Identification of γ-Secretase Inhibitor Potency Determinants on Presenilin

Name: Work Video:
Duration: 3 min 30 s
Byron Zhao; Yu Mei; Martin L. Neitzel; Jennifer L. Marugg; Jacek Jagodziński; Mike Lee; Kang Hu; Dale Schenk; Ted Yednock; Guriqbal S. Basi
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1100, 1102, 1594, 2214, 2269, 2271, 2564, 3121, 3123, 3189, 3200, 3217, 3527, 3717, 3794, 3801, 3809, 3821, 3876, 4135, 4236], 'plaques,': [15, 252], 'contributes': [16, 253, 1614, 1627], 'to': [17, 47, 75, 100, 134, 184, 254, 284, 312, 337, 371, 421, 574, 999, 1072, 1087, 1122, 1593, 1615, 1628, 1818, 2006, 2191, 2238, 2254, 2407, 2477, 2504, 2529, 2551, 2701, 3227, 3321, 3337, 3482, 3649, 3914, 4024, 4304, 4323], 'hallmark': [19, 256], 'pathology': [20, 257], 'Alzheimer': [22, 40, 259, 277, 484, 502, 527, 937, 952, 967, 982], 'disease.': [23, 41, 260, 278], 'The': [24, 261, 474, 608, 2206, 2380, 2402, 2409, 2431, 2461, 2525, 3067, 3110, 3205, 3231, 3268, 3287, 3304, 3409, 3429, 3452, 3521, 3563, 3589, 3621, 3711], 'enzymes': [25, 262], 'responsible': [26, 263], 'for': [27, 37, 79, 104, 123, 187, 264, 274, 316, 341, 360, 424, 1095, 1543, 1560, 2025, 2182, 2194, 2218, 2301, 2308, 2355, 2387, 3032, 3052, 3117, 3192, 3347, 3754, 3771, 3787, 3799, 3814, 3965, 3988, 4343], 'production': [28, 170, 233, 265, 407, 470, 562, 1620, 2029, 3106, 3183, 3311, 3327, 3349], 'Aβ,': [30, 267, 3758], 'BACE1': [31, 268], 'and': [32, 50, 88, 97, 117, 148, 171, 194, 223, 234, 269, 287, 325, 334, 354, 385, 408, 431, 460, 471, 544, 551, 563, 606, 628, 1006, 1045, 1079, 1126, 1137, 1596, 2041, 2168, 2203, 2216, 2228, 2275, 2322, 2346, 2371, 2375, 2390, 2397, 2416, 2429, 2447, 2457, 2475, 2492, 2519, 2537, 2605, 2619, 2625, 2675, 2696, 2718, 2727, 2736, 2796, 2801, 2880, 2988, 3008, 3134, 3145, 3175, 3177, 3180, 3240, 3278, 3343, 3358, 3407, 3419, 3436, 3440, 3468, 3515, 3561, 3582, 3587, 3596, 3600, 3636, 3664, 3704, 3773, 3796, 3811, 3935, 3980, 3984, 4139, 4149, 4194, 4232], 'γ-secretase,': [33, 83, 270, 320, 1586, 2034], 'are': [34, 221, 271, 458, 597, 1804, 3350, 3438, 3525, 3598, 3666, 3715, 4203, 4216, 4234], 'therapeutic': [35, 272], 'targets': [36, 273], 'treatment': [38, 275, 1561, 2309], 'Two': [42, 279, 1589], 'presenilin': [43, 60, 172, 280, 297, 409, 959, 989, 1590, 1991], '(PS)': [44, 281], 'homologues,': [45, 282, 1591], 'referred': [46, 283, 1086, 1592], 'PS1': [49, 120, 203, 286, 357, 440, 1595, 1794, 2001, 2031, 2185, 2195, 2259, 2881, 3263, 3406, 3426, 3435, 3467, 3485, 3560, 3595, 3635, 3652, 3682, 4111, 4187, 4299, 4334, 4346], 'PS2,': [51, 288, 1597, 2624, 3040, 4348], 'comprise': [52, 289, 1598], 'catalytic': [54, 291, 1600], 'core': [55, 292, 1601], 'γ-secretase.': [57, 294, 607, 1603, 2186], 'In': [58, 295, 997, 3341, 4338], 'comparing': [59, 296, 4175], 'selectivity': [61, 298, 2181, 2196, 2222, 2241, 3390, 3544, 4112], 'several': [63, 300], 'classes': [64, 301, 2013], 'γ-secretase': [66, 188, 211, 220, 303, 425, 448, 457, 609, 1010, 1114, 1536, 1559, 1613, 1626, 2303, 3078, 3905, 4210, 4255, 4261], 'inhibitors,': [67, 166, 304, 403], 'we': [68, 305, 2016, 2018], 'observed': [69, 306, 2220, 2240], 'that': [70, 154, 216, 307, 391, 453, 1570, 1609, 1793, 1807, 2020, 2260, 2272, 2292, 3292, 3300], 'sulfonamides': [71, 162, 308, 399, 2035, 2199, 2268], 'general': [73, 310], 'tend': [74, 311], 'be': [76, 185, 313, 422, 1819], 'more': [77, 314], 'selective': [78, 315, 1568, 2293, 4207], 'inhibition': [80, 106, 125, 137, 229, 317, 343, 362, 374, 466, 1108, 2026, 2183, 4208, 4252], 'PS1-comprising': [82, 319], 'exemplified': [85, 322, 2036], 'ELN318463': [87, 324, 2038, 3518, 3708, 4091], 'BMS299897.': [89, 139, 326, 376, 2243, 3520, 3710], 'We': [90, 327, 1986, 2187, 2244, 4249], 'employed': [91, 328, 1987, 3764, 3791, 3806], 'a': [92, 195, 329, 432, 569, 612, 1084, 1539, 1553, 2298, 2372, 2505, 2847, 3045, 3060, 3190, 3218, 3484, 3490, 3651, 3657, 3739, 3750, 3911, 3969, 4011, 4031, 4042, 4057, 4060, 4159], 'combination': [93, 330], 'chimeric': [95, 332, 2201, 4125], 'constructs': [96, 333, 2202, 3170, 4035, 4224, 4303, 4342], 'point': [98, 335, 2204, 3167, 3513, 3702, 4133], 'mutants': [99, 336, 3199, 3236, 3291, 3299, 3315, 3331, 3373, 3514, 3703, 4134], 'identify': [101, 338, 2007, 2211, 2255], 'structural': [102, 339], 'determinants': [103, 340, 2193, 3391, 3545], 'PS1-selective': [105, 124, 136, 342, 361, 373], 'ELN318463.': [108, 127, 345, 364], 'Our': [109, 213, 346, 450, 2277], 'studies': [110, 347, 553, 2210, 4123, 4131], 'identified': [111, 150, 182, 348, 387, 419, 3274], 'amino': [112, 152, 349, 389, 3397, 3430, 3462, 3486, 3492, 3551, 3590, 3630, 3653, 3659], 'acid': [113, 350, 3398, 3431, 3463, 3487, 3493, 3552, 3591, 3631, 3654, 3660], 'residues': [114, 129, 179, 351, 366, 416, 2213, 2233, 2253, 2257, 3376, 3432, 3464, 3592, 3632], 'Leu172,': [115, 146, 352, 383, 2226], 'Thr281,': [116, 147, 353, 384, 2227], 'Leu282': [118, 149, 355, 386, 2229, 3614], 'necessary': [122, 359, 2215], 'These': [128, 190, 365, 427, 2232], 'also': [130, 164, 367, 401, 1012, 2234], 'contributed': [131, 368], 'part': [133, 370, 2237], 'Alanine': [140, 377, 2712], 'scanning': [141, 378, 2247, 2713, 3198, 3235, 3314, 3330, 4144], 'mutagenesis': [142, 379, 2248, 2714, 2731, 4145], 'areas': [144, 381], 'flanking': [145, 382, 2251], 'additional': [151, 388, 1019, 2256], 'acids': [153, 390], 'affect': [155, 392, 1123, 2261], 'inhibitor': [156, 393, 2263, 4014, 4039, 4063], 'potency': [157, 394, 2264, 3283, 3294, 3302, 4064, 4082, 4092, 4157, 4253], 'not': [159, 396], 'only': [160, 397], 'these': [161, 177, 398, 414, 2198, 2252, 2287, 4310], 'but': [163, 400], 'nonsulfonamide': [165, 402], 'without': [167, 404, 1576, 4312], 'affecting': [168, 405], 'Aβ': [169, 231, 406, 468, 566, 595, 1007, 1573, 1619, 1632, 1816, 2028, 3105, 3113, 3140, 3182, 3203, 3211, 3221, 3250, 3259, 3310, 3326, 3348, 3760, 3768, 3777, 3819, 3867, 3916, 4002], 'endoproteolysis.': [173, 410], 'Interestingly,': [174, 411], 'many': [175, 412, 1018], 'same': [178, 415, 3266], 'have': [180, 417, 559], 'been': [181, 418, 1120], 'previously': [183, 420], 'important': [186, 423], 'function.': [189, 426], 'findings': [191, 428, 2278], 'implicate': [192, 429], 'TM3': [193, 430, 3586], 'second': [196, 433], 'region': [197, 434, 3565, 3626], 'near': [198, 435], 'carboxyl': [200, 437, 3816], 'terminus': [201, 438, 3817], 'aminoterminal': [204, 441], 'fragment': [205, 442, 958, 988], 'mediating': [207, 444], 'activity': [209, 446, 3232], 'inhibitors.': [212, 449, 2009], 'observations': [214, 451], 'demonstrate': [215, 452, 2291], 'PS-selective': [217, 454, 2008], 'inhibitors': [218, 225, 455, 462, 1115, 1537, 1557, 1569, 1809, 2015, 2288, 3079, 3906, 3990, 4256], 'feasible,': [222, 459], 'such': [224, 461], 'may': [226, 463, 1810], 'allow': [227, 464], 'differential': [228, 465], 'peptide': [232, 469, 941, 971, 1008, 1574, 3868], 'Notch': [235, 472, 1026, 1070, 1076, 1089, 1091, 1110, 1532, 1812], 'signaling.': [236, 473, 1090], 'most': [475, 1024, 2022], 'common': [476], 'cause': [477], 'dementia': [479], 'elderly': [482], 'is': [483, 611, 1011, 1093, 1538, 1564, 2297, 3307, 3615, 4087], 'disease': [485, 938, 953, 968, 983], '(AD),': [486], '3The': [487, 512], 'abbreviations': [488, 513], 'used': [489, 514, 3188, 3875], 'are:': [490, 515], 'ADAlzheimer': [491, 516], 'diseaseAβamyloid': [492, 517], 'peptideAPPamyloid': [494, 519], 'precursor': [495, 520, 943, 973, 1003], 'proteinAPPswSwedish': [496, 521], 'mutant': [497, 522, 946, 976, 3168, 3225, 3255, 4162, 4183, 4333], 'version': [498, 523, 947, 977], 'APP751': [500, 525, 949, 979, 1998], 'isoformFADfamilial': [501, 526], 'diseasedKO,': [503, 528], 'cellsdouble': [504, 529], 'knock-out': [505, 530, 955, 985, 2710, 2744, 4271], 'cellsNTFN-terminal': [506, 531], 'fragmentPSpresenilinTMDtransmembrane': [507, 532], 'domainWTwild': [508, 533], 'typeELISAenzyme-linked': [509, 534], 'immunosorbent': [510, 535, 965, 995], 'assay.': [511, 536, 966, 996], 'which': [537, 2634, 3280, 3613], 'bears': [538], 'pathological': [539], 'hallmarks': [540], 'plaques': [543], 'neurofibrillary': [545], 'tangles.': [546], 'Extensive': [547], 'genetic,': [548], 'biochemical,': [549], 'molecular,': [550], 'cellular': [552, 1096], 'over': [554, 4085], 'last': [556], '2': [557, 2802, 3963, 4220], 'decades': [558], 'implicated': [560], 'critical': [570, 1094], 'initiating': [571], 'event': [572], 'leading': [573], 'pathogenesis': [576], 'AD': [578, 1563], '(reviewed': [579, 891, 1027], 'Ref.': [581], '1Hardy': [582], 'J.': [583, 768, 811, 817, 831, 1144, 1163, 1176, 1178, 1225, 1267, 1399, 1405, 1749, 1774, 1863, 1888, 1905, 2104, 2121, 2324, 2655], 'Selkoe': [584, 1912, 2869], 'D.J.': [585, 1299, 1516, 1913, 2870], 'Science.': [586, 797, 2977], '2002;': [587, 848, 876, 929, 1037], '297:': [588], '353-356Crossref': [589], 'PubMed': [590, 702, 754, 801, 856, 879, 900, 917, 932, 1040, 1062, 1170, 1200, 1236, 1278, 1314, 1342, 1393, 1423, 1446, 1469, 1490, 1525, 1656, 1707, 1731, 1785, 1845, 1899, 1925, 1959, 1981, 2076, 2128, 2660, 2773, 2875, 2954, 2981, 3862, 4292], 'Scopus': [591, 703, 755, 802, 857, 880, 901, 918, 933, 1041, 1063, 1171, 1201, 1237, 1279, 1315, 1343, 1394, 1424, 1447, 1470, 1491, 1526, 1657, 1708, 1732, 1786, 1846, 1900, 1926, 1960, 1982, 2077, 2129, 2774, 2876, 2955, 2982, 3863, 4293], '(10860)': [592], 'Google': [593, 705, 757, 804, 859, 882, 903, 920, 935, 1043, 1065, 1173, 1203, 1239, 1281, 1317, 1345, 1396, 1426, 1449, 1472, 1493, 1528, 1659, 1710, 1734, 1788, 1848, 1902, 1928, 1962, 1984, 2079, 2131, 2661, 2776, 2878, 2957, 2984, 3865, 4295], 'Scholar).': [594, 883, 936, 1066, 1529, 1789, 1985, 2616, 3866], 'produced': [598, 3114, 3141, 3222, 3251], 'action': [601], 'two': [603, 2267], 'enzymes,': [604], 'β-secretase': [605], 'enzyme': [610, 4307], 'large': [613, 4032], 'molecular': [614], 'complex': [615], 'composed': [616, 2850], 'four': [618], 'principal': [619], 'subunits,': [620], 'presenilins': [622, 2296], '(PS1': [623], 'or': [624, 2002, 2032, 2959, 3427, 3508, 3519, 3697, 3709, 3759, 3893, 3907, 4045, 4059, 4259, 4300, 4332, 4335, 4347], 'PS2),': [625], 'nicastrin,': [626], 'Aph-1,': [627], 'Pen-2': [629], '(2Sherrington': [630, 2882], 'R.': [631, 710, 807, 839, 1186, 1370, 1411, 1454, 1684, 1759, 1771, 1873, 1885, 1954, 2114, 2839, 2883, 3829, 3835], 'Rogaev': [632, 2884], 'E.I.': [633, 708, 2885], 'Liang': [634, 717, 2886], 'Y.': [635, 718, 2887], 'Rogaeva': [636, 711, 2888], 'E.A.': [637, 712, 2889], 'Levesque': [638, 713, 2890], 'G.': [639, 647, 714, 809, 1329, 1482, 1643, 1832, 2046, 2891, 2899, 3833], 'Ikeda': [640, 715, 1968, 2892], 'M.': [641, 716, 815, 819, 821, 833, 864, 1256, 1305, 1409, 1506, 1508, 1512, 1753, 1757, 1765, 1867, 1871, 1879, 1969, 2050, 2092, 2151, 2160, 2320, 2588, 2597, 2854, 2893, 3827, 3839], 'Chi': [642, 719, 2894], 'H.': [643, 720, 906, 1152, 1218, 1250, 1293, 1309, 1327, 1366, 1510, 1520, 1641, 1680, 1737, 1743, 1830, 1851, 1857, 1971, 2170, 2171, 2607, 2608, 2895, 3841], 'Lin': [644, 721, 2896], 'C.': [645, 722, 841, 862, 908, 1180, 1773, 1887, 2141, 2163, 2578, 2600, 2858, 2866, 2897], 'Li': [646, 830, 1292, 2898], 'Holman': [648, 723, 2900], 'K.': [649, 724, 778, 1325, 1334, 1356, 1639, 1648, 1670, 1739, 1755, 1828, 1837, 1853, 1869, 1940, 2062, 2066, 2096, 2901, 3825, 3831, 3837], 'Tsuda': [650, 725, 2902], 'T.': [651, 726, 1154, 1252, 1301, 1484, 1767, 1769, 1881, 1883, 2856, 2903], 'Mar': [652, 727, 2904], 'L.': [653, 665, 667, 728, 736, 742, 1158, 1182, 1254, 1262, 1295, 1358, 1360, 1672, 1674, 1715, 1721, 2757, 2763, 2860, 2905, 2917, 2919, 2968, 3851, 4276, 4282], 'Foncin': [654, 2906], 'J.F.': [655, 2907], 'Bruni': [656, 2908], 'A.C.': [657, 780, 2909], 'Montesi': [658, 2910], 'M.P.': [659, 2911], 'Sorbi': [660, 729, 2912], 'S.': [661, 730, 734, 874, 1388, 1441, 1464, 1514, 1702, 1747, 1763, 1861, 1877, 1915, 2176, 2613, 2913, 3857], 'Rainero': [662, 2914], 'I.': [663, 669, 738, 2064, 2868, 2915, 2921, 3845], 'Pinessi': [664, 2916], 'Nee': [666, 2918], 'Chumakov': [668, 737, 2920], 'Pollen': [670, 2922], 'D.': [671, 740, 786, 845, 1049, 1148, 1244, 1350, 1374, 1664, 1688, 1719, 2060, 2134, 2154, 2571, 2591, 2761, 2923, 3843, 3847, 4280], 'Brookes': [672, 2924], 'A.': [673, 875, 1190, 1291, 1348, 1376, 1389, 1442, 1465, 1662, 1690, 1703, 1713, 1741, 1855, 1952, 1975, 2088, 2755, 2925, 3858, 4274], 'Sanseau': [674, 2926], 'P.': [675, 764, 1297, 1323, 1354, 1372, 1403, 1415, 1637, 1668, 1686, 1826, 1936, 1938, 2146, 2583, 2864, 2927, 3849], 'Polinsky': [676, 2928], 'R.J.': [677, 2929], 'Wasco': [678, 761, 2930], 'W.': [679, 762, 829, 1331, 1352, 1645, 1666, 1717, 1834, 1911, 1934, 2157, 2594, 2759, 2931, 4278], 'Da': [680, 2932], 'Silva': [681, 2933], 'H.A.R.': [682, 2934], 'Haines': [683, 2935], 'J.L.': [684, 2936, 2972], 'Pericak-Vance': [685, 2937], 'M.A.': [686, 1220, 2938], 'Tanzi': [687, 795, 2939], 'R.E.': [688, 796, 2940], 'Roses': [689, 2941], 'A.D.': [690, 2942], 'Fraser': [691, 743, 2943], 'P.E.': [692, 744, 2944], 'Rommens': [693, 745, 2945], 'J.M.': [694, 746, 2946], 'St': [695, 747, 2947], 'George-Hyslop': [696, 748, 2948], 'P.H.': [697, 749, 2949], 'Nature.': [698, 750, 1310, 1338, 1521, 1652, 1841, 1955, 2871, 2950], '1995;': [699, 751, 798, 2951, 2978], '375:': [700, 2952], '754-760Crossref': [701, 2953], '(3565)': [704, 2956], 'Scholar,': [706, 758, 805, 860, 904, 921, 1174, 1204, 1240, 1318, 1346, 1397, 1427, 1450, 1473, 1494, 1660, 1711, 1735, 1849, 1903, 1929, 1963, 2080, 2132], '3Rogaev': [707], 'Sherrington': [709], 'Nacmias': [731], 'B.': [732, 823, 1052, 1192, 1321, 1382, 1635, 1696, 1724, 1761, 1824, 1875, 1932, 2052, 2054, 2068, 2094, 2098, 2766, 4285], 'Piacentini': [733], 'Amaducci': [735], 'Cohen': [739], 'Lannfelt': [741], '376:': [752], '775-778Crossref': [753], '(1782)': [756], '4Levy-Lahad': [759], 'E.': [760, 788, 1047, 2962, 2966], 'Poorkaj': [763], 'Romano': [765], 'D.M.': [766, 2082], 'Oshima': [767], 'Pettingell': [769], 'W.H.': [770, 1208], 'Yu': [771, 1750, 1864], 'C.E.': [772, 1477], 'Jondro': [773], 'P.D.': [774], 'Schmidt': [775], 'S.D.': [776], 'Wang': [777, 2053, 2097, 2103], 'Crowley': [779], 'Fu': [781], 'Y.-H.': [782], 'Guenette': [783], 'S.Y.': [784], 'Galas': [785], 'Nemens': [787, 2965], 'Wijsman': [789, 2963], 'E.M.': [790, 1160, 1266, 2964], 'Bird': [791, 2973], 'T.D.': [792, 2974], 'Schellenerg': [793], 'G.D.': [794, 2976], '269:': [799, 2979], '973-977Crossref': [800], '(2220)': [803], '5Francis': [806], 'McGrath': [808], 'Zhang': [810, 1145, 1157, 1247, 1261], 'Ruddy': [812], 'D.A.': [813, 1435, 1458], 'Sym': [814], 'Apfeld': [816], 'Nicoll': [818], 'Maxwell': [820], 'Hai': [822], 'Ellis': [824], 'M.C.': [825], 'Parks': [826], 'A.L.': [827], 'Xu': [828], 'Gurney': [832], 'Myers': [834], 'R.L.': [835], 'Himes': [836], 'C.S.': [837], 'Hiebsch': [838], 'Ruble': [840], 'Nye': [842], 'J.S.': [843, 1258, 1942], 'Curtis': [844], 'Dev.': [846, 1486, 1977], 'Cell.': [847, 1916], '3:': [849, 930, 1038], '85-97Abstract': [850], 'Full': [851, 853, 1057, 1059, 1231, 1233, 1273, 1275, 1780, 1782, 1894, 1896, 1920, 1922], 'Text': [852, 854, 1058, 1060, 1232, 1234, 1274, 1276, 1781, 1783, 1895, 1897, 1921, 1923], 'PDF': [855, 1061, 1235, 1277, 1784, 1898, 1924], '(710)': [858], '6Goutte': [861], 'Tsunozaki': [863], 'Hale': [865], 'V.A.': [866], 'Priess': [867], 'J.R.': [868], 'Proc.': [869, 1383, 1436, 1459, 1697, 3852], 'Natl.': [870, 1384, 1437, 1460, 1698, 3853], 'Acad.': [871, 1385, 1438, 1461, 1699, 3854], 'Sci.': [872, 1196, 1386, 1439, 1462, 1700, 3855], 'U.': [873, 1307, 1387, 1440, 1463, 1701, 2175, 2612, 3856], '99:': [877], '775-779Crossref': [878], '(371)': [881], 'γ-Secretase': [884, 1067], 'functions': [885], 'an': [887, 2305, 4080, 4166], 'intramembrane-cleaving': [888], 'aspartyl': [889], 'protease': [890], 'Refs.': [893, 1029], '7Wolfe': [894], 'M.S.': [895, 1948], 'Biochemistry.': [896], '2006;': [897, 1167], '45:': [898], '7931-7939Crossref': [899], '(179)': [902], '8Steiner': [905], 'Haass': [907, 1772, 1886, 2857], 'Nat.': [909, 924, 1032, 1418, 1725, 2767, 4286], 'Rev.': [910, 925, 1033], 'Mol.': [911, 926, 1034], 'Cell': [912, 927, 1035, 1726, 2734, 2768, 4287], 'Biol.': [913, 928, 1036, 1226, 1268, 1727, 1775, 1889, 2769, 4288], '2000;': [914, 1420, 1728, 2770, 4289], '1:': [915], '217-224Crossref': [916], '(144)': [919], '9Fortini': [922, 1030], 'M.E.': [923, 1031, 1500], '673-684Crossref': [931, 1039], '(342)': [934, 1042], 'protein': [944, 974, 1004, 3098], 'Swedish': [945, 975, 1997], 'isoform': [950, 980], 'familial': [951, 981], 'double': [954, 984, 2709, 2743], 'cells': [956, 986, 2745, 2998, 3041, 3056, 3068, 3500, 3689, 4008], 'N-terminal': [957, 987], 'transmembrane': [960, 990, 1022, 3571], 'domain': [961, 991, 1078], 'wild': [962, 992, 3228, 3261, 3322, 3338, 4185, 4330], 'type': [963, 993, 3229, 3262, 3323, 3339, 4186, 4331], 'enzyme-linked': [964, 994], 'addition': [998, 3016], 'processing': [1000, 1016, 1581], 'β-amyloid': [1002], '(APP)': [1005], 'production,': [1009, 1575], 'involved': [1013], 'Type': [1020], 'I': [1021], 'proteins,': [1023], 'notably': [1025], 'Scholar': [1044], '10Marjaux': [1046], 'Hartmann': [1048, 1349, 1663], 'De': [1050, 1380, 1694, 1722, 2752, 2764, 4283], 'Strooper': [1051, 1320, 1381, 1634, 1695, 1723, 1823, 1931, 2765, 4284], 'Neuron.': [1053], '2004;': [1054, 1197, 1270], '42:': [1055], '189-192Abstract': [1056], '(63)': [1064], 'cleavage': [1068], 'leads': [1071], 'nuclear': [1073], 'translocation': [1074], 'intracellular': [1077], 'expression': [1080, 3119, 3125, 4302, 4341], 'downstream': [1082], 'genes,': [1083], 'process': [1085], 'signaling': [1092, 1111, 1533, 1813], 'differentiation': [1097, 1125], 'during': [1098], 'development,': [1099], 'well': [1101, 2270, 3122], 'tissue': [1103, 1124], 'homeostasis': [1104, 1128], 'adults.': [1106], 'Pharmacological': [1107], 'nonselective': [1113, 1535], 'adult': [1117], 'mice': [1118, 1607, 1796, 1803, 1993, 4272], 'has': [1119], 'demonstrated': [1121], 'cell': [1127, 2830, 2842], 'multiple': [1130, 3285], 'systems': [1131], '(e.g.': [1132, 4089], 'gastrointestinal': [1133], 'tract,': [1134], 'pancreas,': [1135], 'skin,': [1136], 'lymphocytes)': [1138], '(11Hyde': [1139], 'L.A.': [1140], 'McHugh': [1141], 'N.A.': [1142], 'Chen': [1143, 1908], 'Q.': [1146, 1248], 'Manfra': [1147, 1243], 'Nomeir': [1149], 'A.A.': [1150], 'Josien': [1151, 1249], 'Bara': [1153, 1251], 'Clader': [1155], 'J.W.': [1156], 'Parker': [1159, 1265], 'Higgins': [1161, 1219, 1263], 'G.A.': [1162, 1264], 'Pharmacol.': [1164, 2072, 2122], 'Exp.': [1165, 2123], 'Ther.': [1166, 2124], '319:': [1168], '1133-1143Crossref': [1169], '(64)': [1172], '12Milano': [1175], 'McKay': [1177], 'Dagenais': [1179], 'Foster-Brown': [1181], 'Pognan': [1183], 'F.': [1184, 1337, 1364, 1379, 1413, 1518, 1651, 1678, 1693, 1840], 'Gadient': [1185], 'Jacobs': [1187], 'R.T.': [1188, 1907], 'Zacco': [1189], 'Greenberg': [1191], 'Ciaccio': [1193], 'P.J.': [1194, 1475], 'Toxicol.': [1195], '82:': [1198], '341-358Crossref': [1199], '(471)': [1202], '13Searfoss': [1205], 'G.H.': [1206], 'Jordan': [1207], 'Calligaro': [1209], 'D.O.': [1210], 'Galbreath': [1211], 'E.J.': [1212], 'Schirtzinger': [1213], 'L.M.': [1214], 'Berridge': [1215], 'B.R.': [1216], 'Gao': [1217], 'May': [1221], 'P.C.': [1222], 'Ryan': [1223], 'T.P.': [1224], 'Chem.': [1227, 1269, 1776, 1890], '2003;': [1228, 1443], '278:': [1229], '46107-46116Abstract': [1230], '(323)': [1238], '14Wong': [1241], 'G.T.': [1242], 'Poulet': [1245], 'F.M.': [1246], 'Engstrom': [1253], 'Pinzon-Ortiz': [1255], 'Fine': [1257], 'Lee': [1259, 3826], 'H.J.': [1260], '279:': [1271], '12876-12882Abstract': [1272], '(654)': [1280], 'Scholar),': [1282, 2879], 'consistent': [1283, 3144], 'with': [1284, 1579, 1996, 2342, 2400, 2422, 2437, 2469, 2541, 2545, 2724, 2814, 3027, 3074, 3104, 3149, 3166, 3257, 3503, 3517, 3692, 3706, 3779, 3904, 3925, 3951, 3962, 3968, 4010, 4096, 4124, 4132, 4298, 4350], 'predictions': [1285], 'from': [1286, 1605, 1990, 2030, 2451, 2637, 2707, 2740, 2749, 3107, 3184, 3223, 3253, 3260, 3312, 3328, 3352, 3370, 3499, 3619, 3688, 3897, 4007, 4049, 4071, 4121, 4217, 4268], 'KO': [1287, 1606, 1795, 1802], 'mouse': [1288], 'models': [1289], '(15Apelqvist': [1290], 'Sommer': [1294], 'Beatus': [1296], 'Anderson': [1298, 2109, 2967], 'Honjo': [1300], 'Hrabe': [1302], 'de': [1303], 'Angelis': [1304], 'Lendahl': [1306], 'Edlund': [1308], '1999;': [1311, 1390, 1704, 1777, 1891, 1956, 1978], '400:': [1312], '877-881Crossref': [1313], '(970)': [1316], '16De': [1319], 'Saftig': [1322, 1353, 1636, 1667, 1825, 1937], 'Craessaerts': [1324, 1355, 1638, 1669, 1827, 1939], 'Vanderstichele': [1326, 1365, 1640, 1679, 1829], 'Guhde': [1328, 1642, 1831], 'Annaert': [1330, 1351, 1644, 1665, 1716, 1833, 1933, 2758, 4277], 'Von': [1332, 1646, 1835], 'Figura': [1333, 1647, 1836], 'Van': [1335, 1377, 1649, 1691, 1838], 'Leuven': [1336, 1378, 1650, 1692, 1839], '1998;': [1339, 1653, 1842], '391:': [1340, 1654, 1843], '387-390Crossref': [1341, 1655, 1844], '(1544)': [1344, 1658, 1847], '17Herreman': [1347, 1661], 'Serneels': [1357, 1671, 1714, 2756, 4275], 'Umans': [1359, 1673], 'Schrijvers': [1361, 1675, 1945], 'V.': [1362, 1368, 1676, 1682, 1946], 'Checler': [1363, 1677], 'Baekelandt': [1367, 1681], 'Dressel': [1369, 1683], 'Cupers': [1371, 1685, 1935], 'Huylebroeck': [1373, 1687], 'Zwijsen': [1375, 1689], '96:': [1391, 1705], '11872-11877Crossref': [1392, 1706], '(432)': [1395, 1709], '18Jensen': [1398], 'Pedersen': [1400], 'E.E.': [1401], 'Galante': [1402], 'Hald': [1404], 'Heller': [1406], 'R.S.': [1407], 'Ishibashi': [1408], 'Kageyama': [1410], 'Guillemot': [1412], 'Serup': [1414], 'Madsen': [1416], 'O.D.': [1417], 'Genet.': [1419], '24:': [1421], '36-44Crossref': [1422], '(943)': [1425], '19Murtaugh': [1428], 'L.C.': [1429, 1456], 'Stanger': [1430], 'B.Z.': [1431, 1452], 'Kwan': [1432], 'K.M.': [1433, 2120], 'Melton': [1434, 1457], '100:': [1444], '14920-14925Crossref': [1445], '(606)': [1448], '20Stanger': [1451], 'Datar': [1453], 'Murtaugh': [1455], '2005;': [1466, 1522, 2073, 2125], '102:': [1467], '12443-12448Crossref': [1468], '(240)': [1471], '21Swiatek': [1474], 'Lindsell': [1476], 'del': [1478], 'Amo': [1479], 'F.F.': [1480], 'Weinmaster': [1481], 'Gridley': [1483], 'Genes': [1485, 1976], '1994;': [1487], '8:': [1488], '707-719Crossref': [1489], '(605)': [1492], '22van': [1495], 'Es': [1496], 'J.H.': [1497], 'van': [1498, 1503], 'Gijn': [1499], 'Riccio': [1501], 'O.': [1502, 2166, 2603], 'den': [1504], 'Born': [1505], 'Vooijs': [1507], 'Begthel': [1509], 'Cozijnsen': [1511], 'Robine': [1513], 'Winton': [1515], 'Radtke': [1517], 'Clevers': [1519], '435:': [1523], '959-963Crossref': [1524], '(1249)': [1527], 'Inhibition': [1530], 'potentially': [1540], 'limiting': [1541], 'issue': [1542], 'clinical': [1545], 'development': [1546, 1566], 'this': [1548, 2189, 2841, 3089, 3993, 4101], 'class': [1549], 'therapeutics.': [1551], 'Hence,': [1552], 'major': [1554], 'objective': [1555], 'targeting': [1558, 2294], 'can': [1571], 'reduce': [1572], 'significantly': [1577], 'interfering': [1578], 'other': [1583], 'substrates': [1584], 'principally': [1587], 'Notch.': [1588], 'Observations': [1604], 'show': [1608, 3208, 3362], 'Presenilin': [1610, 2679], '1': [1611, 3003, 3179, 3277, 3783, 4095], 'containing': [1612, 1625, 2791], '∼80%': [1616], 'total': [1618, 1631, 3249, 3258], 'brain,': [1622], 'whereas': [1623, 1800, 3679], 'PS2': [1624, 1801, 2005, 2033, 2960, 3437, 3491, 3597, 3658, 3677, 4301, 4336], '∼20%': [1629], '(16De': [1633, 1822], '23Herreman': [1712], 'Collen': [1718, 2760, 4279], 'Schoonjans': [1720, 2762, 4281], '2:': [1729, 2771, 4290], '461-462Crossref': [1730, 2772, 4291], '(450)': [1733, 2775, 4294], '24Steiner': [1736, 1850], 'Duff': [1738, 1852], 'Capell': [1740, 1854], 'Romig': [1742, 1856], 'Grim': [1744, 1858], 'M.G.': [1745, 1859], 'Lincoln': [1746, 1860], 'Hardy': [1748, 1862], 'X.': [1751, 1865], 'Picciano': [1752, 1866], 'Fechteler': [1754, 1868], 'Citron': [1756, 1870], 'Kopan': [1758, 1872, 1953], 'Pesold': [1760, 1874], 'Keck': [1762, 1876], 'Baader': [1764, 1878], 'Tomita': [1766, 1880], 'Iwatsubo': [1768, 1882], 'Baumeister': [1770, 1884], '274:': [1778, 1892], '28669-28673Abstract': [1779, 1893], '(272)': [1787, 1901], 'Furthermore,': [1790, 4118], 'observation': [1792, 2190], 'exhibit': [1797], 'perinatal': [1798], 'lethality,': [1799], 'viable': [1805, 1820], 'suggests': [1806], 'PS2-selective': [1808], 'spare': [1811], 'while': [1814], 'lowering': [1815], 'appreciably': [1817], 'therapeutics': [1821], '25Shen': [1904], 'Bronson': [1906], 'D.F.': [1909], 'Xia': [1910], 'Tonegawa': [1914], '1997;': [1917, 3859], '89:': [1918], '629-639Abstract': [1919], '(845)': [1927], '26De': [1930], 'Mumm': [1941], 'Schroeter': [1943], 'E.H.': [1944], 'Wolfe': [1947], 'Ray': [1949], 'W.J.': [1950], 'Goate': [1951], '398:': [1957], '518-522Crossref': [1958], '(1792)': [1961], '27Donoviel': [1964], 'D.B.': [1965], 'Hadjantonakis': [1966], 'A.K.': [1967], 'Zheng': [1970, 2091], 'Hyslop': [1972], 'P.S.': [1973], 'Bernstein': [1974], '13:': [1979], '2801-2810Crossref': [1980], '(409)': [1983], 'transformed': [1988, 2704, 4263], 'fibroblasts': [1989, 2705, 2738, 4266], 'double-KO': [1992], 'transiently': [1994, 4353], 'transfected': [1995, 3185, 3502, 3691, 3901, 4297], '(APPsw)': [1999], '+': [2000, 2004], 'APPsw': [2003, 2626], 'Among': [2010], 'different': [2012, 3075, 3465, 3593, 3633], 'tested,': [2017], 'noted': [2019], 'although': [2021], 'were': [2023, 2405, 2441, 2629, 2681, 2778, 2806, 2999, 3042, 3057, 3069, 3093, 3115, 3883, 3920, 3947, 3960, 3995, 4047, 4065, 4127, 4225, 4352], 'equipotent': [2024], '(this': [2039], 'report)': [2040], 'BMS299897': [2042, 2561], '(28Anderson': [2043], 'J.J.': [2044, 2110], 'Holtz': [2045], 'Baskin': [2047], 'P.P.': [2048], 'Turner': [2049], 'Rowe': [2051], 'Kounnas': [2055], 'M.Z.': [2056], 'Lamb': [2057], 'B.T.': [2058], 'Barten': [2059], 'Felsenstein': [2061, 2119], 'McDonald': [2063], 'Srinivasan': [2065, 2095], 'Munoz': [2067, 2093], 'Wagner': [2069], 'S.L.': [2070], 'Biochem.': [2071], '69:': [2074], '689-698Crossref': [2075], '(99)': [2078], '29Barten': [2081], 'Guss': [2083], 'V.L.': [2084], 'Corsa': [2085], 'J.A.': [2086], 'Loo': [2087], 'Hansel': [2089], 'S.B.': [2090, 2106], 'Robertson': [2099], 'B.J.': [2100], 'Polson': [2101], 'C.T.': [2102], 'Roberts': [2105, 2651], 'Hendrick': [2107], 'J.P.': [2108], 'Loy': [2111], 'J.K.': [2112], 'Denton': [2113], 'Verdoorn': [2115], 'T.A.': [2116], 'Smith': [2117, 2567], 'D.W.': [2118], '312:': [2126], '635-643Crossref': [2127], '(154)': [2130], '30Smith,': [2133], 'W.,': [2135, 2572], 'Munoz,': [2136, 2573], 'B.,': [2137, 2167, 2574, 2604], 'Srinivasan,': [2138, 2575], 'K.,': [2139, 2576], 'Bergstrom,': [2140, 2577], 'P.,': [2142, 2164, 2579, 2601], 'Prasad,': [2143, 2580], 'V.,': [2144, 2147, 2581, 2584], 'Chaturvedula,': [2145, 2582], 'Milind,': [2148, 2585], 'S.,': [2149, 2152, 2321, 2586, 2589], 'Deshpande,': [2150, 2587], 'Keavy,': [2153, 2590], 'J.,': [2155, 2592], 'Lau,': [2156, 2593], 'Y.,': [2158, 2595], 'Parker,': [2159, 2596], 'F.,': [2161, 2598], 'Solan,': [2162, 2599], 'Wallace,': [2165, 2602], 'Wang,': [2169, 2606], '(February': [2172, 2609], '22,': [2173, 2610], '2000)': [2174, 2611], 'Patent': [2177, 2614], '6967196Google': [2178, 2615], 'Scholar)': [2179, 2333, 2662, 2777, 2958, 2985, 4296], 'displayed': [2180], 'exploited': [2188], 'map': [2192], 'using': [2200, 2808, 2821, 3039, 3095, 3127, 3888, 4016, 4165, 4262], 'mutants.': [2205], 'results': [2207], 'our': [2209, 4119], '3': [2212, 3355, 3572], 'sufficient': [2217], 'PS-1': [2221], 'sulfonamide': [2224], 'ELN318463:': [2225], 'PS1.': [2231, 3230, 3324, 3340], 'contribute': [2235], 'performed': [2245, 2807, 3884], 'alanine': [2246, 3197, 3234, 3313, 3329, 3372, 3734, 3745, 4143, 4161], 'regions': [2250, 3242], 'DAPT': [2274], 'L-685,458.': [2276], 'provide': [2279], 'insights': [2280], 'into': [2281, 2631, 2703, 3002, 3019, 3034, 3489, 3656], 'possible': [2283], 'binding': [2284], 'sites': [2285], 'and,': [2289], 'furthermore,': [2290], 'feasible': [2299], 'strategy': [2300], 'inhibiting': [2302], 'isoform-specific': [2306], 'manner': [2307], 'AD.': [2311], 'Chemical': [2312], 'Synthesis—Synthesis': [2313], '(R)-3-(4-bromobenzylamino)azepan-2-one.': [2315], 'd-α-Amino-ϵ-caprolactam': [2316], '(63Neitzel,': [2317], 'M.,': [2318], 'Dappen,': [2319], 'Marugg,': [2323], '(May': [2325], '12,': [2326], '2005)': [2327], 'PCT': [2328], 'International': [2329], 'Application': [2330], 'WO': [2331], '2005042489Google': [2332], '(0.04': [2334], 'm)': [2335], 'methanol': [2337], '(100': [2338], 'ml)': [2339, 2456, 2511], 'was': [2340, 2350, 2366, 2378, 2382, 2393, 2411, 2420, 2434, 2445, 2449, 2464, 2499, 2527, 2535, 2539, 2562, 2635, 2698, 2721, 2832, 2986, 2992, 3142, 3187, 3245, 3475, 3643, 3874, 4163], 'treated': [2341, 3070, 3516, 3705, 3903, 4009], '4-bromobenzaldehyde': [2343], '(0.046': [2344], 'm),': [2345], 'resulting': [2348], 'solution': [2349, 2512], 'stirred': [2351, 2383], 'at': [2352, 2384, 2780, 3044, 3059, 3885], 'room': [2353, 2385, 2530, 3886], 'temperature': [2354, 2386, 3887], '24': [2356], 'h.': [2357], 'Polymer-supported': [2358], 'borohydride': [2359], '(40': [2360, 2510], 'g;': [2361], 'Aldrich': [2362], 'on': [2363, 4062, 4067], 'Amberlite': [2364], 'IRA-400)': [2365], 'added': [2367, 2500], 'one': [2369, 2502, 3509, 3698], 'portion,': [2370], 'slight': [2373], 'exotherm': [2374], 'some': [2376], 'bubbling': [2377], 'observed.': [2379], 'mixture': [2381, 2849, 2991], '20': [2388], 'h,': [2389], 'resin': [2392], 'then': [2394, 2435, 3009], 'filtered': [2395, 2442, 2465], 'off': [2396], 'thoroughly': [2398], 'washed': [2399, 2421, 2467, 3948], 'methanol.': [2401], 'combined': [2403], 'filtrates': [2404], 'evaporated': [2406], 'dryness.': [2408], 'residue': [2410, 2448, 2538, 3488, 3655], 'dissolved': [2412], 'ethyl': [2414, 2453, 2471, 2549], 'acetate,': [2415], 'organic': [2418, 2432], 'phase': [2419, 2433], 'water,': [2423, 2428], 'saturated': [2424], 'aqueous': [2425], 'sodium': [2426, 2438], 'bicarbonate,': [2427], 'brine.': [2430], 'dried': [2436], 'sulfate.': [2439], 'Solids': [2440], 'off,': [2443, 2466], 'filtrate': [2444], 'evaporated,': [2446], 'recrystallized': [2450], 'hot': [2452], 'acetate': [2454, 2550], '(20': [2455], 'hexane': [2458, 2547], '(150': [2459], 'ml).': [2460, 2524], 'crystalline': [2462], 'product': [2463], 'briefly': [2468], 'cold': [2470], 'acetate/hexane': [2472], '(1:1)': [2473], 'mixture,': [2474], 'air-dried': [2476], 'yield': [2478], '7.8': [2479], 'g': [2480, 2554], '(R)-3-(4-bromobenzylamino)azepan-2-one': [2482], 'having': [2483, 2557], 'm/z': [2484, 2558], '=': [2485, 2559, 3354, 3378, 3532, 3722, 4189, 4219], '299.0.': [2486], 'Synthesis': [2487], '(R)-N-(4-bromobenzyl)-4-chloro-N-(2-oxoazepan-3-yl)': [2489], 'benzenesulfonamide': [2490], '(ELN318463)': [2491], 'BMS299897—4-Chlorobenzenesulfonyl': [2493], 'chloride': [2494, 2509], '(11.24': [2495], 'mmol,': [2496, 2516, 2522], '2.37': [2497], 'g)': [2498, 2518], 'portion': [2503], '0': [2506], '°C': [2507, 2782], 'methylene': [2508], '(R)-3-(4-bromobenzylamino)-azepan-2-one': [2514], '(7.49': [2515], '2.23': [2517], 'N,N-diisopropylethylamine': [2520], '(60': [2521], '8': [2523], 'reaction': [2526], 'warmed': [2528], 'temperature,': [2531], 'stirring': [2532], 'overnight.': [2533], 'Solvent': [2534], 'removed,': [2536], 'chromatographed': [2540], 'silica': [2542], 'gel': [2543], 'eluting': [2544], '1:1': [2546], 'obtain': [2552], '2.61': [2553], '(R)-N-(4-bromobenzyl)-4-chloro-N-(2-oxoazepan-3-yl)benzenesulfonamide': [2556], '473.0.': [2560], 'synthesized': [2563], 'described': [2565, 3156, 3991], 'et': [2568], 'al.': [2569], '(30Smith,': [2570], 'Molecular': [2617], 'Cloning': [2618], 'Construction': [2620], 'Chimeras—Human': [2622], 'PS1,': [2623, 3055], 'cDNA': [2627], 'inserts': [2628], 'subcloned': [2630], 'pCF': [2632], 'vector,': [2633], 'modified': [2636, 2788, 3024], 'pcDNA3': [2638], '(Invitrogen)': [2639], 'inserting': [2641], 'adenoviral': [2643], 'tripartite': [2644], 'leader': [2645], 'sequence': [2646, 2697, 3399, 3553], '(31Berkner': [2647], 'K.L.': [2648], 'Schaffhausen': [2649], 'B.S.': [2650], 'T.M.': [2652], 'Sharp': [2653], 'P.A.': [2654], 'Virol.': [2656], '1987;': [2657], '61:': [2658], '1213-1220Crossref': [2659], '38': [2663], 'bp': [2664], 'upstream': [2665], 'starting': [2668], 'ATG': [2669], 'codon,': [2670], 'between': [2671, 3405, 3434, 3466, 3559, 3585, 3594, 3634, 3949, 4083], 'cytomegalovirus': [2673], 'promoter': [2674], 'EcoRI': [2677], 'site.': [2678], 'chimeras': [2680], 'constructed': [2682], 'blunt': [2684], 'end': [2685], 'ligation': [2686], 'PCR-amplified': [2688], 'fragments': [2689], '(Pfu': [2690], 'Turbo': [2691], 'DNA': [2692, 2848], 'polymerase': [2693], 'kit;': [2694], 'Stratagene),': [2695], 'verified': [2699], 'prior': [2700], 'transfection': [2702, 2822, 3091, 3151, 3193, 4029], 'derived': [2706, 2739, 3351, 3996, 4267], 'PS1/PS2': [2708], 'mice.': [2711], 'C2': [2717, 3239, 3318, 3548, 3557, 3564, 3625, 3673, 4148, 4193], 'C5': [2719, 3241, 3334, 3394, 3403, 3410, 3457, 4150, 4195], 'subregions': [2720, 4196], 'carried': [2722], 'out': [2723], 'mutagenic': [2725], 'primers': [2726], 'QuikChange': [2729], 'site-directed': [2730], 'kit': [2732], '(Stratagene).': [2733], 'Culture': [2735], 'Transfection—Mouse': [2737], 'PS1-/-/PS2-/-': [2742], '(dKO': [2746], 'cells;': [2747], 'gift': [2748], 'Dr.': [2750], 'Bart': [2751], 'Strooper)': [2753], '(23Herreman': [2754, 4273], 'grown': [2779], '37': [2781], 'under': [2783, 3152, 4137], '10%': [2784, 3028], 'CO2': [2785], "Dulbecco's": [2787, 3023], "Eagle's": [2789, 3025], 'medium': [2790, 3026, 3896], '2-10%': [2792], 'fetal': [2793, 3029], 'bovine': [2794, 3030], 'serum': [2795], '100': [2797, 2835], 'μg/ml': [2798], 'penicillin/streptomycin': [2799], '(Invitrogen),': [2800], 'μml-glutamine': [2803], '(Invitrogen).': [2804], 'Transfections': [2805], 'Nucleofector': [2809], 'II': [2810], '(Amaxa': [2811], 'GmbH,': [2812], 'Germany)': [2813], 'about': [2815], '1-10': [2816], 'million': [2817], 'PS1-/-PS2-/-': [2819], 'cells,': [2820, 3902, 4311], 'reagents': [2823], 'supplied': [2824], 'manufacturer.': [2827], 'An': [2828], 'RPMI-washed': [2829], 'pellet': [2831], 'resuspended': [2833], 'μl': [2836, 3890], 'Solution': [2838], 'To': [2840], 'suspension,': [2843], '1-2': [2844], 'μg': [2845], 'APPsw,': [2852, 4351], '(32Citron': [2853], 'Oltersdorf': [2855], 'McConlogue': [2859, 3850], 'Hung': [2861], 'A.Y.': [2862], 'Seubert': [2863, 3848], 'Vigo-Pelfrey': [2865], 'Lieberburg': [2867, 3844], '1992;': [2872], '360:': [2873], '672-674Crossref': [2874], '(1527)': [2877], '(33Levy-Lahad': [2961], 'Goddard': [2969], 'K.A.': [2970], 'Weber': [2971], 'Schellenberg': [2975], '970-973Crossref': [2980], '(689)': [2983], 'added,': [2987], 'cell-DNA': [2990], 'electroporated': [2993], 'immediately': [2994], '(program': [2995], 'T-20).': [2996], 'Electroporated': [2997], 'first': [3000], 'suspended': [3001], 'ml': [3004, 3021], 'warm': [3006], 'RPMI': [3007], 'transferred': [3010], '(within': [3011], '2-5': [3012], 'min': [3013], 'after': [3014], 'RPMI)': [3018], '5-10': [3020], 'serum,': [3031], 'plating': [3033], '96-well': [3035, 3050, 3065], 'plates.': [3036, 3066], 'For': [3037, 4141], 'experiments': [3038, 3053, 3148, 3165, 4084], 'plated': [3043, 3058], 'density': [3046, 3061], '∼50,000/well': [3048], 'plates;': [3051], 'involving': [3054, 4027], '∼15,000/well': [3063], 'overnight': [3071, 3898], '(14-20': [3072], 'h)': [3073], 'concentrations': [3076, 4015], '1-3': [3080], 'h': [3081], 'following': [3082, 3423], 'plating.': [3083], 'During': [3084], 'initial': [3086], 'phases': [3087], 'work,': [3090], 'efficiencies': [3092], 'monitored': [3094], 'green': [3096], 'fluorescent': [3097], 'reporter': [3099], 'plasmid': [3100], '(∼90%)': [3101], 'conjunction': [3103], 'parallel': [3108], 'transfections.': [3109], 'levels': [3111, 3120, 3212, 4003], 'normalized': [3116], 'APP': [3118], 'PS': [3124, 3169, 3244], 'levels,': [3126], 'Western': [3128], 'blot': [3129], 'analysis': [3130], '(see': [3131], 'Figs.': [3132, 3173], 'S1': [3133], '9).': [3135], 'Since': [3136], 'level': [3138], 'highly': [3143], 'reproducible': [3146], 'across': [3147], 'Nucleofector-mediated': [3150], 'experimental': [3154, 4025, 4102, 4319], 'conditions': [3155], 'above': [3157, 3207, 3455, 3579, 3623], '(as': [3158], 'illustrated': [3159], 'Fig.': [3161, 4094, 4097], '8),': [3162], 'subsequent': [3164, 4130], 'shown': [3171, 3526, 3716], '5': [3174, 3461], '6': [3176], 'Tables': [3178, 3276], '2,': [3181, 3279], 'cultures': [3186], 'surrogate': [3191], 'efficiency.FIGURE': [3194], '8Activity': [3195], 'assessed': [3201, 3246], 'production.': [3204], 'graphs': [3206], 'relative': [3210, 3226, 3320, 3336], 'mutants,': [3215], 'expressed': [3216], 'ratio': [3219, 3369], 'measuring': [3248], '(1-x)': [3252], 'compared': [3256], 'within': [3264], 'experiment.': [3267], 'arrows': [3269, 3289, 3297, 3454, 3622], 'denote': [3270], 'select': [3272, 3371], 'mutations': [3273], 'affected': [3281], 'compounds.': [3286], 'red': [3288, 3443, 3603], 'indicate': [3290, 3298, 3627], 'increased': [3293], '>2-fold;': [3295], 'black': [3296], 'decreased': [3301], '>2-fold.': [3303], 'Y288A': [3305], 'mutation': [3306, 4061], 'inactive.': [3308], 'A,': [3309, 3396, 3550], 'subregion': [3319, 3335, 3404, 3411, 3458, 3558, 3733, 3744], 'B,': [3325, 3344, 3446, 3606], 'A': [3342], 'values': [3346, 3497, 3523, 3686, 3713, 3987, 4070, 4233], 'n': [3353, 4218], 'independent': [3356, 4221], 'experiments,': [3357, 4222], 'error': [3360], 'bars': [3361], 'S.E.': [3363, 3530, 3720], 'C,': [3364, 3495, 3662], 'assessment': [3365], 'Aβ42/Aβ': [3367], '1-x': [3368, 3762], 'FAD': [3375], '(n': [3377, 3531, 3721, 4188], '2).View': [3379, 3533, 3723], 'Large': [3380, 3534, 3724, 4241], 'Image': [3381, 3535, 3725, 4242], 'Figure': [3382, 3536, 3726, 4243], 'ViewerDownload': [3383, 3537, 3727, 4244], 'Hi-res': [3384, 3538, 3728, 4245], 'image': [3385, 3539, 3729, 4246], 'Download': [3386, 3540, 3730, 4247], '(PPT)FIGURE': [3387, 3541], '5Fine': [3388], 'mapping': [3389, 3543], 'subregion.': [3395, 3549], 'alignment': [3400, 3554], 'PS2.': [3408, 3428, 3469, 3562, 3620, 3637], 'contains': [3412, 3566], 'half': [3413], 'loop': [3416, 3584], 'connecting': [3417], 'TM6': [3418, 3424], 'conserved': [3421], 'segment': [3422], 'differing': [3433], 'boxed': [3439, 3599], 'highlighted': [3441, 3601], 'boldface': [3444, 3604], 'type.': [3445, 3605], 'diagram': [3447, 3607], 'parental': [3449, 3609], 'construct': [3450, 3506, 3695, 4044, 4126], 'PS1/2C2.': [3451], 'five': [3453, 3473, 3512], 'illustrate': [3459], 'Each': [3470, 3638], 'positions': [3474, 3642], 'mutated': [3476, 3644], 'chimera': [3479, 4046, 4058], 'PS1/2C2': [3480, 3507], 'backbone': [3481, 3648], 'convert': [3483, 3650], 'residue.': [3494, 3661], 'EC50': [3496, 3522, 3685, 3712, 3986, 4069, 4105, 4177, 4238], 'determined': [3498, 3687, 4048, 4164], 'individually': [3501, 3690], 'control': [3505, 3694], '(nm)': [3524, 3714], 'mean': [3528, 3718, 4237], '±': [3529, 3719, 4239], '6Fine': [3542], 'majority': [3568], '(TM3)': [3573], 'segment,': [3574], 'indicated': [3575], 'line': [3578], 'sequences,': [3581], 'TM4.': [3588], 'construct,': [3610], 'PS1(L282I),': [3611], 'replaced': [3616], 'Ile': [3618], '7': [3629], 'seven': [3641, 3701], 'PS1(L282I)': [3647, 3665, 3680], 'PS1/2C2(L282I)': [3663, 3675, 3696], 'same,': [3668], 'except': [3669], 'that,': [3670], 'region,': [3674], 'harbors': [3676, 3681], 'sequence,': [3678], 'sequence.': [3683], 'D,': [3684], 'either': [3707, 4344], '(PPT)TABLE': [3731], '1C2': [3732], 'scan': [3735, 3746], 'Open': [3736, 3747], 'table': [3737, 3748], 'new': [3740, 3751], 'tab': [3741, 3752], 'TABLE': [3742], '2C5': [3743], 'ELISAs': [3753, 3882], 'Aβ40,': [3755], 'Aβ42,': [3756], 'Total': [3757], '1-x—Aβ': [3761], 'ELISA': [3763, 3790, 3805], 'antibody': [3765, 3774, 3928], '266': [3766, 3793, 3808], '(recognizing': [3767, 3776], '16-23;': [3769], 'Elan)': [3770, 3786], 'capture': [3772, 3795, 3810, 3915], '3D6': [3775], '1-5,': [3778], 'specificity': [3780], 'position': [3782], 'Aβ;': [3785], 'detection.': [3788], 'Aβ40': [3789], 'antibodies': [3792, 3807], '2G3': [3797], '(specific': [3798, 3813], 'Aβ40)': [3800], 'detection,': [3802, 3822], 'respectively.': [3803], 'Aβ42': [3804], '21F12': [3812], '42)': [3820], 'respectively': [3823], '(34Johnson-Wood': [3824], 'Motter': [3828], 'Hu': [3830], 'Gordon': [3832, 3838], 'Barbour': [3834], 'Khan': [3836], 'Tan': [3840], 'Games': [3842], 'Schenk': [3846], '94:': [3860], '1550-1555Crossref': [3861], '(582)': [3864], '(California': [3869], 'Peptide': [3870], 'Research,': [3871], 'Napa,': [3872], 'CA)': [3873], 'concentration': [3877], 'standard': [3878], 'ELISA.': [3881], '50': [3889], 'diluted': [3892], 'original': [3894], 'conditioned': [3895], 'culture': [3899], 'Me2SO': [3908], 'control.': [3909], 'Following': [3910], '1-h': [3912], 'incubation': [3913], 'peptide,': [3917], 'plates': [3919], 'incubated': [3921], 'sequentially': [3922], '(45': [3923], 'min/incubation)': [3924], 'biotinylated': [3926], 'detecting': [3927], '(0.5': [3929], 'mg/ml),': [3930], 'horseradish': [3933, 3936], 'peroxidase-strepavidin': [3934], 'peroxidase': [3937], 'substrate': [3938], '(one-step': [3939], 'slow': [3940], 'TMB-Elisa;': [3941], 'Pierce;': [3942], 'catalogue': [3943], 'number': [3944, 4033], '34024).': [3945], 'Plates': [3946], 'incubations': [3950], 'Tris-buffered': [3952], 'saline': [3953], 'plus': [3954], '0.05%': [3955], 'Tween': [3956], '20.': [3957], 'Substrate': [3958], 'reactions': [3959], 'terminated': [3961], 'NH2SO4,': [3964], 'absorbance': [3966], 'readings': [3967], 'SpectraMax': [3970], 'Plus': [3971], '(Molecular': [3972], 'Devices,': [3973], 'Sunnyvale,': [3974], 'CA).': [3975, 4022], 'Determination': [3976], 'Inhibitor': [3978], 'Potencies': [3979, 4213], 'Statistical': [3981], 'Analyses—Dose-response': [3982], 'curves': [3983], 'corresponding': [3985], 'report': [3994], 'curve': [3998], 'fitting': [3999], 'secreted': [4001], '(determined': [4004], 'ELISA)': [4006], 'range': [4012], 'ELfit': [4018], 'program': [4019], '(IDBS,': [4020], 'Alameda,': [4021], 'Due': [4023], 'limitations': [4026], 'transient': [4028], 'per': [4036], 'experiment,': [4037, 4231, 4340], 'potencies': [4040], 'against': [4041, 4158, 4181, 4257], 'given': [4043], 'individual': [4050], 'experiments.': [4051, 4073], 'Conclusions': [4052], 'regarding': [4053], 'effect': [4055], 'based': [4066], 'average': [4068], 'replicate': [4072], 'Drift': [4074], 'absolute': [4077], 'value': [4078], "inhibitor's": [4081], 'time': [4086], 'evident': [4088], 'compare': [4090, 4325], '4).': [4098], 'However,': [4099], 'despite': [4100], 'drift': [4103], 'values,': [4106], 'rank': [4108], 'order': [4109], '(ELN318463': [4113], '>': [4114], 'BMS299897)': [4115], 'remained': [4116], 'invariant.': [4117], 'conclusions': [4120], 'early': [4122], 'corroborated': [4128], 'elaborated': [4136], '"Results"': [4138], '"Discussion."': [4140], 'subregions,': [4151], 'statistical': [4153], 'significance': [4154], 'compound': [4156, 4180], 'particular': [4160], 'unpaired': [4167], 't': [4168], 'test': [4169], '(GraphPad': [4170], 'Prism': [4171], 'software': [4172], 'package)': [4173], 'versus': [4184], '2-4': [4190], 'each).FIGURE': [4191], '4PS1': [4192], 'middle': [4199], 'third': [4200], 'presenilin-1': [4202], 'dominant': [4204], 'contributors': [4205], 'sulfonamides.': [4212], 'compounds': [4215], 'all': [4223], 'assayed': [4226], 'triplicate': [4228], 'each': [4230, 4339], 'reported': [4235], 'S.E.).View': [4240], '(PPT)': [4248], 'examined': [4250], 'PS1-': [4258], 'PS2-comprised': [4260], 'primary': [4264], 'embryonic': [4265], 'PS1-/-': [4269], 'PS2-/-': [4270], 'reconstitute': [4305], 'homogenous': [4306], 'complexes': [4308], 'complication': [4314], 'endogenous': [4316], 'presenilins.': [4317], 'This': [4318], 'system': [4320], 'allowed': [4321], 'us': [4322], 'unambiguously': [4324], 'functional': [4326], 'properties': [4327], 'reconstituted': [4329], 'γ-secretases.': [4337], 'human': [4345], 'together': [4349], 'transfect': [4354]}, 'cited_by_api_url': 'https://api.openalex.org/works?filter=cites:W1987831563', 'counts_by_year': [{'year': 2024, 'cited_by_count': 1}, {'year': 2023, 'cited_by_count': 2}, {'year': 2022, 'cited_by_count': 1}, {'year': 2021, 'cited_by_count': 3}, {'year': 2020, 'cited_by_count': 2}, {'year': 2019, 'cited_by_count': 3}, {'year': 2018, 'cited_by_count': 1}, {'year': 2017, 'cited_by_count': 1}, {'year': 2016, 'cited_by_count': 4}, {'year': 2015, 'cited_by_count': 2}, {'year': 2014, 'cited_by_count': 2}, {'year': 2013, 'cited_by_count': 6}, {'year': 2012, 'cited_by_count': 3}], 'updated_date': '2024-12-13T12:04:39.088585', 'created_date': '2016-06-24'}
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