519:, and does not disrupt cell functions or embryo development. Moreover, the light emitted by the oxidation of coelenterazine does not depend on any optical excitation, so problems with auto-fluorescence are eliminated. The primary limitation of aequorin is that the prosthetic group coelenterazine is irreversibly consumed to produce light, and requires continuous addition of coelenterazine into the media. Such issues led to developments of other genetically encoded calcium sensors including the
3074:
40:
330:, coelenterazine-2-hydroperoxide. The binding site for the first two calcium atoms show a 20 times greater affinity for calcium than the third site. However, earlier claims that only two EF-hands bind calcium were questioned when later structures indicated that all three sites can indeed bind calcium. Thus,
585:
ruled that the FTC and the state of New York could proceed with their lawsuit against Quincy
Bioscience for its claims that Prevagen can improve memory. The order came less than two weeks after the parties argued the case before a three-judge panel of the circuit, where company lawyers admitted they
448:
for the measurement of intracellular Ca levels. The early successful purification of aequorin led to the first experiments involving the injection of the protein into the tissues of living animals to visualize the physiological release of calcium in the muscle fibers of a barnacle. Since then, the
604:
As of
September 21, 2020, Quincy Bioscience agreed to settle the claims that it misrepresented its Prevagen products as supporting brain health and helping with memory loss. Under the terms of the settlement, eligible purchasers applying by October 26, 2020, for purchases made from 2007
360:
Chemical characterization of aequorin indicates the protein is somewhat resilient to harsh treatments. Aequorin is heat resistant. Held at 95 °C for 2 minutes the protein lost only 25% activity. Denaturants such as 6-M urea or 4-M guanidine hydrochloride did not destroy the protein.
586:
did not "dispute that if you look across the entire 211 people who completed the study there was no statistically significant difference". The court vigorously dismissed allegations by the company lawyers that the FTC pursued its action for political reasons.
562:
Prior to the suit, a clinical trial run by researchers employed by Quincy
Bioscience "found no overall benefit compared to a placebo for its primary endpoints involving memory and cognition", while the company's advertising misleadingly cited a few contested
401:, and led to the idea that the animals somehow store oxygen. It was later discovered that the apoprotein can stably bind coelenterazine-2-hydroperoxide, and oxygen is required for the regeneration to this active form of aequorin. However, in the presence of
594:
1875:
Yamano K, Mori K, Nakano R, Kusunoki M, Inoue M, Satoh M (2007). "Identification of the functional expression of adenosine A3 receptor in pancreas using transgenic mice expressing jellyfish apoaequorin".
574:, Case No. 18-cv-12416, D. NJ.) was dismissed in the District court, but an appeal seeking to overturn the dismissal was filed. The suit was consolidated with another against Quincy Pharmaceuticals,
555:
that the product improves memory, provides cognitive benefits, and is "clinically shown" to work. According to the FTC, "the marketers of
Prevagen preyed on the fears of older consumers experiencing
1840:
Rembold CM, Kendall JM, Campbell AK (January 1997). "Measurement of changes in sarcoplasmic reticulum in rat tail artery with targeted apoaequorin delivered by an adenoviral vector".
582:
315:
of the animal, and coelenterazine is the substrate whose oxidation the enzyme catalyzes. When coelenterazine is bound, it is called aequorin. Notably, the protein contains three
397:
had noted that the bioluminescence appears as a ring around the bell, and occurs even in the absence of air. This was remarkable because most bioluminescence reactions require
1387:
Masuda H, Takenaka Y, Shikamoto Y, Kagawa M, Mizuno H, Tsuji FI (2003). "Chromatography of isoforms of recombinant apoaequorin and method for the preparation of aequorin".
319:
motifs that function as binding sites for Ca ions. The protein is a member of the superfamily of the calcium-binding proteins, of which there are some 66 subfamilies.
2251:
957:
Zhou Y, Yang W, Kirberger M, Lee HW, Ayalasomayajula G, Yang JJ (2006). "Prediction of EF-hand calcium-binding proteins and analysis of bacterial EF-hand proteins".
1660:
695:
Shimomura O, Johnson FH, Saiga Y (1962). "Extraction, purification and properties of aequorin, a bioluminescent protein from the luminous hydromedusan, Aequorea".
2504:
922:
Charbonneau H, Walsh KA, McCann RO, Prendergast FG, Cormier MJ, Vanaman TC (1985). "Amino acid sequence of the calcium-dependent photoprotein aequorin".
2377:
1615:"Blue fluorescent protein from the calcium-sensitive photoprotein aequorin: catalytic properties for the oxidation of coelenterazine as an oxygenase"
2618:
2373:
420:
of 465 nm) is emitted. Before coelenteramide is exchanged out, the entire protein is still fluorescent blue. because of the connection between
377:
from the animal. Because the genome has not been sequenced, it is unclear if the cDNA variants can account for all of the isoforms of the protein.
1254:"Blue fluorescent protein from the calcium-sensitive photoprotein aequorin is a heat-resistant enzyme, catalyzing the oxidation of coelenterazine"
1801:"Transient expression of apoaequorin in zebrafish embryos: extending the ability to image calcium transients during later stages of development"
1293:
Prasher D, McCann RO, Cormier MJ (1985). "Cloning and expression of the cDNA coding for aequorin, a bioluminescent calcium-binding protein".
507:
Aequorin has a number of advantages over other Ca indicators. Because the protein is large, it has a low leakage rate from cells compared to
2533:
178:
2712:
2432:
2402:
2338:
2279:
2105:"Recombinant apoaequorin acting as a pseudo-luciferase reports micromolar changes in the endoplasmic reticulum free Ca of intact cells"
1961:
1123:"All three Ca2+-binding loops of photoproteins bind calcium ions: the crystal structures of calcium-loaded apo-aequorin and apo-obelin"
622:
to find favorable results. She wrote that their cited safety studies were all rat studies and their claim that apoaequorin crosses the
2793:
2414:
405:
ions, the protein undergoes a conformational change and converts its prosthetic group, coelenterazine-2-hydroperoxide, into excited
2560:
2419:, United States Court of Appeals for the Second Circuit, Case 17-3745, Document 257, February 21, 2019. Retrieved March 26, 2019.
627:
492:
to measure Ca concentration. Coelenterazine is a hydrophobic molecule, and therefore is easily taken up across plant and fungal
601:
for the class of consumers who purchased
Prevagen over the previous four years. The trial in the case was set for October 2020.
1000:
Head JF, Inouye S, Teranishi K, Shimomura O (2000). "The crystal structure of the photoprotein aequorin at 2.3 Ă… resolution".
2307:
590:
334:
studies show that all three calcium-binding sites are active but only two ions are needed to trigger the enzymatic reaction.
2949:
2478:
2334:
547:
Apoaequorin is an ingredient in "Prevagen", which is marketed by Quincy
Bioscience as a memory supplement. In 2017, the US
2702:
185:
3064:
2678:
2664:
2611:
3099:
2717:
2673:
2659:
618:, noted that the Quincy-sponsored study (known as "Madison Memory Study") was negative, but that the company utilized
1562:
Shimomura O, Johnson FH (1970). "Calcium binding, quantum yield, and emitting molecule in aequorin bioluminescence".
630:
warns that
Apoaequorin "is unlikely to be absorbed to a significant degree; instead it degrades into amino acids".
2934:
3050:
3037:
3024:
3011:
2998:
2985:
2972:
2751:
2732:
2687:
2644:
2587:
273:
254:
246:
174:
2944:
2449:
3109:
3094:
2898:
2841:
2635:
2211:"Genetically encoded indicators of cellular calcium dynamics based on troponin C and green fluorescent protein"
548:
200:
100:
1527:
Shimomura O, Johnson FH, Morise H (1974). "Mechanism of the luminescent intramolecular reaction of aequorin".
623:
2398:
2846:
2604:
150:
67:
2528:
614:
249:. It was determined that light could be produced from extracts with seawater, and more specifically, with
2867:
2786:
516:
2939:
2707:
2697:
2523:
2165:
1669:
1571:
1485:
1341:
1009:
876:
2428:
2374:"Prevagen: How Can This Memory Supplement Flunk Its One Trial and Still Be Advertised as Effective?"
253:. It was also noted during the extraction the animal creates green light due to the presence of the
3104:
2903:
2256:
192:
the green fluorescent protein, not aequorin, although both originally derive from the same animal.
2056:"Monitoring dynamic changes in free Ca concentration in the endoplasmic reticulum of intact cells"
1424:"Oxygen and Luminescence, with a Description of Methods for Removing Oxygen from Cells and Fluids"
2836:
2760:
2722:
2191:
1901:
1595:
1509:
1443:
1033:
982:
845:
802:
759:
751:
666:
524:
515:. It lacks phenomena of intracellular compartmentalization or sequestration as is often seen for
501:
196:
1086:
Shimomura O (1995). "Luminescence of aequorin is triggered by the binding of two calcium ions".
1051:
Shimomura O (1995). "Luminescence of aequorin is triggered by the binding of two calcium ions".
2232:
2183:
2134:
2085:
2036:
1991:
1942:
1893:
1857:
1822:
1781:
1746:
1697:
1636:
1587:
1544:
1501:
1404:
1369:
1310:
1275:
1234:
1193:
1152:
1103:
1068:
1025:
974:
939:
904:
837:
794:
712:
674:
564:
552:
445:
374:
346:
323:
245:
in 1961. This involved tedious harvesting of tens of thousands of jellyfish from the docks in
204:
161:
49:
1921:"Measurement of intracellular calcium using bioluminescent aequorin expressed in human cells"
1717:"Recombinant aequorin and recombinant semi-synthetic aequorins. Cellular Ca2+ ion indicators"
2882:
2877:
2851:
2779:
2596:
2556:
2485:. United States District Court, Southern District of Florida, Miami Division. March 19, 2020
2450:"Federal Magistrate Judge Recommends Certifying Nationwide Prevagen Class Action in Florida"
2222:
2173:
2124:
2116:
2075:
2067:
2026:
1999:
1981:
1973:
1932:
1885:
1849:
1812:
1773:
1736:
1728:
1687:
1677:
1626:
1579:
1536:
1493:
1435:
1396:
1359:
1349:
1302:
1265:
1224:
1183:
1142:
1134:
1095:
1060:
1017:
966:
931:
894:
884:
829:
786:
743:
731:
704:
658:
556:
394:
301:
297:
216:
105:
2929:
2913:
2826:
2591:
497:
488:
into the culture medium of the cells to obtain a functional protein and thus use its blue
477:
421:
386:
236:
232:
170:
166:
124:
1328:
Inouye S, Noguchi M, Sakaki Y, Takagi Y, Miyata T, Iwanaga S, Miyata T, Tsuji FI (1985).
2169:
1673:
1575:
1489:
1345:
1013:
880:
3078:
2967:
2908:
2627:
2129:
2104:
2071:
1741:
1716:
1147:
1122:
489:
485:
450:
429:
410:
406:
338:
304:
261:
260:
While the main focus of his work was on the bioluminescence, Shimomura and two others,
45:
2080:
2055:
1986:
1853:
1692:
1655:
1400:
1364:
1329:
899:
864:
3088:
2872:
2831:
2457:
2312:
2031:
2014:
1800:
1777:
1306:
1229:
1212:
833:
508:
2195:
1905:
849:
806:
763:
2821:
2654:
2252:"Does the supplement Prevagen improve memory? A court case is asking that question"
1599:
1513:
1037:
986:
609:
598:
466:
425:
189:
153:
2154:"Fluorescent indicators for Ca based on green fluorescent proteins and calmodulin"
1631:
1614:
1270:
1253:
1423:
341:
that maintains the structure of aequorin. This has also explained the need for a
3045:
2980:
2816:
2152:
Miyawaki A, Llopis J, Heim R, McCaffery JM, Adams JA, Ikura M, Tsien RY (1997).
2054:
Montero M, Brini M, Marsault R, Alvarez J, Sitia R, Pozzan T, Rizzuto R (1995).
528:
441:
285:
269:
265:
134:
17:
3073:
820:
Shimomura O (2005). "The discovery of aequorin and green fluorescent protein".
2741:
1889:
520:
493:
417:
350:
228:
220:
184:
Discussions of "jellyfish DNA" that can make "glowing" animals often refer to
83:
1476:
Shimomura O, Johnson FH (1975). "Regeneration of the photoprotein aequorin".
3019:
2993:
2631:
1764:
Ridgway EB, Ashley CC (1967). "Calcium transients in single muscle fibers".
1354:
1330:"Cloning and sequence analysis of cDNA for the luminescent protein aequorin"
777:
Morin JG, Hastings JW (1971). "Energy transfer in a bioluminescent system".
619:
481:
454:
331:
312:
289:
224:
157:
2236:
2227:
2210:
1995:
1962:"Aequorin-based measurements of intracellular Ca signatures in plant cells"
1937:
1920:
1897:
1826:
1682:
1640:
1408:
1279:
1213:"Mass spectrometric evidence for a disulfide bond in aequorin regeneration"
1188:
1171:
1156:
1099:
1064:
1029:
978:
889:
865:"Peroxidized coelenterazine, the active group in the photoprotein aequorin"
841:
790:
716:
708:
428:, this property was ultimately important in the discovery of the luciferin
39:
2479:"Report and Recommendations on Plaintiff's Motion for Class Certification"
2187:
2138:
2089:
2040:
1946:
1861:
1817:
1785:
1750:
1591:
1548:
1373:
1314:
1238:
1197:
1107:
1072:
943:
798:
678:
2284:
2103:
Kendall JM, Badminton MN, Sala-Newby GB, Campbell AK, Rembold CM (1996).
1701:
1505:
1138:
908:
532:
416:. As the excited coelenteramide relaxes to the ground state, blue light (
354:
327:
241:
88:
1540:
1121:
Deng L, Vysotski ES, Markova SV, Liu ZJ, Lee J, Rose J, Wang BC (2005).
935:
326:
revealed that aequorin binds coelenterazine and oxygen in the form of a
1447:
970:
755:
670:
402:
316:
250:
231:
and that light could be produced even in the absence of oxygen. Later,
169:
was studied decades before the protein was isolated from the animal by
2584:
2120:
1732:
1583:
195:
Apoaequorin, the protein portion of aequorin, is an ingredient in the
3032:
2802:
2682:
2668:
1497:
1021:
398:
370:
308:
1439:
747:
662:
732:"Studies on Bioluminescence. XIII. Luminescence in the CĹ“lenterate"
3006:
2178:
2153:
1977:
349:
in the regeneration of the protein since such reagents weaken the
342:
2335:"Prevagen's Fishy Memory Claims Under Fire by Federal Regulators"
595:
United States
District Court for the Southern District of Florida
572:
Spath, et al. v. Quincy
Bioscience Holding Company, Inc., et al.
473:
462:
373:
of
Aequorea. At least four copies of the gene were recovered as
2775:
2600:
2308:"Schneiderman slams Prevagen as a 'clear-cut fraud' in lawsuit"
512:
458:
227:
reaction, he showed that water could produce light from dried
1656:"Chemical nature of bioluminescence systems in coelenterates"
605:
through July 31, 2020, could recover refunds of up to $ 70.
597:
entered a report and recommendations certifying a nationwide
219:
in 1921. Though Harvey was unable to demonstrate a classical
173:
in 1962. In the animal, the protein occurs together with the
257:, which changes the native blue light of aequorin to green.
2359:
University of California Berkeley School of Public Health,
2771:
2505:"Prevagen Brain Health Supplement Class Action Settlement"
2280:"Jellyfish Memory Supplement Prevagen Is a Hoax, FTC Says"
1211:
Ohmiya Y, Kurono S, Ohashi M, Fagan TF, Tsuji FI (1993).
1172:"Titration of recombinant aequorin with calcium chloride"
357:
residues, expediting the regeneration of the aequorin.
2399:"Quincy Bioscience's Prevagen Supplement October 2018"
644:
642:
578:(Case No. 17-cv-784, D. NJ), which was the lead case.
440:
Since the emitted light can be easily detected with a
3062:
583:
United States Court of Appeals for the Second Circuit
337:
Other studies have shown the presence of an internal
500:
of higher eukaryotes, making aequorin suitable as a
307:, the luciferin. This is to say, apoaequorin is the
2958:
2922:
2891:
2860:
2809:
2750:
2731:
2643:
2363:, "Forget Jellyfish Protein", Winter, 2017–18, p. 6
2013:Blinks JR, Wier WG, Hess P, Prendergast FG (1982).
1088:
Biochemical and Biophysical Research Communications
130:
120:
115:
99:
94:
82:
74:
62:
57:
32:
2015:"Measurement of Ca concentrations in living cells"
1715:Shimomura O, Inouye S, Musicki B, Kishi Y (1990).
296:, which has an approximate molecular weight of 21
649:Shimomura O (1995). "A short story of aequorin".
476:can effectively synthesize apoaequorin; however,
181:, while aequorin by itself generates blue light.
52:1ej3 with prosthetic group coelenterazine in blue
690:
688:
559:". Quincy said that it would fight the charges.
1661:Proceedings of the National Academy of Sciences
2435:, February 22, 2019. Retrieved March 26, 2019.
1799:Cheung CY, Webb SE, Meng A, Miller AL (2006).
2787:
2612:
8:
2405:, October 2018. Retrieved November 14, 2018.
2794:
2780:
2772:
2619:
2605:
2597:
2250:Hamilton, Martha M. (September 11, 2021).
112:
38:
2416:FTC vs. Quincy Bioscience Holding Company
2378:Center for Science in the Public Interest
2226:
2177:
2128:
2079:
2030:
1985:
1936:
1919:Sheu YA, Kricka LJ, Pritchett DB (1993).
1816:
1740:
1691:
1681:
1630:
1363:
1353:
1269:
1228:
1187:
1146:
898:
888:
3069:
638:
504:in plants, fungi, and mammalian cells.
472:Cultured cells expressing the aequorin
444:, aequorin has become a useful tool in
2443:
2441:
369:Aequorin is presumably encoded in the
29:
2557:"Apoaequorin for memory enhancement?"
626:was based solely on a dog study. The
449:protein has been widely used in many
7:
2563:from the original on 5 December 2018
2536:from the original on 5 December 2018
288:composed of two distinct units, the
2713:4-Hydroxyphenylpyruvate dioxygenase
2524:"Reader's Digest Promotes Prevagen"
2448:Mora, Michael A. (March 24, 2020).
484:. Therefore it is necessary to add
207:for its memory improvement claims.
2072:10.1002/j.1460-2075.1995.tb00233.x
25:
2522:Hall, Harriet (4 December 2018).
567:that showed slight improvements.
539:, developed by Oliver Griesbeck.
203:(FTC) has charged the maker with
3072:
1654:Shimomura O, Johnson FH (1975).
863:Shimomura O, Johnson FH (1978).
834:10.1111/j.0022-2720.2005.01441.x
628:American Pharmacists Association
576:Vanderwerff v. Quincy Bioscience
2429:"Prevagen Is Going to the Dogs"
657:(1). Biological Bulletin: 1–5.
1170:Shimomura O, Inouye S (1996).
543:Marketing and legal challenges
27:Calcium-activated photoprotein
1:
2703:Homogentisate 1,2-dioxygenase
1960:Mithöfer A, Mazars C (2002).
1854:10.1016/s0143-4160(97)90098-1
1766:Biochem. Biophys. Res. Commun
1632:10.1016/j.febslet.2006.02.065
1401:10.1016/s1046-5928(03)00186-4
1295:Biochem. Biophys. Res. Commun
1271:10.1016/j.febslet.2004.09.078
1176:Biochem. Biophys. Res. Commun
1053:Biochem. Biophys. Res. Commun
551:(FTC) charged the maker with
68:Aequorea victoria (Jellyfish)
2679:Arachidonate 15-lipoxygenase
2665:Arachidonate 12-lipoxygenase
2209:Heim N, Griesbeck O (2004).
2032:10.1016/0079-6107(82)90011-6
1778:10.1016/0006-291x(67)90592-x
1334:Proc. Natl. Acad. Sci. U.S.A
1307:10.1016/0006-291X(85)90321-3
1230:10.1016/0014-5793(93)80637-a
215:Work on aequorin began with
2718:Indoleamine 2,3-dioxygenase
2674:Arachidonate 8-lipoxygenase
2660:Arachidonate 5-lipoxygenase
1613:Inouye S, Sasaki S (2006).
480:expression yields only the
3126:
581:On February 21, 2019, the
274:green fluorescent proteins
272:in 2008 for their work on
177:to produce green light by
2950:Michaelis–Menten kinetics
2688:Linoleate 11-lipoxygenase
2585:Swiss-Prot Aequorin entry
2306:Li DK (January 9, 2017).
2278:Fox M (January 9, 2017).
1890:10.1007/s11248-007-9084-0
255:green fluorescent protein
247:Friday Harbor, Washington
175:green fluorescent protein
111:
37:
2842:Diffusion-limited enzyme
591:federal magistrate judge
549:Federal Trade Commission
451:model biological systems
201:Federal Trade Commission
179:resonant energy transfer
1355:10.1073/pnas.82.10.3154
557:age-related memory loss
2529:Science-Based Medicine
2228:10.1074/jbc.M312751200
1938:10.1006/abio.1993.1132
1683:10.1073/pnas.72.4.1546
1189:10.1006/bbrc.1996.0548
1100:10.1006/bbrc.1995.1821
1065:10.1006/bbrc.1995.1821
890:10.1073/pnas.75.6.2611
791:10.1002/jcp.1040770305
709:10.1002/jcp.1030590302
615:Science-Based Medicine
517:Voltage-sensitive dyes
2935:Eadie–Hofstee diagram
2868:Allosteric regulation
2647:: two atoms of oxygen
2511:. September 21, 2020.
2454:Daily Business Review
2019:Prog Biophys Mol Biol
1818:10.1387/ijdb.062151cc
589:On March 23, 2020, a
385:Early studies of the
2945:Lineweaver–Burk plot
2735:: one atom of oxygen
2708:Cysteine dioxygenase
2698:Catechol dioxygenase
2433:Truth in Advertising
2403:Truth in Advertising
2339:Truth in Advertising
1966:Biol. Proced. Online
1139:10.1110/ps.041142905
347:beta mercaptoethanol
235:began work into the
2380:. November 20, 2017
2257:The Washington Post
2221:(14): 14280–14286.
2170:1997Natur.388..882M
1674:1975PNAS...72.1546S
1576:1970Natur.227.1356S
1570:(5265): 1356–1357.
1541:10.1021/bi00713a016
1490:1975Natur.256..236S
1428:Biological Bulletin
1389:Protein Expr. Purif
1346:1985PNAS...82.3154I
1014:2000Natur.405..372H
936:10.1021/bi00345a006
881:1978PNAS...75.2611S
736:Biological Bulletin
697:J Cell Comp Physiol
624:blood–brain barrier
553:falsely advertising
381:Mechanism of action
268:, were awarded the
3100:Cnidarian proteins
2904:Enzyme superfamily
2837:Enzyme promiscuity
2761:Inositol oxygenase
2742:Firefly luciferase
2723:Chlorite dismutase
2695:other dioxygenase:
2590:2007-03-23 at the
2559:. Pharmacist.com.
1461:Harvey EN (1952).
1422:Harvey EN (1926).
971:10.1002/prot.21139
730:Harvey EN (1921).
197:dietary supplement
186:transgenic animals
156:isolated from the
3060:
3059:
2769:
2768:
2509:Top Class Actions
2341:. January 9, 2017
2164:(6645): 882–887.
2121:10.1042/bj3180383
2066:(22): 5467–5475.
1805:Int. J. Dev. Biol
1733:10.1042/bj2700309
1584:10.1038/2271356a0
1535:(16): 3278–3286.
1484:(5514): 236–238.
1465:. Academic Press.
1252:Inouye S (2004).
1008:(6784): 372–376.
930:(24): 6762–6771.
565:subgroup analyses
496:, as well as the
446:molecular biology
324:crystal structure
205:false advertising
199:Prevagen. The US
162:Aequorea victoria
151:calcium-activated
144:
143:
140:
139:
16:(Redirected from
3117:
3077:
3076:
3068:
2940:Hanes–Woolf plot
2883:Enzyme activator
2878:Enzyme inhibitor
2852:Enzyme catalysis
2796:
2789:
2782:
2773:
2621:
2614:
2607:
2598:
2573:
2572:
2570:
2568:
2552:
2546:
2545:
2543:
2541:
2519:
2513:
2512:
2501:
2495:
2494:
2492:
2490:
2475:
2469:
2468:
2466:
2464:
2445:
2436:
2426:
2420:
2412:
2406:
2396:
2390:
2389:
2387:
2385:
2370:
2364:
2357:
2351:
2350:
2348:
2346:
2331:
2325:
2324:
2322:
2320:
2303:
2297:
2296:
2294:
2292:
2275:
2269:
2268:
2266:
2264:
2247:
2241:
2240:
2230:
2206:
2200:
2199:
2181:
2149:
2143:
2142:
2132:
2100:
2094:
2093:
2083:
2051:
2045:
2044:
2034:
2010:
2004:
2003:
1998:. Archived from
1989:
1957:
1951:
1950:
1940:
1916:
1910:
1909:
1872:
1866:
1865:
1837:
1831:
1830:
1820:
1796:
1790:
1789:
1761:
1755:
1754:
1744:
1712:
1706:
1705:
1695:
1685:
1668:(4): 1546–1549.
1651:
1645:
1644:
1634:
1625:(8): 1977–1982.
1610:
1604:
1603:
1559:
1553:
1552:
1524:
1518:
1517:
1498:10.1038/256236a0
1473:
1467:
1466:
1458:
1452:
1451:
1419:
1413:
1412:
1384:
1378:
1377:
1367:
1357:
1325:
1319:
1318:
1290:
1284:
1283:
1273:
1264:(1–2): 105–110.
1249:
1243:
1242:
1232:
1208:
1202:
1201:
1191:
1167:
1161:
1160:
1150:
1118:
1112:
1111:
1083:
1077:
1076:
1048:
1042:
1041:
1022:10.1038/35012659
997:
991:
990:
954:
948:
947:
919:
913:
912:
902:
892:
875:(3): 2611–2615.
860:
854:
853:
817:
811:
810:
779:J. Cell. Physiol
774:
768:
767:
727:
721:
720:
692:
683:
682:
646:
395:E. Newton Harvey
311:produced in the
302:prosthetic group
217:E. Newton Harvey
113:
70:
42:
30:
21:
18:Draft:Apoaeqorin
3125:
3124:
3120:
3119:
3118:
3116:
3115:
3114:
3110:Protein methods
3095:Bioluminescence
3085:
3084:
3083:
3071:
3063:
3061:
3056:
2968:Oxidoreductases
2954:
2930:Enzyme kinetics
2918:
2914:List of enzymes
2887:
2856:
2827:Catalytic triad
2805:
2800:
2770:
2765:
2746:
2727:
2639:
2628:Oxidoreductases
2625:
2592:Wayback Machine
2581:
2576:
2566:
2564:
2554:
2553:
2549:
2539:
2537:
2521:
2520:
2516:
2503:
2502:
2498:
2488:
2486:
2477:
2476:
2472:
2462:
2460:
2447:
2446:
2439:
2427:
2423:
2413:
2409:
2397:
2393:
2383:
2381:
2372:
2371:
2367:
2361:Health After 50
2358:
2354:
2344:
2342:
2333:
2332:
2328:
2318:
2316:
2305:
2304:
2300:
2290:
2288:
2277:
2276:
2272:
2262:
2260:
2249:
2248:
2244:
2208:
2207:
2203:
2151:
2150:
2146:
2102:
2101:
2097:
2053:
2052:
2048:
2012:
2011:
2007:
1959:
1958:
1954:
1918:
1917:
1913:
1874:
1873:
1869:
1839:
1838:
1834:
1798:
1797:
1793:
1763:
1762:
1758:
1714:
1713:
1709:
1653:
1652:
1648:
1612:
1611:
1607:
1561:
1560:
1556:
1526:
1525:
1521:
1475:
1474:
1470:
1463:Bioluminescence
1460:
1459:
1455:
1440:10.2307/1536540
1421:
1420:
1416:
1386:
1385:
1381:
1340:(10): 3154–58.
1327:
1326:
1322:
1292:
1291:
1287:
1251:
1250:
1246:
1210:
1209:
1205:
1169:
1168:
1164:
1120:
1119:
1115:
1085:
1084:
1080:
1050:
1049:
1045:
999:
998:
994:
956:
955:
951:
921:
920:
916:
862:
861:
857:
819:
818:
814:
776:
775:
771:
748:10.2307/1536528
729:
728:
724:
694:
693:
686:
663:10.2307/1542194
648:
647:
640:
636:
545:
535:-based sensor,
527:, developed by
498:plasma membrane
438:
422:bioluminescence
414:
387:bioluminescence
383:
367:
292:that is called
282:
237:bioluminescence
233:Osamu Shimomura
213:
171:Osamu Shimomura
167:bioluminescence
66:
53:
28:
23:
22:
15:
12:
11:
5:
3123:
3121:
3113:
3112:
3107:
3102:
3097:
3087:
3086:
3082:
3081:
3058:
3057:
3055:
3054:
3041:
3028:
3015:
3002:
2989:
2976:
2962:
2960:
2956:
2955:
2953:
2952:
2947:
2942:
2937:
2932:
2926:
2924:
2920:
2919:
2917:
2916:
2911:
2906:
2901:
2895:
2893:
2892:Classification
2889:
2888:
2886:
2885:
2880:
2875:
2870:
2864:
2862:
2858:
2857:
2855:
2854:
2849:
2844:
2839:
2834:
2829:
2824:
2819:
2813:
2811:
2807:
2806:
2801:
2799:
2798:
2791:
2784:
2776:
2767:
2766:
2764:
2763:
2757:
2755:
2748:
2747:
2745:
2744:
2738:
2736:
2729:
2728:
2726:
2725:
2720:
2715:
2710:
2705:
2700:
2691:
2690:
2685:
2676:
2671:
2662:
2650:
2648:
2641:
2640:
2632:monooxygenases
2626:
2624:
2623:
2616:
2609:
2601:
2595:
2594:
2580:
2579:External links
2577:
2575:
2574:
2547:
2514:
2496:
2470:
2437:
2421:
2407:
2391:
2365:
2352:
2326:
2298:
2270:
2242:
2201:
2144:
2115:(2): 383–387.
2095:
2046:
2025:(1–2): 1–114.
2005:
2002:on 2005-07-28.
1952:
1931:(2): 343–347.
1911:
1884:(4): 429–435.
1878:Transgenic Res
1867:
1832:
1811:(6): 561–569.
1791:
1772:(2): 229–234.
1756:
1727:(2): 309–312.
1707:
1646:
1605:
1554:
1519:
1468:
1453:
1414:
1395:(2): 181–187.
1379:
1320:
1301:(3): 1259–68.
1285:
1244:
1223:(3): 226–228.
1203:
1162:
1133:(3): 663–675.
1113:
1094:(2): 359–363.
1078:
1059:(2): 359–363.
1043:
992:
965:(3): 643–655.
949:
914:
855:
828:(Pt 1): 1–15.
812:
785:(3): 313–318.
769:
742:(5): 280–287.
722:
684:
637:
635:
632:
612:, writing for
544:
541:
523:-based sensor
490:light emission
486:coelenterazine
467:cultured cells
437:
434:
430:coelenterazine
412:
407:coelenteramide
382:
379:
366:
363:
353:bonds between
305:coelenterazine
284:Aequorin is a
281:
278:
262:Martin Chalfie
212:
209:
142:
141:
138:
137:
132:
128:
127:
122:
118:
117:
109:
108:
103:
97:
96:
92:
91:
86:
80:
79:
76:
72:
71:
64:
60:
59:
55:
54:
46:ribbon diagram
43:
35:
34:
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
3122:
3111:
3108:
3106:
3103:
3101:
3098:
3096:
3093:
3092:
3090:
3080:
3075:
3070:
3066:
3052:
3048:
3047:
3042:
3039:
3035:
3034:
3029:
3026:
3022:
3021:
3016:
3013:
3009:
3008:
3003:
3000:
2996:
2995:
2990:
2987:
2983:
2982:
2977:
2974:
2970:
2969:
2964:
2963:
2961:
2957:
2951:
2948:
2946:
2943:
2941:
2938:
2936:
2933:
2931:
2928:
2927:
2925:
2921:
2915:
2912:
2910:
2909:Enzyme family
2907:
2905:
2902:
2900:
2897:
2896:
2894:
2890:
2884:
2881:
2879:
2876:
2874:
2873:Cooperativity
2871:
2869:
2866:
2865:
2863:
2859:
2853:
2850:
2848:
2845:
2843:
2840:
2838:
2835:
2833:
2832:Oxyanion hole
2830:
2828:
2825:
2823:
2820:
2818:
2815:
2814:
2812:
2808:
2804:
2797:
2792:
2790:
2785:
2783:
2778:
2777:
2774:
2762:
2759:
2758:
2756:
2753:
2749:
2743:
2740:
2739:
2737:
2734:
2730:
2724:
2721:
2719:
2716:
2714:
2711:
2709:
2706:
2704:
2701:
2699:
2696:
2693:
2692:
2689:
2686:
2684:
2680:
2677:
2675:
2672:
2670:
2666:
2663:
2661:
2658:
2656:
2652:
2651:
2649:
2646:
2642:
2637:
2633:
2629:
2622:
2617:
2615:
2610:
2608:
2603:
2602:
2599:
2593:
2589:
2586:
2583:
2582:
2578:
2562:
2558:
2551:
2548:
2535:
2531:
2530:
2525:
2518:
2515:
2510:
2506:
2500:
2497:
2484:
2480:
2474:
2471:
2459:
2455:
2451:
2444:
2442:
2438:
2434:
2430:
2425:
2422:
2418:
2417:
2411:
2408:
2404:
2400:
2395:
2392:
2384:September 20,
2379:
2375:
2369:
2366:
2362:
2356:
2353:
2340:
2336:
2330:
2327:
2315:
2314:
2313:New York Post
2309:
2302:
2299:
2287:
2286:
2281:
2274:
2271:
2263:September 11,
2259:
2258:
2253:
2246:
2243:
2238:
2234:
2229:
2224:
2220:
2216:
2212:
2205:
2202:
2197:
2193:
2189:
2185:
2180:
2179:10.1038/42264
2175:
2171:
2167:
2163:
2159:
2155:
2148:
2145:
2140:
2136:
2131:
2126:
2122:
2118:
2114:
2110:
2106:
2099:
2096:
2091:
2087:
2082:
2077:
2073:
2069:
2065:
2061:
2057:
2050:
2047:
2042:
2038:
2033:
2028:
2024:
2020:
2016:
2009:
2006:
2001:
1997:
1993:
1988:
1983:
1979:
1978:10.1251/bpo40
1975:
1971:
1967:
1963:
1956:
1953:
1948:
1944:
1939:
1934:
1930:
1926:
1925:Anal. Biochem
1922:
1915:
1912:
1907:
1903:
1899:
1895:
1891:
1887:
1883:
1879:
1871:
1868:
1863:
1859:
1855:
1851:
1847:
1843:
1836:
1833:
1828:
1824:
1819:
1814:
1810:
1806:
1802:
1795:
1792:
1787:
1783:
1779:
1775:
1771:
1767:
1760:
1757:
1752:
1748:
1743:
1738:
1734:
1730:
1726:
1722:
1718:
1711:
1708:
1703:
1699:
1694:
1689:
1684:
1679:
1675:
1671:
1667:
1663:
1662:
1657:
1650:
1647:
1642:
1638:
1633:
1628:
1624:
1620:
1616:
1609:
1606:
1601:
1597:
1593:
1589:
1585:
1581:
1577:
1573:
1569:
1565:
1558:
1555:
1550:
1546:
1542:
1538:
1534:
1530:
1523:
1520:
1515:
1511:
1507:
1503:
1499:
1495:
1491:
1487:
1483:
1479:
1472:
1469:
1464:
1457:
1454:
1449:
1445:
1441:
1437:
1433:
1429:
1425:
1418:
1415:
1410:
1406:
1402:
1398:
1394:
1390:
1383:
1380:
1375:
1371:
1366:
1361:
1356:
1351:
1347:
1343:
1339:
1335:
1331:
1324:
1321:
1316:
1312:
1308:
1304:
1300:
1296:
1289:
1286:
1281:
1277:
1272:
1267:
1263:
1259:
1255:
1248:
1245:
1240:
1236:
1231:
1226:
1222:
1218:
1214:
1207:
1204:
1199:
1195:
1190:
1185:
1181:
1177:
1173:
1166:
1163:
1158:
1154:
1149:
1144:
1140:
1136:
1132:
1128:
1124:
1117:
1114:
1109:
1105:
1101:
1097:
1093:
1089:
1082:
1079:
1074:
1070:
1066:
1062:
1058:
1054:
1047:
1044:
1039:
1035:
1031:
1027:
1023:
1019:
1015:
1011:
1007:
1003:
996:
993:
988:
984:
980:
976:
972:
968:
964:
960:
953:
950:
945:
941:
937:
933:
929:
925:
918:
915:
910:
906:
901:
896:
891:
886:
882:
878:
874:
870:
866:
859:
856:
851:
847:
843:
839:
835:
831:
827:
823:
816:
813:
808:
804:
800:
796:
792:
788:
784:
780:
773:
770:
765:
761:
757:
753:
749:
745:
741:
737:
733:
726:
723:
718:
714:
710:
706:
703:(3): 223–39.
702:
698:
691:
689:
685:
680:
676:
672:
668:
664:
660:
656:
652:
645:
643:
639:
633:
631:
629:
625:
621:
617:
616:
611:
606:
602:
600:
596:
592:
587:
584:
579:
577:
573:
568:
566:
560:
558:
554:
550:
542:
540:
538:
534:
530:
526:
522:
518:
514:
511:dyes such as
510:
505:
503:
499:
495:
491:
487:
483:
479:
475:
470:
468:
464:
460:
456:
452:
447:
443:
435:
433:
431:
427:
423:
419:
415:
408:
404:
400:
396:
392:
388:
380:
378:
376:
372:
364:
362:
358:
356:
352:
348:
345:reagent like
344:
340:
339:cysteine bond
335:
333:
329:
325:
320:
318:
314:
310:
306:
303:
299:
295:
291:
287:
279:
277:
275:
271:
267:
263:
258:
256:
252:
248:
244:
243:
238:
234:
230:
226:
222:
218:
210:
208:
206:
202:
198:
193:
191:
187:
182:
180:
176:
172:
168:
164:
163:
159:
155:
152:
148:
136:
133:
129:
126:
123:
119:
114:
110:
107:
104:
102:
98:
93:
90:
87:
85:
81:
77:
73:
69:
65:
61:
56:
51:
47:
41:
36:
31:
19:
3046:Translocases
3043:
3030:
3017:
3004:
2991:
2981:Transferases
2978:
2965:
2822:Binding site
2694:
2655:lipoxygenase
2653:
2565:. Retrieved
2555:Hume, Anne.
2550:
2538:. Retrieved
2527:
2517:
2508:
2499:
2487:. Retrieved
2482:
2473:
2461:. Retrieved
2453:
2424:
2415:
2410:
2394:
2382:. Retrieved
2368:
2360:
2355:
2343:. Retrieved
2329:
2317:. Retrieved
2311:
2301:
2289:. Retrieved
2283:
2273:
2261:. Retrieved
2255:
2245:
2218:
2214:
2204:
2161:
2157:
2147:
2112:
2108:
2098:
2063:
2059:
2049:
2022:
2018:
2008:
2000:the original
1969:
1965:
1955:
1928:
1924:
1914:
1881:
1877:
1870:
1848:(1): 69–79.
1845:
1842:Cell Calcium
1841:
1835:
1808:
1804:
1794:
1769:
1765:
1759:
1724:
1720:
1710:
1665:
1659:
1649:
1622:
1618:
1608:
1567:
1563:
1557:
1532:
1529:Biochemistry
1528:
1522:
1481:
1477:
1471:
1462:
1456:
1434:(2): 89–97.
1431:
1427:
1417:
1392:
1388:
1382:
1337:
1333:
1323:
1298:
1294:
1288:
1261:
1257:
1247:
1220:
1216:
1206:
1182:(1): 77–81.
1179:
1175:
1165:
1130:
1126:
1116:
1091:
1087:
1081:
1056:
1052:
1046:
1005:
1001:
995:
962:
958:
952:
927:
924:Biochemistry
923:
917:
872:
868:
858:
825:
821:
815:
782:
778:
772:
739:
735:
725:
700:
696:
654:
650:
613:
610:Harriet Hall
607:
603:
599:class action
588:
580:
575:
571:
569:
561:
546:
536:
506:
471:
453:, including
439:
436:Applications
426:fluorescence
390:
384:
368:
359:
336:
321:
293:
283:
259:
240:
214:
194:
183:
160:
154:photoprotein
146:
145:
2817:Active site
2489:October 24,
2483:Google Docs
2215:J Biol Chem
1972:: 105–118.
1127:Protein Sci
529:Roger Tsien
502:Ca reporter
478:recombinant
442:luminometer
294:apoaequorin
286:holoprotein
270:Nobel Prize
266:Roger Tsien
125:Swiss-model
58:Identifiers
3105:EC 1.13.12
3089:Categories
3020:Isomerases
2994:Hydrolases
2861:Regulation
2567:5 December
2540:5 December
2345:January 9,
2319:January 9,
2291:January 9,
1721:Biochem. J
651:Biol. Bull
634:References
570:The suit (
521:calmodulin
509:lipophilic
494:cell walls
482:apoprotein
418:wavelength
351:sulfhydryl
313:photocytes
300:, and the
290:apoprotein
229:photocytes
221:luciferase
121:Structures
116:Search for
95:Other data
33:Aequorin 1
2899:EC number
2463:March 24,
2109:Biochem J
1619:FEBS Lett
1258:FEBS Lett
1217:FEBS Lett
822:J Microsc
620:p-hacking
455:zebrafish
332:titration
280:Structure
225:luciferin
211:Discovery
158:hydrozoan
106:1.13.12.5
101:EC number
44:Aequorin
2923:Kinetics
2847:Cofactor
2810:Activity
2588:Archived
2561:Archived
2534:Archived
2285:NBC News
2237:14742421
2196:13745050
1996:12734562
1906:19339429
1898:17387626
1827:16741871
1641:16545379
1409:14550635
1280:15527769
1157:15689515
1030:10830969
979:16981205
959:Proteins
869:PNAS USA
850:36316988
842:15655058
807:42494355
764:10826363
717:13911999
533:troponin
531:and the
525:cameleon
391:Aequorea
365:Genetics
355:cysteine
328:peroxide
242:Aequorea
147:Aequorin
135:InterPro
63:Organism
3079:Biology
3033:Ligases
2803:Enzymes
2754:: other
2752:1.13.99
2733:1.13.12
2645:1.13.11
2458:law.com
2188:9278050
2166:Bibcode
2139:8809023
2130:1217633
2090:8521803
2041:6758036
1947:8470808
1862:9056079
1786:4383681
1751:2400391
1742:1131721
1670:Bibcode
1600:4284185
1592:4393938
1572:Bibcode
1549:4152180
1514:4176627
1486:Bibcode
1448:1536540
1374:3858813
1342:Bibcode
1315:2579647
1239:8405461
1198:8660347
1148:2279293
1108:7794244
1073:7794244
1038:4425033
1010:Bibcode
987:8904181
944:2866797
877:Bibcode
799:4397528
756:1536528
679:7654844
671:1542194
593:in the
403:calcium
317:EF hand
251:calcium
190:express
131:Domains
84:UniProt
3065:Portal
3007:Lyases
2683:ALOX15
2669:ALOX12
2235:
2194:
2186:
2158:Nature
2137:
2127:
2088:
2081:394660
2078:
2060:EMBO J
2039:
1994:
1987:145563
1984:
1945:
1904:
1896:
1860:
1825:
1784:
1749:
1739:
1702:236561
1700:
1693:432574
1690:
1639:
1598:
1590:
1564:Nature
1547:
1512:
1506:239351
1504:
1478:Nature
1446:
1407:
1372:
1365:397733
1362:
1313:
1278:
1237:
1196:
1155:
1145:
1106:
1071:
1036:
1028:
1002:Nature
985:
977:
942:
909:275832
907:
900:392612
897:
848:
840:
805:
797:
762:
754:
715:
677:
669:
537:TN-XXL
465:, and
399:oxygen
371:genome
309:enzyme
165:. Its
89:P07164
75:Symbol
2959:Types
2638:1.13)
2192:S2CID
1902:S2CID
1596:S2CID
1510:S2CID
1444:JSTOR
1034:S2CID
983:S2CID
846:S2CID
803:S2CID
760:S2CID
752:JSTOR
667:JSTOR
343:thiol
188:that
149:is a
48:from
3051:list
3044:EC7
3038:list
3031:EC6
3025:list
3018:EC5
3012:list
3005:EC4
2999:list
2992:EC3
2986:list
2979:EC2
2973:list
2966:EC1
2569:2018
2542:2018
2491:2020
2465:2020
2386:2018
2347:2017
2321:2017
2293:2017
2265:2021
2233:PMID
2184:PMID
2135:PMID
2086:PMID
2037:PMID
1992:PMID
1943:PMID
1894:PMID
1858:PMID
1823:PMID
1782:PMID
1747:PMID
1698:PMID
1637:PMID
1588:PMID
1545:PMID
1502:PMID
1405:PMID
1370:PMID
1311:PMID
1276:PMID
1235:PMID
1194:PMID
1153:PMID
1104:PMID
1069:PMID
1026:PMID
975:PMID
940:PMID
905:PMID
838:PMID
795:PMID
713:PMID
675:PMID
608:Dr.
474:gene
463:mice
459:rats
424:and
409:and
375:cDNA
322:The
264:and
2223:doi
2219:279
2174:doi
2162:388
2125:PMC
2117:doi
2113:318
2076:PMC
2068:doi
2027:doi
1982:PMC
1974:doi
1933:doi
1929:209
1886:doi
1850:doi
1813:doi
1774:doi
1737:PMC
1729:doi
1725:270
1688:PMC
1678:doi
1627:doi
1623:580
1580:doi
1568:227
1537:doi
1494:doi
1482:256
1436:doi
1397:doi
1360:PMC
1350:doi
1303:doi
1299:126
1266:doi
1262:577
1225:doi
1221:332
1184:doi
1180:221
1143:PMC
1135:doi
1096:doi
1092:211
1061:doi
1057:211
1018:doi
1006:405
967:doi
932:doi
895:PMC
885:doi
830:doi
826:217
787:doi
744:doi
705:doi
659:doi
655:189
513:DiI
393:by
389:of
298:kDa
239:of
78:N/A
50:PDB
3091::
2636:EC
2630::
2532:.
2526:.
2507:.
2481:.
2456:.
2452:.
2440:^
2431:,
2401:,
2376:.
2337:.
2310:.
2282:.
2254:.
2231:.
2217:.
2213:.
2190:.
2182:.
2172:.
2160:.
2156:.
2133:.
2123:.
2111:.
2107:.
2084:.
2074:.
2064:14
2062:.
2058:.
2035:.
2023:40
2021:.
2017:.
1990:.
1980:.
1968:.
1964:.
1941:.
1927:.
1923:.
1900:.
1892:.
1882:16
1880:.
1856:.
1846:21
1844:.
1821:.
1809:50
1807:.
1803:.
1780:.
1770:29
1768:.
1745:.
1735:.
1723:.
1719:.
1696:.
1686:.
1676:.
1666:72
1664:.
1658:.
1635:.
1621:.
1617:.
1594:.
1586:.
1578:.
1566:.
1543:.
1533:13
1531:.
1508:.
1500:.
1492:.
1480:.
1442:.
1432:51
1430:.
1426:.
1403:.
1393:31
1391:.
1368:.
1358:.
1348:.
1338:82
1336:.
1332:.
1309:.
1297:.
1274:.
1260:.
1256:.
1233:.
1219:.
1215:.
1192:.
1178:.
1174:.
1151:.
1141:.
1131:14
1129:.
1125:.
1102:.
1090:.
1067:.
1055:.
1032:.
1024:.
1016:.
1004:.
981:.
973:.
963:65
961:.
938:.
928:24
926:.
903:.
893:.
883:.
873:75
871:.
867:.
844:.
836:.
824:.
801:.
793:.
783:77
781:.
758:.
750:.
740:41
738:.
734:.
711:.
701:59
699:.
687:^
673:.
665:.
653:.
641:^
469:.
461:,
457:,
432:.
411:CO
276:.
3067::
3053:)
3049:(
3040:)
3036:(
3027:)
3023:(
3014:)
3010:(
3001:)
2997:(
2988:)
2984:(
2975:)
2971:(
2795:e
2788:t
2781:v
2681:/
2667:/
2657::
2634:(
2620:e
2613:t
2606:v
2571:.
2544:.
2493:.
2467:.
2388:.
2349:.
2323:.
2295:.
2267:.
2239:.
2225::
2198:.
2176::
2168::
2141:.
2119::
2092:.
2070::
2043:.
2029::
1976::
1970:4
1949:.
1935::
1908:.
1888::
1864:.
1852::
1829:.
1815::
1788:.
1776::
1753:.
1731::
1704:.
1680::
1672::
1643:.
1629::
1602:.
1582::
1574::
1551:.
1539::
1516:.
1496::
1488::
1450:.
1438::
1411:.
1399::
1376:.
1352::
1344::
1317:.
1305::
1282:.
1268::
1241:.
1227::
1200:.
1186::
1159:.
1137::
1110:.
1098::
1075:.
1063::
1040:.
1020::
1012::
989:.
969::
946:.
934::
911:.
887::
879::
852:.
832::
809:.
789::
766:.
746::
719:.
707::
681:.
661::
413:2
223:-
20:)
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
