493:), gramicidin S synthetase I (GrsA) and gramicidin S synthetase II (GrsB), to give a product as a cyclic decapeptide. Within the biosynthetic pathway, there are total of five modules that specifically recognize, activate, and condense the amino acids to gramicidin S. Starting module GrsA consists of three domains: Adenylation (A) domain where it incorporates the amino acid and activates it by adenylation using ATP, Thiolation (T) domain or peptidyl carrier protein (PCP) in which the adenylated amino acid gets covalently attached to the 4´-phosphopantetheine group and this gets loaded onto the conserved serine in the T domain, Epimerization (E) domain where it epimerizes L-amino acid to D-amino acid. Starting module GrsA loads D-Phe onto the system.
580:
255:
40:
374:
InChI=1S/C60H92N12O10/c1-35(2)31-43-53(75)67-45(33-39-19-11-9-12-20-39)59(81)71-29-17-25-47(71)55(77)70-50(38(7)8)58(80)64-42(24-16-28-62)52(74)66-44(32-36(3)4)54(76)68-46(34-40-21-13-10-14-22-40)60(82)72-30-18-26-48(72)56(78)69-49(37(5)6)57(79)63-41(23-15-27-61)51(73)65-43/h9-14,19-22,35-38,41-50H,15-18,23-34,61-62H2,1-8H3,(H,63,79)(H,64,80)(H,65,73)(H,66,74)(H,67,75)(H,68,76)(H,69,78)(H,70,77)/t41-,42-,43-,44-,45+,46+,47-,48-,49-,50-/m0/s1
332:
31:
509:
504:
domain (TE) at the end. C domain forms a peptide bond between two amino acids, D-Phe and L-Pro. L-Val, L-Orn, and L-Leu are incorporated sequentially by the next three modules of GrsB. After repeating the whole module synthesis once again, TE domain cyclizes and releases the two peptides and dimerize
611:
and even several pathogenic fungi. The mode of action is not entirely agreed upon, but it is generally accepted that it is disruption of the lipid membrane and enhancement of the permeability of the bacterial cytoplasmic membrane. Unfortunately, being
998:
Yamada K, Unno M, Kobayashi K, Oku H, Yamamura H, Araki S, et al. (October 2002). "Stereochemistry of protected ornithine side chains of gramicidin S derivatives: X-ray crystal structure of the bis-Boc-tetra-N-methyl derivative of gramicidin S".
562:
worked for a term in 1947 with
Gerhard Schmidt on the antibiotic Gramicidin S, as an undergraduate research project. The importance of Gramicidin S and antibiotic research in general was so great that Gause was not persecuted during the period of
1087:
Prenner EJ, Lewis RN, Neuman KC, Gruner SM, Kondejewski LH, Hodges RS, McElhaney RN (June 1997). "Nonlamellar phases induced by the interaction of gramicidin S with lipid bilayers. A possible relationship to membrane-disrupting activity".
525:
and his wife Maria
Brazhnikova in 1942. Within the year Gramicidin S was being used in Soviet military hospitals to treat infection and eventually found usage at the front lines of combat by 1946. Gause was awarded the
688:
Llamas-Saiz AL, Grotenbreg GM, Overhand M, van Raaij MJ (March 2007). "Double-stranded helical twisted beta-sheet channels in crystals of gramicidin S grown in the presence of trifluoroacetic and hydrochloric acids".
952:
Gall YM, Konashev MB (2001). "The discovery of
Gramicidin S: the intellectual transformation of G.F. Gause from biologist to researcher of antibiotics and on its meaning for the fate of Russian genetics".
465:. That is to say, it forms a ring structure composed of five different amino acids, each one used twice within the structure. Another interesting point is that it utilizes two amino acids uncommon in
616:
at even low concentrations, gramicidin S is only used as topical applications at present. Additionally, Gramicidin S has been employed as a spermicide and therapeutic for genital ulcers caused by
567:
in the USSR, while many of his colleagues were. Indeed, it was his need for developing new strains to mass-produce antibiotics that allowed politically sanctioned collaborations with
1156:
599:
Gramicidin S differs from other gramicidin types in that it is a cationic cyclic decapeptide and has a structure of an anti-parallel beta-sheet. Gramicidin S molecule is
1590:
1650:
346:
1149:
1386:
1381:
1134:
584:
1142:
603:, with hydrophobic amino acids (D-Phe, Val, Leu side chains) and charged aminoacid (L-Orn). It exhibits strong antibiotic activity towards
865:
Sieber SA, Marahiel MA (February 2005). "Molecular mechanisms underlying nonribosomal peptide synthesis: approaches to new antibiotics".
1685:
1353:
555:
546:
proved that the compound was an original antibiotic and a polypeptide using paper chromatography. He would later go on to receive the
354:
CC(C)C1C(=O)N(C(=O)N2CCC2C(=O)N(C(=O)N(C(=O)N(C(=O)N(C(=O)N3CCC3C(=O)N(C(=O)N(C(=O)N1)CCCN)C(C)C)Cc4ccccc4)CC(C)C)CCCN)C(C)C)Cc5ccccc5
531:
366:
72:
902:"Parallel interrogation of covalent intermediates in the biosynthesis of gramicidin S using high-resolution mass spectrometry"
1358:
617:
154:
234:
1680:
1341:
522:
579:
571:
like Joseph
Rapoport and Alexander Malinovsky, who would both actively participate in the downfall of Lysenkoism.
1675:
1040:"Modulation of structure and antibacterial and hemolytic activity by ring size in cyclic gramicidin S analogs"
1622:
539:
52:
413:
409:
203:
1346:
1173:
734:"Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S"
508:
1670:
1373:
1329:
1223:
698:
652:
490:
429:
783:"Modular structure of peptide synthetases revealed by dissection of the multifunctional enzyme GrsA"
1363:
434:
250:
89:
830:
von Döhren H, Keller U, Vater J, Zocher R (November 1997). "Multifunctional
Peptide Synthetases".
223:
1069:
812:
670:
1105:
1061:
1016:
962:
931:
882:
847:
804:
763:
714:
559:
1569:
1564:
1509:
1499:
1494:
1484:
1479:
1474:
1454:
183:
1595:
1424:
1404:
1311:
1306:
1301:
1296:
1291:
1286:
1276:
1266:
1261:
1251:
1246:
1169:
1097:
1051:
1035:
1008:
921:
913:
874:
839:
794:
753:
745:
706:
660:
643:
527:
489:
Gramicidin S biosynthetic pathway consists of two-enzyme of nonribosomal peptide synthases (
417:
271:
1281:
1256:
163:
143:
1208:
1203:
551:
980:
254:
98:
702:
656:
926:
901:
758:
733:
1664:
608:
604:
543:
535:
478:
454:
816:
500:, each containing condensation (C), adenylation (A), and thiolation (T) domains and
39:
1181:
1073:
674:
501:
474:
214:
123:
550:
for his work in chromatography. The crystal structure was finally established by
1534:
1396:
600:
592:
547:
749:
1617:
1600:
1198:
710:
568:
564:
530:
for
Medicine for his discovery in 1946. In 1944, Gramicidin S was sent by the
497:
424:
304:
134:
1056:
1039:
22:
1627:
799:
782:
613:
588:
542:
in a collaborative effort to establish the exact structure. English chemist
470:
446:
1020:
966:
935:
886:
851:
718:
1109:
1065:
808:
767:
30:
1585:
1190:
917:
1559:
1554:
1514:
1504:
1489:
1469:
1464:
1459:
1449:
1165:
466:
458:
450:
109:
1101:
1012:
878:
843:
1444:
1439:
1434:
1429:
1419:
1414:
1409:
1321:
1177:
665:
638:
442:
194:
433:. Gramicidin S is a cyclodecapeptide, constructed as two identical
1610:
1605:
1519:
1271:
1241:
1236:
583:
Crystal structure of modified
Gramicidin S. Modification includes
507:
331:
322:
174:
1637:
1632:
1549:
1539:
1529:
1524:
1334:
1231:
1213:
900:
Miller LM, Mazur MT, McLoughlin SM, Kelleher NL (October 2005).
1138:
1544:
639:"Gramicidin S and its use in the Treatment of Infected Wounds"
691:
239:
732:
Conti E, Stachelhaus T, Marahiel MA, Brick P (July 1997).
595:
of select amide nitrogens to force cyclic conformation.
391:
521:
Gramicidin S was discovered by
Russian microbiologist
1127:(in Russian). Moscow: Inpharmchem Press. p. 343.
1578:
1395:
1372:
1320:
1222:
1189:
320:
303:
270:
265:
233:
213:
193:
173:
153:
133:
108:
88:
63:
51:
46:
1038:, Kay CM, Hancock RE, Hodges RS (October 1996).
481:. It is synthesized by gramicidin S synthetase.
408:is an antibiotic that is effective against some
122:
1591:LDL-receptor-related protein-associated protein
97:
947:
945:
1150:
8:
222:
21:
955:History and Philosophy of the Life Sciences
1157:
1143:
1135:
1125:Compendium of Medicinal Products of Russia
427:, produced by the gram-positive bacterium
253:
142:
1387:Pulmonary surfactant-associated protein C
1382:Pulmonary surfactant-associated protein B
1055:
925:
798:
781:Stachelhaus T, Marahiel MA (March 1995).
757:
664:
505:them together to form the final product.
496:Second enzyme cluster GrsB contains four
437:joined head to tail, formally written as
162:
1001:Journal of the American Chemical Society
578:
629:
371:
351:
249:
77:
20:
1651:other cell membrane protein disorders
202:
182:
7:
575:Structure and pharmacological effect
512:Biosynthetic pathway of gramicidin S
1354:Myelin oligodendrocyte glycoprotein
1044:The Journal of Biological Chemistry
981:"R.L.M. Synge (British biochemist)"
787:The Journal of Biological Chemistry
113:
14:
637:Gause GF, Brazhnikova MG (1944).
288:
282:
38:
29:
379:Key:IUAYMJGZBVDSGL-XNNAEKOYSA-N
1623:Phospholipid transfer proteins
1359:Myelin-associated glycoprotein
985:Britannica Online Encyclopedia
532:Ministry of Health of the USSR
294:
276:
1:
618:sexually transmitted disease
1034:Kondejewski LH, Farmer SW,
1702:
1686:Health in the Soviet Union
1342:Myelin proteolipid protein
523:Georgyi Frantsevitch Gause
266:Chemical and physical data
1646:
711:10.1107/S0907444906056435
387:
362:
342:
68:
37:
28:
1057:10.1074/jbc.271.41.25261
750:10.1093/emboj/16.14.4174
473:as well as the atypical
800:10.1074/jbc.270.11.6163
540:International Red Cross
596:
513:
423:It is a derivative of
414:gram-negative bacteria
1174:Cell surface receptor
582:
511:
1374:Pulmonary surfactant
1330:Myelin basic protein
1224:Membrane-spanning 4A
918:10.1110/ps.051553705
430:Brevibacillus brevis
1364:Myelin protein zero
703:2007AcCrD..63..401L
657:1944Natur.154..703G
25:
1123:Krylov YF (1993).
987:. 24 October 2023.
597:
514:
1681:Soviet inventions
1658:
1657:
1170:membrane proteins
1102:10.1021/bi962785k
1013:10.1021/ja020307t
879:10.1021/cr0301191
844:10.1021/cr9600262
560:Margaret Thatcher
406:Gramicidin Soviet
399:
398:
333:Interactive image
235:CompTox Dashboard
16:Chemical compound
1693:
1159:
1152:
1145:
1136:
1129:
1128:
1120:
1114:
1113:
1084:
1078:
1077:
1059:
1031:
1025:
1024:
995:
989:
988:
977:
971:
970:
949:
940:
939:
929:
897:
891:
890:
867:Chemical Reviews
862:
856:
855:
838:(7): 2675–2706.
832:Chemical Reviews
827:
821:
820:
802:
778:
772:
771:
761:
738:The EMBO Journal
729:
723:
722:
685:
679:
678:
668:
666:10.1038/154703a0
634:
416:as well as some
395:
394:
335:
315:
313:
296:
290:
284:
278:
258:
257:
243:
241:
226:
206:
186:
166:
146:
126:
116:
115:
101:
42:
33:
26:
24:
1701:
1700:
1696:
1695:
1694:
1692:
1691:
1690:
1676:Cyclic peptides
1661:
1660:
1659:
1654:
1642:
1596:Neurofibromin 2
1579:Other/ungrouped
1574:
1391:
1368:
1316:
1218:
1185:
1163:
1133:
1132:
1122:
1121:
1117:
1096:(25): 7906–16.
1086:
1085:
1081:
1050:(41): 25261–8.
1033:
1032:
1028:
1007:(43): 12684–8.
997:
996:
992:
979:
978:
974:
951:
950:
943:
912:(10): 2702–12.
906:Protein Science
899:
898:
894:
864:
863:
859:
829:
828:
824:
780:
779:
775:
744:(14): 4174–83.
731:
730:
726:
697:(Pt 3): 401–7.
687:
686:
682:
636:
635:
631:
626:
577:
556:Gerhard Schmidt
552:Dorothy Hodgkin
519:
487:
464:
390:
388:
383:
380:
375:
370:
369:
358:
355:
350:
349:
338:
311:
309:
299:
293:
287:
281:
261:
237:
229:
209:
189:
169:
149:
129:
112:
104:
84:
81:
76:
75:
54:
17:
12:
11:
5:
1699:
1697:
1689:
1688:
1683:
1678:
1673:
1663:
1662:
1656:
1655:
1647:
1644:
1643:
1641:
1640:
1635:
1630:
1625:
1620:
1615:
1614:
1613:
1608:
1598:
1593:
1588:
1582:
1580:
1576:
1575:
1573:
1572:
1567:
1562:
1557:
1552:
1547:
1542:
1537:
1532:
1527:
1522:
1517:
1512:
1507:
1502:
1497:
1492:
1487:
1482:
1477:
1472:
1467:
1462:
1457:
1452:
1447:
1442:
1437:
1432:
1427:
1422:
1417:
1412:
1407:
1401:
1399:
1393:
1392:
1390:
1389:
1384:
1378:
1376:
1370:
1369:
1367:
1366:
1361:
1356:
1351:
1350:
1349:
1339:
1338:
1337:
1326:
1324:
1318:
1317:
1315:
1314:
1309:
1304:
1299:
1294:
1289:
1284:
1279:
1274:
1269:
1264:
1259:
1254:
1249:
1244:
1239:
1234:
1228:
1226:
1220:
1219:
1217:
1216:
1211:
1206:
1201:
1195:
1193:
1187:
1186:
1164:
1162:
1161:
1154:
1147:
1139:
1131:
1130:
1115:
1079:
1026:
990:
972:
941:
892:
857:
822:
793:(11): 6163–9.
773:
724:
680:
628:
627:
625:
622:
576:
573:
518:
515:
486:
483:
462:
397:
396:
385:
384:
382:
381:
378:
376:
373:
365:
364:
363:
360:
359:
357:
356:
353:
345:
344:
343:
340:
339:
337:
336:
328:
326:
318:
317:
307:
301:
300:
297:
291:
285:
279:
274:
268:
267:
263:
262:
260:
259:
246:
244:
231:
230:
228:
227:
219:
217:
211:
210:
208:
207:
199:
197:
191:
190:
188:
187:
179:
177:
171:
170:
168:
167:
159:
157:
151:
150:
148:
147:
139:
137:
131:
130:
128:
127:
119:
117:
106:
105:
103:
102:
94:
92:
86:
85:
83:
82:
79:
71:
70:
69:
66:
65:
61:
60:
57:
55:administration
49:
48:
44:
43:
35:
34:
15:
13:
10:
9:
6:
4:
3:
2:
1698:
1687:
1684:
1682:
1679:
1677:
1674:
1672:
1669:
1668:
1666:
1653:
1652:
1645:
1639:
1636:
1634:
1631:
1629:
1626:
1624:
1621:
1619:
1616:
1612:
1609:
1607:
1604:
1603:
1602:
1599:
1597:
1594:
1592:
1589:
1587:
1584:
1583:
1581:
1577:
1571:
1568:
1566:
1563:
1561:
1558:
1556:
1553:
1551:
1548:
1546:
1543:
1541:
1538:
1536:
1533:
1531:
1528:
1526:
1523:
1521:
1518:
1516:
1513:
1511:
1508:
1506:
1503:
1501:
1498:
1496:
1493:
1491:
1488:
1486:
1483:
1481:
1478:
1476:
1473:
1471:
1468:
1466:
1463:
1461:
1458:
1456:
1453:
1451:
1448:
1446:
1443:
1441:
1438:
1436:
1433:
1431:
1428:
1426:
1423:
1421:
1418:
1416:
1413:
1411:
1408:
1406:
1403:
1402:
1400:
1398:
1394:
1388:
1385:
1383:
1380:
1379:
1377:
1375:
1371:
1365:
1362:
1360:
1357:
1355:
1352:
1348:
1345:
1344:
1343:
1340:
1336:
1333:
1332:
1331:
1328:
1327:
1325:
1323:
1319:
1313:
1310:
1308:
1305:
1303:
1300:
1298:
1295:
1293:
1290:
1288:
1285:
1283:
1280:
1278:
1275:
1273:
1270:
1268:
1265:
1263:
1260:
1258:
1255:
1253:
1250:
1248:
1245:
1243:
1240:
1238:
1235:
1233:
1230:
1229:
1227:
1225:
1221:
1215:
1212:
1210:
1207:
1205:
1202:
1200:
1197:
1196:
1194:
1192:
1188:
1183:
1179:
1175:
1171:
1167:
1160:
1155:
1153:
1148:
1146:
1141:
1140:
1137:
1126:
1119:
1116:
1111:
1107:
1103:
1099:
1095:
1091:
1083:
1080:
1075:
1071:
1067:
1063:
1058:
1053:
1049:
1045:
1041:
1037:
1030:
1027:
1022:
1018:
1014:
1010:
1006:
1002:
994:
991:
986:
982:
976:
973:
968:
964:
961:(1): 137–50.
960:
956:
948:
946:
942:
937:
933:
928:
923:
919:
915:
911:
907:
903:
896:
893:
888:
884:
880:
876:
873:(2): 715–38.
872:
868:
861:
858:
853:
849:
845:
841:
837:
833:
826:
823:
818:
814:
810:
806:
801:
796:
792:
788:
784:
777:
774:
769:
765:
760:
755:
751:
747:
743:
739:
735:
728:
725:
720:
716:
712:
708:
704:
700:
696:
692:
684:
681:
676:
672:
667:
662:
658:
654:
651:(3918): 703.
650:
646:
645:
640:
633:
630:
623:
621:
619:
615:
610:
609:Gram-positive
606:
605:Gram-negative
602:
594:
590:
586:
581:
574:
572:
570:
566:
561:
557:
553:
549:
545:
544:Richard Synge
541:
537:
536:Great Britain
533:
529:
524:
516:
510:
506:
503:
499:
494:
492:
484:
482:
480:
479:phenylalanine
476:
472:
468:
460:
456:
452:
448:
444:
440:
436:
435:pentapeptides
432:
431:
426:
421:
419:
415:
411:
410:gram-positive
407:
403:
393:
386:
377:
372:
368:
361:
352:
348:
341:
334:
330:
329:
327:
324:
319:
308:
306:
302:
275:
273:
269:
264:
256:
252:
251:DTXSID6046008
248:
247:
245:
236:
232:
225:
221:
220:
218:
216:
212:
205:
201:
200:
198:
196:
192:
185:
181:
180:
178:
176:
172:
165:
161:
160:
158:
156:
152:
145:
141:
140:
138:
136:
132:
125:
121:
120:
118:
111:
107:
100:
96:
95:
93:
91:
87:
78:
74:
67:
62:
58:
56:
50:
47:Clinical data
45:
41:
36:
32:
27:
19:
1648:
1182:cytoskeleton
1172:(other than
1124:
1118:
1093:
1090:Biochemistry
1089:
1082:
1047:
1043:
1029:
1004:
1000:
993:
984:
975:
958:
954:
909:
905:
895:
870:
866:
860:
835:
831:
825:
790:
786:
776:
741:
737:
727:
694:
690:
683:
648:
642:
632:
598:
528:Stalin Prize
520:
502:thioesterase
495:
488:
485:Biosynthesis
475:stereoisomer
438:
428:
422:
405:
402:Gramicidin S
401:
400:
389:
215:NIAID ChemDB
204:ChEMBL373496
80:Gramicidin S
23:Gramicidin S
18:
1671:Antibiotics
1397:Tetraspanin
601:amphiphilic
593:methylation
591:as well as
569:geneticists
548:Nobel Prize
316: g·mol
64:Identifiers
1665:Categories
1601:Presenilin
1036:Wishart DS
624:References
585:Boc groups
565:Lysenkoism
425:gramicidin
321:3D model (
305:Molar mass
184:CHEBI:5530
164:WHM29QA23F
135:ChemSpider
90:CAS Number
73:IUPAC name
1649:see also
1628:Dysferlin
614:hemolytic
589:ornithine
471:ornithine
53:Routes of
1586:Calnexin
1191:Arrestin
1021:12392415
967:12212443
936:16195555
887:15700962
852:11851477
817:10325408
719:17327677
538:via the
467:peptides
392:(verify)
99:113-73-5
1570:TSPAN34
1565:TSPAN33
1560:TSPAN32
1555:TSPAN31
1550:TSPAN30
1545:TSPAN29
1540:TSPAN28
1535:TSPAN27
1530:TSPAN26
1525:TSPAN25
1520:TSPAN24
1515:TSPAN23
1510:TSPAN22
1505:TSPAN21
1500:TSPAN20
1495:TSPAN19
1490:TSPAN18
1485:TSPAN17
1480:TSPAN16
1475:TSPAN15
1470:TSPAN14
1465:TSPAN13
1460:TSPAN12
1455:TSPAN11
1450:TSPAN10
1178:enzymes
1168:: cell
1166:Protein
1110:9201936
1074:2015112
1066:8810288
927:2253301
809:7534306
768:9250661
759:1170043
699:Bibcode
675:4125407
653:Bibcode
587:on the
517:History
498:modules
272:Formula
110:PubChem
59:Topical
1445:TSPAN9
1440:TSPAN8
1435:TSPAN7
1430:TSPAN6
1425:TSPAN5
1420:TSPAN4
1415:TSPAN3
1410:TSPAN2
1405:TSPAN1
1322:Myelin
1312:MS4A18
1307:MS4A15
1302:MS4A14
1297:MS4A13
1292:MS4A12
1287:MS4A10
1277:MS4A8B
1267:MS4A6E
1262:MS4A6A
1252:MS4A4E
1247:MS4A4A
1180:, and
1108:
1072:
1064:
1019:
965:
934:
924:
885:
850:
815:
807:
766:
756:
717:
673:
644:Nature
347:SMILES
224:002002
195:ChEMBL
1611:PSEN2
1606:PSEN1
1282:MS4A9
1272:MS4A7
1257:MS4A5
1242:MS4A3
1237:MS4A2
1232:MS4A1
1209:ARRB2
1204:ARRB1
1070:S2CID
813:S2CID
671:S2CID
491:NRPSs
439:cyclo
418:fungi
367:InChI
323:JSmol
175:ChEBI
144:66085
124:73357
1638:OTOF
1633:STRC
1347:PLP1
1335:PMP2
1214:ARR3
1106:PMID
1062:PMID
1017:PMID
963:PMID
932:PMID
883:PMID
848:PMID
805:PMID
764:PMID
715:PMID
607:and
554:and
412:and
314:.470
155:UNII
1618:HFE
1199:SAG
1098:doi
1052:doi
1048:271
1009:doi
1005:124
922:PMC
914:doi
875:doi
871:105
840:doi
795:doi
791:270
754:PMC
746:doi
707:doi
661:doi
649:154
534:to
477:of
459:Pro
455:Phe
453:-D-
451:Leu
447:Orn
443:Val
404:or
312:141
240:EPA
114:CID
1667::
1176:,
1104:.
1094:36
1092:.
1068:.
1060:.
1046:.
1042:.
1015:.
1003:.
983:.
959:23
957:.
944:^
930:.
920:.
910:14
908:.
904:.
881:.
869:.
846:.
836:97
834:.
811:.
803:.
789:.
785:.
762:.
752:.
742:16
740:.
736:.
713:.
705:.
695:63
693:.
669:.
659:.
647:.
641:.
620:.
558:;
469::
461:-)
441:(-
420:.
298:10
292:12
286:92
280:60
1184:)
1158:e
1151:t
1144:v
1112:.
1100::
1076:.
1054::
1023:.
1011::
969:.
938:.
916::
889:.
877::
854:.
842::
819:.
797::
770:.
748::
721:.
709::
701::
677:.
663::
655::
463:2
457:-
449:-
445:-
325:)
310:1
295:O
289:N
283:H
277:C
242:)
238:(
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.