3, 12, 26, 33, 36, 38, 52, 59, 61, 64, 68, 79, 84, 86, 87, 88, 90, 92, 96, 98, 103, 112, 115, 119, 123, 125, 136, 139, 143, 148, 151, 160, 165, 168] [2, 11, 25, 32, 35, 37, 51, 59, 60, 63, 67, 78, 83, 86, 87, 88, 89, 91, 95, 97, 102, 111, 114, 118, 123, 124, 135, 138, 142, 147, 150, 159, 164, 168, 169] ['As', 'pyruvate', 'dehydrogenase', 'kinase', 'is', 'a', 'mitochondrial', 'protein', ',', 'it', 'was', 'surprising', 'that', 'PDK1', ',', '2', 'and', '3', 'were', 'detected', 'in', 'the', 'sera', ',', 'especially', 'in', 'the', 'sera', 'of', 'patients', 'with', 'CCA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Nevertheless, when the correlation of the PDK3 intensity and clinical parameters of patients was analyzed, a significant correlation was observed between PDK3 and three CCA biomarkers, namely, alkaline phosphatase, total bilirubin and direct bilirubin. [('PMC6507336', 'D02003', 193, 213, 'alkaline phosphatase')] ['Nevertheless', ',', 'when', 'the', 'correlation', 'of', 'the', 'PD', '##K', '##3', 'intensity', 'and', 'clinical', 'parameters', 'of', 'patients', 'was', 'analyzed', ',', 'a', 'significant', 'correlation', 'was', 'observed', 'between', 'PD', '##K', '##3', 'and', 'three', 'CCA', 'biomarkers', ',', 'namely', ',', 'alkaline', 'phosphatase', ',', 'total', 'bilirubin', 'and', 'direct', 'bilirubin', '.'] [0, 12, 14, 19, 23, 35, 38, 42, 44, 45, 47, 57, 61, 70, 81, 84, 93, 97, 105, 107, 109, 121, 133, 137, 146, 154, 156, 157, 159, 163, 169, 173, 183, 185, 191, 193, 202, 213, 215, 221, 231, 235, 242, 251] [12, 13, 18, 22, 34, 37, 41, 44, 45, 46, 56, 60, 69, 80, 83, 92, 96, 105, 106, 108, 120, 132, 136, 145, 153, 156, 157, 158, 162, 168, 172, 183, 184, 191, 192, 201, 213, 214, 220, 230, 234, 241, 251, 252] ['Nevertheless', ',', 'when', 'the', 'correlation', 'of', 'the', 'PDK3', 'intensity', 'and', 'clinical', 'parameters', 'of', 'patients', 'was', 'analyzed', ',', 'a', 'significant', 'correlation', 'was', 'observed', 'between', 'PDK3', 'and', 'three', 'CCA', 'biomarkers', ',', 'namely', ',', 'alkaline', 'phosphatase', ',', 'total', 'bilirubin', 'and', 'direct', 'bilirubin', '.'] [1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Our previous studies revealed that, in CCA, the total serum bile acid correlates with total bilirubin, and total serum bile acid and intercellular adhesion molecule 1 correlate with alkaline phosphatase (23,24). [('PMC6507336', 'D02004', 182, 202, 'alkaline phosphatase')] ['Our', 'previous', 'studies', 'revealed', 'that', ',', 'in', 'CCA', ',', 'the', 'total', 'serum', 'bile', 'acid', 'correlates', 'with', 'total', 'bilirubin', ',', 'and', 'total', 'serum', 'bile', 'acid', 'and', 'intercellular', 'adhesion', 'molecule', '1', 'correlate', 'with', 'alkaline', 'phosphatase', '(', '23', ',', '24', ')', '.'] [0, 4, 13, 21, 30, 34, 36, 39, 42, 44, 48, 54, 60, 65, 70, 81, 86, 92, 101, 103, 107, 113, 119, 124, 129, 133, 147, 156, 165, 167, 177, 182, 191, 203, 204, 206, 207, 209, 210] [3, 12, 20, 29, 34, 35, 38, 42, 43, 47, 53, 59, 64, 69, 80, 85, 91, 101, 102, 106, 112, 118, 123, 128, 132, 146, 155, 164, 166, 176, 181, 190, 202, 204, 206, 207, 209, 210, 211] ['Our', 'previous', 'studies', 'revealed', 'that', ',', 'in', 'CCA', ',', 'the', 'total', 'serum', 'bile', 'acid', 'correlates', 'with', 'total', 'bilirubin', ',', 'and', 'total', 'serum', 'bile', 'acid', 'and', 'intercellular', 'adhesion', 'molecule', '1', 'correlate', 'with', 'alkaline', 'phosphatase', '(', '23', ',', '24', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents. [('PMC6507336', 'F07002', 4, 34, 'pyruvate dehydrogenase complex')] ['The', 'pyruvate', 'dehydrogenase', 'complex', 'in', 'cancer', ':', 'An', 'old', 'metabolic', 'gate', '##ke', '##eper', 'regulated', 'by', 'new', 'pathways', 'and', 'pharmacological', 'agents', '.'] [0, 4, 13, 27, 35, 38, 44, 46, 49, 53, 63, 67, 69, 74, 84, 87, 91, 100, 104, 120, 126] [3, 12, 26, 34, 37, 44, 45, 48, 52, 62, 67, 69, 73, 83, 86, 90, 99, 103, 119, 126, 127] ['The', 'pyruvate', 'dehydrogenase', 'complex', 'in', 'cancer', ':', 'An', 'old', 'metabolic', 'gatekeeper', 'regulated', 'by', 'new', 'pathways', 'and', 'pharmacological', 'agents', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. [('PMC6507336', 'F08002', 70, 92, 'pyruvate dehydrogenase')] ['Evidence', 'for', 'existence', 'of', 'tissue', '-', 'specific', 'regulation', 'of', 'the', 'mammalian', 'pyruvate', 'dehydrogenase', 'complex', '.'] [0, 9, 13, 23, 26, 32, 33, 42, 53, 56, 60, 70, 79, 93, 100] [8, 12, 22, 25, 32, 33, 41, 52, 55, 59, 69, 78, 92, 100, 101] ['Evidence', 'for', 'existence', 'of', 'tissue', '-', 'specific', 'regulation', 'of', 'the', 'mammalian', 'pyruvate', 'dehydrogenase', 'complex', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O']
Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer. [('PMC6507336', 'F17002', 18, 49, 'pyruvate dehydrogenase kinase 3')] ['Overexpression', 'of', 'pyruvate', 'dehydrogenase', 'kinase', '3', 'increases', 'drug', 'resistance', 'and', 'early', 'recurrence', 'in', 'colon', 'cancer', '.'] [0, 15, 18, 27, 41, 48, 50, 60, 65, 76, 80, 86, 97, 100, 106, 112] [14, 17, 26, 40, 47, 49, 59, 64, 75, 79, 85, 96, 99, 105, 112, 113] ['Overexpression', 'of', 'pyruvate', 'dehydrogenase', 'kinase', '3', 'increases', 'drug', 'resistance', 'and', 'early', 'recurrence', 'in', 'colon', 'cancer', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Diversity of the pyruvate dehydrogenase kinase gene family in humans. [('PMC6507336', 'F19002', 17, 46, 'pyruvate dehydrogenase kinase')] ['Diversity', 'of', 'the', 'pyruvate', 'dehydrogenase', 'kinase', 'gene', 'family', 'in', 'humans', '.'] [0, 10, 13, 17, 26, 40, 47, 52, 59, 62, 68] [9, 12, 16, 25, 39, 46, 51, 58, 61, 68, 69] ['Diversity', 'of', 'the', 'pyruvate', 'dehydrogenase', 'kinase', 'gene', 'family', 'in', 'humans', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O']
Among all the candidate proteins, pyruvate dehydrogenase kinase (pyruvate dehydrogenase kinase) 3 showed the highest fold increase. [('PMC6507336', 'I01002', 34, 63, 'pyruvate dehydrogenase kinase'), ('PMC6507336', 'I01002', 65, 94, 'pyruvate dehydrogenase kinase')] ['Among', 'all', 'the', 'candidate', 'proteins', ',', 'pyruvate', 'dehydrogenase', 'kinase', '(', 'pyruvate', 'dehydrogenase', 'kinase', ')', '3', 'showed', 'the', 'highest', 'fold', 'increase', '.'] [0, 6, 10, 14, 24, 32, 34, 43, 57, 64, 65, 74, 88, 94, 96, 98, 105, 109, 117, 122, 130] [5, 9, 13, 23, 32, 33, 42, 56, 63, 65, 73, 87, 94, 95, 97, 104, 108, 116, 121, 130, 131] ['Among', 'all', 'the', 'candidate', 'proteins', ',', 'pyruvate', 'dehydrogenase', 'kinase', '(', 'pyruvate', 'dehydrogenase', 'kinase', ')', '3', 'showed', 'the', 'highest', 'fold', 'increase', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'B', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
pyruvate dehydrogenase kinase is a Ser/Thr kinase that inactivates mitochondrial pyruvate dehydrogenase by site-specific phosphorylation and plays a key role in regulation of the Warburg effect in cancer cells (7). [('PMC6507336', 'I01003', 0, 29, 'pyruvate dehydrogenase kinase'), ('PMC6507336', 'I01003', 35, 49, 'Ser/Thr kinase'), ('PMC6507336', 'I01003', 67, 103, 'mitochondrial pyruvate dehydrogenase')] ['pyruvate', 'dehydrogenase', 'kinase', 'is', 'a', 'Ser', '/', 'Thr', 'kinase', 'that', 'in', '##activ', '##ates', 'mitochondrial', 'pyruvate', 'dehydrogenase', 'by', 'site', '-', 'specific', 'phosphorylation', 'and', 'plays', 'a', 'key', 'role', 'in', 'regulation', 'of', 'the', 'War', '##burg', 'effect', 'in', 'cancer', 'cells', '(', '7', ')', '.'] [0, 9, 23, 30, 33, 35, 38, 39, 43, 50, 55, 57, 62, 67, 81, 90, 104, 107, 111, 112, 121, 137, 141, 147, 149, 153, 158, 161, 172, 175, 179, 182, 187, 194, 197, 204, 210, 211, 212, 213] [8, 22, 29, 32, 34, 38, 39, 42, 49, 54, 57, 62, 66, 80, 89, 103, 106, 111, 112, 120, 136, 140, 146, 148, 152, 157, 160, 171, 174, 178, 182, 186, 193, 196, 203, 209, 211, 212, 213, 214] ['pyruvate', 'dehydrogenase', 'kinase', 'is', 'a', 'Ser', '/', 'Thr', 'kinase', 'that', 'inactivates', 'mitochondrial', 'pyruvate', 'dehydrogenase', 'by', 'site', '-', 'specific', 'phosphorylation', 'and', 'plays', 'a', 'key', 'role', 'in', 'regulation', 'of', 'the', 'Warburg', 'effect', 'in', 'cancer', 'cells', '(', '7', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'E', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
All pyruvate dehydrogenase kinase isoforms are notably expressed in specific tissues (9). [('PMC6507336', 'I01006', 4, 33, 'pyruvate dehydrogenase kinase')] ['All', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'are', 'notably', 'expressed', 'in', 'specific', 'tissues', '(', '9', ')', '.'] [0, 4, 13, 27, 34, 43, 47, 55, 65, 68, 77, 85, 86, 87, 88] [3, 12, 26, 33, 42, 46, 54, 64, 67, 76, 84, 86, 87, 88, 89] ['All', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'are', 'notably', 'expressed', 'in', 'specific', 'tissues', '(', '9', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
At present, there is no report of pyruvate dehydrogenase kinase expression in CCA. [('PMC6507336', 'I01007', 34, 63, 'pyruvate dehydrogenase kinase')] ['At', 'present', ',', 'there', 'is', 'no', 'report', 'of', 'pyruvate', 'dehydrogenase', 'kinase', 'expression', 'in', 'CCA', '.'] [0, 3, 10, 12, 18, 21, 24, 31, 34, 43, 57, 64, 75, 78, 81] [2, 10, 11, 17, 20, 23, 30, 33, 42, 56, 63, 74, 77, 81, 82] ['At', 'present', ',', 'there', 'is', 'no', 'report', 'of', 'pyruvate', 'dehydrogenase', 'kinase', 'expression', 'in', 'CCA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O']
The aims of this study were to examine pyruvate dehydrogenase kinase expression in CCA and evaluate whether the PDKs could be diagnostic/prognostic markers of CCA. [('PMC6507336', 'I01008', 39, 68, 'pyruvate dehydrogenase kinase')] ['The', 'aims', 'of', 'this', 'study', 'were', 'to', 'examine', 'pyruvate', 'dehydrogenase', 'kinase', 'expression', 'in', 'CCA', 'and', 'evaluate', 'whether', 'the', 'PD', '##Ks', 'could', 'be', 'diagnostic', '/', 'prognostic', 'markers', 'of', 'CCA', '.'] [0, 4, 9, 12, 17, 23, 28, 31, 39, 48, 62, 69, 80, 83, 87, 91, 100, 108, 112, 114, 117, 123, 126, 136, 137, 148, 156, 159, 162] [3, 8, 11, 16, 22, 27, 30, 38, 47, 61, 68, 79, 82, 86, 90, 99, 107, 111, 114, 116, 122, 125, 136, 137, 147, 155, 158, 162, 163] ['The', 'aims', 'of', 'this', 'study', 'were', 'to', 'examine', 'pyruvate', 'dehydrogenase', 'kinase', 'expression', 'in', 'CCA', 'and', 'evaluate', 'whether', 'the', 'PDKs', 'could', 'be', 'diagnostic', '/', 'prognostic', 'markers', 'of', 'CCA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The mean ± standard deviation (SD) of age, aspartate transaminase, alanine transaminase and alkaline phosphatase (alkaline phosphatase) of these patients are 57±5.5 years, 61±6.7, 57±51.4 and 154±100.4 U/l, respectively. [('PMC6507336', 'M01003', 43, 65, 'aspartate transaminase'), ('PMC6507336', 'M01003', 67, 87, 'alanine transaminase'), ('PMC6507336', 'M01003', 92, 112, 'alkaline phosphatase'), ('PMC6507336', 'M01003', 114, 134, 'alkaline phosphatase')] ['The', 'mean', '±', 'standard', 'deviation', '(', 'SD', ')', 'of', 'age', ',', 'aspart', '##ate', 'trans', '##aminase', ',', 'alanine', 'trans', '##aminase', 'and', 'alkaline', 'phosphatase', '(', 'alkaline', 'phosphatase', ')', 'of', 'these', 'patients', 'are', '57', '##±', '##5', '.', '5', 'years', ',', '61', '##±', '##6', '.', '7', ',', '57', '##±', '##51', '.', '4', 'and', '154', '##±1', '##00', '.', '4', 'U', '/', 'l', ',', 'respectively', '.'] [0, 4, 9, 11, 20, 30, 31, 33, 35, 38, 41, 43, 49, 53, 58, 65, 67, 75, 80, 88, 92, 101, 113, 114, 123, 134, 136, 139, 145, 154, 158, 160, 161, 162, 163, 165, 170, 172, 174, 175, 176, 177, 178, 180, 182, 183, 185, 186, 188, 192, 195, 197, 199, 200, 202, 203, 204, 205, 207, 219] [3, 8, 10, 19, 29, 31, 33, 34, 37, 41, 42, 49, 52, 58, 65, 66, 74, 80, 87, 91, 100, 112, 114, 122, 134, 135, 138, 144, 153, 157, 160, 161, 162, 163, 164, 170, 171, 174, 175, 176, 177, 178, 179, 182, 183, 185, 186, 187, 191, 195, 197, 199, 200, 201, 203, 204, 205, 206, 219, 220] ['The', 'mean', '±', 'standard', 'deviation', '(', 'SD', ')', 'of', 'age', ',', 'aspartate', 'transaminase', ',', 'alanine', 'transaminase', 'and', 'alkaline', 'phosphatase', '(', 'alkaline', 'phosphatase', ')', 'of', 'these', 'patients', 'are', '57±5.5', 'years', ',', '61±6.7', ',', '57±51.4', 'and', '154±100.4', 'U', '/', 'l', ',', 'respectively', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 5, 1, 5, 1, 5, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'E', 'O', 'B', 'E', 'B', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Then, the endogenous peroxidase activity of the sections was blocked with 3% H2O2 in methanol for 1 h in the dark and non-specific background binding was blocked by incubation with 20% fetal bovine serum (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) for 2 h. [('PMC6507336', 'M04002', 21, 31, 'peroxidase')] ['Then', ',', 'the', 'endogenous', 'peroxidase', 'activity', 'of', 'the', 'sections', 'was', 'blocked', 'with', '3', '%', 'H', '##2', '##O', '##2', 'in', 'methanol', 'for', '1', 'h', 'in', 'the', 'dark', 'and', 'non', '-', 'specific', 'background', 'binding', 'was', 'blocked', 'by', 'incubation', 'with', '20', '%', 'fetal', 'bovine', 'serum', '(', 'Sigma', '-', 'Aldr', '##ich', ';', 'Merck', 'KGaA', ',', 'Darm', '##stad', '##t', ',', 'Germany', ')', 'for', '2', 'h', '.'] [0, 4, 6, 10, 21, 32, 41, 44, 48, 57, 61, 69, 74, 75, 77, 78, 79, 80, 82, 85, 94, 98, 100, 102, 105, 109, 114, 118, 121, 122, 131, 142, 150, 154, 162, 165, 176, 181, 183, 185, 191, 198, 204, 205, 210, 211, 215, 218, 220, 226, 230, 232, 236, 240, 241, 243, 250, 252, 256, 258, 259] [4, 5, 9, 20, 31, 40, 43, 47, 56, 60, 68, 73, 75, 76, 78, 79, 80, 81, 84, 93, 97, 99, 101, 104, 108, 113, 117, 121, 122, 130, 141, 149, 153, 161, 164, 175, 180, 183, 184, 190, 197, 203, 205, 210, 211, 215, 218, 219, 225, 230, 231, 236, 240, 241, 242, 250, 251, 255, 257, 259, 260] ['Then', ',', 'the', 'endogenous', 'peroxidase', 'activity', 'of', 'the', 'sections', 'was', 'blocked', 'with', '3%', 'H2O2', 'in', 'methanol', 'for', '1', 'h', 'in', 'the', 'dark', 'and', 'non', '-', 'specific', 'background', 'binding', 'was', 'blocked', 'by', 'incubation', 'with', '20%', 'fetal', 'bovine', 'serum', '(', 'Sigma-Aldrich', ';', 'Merck', 'KGaA', ',', 'Darmstadt', ',', 'Germany', ')', 'for', '2', 'h', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 4, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To evaluate the expression of four pyruvate dehydrogenase kinase isoforms in CCA, immunohistochemistry was performed on 15 CCA tissues from patients containing cancerous and adjacent non-cancerous tissues. [('PMC6507336', 'R01000', 35, 64, 'pyruvate dehydrogenase kinase')] ['To', 'evaluate', 'the', 'expression', 'of', 'four', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'in', 'CCA', ',', 'immunohist', '##ochemistry', 'was', 'performed', 'on', '15', 'CCA', 'tissues', 'from', 'patients', 'containing', 'cancer', '##ous', 'and', 'adjacent', 'non', '-', 'cancer', '##ous', 'tissues', '.'] [0, 3, 12, 16, 27, 30, 35, 44, 58, 65, 74, 77, 80, 82, 92, 103, 107, 117, 120, 123, 127, 135, 140, 149, 160, 166, 170, 174, 183, 186, 187, 193, 197, 204] [2, 11, 15, 26, 29, 34, 43, 57, 64, 73, 76, 80, 81, 92, 102, 106, 116, 119, 122, 126, 134, 139, 148, 159, 166, 169, 173, 182, 186, 187, 193, 196, 204, 205] ['To', 'evaluate', 'the', 'expression', 'of', 'four', 'pyruvate', 'dehydrogenase', 'kinase', 'isoforms', 'in', 'CCA', ',', 'immunohistochemistry', 'was', 'performed', 'on', '15', 'CCA', 'tissues', 'from', 'patients', 'containing', 'cancerous', 'and', 'adjacent', 'non', '-', 'cancerous', 'tissues', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Using the median cut-off, we found a negative correlation between the serum PDK3 level and the alkaline phosphatase level at a P-value of 0.0307 (Fig. 5A). [('PMC6507336', 'R04001', 95, 115, 'alkaline phosphatase')] ['Using', 'the', 'median', 'cut', '-', 'off', ',', 'we', 'found', 'a', 'negative', 'correlation', 'between', 'the', 'serum', 'PD', '##K', '##3', 'level', 'and', 'the', 'alkaline', 'phosphatase', 'level', 'at', 'a', 'P', '-', 'value', 'of', '0', '.', '03', '##07', '(', 'Fig', '.', '5', '##A', ')', '.'] [0, 6, 10, 17, 20, 21, 24, 26, 29, 35, 37, 46, 58, 66, 70, 76, 78, 79, 81, 87, 91, 95, 104, 116, 122, 125, 127, 128, 129, 135, 138, 139, 140, 142, 145, 146, 149, 151, 152, 153, 154] [5, 9, 16, 20, 21, 24, 25, 28, 34, 36, 45, 57, 65, 69, 75, 78, 79, 80, 86, 90, 94, 103, 115, 121, 124, 126, 128, 129, 134, 137, 139, 140, 142, 144, 146, 149, 150, 152, 153, 154, 155] ['Using', 'the', 'median', 'cut', '-', 'off', ',', 'we', 'found', 'a', 'negative', 'correlation', 'between', 'the', 'serum', 'PDK3', 'level', 'and', 'the', 'alkaline', 'phosphatase', 'level', 'at', 'a', 'P-value', 'of', '0.0307', '(', 'Fig', '.', '5A', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 4, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Sequencing libraries were prepared by amplifying the V3–V4 region of the 16 S rRNA gene using the 341f-805 r primers, as described earlier.10 After the initial amplification, PCR (Polymerase chain reaction) products were confirmed with gel electrophoresis and purified using Agencourt AMPure XP magnetic beads (Beckham Coulter Inc., Bromma, Sweden). [('PMC6683645', 'M03000', 180, 190, 'Polymerase')] ['Sequencing', 'libraries', 'were', 'prepared', 'by', 'amplify', '##ing', 'the', 'V', '##3', '–', 'V', '##4', 'region', 'of', 'the', '16', 'S', 'rRNA', 'gene', 'using', 'the', '34', '##1', '##f', '-', '80', '##5', 'r', 'primers', ',', 'as', 'described', 'earlier', '.', '10', 'After', 'the', 'initial', 'amplification', ',', 'PCR', '(', 'Polymer', '##ase', 'chain', 'reaction', ')', 'products', 'were', 'confirmed', 'with', 'gel', 'electrophoresis', 'and', 'purified', 'using', 'Age', '##nc', '##our', '##t', 'AMP', '##ure', 'XP', 'magnetic', 'beads', '(', 'Beck', '##ham', 'Coul', '##ter', 'Inc', '.', ',', 'Bro', '##mma', ',', 'Sweden', ')', '.'] [0, 11, 21, 26, 35, 38, 45, 49, 53, 54, 55, 56, 57, 59, 66, 69, 73, 76, 78, 83, 88, 94, 98, 100, 101, 102, 103, 105, 107, 109, 116, 118, 121, 131, 138, 139, 142, 148, 152, 160, 173, 175, 179, 180, 187, 191, 197, 205, 207, 216, 221, 231, 236, 240, 256, 260, 269, 275, 278, 280, 283, 285, 288, 292, 295, 304, 310, 311, 315, 319, 323, 327, 330, 331, 333, 336, 339, 341, 347, 348] [10, 20, 25, 34, 37, 45, 48, 52, 54, 55, 56, 57, 58, 65, 68, 72, 75, 77, 82, 87, 93, 97, 100, 101, 102, 103, 105, 106, 108, 116, 117, 120, 130, 138, 139, 141, 147, 151, 159, 173, 174, 178, 180, 187, 190, 196, 205, 206, 215, 220, 230, 235, 239, 255, 259, 268, 274, 278, 280, 283, 284, 288, 291, 294, 303, 309, 311, 315, 318, 323, 326, 330, 331, 332, 336, 339, 340, 347, 348, 349] ['Sequencing', 'libraries', 'were', 'prepared', 'by', 'amplifying', 'the', 'V3–V4', 'region', 'of', 'the', '16', 'S', 'rRNA', 'gene', 'using', 'the', '341f-805', 'r', 'primers', ',', 'as', 'described', 'earlier.10', 'After', 'the', 'initial', 'amplification', ',', 'PCR', '(', 'Polymerase', 'chain', 'reaction', ')', 'products', 'were', 'confirmed', 'with', 'gel', 'electrophoresis', 'and', 'purified', 'using', 'Agencourt', 'AMPure', 'XP', 'magnetic', 'beads', '(', 'Beckham', 'Coulter', 'Inc', '.', ',', 'Bromma', ',', 'Sweden', ')', '.'] [1, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 6, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 2, 1, 1, 1, 1, 2, 2, 1, 1, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
For HP genes, the reaction mixture contained GoTaq buffer (Promega, Madison, Wisconsin, USA), 1.25 mM MgCl2 (Promega), 0.167 mM (each) deoxynucleotides (Roche Diagnostics), 2.5 U GoTaq polymerase (Promega), 333 nM of each primer (Sigma-Aldrich, St Louis, Missouri, USA) and 2 µl un-normalised stock DNA. [('PMC6683645', 'M04005', 179, 195, 'GoTaq polymerase')] ['For', 'HP', 'genes', ',', 'the', 'reaction', 'mixture', 'contained', 'Go', '##Ta', '##q', 'buffer', '(', 'Prom', '##eg', '##a', ',', 'Madison', ',', 'Wisconsin', ',', 'USA', ')', ',', '1', '.', '25', 'mM', 'MgCl', '##2', '(', 'Prom', '##eg', '##a', ')', ',', '0', '.', '167', 'mM', '(', 'each', ')', 'deoxy', '##nucle', '##otides', '(', 'Roche', 'Diagnostics', ')', ',', '2', '.', '5', 'U', 'Go', '##Ta', '##q', 'polymerase', '(', 'Prom', '##eg', '##a', ')', ',', '33', '##3', 'nM', 'of', 'each', 'primer', '(', 'Sigma', '-', 'Aldr', '##ich', ',', 'St', 'Louis', ',', 'Miss', '##ouri', ',', 'USA', ')', 'and', '2', '[UNK]', 'un', '-', 'normal', '##ised', 'stock', 'DNA', '.'] [0, 4, 7, 12, 14, 18, 27, 35, 45, 47, 49, 51, 58, 59, 63, 65, 66, 68, 75, 77, 86, 88, 91, 92, 94, 95, 96, 99, 102, 106, 108, 109, 113, 115, 116, 117, 119, 120, 121, 125, 128, 129, 133, 135, 140, 145, 152, 153, 159, 170, 171, 173, 174, 175, 177, 179, 181, 183, 185, 196, 197, 201, 203, 204, 205, 207, 209, 211, 214, 217, 222, 229, 230, 235, 236, 240, 243, 245, 248, 253, 255, 259, 263, 265, 268, 270, 274, -1, 279, 281, 282, 288, 293, 299, 302] [3, 6, 12, 13, 17, 26, 34, 44, 47, 49, 50, 57, 59, 63, 65, 66, 67, 75, 76, 86, 87, 91, 92, 93, 95, 96, 98, 101, 106, 107, 109, 113, 115, 116, 117, 118, 120, 121, 124, 127, 129, 133, 134, 140, 145, 151, 153, 158, 170, 171, 172, 174, 175, 176, 178, 181, 183, 184, 195, 197, 201, 203, 204, 205, 206, 209, 210, 213, 216, 221, 228, 230, 235, 236, 240, 243, 244, 247, 253, 254, 259, 263, 264, 268, 269, 273, 275, 4, 281, 282, 288, 292, 298, 302, 303] ['For', 'HP', 'genes', ',', 'the', 'reaction', 'mixture', 'contained', 'GoTaq', 'buffer', '(', 'Promega', ',', 'Madison', ',', 'Wisconsin', ',', 'USA', ')', ',', '1.25', 'mM', 'MgCl2', '(', 'Promega', ')', ',', '0.167', 'mM', '(', 'each', ')', 'deoxynucleotides', '(', 'Roche', 'Diagnostics', ')', ',', '2.5', 'U', 'GoTaq', 'polymerase', '(', 'Promega', ')', ',', '333', 'nM', 'of', 'each', 'primer', '(', 'Sigma-Aldrich', ',', 'St', 'Louis', ',', 'Missouri', ',', 'USA', ')', 'and', '2', 'µl', 'un', '-', 'normalised', 'stock', 'DNA', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 3, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Biopsy specimens were taken from the antrum and corpus for a rapid urease test (RUT) and histology. [('PMC6731296', 'M02002', 67, 73, 'urease')] ['Bio', '##ps', '##y', 'specimens', 'were', 'taken', 'from', 'the', 'ant', '##rum', 'and', 'corpus', 'for', 'a', 'rapid', 'urea', '##se', 'test', '(', 'RU', '##T', ')', 'and', 'histology', '.'] [0, 3, 5, 7, 17, 22, 28, 33, 37, 40, 44, 48, 55, 59, 61, 67, 71, 74, 79, 80, 82, 83, 85, 89, 98] [3, 5, 6, 16, 21, 27, 32, 36, 40, 43, 47, 54, 58, 60, 66, 71, 73, 78, 80, 82, 83, 84, 88, 98, 99] ['Biopsy', 'specimens', 'were', 'taken', 'from', 'the', 'antrum', 'and', 'corpus', 'for', 'a', 'rapid', 'urease', 'test', '(', 'RUT', ')', 'and', 'histology', '.'] [3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Prior studies have documented that the expression and activity of key genes in the fatty acid metabolism pathway, including ATP citrate lyase (ATP citrate lyase), acetyl-CoA carboxylase (acetyl-CoA carboxylase), fatty acid synthase, and stearoyl-coenzyme A desaturase, are observed in various tumors and are closely related to poor prognosis of these patients.[48–50] [('PMC6783185', 'D03002', 124, 141, 'ATP citrate lyase'), ('PMC6783185', 'D03002', 143, 160, 'ATP citrate lyase'), ('PMC6783185', 'D03002', 163, 185, 'acetyl-CoA carboxylase'), ('PMC6783185', 'D03002', 187, 209, 'acetyl-CoA carboxylase')] ['Prior', 'studies', 'have', 'documented', 'that', 'the', 'expression', 'and', 'activity', 'of', 'key', 'genes', 'in', 'the', 'fatty', 'acid', 'metabolism', 'pathway', ',', 'including', 'ATP', 'citrate', 'ly', '##ase', '(', 'ATP', 'citrate', 'ly', '##ase', ')', ',', 'acetyl', '-', 'Co', '##A', 'carboxyl', '##ase', '(', 'acetyl', '-', 'Co', '##A', 'carboxyl', '##ase', ')', ',', 'fatty', 'acid', 'synthase', ',', 'and', 'ste', '##aro', '##yl', '-', 'coe', '##n', '##zyme', 'A', 'des', '##atur', '##ase', ',', 'are', 'observed', 'in', 'various', 'tumors', 'and', 'are', 'closely', 'related', 'to', 'poor', 'prognosis', 'of', 'these', 'patients', '.', '[', '48', '–', '50', ']'] [0, 6, 14, 19, 30, 35, 39, 50, 54, 63, 66, 70, 76, 79, 83, 89, 94, 105, 112, 114, 124, 128, 136, 138, 142, 143, 147, 155, 157, 160, 161, 163, 169, 170, 172, 174, 182, 186, 187, 193, 194, 196, 198, 206, 209, 210, 212, 218, 223, 231, 233, 237, 240, 243, 245, 246, 249, 250, 255, 257, 260, 264, 267, 269, 273, 282, 285, 293, 300, 304, 308, 316, 324, 327, 332, 342, 345, 351, 359, 360, 361, 363, 364, 366] [5, 13, 18, 29, 34, 38, 49, 53, 62, 65, 69, 75, 78, 82, 88, 93, 104, 112, 113, 123, 127, 135, 138, 141, 143, 146, 154, 157, 160, 161, 162, 169, 170, 172, 173, 182, 185, 187, 193, 194, 196, 197, 206, 209, 210, 211, 217, 222, 231, 232, 236, 240, 243, 245, 246, 249, 250, 254, 256, 260, 264, 267, 268, 272, 281, 284, 292, 299, 303, 307, 315, 323, 326, 331, 341, 344, 350, 359, 360, 361, 363, 364, 366, 367] ['Prior', 'studies', 'have', 'documented', 'that', 'the', 'expression', 'and', 'activity', 'of', 'key', 'genes', 'in', 'the', 'fatty', 'acid', 'metabolism', 'pathway', ',', 'including', 'ATP', 'citrate', 'lyase', '(', 'ATP', 'citrate', 'lyase', ')', ',', 'acetyl-CoA', 'carboxylase', '(', 'acetyl-CoA', 'carboxylase', ')', ',', 'fatty', 'acid', 'synthase', ',', 'and', 'stearoyl', '-', 'coenzyme', 'A', 'desaturase', ',', 'are', 'observed', 'in', 'various', 'tumors', 'and', 'are', 'closely', 'related', 'to', 'poor', 'prognosis', 'of', 'these', 'patients.[48–50]'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 4, 2, 1, 4, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 7] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'E', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. [('PMC6783185', 'F47001', 7, 24, 'ATP citrate lyase')] ['et', 'al', '.', 'ATP', 'citrate', 'ly', '##ase', ':', 'activation', 'and', 'therapeutic', 'implications', 'in', 'non', '-', 'small', 'cell', 'lung', 'cancer', '.'] [0, 3, 5, 7, 11, 19, 21, 24, 26, 37, 41, 53, 66, 69, 72, 73, 79, 84, 89, 95] [2, 5, 6, 10, 18, 21, 24, 25, 36, 40, 52, 65, 68, 72, 73, 78, 83, 88, 95, 96] ['et', 'al', '.', 'ATP', 'citrate', 'lyase', ':', 'activation', 'and', 'therapeutic', 'implications', 'in', 'non', '-', 'small', 'cell', 'lung', 'cancer', '.'] [1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Cohort study of fatty acid synthase expression and patient survival in colon cancer. [('PMC6783185', 'F48001', 16, 35, 'fatty acid synthase')] ['Coh', '##ort', 'study', 'of', 'fatty', 'acid', 'synthase', 'expression', 'and', 'patient', 'survival', 'in', 'colon', 'cancer', '.'] [0, 3, 7, 13, 16, 22, 27, 36, 47, 51, 59, 68, 71, 77, 83] [3, 6, 12, 15, 21, 26, 35, 46, 50, 58, 67, 70, 76, 83, 84] ['Cohort', 'study', 'of', 'fatty', 'acid', 'synthase', 'expression', 'and', 'patient', 'survival', 'in', 'colon', 'cancer', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival. [('PMC6783185', 'F49001', 0, 19, 'Fatty acid synthase')] ['Fat', '##ty', 'acid', 'synthase', 'polymorphisms', ',', 'tumor', 'expression', ',', 'body', 'mass', 'index', ',', 'prostate', 'cancer', 'risk', ',', 'and', 'survival', '.'] [0, 3, 6, 11, 20, 33, 35, 41, 51, 53, 58, 63, 68, 70, 79, 86, 90, 92, 96, 104] [3, 5, 10, 19, 33, 34, 40, 51, 52, 57, 62, 68, 69, 78, 85, 90, 91, 95, 104, 105] ['Fatty', 'acid', 'synthase', 'polymorphisms', ',', 'tumor', 'expression', ',', 'body', 'mass', 'index', ',', 'prostate', 'cancer', 'risk', ',', 'and', 'survival', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
et al. ATP citrate lyase inhibition can suppress tumor cell growth. [('PMC6783185', 'F50001', 7, 24, 'ATP citrate lyase')] ['et', 'al', '.', 'ATP', 'citrate', 'ly', '##ase', 'inhibition', 'can', 'suppress', 'tumor', 'cell', 'growth', '.'] [0, 3, 5, 7, 11, 19, 21, 25, 36, 40, 49, 55, 60, 66] [2, 5, 6, 10, 18, 21, 24, 35, 39, 48, 54, 59, 66, 67] ['et', 'al', '.', 'ATP', 'citrate', 'lyase', 'inhibition', 'can', 'suppress', 'tumor', 'cell', 'growth', '.'] [1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
With the advent of microarray techniques, many pathological processes can be explored and monitored in a global view by the aid of omics-driven, high-throughput technologies.[15] In several genomics, transcriptomics, and proteomics researches, a series of genes and protein molecules (parathyroid hormone-related protein, nuclear factor Ib, zinc finger protein-14, glutathione peroxidase 1, etc) have been found to be abnormally expressed in GCT patients,[16–19] which were also expected to be potential biomarkers for GCT. [('PMC6783185', 'I02000', 365, 389, 'glutathione peroxidase 1')] ['With', 'the', 'advent', 'of', 'microarray', 'techniques', ',', 'many', 'pathological', 'processes', 'can', 'be', 'explored', 'and', 'monitored', 'in', 'a', 'global', 'view', 'by', 'the', 'aid', 'of', 'om', '##ics', '-', 'driven', ',', 'high', '-', 'throughput', 'technologies', '.', '[', '15', ']', 'In', 'several', 'genomics', ',', 'transcript', '##omics', ',', 'and', 'proteomics', 'researches', ',', 'a', 'series', 'of', 'genes', 'and', 'protein', 'molecules', '(', 'parathyroid', 'hormone', '-', 'related', 'protein', ',', 'nuclear', 'factor', 'Ib', ',', 'zinc', 'finger', 'protein', '-', '14', ',', 'glutathione', 'peroxidase', '1', ',', 'etc', ')', 'have', 'been', 'found', 'to', 'be', 'abnormal', '##ly', 'expressed', 'in', 'GC', '##T', 'patients', ',', '[', '16', '–', '19', ']', 'which', 'were', 'also', 'expected', 'to', 'be', 'potential', 'biomarkers', 'for', 'GC', '##T', '.'] [0, 5, 9, 16, 19, 30, 40, 42, 47, 60, 70, 74, 77, 86, 90, 100, 103, 105, 112, 117, 120, 124, 128, 131, 133, 136, 137, 143, 145, 149, 150, 161, 173, 174, 175, 177, 179, 182, 190, 198, 200, 210, 215, 217, 221, 232, 242, 244, 246, 253, 256, 262, 266, 274, 284, 285, 297, 304, 305, 313, 320, 322, 330, 337, 339, 341, 346, 353, 360, 361, 363, 365, 377, 388, 389, 391, 394, 396, 401, 406, 412, 415, 418, 426, 429, 439, 442, 444, 446, 454, 455, 456, 458, 459, 461, 463, 469, 474, 479, 488, 491, 494, 504, 515, 519, 521, 522] [4, 8, 15, 18, 29, 40, 41, 46, 59, 69, 73, 76, 85, 89, 99, 102, 104, 111, 116, 119, 123, 127, 130, 133, 136, 137, 143, 144, 149, 150, 160, 173, 174, 175, 177, 178, 181, 189, 198, 199, 210, 215, 216, 220, 231, 242, 243, 245, 252, 255, 261, 265, 273, 283, 285, 296, 304, 305, 312, 320, 321, 329, 336, 339, 340, 345, 352, 360, 361, 363, 364, 376, 387, 389, 390, 394, 395, 400, 405, 411, 414, 417, 426, 428, 438, 441, 444, 445, 454, 455, 456, 458, 459, 461, 462, 468, 473, 478, 487, 490, 493, 503, 514, 518, 521, 522, 523] ['With', 'the', 'advent', 'of', 'microarray', 'techniques', ',', 'many', 'pathological', 'processes', 'can', 'be', 'explored', 'and', 'monitored', 'in', 'a', 'global', 'view', 'by', 'the', 'aid', 'of', 'omics', '-', 'driven', ',', 'high', '-', 'throughput', 'technologies.[15]', 'In', 'several', 'genomics', ',', 'transcriptomics', ',', 'and', 'proteomics', 'researches', ',', 'a', 'series', 'of', 'genes', 'and', 'protein', 'molecules', '(', 'parathyroid', 'hormone', '-', 'related', 'protein', ',', 'nuclear', 'factor', 'Ib', ',', 'zinc', 'finger', 'protein-14', ',', 'glutathione', 'peroxidase', '1', ',', 'etc', ')', 'have', 'been', 'found', 'to', 'be', 'abnormally', 'expressed', 'in', 'GCT', 'patients', ',', '[', '16–', '19', ']', 'which', 'were', 'also', 'expected', 'to', 'be', 'potential', 'biomarkers', 'for', 'GCT', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
These differentially abundant proteins were related to nuclear factor κB (NF-κB) and p38 mitogen-activated protein (MAP) kinase pathways and were involved in cellular compromise, inflammatory response, and cancer. [('PMC6801506', 'A00004', 121, 127, 'kinase')] ['These', 'differentially', 'abundant', 'proteins', 'were', 'related', 'to', 'nuclear', 'factor', 'κ', '##B', '(', 'NF', '-', 'κ', '##B', ')', 'and', 'p', '##38', 'mitogen', '-', 'activated', 'protein', '(', 'MAP', ')', 'kinase', 'pathways', 'and', 'were', 'involved', 'in', 'cellular', 'compromise', ',', 'inflammatory', 'response', ',', 'and', 'cancer', '.'] [0, 6, 21, 30, 39, 44, 52, 55, 63, 70, 71, 73, 74, 76, 77, 78, 79, 81, 85, 86, 89, 96, 97, 107, 115, 116, 119, 121, 128, 137, 141, 146, 155, 158, 167, 177, 179, 192, 200, 202, 206, 212] [5, 20, 29, 38, 43, 51, 54, 62, 69, 71, 72, 74, 76, 77, 78, 79, 80, 84, 86, 88, 96, 97, 106, 114, 116, 119, 120, 127, 136, 140, 145, 154, 157, 166, 177, 178, 191, 200, 201, 205, 212, 213] ['These', 'differentially', 'abundant', 'proteins', 'were', 'related', 'to', 'nuclear', 'factor', 'κB', '(', 'NF-κB', ')', 'and', 'p38', 'mitogen', '-', 'activated', 'protein', '(', 'MAP', ')', 'kinase', 'pathways', 'and', 'were', 'involved', 'in', 'cellular', 'compromise', ',', 'inflammatory', 'response', ',', 'and', 'cancer', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 4, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The differentially abundant proteins were mostly related to NF-κB and p38 mitogen-activated protein (MAP) kinase pathways and were involved in cellular compromise, inflammatory response, and cancer. [('PMC6801506', 'D00003', 106, 112, 'kinase')] ['The', 'differentially', 'abundant', 'proteins', 'were', 'mostly', 'related', 'to', 'NF', '-', 'κ', '##B', 'and', 'p', '##38', 'mitogen', '-', 'activated', 'protein', '(', 'MAP', ')', 'kinase', 'pathways', 'and', 'were', 'involved', 'in', 'cellular', 'compromise', ',', 'inflammatory', 'response', ',', 'and', 'cancer', '.'] [0, 4, 19, 28, 37, 42, 49, 57, 60, 62, 63, 64, 66, 70, 71, 74, 81, 82, 92, 100, 101, 104, 106, 113, 122, 126, 131, 140, 143, 152, 162, 164, 177, 185, 187, 191, 197] [3, 18, 27, 36, 41, 48, 56, 59, 62, 63, 64, 65, 69, 71, 73, 81, 82, 91, 99, 101, 104, 105, 112, 121, 125, 130, 139, 142, 151, 162, 163, 176, 185, 186, 190, 197, 198] ['The', 'differentially', 'abundant', 'proteins', 'were', 'mostly', 'related', 'to', 'NF-κB', 'and', 'p38', 'mitogen', '-', 'activated', 'protein', '(', 'MAP', ')', 'kinase', 'pathways', 'and', 'were', 'involved', 'in', 'cellular', 'compromise', ',', 'inflammatory', 'response', ',', 'and', 'cancer', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
HK plays an essential role in the assembly of the plasma kallikrein–kinin system (KKS), which contains two serine proteases and an HK. [('PMC6801506', 'D03002', 107, 123, 'serine proteases')] ['HK', 'plays', 'an', 'essential', 'role', 'in', 'the', 'assembly', 'of', 'the', 'plasma', 'ka', '##ll', '##ik', '##rein', '–', 'kin', '##in', 'system', '(', 'KK', '##S', ')', ',', 'which', 'contains', 'two', 'serine', 'proteases', 'and', 'an', 'HK', '.'] [0, 3, 9, 12, 22, 27, 30, 34, 43, 46, 50, 57, 59, 61, 63, 67, 68, 71, 74, 81, 82, 84, 85, 86, 88, 94, 103, 107, 114, 124, 128, 131, 133] [2, 8, 11, 21, 26, 29, 33, 42, 45, 49, 56, 59, 61, 63, 67, 68, 71, 73, 80, 82, 84, 85, 86, 87, 93, 102, 106, 113, 123, 127, 130, 133, 134] ['HK', 'plays', 'an', 'essential', 'role', 'in', 'the', 'assembly', 'of', 'the', 'plasma', 'kallikrein', '–', 'kinin', 'system', '(', 'KKS', ')', ',', 'which', 'contains', 'two', 'serine', 'proteases', 'and', 'an', 'HK', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O']
Although the mechanism of how RET4 affects insulin sensitivity is not clear, RET4 may cause insulin resistance by inducing the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, in the liver and by impairing insulin signaling in muscles [28]. [('PMC6801506', 'D05006', 149, 182, 'phosphoenolpyruvate carboxykinase')] ['Although', 'the', 'mechanism', 'of', 'how', 'RET', '##4', 'affects', 'insulin', 'sensitivity', 'is', 'not', 'clear', ',', 'RET', '##4', 'may', 'cause', 'insulin', 'resistance', 'by', 'inducing', 'the', 'gluc', '##one', '##ogenic', 'enzyme', ',', 'phospho', '##eno', '##l', '##pyr', '##uvate', 'carb', '##oxy', '##kinase', ',', 'in', 'the', 'liver', 'and', 'by', 'impair', '##ing', 'insulin', 'signaling', 'in', 'muscles', '[', '28', ']', '.'] [0, 9, 13, 23, 26, 30, 33, 35, 43, 51, 63, 66, 70, 75, 77, 80, 82, 86, 92, 100, 111, 114, 123, 127, 131, 134, 141, 147, 149, 156, 159, 160, 163, 169, 173, 176, 182, 184, 187, 191, 197, 201, 204, 210, 214, 222, 232, 235, 243, 244, 246, 247] [8, 12, 22, 25, 29, 33, 34, 42, 50, 62, 65, 69, 75, 76, 80, 81, 85, 91, 99, 110, 113, 122, 126, 131, 134, 140, 147, 148, 156, 159, 160, 163, 168, 173, 176, 182, 183, 186, 190, 196, 200, 203, 210, 213, 221, 231, 234, 242, 244, 246, 247, 248] ['Although', 'the', 'mechanism', 'of', 'how', 'RET4', 'affects', 'insulin', 'sensitivity', 'is', 'not', 'clear', ',', 'RET4', 'may', 'cause', 'insulin', 'resistance', 'by', 'inducing', 'the', 'gluconeogenic', 'enzyme', ',', 'phosphoenolpyruvate', 'carboxykinase', ',', 'in', 'the', 'liver', 'and', 'by', 'impairing', 'insulin', 'signaling', 'in', 'muscles', '[', '28', ']', '.'] [1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 5, 3, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Zhao J., Wang M., Deng W., Zhong D., Jiang Y., Liao Y., Chen B., Zhang X. ADP-ribosylation factor-like GTPase 15 enhances insulin-induced AKT phosphorylation in the IR/IRS1/AKT pathway by interacting with ASAP2 and regulating PDPK1 activity. [('PMC6801506', 'F23001', 74, 112, 'ADP-ribosylation factor-like GTPase 15')] ['Zhao', 'J', '.', ',', 'Wang', 'M', '.', ',', 'Den', '##g', 'W', '.', ',', 'Zhong', 'D', '.', ',', 'Jiang', 'Y', '.', ',', 'Li', '##ao', 'Y', '.', ',', 'Chen', 'B', '.', ',', 'Zhang', 'X', '.', 'ADP', '-', 'rib', '##osyl', '##ation', 'factor', '-', 'like', 'GTP', '##ase', '15', 'enhances', 'insulin', '-', 'induced', 'AKT', 'phosphorylation', 'in', 'the', 'IR', '/', 'IRS', '##1', '/', 'AKT', 'pathway', 'by', 'interacting', 'with', 'ASA', '##P', '##2', 'and', 'regulating', 'PD', '##PK', '##1', 'activity', '.'] [0, 5, 6, 7, 9, 14, 15, 16, 18, 21, 23, 24, 25, 27, 33, 34, 35, 37, 43, 44, 45, 47, 49, 52, 53, 54, 56, 61, 62, 63, 65, 71, 72, 74, 77, 78, 81, 85, 91, 97, 98, 103, 106, 110, 113, 122, 129, 130, 138, 142, 158, 161, 165, 167, 168, 171, 172, 173, 177, 185, 188, 200, 205, 208, 209, 211, 215, 226, 228, 230, 232, 240] [4, 6, 7, 8, 13, 15, 16, 17, 21, 22, 24, 25, 26, 32, 34, 35, 36, 42, 44, 45, 46, 49, 51, 53, 54, 55, 60, 62, 63, 64, 70, 72, 73, 77, 78, 81, 85, 90, 97, 98, 102, 106, 109, 112, 121, 129, 130, 137, 141, 157, 160, 164, 167, 168, 171, 172, 173, 176, 184, 187, 199, 204, 208, 209, 210, 214, 225, 228, 230, 231, 240, 241] ['Zhao', 'J', '.', ',', 'Wang', 'M', '.', ',', 'Deng', 'W', '.', ',', 'Zhong', 'D', '.', ',', 'Jiang', 'Y', '.', ',', 'Liao', 'Y', '.', ',', 'Chen', 'B', '.', ',', 'Zhang', 'X', '.', 'ADP-ribosylation', 'factor', '-', 'like', 'GTPase', '15', 'enhances', 'insulin', '-', 'induced', 'AKT', 'phosphorylation', 'in', 'the', 'IR', '/', 'IRS1', '/', 'AKT', 'pathway', 'by', 'interacting', 'with', 'ASAP2', 'and', 'regulating', 'PDPK1', 'activity', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In addition, urine is considered as a safe and reliable alternative for biomarker studies compared to plasma and tissue samples because of the non-invasive collection procedure, the abundance of specimen, and the relatively stable content of peptides and proteins as it undergoes the complete proteolytic degradation process by endogenous proteases during its storage in the bladder [4]. [('PMC6801506', 'I01004', 328, 348, 'endogenous proteases')] ['In', 'addition', ',', 'urine', 'is', 'considered', 'as', 'a', 'safe', 'and', 'reliable', 'alternative', 'for', 'biomarker', 'studies', 'compared', 'to', 'plasma', 'and', 'tissue', 'samples', 'because', 'of', 'the', 'non', '-', 'invasive', 'collection', 'procedure', ',', 'the', 'abundance', 'of', 'specimen', ',', 'and', 'the', 'relatively', 'stable', 'content', 'of', 'peptides', 'and', 'proteins', 'as', 'it', 'undergoes', 'the', 'complete', 'proteolytic', 'degradation', 'process', 'by', 'endogenous', 'proteases', 'during', 'its', 'storage', 'in', 'the', 'bladder', '[', '4', ']', '.'] [0, 3, 11, 13, 19, 22, 33, 36, 38, 43, 47, 56, 68, 72, 82, 90, 99, 102, 109, 113, 120, 128, 136, 139, 143, 146, 147, 156, 167, 176, 178, 182, 192, 195, 203, 205, 209, 213, 224, 231, 239, 242, 251, 255, 264, 267, 270, 280, 284, 293, 305, 317, 325, 328, 339, 349, 356, 360, 368, 371, 375, 383, 384, 385, 386] [2, 11, 12, 18, 21, 32, 35, 37, 42, 46, 55, 67, 71, 81, 89, 98, 101, 108, 112, 119, 127, 135, 138, 142, 146, 147, 155, 166, 176, 177, 181, 191, 194, 203, 204, 208, 212, 223, 230, 238, 241, 250, 254, 263, 266, 269, 279, 283, 292, 304, 316, 324, 327, 338, 348, 355, 359, 367, 370, 374, 382, 384, 385, 386, 387] ['In', 'addition', ',', 'urine', 'is', 'considered', 'as', 'a', 'safe', 'and', 'reliable', 'alternative', 'for', 'biomarker', 'studies', 'compared', 'to', 'plasma', 'and', 'tissue', 'samples', 'because', 'of', 'the', 'non', '-', 'invasive', 'collection', 'procedure', ',', 'the', 'abundance', 'of', 'specimen', ',', 'and', 'the', 'relatively', 'stable', 'content', 'of', 'peptides', 'and', 'proteins', 'as', 'it', 'undergoes', 'the', 'complete', 'proteolytic', 'degradation', 'process', 'by', 'endogenous', 'proteases', 'during', 'its', 'storage', 'in', 'the', 'bladder', '[', '4', ']', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Here we extended this potential to directly measure pharmacodynamic target engagement following in vivo administration of a specific neutral cholesterol ester hydrolase 1 inhibitor in mice. [('PMC6815137', 'D04002', 133, 170, 'neutral cholesterol ester hydrolase 1')] ['Here', 'we', 'extended', 'this', 'potential', 'to', 'directly', 'measure', 'pharmac', '##odynamic', 'target', 'engagement', 'following', 'in', 'vivo', 'administration', 'of', 'a', 'specific', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', 'inhibitor', 'in', 'mice', '.'] [0, 5, 8, 17, 22, 32, 35, 44, 52, 59, 68, 75, 86, 96, 99, 104, 119, 122, 124, 133, 141, 153, 159, 164, 167, 169, 171, 181, 184, 188] [4, 7, 16, 21, 31, 34, 43, 51, 59, 67, 74, 85, 95, 98, 103, 118, 121, 123, 132, 140, 152, 158, 164, 167, 168, 170, 180, 183, 188, 189] ['Here', 'we', 'extended', 'this', 'potential', 'to', 'directly', 'measure', 'pharmacodynamic', 'target', 'engagement', 'following', 'in', 'vivo', 'administration', 'of', 'a', 'specific', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', 'inhibitor', 'in', 'mice', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O']
Parallel profiling of 2 related enzyme family members showed no effect of the neutral cholesterol ester hydrolase 1-specific inhibitor on their activity, confirming specific target engagement in vivo in a workflow that has minimal processing steps, is benchtop-compatible, and can be performed in a matter of hours. [('PMC6815137', 'D04004', 78, 115, 'neutral cholesterol ester hydrolase 1')] ['Parallel', 'profiling', 'of', '2', 'related', 'enzyme', 'family', 'members', 'showed', 'no', 'effect', 'of', 'the', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', '-', 'specific', 'inhibitor', 'on', 'their', 'activity', ',', 'confirming', 'specific', 'target', 'engagement', 'in', 'vivo', 'in', 'a', 'workflow', 'that', 'has', 'minimal', 'processing', 'steps', ',', 'is', 'ben', '##cht', '##op', '-', 'compatible', ',', 'and', 'can', 'be', 'performed', 'in', 'a', 'matter', 'of', 'hours', '.'] [0, 9, 19, 22, 24, 32, 39, 46, 54, 61, 64, 71, 74, 78, 86, 98, 104, 109, 112, 114, 115, 116, 125, 135, 138, 144, 152, 154, 165, 174, 181, 192, 195, 200, 203, 205, 214, 219, 223, 231, 242, 247, 249, 252, 255, 258, 260, 261, 271, 273, 277, 281, 284, 294, 297, 299, 306, 309, 314] [8, 18, 21, 23, 31, 38, 45, 53, 60, 63, 70, 73, 77, 85, 97, 103, 109, 112, 113, 115, 116, 124, 134, 137, 143, 152, 153, 164, 173, 180, 191, 194, 199, 202, 204, 213, 218, 222, 230, 241, 247, 248, 251, 255, 258, 260, 261, 271, 272, 276, 280, 283, 293, 296, 298, 305, 308, 314, 315] ['Parallel', 'profiling', 'of', '2', 'related', 'enzyme', 'family', 'members', 'showed', 'no', 'effect', 'of', 'the', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1-specific', 'inhibitor', 'on', 'their', 'activity', ',', 'confirming', 'specific', 'target', 'engagement', 'in', 'vivo', 'in', 'a', 'workflow', 'that', 'has', 'minimal', 'processing', 'steps', ',', 'is', 'benchtop', '-', 'compatible', ',', 'and', 'can', 'be', 'performed', 'in', 'a', 'matter', 'of', 'hours', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
For example, we found a significant decrease in the activity of the cathepsin proteases cathepsin L [('PMC6815137', 'D07001', 68, 87, 'cathepsin proteases'), ('PMC6815137', 'D07001', 88, 99, 'cathepsin L')] ['For', 'example', ',', 'we', 'found', 'a', 'significant', 'decrease', 'in', 'the', 'activity', 'of', 'the', 'cathe', '##ps', '##in', 'proteases', 'cathe', '##ps', '##in', 'L'] [0, 4, 11, 13, 16, 22, 24, 36, 45, 48, 52, 61, 64, 68, 73, 75, 78, 88, 93, 95, 98] [3, 11, 12, 15, 21, 23, 35, 44, 47, 51, 60, 63, 67, 73, 75, 77, 87, 93, 95, 97, 99] ['For', 'example', ',', 'we', 'found', 'a', 'significant', 'decrease', 'in', 'the', 'activity', 'of', 'the', 'cathepsin', 'proteases', 'cathepsin', 'L'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'B', 'I', 'I', 'E']
and cathepsin B in the metastatic tumor compartment compared with the primary tumor. [('PMC6815137', 'D07002', 4, 15, 'cathepsin B')] ['and', 'cathe', '##ps', '##in', 'B', 'in', 'the', 'metastatic', 'tumor', 'compartment', 'compared', 'with', 'the', 'primary', 'tumor', '.'] [0, 4, 9, 11, 14, 16, 19, 23, 34, 40, 52, 61, 66, 70, 78, 83] [3, 9, 11, 13, 15, 18, 22, 33, 39, 51, 60, 65, 69, 77, 83, 84] ['and', 'cathepsin', 'B', 'in', 'the', 'metastatic', 'tumor', 'compartment', 'compared', 'with', 'the', 'primary', 'tumor', '.'] [1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
This finding is consistent with previous studies implicating high cathepsin B and cathepsin L protein abundance in aggressive ovarian cancers; however, no previous studies have probed protease activity or tumor compartment-specific activity (37–39). [('PMC6815137', 'D07003', 66, 77, 'cathepsin B'), ('PMC6815137', 'D07003', 82, 93, 'cathepsin L')] ['This', 'finding', 'is', 'consistent', 'with', 'previous', 'studies', 'implic', '##ating', 'high', 'cathe', '##ps', '##in', 'B', 'and', 'cathe', '##ps', '##in', 'L', 'protein', 'abundance', 'in', 'aggressive', 'ovarian', 'cancers', ';', 'however', ',', 'no', 'previous', 'studies', 'have', 'probed', 'protease', 'activity', 'or', 'tumor', 'compartment', '-', 'specific', 'activity', '(', '37', '–', '39', ')', '.'] [0, 5, 13, 16, 27, 32, 41, 49, 55, 61, 66, 71, 73, 76, 78, 82, 87, 89, 92, 94, 102, 112, 115, 126, 134, 141, 143, 150, 152, 155, 164, 172, 177, 184, 193, 202, 205, 211, 222, 223, 232, 241, 242, 244, 245, 247, 248] [4, 12, 15, 26, 31, 40, 48, 55, 60, 65, 71, 73, 75, 77, 81, 87, 89, 91, 93, 101, 111, 114, 125, 133, 141, 142, 150, 151, 154, 163, 171, 176, 183, 192, 201, 204, 210, 222, 223, 231, 240, 242, 244, 245, 247, 248, 249] ['This', 'finding', 'is', 'consistent', 'with', 'previous', 'studies', 'implicating', 'high', 'cathepsin', 'B', 'and', 'cathepsin', 'L', 'protein', 'abundance', 'in', 'aggressive', 'ovarian', 'cancers', ';', 'however', ',', 'no', 'previous', 'studies', 'have', 'probed', 'protease', 'activity', 'or', 'tumor', 'compartment', '-', 'specific', 'activity', '(', '37–', '39', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The relatively high activity in the primary tumor site is in agreement with the roles of microenvironment remodeling factors and proteases during the epithelial-to-mesenchymal transition in primary metastatic tumors (40), and also could be related to microenvironmental conditions in the primary tumor that may promote the activity of these enzymes. [('PMC6815137', 'D07004', 129, 138, 'proteases')] ['The', 'relatively', 'high', 'activity', 'in', 'the', 'primary', 'tumor', 'site', 'is', 'in', 'agreement', 'with', 'the', 'roles', 'of', 'micro', '##environment', 'remodeling', 'factors', 'and', 'proteases', 'during', 'the', 'epithelial', '-', 'to', '-', 'mesenchymal', 'transition', 'in', 'primary', 'metastatic', 'tumors', '(', '40', ')', ',', 'and', 'also', 'could', 'be', 'related', 'to', 'micro', '##environment', '##al', 'conditions', 'in', 'the', 'primary', 'tumor', 'that', 'may', 'promote', 'the', 'activity', 'of', 'these', 'enzymes', '.'] [0, 4, 15, 20, 29, 32, 36, 44, 50, 55, 58, 61, 71, 76, 80, 86, 89, 94, 106, 117, 125, 129, 139, 146, 150, 160, 161, 163, 164, 176, 187, 190, 198, 209, 216, 217, 219, 220, 222, 226, 231, 237, 240, 248, 251, 256, 267, 270, 281, 284, 288, 296, 302, 307, 311, 319, 323, 332, 335, 341, 348] [3, 14, 19, 28, 31, 35, 43, 49, 54, 57, 60, 70, 75, 79, 85, 88, 94, 105, 116, 124, 128, 138, 145, 149, 160, 161, 163, 164, 175, 186, 189, 197, 208, 215, 217, 219, 220, 221, 225, 230, 236, 239, 247, 250, 256, 267, 269, 280, 283, 287, 295, 301, 306, 310, 318, 322, 331, 334, 340, 348, 349] ['The', 'relatively', 'high', 'activity', 'in', 'the', 'primary', 'tumor', 'site', 'is', 'in', 'agreement', 'with', 'the', 'roles', 'of', 'microenvironment', 'remodeling', 'factors', 'and', 'proteases', 'during', 'the', 'epithelial', '-', 'to', '-', 'mesenchymal', 'transition', 'in', 'primary', 'metastatic', 'tumors', '(', '40', ')', ',', 'and', 'also', 'could', 'be', 'related', 'to', 'microenvironmental', 'conditions', 'in', 'the', 'primary', 'tumor', 'that', 'may', 'promote', 'the', 'activity', 'of', 'these', 'enzymes', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Furthermore, we observed significant trends between the activity ratio in the metastatic tumors compared with primary tumors for the lipid-hydrolase enzyme fatty acid amide hydrolase 1. [('PMC6815137', 'D07006', 133, 148, 'lipid-hydrolase'), ('PMC6815137', 'D07006', 156, 184, 'fatty acid amide hydrolase 1')] ['Furthermore', ',', 'we', 'observed', 'significant', 'trends', 'between', 'the', 'activity', 'ratio', 'in', 'the', 'metastatic', 'tumors', 'compared', 'with', 'primary', 'tumors', 'for', 'the', 'lipid', '-', 'hydro', '##las', '##e', 'enzyme', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', '.'] [0, 11, 13, 16, 25, 37, 44, 52, 56, 65, 71, 74, 78, 89, 96, 105, 110, 118, 125, 129, 133, 138, 139, 144, 147, 149, 156, 162, 167, 173, 178, 181, 183, 184] [11, 12, 15, 24, 36, 43, 51, 55, 64, 70, 73, 77, 88, 95, 104, 109, 117, 124, 128, 132, 138, 139, 144, 147, 148, 155, 161, 166, 172, 178, 181, 182, 184, 185] ['Furthermore', ',', 'we', 'observed', 'significant', 'trends', 'between', 'the', 'activity', 'ratio', 'in', 'the', 'metastatic', 'tumors', 'compared', 'with', 'primary', 'tumors', 'for', 'the', 'lipid', '-', 'hydrolase', 'enzyme', 'fatty', 'acid', 'amide', 'hydrolase', '1', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O']
Liu Y., Patricelli M. P., Cravatt B. F., Activity-based protein profiling: The serine hydrolases. [('PMC6815137', 'F05001', 79, 96, 'serine hydrolases')] ['Liu', 'Y', '.', ',', 'Pat', '##ric', '##elli', 'M', '.', 'P', '.', ',', 'Cra', '##va', '##tt', 'B', '.', 'F', '.', ',', 'Activity', '-', 'based', 'protein', 'profiling', ':', 'The', 'serine', 'hydro', '##las', '##es', '.'] [0, 4, 5, 6, 8, 11, 14, 19, 20, 22, 23, 24, 26, 29, 31, 34, 35, 37, 38, 39, 41, 49, 50, 56, 64, 73, 75, 79, 86, 91, 94, 96] [3, 5, 6, 7, 11, 14, 18, 20, 21, 23, 24, 25, 29, 31, 33, 35, 36, 38, 39, 40, 49, 50, 55, 63, 73, 74, 78, 85, 91, 94, 96, 97] ['Liu', 'Y', '.', ',', 'Patricelli', 'M', '.', 'P', '.', ',', 'Cravatt', 'B', '.', 'F', '.', ',', 'Activity', '-', 'based', 'protein', 'profiling', ':', 'The', 'serine', 'hydrolases', '.'] [1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O']
Simon G. M., Cravatt B. F., Activity-based proteomics of enzyme superfamilies: Serine hydrolases as a case study. [('PMC6815137', 'F06001', 79, 96, 'Serine hydrolases')] ['Simon', 'G', '.', 'M', '.', ',', 'Cra', '##va', '##tt', 'B', '.', 'F', '.', ',', 'Activity', '-', 'based', 'proteomics', 'of', 'enzyme', 'superf', '##amilies', ':', 'Ser', '##ine', 'hydro', '##las', '##es', 'as', 'a', 'case', 'study', '.'] [0, 6, 7, 9, 10, 11, 13, 16, 18, 21, 22, 24, 25, 26, 28, 36, 37, 43, 54, 57, 64, 70, 77, 79, 82, 86, 91, 94, 97, 100, 102, 107, 112] [5, 7, 8, 10, 11, 12, 16, 18, 20, 22, 23, 25, 26, 27, 36, 37, 42, 53, 56, 63, 70, 77, 78, 82, 85, 91, 94, 96, 99, 101, 106, 112, 113] ['Simon', 'G', '.', 'M', '.', ',', 'Cravatt', 'B', '.', 'F', '.', ',', 'Activity', '-', 'based', 'proteomics', 'of', 'enzyme', 'superfamilies', ':', 'Serine', 'hydrolases', 'as', 'a', 'case', 'study', '.'] [1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 2, 3, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O']
Zhao Q., et al. , Broad-spectrum kinase profiling in live cells with lysine-targeted sulfonyl fluoride probes. [('PMC6815137', 'F08001', 33, 39, 'kinase')] ['Zhao', 'Q', '.', ',', 'et', 'al', '.', ',', 'Broad', '-', 'spectrum', 'kinase', 'profiling', 'in', 'live', 'cells', 'with', 'lysine', '-', 'targeted', 'sulf', '##onyl', 'fluoride', 'probes', '.'] [0, 5, 6, 7, 9, 12, 14, 16, 18, 23, 24, 33, 40, 50, 53, 58, 64, 69, 75, 76, 85, 89, 94, 103, 109] [4, 6, 7, 8, 11, 14, 15, 17, 23, 24, 32, 39, 49, 52, 57, 63, 68, 75, 76, 84, 89, 93, 102, 109, 110] ['Zhao', 'Q', '.', ',', 'et', 'al', '.', ',', 'Broad', '-', 'spectrum', 'kinase', 'profiling', 'in', 'live', 'cells', 'with', 'lysine', '-', 'targeted', 'sulfonyl', 'fluoride', 'probes', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Saghatelian A., Jessani N., Joseph A., Humphrey M., Cravatt B. F., Activity-based probes for the proteomic profiling of metalloproteases. [('PMC6815137', 'F09001', 120, 136, 'metalloproteases')] ['Sa', '##gh', '##ate', '##li', '##an', 'A', '.', ',', 'Je', '##ss', '##ani', 'N', '.', ',', 'Joseph', 'A', '.', ',', 'Hum', '##ph', '##rey', 'M', '.', ',', 'Cra', '##va', '##tt', 'B', '.', 'F', '.', ',', 'Activity', '-', 'based', 'probes', 'for', 'the', 'proteomic', 'profiling', 'of', 'metall', '##oprot', '##ea', '##ses', '.'] [0, 2, 4, 7, 9, 12, 13, 14, 16, 18, 20, 24, 25, 26, 28, 35, 36, 37, 39, 42, 44, 48, 49, 50, 52, 55, 57, 60, 61, 63, 64, 65, 67, 75, 76, 82, 89, 93, 97, 107, 117, 120, 126, 131, 133, 136] [2, 4, 7, 9, 11, 13, 14, 15, 18, 20, 23, 25, 26, 27, 34, 36, 37, 38, 42, 44, 47, 49, 50, 51, 55, 57, 59, 61, 62, 64, 65, 66, 75, 76, 81, 88, 92, 96, 106, 116, 119, 126, 131, 133, 136, 137] ['Saghatelian', 'A', '.', ',', 'Jessani', 'N', '.', ',', 'Joseph', 'A', '.', ',', 'Humphrey', 'M', '.', ',', 'Cravatt', 'B', '.', 'F', '.', ',', 'Activity', '-', 'based', 'probes', 'for', 'the', 'proteomic', 'profiling', 'of', 'metalloproteases', '.'] [5, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O']
Kato D., et al. , Activity-based probes that target diverse cysteine protease families. [('PMC6815137', 'F10001', 60, 77, 'cysteine protease')] ['Kat', '##o', 'D', '.', ',', 'et', 'al', '.', ',', 'Activity', '-', 'based', 'probes', 'that', 'target', 'diverse', 'cysteine', 'protease', 'families', '.'] [0, 3, 5, 6, 7, 9, 12, 14, 16, 18, 26, 27, 33, 40, 45, 52, 60, 69, 78, 86] [3, 4, 6, 7, 8, 11, 14, 15, 17, 26, 27, 32, 39, 44, 51, 59, 68, 77, 86, 87] ['Kato', 'D', '.', ',', 'et', 'al', '.', ',', 'Activity', '-', 'based', 'probes', 'that', 'target', 'diverse', 'cysteine', 'protease', 'families', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O']
Nomura D. K., et al. , Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. [('PMC6815137', 'F21001', 23, 46, 'Monoacylglycerol lipase')] ['Nom', '##ura', 'D', '.', 'K', '.', ',', 'et', 'al', '.', ',', 'Mon', '##oa', '##cy', '##l', '##glycerol', 'lipase', 'regulates', 'a', 'fatty', 'acid', 'network', 'that', 'promotes', 'cancer', 'pathogenesis', '.'] [0, 3, 7, 8, 10, 11, 12, 14, 17, 19, 21, 23, 26, 28, 30, 31, 40, 47, 57, 59, 65, 70, 78, 83, 92, 99, 111] [3, 6, 8, 9, 11, 12, 13, 16, 19, 20, 22, 26, 28, 30, 31, 39, 46, 56, 58, 64, 69, 77, 82, 91, 98, 111, 112] ['Nomura', 'D', '.', 'K', '.', ',', 'et', 'al', '.', ',', 'Monoacylglycerol', 'lipase', 'regulates', 'a', 'fatty', 'acid', 'network', 'that', 'promotes', 'cancer', 'pathogenesis', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Ahn K., et al. , Discovery and characterization of a highly selective fatty acid amide hydrolase 1 inhibitor that reduces inflammatory pain. [('PMC6815137', 'F28001', 70, 98, 'fatty acid amide hydrolase 1')] ['Ah', '##n', 'K', '.', ',', 'et', 'al', '.', ',', 'Discovery', 'and', 'character', '##ization', 'of', 'a', 'highly', 'selective', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'inhibitor', 'that', 'reduces', 'inflammatory', 'pain', '.'] [0, 2, 4, 5, 6, 8, 11, 13, 15, 17, 27, 31, 40, 48, 51, 53, 60, 70, 76, 81, 87, 92, 95, 97, 99, 109, 114, 122, 135, 139] [2, 3, 5, 6, 7, 10, 13, 14, 16, 26, 30, 40, 47, 50, 52, 59, 69, 75, 80, 86, 92, 95, 96, 98, 108, 113, 121, 134, 139, 140] ['Ahn', 'K', '.', ',', 'et', 'al', '.', ',', 'Discovery', 'and', 'characterization', 'of', 'a', 'highly', 'selective', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'inhibitor', 'that', 'reduces', 'inflammatory', 'pain', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
Robinson P. V., Tsai C. T., de Groot A. E., McKechnie J. L., Bertozzi C. R., Glyco-seek: Ultrasensitive detection of protein-specific glycosylation by proximity ligation polymerase chain reaction. [('PMC6815137', 'F31001', 170, 180, 'polymerase')] ['Robinson', 'P', '.', 'V', '.', ',', 'Ts', '##ai', 'C', '.', 'T', '.', ',', 'de', 'Gro', '##ot', 'A', '.', 'E', '.', ',', 'McK', '##echn', '##ie', 'J', '.', 'L', '.', ',', 'Bert', '##oz', '##zi', 'C', '.', 'R', '.', ',', 'Gly', '##co', '-', 'seek', ':', 'Ultras', '##ensitive', 'detection', 'of', 'protein', '-', 'specific', 'glycosylation', 'by', 'proximity', 'ligation', 'polymerase', 'chain', 'reaction', '.'] [0, 9, 10, 12, 13, 14, 16, 18, 21, 22, 24, 25, 26, 28, 31, 34, 37, 38, 40, 41, 42, 44, 47, 51, 54, 55, 57, 58, 59, 61, 65, 67, 70, 71, 73, 74, 75, 77, 80, 82, 83, 87, 89, 95, 104, 114, 117, 124, 125, 134, 148, 151, 161, 170, 181, 187, 195] [8, 10, 11, 13, 14, 15, 18, 20, 22, 23, 25, 26, 27, 30, 34, 36, 38, 39, 41, 42, 43, 47, 51, 53, 55, 56, 58, 59, 60, 65, 67, 69, 71, 72, 74, 75, 76, 80, 82, 83, 87, 88, 95, 103, 113, 116, 124, 125, 133, 147, 150, 160, 169, 180, 186, 195, 196] ['Robinson', 'P', '.', 'V', '.', ',', 'Tsai', 'C', '.', 'T', '.', ',', 'de', 'Groot', 'A', '.', 'E', '.', ',', 'McKechnie', 'J', '.', 'L', '.', ',', 'Bertozzi', 'C', '.', 'R', '.', ',', 'Glyco', '-', 'seek', ':', 'Ultrasensitive', 'detection', 'of', 'protein', '-', 'specific', 'glycosylation', 'by', 'proximity', 'ligation', 'polymerase', 'chain', 'reaction', '.'] [1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O']
Family-wide chemical proteomic probes are particularly useful because they can report on the activity of large swaths of the active proteome simultaneously, with published examples available for serine hydrolases (6, 7), kinases (8, 9), metalloproteases (10), cysteine proteases (11), and other functionalities that regulate protein activity (12–14). [('PMC6815137', 'I01000', 195, 212, 'serine hydrolases'), ('PMC6815137', 'I01000', 221, 228, 'kinases'), ('PMC6815137', 'I01000', 237, 253, 'metalloproteases'), ('PMC6815137', 'I01000', 260, 278, 'cysteine proteases')] ['Family', '-', 'wide', 'chemical', 'proteomic', 'probes', 'are', 'particularly', 'useful', 'because', 'they', 'can', 'report', 'on', 'the', 'activity', 'of', 'large', 'sw', '##ath', '##s', 'of', 'the', 'active', 'proteome', 'simultaneously', ',', 'with', 'published', 'examples', 'available', 'for', 'serine', 'hydro', '##las', '##es', '(', '6', ',', '7', ')', ',', 'kinases', '(', '8', ',', '9', ')', ',', 'metall', '##oprot', '##ea', '##ses', '(', '10', ')', ',', 'cysteine', 'proteases', '(', '11', ')', ',', 'and', 'other', 'functionalities', 'that', 'regulate', 'protein', 'activity', '(', '12', '–', '14', ')', '.'] [0, 6, 7, 12, 21, 31, 38, 42, 55, 62, 70, 75, 79, 86, 89, 93, 102, 105, 111, 113, 116, 118, 121, 125, 132, 141, 155, 157, 162, 172, 181, 191, 195, 202, 207, 210, 213, 214, 215, 217, 218, 219, 221, 229, 230, 231, 233, 234, 235, 237, 243, 248, 250, 254, 255, 257, 258, 260, 269, 279, 280, 282, 283, 285, 289, 295, 311, 316, 325, 333, 342, 343, 345, 346, 348, 349] [6, 7, 11, 20, 30, 37, 41, 54, 61, 69, 74, 78, 85, 88, 92, 101, 104, 110, 113, 116, 117, 120, 124, 131, 140, 155, 156, 161, 171, 180, 190, 194, 201, 207, 210, 212, 214, 215, 216, 218, 219, 220, 228, 230, 231, 232, 234, 235, 236, 243, 248, 250, 253, 255, 257, 258, 259, 268, 278, 280, 282, 283, 284, 288, 294, 310, 315, 324, 332, 341, 343, 345, 346, 348, 349, 350] ['Family', '-', 'wide', 'chemical', 'proteomic', 'probes', 'are', 'particularly', 'useful', 'because', 'they', 'can', 'report', 'on', 'the', 'activity', 'of', 'large', 'swaths', 'of', 'the', 'active', 'proteome', 'simultaneously', ',', 'with', 'published', 'examples', 'available', 'for', 'serine', 'hydrolases', '(', '6', ',', '7', ')', ',', 'kinases', '(', '8', ',', '9', ')', ',', 'metalloproteases', '(', '10', ')', ',', 'cysteine', 'proteases', '(', '11', ')', ',', 'and', 'other', 'functionalities', 'that', 'regulate', 'protein', 'activity', '(', '12–', '14', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To pilot sADPL, we targeted proteins associated with cancer phenotypes in 2 well-characterized enzyme families, serine hydrolase and cathepsin cysteine protease enzymes, using widely available fluorophosphonate-biotin (FP-Bio) (15) and an acyloxymethylketone-based cathepsin probe (19), respectively. [('PMC6815137', 'R01000', 112, 128, 'serine hydrolase'), ('PMC6815137', 'R01000', 133, 160, 'cathepsin cysteine protease')] ['To', 'pilot', 's', '##AD', '##PL', ',', 'we', 'targeted', 'proteins', 'associated', 'with', 'cancer', 'phenotypes', 'in', '2', 'well', '-', 'characterized', 'enzyme', 'families', ',', 'serine', 'hydro', '##las', '##e', 'and', 'cathe', '##ps', '##in', 'cysteine', 'protease', 'enzymes', ',', 'using', 'widely', 'available', 'fluor', '##ophosph', '##onate', '-', 'biotin', '(', 'FP', '-', 'Bio', ')', '(', '15', ')', 'and', 'an', 'acyl', '##oxy', '##methyl', '##ket', '##one', '-', 'based', 'cathe', '##ps', '##in', 'probe', '(', '19', ')', ',', 'respectively', '.'] [0, 3, 9, 10, 12, 14, 16, 19, 28, 37, 48, 53, 60, 71, 74, 76, 80, 81, 95, 102, 110, 112, 119, 124, 127, 129, 133, 138, 140, 143, 152, 161, 168, 170, 176, 183, 193, 198, 205, 210, 211, 218, 219, 221, 222, 225, 227, 228, 230, 232, 236, 239, 243, 246, 252, 255, 258, 259, 265, 270, 272, 275, 281, 282, 284, 285, 287, 299] [2, 8, 10, 12, 14, 15, 18, 27, 36, 47, 52, 59, 70, 73, 75, 80, 81, 94, 101, 110, 111, 118, 124, 127, 128, 132, 138, 140, 142, 151, 160, 168, 169, 175, 182, 192, 198, 205, 210, 211, 217, 219, 221, 222, 225, 226, 228, 230, 231, 235, 238, 243, 246, 252, 255, 258, 259, 264, 270, 272, 274, 280, 282, 284, 285, 286, 299, 300] ['To', 'pilot', 'sADPL', ',', 'we', 'targeted', 'proteins', 'associated', 'with', 'cancer', 'phenotypes', 'in', '2', 'well', '-', 'characterized', 'enzyme', 'families', ',', 'serine', 'hydrolase', 'and', 'cathepsin', 'cysteine', 'protease', 'enzymes', ',', 'using', 'widely', 'available', 'fluorophosphonate', '-', 'biotin', '(', 'FP-Bio', ')', '(', '15', ')', 'and', 'an', 'acyloxymethylketone', '-', 'based', 'cathepsin', 'probe', '(', '19', ')', ',', 'respectively', '.'] [1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Using monoacylglycerol lipase (MGLL) as a model enzyme, we optimized the absolute and relative concentrations of Ab-oligo and SA-oligo conjugates required for the sADPL signal and dynamic range in whole-cell proteome (SI Appendix, Fig. S2). [('PMC6815137', 'R01002', 6, 29, 'monoacylglycerol lipase')] ['Using', 'mono', '##acyl', '##glycerol', 'lipase', '(', 'MG', '##LL', ')', 'as', 'a', 'model', 'enzyme', ',', 'we', 'optimized', 'the', 'absolute', 'and', 'relative', 'concentrations', 'of', 'Ab', '-', 'olig', '##o', 'and', 'SA', '-', 'olig', '##o', 'conjugates', 'required', 'for', 'the', 's', '##AD', '##PL', 'signal', 'and', 'dynamic', 'range', 'in', 'whole', '-', 'cell', 'proteome', '(', 'SI', 'Appendix', ',', 'Fig', '.', 'S', '##2', ')', '.'] [0, 6, 10, 14, 23, 30, 31, 33, 35, 37, 40, 42, 48, 54, 56, 59, 69, 73, 82, 86, 95, 110, 113, 115, 116, 120, 122, 126, 128, 129, 133, 135, 146, 155, 159, 163, 164, 166, 169, 176, 180, 188, 194, 197, 202, 203, 208, 217, 218, 221, 229, 231, 234, 236, 237, 238, 239] [5, 10, 14, 22, 29, 31, 33, 35, 36, 39, 41, 47, 54, 55, 58, 68, 72, 81, 85, 94, 109, 112, 115, 116, 120, 121, 125, 128, 129, 133, 134, 145, 154, 158, 162, 164, 166, 168, 175, 179, 187, 193, 196, 202, 203, 207, 216, 218, 220, 229, 230, 234, 235, 237, 238, 239, 240] ['Using', 'monoacylglycerol', 'lipase', '(', 'MGLL', ')', 'as', 'a', 'model', 'enzyme', ',', 'we', 'optimized', 'the', 'absolute', 'and', 'relative', 'concentrations', 'of', 'Ab-oligo', 'and', 'SA-oligo', 'conjugates', 'required', 'for', 'the', 'sADPL', 'signal', 'and', 'dynamic', 'range', 'in', 'whole', '-', 'cell', 'proteome', '(', 'SI', 'Appendix', ',', 'Fig', '.', 'S2', ')', '.'] [1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 4, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We then tested the sensitivity and dynamic range of sADPL quantification for diverse protein targets, including the serine hydrolase enzymes neutral cholesterol ester hydrolase 1 (neutral cholesterol ester hydrolase 1), MGLL, fatty acid [('PMC6815137', 'R01003', 116, 132, 'serine hydrolase'), ('PMC6815137', 'R01003', 141, 178, 'neutral cholesterol ester hydrolase 1'), ('PMC6815137', 'R01003', 180, 217, 'neutral cholesterol ester hydrolase 1')] ['We', 'then', 'tested', 'the', 'sensitivity', 'and', 'dynamic', 'range', 'of', 's', '##AD', '##PL', 'quantification', 'for', 'diverse', 'protein', 'targets', ',', 'including', 'the', 'serine', 'hydro', '##las', '##e', 'enzymes', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', '(', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', ')', ',', 'MG', '##LL', ',', 'fatty', 'acid'] [0, 3, 8, 15, 19, 31, 35, 43, 49, 52, 53, 55, 58, 73, 77, 85, 93, 100, 102, 112, 116, 123, 128, 131, 133, 141, 149, 161, 167, 172, 175, 177, 179, 180, 188, 200, 206, 211, 214, 216, 217, 218, 220, 222, 224, 226, 232] [2, 7, 14, 18, 30, 34, 42, 48, 51, 53, 55, 57, 72, 76, 84, 92, 100, 101, 111, 115, 122, 128, 131, 132, 140, 148, 160, 166, 172, 175, 176, 178, 180, 187, 199, 205, 211, 214, 215, 217, 218, 219, 222, 224, 225, 231, 236] ['We', 'then', 'tested', 'the', 'sensitivity', 'and', 'dynamic', 'range', 'of', 'sADPL', 'quantification', 'for', 'diverse', 'protein', 'targets', ',', 'including', 'the', 'serine', 'hydrolase', 'enzymes', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', '(', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', ')', ',', 'MGLL', ',', 'fatty', 'acid'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
amide hydrolase 1 (fatty acid amide hydrolase 1), and dipeptidyl peptidase-4 (dipeptidyl peptidase-4), as well as the cysteine protease enzymes cathepsin B (CTSB) and cathepsin L (CTSL). [('PMC6815137', 'R01004', 19, 47, 'fatty acid amide hydrolase 1'), ('PMC6815137', 'R01004', 54, 76, 'dipeptidyl peptidase-4'), ('PMC6815137', 'R01004', 78, 100, 'dipeptidyl peptidase-4')] ['amide', 'hydro', '##las', '##e', '1', '(', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', ')', ',', 'and', 'dip', '##epti', '##dy', '##l', 'pepti', '##dase', '-', '4', '(', 'dip', '##epti', '##dy', '##l', 'pepti', '##dase', '-', '4', ')', ',', 'as', 'well', 'as', 'the', 'cysteine', 'protease', 'enzymes', 'cathe', '##ps', '##in', 'B', '(', 'CT', '##SB', ')', 'and', 'cathe', '##ps', '##in', 'L', '(', 'CT', '##SL', ')', '.'] [0, 6, 11, 14, 16, 18, 19, 25, 30, 36, 41, 44, 46, 47, 48, 50, 54, 57, 61, 63, 65, 70, 74, 75, 77, 78, 81, 85, 87, 89, 94, 98, 99, 100, 101, 103, 106, 111, 114, 118, 127, 136, 144, 149, 151, 154, 156, 157, 159, 161, 163, 167, 172, 174, 177, 179, 180, 182, 184, 185] [5, 11, 14, 15, 17, 19, 24, 29, 35, 41, 44, 45, 47, 48, 49, 53, 57, 61, 63, 64, 70, 74, 75, 76, 78, 81, 85, 87, 88, 94, 98, 99, 100, 101, 102, 105, 110, 113, 117, 126, 135, 143, 149, 151, 153, 155, 157, 159, 161, 162, 166, 172, 174, 176, 178, 180, 182, 184, 185, 186] ['amide', 'hydrolase', '1', '(', 'fatty', 'acid', 'amide', 'hydrolase', '1', ')', ',', 'and', 'dipeptidyl', 'peptidase-4', '(', 'dipeptidyl', 'peptidase-4', ')', ',', 'as', 'well', 'as', 'the', 'cysteine', 'protease', 'enzymes', 'cathepsin', 'B', '(', 'CTSB', ')', 'and', 'cathepsin', 'L', '(', 'CTSL', ')', '.'] [1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 4, 4, 1, 4, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 3, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Indeed, side-by-side comparison of sADPL, which by design detects only active protein, and Western blot analysis for neutral cholesterol ester hydrolase 1 confirmed a limit of detection at least 6 orders of magnitude lower for sADPL, which could detect active protein in picogram quantities of whole proteome (Fig. 2 C and D). [('PMC6815137', 'R01007', 117, 154, 'neutral cholesterol ester hydrolase 1')] ['Indeed', ',', 'side', '-', 'by', '-', 'side', 'comparison', 'of', 's', '##AD', '##PL', ',', 'which', 'by', 'design', 'detects', 'only', 'active', 'protein', ',', 'and', 'Western', 'blot', 'analysis', 'for', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', 'confirmed', 'a', 'limit', 'of', 'detection', 'at', 'least', '6', 'orders', 'of', 'magnitude', 'lower', 'for', 's', '##AD', '##PL', ',', 'which', 'could', 'detect', 'active', 'protein', 'in', 'pic', '##ogram', 'quantities', 'of', 'whole', 'proteome', '(', 'Fig', '.', '2', 'C', 'and', 'D', ')', '.'] [0, 6, 8, 12, 13, 15, 16, 21, 32, 35, 36, 38, 40, 42, 48, 51, 58, 66, 71, 78, 85, 87, 91, 99, 104, 113, 117, 125, 137, 143, 148, 151, 153, 155, 165, 167, 173, 176, 186, 189, 195, 197, 204, 207, 217, 223, 227, 228, 230, 232, 234, 240, 246, 253, 260, 268, 271, 274, 280, 291, 294, 300, 309, 310, 313, 315, 317, 319, 323, 324, 325] [6, 7, 12, 13, 15, 16, 20, 31, 34, 36, 38, 40, 41, 47, 50, 57, 65, 70, 77, 85, 86, 90, 98, 103, 112, 116, 124, 136, 142, 148, 151, 152, 154, 164, 166, 172, 175, 185, 188, 194, 196, 203, 206, 216, 222, 226, 228, 230, 232, 233, 239, 245, 252, 259, 267, 270, 274, 279, 290, 293, 299, 308, 310, 313, 314, 316, 318, 322, 324, 325, 326] ['Indeed', ',', 'side', '-', 'by', '-', 'side', 'comparison', 'of', 'sADPL', ',', 'which', 'by', 'design', 'detects', 'only', 'active', 'protein', ',', 'and', 'Western', 'blot', 'analysis', 'for', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', 'confirmed', 'a', 'limit', 'of', 'detection', 'at', 'least', '6', 'orders', 'of', 'magnitude', 'lower', 'for', 'sADPL', ',', 'which', 'could', 'detect', 'active', 'protein', 'in', 'picogram', 'quantities', 'of', 'whole', 'proteome', '(', 'Fig', '.', '2', 'C', 'and', 'D', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Each cell line was pulsed with either vehicle control (DMSO) or a combination of serine hydrolase and cathepsin protease probes, followed by sADPL profiling and relative activity quantification of 6 biomarker enzymes (Fig. 2E). [('PMC6815137', 'R02002', 81, 97, 'serine hydrolase'), ('PMC6815137', 'R02002', 102, 120, 'cathepsin protease')] ['Each', 'cell', 'line', 'was', 'pulsed', 'with', 'either', 'vehicle', 'control', '(', 'DMSO', ')', 'or', 'a', 'combination', 'of', 'serine', 'hydro', '##las', '##e', 'and', 'cathe', '##ps', '##in', 'protease', 'probes', ',', 'followed', 'by', 's', '##AD', '##PL', 'profiling', 'and', 'relative', 'activity', 'quantification', 'of', '6', 'biomarker', 'enzymes', '(', 'Fig', '.', '2', '##E', ')', '.'] [0, 5, 10, 15, 19, 26, 31, 38, 46, 54, 55, 59, 61, 64, 66, 78, 81, 88, 93, 96, 98, 102, 107, 109, 112, 121, 127, 129, 138, 141, 142, 144, 147, 157, 161, 170, 179, 194, 197, 199, 209, 217, 218, 221, 223, 224, 225, 226] [4, 9, 14, 18, 25, 30, 37, 45, 53, 55, 59, 60, 63, 65, 77, 80, 87, 93, 96, 97, 101, 107, 109, 111, 120, 127, 128, 137, 140, 142, 144, 146, 156, 160, 169, 178, 193, 196, 198, 208, 216, 218, 221, 222, 224, 225, 226, 227] ['Each', 'cell', 'line', 'was', 'pulsed', 'with', 'either', 'vehicle', 'control', '(', 'DMSO', ')', 'or', 'a', 'combination', 'of', 'serine', 'hydrolase', 'and', 'cathepsin', 'protease', 'probes', ',', 'followed', 'by', 'sADPL', 'profiling', 'and', 'relative', 'activity', 'quantification', 'of', '6', 'biomarker', 'enzymes', '(', 'Fig', '.', '2E', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
neutral cholesterol ester hydrolase 1 and MGLL activities were 12.5- and 13.3-fold higher, respectively, in SKOV3IP1 cells relative to OVCAR3 cells, which matched previous reports using MS-based, gel-based, and imaging-based activity measurements in these cell lines (15, 21, 22). [('PMC6815137', 'R02003', 0, 37, 'neutral cholesterol ester hydrolase 1')] ['neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', 'and', 'MG', '##LL', 'activities', 'were', '12', '.', '5', '-', 'and', '13', '.', '3', '-', 'fold', 'higher', ',', 'respectively', ',', 'in', 'SK', '##OV', '##3', '##IP', '##1', 'cells', 'relative', 'to', 'OV', '##CAR', '##3', 'cells', ',', 'which', 'matched', 'previous', 'reports', 'using', 'MS', '-', 'based', ',', 'gel', '-', 'based', ',', 'and', 'imaging', '-', 'based', 'activity', 'measurements', 'in', 'these', 'cell', 'lines', '(', '15', ',', '21', ',', '22', ')', '.'] [0, 8, 20, 26, 31, 34, 36, 38, 42, 44, 47, 58, 63, 65, 66, 67, 69, 73, 75, 76, 77, 78, 83, 89, 91, 103, 105, 108, 110, 112, 113, 115, 117, 123, 132, 135, 137, 140, 142, 147, 149, 155, 163, 172, 180, 186, 188, 189, 194, 196, 199, 200, 205, 207, 211, 218, 219, 225, 234, 247, 250, 256, 261, 267, 268, 270, 272, 274, 276, 278, 279] [7, 19, 25, 31, 34, 35, 37, 41, 44, 46, 57, 62, 65, 66, 67, 68, 72, 75, 76, 77, 78, 82, 89, 90, 103, 104, 107, 110, 112, 113, 115, 116, 122, 131, 134, 137, 140, 141, 147, 148, 154, 162, 171, 179, 185, 188, 189, 194, 195, 199, 200, 205, 206, 210, 218, 219, 224, 233, 246, 249, 255, 260, 266, 268, 270, 271, 274, 275, 278, 279, 280] ['neutral', 'cholesterol', 'ester', 'hydrolase', '1', 'and', 'MGLL', 'activities', 'were', '12.5-', 'and', '13.3-fold', 'higher', ',', 'respectively', ',', 'in', 'SKOV3IP1', 'cells', 'relative', 'to', 'OVCAR3', 'cells', ',', 'which', 'matched', 'previous', 'reports', 'using', 'MS', '-', 'based', ',', 'gel', '-', 'based', ',', 'and', 'imaging', '-', 'based', 'activity', 'measurements', 'in', 'these', 'cell', 'lines', '(', '15', ',', '21', ',', '22', ')', '.'] [1, 1, 1, 3, 1, 1, 2, 1, 1, 4, 1, 5, 1, 1, 1, 1, 1, 5, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In contrast, fatty acid amide hydrolase 1 activity was approximately 2-fold higher in the nonaggressive OVCAR3 cells relative to SKOV3IP1 cells, consistent with previously published bulk activity-based profiling data in several cancer cell lines (Fig. 2E) (24). [('PMC6815137', 'R02004', 13, 41, 'fatty acid amide hydrolase 1')] ['In', 'contrast', ',', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'activity', 'was', 'approximately', '2', '-', 'fold', 'higher', 'in', 'the', 'non', '##agg', '##ressive', 'OV', '##CAR', '##3', 'cells', 'relative', 'to', 'SK', '##OV', '##3', '##IP', '##1', 'cells', ',', 'consistent', 'with', 'previously', 'published', 'bulk', 'activity', '-', 'based', 'profiling', 'data', 'in', 'several', 'cancer', 'cell', 'lines', '(', 'Fig', '.', '2', '##E', ')', '(', '24', ')', '.'] [0, 3, 11, 13, 19, 24, 30, 35, 38, 40, 42, 51, 55, 69, 70, 71, 76, 83, 86, 90, 93, 96, 104, 106, 109, 111, 117, 126, 129, 131, 133, 134, 136, 138, 143, 145, 156, 161, 172, 182, 187, 195, 196, 202, 212, 217, 220, 228, 235, 240, 246, 247, 250, 252, 253, 254, 256, 257, 259, 260] [2, 11, 12, 18, 23, 29, 35, 38, 39, 41, 50, 54, 68, 70, 71, 75, 82, 85, 89, 93, 96, 103, 106, 109, 110, 116, 125, 128, 131, 133, 134, 136, 137, 143, 144, 155, 160, 171, 181, 186, 195, 196, 201, 211, 216, 219, 227, 234, 239, 245, 247, 250, 251, 253, 254, 255, 257, 259, 260, 261] ['In', 'contrast', ',', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'activity', 'was', 'approximately', '2-fold', 'higher', 'in', 'the', 'nonaggressive', 'OVCAR3', 'cells', 'relative', 'to', 'SKOV3IP1', 'cells', ',', 'consistent', 'with', 'previously', 'published', 'bulk', 'activity', '-', 'based', 'profiling', 'data', 'in', 'several', 'cancer', 'cell', 'lines', '(', 'Fig', '.', '2E', ')', '(', '24', ')', '.'] [1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 3, 3, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Finally, the activity states of both cathepsin enzymes and the peptidase dipeptidyl peptidase-4 were significantly increased in the more aggressive SKOV3IP1 cells (Fig. 2E). [('PMC6815137', 'R02005', 63, 72, 'peptidase'), ('PMC6815137', 'R02005', 73, 95, 'dipeptidyl peptidase-4')] ['Finally', ',', 'the', 'activity', 'states', 'of', 'both', 'cathe', '##ps', '##in', 'enzymes', 'and', 'the', 'pepti', '##dase', 'dip', '##epti', '##dy', '##l', 'pepti', '##dase', '-', '4', 'were', 'significantly', 'increased', 'in', 'the', 'more', 'aggressive', 'SK', '##OV', '##3', '##IP', '##1', 'cells', '(', 'Fig', '.', '2', '##E', ')', '.'] [0, 7, 9, 13, 22, 29, 32, 37, 42, 44, 47, 55, 59, 63, 68, 73, 76, 80, 82, 84, 89, 93, 94, 96, 101, 115, 125, 128, 132, 137, 148, 150, 152, 153, 155, 157, 163, 164, 167, 169, 170, 171, 172] [7, 8, 12, 21, 28, 31, 36, 42, 44, 46, 54, 58, 62, 68, 72, 76, 80, 82, 83, 89, 93, 94, 95, 100, 114, 124, 127, 131, 136, 147, 150, 152, 153, 155, 156, 162, 164, 167, 168, 170, 171, 172, 173] ['Finally', ',', 'the', 'activity', 'states', 'of', 'both', 'cathepsin', 'enzymes', 'and', 'the', 'peptidase', 'dipeptidyl', 'peptidase-4', 'were', 'significantly', 'increased', 'in', 'the', 'more', 'aggressive', 'SKOV3IP1', 'cells', '(', 'Fig', '.', '2E', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 4, 4, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Cathepsin abundance and activity ratios between cell lines were almost identical for cathepsin B, but the cathepsin L activity ratio was moderately increased relative to abundance (Fig. 2F). [('PMC6815137', 'R03002', 85, 96, 'cathepsin B'), ('PMC6815137', 'R03002', 106, 117, 'cathepsin L')] ['Cath', '##eps', '##in', 'abundance', 'and', 'activity', 'ratios', 'between', 'cell', 'lines', 'were', 'almost', 'identical', 'for', 'cathe', '##ps', '##in', 'B', ',', 'but', 'the', 'cathe', '##ps', '##in', 'L', 'activity', 'ratio', 'was', 'moderately', 'increased', 'relative', 'to', 'abundance', '(', 'Fig', '.', '2', '##F', ')', '.'] [0, 4, 7, 10, 20, 24, 33, 40, 48, 53, 59, 64, 71, 81, 85, 90, 92, 95, 96, 98, 102, 106, 111, 113, 116, 118, 127, 133, 137, 148, 158, 167, 170, 180, 181, 184, 186, 187, 188, 189] [4, 7, 9, 19, 23, 32, 39, 47, 52, 58, 63, 70, 80, 84, 90, 92, 94, 96, 97, 101, 105, 111, 113, 115, 117, 126, 132, 136, 147, 157, 166, 169, 179, 181, 184, 185, 187, 188, 189, 190] ['Cathepsin', 'abundance', 'and', 'activity', 'ratios', 'between', 'cell', 'lines', 'were', 'almost', 'identical', 'for', 'cathepsin', 'B', ',', 'but', 'the', 'cathepsin', 'L', 'activity', 'ratio', 'was', 'moderately', 'increased', 'relative', 'to', 'abundance', '(', 'Fig', '.', '2F', ')', '.'] [3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Significant differences were found for neutral cholesterol ester hydrolase 1 and MGLL, with abundance ratios of 37.7-fold and 50.2-fold for each enzyme, respectively, compared with the more modest activity ratios of slightly above 10-fold (Fig. 2F). [('PMC6815137', 'R03003', 39, 76, 'neutral cholesterol ester hydrolase 1')] ['Significant', 'differences', 'were', 'found', 'for', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', 'and', 'MG', '##LL', ',', 'with', 'abundance', 'ratios', 'of', '37', '.', '7', '-', 'fold', 'and', '50', '.', '2', '-', 'fold', 'for', 'each', 'enzyme', ',', 'respectively', ',', 'compared', 'with', 'the', 'more', 'modest', 'activity', 'ratios', 'of', 'slightly', 'above', '10', '-', 'fold', '(', 'Fig', '.', '2', '##F', ')', '.'] [0, 12, 24, 29, 35, 39, 47, 59, 65, 70, 73, 75, 77, 81, 83, 85, 87, 92, 102, 109, 112, 114, 115, 116, 117, 122, 126, 128, 129, 130, 131, 136, 140, 145, 151, 153, 165, 167, 176, 181, 185, 190, 197, 206, 213, 216, 225, 231, 233, 234, 239, 240, 243, 245, 246, 247, 248] [11, 23, 28, 34, 38, 46, 58, 64, 70, 73, 74, 76, 80, 83, 85, 86, 91, 101, 108, 111, 114, 115, 116, 117, 121, 125, 128, 129, 130, 131, 135, 139, 144, 151, 152, 165, 166, 175, 180, 184, 189, 196, 205, 212, 215, 224, 230, 233, 234, 238, 240, 243, 244, 246, 247, 248, 249] ['Significant', 'differences', 'were', 'found', 'for', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', 'and', 'MGLL', ',', 'with', 'abundance', 'ratios', 'of', '37.7-fold', 'and', '50.2-fold', 'for', 'each', 'enzyme', ',', 'respectively', ',', 'compared', 'with', 'the', 'more', 'modest', 'activity', 'ratios', 'of', 'slightly', 'above', '10-fold', '(', 'Fig', '.', '2F', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 5, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In contrast, the activity of fatty acid amide hydrolase 1 was 2-fold lower in SKOV3IP1 cells compared with OVCAR3 cells, whereas abundance was nearly 4-fold lower in SKOV3IP1 cells, indicating that a higher percentage of fatty acid amide hydrolase 1 is active in SKOV3IP1 cells relative to OVCAR3 cells. [('PMC6815137', 'R03004', 29, 57, 'fatty acid amide hydrolase 1'), ('PMC6815137', 'R03004', 221, 249, 'fatty acid amide hydrolase 1')] ['In', 'contrast', ',', 'the', 'activity', 'of', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'was', '2', '-', 'fold', 'lower', 'in', 'SK', '##OV', '##3', '##IP', '##1', 'cells', 'compared', 'with', 'OV', '##CAR', '##3', 'cells', ',', 'whereas', 'abundance', 'was', 'nearly', '4', '-', 'fold', 'lower', 'in', 'SK', '##OV', '##3', '##IP', '##1', 'cells', ',', 'indicating', 'that', 'a', 'higher', 'percentage', 'of', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'is', 'active', 'in', 'SK', '##OV', '##3', '##IP', '##1', 'cells', 'relative', 'to', 'OV', '##CAR', '##3', 'cells', '.'] [0, 3, 11, 13, 17, 26, 29, 35, 40, 46, 51, 54, 56, 58, 62, 63, 64, 69, 75, 78, 80, 82, 83, 85, 87, 93, 102, 107, 109, 112, 114, 119, 121, 129, 139, 143, 150, 151, 152, 157, 163, 166, 168, 170, 171, 173, 175, 180, 182, 193, 198, 200, 207, 218, 221, 227, 232, 238, 243, 246, 248, 250, 253, 260, 263, 265, 267, 268, 270, 272, 278, 287, 290, 292, 295, 297, 302] [2, 11, 12, 16, 25, 28, 34, 39, 45, 51, 54, 55, 57, 61, 63, 64, 68, 74, 77, 80, 82, 83, 85, 86, 92, 101, 106, 109, 112, 113, 119, 120, 128, 138, 142, 149, 151, 152, 156, 162, 165, 168, 170, 171, 173, 174, 180, 181, 192, 197, 199, 206, 217, 220, 226, 231, 237, 243, 246, 247, 249, 252, 259, 262, 265, 267, 268, 270, 271, 277, 286, 289, 292, 295, 296, 302, 303] ['In', 'contrast', ',', 'the', 'activity', 'of', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'was', '2-fold', 'lower', 'in', 'SKOV3IP1', 'cells', 'compared', 'with', 'OVCAR3', 'cells', ',', 'whereas', 'abundance', 'was', 'nearly', '4-fold', 'lower', 'in', 'SKOV3IP1', 'cells', ',', 'indicating', 'that', 'a', 'higher', 'percentage', 'of', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'is', 'active', 'in', 'SKOV3IP1', 'cells', 'relative', 'to', 'OVCAR3', 'cells', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 5, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 3, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 5, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Finally, the correlation between MS-based abundance and activity of dipeptidyl peptidase-4 was highly divergent, with nearly 350-fold higher protein levels observed in SKOV3IP1 cells by LC-MS/MS, contrasted with just a 3.2-fold increase in activity. [('PMC6815137', 'R03005', 68, 90, 'dipeptidyl peptidase-4')] ['Finally', ',', 'the', 'correlation', 'between', 'MS', '-', 'based', 'abundance', 'and', 'activity', 'of', 'dip', '##epti', '##dy', '##l', 'pepti', '##dase', '-', '4', 'was', 'highly', 'divergent', ',', 'with', 'nearly', '350', '-', 'fold', 'higher', 'protein', 'levels', 'observed', 'in', 'SK', '##OV', '##3', '##IP', '##1', 'cells', 'by', 'LC', '-', 'MS', '/', 'MS', ',', 'contrast', '##ed', 'with', 'just', 'a', '3', '.', '2', '-', 'fold', 'increase', 'in', 'activity', '.'] [0, 7, 9, 13, 25, 33, 35, 36, 42, 52, 56, 65, 68, 71, 75, 77, 79, 84, 88, 89, 91, 95, 102, 111, 113, 118, 125, 128, 129, 134, 141, 149, 156, 165, 168, 170, 172, 173, 175, 177, 183, 186, 188, 189, 191, 192, 194, 196, 204, 207, 212, 217, 219, 220, 221, 222, 223, 228, 237, 240, 248] [7, 8, 12, 24, 32, 35, 36, 41, 51, 55, 64, 67, 71, 75, 77, 78, 84, 88, 89, 90, 94, 101, 111, 112, 117, 124, 128, 129, 133, 140, 148, 155, 164, 167, 170, 172, 173, 175, 176, 182, 185, 188, 189, 191, 192, 194, 195, 204, 206, 211, 216, 218, 220, 221, 222, 223, 227, 236, 239, 248, 249] ['Finally', ',', 'the', 'correlation', 'between', 'MS', '-', 'based', 'abundance', 'and', 'activity', 'of', 'dipeptidyl', 'peptidase-4', 'was', 'highly', 'divergent', ',', 'with', 'nearly', '350-fold', 'higher', 'protein', 'levels', 'observed', 'in', 'SKOV3IP1', 'cells', 'by', 'LC-MS', '/', 'MS', ',', 'contrasted', 'with', 'just', 'a', '3.2-fold', 'increase', 'in', 'activity', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 4, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 5, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 5, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To further verify the differences observed for dipeptidyl peptidase-4 and cathepsin L, we measured their protein levels by Western blot analysis. [('PMC6815137', 'R04000', 47, 69, 'dipeptidyl peptidase-4'), ('PMC6815137', 'R04000', 74, 85, 'cathepsin L')] ['To', 'further', 'verify', 'the', 'differences', 'observed', 'for', 'dip', '##epti', '##dy', '##l', 'pepti', '##dase', '-', '4', 'and', 'cathe', '##ps', '##in', 'L', ',', 'we', 'measured', 'their', 'protein', 'levels', 'by', 'Western', 'blot', 'analysis', '.'] [0, 3, 11, 18, 22, 34, 43, 47, 50, 54, 56, 58, 63, 67, 68, 70, 74, 79, 81, 84, 85, 87, 90, 99, 105, 113, 120, 123, 131, 136, 144] [2, 10, 17, 21, 33, 42, 46, 50, 54, 56, 57, 63, 67, 68, 69, 73, 79, 81, 83, 85, 86, 89, 98, 104, 112, 119, 122, 130, 135, 144, 145] ['To', 'further', 'verify', 'the', 'differences', 'observed', 'for', 'dipeptidyl', 'peptidase-4', 'and', 'cathepsin', 'L', ',', 'we', 'measured', 'their', 'protein', 'levels', 'by', 'Western', 'blot', 'analysis', '.'] [1, 1, 1, 1, 1, 1, 1, 4, 4, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The dipeptidyl peptidase-4 level was 3.7-fold higher in SKOV3IP1 cells, which closely matched the activity difference measured by sADPL (SI Appendix, Fig. S3). [('PMC6815137', 'R04001', 4, 26, 'dipeptidyl peptidase-4')] ['The', 'dip', '##epti', '##dy', '##l', 'pepti', '##dase', '-', '4', 'level', 'was', '3', '.', '7', '-', 'fold', 'higher', 'in', 'SK', '##OV', '##3', '##IP', '##1', 'cells', ',', 'which', 'closely', 'matched', 'the', 'activity', 'difference', 'measured', 'by', 's', '##AD', '##PL', '(', 'SI', 'Appendix', ',', 'Fig', '.', 'S', '##3', ')', '.'] [0, 4, 7, 11, 13, 15, 20, 24, 25, 27, 33, 37, 38, 39, 40, 41, 46, 53, 56, 58, 60, 61, 63, 65, 70, 72, 78, 86, 94, 98, 107, 118, 127, 130, 131, 133, 136, 137, 140, 148, 150, 153, 155, 156, 157, 158] [3, 7, 11, 13, 14, 20, 24, 25, 26, 32, 36, 38, 39, 40, 41, 45, 52, 55, 58, 60, 61, 63, 64, 70, 71, 77, 85, 93, 97, 106, 117, 126, 129, 131, 133, 135, 137, 139, 148, 149, 153, 154, 156, 157, 158, 159] ['The', 'dipeptidyl', 'peptidase-4', 'level', 'was', '3.7-fold', 'higher', 'in', 'SKOV3IP1', 'cells', ',', 'which', 'closely', 'matched', 'the', 'activity', 'difference', 'measured', 'by', 'sADPL', '(', 'SI', 'Appendix', ',', 'Fig', '.', 'S3', ')', '.'] [1, 4, 4, 1, 1, 5, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The cathepsin L level was 4.1-fold higher in SKOV3IP1 relative to OVCAR3; however, this measurement recognizes both precursors and mature cathepsin L, again supporting a significant difference between activity and abundance (SI Appendix, Fig. S3). [('PMC6815137', 'R04002', 4, 15, 'cathepsin L'), ('PMC6815137', 'R04002', 138, 149, 'cathepsin L')] ['The', 'cathe', '##ps', '##in', 'L', 'level', 'was', '4', '.', '1', '-', 'fold', 'higher', 'in', 'SK', '##OV', '##3', '##IP', '##1', 'relative', 'to', 'OV', '##CAR', '##3', ';', 'however', ',', 'this', 'measurement', 'recognizes', 'both', 'precursors', 'and', 'mature', 'cathe', '##ps', '##in', 'L', ',', 'again', 'supporting', 'a', 'significant', 'difference', 'between', 'activity', 'and', 'abundance', '(', 'SI', 'Appendix', ',', 'Fig', '.', 'S', '##3', ')', '.'] [0, 4, 9, 11, 14, 16, 22, 26, 27, 28, 29, 30, 35, 42, 45, 47, 49, 50, 52, 54, 63, 66, 68, 71, 72, 74, 81, 83, 88, 100, 111, 116, 127, 131, 138, 143, 145, 148, 149, 151, 157, 168, 170, 182, 193, 201, 210, 214, 224, 225, 228, 236, 238, 241, 243, 244, 245, 246] [3, 9, 11, 13, 15, 21, 25, 27, 28, 29, 30, 34, 41, 44, 47, 49, 50, 52, 53, 62, 65, 68, 71, 72, 73, 81, 82, 87, 99, 110, 115, 126, 130, 137, 143, 145, 147, 149, 150, 156, 167, 169, 181, 192, 200, 209, 213, 223, 225, 227, 236, 237, 241, 242, 244, 245, 246, 247] ['The', 'cathepsin', 'L', 'level', 'was', '4.1-fold', 'higher', 'in', 'SKOV3IP1', 'relative', 'to', 'OVCAR3', ';', 'however', ',', 'this', 'measurement', 'recognizes', 'both', 'precursors', 'and', 'mature', 'cathepsin', 'L', ',', 'again', 'supporting', 'a', 'significant', 'difference', 'between', 'activity', 'and', 'abundance', '(', 'SI', 'Appendix', ',', 'Fig', '.', 'S3', ')', '.'] [1, 3, 1, 1, 1, 5, 1, 1, 5, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To test this, we first treated cultured cells with selective small molecule inhibitors of neutral cholesterol ester hydrolase 1 (JW480) (28) and fatty acid amide hydrolase 1 (PF3845) (29), followed by FP-Bio probe treatment and sADPL processing. [('PMC6815137', 'R05001', 90, 127, 'neutral cholesterol ester hydrolase 1'), ('PMC6815137', 'R05001', 145, 173, 'fatty acid amide hydrolase 1')] ['To', 'test', 'this', ',', 'we', 'first', 'treated', 'cultured', 'cells', 'with', 'selective', 'small', 'molecule', 'inhibitors', 'of', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', '(', 'JW', '##48', '##0', ')', '(', '28', ')', 'and', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', '(', 'PF', '##38', '##45', ')', '(', '29', ')', ',', 'followed', 'by', 'FP', '-', 'Bio', 'probe', 'treatment', 'and', 's', '##AD', '##PL', 'processing', '.'] [0, 3, 8, 12, 14, 17, 23, 31, 40, 46, 51, 61, 67, 76, 87, 90, 98, 110, 116, 121, 124, 126, 128, 129, 131, 133, 134, 136, 137, 139, 141, 145, 151, 156, 162, 167, 170, 172, 174, 175, 177, 179, 181, 183, 184, 186, 187, 189, 198, 201, 203, 204, 208, 214, 224, 228, 229, 231, 234, 244] [2, 7, 12, 13, 16, 22, 30, 39, 45, 50, 60, 66, 75, 86, 89, 97, 109, 115, 121, 124, 125, 127, 129, 131, 133, 134, 135, 137, 139, 140, 144, 150, 155, 161, 167, 170, 171, 173, 175, 177, 179, 181, 182, 184, 186, 187, 188, 197, 200, 203, 204, 207, 213, 223, 227, 229, 231, 233, 244, 245] ['To', 'test', 'this', ',', 'we', 'first', 'treated', 'cultured', 'cells', 'with', 'selective', 'small', 'molecule', 'inhibitors', 'of', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', '(', 'JW480', ')', '(', '28', ')', 'and', 'fatty', 'acid', 'amide', 'hydrolase', '1', '(', 'PF3845', ')', '(', '29', ')', ',', 'followed', 'by', 'FP-Bio', 'probe', 'treatment', 'and', 'sADPL', 'processing', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In addition, sADPL detected graded changes in neutral cholesterol ester hydrolase 1 activity levels in response to increased JW480 concentrations, an indication of direct occupancy of this enzyme by its small molecule inhibitor (IC50 = 10.5 nM; Fig. 3C). [('PMC6815137', 'R05004', 46, 83, 'neutral cholesterol ester hydrolase 1')] ['In', 'addition', ',', 's', '##AD', '##PL', 'detected', 'graded', 'changes', 'in', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', 'activity', 'levels', 'in', 'response', 'to', 'increased', 'JW', '##48', '##0', 'concentrations', ',', 'an', 'indication', 'of', 'direct', 'occupancy', 'of', 'this', 'enzyme', 'by', 'its', 'small', 'molecule', 'inhibitor', '(', 'IC', '##50', '=', '10', '.', '5', 'nM', ';', 'Fig', '.', '3', '##C', ')', '.'] [0, 3, 11, 13, 14, 16, 19, 28, 35, 43, 46, 54, 66, 72, 77, 80, 82, 84, 93, 100, 103, 112, 115, 125, 127, 129, 131, 145, 147, 150, 161, 164, 171, 181, 184, 189, 196, 199, 203, 209, 218, 228, 229, 231, 234, 236, 238, 239, 241, 243, 245, 248, 250, 251, 252, 253] [2, 11, 12, 14, 16, 18, 27, 34, 42, 45, 53, 65, 71, 77, 80, 81, 83, 92, 99, 102, 111, 114, 124, 127, 129, 130, 145, 146, 149, 160, 163, 170, 180, 183, 188, 195, 198, 202, 208, 217, 227, 229, 231, 233, 235, 238, 239, 240, 243, 244, 248, 249, 251, 252, 253, 254] ['In', 'addition', ',', 'sADPL', 'detected', 'graded', 'changes', 'in', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', 'activity', 'levels', 'in', 'response', 'to', 'increased', 'JW480', 'concentrations', ',', 'an', 'indication', 'of', 'direct', 'occupancy', 'of', 'this', 'enzyme', 'by', 'its', 'small', 'molecule', 'inhibitor', '(', 'IC50', '=', '10.5', 'nM', ';', 'Fig', '.', '3C', ')', '.'] [1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Parallel quantification of MGLL activity in response to JW480 treatment showed no effect (Fig. 3C), confirming the specificity of each sADPL signal within the serine hydrolase family. [('PMC6815137', 'R05005', 159, 175, 'serine hydrolase')] ['Parallel', 'quantification', 'of', 'MG', '##LL', 'activity', 'in', 'response', 'to', 'JW', '##48', '##0', 'treatment', 'showed', 'no', 'effect', '(', 'Fig', '.', '3', '##C', ')', ',', 'confirming', 'the', 'specificity', 'of', 'each', 's', '##AD', '##PL', 'signal', 'within', 'the', 'serine', 'hydro', '##las', '##e', 'family', '.'] [0, 9, 24, 27, 29, 32, 41, 44, 53, 56, 58, 60, 62, 72, 79, 82, 89, 90, 93, 95, 96, 97, 98, 100, 111, 115, 127, 130, 135, 136, 138, 141, 148, 155, 159, 166, 171, 174, 176, 182] [8, 23, 26, 29, 31, 40, 43, 52, 55, 58, 60, 61, 71, 78, 81, 88, 90, 93, 94, 96, 97, 98, 99, 110, 114, 126, 129, 134, 136, 138, 140, 147, 154, 158, 165, 171, 174, 175, 182, 183] ['Parallel', 'quantification', 'of', 'MGLL', 'activity', 'in', 'response', 'to', 'JW480', 'treatment', 'showed', 'no', 'effect', '(', 'Fig', '.', '3C', ')', ',', 'confirming', 'the', 'specificity', 'of', 'each', 'sADPL', 'signal', 'within', 'the', 'serine', 'hydrolase', 'family', '.'] [1, 1, 1, 2, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O']
In agreement with previously published pharmacokinetic and pharmacodynamic data on JW480 (28), the neutral cholesterol ester hydrolase 1-dependent sADPL signal was reduced in a dose-dependent manner (Fig. 3F). [('PMC6815137', 'R06002', 99, 136, 'neutral cholesterol ester hydrolase 1')] ['In', 'agreement', 'with', 'previously', 'published', 'pharmacokinetic', 'and', 'pharmac', '##odynamic', 'data', 'on', 'JW', '##48', '##0', '(', '28', ')', ',', 'the', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', '-', 'dependent', 's', '##AD', '##PL', 'signal', 'was', 'reduced', 'in', 'a', 'dose', '-', 'dependent', 'manner', '(', 'Fig', '.', '3', '##F', ')', '.'] [0, 3, 13, 18, 29, 39, 55, 59, 66, 75, 80, 83, 85, 87, 89, 90, 92, 93, 95, 99, 107, 119, 125, 130, 133, 135, 136, 137, 147, 148, 150, 153, 160, 164, 172, 175, 177, 181, 182, 192, 199, 200, 203, 205, 206, 207, 208] [2, 12, 17, 28, 38, 54, 58, 66, 74, 79, 82, 85, 87, 88, 90, 92, 93, 94, 98, 106, 118, 124, 130, 133, 134, 136, 137, 146, 148, 150, 152, 159, 163, 171, 174, 176, 181, 182, 191, 198, 200, 203, 204, 206, 207, 208, 209] ['In', 'agreement', 'with', 'previously', 'published', 'pharmacokinetic', 'and', 'pharmacodynamic', 'data', 'on', 'JW480', '(', '28', ')', ',', 'the', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1-dependent', 'sADPL', 'signal', 'was', 'reduced', 'in', 'a', 'dose', '-', 'dependent', 'manner', '(', 'Fig', '.', '3F', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 3, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Parallel quantification of the activity of fatty acid amide hydrolase 1 and MGLL, 2 related off-target serine hydrolases, showed no significant inhibition of either target at either dose, consistent with previous gel-based profiling in mice treated with JW480 (28). [('PMC6815137', 'R06003', 43, 71, 'fatty acid amide hydrolase 1'), ('PMC6815137', 'R06003', 103, 120, 'serine hydrolases')] ['Parallel', 'quantification', 'of', 'the', 'activity', 'of', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'and', 'MG', '##LL', ',', '2', 'related', 'off', '-', 'target', 'serine', 'hydro', '##las', '##es', ',', 'showed', 'no', 'significant', 'inhibition', 'of', 'either', 'target', 'at', 'either', 'dose', ',', 'consistent', 'with', 'previous', 'gel', '-', 'based', 'profiling', 'in', 'mice', 'treated', 'with', 'JW', '##48', '##0', '(', '28', ')', '.'] [0, 9, 24, 27, 31, 40, 43, 49, 54, 60, 65, 68, 70, 72, 76, 78, 80, 82, 84, 92, 95, 96, 103, 110, 115, 118, 120, 122, 129, 132, 144, 155, 158, 165, 172, 175, 182, 186, 188, 199, 204, 213, 216, 217, 223, 233, 236, 241, 249, 254, 256, 258, 260, 261, 263, 264] [8, 23, 26, 30, 39, 42, 48, 53, 59, 65, 68, 69, 71, 75, 78, 80, 81, 83, 91, 95, 96, 102, 109, 115, 118, 120, 121, 128, 131, 143, 154, 157, 164, 171, 174, 181, 186, 187, 198, 203, 212, 216, 217, 222, 232, 235, 240, 248, 253, 256, 258, 259, 261, 263, 264, 265] ['Parallel', 'quantification', 'of', 'the', 'activity', 'of', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'and', 'MGLL', ',', '2', 'related', 'off', '-', 'target', 'serine', 'hydrolases', ',', 'showed', 'no', 'significant', 'inhibition', 'of', 'either', 'target', 'at', 'either', 'dose', ',', 'consistent', 'with', 'previous', 'gel', '-', 'based', 'profiling', 'in', 'mice', 'treated', 'with', 'JW480', '(', '28', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We first measured the relative activity of 4 serine hydrolases (neutral cholesterol ester hydrolase 1, MGLL, fatty acid amide hydrolase 1 and DPP4) and 2 cathepsin proteases (CTSB and CTSL) in cancer spheroids collected from 15 patients during initial debulking surgery (SI Appendix, Table S1). [('PMC6815137', 'R08003', 45, 62, 'serine hydrolases'), ('PMC6815137', 'R08003', 64, 101, 'neutral cholesterol ester hydrolase 1'), ('PMC6815137', 'R08003', 109, 137, 'fatty acid amide hydrolase 1')] ['We', 'first', 'measured', 'the', 'relative', 'activity', 'of', '4', 'serine', 'hydro', '##las', '##es', '(', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', ',', 'MG', '##LL', ',', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'and', 'DPP', '##4', ')', 'and', '2', 'cathe', '##ps', '##in', 'proteases', '(', 'CT', '##SB', 'and', 'CT', '##SL', ')', 'in', 'cancer', 'sphe', '##roids', 'collected', 'from', '15', 'patients', 'during', 'initial', 'deb', '##ul', '##king', 'surgery', '(', 'SI', 'Appendix', ',', 'Table', 'S', '##1', ')', '.'] [0, 3, 9, 18, 22, 31, 40, 43, 45, 52, 57, 60, 63, 64, 72, 84, 90, 95, 98, 100, 101, 103, 105, 107, 109, 115, 120, 126, 131, 134, 136, 138, 142, 145, 146, 148, 152, 154, 159, 161, 164, 174, 175, 177, 180, 184, 186, 188, 190, 193, 200, 204, 210, 220, 225, 228, 237, 244, 252, 255, 257, 262, 270, 271, 274, 282, 284, 290, 291, 292, 293] [2, 8, 17, 21, 30, 39, 42, 44, 51, 57, 60, 62, 64, 71, 83, 89, 95, 98, 99, 101, 102, 105, 107, 108, 114, 119, 125, 131, 134, 135, 137, 141, 145, 146, 147, 151, 153, 159, 161, 163, 173, 175, 177, 179, 183, 186, 188, 189, 192, 199, 204, 209, 219, 224, 227, 236, 243, 251, 255, 257, 261, 269, 271, 273, 282, 283, 289, 291, 292, 293, 294] ['We', 'first', 'measured', 'the', 'relative', 'activity', 'of', '4', 'serine', 'hydrolases', '(', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', ',', 'MGLL', ',', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'and', 'DPP4', ')', 'and', '2', 'cathepsin', 'proteases', '(', 'CTSB', 'and', 'CTSL', ')', 'in', 'cancer', 'spheroids', 'collected', 'from', '15', 'patients', 'during', 'initial', 'debulking', 'surgery', '(', 'SI', 'Appendix', ',', 'Table', 'S1', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 1, 3, 1, 1, 2, 1, 1, 1, 3, 1, 1, 2, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The resulting activity profile confirmed that neutral cholesterol ester hydrolase 1, MGLL, cathepsin B, and CTSL activities were generally correlated within the same patient spheroids, whereas active FAAH levels were more variable and DPP4 activity was undetectable (SI Appendix, Fig. [('PMC6815137', 'R08005', 46, 83, 'neutral cholesterol ester hydrolase 1'), ('PMC6815137', 'R08005', 91, 102, 'cathepsin B')] ['The', 'resulting', 'activity', 'profile', 'confirmed', 'that', 'neutral', 'cholesterol', 'ester', 'hydro', '##las', '##e', '1', ',', 'MG', '##LL', ',', 'cathe', '##ps', '##in', 'B', ',', 'and', 'CT', '##SL', 'activities', 'were', 'generally', 'correlated', 'within', 'the', 'same', 'patient', 'sphe', '##roids', ',', 'whereas', 'active', 'FA', '##AH', 'levels', 'were', 'more', 'variable', 'and', 'DPP', '##4', 'activity', 'was', 'undetectable', '(', 'SI', 'Appendix', ',', 'Fig', '.'] [0, 4, 14, 23, 31, 41, 46, 54, 66, 72, 77, 80, 82, 83, 85, 87, 89, 91, 96, 98, 101, 102, 104, 108, 110, 113, 124, 129, 139, 150, 157, 161, 166, 174, 178, 183, 185, 193, 200, 202, 205, 212, 217, 222, 231, 235, 238, 240, 249, 253, 266, 267, 270, 278, 280, 283] [3, 13, 22, 30, 40, 45, 53, 65, 71, 77, 80, 81, 83, 84, 87, 89, 90, 96, 98, 100, 102, 103, 107, 110, 112, 123, 128, 138, 149, 156, 160, 165, 173, 178, 183, 184, 192, 199, 202, 204, 211, 216, 221, 230, 234, 238, 239, 248, 252, 265, 267, 269, 278, 279, 283, 284] ['The', 'resulting', 'activity', 'profile', 'confirmed', 'that', 'neutral', 'cholesterol', 'ester', 'hydrolase', '1', ',', 'MGLL', ',', 'cathepsin', 'B', ',', 'and', 'CTSL', 'activities', 'were', 'generally', 'correlated', 'within', 'the', 'same', 'patient', 'spheroids', ',', 'whereas', 'active', 'FAAH', 'levels', 'were', 'more', 'variable', 'and', 'DPP4', 'activity', 'was', 'undetectable', '(', 'SI', 'Appendix', ',', 'Fig', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 2, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
For example, the activities of both cathepsin proteases cathepsin B and cathepsin L were significantly higher in the primary tumor compared with the corresponding metastatic tumor (Fig. 5D). [('PMC6815137', 'R10002', 36, 55, 'cathepsin proteases'), ('PMC6815137', 'R10002', 56, 67, 'cathepsin B'), ('PMC6815137', 'R10002', 72, 83, 'cathepsin L')] ['For', 'example', ',', 'the', 'activities', 'of', 'both', 'cathe', '##ps', '##in', 'proteases', 'cathe', '##ps', '##in', 'B', 'and', 'cathe', '##ps', '##in', 'L', 'were', 'significantly', 'higher', 'in', 'the', 'primary', 'tumor', 'compared', 'with', 'the', 'corresponding', 'metastatic', 'tumor', '(', 'Fig', '.', '5', '##D', ')', '.'] [0, 4, 11, 13, 17, 28, 31, 36, 41, 43, 46, 56, 61, 63, 66, 68, 72, 77, 79, 82, 84, 89, 103, 110, 113, 117, 125, 131, 140, 145, 149, 163, 174, 180, 181, 184, 186, 187, 188, 189] [3, 11, 12, 16, 27, 30, 35, 41, 43, 45, 55, 61, 63, 65, 67, 71, 77, 79, 81, 83, 88, 102, 109, 112, 116, 124, 130, 139, 144, 148, 162, 173, 179, 181, 184, 185, 187, 188, 189, 190] ['For', 'example', ',', 'the', 'activities', 'of', 'both', 'cathepsin', 'proteases', 'cathepsin', 'B', 'and', 'cathepsin', 'L', 'were', 'significantly', 'higher', 'in', 'the', 'primary', 'tumor', 'compared', 'with', 'the', 'corresponding', 'metastatic', 'tumor', '(', 'Fig', '.', '5D', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Intriguingly, the activity ratio for several enzymes, including fatty acid amide hydrolase 1, cathepsin L, and MGLL, showed a significant negative correlation with disease-free survival across the patient cohort (Fig. 5E). [('PMC6815137', 'R11001', 64, 92, 'fatty acid amide hydrolase 1'), ('PMC6815137', 'R11001', 94, 105, 'cathepsin L')] ['Intr', '##igu', '##ingly', ',', 'the', 'activity', 'ratio', 'for', 'several', 'enzymes', ',', 'including', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', ',', 'cathe', '##ps', '##in', 'L', ',', 'and', 'MG', '##LL', ',', 'showed', 'a', 'significant', 'negative', 'correlation', 'with', 'disease', '-', 'free', 'survival', 'across', 'the', 'patient', 'cohort', '(', 'Fig', '.', '5', '##E', ')', '.'] [0, 4, 7, 12, 14, 18, 27, 33, 37, 45, 52, 54, 64, 70, 75, 81, 86, 89, 91, 92, 94, 99, 101, 104, 105, 107, 111, 113, 115, 117, 124, 126, 138, 147, 159, 164, 171, 172, 177, 186, 193, 197, 205, 212, 213, 216, 218, 219, 220, 221] [4, 7, 12, 13, 17, 26, 32, 36, 44, 52, 53, 63, 69, 74, 80, 86, 89, 90, 92, 93, 99, 101, 103, 105, 106, 110, 113, 115, 116, 123, 125, 137, 146, 158, 163, 171, 172, 176, 185, 192, 196, 204, 211, 213, 216, 217, 219, 220, 221, 222] ['Intriguingly', ',', 'the', 'activity', 'ratio', 'for', 'several', 'enzymes', ',', 'including', 'fatty', 'acid', 'amide', 'hydrolase', '1', ',', 'cathepsin', 'L', ',', 'and', 'MGLL', ',', 'showed', 'a', 'significant', 'negative', 'correlation', 'with', 'disease', '-', 'free', 'survival', 'across', 'the', 'patient', 'cohort', '(', 'Fig', '.', '5E', ')', '.'] [3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The activity ratio for fatty acid amide hydrolase 1 was also correlated with overall survival. [('PMC6815137', 'R11003', 23, 51, 'fatty acid amide hydrolase 1')] ['The', 'activity', 'ratio', 'for', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'was', 'also', 'correlated', 'with', 'overall', 'survival', '.'] [0, 4, 13, 19, 23, 29, 34, 40, 45, 48, 50, 52, 56, 61, 72, 77, 85, 93] [3, 12, 18, 22, 28, 33, 39, 45, 48, 49, 51, 55, 60, 71, 76, 84, 93, 94] ['The', 'activity', 'ratio', 'for', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'was', 'also', 'correlated', 'with', 'overall', 'survival', '.'] [1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The mean fatty acid amide hydrolase 1 activity ratio differed significantly among these groups (SI Appendix, Fig. [('PMC6815137', 'R11006', 9, 37, 'fatty acid amide hydrolase 1')] ['The', 'mean', 'fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'activity', 'ratio', 'differed', 'significantly', 'among', 'these', 'groups', '(', 'SI', 'Appendix', ',', 'Fig', '.'] [0, 4, 9, 15, 20, 26, 31, 34, 36, 38, 47, 53, 62, 76, 82, 88, 95, 96, 99, 107, 109, 112] [3, 8, 14, 19, 25, 31, 34, 35, 37, 46, 52, 61, 75, 81, 87, 94, 96, 98, 107, 108, 112, 113] ['The', 'mean', 'fatty', 'acid', 'amide', 'hydrolase', '1', 'activity', 'ratio', 'differed', 'significantly', 'among', 'these', 'groups', '(', 'SI', 'Appendix', ',', 'Fig', '.'] [1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
fatty acid amide hydrolase 1 has been peripherally implicated in tumor metabolism, and thus these data present novel hypotheses for future testing. [('PMC6815137', 'R11008', 0, 28, 'fatty acid amide hydrolase 1')] ['fatty', 'acid', 'amide', 'hydro', '##las', '##e', '1', 'has', 'been', 'peripheral', '##ly', 'implicated', 'in', 'tumor', 'metabolism', ',', 'and', 'thus', 'these', 'data', 'present', 'novel', 'hypotheses', 'for', 'future', 'testing', '.'] [0, 6, 11, 17, 22, 25, 27, 29, 33, 38, 48, 51, 62, 65, 71, 81, 83, 87, 92, 98, 103, 111, 117, 128, 132, 139, 146] [5, 10, 16, 22, 25, 26, 28, 32, 37, 48, 50, 61, 64, 70, 81, 82, 86, 91, 97, 102, 110, 116, 127, 131, 138, 146, 147] ['fatty', 'acid', 'amide', 'hydrolase', '1', 'has', 'been', 'peripherally', 'implicated', 'in', 'tumor', 'metabolism', ',', 'and', 'thus', 'these', 'data', 'present', 'novel', 'hypotheses', 'for', 'future', 'testing', '.'] [1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
There is mounting evidence that enzymes involved in the urea cycle, including two mitochondrial (carbamoyl phosphate synthase 1 and ornithine transcarbamylase) and three cytosolic (argininosuccinate synthase, argininosuccinate lyase, and arginase) enzymes, are differentially expressed in the liver. [('PMC6826937', 'D04005', 97, 127, 'carbamoyl phosphate synthase 1'), ('PMC6826937', 'D04005', 132, 158, 'ornithine transcarbamylase'), ('PMC6826937', 'D04005', 181, 207, 'argininosuccinate synthase'), ('PMC6826937', 'D04005', 209, 232, 'argininosuccinate lyase'), ('PMC6826937', 'D04005', 238, 246, 'arginase')] ['There', 'is', 'mounting', 'evidence', 'that', 'enzymes', 'involved', 'in', 'the', 'urea', 'cycle', ',', 'including', 'two', 'mitochondrial', '(', 'carb', '##am', '##oyl', 'phosphate', 'synthase', '1', 'and', 'or', '##nit', '##hin', '##e', 'transc', '##arb', '##amyl', '##ase', ')', 'and', 'three', 'cytosolic', '(', 'arg', '##inin', '##os', '##ucci', '##nat', '##e', 'synthase', ',', 'arg', '##inin', '##os', '##ucci', '##nat', '##e', 'ly', '##ase', ',', 'and', 'arg', '##inase', ')', 'enzymes', ',', 'are', 'differentially', 'expressed', 'in', 'the', 'liver', '.'] [0, 6, 9, 18, 27, 32, 40, 49, 52, 56, 61, 66, 68, 78, 82, 96, 97, 101, 103, 107, 117, 126, 128, 132, 134, 137, 140, 142, 148, 151, 155, 158, 160, 164, 170, 180, 181, 184, 188, 190, 194, 197, 199, 207, 209, 212, 216, 218, 222, 225, 227, 229, 232, 234, 238, 241, 246, 248, 255, 257, 261, 276, 286, 289, 293, 298] [5, 8, 17, 26, 31, 39, 48, 51, 55, 60, 66, 67, 77, 81, 95, 97, 101, 103, 106, 116, 125, 127, 131, 134, 137, 140, 141, 148, 151, 155, 158, 159, 163, 169, 179, 181, 184, 188, 190, 194, 197, 198, 207, 208, 212, 216, 218, 222, 225, 226, 229, 232, 233, 237, 241, 246, 247, 255, 256, 260, 275, 285, 288, 292, 298, 299] ['There', 'is', 'mounting', 'evidence', 'that', 'enzymes', 'involved', 'in', 'the', 'urea', 'cycle', ',', 'including', 'two', 'mitochondrial', '(', 'carbamoyl', 'phosphate', 'synthase', '1', 'and', 'ornithine', 'transcarbamylase', ')', 'and', 'three', 'cytosolic', '(', 'argininosuccinate', 'synthase', ',', 'argininosuccinate', 'lyase', ',', 'and', 'arginase', ')', 'enzymes', ',', 'are', 'differentially', 'expressed', 'in', 'the', 'liver', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 4, 4, 1, 1, 1, 1, 1, 6, 1, 1, 6, 2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In patients with cirrhosis and HCC, the level of methionine adenosyltransferase (MAT1A), a crucial gene involved in the methionine metabolism, is downregulated, thereby leading to hypermethioninemia and reduced hepatic glutathione concentrations. [('PMC6826937', 'D04010', 49, 79, 'methionine adenosyltransferase')] ['In', 'patients', 'with', 'cirrhosis', 'and', 'HCC', ',', 'the', 'level', 'of', 'methionine', 'aden', '##osyl', '##transferase', '(', 'MAT', '##1', '##A', ')', ',', 'a', 'crucial', 'gene', 'involved', 'in', 'the', 'methionine', 'metabolism', ',', 'is', 'downregulated', ',', 'thereby', 'leading', 'to', 'hyper', '##meth', '##ionine', '##mia', 'and', 'reduced', 'hepatic', 'glutathione', 'concentrations', '.'] [0, 3, 12, 17, 27, 31, 34, 36, 40, 46, 49, 60, 64, 68, 80, 81, 84, 85, 86, 87, 89, 91, 99, 104, 113, 116, 120, 131, 141, 143, 146, 159, 161, 169, 177, 180, 185, 189, 195, 199, 203, 211, 219, 231, 245] [2, 11, 16, 26, 30, 34, 35, 39, 45, 48, 59, 64, 68, 79, 81, 84, 85, 86, 87, 88, 90, 98, 103, 112, 115, 119, 130, 141, 142, 145, 159, 160, 168, 176, 179, 185, 189, 195, 198, 202, 210, 218, 230, 245, 246] ['In', 'patients', 'with', 'cirrhosis', 'and', 'HCC', ',', 'the', 'level', 'of', 'methionine', 'adenosyltransferase', '(', 'MAT1A', ')', ',', 'a', 'crucial', 'gene', 'involved', 'in', 'the', 'methionine', 'metabolism', ',', 'is', 'downregulated', ',', 'thereby', 'leading', 'to', 'hypermethioninemia', 'and', 'reduced', 'hepatic', 'glutathione', 'concentrations', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To traverse the mitochondrial matrix, long-chain acylcarnitines require specific transferases, such as carnitine/acylcarnitine translocase and carnitine palmitoyl transferase. [('PMC6826937', 'D05004', 81, 93, 'transferases'), ('PMC6826937', 'D05004', 103, 138, 'carnitine/acylcarnitine translocase'), ('PMC6826937', 'D05004', 143, 174, 'carnitine palmitoyl transferase')] ['To', 'travers', '##e', 'the', 'mitochondrial', 'matrix', ',', 'long', '-', 'chain', 'acyl', '##car', '##nit', '##ines', 'require', 'specific', 'transfer', '##ases', ',', 'such', 'as', 'car', '##nit', '##ine', '/', 'acyl', '##car', '##nit', '##ine', 'transloc', '##ase', 'and', 'car', '##nit', '##ine', 'palm', '##ito', '##yl', 'transfer', '##ase', '.'] [0, 3, 10, 12, 16, 30, 36, 38, 42, 43, 49, 53, 56, 59, 64, 72, 81, 89, 93, 95, 100, 103, 106, 109, 112, 113, 117, 120, 123, 127, 135, 139, 143, 146, 149, 153, 157, 160, 163, 171, 174] [2, 10, 11, 15, 29, 36, 37, 42, 43, 48, 53, 56, 59, 63, 71, 80, 89, 93, 94, 99, 102, 106, 109, 112, 113, 117, 120, 123, 126, 135, 138, 142, 146, 149, 152, 157, 160, 162, 171, 174, 175] ['To', 'traverse', 'the', 'mitochondrial', 'matrix', ',', 'long', '-', 'chain', 'acylcarnitines', 'require', 'specific', 'transferases', ',', 'such', 'as', 'carnitine', '/', 'acylcarnitine', 'translocase', 'and', 'carnitine', 'palmitoyl', 'transferase', '.'] [1, 2, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 2, 1, 1, 1, 3, 1, 4, 2, 1, 3, 3, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O']
Previous studies demonstrated that carnitine palmitoyltransferase 2 (carnitine palmitoyltransferase 2) expression is downregulated, thereby reducing hepatic beta-oxidation of fatty acids in patients with HCC [('PMC6826937', 'D05006', 35, 67, 'carnitine palmitoyltransferase 2'), ('PMC6826937', 'D05006', 69, 101, 'carnitine palmitoyltransferase 2')] ['Previous', 'studies', 'demonstrated', 'that', 'car', '##nit', '##ine', 'palm', '##ito', '##yl', '##transferase', '2', '(', 'car', '##nit', '##ine', 'palm', '##ito', '##yl', '##transferase', '2', ')', 'expression', 'is', 'downregulated', ',', 'thereby', 'reducing', 'hepatic', 'beta', '-', 'oxidation', 'of', 'fatty', 'acids', 'in', 'patients', 'with', 'HCC'] [0, 9, 17, 30, 35, 38, 41, 45, 49, 52, 54, 66, 68, 69, 72, 75, 79, 83, 86, 88, 100, 101, 103, 114, 117, 130, 132, 140, 149, 157, 161, 162, 172, 175, 181, 187, 190, 199, 204] [8, 16, 29, 34, 38, 41, 44, 49, 52, 54, 65, 67, 69, 72, 75, 78, 83, 86, 88, 99, 101, 102, 113, 116, 130, 131, 139, 148, 156, 161, 162, 171, 174, 180, 186, 189, 198, 203, 207] ['Previous', 'studies', 'demonstrated', 'that', 'carnitine', 'palmitoyltransferase', '2', '(', 'carnitine', 'palmitoyltransferase', '2', ')', 'expression', 'is', 'downregulated', ',', 'thereby', 'reducing', 'hepatic', 'beta', '-', 'oxidation', 'of', 'fatty', 'acids', 'in', 'patients', 'with', 'HCC'] [1, 1, 1, 1, 3, 4, 1, 1, 3, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
A lack of carnitine palmitoyltransferase 2 expression ultimately leads to an increased level of long-chain acylcarnitines and reduced level of short- and medium-chain acylcarnitines in circulation [34,35]. [('PMC6826937', 'D05008', 10, 42, 'carnitine palmitoyltransferase 2')] ['A', 'lack', 'of', 'car', '##nit', '##ine', 'palm', '##ito', '##yl', '##transferase', '2', 'expression', 'ultimately', 'leads', 'to', 'an', 'increased', 'level', 'of', 'long', '-', 'chain', 'acyl', '##car', '##nit', '##ines', 'and', 'reduced', 'level', 'of', 'short', '-', 'and', 'medium', '-', 'chain', 'acyl', '##car', '##nit', '##ines', 'in', 'circulation', '[', '34', ',', '35', ']', '.'] [0, 2, 7, 10, 13, 16, 20, 24, 27, 29, 41, 43, 54, 65, 71, 74, 77, 87, 93, 96, 100, 101, 107, 111, 114, 117, 122, 126, 134, 140, 143, 148, 150, 154, 160, 161, 167, 171, 174, 177, 182, 185, 197, 198, 200, 201, 203, 204] [1, 6, 9, 13, 16, 19, 24, 27, 29, 40, 42, 53, 64, 70, 73, 76, 86, 92, 95, 100, 101, 106, 111, 114, 117, 121, 125, 133, 139, 142, 148, 149, 153, 160, 161, 166, 171, 174, 177, 181, 184, 196, 198, 200, 201, 203, 204, 205] ['A', 'lack', 'of', 'carnitine', 'palmitoyltransferase', '2', 'expression', 'ultimately', 'leads', 'to', 'an', 'increased', 'level', 'of', 'long', '-', 'chain', 'acylcarnitines', 'and', 'reduced', 'level', 'of', 'short-', 'and', 'medium', '-', 'chain', 'acylcarnitines', 'in', 'circulation', '[', '34', ',', '35', ']', '.'] [1, 1, 1, 3, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 2, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Spinelli J.B., Yoon H., Ringel A.E., Jeanfavre S., Clish C.B., Haigis M.C. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. [('PMC6826937', 'F26001', 110, 133, 'glutamate dehydrogenase')] ['Spin', '##elli', 'J', '.', 'B', '.', ',', 'Y', '##oon', 'H', '.', ',', 'Ring', '##el', 'A', '.', 'E', '.', ',', 'Jean', '##fa', '##v', '##re', 'S', '.', ',', 'Cl', '##ish', 'C', '.', 'B', '.', ',', 'Ha', '##ig', '##is', 'M', '.', 'C', '.', 'Metabolic', 'recycling', 'of', 'ammonia', 'via', 'glutamate', 'dehydrogenase', 'supports', 'breast', 'cancer', 'biomass', '.'] [0, 4, 9, 10, 11, 12, 13, 15, 16, 20, 21, 22, 24, 28, 31, 32, 33, 34, 35, 37, 41, 43, 44, 47, 48, 49, 51, 53, 57, 58, 59, 60, 61, 63, 65, 67, 70, 71, 72, 73, 75, 85, 95, 98, 106, 110, 120, 134, 143, 150, 157, 164] [4, 8, 10, 11, 12, 13, 14, 16, 19, 21, 22, 23, 28, 30, 32, 33, 34, 35, 36, 41, 43, 44, 46, 48, 49, 50, 53, 56, 58, 59, 60, 61, 62, 65, 67, 69, 71, 72, 73, 74, 84, 94, 97, 105, 109, 119, 133, 142, 149, 156, 164, 165] ['Spinelli', 'J.B', '.', ',', 'Yoon', 'H', '.', ',', 'Ringel', 'A.E', '.', ',', 'Jeanfavre', 'S', '.', ',', 'Clish', 'C.B', '.', ',', 'Haigis', 'M.C', '.', 'Metabolic', 'recycling', 'of', 'ammonia', 'via', 'glutamate', 'dehydrogenase', 'supports', 'breast', 'cancer', 'biomass', '.'] [2, 3, 1, 1, 2, 1, 1, 1, 2, 3, 1, 1, 4, 1, 1, 1, 2, 3, 1, 1, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O']
Metabolic profiling analysis upon acylcarnitines in tissues of hepatocellular carcinoma revealed the inhibited carnitine shuttle system caused by the downregulated carnitine palmitoyltransferase 2. [('PMC6826937', 'F33002', 164, 196, 'carnitine palmitoyltransferase 2')] ['Metabolic', 'profiling', 'analysis', 'upon', 'acyl', '##car', '##nit', '##ines', 'in', 'tissues', 'of', 'hepatocellular', 'carcinoma', 'revealed', 'the', 'inhibited', 'car', '##nit', '##ine', 'shut', '##tle', 'system', 'caused', 'by', 'the', 'downregulated', 'car', '##nit', '##ine', 'palm', '##ito', '##yl', '##transferase', '2', '.'] [0, 10, 20, 29, 34, 38, 41, 44, 49, 52, 60, 63, 78, 88, 97, 101, 111, 114, 117, 121, 125, 129, 136, 143, 146, 150, 164, 167, 170, 174, 178, 181, 183, 195, 196] [9, 19, 28, 33, 38, 41, 44, 48, 51, 59, 62, 77, 87, 96, 100, 110, 114, 117, 120, 125, 128, 135, 142, 145, 149, 163, 167, 170, 173, 178, 181, 183, 194, 196, 197] ['Metabolic', 'profiling', 'analysis', 'upon', 'acylcarnitines', 'in', 'tissues', 'of', 'hepatocellular', 'carcinoma', 'revealed', 'the', 'inhibited', 'carnitine', 'shuttle', 'system', 'caused', 'by', 'the', 'downregulated', 'carnitine', 'palmitoyltransferase', '2', '.'] [1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 3, 2, 1, 1, 1, 1, 1, 3, 4, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O']
We were worried that adding a nuclease for reduction of host DNA would destroy free microbial DNA as well and skew the picture of microbial communities compared to extraction kits without this step. [('PMC6872721', 'D04001', 30, 38, 'nuclease')] ['We', 'were', 'wor', '##ried', 'that', 'adding', 'a', 'nucle', '##ase', 'for', 'reduction', 'of', 'host', 'DNA', 'would', 'destroy', 'free', 'microbial', 'DNA', 'as', 'well', 'and', 'skew', 'the', 'picture', 'of', 'microbial', 'communities', 'compared', 'to', 'extraction', 'kits', 'without', 'this', 'step', '.'] [0, 3, 8, 11, 16, 21, 28, 30, 35, 39, 43, 53, 56, 61, 65, 71, 79, 84, 94, 98, 101, 106, 110, 115, 119, 127, 130, 140, 152, 161, 164, 175, 180, 188, 193, 197] [2, 7, 11, 15, 20, 27, 29, 35, 38, 42, 52, 55, 60, 64, 70, 78, 83, 93, 97, 100, 105, 109, 114, 118, 126, 129, 139, 151, 160, 163, 174, 179, 187, 192, 197, 198] ['We', 'were', 'worried', 'that', 'adding', 'a', 'nuclease', 'for', 'reduction', 'of', 'host', 'DNA', 'would', 'destroy', 'free', 'microbial', 'DNA', 'as', 'well', 'and', 'skew', 'the', 'picture', 'of', 'microbial', 'communities', 'compared', 'to', 'extraction', 'kits', 'without', 'this', 'step', '.'] [1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Nasal samples were also sequenced with shotgun metagenomics to evaluate the usefulness of host DNA depletion applied in two kits by use of lysis of human cells and subsequent addition of nucleases. [('PMC6872721', 'I03004', 187, 196, 'nucleases')] ['Nas', '##al', 'samples', 'were', 'also', 'sequenced', 'with', 'shot', '##gu', '##n', 'meta', '##gen', '##omics', 'to', 'evaluate', 'the', 'usefulness', 'of', 'host', 'DNA', 'depletion', 'applied', 'in', 'two', 'kits', 'by', 'use', 'of', 'lysis', 'of', 'human', 'cells', 'and', 'subsequent', 'addition', 'of', 'nucle', '##ases', '.'] [0, 3, 6, 14, 19, 24, 34, 39, 43, 45, 47, 51, 54, 60, 63, 72, 76, 87, 90, 95, 99, 109, 117, 120, 124, 129, 132, 136, 139, 145, 148, 154, 160, 164, 175, 184, 187, 192, 196] [3, 5, 13, 18, 23, 33, 38, 43, 45, 46, 51, 54, 59, 62, 71, 75, 86, 89, 94, 98, 108, 116, 119, 123, 128, 131, 135, 138, 144, 147, 153, 159, 163, 174, 183, 186, 192, 196, 197] ['Nasal', 'samples', 'were', 'also', 'sequenced', 'with', 'shotgun', 'metagenomics', 'to', 'evaluate', 'the', 'usefulness', 'of', 'host', 'DNA', 'depletion', 'applied', 'in', 'two', 'kits', 'by', 'use', 'of', 'lysis', 'of', 'human', 'cells', 'and', 'subsequent', 'addition', 'of', 'nucleases', '.'] [2, 1, 1, 1, 1, 1, 3, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O']
In the present study, in addition to the bacterial culture, we performed a multiplex polymerase chain reaction (PCR) to detect viruses and a clone library analysis of the bacterial 16S rRNA gene sequence using sputum samples to clarify the microbiological characteristics of LRTIs in NMD patients. [('PMC7105058', 'I01000', 85, 95, 'polymerase')] ['In', 'the', 'present', 'study', ',', 'in', 'addition', 'to', 'the', 'bacterial', 'culture', ',', 'we', 'performed', 'a', 'multiplex', 'polymerase', 'chain', 'reaction', '(', 'PCR', ')', 'to', 'detect', 'viruses', 'and', 'a', 'clone', 'library', 'analysis', 'of', 'the', 'bacterial', '16', '##S', 'rRNA', 'gene', 'sequence', 'using', 'sputum', 'samples', 'to', 'clarify', 'the', 'microbi', '##ological', 'characteristics', 'of', 'LR', '##TI', '##s', 'in', 'NMD', 'patients', '.'] [0, 3, 7, 15, 20, 22, 25, 34, 37, 41, 51, 58, 60, 63, 73, 75, 85, 96, 102, 111, 112, 115, 117, 120, 127, 135, 139, 141, 147, 155, 164, 167, 171, 181, 183, 185, 190, 195, 204, 210, 217, 225, 228, 236, 240, 247, 256, 272, 275, 277, 279, 281, 284, 288, 296] [2, 6, 14, 20, 21, 24, 33, 36, 40, 50, 58, 59, 62, 72, 74, 84, 95, 101, 110, 112, 115, 116, 119, 126, 134, 138, 140, 146, 154, 163, 166, 170, 180, 183, 184, 189, 194, 203, 209, 216, 224, 227, 235, 239, 247, 255, 271, 274, 277, 279, 280, 283, 287, 296, 297] ['In', 'the', 'present', 'study', ',', 'in', 'addition', 'to', 'the', 'bacterial', 'culture', ',', 'we', 'performed', 'a', 'multiplex', 'polymerase', 'chain', 'reaction', '(', 'PCR', ')', 'to', 'detect', 'viruses', 'and', 'a', 'clone', 'library', 'analysis', 'of', 'the', 'bacterial', '16S', 'rRNA', 'gene', 'sequence', 'using', 'sputum', 'samples', 'to', 'clarify', 'the', 'microbiological', 'characteristics', 'of', 'LRTIs', 'in', 'NMD', 'patients', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 3, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The diagnosis of AMI was made in view of the presence of prolonged chest pain, typical changes in a 12-lead electrocardiogram (ECG), and/or elevated serum creatine kinase (creatine kinase) levels. [('PMC7409576', 'M00001', 155, 170, 'creatine kinase'), ('PMC7409576', 'M00001', 172, 187, 'creatine kinase')] ['The', 'diagnosis', 'of', 'AMI', 'was', 'made', 'in', 'view', 'of', 'the', 'presence', 'of', 'prolonged', 'chest', 'pain', ',', 'typical', 'changes', 'in', 'a', '12', '-', 'lead', 'electrocardi', '##ogram', '(', 'ECG', ')', ',', 'and', '/', 'or', 'elevated', 'serum', 'cre', '##atine', 'kinase', '(', 'cre', '##atine', 'kinase', ')', 'levels', '.'] [0, 4, 14, 17, 21, 25, 30, 33, 38, 41, 45, 54, 57, 67, 73, 77, 79, 87, 95, 98, 100, 102, 103, 108, 120, 126, 127, 130, 131, 133, 136, 137, 140, 149, 155, 158, 164, 171, 172, 175, 181, 187, 189, 195] [3, 13, 16, 20, 24, 29, 32, 37, 40, 44, 53, 56, 66, 72, 77, 78, 86, 94, 97, 99, 102, 103, 107, 120, 125, 127, 130, 131, 132, 136, 137, 139, 148, 154, 158, 163, 170, 172, 175, 180, 187, 188, 195, 196] ['The', 'diagnosis', 'of', 'AMI', 'was', 'made', 'in', 'view', 'of', 'the', 'presence', 'of', 'prolonged', 'chest', 'pain', ',', 'typical', 'changes', 'in', 'a', '12-lead', 'electrocardiogram', '(', 'ECG', ')', ',', 'and', '/', 'or', 'elevated', 'serum', 'creatine', 'kinase', '(', 'creatine', 'kinase', ')', 'levels', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 2, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'B', 'B', 'I', 'E', 'O', 'O', 'O']
The protein-antibody complex was detected by a biotinylated detection antibody specific to the targeted protein and successively was recognised by Avidin-Horseradish Peroxidase (Horseradish Peroxidase) conjugate. [('PMC7409576', 'M07003', 147, 176, 'Avidin-Horseradish Peroxidase'), ('PMC7409576', 'M07003', 178, 200, 'Horseradish Peroxidase')] ['The', 'protein', '-', 'antibody', 'complex', 'was', 'detected', 'by', 'a', 'biotinylated', 'detection', 'antibody', 'specific', 'to', 'the', 'targeted', 'protein', 'and', 'successively', 'was', 'recognised', 'by', 'Av', '##idin', '-', 'Hor', '##ser', '##adish', 'Per', '##oxidase', '(', 'Hor', '##ser', '##adish', 'Per', '##oxidase', ')', 'conjugate', '.'] [0, 4, 11, 12, 21, 29, 33, 42, 45, 47, 60, 70, 79, 88, 91, 95, 104, 112, 116, 129, 133, 144, 147, 149, 153, 154, 157, 160, 166, 169, 177, 178, 181, 184, 190, 193, 200, 202, 211] [3, 11, 12, 20, 28, 32, 41, 44, 46, 59, 69, 78, 87, 90, 94, 103, 111, 115, 128, 132, 143, 146, 149, 153, 154, 157, 160, 165, 169, 176, 178, 181, 184, 189, 193, 200, 201, 211, 212] ['The', 'protein', '-', 'antibody', 'complex', 'was', 'detected', 'by', 'a', 'biotinylated', 'detection', 'antibody', 'specific', 'to', 'the', 'targeted', 'protein', 'and', 'successively', 'was', 'recognised', 'by', 'Avidin-Horseradish', 'Peroxidase', '(', 'Horseradish', 'Peroxidase', ')', 'conjugate', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 6, 2, 1, 3, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O']
Proteolysis of histidine kinase VgrS inhibits its autophosphorylation and promotes osmostress resistance in Xanthomonas campestris. [('PMC7805185', 'F02002', 15, 31, 'histidine kinase')] ['Prote', '##olysis', 'of', 'histidine', 'kinase', 'V', '##gr', '##S', 'inhibits', 'its', 'auto', '##phosphorylation', 'and', 'promotes', 'osm', '##ostr', '##ess', 'resistance', 'in', 'X', '##anth', '##omonas', 'camp', '##estr', '##is', '.'] [0, 5, 12, 15, 25, 32, 33, 35, 37, 46, 50, 54, 70, 74, 83, 86, 90, 94, 105, 108, 109, 113, 120, 124, 128, 130] [5, 11, 14, 24, 31, 33, 35, 36, 45, 49, 54, 69, 73, 82, 86, 90, 93, 104, 107, 109, 113, 119, 124, 128, 130, 131] ['Proteolysis', 'of', 'histidine', 'kinase', 'VgrS', 'inhibits', 'its', 'autophosphorylation', 'and', 'promotes', 'osmostress', 'resistance', 'in', 'Xanthomonas', 'campestris', '.'] [2, 1, 1, 1, 3, 1, 1, 2, 1, 1, 3, 1, 1, 3, 3, 1] ['O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Proteolytic cleavage of a C-terminal prosequence, leading to autoprocessing at the N terminus, activates leucine aminopeptidase from Pseudomonas aeruginosa. [('PMC7805185', 'F03002', 105, 127, 'leucine aminopeptidase')] ['Prote', '##olytic', 'cleavage', 'of', 'a', 'C', '-', 'terminal', 'pros', '##equ', '##ence', ',', 'leading', 'to', 'auto', '##processing', 'at', 'the', 'N', 'terminus', ',', 'activates', 'leucine', 'amino', '##pe', '##pt', '##idase', 'from', 'Pseudomonas', 'aeruginosa', '.'] [0, 5, 12, 21, 24, 26, 27, 28, 37, 41, 44, 48, 50, 58, 61, 65, 76, 79, 83, 85, 93, 95, 105, 113, 118, 120, 122, 128, 133, 145, 155] [5, 11, 20, 23, 25, 27, 28, 36, 41, 44, 48, 49, 57, 60, 65, 75, 78, 82, 84, 93, 94, 104, 112, 118, 120, 122, 127, 132, 144, 155, 156] ['Proteolytic', 'cleavage', 'of', 'a', 'C-', 'terminal', 'prosequence', ',', 'leading', 'to', 'autoprocessing', 'at', 'the', 'N', 'terminus', ',', 'activates', 'leucine', 'aminopeptidase', 'from', 'Pseudomonas', 'aeruginosa', '.'] [2, 1, 1, 1, 2, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O']
On the size of the active site in proteases. [('PMC7805185', 'F33002', 34, 43, 'proteases')] ['On', 'the', 'size', 'of', 'the', 'active', 'site', 'in', 'proteases', '.'] [0, 3, 7, 12, 15, 19, 26, 31, 34, 43] [2, 6, 11, 14, 18, 25, 30, 33, 43, 44] ['On', 'the', 'size', 'of', 'the', 'active', 'site', 'in', 'proteases', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O']
Jr The branched-chain amino acid aminotransferase encoded by ilvE is involved in acid tolerance in Streptococcus mutans. [('PMC7805185', 'F46002', 7, 49, 'branched-chain amino acid aminotransferase')] ['Jr', 'The', 'branched', '-', 'chain', 'amino', 'acid', 'amino', '##transferase', 'encoded', 'by', 'il', '##v', '##E', 'is', 'involved', 'in', 'acid', 'tolerance', 'in', 'Streptococcus', 'mut', '##ans', '.'] [0, 3, 7, 15, 16, 22, 28, 33, 38, 50, 58, 61, 63, 64, 66, 69, 78, 81, 86, 96, 99, 113, 116, 119] [2, 6, 15, 16, 21, 27, 32, 38, 49, 57, 60, 63, 64, 65, 68, 77, 80, 85, 95, 98, 112, 116, 119, 120] ['Jr', 'The', 'branched', '-', 'chain', 'amino', 'acid', 'aminotransferase', 'encoded', 'by', 'ilvE', 'is', 'involved', 'in', 'acid', 'tolerance', 'in', 'Streptococcus', 'mutans', '.'] [1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Steck N, Mueller K, Schemann M, Haller D. Bacterial proteases in IBD and IBS. [('PMC7805185', 'F50001', 42, 61, 'Bacterial proteases')] ['Ste', '##ck', 'N', ',', 'Mu', '##eller', 'K', ',', 'Schem', '##ann', 'M', ',', 'Hall', '##er', 'D', '.', 'Bacterial', 'proteases', 'in', 'IBD', 'and', 'IB', '##S', '.'] [0, 3, 6, 7, 9, 11, 17, 18, 20, 25, 29, 30, 32, 36, 39, 40, 42, 52, 62, 65, 69, 73, 75, 76] [3, 5, 7, 8, 11, 16, 18, 19, 25, 28, 30, 31, 36, 38, 40, 41, 51, 61, 64, 68, 72, 75, 76, 77] ['Steck', 'N', ',', 'Mueller', 'K', ',', 'Schemann', 'M', ',', 'Haller', 'D', '.', 'Bacterial', 'proteases', 'in', 'IBD', 'and', 'IBS', '.'] [2, 1, 1, 2, 1, 1, 2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O']
For instance, proteolytic cleavage of a C-terminal prosequence activates leucine aminopeptidase from Pseudomonas aeruginosa by inducing intramolecular autocatalytic removal of a propeptide at the N terminus [4]. [('PMC7805185', 'I00002', 73, 95, 'leucine aminopeptidase')] ['For', 'instance', ',', 'proteolytic', 'cleavage', 'of', 'a', 'C', '-', 'terminal', 'pros', '##equ', '##ence', 'activates', 'leucine', 'amino', '##pe', '##pt', '##idase', 'from', 'Pseudomonas', 'aeruginosa', 'by', 'inducing', 'intramolecular', 'auto', '##catal', '##ytic', 'removal', 'of', 'a', 'prop', '##eptide', 'at', 'the', 'N', 'terminus', '[', '4', ']', '.'] [0, 4, 12, 14, 26, 35, 38, 40, 41, 42, 51, 55, 58, 63, 73, 81, 86, 88, 90, 96, 101, 113, 124, 127, 136, 151, 155, 160, 165, 173, 176, 178, 182, 189, 192, 196, 198, 207, 208, 209, 210] [3, 12, 13, 25, 34, 37, 39, 41, 42, 50, 55, 58, 62, 72, 80, 86, 88, 90, 95, 100, 112, 123, 126, 135, 150, 155, 160, 164, 172, 175, 177, 182, 188, 191, 195, 197, 206, 208, 209, 210, 211] ['For', 'instance', ',', 'proteolytic', 'cleavage', 'of', 'a', 'C-', 'terminal', 'prosequence', 'activates', 'leucine', 'aminopeptidase', 'from', 'Pseudomonas', 'aeruginosa', 'by', 'inducing', 'intramolecular', 'autocatalytic', 'removal', 'of', 'a', 'propeptide', 'at', 'the', 'N', 'terminus', '[', '4', ']', '.'] [1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 4, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Proteases also play an important role in multidrug tolerance with proteolytic queues at ClpXP increasing antibiotic tolerance ∼80 and ∼60 fold in an Escherichia coli (E. coli) population treated with ampicillin and ciprofloxacin, respectively [5]. [('PMC7805185', 'I00004', 0, 9, 'Proteases')] ['Prote', '##ases', 'also', 'play', 'an', 'important', 'role', 'in', 'multi', '##drug', 'tolerance', 'with', 'proteolytic', 'queues', 'at', 'Cl', '##p', '##X', '##P', 'increasing', 'antibiotic', 'tolerance', '∼', '##80', 'and', '∼', '##60', 'fold', 'in', 'an', 'Escherichia', 'coli', '(', 'E', '.', 'coli', ')', 'population', 'treated', 'with', 'amp', '##icillin', 'and', 'ci', '##prof', '##lo', '##x', '##acin', ',', 'respectively', '[', '5', ']', '.'] [0, 5, 10, 15, 20, 23, 33, 38, 41, 46, 51, 61, 66, 78, 85, 88, 90, 91, 92, 94, 105, 116, 126, 127, 130, 134, 135, 138, 143, 146, 149, 161, 166, 167, 168, 170, 174, 176, 187, 195, 200, 203, 211, 215, 217, 221, 223, 224, 228, 230, 243, 244, 245, 246] [5, 9, 14, 19, 22, 32, 37, 40, 46, 50, 60, 65, 77, 84, 87, 90, 91, 92, 93, 104, 115, 125, 127, 129, 133, 135, 137, 142, 145, 148, 160, 165, 167, 168, 169, 174, 175, 186, 194, 199, 203, 210, 214, 217, 221, 223, 224, 228, 229, 242, 244, 245, 246, 247] ['Proteases', 'also', 'play', 'an', 'important', 'role', 'in', 'multidrug', 'tolerance', 'with', 'proteolytic', 'queues', 'at', 'ClpXP', 'increasing', 'antibiotic', 'tolerance', '∼80', 'and', '∼60', 'fold', 'in', 'an', 'Escherichia', 'coli', '(', 'E', '.', 'coli', ')', 'population', 'treated', 'with', 'ampicillin', 'and', 'ciprofloxacin', ',', 'respectively', '[', '5', ']', '.'] [2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 4, 1, 1, 1, 2, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 1, 1, 1] ['B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The higher percentage of extracellular proteins, which are more susceptible to the gut luminal and mucosal proteases, contributed to the higher proportion of semi-tryptic peptides for human proteins. [('PMC7805185', 'R04002', 83, 116, 'gut luminal and mucosal proteases')] ['The', 'higher', 'percentage', 'of', 'extracellular', 'proteins', ',', 'which', 'are', 'more', 'susceptible', 'to', 'the', 'gut', 'luminal', 'and', 'mucosal', 'proteases', ',', 'contributed', 'to', 'the', 'higher', 'proportion', 'of', 'semi', '-', 'tryp', '##tic', 'peptides', 'for', 'human', 'proteins', '.'] [0, 4, 11, 22, 25, 39, 47, 49, 55, 59, 64, 76, 79, 83, 87, 95, 99, 107, 116, 118, 130, 133, 137, 144, 155, 158, 162, 163, 167, 171, 180, 184, 190, 198] [3, 10, 21, 24, 38, 47, 48, 54, 58, 63, 75, 78, 82, 86, 94, 98, 106, 116, 117, 129, 132, 136, 143, 154, 157, 162, 163, 167, 170, 179, 183, 189, 198, 199] ['The', 'higher', 'percentage', 'of', 'extracellular', 'proteins', ',', 'which', 'are', 'more', 'susceptible', 'to', 'the', 'gut', 'luminal', 'and', 'mucosal', 'proteases', ',', 'contributed', 'to', 'the', 'higher', 'proportion', 'of', 'semi', '-', 'tryptic', 'peptides', 'for', 'human', 'proteins', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In addition, food proteins could be extensively hydrolyzed by gastric pepsin, pancreatic proteases, and small intestinal exopeptidases before they reach the large intestine (colon). [('PMC7805185', 'R05001', 78, 98, 'pancreatic proteases'), ('PMC7805185', 'R05001', 104, 134, 'small intestinal exopeptidases')] ['In', 'addition', ',', 'food', 'proteins', 'could', 'be', 'extensively', 'hydroly', '##zed', 'by', 'gastric', 'pe', '##ps', '##in', ',', 'pancreatic', 'proteases', ',', 'and', 'small', 'intestinal', 'ex', '##ope', '##pt', '##idase', '##s', 'before', 'they', 'reach', 'the', 'large', 'intestine', '(', 'colon', ')', '.'] [0, 3, 11, 13, 18, 27, 33, 36, 48, 55, 59, 62, 70, 72, 74, 76, 78, 89, 98, 100, 104, 110, 121, 123, 126, 128, 133, 135, 142, 147, 153, 157, 163, 173, 174, 179, 180] [2, 11, 12, 17, 26, 32, 35, 47, 55, 58, 61, 69, 72, 74, 76, 77, 88, 98, 99, 103, 109, 120, 123, 126, 128, 133, 134, 141, 146, 152, 156, 162, 172, 174, 179, 180, 181] ['In', 'addition', ',', 'food', 'proteins', 'could', 'be', 'extensively', 'hydrolyzed', 'by', 'gastric', 'pepsin', ',', 'pancreatic', 'proteases', ',', 'and', 'small', 'intestinal', 'exopeptidases', 'before', 'they', 'reach', 'the', 'large', 'intestine', '(', 'colon', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
At enzyme level, 3-hydroxybutyryl-CoA dehydrogenase, which is involved in butyrate metabolism, showed the highest NRASP (median value > 3), followed by 3-hydroxyacyl-CoA dehydrogenase involved in fatty acid beta-oxidation, glycine C-acetyltransferase involved in L-threonine degradation, phosphoenolpyruvate carboxykinase (ATP) involved in gluconeogenesis, ketol-acid reductoisomerase (NADP(+)) involved in the biosynthesis of branched-chain amino acids (BCAA), and superoxide dismutase involved in tolerance to oxidant stress (median NRASP of 2–3, Fig. Fig.22c). [('PMC7805185', 'R09000', 17, 51, '3-hydroxybutyryl-CoA dehydrogenase'), ('PMC7805185', 'R09000', 152, 183, '3-hydroxyacyl-CoA dehydrogenase'), ('PMC7805185', 'R09000', 223, 250, 'glycine C-acetyltransferase'), ('PMC7805185', 'R09000', 288, 327, 'phosphoenolpyruvate carboxykinase (ATP)'), ('PMC7805185', 'R09000', 357, 384, 'ketol-acid reductoisomerase')] ['At', 'enzyme', 'level', ',', '3', '-', 'hydroxy', '##but', '##yr', '##yl', '-', 'Co', '##A', 'dehydrogenase', ',', 'which', 'is', 'involved', 'in', 'but', '##yrate', 'metabolism', ',', 'showed', 'the', 'highest', 'NR', '##ASP', '(', 'median', 'value', '>', '3', ')', ',', 'followed', 'by', '3', '-', 'hydroxy', '##acyl', '-', 'Co', '##A', 'dehydrogenase', 'involved', 'in', 'fatty', 'acid', 'beta', '-', 'oxidation', ',', 'glycine', 'C', '-', 'acetyl', '##transferase', 'involved', 'in', 'L', '-', 'thre', '##onine', 'degradation', ',', 'phospho', '##eno', '##l', '##pyr', '##uvate', 'carb', '##oxy', '##kinase', '(', 'ATP', ')', 'involved', 'in', 'gluc', '##one', '##ogenesis', ',', 'ket', '##ol', '-', 'acid', 'reduc', '##to', '##iso', '##mer', '##ase', '(', 'NAD', '##P', '(', '+', ')', ')', 'involved', 'in', 'the', 'biosynthesis', 'of', 'branched', '-', 'chain', 'amino', 'acids', '(', 'BC', '##AA', ')', ',', 'and', 'superoxide', 'dismutase', 'involved', 'in', 'tolerance', 'to', 'oxid', '##ant', 'stress', '(', 'median', 'NR', '##ASP', 'of', '2', '–', '3', ',', 'Fig', '.', 'Fig', '.', '22', '##c', ')', '.'] [0, 3, 10, 15, 17, 18, 19, 26, 29, 31, 33, 34, 36, 38, 51, 53, 59, 62, 71, 74, 77, 83, 93, 95, 102, 106, 114, 116, 120, 121, 128, 134, 136, 137, 138, 140, 149, 152, 153, 154, 161, 165, 166, 168, 170, 184, 193, 196, 202, 207, 211, 212, 221, 223, 231, 232, 233, 239, 251, 260, 263, 264, 265, 269, 275, 286, 288, 295, 298, 299, 302, 308, 312, 315, 322, 323, 326, 328, 337, 340, 344, 347, 355, 357, 360, 362, 363, 368, 373, 375, 378, 381, 385, 386, 389, 390, 391, 392, 393, 395, 404, 407, 411, 424, 427, 435, 436, 442, 448, 454, 455, 457, 459, 460, 462, 466, 477, 487, 496, 499, 509, 512, 516, 520, 527, 528, 535, 537, 541, 544, 545, 546, 547, 549, 552, 555, 558, 559, 561, 562, 563] [2, 9, 15, 16, 18, 19, 26, 29, 31, 33, 34, 36, 37, 51, 52, 58, 61, 70, 73, 77, 82, 93, 94, 101, 105, 113, 116, 119, 121, 127, 133, 135, 137, 138, 139, 148, 151, 153, 154, 161, 165, 166, 168, 169, 183, 192, 195, 201, 206, 211, 212, 221, 222, 230, 232, 233, 239, 250, 259, 262, 264, 265, 269, 274, 286, 287, 295, 298, 299, 302, 307, 312, 315, 321, 323, 326, 327, 336, 339, 344, 347, 355, 356, 360, 362, 363, 367, 373, 375, 378, 381, 384, 386, 389, 390, 391, 392, 393, 394, 403, 406, 410, 423, 426, 435, 436, 441, 447, 453, 455, 457, 459, 460, 461, 465, 476, 486, 495, 498, 508, 511, 516, 519, 526, 528, 534, 537, 540, 543, 545, 546, 547, 548, 552, 553, 558, 559, 561, 562, 563, 564] ['At', 'enzyme', 'level', ',', '3-hydroxybutyryl-CoA', 'dehydrogenase', ',', 'which', 'is', 'involved', 'in', 'butyrate', 'metabolism', ',', 'showed', 'the', 'highest', 'NRASP', '(', 'median', 'value', '>', '3', ')', ',', 'followed', 'by', '3-hydroxyacyl-CoA', 'dehydrogenase', 'involved', 'in', 'fatty', 'acid', 'beta', '-', 'oxidation', ',', 'glycine', 'C-acetyltransferase', 'involved', 'in', 'L-threonine', 'degradation', ',', 'phosphoenolpyruvate', 'carboxykinase', '(', 'ATP', ')', 'involved', 'in', 'gluconeogenesis', ',', 'ketol', '-', 'acid', 'reductoisomerase', '(', 'NADP(', '+', ')', ')', 'involved', 'in', 'the', 'biosynthesis', 'of', 'branched', '-', 'chain', 'amino', 'acids', '(', 'BCAA', ')', ',', 'and', 'superoxide', 'dismutase', 'involved', 'in', 'tolerance', 'to', 'oxidant', 'stress', '(', 'median', 'NRASP', 'of', '2–', '3', ',', 'Fig', '.', '\u200bFig.22c', ')', '.'] [1, 1, 1, 1, 9, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 7, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 4, 1, 1, 5, 3, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 5, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 2, 1, 1, 1, 1, 4, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
To investigate the association with microbial proteases, we resorted to the transcriptional abundance of microbial protease/peptidase (Fig. (Fig.4b)4b) because protein-level abundance was inaccessible due to the limited sensitivity of current metaproteomics methodology. [('PMC7805185', 'R13004', 36, 55, 'microbial proteases'), ('PMC7805185', 'R13004', 105, 133, 'microbial protease/peptidase')] ['To', 'investigate', 'the', 'association', 'with', 'microbial', 'proteases', ',', 'we', 'res', '##orted', 'to', 'the', 'transcriptional', 'abundance', 'of', 'microbial', 'protease', '/', 'pepti', '##dase', '(', 'Fig', '.', '(', 'Fig', '.', '4', '##b', ')', '4', '##b', ')', 'because', 'protein', '-', 'level', 'abundance', 'was', 'inacc', '##ess', '##ible', 'due', 'to', 'the', 'limited', 'sensitivity', 'of', 'current', 'metap', '##rote', '##omics', 'methodology', '.'] [0, 3, 15, 19, 31, 36, 46, 55, 57, 60, 63, 69, 72, 76, 92, 102, 105, 115, 123, 124, 129, 134, 135, 138, 141, 142, 145, 146, 147, 148, 149, 150, 151, 153, 161, 168, 169, 175, 185, 189, 194, 197, 202, 206, 209, 213, 221, 233, 236, 244, 249, 253, 259, 270] [2, 14, 18, 30, 35, 45, 55, 56, 59, 63, 68, 71, 75, 91, 101, 104, 114, 123, 124, 129, 133, 135, 138, 139, 142, 145, 146, 147, 148, 149, 150, 151, 152, 160, 168, 169, 174, 184, 188, 194, 197, 201, 205, 208, 212, 220, 232, 235, 243, 249, 253, 258, 270, 271] ['To', 'investigate', 'the', 'association', 'with', 'microbial', 'proteases', ',', 'we', 'resorted', 'to', 'the', 'transcriptional', 'abundance', 'of', 'microbial', 'protease', '/', 'peptidase', '(', 'Fig', '.', '\u200b(Fig.4b)4b', ')', 'because', 'protein', '-', 'level', 'abundance', 'was', 'inaccessible', 'due', 'to', 'the', 'limited', 'sensitivity', 'of', 'current', 'metaproteomics', 'methodology', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 8, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
The microbial protease/peptidase transcriptome at feature (PCo3), species (PCo1), genus (PCo2), and family (PCo2) levels showed moderate correlations with semi-tryptic peptide LFQ intensity (PCo1), stronger than those of β-diversity (Fig. (Fig.4d,4d, − 0.55 < [('PMC7805185', 'R13005', 4, 32, 'microbial protease/peptidase')] ['The', 'microbial', 'protease', '/', 'pepti', '##dase', 'transcriptome', 'at', 'feature', '(', 'PC', '##o', '##3', ')', ',', 'species', '(', 'PC', '##o', '##1', ')', ',', 'genus', '(', 'PC', '##o', '##2', ')', ',', 'and', 'family', '(', 'PC', '##o', '##2', ')', 'levels', 'showed', 'moderate', 'correlations', 'with', 'semi', '-', 'tryp', '##tic', 'peptide', 'LF', '##Q', 'intensity', '(', 'PC', '##o', '##1', ')', ',', 'stronger', 'than', 'those', 'of', 'β', '-', 'diversity', '(', 'Fig', '.', '(', 'Fig', '.', '4', '##d', ',', '4', '##d', ',', '−', '0', '.', '55', '<'] [0, 4, 14, 22, 23, 28, 33, 47, 50, 58, 59, 61, 62, 63, 64, 66, 74, 75, 77, 78, 79, 80, 82, 88, 89, 91, 92, 93, 94, 96, 100, 107, 108, 110, 111, 112, 114, 121, 128, 137, 150, 155, 159, 160, 164, 168, 176, 178, 180, 190, 191, 193, 194, 195, 196, 198, 207, 212, 218, 221, 222, 223, 233, 234, 237, 240, 241, 244, 245, 246, 247, 248, 249, 250, 252, 254, 255, 256, 259] [3, 13, 22, 23, 28, 32, 46, 49, 57, 59, 61, 62, 63, 64, 65, 73, 75, 77, 78, 79, 80, 81, 87, 89, 91, 92, 93, 94, 95, 99, 106, 108, 110, 111, 112, 113, 120, 127, 136, 149, 154, 159, 160, 164, 167, 175, 178, 179, 189, 191, 193, 194, 195, 196, 197, 206, 211, 217, 220, 222, 223, 232, 234, 237, 238, 241, 244, 245, 246, 247, 248, 249, 250, 251, 253, 255, 256, 258, 260] ['The', 'microbial', 'protease', '/', 'peptidase', 'transcriptome', 'at', 'feature', '(', 'PCo3', ')', ',', 'species', '(', 'PCo1', ')', ',', 'genus', '(', 'PCo2', ')', ',', 'and', 'family', '(', 'PCo2', ')', 'levels', 'showed', 'moderate', 'correlations', 'with', 'semi', '-', 'tryptic', 'peptide', 'LFQ', 'intensity', '(', 'PCo1', ')', ',', 'stronger', 'than', 'those', 'of', 'β-diversity', '(', 'Fig', '.', '\u200b(Fig.4d,4d', ',', '−', '0.55', '<'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 2, 1, 1, 3, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 8, 1, 1, 3, 1] ['O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In regulating cellular processes, chaperones and proteases both respond to protein misfolding and play important roles in protein homeostasis. [('PMC7805185', 'R13008', 49, 58, 'proteases')] ['In', 'regulating', 'cellular', 'processes', ',', 'chaperone', '##s', 'and', 'proteases', 'both', 'respond', 'to', 'protein', 'mis', '##fold', '##ing', 'and', 'play', 'important', 'roles', 'in', 'protein', 'homeostasis', '.'] [0, 3, 14, 23, 32, 34, 43, 45, 49, 59, 64, 72, 75, 83, 86, 90, 94, 98, 103, 113, 119, 122, 130, 141] [2, 13, 22, 32, 33, 43, 44, 48, 58, 63, 71, 74, 82, 86, 90, 93, 97, 102, 112, 118, 121, 129, 141, 142] ['In', 'regulating', 'cellular', 'processes', ',', 'chaperones', 'and', 'proteases', 'both', 'respond', 'to', 'protein', 'misfolding', 'and', 'play', 'important', 'roles', 'in', 'protein', 'homeostasis', '.'] [1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'S', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Four out of 32 major enzyme sub-classes exhibited inter-group difference (Additional file 1: Table S19): superoxide dismutase in UC, protein-synthesizing GTPase in CD, and short-chain acyl-CoA dehydrogenase in both CD and UC have increased NRASP compared with the control group (Fig. (Fig.55c). [('PMC7805185', 'R15004', 133, 160, 'protein-synthesizing GTPase'), ('PMC7805185', 'R15004', 172, 206, 'short-chain acyl-CoA dehydrogenase')] ['Four', 'out', 'of', '32', 'major', 'enzyme', 'sub', '-', 'classes', 'exhibited', 'inter', '-', 'group', 'difference', '(', 'Additional', 'file', '1', ':', 'Table', 'S', '##19', ')', ':', 'superoxide', 'dismutase', 'in', 'UC', ',', 'protein', '-', 'synthe', '##sizing', 'GTP', '##ase', 'in', 'CD', ',', 'and', 'short', '-', 'chain', 'acyl', '-', 'Co', '##A', 'dehydrogenase', 'in', 'both', 'CD', 'and', 'UC', 'have', 'increased', 'NR', '##ASP', 'compared', 'with', 'the', 'control', 'group', '(', 'Fig', '.', '(', 'Fig', '.', '55', '##c', ')', '.'] [0, 5, 9, 12, 15, 21, 28, 31, 32, 40, 50, 55, 56, 62, 73, 74, 85, 90, 91, 93, 99, 100, 102, 103, 105, 116, 126, 129, 131, 133, 140, 141, 147, 154, 157, 161, 164, 166, 168, 172, 177, 178, 184, 188, 189, 191, 193, 207, 210, 215, 218, 222, 225, 230, 240, 242, 246, 255, 260, 264, 272, 278, 279, 282, 285, 286, 289, 290, 292, 293, 294] [4, 8, 11, 14, 20, 27, 31, 32, 39, 49, 55, 56, 61, 72, 74, 84, 89, 91, 92, 98, 100, 102, 103, 104, 115, 125, 128, 131, 132, 140, 141, 147, 153, 157, 160, 163, 166, 167, 171, 177, 178, 183, 188, 189, 191, 192, 206, 209, 214, 217, 221, 224, 229, 239, 242, 245, 254, 259, 263, 271, 277, 279, 282, 283, 286, 289, 290, 292, 293, 294, 295] ['Four', 'out', 'of', '32', 'major', 'enzyme', 'sub', '-', 'classes', 'exhibited', 'inter', '-', 'group', 'difference', '(', 'Additional', 'file', '1', ':', 'Table', 'S19', ')', ':', 'superoxide', 'dismutase', 'in', 'UC', ',', 'protein', '-', 'synthesizing', 'GTPase', 'in', 'CD', ',', 'and', 'short', '-', 'chain', 'acyl-CoA', 'dehydrogenase', 'in', 'both', 'CD', 'and', 'UC', 'have', 'increased', 'NRASP', 'compared', 'with', 'the', 'control', 'group', '(', 'Fig', '.', '\u200b(Fig.55c)', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 6, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
NRASP of superoxide dismutase significantly increased in UC (Fig. (Fig.5c),5c), but the relative abundance of this enzyme did not differ between groups (Additional file 1: Fig. S1c). [('PMC7805185', 'R16009', 9, 29, 'superoxide dismutase')] ['NR', '##ASP', 'of', 'superoxide', 'dismutase', 'significantly', 'increased', 'in', 'UC', '(', 'Fig', '.', '(', 'Fig', '.', '5', '##c', ')', ',', '5', '##c', ')', ',', 'but', 'the', 'relative', 'abundance', 'of', 'this', 'enzyme', 'did', 'not', 'differ', 'between', 'groups', '(', 'Additional', 'file', '1', ':', 'Fig', '.', 'S', '##1', '##c', ')', '.'] [0, 2, 6, 9, 20, 30, 44, 54, 57, 60, 61, 64, 67, 68, 71, 72, 73, 74, 75, 76, 77, 78, 79, 81, 85, 89, 98, 108, 111, 116, 123, 127, 131, 138, 146, 153, 154, 165, 170, 171, 173, 176, 178, 179, 180, 181, 182] [2, 5, 8, 19, 29, 43, 53, 56, 59, 61, 64, 65, 68, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 84, 88, 97, 107, 110, 115, 122, 126, 130, 137, 145, 152, 154, 164, 169, 171, 172, 176, 177, 179, 180, 181, 182, 183] ['NRASP', 'of', 'superoxide', 'dismutase', 'significantly', 'increased', 'in', 'UC', '(', 'Fig', '.', '\u200b(Fig.5c),5c', ')', ',', 'but', 'the', 'relative', 'abundance', 'of', 'this', 'enzyme', 'did', 'not', 'differ', 'between', 'groups', '(', 'Additional', 'file', '1', ':', 'Fig', '.', 'S1c', ')', '.'] [2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 9, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
We also observed that some taxonomic and functional alterations were identified by both NRASP and full-tryptic peptide-based comparison, such as taxonomic groups of family Ruminococcaceae and species Prevotella copri, biological processes of bacterial-type flagellum-dependent cell motility and polysaccharide catabolic process, as well as enzyme short-chain acyl-CoA dehydrogenase (Fig. (Fig.5a–c5a–c and Additional file 1: Fig. S1). [('PMC7805185', 'R16010', 347, 381, 'short-chain acyl-CoA dehydrogenase')] ['We', 'also', 'observed', 'that', 'some', 'taxonomic', 'and', 'functional', 'alterations', 'were', 'identified', 'by', 'both', 'NR', '##ASP', 'and', 'full', '-', 'tryp', '##tic', 'peptide', '-', 'based', 'comparison', ',', 'such', 'as', 'taxonomic', 'groups', 'of', 'family', 'Ru', '##min', '##ococc', '##aceae', 'and', 'species', 'Prev', '##ote', '##lla', 'cop', '##ri', ',', 'biological', 'processes', 'of', 'bacterial', '-', 'type', 'flag', '##ellum', '-', 'dependent', 'cell', 'motility', 'and', 'polysaccharide', 'cat', '##abolic', 'process', ',', 'as', 'well', 'as', 'enzyme', 'short', '-', 'chain', 'acyl', '-', 'Co', '##A', 'dehydrogenase', '(', 'Fig', '.', '(', 'Fig', '.', '5', '##a', '–', 'c', '##5', '##a', '–', 'c', 'and', 'Additional', 'file', '1', ':', 'Fig', '.', 'S', '##1', ')', '.'] [0, 3, 8, 17, 22, 27, 37, 41, 52, 64, 69, 80, 83, 88, 90, 94, 98, 102, 103, 107, 111, 118, 119, 125, 135, 137, 142, 145, 155, 162, 165, 172, 174, 177, 182, 188, 192, 200, 204, 207, 211, 214, 216, 218, 229, 239, 242, 251, 252, 257, 261, 266, 267, 277, 282, 291, 295, 310, 313, 320, 327, 329, 332, 337, 340, 347, 352, 353, 359, 363, 364, 366, 368, 382, 383, 386, 389, 390, 393, 394, 395, 396, 397, 398, 399, 400, 401, 403, 407, 418, 423, 424, 426, 429, 431, 432, 433, 434] [2, 7, 16, 21, 26, 36, 40, 51, 63, 68, 79, 82, 87, 90, 93, 97, 102, 103, 107, 110, 118, 119, 124, 135, 136, 141, 144, 154, 161, 164, 171, 174, 177, 182, 187, 191, 199, 204, 207, 210, 214, 216, 217, 228, 238, 241, 251, 252, 256, 261, 266, 267, 276, 281, 290, 294, 309, 313, 319, 327, 328, 331, 336, 339, 346, 352, 353, 358, 363, 364, 366, 367, 381, 383, 386, 387, 390, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 406, 417, 422, 424, 425, 429, 430, 432, 433, 434, 435] ['We', 'also', 'observed', 'that', 'some', 'taxonomic', 'and', 'functional', 'alterations', 'were', 'identified', 'by', 'both', 'NRASP', 'and', 'full', '-', 'tryptic', 'peptide', '-', 'based', 'comparison', ',', 'such', 'as', 'taxonomic', 'groups', 'of', 'family', 'Ruminococcaceae', 'and', 'species', 'Prevotella', 'copri', ',', 'biological', 'processes', 'of', 'bacterial', '-', 'type', 'flagellum', '-', 'dependent', 'cell', 'motility', 'and', 'polysaccharide', 'catabolic', 'process', ',', 'as', 'well', 'as', 'enzyme', 'short', '-', 'chain', 'acyl-CoA', 'dehydrogenase', '(', 'Fig', '.', '\u200b(Fig.5a', '–', 'c5a', '–', 'c', 'and', 'Additional', 'file', '1', ':', 'Fig', '.', 'S1', ')', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 5, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Liver enzymes, especially Alanine Aminotransferase and Aspartate Aminotransferase, are the first laboratory tests every clinician will consider worth evaluating in a patient with liver diseases. [('PMC8050915', 'D02000', 26, 50, 'Alanine Aminotransferase'), ('PMC8050915', 'D02000', 55, 81, 'Aspartate Aminotransferase')] ['Liver', 'enzymes', ',', 'especially', 'Ala', '##nine', 'Amin', '##otransferase', 'and', 'Asp', '##art', '##ate', 'Amin', '##otransferase', ',', 'are', 'the', 'first', 'laboratory', 'tests', 'every', 'clinician', 'will', 'consider', 'worth', 'evaluating', 'in', 'a', 'patient', 'with', 'liver', 'diseases', '.'] [0, 6, 13, 15, 26, 29, 34, 38, 51, 55, 58, 61, 65, 69, 81, 83, 87, 91, 97, 108, 114, 120, 130, 135, 144, 150, 161, 164, 166, 174, 179, 185, 193] [5, 13, 14, 25, 29, 33, 38, 50, 54, 58, 61, 64, 69, 81, 82, 86, 90, 96, 107, 113, 119, 129, 134, 143, 149, 160, 163, 165, 173, 178, 184, 193, 194] ['Liver', 'enzymes', ',', 'especially', 'Alanine', 'Aminotransferase', 'and', 'Aspartate', 'Aminotransferase', ',', 'are', 'the', 'first', 'laboratory', 'tests', 'every', 'clinician', 'will', 'consider', 'worth', 'evaluating', 'in', 'a', 'patient', 'with', 'liver', 'diseases', '.'] [1, 1, 1, 1, 2, 2, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Higher concentrations of alanine aminotransferase within the reference interval predict nonalcoholic fatty liver disease. [('PMC8050915', 'F45002', 25, 49, 'alanine aminotransferase')] ['Higher', 'concentrations', 'of', 'alanine', 'amino', '##transferase', 'within', 'the', 'reference', 'interval', 'predict', 'non', '##alc', '##oh', '##olic', 'fatty', 'liver', 'disease', '.'] [0, 7, 22, 25, 33, 38, 50, 57, 61, 71, 80, 88, 91, 94, 96, 101, 107, 113, 120] [6, 21, 24, 32, 38, 49, 56, 60, 70, 79, 87, 91, 94, 96, 100, 106, 112, 120, 121] ['Higher', 'concentrations', 'of', 'alanine', 'aminotransferase', 'within', 'the', 'reference', 'interval', 'predict', 'nonalcoholic', 'fatty', 'liver', 'disease', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1] ['O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Alanine aminotransferase (Alanine Aminotransferase) and aspartate aminotransferase (Aspartate Aminotransferase) are the most common blood indicators; however, such liver enzymes may not elevate until histological injury of the liver occurs [14]. [('PMC8050915', 'I01005', 0, 24, 'Alanine aminotransferase'), ('PMC8050915', 'I01005', 26, 50, 'Alanine Aminotransferase'), ('PMC8050915', 'I01005', 56, 82, 'aspartate aminotransferase'), ('PMC8050915', 'I01005', 84, 110, 'Aspartate Aminotransferase')] ['Ala', '##nine', 'amino', '##transferase', '(', 'Ala', '##nine', 'Amin', '##otransferase', ')', 'and', 'aspart', '##ate', 'amino', '##transferase', '(', 'Asp', '##art', '##ate', 'Amin', '##otransferase', ')', 'are', 'the', 'most', 'common', 'blood', 'indicators', ';', 'however', ',', 'such', 'liver', 'enzymes', 'may', 'not', 'elev', '##ate', 'until', 'histological', 'injury', 'of', 'the', 'liver', 'occurs', '[', '14', ']', '.'] [0, 3, 8, 13, 25, 26, 29, 34, 38, 50, 52, 56, 62, 66, 71, 83, 84, 87, 90, 94, 98, 110, 112, 116, 120, 125, 132, 138, 148, 150, 157, 159, 164, 170, 178, 182, 186, 190, 194, 200, 213, 220, 223, 227, 233, 240, 241, 243, 244] [3, 7, 13, 24, 26, 29, 33, 38, 50, 51, 55, 62, 65, 71, 82, 84, 87, 90, 93, 98, 110, 111, 115, 119, 124, 131, 137, 148, 149, 157, 158, 163, 169, 177, 181, 185, 190, 193, 199, 212, 219, 222, 226, 232, 239, 241, 243, 244, 245] ['Alanine', 'aminotransferase', '(', 'Alanine', 'Aminotransferase', ')', 'and', 'aspartate', 'aminotransferase', '(', 'Aspartate', 'Aminotransferase', ')', 'are', 'the', 'most', 'common', 'blood', 'indicators', ';', 'however', ',', 'such', 'liver', 'enzymes', 'may', 'not', 'elevate', 'until', 'histological', 'injury', 'of', 'the', 'liver', 'occurs', '[', '14', ']', '.'] [2, 2, 1, 2, 2, 1, 1, 2, 2, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'E', 'O', 'O', 'B', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
A number of patients with normal Alanine Aminotransferase levels may also have NAFLD and even advanced fibrosis. [('PMC8050915', 'I01006', 33, 57, 'Alanine Aminotransferase')] ['A', 'number', 'of', 'patients', 'with', 'normal', 'Ala', '##nine', 'Amin', '##otransferase', 'levels', 'may', 'also', 'have', 'NA', '##FLD', 'and', 'even', 'advanced', 'fibrosis', '.'] [0, 2, 9, 12, 21, 26, 33, 36, 41, 45, 58, 65, 69, 74, 79, 81, 85, 89, 94, 103, 111] [1, 8, 11, 20, 25, 32, 36, 40, 45, 57, 64, 68, 73, 78, 81, 84, 88, 93, 102, 111, 112] ['A', 'number', 'of', 'patients', 'with', 'normal', 'Alanine', 'Aminotransferase', 'levels', 'may', 'also', 'have', 'NAFLD', 'and', 'even', 'advanced', 'fibrosis', '.'] [1, 1, 1, 1, 1, 1, 2, 2, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Measurements of blood glucose, Alanine Aminotransferase, Aspartate Aminotransferase, TB, DB, TP, ALB, Che, ALP, γ—GT, TG, TC, HDL-C, LDL-C and other serum indicators were performed on an automated chemistry analyzer (Hitachi 7600d-210, Japan). [('PMC8050915', 'M07001', 31, 55, 'Alanine Aminotransferase'), ('PMC8050915', 'M07001', 57, 83, 'Aspartate Aminotransferase')] ['Measurements', 'of', 'blood', 'glucose', ',', 'Ala', '##nine', 'Amin', '##otransferase', ',', 'Asp', '##art', '##ate', 'Amin', '##otransferase', ',', 'TB', ',', 'DB', ',', 'TP', ',', 'AL', '##B', ',', 'Che', ',', 'ALP', ',', 'γ', '—', 'GT', ',', 'TG', ',', 'TC', ',', 'HDL', '-', 'C', ',', 'LDL', '-', 'C', 'and', 'other', 'serum', 'indicators', 'were', 'performed', 'on', 'an', 'automated', 'chemistry', 'analyzer', '(', 'Hi', '##ta', '##chi', '76', '##00', '##d', '-', '210', ',', 'Japan', ')', '.'] [0, 13, 16, 22, 29, 31, 34, 39, 43, 55, 57, 60, 63, 67, 71, 83, 85, 87, 89, 91, 93, 95, 97, 99, 100, 102, 105, 107, 110, 112, 113, 114, 116, 118, 120, 122, 124, 126, 129, 130, 131, 133, 136, 137, 139, 143, 149, 155, 166, 171, 181, 184, 187, 197, 207, 216, 217, 219, 221, 225, 227, 229, 230, 231, 234, 236, 241, 242] [12, 15, 21, 29, 30, 34, 38, 43, 55, 56, 60, 63, 66, 71, 83, 84, 87, 88, 91, 92, 95, 96, 99, 100, 101, 105, 106, 110, 111, 113, 114, 116, 117, 120, 121, 124, 125, 129, 130, 131, 132, 136, 137, 138, 142, 148, 154, 165, 170, 180, 183, 186, 196, 206, 215, 217, 219, 221, 224, 227, 229, 230, 231, 234, 235, 241, 242, 243] ['Measurements', 'of', 'blood', 'glucose', ',', 'Alanine', 'Aminotransferase', ',', 'Aspartate', 'Aminotransferase', ',', 'TB', ',', 'DB', ',', 'TP', ',', 'ALB', ',', 'Che', ',', 'ALP', ',', 'γ—', 'GT', ',', 'TG', ',', 'TC', ',', 'HDL-C', ',', 'LDL-C', 'and', 'other', 'serum', 'indicators', 'were', 'performed', 'on', 'an', 'automated', 'chemistry', 'analyzer', '(', 'Hitachi', '7600d-210', ',', 'Japan', ')', '.'] [1, 1, 1, 1, 1, 2, 2, 1, 3, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 5, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
From Table Table1,1, we found that there was no remarkable difference in biochemical indexes (including TBA, CHE, TB, DB, TP, ALB, γ-Glutamyltransferase, ALP, Aspartate Aminotransferase, ALT and GLU) between the NAFLD group and the control group (p > 0.05). [('PMC8050915', 'R01000', 132, 153, 'γ-Glutamyltransferase'), ('PMC8050915', 'R01000', 160, 186, 'Aspartate Aminotransferase')] ['From', 'Table', 'Table', '##1', ',', '1', ',', 'we', 'found', 'that', 'there', 'was', 'no', 'remarkable', 'difference', 'in', 'biochemical', 'indexes', '(', 'including', 'TB', '##A', ',', 'CH', '##E', ',', 'TB', ',', 'DB', ',', 'TP', ',', 'AL', '##B', ',', 'γ', '-', 'Glut', '##amyl', '##transferase', ',', 'ALP', ',', 'Asp', '##art', '##ate', 'Amin', '##otransferase', ',', 'ALT', 'and', 'GL', '##U', ')', 'between', 'the', 'NA', '##FLD', 'group', 'and', 'the', 'control', 'group', '(', 'p', '>', '0', '.', '05', ')', '.'] [0, 5, 12, 17, 18, 19, 20, 22, 25, 31, 36, 42, 46, 49, 60, 71, 74, 86, 94, 95, 105, 107, 108, 110, 112, 113, 115, 117, 119, 121, 123, 125, 127, 129, 130, 132, 133, 134, 138, 142, 153, 155, 158, 160, 163, 166, 170, 174, 186, 188, 192, 196, 198, 199, 201, 209, 213, 215, 219, 225, 229, 233, 241, 247, 248, 250, 252, 253, 254, 256, 257] [4, 10, 17, 18, 19, 20, 21, 24, 30, 35, 41, 45, 48, 59, 70, 73, 85, 93, 95, 104, 107, 108, 109, 112, 113, 114, 117, 118, 121, 122, 125, 126, 129, 130, 131, 133, 134, 138, 142, 153, 154, 158, 159, 163, 166, 169, 174, 186, 187, 191, 195, 198, 199, 200, 208, 212, 215, 218, 224, 228, 232, 240, 246, 248, 249, 251, 253, 254, 256, 257, 258] ['From', 'Table', '\u200bTable1', ',', '1', ',', 'we', 'found', 'that', 'there', 'was', 'no', 'remarkable', 'difference', 'in', 'biochemical', 'indexes', '(', 'including', 'TBA', ',', 'CHE', ',', 'TB', ',', 'DB', ',', 'TP', ',', 'ALB', ',', 'γ-Glutamyltransferase', ',', 'ALP', ',', 'Aspartate', 'Aminotransferase', ',', 'ALT', 'and', 'GLU', ')', 'between', 'the', 'NAFLD', 'group', 'and', 'the', 'control', 'group', '(', 'p', '>', '0.05', ')', '.'] [1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 5, 1, 1, 1, 3, 2, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Insulin resistance in PCOS patients enhances oxidative stress and leukocyte adhesion: role of myeloperoxidase. [('PMC8168315', 'F36002', 94, 109, 'myeloperoxidase')] ['Insulin', 'resistance', 'in', 'PC', '##OS', 'patients', 'enhances', 'oxidative', 'stress', 'and', 'leukocyte', 'adhesion', ':', 'role', 'of', 'myel', '##oper', '##oxidase', '.'] [0, 8, 19, 22, 24, 27, 36, 45, 55, 62, 66, 76, 84, 86, 91, 94, 98, 102, 109] [7, 18, 21, 24, 26, 35, 44, 54, 61, 65, 75, 84, 85, 90, 93, 98, 102, 109, 110] ['Insulin', 'resistance', 'in', 'PCOS', 'patients', 'enhances', 'oxidative', 'stress', 'and', 'leukocyte', 'adhesion', ':', 'role', 'of', 'myeloperoxidase', '.'] [1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O']
Moreover, the candidate genes and locus of the studied serum (vitamin D-binding protein, lipocalin-type prostaglandin D2 synthase, apolipoprotein E, etc.) and urine proteomic biomarkers (uromodulin, alpha-1-microglobulin, zinc-alpha-2-glycoprotein, etc.) of MOH are presented in this review. [('PMC8396559', 'A00006', 89, 129, 'lipocalin-type prostaglandin D2 synthase')] ['Moreover', ',', 'the', 'candidate', 'genes', 'and', 'locus', 'of', 'the', 'studied', 'serum', '(', 'vitamin', 'D', '-', 'binding', 'protein', ',', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', ',', 'apo', '##lip', '##oprotein', 'E', ',', 'etc', '.', ')', 'and', 'urine', 'proteomic', 'biomarkers', '(', 'uro', '##mod', '##ulin', ',', 'alpha', '-', '1', '-', 'microgl', '##ob', '##ulin', ',', 'zinc', '-', 'alpha', '-', '2', '-', 'glycoprotein', ',', 'etc', '.', ')', 'of', 'MO', '##H', 'are', 'presented', 'in', 'this', 'review', '.'] [0, 8, 10, 14, 24, 30, 34, 40, 43, 47, 55, 61, 62, 70, 71, 72, 80, 87, 89, 92, 96, 98, 99, 104, 118, 119, 121, 129, 131, 134, 137, 146, 147, 149, 152, 153, 155, 159, 165, 175, 186, 187, 190, 193, 197, 199, 204, 205, 206, 207, 214, 216, 220, 222, 226, 227, 232, 233, 234, 235, 247, 249, 252, 253, 255, 258, 260, 262, 266, 276, 279, 284, 290] [8, 9, 13, 23, 29, 33, 39, 42, 46, 54, 60, 62, 69, 71, 72, 79, 87, 88, 92, 96, 98, 99, 103, 117, 119, 120, 129, 130, 134, 137, 145, 147, 148, 152, 153, 154, 158, 164, 174, 185, 187, 190, 193, 197, 198, 204, 205, 206, 207, 214, 216, 220, 221, 226, 227, 232, 233, 234, 235, 247, 248, 252, 253, 254, 257, 260, 261, 265, 275, 278, 283, 290, 291] ['Moreover', ',', 'the', 'candidate', 'genes', 'and', 'locus', 'of', 'the', 'studied', 'serum', '(', 'vitamin', 'D-', 'binding', 'protein', ',', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', ',', 'apolipoprotein', 'E', ',', 'etc', '.', ')', 'and', 'urine', 'proteomic', 'biomarkers', '(', 'uromodulin', ',', 'alpha-1-microglobulin', ',', 'zinc-alpha-2-glycoprotein', ',', 'etc', '.', ')', 'of', 'MOH', 'are', 'presented', 'in', 'this', 'review', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 7, 1, 7, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Thus, lipocalin-type prostaglandin D2 synthase (lipocalin-type prostaglandin D2 synthase) is both a serum and urine proteomic biomarker. [('PMC8396559', 'D02001', 6, 46, 'lipocalin-type prostaglandin D2 synthase'), ('PMC8396559', 'D02001', 48, 88, 'lipocalin-type prostaglandin D2 synthase')] ['Thus', ',', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', '(', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', ')', 'is', 'both', 'a', 'serum', 'and', 'urine', 'proteomic', 'biomarker', '.'] [0, 4, 6, 9, 13, 15, 16, 21, 35, 36, 38, 47, 48, 51, 55, 57, 58, 63, 77, 78, 80, 88, 90, 93, 98, 100, 106, 110, 116, 126, 135] [4, 5, 9, 13, 15, 16, 20, 34, 36, 37, 46, 48, 51, 55, 57, 58, 62, 76, 78, 79, 88, 89, 92, 97, 99, 105, 109, 115, 125, 135, 136] ['Thus', ',', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', '(', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', ')', 'is', 'both', 'a', 'serum', 'and', 'urine', 'proteomic', 'biomarker', '.'] [1, 1, 3, 1, 1, 1, 2, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
lipocalin-type prostaglandin D2 synthase is expressed in various tissues, such as the brain, retina, cochlea, and male reproductive organs, and it is found in different biological fluids, such as cerebrospinal fluid (CSF), ascites, seminal plasma, serum, urine, and amniotic fluid. [('PMC8396559', 'D02004', 0, 40, 'lipocalin-type prostaglandin D2 synthase')] ['lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', 'is', 'expressed', 'in', 'various', 'tissues', ',', 'such', 'as', 'the', 'brain', ',', 'retina', ',', 'coch', '##le', '##a', ',', 'and', 'male', 'reproductive', 'organs', ',', 'and', 'it', 'is', 'found', 'in', 'different', 'biological', 'fluids', ',', 'such', 'as', 'cerebrospinal', 'fluid', '(', 'CSF', ')', ',', 'ascites', ',', 'seminal', 'plasma', ',', 'serum', ',', 'urine', ',', 'and', 'am', '##ni', '##otic', 'fluid', '.'] [0, 3, 7, 9, 10, 15, 29, 30, 32, 41, 44, 54, 57, 65, 72, 74, 79, 82, 86, 91, 93, 99, 101, 105, 107, 108, 110, 114, 119, 132, 138, 140, 144, 147, 150, 156, 159, 169, 180, 186, 188, 193, 196, 210, 216, 217, 220, 221, 223, 230, 232, 240, 246, 248, 253, 255, 260, 262, 266, 268, 270, 275, 280] [3, 7, 9, 10, 14, 28, 30, 31, 40, 43, 53, 56, 64, 72, 73, 78, 81, 85, 91, 92, 99, 100, 105, 107, 108, 109, 113, 118, 131, 138, 139, 143, 146, 149, 155, 158, 168, 179, 186, 187, 192, 195, 209, 215, 217, 220, 221, 222, 230, 231, 239, 246, 247, 253, 254, 260, 261, 265, 268, 270, 274, 280, 281] ['lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', 'is', 'expressed', 'in', 'various', 'tissues', ',', 'such', 'as', 'the', 'brain', ',', 'retina', ',', 'cochlea', ',', 'and', 'male', 'reproductive', 'organs', ',', 'and', 'it', 'is', 'found', 'in', 'different', 'biological', 'fluids', ',', 'such', 'as', 'cerebrospinal', 'fluid', '(', 'CSF', ')', ',', 'ascites', ',', 'seminal', 'plasma', ',', 'serum', ',', 'urine', ',', 'and', 'amniotic', 'fluid', '.'] [3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1] ['B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Alongside hematopoietic-type PGDS (H-PGDS), lipocalin-type prostaglandin D2 synthase is related to a group of prostaglandin D synthases (PGDS) responsible for converting PGH2 to PGD2 [57], which is involved in a variety of central nervous system (CNS) functions, such as sedation, nonrapid eye movement (NREM) sleep and PGD2-allodynia. [('PMC8396559', 'D02005', 44, 84, 'lipocalin-type prostaglandin D2 synthase'), ('PMC8396559', 'D02005', 110, 135, 'prostaglandin D synthases')] ['Along', '##side', 'hematopoietic', '-', 'type', 'PG', '##DS', '(', 'H', '-', 'PG', '##DS', ')', ',', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', 'is', 'related', 'to', 'a', 'group', 'of', 'prostaglandin', 'D', 'synthase', '##s', '(', 'PG', '##DS', ')', 'responsible', 'for', 'converting', 'PG', '##H', '##2', 'to', 'PG', '##D', '##2', '[', '57', ']', ',', 'which', 'is', 'involved', 'in', 'a', 'variety', 'of', 'central', 'nervous', 'system', '(', 'CNS', ')', 'functions', ',', 'such', 'as', 'sedation', ',', 'non', '##rap', '##id', 'eye', 'movement', '(', 'NR', '##EM', ')', 'sleep', 'and', 'PG', '##D', '##2', '-', 'allo', '##dy', '##nia', '.'] [0, 5, 10, 23, 24, 29, 31, 34, 35, 36, 37, 39, 41, 42, 44, 47, 51, 53, 54, 59, 73, 74, 76, 85, 88, 96, 99, 101, 107, 110, 124, 126, 134, 136, 137, 139, 141, 143, 155, 159, 170, 172, 173, 175, 178, 180, 181, 183, 184, 186, 187, 189, 195, 198, 207, 210, 212, 220, 223, 231, 239, 246, 247, 250, 252, 261, 263, 268, 271, 279, 281, 284, 287, 290, 294, 303, 304, 306, 308, 310, 316, 320, 322, 323, 324, 325, 329, 331, 334] [5, 9, 23, 24, 28, 31, 33, 35, 36, 37, 39, 41, 42, 43, 47, 51, 53, 54, 58, 72, 74, 75, 84, 87, 95, 98, 100, 106, 109, 123, 125, 134, 135, 137, 139, 141, 142, 154, 158, 169, 172, 173, 174, 177, 180, 181, 182, 184, 186, 187, 188, 194, 197, 206, 209, 211, 219, 222, 230, 238, 245, 247, 250, 251, 261, 262, 267, 270, 279, 280, 284, 287, 289, 293, 302, 304, 306, 308, 309, 315, 319, 322, 323, 324, 325, 329, 331, 334, 335] ['Alongside', 'hematopoietic', '-', 'type', 'PGDS', '(', 'H-PGDS', ')', ',', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', 'is', 'related', 'to', 'a', 'group', 'of', 'prostaglandin', 'D', 'synthases', '(', 'PGDS', ')', 'responsible', 'for', 'converting', 'PGH2', 'to', 'PGD2', '[', '57', ']', ',', 'which', 'is', 'involved', 'in', 'a', 'variety', 'of', 'central', 'nervous', 'system', '(', 'CNS', ')', 'functions', ',', 'such', 'as', 'sedation', ',', 'nonrapid', 'eye', 'movement', '(', 'NREM', ')', 'sleep', 'and', 'PGD2-allodynia', '.'] [2, 1, 1, 1, 2, 1, 4, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 2, 1, 1, 1, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 7, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
In addition to synthesizing PGD2, a potent endogenous nociceptive modulator [58] within the cells, in the extracellular space and body fluids lipocalin-type prostaglandin D2 synthase binds various small nonsubstrate lipophilic molecules such as retinal, retinoic acid [59], bilirubin, biliverdin [60], gangliosides [61], amyloid β peptides [62]. [('PMC8396559', 'D02006', 142, 182, 'lipocalin-type prostaglandin D2 synthase')] ['In', 'addition', 'to', 'synthe', '##sizing', 'PG', '##D', '##2', ',', 'a', 'potent', 'endogenous', 'nocic', '##eptive', 'modulator', '[', '58', ']', 'within', 'the', 'cells', ',', 'in', 'the', 'extracellular', 'space', 'and', 'body', 'fluids', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', 'binds', 'various', 'small', 'nons', '##ubs', '##trate', 'lip', '##ophilic', 'molecules', 'such', 'as', 'retinal', ',', 'retin', '##oic', 'acid', '[', '59', ']', ',', 'bilirubin', ',', 'bil', '##iver', '##din', '[', '60', ']', ',', 'gangl', '##ios', '##ides', '[', '61', ']', ',', 'amyloid', 'β', 'peptides', '[', '62', ']', '.'] [0, 3, 12, 15, 21, 28, 30, 31, 32, 34, 36, 43, 54, 59, 66, 76, 77, 79, 81, 88, 92, 97, 99, 102, 106, 120, 126, 130, 135, 142, 145, 149, 151, 152, 157, 171, 172, 174, 183, 189, 197, 203, 207, 210, 216, 219, 227, 237, 242, 245, 252, 254, 259, 263, 268, 269, 271, 272, 274, 283, 285, 288, 292, 296, 297, 299, 300, 302, 307, 310, 315, 316, 318, 319, 321, 329, 331, 340, 341, 343, 344] [2, 11, 14, 21, 27, 30, 31, 32, 33, 35, 42, 53, 59, 65, 75, 77, 79, 80, 87, 91, 97, 98, 101, 105, 119, 125, 129, 134, 141, 145, 149, 151, 152, 156, 170, 172, 173, 182, 188, 196, 202, 207, 210, 215, 219, 226, 236, 241, 244, 252, 253, 259, 262, 267, 269, 271, 272, 273, 283, 284, 288, 292, 295, 297, 299, 300, 301, 307, 310, 314, 316, 318, 319, 320, 328, 330, 339, 341, 343, 344, 345] ['In', 'addition', 'to', 'synthesizing', 'PGD2', ',', 'a', 'potent', 'endogenous', 'nociceptive', 'modulator', '[', '58', ']', 'within', 'the', 'cells', ',', 'in', 'the', 'extracellular', 'space', 'and', 'body', 'fluids', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', 'binds', 'various', 'small', 'nonsubstrate', 'lipophilic', 'molecules', 'such', 'as', 'retinal', ',', 'retinoic', 'acid', '[', '59', ']', ',', 'bilirubin', ',', 'biliverdin', '[', '60', ']', ',', 'gangliosides', '[', '61', ']', ',', 'amyloid', 'β', 'peptides', '[', '62', ']', '.'] [1, 1, 1, 2, 3, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 3, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Therefore, lipocalin-type prostaglandin D2 synthase can potentially be a promising proteomic biomarker as the entire prostaglandin system plays a huge role in pain and central sensitization development. [('PMC8396559', 'D02007', 11, 51, 'lipocalin-type prostaglandin D2 synthase')] ['Therefore', ',', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', 'can', 'potentially', 'be', 'a', 'promising', 'proteomic', 'biomarker', 'as', 'the', 'entire', 'prostaglandin', 'system', 'plays', 'a', 'huge', 'role', 'in', 'pain', 'and', 'central', 'sensitization', 'development', '.'] [0, 9, 11, 14, 18, 20, 21, 26, 40, 41, 43, 52, 56, 68, 71, 73, 83, 93, 103, 106, 110, 117, 131, 138, 144, 146, 151, 156, 159, 164, 168, 176, 190, 201] [9, 10, 14, 18, 20, 21, 25, 39, 41, 42, 51, 55, 67, 70, 72, 82, 92, 102, 105, 109, 116, 130, 137, 143, 145, 150, 155, 158, 163, 167, 175, 189, 201, 202] ['Therefore', ',', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', 'can', 'potentially', 'be', 'a', 'promising', 'proteomic', 'biomarker', 'as', 'the', 'entire', 'prostaglandin', 'system', 'plays', 'a', 'huge', 'role', 'in', 'pain', 'and', 'central', 'sensitization', 'development', '.'] [1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Moreover, by inhibiting nitric oxide (NO) synthase expression, vitamin D reduces the production of NO, a key endogenous mediator in headaches, such as migraine [70] and tension-type headaches [71], deficient levels of VDBP in MOH patients can be associated with a decreased level of vitamin D, which can be one of the mechanisms of chronic headache development. [('PMC8396559', 'D03008', 24, 50, 'nitric oxide (NO) synthase')] ['Moreover', ',', 'by', 'inhibiting', 'nitric', 'oxide', '(', 'NO', ')', 'synthase', 'expression', ',', 'vitamin', 'D', 'reduces', 'the', 'production', 'of', 'NO', ',', 'a', 'key', 'endogenous', 'mediator', 'in', 'headache', '##s', ',', 'such', 'as', 'migraine', '[', '70', ']', 'and', 'tension', '-', 'type', 'headache', '##s', '[', '71', ']', ',', 'deficient', 'levels', 'of', 'VD', '##BP', 'in', 'MO', '##H', 'patients', 'can', 'be', 'associated', 'with', 'a', 'decreased', 'level', 'of', 'vitamin', 'D', ',', 'which', 'can', 'be', 'one', 'of', 'the', 'mechanisms', 'of', 'chronic', 'headache', 'development', '.'] [0, 8, 10, 13, 24, 31, 37, 38, 40, 42, 51, 61, 63, 71, 73, 81, 85, 96, 99, 101, 103, 105, 109, 120, 129, 132, 140, 141, 143, 148, 151, 160, 161, 163, 165, 169, 176, 177, 182, 190, 192, 193, 195, 196, 198, 208, 215, 218, 220, 223, 226, 228, 230, 239, 243, 246, 257, 262, 264, 274, 280, 283, 291, 292, 294, 300, 304, 307, 311, 314, 318, 329, 332, 340, 349, 360] [8, 9, 12, 23, 30, 36, 38, 40, 41, 50, 61, 62, 70, 72, 80, 84, 95, 98, 101, 102, 104, 108, 119, 128, 131, 140, 141, 142, 147, 150, 159, 161, 163, 164, 168, 176, 177, 181, 190, 191, 193, 195, 196, 197, 207, 214, 217, 220, 222, 225, 228, 229, 238, 242, 245, 256, 261, 263, 273, 279, 282, 290, 292, 293, 299, 303, 306, 310, 313, 317, 328, 331, 339, 348, 360, 361] ['Moreover', ',', 'by', 'inhibiting', 'nitric', 'oxide', '(', 'NO', ')', 'synthase', 'expression', ',', 'vitamin', 'D', 'reduces', 'the', 'production', 'of', 'NO', ',', 'a', 'key', 'endogenous', 'mediator', 'in', 'headaches', ',', 'such', 'as', 'migraine', '[', '70', ']', 'and', 'tension', '-', 'type', 'headaches', '[', '71', ']', ',', 'deficient', 'levels', 'of', 'VDBP', 'in', 'MOH', 'patients', 'can', 'be', 'associated', 'with', 'a', 'decreased', 'level', 'of', 'vitamin', 'D', ',', 'which', 'can', 'be', 'one', 'of', 'the', 'mechanisms', 'of', 'chronic', 'headache', 'development', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 2, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Alpha-1 antitrypsin (A1AT), also known as alpha-1 proteinase inhibitor, is an acute phase reactant and serine protease inhibitor (serpin) whose targets are elastase, plasmin, thrombin, trypsin, chymotrypsin, plasminogen activator, and is mostly produced in the liver and expressed by hepatocytes [76]. [('PMC8396559', 'D05000', 42, 60, 'alpha-1 proteinase'), ('PMC8396559', 'D05000', 156, 164, 'elastase')] ['Alpha', '-', '1', 'antit', '##ryp', '##sin', '(', 'A', '##1', '##AT', ')', ',', 'also', 'known', 'as', 'alpha', '-', '1', 'protein', '##ase', 'inhibitor', ',', 'is', 'an', 'acute', 'phase', 'react', '##ant', 'and', 'serine', 'protease', 'inhibitor', '(', 'ser', '##pin', ')', 'whose', 'targets', 'are', 'elast', '##ase', ',', 'plasmin', ',', 'thrombin', ',', 'trypsin', ',', 'ch', '##ym', '##otr', '##yp', '##sin', ',', 'plasmin', '##ogen', 'activator', ',', 'and', 'is', 'mostly', 'produced', 'in', 'the', 'liver', 'and', 'expressed', 'by', 'hepatocytes', '[', '76', ']', '.'] [0, 5, 6, 8, 13, 16, 20, 21, 22, 23, 25, 26, 28, 33, 39, 42, 47, 48, 50, 57, 61, 70, 72, 75, 78, 84, 90, 95, 99, 103, 110, 119, 129, 130, 133, 136, 138, 144, 152, 156, 161, 164, 166, 173, 175, 183, 185, 192, 194, 196, 198, 201, 203, 206, 208, 215, 220, 229, 231, 235, 238, 245, 254, 257, 261, 267, 271, 281, 284, 296, 297, 299, 300] [5, 6, 7, 13, 16, 19, 21, 22, 23, 25, 26, 27, 32, 38, 41, 47, 48, 49, 57, 60, 70, 71, 74, 77, 83, 89, 95, 98, 102, 109, 118, 128, 130, 133, 136, 137, 143, 151, 155, 161, 164, 165, 173, 174, 183, 184, 192, 193, 196, 198, 201, 203, 206, 207, 215, 219, 229, 230, 234, 237, 244, 253, 256, 260, 266, 270, 280, 283, 295, 297, 299, 300, 301] ['Alpha-1', 'antitrypsin', '(', 'A1AT', ')', ',', 'also', 'known', 'as', 'alpha-1', 'proteinase', 'inhibitor', ',', 'is', 'an', 'acute', 'phase', 'reactant', 'and', 'serine', 'protease', 'inhibitor', '(', 'serpin', ')', 'whose', 'targets', 'are', 'elastase', ',', 'plasmin', ',', 'thrombin', ',', 'trypsin', ',', 'chymotrypsin', ',', 'plasminogen', 'activator', ',', 'and', 'is', 'mostly', 'produced', 'in', 'the', 'liver', 'and', 'expressed', 'by', 'hepatocytes', '[', '76', ']', '.'] [3, 3, 1, 3, 1, 1, 1, 1, 1, 3, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 5, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
However, some reports have suggested that AMBP may be involved in oxidant-scavenging and have enzymatic reductase properties as an antioxidant [84]. [('PMC8396559', 'D11004', 94, 113, 'enzymatic reductase')] ['However', ',', 'some', 'reports', 'have', 'suggested', 'that', 'AM', '##BP', 'may', 'be', 'involved', 'in', 'oxid', '##ant', '-', 'scavenging', 'and', 'have', 'enzymatic', 'reductase', 'properties', 'as', 'an', 'antioxidant', '[', '84', ']', '.'] [0, 7, 9, 14, 22, 27, 37, 42, 44, 47, 51, 54, 63, 66, 70, 73, 74, 85, 89, 94, 104, 114, 125, 128, 131, 143, 144, 146, 147] [7, 8, 13, 21, 26, 36, 41, 44, 46, 50, 53, 62, 65, 70, 73, 74, 84, 88, 93, 103, 113, 124, 127, 130, 142, 144, 146, 147, 148] ['However', ',', 'some', 'reports', 'have', 'suggested', 'that', 'AMBP', 'may', 'be', 'involved', 'in', 'oxidant', '-', 'scavenging', 'and', 'have', 'enzymatic', 'reductase', 'properties', 'as', 'an', 'antioxidant', '[', '84', ']', '.'] [1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Nonsecretory ribonuclease (RNAS2) is a pyrimidine specific nuclease with a slight preference for cytotoxin and helminthotoxin. [('PMC8396559', 'D15000', 0, 25, 'Nonsecretory ribonuclease'), ('PMC8396559', 'D15000', 39, 67, 'pyrimidine specific nuclease')] ['Non', '##sec', '##ret', '##ory', 'rib', '##onuclease', '(', 'RNA', '##S', '##2', ')', 'is', 'a', 'pyr', '##imid', '##ine', 'specific', 'nucle', '##ase', 'with', 'a', 'slight', 'preference', 'for', 'cyt', '##otoxin', 'and', 'hel', '##min', '##th', '##otoxin', '.'] [0, 3, 6, 9, 13, 16, 26, 27, 30, 31, 32, 34, 37, 39, 42, 46, 50, 59, 64, 68, 73, 75, 82, 93, 97, 100, 107, 111, 114, 117, 119, 125] [3, 6, 9, 12, 16, 25, 27, 30, 31, 32, 33, 36, 38, 42, 46, 49, 58, 64, 67, 72, 74, 81, 92, 96, 100, 106, 110, 114, 117, 119, 125, 126] ['Nonsecretory', 'ribonuclease', '(', 'RNAS2', ')', 'is', 'a', 'pyrimidine', 'specific', 'nuclease', 'with', 'a', 'slight', 'preference', 'for', 'cytotoxin', 'and', 'helminthotoxin', '.'] [4, 2, 1, 3, 1, 1, 1, 3, 1, 2, 1, 1, 1, 1, 1, 2, 1, 4, 1] ['B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
CYTC is a potent inhibitor of lysosomal proteinases and extracellular inhibitors of cysteine proteases that play a huge role in human vascular pathophysiology [91]. [('PMC8396559', 'D16002', 30, 51, 'lysosomal proteinases'), ('PMC8396559', 'D16002', 84, 102, 'cysteine proteases')] ['CY', '##TC', 'is', 'a', 'potent', 'inhibitor', 'of', 'lysosomal', 'protein', '##ases', 'and', 'extracellular', 'inhibitors', 'of', 'cysteine', 'proteases', 'that', 'play', 'a', 'huge', 'role', 'in', 'human', 'vascular', 'pathophysiology', '[', '91', ']', '.'] [0, 2, 5, 8, 10, 17, 27, 30, 40, 47, 52, 56, 70, 81, 84, 93, 103, 108, 113, 115, 120, 125, 128, 134, 143, 159, 160, 162, 163] [2, 4, 7, 9, 16, 26, 29, 39, 47, 51, 55, 69, 80, 83, 92, 102, 107, 112, 114, 119, 124, 127, 133, 142, 158, 160, 162, 163, 164] ['CYTC', 'is', 'a', 'potent', 'inhibitor', 'of', 'lysosomal', 'proteinases', 'and', 'extracellular', 'inhibitors', 'of', 'cysteine', 'proteases', 'that', 'play', 'a', 'huge', 'role', 'in', 'human', 'vascular', 'pathophysiology', '[', '91', ']', '.'] [2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'E', 'O', 'O', 'O', 'O', 'B', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Lee S., Jang E., Kim J.-H., Kim J.-H., Lee W.-H., Suk K. Lipocalin-type Prostaglandin D2 Synthase Protein Regulates Glial Cell Migration and Morphology through Myristoylated Alanine-rich C-Kinase Substrate. [('PMC8396559', 'F56001', 57, 97, 'Lipocalin-type Prostaglandin D2 Synthase'), ('PMC8396559', 'F56001', 160, 195, 'Myristoylated Alanine-rich C-Kinase')] ['Lee', 'S', '.', ',', 'Jan', '##g', 'E', '.', ',', 'Kim', 'J', '.', '-', 'H', '.', ',', 'Kim', 'J', '.', '-', 'H', '.', ',', 'Lee', 'W', '.', '-', 'H', '.', ',', 'Su', '##k', 'K', '.', 'Lip', '##ocal', '##in', '-', 'type', 'Pros', '##tag', '##land', '##in', 'D', '##2', 'Syn', '##th', '##ase', 'Protein', 'Reg', '##ulates', 'Gl', '##ial', 'Cell', 'Mi', '##gr', '##ation', 'and', 'Morph', '##ology', 'through', 'My', '##ris', '##to', '##ylated', 'Ala', '##nine', '-', 'rich', 'C', '-', 'Kin', '##ase', 'Subst', '##rate', '.'] [0, 4, 5, 6, 8, 11, 13, 14, 15, 17, 21, 22, 23, 24, 25, 26, 28, 32, 33, 34, 35, 36, 37, 39, 43, 44, 45, 46, 47, 48, 50, 52, 54, 55, 57, 60, 64, 66, 67, 72, 76, 79, 83, 86, 87, 89, 92, 94, 98, 106, 109, 116, 118, 122, 127, 129, 131, 137, 141, 146, 152, 160, 162, 165, 167, 174, 177, 181, 182, 187, 188, 189, 192, 196, 201, 205] [3, 5, 6, 7, 11, 12, 14, 15, 16, 20, 22, 23, 24, 25, 26, 27, 31, 33, 34, 35, 36, 37, 38, 42, 44, 45, 46, 47, 48, 49, 52, 53, 55, 56, 60, 64, 66, 67, 71, 76, 79, 83, 85, 87, 88, 92, 94, 97, 105, 109, 115, 118, 121, 126, 129, 131, 136, 140, 146, 151, 159, 162, 165, 167, 173, 177, 181, 182, 186, 188, 189, 192, 195, 201, 205, 206] ['Lee', 'S', '.', ',', 'Jang', 'E', '.', ',', 'Kim', 'J.-H', '.', ',', 'Kim', 'J.-H', '.', ',', 'Lee', 'W.-H', '.', ',', 'Suk', 'K', '.', 'Lipocalin', '-', 'type', 'Prostaglandin', 'D2', 'Synthase', 'Protein', 'Regulates', 'Glial', 'Cell', 'Migration', 'and', 'Morphology', 'through', 'Myristoylated', 'Alanine', '-', 'rich', 'C-Kinase', 'Substrate', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 1, 4, 1, 1, 1, 4, 1, 1, 1, 4, 1, 1, 2, 1, 1, 3, 1, 1, 4, 2, 3, 1, 2, 2, 1, 3, 1, 2, 1, 4, 2, 1, 1, 4, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O']
Tanaka T., Urade Y., Kimura H., Eguchi N., Nishikawa A., Hayaishi O. Lipocalin-type Prostaglandin D Synthase (β-Trace) Is a Newly Recognized Type of Retinoid Transporter. [('PMC8396559', 'F58001', 69, 108, 'Lipocalin-type Prostaglandin D Synthase')] ['Tanaka', 'T', '.', ',', 'Ur', '##ade', 'Y', '.', ',', 'Kim', '##ura', 'H', '.', ',', 'Eg', '##uchi', 'N', '.', ',', 'Nish', '##ikawa', 'A', '.', ',', 'Hay', '##ais', '##hi', 'O', '.', 'Lip', '##ocal', '##in', '-', 'type', 'Pros', '##tag', '##land', '##in', 'D', 'Syn', '##th', '##ase', '(', 'β', '-', 'Trace', ')', 'Is', 'a', 'New', '##ly', 'Rec', '##ogni', '##zed', 'Type', 'of', 'Ret', '##ino', '##id', 'Transport', '##er', '.'] [0, 7, 8, 9, 11, 13, 17, 18, 19, 21, 24, 28, 29, 30, 32, 34, 39, 40, 41, 43, 47, 53, 54, 55, 57, 60, 63, 66, 67, 69, 72, 76, 78, 79, 84, 88, 91, 95, 98, 100, 103, 105, 109, 110, 111, 112, 117, 119, 122, 124, 127, 130, 133, 137, 141, 146, 149, 152, 155, 158, 167, 169] [6, 8, 9, 10, 13, 16, 18, 19, 20, 24, 27, 29, 30, 31, 34, 38, 40, 41, 42, 47, 52, 54, 55, 56, 60, 63, 65, 67, 68, 72, 76, 78, 79, 83, 88, 91, 95, 97, 99, 103, 105, 108, 110, 111, 112, 117, 118, 121, 123, 127, 129, 133, 137, 140, 145, 148, 152, 155, 157, 167, 169, 170] ['Tanaka', 'T', '.', ',', 'Urade', 'Y', '.', ',', 'Kimura', 'H', '.', ',', 'Eguchi', 'N', '.', ',', 'Nishikawa', 'A', '.', ',', 'Hayaishi', 'O', '.', 'Lipocalin', '-', 'type', 'Prostaglandin', 'D', 'Synthase', '(', 'β-Trace', ')', 'Is', 'a', 'Newly', 'Recognized', 'Type', 'of', 'Retinoid', 'Transporter', '.'] [1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 3, 1, 1, 3, 1, 1, 4, 1, 3, 1, 3, 1, 1, 1, 2, 3, 1, 1, 3, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Beuckmann C.T., Aoyagi M., Okazaki I., Hiroike T., Toh H., Hayaishi O., Urade Y. Binding of Biliverdin, Bilirubin, and Thyroid Hormones to Lipocalin-Type Prostaglandin D Synthase† Biochemistry. [('PMC8396559', 'F59001', 139, 178, 'Lipocalin-Type Prostaglandin D Synthase')] ['Be', '##uck', '##mann', 'C', '.', 'T', '.', ',', 'A', '##oya', '##gi', 'M', '.', ',', 'Ok', '##aza', '##ki', 'I', '.', ',', 'Hir', '##oi', '##ke', 'T', '.', ',', 'To', '##h', 'H', '.', ',', 'Hay', '##ais', '##hi', 'O', '.', ',', 'Ur', '##ade', 'Y', '.', 'Binding', 'of', 'Bil', '##iver', '##din', ',', 'Bil', '##irubin', ',', 'and', 'Th', '##yroid', 'Horm', '##ones', 'to', 'Lip', '##ocal', '##in', '-', 'Type', 'Pros', '##tag', '##land', '##in', 'D', 'Syn', '##th', '##ase', '†', 'Biochemistry', '.'] [0, 2, 5, 10, 11, 12, 13, 14, 16, 17, 20, 23, 24, 25, 27, 29, 32, 35, 36, 37, 39, 42, 44, 47, 48, 49, 51, 53, 55, 56, 57, 59, 62, 65, 68, 69, 70, 72, 74, 78, 79, 81, 89, 92, 95, 99, 102, 104, 107, 113, 115, 119, 121, 127, 131, 136, 139, 142, 146, 148, 149, 154, 158, 161, 165, 168, 170, 173, 175, 178, 180, 192] [2, 5, 9, 11, 12, 13, 14, 15, 17, 20, 22, 24, 25, 26, 29, 32, 34, 36, 37, 38, 42, 44, 46, 48, 49, 50, 53, 54, 56, 57, 58, 62, 65, 67, 69, 70, 71, 74, 77, 79, 80, 88, 91, 95, 99, 102, 103, 107, 113, 114, 118, 121, 126, 131, 135, 138, 142, 146, 148, 149, 153, 158, 161, 165, 167, 169, 173, 175, 178, 179, 192, 193] ['Beuckmann', 'C.T', '.', ',', 'Aoyagi', 'M', '.', ',', 'Okazaki', 'I', '.', ',', 'Hiroike', 'T', '.', ',', 'Toh', 'H', '.', ',', 'Hayaishi', 'O', '.', ',', 'Urade', 'Y', '.', 'Binding', 'of', 'Biliverdin', ',', 'Bilirubin', ',', 'and', 'Thyroid', 'Hormones', 'to', 'Lipocalin', '-', 'Type', 'Prostaglandin', 'D', 'Synthase†', 'Biochemistry', '.'] [3, 3, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 3, 1, 2, 1, 1, 2, 2, 1, 3, 1, 1, 4, 1, 4, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O']
Lipocalin-type prostaglandin D synthase is up-regulated in oligodendrocytes in lysosomal storage diseases and binds gangliosides. [('PMC8396559', 'F60002', 0, 39, 'Lipocalin-type prostaglandin D synthase')] ['Lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', 'synthase', 'is', 'up', '-', 'regulated', 'in', 'oligodend', '##rocytes', 'in', 'lysosomal', 'storage', 'diseases', 'and', 'binds', 'gangl', '##ios', '##ides', '.'] [0, 3, 7, 9, 10, 15, 29, 31, 40, 43, 45, 46, 56, 59, 68, 76, 79, 89, 97, 106, 110, 116, 121, 124, 128] [3, 7, 9, 10, 14, 28, 30, 39, 42, 45, 46, 55, 58, 68, 75, 78, 88, 96, 105, 109, 115, 121, 124, 128, 129] ['Lipocalin', '-', 'type', 'prostaglandin', 'D', 'synthase', 'is', 'up', '-', 'regulated', 'in', 'oligodendrocytes', 'in', 'lysosomal', 'storage', 'diseases', 'and', 'binds', 'gangliosides', '.'] [3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1] ['B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid. [('PMC8396559', 'F61002', 0, 39, 'Lipocalin-type prostaglandin D synthase')] ['Lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', 'synthase', '/', 'beta', '-', 'trace', 'is', 'a', 'major', 'amyloid', 'beta', '-', 'chaperone', 'in', 'human', 'cerebrospinal', 'fluid', '.'] [0, 3, 7, 9, 10, 15, 29, 31, 39, 40, 44, 45, 51, 54, 56, 62, 70, 74, 75, 85, 88, 94, 108, 113] [3, 7, 9, 10, 14, 28, 30, 39, 40, 44, 45, 50, 53, 55, 61, 69, 74, 75, 84, 87, 93, 107, 113, 114] ['Lipocalin', '-', 'type', 'prostaglandin', 'D', 'synthase', '/', 'beta', '-', 'trace', 'is', 'a', 'major', 'amyloid', 'beta', '-', 'chaperone', 'in', 'human', 'cerebrospinal', 'fluid', '.'] [3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1] ['B', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Few studies have shown the potential biomarkers of headache chronicity caused by medication overuse, such as SNVs of the angiotensin-converting enzyme, brain-derived neurotropic factor, catechol-O-methyltransferase genes, altered neurotransmitters metabolism, neurophysiological and neuroimaging changes [27]. [('PMC8396559', 'R01001', 121, 150, 'angiotensin-converting enzyme'), ('PMC8396559', 'R01001', 186, 214, 'catechol-O-methyltransferase')] ['Few', 'studies', 'have', 'shown', 'the', 'potential', 'biomarkers', 'of', 'headache', 'chronic', '##ity', 'caused', 'by', 'medication', 'over', '##use', ',', 'such', 'as', 'SN', '##Vs', 'of', 'the', 'angiotensin', '-', 'converting', 'enzyme', ',', 'brain', '-', 'derived', 'neurot', '##ropic', 'factor', ',', 'catechol', '-', 'O', '-', 'methyl', '##transferase', 'genes', ',', 'altered', 'neurotransmit', '##ters', 'metabolism', ',', 'neurop', '##hy', '##si', '##ological', 'and', 'neuroimaging', 'changes', '[', '27', ']', '.'] [0, 4, 12, 17, 23, 27, 37, 48, 51, 60, 67, 71, 78, 81, 92, 96, 99, 101, 106, 109, 111, 114, 117, 121, 132, 133, 144, 150, 152, 157, 158, 166, 172, 178, 184, 186, 194, 195, 196, 197, 203, 215, 220, 222, 230, 243, 248, 258, 260, 266, 268, 270, 279, 283, 296, 304, 305, 307, 308] [3, 11, 16, 22, 26, 36, 47, 50, 59, 67, 70, 77, 80, 91, 96, 99, 100, 105, 108, 111, 113, 116, 120, 132, 133, 143, 150, 151, 157, 158, 165, 172, 177, 184, 185, 194, 195, 196, 197, 203, 214, 220, 221, 229, 243, 247, 258, 259, 266, 268, 270, 278, 282, 295, 303, 305, 307, 308, 309] ['Few', 'studies', 'have', 'shown', 'the', 'potential', 'biomarkers', 'of', 'headache', 'chronicity', 'caused', 'by', 'medication', 'overuse', ',', 'such', 'as', 'SNVs', 'of', 'the', 'angiotensin', '-', 'converting', 'enzyme', ',', 'brain', '-', 'derived', 'neurotropic', 'factor', ',', 'catechol-O-methyltransferase', 'genes', ',', 'altered', 'neurotransmitters', 'metabolism', ',', 'neurophysiological', 'and', 'neuroimaging', 'changes', '[', '27', ']', '.'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 6, 1, 1, 1, 2, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Thus, Pellesi et al. (2019) showed the overexpression of lipocalin-type prostaglandin D2 synthase (lipocalin-type prostaglandin D2 synthase) in the serum of MOH patients compared to healthy controls (219.2 ± 58.2 vs. 188.7 ± 39.2 ng/mL, p = 0.0038) and a not significant increase of apolipoprotein A1 (APOA1) (49.8 ± 23.7 vs. 46.9 ± 17.5 μg/mL, p = 0.546). [('PMC8396559', 'R02000', 57, 97, 'lipocalin-type prostaglandin D2 synthase'), ('PMC8396559', 'R02000', 99, 139, 'lipocalin-type prostaglandin D2 synthase')] ['Thus', ',', 'Pel', '##les', '##i', 'et', 'al', '.', '(', '201', '##9', ')', 'showed', 'the', 'overexpression', 'of', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', '(', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', ')', 'in', 'the', 'serum', 'of', 'MO', '##H', 'patients', 'compared', 'to', 'healthy', 'controls', '(', '219', '.', '2', '±', '58', '.', '2', 'vs', '.', '188', '.', '7', '±', '39', '.', '2', 'ng', '/', 'mL', ',', 'p', '=', '0', '.', '00', '##38', ')', 'and', 'a', 'not', 'significant', 'increase', 'of', 'apo', '##lip', '##oprotein', 'A', '##1', '(', 'AP', '##OA', '##1', ')', '(', '49', '.', '8', '±', '23', '.', '7', 'vs', '.', '46', '.', '9', '±', '17', '.', '5', 'μ', '##g', '/', 'mL', ',', 'p', '=', '0', '.', '54', '##6', ')', '.'] [0, 4, 6, 9, 12, 14, 17, 19, 21, 22, 25, 26, 28, 35, 39, 54, 57, 60, 64, 66, 67, 72, 86, 87, 89, 98, 99, 102, 106, 108, 109, 114, 128, 129, 131, 139, 141, 144, 148, 154, 157, 159, 161, 170, 179, 182, 190, 199, 200, 203, 204, 206, 208, 210, 211, 213, 215, 217, 220, 221, 223, 225, 227, 228, 230, 232, 233, 235, 237, 239, 241, 242, 243, 245, 247, 249, 253, 255, 259, 271, 280, 283, 286, 289, 298, 299, 301, 302, 304, 306, 307, 309, 310, 312, 313, 315, 317, 319, 320, 322, 324, 326, 328, 329, 331, 333, 335, 336, 338, 339, 340, 341, 343, 345, 347, 349, 350, 351, 353, 354, 355] [4, 5, 9, 12, 13, 16, 19, 20, 22, 25, 26, 27, 34, 38, 53, 56, 60, 64, 66, 67, 71, 85, 87, 88, 97, 99, 102, 106, 108, 109, 113, 127, 129, 130, 139, 140, 143, 147, 153, 156, 159, 160, 169, 178, 181, 189, 198, 200, 203, 204, 205, 207, 210, 211, 212, 215, 216, 220, 221, 222, 224, 227, 228, 229, 232, 233, 235, 236, 238, 240, 242, 243, 245, 247, 248, 252, 254, 258, 270, 279, 282, 286, 289, 297, 299, 300, 302, 304, 306, 307, 308, 310, 312, 313, 314, 316, 319, 320, 321, 324, 325, 328, 329, 330, 332, 335, 336, 337, 339, 340, 341, 343, 344, 346, 348, 350, 351, 353, 354, 355, 356] ['Thus', ',', 'Pellesi', 'et', 'al', '.', '(', '2019', ')', 'showed', 'the', 'overexpression', 'of', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', '(', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', ')', 'in', 'the', 'serum', 'of', 'MOH', 'patients', 'compared', 'to', 'healthy', 'controls', '(', '219.2', '±', '58.2', 'vs', '.', '188.7', '±', '39.2', 'ng', '/', 'mL', ',', 'p', '=', '0.0038', ')', 'and', 'a', 'not', 'significant', 'increase', 'of', 'apolipoprotein', 'A1', '(', 'APOA1', ')', '(', '49.8', '±', '23.7', 'vs', '.', '46.9', '±', '17.5', 'μg', '/', 'mL', ',', 'p', '=', '0.546', ')', '.'] [1, 1, 3, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 3, 1, 3, 1, 1, 3, 1, 3, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 3, 2, 1, 3, 1, 1, 3, 1, 3, 1, 1, 3, 1, 3, 2, 1, 1, 1, 1, 1, 4, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'B', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
This finding of a higher level of lipocalin-type prostaglandin D2 synthase in a serum shows that it may be the proteomic biomarker of headache chronicity associated with excessive intake of AHMs. [('PMC8396559', 'R02002', 34, 74, 'lipocalin-type prostaglandin D2 synthase')] ['This', 'finding', 'of', 'a', 'higher', 'level', 'of', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', 'in', 'a', 'serum', 'shows', 'that', 'it', 'may', 'be', 'the', 'proteomic', 'biomarker', 'of', 'headache', 'chronic', '##ity', 'associated', 'with', 'excessive', 'intake', 'of', 'AH', '##Ms', '.'] [0, 5, 13, 16, 18, 25, 31, 34, 37, 41, 43, 44, 49, 63, 64, 66, 75, 78, 80, 86, 92, 97, 100, 104, 107, 111, 121, 131, 134, 143, 150, 154, 165, 170, 180, 187, 190, 192, 194] [4, 12, 15, 17, 24, 30, 33, 37, 41, 43, 44, 48, 62, 64, 65, 74, 77, 79, 85, 91, 96, 99, 103, 106, 110, 120, 130, 133, 142, 150, 153, 164, 169, 179, 186, 189, 192, 194, 195] ['This', 'finding', 'of', 'a', 'higher', 'level', 'of', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', 'in', 'a', 'serum', 'shows', 'that', 'it', 'may', 'be', 'the', 'proteomic', 'biomarker', 'of', 'headache', 'chronicity', 'associated', 'with', 'excessive', 'intake', 'of', 'AHMs', '.'] [1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 2, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
It is interesting to note that according to the prevalent acute headache medication, patients who assumed mixtures had a higher serum level of lipocalin-type prostaglandin D2 synthase compared to those who assumed NSAIDs or triptans (266.0 ± 44.6 vs. 214.9 ± 53.5 and 209.4 ± 57.5 μg/mL) [('PMC8396559', 'R02003', 143, 183, 'lipocalin-type prostaglandin D2 synthase')] ['It', 'is', 'interesting', 'to', 'note', 'that', 'according', 'to', 'the', 'prevalent', 'acute', 'headache', 'medication', ',', 'patients', 'who', 'assumed', 'mixtures', 'had', 'a', 'higher', 'serum', 'level', 'of', 'lip', '##ocal', '##in', '-', 'type', 'prostaglandin', 'D', '##2', 'synthase', 'compared', 'to', 'those', 'who', 'assumed', 'NSA', '##IDs', 'or', 'trip', '##tan', '##s', '(', '266', '.', '0', '±', '44', '.', '6', 'vs', '.', '214', '.', '9', '±', '53', '.', '5', 'and', '209', '.', '4', '±', '57', '.', '5', 'μ', '##g', '/', 'mL', ')'] [0, 3, 6, 18, 21, 26, 31, 41, 44, 48, 58, 64, 73, 83, 85, 94, 98, 106, 115, 119, 121, 128, 134, 140, 143, 146, 150, 152, 153, 158, 172, 173, 175, 184, 193, 196, 202, 206, 214, 217, 221, 224, 228, 231, 233, 234, 237, 238, 240, 242, 244, 245, 247, 249, 251, 254, 255, 257, 259, 261, 262, 264, 268, 271, 272, 274, 276, 278, 279, 281, 282, 283, 284, 286] [2, 5, 17, 20, 25, 30, 40, 43, 47, 57, 63, 72, 83, 84, 93, 97, 105, 114, 118, 120, 127, 133, 139, 142, 146, 150, 152, 153, 157, 171, 173, 174, 183, 192, 195, 201, 205, 213, 217, 220, 223, 228, 231, 232, 234, 237, 238, 239, 241, 244, 245, 246, 249, 250, 254, 255, 256, 258, 261, 262, 263, 267, 271, 272, 273, 275, 278, 279, 280, 282, 283, 284, 286, 287] ['It', 'is', 'interesting', 'to', 'note', 'that', 'according', 'to', 'the', 'prevalent', 'acute', 'headache', 'medication', ',', 'patients', 'who', 'assumed', 'mixtures', 'had', 'a', 'higher', 'serum', 'level', 'of', 'lipocalin', '-', 'type', 'prostaglandin', 'D2', 'synthase', 'compared', 'to', 'those', 'who', 'assumed', 'NSAIDs', 'or', 'triptans', '(', '266.0', '±', '44.6', 'vs', '.', '214.9', '±', '53.5', 'and', '209.4', '±', '57.5', 'μg', '/', 'mL', ')'] [1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 3, 1, 3, 1, 1, 3, 1, 3, 1, 3, 1, 3, 2, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'I', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']
Researchers have found seven proteins oversecreted by the kidneys in MOH patients, especially NSAIDs abusers, compared to healthy controls: uromodulin (UROM), alpha-1-microglobulin (AMBP), zinc-alpha-2-glycoprotein (ZAZG), inter-alpha-trypsin heavy chain H4 (ITIH4), Ig kappa chain C region (IGKC), non-secretory ribonuclease (RNAS2), and cystatin C (CYTC) (OR = 49, 95% CI 2.53–948.67 vs. controls; OR = 11.6, 95% CI 0.92–147.57 vs. triptans and mixtures groups). [('PMC8396559', 'R05001', 299, 325, 'non-secretory ribonuclease')] ['Researchers', 'have', 'found', 'seven', 'proteins', 'over', '##sec', '##reted', 'by', 'the', 'kidneys', 'in', 'MO', '##H', 'patients', ',', 'especially', 'NSA', '##IDs', 'abuse', '##rs', ',', 'compared', 'to', 'healthy', 'controls', ':', 'uro', '##mod', '##ulin', '(', 'U', '##ROM', ')', ',', 'alpha', '-', '1', '-', 'microgl', '##ob', '##ulin', '(', 'AM', '##BP', ')', ',', 'zinc', '-', 'alpha', '-', '2', '-', 'glycoprotein', '(', 'Z', '##A', '##Z', '##G', ')', ',', 'inter', '-', 'alpha', '-', 'trypsin', 'heavy', 'chain', 'H', '##4', '(', 'IT', '##IH', '##4', ')', ',', 'Ig', 'kappa', 'chain', 'C', 'region', '(', 'IG', '##K', '##C', ')', ',', 'non', '-', 'secretory', 'rib', '##onuclease', '(', 'RNA', '##S', '##2', ')', ',', 'and', 'cyst', '##atin', 'C', '(', 'CY', '##TC', ')', '(', 'OR', '=', '49', ',', '95', '%', 'CI', '2', '.', '53', '–', '94', '##8', '.', '67', 'vs', '.', 'controls', ';', 'OR', '=', '11', '.', '6', ',', '95', '%', 'CI', '0', '.', '92', '–', '147', '.', '57', 'vs', '.', 'trip', '##tan', '##s', 'and', 'mixtures', 'groups', ')', '.'] [0, 12, 17, 23, 29, 38, 42, 45, 51, 54, 58, 66, 69, 71, 73, 81, 83, 94, 97, 101, 106, 108, 110, 119, 122, 130, 138, 140, 143, 146, 151, 152, 153, 156, 157, 159, 164, 165, 166, 167, 174, 176, 181, 182, 184, 186, 187, 189, 193, 194, 199, 200, 201, 202, 215, 216, 217, 218, 219, 220, 221, 223, 228, 229, 234, 235, 243, 249, 255, 256, 258, 259, 261, 263, 264, 265, 267, 270, 276, 282, 284, 291, 292, 294, 295, 296, 297, 299, 302, 303, 313, 316, 326, 327, 330, 331, 332, 333, 335, 339, 343, 348, 350, 351, 353, 355, 357, 358, 361, 363, 365, 367, 369, 371, 374, 375, 376, 378, 379, 381, 382, 383, 386, 388, 390, 398, 400, 403, 405, 407, 408, 409, 411, 413, 415, 418, 419, 420, 422, 423, 426, 427, 430, 432, 434, 438, 441, 443, 447, 456, 462, 463] [11, 16, 22, 28, 37, 42, 45, 50, 53, 57, 65, 68, 71, 72, 81, 82, 93, 97, 100, 106, 108, 109, 118, 121, 129, 138, 139, 143, 146, 150, 152, 153, 156, 157, 158, 164, 165, 166, 167, 174, 176, 180, 182, 184, 186, 187, 188, 193, 194, 199, 200, 201, 202, 214, 216, 217, 218, 219, 220, 221, 222, 228, 229, 234, 235, 242, 248, 254, 256, 257, 259, 261, 263, 264, 265, 266, 269, 275, 281, 283, 290, 292, 294, 295, 296, 297, 298, 302, 303, 312, 316, 325, 327, 330, 331, 332, 333, 334, 338, 343, 347, 349, 351, 353, 355, 356, 358, 360, 362, 365, 366, 369, 370, 373, 375, 376, 378, 379, 381, 382, 383, 385, 388, 389, 398, 399, 402, 404, 407, 408, 409, 410, 413, 414, 417, 419, 420, 422, 423, 426, 427, 429, 432, 433, 438, 441, 442, 446, 455, 462, 463, 464] ['Researchers', 'have', 'found', 'seven', 'proteins', 'oversecreted', 'by', 'the', 'kidneys', 'in', 'MOH', 'patients', ',', 'especially', 'NSAIDs', 'abusers', ',', 'compared', 'to', 'healthy', 'controls', ':', 'uromodulin', '(', 'UROM', ')', ',', 'alpha-1-microglobulin', '(', 'AMBP', ')', ',', 'zinc-alpha-2-glycoprotein', '(', 'ZAZG', ')', ',', 'inter', '-', 'alpha', '-', 'trypsin', 'heavy', 'chain', 'H4', '(', 'ITIH4', ')', ',', 'Ig', 'kappa', 'chain', 'C', 'region', '(', 'IGKC', ')', ',', 'non', '-', 'secretory', 'ribonuclease', '(', 'RNAS2', ')', ',', 'and', 'cystatin', 'C', '(', 'CYTC', ')', '(', 'OR', '=', '49', ',', '95%', 'CI', '2.53', '–', '948.67', 'vs', '.', 'controls', ';', 'OR', '=', '11.6', ',', '95%', 'CI', '0.92', '–', '147.57', 'vs', '.', 'triptans', 'and', 'mixtures', 'groups', ')', '.'] [1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 2, 1, 1, 1, 2, 2, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 1, 7, 1, 2, 1, 1, 7, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 2, 1, 3, 1, 1, 1, 2, 1, 1, 2, 1, 1, 1, 1, 1, 1, 2, 1, 3, 1, 4, 1, 1, 1, 1, 1, 1, 3, 1, 2, 1, 3, 1, 3, 1, 1, 3, 1, 1, 1, 1, 1] ['O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'B', 'I', 'I', 'I', 'E', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O', 'O']