text
stringlengths 0
1.67M
|
|---|
Washing machine and dryer having being improved duct structure thereof |
The present invention relates to a washing machine and dryer with an improved duct structure. A cabinet (100) form a an outer shell of the washing machine and dryer, and a tub (200) is installed within the cabinet (100). A drum (250) is rotatably installed within the tub (200). Since a drying duct (300) is installed in an upper portion of the tub (200) that is eccentric toward one side when viewed from the front of the tub (200), an internal space utilization of the cabinet (100) is enhanced and the equipment can be compact. The drying duct (300) is manufactured with two bodies that are a lower part (310) and an upper part (320) formed by extending a discharge part (330) from one end portion of the drying duct (300), so that the number of parts and the number of assemble processes are reduced and the productivity is improved. Since the discharge part (330) and the lower part (310) are formed in one body, it can prevent the damage and the air leakage, caused in a connection portion due to vibration, and the flowing noise caused by them. The discharge part (330) is extended to be slant in a rotation direction of the drum (250) and a guidance part is extended in a tangential direction with respect to a rotation direction of the drum (250) at one end portion of the discharge part (330), thus smoothly supplying air to the drum (250). A condensation duct (400) has one end connected to the drying duct (300) and the other end connected to an inside of the tub (200). A heater (800) is installed within the drying duct (300) and a circulation fan (350) is installed in the other end of the drying duct (300) to which the condensation duct is connected. |
1. A washing machine and dryer comprising: a cabinet; a cylinder-shaped tub installed within the cabinet; a drum, rotatably installed within the tub; a drying duct having one end connected to an inner side of the tub, the drying duct being installed in an upper portion of the tub to be eccentric toward one side of the tub when viewed from the front of the tub; a condensation duct having one end connected to the drying duct and the other end connected to an inner side of the tub; a circulation fan for circulating air existing within the tub through the condensation duct and the drying duct; and a heater for heating the air. 2. The washing machine and dryer of claim 1, wherein an upper face of the drying duct is installed in a lower portion than that of the tub. 3. The washing machine and dryer of claim 1, wherein a surface of the drying duct, which is adjacent to the tub, is formed to be slant. 4. The washing machine and dryer of claim 3, wherein the adjacent surface of the drying duct is formed in a curved surface with the same curvature as an outer surface of the tub. 5. The washing machine and dryer of claim 1, wherein the drying duct includes: a lower part of which an upper portion is opened, in which a discharge part connected to a front side of the tub is downwardly extended from one end in one body and a communication hole for connecting the lower part with the condensation duct is formed in a lower portion of the other end; and an upper part covering the opened upper portion of the lower part. 6. The washing machine and dryer of claim 5, wherein the other end of the lower part in which the communication hole is formed is widely formed. 7. The washing machine and dryer of claim 6, wherein the circulation fan is inserted into the other end of the lower part. 8. The washing machine and dryer of claim 5, wherein a surface of the lower part, which is adjacent to the outer surface of the tub, is formed to be slant. 9. The washing machine and dryer of claim 5, wherein the adjacent surface of the lower part is formed in a curved surface with the same curvature as an outer surface of the tub. 10. The washing machine and dryer of claim 5, wherein a portion in which the discharge part is extended from one end of the lower part is formed roundly so as to smoothly guide air. 11. The washing machine and dryer of claim 5, wherein the discharge part is extended to be slant from the lower part in a downward direction. 12. The washing machine and dryer of claim 11, wherein the discharge part is formed to be slant when viewed from the front of the tub so as to discharge air in a rotation direction of the drum. 13. The washing machine and dryer of claim 12, further comprising a guidance part extended from one end portion of the discharge part in a tangential direction with respect to the rotation direction of the tub when viewed from the front of the tub so as to discharge air in the tangential direction with respect to the rotation direction of the drum. 14. The washing machine and dryer of claim 1, wherein the drying duct has both ends fixed and supported to an inner surface of the cabinet by a first fixing member and a second fixing member. 15. The washing machine and dryer of claim 14, wherein the first fixing member includes: a plurality of brackets protruded at one portion of an inner surface of the cabinet; and a fixing load protruded at one end portion of the drying duct and fixedly inserted between the plurality of brackets. 16. The washing machine and dryer of claim 15, wherein the brackets and the fixing load are connected to each other by bolts and nuts. 17. The washing machine and dryer of claim 15, further comprising a plurality of reinforcement ribs for connecting a side surface of the fixing load with the drying duct, thereby reinforcing the fixing load. 18. The washing machine and dryer of claim 14, wherein the second fixing member includes: a fixing projection protruded at the other end of the drying duct; and a fixing angle protruded at other portion of an inner surface of the cabinet, for supporting the fixing projection at a lower portion. 19. The washing machine and dryer of claim 18, wherein the fixing projection and the fixing angle are fixedly connected with each other by a bolt and a nut. 20. The washing machine and dryer of claim 1, wherein the heater is installed in an inside of the drying duct. 21. The washing machine and dryer of claim 1, wherein the condensation duct has one end connected to the drying duct and the other end connected to a rear lower portion of the tub. 22. The washing machine and dryer of claim 1, wherein the tub and the drum are installed in parallel with a horizontal plane. 23. The washing machine and dryer of claim 1, wherein the tub and the drum are installed to be slant, such that openings of the tub and the drum are disposed at an upper portion with respect to a horizontal plane. |
<SOH> BACKGROUND ART <EOH>Generally, a washing machine is an apparatus which performs washing, rinsing and dewatering so as to separate dirt from clothes by the interaction of detergent and water, and is classified into agitator type, pulsator type and drum type washing machines. Among them, In the drum type washing machine, water, detergent and laundry are loaded into a drum with a plurality of protruded tumbling ribs installed in an inner surface of the drum and the drum is rotated at a low speed. Then, the laundry is washed due to an impact caused when the laundry is lifted by the tumbling ribs and then drops. The drum type washing machine has an advantage in that the laundry is not damaged. In addition, a small amount of water is consumed and the laundry is not tangled with each other. Meanwhile, a dryer is a machine for automatically drying a wet laundry after completing a washing operation. In general, the wet laundry is loaded into a drum installed in an inner side of a cabinet and the drum is rotated. Then, a hot wind is supplied to an inside of the drum to thereby dry the wet laundry. Recently, a combination dryer and drum washing machine, in which a dryer function as well as a washing function is added to the drum type washing machine, is practically available and its use increases gradually. FIG. 1 is a cross-sectional perspective view showing a duct structure of a conventional washing machine and dryer, and FIG. 2 is a cross-sectional view showing an internal structure of the conventional washing machine and dryer. Referring to FIGS. 1 and 2 , the conventional washing machine and dryer includes a cabinet 10 , a tub 20 , a drum 25 , a condensation duct 40 , a motor 5 , a heater 50 , a circulation fan 35 and a drain pump 6 . The cabinet 10 constitutes an outer shell of the washing machine and dryer, and includes a loading portion 11 and a door 15 for opening/closing the loading portion 11 , which are formed at one portion thereof. The tub 20 is formed in a cylinder shape. The tub 20 is installed within the cabinet 10 and supported by a spring 3 and a damper 4 . The drum 25 is rotatably installed within the tub 20 and the motor 5 is installed in order to enable the drum 25 to be rotated. The condensation duct 40 is connected with the tub 20 , and a drying duct 30 has one end connected to the tub 20 and the other end connected to the condensation duct 40 . Here, as shown in FIGS. 1 and 2 , the drying duct 30 is disposed at a middle upper portion of the tub 20 . One end of the drying duct 30 is connected to a discharge part 33 at a lower portion, in which the discharge part 33 is directly connected with an inside of the tub 20 . The drying duct 30 installed as above is fixedly connected to a support bar 35 using a fastener member such as a bolt, in which the support bar 35 crosses an upper portion of an inner space of the cabinet 10 . The heater 50 is installed within the drying duct 30 , and the circulation fan 35 is installed in a portion to which the drying duct 30 and the condensation duct 40 are connected. In addition, the drain pump 6 is installed so as to drain water gathered in a lower portion of the tub 20 . A reference numeral 9 denotes a cooling-water supplying unit for supplying cooling water to an inside of the condensation duct 40 . Meanwhile, as shown in FIG. 3 , in the conventional washing machine and dryer constructed as above, the drying duct 30 includes a lower part 31 whose upper portion is opened, an upper part 32 covering the opened upper portion of the lower part 31 , and the discharge part 33 connected to a lower portion of one end of the lower part 31 . Further, a communication hole 31 a is formed at a lower portion of the other end of the lower part 31 in order to connect the drying duct 30 with the condensation duct 40 . Hereinafter, a drying operation of the conventional washing machine and dryer will be described in detail. First, a wet laundry is loaded into the drum 25 and the drum 25 is rotated. Then, the circulation fan 35 is rotated to circulate internal air of the drum 25 via the condensation duct 40 and the drying duct 30 . The heater is operated to heat air. The air heated by the heater 50 dries the laundry within the drum 25 . At this time, moisture evaporated from the laundry is contained in air and introduced into the condensation duct 40 . In the condensation duct 40 , a heat exchange happens between the cooling water supplied from the cooling-water supplying unit 9 and air, so that moisture contained in the air is condensed and removed. The dried air whose moisture is removed is introduced into the drying duct 30 . The air introduced into the drying duct 30 is heated by the heater 50 and then again introduced into the drum 25 . By repeatedly performing the above procedures, the conventional washing machine and dryer removes the moisture of the wet laundry loaded into the drum 25 , thus drying the wet laundry. However, the conventional washing machine and dryer with the above-described duct structure has following problems. First, because the drying duct is disposed at the middle upper portion of the tub, the internal space utilization of the cabinet is degraded and the equipment generally increases in height. Second, after the lower part, the upper part and the discharge part contained in the drying duct are separately manufactured, the respective parts are assembled so that the number of parts increases. Further, the number of assembly processes also increases, thereby causing a degradation of productivity. Third, when the drum is rotated, the tub and the drying duct connected thereto are vibrated together. In this case, the connection portion between the lower part and the discharge part perpendicularly connected thereto may be loose and a gap therebetween may occur. In an excessive case, the connection portion between the lower part and the discharge part may be broken. Fourth, because the vibration causes a gap in the connection portion between the lower part and the discharge part, air flowing in the drying duct may be leaked out and thus noise may occur. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention. In the drawings: FIG. 1 is a partial cross-sectional perspective view showing a duct structure of a conventional washing machine and dryer; FIG. 2 is a cross-sectional view showing an internal structure of the conventional washing machine and dryer; FIG. 3 is an exploded perspective view showing the drying duct structure of the conventional washing machine and dryer; FIG. 4 is a partial cross-sectional perspective view showing a duct structure of a washing machine and dryer in accordance with an embodiment of the present invention; FIG. 5 is a cross-sectional view showing an internal structure of the washing machine and dryer in accordance with the present invention; FIG. 6 is an exploded perspective view of the drying duct in accordance with an embodiment of the present invention; FIG. 7 is a cross-sectional perspective view of the drying duct installed in accordance with the present invention; FIG. 8 is a partial cross-sectional perspective view showing a duct structure of a washing machine and dryer in accordance with another embodiment of the present invention; FIG. 9 is a cross-sectional view showing the drying duct fixed to the cabinet by the first fixing member; and FIG. 10 is a cross-sectional view showing the drying duct fixed to the cabinet by the second fixing member. detailed-description description="Detailed Description" end="lead"? |
Thermophilic microorganism bacillus coagulans strain sim-t dsm 14043 for the production of l(+)-lactate from fermentable sugars and their mixtures |
Thermophilic microorganism Bacillus coagulans strain SIM-7 DSM 14043 for the production of L(+)-lactate from fermentable sugars, including dextrines and starch. The temperature of cultivation is 53-65° C. being the optimal. The final concentration of L(+)-lactate in fermentation is 12% with the yield of 95%. The cultivation of this strain of microorganism is possible without the high-temperature sterilization of equipment and media. Using cereal flour as the source of fermentable sugars, the need of the strain of the microorganism for mineral and nitrogen salts will be covered by the compounds present in the cereals. |
1. The strain of the microorganism Bacillus coagulans SIM-7 DSM14043. 2. The method for the production of L(+)-lactate from fermentable sugars and its mixtures by means of microorganisms of claim 1, characterized in that the strain of microorganism will be cultivated at the temperature between 53-6520 C. and the fermentation medium contains partially fermentable sugars, including dextrines and starch and other nutrients. 3. The method according to the claim 2, characterized in that the cultivation of the strain of microorganism will be carried out at the temperature 57° C. 4. The method according to the claim 2, characterized in that the cultivation of the strain of microorganism will be carried out without high temperature sterilization of equipment and media. 5. The method according to the claim 2, characterized in that the flour of cereals will be used as the source of fermentable sugars. |
<SOH> BACKGROUND ART <EOH>Microbiological synthesis of L(+)-lactate is based on homolactic fermentation, resulting in two molecules of lactate from one molecule of hexose fermented (for example glucose or galactose). Industrial chemical synthesis of pure L(+)-lactate is not resolved up to know, therefore there is no alternative to the microbiological synthesis of this compound. In microbiological synthesis of L(+)-lactate, from the point of view of efficiency of energy consumption the maximum possible cultivation temperature of the microbial strain favouring set up the fermentation process without a high temperature sterilization steps of equipment and fermentation media is crucial. In currently available processes based on Lactobacillus species the cultivation temperature does not exceed 45° C. that does not exclude contamination with thermophilic microorganisms if cultivation proceeds in rich nutrient media in nonsterile conditions. (J. H. Litchfield; In Advances in Applied Microbiology, Neidleman S. L. ed, Vol. 42, pp 45-95, 1996). The optimal cultivation temperature is 52° C. in processes based on Bacillus coagulans TB/04 (T. Payot, Z.Chemaly, F. Fick Enzyme and Microbial Technology, 24, pp 191-199). The disadvantage in this case is inhibition of the process at high concentrations of sugars (over 7.5%) complicating the use of this strain in industrial scale. The prototype to the present invention is the microbial strain Bacillus coagulans DSM 5196. (U.S. Pat. No. 5,079,164; C12P 7/56, C12R 1/07; Jungbunzlauer Aktiengesellschaft, 1992). In the processes based on this organism the optimum cultivation temperature is 52° C. It is possible to cultivate this organism at the initial concentration of sugars up to 20%. However, this organism can convert only 70% of glucose or sucrose of the growth media to lactate that is less than in current industrial applications (85-90%). Furthermore, Bacillus coagulans DSM 5196 is not able to hydrolyse starch, dictating the need of preliminary treatment of the starch as a cheep raw material (liquefaction and saccharification) in the separate technological process. |
Laminated plate and part using the laminated plate |
A laminated plate formed of a base material and a high molecular plate laminated with each other without using adhesive agent and a part using the laminated plate, wherein the laminated plate is formed by laminatedly sticking the base plate to the high molecular plate after applying an activating treatment onto the opposed surfaces of the base plate and the high molecular plate, and the part is formed by using the laminated plate. |
1. A laminated plate formed by laminating a high molecular plate on at least one surface of a base material wherein the surfaces of the base material and the high molecular plate to be bonded are previously applied with an activation treatment and then the base material and the high molecular plate are abutted and stacked against each other such that the activated surfaces thereof are opposed to each other and press bonding them. 2. A laminated plate according to claim 1, wherein the activation treatment comprises conducting electric discharge in an inert gas atmosphere and applying a sputter etching treatment to each of the surfaces of the base material and the high molecular plate. 3. A laminated plate according to claim 1 or 2, wherein the base material comprises one of liquid crystal polymer, polyimide and glass epoxy, and the high molecular plate comprises liquid crystal polymer or polyimide. 4. A part using a laminated plate as described in claim 1 or 2. 5. A part according to claim 4 wherein the part is a printed wiring board. 6. A part according to claim 5 wherein the part is an IC package. |
<SOH> BACKGROUND ART <EOH>Heretofore, various laminated plates formed by laminating plates such as made of high molecular materials to base materials such as printed wiring board have been proposed and a method of bonding by using adhesive agents has been proposed as the lamination method. However, in the existent lamination method as described above, since the heat resistance of the adhesive agent is poor, it involves problems such that the heat resistance as the laminated plate is limited or the thickness and the weight are increased by so much as the layer of the adhesive agent and, accordingly, it is not suitable to the decrease of weight and reduction of thickness. In view of the technical background as described above, it is a subject of the present invention to provide a laminated plate formed by laminating a base material and a high molecular plate with no deterioration of electrical characteristics caused by the adhesive agent layer and without using the adhesive agent, as well as parts, printed wiring boards and IC packages using the laminated plate. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a schematic cross sectional view showing an embodiment of a laminated plate according to the present invention. FIG. 2 is a schematic cross sectional view showing another embodiment of a laminated plate according to the present invention. detailed-description description="Detailed Description" end="lead"? |
Method for laser-cutting structural components to be joined |
In a method for cutting structural components to be joined by laser radiation that is guided by a computer-controlled manipulation system provided with a nominal path for each structural component corresponding to a joining line that is curved as a result of at least one of the structural components being three-dimensionally shaped, the structural component surfaces of the structural components including the joining line are determined measuring technologically. Based on measuring results, the nominal path corresponding to a penetration line of the structural components to be joined is calculated. A marking is formed on a first one of the structural component surfaces. When performing the cut on the structural component surface provided with the marking, the resulting cutting gap and the marking are determining measuring technologically. When a deviation of the cutting gap from the nominal path is detected, the manipulation system is controlled to correct the deviation. |
1-11. (canceled) 12. A method for cutting structural components to be joined by laser radiation that is guided by means of a computer-controlled manipulation system, wherein the manipulation system has preset a nominal path for each structural component, wherein the nominal path corresponds to a joining line that is curved as a result of at least one of the structural components being three-dimensionally shaped, the method comprising the steps of: a) determining measuring technologically structural component surfaces of the structural components to be joined, which structural component surfaces comprise the joining line; b) calculating, based on measuring results obtained in the step a), the nominal path corresponding to a penetration line of the structural components to be joined; c) providing a marking on one of the structural component surfaces; d) performing a cut on the structural component surface provided with the marking; e) when performing the cut, determining measuring technologically a resulting cutting gap and the marking and comparing the cutting gap and the nominal path, using the marking as a reference; f) when a deviation of the cutting gap from the nominal path is detected in step e), controlling the manipulation system to correct the deviation. 13. The method according to claim 12, wherein the step c) and the step e) are carried out simultaneously. 14. The method according to claim 12, wherein the marking is formed by a laser performing the cut in step d). 15. The method according to claim 12, wherein the marking is formed on the nominal path or in the vicinity of the nominal path. 16. The method according to claim 12, wherein the marking is formed only at some locations. 17. The method according to claim 12, wherein the marking is the cutting gap. 18. The method according to claim 12, wherein in the step e) one and the same sensor is used for determining measuring technologically the marking and the cutting gap. 19. The method according to claim 12, wherein in the step a) and the step e) an imaging sensor is used for measuring technologically determination. 20. The method according to claim 19, wherein the imaging sensor is a CCD camera. 21. The method according to claim 12, wherein in the step a) the structural components are positioned in a predetermined relative arrangement to one another. 22. The method according to claim 12, wherein in the step a) two distance measuring devices are employed and are positioned in a predetermined relative arrangement to one another. |
Staphylococcus aureus proteins and nucleic acids |
The invention provides proteins from Staphylococcus aureus including amino acid sequences and the corresponding nucleotide sequences. The proteins are useful for vaccines, immunogenic compositions, diagnostics, enzymatic studies and also as targets for antibiotics. |
1. A protein comprising an amino acid sequence selected from the group consisting of SEQ IDs 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, 1040, 1042, 1044, 1046, 1048, 1050, 1052, 1054, 1056, 1058, 1060, 1062, 1064, 1066, 1068, 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084, 1086, 1088, 1090, 1092, 1094, 1096, 1098, 1100, 1102, 1104, 1106, 1108, 1110, 1112, 1114, 1116, 1118, 1120, 1122, 1124, 1126, 1128, 1130, 1132, 1134, 1136, 1138, 1140, 1142, 1144, 1146, 1148, 1150, 1152, 1154, 1156, 1158, 1160, 1162, 1164, 1166, 1168, 1170, 1172, 1174, 1176, 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1242, 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, 1300, 1302, 1304, 1306, 1308, 1310, 1312, 1314, 1316, 1318, 1320, 1322, 1324, 1326, 1328, 1330, 1332, 1334, 1336, 1338, 1340, 1342, 1344, 1346, 1348, 1350, 1352, 1354, 1356, 1358, 1360, 1362, 1364, 1366, 1368, 1370, 1372, 1374, 1376, 1378, 1380, 1382, 1384, 1386, 1388, 1390, 1392, 1394, 1396, 1398, 1400, 1402, 1404, 1406, 1408, 1410, 1412, 1414, 1416, 1418, 1420, 1422, 1424, 1426, 1428, 1430, 1432, 1434, 1436, 1438, 1440, 1442, 1444, 1446, 1448, 1450, 1452, 1454, 1456, 1458, 1460, 1462, 1464, 1466, 1468, 1470, 1472, 1474, 1476, 1478, 1480, 1482, 1484, 1486, 1488, 1490, 1492, 1494, 1496, 1498, 1500, 1502, 1504, 1506, 1508, 1510, 1512, 1514, 1516, 1518, 1520, 1522, 1524, 1526, 1528, 1530, 1532, 1534, 1536, 1538, 1540, 1542, 1544, 1546, 1548, 1550, 1552, 1554, 1556, 1558, 1560, 1562, 1564, 1566, 1568, 1570, 1572, 1574, 1576, 1578, 1580, 1582, 1584, 1586, 1588, 1590, 1592, 1594, 1596, 1598, 1600, 1602, 1604, 1606, 1608, 1610, 1612, 1614, 1616, 1618, 1620, 1622, 1624, 1626, 1628, 1630, 1632, 1634, 1636, 1638, 1640, 1642, 1644, 1646, 1648, 1650, 1652, 1654, 1656, 1658, 1660, 1662, 1664, 1666, 1668, 1670, 1672, 1674, 1676, 1678, 1680, 1682, 1684, 1686, 1688, 1690, 1692, 1694, 1696, 1698, 1700, 1702, 1704, 1706, 1708, 1710, 1712, 1714, 1716, 1718, 1720, 1722, 1724, 1726, 1728, 1730, 1732, 1734, 1736, 1738, 1740, 1742, 1744, 1746, 1748, 1750, 1752, 1754, 1756, 1758, 1760, 1762, 1764, 1766, 1768, 1770, 1772, 1774, 1776, 1778, 1780, 1782, 1784, 1786, 1788, 1790, 1792, 1794, 1796, 1798, 1800, 1802, 1804, 1806, 1808, 1810, 1812, 1814, 1816, 1818, 1820, 1822, 1824, 1826, 1828, 1830, 1832, 1834, 1836, 1838, 1840, 1842, 1844, 1846, 1848, 1850, 1852, 1854, 1856, 1858, 1860, 1862, 1864, 1866, 1868, 1870, 1872, 1874, 1876, 1878, 1880, 1882, 1884, 1886, 1888, 1890, 1892, 1894, 1896, 1898, 1900, 1902, 1904, 1906, 1908, 1910, 1912, 1914, 1916, 1918, 1920, 1922, 1924, 1926, 1928, 1930, 1932, 1934, 1936, 1938, 1940, 1942, 1944, 1946, 1948, 1950, 1952, 1954, 1956, 1958, 1960, 1962, 1964, 1966, 1968, 1970, 1972, 1974, 1976, 1978, 1980, 1982, 1984, 1986, 1988, 1990, 1992, 1994, 1996, 1998, 2000, 2002, 2004, 2006, 2008, 2010, 2012, 2014, 2016, 2018, 2020, 2022, 2024, 2026, 2028, 2030, 2032, 2034, 2036, 2038, 2040, 2042, 2044, 2046, 2048, 2050, 2052, 2054, 2056, 2058, 2060, 2062, 2064, 2066, 2068, 2070, 2072, 2074, 2076, 2078, 2080, 2082, 2084, 2086, 2088, 2090, 2092, 2094, 2096, 2098, 2100, 2102, 2104, 2106, 2108, 2110, 2112, 2114, 2116, 2118, 2120, 2122, 2124, 2126, 2128, 2130, 2132, 2134, 2136, 2138, 2140, 2142, 2144, 2146, 2148, 2150, 2152, 2154, 2156, 2158, 2160, 2162, 2164, 2166, 2168, 2170, 2172, 2174, 2176, 2178, 2180, 2182, 2184, 2186, 2188, 2190, 2192, 2194, 2196, 2198, 2200, 2202, 2204, 2206, 2208, 2210, 2212, 2214, 2216, 2218, 2220, 2222, 2224, 2226, 2228, 2230, 2232, 2234, 2236, 2238, 2240, 2242, 2244, 2246, 2248, 2250, 2252, 2254, 2256, 2258, 2260, 2262, 2264, 2266, 2268, 2270, 2272, 2274, 2276, 2278, 2280, 2282, 2284, 2286, 2288, 2290, 2292, 2294, 2296, 2298, 2300, 2302, 2304, 2306, 2308, 2310, 2312, 2314, 2316, 2318, 2320, 2322, 2324, 2326, 2328, 2330, 2332, 2334, 2336, 2338, 2340, 2342, 2344, 2346, 2348, 2350, 2352, 2354, 2356, 2358, 2360, 2362, 2364, 2366, 2368, 2370, 2372, 2374, 2376, 2378, 2380, 2382, 2384, 2386, 2388, 2390, 2392, 2394, 2396, 2398, 2400, 2402, 2404, 2406, 2408, 2410, 2412, 2414, 2416, 2418, 2420, 2422, 2424, 2426, 2428, 2430, 2432, 2434, 2436, 2438, 2446, 2442, 2444, 2446, 2448, 2450, 2452, 2454, 2456, 2458, 2460, 2462, 2464, 2466, 2468, 2470, 2472, 2474, 2476, 2478, 2480, 2482, 2484, 2486, 2488, 2490, 2492, 2494, 2496, 2498, 2500, 2502, 2504, 2506, 2508, 2510, 2512, 2514, 2516, 2518, 2520, 2522, 2524, 2526, 2528, 2530, 2532, 2534, 2536, 2538, 2540, 2542, 2544, 2546, 2548, 2550, 2552, 2554, 2556, 2558, 2560, 2562, 2564, 2566, 2568, 2570, 2572, 2574, 2576, 2578, 2580, 2582, 2584, 2586, 2588, 2590, 2592, 2594, 2596, 2598, 2600, 2602, 2604, 2606, 2608, 2610, 2612, 2614, 2616, 2618, 2620, 2622, 2624, 2626, 2628, 2630, 2632, 2634, 2636, 2638, 2640, 2642, 2644, 2646, 2648, 2650, 2652, 2654, 2656, 2658, 2660, 2662, 2664, 2666, 2668, 2670, 2672, 2674, 2676, 2678, 2680, 2682, 2684, 2686, 2688, 2690, 2692, 2694, 2696, 2698, 2700, 2702, 2704, 2706, 2708, 2710, 2712, 2714, 2716, 2718, 2720, 2722, 2724, 2726, 2728, 2730, 2732, 2734, 2736, 2738, 2740, 2742, 2744, 2746, 2748, 2750, 2752, 2754, 2756, 2758, 2760, 2762, 2764, 2766, 2768, 2770, 2772, 2774, 2776, 2778, 2780, 2782, 2784, 2786, 2788, 2790, 2792, 2794, 2796, 2798, 2800, 2802, 2804, 2806, 2808, 2810, 2812, 2814, 2816, 2818, 2820, 2822, 2824, 2826, 2828, 2830, 2832, 2834, 2836, 2838, 2840, 2842, 2844, 2846, 2848, 2850, 2852, 2854, 2856, 2858, 2860, 2862, 2864, 2866, 2868, 2870, 2872, 2874, 2876, 2878, 2880, 2882, 2884, 2886, 2888, 2890, 2892, 2894, 2896, 2898, 2900, 2902, 2904, 2906, 2908, 2910, 2912, 2914, 2916, 2918, 2920, 2922, 2924, 2926, 2928, 2930, 2932, 2934, 2936, 2938, 2940, 2942, 2944, 2946, 2948, 2950, 2952, 2954, 2956, 2958, 2960, 2962, 2964, 2966, 2968, 2970, 2972, 2974, 2976, 2978, 2980, 2982, 2984, 2986, 2988, 2990, 2992, 2994, 2996, 2998, 3000, 3002, 3004, 3006, 3008, 3010, 3012, 3014, 3016, 3018, 3020, 3022, 3024, 3026, 3028, 3030, 3032, 3034, 3036, 3038, 3040, 3042, 3044, 3046, 3048, 3050, 3052, 3054, 3056, 3058, 3060, 3062, 3064, 3066, 3068, 3070, 3072, 3074, 3076, 3078, 3080, 3082, 3084, 3086, 3088, 3090, 3092, 3094, 3096, 3098, 3100, 3102, 3104, 3106, 3108, 3110, 3112, 3114, 3116, 3118, 3120, 3122, 3124, 3126, 3128, 3130, 3132, 3134, 3136, 3138, 3140, 3142, 3144, 3146, 3148, 3150, 3152, 3154, 3156, 3158, 3160, 3162, 3164, 3166, 3168, 3170, 3172, 3174, 3176, 3178, 3180, 3182, 3184, 3186, 3188, 3190, 3192, 3194, 3196, 3198, 3200, 3202, 3204, 3206, 3208, 3210, 3212, 3214, 3216, 3218, 3220, 3222, 3224, 3226, 3228, 3230, 3232, 3234, 3236, 3238, 3240, 3242, 3244, 3246, 3248, 3250, 3252, 3254, 3256, 3258, 3260, 3262, 3264, 3266, 3268, 3270, 3272, 3274, 3276, 3278, 3280, 3282, 3284, 3286, 3288, 3290, 3292, 3294, 3296, 3298, 3300, 3302, 3304, 3306, 3308, 3310, 3312, 3314, 3316, 3318, 3320, 3322, 3324, 3326, 3328, 3330, 3332, 3334, 3336, 3338, 3340, 3342, 3344, 3346, 3348, 3350, 3352, 3354, 3356, 3358, 3360, 3362, 3364, 3366, 3368, 3370, 3372, 3374, 3376, 3378, 3380, 3382, 3384, 3386, 3388, 3390, 3392, 3394, 3396, 3398, 3400, 3402, 3404, 3406, 3408, 3410, 3412, 3414, 3416, 3418, 3420, 3422, 3424, 3426, 3428, 3430, 3432, 3434, 3436, 3438, 3440, 3442, 3444, 3446, 3448, 3450, 3452, 3454, 3456, 3458, 3460, 3462, 3464, 3466, 3468, 3470, 3472, 3474, 3476, 3478, 3480, 3482, 3484, 3486, 3488, 3490, 3492, 3494, 3496, 3498, 3500, 3502, 3504, 3506, 3508, 3510, 3512, 3514, 3516, 3518, 3520, 3522, 3524, 3526, 3528, 3530, 3532, 3534, 3536, 3538, 3540, 3542, 3544, 3546, 3548, 3550, 3552, 3554, 3556, 3558, 3560, 3562; 3564, 3566, 3568, 3570, 3572, 3574, 3576, 3578, 3580, 3582, 3584, 3586, 3588, 3590, 3592, 3594, 3596, 3598, 3600, 3602, 3604, 3606, 3608, 3610, 3612, 3614, 3616, 3618, 3620, 3622, 3624, 3626, 3628, 3630, 3632, 3634, 3636, 3638, 3640, 3642, 3644, 3646, 3648, 3650, 3652, 3654, 3656, 3658, 3660, 3662, 3664, 3666, 3668, 3670, 3672, 3674, 3676, 3678, 3680, 3682, 3684, 3686, 3688, 3690, 3692, 3694, 3696, 3698, 3700, 3702, 3704, 3706, 3708, 3710, 3712, 3714, 3716, 3718, 3720, 3722, 3724, 3726, 3728, 3730, 3732, 3734, 3736, 3738, 3740, 3742, 3744, 3746, 3748, 3750, 3752, 3754, 3756, 3758, 3760, 3762, 3764, 3766, 3768, 3770, 3772, 3774, 3776, 3778, 3780, 3782, 3784, 3786, 3788, 3790, 3792, 3794, 3796, 3798, 3800, 3802, 3804, 3806, 3808, 3810, 3812, 3814, 3816, 3818, 3820, 3822, 3824, 3826, 3828, 3830, 3832, 3834, 3836, 3838, 3840, 3842, 3844, 3846, 3848, 3850, 3852, 3854, 3856, 3858, 3860, 3862, 3864, 3866, 3868, 3870, 3872, 3874, 3876, 3878, 3880, 3882, 3884, 3886, 3888, 3890, 3892, 3894, 3896, 3898, 3900, 3902, 3904, 3906, 3908, 3910, 3912, 3914, 3916, 3918, 3920; 3922, 3924, 3926, 3928, 3930, 3932, 3934, 3936, 3938, 3940, 3942, 3944, 3946, 3948, 3950, 3952, 3954, 3956, 3958, 3960, 3962, 3964, 3966, 3968, 3970, 3972, 3974, 3976, 3978, 3980, 3982, 3984, 3986, 3988, 3990, 3992, 3994, 3996, 3998, 4000, 4002, 4004, 4006, 4008, 4010, 4012, 4014, 4016, 4018, 4020, 4022, 4024, 4026, 4028, 4030, 4032, 4034, 4036, 4038, 4040, 4042, 4044, 4046, 4048, 4050, 4052, 4054, 4056, 4058, 4060, 4062, 4064, 4066, 4068, 4070, 4072, 4074, 4076, 4078, 4080, 4082, 4084, 4086, 4088, 4090, 4092, 4094, 4096, 4098, 4100, 4102, 4104, 4106, 4108, 4110, 4112, 4114, 4116, 4118, 4120, 4122, 4124, 4126, 4128, 4130, 4132, 4134, 4136, 4138, 4140, 4142, 4144, 4146, 4148, 4150, 4152, 4154, 4156, 4158, 4160, 4162, 4164, 4166, 4168, 4170, 4172, 4174, 4176, 4178, 4180, 4182, 4184, 4186, 4188, 4190, 4192, 4194, 4196, 4198, 4200, 4202, 4204, 4206, 4208, 4210, 4212, 4214, 4216, 4218, 4220, 4222, 4224, 4226, 4228, 4230, 4232, 4234, 4236, 4238, 4240, 4242, 4244, 4246, 4248, 4250, 4252, 4254, 4256, 4258, 4260, 4262, 4264, 4266, 4268, 4270, 4272, 4274, 4276, 4278, 4280, 4282, 4284, 4286, 4288, 4290, 4292, 4294, 4296, 4298, 4300, 4302, 4304, 4306, 4308, 4310, 4312, 4314, 4316, 4318, 4320, 4322, 4324, 4326, 4328, 4330, 4332, 4334, 4336, 4338, 4340, 4342, 4344, 4346, 4348, 4350, 4352, 4354, 4356, 4358, 4360, 4362, 4364, 4366, 4368, 4370, 4372, 4374, 4376, 4378, 4380, 4382, 4384, 4386, 4388, 4390, 4392, 4394, 4396, 4398, 4400, 4402, 4404, 4406, 4408, 4410, 4412, 4414, 4416, 4418, 4420, 4422, 4424, 4426, 4428, 4430, 4432, 4434, 4436, 4438, 4440, 4442, 4444, 4446, 4448, 4450, 4452, 4454, 4456, 4458, 4460, 4462, 4464, 4466, 4468, 4470, 4472, 4474, 4476, 4478, 4480, 4482, 4484, 4486, 4488, 4490, 4492, 4494, 4496, 4498, 4500, 4502, 4504, 4506, 4508, 4510, 4512, 4514, 4516, 4518, 4520, 4522, 4524, 4526, 4528, 4530, 4532, 4534, 4536, 4538, 4540, 4542, 4544, 4546, 4548, 4550, 4552, 4554, 4556, 4558, 4560, 4562, 4564, 4566, 4568, 4570, 4572, 4574, 4576, 4578, 4580, 4582, 4584, 4586, 4588, 4590, 4592, 4594, 4596, 4598, 4600, 4602, 4604, 4606, 4608, 4610, 4612, 4614, 4616, 4618, 4620, 4622, 4624, 4626, 4628, 4630, 4632, 4634, 4636, 4638, 4646, 4642, 4644, 4646, 4648, 4650, 4652, 4654, 4656, 4658, 4660, 4662, 4664, 4666, 4668, 4670, 4672, 4674, 4676, 4678, 4680, 4682, 4684, 4686, 4688, 4690, 4692, 4694, 4696, 4698, 4700, 4702, 4704, 4706, 4708, 4710, 4712, 4714, 4716, 4718, 4720, 4722, 4724, 4726, 4728, 4730, 4732, 4734, 4736, 4738, 4740, 4742, 4744, 4746, 4748, 4750, 4752, 4754, 4756, 4758, 4760, 4762, 4764, 4766, 4768, 4770, 4772, 4774, 4776, 4778, 4780, 4782, 4784, 4786, 4788, 4790, 4792, 4794, 4796, 4798, 4800, 4802, 4804, 4806, 4808, 4810, 4812, 4814, 4816, 4818, 4820, 4822, 4824, 4826, 4828, 4830, 4832, 4834, 4836, 4838, 4840, 4842, 4844, 4846, 4848, 4850, 4852, 4854, 4856, 4858, 4860, 4862, 4864, 4866, 4868, 4870, 4872, 4874, 4876, 4878, 4880, 4882, 4884, 4886, 4888, 4890, 4892, 4894, 4896, 4898, 4900, 4902, 4904, 4906, 4908, 4910, 4912, 4914, 4916, 4918, 4920, 4922, 4924, 4926, 4928, 4930, 4932, 4934, 4936, 4938, 4940, 4942, 4944, 4946, 4948, 4950, 4952, 4954, 4956, 4958, 4960, 4962, 4964, 4966, 4968, 4970, 4972, 4974, 4976, 4978, 4980, 4982, 4984, 4986, 4988, 4990, 4992, 4994, 4996, 4998, 5000, 5002, 5004, 5006, 5008, 5010, 5012, 5014, 5016, 5018, 5020, 5022, 5024, 5026, 5028, 5030, 5032, 5034, 5036, 5038, 5040, 5042, 5044, 5046, 5048, 5050, 5052, 5054, 5056, 5058, 5060, 5062, 5064, 5066, 5068, 5070, 5072, 5074, 5076, 5078, 5080, 5082, 5084, 5086, 5088, 5090, 5092, 5094, 5096, 5098, 5100, 5102, 5104, 5106, 5108, 5110, 5112, 5114, 5116, 5118, 5120, 5122, 5124, 5126, 5128, 5130, 5132, 5134, 5136, 5138, 5140, 5142, 5144, 5146, 5148, 5150, 5152, 5154, 5156, 5158, 5160, 5162, 5164, 5166, 5168, 5170, 5172, 5174, 5176, 5178, 5180, 5182, 5184, 5186, 5188, 5190, 5192, 5194, 5196, 5198, 5200, 5202, 5204, 5206, 5208, 5210, 5212, 5214, 5216, 5218, 5220, 5222, 5224, 5226, 5228, 5230, 5232, 5234, 5236, 5238, 5240, 5242, 5244, 5246, 5248, 5250, 5252, 5254, 5256, 5258, 5260, 5262, 5264, 5266, 5268, 5270, 5272, 5274, 5276, 5278, 5280, 5282, 5284, 5286, 5288, 5290, 5292, 5294, 5296, 5298, 5300, 5302, 5304, 5306, 5308, 5310, 5312, 5314, 5316, 5318, 5320, 5322, 5324, 5326, 5328, 5330, 5332, 5334, 5336, 5338, 5340, 5342, 5344, 5346, 5348, 5350, 5352, 5354, 5356, 5358, 5360, 5362, 5364, 5366, 5368, 5370, 5372, 5374, 5376, 5378, 5380, 5382, 5384, 5386, 5388, 5390, 5392, 5394, 5396, 5398, 5400, 5402, 5404, 5406, 5408, 5410, 5412, 5414, 5416, 5418, 5420, 5422, 5424, 5426, 5428, 5430, 5432, 5434, 5436, 5438, 5440, 5442, 5444, 5446, 5448, 5450, 5452, 5454, 5456, 5458, 5460, 5462, 5464, 5466, 5468, 5470, 5472, 5474, 5476, 5478, 5480, 5482, 5484, 5486, 5488, 5490, 5492, 5494, 5496, 5498, 5500, 5502, 5504, 5506, 5508, 5510, 5512, 5514, 5516, 5518, 5520, 5522, 5524, 5526, 5528, 5530, 5532, 5534, 5536, 5538, 5540, 5542, 5544, 5546, 5548, 5550, 5552, 5554, 5556, 5558, 5560, 5562, 5564, 5566, 5568, 5570, 5572, 5574, 5576, 5578, 5580, 5582, 5584, 5586, 5588, 5590, 5592, 5594, 5596, 5598, 5600, 5602, 5604, 5606, 5608, 5610, 5612, 5614, 5616, 5618, 5620, 5622, 5624, 5626, 5628, 5630, 5632, 5634, 5636, 5638, 5640, 5642. 2. A protein having 50% or greater sequence identity to a protein according to claim 1. 3. A protein comprising a fragment of an amino acid sequence selected from the group consisting of SEQ IDs 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, 1040, 1042, 1044, 1046, 1048, 1050, 1052, 1054, 1056, 1058, 1060, 1062, 1064, 1066, 1068, 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084, 1086, 1088, 1090, 1092, 1094, 1096, 1098, 1100, 1102, 1104, 1106, 1108, 1110, 1112, 1114, 1116, 1118, 1120, 1122, 1124, 1126, 1128, 1130, 1132, 1134, 1136, 1138, 1140, 1142, 1144, 1146, 1148, 1150, 1152, 1154, 1156, 1158, 1160, 1162, 1164, 1166, 1168, 1170, 1172, 1174, 1176, 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1242, 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, 1300, 1302, 1304, 1306, 1308, 1310, 1312, 1314, 1316, 1318, 1320, 1322, 1324, 1326, 1328, 1330, 1332, 1334, 1336, 1338, 1340, 1342, 1344, 1346, 1348, 1350, 1352, 1354, 1356, 1358, 1360, 1362, 1364, 1366, 1368, 1370, 1372, 1374, 1376, 1378, 1380, 1382, 1384, 1386, 1388, 1390, 1392, 1394, 1396, 1398, 1400, 1402, 1404, 1406, 1408, 1410, 1412, 1414, 1416, 1418, 1420, 1422, 1424, 1426, 1428, 1430, 1432, 1434, 1436, 1438, 1440, 1442, 1444, 1446, 1448, 1450, 1452, 1454, 1456, 1458, 1460, 1462, 1464, 1466, 1468, 1470, 1472, 1474, 1476, 1478, 1480, 1482, 1484, 1486, 1488, 1490, 1492, 1494, 1496, 1498, 1500, 1502, 1504, 1506, 1508, 1510, 1512, 1514, 1516, 1518, 1520, 1522, 1524, 1526, 1528, 1530, 1532, 1534, 1536, 1538, 1540, 1542, 1544, 1546, 1548, 1550, 1552, 1554, 1556, 1558, 1560, 1562, 1564, 1566, 1568, 1570, 1572, 1574, 1576, 1578, 1580, 1582, 1584, 1586, 1588, 1590, 1592, 1594, 1596, 1598, 1600, 1602, 1604, 1606, 1608, 1610, 1612, 1614, 1616, 1618, 1620, 1622, 1624, 1626, 1628, 1630, 1632, 1634, 1636, 1638, 1640, 1642, 1644, 1646, 1648, 1650, 1652, 1654, 1656, 1658, 1660, 1662, 1664, 1666, 1668, 1670, 1672, 1674, 1676, 1678, 1680, 1682, 1684, 1686, 1688, 1690, 1692, 1694, 1696, 1698, 1700, 1702, 1704, 1706, 1708, 1710, 1712, 1714, 1716, 1718, 1720, 1722, 1724, 1726, 1728, 1730, 1732, 1734, 1736, 1738, 1740, 1742, 1744, 1746, 1748, 1750, 1752, 1754, 1756, 1758, 1760, 1762, 1764, 1766, 1768, 1770, 1772, 1774, 1776, 1778, 1780, 1782, 1784, 1786, 1788, 1790, 1792, 1794, 1796, 1798, 1800, 1802, 1804, 1806, 1808, 1810, 1812, 1814, 1816, 1818, 1820, 1822, 1824, 1826, 1828, 1830, 1832, 1834, 1836, 1838, 1840, 1842, 1844, 1846, 1848, 1850, 1852, 1854, 1856, 1858, 1860, 1862, 1864, 1866, 1868, 1870, 1872, 1874, 1876, 1878, 1880, 1882, 1884, 1886, 1888, 1890, 1892, 1894, 1896, 1898, 1900, 1902, 1904, 1906, 1908, 1910, 1912, 1914, 1916, 1918, 1920, 1922, 1924, 1926, 1928, 1930, 1932, 1934, 1936, 1938, 1940, 1942, 1944, 1946, 1948, 1950, 1952, 1954, 1956, 1958, 1960, 1962, 1964, 1966, 1968, 1970, 1972, 1974, 1976, 1978, 1980, 1982, 1984, 1986, 1988, 1990, 1992, 1994, 1996, 1998, 2000, 2002, 2004, 2006, 2008, 2010, 2012, 2014, 2016, 2018, 2020, 2022, 2024, 2026, 2028, 2030, 2032, 2034, 2036, 2038, 2040, 2042, 2044, 2046, 2048, 2050, 2052, 2054, 2056, 2058, 2060, 2062, 2064, 2066, 2068, 2070, 2072, 2074, 2076, 2078, 2080, 2082, 2084, 2086, 2088, 2090, 2092, 2094, 2096, 2098, 2100, 2102, 2104, 2106, 2108, 2110, 2112, 2114, 2116, 2118, 2120, 2122, 2124, 2126, 2128, 2130, 2132, 2134, 2136, 2138, 2140, 2142, 2144, 2146, 2148, 2150, 2152, 2154, 2156, 2158, 2160, 2162, 2164, 2166, 2168, 2170, 2172, 2174, 2176, 2178, 2180, 2182, 2184, 2186, 2188, 2190, 2192, 2194, 2196, 2198, 2200, 2202, 2204, 2206, 2208, 2210, 2212, 2214, 2216, 2218, 2220, 2222, 2224, 2226, 2228, 2230, 2232, 2234, 2236, 2238, 2240, 2242, 2244, 2246, 2248, 2250, 2252, 2254, 2256, 2258, 2260, 2262, 2264, 2266, 2268, 2270, 2272, 2274, 2276, 2278, 2280, 2282, 2284, 2286, 2288, 2290, 2292, 2294, 2296, 2298, 2300, 2302, 2304, 2306, 2308, 2310, 2312, 2314, 2316, 2318, 2320, 2322, 2324, 2326, 2328, 2330, 2332, 2334, 2336, 2338, 2340, 2342, 2344, 2346, 2348, 2350, 2352, 2354, 2356, 2358, 2360, 2362, 2364, 2366, 2368, 2370, 2372, 2374, 2376, 2378, 2380, 2382, 2384, 2386, 2388, 2390, 2392, 2394, 2396, 2398, 2400, 2402, 2404, 2406, 2408, 2410, 2412, 2414, 2416, 2418, 2420, 2422, 2424, 2426, 2428, 2430, 2432, 2434, 2436, 2438, 2440, 2442, 2444, 2446, 2448, 2450, 2452, 2454, 2456, 2458, 2460, 2462, 2464, 2466, 2468, 2470, 2472, 2474, 2476, 2478, 2480, 2482, 2484, 2486, 2488, 2490, 2492, 2494, 2496, 2498, 2500, 2502, 2504, 2506, 2508, 2510, 2512, 2514, 2516, 2518, 2520, 2522, 2524, 2526, 2528, 2530, 2532, 2534, 2536, 2538, 2540, 2542, 2544, 2546, 2548, 2550, 2552, 2554, 2556, 2558, 2560, 2562, 2564, 2566, 2568, 2570, 2572, 2574, 2576, 2578, 2580, 2582, 2584, 2586, 2588, 2590, 2592, 2594, 2596, 2598, 2600, 2602, 2604, 2606, 2608, 2610, 2612, 2614, 2616, 2618, 2620, 2622, 2624, 2626, 2628, 2630, 2632, 2634, 2636, 2638, 2640, 2642, 2644, 2646, 2648, 2650, 2652, 2654, 2656, 2658, 2660, 2662, 2664, 2666, 2668, 2670, 2672, 2674, 2676, 2678, 2680, 2682, 2684, 2686, 2688, 2690, 2692, 2694, 2696, 2698, 2700, 2702, 2704, 2706, 2708, 2710, 2712, 2714, 2716, 2718, 2720, 2722, 2724, 2726, 2728, 2730, 2732, 2734, 2736, 2738, 2740, 2742, 2744, 2746, 2748, 2750, 2752, 2754, 2756, 2758, 2760, 2762, 2764, 2766, 2768, 2770, 2772, 2774, 2776, 2778, 2180, 2782, 2784, 2786, 2788, 2790, 2792, 2794, 2796, 2798, 2800, 2802, 2804, 2806, 2808, 2810, 2812, 2814, 2816, 2818, 2820, 2822, 2824, 2826, 2828, 2830, 2832, 2834, 2836, 2838, 2840, 2842, 2844, 2846, 2848, 2850, 2852, 2854, 2856, 2858, 2860, 2862, 2864, 2866, 2868, 2870, 2872, 2874, 2876, 2878, 2880, 2882, 2884, 2886, 2888, 2890, 2892, 2894, 2896, 2898, 2900, 2902, 2904, 2906, 2908, 2910, 2912, 2914, 2916, 2918, 2920, 2922, 2924, 2926, 2928, 2930, 2932, 2934, 2936, 2938, 2940, 2942, 2944, 2946, 2948, 2950, 2952, 2954, 2956, 2958, 2960, 2962, 2964, 2966, 2968, 2970, 2972, 2974, 2976, 2978, 2980, 2982, 2984, 2986, 2988, 2990, 2992, 2994, 2996, 2998, 3000, 3002, 3004, 3006, 3008, 3010, 3012, 3014, 3016, 3018, 3020, 3022, 3024, 3026, 3028, 3030, 3032, 3034, 3036, 3038, 3040, 3042, 3044, 3046, 3048, 3050, 3052, 3054, 3056, 3058, 3060, 3062, 3064, 3066, 3068, 3070, 3072, 3074, 3076, 3078, 3080, 3082, 3084, 3086, 3088, 3090, 3092, 3094, 3096, 3098, 3100, 3102, 3104, 3106, 3108, 3110, 3112, 3114, 3116, 3118, 3120, 3122, 3124, 3126, 3128, 3130, 3132, 3134, 3136, 3138, 3140, 3142, 3144, 3146, 3148, 3150, 3152, 3154, 3156, 3158, 3160, 3162, 3164, 3166, 3168, 3170, 3172, 3174, 3176, 3178, 3180, 3182, 3184, 3186, 3188, 3190, 3192, 3194, 3196, 3198, 3200, 3202, 3204, 3206, 3208, 3210, 3212, 3214, 3216, 3218, 3220, 3222, 3224, 3226, 3228, 3230, 3232, 3234, 3236, 3238, 3240, 3242, 3244, 3246, 3248, 3250, 3252, 3254, 3256, 3258, 3260, 3262, 3264, 3266, 3268, 3270, 3272, 3274, 3276, 3278, 3280, 3282, 3284, 3286, 3288, 3290, 3292, 3294, 3296, 3298, 3300, 3302, 3304, 3306, 3308, 3310, 3312, 3314, 3316, 3318, 3320, 3322, 3324, 3326, 3328, 3330, 3332, 3334, 3336, 3338, 3340, 3342, 3344, 3346, 3348, 3350, 3352, 3354, 3356, 3358, 3360, 3362, 3364, 3366, 3368, 3370, 3372, 3374, 3376, 3378, 3380, 3382, 3384, 3386, 3388, 3390, 3392, 3394, 3396, 3398, 3400, 3402, 3404, 3406, 3408, 3410, 3412, 3414, 3416, 3418, 3420, 3422, 3424, 3426, 3428, 3430, 3432, 3434, 3436, 3438, 3440, 3442, 3444, 3446, 3448, 3450, 3452, 3454, 3456, 3458, 3460, 3462, 3464, 3466, 3468, 3470, 3472, 3474, 3476, 3478, 3480, 3482, 3484, 3486, 3488, 3490, 3492, 3494, 3496, 3498, 3500, 3502, 3504, 3506, 3508, 3510, 3512, 3514, 3516, 3518, 3520, 3522, 3524, 3526, 3528, 3530, 3532, 3534, 3536, 3538, 3540, 3542, 3544, 3546, 3548, 3550, 3552, 3554, 3556, 3558, 3560, 3562, 3564, 3566, 3568, 3570, 3572, 3574, 3576, 3578, 3580, 3582, 3584, 3586, 3588, 3590, 3592, 3594, 3596, 3598, 3600, 3602, 3604, 3606, 3608, 3610, 3612, 3614, 3616, 3618, 3620, 3622, 3624, 3626, 3628, 3630, 3632, 3634, 3636, 3638, 3640, 3642, 3644, 3646, 3648, 3650, 3652, 3654, 3656, 3658, 3660, 3662, 3664, 3666, 3668, 3670, 3672, 3674, 3676, 3678, 3680, 3682, 3684, 3686, 3688, 3690, 3692, 3694, 3696, 3698, 3700, 3702, 3704, 3706, 3708, 3710, 3712, 3714, 3716, 3718, 3720, 3722, 3724, 3726, 3728, 3730, 3732, 3734, 3736, 3738, 3740, 3742, 3744, 3746, 3748, 3750, 3752, 3754, 3756, 3758, 3760, 3762, 3764, 3766, 3768, 3770, 3772, 3774, 3776, 3778, 3780, 3782, 3784, 3786, 3788, 3790, 3792, 3794, 3796, 3798, 3800, 3802, 3804, 3806, 3808, 3810, 3812, 3814, 3816, 3818, 3820, 3822, 3824, 3826, 3828, 3830, 3832, 3834, 3836, 3838, 3840, 3842, 3844, 3846, 3848, 3850, 3852, 3854, 3856, 3858, 3860, 3862, 3864, 3866, 3868, 3870, 3872, 3874, 3876, 3878, 3880, 3882, 3884, 3886, 3888, 3890, 3892, 3894, 3896, 3898, 3900, 3902, 3904, 3906, 3908, 3910, 3912, 3914, 3916, 3918, 3920, 3922, 3924, 3926, 3928, 3930, 3932, 3934, 3936, 3938, 3940, 3942, 3944, 3946, 3948, 3950, 3952, 3954, 3956, 3958, 3960, 3962, 3964,.3966, 3968, 3970, 3972, 3974, 3976, 3978, 3980, 3982, 3984, 3986, 3988, 3990, 3992, 3994, 3996, 3998, 4000, 4002, 4004, 4006, 4008, 4010, 4012, 4014, 4016, 4018, 4020, 4022, 4024, 4026, 4028, 4030, 4032, 4034, 4036, 4038, 4040, 4042, 4044, 4046, 4048, 4050, 4052, 4054, 4056, 4058, 4060, 4062, 4064, 4066, 4068, 4070, 4072, 4074, 4076, 4078, 4080, 4082, 4084, 4086, 4088, 4090, 4092, 4094, 4096, 4098, 4100, 4102, 4104, 4106, 4108, 4110, 4112, 4114, 4116, 4118, 4120, 4122, 4124, 4126, 4128, 4130, 4132, 4134, 4136, 4138, 4140, 4142, 4144, 4146, 4148, 4150, 4152, 4154, 4156, 4158, 4160, 4162, 4164, 4166, 4168, 4170, 4172, 4174, 4176, 4178, 4180, 4182, 4184, 4186, 4188, 4190, 4192, 4194, 4196, 4198, 4200, 4202, 4204, 4206, 4208, 4210, 4212, 4214, 4216, 4218, 4220, 4222, 4224, 4226, 4228, 4230, 4232, 4234, 4236, 4238, 4240, 4242, 4244, 4246, 4248, 4250, 4252, 4254, 4256, 4258, 4260, 4262, 4264, 4266, 4268, 4270, 4272, 4274, 4276, 4278, 4280, 4282, 4284, 4286, 4288, 4290, 4292, 4294, 4296, 4298, 4300, 4302, 4304, 4306, 4308, 4310, 4312, 4314, 4316, 4318, 4320, 4322, 4324, 4326, 4328, 4330, 4332, 4334, 4336, 4338, 4340, 4342, 4344, 4346, 4348, 4350, 4352, 4354, 4356, 4358, 4360, 4362, 4364, 4366, 4368, 4370, 4372, 4374, 4376, 4378, 4380, 4382, 4384, 4386, 4388, 4390, 4392, 4394, 4396, 4398, 4400, 4402, 4404, 4406, 4408, 4410, 4412, 4414, 4416, 4418, 4420, 4422, 4424, 4426, 4428, 4430, 4432, 4434, 4436, 4438, 4440, 4442, 4444, 4446, 4448, 4450, 4452, 4454, 4456, 4458, 4460, 4462, 4464, 4466, 4468, 4470, 4472, 4474, 4476, 4478; 4480, 4482, 4484, 4486, 4488, 4490, 4492, 4494, 4496, 4498, 4500, 4502, 4504, 4506, 4508, 4510, 4512, 4514, 4516, 4518, 4520, 4522, 4524, 4526, 4528, 4530, 4532, 4534, 4536, 4538, 4540, 4542, 4544, 4546, 4548, 4550, 4552, 4554, 4556, 4558, 4560, 4562, 4564, 4566, 4568, 4570, 4572, 4574, 4576, 4578, 4580, 4582, 4584, 4586, 4588, 4590, 4592, 4594, 4596, 4598, 4600, 4602, 4604, 4606, 4608, 4610, 4612, 4614, 4616, 4618, 4620, 4622, 4624, 4626, 4628, 4630, 4632, 4634, 4636, 4638, 4640, 4642, 4644, 4646, 4648, 4650, 4652, 4654, 4656, 4658, 4660, 4662, 4664, 4666, 4668, 4670, 4672, 4674, 4676, 4678, 4680, 4682, 4684, 4686, 4688, 4690, 4692, 4694, 4696, 4698, 4700, 4702, 4704, 4706, 4708, 4710, 4712, 4714, 4716, 4718, 4720, 4722, 4724, 4726, 4728, 4730, 4732, 4734, 4736, 4738, 4740, 4742, 4744, 4746, 4748, 4750, 4752, 4754, 4756, 4758, 4760, 4762, 4764, 4766, 4768, 4770, 4772, 4774, 4776, 4778, 4780, 4782, 4784, 4786, 4788, 4790, 4792, 4794, 4796, 4798, 4800, 4802, 4804, 4806, 4808, 4810, 4812, 4814, 4816, 4818, 4820, 4822, 4824, 4826, 4828; 4830, 4832, 4834, 4836, 4838, 4840, 4842, 4844, 4846, 4848, 4850, 4852, 4854, 4856, 4858, 4860, 4862, 4864, 4866, 4868, 4870, 4872, 4874, 4876, 4878, 4880, 4882, 4884, 4886, 4888, 4890, 4892, 4894, 4896, 4898, 4900, 4902, 4904, 4906, 4908, 4910, 4912, 4914, 4916, 4918, 4920, 4922, 4924, 4926, 4928, 4930, 4932, 4934, 4936, 4938, 4940, 4942, 4944, 4946, 4948, 4950, 4952, 4954, 4956, 4958, 4960, 4962, 4964, 4966, 4968, 4970, 4972, 4974, 4976, 4978, 4980, 4982, 4984, 4986, 4988, 4990, 4992, 4994, 4996, 4998, 5000, 5002, 5004, 5006, 5008, 5010, 5012, 5014, 5016, 5018, 5020, 5022, 5024, 5026, 5028, 5030, 5032, 5034, 5036, 5038, 5040, 5042, 5044, 5046, 5048, 5050, 5052, 5054, 5056, 5058, 5060, 5062, 5064, 5066, 5068, 5070, 5072, 5074, 5076, 5078, 5080, 5082, 5084, 5086, 5088, 5090, 5092, 5094, 5096, 5098, 5100, 5102, 5104, 5106, 5108, 5110, 5112, 5114, 5116, 5118, 5120, 5122, 5124, 5126, 5128, 5130, 5132, 5134, 5136, 5138, 5140, 5142, 5144, 5146, 5148, 5150, 5152, 5154, 5156, 5158, 5160, 5162, 5164, 5166, 5168, 5170, 5172, 5174, 5176, 5178, 5180, 5182, 5184, 5186, 5188, 5190, 5192, 5194, 5196, 5198, 5200, 5202, 5204, 5206, 5208, 5210, 5212, 5214, 5216, 5218, 5220, 5222, 5224, 5226, 5228, 5230, 5232, 5234, 5236, 5238, 5240, 5242, 5244, 5246, 5248, 5250, 5252, 5254, 5256, 5258, 5260, 5262, 5264, 5266, 5268, 5270, 5272, 5274, 5276, 5278, 5280, 5282, 5284, 5286, 5288, 5290, 5292, 5294, 5296, 5298, 5300, 5302, 5304, 5306, 5308, 5310, 5312, 5314, 5316, 5318, 5320, 5322, 5324, 5326, 5328, 5330, 5332, 5334, 5336, 5338, 5340, 5342, 5344, 5346, 5348, 5350, 5352, 5354, 5356, 5358, 5360, 5362, 5364, 5366, 5368, 5370, 5372, 5374, 5376, 5378, 5380, 5382, 5384, 5386, 5388, 5390, 5392, 5394, 5396, 5398, 5400, 5402, 5404, 5406, 5408, 5410, 5412, 5414, 5416, 5418, 5420, 5422, 5424, 5426, 5428, 5430, 5432, 5434, 5436, 5438, 5440, 5442, 5444, 5446, 5448, 5450, 5452, 5454, 5456, 5458, 5460, 5462, 5464, 5466, 5468, 5470, 5472, 5474, 5476, 5478, 5480, 5482, 5484, 5486, 5488, 5490, 5492, 5494, 5496, 5498, 5500, 5502, 5504, 5506, 5508, 5510, 5512, 5514, 5516, 5518, 5520, 5522, 5524, 5526, 5528, 5530, 5532, 5534, 5536, 5538, 5540, 5542, 5544, 5546, 5548, 5550, 5552, 5554, 5556, 5558, 5560, 5562, 5564, 5566, 5568, 5570, 5572, 5574, 5576, 5578, 5580, 5582, 5584, 5586, 5588, 5590, 5592, 5594, 5596, 5598, 5600, 5602, 5604, 5606, 5608, 5610, 5612, 5614, 5616, 5618, 5620, 5622, 5624, 56261, 5628, 5630, 5632, 5634, 5636, 5638, 5640, 5642. 4. An antibody which binds to a protein according to any one of claims 1 to 3. 5. A nucleic acid molecule which encodes a protein according to any one of claims 1 to 3. 6. A nucleic acid molecule according to claim 5, comprising a nucleotide sequence selected from the group consisting of SEQ IDs 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 573, 575, 577, 579, 581, 583, 585, 587, 589, 591, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767, 769, 771, 773, 775, 777, 779, 781; 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 843, 845, 847, 849, 851, 853, 855, 857, 859, 861, 863, 865, 867, 869, 871, 873, 875, 877, 879, 881, 883, 885, 887, 889, 891, 893, 895, 897, 899, 901, 903, 905, 907, 909, 911, 913, 915, 917, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, 1039, 1041, 1043, 1045, 1047, 1049, 1051, 1053, 1055, 1057, 1059, 1061, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1077, 1079, 1081, 1083, 1085, 1087, 1089, 1091, 1093, 1095, 1097, 1099, 1101, 1103, 1105, 1107, 1109, 1111, 1113, 1115, 1117, 1119, 1121, 1123, 1125, 1127, 1129, 1131, 1133, 1135, 1137, 1139, 1141, 1143, 1145, 1147, 1149, 1151, 1153, 1155, 1157, 1159, 1161, 1163, 1165, 1167, 1169, 1171, 1173, 1175, 1177, 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1233, 1235, 1237, 1239, 1241, 1243, 1245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, 1301, 1303, 1305, 1307; 1309, 1311, 1313, 1315, 1317, 1319, 1321, 1323, 1325, 1327, 1329, 1331, 1333, 1335, 1337, 1339, 1341, 1343, 1345; 1347, 1349, 1351, 1353, 1355, 1357, 1359, 1361, 1363, 1365, 1367, 1369, 1371, 1373, 1375, 1377, 1379, 1381, 1383, 1385, 1387, 1389, 1391, 1393, 1395, 1397, 1399, 1401, 1403, 1405, 1407, 1409, 1411, 1413, 1415, 1417, 1419, 1421, 1423, 1425, 1427, 1429, 1431, 1433, 1435, 1437, 1439, 1441, 1443, 1445, 1447, 1449, 1451, 1453, 1455, 1457, 1459, 1461, 1463, 1465, 1467, 1469, 1471, 1473, 1475, 1477, 1479, 1481, 1483, 1485, 1487, 1489, 1491, 1493, 1495, 1497, 1499, 1501, 1503, 1505, 1507, 1509, 1511, 1513, 1515, 1517, 1519, 1521, 1523, 1525, 1527, 1529, 1531, 1533, 1535, 1537, 1539, 1541, 1543, 1545, 1547, 1549, 1551, 1553, 1555, 1557, 1559, 1561, 1563, 1565, 1567, 1569, 1571, 1573, 1575, 1577, 1579, 1581, 1583, 1585, 1587, 1589, 1591, 1593, 1595, 1597, 1599, 1601, 1603, 1605, 1607, 1609, 1611, 1613, 1615, 1617, 1619, 1621, 1623, 1625, 1627, 1629, 1631, 1633, 1635, 1637, 1639, 1641, 1643, 1645, 1647, 1649, 1651, 1653, 1655, 1657, 1659, 1661, 1663, 1665, 1667, 1669, 1671, 1673, 1675, 1677, 1679, 1681, 1683, 1685, 1687, 1689, 1691, 1693, 1695, 1697, 1699, 1701, 1703, 1705, 1707, 1709, 1711, 1713, 1715, 1717, 1719, 1721, 1723, 1725, 1727, 1729, 1731, 1733, 1735, 1737, 1739, 1741, 1743, 1745, 1747, 1749, 1751, 1753, 1755, 1757, 1759, 1761, 1763, 1765, 1767, 1769, 1771, 1773, 1775, 1777, 1779, 1781, 1783, 1785, 1787, 1789, 1791, 1793, 1795, 1797, 1799, 1801, 1803, 1805, 1807, 1809, 1811, 1813, 1815, 1817, 1819, 1821, 1823, 1825, 1827, 1829, 1831, 1833, 1835, 1837, 1839, 1841, 1843, 1845, 1847, 1849, 1851, 1853, 1855, 1857, 1859, 1861, 1863, 1865, 1867, 1869, 1871, 1873, 1875, 1877, 1879, 1881, 1883, 1885, 1887, 1889, 1891, 1893, 1895, 1897, 1899, 1901, 1903, 1905, 1907, 1909, 1911, 1913, 1915, 1917, 1919, 1921, 1923, 1925, 1927, 1929, 1931, 1933, 1935, 1937, 1939, 1941, 1943, 1945, 1947, 1949, 1951, 1953, 1955, 1957, 1959, 1961, 1963, 1965, 1967, 1969, 1971, 1973, 1975, 1977, 1979, 1981, 1983, 1985, 1987, 1989, 1991, 1993, 1995, 1997, 1999, 2001, 2003, 2005, 2007, 2009, 2011, 2013, 2015, 2017, 2019, 2021, 2023, 2025, 2027, 2029, 2031, 2033, 2035, 2037, 2039, 2041, 2043, 2045, 2047, 2049, 2051, 2053, 2055, 2057, 2059, 2061, 2063, 2065, 2067, 2069, 2071, 2073, 2075, 2077, 2079, 2081, 2083, 2085, 2087, 2089, 2091, 2093, 2095, 2097, 2099, 2101, 2103, 2105, 2107, 2109, 2111, 2113, 2115, 2117, 2119, 2121, 2123, 2125, 2127, 2129, 2131, 2133, 2135, 2137, 2139, 2141, 2143, 2145, 2147, 2149, 2151, 2153, 2155, 2157, 2159, 2161, 2163, 2165, 2167, 2169, 2171, 2173, 2175, 2177, 2179, 2181, 2183, 2185, 2187, 2189, 2191, 2193, 2195, 2197, 2199, 2201, 2203, 2205, 2207, 2209, 2211, 2213, 2215, 2217, 2219, 2221, 2223, 2225, 2227, 2229, 2231, 2233, 2235, 2237, 2239, 2241, 2243, 2245, 2247, 2249, 2251, 2253, 2255, 2257, 2259, 2261, 2263, 2265, 2267, 2269, 2271, 2273, 2275, 2277, 2279, 2281, 2283, 2285, 2287, 2289, 2291, 2293, 2295, 2297, 2299, 2301, 2303, 2305, 2307, 2309, 2311, 2313, 2315, 2317, 2319, 2321, 2323, 2325, 2327, 2329, 2331, 2333, 2335, 2337, 2339, 2341, 2343, 2345, 2347, 2349, 2351, 2353, 2355, 2357, 2359, 2361, 2363, 2365, 2367, 2369, 2371, 2373, 2375, 2377, 2379, 2381, 2383, 2385, 2387, 2389, 2391, 2393, 2395, 2397, 2399, 2401, 2403, 2405, 2407, 2409, 2411, 2413, 2415, 2417, 2419, 2421, 2423, 2425, 2427, 2429, 2431, 2433, 2435, 2437, 2439, 2441, 2443, 2445, 2447, 2449, 2451, 2453, 2455, 2457, 2459, 2461, 2463, 2465, 2467, 2469, 2471, 2473, 2475, 2477, 2479, 2481, 2483, 2485, 2487, 2489, 2491, 2493, 2495, 2497, 2499, 2501, 2503, 2505, 2507, 2509, 2511, 2513, 2515, 2517, 2519, 2521, 2523, 2525, 2527, 2529, 2531, 2533, 2535, 2537, 2539, 2541, 2543, 2545, 2547, 2549, 2551, 2553, 2555, 2557, 2559, 2561, 2563, 2565, 2567, 2569, 2571, 2573, 2575, 2577, 2579, 2581, 2583, 2585, 2587, 2589, 2591, 2593, 2595, 2597, 2599, 2601, 2603, 2605, 2607, 2609, 2611, 2613, 2615, 2617, 2619, 2621, 2623, 2625, 2627, 2629, 2631, 2633, 2635, 2637, 2639, 2641, 2643, 2645, 2647, 2649, 2651, 2653, 2655, 2657, 2659, 2661, 2663, 2665, 2667, 2669, 2671, 2673, 2675, 2677, 2679, 2681, 2683, 2685, 2687, 2689, 2691, 2693, 2695, 2697, 2699, 2701, 2703, 2705, 2707, 2709, 2711, 2713, 2715, 2717, 2719, 2721, 2723, 2725, 2727, 2729, 2731, 2733, 2735, 2737, 2739, 2741, 2743, 2745, 2747, 2749, 2751, 2753, 2755, 2757, 2759, 2761, 2763, 2765, 2767, 2769, 2771, 2773, 2775, 2777, 2779, 2781, 2783, 2785, 2787, 2789, 2791, 2793, 2795, 2797, 2799, 2801, 2803, 2805, 2807, 2809, 2811, 2813, 2815, 2817, 2819, 2821, 2823, 2825, 2827, 2829, 2831, 2833, 2835, 2837, 2839, 2841, 2843, 2845, 2847, 2849, 2851, 2853, 2855, 2857, 2859, 2861, 2863, 2865, 2867, 2869, 2871, 2873, 2875, 2877, 2879, 2881, 2883, 2885, 2887, 2889, 2891, 2893, 2895, 2897, 2899, 2901, 2903, 2905, 2907, 2909, 2911, 2913, 2915, 2917, 2919, 2921, 2923, 2925, 2927, 2929, 2931, 2933, 2935, 2937, 2939, 2941, 2943, 2945, 2947, 2949, 2951, 2953, 2955, 2957, 2959, 2961, 2963, 2965, 2967, 2969, 2971, 2973, 2975, 2977, 2979, 2981, 2983, 2985, 2987, 2989, 2991, 2993, 2995, 2997, 2999, 3001, 3003, 3005, 3007, 3009, 3011, 3013, 3015, 3017, 3019, 3021, 3023, 3025, 3027, 3029, 3031, 3033, 3035, 3037, 3039, 3041, 3043, 3045, 3047, 3049, 3051, 3053, 3055, 3057, 3059, 3061, 3063, 3065, 3067, 3069, 3071, 3073, 3075, 3077, 3079, 3081, 3083, 3085, 3087, 3089, 3091, 3093, 3095, 3097, 3099, 3101, 3103, 3105, 3107, 3109, 3111, 3113, 3115, 3117, 3119, 3121, 3123, 3125, 3127, 3129, 3131, 3133, 3135, 3137, 3139, 3141, 3143, 3145, 3147, 3149, 3151, 3153, 3155, 3157, 3159, 3161, 3163, 3165, 3167, 3169, 3171, 3173, 3175, 3177, 3179, 3181, 3183, 3185, 3187, 3189, 3191, 3193, 3195, 3197, 3199, 3201, 3203, 3205, 3207, 3209, 3211, 3213, 3215, 3217, 3219, 3221, 3223, 3225, 3227, 3229, 3231, 3233, 3235, 3237, 3239, 3241, 3243, 3245, 3247, 3249, 3251, 3253, 3255, 3257, 3259, 3261, 3263, 3265, 3267, 3269, 3271, 3273, 3275, 3277, 3279, 3281, 3283, 3285, 3287, 3289, 3291, 3293, 3295, 3297, 3299, 3301, 3303, 3305, 3307, 3309, 3311, 3313, 3315, 3317, 3319, 3321, 3323, 3325, 3327, 3329, 3331, 3333, 3335, 3337, 3339, 3341, 3343, 3345, 3347, 3349, 3351, 3353, 3355, 3357, 3359, 3361, 3363, 3365, 3367, 3369, 3371, 3373, 3375, 3377, 3379, 3381, 3383, 3385, 3387, 3389, 3391, 3393, 3395, 3397, 3399, 3401, 3403, 3405, 3407, 3409, 3411, 3413, 3415, 3417, 3419, 3421, 3423, 3425, 3427, 3429, 3431, 3433, 3435, 3437, 3439, 3441, 3443, 3445, 3447, 3449, 3451, 3453, 3455, 3457, 3459, 1461, 3463, 3465, 3467, 3469, 3471, 3473, 3475, 3477, 3479, 3481, 3483, 3485, 3487, 3489, 3491, 3493, 3495, 3497, 3499, 3501, 3503, 3505, 3507, 3509, 3511, 3513, 3515, 3517, 3519, 3521, 3523, 3525, 3527, 3529, 3531, 3533, 3535, 3537, 3539, 3541, 3543, 3545, 3547, 3549, 3551, 3553, 3555, 3557, 3559, 3561, 3563, 3565, 3567, 3569, 3571, 3573, 3575, 3577, 3579, 3581, 3583, 3585, 3587, 3589, 3591, 3593, 3595, 3597, 3599, 3601, 3603, 3605, 3607, 3609, 3611, 3613, 3615, 3617, 3619, 3621, 3623, 3625, 3627, 3629, 3631, 3633, 3635, 3637, 3639, 3641, 3643, 3645, 3647, 3649, 3651, 3653, 3655, 3657, 3659, 3661, 3663, 3665, 3667, 3669, 3671, 3673, 3675, 3677, 3679, 3681, 3683, 3685, 3687, 3689, 3691, 3693, 3695, 3697, 3699, 3701, 3703, 3705, 3707, 3709, 3711, 3713, 3715, 3717, 3719, 3721, 3723, 3725, 3727, 3729, 3731, 3733, 3735, 3737, 3739, 3741, 3743, 3745, 3747, 3749, 3751, 3753, 3755, 3757, 3759, 3761, 3763, 3765, 3767, 3769, 3771, 3773, 3775, 3777, 3779, 3781, 3783, 3785, 3787, 3789, 3791, 3793, 3795, 3797, 3799, 3801, 3803, 3805, 3807, 3809, 3811, 3813, 3815, 3817, 3819, 3821, 3823, 3825, 3827, 3829, 3831, 3833, 3835, 3837, 3839, 3841, 3843, 3845, 3847, 3849, 3851, 3853, 3855, 3857, 3859, 3861, 3863, 3865, 3867, 3869, 3871, 3873, 3875, 3877, 3879, 3881, 3883, 3885, 3887, 3889, 3891, 3893, 3895, 3897, 3899, 3901, 3903, 3905, 3907, 3909, 3911, 3913, 3915, 3917, 3919, 3921, 3923, 3925, 3927, 3929, 3931, 3933, 3935, 3937, 3939, 3941, 3943, 3945, 3947, 3949, 3951, 3953, 3955, 3957, 3959, 3961, 3963, 3965, 3967, 3969, 3971, 3973, 3975, 3977, 3979, 3981, 3983, 3985, 3987, 3989, 3991, 3993, 3995, 3997, 3999, 4001, 4003, 4005, 4007, 4009, 4011, 4013, 4015, 4017, 4019, 4021, 4023, 4025, 4027, 4029, 4031, 4033, 4035, 4037, 4039, 4041, 4043, 4045, 4047, 4049, 4051, 4053, 4055, 4057, 4059, 4061, 4063, 4065, 4067, 4069, 4071, 4073, 4075, 4077, 4079, 4081, 4083, 4085, 4087, 4089, 4091, 4093, 4095, 4097, 4099, 4101, 4103, 4105, 4107, 4109, 4111, 4113, 4115, 4117, 4119, 4121, 4123, 4125, 4127, 4129, 4131, 4133, 4135, 4137, 4139, 4141, 4143, 4145, 4147, 4149, 4151, 4153, 4155, 4157, 4159, 4161, 4163, 4165, 4167, 4169, 4171, 4173, 4175, 4177, 4179, 4181, 4183, 4185, 4187, 4189, 4191, 4193, 4195, 4197, 4199, 4201, 4203, 4205, 4207, 4209, 4211, 4213, 4215, 4217, 4219, 4221, 4223, 4225, 4227, 4229, 4231, 4233, 4235, 4237, 4239, 4241, 4243, 4245, 4247, 4249, 4251, 4253, 4255, 4257, 4259, 4261, 4263, 4265, 4267, 4269, 4271, 4273, 4275, 4277, 4279, 4281, 4283, 4285, 4287, 4289, 4291, 4293, 4295, 4297, 4299, 4301, 4303, 4305, 4307, 4309, 4311, 4313, 4315, 4317, 4319, 4321, 4323, 4325, 4327, 4329, 4331, 4333, 4335, 4337, 4339, 4341, 4343, 4345, 4347, 4349, 4351, 4353, 4355, 4357, 4359, 4361, 4363, 4365, 4367, 4369, 4371, 4373, 4375, 4377, 4379, 4381, 4383, 4385, 4387, 4389, 4391, 4393, 4395, 4397, 4399, 4401, 4403, 4405, 4407, 4409, 4411, 4413, 4415, 4417, 4419, 4421, 4423, 4425, 4427, 4429, 4431, 4433, 4435, 4437, 4439, 4441, 4443, 4445, 4447, 4449, 4451, 4453, 4455, 4457, 4459, 4461, 4463, 4465, 4467, 4469, 4471, 4473, 4475, 4477, 4479, 4481, 4483, 4485, 4487, 4489, 4491, 4493, 4495, 4497, 4499, 4501, 4503, 4505, 4507, 4509, 4511, 4513, 4515, 4517, 4519, 4521, 4523, 4525, 4527, 4529, 4531, 4533, 4535, 4537, 4539, 4541, 4543, 4545, 4547, 4549, 4551, 4553, 4555, 4557, 4559, 4561, 4563, 4565, 4567, 4569, 4571, 4573, 4575, 4577, 4579, 4581, 4583, 4585, 4587, 4589, 4591, 4593, 4595, 4597, 4599, 4601, 4603, 4605, 4607, 4609, 4611, 4613, 4615, 4617, 4619, 4621, 4623, 4625, 4627, 4629, 4631, 4633, 4635, 4637, 4639, 4641, 4643, 4645, 4647, 4649, 4651, 4653, 4655, 4657, 4659, 4661, 4663, 4665, 4667, 4669, 4671, 4673, 4675, 4677, 4679, 4681, 4683, 4685, 4687, 4689, 4691, 4693, 4695, 4697, 4699, 4701, 4703, 4705, 4707, 4709, 4711, 4713, 4715, 4717, 4719, 4721, 4723, 4725, 4727, 4729, 4731, 4733, 4735, 4737, 4739, 4741, 4743, 4745, 4747, 4749, 4751, 4753, 4755, 4757, 4759, 4761, 4763, 4765, 4767, 4769, 4771, 4773, 4775, 4777, 4779, 4781, 4783, 4785, 4787, 4789, 4791, 4793, 4795, 4797, 4799, 4801, 4803, 4805, 4807, 4809, 4811, 4813, 4815, 4817, 4819, 4821, 4823, 4825, 4827, 4829, 4831, 4833, 4835, 4837, 4839, 4841, 4843, 4845, 4847, 4849, 4851, 4853, 4855, 4857, 4859, 4861, 4863, 4865, 4867, 4869, 4871, 4873, 4875, 4877, 4879, 4881, 4883, 4885, 4887, 4889, 4891, 4893, 4895, 4897, 4899, 4901, 4903, 4905, 4907, 4909, 4911, 4913, 4915, 4917, 4919, 4921, 4923, 4925, 4927, 4929, 4931, 4933, 4935, 4937, 4939, 4941, 4943, 4945, 4947, 4949, 4951, 4953, 4955, 4957, 4959, 4961, 4963, 4965, 4967, 4969, 4971, 4973, 4975, 4977, 4979, 4981, 4983, 4985, 4987, 4989, 4991, 4993, 4995, 4997, 4999, 5001, 5003, 5005, 5007, 5009, 5011, 5013, 5015, 5017, 5019, 5021, 5023, 5025, 5027, 5029, 5031, 5033, 5035, 5037, 5039, 5041, 5043, 5045, 5047, 5049, 5051, 5053, 5055, 5057, 5059, 5061, 5063, 5065, 5067, 5069, 5071, 5073, 5075, 5077, 5079, 5081, 5083, 5085, 5087, 5089, 5091, 5093, 5095, 5097, 5099, 5101, 5103, 5105, 5107, 5109, 5111, 5113, 5115, 5117, 5119, 5121, 5123, 5125, 5127, 5129, 5131, 5133, 5135, 5137, 5139, 5141, 5143, 5145, 5147, 5149, 5151, 5153, 5155, 5157, 5159, 5161, 5163, 5165, 5167, 5169, 5171, 5173, 5175, 5177, 5179, 5181, 5183, 5185, 5187, 5189, 5191, 5193, 5195, 5197, 5199, 5201, 5203, 5205, 5207, 5209, 5211, 5213, 5215, 5217, 5219, 5221, 5223, 5225, 5227, 5229, 5231, 5233, 5235, 5237, 5239, 5241, 5243, 5245, 5247, 5249, 5251, 5253, 5255, 5257, 5259, 5261, 5263, 5265, 5267, 5269, 5271, 5273, 5275, 5277, 5279, 5281, 5283, 5285, 5287, 5289, 5291, 5293, 5295, 5297, 5299, 5301, 5303, 5305, 5307, 5309, 5311, 5313, 5315, 5317, 5319, 5321, 5323, 5325, 5327, 5329, 5331, 5333, 5335, 5337, 5339, 5341, 5343, 5345, 5347, 5349, 5351, 5353, 5355, 5357, 5359, 5361, 5363, 5365, 5367, 5369, 5371, 5373, 5375, 5377, 5379, 5381, 5383, 5385, 5387, 5389, 5391, 5393, 5395, 5397, 5399, 5401, 5403, 5405, 5407, 5409, 5411, 5413, 5415, 5417, 5419, 5421, 5423, 5425, 5427, 5429, 5431, 5433, 5435, 5437, 5439, 5441, 5443, 5445, 5447, 5449, 5451, 5453, 5455, 5457, 5459, 5461, 5463, 5465, 5467, 5469, 5471, 5473, 5475, 5477, 5479, 5481, 5483, 5485, 5487, 5489, 5491, 5493, 5495, 5497, 5499, 5501, 5503, 5505, 5507, 5509, 5511, 5513, 5515, 5517, 5519, 5521, 5523, 5525, 5527, 5529, 5531, 5533, 5535, 5537, 5539, 5541, 5543, 5545, 5547, 5549, 5551, 5553, 5555, 5557, 5559, 5561, 5563, 5565, 5567, 5569, 5571, 5573, 5575, 5577, 5579, 5581, 5583, 5585, 5587, 5589, 5591, 5593, 5595, 5597, 5599, 5601, 5603, 5605, 5607, 5609, 5611, 5613, 5615, 5617, 5619, 5621, 5623, 5625, 5627, 5629, 5631, 5633, 5635, 5637, 5639, 5641. 7. A nucleic acid molecule comprising a fragment of a nucleotide sequence selected from the group consisting of SEQ IDs 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, 413, 415, 417, 419, 421, 423, 425, 427, 429, 431, 433, 435, 437, 439, 441, 443, 445, 447, 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541; 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 573, 575, 577, 579, 581, 583, 585, 587, 589, 591, 593, 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 691, 693, 695, 697, 699, 701, 703, 705, 707, 709, 711, 713, 715, 717, 719, 721, 723, 725, 727, 729, 731, 733, 735, 737, 739, 741, 743, 745, 747, 749, 751, 753, 755, 757, 759, 761, 763, 765, 767, 769, 771, 773, 775, 777, 779, 781, 783, 785, 787, 789, 791, 793, 795, 797, 799, 801, 803, 805, 807, 809, 811, 813, 815, 817, 819, 821, 823, 825, 827, 829, 831, 833, 835, 837, 839, 841, 843, 845, 847, 849, 851, 853, 855, 857, 859,.861, 863, 865, 867, 869, 871, 873, 875, 877, 879, 881, 883, 885, 887, 889, 891, 893, 895, 897, 899, 901, 903, 905, 907, 909, 911, 913, 915, 917, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1031, 1033, 1035, 1037, 1039, 1041, 1043, 1045, 1047, 1049, 1051, 1053, 1055, 1057, 1059, 1061, 1063, 1065, 1067, 1069, 1071, 1073, 1075, 1077, 1079, 1081, 1083, 1085, 1087, 1089, 1091, 1093, 1095, 1097, 1099, 1101, 1103, 1105, 1107, 1109, 1111, 1113, 1115, 1117, 1119, 1121, 1123, 1125, 1127, 1129, 1131, 1133, 1135, 1137, 1139, 1141, 1143, 1145, 1147, 1149, 1151, 1153, 1155, 1157, 1159, 1161, 1163, 1165, 1167, 1169, 1171, 1173, 1175, 1177, 1179, 1181, 1183, 1185, 1187, 1189, 1191, 1193, 1195, 1197, 1199, 1201, 1203, 1205, 1207, 1209, 1211, 1213, 1215, 1217, 1219, 1221, 1223, 1225, 1227, 1229, 1231, 1233, 1235, 1237, 1239, 1241, 1243, 1245, 1247, 1249, 1251, 1253, 1255, 1257, 1259, 1261, 1263, 1265, 1267, 1269, 1271, 1273, 1275, 1277, 1279, 1281, 1283, 1285, 1287, 1289, 1291, 1293, 1295, 1297, 1299, 1301, 1303, 1305, 1307, 1309, 1311, 1313, 1315, 1317, 1319, 1321, 1323, 1325, 1327, 1329, 1331, 1333, 1335, 1337, 1339, 1341, 1343, 1345, 1347, 1349, 1351, 1353, 1355, 1357, 1359, 1361, 1363, 1365, 1367, 1369, 1371, 1373, 1375, 1377, 1379, 1381, 1383, 1385, 1387, 1389, 1391, 1393, 1395, 1397, 1399, 1401, 1403, 1405, 1407, 1409, 1411, 1413, 1415, 1417, 1419, 1421, 1423, 1425, 1427, 1429, 1431, 1433, 1435, 1437, 1439, 1441, 1443, 1445, 1447, 1449, 1451, 1453, 1455, 1457, 1459, 1461, 1463, 1465, 1467, 1469, 1471, 1473, 1475, 1477, 1479, 1481, 1483, 1485, 1487, 1489, 1491, 1493, 1495, 1497, 1499, 1501, 1503, 1505, 1507, 1509, 1511, 1513, 1515, 1517, 1519, 1521, 1523, 1525, 1527, 1529, 1531, 1533, 1535, 1537, 1539, 1541, 1543, 1545, 1547, 1549, 1551, 1553, 1555, 1557, 1559, 1561, 1563, 1565, 1567, 1569, 1571, 1573, 1575, 1577, 1579, 1581, 1583, 1585, 1587, 1589, 1591, 1593, 1595, 1597, 1599, 1601, 1603, 1605, 1607, 1609, 1611, 1613, 1615, 1617, 1619, 1621, 1623, 1625, 1627, 1629, 1631, 1633, 1635, 1637, 1639, 1641, 1643, 1645, 1647, 1649, 1651, 1653, 1655, 1657, 1659, 1661, 1663, 1665, 1667, 1669, 1671, 1673, 1675, 1677, 1679, 1681, 1683, 1685, 1687, 1689, 1691, 1693, 1695, 1697, 1699, 1701, 1703, 1705, 1707, 1709, 1711, 1713, 1715, 1717, 1719, 1721, 1723, 1725, 1727, 1729, 1731, 1733, 1735, 1737, 1739, 1741, 1743, 1745, 1747, 1749, 1751, 1753, 1755, 1757, 1759, 1761, 1763, 1765, 1767, 1769, 1771, 1773, 1775, 1777, 1779, 1781, 1783, 1785, 1787, 1789, 1791, 1793, 1795, 1797, 1799, 1801, 1803, 1805, 1807, 1809, 1811, 1813, 1815, 1817, 1819, 1821, 1823, 1825, 1827, 1829, 1831, 1833, 1835, 1837, 1839, 1841, 1843, 1845, 1847, 1849, 1851, 1853, 1855, 1857, 1859, 1861, 1863, 1865, 1867, 1869, 1871, 1873, 1875, 1877, 1879, 1881, 1883, 1885, 1887, 1889, 1891, 1893, 1895, 1897, 1899, 1901, 1903, 1905, 1907, 1909, 1911, 1913, 1915, 1917, 1919, 1921, 1923, 1925, 1927, 1929, 1931, 1933, 1935, 1937, 1939, 1941, 1943, 1945, 1947, 1949, 1951, 1953, 1955; 1957, 1959, 1961, 1963, 1965, 1967, 1969, 1971, 1973, 1975, 1977, 1979, 1981, 1983, 1985, 1987, 1989, 1991, 1993, 1995, 1997, 1999, 2001, 2003, 2005, 2007, 2009, 2011, 2013, 2015, 2017, 2019, 2021, 2023, 2025, 2027, 2029, 2031, 2033, 2035, 2037, 2039, 2041, 2043, 2045, 2047, 2049, 2051, 2053, 2055, 2057, 2059, 2061, 2063, 2065, 2067, 2069, 2071, 2073, 2075, 2077, 2079, 2081, 2083, 2085, 2087, 2089, 2091, 2093, 2095, 2097, 2099, 2101, 2103, 2105, 2107, 2109, 2111, 2113, 2115, 2117, 2119, 2121, 2123, 2125, 2127, 2129, 2131, 2133, 2135, 2137, 2139, 2141, 2143, 2145, 2147, 2149, 2151, 2153, 2155, 2157, 2159, 2161, 2163, 2165, 2167, 2169, 2171, 2173, 2175, 2177, 2179, 2181, 2183, 2185, 2187, 2189, 2191, 2193, 2195, 2197, 2199, 2201, 2203, 2205, 2207, 2209, 2211, 2213, 2215, 2217, 2219, 2221, 2223, 2225, 2227, 2229, 2231, 2233, 2235, 2237, 2239, 2241, 2243, 2245, 2247, 2249, 2251, 2253, 2255, 2257, 2259, 2261, 2263, 2265, 2267, 2269, 2271, 2273, 2275, 2277, 2279, 2281, 2283, 2285, 2287, 2289, 2291, 2293, 2295, 2297, 2299, 2301, 2303, 2305, 2307, 2309, 2311, 2313, 2315, 2317, 2319, 2321, 2323, 2325, 2327, 2329, 2331, 2333, 2335, 2337, 2339, 2341, 2343, 2345, 2347, 2349, 2351, 2353, 2355, 2357, 2359, 2361, 2363, 2365, 2367, 2369, 2371, 2373, 2375, 2377, 2379, 2381, 2383, 2385, 2387, 2389, 2391, 2393, 2395, 2397, 2399, 2401, 2403, 2405, 2407, 2409, 2411, 2413, 2415, 2417, 2419, 2421, 2423, 2425, 2427, 2429, 2431, 2433, 2435, 2437, 2439, 2441, 2443, 2445, 2447, 2449, 2451, 2453, 2455, 2457, 2459, 2461, 2463, 2465, 2467, 2469, 2471, 2473, 2475, 2477, 2479, 2481, 2483, 2485, 2487, 2489, 2491, 2493, 2495, 2497, 2499, 2501, 2503, 2505, 2507, 2509, 2511, 2513, 2515, 2517, 2519, 2521, 2523, 2525, 2527, 2529, 2531, 2533, 2535, 2537, 2539, 2541, 2543, 2545, 2547, 2549, 2551, 2553, 2555, 2557, 2559, 2561, 2563, 2565, 2567, 2569, 2571, 2573, 2575, 2577, 2579, 2581, 2583, 2585, 2587, 2589, 2591, 2593, 2595, 2597, 2599, 2601, 2603, 2605, 2607, 2609, 2611, 2613, 2615, 2617, 2619, 2621, 2623, 2625, 2627, 2629, 2631, 2633, 2635, 2637, 2639, 2641, 2643, 2645, 2647, 2649, 2651, 2653, 2655, 2657, 2659, 2661, 2663, 2665, 2667, 2669, 2671, 2673, 2675, 2677, 2679, 2681, 2683, 2685, 2687, 2689, 2691, 2693, 2695, 2697, 2699, 2701, 2703, 2705, 2707, 2709, 2711, 2713, 2715, 2717, 2719, 2721, 2723, 2725, 2727, 2729, 2731, 2733, 2735, 2737, 2739, 2741, 2743, 2745, 2747, 2749, 2751, 2753, 2755, 2757, 2759, 2761, 2763, 2765, 2767, 2769, 2771, 2773, 2775, 2777, 2779, 2781, 2783, 2785, 2787, 2789, 2791, 2793, 2795, 2797, 2799, 2801, 2803, 2805, 2807, 2809, 2811, 2813, 2815, 2817, 2819, 2821, 2823, 2825, 2827, 2829, 2831, 2833, 2835, 2837, 2839, 2841, 2843, 2845, 2847, 2849, 2851, 2853, 2855, 2857, 2859, 2861, 2863, 2865, 2867, 2869, 2871, 2873, 2875, 2877, 2879, 2881, 2883, 2885, 2887, 2889, 2891, 2893, 2895, 2897, 2899, 2901, 2903, 2905, 2907, 2909, 2911, 2913, 2915, 2917, 2919, 2921, 2923, 2925, 2927, 2929, 2931, 2933, 2935, 2937, 2939, 2941, 2943, 2945, 2947, 2949, 2951, 2953, 2955, 2957, 2959, 2961, 2963, 2965, 2967, 2969, 2971, 2973, 2975, 2977, 2979, 2981, 2983, 2985, 2987, 2989, 2991, 2993, 2995, 2997, 2999, 3001, 3003, 3005, 3007, 3009, 3011, 3013, 3015, 3017, 3019, 3021, 3023, 3025, 3027, 3029, 3031, 3033, 3035, 3037, 3039, 3041, 3043, 3045, 3047, 3049, 3051, 3053, 3055, 3057, 3059, 3061, 3063, 3065, 3067, 3069, 3071, 3073, 3075, 3077, 3079, 3081, 3083, 3085, 3087, 3089, 3091, 3093, 3095, 3097, 3099, 3101, 3103, 3105, 3107, 3109, 3111, 3113, 3115, 3117, 3119, 3121, 3123, 3125, 3127, 3129, 3131, 3133, 3135, 3137, 3139, 3141, 3143, 3145, 3147, 3149, 3151, 3153, 3155, 3157, 3159, 3161, 3163, 3165, 3167, 3169, 3171, 3173, 3175, 3177, 3179, 3181, 3183, 3185, 3187, 3189, 3191, 3193, 3195, 3197, 3199, 3201, 3203, 3205, 3207, 3209, 3211, 3213, 3215, 3217, 3219, 3221, 3223, 3225, 3227, 3229, 3231, 3233, 3235, 3237, 3239, 3241, 3243, 3245, 3247, 3249, 3251, 3253, 3255, 3257, 3259, 3261, 3263, 3265, 3267, 3269, 3271, 3273, 3275, 3277, 3279, 3281, 3283, 3285, 3287, 3289, 3291, 3293, 3295, 3297, 3299, 3301, 3303, 3305, 3307, 3309, 3311, 3313, 3315, 3317, 3319, 3321, 3323, 3325, 3327, 3329, 3331, 3333, 3335, 3337, 3339, 3341, 3343, 3345, 3347, 3349, 3351, 3353, 3355, 3357, 3359, 3361, 3363, 3365, 3367, 3369, 3371, 3373, 3375, 3377, 3379, 3381, 3383, 3385, 3387, 3389, 3391, 3393, 3395, 3397, 3399, 3401, 3403, 3405, 3407, 3409, 3411, 3413, 3415, 3417, 3419, 3421, 3423, 3425, 3427, 3429, 3431, 3433, 3435, 3437, 3439, 3441, 3443, 3445, 3447, 3449, 3451, 3453, 3455, 3457, 3459, 3461, 3463, 3465, 3467, 3469, 3471, 3473, 3475, 3477, 3479, 3481, 3483, 3485, 3487, 3489, 3491, 3493, 3495, 3497, 3499, 3501, 3503, 3505, 3507, 3509, 3511, 3513, 3515, 3517, 3519, 3521, 3523, 3525, 3527, 3529, 3531, 3533, 3535, 3537, 3539, 3541, 3543, 3545, 3547, 3549, 3551, 3553, 3555, 3557, 3559, 3561, 3563, 3565, 3567, 3569, 3571, 3573, 3575, 3577, 3579, 3581, 3583, 3585, 3587, 3589, 3591, 3593, 3595, 3597, 3599, 3601, 3603, 3605, 3607, 3609, 3611, 3613, 3615, 3617, 3619, 3621, 3623, 3625, 3627, 3629, 3631, 3633, 3635, 3637, 3639, 3641, 3643, 3645, 3647, 3649, 3651, 3653, 3655, 3657, 3659, 3661, 3663, 3665, 3667, 3669, 3671, 3673, 3675, 3677, 3679, 3681, 3683, 3685, 3687, 3689, 3691, 3693, 3695, 3697, 3699, 3701, 3703, 3705, 3707, 3709, 3711, 3713, 3715, 3717, 3719, 3721, 3723, 3725, 3727, 3729, 3731, 3733, 3735, 3737, 3739, 3741, 3743, 3745, 3747, 3749, 3751, 3753, 3755, 3757, 3759, 3761, 3763, 3765, 3767, 3769, 3771, 3773, 3775, 3777, 3779, 3781, 3783, 3785, 3787, 3789, 3791, 3793, 3795, 3797, 3799, 3801, 3803, 3805, 3807, 3809, 3811, 3813, 3815, 3817, 3819, 3821, 3823, 3825, 3827, 3829, 3831, 3833, 3835, 3837, 3839, 3841, 3843, 3845, 3847, 3849, 3851, 3853, 3855, 3857, 3859, 3861, 3863, 3865, 3867, 3869, 3871, 3873, 3875, 3877, 3879, 3881, 3883, 3885, 3887, 3889, 3891, 3893, 3895, 3897, 3899, 3901, 3903, 3905, 3907, 3909, 3911, 3913, 3915, 3917, 3919, 3921, 3923, 3925, 3927, 3929, 3931, 3933, 3935, 3937, 3939, 3941, 3943, 3945, 3947, 3949, 3951, 3953, 3955, 3957, 3959, 3961, 3963, 3965, 3967, 3969, 3971, 3973, 3975, 3977, 3979, 3981, 3983, 3985, 3987, 3989, 3991, 3993, 3995, 3997, 3999, 4001, 4003, 4005, 4007, 4009, 4011, 4013, 4015, 4017, 4019, 4021, 4023, 4025, 4027, 4029, 4031, 4033, 4035, 4037, 4039, 4041, 4043, 4045, 4047, 4049, 4051, 4053, 4055, 4057, 4059, 4061, 4063, 4065, 4067, 4069, 4071, 4073, 4075, 4077, 4079, 4081, 4083, 4085, 4087, 4089, 4091, 4093, 4095, 4097, 4099, 4101, 4103, 4105, 4107, 4109, 4111, 4113, 4115, 4117, 4119, 4121, 4123, 4125, 4127, 4129, 4131, 4133, 4135, 4137, 4139, 4141, 4143, 4145, 4147, 4149, 4151, 4153, 4155, 4157, 4159, 4161, 4163, 4165, 4167, 4169, 4171, 4173, 4175, 4177, 4179, 4181, 4183, 4185, 4187, 4189, 4191, 4193, 4195, 4197, 4199, 4201, 4203, 4205, 4207, 4209, 4211, 4213, 4215, 4217, 4219, 4221, 4223, 4225, 4227, 4229, 4231, 4233, 4235, 4237, 4239, 4241, 4243, 4245, 4247, 4249, 4251, 4253, 4255, 4257, 4259, 4261, 4263, 4265, 4267, 4269, 4271, 4273, 4275, 4277, 4279, 4281, 4283, 4285, 4287, 4289, 4291, 4293, 4295, 4297, 4299, 4301, 4301, 4305, 4307, 4309, 4311, 4313, 4315, 4317, 4319, 4321, 4323, 4325, 4327, 4329, 4331, 4333, 4335, 4337, 4339, 4341, 4343, 4345, 4347, 4349, 4351, 4353, 4355, 4357, 4359, 4361, 4363, 4365, 4367, 4369, 4371, 4373, 4375, 4377, 4379, 4381, 4383, 4385, 4387, 4389, 4391, 4393, 4395, 4397, 4399, 4401, 4403, 4405, 4407, 4409, 4411, 4413, 4415, 4417, 4419, 4421, 4423, 4425, 4427, 4429, 4431, 4433, 4435, 4437, 4439, 4441, 4443, 4445, 4447, 4449, 4451, 4453, 4455, 4457, 4459, 4461, 4463, 4465, 4467, 4469, 4471, 4473, 4475, 4477, 4479, 4481, 4483, 4485, 4487, 4489, 4491, 4493, 4495, 4497, 4499, 4501, 4503, 4505, 4507, 4509, 4511, 4513, 4515, 4517, 4519, 4521, 4523, 4525, 4527, 4529, 4531, 4533, 4535, 4537, 4539, 4541, 4543, 4545, 4547, 4549, 4551, 4553, 4555, 4557, 4559, 4561, 4563, 4565, 4567, 4569, 4571, 4573, 4575, 4577, 4579, 4581, 4583, 4585, 4587, 4589, 4591, 4593, 4595, 4597, 4599, 4601, 4603, 4605, 4607, 4609, 4611, 4613, 4615, 4617, 4619, 4621, 4623, 4625, 4627, 4629, 4631, 4633, 4635, 4637, 4639, 4641, 4643, 4645, 4647, 4649, 4651, 4653, 4655, 4657, 4659, 4661, 4663, 4665, 4667, 4669, 4671, 4673, 4675, 4677, 4679, 4681, 4683, 4685, 4687, 4689i 4691, 4693, 4695, 4697, 4699, 4701, 4703, 4705, 4707, 4709, 4711, 4713, 4715, 4717, 4719, 4721, 4723, 4725, 4727, 4729, 4731, 4733, 4735, 4737, 4739, 4741, 4743, 4745, 4747, 4749, 4751, 4753, 4755, 4757, 4759, 4761, 4763, 4765, 4767, 4769, 4771, 4773, 4775, 4777, 4779, 4781, 4783, 4785, 4787, 4789, 4791, 4793, 4795, 4797, 4799, 4801, 4803, 4805, 4807, 4809, 4811, 4813, 4815, 4817, 4819, 4821, 4823, 4825, 4827, 4829, 4831, 4833, 4835, 4837, 4839, 4841, 4843, 4845, 4847, 4849, 4851, 4853, 4855, 4857, 4859, 4861, 4863, 4865, 4867, 4869, 4871, 4873, 4875, 4877, 4879, 4881, 4883, 4885, 4887, 4889, 4891, 4893, 4895, 4897, 4899, 4901, 4903, 4905, 4907, 4909, 4911, 4913, 4915, 4917, 4919, 4921, 4923, 4925, 4927, 4929, 4931, 4933, 4935, 4937, 4939, 4941, 4943, 4945, 4947, 4949, 4951, 4953, 4955, 4957, 4959, 4961, 4963, 4965, 4967, 4969, 4971, 4973, 4975, 4977, 4979, 4981, 4983, 4985, 4987, 4989, 4991, 4993, 4995, 4997, 4999, 5001, 5003, 5005, 5007, 5009, 5011, 5013, 5015, 5017, 5019, 5021, 5023, 5025, 5027, 5029, 5031, 5033, 5035, 5037, 5039, 5041, 5043, 5045, 5047, 5049, 5051, 5053, 5055, 5057, 5059, 5061, 5063, 5065, 5067, 5069, 5071, 5073, 5075, 5077, 5079, 5081, 5083, 5085, 5087, 5089, 5091, 5093, 5095, 5097, 5099, 5101, 5103, 5105, 5107, 5109, 5111, 5113, 5115, 5117, 5119, 5121, 5123, 5125, 5127, 5129, 5131, 5133, 5135, 5137, 5139, 5141, 5143, 5145, 5147, 5149, 5151, 5153, 5155, 5157, 5159, 5161, 5163, 5165, 5167, 5169, 5171, 5173, 5175, 5177, 5179, 5181, 5183, 5185, 5187, 5189, 5191, 5193, 5195, 5197, 5199, 5201, 5203, 5205, 5207, 5209, 5211, 5213, 5215, 5217, 5219, 5221, 5223, 5225, 5227, 5229, 5231, 5233, 5235, 5237, 5239, 5241, 5243, 5245, 5247, 5249, 5251, 5253, 5255, 5257, 5259, 5261, 5263, 5265, 5267, 5269, 5271, 5273, 5275, 5277, 5279, 5281, 5283, 5285, 5287, 5289, 5291, 5293, 5295, 5297, 5299, 5301, 5303, 5305, 5307, 5309, 5311, 5313, 5315, 5317, 5319, 5321, 5323, 5325, 5327, 5329, 5331, 5333, 5335, 5337, 5339, 5341, 5343, 5345, 5347, 5349, 5351, 5353, 5355, 5357, 5359, 5361, 5363, 5365, 5367, 5369, 5371, 5373, 5375, 5377, 5379, 5381, 5383, 5385, 5387, 5389, 5391, 5393, 5395, 5397, 5399, 5401, 5403, 5405, 5407, 5409, 5411, 5413, 5415, 5417, 5419, 5421, 5423, 5425, 5427, 5429, 5431, 5433, 5435, 5437, 5439, 5441, 5443, 5445, 5447, 5449, 5451, 5453, 5455, 5457, 5459, 5461, 5463, 5465, 5467, 5469, 5471, 5473, 5475, 5477, 5479, 5481, 5483, 5485, 5487, 5489, 5491, 5493, 5495, 5497, 5499, 5501, 5503, 5505, 5507, 5509, 5511, 5513, 5515, 5517, 5519, 5521, 5523, 5525, 5527, 5529, 5531, 5533, 5535, 5537, 5539, 5541, 5543, 5545, 5547, 5549, 5551, 5553, 5555, 5557, 5559, 5561, 5563, 5565, 5567, 5569, 5571, 5573, 5575, 5577, 5579, 5581, 5583, 5585, 5587, 5589, 5591, 5593, 5595, 5597, 5599, 5601, 5603, 5605, 5607, 5609, 5611, 5613, 5615, 5617, 5619, 5621, 5623, 5625, 5627, 5629, 5631, 5633, 5635, 5637, 5639, 5641. 8. A nucleic acid molecule comprising a nucleotide sequence complementary to a nucleic acid molecule according to any one of claims 5 to 7. 9. A nucleic acid molecule comprising a nucleotide sequences having 50% or greater sequence identity to a nucleic acid molecule according to any one of claims 5 to 8. 10. A nucleic acid molecule which can hybridise to a nucleic acid molecule according to any one of claims 5 to 9 under high stringency conditions. 11. A composition comprising a protein, a nucleic acid molecule, or an antibody according to any preceding claim. 12. A composition according to claim 11 being a vaccine composition or a diagnostic composition. 13. A composition according to claim 11 or claim 12 for use as a pharmaceutical. 14. The use of a composition according to claim 13 in the manufacture of a medicament for the treatment or prevention of infection due to staphylococcus bacteria, particularly S.aureus. 15. The use of claim 14, wherein the disease is sepsis. 16. A method of treating a patient, comprising administering to the patient a therapeutically effective amount of a composition according to claim 13. 17. A kit comprising primers for amplifying a target sequence contained within a Staphylococcus nucleic acid sequence, the kit comprising a first primer and a second primer, wherein the first primer is substantially complementary to said target sequence and the second primer is substantially complementary to a complement of said target sequence, wherein the parts of said primers which have substantial complementarity define the termini of the target sequence to be amplified, and wherein the first and/or second primer is a nucleic acid according to any one of claims 5 to 10. 18. A kit comprising first and second single-stranded oligonucleotides which allow amplification of a Staphylococcus template nucleic acid sequence contained in a single- or double-stranded nucleic acid (or mixture thereof, wherein: (a) the first oligonucleotide comprises a primer sequence which is substantially complementary to said template nucleic acid sequence; (b) the second oligonucleotide comprises a primer sequence which is substantially complementary to the complement of said template nucleic acid sequence; (c) the first oligonucleotide and/or the second oligonucleotide comprise(s) sequence which is not complementary to said template nucleic acid; (d) said primer sequences define the termini of the template sequence to be amplified; and (e) the first and/or second oligonucleotide is a nucleic acid according to any one of claims 5 to 10. 19. A hybrid protein represented by the formula NH2-A-[-X-L-]n-B—COOH, wherein X is the amino acid sequence of a protein according to claim 1, claim 2 or claim 3, L is an optional linker amino acid sequence, A is an optional N-terminal amino acid sequence, B is an optional C-terminal amino acid sequence, and n is an integer greater than 1. 20. An assay comprising the steps of contacting a test compound with a protein according to any one of claims 1 to 3, and determining whether the test compound binds to said protein. 21. The composition of claim 13 further comprising one or more of the following antigens: a protein antigen from Helicobacter pylori; a protein antigen from N.meningitidis serogroup B; an outer-membrane vesicle (OMV) preparation from N.meningitidis; a saccharide antigen from N.meningitidis serogroup A, C, W135 and/or Y; a saccharide antigen from Streptococcus pneumoniae; an antigen from hepatitis A virus; an antigen from hepatitis B virus; an antigen from hepatitis C virus; an antigen from Bordetella pertussis; a diphtheria antigen; a tetanus antigen; a saccharide antigen from Haemophilus influenzae B. an antigen from N.gonorrhoeae; an antigen from Chlamydia pneumoniae; an antigen from Streptococcus agalactiae; an antigen from Streptococcus pyogenes an antigen from Chlamydia trachomatis an antigen from Porphyromonas gingivalis; polio antigen(s); rabies antigen(s); measles, mumps and/or rubella antigens; influenza antigen(s); an antigen from Moraxella catarrhalis; and/or 22. A composition comprising two or more proteins of any one of claims 1 to 3. |
<SOH> BACKGROUND ART <EOH>Staphylococcus aureus is a Gram-positive spherical bacterium which, on microscopic examination, appears in pairs, short chains, or bunched clusters. Some strains are capable of producing a highly heat-stable protein enterotoxin that causes food poisoning (staphyloenterotoxicosis) in humans. Of particular clinical concern are strains which are resistant to a wide range of antibiotics (‘MRSA’). There is currently no effective vaccine against S.aureus , although a polysaccharide conjugate vaccine is currently undergoing clinical trials (StaphVAX™ from Nabi). It is an object of the invention to provide proteins which can be used in the development of vaccines. Further objects are to provide proteins and nucleic acid which can be used in the diagnosis of S.aureus infection, to provide proteins and nucleic acid which can be used for the detection of S.aureus , to provide nucleic acid which is useful for the expression of S.aureus proteins, and to provide proteins which are useful targets for antibiotic research. detailed-description description="Detailed Description" end="lead"? |
Inhibitors of plasmepsins |
Compounds and methods for the inhibition of anti-malarial target aspartyl protease plasmepsins (e.g. Plasmepsin I, Plasmepsin II, Plasmepsin IV and HAP) are provided. The compounds are based on allophenylnorstatine substituted at positions R1-R4, such that R1 is isoquinoline, carboxyl, naphtalene, phenyl, phenol, benzene, an amino acid, and derivatives thereof; R2 and R3 are aliphatic groups; and R4 is indan, naphthalene, benzylamine, phenyl, phenol, cyclopentane, tert-butylamine, or derivatives thereof. The compounds may be used to inhibit Plasmepsin II, to kill malarial parasites, and to treat malaria in a patient. Certain of the substituted allophenylnorstatine-based compounds also exhibit inhibitory activity against Cathepsin D. |
1. A method of inhibiting a plasmepsin, comprising, exposing said plasmepsin to an allophenylnorstatine-based compound. 2. The method of claim 1 wherein said plasmepsin is selected from the group consisting of Plasmepsin I, Plasmepsin II, Plasmepsin IV, and HAP. 3. The method of claim 1 wherein said plasmepsin is Plasmepsin II. 4. The method of claim 1 wherein said allophenylnorstatine-based compound is substituted at positions R1, R2, R3 and R4 such that R1 is A or A-B, wherein A is selected from the group consisting of a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms which may be substituted by at least one carboxyl group; a 6-membered monocyclic hydrocarbon which may be substituted with a substituent selected from the group consisting of alkyl, amino, alkylamino, arylamino, hydroxy, alkloxy and halogen atom; a bicyclic hydrocarbon having 7-10 carbon atoms which may be substituted by a substituent selected from the group consisting of alkyl, amino, alkylamino, arylamino, hydroxy, alkyloxy and halogen atom; and a monocyclic or bicyclic hydrocarbon wherein more than one carbon atom is substituted; and B is selected from the group consisting of —CO—NH—CH(Ra)—, —CH2—CO—NH(Ra)—, —O—CH2—CO—NH—CH(Ra)—, —OCH2— and —CH2O, wherein Ra is a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms that may be substituted with a substituent selected from the group consisting of alkylthio, hydroxy, aromatic hydrocarbons, and carbamoyl; R2 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; R3 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; and R4 is selected from the group consisting of a linear or branched aliphatic hydrocarbon having 1-10 carbons which can be substituted with a substituent selected from the group consisting of aryl, hydroxyl, alkyloxy, amino, alkylamino and halogen; a monovalent moiety derived from an aromatic mono- or bicyclic hydrocarbon having 12 or fewer carbons, and wherein said moiety, can be substituted by a substituent selected from the group consisting of alkyl, aryl, hydroxyl, alkyloxy, amino, alkylamino, or halogen; a monovalent moiety derived from a heterocycle in which more than one carbon atom is substituted with a hetero atom, wherein said moiety can be substituted by a substituent selected from the group consisting of alkyl, aryl, hydroxyl, alkyloxy, amino, alkylamino, and halogen. 5. The method of claim 4 wherein A is selected from the group consisting of HOOC—CRbRb-CRbRb- wherein Rb is hydrogen or methyl; phenyl; 3-hydroxy-2-methylphenyl; 2,6-dimethylphenyl; 3-chlorophenyl; 3-phenylaminophenyl; 3-dimethylaminophenyl; 1-naphtyl; 2-naphtyl; 2-pyridyl; 5-isoquinolyl; 2-quinolyl; 2-benzofuranyl; and 2-chromonyl; B is selected from the group consisting of —CO—NH—CH(Ra)—, —CH2—CO—NH(Ra)—, —O—CH2—CO—NH—CH(Ra)—, —OCH2— and —CH2O, wherein Ra is propyl, isopropyl, isobutyl, sec-butyl, methylthiomethyl, methylthioethyl, ethylthiomethyl, phenylmethyl, carbamoylethyl, or 1-hydroxyethyl; R2 is hydrogen or methyl; R3 is hydrogen or methyl; and R4 is selected from the group consisting of benzyl; tert-butyl; 2-hydroxybenzyl; 3-hydroxybenzyl; 4-hydroxybenzyl; 2-hydroxyindanylyl; 2-hydroxy-1-phenethyl; 1-indanyl; 2-methoxybenzyl; 3-methoxybenzyl; 4-methoxybenzyl; 4-methoxyphenethyl; 2-methylbenzyl; 3-methylbenzyl; 4-methylbenzyl; naphtyl; and 1-phenethyl. 6. The method of claim 5 wherein said plasmepsin is Plasmepsin II and R1 is selected from the group consisting of 2,6-dimethylphenyl-OCH2—, 3-hydroxy-2 methylphenyl and 5-isoquinolyl-O—CH2—CO—NH—CH(Ra) where Ra is methylthiomethyl; R2 is methyl; R3 is methyl; and R4 is selected from the group consisting of benzyl; tert-butyl; 2-hydroxybenzyl; 3-hydroxybenzyl; (1S, 2R)-2-hydroxyindanyl; (1R,2S)-2-hydroxyindanyl; (S)-2-hydroxy-1-phenethyl; (S)-indanyl; 4-methoxyphenethyl; 2-methylbenzyl; 3-methylbenzyl; naphthyl; and (R)-1-phenethyl. 7. The method of claim 1 wherein said allophenylnorstatine-based compound is a di-peptide. 8. The method of claim 7 wherein R1 is selected from the group consisting of methylphenol. methylated derivatives of carboxyl, and chlorobenzene. 9. The method of claim 1 wherein said allophenylnorstatine-based compound is a tri-peptide. 10. The method of claim 9 wherein R1 is selected from the group consisting of methylphenol, methylated derivatives of carboxyl, chlorobenzene, valine, leucine, isoleucine, methionine, phenylalanine, glutamine, and derivatives thereof. 11. The method of claim 4 wherein R2 and R3 are selected from the group consisting of hydrogen, methyl and ethyl. 12. The method of claim 4 wherein R4 is aminoindanol. 13. The method of claim 4 wherein said allophenylnorstatine-based compound is a tri-peptide and: R1 is isoquinolineoxyacetyl at position P3 and methylthioalanine at position P2, R2 and R3 are methyl, and R4 is selected from the group consisting of (1S,2R)-aminoindanol and tert-butylamine. 14. The method of claim 1 wherein said allophenylnorstatine-based compound exhibits a Ki for Plasmepsin II from P. falciparum in the nanomolar to subnanomolar range. 15. The method of claim 1 wherein said allophenylnorstatine-based compound is selected from the group consisting of KNI-727, KNI-764, KNI-840, KNI-227, KNI-10006, KNI-10026, KNI-10033, KNI-10043 and KNI-10053. 16. The method of claim 1 wherein said plasmepsin is Plasmepsin II that originates from a genus of Plasmodium selected from the group consisting of P. falciparum, P. vivax, P. malariae or P. ovale. 17. A method of killing a malarial parasite comprising, exposing said malarial parasite to an allophenylnorstatine-based compound in a quantity sufficient to inhibit at least one plasmepsin of said malarial parasite and to kill said malarial parasite. 18. The method of claim 17 wherein said malarial parasite is within a red blood cell. 19. The method of claim 17 wherein said malarial parasite is within a host. 20. The method of claim 17 wherein said plasmepsin is selected from the group consisting of Plasmepsin I, Plasmepsin II, Plasmepsin IV, and HAP. 21. The method of claim 17 wherein said plasmepsin is Plasmepsin II. 22. The method of claim 17 wherein said allophenylnorstatine-based compound is substituted at positions R1, R2, R3 and R4 such that R1 is A or A-B, wherein A is selected from the group consisting of a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms which may be substituted by at least one carboxyl group; a 6-membered monocyclic hydrocarbon which may be substituted with a substituent selected from the group consisting of alkyl, amino, alkylamino, arylamino, hydroxy, alkyloxy and halogen atom; a bicyclic hydrocarbon having 7-10 carbon atoms which may be substituted by a substituent selected from the group consisting of alkyl, amino, alkylamino, arylamino, hydroxy, alkyloxy and halogen atom; and a monocyclic or bicyclic hydrocarbon wherein more than one carbon atom is substituted; and B is selected from the group consisting of —CO—NH—CH(Ra)—, —CH2—CO—NH(Ra)—, —O—CH2—CO—NH—CH(Ra)—, —OCH2— and —CH2O, wherein Ra is a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms that may be substituted with a substituent selected from the group consisting of alkylthio, hydroxy, aromatic hydrocarbons, and carbamoyl; R2 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; R3 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; and R4 is selected from the group consisting of a linear or branched aliphatic hydrocarbon having 1-10 carbons which can be substituted with a substituent selected from the group consisting of aryl, hydroxyl, alkyloxy, amino, alkylamino and halogen; a monovalent moiety derived from an aromatic mono- or bicyclic hydrocarbon having 12 or fewer carbons, and wherein said moiety can be substituted by a substituent selected from the group consisting of alkyl, aryl, hydroxyl, alkyloxy, amino, alkylamino, or halogen; a monovalent moiety derived from a heterocycle in which more than one carbon atom is substituted with a hetero atom, wherein said moiety can be substituted by a substituent selected from the group consisting of alkyl, aryl, hydroxyl, alkyloxy, amino, alkylamino, and halogen. 23. The method of claim 17 wherein said allophenylnorstatine-based compound is selected from the group consisting of KNI-727, KNI-764, KNI-840, KNI-227, KNI-10006, KNI-10026, KNI-10033, KNI-10043 and KNI-10053. 24. The method of claim 17 wherein said malarial parasite is selected from the group consisting of P. falciparum, P. viva, P. malariae or P. ovale. 25. A method of treating malaria in a patient in need thereof, comprising, administering to said patient a quantity of an allophenylnorstatine-based compound sufficient to alleviate symptoms of said malaria. 26. The method of claim 25 wherein said allophenylnorstatine-based compound is substituted at positions R1, R2, R3 and R4 such that R1 is A or A-B, wherein A is selected from the group consisting of a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms which may be substituted by at least one carboxyl group; a 6-membered monocyclic hydrocarbon which may be substituted with a substituent selected from the group consisting of alkyl, amino, alkylamino, arylamino, hydroxy, alkyloxy and halogen atom; a bicyclic hydrocarbon having 7-10 carbon atoms which may be substituted by a substituent selected from the group consisting of alkyl, amino, alkylamino, arylamino, hydroxy, alkyloxy and halogen atom; and a monocyclic or bicyclic hydrocarbon wherein more than one carbon atom is substituted; and B is selected from the group consisting of —CO—NH—CH(Ra)—, —CH2—CO—NH(Ra)—, —O—CH2—CO—NH—CH(Ra)—, —OCH2— and —CH2O, wherein Ra is a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms that may be substituted with a substituent selected from the group consisting of alkylthio, hydroxy, aromatic hydrocarbons, and carbamoyl; R2 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; R3 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; and R4 is selected from the group consisting of a linear or branched aliphatic hydrocarbon having 1-10 carbons which can be substituted with a substituent selected from the group consisting of aryl, hydroxyl, alkyloxy, amino, alkylamino and halogen; a monovalent moiety derived from an aromatic mono- or bicyclic hydrocarbon having 12 or fewer carbons, and wherein said moiety can be substituted by a substituent selected from the group consisting of alkyl, aryl, hydroxyl, alkyloxy, amino, alkylamino, or halogen; a monovalent moiety derived from a heterocycle in which more than one carbon atom is substituted with a hetero atom, wherein said moiety can be substituted by a substituent selected from the group consisting of alkyl, aryl, hydroxyl, alkyloxy, amino, alkylamino, and halogen. 27. The method of claim 25 wherein said allophenylnorstatine-based compound is selected from the group consisting of KNI-727, KNI-764, KNI-840, KNI-227, KNI-10006, KNI-10026, KNI-10033, KNI-10043 and KNI-10053. 28. The method of claim 25 wherein said allophenylnorstatine-based compound has high selectivity for plasmepsin rather than Cathepsin D. 29. A method of inhibiting the enzyme Cathepsin D, comprising, exposing said enzyme to an allophenylnorstatine-based compound. cm 30. The method of claim 29 wherein said allophenylnorstatine-based compound is substituted at positions R1, R2, R3 and R4 wherein R1 is 2,6-dimethylphenyl-OCH2— or 5-isoquinolyl-O—CH2—CO—NH—CH(Ra)— wherein Ra is methylthiomethyl; R2 is methyl or hydrogen; R3 is methyl or hydrogen; and R4 is selected from the group consisting of (1S, 2R)-2-hydroxyindanyl; (S)-2-hydroxy-1-phenethyl; (S)-indanyl; and (R)-1-phenethyl. 31. The method of claim 29 wherein said allophenylnorstatine-based compound is substituted at positions R1, R2, R3 and R4 wherein when said allophenylnorstatine-based compound is a dipeptide R1 is carboxyl or a derivative thereof at position P2 and when said allophenylnorstatine-based compound is a tripeptide R1 is chromen-4-one at position P3 or valine at position P3; R2 and R3 are hydrogen; and R4 is selected from the group consisting of indanol and tert-butylamine. 32. The method of claim 29 wherein said allophenylnorstatine-based compound is selected from the group consisting of KNI-391, KNI-10033, KNI-10006 and KNI-840. 33. KNI-10006 34. KNI-10007 35. KNI-10026 36. KNI-10031 37. KNI-10061. 38. KNI-10062. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The invention generally relates to plasmepsin inhibitors and the treatment of malaria. In particular, the invention provides methods and compositions for the use of peptidomimetic allophenylnorstatine based inhibitors of the antimalarial target aspartyl protease Plasmepsin II. More generally, the invention provides compounds and methods for inhibiting plasmepsins (e.g. Plasmepsin I, Plasmepsin II, Plasmepsin IV, HAP) which may provide a number of different pharmaceutical and medical benefits. 2. Background of the Invention Malaria is one of the most serious infectious diseases in the world, affecting close to 300 million individuals each year. It has been estimated that approximately 40% of the world population lives in regions where malaria is endemic. Each year between 1 and 1.5 million people, mainly children, die from malaria, a number that is continuously increasing due to the proliferation of parasites that are resistant to conventional drug therapies (Wyler, 1993). The rapid spread of drug resistant parasites clearly underscores the need for new therapies and consequently the identification of novel targets for drug development. The malaria parasite uses the hemoglobin of the infected victim as a source of nutrients and energy. One of the key enzymes involved in the degradation of hemoglobin is Plasmepsin II, an aspartic protease of 37 kDa. Since the inhibition of this enzyme leads to starvation of the parasite, Plasmepsin II has been acknowledged to be an important target for the development of new antimalarials. Four species of protozoan parasites of the genus Plasmodium ( P. falciparum, P. vivax, P. malariae and P. ovale ) are responsible for malaria in humans; P. vivax is the most common but P. falciparum causes the most fatalities (Butler et al., 1997; Miller et al., 1994). The Plasmodium parasite invades red blood cells and consumes tip to 75% of their hemoglobin content (Goldberg, 1993). The process takes place in an acidic digestive vacuole in the parasite. Three enzymes that digest hemoglobin have been identified in the food vacuole, one cysteine protease (falcipain) and two aspartic proteases (Plasmepsin I and Plasmepsin II) (Francis et al., 1997b). The inhibition of any of these enzymes leads to the starvation of the parasite and has been proposed as a viable strategy for drug development Plasmepsin I and Plasmepsin II are 73% sequence identical. They have different substrate specificities and both contribute to the degradation of hemoglobin. Plasmepsin I is synthesized and processed to a mature form soon after the parasite invades the red blood cell, while the appearance of Plasmepsin II occurs later in development (Francis et al., 1997a). The expression and production of active recombinant Plasmepsin I has been shown to be difficult, yielding a truncated protein that lacks the kinetic properties of the native enzyme (Luker et al., 1996). Plasmepsin U, on the other hand, has been successfully expressed, the recombinant protein behaves identically to the protein isolated from the parasite and its high resolution structure has been determined by x-ray crystallography (Luker et al., 1996; Silva et al., 1996). For those reasons, Plasmepsin II is the target of choice for structure-based drug D5 design, even though the targeting of Plasmepsin I and other plasmepsins is also expected. Plasmepsin II is a protein of 37 kDa (329 amino acids). The crystallographic structure of Plasmepsin II in complex with the generic statine-based aspartic protease inhibitor pepstatin A (IvaValValStaAlaSta) has been obtained at 2.7 Å for the Plasmodium falciparum enzyme (pdb file 1 sme) (Silva et al., 1996) and 2.5 Å for the Plasmodium vivax enzyme (pdb file 1 qs8). Plasmepsin II has the typical bilobal structure and topology of eukaryotic aspartic proteases. The active site is located at the interface between the two lobes and is partially covered by a characteristic β-hairpin structure known as the flap. The secondary structure of Plasmepsin II is predominantly beta with only a small fraction (˜10%) of amino acids in alpha-helix. Even though pepstatin A and other related statine-containing peptides are known to inhibit Plasmepsin II and other aspartic proteases, very few non-peptidic inhibitors have been described. A common problem with these inhibitors is their poor selectivity and discrimination versus the human aspartic protease Cathepsin D. Cathepsin D is a human protease in the endosomal-lysosomal pathway involved in lysosomal biogenesis and protein targeting, it has 35% overall sequence homology and even higher binding site homology with Plasmepsin II, thus representing a target that needs to be avoided in the development of Plasmepsin II inhibitors. Allophenylnorstatine-based compounds have been described before in relation to the development of HIV-1 protease inhibitors (Kiso, 1996; Kiso, 1998; Kiso et al., 1999; Mimoto et al., 1999). These compounds are characterized by containing a unique unnatural amino acid, allophenylnorstatine ((2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) containing a hydroxymethylcarbonyl isostere. Some of these compounds have been shown to be high affinity inhibitors of the HIV-1 protease, they have low toxicity and excellent bioavailability (Kiso, 1996; Kiso, 1998; Kiso et al., 1999; Mimoto et al., 1999). |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides compounds and methods for their use to treat malaria. The compounds work by inhibiting plasmepsins, aspartyl proteases of the malarial parasite that are essential for the parasite's survival. Examples of the Plasmepsins are, for example. Plasmepsin 1, Plasmepsin II, Plasmepsin IV, and HAP. Methods are also provided for inhibiting Plasmepsin proteases, and for killing malarial parasites. The compounds themselves are synthesized based on the allophenylnorstatine “scaffolding” with various functional groups being substituted at positions R1, R2, R3 and R4 of the structure. R1 is A or A-B, wherein A may be a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms which may be substituted by at least one carboxyl group; a 6-membered monocyclic hydrocarbon which may be substituted with a substituent selected from the group consisting of alkyl amino, alkylamino, arylamino, hydroxy, alkyloxy and halogen atom; a bicyclic hydrocarbon having 7-10 carbon atoms which may be substituted by a substituent selected from the group consisting of alkyl, amino, alkylamino, arylamino, hydroxy, alkyloxy and halogen atom; or a monocyclic or bicyclic hydrocarbon wherein more than one carbon atom is substituted; and B is —CO—NH—CH(Ra)—, —CH 2 —CO—NH(Ra)—, —O—CH 2 —CO—NH—CH(Ra)—, —OCH 2 — and —CH 2 O, where Ra is a linear or branched aliphatic hydrocarbon having 1-7 carbon atoms that may be substituted with a substituent such as alkylthio, hydroxy, aromatic hydrocarbons, and carbamoyl; R2 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; R3 is hydrogen or a linear or branched aliphatic hydrocarbon having 1-6 carbons; and R4 is a linear or branched aliphatic hydrocarbon having 1-10 carbons which can be substituted with a substituent such as aryl, hydroxyl, alkyloxy, amino, alkylamino and halogen; a monovalent moiety derived from an aromatic mono- or bicyclic hydrocarbon having 12 or fewer carbons, and wherein said moiety can be substituted by a substituent such as alkyl, aryl, hydroxyl, allkyloxy, amino, alkylamino, or halogen; a monovalent moiety derived from a heterocycle in which more than one carbon atom is substituted with a hetero atom, in which the moiety can be substituted by a substituent such as alkyl, aryl, hydroxyl, alkyloxy, amino, alkylamino, and halogen. In preferred embodiments, A is: HOOC—CRbRb-CRbRb- wherein Rb is hydrogen or methyl; phenyl; 3-hydroxy-2-methylphenyl; 2,6-dimethylphenyl; 3-chlorophenyl; 3-phenylaminophenyl; 3-dimethylaminophenyl; 1-naphtyl; 2-naphtyl; 2-pyridyl; 5-isoquinolyl; 2-quinolyl; 2-benzofuranyl; and 2-chromonyl; and B is —CO—NH—CH(Ra)—, —CH 2 —CO—NH(Ra)—, —O—CH 2 —CO—NH—CH(Ra)—, —OCH 2 — or —CH 2 O, wherein Ra is propyl, isopropyl, isobutyl, sec-butyl, methylthiomethyl, methylthioethyl, methylthiomethyl, phenylmethyl, carbamoylethyl, or 1-hydroxyethyl; R2 is hydrogen or methyl; R3 is hydrogen or methyl; and R4 is benzyl; tert-butyl; 2-hydroxybenzyl; 3-hydroxybenzyl; 4-hydroxybenzyl; 2-hydroxyindanylyl; 2-hydroxy-1-phenethyl; 1-indanyl; 2-methoxybenzyl; 3-methoxybenzyl; 4-methoxybenzyl; 4-methoxyphenethyl; 2-methylbenzyl; 3-methylbenzyl; 4-methylbenzyl; naphtyl; and 1-phenethyl. In yet another preferred embodiment, the allophenylnorstatine-based compound is a di-peptide and R1 is methylphenol, methylated derivatives of carboxyl, or chlorobenzene. Alternatively, the allophenylnorstatine-based compound may be a tri-peptide, in which case R1 may be methylphenol, methylated derivatives of carboxyl, chlorobenzene, valine, leucine, isoleucine, methionine, phenylalanine, glutamine, or derivatives thereof. In preferred embodiments, R2 and R3 are hydrogen, methyl or ethyl, and R4 is aminoindanol. In yet another embodiment, the allophenylnorstatine-based compound is a tri-peptide and: R1 is isoquinolineoxyacetyl at position P3 and methylthioalanine at position P2, R2 and R3 are methyl, and R4 is (1S,2R)-aminoindanol or tert-butylamine. In a preferred embodiment, the allophenylnorstatine-based compound exhibits a Ki for Plasmepsin II from P. falciparum in the nanomolar to subnanomolar range. Representative allophenylnorstatine-based compounds are KNI-727, KNI-764, KNI-840, KNI-227, KNI-10006, KNI-10026, KNI-10033, KNI-10043 and KNI-10053. The plasmepsin which is inhibited may be Plasmepsin II that originates from a genus of Plasmodium , for example, P. falciparum, P. vivax, P. malariae or P. ovale. The present invention also provides a method of killing malarial parasites by exposing them to an allophenylnorstatine-based compound in a quantity sufficient to inhibit at least one plasmepsin of the malarial parasite. The malarial parasite may be within a red blood cell and/or within a host, and may be Plasmepsin I, Plasmepsin II, Plasmepsin IV or HAP. The allophenylnorstatine-based compound may be substituted at positions R1, R2, R3 and R4 as described above for inhibiting plasmepsins. Examples of the allophenylnorstatine-based compounds include KNI-727, KNI-764, KNI-840, KNI-227, KNI-10006, KNI-10026, KNI-10033, KNI-10043 and KNI-10053. The malarial parasite may be from P. falciparum, P. vivax, P. malariae or P. ovale. The present invention also provides a method of treating malaria which comprises administering a quantity of an allophenylnorstatine-based compound sufficient to alleviate the symptoms of malaria. The allophenylnorstatine-based compound may be substituted at positions R1, R2, R3, and R4 as described above for inhibiting plasmepsins. Examples of such compounds include KNI-727, KNI-764, KNI-840, KNI-227, KNI-10006, KNI-10026, KNI-10033, KNI-10043 and KNI-10053. In a preferred embodiment, the allophenylnorstatine-based compound has high selectivity for plasmepsin rather than cathepsin D. The present invention also provides a method of inhibiting the enzyme cathepsin D, comprising, exposing the enzyme to an allophenylnorstatine-based compound. The allophenylnorstatine-based compound may be substituted at positions R1, R2, R3 and R4. R1 may be 2,6-dimethylphenyl-OCH 2 — or 5-isoquinolyl-O—CH 2 —CO—NH—CH(Ra)— in which Ra is methylthiomethyl; R2 may be methyl or hydrogen; R3 may be methyl or hydrogen: and R4 may be (1S, 2R)-2-hydroxyindanyl; (S)-2-hydroxy-1-phenethyl; (S)-indanyl; or (R)-1-phenethyl. Exemplary compounds include KNI-391, KNI-10033, KNI-10006 and KNI-840. The present invention also provides compositions of matter in the form of compounds KNI-10006 ( FIG. 3J ); KNI-10007 ( FIG. 4A ); KNI-10026 ( FIG. 4G ); KNI-10031 ( FIG. 5B ); KNI-10033 ( FIG. 5D ); and KNI-10061, and KNI-10062 ( FIGS. 10A and B). |
Remedies and/or preventives for diabetic ischemic heart diseases |
An agent for therapeutic and/or prophylactic treatment of heart failure or arrhythmia in diabetic ischemic heart disease, which comprises as an active ingredient an aminobenzenesulfonic acid derivative represented by the following general formula (I): (wherein R1 represents, for example, hydrogen atom; R2 represents, for example, hydrogen atom; and n represents an integer of from 1 to 4) or a salt thereof, or a hydrate thereof or a solvate thereof, and an agent for therapeutic and/or prophylactic treatment of diabetic ischemic heart disease wherein said agent improves a cardiac dysfunction in diabetic ischemic heart disease. |
1. A method for therapeutic and/or prophylactic treatment of heart failure or arrhythmia in diabetic ischemic heart disease, which comprises administering to a patient in need thereof a therapeutically effective amount of an aminobenzenesulfonic acid derivative represented by the following general formula (I) (wherein R1 represents hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C4 halogenated alkyl group, a halogen atom, or a C6-C12 aryl group; R2 represents hydrogen atom, a C1-C6 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of cyano group, nitro group, a C1-C6 alkoxy group, a halogen atom, a C1-C6 alkyl group, and amino group; and n represents an integer of from 1 to 4, or a salt thereof, or a hydrate thereof, or a solvate thereof. 2. The method according to claim 1, characterized in that the diabetic ischemic heart disease is diabetic cardiomyopathy. 3. The method according to claim 1, characterized in that said derivative inhibits a leak of calcium ion from sarcoplasmic reticulum in the diabetic ischemic heart disease. 4. A method for therapeutic and/or prophylactic treatment of a disease caused by a leak of calcium ion from sarcoplasmic reticulum, which comprises administering to a patient in need thereof a therapeutically effective amount of an aminobenzenesulfonic acid derivative represented by the following general formula (I) (wherein R1 represents hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C4 halogenated alkyl group, a halogen atom, or a C6-C12 aryl group; R2 represents hydrogen atom, a C1-C6 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of cyano group, nitro group, a C1-C6 alkoxy group, a halogen atom, a C1-C6 alkyl group, and amino group; and n represents an integer of from 1 to 4, or a salt thereof, or a hydrate thereof, or a solvate thereof. 5. A method for therapeutic and/or prophylactic treatment of diabetic ischemic heart disease, which method improves a cardiac dysfunction in diabetic ischemic heart disease, and which comprises administering to a patient in need thereof a therapeutically effective amount of an aminobenzenesulfonic acid derivative represented by the following general formula (I) (wherein R1 represents hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C4 halogenated alkyl group, a halogen atom, or a C6-C12 aryl group; R2 represents hydrogen atom, a C1-C6 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of cyano group, nitro group, a C1-C6 alkoxy group, a halogen atom, a C1-C6 alkyl group, and amino group; and n represents an integer of from 1 to 4, or a salt thereof, or a hydrate thereof, or a solvate thereof. 6. The method according to claim 5, characterized in that the diabetic ischemic heart disease is diabetic cardiomyopathy. 7. The method according to claim 5, characterized in that the cardiac dysfunction is cardiac dysfunction resistant to acidosis. 8. A method for therapeutic and/or prophylactic treatment of a disease caused by a cardiac dysfunction resistant to acidosis, which comprises administering to a patient in need thereof a therapeutically effective amount of an aminobenzenesulfonic acid derivative represented by the following general formula (I) (wherein R1 represents hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C4 halogenated alkyl group, a halogen atom, or a C6-C12 aryl group; R2 represents hydrogen atom, a C1-C6 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of cyano group, nitro group, a C1-C6 alkoxy group, a halogen atom, a C1-C6 alkyl group, and amino group; and n represents an integer of from 1 to 4, or a salt thereof, or a hydrate thereof, or a solvate thereof. 9. The method according to any one of claims 1, 4, 5 or 8, wherein the substitution position of R1 is 5-position. 10. The method according to any one of claims 1, 4, 5 or 8, wherein n is 2. 11. The method according to any one of claims 1, 4, 5 or 8, wherein R2 is hydrogen atom, a C1-C3 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of a C1-C3 alkyl group, a C1-C3 alkoxy group, and a halogen atom. 12. The method according to any one of claims 1, 4, 5 or 8, wherein R2 is hydrogen atom or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of a C1-C3 alkoxy group. 13. The method according to any one of claims 1, 4, 5 or 8, wherein R2 is hydrogen atom. 14. The method according to any one of claims 1, 4, 5 or 8, wherein R1 is hydrogen atom, a C1-C6 alkyl group, a C5-C6 cycloalkyl group, trifluoromethyl group, a halogen atom, or phenyl group. 15. The method according to any one of claims 1, 4, 5 or 8, wherein R1 is a C1-C3 alkyl group, cyclohexyl group, trifluoromethyl group, chlorine atom, bromine atom, or phenyl group. 16. The method according to any one of claims 1, 4, 5 or 8, wherein R1 is methyl group or propyl group. 17. The method according to any one of claims 1, 4, 5 or 8, wherein the derivative is selected from the following compounds: 5-methyl-2-(1-piperazinyl)benzenesulfonic acid; 5-trifluoromethyl-2-(1-piperazinyl)benzenesulfonic acid; 5-n-propyl-2-(1-piperazinyl)benzenesulfonic acid; 5-phenyl-2-(1-piperazinyl)benzenesulfonic acid; 5-chloro-2-(1-piperazinyl)benzenesulfonic acid; 5-bromo-2-(1-piperazinyl)benzenesulfonic acid; 5-isopropyl-2-(1-piperazinyl)benzenesulfonic acid; 5-cyclohexyl-2-(1-piperazinyl)benzenesulfonic acid; 5-n-propyl-2-(1-homopiperazinyl)benzenesulfonic acid; 5-n-propyl-2-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]benzenesulfonic acid; and 5-n-propyl-2-[4-(3,4-dimethoxybenzyl)-1-piperazinyl]benzenesulfonic acid. 18. The method according to claim 17, wherein the derivative is selected from the following compounds: 5-methyl-2-(1-piperazinyl)benzenesulfonic acid; and 5-n-propyl-2-(1-piperazinyl)benzenesulfonic acid. 19. The method according to any one of claims 1, 4, 5 or 8, wherein the derivative is 5-methyl-2-(1-piperazinyl)benzenesulfonic acid monohydrate. 20. A method for inhibiting a leak of calcium ion from sarcoplasmic reticulum in diabetic ischemic heart disease, which comprises administering to a patient in need thereof a therapeutically effective amount of an aminobenzenesulfonic acid derivative represented by the following general formula (I) (wherein R1 represents hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C4 halogenated alkyl group, a halogen atom, or a C6-C12 aryl group; R2 represents hydrogen atom, a C1-C6 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of cyano group, nitro group, a C1-C6 alkoxy group, a halogen atom, a C1-C6 alkyl group, and amino group; and n represents an integer of from 1 to 4, or a salt thereof, or a hydrate thereof, or a solvate thereof. 21. A method for acidosis-resistant improvement of cardiac dysfunction in diabetic ischemic heart disease, which comprises administering to a patient in need thereof a therapeutically effective amount of an aminobenzenesulfonic acid derivative represented by the following general formula (I) (wherein R1 represents hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C4 halogenated alkyl group, a halogen atom, or a C6-C12 aryl group; R2 represents hydrogen atom, a C1-C6 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of cyano group, nitro group, a C1-C6 alkoxy group, a halogen atom, a C1-C6 alkyl group, and amino group; and n represents an integer of from 1 to 4, or a salt thereof, or a hydrate thereof, or a solvate thereof. 22. The method according to claim 20 or 21, wherein the substitution position of R1 is 5-position. 23. The method according to claim 20 or 21, wherein n is 2. 24. The method according to claim 20 or 21, wherein R2 is hydrogen atom, a C1-C3 alkyl group, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of a C1-C3 alkyl group, a C1-C3 alkoxy group, and a halogen atom. 25. The method according to claim 20 or 21, wherein R2 is hydrogen atom, or a C7-C12 aralkyl group which may have one or more substituents selected from the group consisting of a C1-C3 alkoxy group. 26. The method according to claim 20 or 21, wherein R2 is hydrogen atom. 27. The method according to claim 20 or 21, wherein R1 is hydrogen atom, a C1-C6 alkyl group, a C5-C6 cycloalkyl group, trifluoromethyl group, a halogen atom, or phenyl group. 28. The method according to claim 20 or 21, wherein R1 is a C1-C3 alkyl group, cyclohexyl group, trifluoromethyl group, chlorine atom, bromine atom, or phenyl group. 29. The method according to claim 20 or 21, wherein R1 is methyl group or propyl group. 30. The method according to claim 20 or 21, wherein the derivative is selected from the following compounds: 5-methyl-2-(1-piperazinyl)benzenesulfonic acid; 5-trifluoromethyl-2-(1-piperazinyl)benzenesulfonic acid; 5-n-propyl-2-(1-piperazinyl)benzenesulfonic acid; 5-phenyl-2-(1-piperazinyl)benzenesulfonic acid; 5-chloro-2-(1-piperazinyl)benzenesulfonic acid; 5-bromo-2-(1-piperazinyl)benzenesulfonic acid; 5-isopropyl-2-(1-piperazinyl)benzenesulfonic acid; 5-cyclohexyl-2-(1-piperazinyl)benzenesulfonic acid; 5-n-propyl-2-(1-homopiperazinyl)benzenesulfonic acid; 5-n-propyl-2-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]benzenesulfonic acid; and 5-n-propyl-2-[4-(3,4-dimethoxybenzyl)-1-piperazinyl]benzenesulfonic acid. 31. The method according to claim 30, wherein the derivative is selected from the following compounds: 5-methyl-2-(1-piperazinyl)benzenesulfonic acid; and 5-n-propyl-2-(1-piperazinyl)benzenesulfonic acid. 32. The method according to claim 20 or 21, wherein the derivative is 5-methyl-2-(1-piperazinyl)benzenesulfonic acid monohydrate. |
<SOH> BACKGROUND ART <EOH>It is known that cardiac myocytes are damaged along progress of diabetes, which later leads to cardiomyopathy or heart failure. A leak of calcium ion from sarcoplasmic reticulum in a cardiac myocyte arises to increase a concentration of free calcium ion to induce a systolic and diastolic dysfunction or arrhythmia is considered to be a cause of the damage. Therefore, a medicament which inhibits the leak of calcium ion from sarcoplasmic reticulum is expected to have a high therapeutic effect on heart failure or arrhythmia in diabetic cardiomyopathy. However, no medicament which directly inhibits a leak of calcium ion from sarcoplasmic reticulum has been known so far. Resistances against acidosis due to ischemia or the like is significantly decreased in patients with diabetes. For example, when patients with diabetes have ischemic heart disease such as myocardial infarction, mortality significantly increases because of severe heart failure. An exacerbated cardiac dysfunction due to decreased action of calcium ion on contractile protein system caused by acidosis is considered to be a cause of decreased resistance. For a therapeutic treatment of the aforementioned disease, positive inotropic effect by cardiotonic agents and a cardiac protection by ACE inhibitors have been expected to be useful. However, an improvement of contractility by cardiotonic agents in the acidosis was not so effective as expected. In addition, improvement of cardiac function by ACE inhibitors has not been sufficient, because the effect of ACE inhibitors is not improvement of cardiac function but secondary to cardiac protection. Therefore, a medicament for improving a cardiac dysfunction in diabetic ischemic heart disease, which is resistant to acidosis, has been desired. Aminobenzenesulfonic acid derivatives, which have inhibitory action on excessive accumulation of intracellular calcium ions in cardiac muscle and vascular smooth muscle, are known (Japanese Patent Unexamined Publication (KOKAI) No. Hei 3-7263). As for these compounds, publications disclose that they inhibit or reduce a myocardial injury, cardiac conduction system disorder and the like, without a β receptor stimulator-like action, a β receptor antagonist-like action, a calcium channel antagonist-like action, and thus they could be potential agents useful for prophylactic or therapeutic treatment for ischemic heart disease, heart failure, hypertension, arrhythmia, and the like (Japanese Patent Unexamined Publication (KOKAI) No. Hei 3-7263 and Japanese Patent Unexamined Publication (KOKAI) No. Hei 4-139127). Japanese Patent Unexamined Publication (KOKAI) No. Hei 10-298077 discloses that the aforementioned compounds have an action of significantly improving cardiac dysfunction under pathological condition of cardiomyopathy and improving long-term survival rate in idiopathic cardiomyopathy to achieve apothanasia; and WO99/40919 discloses that the aforementioned compounds have an action of enhancing calcium ion uptake into cardiac sarcoplasmic reticulum, and thus they are useful for therapeutic and/or prophylactic treatment of diastolic dysfunction. However, these publications neither suggest nor instruct that the aforementioned compounds have an inhibitory action against the leak of calcium ion from sarcoplasmic reticulum in a diabetic ischemic heart disease, which has not been known for any conventional medicaments. Further, these publications neither suggest nor instruct that the aforementioned compound have an acidosis-resistant action of improving cardiac dysfunction in diabetic ischemic heart disease, which has not been known for any conventional medicaments. An object of the present invention is to provide a medicament for improving cardiac dysfunction in a diabetic ischemic heart disease. More specifically, the object is to provide a medicament for acidosis-resistant improvement of cardiac dysfunction in diabetic ischemic heart disease. In addition, the object of the present invention is to provide a medicament for therapeutic and/or prophylactic treatment of heart failure or arrhythmia in a diabetic ischemic heart disease. More specifically, the object of the present invention is to provide a medicament which has an action of inhibiting a leak of calcium ion from sarcoplasmic reticulum in diabetic ischemic heart disease, and thus having a high therapeutic and/or prophylactic effect for heart failure or arrhythmia in diabetic ischemic heart disease. |
Treatment of restenosis |
This invention relates to a method for inhibiting expression or activity of an adhesion molecule associated with an endothelial cell by contacting the adhesion molecule or endothelial cell with one or more isoflavone compounds or derivatives thereof. The invention also relates to a method of preventing or reducing the risk of restenosis after angioplasty, and to a method for the treatment or prophylaxis of atherosclerosis, coronary artery diseases, other cardiovascular diseases and inflammatory diseases mediated by adhesion molecules. The invention further relates to pharmaceutical compositions useful in these methods, and to methods for the manufacture of such medicaments. |
1. A method for inhibiting expression or activity of an adhesion molecule associated with an endothelial cell, which method comprises the step of contacting the adhesion molecule or endothelial cell with one or more compounds of formula I in an amount sufficient to inhibit said expression or activity, wherein formula I is represented by: in which R1, R2 and Z are independently hydrogen, hydroxy, OR9, OC(O)R10, OS(O)R10, CHO, C(O)R10, COOH, CO2R10, CONR3R4, alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, or R2 is as previously defined, and R1 and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from R1 is as previously defined, and R2 and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from and W is R1, A is hydrogen, hydroxy, NR3R4 or thio, and B is selected from W is R1, and A and B taken together with the carbon atoms to which they are attached form a six-membered ring selected from W, A and B taken together with the groups to which they are associated are selected from W and A taken together with the groups to which they are associated are selected from and B is selected from wherein R3 is hydrogen, alkyl, arylalkyl, alkenyl, aryl, an amino acid, C(O)R11 where R11 is hydrogen, alkyl, aryl, arylalkyl or an amino acid, or CO2R12 where R12 is hydrogen, alkyl, haloalkyl, aryl or arylalkyl, R4 is hydrogen, alkyl or aryl, or R3 and R4 taken together with the nitrogen to which they are attached comprise pyrrolidinyl or piperidinyl, R5 is hydrogen, C(O)R11 where R11 is as previously defined, or CO2R12 where R12 is as previously defined, R6 is hydrogen, hydroxy, alkyl, aryl, amino, thio, NR3R4, COR11 where R11 is as previously defined, CO2R12 where R12 is as previously defined or CONR3R4, R7 is hydrogen, C(O)R11 where R11 is as previously defined, alkyl, haloalkyl, alkenyl, aryl, arylalkyl or Si(R13)3 where each R13 is independently hydrogen, alkyl or aryl, R8 is hydrogen, hydroxy, alkoxy or alkyl, R9 is alkyl, haloalkyl, aryl, arylalkyl, C(O)R11 where R11 is as previously defined, or Si(R13)3 where R13 is as previously defined, R10 is hydrogen, alkyl, haloalkyl, amino, aryl, arylalkyl, an amino acid, alkylamino or dialkylamino, the drawing represents either a single bond or a double bond, T is independently hydrogen, alkyl or aryl, X is O, NR4 or S, and Y is wherein R14, R15 and R16 are independently hydrogen, hydroxy, OR9, OC(O)R10, OS(O)R10, CHO, C(O)R10, COOH, CO2R10, CONR3R4, alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, including pharmaceutically acceptable salts thereof. 2. A method of claim 1, wherein the compounds of formula I are represented by formulae II-VIII: in which R1, R2, R5, R6, R14, R15, W and Z are as defined above, in claim 1, including pharmaceutically acceptable salts thereof. 3. A method of claim 2, wherein R1, R2, R14, R15, W and Z are independently hydrogen, hydroxy, OR9, OC(O)R10, C(O)R10, COOH, CO2R10, alky, haloalkyl, arylalkyl, aryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, R5 is hydrogen, C(O)R11 where R11 is hydrogen, alky, aryl, or an amino acid, or CO2R12 where R12 is hydrogen, alkyl or aryl, R6 is hydrogen, hydroxy, alkyl, aryl, COR11 where R11 is as previously defined, or CO2R12 where R12 is as previously defined, R9 is alkyl, haloalkyl, arylalkyl, or C(O)R11 where R11 is as previously defined, and R10 is hydrogen, alkyl, amino, aryl, an amino acid, alkylamino or dialkylamino, including pharmaceutically acceptable salts thereof. 4. A method of claim 2, wherein R1 and R14 are independently hydroxy, OR9, OC(O)R10 or halo, R2, R15, W and Z are independently hydrogen, hydroxy, OR9, OC(O)R10, C(O)R10, COOH, CO2R10, alkyl, haloalkyl, or halo, R5 is hydrogen, C(O)R11 where R11 is hydrogen or alkyl, or CO2R12 where R12 is hydrogen or alkyl, R6 is hydrogen or hydroxy, R9 is alkyl, arylalkyl or C(O)R11 where R11 is as previously defined, and R10 is hydrogen or alkyl, including pharmaceutically acceptable salts thereof. 5. A method of claim 2, wherein R1 and R14 are independently hydroxy, methoxy, benzyloxy, acetyloxy or chloro, R2, R15, W and Z are independently hydrogen, hydroxy, methoxy, benzyloxy, acetyloxy, methyl, trifuoromethyl or chloro, R5 is hydrogen or CO2R12 where R12 is hydrogen or methyl, and R6 is hydrogen, including pharmaceutically acceptable salts thereof. 6. A method of claim 1, wherein the compounds of formula I are selected from: including pharmaceutically acceptable salts thereof. 7. A method of any of claims 1 to 6, wherein the adhesion molecule is E-selectin or vascular cell surface adhesion molecule (VCAM-1). 8. A method for inhibiting the expression or activity of adhesion molecules associated with endothelial cells in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I as defined in any of claims 1 to 6. 9. A method of claim 8, wherein the adhesion molecule is E-selectin or vascular cell surface adhesion molecule (VCAM-1). 10. A method of claim 8 or claim 9, wherein the subject is a human. 11. A method of treating a disease mediated by expression or activity of adhesion molecules associated with endothelial cells in a subject, which method comprises the step of administering to, the subject one or more compounds of formula I as defined in any of claims 1 to 6 in an amount sufficient to inhibit said expression of activity of the adhesion molecules associated with the endothelial cells. 12. A method of claim 11, wherein the disease is a vascular disease. 13. A method of claim 12, wherein the vascular disease is selected from restenosis, inflammatory disease, coronary artery disease, angina and small vessel disease. 14. A method of claim 13, wherein the vascular disease is post-angioplasty restenosis. 15. A method for the treatment, amelioration, prophylaxis or reduction in the risk of restenosis in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I as defined in any of claims 1 to 6. 16. A method of claim 15, wherein the restenosis is associated with vascular intervention selected from percutaneous transluminal coronary angioplasty, direction coronary atherectomy and stent. 17. A method for the treatment of procedural vascular trauma in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I as defined in any of claims 1 to 6. 18. A method of claim 17, wherein the procedural vascular trauma is selected from angioplasty, vascular surgery, graft and transplant procedure. 19. A method for the treatment or prophylaxis of vascular disease in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I as defined in any of claims 1 to 6. 20. A method of claim 19, wherein the vascular disease is selected from atherosclerosis, restenosis, hypertension, inflammatory disease, coronary artery disease, angina and small vessel disease. 21. A method of claim 20, wherein the vascular disease is post-angioplasty restenosis. 22. A pharmaceutical composition in a dosage form suitable for use in the treatment of a disease mediated by expression or activity of adhesion molecules associated with endothelial cells in a subject, which composition comprises one or more compounds of formula I as defined in any of claims 1 to 6 in association with a pharmaceutical acceptable carrier. 23. A pharmaceutical composition in a dosage form suitable for use in preventing or reducing the risk of vascular disease in a subject, which composition comprises one or more compounds of formula I as defined in any of claims 1 to 6 in association with a pharmaceutical acceptable carrier. 24. Use of one or more compounds of formula I as defined in any of claims 1 to 6 in the manufacture of a medicament for inhibiting the expression or activity of adhesion molecules associated with endothelial cells in a subject. 25. Use of one or more compounds of formula I as defined in any of claims 1 to 6 in the manufacture of a medicament for the treatment of a disease mediated by expression or activity of adhesion molecules associated with endothelial cells. 26. Use of one or more compounds of formula I as defined in any of claims 1 to 6 in the manufacture of a medicament for the treatment, amelioration, prophylaxis or reduction in the risk of restenosis. 27. Use of one or more compounds of formula I as defined in any of claims 1 to 6 in the manufacture of a medicament for the treatment of vascular disease and/or procedural vascular trauma. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Note: Bibliographic details of the publications referred to by author in this specification are colleted at the end of the description. Atherosclerosis is a chronic inflammatory disease of the arterial intima characterised by the focal accumulation of leukocytes, smooth muscle cells, lipids and extra cellular matrix. Deposits of lipids and other blood derivatives in blood vessel walls, especially of the large arteries, results in the formation of plaques. As the adherence of lipids and leukocytes to the blood vessel wall continues, there is a concomitant thickening of the vessel wall. The size increase of the plaque gains a stenosing character which becomes responsible for vascular occlusions by atheroma, thrombosis or embolism. Serious vascular problems can result including infarction, cardiac insufficiency, stroke and sudden death. An important predisposing factor to the development of atherosclerosis is the level of cholesterol in the blood. Atheromatous plaque is composed primarily of cells containing cholesterol; consequently a high blood cholesterol level is associated with increased risk of atherosclerosis. While a high absolute cholesterol level is an important risk factor, the risk is more specifically associated with the type of lipoprotein present in the blood. The widespread medical view is that in terms of risk of development of atherosclerosis, low density (LDL) and very low density (VLDL) lipoproteins are detrimental, whereas high density lipoprotein (HDL) has been shown to be a beneficial factor. It follows that the ratio of HDL to LDL in the blood stream is the important factor. The higher the ratio of HDL to LDL, the more a patient appears to be protected against developing atherosclerosis, even if their total cholesterol level is slightly elevated. Clinical studies conducted in many centres and countries support this view. Many clinical and epidemiological studies have identified a high blood level of total cholesterol, and more particularly a high blood level of low density cholesterol, and more particularly a high LDL:HDL cholesterol ratio, as prime risk factors in the development of atherosclerosis. This has led to a variety of therapeutic strategies designed to reduce this risk. There are two broad strategies which show varying degrees of success. The first is the use of drugs that interfere with cholesterol synthesis. The second strategy is to reduce cholesterol absorption from the gut by the use of resins, thereby reducing the pool of cholesterol available within the body. Generally though, neither of these two strategies is optimal because of resulting adverse side effects and limited efficacy. The development of atherosclerosis is progressed by the oxidation of LDL cholesterol in the arterial wall, leading to an inflammatory lesion. If left unchecked the inflammatory process proceeds until the lesion causes vascular construction, obstruction and infarct. Antioxidants are molecules or compounds that can inhibit oxidation (i.e. damage) by chemically inactivating the free radicals produced during normal physiological function. If the body is lacking in a supply of antioxidants, some free radicals remain active and attack healthy cells or convert safe compounds into damaging ones. Antioxidants play many important roles in cardiovascular disease. They have attracted particular interest as potential inhibitors of atherosclerosis via inhibition of the oxidative modification of the low density lipoprotein (LDL). Lipoproteins are the major carriers of cholesterol in the body. The majority of the cholesterol associates with LDL to be distributed throughout the body from the liver. The high density lipoprotein (HDL) “mops up” excess cholesterol present in the blood and returns it to the liver. Lipoproteins are very susceptible to oxidation, and once oxidised can accumulate in healthy arterial and vascular walls without being metabolised. Such gathering of lipoproteins greatly increases the risk of atherosclerosis. In particular, the oxidation of LDL in the sub-endothelial space represent an early and causative step in atherogenesis (Steinberg et al., 1989). Thus inhibition of ‘oxidized LDL’ formation by antioxidants is generally thought to slow down the progression of the disease. This is another area of protection in cardiovascular disease that cardioprotective agents can have utility, and in which more and better agents are sought. Another area in the development of vascular disease and the formation of plaques is the role played by cell adhesion molecules, as reviewed by Hillis and Flapan (1998). Cell adhesion molecules are involved in the adhesion of leukocytes and monocytes to tissues including the vascular endothelium. Known cell adhesion molecules include intercellular adhesion molecules (ICAM 1, 2 and 3), vascular cell-adhesion molecule-1 (VCAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1). The role of adhesion molecules in the pathogenesis of cardiovascular disease is supported by the observation that cell adhesion molecules are expressed in atherosclerotic lesions. In addition, cell adhesion molecules are upregulated by several coronary heart disease risk factors and antibodies to cell adhesion molecules are believed to prevent reperfusion injury in animal models. Accordingly, modulation of the expression or activity of adhesion molecules associated with endothelial cells may be useful in the treatment or prevention of cardiovascular pathology by limiting the development of atherosclerotic plaque. Other molecules such as E-selectin, P-selectin and L-selectin exhibit an adhesion function. In particular, E-selectin is a cell surface protein inducibly expressed in cytokine-activated endothelial cells in response to inflammatory factors such as occurs with tissue injury. The expression of E-selectin by endothelial cells can also be induced by inflammatory factors including interleukin-1 (IL-1), tumour necrosis factor-α (TNF-α) and various endotoxins. Expression of E-selectin is associated with the binding of endothelial cells and platelets with leukocytes and lipids. The binding of leukocytes to endothelial cells is observed at an early stage after tissue injury and is associated with various acute and chronic inflammation. Suppression or inhibition of the expression or activity of adhesion molecules associated with endothelial cells will limit the focal accumulation and adhesion of leukocytes to vessel walls, particularly at areas of injury, damage or infection. In the treatment of atherosclerosis, angioplasty has been developed to permit non-surgical intervention of the atherosclerotic plaque. During angioplasty treatment dilation of the blood vessel beyond its ability to recoil completely with a balloon catheter increases the vessel lumen, thereby allowing for increased blood flow. This procedure however causes mechanical injury of the arterial wall, following which restenosis commonly occurs. In fact, restenosis is a major problem following traumatic injury rendered to vessels during vascular surgery and treatment. To counter the onset of restenosis, various other treatments have been proposed including surgical intervention and drug and gene therapy. Such therapies include the administration of compounds which arrest cell division and hyperproliferative disorders, necrose vascular smooth-muscle cells and block the expression of endothelial cell adhesion molecules. Further compounds useful in addressing restenosis include lipid lowering agents, anti-platelet agents, anti-thrombotic agents, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors and β-blockers. Generally though, as therapeutic agents are not selective, there are often side effects which need to be monitored or countered. In this regard reference is made to drugs currently in use such as Ticlid (ticlopidine), Plavix (clopidrogel) and Cardiprin (aspirin). Typically gastrointestinal disturbances and skin rashes are commonly reported side effects with their use. Other agents such as heparin reportedly inhibits smooth muscle cell proliferation in vitro but when used in vivo has the adverse side effect of inhibiting coagulation. Given that vascular disease is currently a leading cause of death in today's society, there is a strong need to identify new, improved, better and alternative methods and pharmaceutical agents for its treatment and prevention. Thus it is a preferred object of the present invention to provide a method for the treatment, amelioration or prophylaxis of vascular and inflammatory diseases, and in particular restenosis associated with vascular intervention. It is a further preferred object of the present invention to provide pharmaceutical compositions for the treatment, amelioration or prophylaxis of vascular and inflammatory diseases, in particular cardiovascular diseases. It is still another preferred object of the present invention to provide methods and compositions to inhibit the expression or activity of adhesion molecules in endothelial cells. |
<SOH> SUMMARY OF THE INVENTION <EOH>Surprisingly the present inventors have found that isoflavone compounds, metabolites and derivatives thereof are particularly useful for inhibiting or down-regulating the expression or activity of adhesion molecules in endothelial cells. It has also been found that isoflavones and derivatives thereof are particularly useful for inhibiting endothelial cell surface adhesion molecules, and in particular E-selectin and VCAM-1. The present inventors have also surprisingly found that isoflavones and derivatives thereof find use in preventing or reducing the risks of restenosis associated with vascular intervention including angioplasty treatment of atherosclerosis, and the resultant mechanical injury at the angioplasty site during treatment of an atherosclerotic lesion. Isoflavone compounds, metabolites, derivatives and analogues thereof useful in the methods of the present invention are depicted by the general formula I as set out below. Thus, according to a first aspect of the invention there is provided a method for inhibiting expression or activity of an adhesion molecule associated with an endothelial cell, which method comprises the step of contacting the adhesion molecule or endothelial cell with one or more compounds of formula I in an amount sufficient to inhibit said expression or activity. Preferably the adhesion molecule is E-selectin or vascular cell surface adhesion molecule (VCAM-1). According to a second aspect of the invention there is provided a method for inhibiting the expression or activity of adhesion molecules associated with endothelial cells in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I. According to a third aspect of the invention there is provided a method of treating a disease mediated by expression or activity of adhesion molecules associated with endothelial cells in a subject, which method comprises the step of administering to the subject one or more compounds of formula I in an amount sufficient to inhibit said expression or activity of the adhesion molecules associated with the endothelial cells. Preferably the disease is a vascular disease including restenosis, inflammatory disease, coronary artery disease, angina or small vessel disease, more preferably post-angioplasty restenosis. According to a fourth aspect of the invention there is provided a method for the treatment, amelioration, prophylaxis or reduction in the risk of restenosis in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I. Typically the restenosis is associated with vascular intervention such as coronary intervention. Preferably the vascular coronary intervention is percutaneous transluminal coronary angioplasty, direction coronary atherectomy or stent, more preferably angioplasty. According to a fifth aspect of the invention there is provided a method for the treatment of procedural vascular trauma in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I. Preferably the procedural vascular trauma is angioplasty, vascular surgery, graft or transplant procedure. According to a sixth aspect of the invention there is provided a method for the treatment or prophylaxis of vascular disease in a subject, which method comprises the step of administering to the subject a therapeutically effective amount of one or more compounds of formula I. Preferably the vascular disease is restenosis, inflammatory disease, coronary artery disease, angina or small vessel disease, more preferably post-angioplasty restenosis. According to a seventh aspect of the invention there is provided a pharmaceutical composition in a dosage form suitable for use in the treatment of a disease mediated by expression or activity of adhesion molecules associated with endothelial cells in a subject, which composition comprises one or more compounds of formula I in association with a pharmaceutical acceptable carrier. According to an eighth aspect of the invention there is provided a pharmaceutical composition in a dosage form suitable for use in preventing or reducing the risk of vascular disease in a subject, which composition comprises one or more compounds of formula I in association with a pharmaceutical acceptable carrier. According to a ninth aspect of the invention there is provided the use of one or more compounds of Formula I in the manufacture of a medicament for the treatment of a disease mediated by expression or activity of adhesion molecules associated with endothelial cells. According to a tenth aspect of the invention there is provided the use of one or more compounds of formula I in the manufacture of a medicament for the treatment of vascular disease and/or procedural vascular trauma. These and other aspects of the invention will become evident from the description and claims which follow, together with the accompanying drawings. Throughout this specification and the claims which follow, unless the text requires otherwise, the word “comprise”, and variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. |
N-phenylarylsulfonamide compound drug containing the compound as active ingredient intermediate for the compound and processes for producing the same |
An N-phenylarylsulfonylamide compound of formula (I) (R1 is COOH etc.; R2 is hydrogen, methyl, etc.; R3 and R4 are a combination of methyl and methyl, etc.; R5 is isopropyl etc.; Ar is thiazolyl, pyridyl, 5-methyl-2-furyl each optionally substituted with methyl; n is zero or 1), a synthetic intermediate for the compound and a process for its preparation. The compound of formula (I) binds to a prostaglandin E2 receptor, especially an EP1 subtype receptor, and antagonizes it. It is less affected by protein binding, so it has a satisfactory in vivo activity. Therefore, it is considered to be useful as an analgesic, an antipyretic agent, an agent for the treatment of pollakiuria (frequent urination) and/or lower urinary tract disease syndrome or an antineoplastic agent. |
1. An N-phenylarylsulfonylamide compound of formula (I) wherein R1 is COOH, 5-tetrazolyl, 5-oxo-1,2,4-oxadiazolyl, CH2OH or 5-oxo-1,2,4-thiadiazolyl; R2 is hydrogen, methyl, methoxy or chloro; R3 and R4 are a combination of (1) methyl and methyl, (2) methyl and chloro, (3) chloro and methyl, or (4) trifluoromethyl and hydrogen; or R3 and R4 are taken together with the carbon to which R3 and R4 are attached to form (5) cyclopentene, (6) cyclohexene or (7) benzene ring; R5 is isopropyl, isobutyl, 2-methyl-2-propenyl, cyclopropylmethyl, methyl, ethyl, propyl, 2-propenyl or 2-hydroxy-2-methylpropyl; Ar is thiazolyl optionally substituted with methyl, pyridyl or 5-methyl-2-furyl; and n is zero or 1, and when R1 is 5-tetrazolyl, 5-oxo-1,2,4-oxadiazolyl or 5-oxo-1,2,4-thiadiazolyl, n is zero, an alkyl ester thereof or a non-toxic salt thereof. 2. The compound according to claim 1, wherein Ar is 5-methyl-2-furyl, 2-thiazolyl, 5-methyl-2-thiazolyl, 2-pyridyl or 3-pyridyl. 3. The compound according to claim 1, wherein Ar is 5-methyl-2-furyl. 4. The compound according to claim 1 or 3, which is selected from the group consisting of (1) 4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (2) 4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (3) 4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (4) 4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (5) 4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (6) 4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (7) 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (8) 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (9) 3-chloro-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (10) 3-chloro-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (11) 3-methoxy-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (12) 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (13) 3-methoxy-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (14) 3-methoxy-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (15) 3-methoxy-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (16) 3-chloro-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (17) 3-chloro-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (18) 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]cinnamic acid, (19) 4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (20) 4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (21) 4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (22) 3-methyl-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (23) 3-methyl-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (24) 3-methyl-4-[2-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (25) 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (26) 4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (27) N-[4-chloro-5-methyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, (28) 3-methoxy-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (29) N-[4,5-dimethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, (30) N-[4,5-dimethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(5-methyl-2-furyl)sulfonylamide, (31) N-[4-chloro-5-methyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, N-[4-chloro-5-methyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-(5-methyl-2-furyl)sulfonylamide, (33) N-[4-chloro-5-methyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, (34) 4-[6-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (35) 4-[6-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (36) 4-[7-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-1,2,3,4-tetrahydronaphtharen-6-yloxymethyl]benzoic acid, (37) 4-[7-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]-1,2,3,4-tetrahydronaphtharen-6-yloxymethyl]benzoic acid, (38) N-[4,5-dimethyl-2-[2-methyl-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-(5-methyl-2-furyl)sulfonylamide, (39) N-[4,5-dimethyl-2-[2-methyl-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, (40) N-[4,5-dimethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(5-methyl-2-furyl)sulfonylamide, (41) N-[4,5-dimethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, (42) N-[4,5-dimethyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, (43) 3-methyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (44) N-[4,5-dimethyl-2-[2-methoxy-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(5-methyl-2-furyl)sulfonylamide, (45) N-[4,5-dimethyl-2-[2-methoxy-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-(5-methyl-2-furyl)sulfonylamide, (46) 4-[6-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (47) 3-methyl-4-[6-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (48) 3-methyl-4-[6-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (49) 4-[2-[N-(2-methyl-2-propenyl)-N-(5-methyl-2-furylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (50) 3-methyl-4-[6-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (51) 3-methyl-4-[6-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (52) 4-[6-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (53) 4-[3-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-2-naphthyloxymethyl]benzoic acid, (54) 3,5-dimethyl-4-[2-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (55) 3-methyl-4-[6-[N-(2-methyl-2-propenyl)-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (56) 4-[6-[N-cyclopropylmethyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]-3-methylbenzoic acid, (57) 4-[6-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]-3-methylbenzylalcohol, (58) 3-methyl-4-[6-[N-methyl-N-(5-methyl-2-furylsulfonyl)amino] indan-5-yloxymethyl]benzoic acid, (59) 4-[6-[N-ethyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]-3-methylbenzoic acid, (60) 4-[6-[N-methyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (61) 4-[6-[N-ethyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (62) 4-[6-[N-propyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (63) 4-[4,5-dimethyl-2-[N-(2-methyl-2-propenyl)-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (64) 4-[6-[N-(2-methyl-2-propenyl)-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (65) 4-[6-[N-cyclopropylmethyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (66) 4-[6-[N-(2-propenyl)-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (67) 3-methyl-4-[6-[N-propyl-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (68) 3-methyl-4-[6-[N-(2-propenyl)-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (69) 4-[4,5-dimethyl-2-[N-methyl-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]benzoic acid, (70) 4-[4,5-dimethyl-2-[N-ethyl-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]benzoic acid, (71) 4-[4,5-dimethyl-2-[N-(5-methyl-2-furylsulfonyl)-N-propylamino]phenoxymethyl]benzoic acid, (72) 4-[3-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]naphtharen-2-yloxymethyl]-3-methylbenzoic acid, (73) 4-[3-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]naphtharen-2-yloxymethyl]-3-methylbenzoic acid, (74) 4-[3-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]naphtharen-2-yloxymethyl]cinnamic acid, (75) 4-[3-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]naphtharen-2-yloxymethyl]cinnamic acid, (76) 3-methyl-4-[3-[N-isopropyl-N-(5-methyl-2-furylsulfonyl)amino]naphtharen-2-yloxymethyl]cinnamic acid, (77) 3-methyl-4-[3-[N-isobutyl-N-(5-methyl-2-furylsulfonyl)amino]naphtharen-2-yloxymethyl]cinnamic acid, (78) 4-[4,5-dimethyl-2-[N-[(5-methyl-2-furyl)sulfonyl]-N-2-propenylamino]phenoxymethyl]benzoic acid, (79) 4-[4,5-dimethyl-2-[N-methyl-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (80) 4-[4,5-dimethyl-2-[N-ethyl-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (81) 4-[4,5-dimethyl-2-[N-(5-methyl-2-furylsulfonyl)-N-propylamino]phenoxymethyl]-3-methylbenzoic acid, (82) 4-[4,5-dimethyl-2-[N-(5-methyl-2-furylsulfonyl)-N-(2-propenyl)amino]phenoxymethyl]-3-methylbenzoic acid, (83) 4-[4,5-dimethyl-2-[N-(2-hydroxy-2-methylpropyl)-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (84) 4-[6-[N-(2-hydroxy-2-methylpropyl)-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]-3-methylbenzoic acid, (85) 4-[4,5-dimethyl-2-[N-cyclopropylmethyl-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]benzoic acid, (86) 4-[4,5-dimethyl-2-[N-(2-hydroxy-2-methylpropyl)-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]benzoic acid, (87) 4-[6-[N-(2-hydroxy-2-methylpropyl)-N-(5-methyl-2-furylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, and (88) 4-[4,5-dimethyl-2-[N-cyclopropylmethyl-N-(5-methyl-2-furylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid. 5. The compound according to claim 1, wherein Ar is 2-thiazolyl or 5-methyl-2-thiazolyl 6. The compound according to claim 1 or 5, which is selected from the group consisting of (1) 4-[2-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (2) 4-[2-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (3) 4-[2-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (4) 4-[2-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (5) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (6) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (7) 4-[2-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (8) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-2-thiazolylsulfonylamide, (9) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-2-thiazolylsulfonylamide, (10) N-[4-trifluoromethyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-2-thiazolylsulfonylamide, (11) N-[4-trifluoromethyl-2-[4-(5-oxo-1,2,4-thiadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-2-thiazolylsulfonylamide, (12) 4-[2-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (13) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (14) 3-chloro-4-[2-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (15) 3-methyl-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (16) 3-methyl-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (17) 3-methoxy-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (18) 3-methoxy-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (19) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (20) N-[4-trifluoromethyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (21) N-[4-trifluoromethyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (22) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (23) 3-chloro-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (24) 3-methoxy-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (25) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (26) 3-methyl-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (27) 3-methyl-4-[2-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (28) 3-methoxy-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (29) 3-chloro-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (30) 3-chloro-4-[2-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (31) 4-[2-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (32) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (33) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]cinnamic acid, (34) 3-methyl-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (35) 3-chloro-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (36) 3-methyl-4-[2-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (37) 3-methyl-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (38) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (39) 3-methyl-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (40) 3-methyl-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]cinnamic acid, (41) N-[4-chloro-5-methyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (42) N-[4-chloro-5-methyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (43) 4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (44) N-[4-trifluoromethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (45) N-[4-trifluoromethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (46) 3-chloro-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (47) N-[4,5-dimethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (48) N-[4,5-dimethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (49) N-[4,5-dimethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (50) N-[4,5-dimethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (51) N-[4-chloro-5-methyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (52) N-[4-chloro-5-methyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (53) N-[4-chloro-5-methyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (54) N-[4-chloro-5-methyl-2-[2-methyl-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (55) 3-methoxy-4-[2-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (56) N-[4,5-dimethyl-2-[2-methyl-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (57) N-[4,5-dimethyl-2-[2-methyl-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (58) N-[4,5-dimethyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (59) N-[4,5-dimethyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-(4-methyl-2-thiazolyl)sulfonylamide, (60) N-[4,5-dimethyl-2-[2-methoxy-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (61) N-[4,5-dimethyl-2-[2-methoxy-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-(4-methyl-2-thiazolyl)sulfonylamide, (62) 4-[6-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (63) 4-[6-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (64) 3-methyl-4-[6-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (65) 3-methyl-4-[6-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (66) 3-methyl-4-[2-[N-(2-methyl-2-propenyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (67) 4-[2-[N-(2-methyl-2-propenyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (68) 3-methyl-4-[2-[N-(2-methyl-2-propenyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (69) 3-methyl-4-[6-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (70) 3-methyl-4-[6-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (71) 3-methyl-4-[6-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (72) 4-[6-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (73) 4-[6-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (74) 4-[6-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (75) 4-[6-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (76) 3-methyl-4-[6-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (77) 4-[2-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (78) 4-[2-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (79) 4-[2-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (80) 4-[2-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (81) 4-[6-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (82) 4-[6-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (83) 3-methyl-4-[2-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (84) 3-methyl-4-[2-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (85) 3-methyl-4-[2-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (86) 3-methyl-4-[2-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (87) 3-methyl-4-[6-[N-isopropyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (88) 3-methyl-4-[6-[N-isobutyl-N-(2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (89) 4-[3-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]naphtharen-2-yloxymethyl]benzoic acid, (90) 4-[3-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]naphtharen-2-yloxymethyl]benzoic acid, (91) 4-[3-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]naphtharen-2-yloxymethyl]-3-methylbenzoic acid, (92) 4-[3-[N-isopropyl-N-[2-(4-methylthiazolyl)sulfonyl]amino]naphtharen-2-yloxymethyl]-3-methylbenzoic acid, (93) 4-[3-[N-isobutyl-N-(4-methyl-2-thiazolylsulfonyl)amino]naphtharen-2-yloxymethyl]cinnamic acid, (94) 4-[3-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]naphtharen-2-yloxymethyl]cinnamic acid, (95) 4-[4,5-dimethyl-2-[N-methyl-N-(4-methyl-2-thiazolylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (96) 4-[4,5-dimethyl-2-[N-ethyl-N-(4-methyl-2-thiazolylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (97) 4-[4,5-dimethyl-2-[N-propyl-N-(4-methyl-2-thiazolylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (98) 4-[4,5-dimethyl-2-[N-(2-propenyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (99) 4-[4,5-dimethyl-2-[N-cyclopropylmethyl-N-(4-methyl-2-thiazolylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (100) 4-[4,5-dimethyl-2-[N-(2-hydroxy-2-methylpropyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]phenoxymethyl]-3-methylbenzoic acid, (101) 4-[6-[N-(2-methyl-2-propenyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (102) 4-[6-[N-(4-methyl-2-thiazolylsulfonyl)-N-(2-propenyl)amino]indan-5-yloxymethyl]benzoic acid, (103) 4-[6-[N-cyclopropylmethyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (104) 4-[3-[N-isobutyl-N-[2-(4-methylthiazolyl)sulfonyl]amino]naphtharen-2-yloxymethyl]benzoic acid, (105) 4-[3-[N-isopropyl-N-(4-methyl-2-thiazolylsulfonyl)amino]naphtharen-2-yloxymethyl]-3-methylbenzoic acid, (106) 4-[6-[N-ethyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (107) 4-[6-[N-(4-methyl-2-thiazolylsulfonyl)-N-propylamino]indan-5-yloxymethyl]benzoic acid, (108) 4-[6-[N-methyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid, (109) 3-methyl-4-[6-[N-methyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (110) 4-[6-[N-ethyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]-3-methylcinnamic acid, (111) 3-methyl-4-[6-[N-(2-methyl-2-propenyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]cinnamic acid, (112) 4-[6-[N-cyclopropylmethyl-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]-3-methylcinnamic acid, (113) 3-methyl-4-[6-[N-(4-methyl-2-thiazolylsulfonyl)-N-(2-propenyl)amino]indan-5-yloxymethyl]cinnamic acid, (114) 4-[6-[N-(2-hydroxy-2-methylpropyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]-3-methylcinnamic acid, (115) 3-methyl-4-[6-[N-(4-methyl-2-thiazolylsulfonyl)-N-propylamino]indan-5-yloxymethyl]cinnamic acid, and (116) 4-[6-[N-(2-hydroxy-2-methylpropyl)-N-(4-methyl-2-thiazolylsulfonyl)amino]indan-5-yloxymethyl]benzoic acid. 7. The compound according to claim 1, wherein Ar is 2-pyridyl or 3-pyridyl. 8. The compound according to claim 1 or 7, which is selected from the group consisting of (1) 4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (2) 4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]benzoic acid, (3) 3-chloro-4-[2-[N-isopropyl-N-(2-pyridylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (4) 3-methyl-4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (5) 3-methyl-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]benzoic acid, (6) 3-methyl-4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (7) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-3-pyridylsulfonylamide, (8) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-3-pyridylsulfonylamide, (9) 4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (10) 3-chloro-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (11) 3-methyl-4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (12) 3-methoxy-4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (13) 3-methoxy-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (14) 3-methyl-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (15) 3-methyl-4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (16) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-2-pyridylsulfonylamide, (17) N-[4-trifluoromethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, (18) 3-methyl-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]benzoic acid, (19) 4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]benzoic acid, (20) N-[4-trifluoromethyl-2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, (21) 4-[2-[N-isopropyl-N-(2-pyridylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (22) 3-methyl-4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-4-methyl-5-chlorophenoxymethyl]cinnamic acid, (23) 3-methyl-4-[2-[N-isobutyl-N-(2-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (24) 4-[2-[N-iso butyl-N-(3-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (25) 3-methyl-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (26) N-[4-trifluoromethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-2-pyridylsulfonylamide, (27) 3-chloro-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4,5-dimethylphenoxymethyl]cinnamic acid, (28) N-[4,5-dimethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, (29) N-[4,5-dimethyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-3-pyridylsulfonylamide, (30) N-[4-chloro-5-methyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-3-pyridylsulfonylamide, (31) N-[4,5-dimethyl-2-[2-chloro-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, (32) N-[4,5-dimethyl-2-[2-chloro-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-3-pyridylsulfonylamide, (33) N-[4,5-dimethyl-2-[2-chloro-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-3-pyridylsulfonylamide, (34) 3-methyl-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-4-chloro-5-methylphenoxymethyl]cinnamic acid, (35) N-[4,5-dimethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-2-pyridylsulfonylamide, (36) N-[4,5-dimethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, (37) N-[4,5-dimethyl-2-[4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-3-pyridylsulfonylamide, (38) 3-chloro-4-[2-[N-isobutyl-N-(3-pyridylsulfonyl)amino]-5-trifluoromethylphenoxymethyl]cinnamic acid, (39) N-[4-chloro-5-methyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-2-pyridylsulfonylamide, (40) N-[4-chloro-5-methyl-2-[2-methyl-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, (41) N-[4,5-dimethyl-2-[2-methyl-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-2-pyridylsulfonylamide, (42) N-[4,5-dimethyl-2-[2-methyl-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-3-pyridylsulfonylamide, (43) N-[4,5-dimethyl-2-[2-methoxy-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, (44) N-[4,5-dimethyl-2-[2-methoxy-4-(5-tetrazolyl)phenylmethyloxy]phenyl]-N-isopropyl-2-pyridylsulfonylamide, (45) N-[4,5-dimethyl-2-[2-methoxy-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isobutyl-2-pyridylsulfonylamide, and (46) N-[4,5-dimethyl-2-[2-methoxy-4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylmethyloxy]phenyl]-N-isopropyl-2-pyridylsulfonylamide. 9. An antagonist of EP1 receptor which is a prostaglandin E2 receptor subtype, comprising the N-phenylarylsulfonylamide compound of formula (I) according to claim 1, an ester thereof or a non-toxic salt thereof as an active ingredient. 10. A pharmaceutical composition for the prevention and/or treatment of algia, pyrexia (induction fever), pollakiuria (frequent urination), acraturesis (urinary incontinence), lower urinary tract disease syndrome and cancer, which comprises the compound of formula (I) according to claim 1 as an active ingredient. 11. A compound of formula (II) wherein Ar′ is an optionally substituted 5˜10 membered heterocyclic ring and R6 is 12. The compound according to claim 11, which is the compound of formula (II) wherein Ar′ is an optionally substituted 5 to 10 membered heterocyclic ring comprising 1 to 4 of nitrogen atom(s), 1 to 2 of oxygen atom(s) and/or 1 of sulfur atom. 13. The compound according to claim 11, which is the compound of formula (II) wherein Ar′ is thiazole, isothiazole, isoxazole, pyrazine, pyrimidine, pyridazine, pyridine, pyrrole, imidazole, pyrazole, triazole, indole, indoline, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, pyrrolidine, pyrroline, imidazolidine, imidazoline or pyrazoline ring. 14. The compound according to claim 11, which is the compound of formula (II) wherein Ar′ is thiazole or pyridine ring. 15. A method for the preparation of a compound of formula (II) wherein Ar′ and R6 have the same meanings as defined in claim 11, which comprises reacting a compound of formula (III) wherein X is a halogen atom, and Ar′ has the same meaning as former, with 1-hydroxybenzotirazole or N-methylimidazole hydrochloride. 16. The method for the preparation according to claim 15, which further comprises preparing the compound of formula (III) according to claim 15 and using the obtained reaction solution without concentration. 17. The method for the preparation according to claim 15, wherein said reaction is carried out at a temperature of from −20 to 30° C. |
<SOH> BACKGROUND ART <EOH>Prostaglandin E 2 (abbreviated as PGE 2 ) has been known as a metabolite in the arachidonate cascade. It has also been known that PGE 2 possesses a cyto-protective activity, a uterine contractive activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, a hypotensive effect, a diuretic activity and so on. In a recent study, it was found that a PGE 2 receptor is divided into some subtypes which possess different physical roles from each other. At present, four receptor subtypes are known and they are called EP 1 , EP 2 , EP 3 and EP 4 respectively (Negishi M. et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)). PGE 2 possesses a variety of physiological activities, so the undesired action other than the aimed one is shown as side effect. The research for the role of each receptor subtype and the investigation of the compound which only shows the effect on the specific subtype have been carried out to overcome such a problem. Among these subtypes, it has been known that EP 1 subtype relates to induction pain, pyrexia (induction fever) and diuresis (ref Br. J. Pharmacol., 112, 735-740 (1994); European J. Pharmacol., 152 273-279 (1988); Gen Pharmacol., September 1992, 23(5) 805-809). Therefore, compounds which antagonize this receptor are considered to be useful as analgesics, as antipyretic agents and as agents for treating pollakiuria (frequent urination). It has also been known that EP, antagonists possess a suppressive effect on aberrantcryptfoci and formation of intestinal polyps, and that they indicate an effective anti-tumor activity (ref WO00/69465). After drugs are absorbed in the body, they mainly migrate into the bloodstream. Then they are transported in the blood and are delivered to target organs. Finally they exert their potency. However, some drugs do not exert their potency because they combine with some proteins, which is contained in blood as nutritive substances. While some compounds are effective in in vitro experiment, it may often turn out that they are not effective in in vivo experiment. And it has been well known that there is not a specific structure-activity relationship on binding between drugs and proteins, and that it is very difficult to find out the ordinality. The present inventors found a useful compound which is an EP 1 antagonist, and filed a patent application. In the specification of WO98/27053 (EP947500), it is disclosed that a sulfonamide compound of formula (A) wherein the group are each independently C5-15 carbocyclic ring etc.; Z 1A is —COR 1 etc.; Z 2A is hydrogen etc.; R 1A is hydroxy etc.; Z 3A is single bond etc.; Z 4A is SO 2 etc.; Z 5A is 5 to 7 membered heterocyclic ring containing one or two oxygen, sulfur or nitrogen atom(s), which may be substituted with 1 to 5 R 5A etc.; R 5A (if two or more R 5A , each independently) is hydrogen, C1-6 alkyl, etc.; R 2A is Z 7A -C1-4 alkylene etc.; Z 7A is oxygen etc.; R 3A is trifluoromethyl etc.; R 4 A is C1-8 alkyl etc.; n A and t A are each independently 1 to 4 (as excerpt), binds to a PGE 2 receptor, especially the EP 1 receptor, to show an agonistic or an antagonistic activity. The specification disclosed that the compound having the antagonistic activity is useful for the prevention of abortion, as an analgesic, as an antidiarrhoic, as a hypnagogic agent and for treating pollakiuria (frequent urination), while the one having an agonistic activity is useful for abortion, as an abstergent, as an antiulcer agent, as an antigastritis agent, as an antihypertensive agent, as a diuretic agent. In this patent application, for example, the following compounds are disclosed specifically. |
Optical data receiver systems |
Improvements in or relating to optical data receiver systems. An optical data receiver for the distribution and demodulation of compressed TDM data packages comprises, optical distributor means to which the data packages are applied for selective distribution to a plurality of AWG optical demultiplexer/detector arrays, so that each demultiplexer/detector array provides in respect of each data package fed thereto from the optical distributor, a data word the bits of which are presented in parallel. |
1. A method for transmitting data, comprising the steps of: generating a chirped optical carrier pulse; serially modulating the carrier pulse with a data word; compressing the modulated pulse; transmitting the compressed modulated pulse over a transport medium; receiving the compressed modulated pulse; and decompressing the modulated pulse; characterised in that the method further comprises the step of; wavelength demodulating the modulated pulse into a plurality of wavelength components, each wavelength component representing one bit of the data word, the data word being represented in parallel by the plurality of wavelength components. 2. A method according to claim 1, wherein a plurality of data words are encoded into a sequential plurality of compressed modulated pulses transmitted over the transport medium, further comprising the steps of: selecting one of the plurality of compressed modulated pulses; and decompressing and wavelength demodulating the selected modulated pulse into a plurality of wavelength components, each wavelength component representing one bit of the data word, the data word being represented in parallel by the plurality of wavelength components. 3. A method according to claim 2, further comprising the steps of providing a plurality of selecting means, each with respective associated decompression means and wavelength demodulating means, in parallel; arranging for the sequential plurality of compressed modulated pulses to be applied to each of the selecting means; in each of the selecting means, selecting a respective one of the sequential plurality of compressed modulated pulses; and decompressing and wavelength demodulating the respective selected compressed modulated pulses, each into a plurality of wavelength components, each wavelength component representing one bit of the data word, the data word being represented in parallel by the plurality of wavelength components. 4. A method according to any preceding claim, wherein the steps of decompressing and wavelength demodulating are performed by applying the respective compressed modulated pulse to an optical demultiplexer/detector array. 5. A method according to claim 4, wherein the step of applying the respective compressed modulated pulse to an optical demultiplexer/detector array comprises applying the respective compressed modulated pulse to an arrayed waveguide grating (AWG). 6. A method according to claim 5, wherein a detector array is provided, integrated with the AWG. 7. A method according to claim 3, or any claim dependent on claim 3, wherein the selecting means comprise optical modulators. 8. A method according to claim 7 wherein the optical modulators each embody a semiconductor optical amplifier (SOA). 9. A method according to claim 7 wherein the optical modulators comprise erbium doped optical amplifiers (EDOA). 10. A method substantially as hereinbefore described. 11. A signal router arranged to operate according to a method as defined in any preceding claim. |
Method and system for dynamic spectrum allocation and management |
An arrangement for dynamic account allocation is achieved by pooling together spectrum and network availability, as well as congestion information, from different service providers in a central database and by the purchase of wholesale volume of network capacity or accounts with predetermined monthly usage. The purchased network capacity is dynamically allocated of devices of different origin and ownership. The central system operator administrates the rebilling and reconciliation of any fractional usage to each device. Unlike other proposed solutions that require the carriers to bet on proprietary technologies and involve changes to the network and high capital expenditures to build and operate the network, the present invention requires no changes to the carrier's network and no investment in a proprietary solution. |
1. A method for dynamically allocating spectrum bandwidth, comprising: detecting a first criteria data set of a first carrier currently in use by a wireless device having a first transceiver; detecting a second criteria data set of a second carrier; determining to switch from the first carrier to the second carrier; transmitting a request over a control channel to switch to the second carrier; receiving an authorization data over the control channel to switch to the second carrier; and switching to the second carrier using a second transceiver. 2. The method of claim 1, wherein detecting a first criteria data set further comprises: storing the first criteria data set in a memory. 3. The method of claim 1, wherein the first criteria data set has at least one of following: a quality of service field; a pricing plan field; and a power level field. 4. The method of claim 1, wherein detecting a second criteria data set further comprises: accessing the second criteria data set of the second carrier; and storing criteria data set in a database. 5. The method of claim 1, wherein detecting a second criteria data set is performed at a predefined polling interval. 6. The method of claim 1, wherein the determining step determines to switch if the second criteria data set has a higher priority level than the first criteria data set. 7. The method of claim 1, wherein the determining step further comprises: transmitting a request over a control channel for updated criteria data sets for the first and second carrier; and receiving the updated criteria data sets. 8. The method of claim 1, wherein the authorization data contain at least one of the following: an address data field of a proxy server associated with the second carrier; and an authentication key data field to establish a connection with the second carrier. 9. The method of claim 1, wherein the switching step further comprises: transmitting to a proxy server a request to switch; and receiving an approval data from the proxy server. 10. The method of claim 1, further comprising: detecting a third criteria data set of a third carrier using the first transceiver. 11. The method of claim 1, wherein transmitting the request over the control channel is done using a third transceiver. 12. The method of claim 1, wherein switching to the second carrier is done using a third transceiver. 13. The method of claim 1, wherein the first and second carriers use at least one of the following modes: Global System for Mobile Communication; Time Division Multiple Access; and Code Division Multiple Access. 14. The method of claim 4, further comprising: accessing the database for the second criteria data set; and comparing the second criteria data set with the first criteria data set. 15. The method of claim 14, further comprising: detecting a second criteria data set with a higher priority level than the first criteria data set. 16. The method of claim 15, wherein the second carrier is determined to have a higher priority level from at least one of the following: higher quality of service rating; lowering pricing; and higher signal power. 17. The method of claim 5, wherein the polling interval is stored in memory. 18. The method of claim 6, wherein the second carrier is determined to have a higher priority from at least one of the following: higher quality of service rating; lowering pricing; and higher signal power. 19. The method of claim 7, further comprising; determining that the updated criteria data set of the second carrier still has a higher priority level than the first criteria data set. 20. The method of claim 19, further comprising: checking a user preference database; and determining that the user prefers to perform the switch when the switch is to the second carrier with the second criteria data set having a higher priority level than the first criteria data set. 21. The method of claim 9, wherein the approval data contains at least a port address associated with the second carrier. 22. The method of claim 9, further comprising: authenticating the connection with the proxy server using the second carrier; and establishing communication over the second carrier. 23. The method of claim 22, further comprising: terminating connection with the first carrier after communication is established over the second carrier. 24. The method of claim 13, wherein the first and second carriers uses two different modes. 25. The method of claim 13 wherein the first and second carriers use the same mode. 26. The method of claim 13 wherein the first and second carriers use different frequencies of the same mode. 27. A method for dynamically allocating spectrum bandwidth, comprising: receiving a request over a control channel for a first and a second criteria data set for a first and a second carrier; transmitting the first and second criteria data set over the control channel; receiving a request over the control channel for a wireless device to switch from the first carrier to the second carrier; and transmitting a reply to the request to switch over the control channel. 28. The method of claim 27, wherein the request for criteria data sets further comprises identification data for the first and the second carrier. 29. The method of claim 27, wherein the first and second criteria data set has at least one of following: a quality of service field; a pricing plan field; and a power level field. 30. The method of claim 27, wherein transmitting the first and second criteria data set further comprises: accessing the first and second carrier using identification data attached in the request for the first and second criteria data set; reading the first and second criteria data set; and storing first and second criteria data set in memory. 31. The method of claim 27, wherein transmitting the reply to the request to switch further comprises: accessing the second carrier to determine whether the second carrier is available. 32. The method of claim 27, wherein the first and the second carrier use at least one of the following modes: Global System for Mobile Communication; Time Division Multiple Access; and Code Division Multiple Access. 33. The method of claim 31, further comprising: transmitting an authorization data with the reply to the request to switch if the second carrier is available. 34. The method of claim 33, wherein the authorization data contain at least one of the following: an address data field of a proxy server associated with the second carrier; and an authentication key data field to establish a connection with the second carrier. 35. The method of claim 31, further comprising: transmitting a denial data with the reply to the request to switch if the second carrier is not available. 36. The method of claim 32, wherein the first and second carriers uses two different modes. 37. The method of claim 27 wherein the first and second carriers use the same mode. 38. The method of claim 27 wherein the first and second carriers use different frequencies of the same mode. 39. A method for dynamically allocating spectrum bandwidth, comprising: establishing a first connection with an application server; establishing a second connection with a wireless device using a first carrier; receiving a request over a control channel to establish a third connection using a second carrier with the wireless device and to terminate the second connection; establishing the third connection with the wireless device; and terminating the second connection with the wireless device. 40. The method of claim 39, wherein establishing the third connection further comprises; transmitting an approval data to the wireless device for approving the request. 41. The method of claim 39, wherein terminating the second connection is done without interrupting the first connection. 42. The method of claim 39, wherein terminating the second connection is done after communication is established using the third connection. 43. The method of claim 39, wherein the first, second, and third connections use at least one of the following modes: Global System for Mobile Communication; Time Division Multiple Access; and Code Division Multiple Access. 44. The method of claim 40, wherein the approval data contains at least a port address associated with the second carrier. 45. The method of claim 40, further comprising: authenticating with the wireless device to establish the third connection. 46. The method of claim 43, wherein the second and third connections uses two different modes. 47. The method of claim 39 wherein the first and second carriers use the same mode. 48. The method of claim 39 wherein the first and second carriers use different frequencies of the same mode. 49. A method for dynamically allocating spectrum bandwidth, comprising: establishing communication over a first carrier using a first transceiver; receiving an authorization data over a control channel to switch to a second carrier; and switching to the second carrier using a second transceiver. 50. The method of claim 49, further comprising: checking a user preference database; and determining that the user prefers to perform the switch when the switch is to the second carrier with a second criteria data set having a higher priority level than a first criteria data set of the first carrier. 51. The method of claim 49, wherein the authorization data contain at least one of the following: an address data field of a proxy server associated with the second carrier; and an authentication key data field to establish a connection with the second carrier. 52. The method of claim 49, wherein switching further comprises: transmitting to a proxy server a request to switch; and receiving an approval data from the proxy server. 53. The method of claim 49, wherein the first and second carriers use at least one of the following modes: Global System for Mobile Communication; Time Division Multiple Access; and Code Division Multiple Access. 54. The method of claim 52, wherein the approval data contains at least a port address associated with the second carrier. 55. The method of claim 52, further comprising: authenticating the connection with the proxy server using the second carrier; and establishing communication over the second carrier. 56. The method of claim 55, further comprising: terminating connection with the first carrier after communication is established over the second carrier. 57. The method of claim 53, wherein the first and second carriers uses two different modes. 58. A method for dynamically allocating spectrum bandwidth, comprising: detecting a first criteria data set of a first carrier currently in use by a wireless device having a first transceiver; detecting a second criteria data set of a second carrier; determining to switch from the first carrier to the second carrier; and transmitting an authorization data over the control channel for the wireless device to switch to the second carrier. 59. The method of claim 58, wherein detecting a first criteria data set further comprises: storing the first criteria data set in a memory. 60. The method of claim 58, wherein the first criteria data set has at least one of following: a quality of service field; a pricing plan field; and a power level field. 61. The method of claim 58, wherein detecting a second criteria data set further comprises: accessing the second criteria data set of the second carrier; and storing criteria data set in a database. 62. The method of claim 58, wherein detecting a second criteria data set is performed at a predefined polling interval. 63. The method of claim 58, wherein the determining step determines to switch if the second criteria data set has a higher priority level than the first criteria data set. 64. The method of claim 58, wherein the authorization data contain at least one of the following: an address data field of a proxy server associated with the second carrier; and an authentication key data field to establish a connection with the second carrier. 65. The method of claim 58, further comprising: detecting a third criteria data set of a third carrier using the first transceiver. 66. The method of claim 58, wherein the first and second carriers use at least one of the following modes: Global System for Mobile Communication; Time Division Multiple Access; and Code Division Multiple Access. 67. The method of claim 61, further comprising: accessing the database for the second criteria data set; and comparing the second criteria data set with the first criteria data set. 68. The method of claim 67, further comprising: detecting a second criteria data set with a higher priority level than the first criteria data set. 69. The method of claim 68, wherein the second carrier is determined to have a higher priority level from at least one of the following: higher quality of service rating; lowering pricing; and higher signal power. 70. The method of claim 62, wherein the polling interval is stored in memory. 71. The method of claim 63, wherein the second carrier is determined to have a higher priority from at least one of the following: higher quality of service rating; lowering pricing; and higher signal power. 72. The method of claim 66, wherein the first and second carriers uses two different modes. 73. A method for managing available spectrum in a wireless network having at least two available network carriers, comprising: receiving a request at a management server for account data from a wireless device, the request containing at least a device ID and a current carrier ID; validating the request; returning the requested account data to the wireless device requesting the account data; and updating an account usage database to reflect the account usage of the wireless device. 74. The method according to claim 73, further comprising transmitting data from the wireless device to the management server indicating that the account is no longer required. 75. The method according to claim 74, further comprising updating the account usage database to reflect that the account is available. 76. The method according to claim 75, further comprising generating an invoice for the amount of account usage and storing the invoice in a billing database. 77. The method according to claim 73, wherein the step of validating the request further comprises: comparing the device ID with a plurality of authorized device IDs stored in an authorized user database; and authorizing the release of account data if the device ID matches one of the authorized device IDs. 78. The method according to claim 73, wherein the step of returning account data further comprises accessing a network resources database containing at least a list of available wireless carriers in a given geographic region; determining a suitable account using at least one predetermined selection criteria. 79. The method according to claim 78 wherein the at least one predetermined selection criteria is selected from the group consisting of Quality of Service (QoS), price per minute, available unused spectrum and signal strength. 80. The method according to claim 73, wherein the request is communicated over an in-band control channel. 81. The method according to claim 73 wherein the request is communicated over an out-of-band control channel. 82. A method for managing available spectrum in a wireless network having at least two available network carriers, comprising: receiving a network status update containing network information from a wireless device to a management server, the status update information containing at least a device ID and a current carrier ID; storing the status update information in a network resources database; and switching the carrier of the wireless device in response to the update information and at least one predetermined selection criteria. 83. The method according to claim 82 wherein the at least one predetermined selection criteria is selected from the group consisting of Quality of Service (QoS), price per minute, available unused spectrum and signal strength. 84. The method according to claim 82, wherein the network information further contains a signal strength reading. 85. The method according to claim 82, wherein the network information further contains a plurality of available Carrier IDs. 86. The method according to claim 82, wherein the step of switching further comprises transmitting to a proxy server over a connection a request to switch, and receiving an approval data from the proxy server to switch. 87. The method according to claim 86, wherein the approval data contains at least a port address associated with a new carrier. 88. The method of claim 87, further comprising: authenticating the connection with the proxy server using the new carrier port address; and establishing communication over the new carrier. 89. The method of claim 88, further comprising: terminating the connection with the current carrier after communication is established over the new carrier. 90. The method of claim 87, wherein the current and new carriers use two different communication modes. 91. A device for dynamically switching communication modes in a wireless network having at least two available communication modes, the device comprising: an antenna capable of receiving a plurality of wireless signals; at least two transceivers connected to the antenna, the transceivers being capable of transmitting and receiving wireless signals in connection with the available communication modes; a controller connected to the at least two transceivers that detects a first criteria data set of a first communication mode currently in use by the device using a first transceiver, detects a second criteria data set of a second communication mode using a second transceiver, determines to switch from the first mode to the second mode, transmits a request over a control channel to switch to the second mode, receives an authorization data over the control channel to switch to the second mode; and dynamically switches to the second mode using the second transceiver. 92. The device of claim 91, wherein the controller further stores the first criteria data set in a memory device. 93. The device of claim 91, wherein the first criteria data set has at least one of following data fields: a quality of service field; a pricing plan field; and a power level field. 94. The device of claim 92, wherein the controller further accesses the second criteria data set of the second mode and stores the criteria data set in the memory device. 95. The device of claim 91, wherein the controller determines to switch if the second criteria data set has a higher priority level than the first criteria data set. 96. The device of claim 94, wherein the controller transmits a request over a control channel for updated criteria data sets for the first and second mode and stores the updated criteria data sets in the memory device. 97. The device of claim 91, wherein the authorization data contain at least one of the following: an address data field of a proxy server associated with the second mode; and an authentication key data field to establish a connection over the second mode. 98. The device of claim 91, wherein the controller further transmits to a proxy server a request to switch and receives an approval data from the proxy server. 99. The method of claim 91, wherein the first and second communication modes are different modes. 100. A system for managing available spectrum in a wireless network having at least two available network carriers, comprising: means for receiving a network status update containing network information from a wireless device to a management server, the status update information containing at least a device ID and a current carrier ID; means for storing the status update information in a network resources database; and means for switching the carrier of the wireless device in response to the update information and at least one predetermined selection criteria. 101. The system according to claim 101, wherein the at least one predetermined selection criteria is selected from the group consisting of Quality of Service (QOS), price per minute, available unused spectrum and signal strength. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The current wireless telecommunications industry faces several challenges to growing and expanding the services that are offered. The first challenge is that spectrum availability for wireless communications is highly sought after but exceedingly scarce. The shear magnitude of the cost for spectrum licenses confirms this challenge. For example, $32 billion dollars were raised in spectrum auctions in the U.S. between 1994-1999. In the United Kingdom and Germany, $35 and $46 billion dollars were raised, respectively, for spectrum licenses. The second challenge facing the wireless industry is that demand for wireless services is growing at a phenomenal rate, including demand for both voice and data transmission services. Some organizations predict that the number of wireless subscribers will exceed 1 billion by 2004 while other groups predict that wireless web surfers will grow from 6 million in January, 2000 to 484 million in 2005. Still others predict that global data revenues will grow from $7.3 to $65.2 billion and the wireless data market will exceed $82 billion by 2012. Beyond these fundamental economic problems, there are key obstacles to overcome with the design and implementation of today's wireless networks to facilitate new growth. One of the biggest obstacles in the industry is the coupling between wireless devices and specific carrier networks. This coupling restricts which devices can talk to which network towers, which in turn greatly diminishes the efficiency of capacity distribution. The restrictions occur in two forms. The first form involves physical incompatibilities between the devices of one carrier, and the network towers of another carrier. These incompatibilities occur at the level of the “air interface.” There are approximately 5 voice interfaces (AMPS, CDMA, TDMA, GSM, iDEN) and 6 data interfaces (GPRS, CDMA 1×, Wi-Fi, CDPD, DataTAC, Mobitex) in broadscale use within the U.S. alone. The second form of access restriction involves carrier support for inter-carrier operation. Assuming a device from Carrier A is physically compatible with a network of Carrier B, the device can not access Carrier B's network unless the two carriers have expressly made arrangements for such “roaming” between carriers. In many cases, such inter-carrier access is not possible because the necessary agreements have not been obtained. These restrictions have the overall effect of diminishing the efficiency of the network system. This effect, which may be called “unbalanced usage”, can be demonstrated with reference to three network entities: a tower from Carrier A, a wireless device subscribing to Carrier A and a tower from Carrier B. Suppose the device is within range of only these two towers. Suppose further that the tower from Carrier A is at capacity and cannot accommodate communication with the device while the tower from Carrier B is underutilized. It is beneficial for the device to access the tower from Carrier B because the device gets a communication channel and Carrier B gets to sell unused available capacity. Since unbalanced usage is a common problem in the art, there are several existing systems that attempt to alleviate the problem. However, an overwhelming majority of the systems only reduce unbalanced usage within a single band, such as TDMA or CDMA. One such system dynamically controls a time slot in a TDMA system by constantly exchanging information regarding a data transfer between a central controller and a wireless device. In that manner, the time slot is dynamically allocated in response to constantly changing system requirements, and the overall capacity consumed for the transfer is minimized. In another system, the usage of a wireless network is monitored so that different channel allocations can be made to best suit the usage patterns of the wireless network. All of these systems operate exclusively within one mode, such as TDMA, and these systems cannot alleviate unbalanced usage between two or more modes, for example an overloaded CDMA network and an underutilized GSM network. While there are other unimplemented systems in the art designed to alleviate unbalanced usage between two or more modes, these systems require base stations that are each capable of processing several different modes, unlike the existing base stations, which can only operate in one mode. In addition, the system is incapable of dynamically changing modes during an existing session. These systems have the disadvantage of prohibitively high cost since all base stations in the network would have to be modified. Given the networks already exorbitant outlays of money for government licenses and base station development, networks are loath to reconfigure every base station in this manner. A further obstacle in the industry is that carriers couple application services to their own proprietary network. This results in a limited selection of quality content and applications for wireless subscribers. Overcoming this problem would require that all wireless systems adopt an open transport system with a common addressing scheme, such as TCP/IP, and that devices are capable of freely downloading new client applications for network services that make use of this transport. Indeed, there seems to be a trend along these lines, but this trend will require technology solutions such as the present invention to facilitate multi-network access in order to gain broad adoption. A further obstacle in the current wireless systems is the lack of support for administration of spectrum usage. For example, in times of crisis the need arises to enforce a priority access mechanism across all available networks. Current network technology does not provide for this. Yet another obstacle in the current wireless systems is the lack of a system for the real time collection and analysis of operational data, such as usage, QOS, pricing, capacity, etc. Such capabilities are only just now being introduced on a per-network basis, and are only appearing in limited forms. Clearly, the need remains for a powerful, inter-network system that offers these capabilities in order to optimize the distribution and consumption of wireless capacity. Moreover, the availability of such a system would enable for the first time a real-time analysis that correlates spectrum supply with demand across parameters such as price, mode, capacity, geography, etc. Referring to FIG. 1 , there is shown a general overview of a prior art wireless network architecture. There are several proprietary networks 12 that each typically work on a single frequency (e.g., 700 MHz or 1900 MHz). The owners of the networks generally utilize a plurality of proprietary application servers 10 that provide service only to the network that they are attached to. In addition, they may utilize one or more third party applications servers 10 a which are often shared over multiple carrier networks. A plurality of wireless telephones 16 are equipped to function on only the frequency/mode pair of one specified network 12 . Additionally, the wireless networks may be used to support communication between two wireless devices, or between a wireless device and a wireline device other than a server, such as a landline phone. Currently, there are multi-mode devices that can operate on more than one frequency (e.g., 800 Mhz and 1900 Mhz) and more than one mode (i.e. AMPS and CDMA), but they cannot dynamically choose a mode. The plurality of wireless telephones 16 communicate with networks 12 through a plurality of base stations 14 , often called Base Station Systems (BSSs) and Mobile Switching Centers (MSCs). The base stations 14 are typically outfitted with a particular network technology, and are not easily hardware upgradeable. While third party application servers 10 a must work with the owners of the network 12 to provide services/content (e.g., stock quotes, weather, etc.), most providers of servers 10 a have difficulty bringing new offerings to market because typically the networks 12 want to rely on their own application servers 10 , which provide better profit margins. A developing technology called Software Defined Radio (SDR) overcomes many of the limitations of the current systems and provides many benefits to users, operators, and manufacturers in the wireless industry. SDR is defined by the Federal Communications Commission (FCC) as a transceiver with operating parameters that can be altered via software. Some of the specific opportunities that SDR helps to enable include interoperability between different cellular telephone standards and easier deployment of new applications. While SDR lowers the existing physical barriers to achieving a more efficient wireless system, SDR alone will merely exaggerate the remaining shortcomings of wireless systems. Accordingly, there remains a need for a method and system for dynamic spectrum allocation and management across multiple wireless networks that does not require substantial changes to the existing network architecture. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is therefore an aspect of the present invention to provide for the dynamic allocation of segments of spectrum which may be available from different providers in a manner best suited to realize the objectives of various network entities. It is an additional aspect of the present invention to balance the use of network systems in times of a crisis and provide near exclusive use to emergency workers by artificially inflating the priority of certain calls. It is a further aspect of the invention to allow a service provider to purchase a small number of accounts from each network targeted for roaming, and then loan those accounts on an as needed basis to devices based on where they are currently roaming. It is still a further aspect of the present invention to dramatically increase the longevity of the battery used in such wireless devices by allowing devices to dynamically select a provider based on power needs in addition to other criteria such as price and throughput. It is a further aspect of the invention to enable a common transport and addressing scheme across multiple networks operated by different carriers using different network technologies. To achieve the above and other aspects of the present invention, there is provided a process and system that allows for any device compliant with one or many networks to “borrow” an account, authenticate in that specific network, use it for a period of time and then use some other network as necessary. The decision to select a different network may be initiated by various network entities, including wireless devices, carriers, spectrum owners and spectrum administrators, thereby decoupling wireless subscribers from specific carriers, and decoupling subscriber accounts from specific devices. The ability to borrow an account facilitates authentication and billing. The invention applies to any and all wireless devices, whether fixed or mobile, or used for voice, data or device to device (i.e. telemetry) applications. This invention maximizes the allocations of a device within its own network, across multiple networks or as an unaffiliated user with an on demand access request. By using existing in-band control channels or out-of-band (not same providers) control channels, a multimode/SDR equipped wireless device according to the present invention can detect a signal sent by all providers in an area and store pertinent information for later use in an internal or external database (“DB”). This information is used to select which network to access for the service. |
Methods for modification of plant inflorescence architecture |
The present invention relates to methods for the use of the Arabidopsis “BREVIPEDICELLUS” (BP) gene for alteration of plant architecture, in particular alteration of the morphology of the inflorescence of a flowering plant. The methods of the present invention provide a means to alter the development of the peduncle, notably the inflorescence branches, and the pedicels that subtend the individual flowers as well as aspects of flower structure such as the style, and subsequent seed pods, of a flowering plant. The invention also relates to methods to identify and isolate polynucleotides encoding genes with BP-related functions from other plant species and methods for utilizing said polynucleotides to alter the inflorescence of said plant species. Furthermore, the invention encompasses transgenic plants generated by the methods disclosed, and nucleotide sequences for use in generating the transgenic plants. |
1. A method of producing a transgenic plant with a modified inflorescence architecture characterised in that the method comprises the steps of: (a) introducing into a plant cell capable of being transformed and regenerated into a whole plant a construct comprising, in addition to the DNA sequences required for transformation and selection in plants, a nucleotide sequence derived from a KNAT1 gene and encoding at least part of a KNAT1 gene product operably linked to a promoter; and (b) recovery of a plant which contains said nucleotide sequence and has a modified inflorescence architecture compared to an unmodified plant. 2. A method according to claim 1, characterised in that said nucleotide sequence encodes a peptide having at least 50% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 3. A method according to claim 1, characterised in that said nucleotide sequence encodes a peptide having at least 70% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 4. A method according to claim 1, characterised in that said nucleotide sequence encodes a peptide having at least 90% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 5. A method according to claim 1, characterised in that said nucleotide sequence encodes a peptide having at least 95% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 6. A method according to claim 1, characterised in that said nucleotide sequence encodes a peptide having at least 99% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 7. A method according to claim 1, characterised in that said nucleotide sequence is SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof, or a nucleotide sequence that binds under stringent conditions to SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof 8. A method according to claim 1, characterised in that said modified inflorescence architecture comprises an altered pedicel, peduncle or style. 9. A method according to claim 8, characterised in that said pedicel has an altered length compared to an unmodified plant. 10. A method according to claim 1, characterised in that said modified inflorescence architecture comprises downwardly pointing flowers. 11. A method according to claim 1, characterised in that said nucleotide sequence is derived from a plant of the genus Arabidopsis. 12. A method according to claim 1, characterised in that said nucleotide sequence is derived from a plant of the genus Brassica. 13. A method according to claim 1, characterised in that said plant is of the genus Arabidopsis. 14. A method according to claim 1, characterised in that said plant is of the genus Brassica. 15. A method according to claim 1, characterised in that said plant is selected from the group consisting of: a dicot, a monocot, and a member of Cruciferae. 16. A method according to claim 1, characterised in that expression of said nucleotide sequence in said plant generates a plant having a compact inflorescence compared to an unmodified plant. 17. A method according to claim 1, characterised in that expression of said nucleotide sequence in said plant generates a plant having an open inflorescence compared to an unmodified plant. 18. A method according to claim 1, characterised in that said nucleotide sequence is expressed in a sense direction for complementary inhibition of an endogenous KNAT1 gene in said plant, said plant having a compact inflorescence architecture compared to an unmodified plant. 19. A method according to claim 18, characterised in that said nucleotide sequence is a mutated KNAT1 gene. 20. A method according to claim 1, characterised in that said nucleotide sequence is expressed in an antisense direction for antisense inhibition of an endogenous KNAT1 gene of said plant, said plant having a compact inflorescence architecture and/or decreased pedicel length compared to an unmodified plant. 21. A method according to claim 1, characterised in that said nucleotide sequence is overexpressed in a sense direction, said plant having an open inflorescence architecture and/or increased pedicel length compared to an unmodified plant. 22. A method according to claim 1, characterised in that said plant harbours a bp mutation and expression of said nucleotide sequence is complementary to said mutation, said plant exhibiting a wild-type phenotype. 23. A method according to claim 1, characterised in that said promoter comprises a transcriptional regulatory region normally in operable association with an endogenous KNAT1 gene or homologue thereof. 24. A method according to claim 1, characterised in that said promoter comprises a transcriptional regulatory region that is not normally in operable association with an endogenous KNAT1 gene or homologue thereof. 25. A method according to claim 1, characterised in that said promoter is selected from the group consisting of: a constitutive promoter, an inducible promoter, an organ specific promoter, a strong promoter, a weak promoter, and an endogenous KNAT1 promoter from Arabidopsis. 26. A method according to claim 1, characterised in that said nucleotide sequence is derived from a nucleotide sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 20. 27. A method according to claim 1, characterised in that said promoter is derived from a functional portion of SEQ ID NO: 23 or SEQ ID NO: 24. 28. A method of identifying a plant that has been successfully transformed with a construct, characterised in that the method comprises the steps of: (a) introducing into plant cells capable of being transformed and regenerated into whole plants a construct comprising, in addition to the DNA sequences required for transformation and selection in plants, a nucleotide sequence derived from a KNAT1 gene and encoding at least part of a KNAT1 gene product, operably linked to a promoter; (b) regenerating said plant cells into whole plants; and (c) inspecting the inflorescences of said plants to determine those plants successfully transformed with said construct, and expressing said nucleotide sequence. 29. A method according to claim 28, characterised in that said plant cells and said regenerated whole plants harbour a bp mutation, and successful transformation and expression of said nucleotide sequence complements said mutation, thereby generating a plant exhibiting a wild-type phenotype. 30. A method according to 29, characterised in that said construct is bicistronic and further comprises a second DNA expression cassette for generating a transcript unrelated to said nucleotide sequence derived from a KNAT1 gene. 31. A transgenic plant generated by the method according to claim 1. 32. The transgenic plant according to claim 31 characterised in that said transgenic plant is of the genus Arabidopsis. 33. The transgenic plant according to claim 31, characterised in that said transgenic plant is of the genus Brassica. 34. The transgenic plant according to claim 31, characterised in that said nucleotide sequence is derived from an Arabidopsis KNAT1 gene. 35. The transgenic plant according to claim 31, characterised in that said nucleotide sequence is derived from a Brassica KNAT1 gene. 36. The transgenic plant according to claim 31, characterised in that said plant is selected from the group consisting of: a dicot, a monocot, and a member of Cruciferae. 37. The transgenic plant according to claim 31, characterised in that said modified inflorescence is compact compared to an unmodified plant. 38. The transgenic plant according to claim 31, characterised in that said modified inflorescence is open compared to an unmodified plant. 39. The transgenic plant according to claim 31, characterised in that said modified inflorescence architecture comprises an altered pedicel, peduncle or style. 40. The transgenic plant according to claim 39, characterised in that said altered pedicel has an altered length compared to an unmodified plant. 41. The transgenic plant according to claim 31, characterised in that said modified inflorescence architecture comprises downwardly pointing flowers. 42. An isolated nucleotide sequence for generating a transgenic plant with modified inflorescence architecture, characterised in that said isolated nucleotide sequence is derived from a KNAT1 gene and encodes at least part of a KNAT1 gene product. 43. The isolated nucleotide sequence according to claim 42, characterised in that said nucleotide sequence comprises a sequence selected from: (a) SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof; and (b) a nucleotide sequence encoding a peptide having at least 50% homology to the peptide encoded by the nucleotide sequence defined in (a). 44. The isolated nucleotide sequence according to claim 42, characterised in that said nucleotide sequence encodes a peptide having at least 70% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 45. The isolated nucleotide sequence according to claim 42, characterised in that said nucleotide sequence encodes a peptide having at least 90% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 46. The isolated nucleotide sequence according to claim 42, characterised in that said nucleotide sequence encodes a peptide having at least 95% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof 47. The isolated nucleotide sequence according to claim 42, characterised in that said nucleotide sequence encodes a peptide having at least 99% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. 48. The isolated nucleotide sequence according to claim 42, characterised in that said nucleotide sequence hybridises under stringent conditions to the nucleotide sequence of SEQ ID NO: 5 or 6, or a part thereof or a complement thereof. 49. The isolated nucleotide sequence according to claim 42 for generating a transgenic plant with a modified inflorescence architecture compared to an unmodified plant, characterised in that said nucleotide sequence is derived from a construct selected from the group consisting of: pRD400-951/955, pRD400-951/956, pRD400-35S::AtBPS, pRD400-35S::AtBPA/S, pRD400-35S::Atbp-2, pRD400-951/952::Atbp-2, pRD400-951/952::BnBPS, pRD400-35S::BnBPS, and pRD400-35S::BnBPA/S. 50. Use of an isolated nucleotide sequence according to claim 42, for generating a transgenic plant with a modified inflorescence architecture. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Plant architecture plays a very important role in overall crop performance. The characteristics of the inflorescence, flower, silique/fruit, and stem internodes have broad agronomic implications in the overall productivity of any crop plant. Compact architecture can contribute to productivity. For example, flowering stalks or inflorescences that are compact in nature and do not shade lower photosynthetic tissue can allow for greater productivity. Similarly, a flowering stalk or inflorescence that is spread out may allow for more photosynthesis to take place during seed development within the flowering stalk. Thus, different inflorescence architectures may be desired for different crops. Since most crop varieties have been derived directly or indirectly through breeding from wild species, productivity of crops may be affected by characteristics that are evolutionarily beneficial to wild species but impair performance in an agricultural setting. For example, well spread-out flowers and siliques with long pedicels on the inflorescence (along with genes controlling seed dispersal mechanisms such as shattering) may be evolutionarily beneficial to wild species, while in a crop setting this confers significant disadvantages in terms of overall productivity as measured by harvested seed. An example of this is canola species, in which the shoot architecture, especially involving inflorescence and siliques, is not ideal for optimal productivity and recovery of seed. Though there have been concerted efforts to produce crop plants with ideal architecture, it has not been achieved in many crop species. It widely known that the growth and developmental programs of a plant species control pedicel development and determine its length, attachment angle of the flowers and seed pods, and contribute significantly towards the overall architecture of the flower and/or inflorescence. Despite significant advances in the understanding of flower development, very little is known about the genetic and molecular control of pedicel development. Plant architecture or morphology is a major determining factor in plant productivity under agricultural settings. Plant varieties that have well-defined morphology of a uniform nature and pattern are preferred since they are amenable to mechanical cultivation. In particular, plant species that produce seed are selected for the uniformity of the placement of seed forming structures (typically seed pods or cobs) to allow efficient mechanical harvesting of seed. Plant varieties are also selected on the basis of other seed forming characteristics, such as strong pods to ensure no seed is lost or dispersed prior to harvesting, or compact nature of the raceme of the plant that contains the seedpods. Not all plants have these ideal characteristics. Thus, there is a strong interest in modifying the placement of seed pods and overall physical characteristics, of many seed plants to produce plants with desirable plant architecture and overall morphology. Compact plants, with clustered seed pods can provide many benefits for mechanical production of the crop, as well as lead to increased productivity. Accordingly, control of plant form and plant architecture is a desirable goal for the industry. The building blocks of the plant architecture (body plan) are composed of reiterative units referred to as phytomers and these are elaborated during different phases of development (Sussex, I. M. & Kerk, N. M. (2001) Curr. Opin. Plant Biol. 4, 33-37). In Arabidopsis thaliana, three types of phytomers have been described (Schultz, E. A. & Hauglm, G. W. (1991) Plant Cell 3, 771-781.). The variations in the number of units and their size among these three main types of phytomers in different plant species contribute to the tremendous architectural diversity observed in flowering plants (Steeves, T. A. & Sussex, I. M. (1989) Patterns in plant development (Cambridge University Press, Cambridge). The activity of the shoot apical meristem (SAM), together with additional meristems, regulates the growth and development of all three types of phytomers (Medford, J. I., Behringer, F. J., Callos, J. D. & Feldmann, K. A. (1992)Plant Cell 4, 631-643 & Simon, R. (2001) Semin. Cell Dev. Biol. 12, 357-362). The SAM contains three major domains defined by cytoplasmic densities and cell division rates: the central zone (CZ), which is responsible for maintaining the pluripotent stem cells; the peripheral zone (PZ), which is involved in the production of lateral organs; and the rib zone (RZ), from which the bulk of the stem is derived (Bowman, J. L. & Eshed, Y. (2000) Trends Plant Sci. 5, 110-115). Recent studies in Arabidopsis have shown that several genes, including SHOOTMERISTEMLESS (STM), WUSCHEL and CLAVATA-family receptor kinases and their putative ligands define key functions in the SAM (Brand, U., Hobe, M. & Simon, R. (2001) BioEssays 23, 134-141., Long, J. A., Moan, E. I., Medford, J. I. & Barton, M. K. (1996) Nature 379,66-69., Mayer, K. F., Schoof, H., Haecker, A., Lenhard, A., Jurgens, G. & Laux, T.(1998) Cell 95, 805-815., & Clark, S. E. (2001) Nat. Mol. Cell Biol. 2, 276-284.) In Arabidopsis the inflorescence constitutes the major part of the shoot and thus contributes significantly to the overall shoot architecture. Several genes have been identified in Arabidopsis that play key roles in defining the architecture of the shoot/inflorescence. For example, dwarf plants with uniform effects on all phytomers have been associated with altered levels of or defects in the signaling pathways of certain plant hormones (gibberellins or brassinosteriods—Hedden, N. P. & Kamiya, Y. (1997) Annu. Rev. Plant Physiol. Plant Mol. Biol. 48, 431-460., & Richards, D. E., King, K. E., Ait-ali, T. & Harberd, N. P. (2001) Annu. Rev.Plant Physiol. Plant Mol. Biol. 52, 67-88., and references therein). The supershoot (Tantikanjana, T., Yong, J. W., Letham, D. S., Griffith, M., Hussain, M., Ljung, K., Sandberg, G. & Sundaresan, V. (2001) Genes Dev 15, 1577-1588.) and altered meristem program (Chaudhury, A. M., Letham, S., Craig, S. & Dennis; E. S. (1993) Plant J. 4,907-916.) mutants display abnormally high levels of cytokinins and produce extensive branching and altered shoot and inflorescence architecture. Auxin polar transport mutants, such as pinformed (Okada, K., Ueda, J., Komaki, M. K., Bell, C. J. & Shimura, Y. (1991) Plant Cell 3, 677-684.) and pinoid (Bennett, S. R. M., Alvarez, J., Bossinger, G. & Smyth, D. R. (1995) Plant J. 8, 505-520.), form inflorescences that are reduced to pin-like structures that do not produce any lateral organs or meristems. A compact inflorescence is caused by the erecta mutation, which involves a putative receptor kinase (Torii, K. U., Mitsukawa, N., Oosumi, T., Matsuura, Y., Yokoyama, R., Whittier, R. F. & Komeda, Y. (1996) Plant Cell 8, 735-746.). An even stronger effect on inflorescence architecture is conferred in a Landsberg erecta (Ler) background by the brevipedicellus (BP) mutation, which is defined by a recessive mutant with compact intemodes and short, downward-pointing pedicels (Koornneef, M., Eden, J. v., Hanhart, C. J., Stam, P., Braaksma, F. J. & Feenstra, W. J. (1983) J. Hered. 74, 265-272). Thus, mutants that exhibit altered architecture provide an indication that architecture can be altered, but there is no indication as to the molecular nature of the gene or the mechanisms by which these changes are manifested. The role of homeobox genes in defining body plan and their evolutionary relationships in animals is well documented (Gehring, W. J., Affolter, M. & Burglin, T. (1994) Annu. Rev. Biochem. 63,487-526., Kappen, C. (2000) Proc. Natl. Acad. Sci. USA 97, 4481-4486.) More recently, several plant knotted-like homeobox (KNOX) genes have been identified, which form two classes based upon sequence similarities and expression domains (Bharathan, G., Janssen, B., Kellogg, E. & Sinha, N. (1999) Mol. Biol. Evol. 16, 553-563., Reiser, L., Sanchez, B. P. & Hake, S. (2000) Plant Mol. Biol. 42, 151-166., Serikawa, K. A., Martinez-Laborda, A. & Zambryski, P. (1996) Plant Mol. Biol. 32, 673-693.) In Arabidopsis, there are four different class I KNOX genes, STM, KNAT1, KNAT2,and KNAT6 (Long, ibid., Lincoln, C., Long, J., Yamaguchi, J., Serikawa, K. & Hake, S. (1994) Plant Cell 6, 1859-1876. & Semiarti, E., Ueno, Y., Tsukaya, H., Iwakawa, H., Machida, C. & Machida, Y. (2001) Development 128, 1771-1783.) STMis expressed in the SAM, whereas KNAT1 and KNAT2 expression observed in the PZ of the SAM. KNAT1 is also expressed in the cortical cell layers of the peduncle and pedicel. STM, KNAT1 and KNAT2 expression is excluded from the leaf primordia and developing leaves by ASYMMETRICLEA VES 1 and 2 genes (Ori, N., Eshed, Y., Chuck, G., Bowman, J. L. & Hake, S. (2000) Development 127, 5523-5532., & Byrne, M., Barley, R., Curtis, M., Arroyo, J., Dunham, M., Hudson, A. & Martienssen, R. (2000) Nature 408, 967-971). Ectopic expression of KNAT1 and KNAT2 in leaves induces altered symmetry and cell fate, and ectopic meristem/shoot formation from the adaxial surface (Chuck, G., Lincoln, C. & Hake, S. (1996) Plant Cell 8, 1277-1289). To date, loss-of-function mutations in class I KNOX genes are known only for STM and these suggest a critical role in SAM maintenance and function. Significantly, however, no such mutations have previously been described for KNAT1, hampering study of the role of this homeobox gene in plant development. The future prospects of engineering optimal plant architectures in plant species will depend on the availability of critical morphology controlling genes and knowledge of their functional regulatory properties. For example in canola, the occurrence of an inflorescence and silique with long pedicels may offer some unique challenges and opportunities to develop an ideal architecture for improving productivity. In summary, there remains a continuing need to develop novel and efficient techniques for modifying the morphology and architecture of plants, such as for example Brassica and other plant types, to improve photosynthetic efficiency, overall yield, and harvestability. This need extends to both crops and to horticulturally grown species to improve aesthetic appeal. |
<SOH> SUMMARY OF THE INVENTION <EOH>The inventors of the present application have successfully identified the gene responsible for the brevipedicellus (bp) mutant in Arabidopsis. This mutation is known to give rise to plants having a very compact architecture with shortened siliques pointing downwards. Importantly, the inventors have realized that the successful identification of this gene has important implications on the generation of new crops and other plant species that exhibit advantageously modified morphological features. In this regard, the inventors have discovered that the bp mutation has several productivity advantages if introduced for example, into canola crop species. In Arabidopsis, the mutation results in reduced pedicel length, and siliques pointing downward with compact architecture. These features can improve exposure of upper leaves to sunlight and thereby enhance their photosynthetic efficiency: a well recognized problem in canola, especially during the pod setting and maturation stages. In addition, during harvesting the altered pod dynamics can reduce shattering losses, an important problem facing canola farmers. Further, the downward-pointing flowers may help in reducing disease incidence. Therefore, the present invention relates, in one embodiment, to nucleic acid sequences derived from Arabidopsis encoding a homeobox gene involved in the control of inflorescence architecture, for use in modifying plant inflorescence architecture. In addition, the present invention relates in other embodiments to methods for modifying the morphological phenotype of plants, by introducing the nucleotide sequences encompassed by the present invention into a plant, and expressing the nucleotide sequences as appropriate. In another embodiment, the present invention relates to nucleic acid sequences derived from Arabidopsis encoding a homeobox gene involved in the control of inflorescence architecture, said homeobox gene differing from wild type by at least a change in an amino acid codon to produce a truncated protein. The invention further relates to the proteins encoded by the nucleic acids encompassed by the invention, and their use. The present invention also relates to methods for alteration of the expression of a native gene related to inflorescence structure, in particular the reduction in the expression of said gene. In one aspect of the invention, nucleic acid sequences are provided that encode an altered protein that when expressed confers an altered inflorescence architecture phenotype in Arabidopsis, particularly an inflorescence with an altered pedicel, peduncle or style. In one aspect of the invention, nucleic acid sequences are provided that encode an altered protein that when expressed confers an altered inflorescence architecture phenotype in Brassica, particularly an inflorescence with an altered pedicel, peduncle or style. In another aspect of the present invention methods are described that enable the heterologous expression of the nucleic acid or portions or homologues thereof, described in SEQ ID NO: 5 in a host cell to obtain a plant with an altered inflorescence, more particularly an inflorescence with an altered pedicel, peduncle or style. In yet another aspect of the present invention, methods are described wherein the nucleic acid sequence or regions thereof as described in SEQ ID NO: 6 and nucleic acids homologous to same are used to alter the architecture of a flowering plant, in particular the inflorescence, more particularly the pedicel, peduncle or style. In yet another aspect of the present invention, methods are described wherein nucleic acid sequence or regions thereof as described in SEQ ID. NO: 6 and nucleic acids homologous to same are used to alter the architecture of the inflorescence of a plant from the Crucifer ( Cruciferae ) family, particularly the pedicel, peduncle or style of said plant. In yet another aspect of the present invention methods are described wherein nucleic acid sequence or regions thereof as described in SEQ ID. NO: 6 and nucleic acids homologous to same are used to alter the architecture of the inflorescence of a plant from the Crucifer ( Cruciferae ) family, particularly the pedicel of said plant, said plant exhibiting an altered inflorescence, with compact internodes, downward pointing pedicels and siliques that point downward relative to the normal presentation of siliques. In one embodiment, the present invention provides a method of producing a transgenic plant with a modified inflorescence architecture characterised in that the method comprises the steps of: (a) introducing into a plant cell capable of being transformed and regenerated into a whole plant a construct comprising, in addition to the DNA sequences required for transformation and selection in plants, a nucleotide sequence derived from a KNAT1 gene and encoding at least part of a KNAT1 gene product operably linked to a promoter; and (b) recovery of a plant which contains said nucleotide sequence and has a modified inflorescence architecture compared to an unmodified plant. Preferably, the method involves nucleotide sequences encoding a peptide having at least 50%, preferably 70%, more preferably 90%, more preferably 95%, most preferably 99% homology to the peptide encoded by SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. Preferably, the method involves nucleotide sequences that are able to bind under stringent conditions to SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof. Preferably, the modification of inflorescence architecture comprises an altered pedicel, peduncle or style, and more preferably the altered pedicel has an altered length compared to an unmodified plant. Moreover, the modified inflorescence architecture preferably comprises downwardly pointing flowers. In alternative embodiments, the invention provides methods characterised in that the nucleotide sequences are derived from a plant of the genus Arabidopsis or Brassica and/or the transformed plants are of the genus Arabidopsis or Brassica or are selected from the group consisting of: a dicot, a monocot, and a member of Cruciferae. Preferably, the methods of the invention can generate a plant having either a compact or an open inflorescence compared to an unmodified plant. The nucleotide sequences may be expressed in a sense direction for complementary inhibition of an endogenous KNAT1 gene in the transgenic plant, such that the plant has a compact inflorescence architecture compared to an unmodified plant. Preferably, the KNAT1 gene may be in a mutated form. In an alternative embodiment, the nucleotide sequence may be expressed in an antisense direction for antisense inhibition of an endogenous KNAT1 gene such that the plant has a compact inflorescence architecture and/or decreased pedicel length compared to an unmodified plant. In an further alternative embodiment, the nucleotide sequence may be overexpressed in a sense direction, such that the plant has an open inflorescence architecture and/or increased pedicel length compared to an unmodified plant. In one aspect, the plant may harbour a bp mutation such that expression of said nucleotide sequence is complementary to said mutation, inducing the plant exhibit a wild-type phenotype. The promoters for use in accordance with the methods of the present invention may take various forms. For example, the promoter may comprise, in one embodiment a transcriptional regulatory region normally in operable association with an endogenous KNAT1 gene or homologue thereof. Alternatively, the promoter may comprise a transcriptional regulatory region that is not normally in operable association with an endogenous KNAT1 gene or homologue thereof. Further, the promoter may be selected from the group consisting of: a constitutive promoter, an inducible promoter, an organ specific promoter, a strong promoter, a weak promoter, and an endogenous KNAT1 promoter from Arabidopsis. Alternatively, the promoter may be derived from a functional portion of SEQ ID NO: 23 or SEQ ID NO: 24. The present invention further encompasses methods for modifying the infloresence architecture of a plant involving the use of sequences homologous to SEQ ID NO: 5 or 6, such as., for example, SEQ ID NOS: 11., 14, 15, and 20. In another embodiment, the present invention provides a method of identifying a plant that has been successfully transformed with a construct, characterised in that the method comprises the steps of: (a) introducing into plant cells capable of being transformed and regenerated into whole plants a construct comprising, in addition to the DNA sequences required for transformation and selection in plants, a nucleotide sequence derived from a KNAT1 gene and encoding at least part of a KNAT1 gene product, operably linked to a promoter; ((b) regenerating said plant cells into whole plants; and (c) inspecting the inflorescences of said plants to determine those plants successfully transformed with said construct, and expressing said nucleotide sequence. In a preferred embodiment, the plant cells and the regenerated whole plants harbour a bp mutation, and successful transformation and expression of said nucleotide sequence complements said mutation, thereby generating a plant exhibiting a wild-type phenotype. More preferably, the construct is bicistronic and further comprises a second DNA expression cassette for generating a transcript unrelated to said nucleotide sequence derived from a KNAT1 gene. In this way, the KNAT1-related portion of the construct can complement a known mutation in a plant and positively confirm transformation, and simultaneously a second transcript can be produced from a second region of the bicistronic construct, conferring desirable or otherwise properties to the transgenic plant. The present invention further encompasses transgenic plants generated by any of the methods of the present invention. In this regard, the transgenic plants are preferably of the genus Arabidopsis or Brassica or plants selected from the group consisting of: a dicot, a monocot, and a member of Cruciferae. Moreover, the exogenous DNA or construct introduced into the plant may preferably be derived from plants of the genus Arabidopsis or Brassica. The transgenic plants of the present invention preferably comprise a modified inflorescence (e.g. compact or open) compared to an unmodified plant. Preferably the modified inflorescence architecture comprises an altered pedicel, peduncle or style, more preferably a plant with altered pedicel length or downwardly pointing flowers compared to an unmodified plant. The present invention further encompasses, in other embodiments, isolated nucleotide sequences for generating a transgenic plant with modified inflorescence architecture, characterised in that the isolated nucleotide sequences are derived from a KNAT1 gene and encode at least part of a KNAT1 gene product. The isolated nucleotide sequences preferably comprise a sequence selected from: (a) SEQ ID NO: 5 or 6, or a part thereof, or a complement thereof; and (b) a nucleotide sequence encoding a peptide having at least 50%, preferably 70%, more preferably 90%, more preferably 95%, and most preferably 99% homology to the peptide encoded by the nucleotide sequence defined in (a). Preferably the isolated nucleotide sequences of the present invention are characterised in that the nucleotide sequences hybridise under stringent conditions to the nucleotide sequence of SEQ ID NO: 5 or 6, or a part thereof or a complement thereof. The isolated nucleotide sequences for generating a transgenic plant with a modified inflorescence architecture compared to an unmodified plant, include sequences derived from a construct selected from the group consisting of: pRD400-951/955, pRD400-951/956, pRD400-35S::AtBPS, pRD400-35S::AtBPA/S, pRD400-35S::Atbp-2, pRP400-951/952: :Atbp-2, pRD400-951/952: :BnBPS, pRD400-35S: :BnBPS, and pRD400-35S::BnBPA/S. The present invention further encompasses, in further embodiments, the use of isolated nucleotide sequences related to the KNAT1 gene, for generating a transgenic plant with a modified inflorescence architecture. |
Method and device for attaching support sections for rubber seals to automobile body parts and corresponding support section |
Methods, devices and support profiles are configured to match the method and device in profiles used to attach a support section for rubber seals to automobile body parts in the shortest possible time with the minimum of tools and personnel. The methods and devices are adaptable in such a way that modifications to the geometry of the sealing section and to the contours of the body parts are accommodated without long stoppages of the assembly line. The support sections and connecting regions mold to all the contours of automobile bodyworks, in particular corner regions, and permit the attachment of various sealing regions and application of extreme detachment forces. The support section for the sealing section is attached to the support surface in one single operation. The sub-steps of said operation are carried out by an industrial robot. Adhesive is applied to the support section during its production. |
1. Method for positioning support sections (1) for rubber seals (11) on support surfaces (4), such as, for example, door bodies and trunk seals of automobiles using an application apparatus (3) in the form of an industrial robot which follows the contour of the support surface (4), whereby the support section (1) is pulled out of a drum-like storage device (2) by the application apparatus (3), guided by the application apparatus using guide rollers (5) after leaving the storage device (2), cut after attaining its final length by a path-controlled cutting unit (6) in the application apparatus (3) and pressed by the application apparatus (3) upon the support surface (4) using pressing and guide rollers (8), wherein the support section (1) is brought into adhering connection to the support surface (4) by the application device (3). 2. Method according to claim 1, wherein the application apparatus (3) applies the adhesive system to the support surface (4) using a coat of adhesive (7). 3. Device for positioning support sections (1) for rubber seals (11) on support surfaces (4), such as, for example, door bodies and trunk seals of automobiles, consisting of a storage unit (2) on which the support section (1) is rolled up, of an application apparatus (3) which includes at least 2 guide rollers (5), a path-controlled cutting unit (6) as well as at least one pressing and guide roller (8), wherein the application apparatus (3) is constructed with a coat of adhesive (7). 4. Self-adherent support section (9) for sealing sections (11) on support surfaces (4), such as, for example, door bodies and trunk seals of automobiles, wherein a gutter-like groove is hollowed out on the side which is to be joined with the support surface into which an adhesive system (12) is applied already during the manufacture of the self-adherent support section whose adhesive action is nonetheless first set into motion upon positioning the self-adherent support section on the support surface. 5. Method according to claim 1, wherein the application apparatus (3) sets the adhesive action of the adhesive system (12) into motion on the self-adherent support section (9) using an activation unit (10). 6. Device for applying self-adherent support sections (9) for rubber seals (11) on support surfaces (4), such as, for example, door bodies and trunk seals of automobiles, consisting of a storage device (2) on which the self-adherent support section (9) is rolled up, and of an application apparatus (3) which includes at least 2 guide rollers (5), a path-controlled cutting unit (6) as well as at least one pressing and guide roller (8), wherein the application apparatus (3) is constructed with an activation unit (10). 7. Support section (1) and connection region (13) for fastening sealing sections (11) to support surfaces (4) of automobile bodies, wherein the support section (1) is constructed in the form of a long, straight line segment (15) which is positioned on the support surface (4) using an adhesive system (12) and which runs somewhat parallel to the support surface (4) of the automobile body in the region of the adhesive surface, wherein the support section (1) has a retention peg (16) which points in the direction of the sealing section (11) and ends in a trapezoidal slip-fit flange (17), wherein the connection region (13) is constructed C-shaped and embraces the trapezoidal slip-fit flange (17) form-locking, wherein the connection region (13) is connected with the sealing region (140 of the sealing section (11). 8. Support section (1) according to claim 8, wherein the end of the segment (15) which lies opposite the retention peg (16) is constructed as a lip (18) which points toward the support surface (4) of the automobile body. 9. Support section (1) according to claim 8, wherein the surface of the segment (15) pointing toward the support surface (4) of the automobile body has an adhesive system (12) which was already applies at the manufacturer. |
Assay |
A method for the identification of a modular of the interaction between latency associated peptide (LAP) of transforming growth factor β3 (TGF-β3) and αv integrin, which method comprises: (a) providing, as a first component, LAP-β3 or a functional variant thereof; (b) providing, as a second component, and αv integrin or a functional variant thereof; (c) contacting the two components with a test product under conditions that, in the absence of the test product, would permit the two components to interact; and (d) determining whether the test product is capable of modulating the interaction between the first and second components, thereby to determine whether the test product is a modulator of the interaction between LAP-β3 and the integrin. |
1. A method for the identification of a modulator of the interaction between latency associated peptide LAP of transforming growth factor-β3 (TGF-β3) and an αv integrin which method comprises: (a) providing, as a first component, latency-associated peptide-β3 (LAP-β3) or a functional variant thereof; (b) providing, as a second component, an αv integrin thereof or a functional variant thereof; (c) contacting the two components with a test product under conditions that, in the absence of the test product, would permit the two components to interact; and (d) determining whether the test product is capable of modulating the interaction between the first and second components, thereby to determine whether the test product is a modulator of the interaction between LAP-β3 and the αv integrin. 2. A method according to claim 1, wherein in step (a) LAP-β3 or a functional variant thereof is in the form of a monomer. 3. A method according to claim 1, wherein in step (a) LAP-β3 or a functional variant thereof is in the form of a dimer. 4. A method according to claim 1, wherein in step (a) LAP-β3 or a functional variant thereof is provided as a component of a small latency complex (SLC). 5. A method according to claim 1, wherein in step (a) LAP-β3 or a functional variant thereof is provided as a component of a large latency complex (LLC). 6. A method according to claim 1, wherein LAP-β3 or a functional variant thereof is fused to a carrier polypeptide. 7. A method according to claim 1, wherein in step (b) the integrin is provided in the form of a cell line which expresses said integrin. 8. A method according to claim 1, wherein the modulator is an inhibitor of the interaction between LAP-β3 and the αv integrin. 9. A method according to claim 1, wherein the modulator is an activator of the interaction between LAP-β3 and the αv integrin. 10. A test kit for the identification of a modulator of the interaction between LAP-β3 and an αv integrin, which kit comprises: (i) a first component as defined in step (i) of claim 1; and (ii) a second component as defined in step (ii) of claim 1. 11. A test kit according to claim 10, which kit further comprises: (iii) means for determining whether a test product modulates the interaction between the first component and the second component. 12. A modulator of the interaction between LAP-β3 and an αv integrin. 13. A modulator according to claim 12 which is an inhibitor of the interaction between LAP-β3 and the integrin. 14. A modulator according to claim 12 which is an activator of the interaction between LAP-β3 and the integrin. 15. A modulator according to claim 13 for use in a method of immuno-modulation or in a method of treatment an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis. 16. A modulator according to claim 14 for use in a method of preventing apoptosis. 17-18. (Cancelled) 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a product which is a modulator of the interaction between LAP-β3 and an αv integrin. 20. A method for treating a host requiring immuno-modulation or suffering from an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis which method comprises administering to the host an effective amount of a product which is an inhibitor of the interaction between LAP-β3 and an αv integrin. 21. A method for treating a host requiring prevention of apoptosis which method comprises administering to the host an effective amount of an activator of the interaction between LAP-β3 and an integrin αv integrin. 22. A modulator of the interaction between LAP-∃3 and an αv integrin identified by a method according to claim 1. 23. A modulator according to claim 22 which is an inhibitor of the interaction between LAP-∃3 and the integrin. 24. A modulator according to claim 22 which is an activator of the interaction between LAP-∃3 and the integrin. 25-29. (Cancelled) 30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a modulator according to claim 22. 31. A method for treating a host requiring immuno-modulation or suffering from an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis, which method comprises administering to the host an effective amount of a modulator according to claim 23. 32. A method for treating a host requiring prevention of apoptosis, which method comprises administering to the host an effective amount of a modulator according to claim 24. 33. A method for identifying a product which can be used in a method of immuno-modulation or in a method of treatment of an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis, which method comprises: (a) providing, as a first component, latency-associated peptide-β3 (LAP-β3) or a functional variant thereof; (b) providing, as a second component, an αv integrin or a functional variant thereof; (c) contacting the two components with a test product under conditions that, in the absence of the test product, would permit the two components to interact; (d) determining whether the test product is capable of inhibiting the interaction between the first and second components; and (e) determining whether a product identified in step (d) can be used in a method of immuno-modulation or in a method of treatment of an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis. 34. A method for identifying a product which can be used in a method of preventing apoptosis, which method comprises: (a) providing, as a first component, latency-associated peptide-β3 (LAP-β3) or a functional variant thereof; (b) providing, as a second component, an αv integrin or a functional variant of any of these integrins; (c) contacting the two components with a test product under conditions that, in the absence of the test product, would permit the two components to interact; (d) determining whether the test product is capable of activating the interaction between the first and second components; and (e) determining whether a product identified in step (d) can be used in a method of preventing apoptosis. 35. A method for treating a host requiring immuno-modulation or suffering from an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis, which method comprises: (a) identifying a product by use of a method according to claim 33; and (b) administering to the host an effective amount of the product. 36. A method for treating a host requiring prevention of apoptosis, which method comprises: (a) identifying a product by use of a method according to claim 34; and (b) administering to the host an effective amount of the product. 37. (Cancelled) |
<SOH> BACKGROUND TO THE INVENTION <EOH>The integrins comprise a large family of heterodimeric transmembrane receptors that mediate both cell-cell and cell-matrix interactions. They engage numerous ligands and regulate a variety of cellular and physiological processes such as cell proliferation, apoptosis, migration, differentiation, inflammation, and tissue remodelling. The α v integrin family comprises the integrins α v β 1 , α v β 3 , α v β 5 , α v β 6 and α v β 8 . The family members are expressed on a wide variety of cells with one or more members being expressed on virtually all cell types. For example, α v β 3 has been shown to be expressed on endothelial cells, smooth muscle cells, a variety of monocyte-derived cells, tumor cells, platelets, mesenchymal fibroblasts, T lymphocytes, and dendritic cells. α v β 6 appears to have a more restricted distribution, being present on epithelial cells, tumor cells, and possibly some inflammatory cell types. The transforming growth factor-β (TGF-β) isoforms TGF-β1, TGF-β2 and TGF-β3 are expressed from numerous cell types and are present in virtually all tissues. They potently inhibit cellular proliferation of many cell types, and also induce extracellular matrix synthesis, integrin expression, and modulate immune responses. They are synthesised as large precursor proteins that are proteolytically processed in the golgi to yield a mature TGF-β protein of approximately 110 amino acids and an amino terminal protein called latency associated protein-β (LAP-β) of approximately 280 amino acids. These two proteins homodimerise and the two dimers also interact to form a LAP-β-TGF-β complex containing two parts of each protein. This complex renders TGF-β inactive, and activation requires some conformational change and/or proteolysis of the LAP-β protein. |
<SOH> SUMMARY OF THE INVENTION <EOH>This invention is based on our finding that the α v family of integrins bind the latency associated peptide-β3 (LAP-β3) of transforming growth factor-β3 (TGF-β3). The interaction between these integrins and LAP-β3 of TGF-β3 provides a link between the interaction and a number of biologically significant processes. According to the present invention there is thus provided a method for the identification of a modulator of the interaction between latency associated peptide-β3 and an α v integrin, which method comprises: (a) providing, as a first component, latency-associated peptide-β3 (LAP-β3) or a functional variant thereof; (b) providing, as a second component, an α v integrin or a functional variant thereof; (c) contacting the two components with a test product under conditions that, in the absence of the test product, would permit the two components to interact; and (d) determining whether the test product is capable of modulating the interaction between the first and second components, thereby to determine whether the test product is a modulator of the interaction between LAP-β3 and the α v integrin. The method of the invention may also be used to identify modulators of TGF-β3 activity. The invention also provides: a test kit for the identification of a modulator of the interaction between LAP-β3 and an α v integrin, which kit comprises: (i) a first component which is latency-associated peptide-β3 (LAP-β3) or a functional variant thereof; and (ii) a second component which is, an α v integrin or a functional variant thereof; a modulator of the interaction between LAP-β3 and an α v integrin for use in a method of treatment of the human or animal body; use of a modulator which is an inhibitor of the interaction between LAP-β3 and an α v integrin in the manufacture of a medicament for use in a method of immuno-modulation or in a method of treatment of an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis; use of a modulator which is an activator of the interaction between LAP-β3 and an α v integrin in the manufacture of a medicament for use in a method of preventing apoptosis; a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a product which is a modulator of the interaction between LAP-β3 and an α v integrin; a method for treating a host requiring immuno-modulation or suffering from an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis which method comprises administering to the host an effective amount of a product which is an inhibitor of the interaction between LAP-β3 and an α v integrin; a method for treating a host requiring prevention of apoptosis which method comprises administering to the host an effective amount of an activator of the interaction between LAP-β3 and an α v integrin; a modulator of the interaction between LAP-β3 and an α v integrin identified by a method of the invention or a test kit of the invention; a modulator of the interaction between LAP-β3 and an α v integrin identified by a method of the invention or a test kit of the invention for use in a method of treatment of the human or animal body by therapy; use of a modulator of the interaction between LAP-β3 and an α v integrin identified by a method of the invention or a test kit of the invention in the manufacture of a medicament for use in a method of immuno-modulation or a method of treatment of an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis; use of a modulator of the interaction between LAP-β3 and an α v integrin identified by a method of the invention or a test kit of the invention in the manufacture of a medicament for use in a method of preventing apoptosis; a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a modulator of the interaction between LAP-β3 and an α v integrin identified by a method of the invention or a test kit of the invention; a method for treating a host requiring immuno-modulation or suffering from an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis, which method comprises administering to the host an effective amount of a modulator of the interaction between LAP-β3 and an α v integrin identified by a method of the invention or a test kit of the invention; a method for treating a host requiring prevention of apoptosis, which method comprises administering to the host an effective amount of a modulator of the interaction between LAP-β3 and an α v integrin identified by a method of the invention or a test kit of the invention; a method for identifying a product which can be used in a method of immuno-modulation or in a method of treatment of an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis, which method comprises: (a) providing, as a first component, latency-associated peptide-β3 (LAP-β3) or a functional variant thereof; (b) providing, as a second component, an α v integrin or a functional variant thereof; (c) contacting the two components with a test product under conditions that, in the absence of the test product, would permit the two components to interact; (d) determining whether the test product is capable of inhibiting the interaction between the first and second components; and (e) determining whether a product identified in step (d) can be used in a method of immuno-modulation or in the treatment of an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis; a method for identifying a product which can be used in a method of preventing apoptosis, which method comprises: (a) providing, as a first component, latency-associated peptide-β3 (LAP-β3) or a functional variant thereof; (b) providing, as a second component, an α v integrin or a functional variant of a functional variant thereof; (c) contacting the two components with a test product under conditions that, in the absence of the test product, would permit the two components to interact; (d) determining whether the test product is capable of activating the interaction between the first and second components; and (e) determining whether a product identified in step (d) can be used in a method of preventing apoptosis; a method for treating a host requiring immuno-modulation or suffering from an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis, which method comprises: (a) identifying a product by use of a method for identifying a product which can be used in a method of immuno-modulation or in a method of treatment of an inflammatory disease, a fibrotic disease, cancer, diabetic retinopathy, bone resorption or osteoporosis, which method comprises; and (b) administering to the host an effective amount of the product; and a method for treating a host requiring prevention of apoptosis, which method comprises: (a) identifying a product by use of a method for identifying a product which can be used in a method of preventing apoptosis; and (b) administering to the host an effective amount of the product. |
Method for the application of mortar to an application surface |
In a method for applying a mortar mixture onto an application surface, a dry mortar starting mixture is prepared and conveyed by carrier air in a thin stream into a mixer arranged immediately upstream of a spray nozzle. The dry mortar starting mixture is mixed in the mixer with water to form a mortar-water mixture. The mortar-water mixture is moved in a dense stream to the spray nozzle. Compressed air is introduced into the spray nozzle and the mortar-water mixture is sprayed under the pressure of compressed air onto the application surface. |
1.-6. (canceled) 7. A method for applying a mortar mixture onto an application surface, the method comprising the steps of: preparing a dry mortar starting mixture; conveying the dry mortar starting mixture by carrier air in a thin stream into a mixer arranged immediately upstream of a spray nozzle; mixing the dry mortar starting mixture in the mixer with water to form a mortar-water mixture; moving the mortar-water mixture in a dense stream to the spray nozzle; and introducing compressed air into the spray nozzle and spraying the mortar-water mixture under the pressure of compressed air onto the application surface. 8. The method according to claim 7, further comprising the step of controlling a speed of the mixer such that at an intake side of the mixer, as a result of a backing-up process, a mortar layer having a thickness of a few centimeters is formed in which mixture particles supplied in the trailing thin stream are caught before they reach the mixing and conveying members of the mixer. 9. The method according to claim 8, further comprising the step of measuring with a sensor a thickness of the mortar layer forming at the intake side of the mixer and controlling the rotational speed of the mixing and conveying members of the mixer based on the thickness measured by the sensor. 10. The method according to claim 7, further comprising the step of branching off the carrier air conveying the dry mortar starting mixture to the mixer in a thin stream in an area of backed-up air generated at an end of a transport hose conveying the thin stream and supplying the branched-off carrier air, controlled by a three-way valve, via an air hose extending parallel to the dense stream to the spray nozzle. 11. The method according to claim 7, wherein the mixer has mixing and conveying members in the form of a mixing and conveying shaft. 12. The method according to claim 11, further comprising the step of controlling a speed of the mixing and conveying shaft. 13. The method according to claim 7, further comprising the step of driving the mixing and conveying member of the mixer by carrier air or an electric motor. |
Recirculation structure for a turbocompressor |
A recirculation structure for turbo-compressors has an annular chamber that is positioned in the area of the free blade ends of a rotating blade ring and that radially borders the main flow channel, and has a multitude of guide vanes arranged in the annular chamber and distributed around its circumference. The annular chamber enables the passage of air flow in the forward and/or rear areas, and the guide vanes are firmly fixed to at least one wall of the annular chamber and otherwise are designed to be free-standing. The tips of the guide vanes that face the annular chamber extend along and/or near the contour of the main flow channel, and axially overlap the free blade ends or axially border the area of the free blade ends. |
1-23. (cancelled) 24. A recirculation structure for a turbo-compressor, comprising: an annular chamber oriented concentrically with a compressor axis in an area of free blade ends of a rotating blade ring, an axial center of the annular chamber lying in front of an axial center of the free blade ends, said annular chamber radially bordering a contour of a main flow channel, and a multitude of guide vanes arranged in the annular chamber and distributed around its circumference, wherein the annular chamber permits flow to pass through circumferentially in at least one of forward and rear areas thereof, wherein the guide vanes are connected to at least one wall of the annular chamber and are free-standing, wherein tips of the guide vanes face toward the annular chamber and run at least one of along and near the contour of the main flow channel, and wherein the tips of the guide vanes axially overlap or axially border the area of the free blade ends. 25. The recirculation structure according to claim 24, wherein a ratio of an axial length of the annular chamber along the contour of the main flow channel to an axial length of the blade ends is 0.2 to 1.5. 26. The recirculation structure according to claim 24, wherein a ratio of a radial height to an axial length of the annular chamber is 0.1 to 1.0. 27. The recirculation structure according to claim 24, wherein an axial forward wall and an axial rear wall of the annular chamber, beginning at their circular rotating edges, are tilted upstream along the contour of the main flow channel. 28. The recirculation structure according to claim 27, wherein the axial forward wall and the axial rear wall of the annular chamber, starting from a radial direction, are tilted at an angle having a value ranging from 30° to 60°. 29. The recirculation structure according to claim 24, wherein the guide vanes are designed to be blade-like, spatially curved, and with varying thicknesses and defined profiles. 30. The recirculation structure according to claim 24, wherein the guide vanes, from an axial view, are tilted circumferentially at an angle, and wherein the angle can vary over the length of the guide vanes and is selected such that intake of the recirculation flow into the annular chamber is facilitated in terms of fluid mechanics and takes place in a manner that is favorable in terms of flow. 31. The recirculation structure according to claim 24, wherein the tips of the guide vanes are recessed radially, at least in the area of the free blade ends, far enough so that, during normal operation of the turbo-compressor, the blade ends and the guide vanes cannot come into contact with one another. 32. The recirculation structure according to claim 24, wherein the guide vanes are made of a metal, a light metal, or a plastic. 33. The recirculation structure according to claim 32, wherein the guide vanes are made of a light metal or plastic, and wherein the tips of the guide vanes are near enough to the free blade ends that they may come into contact with one another during operation. 34. The recirculation structure according to claim 24, wherein the circumferential flow passes through openings in forward areas, in rear areas, or in both forward and rear areas of the guide vanes. 35. The recirculation structure according to claim 24, wherein the annular chamber and the guide vanes are designed to be integral parts of a component that encompasses them. 36. The recirculation structure according to claim 24, wherein the annular chamber and the guide vanes are designed to be a single piece or at least two segments that border one another circumferentially, and wherein said annular chamber is separably mounted in a component that encompasses it. 37. The recirculation structure according to claim 35, wherein the structure is cast, machined, or electrochemically machined. 38. The recirculation structure according to claim 24, wherein the guide vanes are designed to be separate, individual components or component groups and are separably mounted in the annular chamber. 39. The recirculation structure according to claim 38, wherein the guide vanes are at least one of forged, cast, manufactured via electrochemical machining, and machined. 40. The recirculation structure according to claim 38, wherein the annular chamber is at least one of machined, manufactured via casting, and manufactured via forging. 41. The recirculation structure according to claim 24, wherein the structure is singly or plurally fixed in a casing so as to be static in an area of at least one rotating blade ring. 42. The recirculation structure according to claim 24, wherein the circumferential flow passes through recesses. 43. The recirculation structure according to claim 24, wherein the circumferential flow passes through at least one of recesses and openings in the guide vanes in forward or in forward and rear areas of the annular chamber. 44. A turbo-compressor, with at least one of an axial, a diagonal, and a radial construction, comprising at least one recirculation structure according to claim 24. 45. An aircraft engine comprising a turbo-compressor according to claim 44. 46. A stationary gas turbine comprising a turbo-compressor according to claim 44. 47. The recirculation structure according to claim 32, wherein the guide vanes are made of at least one of steel, a Ni-based alloy, a Co-based alloy, Al, a thermoplastic, a thermosetting plastic, and an elastomer. 48. The recirculation structure according to claim 37, wherein casting is waste-wax casting. 49. The recirculation structure according to claim 38, wherein the separate, individual components are guide vane segments. 50. The recirculation structure according to claim 24, wherein the structure is singly or plurally fixed in a hub so as to be rotatable in an area of at least one vane ring. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>This invention relates to a recirculation structure for turbo-compressors, a turbo-compressor, an aircraft engine, and a stationary gas turbine. Recirculation structures for turbo-compressors have been known in the art for quite a long time, and in the trade are generally referred to as “casing treatments”. Their primary function is to increase the aerodynamically stable operating range of the compressor, wherein the so-called surge margin is shifted to higher compressor pressures, i.e. to a higher compressor load. The failures that are responsible for localized stalling and ultimately for the surging of the compressor occur on the casing side at the ends of the rotating blades of one or more compressor stages, and on the hub side at the ends of the vanes that lie radially inside, because in these areas the aerodynamic load is the highest. By recirculating the “air particles” that circulate between the blade tips at blade speed, and whose energy level is reduced, into the main stream with an increase in energy, the flow in the area of the blade ends is again stabilized. Because flow disruptions as a rule do not occur evenly over all the stages, in terms of fluid mechanics, a circumferential balancing, in addition to the essentially axial recirculation, should also be possible. The primary disadvantage of known “casing treatments” is that, although they do increase the surge margin, they also reduce the efficiency level of the compressor. German publication DE 33 22 295 C3 protects an axial fan with a “casing treatment”. Recognizable therein is an annular chamber ( 8 ) in which guide vanes ( 9 ) are fixed. In the downstream area over the ends of the rotating blades is an area that is open circumferentially into which the guide vanes do not extend. Characteristic of this type of “casing treatment” is a closed ring ( 7 ) that is aligned generally with the shape of the main flow channel, with the ring separating the rear intake area from the forward outlet area of the recirculation structure, and forming a smooth, closed surface area. A quite similar “casing treatment” is known from German publication DE 35 39 604 C1, wherein an area that is open circumferentially is present in the forward and rear areas of the annular chamber ( 7 ). The radially inside ring 6 is also seen here. A more recent “casing treatment” is known from U.S. Pat. No. 5,282,718. Here, the annular chamber ( 18 , 28 ) and the guide vanes ( 24 ) are improved in terms of fluid mechanics. Here again, the intake and outlet of the recirculation flow are separated by a solid ring that is smooth and closed on the side of the blades. Rings of this type in the blade area must ordinarily be provided with a contact or intake coating in case they should come in contact with the blade tips. Further “casing treatments” having axial or axially angled grooves are disclosed e.g. in U.S. Pat. No. 5,137,419. These are not taken into consideration here, however, because the grooves are not connected to one another in these versions; hence no circumferential flow comparison is possible. U.S. Pat. No. 4,511,308 relates to ventilators (fans, blowers) having various “casing treatment” designs. The simplest design according to FIG. 6 possesses only one annular chamber without guide vanes. In the embodiments according to FIGS. 1 and 3 , guide vanes are mounted in the annular chamber, and the upstream casing wall ( 22 ) is extended beyond the radial inside edges of the guide vanes ( 21 ) like a cylindrical or conical socket piece, so that on the upstream, forward end of the annular chamber no outlet of the recirculation flow into the main flow is possible. FIG. 5 shows guide vanes ( 21 ) that are mounted on the forward end wall and on the outer circumference of the annular chamber, and are further designed to be freestanding. Here there is no socket- or ring-like element that connects or covers the guide vanes circumferentially. The free, radially inside edges of the guide vanes ( 21 ) rise from the front to the back from the diameter of the intake casing ( 15 ) up to the greatest diameter of the annular chamber ( 16 ). In this manner, although in the downstream area the guide vanes axially overlap the upstream area of the blade ends ( 14 ), due to the great radial distance between the guide vanes ( 21 ) and the blade ends ( 14 ), no effective and defined guidance of the recirculation air is possible. Of further disadvantage is the large volume of the annular chamber ( 16 ) in relation to the blade dimensions. This type of embodiment is neither aerodynamically nor constructively suitable for a turbo-compressor. In view of the disadvantages of the state of the art solutions, the object of the invention is to provide a recirculation structure for turbo-compressors that will enable a substantial enhancement of the surge margin, and thus a clear expansion of the stable operating range, without a significant reduction of the efficiency of the compressor. The essence of the invention is to have the tips of the guide vanes that face the annular chamber lie on or near the contour of the main flow channel, and axially overlap the free ends of the blades or axially border the area of the free ends of the blades. In this manner, annular elements with contact coatings, etc. can be eliminated. The above-cited patent specifications show that up to now the professional world has consistently tried to design recirculation structures that will be smooth, without gaps, and closed over the largest possible axial range, up to the main flow channel, i.e. up to the so-called annular chamber, in order to effect an extension of the contours of the main flow channel that will be as favorable in terms of flow and loss as possible. The invention, in contrast, leads to gaps, fissured surfaces, etc., and thus would appear to be disadvantageous and inexpedient. Test have shown, however, that the recirculation structure of the invention is superior to known solutions in terms of both enhancing the surge margin and improving the level of efficiency. This can be explained in aerodynamic terms in that the free, informal design of the recirculation flow in the open annular chamber with free-standing guide vanes and circumferential flow links is more important than the greatest possible gap-free extension of the contour of the main flow channel. The absence of a closed ring has the further advantages that no contact or intake coating of the guide vanes is necessary, and radial space and weight are saved, resulting in structural mechanical advantages. However, a defined control of the recirculation flow—without annular elements—is achieved only if the free edges of the guide vanes run relatively close to the edges of the blades, partially overlapping them axially, or at least lying adjacent to their space. Only in this way can a compact “casing treatment” that is suitable for use in a compressor ultimately be achieved. The ratio of the axial length of the annular chamber to the axial length of the blade ends preferably is 0.2 to 1.5. In the case of wide blades having a large axial span at the blade end, the ratio will be closer to 0.2; with narrow blades having a small axial span at the blade end, the ratio will be closer to 1.5. In the preferred embodiment, the ratio of the radial height to the axial length of the annular chamber is 0.1 to 1.0. With aircraft engines having very strict standards in terms of space requirements, contours, etc., attempts will be made to manage with a smaller ratio, i.e. a smaller radial height. For stationary applications having adequate space available it is possible to go closer to the upper limit. With axially short annular chambers one would also tend more to approach the upper limit. It is further preferred that the tips of the guide vanes that face toward the annular chamber are radially recessed, at least in the area of the free blade ends, far enough that during normal operation the ends of the blades will not come into contact with the guide vanes. This is due to the fact that the tips of the blades may be damaged by brushing against something, especially against hard, inflexible guide vane tips. The recessing of the guide vane tips is not in contradiction to the requirement that the tips should lie on or near the contour of the main flow channel, because the small radial gap dimensions required to prevent contact are practically without consequence in terms of fluid mechanics, i.e. they do not negatively affect recirculation. In the sub-claims, preferred embodiments of the recirculation structure according to the main claim, as well as a turbo-compressor, an aircraft gas turbine, and a stationary gas turbine are characterized. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>This invention relates to a recirculation structure for turbo-compressors, a turbo-compressor, an aircraft engine, and a stationary gas turbine. Recirculation structures for turbo-compressors have been known in the art for quite a long time, and in the trade are generally referred to as “casing treatments”. Their primary function is to increase the aerodynamically stable operating range of the compressor, wherein the so-called surge margin is shifted to higher compressor pressures, i.e. to a higher compressor load. The failures that are responsible for localized stalling and ultimately for the surging of the compressor occur on the casing side at the ends of the rotating blades of one or more compressor stages, and on the hub side at the ends of the vanes that lie radially inside, because in these areas the aerodynamic load is the highest. By recirculating the “air particles” that circulate between the blade tips at blade speed, and whose energy level is reduced, into the main stream with an increase in energy, the flow in the area of the blade ends is again stabilized. Because flow disruptions as a rule do not occur evenly over all the stages, in terms of fluid mechanics, a circumferential balancing, in addition to the essentially axial recirculation, should also be possible. The primary disadvantage of known “casing treatments” is that, although they do increase the surge margin, they also reduce the efficiency level of the compressor. German publication DE 33 22 295 C3 protects an axial fan with a “casing treatment”. Recognizable therein is an annular chamber ( 8 ) in which guide vanes ( 9 ) are fixed. In the downstream area over the ends of the rotating blades is an area that is open circumferentially into which the guide vanes do not extend. Characteristic of this type of “casing treatment” is a closed ring ( 7 ) that is aligned generally with the shape of the main flow channel, with the ring separating the rear intake area from the forward outlet area of the recirculation structure, and forming a smooth, closed surface area. A quite similar “casing treatment” is known from German publication DE 35 39 604 C1, wherein an area that is open circumferentially is present in the forward and rear areas of the annular chamber ( 7 ). The radially inside ring 6 is also seen here. A more recent “casing treatment” is known from U.S. Pat. No. 5,282,718. Here, the annular chamber ( 18 , 28 ) and the guide vanes ( 24 ) are improved in terms of fluid mechanics. Here again, the intake and outlet of the recirculation flow are separated by a solid ring that is smooth and closed on the side of the blades. Rings of this type in the blade area must ordinarily be provided with a contact or intake coating in case they should come in contact with the blade tips. Further “casing treatments” having axial or axially angled grooves are disclosed e.g. in U.S. Pat. No. 5,137,419. These are not taken into consideration here, however, because the grooves are not connected to one another in these versions; hence no circumferential flow comparison is possible. U.S. Pat. No. 4,511,308 relates to ventilators (fans, blowers) having various “casing treatment” designs. The simplest design according to FIG. 6 possesses only one annular chamber without guide vanes. In the embodiments according to FIGS. 1 and 3 , guide vanes are mounted in the annular chamber, and the upstream casing wall ( 22 ) is extended beyond the radial inside edges of the guide vanes ( 21 ) like a cylindrical or conical socket piece, so that on the upstream, forward end of the annular chamber no outlet of the recirculation flow into the main flow is possible. FIG. 5 shows guide vanes ( 21 ) that are mounted on the forward end wall and on the outer circumference of the annular chamber, and are further designed to be freestanding. Here there is no socket- or ring-like element that connects or covers the guide vanes circumferentially. The free, radially inside edges of the guide vanes ( 21 ) rise from the front to the back from the diameter of the intake casing ( 15 ) up to the greatest diameter of the annular chamber ( 16 ). In this manner, although in the downstream area the guide vanes axially overlap the upstream area of the blade ends ( 14 ), due to the great radial distance between the guide vanes ( 21 ) and the blade ends ( 14 ), no effective and defined guidance of the recirculation air is possible. Of further disadvantage is the large volume of the annular chamber ( 16 ) in relation to the blade dimensions. This type of embodiment is neither aerodynamically nor constructively suitable for a turbo-compressor. In view of the disadvantages of the state of the art solutions, the object of the invention is to provide a recirculation structure for turbo-compressors that will enable a substantial enhancement of the surge margin, and thus a clear expansion of the stable operating range, without a significant reduction of the efficiency of the compressor. The essence of the invention is to have the tips of the guide vanes that face the annular chamber lie on or near the contour of the main flow channel, and axially overlap the free ends of the blades or axially border the area of the free ends of the blades. In this manner, annular elements with contact coatings, etc. can be eliminated. The above-cited patent specifications show that up to now the professional world has consistently tried to design recirculation structures that will be smooth, without gaps, and closed over the largest possible axial range, up to the main flow channel, i.e. up to the so-called annular chamber, in order to effect an extension of the contours of the main flow channel that will be as favorable in terms of flow and loss as possible. The invention, in contrast, leads to gaps, fissured surfaces, etc., and thus would appear to be disadvantageous and inexpedient. Test have shown, however, that the recirculation structure of the invention is superior to known solutions in terms of both enhancing the surge margin and improving the level of efficiency. This can be explained in aerodynamic terms in that the free, informal design of the recirculation flow in the open annular chamber with free-standing guide vanes and circumferential flow links is more important than the greatest possible gap-free extension of the contour of the main flow channel. The absence of a closed ring has the further advantages that no contact or intake coating of the guide vanes is necessary, and radial space and weight are saved, resulting in structural mechanical advantages. However, a defined control of the recirculation flow—without annular elements—is achieved only if the free edges of the guide vanes run relatively close to the edges of the blades, partially overlapping them axially, or at least lying adjacent to their space. Only in this way can a compact “casing treatment” that is suitable for use in a compressor ultimately be achieved. The ratio of the axial length of the annular chamber to the axial length of the blade ends preferably is 0.2 to 1.5. In the case of wide blades having a large axial span at the blade end, the ratio will be closer to 0.2; with narrow blades having a small axial span at the blade end, the ratio will be closer to 1.5. In the preferred embodiment, the ratio of the radial height to the axial length of the annular chamber is 0.1 to 1.0. With aircraft engines having very strict standards in terms of space requirements, contours, etc., attempts will be made to manage with a smaller ratio, i.e. a smaller radial height. For stationary applications having adequate space available it is possible to go closer to the upper limit. With axially short annular chambers one would also tend more to approach the upper limit. It is further preferred that the tips of the guide vanes that face toward the annular chamber are radially recessed, at least in the area of the free blade ends, far enough that during normal operation the ends of the blades will not come into contact with the guide vanes. This is due to the fact that the tips of the blades may be damaged by brushing against something, especially against hard, inflexible guide vane tips. The recessing of the guide vane tips is not in contradiction to the requirement that the tips should lie on or near the contour of the main flow channel, because the small radial gap dimensions required to prevent contact are practically without consequence in terms of fluid mechanics, i.e. they do not negatively affect recirculation. In the sub-claims, preferred embodiments of the recirculation structure according to the main claim, as well as a turbo-compressor, an aircraft gas turbine, and a stationary gas turbine are characterized. |
Process for the manufacturing of decorative boards |
A process of the manufacturing of decorative boards with an abrasion resistant surface and edges with joining functionality, the process comprising the steps: a) cutting a carrier board to the desired dimension and molding edges with joining functionality, b) treating at least the upper surface of the board, c) applying radiation curable dry acrylic lacquer powder by means of electrostatic spray nozzles, d) heating the acrylic lacquer so that it melts, e) curing the acrylic lacquer by means of radiation being selected from the group consisting of UV-radiation and electron beam radiation. |
1. A process for the manufacturing of decorative boards with an abrasion resistant surface and edges with joining functionality, the process comprising the steps: a) cutting a carrier board to the desired dimension and molding edges with joining functionality, b) treating at least the upper surface of the board, c) applying radiation curable dry acrylic lacquer powder by means of electrostatic spray nozzles, d) heating the acrylic lacquer so that it melts, e) curing the acrylic lacquer by means of radiation, the radiation being selected from the group consisting of UV-radiation and electron beam radiation. 2. A process according to claim 1, wherein at least the upper surface of the board is sanded smooth before applying the acrylic lacquer. 3. A process according to claim 1, wherein at least the upper surface of the board is pressed with a heated calendar roller, the surface temperature of the calendar roller being in the range 45-150° C. and that the calendar roller exerts a pressure on the board in the range 10-100 bar. 4. A process according to claim 1, wherein a primer is applied on the board before applying the acrylic lacquer. 5. A process according to claim 1, wherein a decorative foil is applied on the board before applying the acrylic lacquer. 6. A process according to claim 1, wherein a decor is printed on the upper surface before applying the acrylic lacquer. 7. A process according to claim 1, wherein an upper surface of the board is coated with a bonding layer to an amount of 10-40 g/m2, that hard particles with an average particle size in the range 40-150 μm are sprinkled to an amount of 1-30 g/m2 on the sticky bonding layer, that the hard particles are selected from the group consisting of aluminum oxide, silicon oxide, silicon carbide and mixtures thereof. 8. A process according to claim 7, wherein the bonding layer is a wet UV-curable acrylic lacquer, which bonding layer is cured after having applied the hard particles. 9. A process according to claim 7, wherein the bonding layer is a UV- or electron beam curable acrylic lacquer. 10. A process according to claim 1, wherein the board is preheated before applying the acrylic lacquer. 11. A process according to claim 10, wherein the preheating is arranged so that a surface temperature of the board is in the range 40-150° C. when the application of acrylic lacquer is initiated. 12. A process according to claim 10, wherein the preheating is arranged so that a core temperature of the board is in the range 40-150° C. when the application of acrylic lacquer is initiated. 13. A process according to claim 1, wherein the acrylic lacquer is applied to an amount of 10-250 g/m2. 14. A process according to claim 13, wherein the acrylic lacquer is applied to an amount of 50-250 g/m2 on an upper surface of the board. 15. A process according to claim 13, wherein the acrylic lacquer is applied to an amount of 10-70 g/m2 on a lower surface of the board. 16. A process according to claim 13, wherein the acrylic lacquer is applied to an amount of 10-100 g/m2 on the edges of the board. 17. A process according to claim 13, wherein the acrylic lacquer applied on an upper surface comprises hard particles selected from the group consisting of aluminum oxide, silicon oxide and silicon carbide. 18. A process according to claim 17, wherein the hard particles have an average particle size in the range 1-150 μm. 19. A process according to claim 17, wherein the hard particles have an average particle size in the range 1-50 μm. 20. A process according to claim 13, wherein the hard particles are mixed with the acrylic lacquer in the nozzles during the coating process. 21. A process according to claim 13, wherein the acrylic lacquer is applied by separate groups of nozzles, the groups comprising an upper surface coating group, a rear surface coating group and at least one edge coating group. 22. A process according to claim 13, wherein the acrylic lacquer is applied by separate groups of nozzles, the groups comprising an upper surface coating group, a rear surface coating group and two edge coating groups. 23. A process according to claim 13, wherein the acrylic lacquer is applied by separate groups of nozzles, the groups comprising an upper surface coating group, a rear surface coating group and four edge coating groups. 24. A process according to claim 21, wherein the acrylic lacquer applied on the edges is guided by means of an air stream, the air stream being achieved by means of a narrow air evacuation tube, the air evacuation tube having a suction nozzle which is arranged adjacent to recesses and pockets molded in the edge whereby a more uniform coating is achieved on the edge. 25. A process according to claim 13, wherein the acrylic lacquer is melted by means of hot air environment. 26. A process according to claim 13, wherein the acrylic lacquer is melted by means of infrared radiation. 27. A process according to claim 26, wherein the acrylic lacquer applied on the edges is illuminated with the infrared radiation via reflectors. 28. A process according to claim 1, wherein the molten acrylic lacquer is cured by means of UV radiation, that the acrylic lacquer applied on the edges are illuminated with UV light via reflectors. 29. (Cancelled) |
Subsets and Splits