KR20180137813A - Lytic bacteriophage specific for klebsiella genus resistant to antibiotics - Google Patents
Lytic bacteriophage specific for klebsiella genus resistant to antibiotics Download PDFInfo
- Publication number
- KR20180137813A KR20180137813A KR1020170077538A KR20170077538A KR20180137813A KR 20180137813 A KR20180137813 A KR 20180137813A KR 1020170077538 A KR1020170077538 A KR 1020170077538A KR 20170077538 A KR20170077538 A KR 20170077538A KR 20180137813 A KR20180137813 A KR 20180137813A
- Authority
- KR
- South Korea
- Prior art keywords
- bacteriophage
- klebsiella
- ymc15
- antibiotic
- present
- Prior art date
Links
- 241001515965 unidentified phage Species 0.000 title claims abstract description 114
- 241000588748 Klebsiella Species 0.000 title claims description 31
- 239000003242 anti bacterial agent Substances 0.000 title claims description 31
- 229940088710 antibiotic agent Drugs 0.000 title description 17
- 230000002101 lytic effect Effects 0.000 title description 5
- 230000003115 biocidal effect Effects 0.000 claims abstract description 60
- 241000588754 Klebsiella sp. Species 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims abstract description 6
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 32
- 241000894006 Bacteria Species 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 235000013305 food Nutrition 0.000 claims description 15
- 229940096118 ella Drugs 0.000 claims description 12
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 9
- 206010035664 Pneumonia Diseases 0.000 claims description 8
- 239000000645 desinfectant Substances 0.000 claims description 8
- 206010057190 Respiratory tract infections Diseases 0.000 claims description 6
- 241000702202 Siphoviridae Species 0.000 claims description 5
- 206010014561 Emphysema Diseases 0.000 claims description 4
- 206010040047 Sepsis Diseases 0.000 claims description 4
- 230000000877 morphologic effect Effects 0.000 claims description 4
- 230000030833 cell death Effects 0.000 claims description 3
- 241000588749 Klebsiella oxytoca Species 0.000 claims description 2
- 241000588746 Raoultella planticola Species 0.000 claims description 2
- 241000588756 Raoultella terrigena Species 0.000 claims description 2
- 210000000234 capsid Anatomy 0.000 claims 2
- 230000002147 killing effect Effects 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 description 13
- 208000015181 infectious disease Diseases 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 108700026244 Open Reading Frames Proteins 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 241000456882 Salmonella virus FSLSP030 Species 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 4
- 241001641016 Salmonella phage 35 Species 0.000 description 4
- 241001640996 Salmonella phage 37 Species 0.000 description 4
- 238000012300 Sequence Analysis Methods 0.000 description 4
- 101710173665 Uncharacterized 5.8 kDa protein Proteins 0.000 description 4
- 101710172361 Uncharacterized protein ycf17 Proteins 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 4
- 229960000723 ampicillin Drugs 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 235000013361 beverage Nutrition 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 3
- 101100351191 Autographa californica nuclear polyhedrosis virus PCNA gene Proteins 0.000 description 3
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- -1 Levoflocacin Chemical compound 0.000 description 3
- 101150050790 ORF49 gene Proteins 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229960004821 amikacin Drugs 0.000 description 3
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 3
- 229960003644 aztreonam Drugs 0.000 description 3
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 3
- 229960001139 cefazolin Drugs 0.000 description 3
- 210000002421 cell wall Anatomy 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229960002770 ertapenem Drugs 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229960002260 meropenem Drugs 0.000 description 3
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- LITBAYYWXZOHAW-XDZRHBBOSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]hept Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 LITBAYYWXZOHAW-XDZRHBBOSA-N 0.000 description 2
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 2
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 241000639569 Erwinia phage PEp14 Species 0.000 description 2
- 239000004386 Erythritol Substances 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101000976889 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 19.2 kDa protein in cox-rep intergenic region Proteins 0.000 description 2
- 101000768938 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 8.9 kDa protein in int-C1 intergenic region Proteins 0.000 description 2
- 101700012268 Holin Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
- 101710118890 Photosystem II reaction center protein Ycf12 Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108091075982 RecT family Proteins 0.000 description 2
- 241001518594 Salmonella phage BP12C Species 0.000 description 2
- 241000456879 Salmonella phage FSL SP-019 Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 101710166729 Tail fiber protein Proteins 0.000 description 2
- 101710198378 Uncharacterized 10.8 kDa protein in cox-rep intergenic region Proteins 0.000 description 2
- 101710110895 Uncharacterized 7.3 kDa protein in cox-rep intergenic region Proteins 0.000 description 2
- 101710134973 Uncharacterized 9.7 kDa protein in cox-rep intergenic region Proteins 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229940043312 ampicillin / sulbactam Drugs 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229960002100 cefepime Drugs 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 2
- 229960002682 cefoxitin Drugs 0.000 description 2
- 229960000484 ceftazidime Drugs 0.000 description 2
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- NWOYIVRVSJDTLK-YSDBFZIDSA-L disodium;(2s,5r,6r)-6-[[(2r)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(1r,4s)-3,3-dimethyl-2,2,6-trioxo-2$l^{6}-thiabicyclo[3.2.0]heptane-4-carboxylate Chemical compound [Na+].[Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)C2C(=O)C[C@H]21.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 NWOYIVRVSJDTLK-YSDBFZIDSA-L 0.000 description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 2
- 235000019414 erythritol Nutrition 0.000 description 2
- 229940009714 erythritol Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- CEAZRRDELHUEMR-UHFFFAOYSA-N gentamicin Chemical compound O1C(C(C)NC)CCC(N)C1OC1C(O)C(OC2C(C(NC)C(C)(O)CO2)O)C(N)CC1N CEAZRRDELHUEMR-UHFFFAOYSA-N 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229940104641 piperacillin / tazobactam Drugs 0.000 description 2
- 230000007505 plaque formation Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 101710115267 ATP synthase protein MI25 Proteins 0.000 description 1
- 101000621943 Acholeplasma phage L2 Probable integrase/recombinase Proteins 0.000 description 1
- 101000748061 Acholeplasma phage L2 Uncharacterized 16.1 kDa protein Proteins 0.000 description 1
- 101000818123 Acholeplasma phage L2 Uncharacterized 17.2 kDa protein Proteins 0.000 description 1
- 101000818089 Acholeplasma phage L2 Uncharacterized 25.6 kDa protein Proteins 0.000 description 1
- 101000827329 Acholeplasma phage L2 Uncharacterized 26.1 kDa protein Proteins 0.000 description 1
- 101000768957 Acholeplasma phage L2 Uncharacterized 37.2 kDa protein Proteins 0.000 description 1
- 101000818108 Acholeplasma phage L2 Uncharacterized 81.3 kDa protein Proteins 0.000 description 1
- 101000823746 Acidianus ambivalens Uncharacterized 17.7 kDa protein in bps2 3'region Proteins 0.000 description 1
- 101000916369 Acidianus ambivalens Uncharacterized protein in sor 5'region Proteins 0.000 description 1
- 101000769342 Acinetobacter guillouiae Uncharacterized protein in rpoN-murA intergenic region Proteins 0.000 description 1
- 101000823696 Actinobacillus pleuropneumoniae Uncharacterized glycosyltransferase in aroQ 3'region Proteins 0.000 description 1
- 101000786513 Agrobacterium tumefaciens (strain 15955) Uncharacterized protein outside the virF region Proteins 0.000 description 1
- 101000618005 Alkalihalobacillus pseudofirmus (strain ATCC BAA-2126 / JCM 17055 / OF4) Uncharacterized protein BpOF4_00885 Proteins 0.000 description 1
- 101000618348 Allochromatium vinosum (strain ATCC 17899 / DSM 180 / NBRC 103801 / NCIMB 10441 / D) Uncharacterized protein Alvin_0065 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102100020724 Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1 Human genes 0.000 description 1
- 101000748781 Anthoceros angustus Uncharacterized 3.0 kDa protein in psbT-psbN intergenic region Proteins 0.000 description 1
- 101000812031 Anthoceros angustus Uncharacterized 5.9 kDa protein in rps16-psbA intergenic region Proteins 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 101100214868 Autographa californica nuclear polyhedrosis virus AC54 gene Proteins 0.000 description 1
- 101100074342 Autographa californica nuclear polyhedrosis virus LEF-11 gene Proteins 0.000 description 1
- 101000781117 Autographa californica nuclear polyhedrosis virus Uncharacterized 12.4 kDa protein in CTL-LEF2 intergenic region Proteins 0.000 description 1
- 101000770875 Autographa californica nuclear polyhedrosis virus Uncharacterized 14.2 kDa protein in PK1-LEF1 intergenic region Proteins 0.000 description 1
- 101000781183 Autographa californica nuclear polyhedrosis virus Uncharacterized 20.4 kDa protein in IAP1-SOD intergenic region Proteins 0.000 description 1
- 101000847476 Autographa californica nuclear polyhedrosis virus Uncharacterized 54.7 kDa protein in IAP1-SOD intergenic region Proteins 0.000 description 1
- 101000967489 Azorhizobium caulinodans (strain ATCC 43989 / DSM 5975 / JCM 20966 / LMG 6465 / NBRC 14845 / NCIMB 13405 / ORS 571) Uncharacterized protein AZC_3924 Proteins 0.000 description 1
- 101000708323 Azospirillum brasilense Uncharacterized 28.8 kDa protein in nifR3-like 5'region Proteins 0.000 description 1
- 101000770311 Azotobacter chroococcum mcd 1 Uncharacterized 19.8 kDa protein in nifW 5'region Proteins 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 101000823761 Bacillus licheniformis Uncharacterized 9.4 kDa protein in flaL 3'region Proteins 0.000 description 1
- 101000819719 Bacillus methanolicus Uncharacterized N-acetyltransferase in lysA 3'region Proteins 0.000 description 1
- 101000789586 Bacillus subtilis (strain 168) UPF0702 transmembrane protein YkjA Proteins 0.000 description 1
- 101000748761 Bacillus subtilis (strain 168) Uncharacterized MFS-type transporter YcxA Proteins 0.000 description 1
- 101000792624 Bacillus subtilis (strain 168) Uncharacterized protein YbxH Proteins 0.000 description 1
- 101000736075 Bacillus subtilis (strain 168) Uncharacterized protein YcbP Proteins 0.000 description 1
- 101000736076 Bacillus subtilis (strain 168) Uncharacterized protein YcbR Proteins 0.000 description 1
- 101000790792 Bacillus subtilis (strain 168) Uncharacterized protein YckC Proteins 0.000 description 1
- 101000765620 Bacillus subtilis (strain 168) Uncharacterized protein YlxP Proteins 0.000 description 1
- 101000819705 Bacillus subtilis (strain 168) Uncharacterized protein YlxR Proteins 0.000 description 1
- 101000786247 Bacillus subtilis (strain 168) Uncharacterized protein YqaT Proteins 0.000 description 1
- 101000916131 Bacillus subtilis (strain 168) Uncharacterized protein YqxA Proteins 0.000 description 1
- 101000916134 Bacillus subtilis (strain 168) Uncharacterized protein YqxJ Proteins 0.000 description 1
- 101000948218 Bacillus subtilis (strain 168) Uncharacterized protein YtxJ Proteins 0.000 description 1
- 101000718627 Bacillus thuringiensis subsp. kurstaki Putative RNA polymerase sigma-G factor Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 101000641200 Bombyx mori densovirus Putative non-structural protein Proteins 0.000 description 1
- 101000754349 Bordetella pertussis (strain Tohama I / ATCC BAA-589 / NCTC 13251) UPF0065 protein BP0148 Proteins 0.000 description 1
- 101000774107 Borrelia burgdorferi (strain ATCC 35210 / B31 / CIP 102532 / DSM 4680) Uncharacterized protein BB_0266 Proteins 0.000 description 1
- 101000631235 Borrelia burgdorferi (strain ATCC 35210 / B31 / CIP 102532 / DSM 4680) Uncharacterized protein BB_0268 Proteins 0.000 description 1
- 201000004813 Bronchopneumonia Diseases 0.000 description 1
- 241000671907 Burkholderia phage AH2 Species 0.000 description 1
- 241000997471 Burkholderia phage BcepNazgul Species 0.000 description 1
- 101000827633 Caldicellulosiruptor sp. (strain Rt8B.4) Uncharacterized 23.9 kDa protein in xynA 3'region Proteins 0.000 description 1
- 101000736909 Campylobacter jejuni Probable nucleotidyltransferase Proteins 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 101000748745 Chlamydomonas reinhardtii Uncharacterized 6.2 kDa protein in psaC-petL intergenic region Proteins 0.000 description 1
- 101000626907 Chlamydomonas reinhardtii Uncharacterized 7.3 kDa protein in petA 5'region Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 101000947628 Claviceps purpurea Uncharacterized 11.8 kDa protein Proteins 0.000 description 1
- 101000947633 Claviceps purpurea Uncharacterized 13.8 kDa protein Proteins 0.000 description 1
- 241000218158 Clematis Species 0.000 description 1
- 101000686796 Clostridium perfringens Replication protein Proteins 0.000 description 1
- 101000947615 Clostridium perfringens Uncharacterized 38.4 kDa protein Proteins 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102100039200 Constitutive coactivator of PPAR-gamma-like protein 2 Human genes 0.000 description 1
- 102100031725 Cortactin-binding protein 2 Human genes 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- 101000792449 Cyanophora paradoxa Uncharacterized 3.4 kDa protein in atpE-petA intergenic region Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 101150026402 DBP gene Proteins 0.000 description 1
- 102000004594 DNA Polymerase I Human genes 0.000 description 1
- 108010017826 DNA Polymerase I Proteins 0.000 description 1
- 101710159129 DNA adenine methylase Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 102100024101 DnaJ homolog subfamily C member 28 Human genes 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000009025 Endorphins Human genes 0.000 description 1
- 108010049140 Endorphins Proteins 0.000 description 1
- 241001370343 Enterobacter phage Enc34 Species 0.000 description 1
- 101000747774 Enterobacteria phage 82 Uncharacterized protein in rusA 3'region Proteins 0.000 description 1
- 101000948901 Enterobacteria phage T4 Uncharacterized 16.0 kDa protein in segB-ipI intergenic region Proteins 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 101000964391 Enterococcus faecalis UPF0145 protein Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101000805958 Equine herpesvirus 4 (strain 1942) Virion protein US10 homolog Proteins 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 101100173936 Escherichia coli (strain K12) flmA gene Proteins 0.000 description 1
- 101000790442 Escherichia coli Insertion element IS2 uncharacterized 11.1 kDa protein Proteins 0.000 description 1
- 101000788129 Escherichia coli Uncharacterized protein in sul1 3'region Proteins 0.000 description 1
- 241000068902 Escherichia phage K1-ind(3) Species 0.000 description 1
- 101000788370 Escherichia phage P2 Uncharacterized 12.9 kDa protein in GpA 3'region Proteins 0.000 description 1
- 101000788354 Escherichia phage P2 Uncharacterized 8.2 kDa protein in gpA 5'region Proteins 0.000 description 1
- 101000748786 Euglena longa Uncharacterized 7.2 kDa protein in rps2-rps9 intergenic region Proteins 0.000 description 1
- 101000792446 Euglena longa Uncharacterized 8.7 kDa protein in rpl22-rpl23 intergenic region Proteins 0.000 description 1
- 101000748747 Euglena longa Uncharacterized 9.2 kDa protein in rpl23-rpl2 intergenic region Proteins 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 239000001512 FEMA 4601 Substances 0.000 description 1
- 208000034347 Faecal incontinence Diseases 0.000 description 1
- 101000770304 Frankia alni UPF0460 protein in nifX-nifW intergenic region Proteins 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 101000797344 Geobacillus stearothermophilus Putative tRNA (cytidine(34)-2'-O)-methyltransferase Proteins 0.000 description 1
- 101000748410 Geobacillus stearothermophilus Uncharacterized protein in fumA 3'region Proteins 0.000 description 1
- 101000787096 Geobacillus stearothermophilus Uncharacterized protein in gldA 3'region Proteins 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 101000626903 Guillardia theta Uncharacterized 6.1 kDa protein Proteins 0.000 description 1
- 101000792437 Guillardia theta Uncharacterized 7.8 kDa protein Proteins 0.000 description 1
- 101000626971 Guillardia theta Uncharacterized 8.1 kDa protein Proteins 0.000 description 1
- 101000772675 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) UPF0438 protein HI_0847 Proteins 0.000 description 1
- 101000631019 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) Uncharacterized protein HI_0350 Proteins 0.000 description 1
- 101000912350 Haemophilus phage HP1 (strain HP1c1) DNA N-6-adenine-methyltransferase Proteins 0.000 description 1
- 101000933958 Haemophilus phage HP1 (strain HP1c1) Major capsid protein Proteins 0.000 description 1
- 101000743338 Haemophilus phage HP1 (strain HP1c1) Probable head completion/stabilization protein Proteins 0.000 description 1
- 101001066788 Haemophilus phage HP1 (strain HP1c1) Probable portal protein Proteins 0.000 description 1
- 101001052021 Haemophilus phage HP1 (strain HP1c1) Probable tail fiber protein Proteins 0.000 description 1
- 101000854890 Haemophilus phage HP1 (strain HP1c1) Probable terminase, ATPase subunit Proteins 0.000 description 1
- 101000743335 Haemophilus phage HP1 (strain HP1c1) Probable terminase, endonuclease subunit Proteins 0.000 description 1
- 101000748063 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 11.1 kDa protein in rep-hol intergenic region Proteins 0.000 description 1
- 101000758973 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 11.3 kDa protein in lys 3'region Proteins 0.000 description 1
- 101000758963 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 12.7 kDa protein in lys 3'region Proteins 0.000 description 1
- 101000976893 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 14.1 kDa protein in cox-rep intergenic region Proteins 0.000 description 1
- 101000818057 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 14.9 kDa protein in rep-hol intergenic region Proteins 0.000 description 1
- 101000818121 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 18.2 kDa protein in rep-hol intergenic region Proteins 0.000 description 1
- 101000786896 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 19.2 kDa protein in rep-hol intergenic region Proteins 0.000 description 1
- 101000708358 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 23.3 kDa protein in lys 3'region Proteins 0.000 description 1
- 101000786921 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 26.0 kDa protein in rep-hol intergenic region Proteins 0.000 description 1
- 101000948764 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 58.7 kDa protein in lys 3'region Proteins 0.000 description 1
- 101000768945 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 7.9 kDa protein in int-C1 intergenic region Proteins 0.000 description 1
- 101000748060 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 8.3 kDa protein in rep-hol intergenic region Proteins 0.000 description 1
- 101000977016 Haemophilus phage HP1 (strain HP1c1) Uncharacterized 8.9 kDa protein in int-C1 intergenic region Proteins 0.000 description 1
- 101710115484 Head-tail joining protein Proteins 0.000 description 1
- 101000626607 Herpetosiphon aurantiacus Putative type II restriction enzyme HgiDII Proteins 0.000 description 1
- 101000623276 Herpetosiphon aurantiacus Uncharacterized 10.2 kDa protein in HgiBIM 5'region Proteins 0.000 description 1
- 101000623175 Herpetosiphon aurantiacus Uncharacterized 10.2 kDa protein in HgiCIIM 5'region Proteins 0.000 description 1
- 101000626850 Herpetosiphon aurantiacus Uncharacterized 10.2 kDa protein in HgiEIM 5'region Proteins 0.000 description 1
- 101000748192 Herpetosiphon aurantiacus Uncharacterized 15.4 kDa protein in HgiDIIM 5'region Proteins 0.000 description 1
- 101000785414 Homo sapiens Ankyrin repeat, SAM and basic leucine zipper domain-containing protein 1 Proteins 0.000 description 1
- 101001053999 Homo sapiens DnaJ homolog subfamily C member 28 Proteins 0.000 description 1
- 101000833492 Homo sapiens Jouberin Proteins 0.000 description 1
- 101001028836 Homo sapiens M-phase-specific PLK1-interacting protein Proteins 0.000 description 1
- 101000651236 Homo sapiens NCK-interacting protein with SH3 domain Proteins 0.000 description 1
- 101000652805 Homo sapiens Protein shisa-8 Proteins 0.000 description 1
- 101000820589 Homo sapiens Succinate-hydroxymethylglutarate CoA-transferase Proteins 0.000 description 1
- 101000667300 Homo sapiens WD repeat-containing protein 19 Proteins 0.000 description 1
- 101100064352 Human herpesvirus 8 type P (isolate GK18) DUT gene Proteins 0.000 description 1
- 101100100297 Human herpesvirus 8 type P (isolate GK18) TRM3 gene Proteins 0.000 description 1
- 101100283436 Human herpesvirus 8 type P (isolate GK18) gM gene Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 102100024407 Jouberin Human genes 0.000 description 1
- 101000782488 Junonia coenia densovirus (isolate pBRJ/1990) Putative non-structural protein NS2 Proteins 0.000 description 1
- 238000002768 Kirby-Bauer method Methods 0.000 description 1
- 201000008225 Klebsiella pneumonia Diseases 0.000 description 1
- 101000578717 Klebsiella pneumoniae Mannose-1-phosphate guanylyltransferase Proteins 0.000 description 1
- 101000957786 Klebsiella pneumoniae Phosphomannomutase Proteins 0.000 description 1
- 101000827627 Klebsiella pneumoniae Putative low molecular weight protein-tyrosine-phosphatase Proteins 0.000 description 1
- 101001015100 Klebsiella pneumoniae UDP-glucose:undecaprenyl-phosphate glucose-1-phosphate transferase Proteins 0.000 description 1
- 101000790838 Klebsiella pneumoniae UPF0053 protein in cps region Proteins 0.000 description 1
- 101000790837 Klebsiella pneumoniae Uncharacterized 18.9 kDa protein in cps region Proteins 0.000 description 1
- 101000790844 Klebsiella pneumoniae Uncharacterized 24.8 kDa protein in cps region Proteins 0.000 description 1
- 101000790840 Klebsiella pneumoniae Uncharacterized 49.5 kDa protein in cps region Proteins 0.000 description 1
- 101000811523 Klebsiella pneumoniae Uncharacterized 55.8 kDa protein in cps region Proteins 0.000 description 1
- 101000790842 Klebsiella pneumoniae Uncharacterized 65.4 kDa protein in cps region Proteins 0.000 description 1
- 101000768313 Klebsiella pneumoniae Uncharacterized membrane protein in cps region Proteins 0.000 description 1
- 101000818409 Lactococcus lactis subsp. lactis Uncharacterized HTH-type transcriptional regulator in lacX 3'region Proteins 0.000 description 1
- 101000904276 Lactococcus phage P008 Gene product 38 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108091071262 Lambda family Proteins 0.000 description 1
- 101000878851 Leptolyngbya boryana Putative Fe(2+) transport protein A Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 239000006142 Luria-Bertani Agar Substances 0.000 description 1
- 101000756286 Lymantria dispar multicapsid nuclear polyhedrosis virus Uncharacterized 10.9 kDa protein in LEF8-FP intergenic region Proteins 0.000 description 1
- 101000759330 Lymantria dispar multicapsid nuclear polyhedrosis virus Uncharacterized protein in LEF8-FP intergenic region Proteins 0.000 description 1
- 102100037185 M-phase-specific PLK1-interacting protein Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101000626970 Marchantia polymorpha Uncharacterized 3.3 kDa protein in psbT-psbN intergenic region Proteins 0.000 description 1
- 101000626905 Marchantia polymorpha Uncharacterized 3.8 kDa protein in ycf12-psaM intergenic region Proteins 0.000 description 1
- 101000748779 Marchantia polymorpha Uncharacterized 6.4 kDa protein in atpA-psbA intergenic region Proteins 0.000 description 1
- 101000788536 Marchantia polymorpha Uncharacterized mitochondrial protein ymf22 Proteins 0.000 description 1
- 101000788487 Marchantia polymorpha Uncharacterized mitochondrial protein ymf25 Proteins 0.000 description 1
- 101000788489 Marchantia polymorpha Uncharacterized mitochondrial protein ymf26 Proteins 0.000 description 1
- 101000788491 Marchantia polymorpha Uncharacterized mitochondrial protein ymf27 Proteins 0.000 description 1
- 101000747938 Marchantia polymorpha Uncharacterized mitochondrial protein ymf31 Proteins 0.000 description 1
- 101000747949 Marchantia polymorpha Uncharacterized mitochondrial protein ymf32 Proteins 0.000 description 1
- 101000747945 Marchantia polymorpha Uncharacterized mitochondrial protein ymf34 Proteins 0.000 description 1
- 101710159527 Maturation protein A Proteins 0.000 description 1
- 101710091157 Maturation protein A2 Proteins 0.000 description 1
- 101000758828 Methanosarcina barkeri (strain Fusaro / DSM 804) Uncharacterized protein Mbar_A1602 Proteins 0.000 description 1
- 101000804418 Methanothermobacter thermautotrophicus (strain ATCC 29096 / DSM 1053 / JCM 10044 / NBRC 100330 / Delta H) Uncharacterized protein MTH_1463 Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101001122401 Middle East respiratory syndrome-related coronavirus (isolate United Kingdom/H123990006/2012) Non-structural protein ORF3 Proteins 0.000 description 1
- 101001130841 Middle East respiratory syndrome-related coronavirus (isolate United Kingdom/H123990006/2012) Non-structural protein ORF5 Proteins 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 101001055788 Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) Pentapeptide repeat protein MfpA Proteins 0.000 description 1
- 101000774651 Naja atra Zinc metalloproteinase-disintegrin-like kaouthiagin-like Proteins 0.000 description 1
- 101100521838 Nicotiana tabacum pbf1 gene Proteins 0.000 description 1
- 108050000938 Nucleoside 2-deoxyribosyltransferases Proteins 0.000 description 1
- 102000008973 Nucleoside 2-deoxyribosyltransferases Human genes 0.000 description 1
- 101150101223 ORF29 gene Proteins 0.000 description 1
- 101150020791 ORF37 gene Proteins 0.000 description 1
- 101150016564 ORF39 gene Proteins 0.000 description 1
- 101150075249 ORF40 gene Proteins 0.000 description 1
- 101150006817 ORF43 gene Proteins 0.000 description 1
- 101150104094 ORF52 gene Proteins 0.000 description 1
- 101150098690 ORF54 gene Proteins 0.000 description 1
- 101710087110 ORF6 protein Proteins 0.000 description 1
- 101150092861 ORF71 gene Proteins 0.000 description 1
- 101100389785 Orgyia pseudotsugata multicapsid polyhedrosis virus ETM gene Proteins 0.000 description 1
- 101100069690 Orgyia pseudotsugata multicapsid polyhedrosis virus GTA gene Proteins 0.000 description 1
- 101100306237 Orgyia pseudotsugata multicapsid polyhedrosis virus LEF-8 gene Proteins 0.000 description 1
- 101000740670 Orgyia pseudotsugata multicapsid polyhedrosis virus Protein C42 Proteins 0.000 description 1
- 101100096140 Orgyia pseudotsugata multicapsid polyhedrosis virus SOD gene Proteins 0.000 description 1
- 101000783504 Orgyia pseudotsugata multicapsid polyhedrosis virus Uncharacterized 15.4 kDa protein Proteins 0.000 description 1
- 101000666843 Orgyia pseudotsugata multicapsid polyhedrosis virus Uncharacterized 24.0 kDa protein Proteins 0.000 description 1
- 101000770899 Orgyia pseudotsugata multicapsid polyhedrosis virus Uncharacterized 24.3 kDa protein Proteins 0.000 description 1
- 101000781204 Orgyia pseudotsugata multicapsid polyhedrosis virus Uncharacterized 36.6 kDa protein Proteins 0.000 description 1
- 101000770870 Orgyia pseudotsugata multicapsid polyhedrosis virus Uncharacterized 37.2 kDa protein Proteins 0.000 description 1
- 101000805098 Orgyia pseudotsugata multicapsid polyhedrosis virus Uncharacterized 73.1 kDa protein Proteins 0.000 description 1
- 101000768120 Oryza nivara Uncharacterized protein ycf76 Proteins 0.000 description 1
- 101100378791 Paenarthrobacter nicotinovorans aldh gene Proteins 0.000 description 1
- 101100156835 Paenarthrobacter nicotinovorans xdh gene Proteins 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 101000769182 Photorhabdus luminescens Uncharacterized protein in pnp 3'region Proteins 0.000 description 1
- 101100481711 Pneumococcus phage Dp-1 TMP gene Proteins 0.000 description 1
- 206010035717 Pneumonia klebsiella Diseases 0.000 description 1
- 101710159752 Poly(3-hydroxyalkanoate) polymerase subunit PhaE Proteins 0.000 description 1
- 101000764206 Porphyra purpurea Uncharacterized protein in rpl9-rpl11 intergenic region Proteins 0.000 description 1
- 101710149744 Portal protein B Proteins 0.000 description 1
- 101710130262 Probable Vpr-like protein Proteins 0.000 description 1
- 101710197985 Probable protein Rev Proteins 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 101710146616 Prohead protease Proteins 0.000 description 1
- 101710188053 Protein D Proteins 0.000 description 1
- 102100040307 Protein FAM3B Human genes 0.000 description 1
- 241000417109 Providencia phage Redjac Species 0.000 description 1
- 101000961392 Pseudescherichia vulneris Uncharacterized 29.9 kDa protein in crtE 3'region Proteins 0.000 description 1
- 101000731030 Pseudomonas oleovorans Poly(3-hydroxyalkanoate) polymerase 2 Proteins 0.000 description 1
- 241000954595 Pseudomonas phage MP1412 Species 0.000 description 1
- 241000476554 Pseudomonas phage PaMx11 Species 0.000 description 1
- 241001610516 Pseudomonas phage vB_PaeS_PAO1_Ab18 Species 0.000 description 1
- 101001065485 Pseudomonas putida Probable fatty acid methyltransferase Proteins 0.000 description 1
- 101000708297 Pseudomonas stutzeri Uncharacterized 8.5 kDa protein in nirQ 3'region Proteins 0.000 description 1
- 101710089184 Putative uncharacterized protein ycf15 Proteins 0.000 description 1
- HELXLJCILKEWJH-SEAGSNCFSA-N Rebaudioside A Natural products O=C(O[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@@]1(C)[C@@H]2[C@](C)([C@H]3[C@@]4(CC(=C)[C@@](O[C@H]5[C@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O6)[C@H](O)[C@@H](CO)O5)(C4)CC3)CC2)CCC1 HELXLJCILKEWJH-SEAGSNCFSA-N 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 101710124818 Recombination-associated protein RdgC Proteins 0.000 description 1
- 101710132893 Resolvase Proteins 0.000 description 1
- 101000711023 Rhizobium leguminosarum bv. trifolii Uncharacterized protein in tfuA 3'region Proteins 0.000 description 1
- 101000974028 Rhizobium leguminosarum bv. viciae (strain 3841) Putative cystathionine beta-lyase Proteins 0.000 description 1
- 101000756519 Rhodobacter capsulatus (strain ATCC BAA-309 / NBRC 16581 / SB1003) Uncharacterized protein RCAP_rcc00048 Proteins 0.000 description 1
- 101000748499 Rhodobacter capsulatus Uncharacterized 104.1 kDa protein in hypE 3'region Proteins 0.000 description 1
- 101000748505 Rhodobacter capsulatus Uncharacterized 16.1 kDa protein in hypE 3'region Proteins 0.000 description 1
- 101000827754 Rhodobacter capsulatus Uncharacterized 5.8 kDa protein in puhA 5'region Proteins 0.000 description 1
- 101000948219 Rhodococcus erythropolis Uncharacterized 11.5 kDa protein in thcD 3'region Proteins 0.000 description 1
- 101000948156 Rhodococcus erythropolis Uncharacterized 47.3 kDa protein in thcA 5'region Proteins 0.000 description 1
- 101000917565 Rhodococcus fascians Uncharacterized 33.6 kDa protein in fasciation locus Proteins 0.000 description 1
- 101000768117 Saccharum officinarum Uncharacterized protein ycf70 Proteins 0.000 description 1
- 101000790284 Saimiriine herpesvirus 2 (strain 488) Uncharacterized 9.5 kDa protein in DHFR 3'region Proteins 0.000 description 1
- 241000456876 Salmonella phage FSL SP-124 Species 0.000 description 1
- 101000814063 Salmonella phage P22 Uncharacterized 6.6 kDa protein in eae-abc2 intergenic region Proteins 0.000 description 1
- 101000953980 Salmonella phage P22 Uncharacterized 7.7 kDa protein in gp5-gp4 intergenic region Proteins 0.000 description 1
- 101000953981 Salmonella phage P22 Uncharacterized 7.8 kDa protein in ral-gp17 intergenic region Proteins 0.000 description 1
- 101000736813 Salmonella phage P22 Uncharacterized 8.6 kDa protein in ral-gp17 intergenic region Proteins 0.000 description 1
- 101000953093 Salmonella phage P22 Uncharacterized 9.0 kDa protein in gp15-gp3 intergenic region Proteins 0.000 description 1
- 101000788145 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) Uncharacterized protein YpfL Proteins 0.000 description 1
- 241001541326 Salmonella virus Chi Species 0.000 description 1
- 241000456873 Salmonella virus FSLSP088 Species 0.000 description 1
- 241001010516 Salmonella virus SPN19 Species 0.000 description 1
- 241001558040 Salmonella virus iEPS5 Species 0.000 description 1
- 101000992423 Severe acute respiratory syndrome coronavirus 2 Putative ORF9c protein Proteins 0.000 description 1
- 241000009028 Staphylococcus phage SA1 Species 0.000 description 1
- 241000543700 Staphylococcus virus Twort Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 101000936719 Streptococcus gordonii Accessory Sec system protein Asp3 Proteins 0.000 description 1
- 101000936711 Streptococcus gordonii Accessory secretory protein Asp4 Proteins 0.000 description 1
- 101000929863 Streptomyces cinnamonensis Monensin polyketide synthase putative ketoacyl reductase Proteins 0.000 description 1
- 101000788499 Streptomyces coelicolor Uncharacterized oxidoreductase in mprA 5'region Proteins 0.000 description 1
- 101000788468 Streptomyces coelicolor Uncharacterized protein in mprR 3'region Proteins 0.000 description 1
- 101001102841 Streptomyces griseus Purine nucleoside phosphorylase ORF3 Proteins 0.000 description 1
- 101000708364 Streptomyces griseus Uncharacterized 31.2 kDa protein in rplA-rplJ intergenic region Proteins 0.000 description 1
- 101000708557 Streptomyces lincolnensis Uncharacterized 17.2 kDa protein in melC2-rnhH intergenic region Proteins 0.000 description 1
- 101000953979 Streptomyces lividans Uncharacterized 6.6 kDa protein Proteins 0.000 description 1
- 101000845085 Streptomyces violaceoruber Granaticin polyketide synthase putative ketoacyl reductase 1 Proteins 0.000 description 1
- 102100021652 Succinate-hydroxymethylglutarate CoA-transferase Human genes 0.000 description 1
- 101710128479 Tail assembly protein G Proteins 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 101000649826 Thermotoga neapolitana Putative anti-sigma factor antagonist TM1081 homolog Proteins 0.000 description 1
- 101000711771 Thiocystis violacea Uncharacterized 76.5 kDa protein in phbC 3'region Proteins 0.000 description 1
- 101000764204 Trieres chinensis Uncharacterized 3.3 kDa protein in rpl11-trnW intergenic region Proteins 0.000 description 1
- 101000792450 Trieres chinensis Uncharacterized 4.7 kDa protein in ycf33-trnY intergenic region Proteins 0.000 description 1
- 101000748762 Trieres chinensis Uncharacterized 5.4 kDa protein in trnK-psbC intergenic region Proteins 0.000 description 1
- 101000626900 Trieres chinensis Uncharacterized 5.5 kDa protein in ccsA-rps6 intergenic region Proteins 0.000 description 1
- 101000768114 Triticum aestivum Uncharacterized protein ycf70 Proteins 0.000 description 1
- 101710095001 Uncharacterized protein in nifU 5'region Proteins 0.000 description 1
- 101000711318 Vibrio alginolyticus Uncharacterized 11.6 kDa protein in scrR 3'region Proteins 0.000 description 1
- 101000827562 Vibrio alginolyticus Uncharacterized protein in proC 3'region Proteins 0.000 description 1
- 101000778915 Vibrio parahaemolyticus serotype O3:K6 (strain RIMD 2210633) Uncharacterized membrane protein VP2115 Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 102100039744 WD repeat-containing protein 19 Human genes 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 101000736254 Zea mays Uncharacterized protein ycf70 Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 108010068385 carbapenemase Proteins 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000014171 carbonated beverage Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013211 curve analysis Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000000635 electron micrograph Methods 0.000 description 1
- 238000010218 electron microscopic analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- HELXLJCILKEWJH-UHFFFAOYSA-N entered according to Sigma 01432 Natural products C1CC2C3(C)CCCC(C)(C(=O)OC4C(C(O)C(O)C(CO)O4)O)C3CCC2(C2)CC(=C)C21OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O HELXLJCILKEWJH-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 101150055782 gH gene Proteins 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001320 lysogenic effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 101150055367 orf47 gene Proteins 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000019203 rebaudioside A Nutrition 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/127—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2795/00—Bacteriophages
- C12N2795/00011—Details
- C12N2795/00021—Viruses as such, e.g. new isolates, mutants or their genomic sequences
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2795/00—Bacteriophages
- C12N2795/00011—Details
- C12N2795/00031—Uses of virus other than therapeutic or vaccine, e.g. disinfectant
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2795/00—Bacteriophages
- C12N2795/00011—Details
- C12N2795/00032—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Wood Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Environmental Sciences (AREA)
- Biochemistry (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dentistry (AREA)
- General Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
본 발명은 항생제에 대한 내성을 갖는 클렙시엘라(Klebsiella)속 균을 용균시키는 박테리오파지에 관한 것이다.The present invention relates to a bacteriophage which lyses Klebsiella sp. Having resistance to an antibiotic.
클렙시엘라(Klebsiella)속 균에 해당하는 클렙시엘라 뉴모니아(Klebsiella pneumoniae)는 그람 음성의 피막을 가진 혐기성 세균으로 입, 피부, 장 등의 정상세균총에서 발견된다. 병원 밖 클렙시엘라 세균에 의해 유발되는 가장 흔한 감염질환은 폐렴이 있으며, 전형적으로 기관지폐렴 및 기관지염의 형태로 나타난다. 크렙시엘라 뉴모니아는 감염 및 출혈을 통해 인간 폐를 파괴할 수 있고, 때로는 점액성 객담을 생성하기도 한다. 상기 세균은 전형적으로 구강 인두에 대량으로 서식하는 미생물 흡입에 의해 기도로 들어가 감염을 유발하는 것으로 알려져 있다.Keulrep when Ella (Klebsiella) Oh keulrep when Ella pneumoniae for the Species (Klebsiella pneumoniae) are found in the normal flora of the mouth, skin, intestinal anaerobic bacteria such as with a coat of Gram-negative. The most common infectious disease caused by Klebsiella bacteria outside the hospital is pneumonia, typically in the form of bronchopneumonia and bronchitis. Klebsiella pneumoniae can destroy the human lungs through infection and bleeding, and sometimes produce mucus sputum. The bacteria are known to enter the airways and induce infection, typically by inhalation of microorganisms inhaled in large quantities in the oral pharynx.
상기 클렙시엘라속 균의 감음은 대부분 면역력이 약한 사람에게서 두드러지게 나타나며, 항균치료를 수행하더라도 약 50%의 높은 사망률을 나타내고 있다. 특히, 클렙시엘라 뉴모니아는 구강 등의 흡입 이외에도 비뇨기관, 쓸개관, 및 수술에 의한 상처부위에서도 감염을 유발할 수 있다. 최근, 클렙시엘라 뉴모니아가 병원 내 감염에 있어서 매우 중요한 병원균으로 인식되고 있다.The hypothalamus of the Klebsiella spp. Is predominant in most immunocompromised persons, and even when the antibacterial treatment is performed, the mortality rate is about 50%. In particular, Klebsiella spp. Can cause infection in urinary organs as well as oral inhalation, as well as in wounds due to surgery and surgery. Recently, Klebsiella pneumoniae has been recognized as a very important pathogen in hospital infections.
항생제 오남용 및 이로 인한 내성균 출현 등으로 대표되는 기존 합성 항생제의 문제점이 세계적으로 크게 이슈화되어 있는 상황에서 이에 대한 해결책을 제시해 줄 수 있는 대상으로 주목을 받고 있는 것이 바로 박테리오파지(Bacteriophage) 및 박테리오파지 유래의 리신(Lysin) 단백질이다. 박테리오파지 및 리신 단백질은 기존 항생 물질과는 완전히 다른 계열이라 할 수 있으며 이에 따라 전혀 다른 항균(antibacterial) 작용 기작(mode of action)을 갖고 있다. 따라서 기존 항생제의 사용에서 나타나던 여러 부작용(side effect)이나 문제점을 개선할 수 있을 것으로 기대를 모으고 있다.The problem of existing synthetic antibiotics such as abuse of antibiotics and the emergence of resistant bacteria caused by the antibiotics has been a major issue in the world, and it has been attracting attention as a possible solution for this problem. Bacteriophages and bacteriophage-derived lysine (Lysin) protein. Bacteriophages and lysine proteins are completely different from existing antibiotics and thus have completely different antibacterial mode of action. Therefore, it is anticipated that it will be possible to improve various side effects or problems in the use of existing antibiotics.
박테리오파지는 박테리아를 감염시킬 수 있으며 보통 파지(phage)라고 줄여서 부르기도 한다. 박테리오파지는 핵산으로 이루어진 유전물질 중심부를 단백질 외피가 싸고 있는 단순한 구조의 유기체이며, 핵산은 단일 사슬이거나 이중 사슬인 DNA 또는 RNA로 되어있다. 박테리오파지는 생존에 숙주(host)가 반드시 필요하며, 모든 박테리아에는 특정 박테리오파지가 존재한다고 알려져 있다. 박테리오파지는 박테리아의 세포벽(cell wall)의 펩티도글리칸(peptidoglycan) 층(layer)을 공격하여 세포벽을 파괴함으로써 박테리아를 사멸시킬 수 있다. 박테리오파지는 1915년 영국의 세균학자 Twort와 1917년 프랑스의 dHerelle에 의해 독립적으로 규명되었으며 세균을 잡아먹는다는 뜻에서 박테리오파지라고 명명되었다. 박테리오파지의 항 박테리아 활성(antibacterial activity) 때문에 발견 직후부터 인체와 동물의 질병 치료에 사용되었다. 그러나 Flemming에 의해 페니실린이 발견된 이후, 계속된 다양한 항생제의 등장 및 보급화로 인하여 서구에서는 관심이 점차 줄어들게 되었다. 그러나 러시아와 독일 등의 동구권 나라들은 박테리오파지 연구를 계속 해왔으며 관련하여 다수의 제품들이 산업화된 바도 있다. 하지만, 2000년대에 이르러 항생제 내성균 문제가 부각되면서 서구에서도 다시 박테리오파지에 대하여 관심을 갖게 되었으며 그 후 약 7~8년이 흐른 최근, 산업화 사례들이 속속 보고되고 있다. 즉, 박테리오파지가 세계적으로 새롭게 재조명되기 시작한 시기는 2000년대 초반으로, 실질적 산업화 노력이 약 7 ~ 8 여년 정도 진행된 신규한 분야로서, 생명공학기술의 발전과 맞물려 최근 매우 활발히 관련 개발이 진행되고 있는 분야라 할 수 있다.Bacteriophages can infect bacteria and are often called phages. A bacteriophage is a simple structure organism with a protein envelope wrapped around a nucleus of genetic material, and the nucleic acid is a single chain or double-stranded DNA or RNA. A bacteriophage is a host that is required to survive, and all bacteria are known to have certain bacteriophages. Bacteriophages can kill bacteria by attacking the peptidoglycan layer of the cell wall of bacteria and destroying the cell walls. The bacteriophage was independently identified by the British bacteriologist Twort in 1915 and dHerelle in France in 1917 and was named bacteriophage in order to eat bacteria. Because of the antibacterial activity of bacteriophage, it was used for the treatment of diseases of humans and animals immediately after its discovery. However, since the discovery of penicillin by Flemming, interest has gradually diminished in the West due to the emergence and spread of various antibiotics. However, the Eastern bloc countries such as Russia and Germany have continued to study bacteriophage, and many products have been industrialized. However, as the problem of antibiotic-resistant bacteria has emerged in the 2000s, the bacteriophage became interested in the bacteriophage again in the West. Recently, industrialization cases have been reported about 7 ~ 8 years later. In other words, bacteriophage began to be reemerged in the world in the early 2000s, and it is a new field where practical industrialization efforts have been carried out for about 7 to 8 years. In the field of biotechnology, .
박테리오파지의 가장 큰 특징으로는, 감염성 박테리아 속에 침투한 다음 박테리아의 세포벽을 파괴하여 박테리아의 사멸을 유도한다는 것이며, 이러한 박테리오파지에 의한 세포 사멸의 기작은 세균의 세포벽 합성을 방해하는 방식의 기존 합성 항생제의 기작과는 완전히 다르다. 따라서 기존 합성 항생제에 대한 감수성에 관계없이 자신의 항균 활성을 발휘할 수 있다. 이로 인하여 특히 기존 항생제에 대하여 이미 내성을 획득한 내성균에 대해서도 항균 효과가 있다. 또한, 박테리아에 대해서는 매우 특이적인 항균 활성을 가지고 있기 때문에 인간을 포함한 동물을 구성하는 세포인 진핵세포(eukaryotic cell)에는 영향을 주지 않는다는 장점을 갖고 있다.The major feature of bacteriophage is that it penetrates into infectious bacteria and then destroys the cell walls of the bacteria to induce the death of the bacteria. The mechanism of this cell death by bacteriophage is that of existing synthetic antibiotics It is completely different from the mechanism. Therefore, it can exert its antimicrobial activity irrespective of susceptibility to existing synthetic antibiotics. Therefore, it has an antibacterial effect against resistant bacteria that have already acquired tolerance to existing antibiotics. In addition, it has an advantage that it does not affect eukaryotic cells, which constitute animals including humans, because they have a very specific antibacterial activity against bacteria.
본 발명의 일 목적은 항생제 내성 클렙시엘라속 균에 대하여 특이적인 감염 및 세포 사멸 능력을 갖는 신규한 박테리오파지를 제공하는 것이다.It is an object of the present invention to provide a novel bacteriophage having an infection and apoptotic ability specific to antibiotic-resistant Klebsiella spp.
본 발명의 다른 목적은 클렙시엘라속 균에 대하여 특이적인 세포 사멸 능력을 갖는 신규한 박테리오파지를 유효성분으로 포함하여, 상기 클렙시엘라속 균에 의해 유발되는 질환의 예방 또는 치료용 약학 조성물 및 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition and an improvement for prevention or treatment of diseases caused by said Klebsiella spp., Including a novel bacteriophage having an apoptotic ability specific to Klebsiella sp. And a food composition.
본 발명의 또 다른 목적은 본 발명에 따른 상기 박테리오파지를 포함하는 항생제 및 소독제를 제공하는 것이다.It is another object of the present invention to provide an antibiotic and disinfectant containing the bacteriophage according to the present invention.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
본 발명의 발명자들은 항생제 내성 세균 감염증 치료의 대안 물질로 기존의 화학 용법 제제를 보완할 수 있는 박테리오파지를 검토하던 중 항생제 내성 클렙시엘라(Klebsiella)속 균을 선택적으로 사멸시킬 수 있는 박테리오파지를 분리하고, 분리된 박테리오파지의 형태적 및 유전적 특성을 분석하여 이를 타 박테리오파지와 구별하여 특정 지을 수 있는 유전체(genome)의 유전자 서열을 제공하며, 더 나아가 항생제 내성 클렙시엘라속 균에 특이적 사멸능을 갖는 분리된 박테리오파지를 이용하여 상기 항생제 내성 클렙시엘라속 균에 의해 유발되는 질환의 예방 및 치료 목적으로 이용함으로써 본 발명을 완성하였다.The inventors of the present invention and remove the bacteriophage capable of selectively killing the spp antibiotic resistance keulrep when Ella (Klebsiella) While reviewing a bacteriophage that can complement existing chemical usage agents as an alternative material of the antibiotic-resistant bacterial infection therapy , The morphological and genetic characteristics of isolated bacteriophages can be analyzed to provide a genome sequence that can be distinguished from other bacteriophages, The present invention has been accomplished by using the isolated bacteriophage having the above antibiotic resistance for the prevention and treatment of the diseases caused by the antibiotic resistant Klebsiella spp.
구체적으로, 본 발명자들은 항생제 내성 클렙시엘라속 균에 대하여 선택적으로 사멸시키기 위해 노력한 결과, 병원체로부터 카바페넴 내성을 갖는 클렙시엘라 뉴모니아(Klebsiella pneumoniae)를 분리하였고, 상기 카바페넴 내성 클렙시엘라 뉴모니아를 특이적으로 사멸시킬 수 있는 신규한 박테리오파지를 선별하여, 이를 "YMC15/11/N54_KPN_BP"로 명명하였다. 이렇게 선별된 상기 박테리오파지를 2017년 5월 11일자로 한국생명공학연구원 미생물자원센터(기탁번호: [KCTC18572P])에 기탁하였다.Specifically, the present inventors have made efforts to selectively kill antibiotic resistant Klebsiella spp., And as a result, Klebsiella pneumoniae resistant to carbapenem was isolated from a pathogen. The Klebsiella pneumoniae resistant to carbapenem New bacteriophages capable of specifically killing ellahuimonia were selected and named "YMC15 / 11 / N54_KPN_BP". The bacteriophage thus selected was deposited on May 11, 2017 with the Center for Microbial Resources, Korea Research Institute of Bioscience and Biotechnology (Accession No .: KCTC18572P).
본 발명의 일 구현 예는 항생제 내성 클렙시엘라(Klebsiella)속 균에 대하여 특이적인 세포 사멸능을 갖고, 서열번호 2 또는 3으로 표시되는 유전체를 포함하는 박테리오파지일 수 있다.In one embodiment of the present invention has a specific function with respect to cell death in bacteria Ella (Klebsiella) when keulrep antibiotic resistance, may be a bacteriophage comprising the dielectric shown in SEQ ID NO: 2 or 3;
본 발명에서 상기 클렙시엘라(Klebsiella)속 균은 장내세균과의 한 속으로, 협막을 지니며 점액을 생산하고, 탄소원으로서 구연산염을 이용하는 균으로, 자연계에 널리 존재하며 사람의 호흡기, 장관 및 비뇨기에서 검출된다. 일반적으로 상기 균은 비병원성이지만 다양한 질병의 2차 감염과 폐렴 등의 질환의 원인이 될 수 있다. The keulrep when Ella (Klebsiella) Species In the present invention, in one genus of Enterobacteriaceae, said Genie the capsular producing mucus, a fungus using a citrate as a carbon source, widely present in the natural world, and respiratory tract of the person, secretary and urinary . Generally, the bacterium is non-pathogenic but may cause diseases such as secondary infections of various diseases and pneumonia.
본 발명에서, 상기 클렙시엘라속 균은 클렙시엘라 뉴모니아(Klebsiella pneumoniae), 클렙시엘라 옥시토카(Klebsiella oxytoca), 클렙시엘라 플란티콜라(Klebsiella planticola) 및 클렙시엘라 테리게나(Klebsiella terrigena)로 구성된 군으로부터 선택되는 어느 한종일 수 있으며, 바람직하게는 클렙시엘라 뉴모니아(Klebsiella pneumoniae)일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the keulrep when Ella spp ah keulrep when Ella pneumoniae (Klebsiella pneumoniae), keulrep when Ella oxy cytokine (Klebsiella oxytoca), keulrep when Ella Plane tee coke (Klebsiella planticola) and keulrep when Ella Terry dehydrogenase (Klebsiella terrigena , and preferably Klebsiella pneumoniae . However, the present invention is not limited thereto.
단, 본 발명에서 상기 클렙시엘라 뉴모니아(Klebsiella pneumoniae)는 간균으로도 불리우며, 아종으로 뉴모니아(Pneumoniae), 아자니아(azaenae) 및 리노스틸레로마티스(rhinoscleromatis)가 존재하며, 상기 균은 급성폐렴, 취비증, 비경종증을 유발할 수 있다. 또한, 항생 물질에 내성이 존재하고, 건조하지 않는 경우 실온에서 수개월 동안 생존할 수 있다. Provided that the clematis (rhinoscleromatis) to the keulrep when Ella pneumoniae (Klebsiella pneumoniae) is bulriwoomyeo also as bacillus, pneumoniae in subspecies O (Pneumoniae), aza California (azaenae) and Reno steel rail present in the present invention, the Acute pneumonia, acute pneumonia, and non-adenocarcinoma can cause. In addition, there is resistance to antibiotics and, if not dry, can survive for several months at room temperature.
본 발명에서 상기 "항생제 내성"은 특정 항생제에 내성을 보여 약효가 듣지 않는 것을 의미하며, 본 발명의 목적상 상기 항생제는 카바페넴(Carbapenem)의 구조를 갖는 항생제일 수 있다. 구체적으로, 아미카신(Amicacin), 앰피실린(Ampicillin), 엠피실린/설벡탐(Ampicillin/Sulbactam), 아즈트레오남(Aztreonam), 세즈타지딤(Ceftazidime), 세파졸린(Cefazolin), 에르타페넴(Ertapenem), 세페핌(Cefepime), 세폭시틴(Cefoxitin), 세포탁심(Cefotaxime), 젠타마이신(Gentamicine), 레보플록세신(Levoflocacin), 메로페넴(Meropenem), 피페라실린/타조박탐(Piperacillin/Tazobactam), 코트리목사(Cortrimoxa), 및 티게틸린(Tigecyline)으로 구성된 군으로부터 선택되는 어느 하나일 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 목적상 상기 클렙시엘라 뉴모니아는 항생제 내성을 갖는 것일 수 있고, 상기 항생제 내성은 상기 카바페넴을 분해하여 효과의 발휘를 억제하는 카바페넴아제 효소(carbapenemase)를 생산함으로써 발생될 수 있다.In the present invention, the " antibiotic resistance " means resistance to certain antibiotics, meaning that the antibiotic is not effective. For the purpose of the present invention, the antibiotic may be an antibiotic having the structure of Carbapenem. Specifically, there may be mentioned amicacin, ampicillin, ampicillin / sulbactam, aztreonam, ceftazidime, cefazolin, erthapenem, Erophenol, Ertapenem, Cefepime, Cefoxitin, Cefotaxime, Gentamicine, Levoflocacin, Meropenem, Piperacillin / / Tazobactam, Cortrimoxa, and Tigecyline, but is not limited thereto. For the purpose of the present invention, the Klebsiella pneumoniae may have antibiotic resistance, and the antibiotic resistance may be generated by producing a carbapenemase which inhibits the action of degrading the carbapenem .
또한, 본 발명에서 상기 “박테리오파지”는 세균을 숙주세포로 하는 바이러스 일군의 총칭으로, 숙주에 감염된 후 증식하여 자손 파지를 방출하는 용균성을 갖는 회로 또는 숙주 염색체와 공존한 상태에서 숙주는 생존하고, 파지 DNA는 복제하는 회로를 갖는다. 본 발명의 목적상 상기 박테리오파지는 전체 게놈 크기가 59087bp 의 서열번호 1로 표시되는 유전체로 이루어진 것일 수 있고, 서열번호 2 또는 3으로 표시되는 유전체를 포함하는 것일 수 있다. 구체적으로, 상기 서열번호 2 또는 3은 상기 박테리오파지의 ORF(Open reading frame)로, 상기 클렙시엘라속 균에 흡착 및 용균의 기능을 수행하는 단백질 중에서도 특히 홀린(holin) 및 엔돌리신(endolysin)을 코딩하는 유전체를 표시하는 염기 서열일 수 있으며, 보다 상세하게는 상기 서열번호 2는 ORF48로 홀린을 코딩하는 유전체의 염기 서열이고, 서열번호 3은 ORF49로 엔돌리신을 코딩하는 유전체의 염기 서열이다.In the present invention, the term " bacteriophage " is a collective term for a virus group in which a bacterium is used as a host cell. The bacteriophage is in a condition where it coexists with a host cell or host chromosome , The phage DNA has a circuit for copying. For the purpose of the present invention, the bacteriophage may consist of a genome of SEQ ID NO: 1 with a total genome size of 59087 bp and may comprise a genome of SEQ ID NO: 2 or 3. [ Specifically, SEQ ID NO: 2 or 3 is an ORF (open reading frame) of the bacteriophage, and among the proteins that function as adsorbing and lytic bacteria in the Klebsiella sp., Particularly holin and endolysin, 2 is the nucleotide sequence of the genome that encodes ollein in ORF48, and SEQ ID NO: 3 is the nucleotide sequence of the genome that encodes endrhosine in ORF49 .
또한, 본 발명에서 상기 박테리오파지는 시포비리데(siphoviridae)에 속하는 박테리오파지일 수 있다.In addition, in the present invention, the bacteriophage may be a bacteriophage belonging to siphoviridae.
단, 본 발명에서 상기 “시포비리데(siphoviridae)”는 박테리오파지를 전자현미경을 통한 형태 관찰에 의해 분류 및 동정하는 방법에 의해 분류된 것으로, 수축성이 없는 수축성이 없는 긴 꼬리(a long non-contractile tail)를 갖는 복합형의 형태를 나타낸 것일 수 있다.However, in the present invention, the term " siphoviridae " is classified by a method of classifying and identifying bacteriophage by morphological observation through an electron microscope, and is a long non-contractile tail < / RTI >
본 발명의 다른 구현 예는 본 발명에 따른 상기 박테리오파지 YMC15/11/N54_KPN_BP를 유효성분으로 포함하는 항생제 내성 클렙시엘라속 균 유발성 질환의 예방 또는 치료용 약학 조성물을 제공한다.Another embodiment of the present invention provides a pharmaceutical composition for preventing or treating an antibiotic-resistant Klebsiella sp. Causative disease comprising the bacteriophage YMC15 / 11 / N54_KPN_BP according to the present invention as an active ingredient.
본 발명의 약학 조성물은 1 × 103 내지 1 × 1010 pfu/㎖의 박테리오파지를 포함하며, 바람직하게는 1 × 106 내지 1 × 109 pfu/㎖의 박테리오파지를 포함할 수 있다.The pharmaceutical composition of the present invention comprises 1 × 10 3 to 1 × 10 10 pfu / ml of bacteriophage, preferably 1 × 10 6 to 1 × 10 9 pfu / ml of bacteriophage.
본 발명의 약학 조성물에 포함되는 박테리오파지 YMC15/11/N54_KPN_BP는 상술한 바와 같이, 항생제 내성 클렙시엘라속 균, 바람직하게는 카바페넴 내성 클렙시엘라속, 보다 바람직하게는 카바페넴 내성 클렙시엘라 뉴모니아를 특이적으로 사멸시킬 수 있는 용균능 및 흡착능이 존재하므로, 본 발명의 약학 조성물을 사용하는 경우 상기 항생제 내성 클렙시엘라속 균을 용균 및 사멸시켜 인체 내에서 상기 항생제 내성 클렙시엘라 속 균의 감염으로 인하여 유발되는 다양한 질환을 효과적으로 예방 또는 치료할 수 있다. As described above, the bacteriophage YMC15 / 11 / N54_KPN_BP contained in the pharmaceutical composition of the present invention is an antibiotic resistant Klebsiella sp., Preferably a carbapenem resistant Klebsiella sp., More preferably a carbapenem resistant Klebsiella sp. Since the pharmaceutical composition of the present invention is used to specifically kill mononuclear cells, when the pharmaceutical composition of the present invention is used, the antibiotic-resistant Klebsiella sp. Strain is killed and killed by the antibiotic-resistant Klebsiella sp. It is possible to effectively prevent or treat various diseases caused by the infection of bacteria.
본 발명의 약학 조성물에서 상기 클렙시엘라속, 유전체, 박테리오파지, 항생제 내성, 시포비리데, 기탁번호, 및 클렙시엘라 뉴모니아에 대한 내용은 상기 박테리오파지에서 기재한 바와 중복되어, 이하 구체적인 기재를 생략한다.In the pharmaceutical composition of the present invention, the content of the Klebsiella genus, the genome, the bacteriophage, the antibiotic resistance, the cytoplasmid, the deposit number, and the Klebsiella pneumoniae overlap with those described in the above bacteriophage, It is omitted.
본 발명에서 상기 클렙시엘라속 균 유발성 질환은 패혈증, 폐렴 및 폐기종으로 이루어진 군에서 선택되는 어느 하나인 것일 수 있다. 본 발명의 목적상 상기 항생제 내성 클렙시엘라속 균에 의해 유발되는 질환은 패혈증, 폐렴 및 폐기종으로 이루어진 군으로부터 선택되는 어느 하나일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the Klebsiella spp. -Induced disease may be any one selected from the group consisting of sepsis, pneumonia and emphysema. For the purpose of the present invention, the disease caused by the antibiotic-resistant Klebsiella spp. May be selected from the group consisting of sepsis, pneumonia and emphysema, but is not limited thereto.
본 발명에서 상기 "치료"는 (ⅰ) 클렙시엘라속 균 에 의해 유발된 질환의 예방; (ⅱ) 클렙시엘라속 균 에 의해 유발된 질환의 억제; 및 (ⅲ) 클렙시엘라속 균 에 의해 유발된 질환의 경감을 의미한다.In the present invention, the above-mentioned " treatment " means (i) prevention of diseases caused by Klebsiella spp.; (Ii) inhibition of diseases caused by Klebsiella spp .; And (iii) relieving the disease caused by Klebsiella spp.
본 발명에서 상기 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages. The pharmaceutical composition may be a human.
본 발명에서 상기 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화될 수 있다.The pharmaceutical composition according to the present invention may be formulated into oral formulations, such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories and sterilized injection solutions according to a conventional method, . The pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring matter, a perfume or the like in the case of oral administration. A solubilizing agent, an isotonic agent, a stabilizer and the like may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative and the like may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in various manners by mixing with pharmaceutically acceptable carriers as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. In the case of injections, they may be formulated in unit dosage ampoules or in multiple dosage forms have. Other, solutions, suspensions, tablets, capsules, sustained release formulations and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltoditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.
본 발명에 상기 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition according to the present invention is not limited to the oral route, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, Sublingual or rectal. Oral or parenteral administration is preferred.
본 발명에서 상기 "비경구"란, 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration.
본 발명의 상기 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally depending on various factors including the activity, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and severity of the particular disease to be prevented or treated, And the dose of the pharmaceutical composition may be appropriately selected by a person skilled in the art depending on the condition of the patient, the body weight, the degree of disease, the type of administration, the route of administration and the period of time, and is preferably from 0.0001 to 50 mg / kg Or 0.001 to 50 mg / kg. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way. The pharmaceutical composition according to the present invention can be formulated into pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명의 또 다른 구현 예는 본 발명에 따른 박테리오파지 YMC15/11/N54_KPN_BP를 유효성분으로 포함하는 항생제 내성 클렙시엘라속 균 유발성 질환의 예방 또는 개선용 식품 조성물을 제공한다.Another embodiment of the present invention provides a food composition for preventing or ameliorating an antibiotic-resistant Klebsiella sp. Causative disease comprising the bacteriophage YMC15 / 11 / N54_KPN_BP according to the present invention as an active ingredient.
본 발명의 식품 조성물은 1 × 103 내지 1 × 1010 pfu/㎖의 박테리오파지를 포함하며, 바람직하게는 1 × 106 내지 1 × 109 pfu/㎖의 박테리오파지를 포함할 수 있다.The food composition of the present invention contains 1 × 10 3 to 1 × 10 10 pfu / ml of bacteriophage, preferably 1 × 10 6 to 1 × 10 9 pfu / ml of bacteriophage.
본 발명의 식품 조성물에 포함되는 박테리오파지 YMC15/11/N54_KPN_BP는 상술한 바와 같이, 항생제 내성 클렙시엘라속 균, 바람직하게는 카바페넴 내성 클렙시엘라속, 보다 바람직하게는 카바페넴 내성 클렙시엘라 뉴모니아를 특이적으로 사멸시킬 수 있는 용균능 및 흡착능이 존재하므로, 본 발명의 약학 조성물을 사용하는 경우 상기 항생제 내성 클렙시엘라속 균을 용균 및 사멸시켜 인체 내에서 상기 항생제 내성 클렙시엘라 속 균의 감염으로 인하여 유발되는 다양한 질환을 효과적으로 예방 또는 개선할 수 있다.As described above, the bacteriophage YMC15 / 11 / N54_KPN_BP contained in the food composition of the present invention is an antibiotic resistant Klebsiella sp., Preferably a carbapenem resistant Klebsiella sp., More preferably a carbapenem resistant Klebsiella sp. Since the pharmaceutical composition of the present invention is used to specifically kill mononuclear cells, when the pharmaceutical composition of the present invention is used, the antibiotic-resistant Klebsiella sp. Strain is killed and killed by the antibiotic-resistant Klebsiella sp. It is possible to effectively prevent or ameliorate various diseases caused by infection of a germ.
본 발명에서 상기 클렙시엘라속 균 유발성 질환은 패혈증, 폐렴 및 폐기종으로 이루어진 군에서 선택되는 어느 하나인 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the Klebsiella spp. -Induced disease may be any one selected from the group consisting of sepsis, pneumonia and emphysema, but is not limited thereto.
본 발명의 식품 조성물에서 상기 클렙시엘라속, 유전체, 박테리오파지, 항생제 내성, 시포비리데, 기탁번호, 클렙시엘라 뉴모니아, 클렙시엘라속 유발성 질환 및 예방에 대한 내용은 상기 박테리오파지에서 기재한 바와 중복되어, 이하 구체적인 기재를 생략한다.The content of the Klebsiella genus, genome, bacteriophage, antibiotic resistance, sipoviride, accession number, Klebsiella pneumoniae, Klebsiella genus-induced diseases and prevention in the food composition of the present invention is described in And the detailed description thereof will be omitted.
한편, 본 발명에서, “개선”은 본 발명의 식품 조성물을 이용하여 클렙시엘라속 균의 감염으로 인해 발생한 증상이 호전 또는 이롭게 변경되는 모든 행위라면 제한없이 포함할 수 있다.On the other hand, in the present invention, " improvement " may include, without limitation, any action that improves or alleviates symptoms caused by infection with Klebsiella spp. Using the food composition of the present invention.
본 발명의 상기 화합물을 유효성분으로 포함하는 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. The food composition comprising the compound of the present invention as an active ingredient may be prepared in the form of various foods such as beverage, gum, tea, vitamin complex, powder, granule, tablet, capsule, have.
본 발명에서 상기 화합물이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when the compound is included in the food composition, the amount thereof may be added in a proportion of 0.1 to 50% of the total weight, but is not limited thereto.
본 발명에서 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다. In the present invention, when the food composition is prepared in a beverage form, there are no particular limitations other than that the food composition is contained at the specified ratio, and it may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages . Specific examples of the natural carbohydrates include monosaccharides such as glucose, disaccharides such as fructose, sucrose and the like, and sugar sugars such as polysaccharide, dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol . Examples of the flavoring agents include natural flavoring agents (such as tau martin, stevia extract (for example, rebaudioside A and glycyrrhizin) and synthetic flavorings (for example, saccharin and aspartame).
본 발명에서, 그 외 본 발명의 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 포함할 수 있다.In the present invention, the food composition of the present invention may further contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants, pectic acid and its salts, alginic acid and its salts, , Protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like.
본 발명에서 상기 성분은 독립적 또는 조합하여 사용할 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the above components can be used independently or in combination. The proportion of the additive is not critical to the present invention, but may be selected from the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
본 발명의 또 다른 구현 예는 본 발명에 따른 상기 박테리오파지 YMC15/11/N54_KPN_BP를 유효성분으로 포함하는 항생제를 제공한다.Another embodiment of the present invention provides an antibiotic comprising the bacteriophage YMC15 / 11 / N54_KPN_BP according to the present invention as an active ingredient.
본 발명에서 상기 항생제는, 대부분의 다른 항생 물질들은 대상체인 균주의 내성이 증가함에 따라 갈수록 사용범위가 줄어들 수 밖에 없는데에 반하여, 본 발명의 상기 항생제는 상기와 같은 문제점과 무관하게 사용될 수 있으므로 항생제로 사용될 수 있는 수명이 길어질 수 있다.In the present invention, the antibiotics of the present invention can be used irrespective of the above-mentioned problems, while the antibiotics of most of other antibiotics are inevitably reduced in use as the tolerance of the strains of interest increases. On the other hand, The lifetime that can be used as the lifetime can be prolonged.
단, 본 발명에서 상기 "항생제"는 방부제, 살균제 및 항균제를 총칭하는 의미를 나타낸다.In the present invention, the term " antibiotic " means a generic term for an antiseptic, a bactericide and an antibacterial agent.
본 발명의 또 다른 구현 예는 본 발명에 따른 상기 박테리오파지 YMC15/11/N54_KPN_BP를 유효성분으로 포함하는 소독제를 제공한다.Another embodiment of the present invention provides a disinfectant comprising the bacteriophage YMC15 / 11 / N54_KPN_BP according to the present invention as an active ingredient.
본 발명에서 상기 소독제는 항생제 내성 클렙시엘라속 균에 대하여 특이적 사멸능을 갖는 박테리오파지를 유효성분으로 하고 있으므로, 병원에서의 감염을 방지하기 위한 병원 및 보건용 도구 등의 소독제로 유용하게 사용될 수 있고, 일반 생활 소독제, 식품 및 조리 장소 및 설비의 소독제, 축산 산업의 축사 소독제로 유용하게 사용될 수 있다.Since the disinfectant of the present invention contains the bacteriophage having the specific killing activity against the antibiotic-resistant Klebsiella sp. As an active ingredient, it can be effectively used as a disinfectant for hospitals and healthcare tools to prevent infection in hospitals And can be usefully used as general disinfectants, disinfectants for food and cooking places and facilities, and disinfectants for livestock industry.
본 발명에 따른 신규한 박테리오파지는 항생제 내성 클렙시엘라속 균에 대하여 특이적 사멸능을 가지므로, 항생제 내성 클렙시엘라속 균에 의해 유발되는 질환의 예방 및 치료 목적으로 활용할 수 있다.The novel bacteriophage according to the present invention has a specific killing activity against the antibiotic-resistant Klebsiella spp., And thus can be used for the prevention and treatment of diseases caused by the antibiotic-resistant Klebsiella spp.
도 1은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 전자 현미경 사진을 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 흡창능을 그래프로 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 1단 증식 곡선을 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 생체 외에서 박테리오파지의 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균능을 그래프로 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 pH 안정성을 그래프로 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 온도 안정성을 그래프로 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 전체 유전체 서열분석 결과를 나타낸 것이다.FIG. 1 is an electron micrograph of a bacteriophage bacteriophage against Klebsiella sp. Having antibiotic resistance according to an embodiment of the present invention.
FIG. 2 is a graph showing the absorptive ability of a bactericidal bacteriophage against Klebsiella sp. Having antibiotic resistance according to an embodiment of the present invention.
FIG. 3 shows a single-step growth curve of a bacteriophage bacteriophage against Klebsiella sp. Having antibiotic resistance according to an embodiment of the present invention.
FIG. 4 is a graph showing the antimicrobial activity against Klebsiella sp. Having an antibiotic resistance of bacteriophage in vitro in accordance with an embodiment of the present invention.
FIG. 5 is a graph showing the pH stability of a bactericidal bacteriophage against Klebsiella sp. Having antibiotic resistance according to an embodiment of the present invention.
FIG. 6 is a graph showing the temperature stability of a bacterial bacteriophage against an antibiotic-resistant Klebsiella sp. According to an embodiment of the present invention.
FIG. 7 shows a result of a total genome sequence analysis of a fungus bacteriophage against a Klebsiella sp. Having antibiotic resistance according to an embodiment of the present invention.
이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.
실시예Example
[실시예 1] 임상검체 분리 및 항생제 내성 균주 선별[Example 1] Separation of clinical specimens and selection of antibiotic resistant strains
세브란스 병원 환자들로부터 환자의 분변 내 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 균을 배양하여 분리하였다. 그 뒤, 감수성 결과는 Clinical and Laboratory Standards Institute (CLSI, 2009)를 기준으로 판독하였다. 감수성 시험은 뮬러-힌튼(Mueller-Hinton) 아가를 사용하여 외기 37에서 하룻밤 동안 배양하는 CLSI 디스크 확산 시험방법을 사용하였다. 클렙시엘라 뉴모니아 균에 대한 시험 항생제는 아미카신(Amicacin), 앰피실린(Ampicillin), 엠피실린/설벡탐(Ampicillin/Sulbactam), 아즈트레오남(Aztreonam), 세즈타지딤(Ceftazidime), 세파졸린(Cefazolin), 에르타페넴(Ertapenem), 세페핌(Cefepime), 세폭시틴(Cefoxitin), 세포탁심(Cefotaxime), 젠타마이신(Gentamicine), 레보플록세신(Levoflocacin), 메로페넴(Meropenem), 피페라실린/타조박탐(Piperacillin/Tazobactam), 코트리목사(Cortrimoxa), 및 티게틸린(Tigecyline)을 사용하였다. 수집된 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 53개 주의 항생제 내성 프로파일은 하기 표 1에 나타내었다. 단, 하기 표 1에서 S, I 및 R은 항균제에 대한 감수성을 평가한 결과로, 'S'는 민감(Susceptible), 'I'는 중간(Intermediate), 'R'은 내성(Resistant)를 의미한다. Klebsiella pneumoniae was isolated from patients at Severance Hospital by fecal incontinence. The susceptibility results were then read on the basis of the Clinical and Laboratory Standards Institute (CLSI, 2009). The susceptibility test was performed using a CLSI disk diffusion test method in which Mueller-Hinton agar was used to culture at ambient temperature 37 overnight. The test antibiotics against Klebsiella pneumoniae include Amicacin, Ampicillin, Ampicillin / Sulbactam, Aztreonam, Ceftazidime, Cefazolin, Ertapenem, Cefepime, Cefoxitin, Cefotaxime, Gentamicine, Levoflocacin, Meropenem, , Piperacillin / Tazobactam, Cortrimoxa, and Tigecyline were used. The antibiotic resistance profiles of the 53 Klebsiella pneumoniae strains collected are shown in Table 1 below. In Table 1, S, I, and R indicate the susceptibility to antimicrobial agents. S denotes susceptible, I denotes intermediate, and R denotes resistant. do.
상기 표 1에서 보는 바와 같이, 수집된 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 중 53개 주에서 항생제 내성을 가지며, 특히, 클렙시엘라 뉴모니아 YMC15/11/N54는 카바페넴 분해 효소인 bla KPC 유전자를 갖는 다재내성 균주임을 확인하였다.As shown in Table 1 above, 53 of the collected Klebsiella pneumoniae were resistant to antibiotics. In particular, Klebsiella pneumonia YMC15 / 11 / N54 was resistant to carbapenemolytic enzyme bla Resistant strain with the KPC gene.
[실시예 2] 박테리오파지 검체 수집[Example 2] Bacteriophage sample collection
2-1 파지 은행 구축을 위한 검체 수집2-1 Collection of specimens for phage bank establishment
세브란스 병원의 하수 처리시설에서 최초 침전지 거친 후 부유물질 및 침사물이 제거된 원수를 확보하였다. 이는 화학 처리 시설 전 단계의 하수로 제한하였다. 수집한 시료에 1L 당 염화나트륨 58g을 첨가한 후 10,000g에서 10분간 원심 분리하여 220nm 밀리포어 필터로 여과하였다. 얻어진 여과액에 폴리에틸렌글리콜(PEG, 분자량 8000)을 10% W/V으로 첨가하고 4에서 12시간 동안 냉장 보관하였다. 12시간 냉장 보관된 여과액을 12,000g에서 20분간 원심 분리하여 침전물을 파지 희석 완충액 (SM 완충액)에 재부유한 뒤, 동일한 양의 클로로포름을 첨가하여 냉동 보관하였다. 이를 3회 반복하여 300mL의 박테리오파지 부유액을 채취하였다.At the sewage treatment facility in Severance Hospital, raw water from which the suspended sediment and sediment were removed after the first sedimentation basin was rough. This was limited to the sewage at the previous stage of the chemical treatment facility. 58 g of sodium chloride per liter was added to the collected samples, followed by centrifugation at 10,000 g for 10 minutes and filtration with a 220 nm Millipore filter. To the obtained filtrate, polyethylene glycol (PEG, molecular weight 8000) was added at 10% W / V and stored for 4 to 12 hours in the refrigerator. The filtrate was centrifuged at 12,000 g for 20 minutes. The precipitate was resuspended in a buffer solution (SM buffer), and the same amount of chloroform was added thereto. This was repeated three times to collect 300 mL of the bacteriophage suspension.
2-2 용균성 파지 선별 및 용균역가 측정2-2 Screening of bacterial phage and measurement of bacterial activity
용균성 파지의 분리 정제는 스팟 테스트(Spot Test)법 (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds. Humana Press. 2009)으로 실행하였다. 확보된 균주를 맥콘키 한천배지에서 접종 후 외기 35에서 하룻밤 동안 배양하였다. 배양 후, 투명한 플라크 형성을 보고 파지에 감수성인 균주를 선별하였다. 감수성인 균주를 맥콘키 한천 배지에 접종하여 35에서 12시간 동안 배양하였다. 살린 1ml 튜브에 McFarland 0.5 탁도로 각 균주의 현탁액 제조하고 H 탑 아가 (3 ml), 감수성 박테리아 100 ㎕ 및 파지 용액 (각각 1 ㎕, 10 ㎕ 및 50 ㎕)을 섞어 LB 아가에 도포한 후, 35에서 12시간 동안 배양하였다. 플라크 관찰한 후에 파스퇴르 파이펫으로 플라크를 채취하여 SM 완충 용액에 희석하고, 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지는 SM 완충 용액에 희석하고 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지는 SM 완충 용액에 희석하여 보관하였다.The separation and purification of the soluble phage was carried out by the spot test method (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds Humana Press. The obtained strains were inoculated on a McConki agar medium and incubated overnight at ambient temperature. After culture, transparent plaque formation was observed, and strains susceptible to phage were selected. Susceptible strains were inoculated on McConki agar medium and cultured for 35 to 12 hours. (1 ml, 10 [mu] l and 50 [mu] l, respectively) were applied to a LB agar, followed by the addition of 35 [mu] l of a suspension of 35 Lt; / RTI > for 12 hours. After plaque observation, plaques were taken with Pasteur pipette, diluted in SM buffer, and further purified three times using a susceptible strain suspension. The pure bacteriophage thus obtained was diluted in SM buffer solution and subjected to repeated purification three times using a susceptible strain suspension. The pure bacteriophage thus obtained was diluted with SM buffer solution and stored.
실시예 1에서 확인한 항생제 내성 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 53주 각각을 맥콘키 한천배지에서 접종하여 배양한 후, 상기 과정에 의해 정제된 박테리오파지 YMC15/11/N54_KPN_BP를 도말된 각각의 내성 균주에 5 ㎕로 접종하여 플라그 형성을 확인하고, 역가 범위를 확인하여, 용균성을 하기 표 2에 나타내었다.53 strains of antibiotic-resistant Klebsiella pneumoniae identified in Example 1 were inoculated and cultured on a McConki agar medium. Then, the bacteriophage YMC15 / 11 / N54_KPN_BP purified by the above procedure was inoculated with each of the
단, 상기 표 2에서 + 및 -는 수집된 균주에 대한 플라크 활성을 평가한 것으로, '+'는 투명한 플라크(clear plaque)를 의미하고, '-'는 용균이 일어나지 않은 것을 의미한다.In Table 2, + and - indicate the plaque activity for the collected strains. '+' Means clear plaque and '-' means no lysis.
상기 표 2에서 보는 바와 같이, 박테리오파지 YMC15/11/N54_KPN_BP는 항생제 내성 클렙시엘라 뉴모니아 53주 중 49주(약 92%)를 용균 시키는 것을 확인할 수 있었다.As shown in the above Table 2, it was confirmed that the bacteriophage YMC15 / 11 / N54_KPN_BP lysed 49 weeks (about 92%) out of 53 antibiotic-resistant Klebsiella pneumoniae.
[실시예 3] 항생제 내성 클렙시엘라 뉴모니아균에 대한 용균성 박테리오파지의 전자 현미경 분석[Example 3] Electron microscopic analysis of soluble bacteriophage against antibiotic-resistant Klebsiella pneumoniae
상기 실시예 2의 방법에 의해 정제된 박테리오파지를 감수성 균주 배양 배지(20ml LB 배지)에 접종 및 배양한 뒤 220nm 밀리포어 필터로 여과하고, 상청액에 폴리에틸렌글리콜(MW 8,000)을 10%(w/v)의 양으로 첨가한 후 밤새 냉장 보관하였다. 이후 12,000g의 조건으로 20분 동안 원심 분리한 뒤, 에너지 여과 투과 전자현미경(Energy-Filtering Transmission Electron Microscope)을 이용하여 박테리오파지의 형태를 분석하여, 그 결과를 도 1에 나타내었다.The bacteriophages purified by the method of Example 2 were inoculated and cultured in a susceptible strain culture medium (20 ml of LB medium) and then filtered with a 220 nm Millipore filter. To the supernatant, polyethylene glycol (MW 8,000) was added at 10% ), And stored overnight in a refrigerator. After centrifugation at 12,000 g for 20 minutes, the shape of the bacteriophage was analyzed using an energy-filtering transmission electron microscope. The results are shown in FIG.
도 1에서 보는 바와 같이, 본 발명에 따른 상기 YMC15/11/N54_KPN_BP 박테리오파지를 모양으로 분류하는 기준으로 보았을 때, 파지가 수축성이 없는 긴 꼬리(a long non-contractile tail)를 갖고, 시스(sheath)가 없으므로 시포비리대(Siphoviridae)에 속하는 것으로 분류하였다.As shown in FIG. 1, the
[실시예 4] 박페리오파지의 흡착능 및 1단 증식 곡선(One-step growth curve) 분석[Example 4] Adsorption capacity and one-step growth curve analysis of the peri-phage phage
항생제 내성을 갖는 클렙시엘라 뉴모니아균을 OD 값이 0.5가 되도록 배양한 뒤, 클렙시엘라 뉴모니아균에 상기 실시예 2에서 정제된 박테리오파지 YMC15/11/N54_KPN_BP를 MOI 0.001로 넣고 상온에서 배양한 뒤, 100ul 시료를 1, 2, 3, 4, 5분에 1ml씩 채취하여 LB 배지에 희석한 뒤 플라그 분석을 통해 상기 박테리오파지의 흡착능을 평가하여, 그 결과를 도 2에 나타내었다.Klebsiella pneumoniae bacteria having antibiotic resistance were cultured to an OD value of 0.5, and the bacteriophage YMC15 / 11 / N54_KPN_BP purified in Example 2 was added to Klebsiella pneumoniae at an MOI of 0.001 and cultured at room temperature Next, 1 ml of each 100 μl sample was collected at 1, 2, 3, 4, and 5 minutes, diluted in LB medium, and analyzed by plaque analysis to evaluate the adsorption capacity of the bacteriophage. The results are shown in FIG.
또한, 항생제 내성을 갖는 클렙시엘라 뉴모니아균을 OD 값이 0.3이 되도록 배양한 뒤, 4에서 5분 동안 7,000g로 원심 분리하여 세포를 침전시킨 후, 0.5ml의 LB 배지에 희석시키고, 상기 실시예 2에서 정제된 박테리오파지를 MOI 0.001(titer 108 pfu/cells)를 넣고 37에서 5분 동안 배양하였다. 배양된 혼합 시료를 13,000g에서 1분 동안 원심 분리하여 얻어진 펠렛을 10ml의 LB 배지에 희석시키고 37℃℃에서 배양하였다. 배양 도중 10분 마다 시료를 채취하여 플라그 분석을 통해 상기 박테리오파지의 1단 증식 곡선을 평가하여, 그 결과를 도 3에 나타내었다.Further, Klebsiella pneumoniae bacteria having antibiotic resistance were cultured to an OD value of 0.3, followed by centrifugation at 7,000 g for 4 to 5 minutes to precipitate the cells. Then, the cells were diluted with 0.5 ml of LB medium, The bacteriophage purified in Example 2 was incubated at 37 for 5 minutes with an MOI of 0.001 (
도 2에서 보는 바와 같이, 상기 YMC15/11/N54_KPN_BP 박테리오파지의 접종 후 5분 이내에 박테리오파지의 99% 정도가 클렙시엘라 뉴모니아균에 흡착하였다.As shown in FIG. 2, about 99% of the bacteriophages were adsorbed to Klebsiella pneumoniae bacteria within 5 minutes after the inoculation of the YMC15 / 11 / N54_KPN_BP bacteriophage.
또한, 도 3에서 보는 바와 같이, 1단 증식 곡선 결과 71 PFU/감염 세포의 높은 버스트 사이즈를 나타내었다.Also, as shown in FIG. 3, the single-strand extension curve showed a high burst size of 71 PFU / infected cells.
상기 결과를 통해 본 발명에 따른 상기 YMC15/11/N54_KPN_BP 박테리오파지는 항생제 내성을 갖는 클렙시엘라 뉴모니아균에 매우 빠른 시간 내에 흡착할 수 있고, 현저하게 높은 버스트 사이즈를 나타내 항생제 내성 균주의 용균 효과를 발휘하는 것을 알 수 있다.As a result, the YMC15 / 11 / N54_KPN_BP bacteriophage according to the present invention can adsorb to K. pneumoniae strains having antibiotic resistance very rapidly and exhibits a remarkably high burst size and exhibits a lytic effect of an antibiotic resistant strain It can be seen that it exerts.
[실시예 5] 생체 외 항생제 내성 클렙시엘라 속 균에 대한 박테리오파지의 용균능 검증[Example 5] Validation of bacteriophage resistance against in vitro antibiotic-resistant Klebsiella spp.
항생제 내성 클렙시엘라 뉴모니아균 1 X 109 CFU/ml에 준비된 박테리오파지 YMC15/11/N54_KPN_BP를 1 X 108 CFU/ml(MOI: 0.1), 1 X 109 PFU/ml(MOI: 1), 1 X 1010 PFU/ml(MOI: 10)의 양으로 각각 처리하고 시간 별로 OD 값(파장 600nm)을 측정하였다. 단, 음성 대조군으로는 PBS+SM 버퍼를 처리하여, 그 값을 도 4에 나타내었다.Antibiotic resistance keulrep when Ella pneumoniae ahgyun 1
도 4에서 보는 바와 같이, 음성 대조군과 비교할 때, 클렙시엘라 뉴모니아균에 대하여 박테리오파지를 처리한 경우 OD 값이 감소하였고, MOI 값이 증가할수록 OD 값은 더욱 감소하였다.As shown in FIG. 4, the OD value decreased when the bacteriophage was treated against Klebsiella pneumoniae, and the OD value further decreased as the MOI value increased, as compared with the negative control.
상기 결과를 통해, 본 발명에 따른 박테리오파지는 항생제 내성 클렙시엘라 뉴모니아균에 대하여 용균성을 갖는 것을 알 수 있다.From the above results, it can be seen that the bacteriophage according to the present invention has a tolerance to antibiotic-resistant Klebsiella pneumoniae bacteria.
[실시예 6] 항생제 내성 클렙시엘라 속 균에 대한 박테리오파지의 안정성 평가[Example 6] Evaluation of stability of bacteriophage against antibiotic-resistant Klebsiella sp.
본 발명에 따른 YMC15/11/N54_KPN_BP 박테리오파지가 온도 및 알칼리에서 파괴되지 않고 안정성을 유지하는지 확인하였다.It was confirmed that the YMC15 / 11 / N54_KPN_BP bacteriophage according to the present invention was stable without being destroyed in temperature and alkali.
상기 실시예 2의 방법에 의해 정제된 박테리오 파지 1 ㎕를 4, 5, 6, 7, 8, 9 및 10의 pH로 맞춘 SM 버퍼 40 ㎕에 넣은 뒤, 37℃에서 1시간 동안 배양한 뒤 항생제 내성 클렙시엘라 뉴모니아균과 함께 상기 실시예 4의 방법으로 플라크 분석을 실시하여 그 결과를 도 5에 나타내었다.1 μl of the bacteriophage purified by the method of Example 2 was added to 40 μl of the SM buffer adjusted to the pH of 4, 5, 6, 7, 8, 9 and 10, followed by incubation at 37 ° C. for 1 hour, The plaque analysis was carried out by the method of Example 4 with the resistant Klebsiella pneumoniae bacteria, and the results are shown in Fig.
또한, 상기 박테리오파지 용액을 각각 40℃, 50℃, 60℃ 및 70℃에서 배양하는 1시간 동안 10분 단위로 각각의 샘플을 클렙시엘라 뉴모니아균과 함께 상기 실시예 4의 방법으로 플라크 분석을 실시하여 그 결과를 도 6에 나타내었다.Each of the samples was subjected to plaque analysis in the same manner as in Example 4 with the Klebsiella pneumoniae bacteria in units of 10 minutes for 1 hour in which the bacteriophage solution was cultured at 40 ° C, 50 ° C, 60 ° C, and 70 ° C, respectively The results are shown in Fig.
도 5에서 보는 바와 같이, 본 발명에 따른 상기 파지는 pH 7에 해당하는 중성에서 가장 안정성을 나타내었고, 14일 동안 상기 파지는 알칼리성에서 좀 더 안정성을 나타내었다.As shown in FIG. 5, the phage according to the present invention showed the most stability at neutral to
또한, 도 6에서 보는 바와 같이, 상기 파지는 40℃에서는 20분까지 약 40%의 PFU를 유지하였으나, 그 이상의 온도에서는 활성도를 나타내지 않았다.Also, as shown in FIG. 6, the phage retained about 40% PFU at 40 ° C. for 20 minutes, but did not show activity at temperatures above that.
[실시예 7] 항생제 내성 클렙시엘라 속 균에 대한 박테리오파지의 전체 게놈 서열 분석[Example 7] Whole genome sequence analysis of bacteriophage against antibiotic-resistant Klebsiella sp.
본 발명에 따른 상기 YMC15/11/N54_KPN_BP 박테리오파지의 특성을 규명하기 위하여 전체 유전자 서열 분석을 Illumina sequencer(Roche)를 통하여 통상의 기술자에게 자명한 전체 게놈 서열 분석 방법을 기초로 분석하여, 그 결과를 도 7 및 하기 표 3에 나타내었다.In order to characterize the YMC15 / 11 / N54_KPN_BP bacteriophage according to the present invention, the entire gene sequence analysis was analyzed on the basis of the whole genome sequence analysis method known to the ordinarily skilled artisan through Illumina sequencer (Roche) 7 and Table 3 below.
(Putative function)Estimation function
(Putative function)
(Annotation source)Annotation source
(Annotation source)
도 7 및 상기 표 3에서 보는 바와 같이, 상기 박테리오파지의 전체 유전자는 59087bp/ GC:56.33%의 linear dsDNA로, 82개의 ORF로 구성되어 있었다. 또한, 본 발명의 상기 ORF 중 용원성 유전자(lysogenic gene) 또는 독성 관련 유전자(toxin related gene)은 존재하지 않았다.As shown in FIG. 7 and Table 3, the total gene of the bacteriophage was composed of 82 ORFs with linear dsDNA of 59087 bp / GC: 56.33%. In addition, there was no lysogenic gene or toxin related gene of the ORF of the present invention.
또한, 본 발명에 따른 YMC15/11/N54_KPN_BP 박테리오파지가 용균 효과를 나타내는 단백질을 코딩하는 유전자의 서열은 서열번호 2로 표시되는 ORF48 및 서열번호 3으로 표시되는 ORF49에 해당하였다.In addition, the sequence of the gene coding for the protein exhibiting the lytic effect of YMC15 / 11 / N54_KPN_BP bacteriophage according to the present invention corresponded to ORF48 of SEQ ID NO: 2 and ORF49 of SEQ ID NO: 3.
상기 ORF48은 에스케리키아 파지(Escherichia phage) SerU-LTllb의 holin과 34%의 유사성을 보였고, ORF49가 코딩하는 엔돌리신(Endolysin)은 에위니아 파지(Erwinia phage) Pep14의 엔돌리신과 66%의 유사성을 보였으나, 본 발명에 따른 상기 박테리오파지의 전체 서열은 기존의 박테리오파지의 서열과 대조한 결과 유사성을 갖는 박테리오파지는 존재하지 않았다.The ORF48 showed 34% similarity with the holin of Escherichia phage SerU-LTllb and the ORF49-encoded Endolysin showed 66% similarity with the endorphin of Erwinia phage Pep14 However, in the entire sequence of the bacteriophage according to the present invention, there was no bacteriophage having similarity as a result of comparison with the sequence of the existing bacteriophage.
상기 결과를 통해 본 발명에 따른 YMC15/11/N54_KPN_BP 박테리오파지는 기존에 발견되지 않은 신규한 박테리오파지에 해당함을 알 수 있다.From the above results, it can be seen that the YMC15 / 11 / N54_KPN_BP bacteriophage according to the present invention corresponds to a novel bacteriophage not found in the past.
이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the scope of the present invention is not limited to the disclosed exemplary embodiments, but various changes and modifications may be made without departing from the scope of the invention. It will be obvious to those who have knowledge of
<110> Industry-Academic Cooperation Foundation, Yonsei University <120> LYTIC BACTERIOPHAGE SPECIFIC FOR KLEBSIELLA GENUS RESISTANT TO <130> DPB172741 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 59100 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15/11/N54_KPN_BP <400> 1 atggccaccg tggcgccgca ggaattttac ctcaaggatt gccgggcatg gccaccggtc 60 aggcccatgg cgccgacctg gctggcgcgg cccgccgccg ggtttcagcc tgccagcttt 120 ttcaagtaag cgcgcaccgc taaaaatttt cagcccgcta ggtttgccaa gtaaggaagc 180 ccaaaatttt tatagaaaat ccggatttcg gcgtccccat ggatcccgaa aaaggtgcga 240 tttctgtaaa ccattgattt tattggttcc gcggggatgg cgccgatggg gcggaaaggc 300 cagcaagcca ggcgtggcgc gggttgcatg ggtatagatc cccgttgggt gacggcgtgg 360 cggcgcgccc tggggtgacg cggaaagcaa aaatgaaata aatctgcatc gaggggttgc 420 acacggaatg agtgcaagtt atgtttatcg aacccggcgg ggatacgcga acaacgaaac 480 aacataaacg aggtaaacga aatgaaaaag attaaacgtc tggcactgtc ctggtctgtc 540 tcccgcggtc gtgacactta cggctacaac atttgccgcc ttgatgacac atcaaccgga 600 gaccgcttta aatgcatggg cggcgggtat gacatggtag ggacggtgtt cggtgactgg 660 ctggccgcaa actatcagcc tgaattgttg gcgctgaaag atcgcgctgg ggccgtgtgg 720 gaagaggcgg gcggccgtaa atcggcggac cgcgcggacc gcctatacgg catggtatac 780 cgggaaaaag atagcgtagt tatccttgat ggcgcttgcg ggcttgattg catgatccgc 840 attgctgagg ctatcgggct ggaagtggag cgcgattata tcgctaaagg ccgccgccgg 900 ggtgagactg tgggctggta tgtaagcgag gccgaataat gataacaata atgtttatcg 960 gttatttcat tatcggcgtt tatatcgggg cggacgtccg ccgcgtttta aagcgttgcc 1020 gtattgagcg ccgcccgtgt tttggtcgca tgactattta tttgcgtgaa cgtaagaccg 1080 gacggttgat cggctgttct aataacattt tcactttaat tttgcagggg tcttgatcat 1140 gagaattaaa atagaatcgc ataaatatgc gccggaatta aaccgcgttt atttaaccgg 1200 aaaaaattca tcgagcgcgg cggtactccg cgccccgtcg gtaacgtccg taaaagatgc 1260 ccgcgcggcg ttattcccta aagcgcttcc attccgccgg gttgtaaccg tggaatcata 1320 ttatgatgat cctcgttttt acgggcttgg ccgccgctat tccggaaccg tggattcata 1380 cgaacatctt aaaaacgtga tcgctaacat taaagcccgt aacactgggg ggccgctgtt 1440 agatgggtcg attctcccgc cagtgaaagt gcgtattgtc tcaataaaag ctatgggggc 1500 ttaattatgt ttacctcaaa cgttgaaaac cgtctggcat tgccagccgt cattaccgcg 1560 cccggcgact acatcacccg gtccggatgc cgcgtcacaa tcatcggggt atcgcctgtt 1620 aatagccatt ataccttccc ttgcaagggg tcagtatggg ttaaattccg cggggcgatg 1680 cggccgcgtg gatataacgt ctggatgcgg tccggtcatt tacacgccgt gggcgatcat 1740 ccgctggata tcgtcgggcc gtgggaggac ttgaaaccat gaatagtgac gcaaaaaagg 1800 ccgtcgtaaa gttctccgcg tgcggcctta tcgctggctt taccgtgatc gccattatcg 1860 cgggcgacgg gggcggcctg ttccgcccga tactttacac cgtggctgga ggggtatgct 1920 gtgggctgat atggcccaca caggaccagg gcgacgccct gctggactgg atcaaagaag 1980 ggcggcgata agccgccttt cttattggcg ctgatacccg aaccgcgaaa accggggtga 2040 cgcggacagc aaaaatgaaa taaatccggc taaggggttg cactcgttcc gtgtgcatat 2100 tatgtttatc ggacccggcg gggatacgca aacaacaata aacgaggttc aaaatgacat 2160 acgacgaaat caccgcaaaa attaacgctt tcaacctgaa agatgggatc acgattcgtt 2220 atacctccga cacggacgga tcaaccctgg ttgaactccg cgacgatagc ggcgctttga 2280 tctggtgtgc ctggtccttt gaggctgatt ttgctttctg cctggatcgc gagctggacc 2340 gctacggcgt gaacaaatca gcggaggcgt attgcgtcgc tgataaccgc cgcccgtccc 2400 acgtaaaccg cgcggactac gcaacggacg ccgaatacag cgccgcgaag gtggcgtttt 2460 atgcgcatat actccgatcc ctgtggtccg tacgcgggaa cagcatttac cgtcgccagg 2520 taaagaaaac cattaaatca ctgcgagact ggaaagcggt cgcacgcaag gacgcggacg 2580 ccgccggggt ggcggcggta ttcggtaacg ccctcatggt taaacccgtc aaaatcacta 2640 cggcgggcgg aatgaccctt atcgcctcgc aatccgatat aaagatctac ccggctttaa 2700 tgcgcctaac ggcattgtgg gatatgcgcc acggcctaac ccgtgacacg cattacaacc 2760 attctctgcc gttccactgc atcgcgggga ttgaatatgc gggctaacga tattcgccgg 2820 gcgcaagccc gttacaccat ggaaaaatgg cacgggaatt tagtcgccaa aggctttaaa 2880 gcggctggcg atctgctgta tagccgaaat gatgccgatc taacgtggga tgacaaggcc 2940 cgcgcctgga cggtgactat ctggaccacc gaggggcggg accgtctcaa agtgctaact 3000 attcgcaaaa atccggtttt accggcgtta cttaaatctt ttttctaggg gtatctatgt 3060 tcgcattccg tgatgttctg gaagtcgttt taccggcggt aatgttcgcc gtggcgcttg 3120 tcgtcatttc cagtgattac cgtcgtaaac tccgcgccag cggtcgtaaa ttcaaaaagt 3180 aagaaggggg gaattattat ggcttcggta tggtttttag tggtgacact gtgcaccgtt 3240 aaccctggcg cgctggcgtc ggattgtgat gactatgtga tcgacgggga tttgtcgtat 3300 agcgattgca tcaagtccat cgcacagttc ccggagaagg ctgcattgtt cgcggtcagc 3360 tgtaagcgcg gggaaccgct ggacggcgta gggggtgaga tgtgagtaac tttaaaacgg 3420 atgtaaaagg gtcagtagtc ctactgtaca aggacgataa cctacaaaag ccggtcgcta 3480 ctgtgaacag cgcggatgac gtggaggata tgcgcgggca aatcagagac gcggttatgg 3540 cggcctatca tatcggcgtt atggagggtt tcaatgaggc taaaagtgaa ccgctgaggg 3600 atgacccgag agttatcaag gcgctacaac gcgccacaaa agccgggcgg gaacagcacg 3660 ccgcgcaact ccgcgcgcta ctgaatgaag gtcttaacta gggggaagaa aaatgaaaaa 3720 acgtctgacc gttctgattt gtaatgatat gcgcgacccg tacgatccga ttgtggtaac 3780 ggtgagcggg gcgacgcctg aagaagtccg cgccagtgcg ataatcgcgc atgctgaggc 3840 ggaaatggcc gactttgacg gcgaccctat gacggcggcg gatctgtggg cggtatcgcg 3900 ggcttacatc ttcgcggcta tccccgggac cgtggatttt tactatgtcg ggatgccatc 3960 ggacacggtc gacaattacg atcacgtgat gggtgagatc ctgcatgtga tgggtgagag 4020 cctggacacg tcgcccctat gcaacatggg cgattaaccg cccgccgtat tcccgcccca 4080 taaggcccgc catttgagcg ggtcttttta cgtctgcctt atacccgaac ctacgtatcg 4140 cagcctatcg ccctggccgc tggcatagcc cccggagtga ccagtggatg aaaagaagtt 4200 gcactcaccc cgtttcataa aatacccctt tacgccgtcc taacagcctt tttgaaatca 4260 gattaattgc acgcggtgca ggtgcatccc tgcccggtgg cgggcgcgtt atatcgtgct 4320 gtgggctttc tgtattgcac acggggcgtg tgttataggc gctgcccttg tgtgaccgta 4380 tcaatgcacc tgatgcatgt tcaatgaggc cgcttatcgt agtgatatgg cctgtttttg 4440 tgtcggggtg gtggtgtgac cgtgtgacct ggtgacggta tgccaattct gccgccgcta 4500 cggggggtag acggggcgat cgtgggggta tgtagtaggg gtataccatg atcggggttg 4560 cggctgtctc cgtggcgctg gcgaaggaat ccggatcgaa ttcaaaaagg tacttcccgg 4620 gggtcctggc gtgccggggg tgcgcagagc cgcggtggaa gaaaatgcgg cgaaaccccc 4680 atagccccac ttcggaaatt cctgatttac aggggttttt tcgagttttg cccataggga 4740 agacgtgatt ttgcgttcca ggggtggtgc cctaaattcc gttttagccc cgcaaccgat 4800 tgattgcatt acatttttgg gcggtgctct tacaggatca ggtgtcgtca cggaaggtgg 4860 tttattacaa attacaagtt tactacaaga cgaacaactt gtaataaacc ggtaagctgc 4920 tgttatttat atcttttcct caatatttat tacaagttac aagaaaacaa ggaaatccat 4980 ataagattaa aagtaaaacg taatcggtat gcatattatg tatatgtata agtaacctca 5040 acttgtaata aataataatc gcgaaaaatg atttgcattc aaacacttgc aaattattac 5100 aagtttgccg ccccccgaaa actggtcaaa aacggccatt tttggggaca aaaaacgcga 5160 tttttcgaca aaaaagaaag gggccgaagc ccctttttag cgatttttct tgctcacact 5220 tcgtcatcgt cttcatcgtc gaacggattt ttcggtttcc cgattttctt ttcgacttcg 5280 gcattgtgtt ttttgagcgt agtttgcgcc cattttgtat tcagcgtacc gttttcctgg 5340 aacgcattac gcacacgttt tctgacgaac actcttccgc ttttactatt gaaacagagt 5400 accccagctt gagtaaaacc gagttccatg agcaggtttt tcatgcgtga agtcttcggc 5460 atctcgatgc cctcggcttc cataaatgcg tcgttcaatg atggtgaaaa gataatgtct 5520 ttgcacacgc ccagtgtcac gccgcccttg atcatgtccg ctataaattc gcctgcgccg 5580 tcgttcgctg catcgcgcat ttcgcggaaa gcattagtat ccaacggggc atggccttta 5640 tggttaaacc cctccgagat ctcccattcc atgaaccact ttttgatggc cgcgctgtga 5700 ttttcgatag cccgataaac gttagagaag aacttctcgc gttccttagc cgagccgtaa 5760 acgcggtcca tgtccatgtg gttttcagcc tgcgtggaga cgaccaggta gcggcgctgg 5820 ttctcatcca gcggaagcgc gttgatgtgg ttggtgaaca tcaatttcga actggtattc 5880 accacgtcac gcggctttac gcctttccct tcaacctgga agcggtcgtt cgagataaat 5940 tccttctgtt tgtcgaccgc gctgtaccga tcacccttgt catacacctc ttccacgatt 6000 ttcagaatgt ggccttccgc ccagtcggtg aaacgaccat tcatgaccga gtttgacacg 6060 tacccgatgt tctgggcgcc gagcatttcc cgcatgagca cgccgatggt cgatttaccc 6120 gaaccgtgag caccgcggat cagaagagag tagttaattc gctttgtcgg gtgctgaacg 6180 acgtgcgcca gccagtccat gacgtaattt cgctctttcg tgtccggaaa caatacgacg 6240 aacaggtctt tgacgatcga gatggccttt ttatccagtt ttgacagctt ttccgctggt 6300 ttagggatac tttcaggcga aaaagtgttt aaacgtagca aaccggcgtc gtcatagaag 6360 aattccggcc ctaaaagtcc ctctttttgg gtccatttcg attcaggcat atccccgtgc 6420 atttcggggt agtacataac atcgtgaata atagggattt ttacgacgtc cgtggcgaac 6480 ttattcggcg ataaaccgcc ttccacgtcg ccgatatcac gcccatggga cgaatcaaac 6540 gcgctttttg acagtaaaat cccggtttta cggctaacaa aggcgtcctg ggcctgggca 6600 aagacgtatt ctttcagcca agtcggggta tccgcacggg aaaagtcgaa actgaggtac 6660 tctttaacgg ctttgttagt cagcgcgctt tcgttcaggc gtttgtaggc tttcttggcc 6720 gcgtcaatag tcggctggcg ctcaatgccg aaaacccgca gcttacggaa gtcgtctgcc 6780 caggctttcc agtccgccat ggtggtgact tcgttgaatg cctcggtgaa ctcggaaacc 6840 tgttcccggg cttccttctc ttcgatttcg tggaccgttt tgatgatggt gccgattgtc 6900 accagcgtct gggcatcatg ggtaaagcct ttttcccact tgtactcgaa ttctgactcg 6960 tcatagttat ccgcctgcat ggaccagtcg cgggcgatct ctttcgcttc atcctgatcg 7020 cggcatgaca cctgcagcgc tgccattacc cggatccagt tttcatagtt ttccgggtca 7080 gggtatttca tgacgatatc gcgcagctcg tcgtaggtgc cgtcccactt ggtgacggtg 7140 gccattgccg cccagtcgtc atcgtccgct tcgccttccg ccgcccgccc gttaatggcc 7200 cgtgcgactt tcatccatcc ctgtttttcg gcataggcgt cgaacgcgtc ggcgatatcg 7260 cgggcgatct ccagcgttat ttccggcagg tccatggcgg ccgcgcagtt caccggggta 7320 tcatcggtga tccaggtgta ttccttgcgc gtatccgggt ggataccgaa ggcgacgaac 7380 tgctggccat cacccaggat ttcgactgca tggcgctgtc cgaagtcatc ttcccaggtg 7440 gcggacttga cctttttgaa cggctcgtcg gtatggcaaa gcaccagttt tttcggttga 7500 cggccaacac gaaccgggcc ggcgccgatt ttcttttcga caacggccat catgtgctta 7560 accccgtctt tgtcgtagac gtcaatgtct accgcggggg tgtgcttggt caggatgccg 7620 atgccagatg acgcgtattt cttcacgaaa ccgttaatct ggccacgggt attctcgatt 7680 ttctgccagt cttcgaacgc aggccgtttt cctgcttttg gcctgggcga gtcaggcgga 7740 atgatgggaa cgacggtgaa gccgttttcc cacagcacta ttccgtattc gttccagtag 7800 ttcattcaag aatttcccct gtatccgggt cgatttttat ccagtccggg ttagtgaacc 7860 aatgtggtcg gatgccagaa gttttagctg cctcacaaat tttgacggcc atctgtccgg 7920 aaacggtgtt gcggatattc cagatcatag tgtcgtaatt tacgccagcc gccttcgcca 7980 gtttggtaag gttgccgtcc gggtctacct ccagggcagc gatacccgcg agataacgcg 8040 gtctcaggga gtggtcttta atagcccacg gtggaaattt catagatgat cctcgcgtgt 8100 gtgtgcgtgt aagtaaaacg gatattagtc tcgcgctgct acaaagtaaa ggggacgata 8160 cccggcgacc cccggccatt tcacaaagat ccccgaaaaa accaatgggt accgaaaaat 8220 atttttgcga aagtgttgac acgggatgcg gcaatggcca tactccaaac cgtcaacacg 8280 acaaacccaa attaaccgaa cgaggattta actatgtcag gtatttttga acagctgctg 8340 gccgaacaac aaaaaaccaa ctccctgctg gaacagctgc tggcgaatgg cggtgtttca 8400 tccgctgcag caggtgaaga cgctggcgcc ggtaagacca ccgccaaagg taaaaccacc 8460 gccaaaggca aatccactgc tgcggcagac aagccgaaac acaccaaaga cgaagtagtc 8520 gctgcggtcg tagcggtgaa agaccgcttt ggcgcaccgg aagccaaaaa gatcaccgct 8580 aaattcggcc tggccaaaat cgccgaagcg aaagaagaac acttcgacgc gatctttgac 8640 ctgtgtgaag ccaaactggc cgaaccggaa gaggatgaag gcaactccga agaagacgac 8700 gtttaatctt cgatcgtgta actcggcccc tgcgggggcc gttttagcag agaggttatt 8760 gtgaataagt tcggaacggc aatagcgatg acgcccggcg gcggagagga agtgcctatg 8820 tgggctgagt tccgcttcga aattggcgac cgtaacccct tattcagagt aacttccccc 8880 gcgcgtggcc agaacggccg gcggattaac ggggaattcc gtttcgtcgt tacccacgtt 8940 gggtccgggt atcgttttac cgatttcagt ttcgacctgt tagcgaaaac ccggtataac 9000 ctgaaacgga ataactacgg aagggccggc gcaatggcgg ttaaaaagac aatcgatgaa 9060 gtaggcgttg aacgaatttt acgcgccata aaaggctacc atgatgagta agtctttcct 9120 ggttcgtgtt atgcaggagt ttgccggcgg cgggcattct atcttcgcgc cgtcagcctc 9180 tgcgatgtgg acggcctgcg gcggaagcct gctggccaac cttttcgaag aggacgagtg 9240 cagctatgaa gcggcggaag gaaccgtcgc ccatggcatc gccgagcagt ggctgaaaac 9300 ggacatccga ccgacgcatc ttatcggaac cacgcaggtc atcgaggaaa aaggcgttcg 9360 gcatgagatt gtcgtcaccc actccatgat cgactacgtt caggattatg ttgactggtg 9420 tcggttcgaa gaaggcatga tgctgacgga aatccgggtc tggttcaccg acctgatgcc 9480 gccagccaac gctgacgagc tggaggaaga cccggacgcc gaagtagtgc cgtttctccc 9540 gcagggcggt accgcggata acatcatcat tcgtgaccgg gtgctgattg tcaccgacct 9600 gaaatacggc accggcgtcc aggttttcgc ggaaggcaac ccccaggcgt tgctctatgc 9660 atacggggcg taccgcgcat tcagcgacga gtacgagttt gaccgggtca tcatccggat 9720 cgcacagccg aggcttgagc atttcgacgt ttgggaagtg acagtcgacg aattgctgga 9780 cttcgccgag tttatccgcg agcgtgcagc ggccgcctgg tcactcaaag ccaaacgcaa 9840 ggcgacgttg aaaggatgcc gatggtgccg ggccgcgcat aattgcgcag cggtggcgta 9900 catgatggaa tgcgccgtcg gtgccgacct cgaattcctg gacactgaat tcggagatta 9960 tgagatgtcg cagttacgct ccgccctggc ggaagaatac aaaatgcgga aggcaaagtt 10020 cggcgatctg tccgttgccg agatggccaa gatcctgccg taccgcaaag tgattgaaaa 10080 ctggttcgcc cgcctggacc tggaacttga gcgggccgcg aaagacggta aggcggttcc 10140 cgggcataag ctggtggaat cacgctctaa ccgtgcgcat accaacgtcg aaaaggccaa 10200 ggagctttat gatttcctcg gccttgacga aaaagactat atgaaaacgg aattgcgctc 10260 gccggcgcag atggaagaag tccttcggga taaacttgga ctgtcacgcg ccggcgcgcc 10320 aatggtcatc gaaagcgtcg tatggaagcc ggaaggcaag ccgaccctgg taccgctcac 10380 tgataagcgg ccaccactgg atcggaaata ttccggcgcc tatgatgacg aagatgacga 10440 tgatgaagtg taaatcggta agatggtaaa cccgtaaatt cgtaacccgg agtagagaaa 10500 tggctgaaaa attaattccc gcgaagaaag ttaaaaacgg cgttctgtat aagagcggtc 10560 acatcaaagt ttccaacgta cgcgcttcat atccgcacct gggcgcccca tacggcggag 10620 acggcgaagg cgagccgaaa tacggtatcg ttgggctttt gccgaagaaa acgcacaaag 10680 agatttacca gctgctgaaa gagcagatcg aagtcgccaa aaagaatcac aaagctggtc 10740 cgctcaaagt ggcgccggcc atgttgttcc tgaaagacgg cgatgtcgat ttcccggaca 10800 aaccggaatg cgctggcatg tgggttctct ctgcgcgcga aagcaaaaag cccgaagtct 10860 ttaacatcga gcgcgaggaa ttaacgacta aggctgagat tgaagaagag atttacggcg 10920 gttgctgggt atccatggtt atccgaccct ggacccagga taacaaatac ggcaaacgcg 10980 taaacgctaa cctgatctct gttttaaagc gtaaagatga cgaaccgttc ggcgaaggtc 11040 gtgttgatac ctccgacgcg tgggatgacg acgaagactg ggaagacgac gaagactggg 11100 aagacgacga cgccggcgac gaagacgacg acgtttaacc cccagcccgt cgggcattga 11160 aaccggaagc ccgcctagtg cgggctttct tataagagga caccatggcc gatattatta 11220 accttgacta cgaaagccgg gcgcgtgcca atctcaaaac gcaaggcctg gaccaatatt 11280 cccgctgccc ggatgcgaaa gtgctgatgg cggcgtattc ccttaacaac ggtaaggtgc 11340 agcacgccga cctatcccgt ggcgcgaaga tgccggcgga gctgaaagaa gcactgcttg 11400 acccctacgt ggagaaatgg gcattcaacg cacaattcga aagggtgatg acccgccgtg 11460 ttcttggtct gaaaaccccg tacaaatcgt ggcgatgcac gatggttctg gcgtacatgc 11520 tcggcttcac tggcgacctt ctgcagatag gtaagcaggt cgggctgaaa gaagaccagc 11580 tgaaagacac ggacggcaag cggctgataa aaatgttctg cgtgcctcaa cgtgtcacca 11640 aaaataaccc ttttgaatgg cgtaacgagc taacggatcc cgaagagtgg tgggggttct 11700 gccggtataa cattcgcgac gttgatactg aaatgctgat caaaaatcgg cttatcaagt 11760 accccatact gccgcaggaa tgggacttat acgccctgga ccagcttatc aatgaccgcg 11820 gcgtaatgat cgacaccgaa ttcgcgcagg ccgcactgga cctggctgaa cgccggaagc 11880 cgcaaatcat agaagagatg aaggatatca ccggccttca aaaccctaac tctgtatccc 11940 agctagtgcc atggcttaaa gagcgagggt acccgtttga cgatgtgcgc caggacacgg 12000 tgaaaaaagt tatccgtgaa caggaagaaa acggcgtcga tgatgaagcg ataaccgttc 12060 tgaaagcccg ccttaacagc gccaaaaact caatcgccaa atataaaacc atgatcgact 12120 gcgccgggga ggacgggcgt ttccgttact ccctgcagtt cgccggcgcc agccgaacaa 12180 atcgctgggc cggacgccgc ctgcagacgc agaacctcgc gcgcaccccg aaatttcttg 12240 agaaagtgga agacctgacg atcgcgaacc ggttcatcgc gaaccgggaa ctggataacc 12300 tggcgctgtt cgccggggaa ccgatggacg cgcttgtcgg ctgcatccgg tcagcaatca 12360 tccccgcgcc gcagcataaa tttatcgtcg ccgacctttc atccatcgaa tcggtagtta 12420 tcggatggtt gaccgactgc aaatggttca tggatacact ggcggcaaag catgacctgt 12480 atcagtcatt tgctgcccac tggctcggaa taccgtacga agacaccctt cctcaccgca 12540 gtaaagccaa acccgctacc ctcggtgcag gttatcgcct tggtggcggc cacctcggcg 12600 atgacgggaa gaaaaccggg ctgtggggat acgcggagaa tatgggcgtt cacatgaccc 12660 agaaagaagc cgcggattcg gtgaaagcgt tccgcgaact ttgcccggaa atagtgaacg 12720 cctggacgca gctggaaaac tgtgtcttcc aggttatccg tacgcaccgt ccggttaagt 12780 ggaaatgcct gaccatcgaa tacaccaagc cattcctgac tattcagctg ccgtcaggcc 12840 gtaagatgta ctacttccgc ccgcgcatcg ctgaacgcca gatgacggtt cagagcggcc 12900 cacgtaaagg cgagaagtac agcacactga acttccagta cgaagggaag attgaaaaat 12960 ccggcggttc gtcctggggc aaagtgttca gccacggggg gaaacttgtg gaaaacatcg 13020 ttcaggccct ggcgcgtgac gtcctcgccg aagggatgaa gaaggcacac cggatgggat 13080 ttaagatcgt catgcacatc cacgatgaga tcgtcaccga agtcccggaa gatagtccgt 13140 taacccttgc tgacctgatc ggctgcatgg cggctgaact gccatgggcg cccggattgc 13200 cgcttggcgc cgccggatgg gaagggtatt tttatcgcaa ggactaattt gcatagaaat 13260 caaagacttg ccggagaaac cgctaatgcc cgaatgggga acccctgtcg tcagggaatc 13320 gaaggtcgaa ggccgctgct gcgagtatgc gcagggccgc ggctggtggg tgtcgaagtt 13380 cacggcacct gggaaaaagg ccgttccgga ccgcgttttt atccggaacg gcgttgtgct 13440 ttttgtggaa ttcaagcgcc cgggcgaaga accaacgctg cagcagcgaa accgccatcg 13500 gcagatgaaa gccaaagggg ctaacgtgac atgggtggac aattttgaag actttaagaa 13560 ctaccttatc tcctttgagt aaggcaatcg cgtattgcca gcgcaacgtg attcaccagc 13620 ggtcggacat gcacggctat caggacgagg gcgtcgactt catcaaagaa acgccgttct 13680 gtggcctgtt cgtcgacctc ggcctgggca agaccgtgat ggccgccact gccgcactag 13740 accgtatcgt agacgggaag gtcaacaaag tgctgatcgt cgggccaaaa cgcgttgcga 13800 aagtgggctg gccaagcgaa ttcgaggaat gggggcacct ctgtttctgg aagatatcgg 13860 tcatcgacgg tgatgcagcg caacgcgagc gcgccgcacg cgaggactgc catttctaca 13920 cggtgagcgt ggataacctc gcgtggctgt gtacgctgtt caaaaagaaa tggccatacg 13980 acatggttat cctggacgag tccagcatgt tcaagtcgca tacctcgcaa cggttcaagc 14040 tgttgcggcg ctgccggccg tacataaact acctggtgga gctgactgcc acccctgccg 14100 ccgaagggta catgggcatt ttcgcacaga cgtacctgct ggacgaaggc gagcgatttg 14160 gcaccacgat caccgggtat caggaaaact atttcatcca gaacaagtac aacttcaagt 14220 tcaagttacg caatggcgcc gaggaagaaa tcatccgtaa gatctccgac atcgtcatgg 14280 tgatgaaggc ggaagattat ctagacgtcg aaaagccaac gctggtaccg ctaccggtag 14340 aactagaccc gcattccgcg gacctgtacc gccagatgga agaagaatcc cttgtcgaaa 14400 tcatgcccga cgaattcgac gaatatctgg atgacccggt gacgattgaa gccgagcagg 14460 cggcggccct gcaggacaaa ttgctgcaac tggcgtccgg atttatctac gataccaaaa 14520 ttgtcgggat caccagtgac gacaaagtag tgaagcagaa agatgcttat cgaattcacg 14580 acctgaaatt cgatgcgctg gaagagttac ttgacagcac cctggagggg gaaaacgtct 14640 ttctggccta tcactttaag ccgaccctgg cccgcctgca ggagcggttc gggaaaaggg 14700 gtctggtcgt catggatgat gacggcaagg cgattaagaa gtggaacgcc ggaaagataa 14760 agctgctggc agcacacccc cagtccgccg gccatgggct taacctgcag cacggtggtc 14820 acatcatcgt atacgttgat aacccgtggt cgcttgaacg gtttctgcaa ttcaatggcc 14880 gcctggcgcg tcagggccag aagcacccgg taacggttta ccagatgaaa gcgatgatcc 14940 gccatccgaa aaccaaggag ctgatcgaca ctgtcgacgg caccgtcatc gaagcgctaa 15000 atactaaggg tgatgtgcaa gatgcttttt ttgatttgct aaaccgcatc aaaggccgca 15060 taactaagcg catgaaggct aagaaaacgg agctatggga tgacgaagac gactaagacc 15120 gccccgctgg cgacccgcaa tcggcgatcg aatgcgccgg acgctgatac cgaggcgatg 15180 attttccagg ggtgcaacat aacgcaactg gcgaagctgt tccgcatgga gcgccgggac 15240 atcacgccga agatcatgga tatcccgccc gtcggggagc gcggcgggta cccaatttac 15300 gccgtccacg aagtcgcgcc gtacctggta aaaccgctgt acgacgtcga gacgtatttg 15360 cgccgcatga acttcaaaga cctgcccaaa gagctgtcga aggagttctg gaacggccag 15420 cgcgcgaagc aggagtatga cctgcgcgca gggaacctgt ggccaacgga agacgtggtc 15480 agcgtattcg gcgaagcgat caaaacgctg cggatgagtc tgctgctgat ccccgacaca 15540 ttatcgcggc aggtagggct taccgaagcg cagcgcaacg tggtgcagtc atcggtggat 15600 tcaatactgg atgacctcgc gaataccctg gaaagacggt tcgcggagga agaagacgat 15660 gaagtttaaa tcgttaaacc acatcatccg gtcggtcgcc agccagctgc ggccaccaat 15720 gcgcatgacg gtcgctgagg cggccgccaa ataccgttac gtgaaccagc ccggcgcata 15780 tgtcgggcct tggcttaata tgaccacgcc atacatggtc gagccgatga acacgctgaa 15840 cagccgccat tacaacaaaa tggcgtttgt cggtccggcg cagagcggga aaacggatgc 15900 gctgatcctc aacggcatta cctattcggt gaaagtagac cccatggata tcatggtgtt 15960 ctgcccgact tctaccgccg cacgcgactt ctcaatgcga cgcgtggacc gactccatcg 16020 gcacagcccg gaagtaggcg ccatgctgat gaagaaccgt gatgccgata acaaattcga 16080 taaacactac accaccggga tcattctgac gcttagttac ccatcggtta cggaactggc 16140 ggggaggccg gtgggccgta tcatcatcac cgactatgac cgtatcgacg atgacatcgg 16200 cggcgacggt aacgcctttg acctcgcatc aaaacgtaca acgaccttcg ggtcgttcgc 16260 catgtgcgcg gcagaatcgt cgccgtcccg cccggtaaaa gacccaaact ggatcaagaa 16320 aacgccgcat gaagcgccac cgtgcgacgg catcgtcggg ctttacaacc gcggcgaccg 16380 ccggcgctgg aaatggccat gcccccattg cgaccagtat ttcgaaggaa cgttccagct 16440 gatgaagtgg gacaccaagt ccgccgatgg ccgaacgctc accaacctgg aaaaagcaga 16500 aacggccaga atggtctgcc catgctgcgg ctgcgaaatc gcgccggaag agaagtacga 16560 gatgaatttg tggggtatgt gggtaccgga aggatgtacg gtaaatgaga aagggcaact 16620 ggtcggcgag ccgattcggg cgacattcgc gtctttctgg ctgcgcggta cggcggcggc 16680 gtttatctca tggcagacgc tggtgctgaa ctacctcgat gcatccgacg actatgagcg 16740 cacgatgtcg gaagagtcgt tgaaaaagtt ctggaacaac gacatgggag aaccctatgt 16800 gccgaagtcg atcgagtcgg ttcgtgttcc ggaaatgctg aaagcccggg cagagccgtg 16860 ggcggaaaaa acggtcccgc ccgccgtacg ttttttggcg gcgacggtgg acgtccagaa 16920 acatcgcttt gaggtggcgg tattcggcgt ggcgccgggg tacccgttcg atatttacct 16980 gattgaccgg ttcaacatca tcaaatcaga gcgtctcgat atagacggcg agcgggagaa 17040 gttaagcccg gcggcgtacc tggaggactg ggatttgatc gagaagcagg tcatgatgaa 17100 gacctatccg ctggccgatg accccagtcg cgtgatgcag gtcaagatga cagcctgtga 17160 ctccggcggt gcagcaggcg taacggccaa tgcgtacgag tattatcgca agctgcgccg 17220 cgaggggaaa aacgggcgat tcatcctggt caaaggcgac cctatgccga aaagcccgcg 17280 tacccatatc gcgacaccgg actctaaccg gaaggacaaa aacgcgatcg cgcgcggcga 17340 cgttccggtg ctgatgataa actccaacat ggtgaaagac atgcttaacg gccgactgga 17400 tgtaacggtt cccggaaaag gcatgtatca tttccctacg tggcttccgg actacgcata 17460 cggcgagatg tgcgccgagc atcgcgacga aaaaggctgg caatgcccgc agggtacccg 17520 aaatgaaacg tgggacttga gttactatct gatcgggatg tgtatcagcg ggcgtgtcct 17580 cgcgatggaa gcaatagact gggataaccc gccagtctgg gctgacgagt gggataaaaa 17640 cccgctggtg gtcacaatag ataaacagga ggccatcgca gaaaaaccag atacaggtta 17700 tagttttgcg caactggccg aaatgttagc atgaggatga ccaccatgac cccagatgaa 17760 tgccgagcca agtaccaaca atggctgaat gacgctatgg acgcctataa ccagctgaac 17820 gtcggtggtt cggtgcgtgt tgtggtggac cagaacggcg aacgcgtaga gtatacggcg 17880 gccaaccgcc agagcctgtg ggcgtatatt ctgcgactgc agaacgcaat taactcaccc 17940 gacccgtgca gagccttctt cggcacgccg agtcgcccag cgaggtttat tttctgatga 18000 gcgaagtcaa gaaagccact cgcgcgagca agaaaaccgc ggttgctacg gtcgacgcct 18060 ctccggcgaa acctgcagcg ggcggcggcc ttgagggtgc tgaacgaaac acccgcgcaa 18120 ccttcaactg gaatcctgcg ataatttcgc cagaccagca gatcgcccgc gataaggata 18180 tggccgatgc ccgcgcacag gacatggtgc agaacgacgg ctatgccttt ggcgccgtgg 18240 cgatccaccg tgacagtatt gtcgggtcac agtacaagct gaacgccaag ccgaattccc 18300 tgatacttgg cgctcctgac ggttgggcgg aggaattcca ggctatcgtt gaatcgcggt 18360 tcaacatggc ggccgagtca ccggaaaact ggttcgacgc ccggcgcgtc aatacgttta 18420 ccggcctggt tcgcctcgcg gtcggcggat ttttgatgac cggggaagtg ctggggtccg 18480 ccgagtgggt caagtctacc ggacgtggcg cattaggccg ccggccattc ggtaccgcca 18540 ttcagtttat ctcgccctac cgactgtcga acccggacat gcagacggat accgaccgga 18600 tccgtaaggg cgtcgagatt gacgagtatg gcgccccgca ggcgtactgg ttccgcgaag 18660 ccttcccggg agactacacc aacattgaag gccagtggcg ctggaagcgc gagcctgcgc 18720 gattcgactg gggccgccgg cgtattatcc acatcatcga acagctgctg cccgggcaga 18780 cccgcgggat cagcgagatg gtgtcggcgt tgaagcagat gcggatgacc cgtaatttcc 18840 aggaagtcac cctgcagaac gccatcgtta acgcgacgta tgccgccgtt atcgaatccg 18900 aattgccgac gcatgaagtc ttctcgcagc tgggcatggg gcagaccgcc ttttcggaat 18960 acttcaacgc ctacatggcg agtatggccg agtatgtcgc cgcgtcgaag aacatcacga 19020 tcgacggcgt taaagtcccg cacctctttc ccggaacgaa gttcaacctg aaacccgccg 19080 gcacaccggg cggcgtcggt actgactatg aagaatcgct gctgcgcaat atcgccgcgg 19140 cgctcggtct ttcctatgag cagttcagcc gcgactacac gaagacgaac tacagttctg 19200 cgcgtgcgtc gatggcggaa acgtggaaat tcatggagag ccgtaagaag ctggtagccg 19260 accgtttcgc gtctatggtc tatacgctat ggctggaaga agagattaac gccggcaatg 19320 tgccgctgcc accgggcaag acctggcgtg acttttacga cccgatgttc cgtgatgcga 19380 tttgcaatgc tgaatggatc ggagccagcc gtggccagat tgacgagaag aaagaaaccg 19440 aagctgcgat cctgcgtatc aagaatggcc tgtcgacata cgaagccgaa attgcgcgcc 19500 tgggtggcga tttccgttcg gtgtttgagc agcgcgcgcg ggaagaaaat ctgattaaat 19560 cgctggattt ggatttttca ggtaaagttg tcgaaggcgc agagacgaca tcatcttcct 19620 cgtcggcgac cgataaccct gataaggaac agaaccaatg aatgcacatg ttcgatccag 19680 cttaatgcaa gcggttcagc gcatgaacgg gtcgccggta gctgtccgtg aaagcgacac 19740 caatttcctg ctgaatatcc agtcggtgtt ccagatgagc gccgacgagg acgactttga 19800 cctcgatgcc gaagaacgta tcgccacgga gcgcaatcgc aatctatgcg cggcttacgg 19860 catggcaccg tcgagcggaa ataaaccttt cgccttttcc ggcggcttcg ccatcatccc 19920 gatccacggc tccctgatta accgctatgg cggctattac tatggctacg tgacgggata 19980 caatttcatc cgctcgcaga tgaacgccgc actggcagat cctgacgtgg aagctattat 20040 tttcgacgtg aactctaacg gcggcgaagc agcgggctgt tttgagctgg cgaacgagat 20100 tttcgcatcc cgcgcagtga agccgtcatt cgctgtcgtg gactccaatg cgtactctgc 20160 ggcttacgcc ctgggcagcg cagcgacgaa aatggcggtc attccgtcgg gcggcgccgg 20220 gtccatcggg gttatctcga tgcacgtcga tatcagtaag atgttggaag acttcggcgt 20280 taaggttagt attattaaat ccggtgcgca caaagccgac ggcaacccgt tcgaatcgct 20340 ttccgatgag acaaaagccc gctggcaggc agatgtcgac accatgcgtg aagacttcgt 20400 caatcttgtc gcacaaaacc gaaatttaga tccgaaagtc gtgcgtgaca ccgaggcatt 20460 atgctataac gccccagaag cactggccct cggactaata gatgcggtca caacgccggc 20520 taaggcagtg gctgaattcc taaacgggcc gtccggtggc tcggatgaac aaccaggagc 20580 aaacgcgatg tttacccaag aacaaatgga cgctgcccgt caagatgcag cagccgaagc 20640 aactgccacg gctaccgcgg cagcgactac ggcggaacgt aatcgcattt ccggtattct 20700 gggatgcgaa gcggcgaaag gccgttcaaa actggcgtca catattgcgt tcaacaccgc 20760 aatgagtgtt gccgatgctg aaaccatgct gggcgcttct gcggtcgagc aggccccggc 20820 atccgcagcg gctaccaatc agccggagaa aggggcagac agcccgttca agacggtgat 20880 ggataacgct gaccacccga atatgggtgc ggaaaacgaa cagcaggctg aacccggcaa 20940 aggtgatggc ctgatggctg cgatggccgc tgtagctggc gactcgttca ctaagtaaga 21000 ggcgactaac atgtctttga tctccctgat ggcaagcctc ccgaactatc tcgctggcaa 21060 cggcgacctt ggttcgtggg aacccactca gctgtttgct ggtgaagctg atatcgtaac 21120 cgacggcggt gaagtcgcag tcgcgtttgc gcgttatcag gtcatcgcca aaaacgcagc 21180 tggcaaactg gtgccttatg acccgaccac tccggccaac ccggaagcga cggccatcgg 21240 tatcgctaac gaagctggtg tcgtgggaac ctacgcaccg tattacatcg gtggtgtgtt 21300 caaccacgaa gcactcgtat ggccagcagc agtcgacact ctgctgaaac gtcaggcggt 21360 gttcgaacgt acgaacatcc acatcggcaa cctgtactaa ggagcagcag aaatggctgg 21420 attgtacgaa actaccgtcc tgatgggagt gcaacgcaag gttaagtccc tgccggcgtt 21480 cttcctgcag tggttcccgc gccagattaa cttcgaggaa gaccagatcg cgttcgataa 21540 ggtcatccag gacgttaccc gcgtcgcgcc gtttgtcgca cctaccgcgc aaggccgtgt 21600 gatcaaggaa caaggttaca acaccaagac cttcaaaccg gcttacgtta aaccgaagca 21660 cgtcattgac ccgaacatga tcgttccgcg tcaacccggc gaagcgctcg gtaccggtag 21720 cctctctaac gagcagcgtc gtgaccgtgt tatcgcattc ctgctgatga agcaccgcgc 21780 gatgcatgaa aacacctggg agtggatggc cgcgcaggct gcgcagtacg gctatgttga 21840 cgtggaaggg caggattacc cgaaaacccg cgtagacttt ggccgtgatg cggcgctgac 21900 catgacttcc gactggaccg ccaccggcgt taccctgatg gacatgatcg ccgacctgcg 21960 cgatggccag cgtctggtgt ccgataagtc actttccggc acggtgatcc gcgattacgt 22020 gttcggcggc gacgcatggg accagttcgt taaagtcggc ggcgcagagc tgtggggcaa 22080 agacggcctg atggatggca atatccgcgg ttccgactcc aacctgaccc gtctgtggga 22140 cgatgtcgaa ggtgttcagc tcatgggtga actggtaggc atcaacggcg ccggccgtat 22200 gcgtttctgg gttaacactc agaaattccg cgactggaaa aatcaggaac agtacctgat 22260 gaaccagaag gccgtcatgg gcatctcgtc tgcgattgaa ggcgttaagt gcttcggtgc 22320 aatcatggat aaagcggccg gctatcgggc gctggaatac ttcccgaaaa tgtgggaaga 22380 agaggatccg agcgtggaat acctgatgac tcagggcgca ccgctgatgg tcccggcaga 22440 cccgaatgcg tcgttcctgc tgaccgtcgt tccgtaacca cctgcaggcc cgtcaataat 22500 ggcgggccaa tttaaaggac agagattatg ccacaacgta aagtagtcca gacggtcatc 22560 gttttccgcg acggccagcg tatccgcccg gcgatcggtg aaatcttcaa cttcacccag 22620 aaagagctgg aatccatcaa cagcatgaac ccgggcgccc ttgaccgtcc tgtcatcgaa 22680 gtcgatgcgg aagagcaggc ggcgaaagag aaagcgcctg cgcaggaaga aaagtctgac 22740 gcgaaagcca ccaccaaaaa aggcggtaag gccggcgcag cggacgaaga ggtctgatat 22800 ggcctctaac ttcgcggcaa tcaaagcgaa ggcacgcagg gacgttcacg cgtccctgtc 22860 tgtatctgcg cggtatgaaa gctattcgca ggaagtcatc gtcgacggtc ttagcgtgcg 22920 ctggcacaac aagcagcaac tggtcggcga tctggatagt ggcggttacg cccagattat 22980 cgatggcatc gagcgaatcg tttttatgca ggacgagctg caggagaaag gcgtcacgct 23040 ggaaggcggt gatgtgatta tcatcacggc ggaaggatac ggcaacgttg gcctggtgct 23100 acagacgcag gaaccgattg tcggtccggt cgaagtgatc tggcaggtgt cgaggaagaa 23160 ctgatgaccg ttaacgttat ttccgtgggc gacctggagc tgcgtgacta tctcaagcgg 23220 cttccggaaa taaccgaact ggcgatgcag atggccatta acaccgtcgc atcgcgcacc 23280 ggcatgtcgt tggtcaagaa aaacatgctg aacgaggtgg ccttcccatc cgggtatctc 23340 aaccccgacc gcctgaaagt caccaagcgc gccaccagaa ccaacctcga agccaccatc 23400 accggacgta aacgggcgac ctccctggcc cggttcgtga cgagtaacag tgttgtgaac 23460 agccggcgaa aggaaggggt atccgttcga gtgaagcgcg gtaagaccac gtacctgaaa 23520 aacgcctttc tcgtcaggct gaaaaaaggc gccagtcttt ccgaagacaa ctacaacatc 23580 ggccttgccg taaggctttc cgccggggag tcattatcga ataagcggac gcagcataaa 23640 tcatggctgg ttccgggcaa ggtggcgttg ctgtatggcc cttcggtaga ccaggtattc 23700 tcggaggtgg ccgagaaggt cgggtcgcaa attgctgaca tggtggcgac ggagtttttc 23760 cgtaatttcg agaggttatc atgagtaagc gcctcgatgt gctgaaagca ttaacggatt 23820 tcctggaagg catttccccg gataacgggt atccgtatga cttccgggga aaggtgtacc 23880 gcggtcggga ccgtttcggc gcggaatacg tggcaaagat gccgttcctg tctattctgg 23940 aagcgaaagc aaccgactac gggaagttcg ctaacgagga acagaccgtc cggatggatg 24000 actgggtgct gctggttcag gggtggtgcg cagatgacgc gcgcaaccca acggacccga 24060 tttacgacat cgtggcagtc gttgaaaagc gcctgtcaat gctcatctcg aaggatgaaa 24120 atggaaaccc ggaattcccg ggggtctatc ggttaaaggg aatgattgct acactgacac 24180 tcgcacagcc ggttgttcgt ccgcccgagg aaggactatc ggacacggcg tttttcttcc 24240 tgcctattag ggtaggacta aaagtagata ttcggaatcc ctaacaggag atgaaagatg 24300 caaagcgatt tccagaacga ctatacgatc ggacgtggga aaacctattt cgataagttc 24360 ttgccgaact ctaaccgcaa gactggcgaa atgtacttcg gcaacggccc ggaattcacg 24420 atcaccactg atacggaaaa cctggaccac tatgcgtcgg attacggcct gcgcgtaaaa 24480 gatgcctccg tcctgctgga agccggcatg accgggactt tcacctgcga caacatcgcg 24540 gcggagaacc tggcgctgtg gttccttggc gacctggtta acatgaccct gaccgaccag 24600 accggcgtca aggaagtgtt caagccggta ctgcgcggta agtattacca gatcggtacc 24660 agcgacgaca cccctaccgg cctgttcaac gtggataacg ttgtggtcgg cgtggcggat 24720 ggtgacgctg aaatcgtccc gggaaccggc gatattagcg gcctggcagg cgtgaccatc 24780 gttaccgccg ctggcaacta cgagctggac ctggcgcaag gccgtatcta catcgagccg 24840 gactccaccg agttcgcggg taacaagcag atgatcatcc agtgcgatat cgctgcgcag 24900 aaccgcaaca tggtgatcgg caagaccaat cagatttacg gcgccctgcg ttacatcgcg 24960 gacaacccgg tcggtaccaa caaaaactac tacttcccga aagtggcgct gcgcccggac 25020 ggggattatg cgctgaaagg cgacgactgg aacgtgatgt cgttctcgtt cgaagcgctg 25080 cagctgaaca acctcaccca gcgtctgtac attgacgtgc tgccgtctgc ggcaaccgtt 25140 gacccgacga cgctgcgtac cgtgtctgta tcgctggcga gcacttcggc ggcgtccggc 25200 ggtgcgggta tcgtggctac cgctacggtt cgtgacggca acggcaccgt ggttcagggt 25260 gaaaccgtga acttcacgac ggacaccggc gctaccgtta ccccggcgag cgcgtccacc 25320 gcgagcacgg gcctggcaac caccacgctg aaccgcgcga cggccggtac cgccaaagtt 25380 accgcaacgc tggcgaacgg caagtccgca gtatcgcaaa ctgcgacctt ctcgtaagag 25440 cagaccgcag tcacaccgga aagcgcctac gggcgctttt cttttatgct tttctgccga 25500 cgtgctacat taacgacgtc aaccaacgaa gaggataaac cccatgtcac tgtcagattt 25560 caccccggat accgaagaaa tcatcgttaa gcgcgctaaa aaaggcgata tgacattcga 25620 ggtccgcggc ctttccttcc aggacatttc gaagatcgtc cgcgtgcatt atgacgacct 25680 ggaagggctg tttgatattt acgaaaccca cggcggcggc gacctttcct acgtggccat 25740 gggcaaattc gccatgggtc tgattaacga tgcgcccggc ctggtagcgc acatcatcgc 25800 gctggcggca gacgacgaag ccaacctgga gaaagcccag cgcctgccgc tgaccgccca 25860 gattgacgcg ctgaaagccg ttggccgcct gaccttctcg gacgttgaag atataaaaaa 25920 gatgctacga aaggccatgg acctgatgag ggaaacaaag gcaagccgga cacccgcgtc 25980 tacagcaaaa gggaaaaagt aatccggttt cacaacgagc tgcgggaagg cgtgtccttc 26040 ctgatgtctc agggacaccc agacgcacgc cggtacccgc tggggtacct gtggtctgaa 26100 atcaagattg cccggcgccg cgtgaatatg cacctggtga cggaaagcac gttactgcag 26160 gcgctactgg cctccgtcat gaacgggaag aaaggtggcc cgcactacaa aaaactgatt 26220 aagggcttga gcgatggcta acagcaaaga cgtcgaacta aggatccggg cgagggattt 26280 cagccagaaa cccctgaaag ccgtggcctc cgcgattgaa gcaatggcga aggcgcagga 26340 cgaccagcgt aaagcggcgg aacggggaga agtctcgacg cgtcagctgg aagcctcgta 26400 caaaaaactt gagcaggccg ggcagcagct gttaaagctg aatgccctgg tggagctgta 26460 caaacgccag aacgccacga tggttgaagc ggcgcaaaag acggaagact tacgggccaa 26520 gcaggcgcag ttgcagcaag cgtatgattc atccacgaag gtaactaaaa aacaggaagc 26580 cgaacttgcc cgtatcaacc gtcaggttga gcgcgcagaa cgcgccgagg cgtcacgcgc 26640 cgcgcaggtg agccggacta ccaaagaact gcagcgatac ggtattgaga cgaaaaacct 26700 tggtgccgcg cagtccagca tcgttaacag cgtggcgagc gttaacaagg tactgcagca 26760 gcaggaaaac atcatcgcta ccgcgcctgc ggcggccgcc caaaataaag tcatacaggg 26820 actgcagcag caagcgcagc aggcactggc ggcggcaaaa gggtattcaa ccctgggccg 26880 ggtcgtacag accaccacgt cgcagatggg gccactggcg tcgcaaatcc agcaaatcgt 26940 aagcccgtca gacgctgcgc gccggacgct gtctggactg cagcagcagg tgacaaccct 27000 tgcgacggag atagcgaata gcggcaaaaa gattaccgat atcacaggga agatccgcca 27060 gctgaatgac gcgaataaaa gtgtttcggc catggcgcac cagatcgata tgtaccgtca 27120 gcaggtggca gcgatccggg cagcgcgggc ggaataccgc acagcaatgg gggcggtaca 27180 gggtttagcg cagcagatgc gaacggccac taccgacacg ggtgaattgt cggtccggat 27240 gcaggcggca cagcagagac ttgcggcggc cgcccggtca ttgcgggaca ccgggactgc 27300 tgcgcgcacg acacaatcgg ctttgcgggc ggcaggcatt gatacccgta atttgaatag 27360 cgccgagcag gcgctgatct ccacaagccg tcagaccacc agttctataa actccctaac 27420 gcaagcattg cggaataacg cgggcgccac gcgcgacggt tcaaaagcct tctctctttt 27480 ccgcgatgag ggacgaacta cgttatcaat gctgcagcgt atccgcggtg aggtcctggg 27540 gctggccacg gcctatgttg gtgtgcaggg ggcgcttaat caggcatccg gtgcggtgga 27600 tgcgtacaag atgcgtcagc aagccctggt taagatctcc accgttgttg gggaaagcca 27660 ggcggcactt aacgacgaat ggcaatatat gctcgggctt tccgacaagc tgggtattga 27720 tatcggagtg gtcgcgaact cgtatacccg gttcgcggta gcggcgaaag ccgtcggtct 27780 gtcgttgcag gattcaaaat tcatattcga aagcgtggcg aaagccggcc gtgttttcca 27840 cctctccgcg gatgacatga acggtatttt ccgcgcactg gaacagatgc tgtcgaaagg 27900 gcaggtttac gccgaagaac tgcgcggcca gctgggcgaa cgtttacccg gggcggtggc 27960 gctgttcgcg aaaggtatga acatgaccac gacgcagctg atgaaggcaa tggagaacgg 28020 cgaggtttcc ggcgaagcgg ttatcaactt cgcccgtgaa caggctaagg ctattgatgc 28080 ccagctggaa accgcgagca aaggcgtgga cgcgatggaa gcccgcgcac gtaacgcgat 28140 gaatgcattc cagctggcgt tagcggactc cggatatatc gatgcatacg ttcagctgct 28200 gcagaaggtc acggacttcc ttaatagctc ggatgggagg gaggccgcgg taaaactggg 28260 tgcggcattc agctacgtgg cggacactct agggtatctg attgacaacc tggacacggt 28320 tatcacggtg ctcggcgttc tggccggcct taaaatcacg cggatggttc tggggttagt 28380 cgggtccatc cgcacgatgt tgccgatgct gaaagaaggc gtcgttctca tccgcggggt 28440 atacactggc cttatgacat gggcgaccgg tcttgcgacg gttgaaggcg cggtcggact 28500 tctcggcgtc gcgttacgcg ggctgctgcg cgttatcccg tttgttggcg cagcgcttat 28560 cgcgtacgac atcgggtcga tcatgtacga ccagtcgtcg accttccggc agggcgttga 28620 cgaggtcatc cgggattaca aaaacctcgg caatcagctg ctggcggtcg gggagtccat 28680 cccgacgatg ctgtacgaca tcctgatcgg ctgggtacga cccgtaacga cgcaattcgc 28740 cacggccacg aagatgatca tgggttggat tgccaatgtg ttgcgcctga tccccggtgt 28800 cggcgaaacg ctggcgaact gggcggatac cctggccgaa gacatgacca aagagcaccg 28860 tgacttcctg gagtccacgg gcaaggtctg ggatgacgtc gataaaaaat gggccgagtt 28920 aaataaaaac atggtcgaca ccaacaagac tgcggtggat gttatccgtg gtcaggtggc 28980 gatgctgatg gccgatatta aggcgatcac aaaccctcaa ttccagtaca ccgctgaccc 29040 ggaaactgga gtcacccagc gcgaccgcga catcaaaggc atgacgaaag accttgccaa 29100 gatggaagaa caggcgaaaa aggctggcgt tgccgcgcag aaagcactgc agcgtaaaaa 29160 cctgccaggc cgcctggcga ttatcgatga ggaatttgcg ccgcagtacg cccgtgccaa 29220 gtcgatcggc ggtgacgaag gtgctgcgat gaccaagcgt ctcgacgcta ttgtggctgc 29280 gcggaagaaa gccgagacgg attcctataa cgccatggaa aacggcagca agggcagggc 29340 gaacgcggcg aagcgggagg aaaacgcgct ggcggcgctg acctctcagt atgaaaaact 29400 ggatgatgcc gttggcgtca agcagtcgaa ggtcgacccg aatgcctcgt ttgatgaccg 29460 actgcaggcc aaactgcagg ccgttaatac ccagtacgac cagctgatcg ccaaggcgaa 29520 aaaactcggt tcgggcgggg cagaactggc cggcaagttt gaagacctgc gcaagcggaa 29580 tctcgaatat gctaccacgc aggcgaagct ggaagagatc aagcgcgtgg aggaccagct 29640 taacgcggtc caggaaacga agaaaagcct gctggatgag ataaacgcca aacgtcaggc 29700 gggcattatc tccgaagatg aggcggtgaa gcagacgtcc gagctgtatg cgacgatgaa 29760 cgtgaacctg cagcagtcgg cgaacacact ggaccagctg gcgcagaaat tccgcaatgt 29820 tatgtcgccg gaagactatg cggcgctcat ggccaaaatt gcgcagatcc gcgcgggcct 29880 gaatgacgtc accggtacct ttacccagat ggatagtacg gtggtgcagg gcgttctgga 29940 tgggctggcg acgggtctac agtcggtcac ggatagcctt gtccaagtcc ttagtggcac 30000 gatgtccctg caggacgcat tccggagcct cggcgctacc gttaccaagt tcttcgcgga 30060 cttcctgatg aagattgcgc aggcgatcct gcagcagatg gtactaaact ccctggcggg 30120 aatgggcggc ggtatcggtg cagcagcggc atcgcttggc ggtgtagcag cgaaacacaa 30180 cggcggcatg gtcggcagca aaacgacggg cggccagcag cggaaaaact ccgtcagccc 30240 gtcgttgttt gtcggggcgc cgcgcttcca tgacggcggc ctgcccgggc ttaaatcgga 30300 cgaggtgcca atcatcgcgc agaaaggcga acagatcctg tccaaagacg acccgaataa 30360 tataatgaac caggggggcg gtagcggcag tggttccggg tcatctaatc tgcaggatat 30420 cagggtcatc aatgcgatag attcggcatc ggttgtcgcc gccgggctaa gtgctccgga 30480 aaatagtaaa gtggtcctca acttcatcaa ggccaataaa caggctgtta aacaaattct 30540 ggggtgatga atggcgagct taaccgacaa tgatgcactg gtcagcagtg atgggctggt 30600 agcgcacagc cttacggatt cgacgactga cgcatcgggc attaatccgg cggcgggaac 30660 gtcgtcggaa cagttccgga tggtgaccgg acttctgcgg gcgcaccgta ttgctccccg 30720 cccggcggcg gtacaactgg caaatcgcat cctgactgca gctgtatcct acctctaccg 30780 tggccagtcg tcagaagccg ggacgtttat cccacactat ctcgtcggcg tccgccataa 30840 cttcacgttg ggtaatggcg acgtggtgca gcccggagac gcataccgta tcgccccgac 30900 ggtggagatt gagccgagta ccgataccga ctcggaaaac catgctttcc gtgatgcgta 30960 tgaagccttc tcgatcggct ccgacgtaat gggggagaac gcctggacgc tcgcaaagga 31020 cgctaccgag cgccagatta aagggtcgat tcgatactcc gggttgtggt atacgccggg 31080 cgcggtaccg gtcattacgc agttcactcc gaatgataat gggtggcggc cgccggcgta 31140 cgttggtcgg cagatagggg cgcagtgggc gtcattcggg gatgcggaag ccaccgacaa 31200 taccgtgttc atgatgaacg acgcacagga cgcatggacc gcgcagaccg gaaaaatcga 31260 tggccttttc atgccggtgt tctacttcga ctctcccggg tcgacctcgt acggcccggc 31320 gaacacgttt gggtggaatg gccccttcga ctcacagagc atgtacgaac agctgtcggc 31380 gatgcgggat gccgttcgca tcgctacaca ggcaggcgag gcgggccgta aagcctacgc 31440 aacggctatc gctacccgtg cgcttaaatg gttcgggaat gaccgcaact ggatcccgtc 31500 gaacccgggc atcgcagacg cctggagcgc ggcgatccgc aaagcggccg ttctggggta 31560 ccaggagggg gataccgtta cgctgcctga actctggttc accgtcccga atcgcctgaa 31620 taccgatggc tcattcccga cgcctgtcta tgagccgggg ctactggcgg tggcgctgca 31680 ggcggcgatc gcggtggata agctgcagcg gccaaacaat gccgcaggtt cgctgtctac 31740 cgaagtggcg cgcgtggtag aaaagtgcat ccagatgttc gacttcacct acgtgaccag 31800 cggagtaatg gccggcacat tcagcccgga cccggcgaac cttaaatggc aagggcgctg 31860 gcatgcggaa ctgctgaatg ccatggtgga cctgtatgac tggtgtgggc agtcgaacaa 31920 taactacacc gccacgcggg cgaaggcgcg agagtggatt acggggctac tggactcggc 31980 ggaagcgcta tcggcagacc agtctggcgg attcatctat ggtcggtcta tgtggccgct 32040 gcagccaaac tggaaagacg gcatgacgga gtcgttcgaa ttttccacgc agatcatcac 32100 ggcggccagt ggcaaagagc agcgcttgtc ccgtcgcacc aaaccgcgcc gggcgctgtc 32160 catgcgccat acgctgacga cggcagacga ggcggcgcag tatcaggcca tcctccggaa 32220 gcgccagtgg cggccaatgc ttgttccgca gtggcacatg gcatcccgca cgctggtagc 32280 cgggaaagtc ggcgatacca ccctggtcct ggacaaagag ccgccggcca cctggggtgt 32340 ggtgaaagcg ctgtacctcg tatcagggga tgaccgccag ctgcttaacg tgctgcgggt 32400 atccgggtcg acggttatgc tgcgcgattc gctgacgttc ccggtaccgc gagggtcaga 32460 tattatgccg gtgcagtacg ggctgctgaa taacgacctg tcgtcttccc gggcgatctc 32520 caccacgatc gaagcgcagg tcggtttcac gatcctgccg cagacggact cgtttaccgt 32580 gccggcggta tcatcgtaca acgacctgat ttcgtttatc gcggaacagg gccatcgctg 32640 ggcgaaatat atccgacggg ccgccgcgct tgatcccgca gtatggccga cgtggccgcc 32700 aatgccgtcg aactatacga cgcgaatgac ctttgaactg aacggcgata cccgcatggt 32760 catcacccgt aaacctaact gggtatccgc ggtgacagtg gccgacgcct ggcagtacga 32820 cctgatcgac tattacaact cggcggttac gccggggtat gcggagaacg ccggacgccg 32880 tacattccag gcgcagtgga ccgcattcac gtatgatgag gttatcgata tcctcgcggt 32940 attctacgcg ctgcgtggta cgcaggtggc ctgctgggta ccatcgtggt cccacgacct 33000 gacggcggca gaggatatgc cggcgccgaa tcagttacga gtggagcgga acgccgtcat 33060 tgacgaagaa atattgcttg acgacccgag tatcgcattg atggttgaaa cgtttgatgg 33120 ccgcatgtat tgcgcggcgg ctaccggggt aacaacgtca gtcggggtat cgactatcac 33180 actggaccgc gagttcctca gcccgctcaa aaaggcggac atgatgcgga tcagcctgat 33240 gtaccgtgta cggcaggcca gtgattcggt ggaactttca tggcatgccc gcggcattgc 33300 cgaattgcag acggccttca tcaccgtcca ggagtaaaac gtgtcatatc ctcaacttga 33360 agacagcgtt gacagcggga aaccgctgta tttttacgag ttcatttacg gcgatgcagc 33420 gacgaatgcg taccgttatg tcgccgcact ggacctcact atctacggcg gccgcccatg 33480 gacccctttc ccgataaagc acagcgatat cgttacatcg gggtcactgg ataagcagac 33540 gctgacggtg acggcgcggg aggatattga tattaccgga ctggtagtga cccgcgcgcc 33600 aagccgggta acgatgctga atatctaccg cggccacgct ggcgatgatg acatgcggat 33660 ggtctggacc gggcgcgtcc tgtccggcaa catgatagag tcgtccgagg tggaactggc 33720 ctgcgagtcc ataagcacat cgcagctgaa tattggtctg cggcgtaagt atcaacgcgg 33780 atgcccgcac gccctttatg gtcgggcctg ttcagctgat aaggcgttgc attcggagac 33840 cggttcgtcc acggcggtcg ctaattcaat gacggtgtcc gttaccctga cgagtgaaga 33900 ccgcgggctg accgaggcta ccctaaccgg tggtatcttc cgcatcacgt tgaagaacgg 33960 cctgaccgaa atccgggcga tctcgtctgc gataaacaac ggcggccgca actggacgtt 34020 aaatatcatc gcgcctattt ccgacatgac cgccggccgt ccggtttctg tatcaaaagg 34080 ttgcctgcat acatacgatg cgtgtaaaaa cgtgtttaac aatgcggata actatggcgg 34140 atgtgccaat atccctatca aaaacccgtt caatgcaaac cagttctagg gggcgccatg 34200 ccagattggg tcgtctatat aattatttcc atcgcgatgt cgctggccag ttacgccctg 34260 actccgcgtg caaaaacgtc cagcgctaac cagtcaccgc agacggtcga cgtgccgacg 34320 gtcgatgcgg gccggtccat ccccgtagtc ttcgggacgg tgcgggtgaa atcgcctaac 34380 ctgttatgga tgggcggaca acggacaacg gagatcaaga aatgagtgat atccgcgtat 34440 tacctactga cctgccgacg gcgggtcttt gcgttaatgg cgctcgcgac tggttcgcga 34500 aacatgggct ggacttccgg gacttcatta agaatggcac tccagtagat gtcatgcggg 34560 cgaccggttg cccactggcg gaacgtgctt gccaggccgc cgagaagcgc gtcaacggag 34620 ataactgatg ggcgggaaaa gcaagaaaaa atcggtcgtc ggctataagt acaacatcgg 34680 cctgcatttc gccatttgtc acggtccgat cgccaagctg caggaaatct ggtgggcgga 34740 taaggtcgcc tggtccggca cgttgaataa ccccggggac gagtcgcagg ggcttgtggc 34800 ggtggacaat accggcctgt ttggcgggga ttcctccgaa ggcggcgtga aagggctggt 34860 ggaaatcggc ttcggtggat gggggcagcg ctgtatcggc gttggatccg acgggtcgta 34920 ttccgcgcca gccatcctgg cctggttcat ctccaaagga tacaactgga agccgcaggt 34980 taaggtgccg gacctcggcc tgaattaccg tgggctggcg gtcgcgctga tgcatgacca 35040 ctacatcggg aacaacgcct acctgaaaga cgtgtcgttc aaggtcagct gcttctgggc 35100 cgactggcac cctgaacttt gctacatcgg cgataacatg aacccggcgc acatcatccg 35160 cgaaggactg gtgaacacgg aatggggtct gggatacgcg ccagccacga tcgatgacgc 35220 cgcatatctt tctgccgcgc agactctgta taacgagggc ttcgggctat ccttcgtctg 35280 ggatgacgac aaagacctct acaccttcat tgacgaggtg aagtcatgca ttaacgccgt 35340 gacgtatctc gatccgcgtt ccgggctatg gacgattaaa cttatccgcg ctggcgagcc 35400 atcggcgctg accatcaacc ccgacaacgc cagcctgaaa tcctttaccc ggaaagcgct 35460 gggcgaaacg tacaacgaga taagcacgaa gtacacgaac ccggaaaacg aagagtacga 35520 gacagttacc gttcaggacc cggctaacat cgaggcgcag ggccgtgttg tgtcgacgac 35580 gaaagagtat gtcggcgtgc gggatgcaaa cctggccatc cggcttaccg aacgtgacct 35640 gcaggtggcc agcgcgcagc tgtgtacagc cgaggtgacg gtgaaccgcg aagcgtgggc 35700 catcgcgccg gggatgaacg ttaccttcaa ctggccgaga cacggcatct cgaacatgat 35760 catgcgtgtc gaagaggtga gcattgctgc tgtcggggat gactcgatct ccctgcgcat 35820 cgtggaggac gtcttctcgc gctcatcggc gaccttcgcc ggctcgcagg ataacggctg 35880 ggtcgacccg gcacaaccgg caacgttgtt cccgtaccgc cattcctggg agtatccgtt 35940 ctggtatctt attcgcgctg caggtctgcc agcagacgtc ctgccgacct tcgccggatt 36000 ctcgacggag attgctaccg gcggcaacga taacgcgcaa tcggtccagc tgttctccta 36060 catcaccacg gacgctggtc catcgtggca gctggtcgca gttggaccgc tgacgccgaa 36120 atccgcgttg tccgatgcgc tggttccgga aatcacctcc ctgatgaagc tgaatacgtc 36180 ggccagctac cgcctggcgg acatggagac gaacagtttt gcgcttctca cggatggtac 36240 caacgaagag atcgtccagg tgacgaactt cgcggatgtc gcgcagcagg cgaccattac 36300 ccgcggcctg atggacacac aaccgcgtaa ctggccggcg gggaccatcg tgtacttcat 36360 cggctccagt tccttcccgg aagacgagtc agtcaggtca ttcggcgaga cggtgcaata 36420 ccggccagtg atgcagacct ccattgacca gatggacatt aataacgttc cgacggatac 36480 catcaccctg cgcgggcggt acgagttgcc gtacccggtt gccaatgtga agatcggcgg 36540 cgcatactgg ccagtgtcgg taaacgtcaa tggcattgac ctcgccgtca cctgggccaa 36600 ccgaaaccgt ctgctgcagg acgcggctac ccaggtacca tgggacgccg gaaacatcat 36660 cccggaagac ggaaccacgg tgacgatcga gctgtggcgc agcggctcaa tggtgtacca 36720 gcagcaaggc atcaccggca cgtcgtttaa catccctgtg gatgccctgt cgaccggctc 36780 ccatgagatc cgcatttaca ccgtgcgcga cggccgccgg aactatacta atttccagca 36840 cacttttaac gtcgtactcc cgtctcgcga tacggggtat ggcaatagtt acggattcac 36900 ttacggagta taaccatggc gcagaaaacg gccccgaacc tgggcatgac ctacggctgg 36960 gatttaggcg aaagcgggtg gaagcctggt atggatgcca acatgaaaaa actggatgca 37020 attgtgggcg ccgcggtgct ggccattgcg aacagtccgt cagttacgga tgacggaacg 37080 cgctacattg tcgggacgtc gccgtccggc gcctttgccg gccaggcggg gaagctggcc 37140 gtacgtgttg aaggcgcatg ggaattctat acgccccggg caggatggtc cgtttacaac 37200 ctggcgaatg gcacggcgta ccggtacact ggttctgcat ggattatccc tgcgattgcg 37260 atccccgcac agccattcct ggaagtatct ggacccggta ccgaaacctt tgataatact 37320 gcgtgggtga aagttccgct gaccgtcatc gcgtcggata cggcagacgg gtgggatgca 37380 acggccaaca ccgactacat catcccgcag gccggcatgt accagattca ggggattgtc 37440 cggcccgcgc gaaccggaag caaccctttc ccggattcaa cggcattcgc cgttggggtc 37500 ggggccacgc cggcagacgg ggatgacgtg gcatgggcgg ttagcccgga cgtggccggc 37560 gcgcagttta ccctgcaggt agccgtattg cggcgctata atgtggggga ccgagtatcg 37620 ctttttgtga aacattctgc gacttctcct gtcgctattt cgcgcgcccg cttacgtgtt 37680 ttgcgtttaa cggattaaat gcgggatgct atagtgggca aacggttaat cgagggtaac 37740 taaaatgtca gatatggacc cgttgtatga attgatgaaa gactcagcgg aggatatgtc 37800 caaggctgtg gttgaaatga aggatatgat gacggaggac caaaacaccg acgtcgtcgt 37860 cgaagggtac ggcccgaagc cttcattcag caaacagata aaagagctgg tggccgggag 37920 gtcagaaggc atatttcggc tgtatgcgac attggccgag gcccaggcgg atatcgcgaa 37980 tacccctgtg gggtctgtaa cctatgtccg gggggcggat agcacgtccc tggccgatga 38040 gtatatcaac aatggcggca ccctaactgc gaccggacgg acgatgccat ccggggtcgc 38100 cgttgagatc atgtccgcta ccgtccagcg tttaatgacg gctttgcacg ttatggcgga 38160 gggcgacgcc ggttcggttt caggtattga cagcagcgat actgtgcagg gcttgatgac 38220 cggattcaac gtactggcgg agtcctttaa taacctttca gtggaaagtc agaaaaatgc 38280 ctccggcctg tccgccctgg tctcatccgt ccagatctgc actgaagcac tgaatacgct 38340 ggcggcccgg gtcgtgaccc cagacggcgc gtcgcagtat gactatatgg cattttccac 38400 gccaggtacc gtcaacgcca gtaacgggac gttcggtagc aacacccaat accgcaggac 38460 cgggatgatc ccggttcgca agggcgacgt tgtacgcctc accgttcaca ccgcaacgac 38520 agtcgcaggc cacgccgccg cattatatga cacagcggga acgtatgtgg gtcccctggg 38580 gatcatgtgc gggacgtatg cggcgtataa ggcgcggtat taccagtgtg aaattaccca 38640 ggatggattt gttgtcgcaa acacgctgga ccagagcgcg tccccttctg cagatgtaac 38700 aggtgcgtca ctgacgattg accatcgtct tcgtggccgg gaagcagaca cggttattaa 38760 gctgacaaag tctgatttga tcccggtccg cctggataac gggaacatca acgccagttc 38820 actcacccag gacggaatcg ttaactattc caccgggctg tattcctgca ccggcggcag 38880 actcctgttc agcggtttac ctgtggcctc atctccgggc cagagcagca gcctctacaa 38940 cgtcgtgttt tatgacgccg ctaaagcgct gatcgcgtac cgccccgtgt tctccagttc 39000 gggctatgtg gttatccccg aaaatgccgc gtactgggcg cagcagataa tcaccgacag 39060 aacacccaac tggtccgagg tctcgatagt ttattacaac tacgtctaca aggatgagtt 39120 gcataagcta ctgtcatcag aacgtgagcg cctcggacgt aactacccta acgaatattg 39180 gctgcaggat ttcagcggca ctaccgatat tgagtggatc cagaacgcaa tggactgggt 39240 gcatgatgct ggtggcgggt ggttgatact gtcatcggat tatgtgaaga aacagttcat 39300 catctccgaa gcggttatcc accgtagcaa tgtgtgggta gttctcgatg gtgtcgagat 39360 taaactgcag gatggcgtgc atgacaatct gtttcgtgct gccggggtta ttgtcaatcc 39420 tgacgacccg tttggtctgt gcctcgatct tgagataacc gacaacgttc gtctgattgg 39480 tacgggatat ccgaagttaa gtggtgccga tgtgccatat tatgccgata tccccgcagg 39540 aaccgggcca cgctactgga tcggcgacga atatggatgg cgaggtacgg ggctgattta 39600 ttatggtacg cagaattttg agatcggtgg ttttaaactc cagaacgtaa aaaactgggg 39660 tactgatttc gggtacggtt ctaaaaatgg ctatatccac gatatcgacc tgtggcagcc 39720 gaacaaaaac ggcgacggca tccacttcac taacggggcc agtcatatgc gcgtccgtca 39780 gattttcggc tatgcgcgcg atgactgcct agctatggtt aatagcgacg actccctggt 39840 ttacggcccg gacaaagtcc cgacaccggg gtcaattcgc cagtggatct accctacatg 39900 tccattctgg tatggttggg cgggaaatga ggccgtgggg accagtaacg acatccacga 39960 tatcgttgct acgaatatcg ggttaaccgg taacgagcag gtcagcacca ttctgaccac 40020 gcagtttaaa atctacaacg tgacaatcag cggtatcagc agcgtcaact atatgactcc 40080 aggccggggc tgggatgaag ttaatgcgat tctgaaatcg tatgcggcat ttggtgacgg 40140 ctccaggtat caggcaggaa atgtcagtaa catccgcatt aataacatca ttgagtgcgc 40200 atcaaaaaat tacagtatcg atataacgct ggaagggcgg gatatccgca tcaaccggta 40260 tatgaaactg gacacccgtg cgaaaacaaa aggcgcgctg aagatcagca gctcggcggc 40320 cccgtatgtg acaacctcta acatcgtgga ataagcagat gactatattg attcaggatt 40380 cattacgtcg cgccgttgaa gcggcctccc gcggtgcgca gactgtgctt tacacccggt 40440 cgggcgaccc gtcgtttgtg aatatcatcc ccaagtttga cgtcagcacg attgatgcct 40500 cgttggggtc tggaacgcat ccggcattta tcgttaacgg caccgaggtt agtcagattt 40560 tcgtcggcac ctaccccggc tgtattgtta acggccaact gctgtccctt ccggaccgga 40620 tacccgccac gtcggtggcc tatgatacgg gcatcggtct cgcccgggcg gccggcatcg 40680 gctggcacgc catgacaaac gcggaatggg cggcaatcgc tttgttgtgc tatgcacagg 40740 ggcaatcacc gcgcggcaat accaaccggg ggctgtcatc ggataacccc agcgagaagg 40800 ggcggcgggc agacgggctg gccgccggga ccgaatccgg aacgggtctg acgctgaccg 40860 gctccggtcc tgtcagctgg cggcacaacc gcgactatgc aggcattgca gacctggcag 40920 gcaacatttg ggagaccgtt accggggtcc gtttctgcgg tggcgagctg cagataatgg 40980 tcaataacga cgccgcgctt tacaccaccg accacacgtt atcctcaacg gcatggaaag 41040 ccgttagtgg tgtggatggg tctcttctta cgccgactgg caccggaacg ccgggaacag 41100 gttcatatgt tccaaccaca cctaactcag ttcgtatcgg cctttcgggg accgggaatt 41160 acacactgat ttatggtgaa aatacgctgt tcaccagtgc cacgaacccc ggggctacgc 41220 cggtatccga tgtcgcgcta agggtgctgc gccgactgat gttgttcccg ctgccgggtc 41280 tgatttccga cgacgcctta tcgtataaag cgggcgggga ggtcatgaca ctccgcggcg 41340 gggcgtatac caacggggct ggcgggggca tcaacgcgct actcgctaac cgtggacgta 41400 cttcagttgg tcgatctaac tctggtgtcc gtcctgttta ctacaagcct tgacattaat 41460 gcgccatacg gcgcatttct ttcctctttc ccggcgtggt gacagaagat gtttatgagg 41520 attagcttta aaaagtcgaa atggtccctc ttgttattta ttaaactgat caccgtggca 41580 gtattgacgc atttgttcgg tatcgggtgg gggcttctgg ctgtcgcggt ggtggagtct 41640 cttccatcca tcgagattaa gaggtcgatg tgaccgccgg gggtaagggg gccgccagac 41700 aaggcgcggg acccggtttt ttgttgacat caatagtgga actttccacc ggaaatgtcc 41760 agaatagtcc gaagcgatcc gctaccccga ctacaggaat attcatatga ctgaaccagt 41820 tatcaccggt accacgttga cgactgcggc tgccgtggtt ggcgccaccg gctggtgggc 41880 cggacttgac ccgggagtcg ctatcggggc tttctggggg gctatcttct ttgtcctgtc 41940 ttccaaggaa ttaacattaa ttgcgaaaac cggattcggg ggagtaagtt tctttttcgg 42000 aattatctgc gcgaattggg cggctgaatt gctaacatgg ggcgtacata agtttgcgtc 42060 aggcgccagc gatgcacccg ccgcaatggg ggccttcatt gcggccgccg tggcgatcca 42120 aaccctcatg gccatcacga cgaaagattt caccaaggcg ttgctcgacc ggttcctggc 42180 atggctgaaa agcgcgctgg tgaagactga tatcggagga ccgaaataat gtctgccttc 42240 gcattttcgg ataccatcat cacgaccttg ccggatagcc cggcattcct tttcatcacc 42300 catacattcg ctattttcaa cgttcttctc tgcctgtcta tcgtgtggcg gctgttcact 42360 ttccagcgga aaggggcgcg ccaccgttta gcaggcggcg tgatcgccat gttgctgatg 42420 gtcttttaca tgtggacacc gttccagttc gtgctgggac gcgtggccat tgtggactgg 42480 gcgaccgtcg gtattaactg catcgtcttc atcgcgatat tccgggcgcg gggaaatgtg 42540 atgcaactat tcaagtcgtg agggggcagc actatgtcgc tatcggatga cgagtaccag 42600 aaggccgcgg cgaagatcgg aatcagtgta cctgcgctgc gggcattcgc ggaagtggaa 42660 agcaatggca gcggctttat cgatggcaaa cggccaaaag ttcagtatga gccgcatgtg 42720 atgtatcagc ggctgaaaga gaacctcggg gttagcgttg ctaatggtgc gctgcggaaa 42780 tggcctgacc tggtggctac caaacccggc agctatcagt cgctgaacaa ggaagatcag 42840 gacatggacc gggcggccaa agagattgac cgcacaagcg cactggaggc cgccagctgg 42900 ggggcgtttc agattatggg ctaccactgg aagacttgcg gatacccggt gctgcaggca 42960 ttcgttaacg cgcaatactc cgaggctggg cagctggaca cactggtccg gttcctgcgt 43020 gcatcgccgg ccatcgtatc tgcggtcaaa agcaagaact ggtcgaaggc ggcgcagctg 43080 tacaatggcc cggcgtataa gaaaaacgcg tacgacgata aactggcgaa ggcatataaa 43140 aaatacgggg gtgtgtgatg cttacgccta ccgttaaaac tgtagtggcg gctatcatgg 43200 ccgccgctgt tatcttcgcc ctggtgtggc tgcataactc gctggccgag cgccactacc 43260 agcctaccat cgatagcctg aataaaacgc ttggcagcgt gaagcagcac aatgccggtc 43320 tgactgccca gctgcaggcg caaaacgctg ccatcgcgtc tatggcggta cagagcgaga 43380 aagataagca acgtatcgcc gaactggaga aagccgcgca gcggggcgct ggcgaggaat 43440 acggcagggc caatgaagtc ctgcaggaac gcaccaccgg ttccgacgtc tgccgggcgg 43500 ccagtgatgc cttcgacgcc gagctgcgga aggagcgggc aaaatgagaa agctgatcgt 43560 gaccatggtc atgctgcttg tcggctgttc cgcccgaacc gaaacgccgc cggccgtcgt 43620 ggaagtcaaa gtgccggtgc tgcagaagtg cgatatccgc cagcctgacg cgccggcgtt 43680 cgcggtggac gcattacctg tcggtgcgcc gatcgatgcc cagatgcgcg ccctgcgagc 43740 ggaacggcac caacggcagg ggtacgagat attactgcga gccgagatag acaagtgcaa 43800 aaagtaagcc cgggaaaccg ggctttttcg ttactggggt ttgcgtttac gccgctggcg 43860 catccggtat ttgaactcgt cccatcccca ctggattaag accagcatta tcgccagcgg 43920 ccaaaagata accgcgaaga accgaccgac tgactcgtcc tctgacgtta tgccggccat 43980 gagcgccata cccagaatcc agaccaccac taacatgatg tcattcagca ttctttaccc 44040 tccacgcgcc gcataacgac tttgaaaatt tcagcgtagt ggtagcgttc ggatgtaccg 44100 ttagcccagt tcaacttaat gattagacca tcaagctgtt cggtgctgtt aacgacatcg 44160 ccgctactta acacgtcgcc cgggcgcagg ttaactgcgg cgacaggggt ttcagttaat 44220 gtcgccagta cacggtcttc cagtttggag aattcatgta cggtcaaagg cccatcggta 44280 tcccacgcct tacctgcgcc cggagacatt tgcatgaaac gccggtgggt ttcttcttcg 44340 ttacggcgca ggagttcata cattccctgt agtccggtac ggtccgggag gatcagctga 44400 atcggcagac ggacgacctg gttttgctgc gcggcccggc gtaacgcgtc aaaactgcgg 44460 tatacctgga tgcccagctg gtacgcgcgg tggacttccg cctttgtgcc ggtgcttacg 44520 acgtccgcgt ttggcatggt tagcagtacg gcgtcgcaac gttccagcat ggccatcgtt 44580 ccgtccaaga aatactggtc gtcgttttgc ttcgcctgat tttcgaagtc ccgggtattg 44640 agatgcggca ccaccgggaa cagtccgaga tggccaagcg tatctaccag gtgaacggcg 44700 gtaagttcgg cgatgctgat attatgggca gtatcgacta acgcgccgca ggcgttggtg 44760 taagggcggt acggcccggc aatgtagatc agtttcattg gctttcccca ttaattcgtt 44820 tcgaacttaa ctttgtccat gtacttgtcg cggaaaggtc cattgcgcac agttcgtctt 44880 cgttgtttaa aaacagaacc cagttacgtt ccgccatttc agcagatatt tcggcgatga 44940 attcgtcggt gatctttaat cgtccggata tatcccgtag ggtattccgg gagaatttat 45000 atcggtttat ctcgcgccct ttctctgtgc cgtatgcatc cgcgttggaa attatcagat 45060 tggcaacgtg acgcgcgccc ctgaccgcca tcatttcata cctttgaagt ttttaggatg 45120 gccgatgtta ctctgaacat cgatagtaat ttcatccatg aagcagggca cgcggacccg 45180 caccagtgtt tttgcgttta ccatgtccac caggcaagtc gtttgcccgg ccactgctgc 45240 gttaacccgt tcatgccctt tcgccttcgc taactcgcta tacgccgcaa ccgtatcggc 45300 gaccatattg gccatgaagt cccactgggc ctcgtttatc ttccgctgga tgtcgtgggg 45360 gatgaccgct ttattcgctt tgaacatatt atttcctccc catggggcga tgtgagccga 45420 tccctttctg gtggccgatg tggatcttgc cgcacagttt gcagtggtag gcatccatcg 45480 gcccgctgta cccgtacgtc cgcttgatat accggatgcc tgccagagcg gccgggatgt 45540 ccggataacg ttgcttcccc tcgcatgact tccggcgcag tctgcgctta ctggccatcg 45600 ttacaggctc cagttaggca ggatgcccat ggcggccagg atggctgcga tgacgaacag 45660 cgcagacagc aggcagcaga taaatccggt gcggcggttc gtcttgtcgc cctccagcgg 45720 caacgactcg atatactctt ccgccttctt acggcctgcc tcccagcgcc agtatgcccg 45780 gcatttcgcc ccggtaccgt tagttgggtc gctgtacggg ttgctttttt cggtggcgcc 45840 ctgcaggccc gccagcacac cttctgcttc ttccagagta cgggccggga tgaattcatg 45900 cgcgccgggt accggtactt cgtagccttt ctcgctttct ttgatcatgg gttaaccctc 45960 gtagttcatg ttaaaggtga tgcgtattac tgacttaata cccaggtgat cggtaatcgc 46020 caggtaattt ggtggctcgc tcatcatggc gaattctttt accgccatat acccgggact 46080 taacggtctc cccctggctt tcatcccggt ttcataggcg gagacgaacg ctttggcgct 46140 gacgacctta cggtccagca caaatcccca ttccatgagc aaggggtaac gcggtggtgc 46200 agttttggcc gttggcttat cagcgaatct acggctgctg cgataaatgc cctgcgggat 46260 ggggtacacc cgacaaaccc cgtgatagcg ccccagttct tccagcccat agaaggtgtt 46320 gcagcggata tcgtattcgc gttcgccgtc cattaatgcg gcaactgcgg ctttcagttc 46380 gtagtaatac tggaaccact ggtggtggcg gttgaccacg cccgaaatga tctgctggtc 46440 aatccggtga acaatctggc tcataatgaa aaactcccgt cgttgccttc gggagtaata 46500 ttagttgcac acgaatcgta tgtcaaacag ttttttaagt tattcaggtt caggttttag 46560 ccgcgggaat ctttccagcc agccgtgatc gataatcacc atatacgcct ggcggtaggc 46620 atcccgtatg gcagtgtgtt gcgctaacgg gcagcgcgct tccgcctgtg cgtcagcgag 46680 ttcccacagg ccgccttctc ccggacggag acggtcccac cgcttcatta gcgtgcgggt 46740 atcgttctca tcccgaaagt cccacggacc ttttccctct ccgccaaaca gcccgttttc 46800 cagttggata atatccacgc gtggtgcatg cccccaaacc tgcgggcgga attcttccca 46860 tgcttgatag aggcccatgt aacccagttc atcctgaccc ggggagcaca tgtattcttt 46920 aagcgcctgg tgtacccagc tcatgaaggt gatacgagcg tcatcgatcg aaaccggttc 46980 agcatcttcc ttcgcgaaaa acgcttccat tgcggcttcc gggttttgca tcgcctgact 47040 gacccaccac ttaaccgttt cagggtcaat gtcgccccgg cggcgacgac cggcaccctt 47100 ggctaacgta acgctgaact cgcggaacca gccttcgtcc gcgtggaaca tgacgcacgc 47160 gaatgacaga aggtagccgt cggtcttgca tgacaggttt tccacgtcga atacgaggtg 47220 gattttgccg atgtgttctg gttttgctct cataggtgtt cctcttcttt ggtccattct 47280 ccgctgccgt cggcgcgggt cactttaata atttcgtctt tttccacgtg catcaccggc 47340 agcggtggaa atgctacggt accgtcggtg tggcataccc gcacttccac ccgccagggc 47400 ttccagaaaa cgggtatcca gtcgcaatgc tcaatcacga tgccggagta ttcccggcca 47460 ttgcatttat cccggaagcg gaccatgtcc ccgtagagcg ggtaatcagg gtccggcggg 47520 agggcggcat atttatccgc aattgatctg caaacgtcat acattgacat attaatcccc 47580 cataaaaggt tcgcagctcg ccgcgcaacc ttcgtaatct tccggagcgt cttcacgaac 47640 cggcactgtc aggtcgaaac tggcgatcag ctgctgcgta tttcggtatc cccggaagaa 47700 gacccgtggg tcgtctacct ttaccccttt gaccatgttg tcgccaacgc ggccatagcg 47760 ttcttccatc tcccgcgtcc actcgaagaa gtccagcacg tccagcttgt cagtcgggaa 47820 ccagtcgatc agcgggtaca cgcggacctg gcccgtctga cggctaaccg tggtcttctt 47880 acgctgcagt tcgtccgtac gaatgccgat cgccgtctgg taggtgccgc gcttccagcc 47940 gatggaccgc atgtacgagt ggatcacgtt ctccttcaat tcccgggtgc aatggatgta 48000 gtttttgttc gggatgccgt actttttgag catctcttcg aacaccctgc cttcccggtc 48060 cgccgtctcg tacgagatga cccgatgggt acagccgcgc tttttgccgt ggtgaacaac 48120 cgcttccagc cataccgtgt tgaagccgaa gtgctggtcg cagtctcgta cgaagtccag 48180 cgtttccgga ttctcacggc cggtattggc gaagcacacg ataatctcgt acttatcggc 48240 gtactctttc aggatccggt aggtcatgta agcggaggtg cgccccccgc tgaacagcac 48300 cagtaagcgc ggctttgcca ttagaaatcc ccgtctaact cgcccaggtc atcggcacgg 48360 ccatacagct cttcgaacag gatcatcgct gcggcgtaca ccagcgtccc gcgaagttcg 48420 ttgatccggg cctgtttagt cggcagcgtg cgggcctcaa tggttttctt gataacctgc 48480 tgcgccaggc cggcgtcgct gtccagcata tgcgccatgg tcagaatcgg ctgttcgata 48540 aacggcaggt cattggcgtg acgctcacgg cctttaccgt acgccgcctg ttccagcgcg 48600 ccgaggaagg tgcgcagcag cggcaggtag tcatcacggt ctttctcgtt tttgaaccgg 48660 aacaaggtcg accggatgcc ggaatcatcg gcgaccatag tcaggtccag gtcgtcatta 48720 gtatccgtgg ttgatgggcg taactccgga gcgaactttt catactctat gccctggcaa 48780 tcctctgctg ccttatcgta cgcagaagcc aggccactcc atttcagttc ttcaaccgca 48840 cctactggca gtgtcacgtg aggccatttt gcaccagcct taatcttgat gcgttgttcc 48900 ggaaacaggt ccggagcggc ttcgtttttg atagtcacgg tatttttagc atgagtgttt 48960 ctacccgcat cggcggactg gcgggcttcc ggttccactg gccggggggc gacgagcgta 49020 tcgatcgctg acaggatgct ttcgtctgac gattcgaaat caagttttaa cgtcgctgca 49080 atcgtttcca aggttgtttg gtgttcaaac gcctgcgcat tcacagcgcc taccatggcc 49140 agcatttcgt cccagctgcg gcctgtaaca cccagcgcgt tcgccagctg gtcacgcatt 49200 tgcgaatcaa tgctgaccgg ttcgtcaatg gacgggttac gcagcgaaag gagtttatgc 49260 ccgttgagat gcgcgaacat gagatagttc atcgcgtcga tcaacttacc cttggccagc 49320 gaatcgcgaa tgcaggtacg gcattcatgc tcggtcagtt ctttccatgg ttcagcggtc 49380 gcccagcctt tgcgcttatc cgcgccgtag taaagacgac caagcatctc atcgaagacg 49440 cctttaactg aggtcaggaa cgcttcattc aataaattgc tatggaaggg cggccagcgg 49500 agttcggttc tcgggtgaac gattctgttt ttggccggca tttctttatt ctctgacatg 49560 gtatatctcc gggttgtttt gttgttcgat tagaatacta gctgcacacg ttttgtgtgt 49620 caaacgtttt ctagaaaatc tacagttccc accataaagt ttcggatgaa ctgggcgccg 49680 acttgaggga cgattgcatt gccgtatccg cgcagtcgca ccactcgggc gggtacccca 49740 ttagccaacg ggaaaacgcc ggatccaacg ggcctgaact tcccatcccg gcatagcagc 49800 cagtcagcat ttgaccacgg gccgtgatcc tgatcgggaa gtcgggggca ggcgtacact 49860 tctccatgcc cttccggtag ctccccgata gctgccccct cgatgccggc gagtccggta 49920 ctgtcagcgg tgtcgggtag ctggcgagac gaaccgcgcc gcccagggtc gtcgaccgat 49980 ccggatggcc cgctgcgccc gcctccccgc gtacctgatt gttgtcgatc gtcgtcaccg 50040 ttggccaggt cgccagctgc gccgccacgt ccagccggtc gacggatagt ttgccattcc 50100 ttatccgccc acccgcgtag ccgcctttcc agtccgtcgc tgacgaggtc ggccaggtcg 50160 atagcgccaa agaaaaggcg atctctttta tgcggggcgc cgacgctgca cgctggcaat 50220 actgccgacc cgcaggcgta accttcttct tccagctcaa cgaatagagc atcgagccac 50280 aattctttaa ttgctgcgct aacctgttcg ccaaaaataa ctggaggtcg cagctctgcg 50340 atgaggtcga gaaaggccgg agccaggtga cgggagtcgt cccgcccgcc tcgttttcca 50400 gccacactaa aaggctggca cggcggactt cccgtacaca ctggcgcata cgccggccat 50460 ccggcgagtt taagggccag cggccatccc ccgataccgg cgaagaagtg ccactgacgg 50520 aaaccccgga ggtcttccgg ggcgacttcg gtgattgatc gttcatcgac aattccatct 50580 ggcaggtggc cgcgcctgat tagttcacga agccacgctg cggttttagc gtcccactcg 50640 ttgtagtagt ggaacggttt agagccgttt atgtatgcca ttctgcgcct tcttctcttc 50700 gcgtcttttg accgcacaat cggcatggat cgtagtccac gttccggacg cagacctttc 50760 aagatacccg gcgccggccg gcactggctt tttgcagtag caacacatag ccacgtattt 50820 atttctggcc atctttgacc ctcgcgaaac aggcatacgg gccatcgaat tccgtcggcg 50880 ccgtatacag gagaaaccag ccggacccgt taagcgacgt cgggcgcggc atccaggtac 50940 gcagcacaga ggcgcgcatc tcgtccgtct tcgcgttgtc gtacgccacc cgcagcggca 51000 cttccagcgc tcgcggatag ccttcgccca ggtagaatcc ctcgcactcc aggttgtatg 51060 catccagcag cgcgtcgaga ttggacccat catagttatt actggcgtgg aagaagacgg 51120 gatggtagta ccaggcgtcc gggtcatacc cgtccgccag gcttacctgc tcgccaatta 51180 cgccatcgtt atacacgttt ggctttggca ttcttccctt cctcttcggc aactgaccag 51240 acgacctcgg tgaacgggtc agggttgatc gtcttcccga ccttattctg gtcgaggtac 51300 cagtcgtcgc cgcaccacag tttgacgccg tgggcatccc ggcggacttc aacgtcgaac 51360 gttttcactt cggtgatctt gccgttacgg gttacagttt tggttaattt catggtcttg 51420 gcctcacgtt tatgaacacg aacctgtttc atgggtcatt ccccgaggta attcatggcg 51480 ccgcaatccc ggcatacaac ttcacgcggt ttcccttccc acgtccattc cgtcacatcg 51540 cattgatagt gactacagct atcctgaatg cgctgcgttt cctgccgttg cgcttcgtat 51600 ttagcgtcct gctcggcgcg gcgttcatcc cgtaaacgct gcttgcgttg ttttgatgat 51660 tcgaatgtca ttgctatacc tcgtcccact gggcgatcca cttctcgcgg acgtcctgca 51720 tgatgttggc catgggcagt ccgatgtcca tgagcgcttc ccgggagatg tactccgggg 51780 catgtttttc ttcgtcttcc ggatcgaaga tgactatcgc ggcgccgaag cccgcggacg 51840 ttgcacctgc ggcgcccgtc ttcgctttga accataccgg cggttcgaaa ccgatacgcc 51900 ctttgatgaa tatggtgcgc gtggcgatgg tatctggcca ccatgtttca gcggtagccg 51960 ctttgatcac ccagaccgta cccgcgcctt tcttccgttc ctcttccgcc ttggccatga 52020 tgttgaccat gccggtcagc ggcacttcca cagcacggtt acggctgtat ggcgggttgc 52080 cgaaacccca tacccgccga acgtggtcgg cgacatcgta cacttccgcc tcggcctcca 52140 gttccgcctg tatccttttc agccggcccg cccagtcctg gcgcagcgcg ttgtcctcgg 52200 cggtgtaata gcgcgtgcat ttggcgttct ggccatcggt gaacaggtcg agcaccagcg 52260 ggccgaacag cttgtccagc gcgaagaaca gccagtcggg tgttcgccac tggtcgccta 52320 tctctttcag gtcatgcgct tcccgggctt tcagcgcgat gaggttgtca acgtattcac 52380 tcacaaatta gcctccatgt atggacttgg tcgccctggg tgatgagatt cacaatgata 52440 aagccgcctt ctttttccat tcgcgcttta tccgcgaatg ccggaattgc ggcaaggaag 52500 tctttccatg gcagggggtt aaacgcgcca atggctaccg agatttccag gtttttattc 52560 ccaccggcct tgtgggaaac gcagcaaagg ctggttccgg ttttatcccg cagccaacgg 52620 tctacgctcc ggaggaattt cccgtctccg gcggttaaaa tgtcgcactg gacaacgata 52680 tttgtcacgt cactcatggc cttttctccg ctaaaaattc gcgtaatacc ttttccatgg 52740 ccaattcgtt tgccgcagcg ccaggccatt taccgagaag ccgcgcatta ttcggtacgg 52800 tctgcatttc cacaagacag actttgttac ccaactcatt gcgagaatgg ttgatactca 52860 ggctgtaaat gctgacgtcg tccgggccat cccataggtc ttttcggata ttaagatatg 52920 cctgaatatt acctgcatcc gggatcgcac ctgcgctcat aatatctacg cacatttcct 52980 ggatgacctt ttggtcgtta attacgtttt tcatttccgt ttttccttct gtcgtgacac 53040 gaactggact ggggtgacga cctcaccgaa attcgggtaa cggctgcgca ccagctcaag 53100 ggtcagcggg ttgatctccg cacgcggcgt cttcacgtcg tacgcgcggt ccgggatgtc 53160 gatgcggcgc atgtacgtcg gtcgcatccc gacgcgtacg gcgtagttat acgcttcctt 53220 cgggccgttc gcccagacca cgaagccgac cccgcggcgc tgcagataat atgcctgcgc 53280 cgtattggag tcatcgcgag gcagattttg tggtatcgcg ggaaaacggg cgctacttcc 53340 tttcacggtt cctgtatacc aattggtcga agcatggcgt tcttccgaac actccggcgg 53400 gtacgggtca ttgatatccc acgtctttcc gcaccaggaa cagaacacct ggtccgattg 53460 ctggatagcg tttttgtggc cgttagtttc catcggtgtc ctccatcatc caggacggcc 53520 atacgccatc gcggatcatc tggcgctggg ccttccagtc ggcctgcgcg agttctttaa 53580 ctcgggtccg gatgacagcg tcgggcataa acgccgtcat tactttcgtc aggaaaactt 53640 tgttgtaggg gtcctccacg cggcagttta acgcccgggc gcaggactgg atcgccgcct 53700 tatcattgcc gtgttctttc atgcacagca tgagcgtaac gatcatgtct atcgcctcgg 53760 cgatatcccg gcacgctttc ttttctggcc cgtggacctc aatggaaata ctggtcgccg 53820 ggaataacag gtggtctttg tacgggcgca gccagtccgc tttcgcccgg tcttctgcgc 53880 tggtggtcat acttcgatgt cctcttcccg gatcagctgc agggcgttgc cgttcactgc 53940 ccacggttgc cacacgtcca ccaccagcgc cgcacggaat gaccggttga agcagttctc 54000 gatcatcgcc cagttatcgt ccggacggtc tgacgcaatg ccattgcgtt cccagtgcca 54060 ctggcgaggc gcctgggcca gctcgcggag gggcgggcgg gggtgtgagt agggattgca 54120 caggccggaa cgcagcaggc cacgctggag ccatgagcgc tgccaccaga ggtcacagcg 54180 ggtcgacccg acggcgtatt cctcttccag catgccgcac atgatcagcg cgcacacagt 54240 atcgcgtggc gccggcgcac cgatgaggtc gaaatcctcc agcctcttcg ccaggcggtc 54300 ggcggaccct tcgtcctgcc cgttgccgtc ggtacggtca tgcagaatta catcgaggat 54360 gatggccgga aaaacgactt gtttgccgtt gcgggtaaag cgggggtccg gctcattgaa 54420 gagggcgtga tacagccgcc cgaaccactc cgacaggtca ggcacgaagt cggcgatatc 54480 cggccagctg cgttcctctg tgttgtggat gcgcacggac gtctcttcct ctatcgggtc 54540 gtactcgacg cggacgatgc agcgcgggcc gtgcgggagg ggaaaaatgt agatggtctg 54600 tttgccgatt cgattctggt caaagcggcc aaacgacatt agatgcttct tcatgggatg 54660 ttcctttttg tggactccca agaaatgtag ctgaacacga ttcgtgtgtc aaacgctttc 54720 tgcaggcaaa aaagaagccc ggacaaagcg tgccgggctt taatgtcagt ggaacaccga 54780 gcatgaagat ttcatcccat gtcccgatca ctatacgtca ggattgcgat aaatcaaatc 54840 ccagtaggtg aatgtttcca ggtcgacttc cgtccagtcc gggtcgtcca ggtacgacag 54900 gcaggtgccg gcatcctcgg cgcagacctg cccggcggcc gcattatgca gcaggcggac 54960 ttcccggaaa tagatgaacc actcgcggca tggcgtatag gactcgggct gacgggtctt 55020 gatgatctgg cccgtctttt tgtcctgcca gtacgccgtc cgtttcttcg ccaggtagcc 55080 catatcagcc caccctcatg acgcgggatc ccatgcggcc gtaaatcggg tcgcgcagca 55140 cccagcggat agccagctta taccccaact ggtaccccag gcgccgcacg tagcccaggt 55200 ccgcaggccg cttgccgctc acgaagaagg actcgccgac agccatagcg ccaagcaggc 55260 gtttatgctc ggcgatatgg gggttcggtt tagcgtgttt acggcctgcc atgtcacacc 55320 tcgtcgtcgt cttccagctg cgcgtcgacc tcaaccgtga tgtccatctt atcgcggaag 55380 acgtcaatga cgtcctgcag cgacagcacc gtctggaaca ggttggccat gtaggtcagg 55440 aacgtaccgc tgtcattgtt gtagcgctcc agcgtggctt cgtagttggc gtcaacatcc 55500 gcctcgccga tgtggatccc ggagatgatc gccttgtcgg taaggcggaa gaacacgttg 55560 cccacgcccg ggcgcatctc gccttcgtcg attcgcatgt tcagcgcccg aaccgtgtaa 55620 tgccgcgcca ggtagtcgag gaccacttcg tccttgtgga tgtcaatgtc cttgaacttc 55680 acgtcatcgc catcgtcgtg cttgatgtgg atgaagtcct cgccggtgac accctcgatg 55740 tcgccgcgta cgaccttctc cattgactga cgcagcacga agtcattgat cagcaggtgt 55800 tccactggcc aggtaccgaa cgcggcacgc agtagggagt taatctcttc ggcggtcctg 55860 gcgctggtgg tgaacacgta gacgtacggg acggcgatga tcacgttgta gcgggtcggg 55920 cggataggcg cggttttcag catttcggct tcaacatcgt ctttcagctg cgcccagtct 55980 ttccgggtcg gctcccagcc ttcaatctct ttctcgcgcc aggtgtccat acgcttcgtc 56040 acttcgttgc gcacgctgac gccgggcagc acgcgttcac gcttttcggc ctgcagcacg 56100 atggcgttag tacccgggat gcccatggca aacttgccgc ccacgtagtc cgcgtacggc 56160 gcaaagccaa tcgtcttata gccgatcggg tctttcactt catgcttcgc cagcagatcg 56220 ctcacacggc cggcggcgaa ttcatggacc gacatttcgt ccatgttcgg cgtgttcagc 56280 agcgtgcggt ggaaactttt taccgacttc tcgccagcgt ttgcggcgcc aaagagcgcg 56340 ccgagatgca gaatgatgac tttctcaaag cctttaactt tcattggggg tatctccgtt 56400 tgcaaacaga ttcaggaatg gcgcacgcac aagggcggcg gttagatggg ccagcagcac 56460 acggttcgtc tcccgggcgc tacgcaggtc tgccgccatt tcggcatact ctttatcgac 56520 tttgacaaag gcaccttcgt cagcgtcagg gtcgaccatc gtgttgccga ggacttcggt 56580 atacacccgg gtcgcttcat cctcgatgtc ggcgataatg ctgttcagga tggcgatctt 56640 actgcgtacc tggtcgagcc ggtcagcgcg ggtcgtcgcg tacgctttca gcagttcagt 56700 gttcatccgc gtgctctctt ttcgttacgg cggcgctggc gctcatcctt gcgcttctcc 56760 acctgtgcat tccagcggtc gcgttcctct gactccgccc ggttcttgag ccagagttcc 56820 tcccgttcgc caagcgcttt actgaccgca ccgtcaataa cttccgtggc ccggaccagc 56880 tcgtcttccg tcatttcagc ggcagagcac ttcccgatct ccgtctgcag caaacggaca 56940 acggcagaga tgccgatcgc gtcgatggcg atacgggcct tttgcgcata cagcagtctt 57000 tggttaaccg gcatcatttc acccccgttg tcaggacgac atagaggacc gccacgcagg 57060 cgaccagctc gatcagcacc atgaacagga tggacgccag cagcagtttc gcaaatgacg 57120 gcaggtatgg agtaaggcgt atgcgagcat gaccgtccag ctctttgtgc ttcattggtc 57180 ggcggttacg tttggtccag cggcgtatcc agttttcgcc gcggcggtgt acgaggctat 57240 cattcatcac ggttccctcg catggcatcg cgcaggtctt tcggcgggta gattttattg 57300 acgccatcac cttcacgcag gaaacggatt aacatggcca gggtctgcac gatctcttct 57360 tcgacatgga cccaggtatc acggcgctcc gcgtaatgca ctgctgcctt gatcacctcg 57420 ccggcctctt ccgagaattt cagcatggtg taattcggct gcgggtattt ttcgatagcc 57480 cgggccgatt cggctcgtgc ctggtcgacg aggatatcga aataatcggc cttcgcttcc 57540 gcctgcgaat tcatctgcag gtaaaagatg gccagcgtcg tgaggaattc cgggctggcg 57600 aaagtgatgt ccccacggcg taccgcatcg cgataccggg cgacgctttc cgggttgact 57660 tctctgaact cattttcatt tgacatgggg tttccttctt agtgtttttc gccagcaatc 57720 tccgccagta cggcagcgac ttccggcgtt ggcatgtggg tgttagccca gtacagcagc 57780 ccgatgatgt agtggatcat ctgaccgacc tctgccgcgc cgcgggcttt tccgcctttg 57840 gctttcgcat aatcgccttc gctgaacagc actttgccgg taccgcggta gccaacaatg 57900 gccgaaccgg tatgcgtgac gtaaatggcc acggcgtatt tgtcttccag ggatcgaaac 57960 gccgggccag cgtcgagtcg tttgcgcggc gccgcaacgc ggttcaccgc cagcgcgaca 58020 ttactcggtg tcgggttttc cattgagcgg ctctccgttc agggtgtaga tgacgacgcc 58080 cggcacgctg acgtcgatcg acagcgatgg cacaaagccg gacatgacgt tctgcggggt 58140 gatggtggcg cgtttcaggc cgttctcgta catgatgttc gcgatgcctg ccatgacgga 58200 cttctccacg atgttctggt tcgtctcttc gcgcatggtc agcagctgtt tcaactcttc 58260 gacttcattt ggaatgtcaa aggtatgctg taacatccgg ataagcgtaa tggcatcatc 58320 acgggtgatc ggggtcagta gctgggcata agcagggtca atatggtcga tcatgatctc 58380 gccatcctgc tgtcctggct tacggtaggt atgcaggact cgcgctaact cagggtagcc 58440 gggcataatt tccgacgttt tcctttggtc atcatatgac atagggtgtc tccgggtgaa 58500 aagggtggta cggcaaaaaa gaggtgccgc gtcctacagg attaaacttc gtcgtcttcc 58560 ggtgtgccgg cgccgtcatc aacgcgcttg atcgccacct ggataaacgc acggcccgac 58620 gggtacatga ccagcgccgt ttccagtgag aactgactat tgcaggcccg tttggcgtta 58680 cgcagggaag acgacacgcc gttacgcatt ttgtagcgca gcgccgtggc ttcggtctgc 58740 aggtctgcca gcgccttgct gctgtccagc tcctgcgcat aaacgtagac ctcgcccggc 58800 ttgaggccga tcaggttgcc agtgatactg ttagcccgga tacctgacgg cagttccacg 58860 tccgtctcca tggtcatcat ggccggcgtc aggtcatcca ggataatcgc gtcgttcatc 58920 ggtattctcc gtcgttaaat ttgcgtatct gtcacgctga aagatagttg catacgttcc 58980 gtgtgtcaat cgttttcact gaacgacaac ctgccagctt tttcaagtaa gaaatttcag 59040 ccggctaact ttttgaagta agacccgaac cgctatggcg ccggccatgg ttattacggg 59100 59100 <210> 2 <211> 333 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15/11/N54_KPN_BP ORF 48 <400> 2 atgtctgcct tcgcattttc ggataccatc atcacgacct tgccggatag cccggcattc 60 cttttcatca cccatacatt cgctattttc aacgttcttc tctgcctgtc tatcgtgtgg 120 cggctgttca ctttccagcg gaaaggggcg cgccaccgtt tagcaggcgg cgtgatcgcc 180 atgttgctga tggtctttta catgtggaca ccgttccagt tcgtgctggg acgcgtggcc 240 attgtggact gggcgaccgt cggtattaac tgcatcgtct tcatcgcgat attccgggcg 300 cggggaaatg tgatgcaact attcaagtcg tga 333 <210> 3 <211> 585 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15/11/N54_KPN_BP ORF 49 <400> 3 atgtcgctat cggatgacga gtaccagaag gccgcggcga agatcggaat cagtgtacct 60 gcgctgcggg cattcgcgga agtggaaagc aatggcagcg gctttatcga tggcaaacgg 120 ccaaaagttc agtatgagcc gcatgtgatg tatcagcggc tgaaagagaa cctcggggtt 180 agcgttgcta atggtgcgct gcggaaatgg cctgacctgg tggctaccaa acccggcagc 240 tatcagtcgc tgaacaagga agatcaggac atggaccggg cggccaaaga gattgaccgc 300 acaagcgcac tggaggccgc cagctggggg gcgtttcaga ttatgggcta ccactggaag 360 acttgcggat acccggtgct gcaggcattc gttaacgcgc aatactccga ggctgggcag 420 ctggacacac tggtccggtt cctgcgtgca tcgccggcca tcgtatctgc ggtcaaaagc 480 aagaactggt cgaaggcggc gcagctgtac aatggcccgg cgtataagaa aaacgcgtac 540 gacgataaac tggcgaaggc atataaaaaa tacgggggtg tgtga 585 <110> Industry-Academic Cooperation Foundation, Yonsei University <120> LYTIC BACTERIOPHAGE SPECIFIC FOR KLEBSIELLA GENUS RESISTANT TO <130> DPB172741 <160> 3 <170> KoPatentin 3.0 <210> 1 <211> 59100 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15 / 11 / N54_KPN_BP <400> 1 atggccaccg tggcgccgca ggaattttac ctcaaggatt gccgggcatg gccaccggtc 60 aggcccatgg cgccgacctg gctggcgcgg cccgccgccg ggtttcagcc tgccagcttt 120 ttcaagtaag cgcgcaccgc taaaaatttt cagcccgcta ggtttgccaa gtaaggaagc 180 ccaaaatttt tatagaaaat ccggatttcg gcgtccccat ggatcccgaa aaaggtgcga 240 tttctgtaaa ccattgattt tattggttcc gcggggatgg cgccgatggg gcggaaaggc 300 cagcaagcca ggcgtggcgc gggttgcatg ggtatagatc cccgttgggt gacggcgtgg 360 cggcgcgccc tggggtgacg cggaaagcaa aaatgaaata aatctgcatc gaggggttgc 420 acacggaatg agtgcaagtt atgtttatcg aacccggcgg ggatacgcga acaacgaaac 480 aacataaacg aggtaaacga aatgaaaaag attaaacgtc tggcactgtc ctggtctgtc 540 tcccgcggtc gtgacactta cggctacaac atttgccgcc ttgatgacac atcaaccgga 600 gaccgcttta aatgcatggg cggcgggtat gacatggtag ggacggtgtt cggtgactgg 660 ctggccgcaa actatcagcc tgaattgttg gcgctgaaag atcgcgctgg ggccgtgtgg 720 gaagaggcgg gcggccgtaa atcggcggac cgcgcggacc gcctatacgg catggtatac 780 cgggaaaaag atagcgtagt tatccttgat ggcgcttgcg ggcttgattg catgatccgc 840 attgctgagg ctatcgggct ggaagtggag cgcgattata tcgctaaagg ccgccgccgg 900 ggtgagactg tgggctggta tgtaagcgag gccgaataat gataacaata atgtttatcg 960 gttatttcat tatcggcgtt tatatcgggg cggacgtccg ccgcgtttta aagcgttgcc 1020 gtattgagcg ccgcccgtgt tttggtcgca tgactattta tttgcgtgaa cgtaagaccg 1080 gacggttgat cggctgttct aataacattt tcactttaat tttgcagggg tcttgatcat 1140 gagaattaaa atagaatcgc ataaatatgc gccggaatta aaccgcgttt atttaaccgg 1200 aaaaaattca tcgagcgcgg cggtactccg cgccccgtcg gtaacgtccg taaaagatgc 1260 ccgcgcggcg ttattcccta aagcgcttcc attccgccgg gttgtaaccg tggaatcata 1320 ttatgatgat cctcgttttt acgggcttgg ccgccgctat tccggaaccg tggattcata 1380 cgaacatctt aaaaacgtga tcgctaacat taaagcccgt aacactgggg ggccgctgtt 1440 agatgggtcg attctcccgc cagtgaaagt gcgtattgtc tcaataaaag ctatgggggc 1500 ttaattatgt ttacctcaaa cgttgaaaac cgtctggcat tgccagccgt cattaccgcg 1560 cccggcgact acatcacccg gtccggatgc cgcgtcacaa tcatcggggt atcgcctgtt 1620 aatagccatt ataccttccc ttgcaagggg tcagtatggg ttaaattccg cggggcgatg 1680 cggccgcgtg gatataacgt ctggatgcgg tccggtcatt tacacgccgt gggcgatcat 1740 ccgctggata tcgtcgggcc gtgggaggac ttgaaaccat gaatagtgac gcaaaaaagg 1800 ccgtcgtaaa gttctccgcg tgcggcctta tcgctggctt taccgtgatc gccattatcg 1860 cgggcgacgg gggcggcctg ttccgcccga tactttacac cgtggctgga ggggtatgct 1920 gtgggctgat atggcccaca caggaccagg gcgacgccct gctggactgg atcaaagaag 1980 ggcggcgata agccgccttt cttattggcg ctgatacccg aaccgcgaaa accggggtga 2040 cgcggacagc aaaaatgaaa taaatccggc taaggggttg cactcgttcc gtgtgcatat 2100 tatgtttatc ggacccggcg gggatacgca aacaacaata aacgaggttc aaaatgacat 2160 acgacgaaat caccgcaaaa attaacgctt tcaacctgaa agatgggatc acgattcgtt 2220 atacctccga cacggacgga tcaaccctgg ttgaactccg cgacgatagc ggcgctttga 2280 tctggtgtgc ctggtccttt gaggctgatt ttgctttctg cctggatcgc gagctggacc 2340 gctacggcgt gaacaaatca gcggaggcgt attgcgtcgc tgataaccgc cgcccgtccc 2400 acgtaaaccg cgcggactac gcaacggacg ccgaatacag cgccgcgaag gtggcgtttt 2460 cgtcgccagg 2520 taaagaaaac cattaaatca ctgcgagact ggaaagcggt cgcacgcaag gacgcggacg 2580 ccgccggggt ggcggcggta ttcggtaacg ccctcatggt taaacccgtc aaaatcacta 2640 cggcgggcgg aatgaccctt atcgcctcgc aatccgatat aaagatctac ccggctttaa 2700 tgcgcctaac ggcattgtgg gatatgcgcc acggcctaac ccgtgacacg cattacaacc 2760 attctctgcc gttccactgc atcgcgggga ttgaatatgc gggctaacga tattcgccgg 2820 gcgcaagccc gttacaccat ggaaaaatgg cacgggaatt tagtcgccaa aggctttaaa 2880 gcggctggcg atctgctgta tagccgaaat gatgccgatc taacgtggga tgacaaggcc 2940 cgcgcctgga cggtgactat ctggaccacc gaggggcggg accgtctcaa agtgctaact 3000 attcgcaaaa atccggtttt accggcgtta cttaaatctt ttttctaggg gtatctatgt 3060 tcgcattccg tgatgttctg gaagtcgttt taccggcggt aatgttcgcc gtggcgcttg 3120 tcgtcatttc cagtgattac cgtcgtaaac tccgcgccag cggtcgtaaa ttcaaaaagt 3180 aagaaggggg gaattattat ggcttcggta tggtttttag tggtgacact gtgcaccgtt 3240 aaccctggcg cgctggcgtc ggattgtgat gactatgtga tcgacgggga tttgtcgtat 3300 agcgattgca tcaagtccat cgcacagttc ccggagaagg ctgcattgtt cgcggtcagc 3360 tgtaagcgcg gggaaccgct ggacggcgta gggggtgaga tgtgagtaac tttaaaacgg 3420 atgtaaaagg gtcagtagtc ctactgtaca aggacgataa cctacaaaag ccggtcgcta 3480 ctgtgaacag cgcggatgac gtggaggata tgcgcgggca aatcagagac gcggttatgg 3540 cggcctatca tatcggcgtt atggagggtt tcaatgaggc taaaagtgaa ccgctgaggg 3600 atgacccgag agttatcaag gcgctacaac gcgccacaaa agccgggcgg gaacagcacg 3660 ccgcgcaact ccgcgcgcta ctgaatgaag gtcttaacta gggggaagaa aaatgaaaaa 3720 acgtctgacc gttctgattt gtaatgatat gcgcgacccg tacgatccga ttgtggtaac 3780 ggtgagcggg gcgacgcctg aagaagtccg cgccagtgcg ataatcgcgc atgctgaggc 3840 ggaaatggcc gactttgacg gcgaccctat gacggcggcg gatctgtggg cggtatcgcg 3900 ggcttacatc ttcgcggcta tccccgggac cgtggatttt tactatgtcg ggatgccatc 3960 ggacacggtc gacaattacg atcacgtgat gggtgagatc ctgcatgtga tgggtgagag 4020 cctggacacg tcgcccctat gcaacatggg cgattaaccg cccgccgtat tcccgcccca 4080 taaggcccgc catttgagcg ggtcttttta cgtctgcctt atacccgaac ctacgtatcg 4140 cagcctatcg ccctggccgc tggcatagcc cccggagtga ccagtggatg aaaagaagtt 4200 gcactcaccc cgtttcataa aatacccctt tacgccgtcc taacagcctt tttgaaatca 4260 gattaattgc acgcggtgca ggtgcatccc tgcccggtgg cgggcgcgtt atatcgtgct 4320 gtgggctttc tgtattgcac acggggcgtg tgttataggc gctgcccttg tgtgaccgta 4380 tcaatgcacc tgatgcatgt tcaatgaggc cgcttatcgt agtgatatgg cctgtttttg 4440 tgtcggggtg gtggtgtgac cgtgtgacct ggtgacggta tgccaattct gccgccgcta 4500 cggggggtag acggggcgat cgtgggggta tgtagtaggg gtataccatg atcggggttg 4560 cggctgtctc cgtggcgctg gcgaaggaat ccggatcgaa ttcaaaaagg tacttcccgg 4620 gt; atagccccac ttcggaaatt cctgatttac aggggttttt tcgagttttg cccataggga 4740 agacgtgatt ttgcgttcca ggggtggtgc cctaaattcc gttttagccc cgcaaccgat 4800 tgattgcatt acatttttgg gcggtgctct tacaggatca ggtgtcgtca cggaaggtgg 4860 tttattacaa attacaagtt tactacaaga cgaacaactt gtaataaacc ggtaagctgc 4920 tgttatttat atcttttcct caatatttat tacaagttac aagaaaacaa ggaaatccat 4980 ataagattaa aagtaaaacg taatcggtat gcatattatg tatatgtata agtaacctca 5040 acttgtaata aataataatc gcgaaaaatg atttgcattc aaacacttgc aaattattac 5100 aagtttgccg ccccccgaaa actggtcaaa aacggccatt tttggggaca aaaaacgcga 5160 tttttcgaca aaaaagaaag gggccgaagc ccctttttag cgatttttct tgctcacact 5220 tcgtcatcgt cttcatcgtc gaacggattt ttcggtttcc cgattttctt ttcgacttcg 5280 gcattgtgtt ttttgagcgt agtttgcgcc cattttgtat tcagcgtacc gttttcctgg 5340 aacgcattac gcacacgttt tctgacgaac actcttccgc ttttactatt gaaacagagt 5400 accccagctt gagtaaaacc gagttccatg agcaggtttt tcatgcgtga agtcttcggc 5460 atctcgatgc cctcggcttc cataaatgcg tcgttcaatg atggtgaaaa gataatgtct 5520 ttgcacacgc ccagtgtcac gccgcccttg atcatgtccg ctataaattc gcctgcgccg 5580 tcgttcgctg catcgcgcat ttcgcggaaa gcattagtat ccaacggggc atggccttta 5640 tggttaaacc cctccgagat ctcccattcc atgaaccact ttttgatggc cgcgctgtga 5700 ttttcgatag cccgataaac gttagagaag aacttctcgc gttccttagc cgagccgtaa 5760 acgcggtcca tgtccatgtg gttttcagcc tgcgtggaga cgaccaggta gcggcgctgg 5820 ttctcatcca gcggaagcgc gttgatgtgg ttggtgaaca tcaatttcga actggtattc 5880 accacgtcac gcggctttac gcctttccct tcaacctgga agcggtcgtt cgagataaat 5940 tccttctgtt tgtcgaccgc gctgtaccga tcacccttgt catacacctc ttccacgatt 6000 ttcagaatgt ggccttccgc ccagtcggtg aaacgaccat tcatgaccga gtttgacacg 6060 tacccgatgt tctgggcgcc gagcatttcc cgcatgagca cgccgatggt cgatttaccc 6120 gaaccgtgag caccgcggat cagaagagag tagttaattc gctttgtcgg gtgctgaacg 6180 acgtgcgcca gccagtccat gacgtaattt cgctctttcg tgtccggaaa caatacgacg 6240 aacaggtctt tgacgatcga gatggccttt ttatccagtt ttgacagctt ttccgctggt 6300 ttagggatac tttcaggcga aaaagtgttt aaacgtagca aaccggcgtc gtcatagaag 6360 aattccggcc ctaaaagtcc ctctttttgg gtccatttcg attcaggcat atccccgtgc 6420 atttcggggt agtacataac atcgtgaata atagggattt ttacgacgtc cgtggcgaac 6480 ttattcggcg ataaaccgcc ttccacgtcg ccgatatcac gcccatggga cgaatcaaac 6540 gcgctttttg acagtaaaat cccggtttta cggctaacaa aggcgtcctg ggcctgggca 6600 aagacgtatt ctttcagcca agtcggggta tccgcacggg aaaagtcgaa actgaggtac 6660 tctttaacgg ctttgttagt cagcgcgctt tcgttcaggc gtttgtaggc tttcttggcc 6720 gcgtcaatag tcggctggcg ctcaatgccg aaaacccgca gcttacggaa gtcgtctgcc 6780 caggctttcc agtccgccat ggtggtgact tcgttgaatg cctcggtgaa ctcggaaacc 6840 tgttcccggg cttccttctc ttcgatttcg tggaccgttt tgatgatggt gccgattgtc 6900 accagcgtct gggcatcatg ggtaaagcct ttttcccact tgtactcgaa ttctgactcg 6960 tcatagttat ccgcctgcat ggaccagtcg cgggcgatct ctttcgcttc atcctgatcg 7020 cggcatgaca cctgcagcgc tgccattacc cggatccagt tttcatagtt ttccgggtca 7080 gggtatttca tgacgatatc gcgcagctcg tcgtaggtgc cgtcccactt ggtgacggtg 7140 gccattgccg cccagtcgtc atcgtccgct tcgccttccg ccgcccgccc gttaatggcc 7200 cgtgcgactt tcatccatcc ctgtttttcg gcataggcgt cgaacgcgtc ggcgatatcg 7260 cgggcgatct ccagcgttat ttccggcagg tccatggcgg ccgcgcagtt caccggggta 7320 tcatcggtga tccaggtgta ttccttgcgc gtatccgggt ggataccgaa ggcgacgaac 7380 tgctggccat cacccaggat ttcgactgca tggcgctgtc cgaagtcatc ttcccaggtg 7440 gcggacttga cctttttgaa cggctcgtcg gtatggcaaa gcaccagttt tttcggttga 7500 cggccaacac gaaccgggcc ggcgccgatt ttcttttcga caacggccat catgtgctta 7560 accccgtctt tgtcgtagac gtcaatgtct accgcggggg tgtgcttggt caggatgccg 7620 atgccagatg acgcgtattt cttcacgaaa ccgttaatct ggccacgggt attctcgatt 7680 ttctgccagt cttcgaacgc aggccgtttt cctgcttttg gcctgggcga gtcaggcgga 7740 atgatgggaa cgacggtgaa gccgttttcc cacagcacta ttccgtattc gttccagtag 7800 ttcattcaag aatttcccct gtatccgggt cgatttttat ccagtccggg ttagtgaacc 7860 aatgtggtcg gatgccagaa gttttagctg cctcacaaat tttgacggcc atctgtccgg 7920 aaacggtgtt gcggatattc cagatcatag tgtcgtaatt tacgccagcc gccttcgcca 7980 gtttggtaag gttgccgtcc gggtctacct ccagggcagc gatacccgcg agataacgcg 8040 gtctcaggga gtggtcttta atagcccacg gtggaaattt catagatgat cctcgcgtgt 8100 gtgtgcgtgt aagtaaaacg gatattagtc tcgcgctgct acaaagtaaa ggggacgata 8160 cccggcgacc cccggccatt tcacaaagat ccccgaaaaa accaatgggt accgaaaaat 8220 atttttgcga aagtgttgac acgggatgcg gcaatggcca tactccaaac cgtcaacacg 8280 acaaacccaa attaaccgaa cgaggattta actatgtcag gtatttttga acagctgctg 8340 gccgaacaac aaaaaaccaa ctccctgctg gaacagctgc tggcgaatgg cggtgtttca 8400 tccgctgcag caggtgaaga cgctggcgcc ggtaagacca ccgccaaagg taaaaccacc 8460 gccaaaggca aatccactgc tgcggcagac aagccgaaac acaccaaaga cgaagtagtc 8520 gctgcggtcg tagcggtgaa agaccgcttt ggcgcaccgg aagccaaaaa gatcaccgct 8580 aaattcggcc tggccaaaat cgccgaagcg aaagaagaac acttcgacgc gatctttgac 8640 ctgtgtgaag ccaaactggc cgaaccggaa gaggatgaag gcaactccga agaagacgac 8700 gtttaatctt cgatcgtgta actcggcccc tgcgggggcc gttttagcag agaggttatt 8760 gtgataagt tcggaacggc aatagcgatg acgcccggcg gcggagagga agtgcctatg 8820 tgggctgagt tccgcttcga aattggcgac cgtaacccct tattcagagt aacttccccc 8880 gcgcgtggcc agaacggccg gcggattaac ggggaattcc gtttcgtcgt tacccacgtt 8940 gggtccgggt atcgttttac cgatttcagt ttcgacctgt tagcgaaaac ccggtataac 9000 ctgaaacgga ataactacgg aagggccggc gcaatggcgg ttaaaaagac aatcgatgaa 9060 gtaggcgttg aacgaatttt acgcgccata aaaggctacc atgatgagta agtctttcct 9120 ggttcgtgtt atgcaggagt ttgccggcgg cgggcattct atcttcgcgc cgtcagcctc 9180 tgcgatgtgg acggcctgcg gcggaagcct gctggccaac cttttcgaag aggacgagtg 9240 cagctatgaa gcggcggaag gaaccgtcgc ccatggcatc gccgagcagt ggctgaaaac 9300 ggacatccga ccgacgcatc ttatcggaac cacgcaggtc atcgaggaaa aaggcgttcg 9360 gcatgagatt gtcgtcaccc actccatgat cgactacgtt caggattatg ttgactggtg 9420 tcggttcgaa gaaggcatga tgctgacgga aatccgggtc tggttcaccg acctgatgcc 9480 gccagccaac gctgacgagc tggaggaaga cccggacgcc gaagtagtgc cgtttctccc 9540 gcagggcggt accgcggata acatcatcat tcgtgaccgg gtgctgattg tcaccgacct 9600 gaaatacggc accggcgtcc aggttttcgc ggaaggcaac ccccaggcgt tgctctatgc 9660 atacggggcg taccgcgcat tcagcgacga gtacgagttt gaccgggtca tcatccggat 9720 cgcacagccg aggcttgagc atttcgacgt ttgggaagtg acagtcgacg aattgctgga 9780 cttcgccgag tttatccgcg agcgtgcagc ggccgcctgg tcactcaaag ccaaacgcaa 9840 ggcgacgttg aaaggatgcc gatggtgccg ggccgcgcat aattgcgcag cggtggcgta 9900 catgatggaa tgcgccgtcg gtgccgacct cgaattcctg gacactgaat tcggagatta 9960 tgagatgtcg cagttacgct ccgccctggc ggaagaatac aaaatgcgga aggcaaagtt 10020 cggcgatctg tccgttgccg agatggccaa gatcctgccg taccgcaaag tgattgaaaa 10080 ctggttcgcc cgcctggacc tggaacttga gcgggccgcg aaagacggta aggcggttcc 10140 cgggcataag ctggtggaat cacgctctaa ccgtgcgcat accaacgtcg aaaaggccaa 10200 ggagctttat gatttcctcg gccttgacga aaaagactat atgaaaacgg aattgcgctc 10260 gccggcgcag atggaagaag tccttcggga taaacttgga ctgtcacgcg ccggcgcgcc 10320 aatggtcatc gaaagcgtcg tatggaagcc ggaaggcaag ccgaccctgg taccgctcac 10380 tgataagcgg ccaccactgg atcggaaata ttccggcgcc tatgatgacg aagatgacga 10440 tgatgaagtg taaatcggta agatggtaaa cccgtaaatt cgtaacccgg agtagagaaa 10500 tggctgaaaa attaattccc gcgaagaaag ttaaaaacgg cgttctgtat aagagcggtc 10560 acatcaaagt ttccaacgta cgcgcttcat atccgcacct gggcgcccca tacggcggag 10620 acggcgaagg cgagccgaaa tacggtatcg ttgggctttt gccgaagaaa acgcacaaag 10680 agatttacca gctgctgaaa gagcagatcg aagtcgccaa aaagaatcac aaagctggtc 10740 cgctcaaagt ggcgccggcc atgttgttcc tgaaagacgg cgatgtcgat ttcccggaca 10800 aaccggaatg cgctggcatg tgggttctct ctgcgcgcga aagcaaaaag cccgaagtct 10860 ttaacatcga gcgcgaggaa ttaacgacta aggctgagat tgaagaagag atttacggcg 10920 gttgctggg atccatggtt atccgaccct ggacccagga taacaaatac ggcaaacgcg 10980 taaacgctaa cctgatctct gttttaaagc gtaaagatga cgaaccgttc ggcgaaggtc 11040 gtgttgatac ctccgacgcg tgggatgacg acgaagactg ggaagacgac gaagactggg 11100 aagacgacga cgccggcgac gaagacgacg acgtttaacc cccagcccgt cgggcattga 11160 aaccggaagc ccgcctagtg cgggctttct tataagagga caccatggcc gatattatta 11220 accttgacta cgaaagccgg gcgcgtgcca atctcaaaac gcaaggcctg gaccaatatt 11280 cccgctgccc ggatgcgaaa gtgctgatgg cggcgtattc ccttaacaac ggtaaggtgc 11340 agcacgccga cctatcccgt ggcgcgaaga tgccggcgga gctgaaagaa gcactgcttg 11400 acccctacgt ggagaaatgg gcattcaacg cacaattcga aagggtgatg acccgccgtg 11460 ttcttggtct gaaaaccccg tacaaatcgt ggcgatgcac gatggttctg gcgtacatgc 11520 tcggcttcac tggcgacctt ctgcagatag gtaagcaggt cgggctgaaa gaagaccagc 11580 tgaaagacac ggacggcaag cggctgataa aaatgttctg cgtgcctcaa cgtgtcacca 11640 aaaataaccc ttttgaatgg cgtaacgagc taacggatcc cgaagagtgg tgggggttct 11700 gccggtataa cattcgcgac gttgatactg aaatgctgat caaaaatcgg cttatcaagt 11760 accccatact gccgcaggaa tgggacttat acgccctgga ccagcttatc aatgaccgcg 11820 gcgtaatgat cgacaccgaa ttcgcgcagg ccgcactgga cctggctgaa cgccggaagc 11880 cgcaaatcat agaagagatg aaggatatca ccggccttca aaaccctaac tctgtatccc 11940 agctagtgcc atggcttaaa gagcgagggt acccgtttga cgatgtgcgc caggacacgg 12000 tgaaaaaagt tatccgtgaa caggaagaaa acggcgtcga tgatgaagcg ataaccgttc 12060 tgaaagcccg ccttaacagc gccaaaaact caatcgccaa atataaaacc atgatcgact 12120 gcgccgggga ggacgggcgt ttccgttact ccctgcagtt cgccggcgcc agccgaacaa 12180 atcgctgggc cggacgccgc ctgcagacgc agaacctcgc gcgcaccccg aaatttcttg 12240 agaaagtgga agacctgacg atcgcgaacc ggttcatcgc gaaccgggaa ctggataacc 12300 tggcgctgtt cgccggggaa ccgatggacg cgcttgtcgg ctgcatccgg tcagcaatca 12360 tccccgcgcc gcagcataaa tttatcgtcg ccgacctttc atccatcgaa tcggtagtta 12420 tcggatggtt gaccgactgc aaatggttca tggatacact ggcggcaaag catgacctgt 12480 atcagtcatt tgctgcccac tggctcggaa taccgtacga agacaccctt cctcaccgca 12540 gtaaagccaa acccgctacc ctcggtgcag gttatcgcct tggtggcggc cacctcggcg 12600 atgacgggaa gaaaaccggg ctgtggggat acgcggagaa tatgggcgtt cacatgaccc 12660 agaaagaagc cgcggattcg gtgaaagcgt tccgcgaact ttgcccggaa atagtgaacg 12720 cctggacgca gctggaaaac tgtgtcttcc aggttatccg tacgcaccgt ccggttaagt 12780 ggaaatgcct gaccatcgaa tacaccaagc cattcctgac tattcagctg ccgtcaggcc 12840 gtaagatgta ctacttccgc ccgcgcatcg ctgaacgcca gatgacggtt cagagcggcc 12900 cggtaaagg cgagaagtac agcacactga acttccagta cgaagggaag attgaaaaat 12960 ccggcggttc gtcctggggc aaagtgttca gccacggggg gaaacttgtg gaaaacatcg 13020 ttcaggccct ggcgcgtgac gtcctcgccg aagggatgaa gaaggcacac cggatgggat 13080 ttaagatcgt catgcacatc cacgatgaga tcgtcaccga agtcccggaa gatagtccgt 13140 taacccttgc tgacctgatc ggctgcatgg cggctgaact gccatgggcg cccggattgc 13200 cgcttggcgc cgccggatgg gaagggtatt tttatcgcaa ggactaattt gcatagaaat 13260 caaagacttg ccggagaaac cgctaatgcc cgaatgggga acccctgtcg tcagggaatc 13320 gaaggtcgaa ggccgctgct gcgagtatgc gcagggccgc ggctggtggg tgtcgaagtt 13380 ccggcacct gggaaaaagg ccgttccgga ccgcgttttt atccggaacg gcgttgtgct 13440 ttttgtggaa ttcaagcgcc cgggcgaaga accaacgctg cagcagcgaa accgccatcg 13500 gcagatgaaa gccaaagggg ctaacgtgac atgggtggac aattttgaag actttaagaa 13560 ctaccttatc tcctttgagt aaggcaatcg cgtattgcca gcgcaacgtg attcaccagc 13620 ggtcggacat gcacggctat caggacgagg gcgtcgactt catcaaagaa acgccgttct 13680 gtggcctgtt cgtcgacctc ggcctgggca agaccgtgat ggccgccact gccgcactag 13740 cgcgttgcga aagtgggctg gccaagcgaa ttcgaggaat gggggcacct ctgtttctgg aagatatcgg 13860 tcatcgacgg tgatgcagcg caacgcgagc gcgccgcacg cgaggactgc catttctaca 13920 cggtgagcgt ggataacctc gcgtggctgt gtacgctgtt caaaaagaaa tggccatacg 13980 acatggttat cctggacgag tccagcatgt tcaagtcgca tacctcgcaa cggttcaagc 14040 tgttgcggcg ctgccggccg tacataaact acctggtgga gctgactgcc acccctgccg 14100 ccgaagggta catgggcatt ttcgcacaga cgtacctgct ggacgaaggc gagcgatttg 14160 gcaccacgat caccgggtat caggaaaact atttcatcca gaacaagtac aacttcaagt 14220 tcaagttacg caatggcgcc gaggaagaaa tcatccgtaa gatctccgac atcgtcatgg 14280 tgatgaaggc ggaagattat ctagacgtcg aaaagccaac gctggtaccg ctaccggtag 14340 aactagaccc gcattccgcg gacctgtacc gccagatgga agaagaatcc cttgtcgaaa 14400 tcatgcccga cgaattcgac gaatatctgg atgacccggt gacgattgaa gccgagcagg 14460 cggcggccct gcaggacaaa ttgctgcaac tggcgtccgg atttatctac gataccaaaa 14520 ttgtcgggat caccagtgac gacaaagtag tgaagcagaa agatgcttat cgaattcacg 14580 acctgaaatt cgatgcgctg gaagagttac ttgacagcac cctggagggg gaaaacgtct 14640 ttctggccta tcactttaag ccgaccctgg cccgcctgca ggagcggttc gggaaaaggg 14700 gtctggtcgt catggatgat gacggcaagg cgattaagaa gtggaacgcc ggaaagataa 14760 agctgctggc agcacacccc cagtccgccg gccatgggct taacctgcag cacggtggtc 14820 acatcatcgt atacgttgat aacccgtggt cgcttgaacg gtttctgcaa ttcaatggcc 14880 gcctggcgcg tcagggccag aagcacccgg taacggttta ccagatgaaa gcgatgatcc 14940 gccatccgaa aaccaaggag ctgatcgaca ctgtcgacgg caccgtcatc gaagcgctaa 15000 atactaaggg tgatgtgcaa gatgcttttt ttgatttgct aaaccgcatc aaaggccgca 15060 taactaagcg catgaaggct aagaaaacgg agctatggga tgacgaagac gactaagacc 15120 gccccgctgg cgacccgcaa tcggcgatcg aatgcgccgg acgctgatac cgaggcgatg 15180 attttccagg ggtgcaacat aacgcaactg gcgaagctgt tccgcatgga gcgccgggac 15240 atcacgccga agatcatgga tatcccgccc gtcggggagc gcggcgggta cccaatttac 15300 gccgtccacg aagtcgcgcc gtacctggta aaaccgctgt acgacgtcga gacgtatttg 15360 cgccgcatga acttcaaaga cctgcccaaa gagctgtcga aggagttctg gaacggccag 15420 cgcgcgaagc aggagtatga cctgcgcgca gggaacctgt ggccaacgga agacgtggtc 15480 agcgtattcg gcgaagcgat caaaacgctg cggatgagtc tgctgctgat ccccgacaca 15540 ttatcgcggc aggtagggct taccgaagcg cagcgcaacg tggtgcagtc atcggtggat 15600 tcaatactgg atgacctcgc gaataccctg gaaagacggt tcgcggagga agaagacgat 15660 gaagtttaaa tcgttaaacc acatcatccg gtcggtcgcc agccagctgc ggccaccaat 15720 gcgcatgacg gtcgctgagg cggccgccaa ataccgttac gtgaaccagc ccggcgcata 15780 tgtcgggcct tggcttaata tgaccacgcc atacatggtc gagccgatga acacgctgaa 15840 cagccgccat tacaacaaaa tggcgtttgt cggtccggcg cagagcggga aaacggatgc 15900 gctgatcctc aacggcatta cctattcggt gaaagtagac cccatggata tcatggtgtt 15960 ctgcccgact tctaccgccg cacgcgactt ctcaatgcga cgcgtggacc gactccatcg 16020 gcacagcccg gaagtaggcg ccatgctgat gaagaaccgt gatgccgata acaaattcga 16080 taaacactac accaccggga tcattctgac gcttagttac ccatcggtta cggaactggc 16140 ggggaggccg gtgggccgta tcatcatcac cgactatgac cgtatcgacg atgacatcgg 16200 cggcgacggt aacgcctttg acctcgcatc aaaacgtaca acgaccttcg ggtcgttcgc 16260 catgtgcgcg gcagaatcgt cgccgtcccg cccggtaaaa gacccaaact ggatcaagaa 16320 aacgccgcat gaagcgccac cgtgcgacgg catcgtcggg ctttacaacc gcggcgaccg 16380 ccggcgctgg aaatggccat gcccccattg cgaccagtat ttcgaaggaa cgttccagct 16440 gatgaagtgg gacaccaagt ccgccgatgg ccgaacgctc accaacctgg aaaaagcaga 16500 aacggccaga atggtctgcc catgctgcgg ctgcgaaatc gcgccggaag agaagtacga 16560 gatgaatttg tggggtatgt gggtaccgga aggatgtacg gtaaatgaga aagggcaact 16620 ggtcggcgag ccgattcggg cgacattcgc gtctttctgg ctgcgcggta cggcggcggc 16680 gtttatctca tggcagacgc tggtgctgaa ctacctcgat gcatccgacg actatgagcg 16740 cacgatgtcg gaagagtcgt tgaaaaagtt ctggaacaac gacatgggag aaccctatgt 16800 gccgaagtcg atcgagtcgg ttcgtgttcc ggaaatgctg aaagcccggg cagagccgtg 16860 ggcggaaaaa acggtcccgc ccgccgtacg ttttttggcg gcgacggtgg acgtccagaa 16920 acatcgcttt gaggtggcgg tattcggcgt ggcgccgggg tacccgttcg atatttacct 16980 gattgaccgg ttcaacatca tcaaatcaga gcgtctcgat atagacggcg agcgggagaa 17040 gttaagcccg gcggcgtacc tggaggactg ggatttgatc gagaagcagg tcatgatgaa 17100 gacctatccg ctggccgatg accccagtcg cgtgatgcag gtcaagatga cagcctgtga 17160 ctccggcggt gcagcaggcg taacggccaa tgcgtacgag tattatcgca agctgcgccg 17220 cgaggggaaa aacgggcgat tcatcctggt caaaggcgac cctatgccga aaagcccgcg 17280 tacccatatc gcgacaccgg actctaaccg gaaggacaaa aacgcgatcg cgcgcggcga 17340 cgttccggtg ctgatgataa actccaacat ggtgaaagac atgcttaacg gccgactgga 17400 tgtaacggtt cccggaaaag gcatgtatca tttccctacg tggcttccgg actacgcata 17460 cggcgagatg tgcgccgagc atcgcgacga aaaaggctgg caatgcccgc agggtacccg 17520 ggcgtgtcct cgcgatggaa gcaatagact gggataaccc gccagtctgg gctgacgagt gggataaaaa 17640 cccgctggtg gtcacaatag ataaacagga ggccatcgca gaaaaaccag atacaggtta 17700 tagttttgcg caactggccg aaatgttagc atgaggatga ccaccatgac cccagatgaa 17760 tgccgagcca agtaccaaca atggctgaat gacgctatgg acgcctataa ccagctgaac 17820 gtcggtggtt cggtgcgtgt tgtggtggac cagaacggcg aacgcgtaga gtatacggcg 17880 gccaaccgcc agagcctgtg ggcgtatatt ctgcgactgc agaacgcaat taactcaccc 17940 gacccgtgca gagccttctt cggcacgccg agtcgcccag cgaggtttat tttctgatga 18000 gcgaagtcaa gaaagccact cgcgcgagca agaaaacccc ggttgctacg gtcgacgcct 18060 ctccggcgaa acctgcagcg ggcggcggcc ttgagggtgc tgaacgaaac acccgcgcaa 18120 ccttcaactg gaatcctgcg ataatttcgc cagaccagca gatcgcccgc gataaggata 18180 tggccgatgc ccgcgcacag gacatggtgc agaacgacgg ctatgccttt ggcgccgtgg 18240 cgatccaccg tgacagtatt gtcgggtcac agtacaagct gaacgccaag ccgaattccc 18300 tgatacttgg cgctcctgac ggttgggcgg aggaattcca ggctatcgtt gaatcgcggt 18360 tcaacatggc ggccgagtca ccggaaaact ggttcgacgc ccggcgcgtc aatacgttta 18420 ccggcctggt tcgcctcgcg gtcggcggat ttttgatgac cggggaagtg ctggggtccg 18480 ccgagtgggt caagtctacc ggacgtggcg cattaggccg ccggccattc ggtaccgcca 18540 ttcagtttat ctcgccctac cgactgtcga acccggacat gcagacggat accgaccgga 18600 tccgtaaggg cgtcgagatt gacgagtatg gcgccccgca ggcgtactgg ttccgcgaag 18660 ccttcccggg agactacacc aacattgaag gccagtggcg ctggaagcgc gagcctgcgc 18720 gattcgactg gggccgccgg cgtattatcc acatcatcga acagctgctg cccgggcaga 18780 cccgcgggat cagcgagatg gtgtcggcgt tgaagcagat gcggatgacc cgtaatttcc 18840 aggaagtcac cctgcagaac gccatcgtta acgcgacgta tgccgccgtt atcgaatccg 18900 aattgccgac gcatgaagtc ttctcgcagc tgggcatggg gcagaccgcc ttttcggaat 18960 acttcaacgc ctacatggcg agtatggccg agtatgtcgc cgcgtcgaag aacatcacga 19020 tcgacggcgt taaagtcccg cacctctttc ccggaacgaa gttcaacctg aaacccgccg 19080 gcacaccggg cggcgtcggt actgactatg aagaatcgct gctgcgcaat atcgccgcgg 19140 cgctcggtct ttcctatgag cagttcagcc gcgactacac gaagacgaac tacagttctg 19200 cgcgtgcgtc gatggcggaa acgtggaaat tcatggagag ccgtaagaag ctggtagccg 19260 accgtttcgc gtctatggtc tatacgctat ggctggaaga agagattaac gccggcaatg 19320 tgccgctgcc accgggcaag acctggcgtg acttttacga cccgatgttc cgtgatgcga 19380 tttgcaatgc tgaatggatc ggagccagcc gtggccagat tgacgagaag aaagaaaccg 19440 aagctgcgat cctgcgtatc aagaatggcc tgtcgacata cgaagccgaa attgcgcgcc 19500 tgggtggcga tttccgttcg gtgtttgagc agcgcgcgcg ggaagaaaat ctgattaaat 19560 cgctggattt ggatttttca ggtaaagttg tcgaaggcgc agagacgaca tcatcttcct 19620 cgtcggcgac cgataaccct gataaggaac agaaccaatg aatgcacatg ttcgatccag 19680 cttaatgcaa gcggttcagc gcatgaacgg gtcgccggta gctgtccgtg aaagcgacac 19740 caatttcctg ctgaatatcc agtcggtgtt ccagatgagc gccgacgagg acgactttga 19800 cctcgatgcc gaagaacgta tcgccacgga gcgcaatcgc aatctatgcg cggcttacgg 19860 catggcaccg tcgagcggaa ataaaccttt cgccttttcc ggcggcttcg ccatcatccc 19920 gatccacggc tccctgatta accgctatgg cggctattac tatggctacg tgacgggata 19980 caatttcatc cgctcgcaga tgaacgccgc actggcagat cctgacgtgg aagctattat 20040 tttcgacgtg aactctaacg gcggcgaagc agcgggctgt tttgagctgg cgaacgagat 20100 tttcgcatcc cgcgcagtga agccgtcatt cgctgtcgtg gactccaatg cgtactctgc 20160 ggcttacgcc ctgggcagcg cagcgacgaa aatggcggtc attccgtcgg gcggcgccgg 20220 gtccatcggg gttatctcga tgcacgtcga tatcagtaag atgttggaag acttcggcgt 20280 taaggttagt attattaaat ccggtgcgca caaagccgac ggcaacccgt tcgaatcgct 20340 ttccgatgag acaaaagccc gctggcaggc agatgtcgac accatgcgtg aagacttcgt 20400 caatcttgtc gcacaaaacc gaaatttaga tccgaaagtc gtgcgtgaca ccgaggcatt 20460 atgctataac gccccagaag cactggccct cggactaata gatgcggtca caacgccggc 20520 taaggcagtg gctgaattcc taaacgggcc gtccggtggc tcggatgaac aaccaggagc 20580 aaacgcgatg tttacccaag aacaaatgga cgctgcccgt caagatgcag cagccgaagc 20640 aactgccacg gctaccgcgg cagcgactac ggcggaacgt aatcgcattt ccggtattct 20700 gggatgcgaa gcggcgaaag gccgttcaaa actggcgtca catattgcgt tcaacaccgc 20760 aatgagtgtt gccgatgctg aaaccatgct gggcgcttct gcggtcgagc aggccccggc 20820 atccgcagcg gctaccaatc agccggagaa aggggcagac agcccgttca agacggtgat 20880 ggataacgct gaccacccga atatgggtgc ggaaaacgaa cagcaggctg aacccggcaa 20940 aggtgatggc ctgatggctg cgatggccgc tgtagctggc gactcgttca ctaagtaaga 21000 ggcgactaac atgtctttga tctccctgat ggcaagcctc ccgaactatc tcgctggcaa 21060 cggcgacctt ggttcgtggg aacccactca gctgtttgct ggtgaagctg atatcgtaac 21120 cgacggcggt gaagtcgcag tcgcgtttgc gcgttatcag gtcatcgcca aaaacgcagc 21180 tggcaaactg gtgccttatg acccgaccac tccggccaac ccggaagcga cggccatcgg 21240 tatcgctaac gaagctggtg tcgtgggaac ctacgcaccg tattacatcg gtggtgtgtt 21300 caaccacgaa gcactcgtat ggccagcagc agtcgacact ctgctgaaac gtcaggcggt 21360 gttcgaacgt acgaacatcc acatcggcaa cctgtactaa ggagcagcag aaatggctgg 21420 attgtacgaa actaccgtcc tgatgggagt gcaacgcaag gttaagtccc tgccggcgtt 21480 cttcctgcag tggttcccgc gccagattaa cttcgaggaa gaccagatcg cgttcgataa 21540 ggtcatccag gacgttaccc gcgtcgcgcc gtttgtcgca cctaccgcgc aaggccgtgt 21600 gatcaaggaa caaggttaca acaccaagac cttcaaaccg gcttacgtta aaccgaagca 21660 cgtcattgac ccgaacatga tcgttccgcg tcaacccggc gaagcgctcg gtaccggtag 21720 cctctctaac gagcagcgtc gtgaccgtgt tatcgcattc ctgctgatga agcaccgcgc 21780 gatgcatgaa aacacctggg agtggatggc cgcgcaggct gcgcagtacg gctatgttga 21840 cgtggaaggg caggattacc cgaaaacccg cgtagacttt ggccgtgatg cggcgctgac 21900 catgacttcc gactggaccg ccaccggcgt taccctgatg gacatgatcg ccgacctgcg 21960 cgatggccag cgtctggtgt ccgataagtc actttccggc acggtgatcc gcgattacgt 22020 gttcggcggc gacgcatggg accagttcgt taaagtcggc ggcgcagagc tgtggggcaa 22080 agacggcctg atggatggca atatccgcgg ttccgactcc aacctgaccc gtctgtggga 22140 cgatgtcgaa ggtgttcagc tcatgggtga actggtaggc atcaacggcg ccggccgtat 22200 gcgtttctgg gttaacactc agaaattccg cgactggaaa aatcaggaac agtacctgat 22260 gaaccagaag gccgtcatgg gcatctcgtc tgcgattgaa ggcgttaagt gcttcggtgc 22320 aatcatggat aaagcggccg gctatcgggc gctggaatac ttcccgaaaa tgtgggaaga 22380 agaggatccg agcgtggaat acctgatgac tcagggcgca ccgctgatgg tcccggcaga 22440 cccgaatgcg tcgttcctgc tgaccgtcgt tccgtaacca cctgcaggcc cgtcaataat 22500 ggcgggccaa tttaaaggac agagattatg ccacaacgta aagtagtcca gacggtcatc 22560 gttttccgcg acggccagcg tatccgcccg gcgatcggtg aaatcttcaa cttcacccag 22620 aaagagctgg aatccatcaa cagcatgaac ccgggcgccc ttgaccgtcc tgtcatcgaa 22680 gtcgatgcgg aagagcaggc ggcgaaagag aaagcgcctg cgcaggaaga aaagtctgac 22740 gcgaaagcca ccaccaaaaa aggcggtaag gccggcgcag cggacgaaga ggtctgatat 22800 ggcctctaac ttcgcggcaa tcaaagcgaa ggcacgcagg gacgttcacg cgtccctgtc 22860 tgtatctgcg cggtatgaaa gctattcgca ggaagtcatc gtcgacggtc ttagcgtgcg 22920 ctggcacaac aagcagcaac tggtcggcga tctggatagt ggcggttacg cccagattat 22980 cgatggcatc gagcgaatcg tttttatgca ggacgagctg caggagaaag gcgtcacgct 23040 ggaaggcggt gatgtgatta tcatcacggc ggaaggatac ggcaacgttg gcctggtgct 23100 acagacgcag gaaccgattg tcggtccggt cgaagtgatc tggcaggtgt cgaggaagaa 23160 ctgatgaccg ttaacgttat ttccgtgggc gacctggagc tgcgtgacta tctcaagcgg 23220 cttccggaaa taaccgaact ggcgatgcag atggccatta acaccgtcgc atcgcgcacc 23280 ggcatgtcgt tggtcaagaa aaacatgctg aacgaggtgg ccttcccatc cgggtatctc 23340 aaccccgacc gcctgaaagt caccaagcgc gccaccagaa ccaacctcga agccaccatc 23400 accggacgta aacgggcgac ctccctggcc cggttcgtga cgagtaacag tgttgtgaac 23460 agccggcgaa aggaaggggt atccgttcga gtgaagcgcg gtaagaccac gtacctgaaa 23520 aacgcctttc tcgtcaggct gaaaaaaggc gccagtcttt ccgaagacaa ctacaacatc 23580 ggccttgccg taaggctttc cgccggggag tcattatcga ataagcggac gcagcataaa 23640 tcatggctgg ttccgggcaa ggtggcgttg ctgtatggcc cttcggtaga ccaggtattc 23700 tcggaggtgg ccgagaaggt cgggtcgcaa attgctgaca tggtggcgac ggagtttttc 23760 cgtaatttcg agaggttatc atgagtaagc gcctcgatgt gctgaaagca ttaacggatt 23820 tcctggaagg catttccccg gataacgggt atccgtatga cttccgggga aaggtgtacc 23880 gcggtcggga ccgtttcggc gcggaatacg tggcaaagat gccgttcctg tctattctgg 23940 aagcgaaagc aaccgactac gggaagttcg ctaacgagga acagaccgtc cggatggatg 24000 actgggtgct gctggttcag gggtggtgcg cagatgacgc gcgcaaccca acggacccga 24060 tttacgacat cgtggcagtc gttgaaaagc gcctgtcaat gctcatctcg aaggatgaaa 24120 atggaaaccc ggaattcccg ggggtctatc ggttaaaggg aatgattgct acactgacac 24180 tcgcacagcc ggttgttcgt ccgcccgagg aaggactatc ggacacggcg tttttcttcc 24240 tgcctattag ggtaggacta aaagtagata ttcggaatcc ctaacaggag atgaaagatg 24300 caaagcgatt tccagaacga ctatacgatc ggacgtggga aaacctattt cgataagttc 24360 ttgccgaact ctaaccgcaa gactggcgaa atgtacttcg gcaacggccc ggaattcacg 24420 atcaccactg atacggaaaa cctggaccac tatgcgtcgg attacggcct gcgcgtaaaa 24480 gatgcctccg tcctgctgga agccggcatg accgggactt tcacctgcga caacatcgcg 24540 gcggagaacc tggcgctgtg gttccttggc gacctggtta acatgaccct gaccgaccag 24600 accggcgtca aggaagtgtt caagccggta ctgcgcggta agtattacca gatcggtacc 24660 agcgacgaca cccctaccgg cctgttcaac gtggataacg ttgtggtcgg cgtggcggat 24720 ggtgacgctg aaatcgtccc gggaaccggc gatattagcg gcctggcagg cgtgaccatc 24780 gttaccgccg ctggcaacta cgagctggac ctggcgcaag gccgtatcta catcgagccg 24840 gactccaccg agttcgcggg taacaagcag atgatcatcc agtgcgatat cgctgcgcag 24900 aaccgcaaca tggtgatcgg caagaccaat cagatttacg gcgccctgcg ttacatcgcg 24960 gacaacccgg tcggtaccaa caaaaactac tacttcccga aagtggcgct gcgcccggac 25020 ggggattatg cgctgaaagg cgacgactgg aacgtgatgt cgttctcgtt cgaagcgctg 25080 cagctgaaca acctcaccca gcgtctgtac attgacgtgc tgccgtctgc ggcaaccgtt 25140 gacccgacga cgctgcgtac cgtgtctgta tcgctggcga gcacttcggc ggcgtccggc 25200 ggtgcgggta tcgtggctac cgctacggtt cgtgacggca acggcaccgt ggttcagggt 25260 gaaaccgtga acttcacgac ggacaccggc gctaccgtta ccccggcgag cgcgtccacc 25320 gcgagcacgg gcctggcaac caccacgctg aaccgcgcga cggccggtac cgccaaagtt 25380 accgcaacgc tggcgaacgg caagtccgca gtatcgcaaa ctgcgacctt ctcgtaagag 25440 cagaccgcag tcacaccgga aagcgcctac gggcgctttt cttttatgct tttctgccga 25500 cgtgctacat taacgacgtc aaccaacgaa gaggataaac cccatgtcac tgtcagattt 25560 caccccggat accgaagaaa tcatcgttaa gcgcgctaaa aaaggcgata tgacattcga 25620 ggtccgcggc ctttccttcc aggacatttc gaagatcgtc cgcgtgcatt atgacgacct 25680 ggaagggctg tttgatattt acgaaaccca cggcggcggc gacctttcct acgtggccat 25740 gggcaaattc gccatgggtc tgattaacga tgcgcccggc ctggtagcgc acatcatcgc 25800 gctggcggca gacgacgaag ccaacctgga gaaagcccag cgcctgccgc tgaccgccca 25860 gattgacgcg ctgaaagccg ttggccgcct gaccttctcg gacgttgaag atataaaaaa 25920 gatgctacga aaggccatgg acctgatgag ggaaacaaag gcaagccgga cacccgcgtc 25980 tacagcaaaa gggaaaaagt aatccggttt cacaacgagc tgcgggaagg cgtgtccttc 26040 ctgatgtctc agggacaccc agacgcacgc cggtacccgc tggggtacct gtggtctgaa 26100 atcaagattg cccggcgccg cgtgaatatg cacctggtga cggaaagcac gttactgcag 26160 gcgctactgg cctccgtcat gaacgggaag aaaggtggcc cgcactacaa aaaactgatt 26220 aagggcttga gcgatggcta acagcaaaga cgtcgaacta aggatccggg cgagggattt 26280 cagccagaaa cccctgaaag ccgtggcctc cgcgattgaa gcaatggcga aggcgcagga 26340 cgaccagcgt aaagcggcgg aacggggaga agtctcgacg cgtcagctgg aagcctcgta 26400 caaaaaactt gagcaggccg ggcagcagct gttaaagctg aatgccctgg tggagctgta 26460 caaacgccag aacgccacga tggttgaagc ggcgcaaaag acggaagact tacgggccaa 26520 gcaggcgcag ttgcagcaag cgtatgattc atccacgaag gtaactaaaa aacaggaagc 26580 cgaacttgcc cgtatcaacc gtcaggttga gcgcgcagaa cgcgccgagg cgtcacgcgc 26640 cgcgcaggtg agccggacta ccaaagaact gcagcgatac ggtattgaga cgaaaaacct 26700 tggtgccgcg cagtccagca tcgttaacag cgtggcgagc gttaacaagg tactgcagca 26760 gcaggaaaac atcatcgcta ccgcgcctgc ggcggccgcc caaaataaag tcatacaggg 26820 actgcagcag caagcgcagc aggcactggc ggcggcaaaa gggtattcaa ccctgggccg 26880 ggtcgtacag accaccacgt cgcagatggg gccactggcg tcgcaaatcc agcaaatcgt 26940 aagcccgtca gacgctgcgc gccggacgct gtctggactg cagcagcagg tgacaaccct 27000 tgcgacggag atagcgaata gcggcaaaaa gattaccgat atcacaggga agatccgcca 27060 gctgaatgac gcgaataaaa gtgtttcggc catggcgcac cagatcgata tgtaccgtca 27120 gcaggtggca gcgatccggg cagcgcgggc ggaataccgc acagcaatgg gggcggtaca 27180 gggtttagcg cagcagatgc gaacggccac taccgacacg ggtgaattgt cggtccggat 27240 gcaggcggca cagcagagac ttgcggcggc cgcccggtca ttgcgggaca ccgggactgc 27300 tgcgcgcacg acacaatcgg ctttgcgggc ggcaggcatt gatacccgta atttgaatag 27360 cgccgagcag gcgctgatct ccacaagccg tcagaccacc agttctataa actccctaac 27420 gcaagcattg cggaataacg cgggcgccac gcgcgacggt tcaaaagcct tctctctttt 27480 ccgcgatgag ggacgaacta cgttatcaat gctgcagcgt atccgcggtg aggtcctggg 27540 gctggccacg gcctatgttg gtgtgcaggg ggcgcttaat caggcatccg gtgcggtgga 27600 tgcgtacaag atgcgtcagc aagccctggt taagatctcc accgttgttg gggaaagcca 27660 ggcggcactt aacgacgaat ggcaatatat gctcgggctt tccgacaagc tgggtattga 27720 tatcggagtg gtcgcgaact cgtatacccg gttcgcggta gcggcgaaag ccgtcggtct 27780 gtcgttgcag gattcaaaat tcatattcga aagcgtggcg aaagccggcc gtgttttcca 27840 cctctccgcg gatgacatga acggtatttt ccgcgcactg gaacagatgc tgtcgaaagg 27900 gcaggtttac gccgaagaac tgcgcggcca gctgggcgaa cgtttacccg gggcggtggc 27960 gctgttcgcg aaaggtatga acatgaccac gacgcagctg atgaaggcaa tggagaacgg 28020 cgaggtttcc ggcgaagcgg ttatcaactt cgcccgtgaa caggctaagg ctattgatgc 28080 ccagctggaa accgcgagca aaggcgtgga cgcgatggaa gcccgcgcac gtaacgcgat 28140 gaatgcattc cagctggcgt tagcggactc cggatatatc gatgcatacg ttcagctgct 28200 gcagaaggtc acggacttcc ttaatagctc ggatgggagg gaggccgcgg taaaactggg 28260 tgcggcattc agctacgtgg cggacactct agggtatctg attgacaacc tggacacggt 28320 tatcacggtg ctcggcgttc tggccggcct taaaatcacg cggatggttc tggggttagt 28380 cgggtccatc cgcacgatgt tgccgatgct gaaagaaggc gtcgttctca tccgcggggt 28440 atacactggc cttatgacat gggcgaccgg tcttgcgacg gttgaaggcg cggtcggact 28500 tctcggcgtc gcgttacgcg ggctgctgcg cgttatcccg tttgttggcg cagcgcttat 28560 cgcgtacgac atcgggtcga tcatgtacga ccagtcgtcg accttccggc agggcgttga 28620 cgaggtcatc cgggattaca aaaacctcgg caatcagctg ctggcggtcg gggagtccat 28680 cccgacgatg ctgtacgaca tcctgatcgg ctgggtacga cccgtaacga cgcaattcgc 28740 cacggccacg aagatgatca tgggttggat tgccaatgtg ttgcgcctga tccccggtgt 28800 cggcgaaacg ctggcgaact gggcggatac cctggccgaa gacatgacca aagagcaccg 28860 tgacttcctg gagtccacgg gcaaggtctg ggatgacgtc gataaaaaat gggccgagtt 28920 aaataaaaac atggtcgaca ccaacaagac tgcggtggat gttatccgtg gtcaggtggc 28980 gatgctgatg gccgatatta aggcgatcac aaaccctcaa ttccagtaca ccgctgaccc 29040 ggaaactgga gtcacccagc gcgaccgcga catcaaaggc atgacgaaag accttgccaa 29100 gatggaagaa caggcgaaaa aggctggcgt tgccgcgcag aaagcactgc agcgtaaaaa 29160 cctgccaggc cgcctggcga ttatcgatga ggaatttgcg ccgcagtacg cccgtgccaa 29220 gtcgatcggc ggtgacgaag gtgctgcgat gaccaagcgt ctcgacgcta ttgtggctgc 29280 gcggaagaaa gccgagacgg attcctataa cgccatggaa aacggcagca agggcagggc 29340 gaacgcggcg aagcgggagg aaaacgcgct ggcggcgctg acctctcagt atgaaaaact 29400 ggatgatgcc gttggcgtca agcagtcgaa ggtcgacccg aatgcctcgt ttgatgaccg 29460 actgcaggcc aaactgcagg ccgttaatac ccagtacgac cagctgatcg ccaaggcgaa 29520 aaaactcggt tcgggcgggg cagaactggc cggcaagttt gaagacctgc gcaagcggaa 29580 tctcgaatat gctaccacgc aggcgaagct ggaagagatc aagcgcgtgg aggaccagct 29640 taacgcggtc caggaaacga agaaaagcct gctggatgag ataaacgcca aacgtcaggc 29700 gggcattatc tccgaagatg aggcggtgaa gcagacgtcc gagctgtatg cgacgatgaa 29760 cgtgaacctg cagcagtcgg cgaacacact ggaccagctg gcgcagaaat tccgcaatgt 29820 tatgtcgccg gaagactatg cggcgctcat ggccaaaatt gcgcagatcc gcgcgggcct 29880 gaatgacgtc accggtacct ttacccagat ggatagtacg gtggtgcagg gcgttctgga 29940 tgggctggcg acgggtctac agtcggtcac ggatagcctt gtccaagtcc ttagtggcac 30000 gatgtccctg caggacgcat tccggagcct cggcgctacc gttaccaagt tcttcgcgga 30060 cttcctgatg aagattgcgc aggcgatcct gcagcagatg gtactaaact ccctggcggg 30120 aatgggcggc ggtatcggtg cagcagcggc atcgcttggc ggtgtagcag cgaaacacaa 30180 cggcggcatg gtcggcagca aaacgacggg cggccagcag cggaaaaact ccgtcagccc 30240 gtcgttgttt gtcggggcgc cgcgcttcca tgacggcggc ctgcccgggc ttaaatcgga 30300 cgaggtgcca atcatcgcgc agaaaggcga acagatcctg tccaaagacg acccgaataa 30360 tataatgaac caggggggcg gtagcggcag tggttccggg tcatctaatc tgcaggatat 30420 cagggtcatc aatgcgatag attcggcatc ggttgtcgcc gccgggctaa gtgctccgga 30480 aaatagtaaa gtggtcctca acttcatcaa ggccaataaa caggctgtta aacaaattct 30540 ggggtgatga atggcgagct taaccgacaa tgatgcactg gtcagcagtg atgggctggt 30600 agcgcacagc cttacggatt cgacgactga cgcatcgggc attaatccgg cggcgggaac 30660 gtcgtcggaa cagttccgga tggtgaccgg acttctgcgg gcgcaccgta ttgctccccg 30720 cccggcggcg gtacaactgg caaatcgcat cctgactgca gctgtatcct acctctaccg 30780 tggccagtcg tcagaagccg ggacgtttat cccacactat ctcgtcggcg tccgccataa 30840 cttcacgttg ggtaatggcg acgtggtgca gcccggagac gcataccgta tcgccccgac 30900 ggtggagatt gagccgagta ccgataccga ctcggaaaac catgctttcc gtgatgcgta 30960 tgaagccttc tcgatcggct ccgacgtaat gggggagaac gcctggacgc tcgcaaagga 31020 cgctaccgag cgccagatta aagggtcgat tcgatactcc gggttgtggt atacgccggg 31080 cgcggtaccg gtcattacgc agttcactcc gaatgataat gggtggcggc cgccggcgta 31140 cgttggtcgg cagatagggg cgcagtgggc gtcattcggg gatgcggaag ccaccgacaa 31200 taccgtgttc atgatgaacg acgcacagga cgcatggacc gcgcagaccg gaaaaatcga 31260 tggccttttc atgccggtgt tctacttcga ctctcccggg tcgacctcgt acggcccggc 31320 gaacacgttt gggtggaatg gccccttcga ctcacagagc atgtacgaac agctgtcggc 31380 gatgcgggat gccgttcgca tcgctacaca ggcaggcgag gcgggccgta aagcctacgc 31440 aacggctatc gctacccgtg cgcttaaatg gttcgggaat gaccgcaact ggatcccgtc 31500 gaacccgggc atcgcagacg cctggagcgc ggcgatccgc aaagcggccg ttctggggta 31560 ccaggagggg gataccgtta cgctgcctga actctggttc accgtcccga atcgcctgaa 31620 taccgatggc tcattcccga cgcctgtcta tgagccgggg ctactggcgg tggcgctgca 31680 ggcggcgatc gcggtggata agctgcagcg gccaaacaat gccgcaggtt cgctgtctac 31740 cgaagtggcg cgcgtggtag aaaagtgcat ccagatgttc gacttcacct acgtgaccag 31800 cggagtaatg gccggcacat tcagcccgga cccggcgaac cttaaatggc aagggcgctg 31860 gcatgcggaa ctgctgaatg ccatggtgga cctgtatgac tggtgtgggc agtcgaacaa 31920 taactacacc gccacgcggg cgaaggcgcg agagtggatt acggggctac tggactcggc 31980 ggaagcgcta tcggcagacc agtctggcgg attcatctat ggtcggtcta tgtggccgct 32040 gcagccaaac tggaaagacg gcatgacgga gtcgttcgaa ttttccacgc agatcatcac 32100 ggcggccagt ggcaaagagc agcgcttgtc ccgtcgcacc aaaccgcgcc gggcgctgtc 32160 catgcgccat acgctgacga cggcagacga ggcggcgcag tatcaggcca tcctccggaa 32220 gcgccagtgg cggccaatgc ttgttccgca gtggcacatg gcatcccgca cgctggtagc 32280 cgggaaagtc ggcgatacca ccctggtcct ggacaaagag ccgccggcca cctggggtgt 32340 ggtgaaagcg ctgtacctcg tatcagggga tgaccgccag ctgcttaacg tgctgcgggt 32400 atccgggtcg acggttatgc tgcgcgattc gctgacgttc ccggtaccgc gagggtcaga 32460 tattatgccg gtgcagtacg ggctgctgaa taacgacctg tcgtcttccc gggcgatctc 32520 caccacgatc gaagcgcagg tcggtttcac gatcctgccg cagacggact cgtttaccgt 32580 gccggcggta tcatcgtaca acgacctgat ttcgtttatc gcggaacagg gccatcgctg 32640 ggcgaaatat atccgacggg ccgccgcgct tgatcccgca gtatggccga cgtggccgcc 32700 aatgccgtcg aactatacga cgcgaatgac ctttgaactg aacggcgata cccgcatggt 32760 catcacccgt aaacctaact gggtatccgc ggtgacagtg gccgacgcct ggcagtacga 32820 cctgatcgac tattacaact cggcggttac gccggggtat gcggagaacg ccggacgccg 32880 tacattccag gcgcagtgga ccgcattcac gtatgatgag gttatcgata tcctcgcggt 32940 attctacgcg ctgcgtggta cgcaggtggc ctgctgggta ccatcgtggt cccacgacct 33000 gacggcggca gaggatatgc cggcgccgaa tcagttacga gtggagcgga acgccgtcat 33060 tgacgaagaa atattgcttg acgacccgag tatcgcattg atggttgaaa cgtttgatgg 33120 ccgcatgtat tgcgcggcgg ctaccggggt aacaacgtca gtcggggtat cgactatcac 33180 actggaccgc gagttcctca gcccgctcaa aaaggcggac atgatgcgga tcagcctgat 33240 gtaccgtgta cggcaggcca gtgattcggt ggaactttca tggcatgccc gcggcattgc 33300 cgaattgcag acggccttca tcaccgtcca ggagtaaaac gtgtcatatc ctcaacttga 33360 agacagcgtt gacagcggga aaccgctgta tttttacgag ttcatttacg gcgatgcagc 33420 gacgaatgcg taccgttatg tcgccgcact ggacctcact atctacggcg gccgcccatg 33480 gacccctttc ccgataaagc acagcgatat cgttacatcg gggtcactgg ataagcagac 33540 gctgacggtg acggcgcggg aggatattga tattaccgga ctggtagtga cccgcgcgcc 33600 aagccgggta acgatgctga atatctaccg cggccacgct ggcgatgatg acatgcggat 33660 ggtctggacc gggcgcgtcc tgtccggcaa catgatagag tcgtccgagg tggaactggc 33720 ctgcgagtcc ataagcacat cgcagctgaa tattggtctg cggcgtaagt atcaacgcgg 33780 atgcccgcac gccctttatg gtcgggcctg ttcagctgat aaggcgttgc attcggagac 33840 cggttcgtcc acggcggtcg ctaattcaat gacggtgtcc gttaccctga cgagtgaaga 33900 ccgcgggctg accgaggcta ccctaaccgg tggtatcttc cgcatcacgt tgaagaacgg 33960 cctgaccgaa atccgggcga tctcgtctgc gataaacaac ggcggccgca actggacgtt 34020 aaatatcatc gcgcctattt ccgacatgac cgccggccgt ccggtttctg tatcaaaagg 34080 ttgcctgcat acatacgatg cgtgtaaaaa cgtgtttaac aatgcggata actatggcgg 34140 atgtgccaat atccctatca aaaacccgtt caatgcaaac cagttctagg gggcgccatg 34200 ccagattggg tcgtctatat aattatttcc atcgcgatgt cgctggccag ttacgccctg 34260 actccgcgtg caaaaacgtc cagcgctaac cagtcaccgc agacggtcga cgtgccgacg 34320 gtcgatgcgg gccggtccat ccccgtagtc ttcgggacgg tgcgggtgaa atcgcctaac 34380 ctgttatgga tgggcggaca acggacaacg gagatcaaga aatgagtgat atccgcgtat 34440 tacctactga cctgccgacg gcgggtcttt gcgttaatgg cgctcgcgac tggttcgcga 34500 aacatgggct ggacttccgg gacttcatta agaatggcac tccagtagat gtcatgcggg 34560 cgaccggttg cccactggcg gaacgtgctt gccaggccgc cgagaagcgc gtcaacggag 34620 ataactgatg ggcgggaaaa gcaagaaaaa atcggtcgtc ggctataagt acaacatcgg 34680 cctgcatttc gccatttgtc acggtccgat cgccaagctg caggaaatct ggtgggcgga 34740 taaggtcgcc tggtccggca cgttgaataa ccccggggac gagtcgcagg ggcttgtggc 34800 ggtggacaat accggcctgt ttggcgggga ttcctccgaa ggcggcgtga aagggctggt 34860 ggaaatcggc ttcggtggat gggggcagcg ctgtatcggc gttggatccg acgggtcgta 34920 ttccgcgcca gccatcctgg cctggttcat ctccaaagga tacaactgga agccgcaggt 34980 taaggtgccg gacctcggcc tgaattaccg tgggctggcg gtcgcgctga tgcatgacca 35040 ctacatcggg aacaacgcct acctgaaaga cgtgtcgttc aaggtcagct gcttctgggc 35100 cgactggcac cctgaacttt gctacatcgg cgataacatg aacccggcgc acatcatccg 35160 cgaaggactg gtgaacacgg aatggggtct gggatacgcg ccagccacga tcgatgacgc 35220 cgcatatctt tctgccgcgc agactctgta taacgagggc ttcgggctat ccttcgtctg 35280 ggatgacgac aaagacctct acaccttcat tgacgaggtg aagtcatgca ttaacgccgt 35340 gacgtatctc gatccgcgtt ccgggctatg gacgattaaa cttatccgcg ctggcgagcc 35400 atcggcgctg accatcaacc ccgacaacgc cagcctgaaa tcctttaccc ggaaagcgct 35460 gggcgaaacg tacaacgaga taagcacgaa gtacacgaac ccggaaaacg aagagtacga 35520 gacagttacc gttcaggacc cggctaacat cgaggcgcag ggccgtgttg tgtcgacgac 35580 gaaagagtat gtcggcgtgc gggatgcaaa cctggccatc cggcttaccg aacgtgacct 35640 gcaggtggcc agcgcgcagc tgtgtacagc cgaggtgacg gtgaaccgcg aagcgtgggc 35700 catcgcgccg gggatgaacg ttaccttcaa ctggccgaga cacggcatct cgaacatgat 35760 catgcgtgtc gaagaggtga gcattgctgc tgtcggggat gactcgatct ccctgcgcat 35820 cgtggaggac gtcttctcgc gctcatcggc gaccttcgcc ggctcgcagg ataacggctg 35880 ggtcgacccg gcacaaccgg caacgttgtt cccgtaccgc cattcctggg agtatccgtt 35940 ctggtatctt attcgcgctg caggtctgcc agcagacgtc ctgccgacct tcgccggatt 36000 ctcgacggag attgctaccg gcggcaacga taacgcgcaa tcggtccagc tgttctccta 36060 catcaccacg gacgctggtc catcgtggca gctggtcgca gttggaccgc tgacgccgaa 36120 atccgcgttg tccgatgcgc tggttccgga aatcacctcc ctgatgaagc tgaatacgtc 36180 ggccagctac cgcctggcgg acatggagac gaacagtttt gcgcttctca cggatggtac 36240 caacgaagag atcgtccagg tgacgaactt cgcggatgtc gcgcagcagg cgaccattac 36300 ccgcggcctg atggacacac aaccgcgtaa ctggccggcg gggaccatcg tgtacttcat 36360 cggctccagt tccttcccgg aagacgagtc agtcaggtca ttcggcgaga cggtgcaata 36420 ccggccagtg atgcagacct ccattgacca gatggacatt aataacgttc cgacggatac 36480 catcaccctg cgcgggcggt acgagttgcc gtacccggtt gccaatgtga agatcggcgg 36540 cgcatactgg ccagtgtcgg taaacgtcaa tggcattgac ctcgccgtca cctgggccaa 36600 ccgaaaccgt ctgctgcagg acgcggctac ccaggtacca tgggacgccg gaaacatcat 36660 cccggaagac ggaaccacgg tgacgatcga gctgtggcgc agcggctcaa tggtgtacca 36720 gcagcaaggc atcaccggca cgtcgtttaa catccctgtg gatgccctgt cgaccggctc 36780 ccatgagatc cgcatttaca ccgtgcgcga cggccgccgg aactatacta atttccagca 36840 cacttttaac gtcgtactcc cgtctcgcga tacggggtat ggcaatagtt acggattcac 36900 ttacggagta taaccatggc gcagaaaacg gccccgaacc tgggcatgac ctacggctgg 36960 gatttaggcg aaagcgggtg gaagcctggt atggatgcca acatgaaaaa actggatgca 37020 attgtgggcg ccgcggtgct ggccattgcg aacagtccgt cagttacgga tgacggaacg 37080 cgctacattg tcgggacgtc gccgtccggc gcctttgccg gccaggcggg gaagctggcc 37140 gtacgtgttg aaggcgcatg ggaattctat acgccccggg caggatggtc cgtttacaac 37200 ctggcgaatg gcacggcgta ccggtacact ggttctgcat ggattatccc tgcgattgcg 37260 atccccgcac agccattcct ggaagtatct ggacccggta ccgaaacctt tgataatact 37320 gcgtgggtga aagttccgct gaccgtcatc gcgtcggata cggcagacgg gtgggatgca 37380 acggccaaca ccgactacat catcccgcag gccggcatgt accagattca ggggattgtc 37440 cggcccgcgc gaaccggaag caaccctttc ccggattcaa cggcattcgc cgttggggtc 37500 ggggccacgc cggcagacgg ggatgacgtg gcatgggcgg ttagcccgga cgtggccggc 37560 gcgcagttta ccctgcaggt agccgtattg cggcgctata atgtggggga ccgagtatcg 37620 ctttttgtga aacattctgc gacttctcct gtcgctattt cgcgcgcccg cttacgtgtt 37680 ttgcgtttaa cggattaaat gcgggatgct atagtgggca aacggttaat cgagggtaac 37740 taaaatgtca gatatggacc cgttgtatga attgatgaaa gactcagcgg aggatatgtc 37800 caaggctgtg gttgaaatga aggatatgat gacggaggac caaaacaccg acgtcgtcgt 37860 cgaagggtac ggcccgaagc cttcattcag caaacagata aaagagctgg tggccgggag 37920 gtcagaaggc atatttcggc tgtatgcgac attggccgag gcccaggcgg atatcgcgaa 37980 tacccctgtg gggtctgtaa cctatgtccg gggggcggat agcacgtccc tggccgatga 38040 gtatatcaac aatggcggca ccctaactgc gaccggacgg acgatgccat ccggggtcgc 38100 cgttgagatc atgtccgcta ccgtccagcg tttaatgacg gctttgcacg ttatggcgga 38160 gggcgacgcc ggttcggttt caggtattga cagcagcgat actgtgcagg gcttgatgac 38220 cggattcaac gtactggcgg agtcctttaa taacctttca gtggaaagtc agaaaaatgc 38280 ctccggcctg tccgccctgg tctcatccgt ccagatctgc actgaagcac tgaatacgct 38340 ggcggcccgg gtcgtgaccc cagacggcgc gtcgcagtat gactatatgg cattttccac 38400 gccaggtacc gtcaacgcca gtaacgggac gttcggtagc aacacccaat accgcaggac 38460 cgggatgatc ccggttcgca agggcgacgt tgtacgcctc accgttcaca ccgcaacgac 38520 agtcgcaggc cacgccgccg cattatatga cacagcggga acgtatgtgg gtcccctggg 38580 gatcatgtgc gggacgtatg cggcgtataa ggcgcggtat taccagtgtg aaattaccca 38640 ggatggattt gttgtcgcaa acacgctgga ccagagcgcg tccccttctg cagatgtaac 38700 aggtgcgtca ctgacgattg accatcgtct tcgtggccgg gaagcagaca cggttattaa 38760 gctgacaaag tctgatttga tcccggtccg cctggataac gggaacatca acgccagttc 38820 actcacccag gacggaatcg ttaactattc caccgggctg tattcctgca ccggcggcag 38880 actcctgttc agcggtttac ctgtggcctc atctccgggc cagagcagca gcctctacaa 38940 cgtcgtgttt tatgacgccg ctaaagcgct gatcgcgtac cgccccgtgt tctccagttc 39000 gggctatgtg gttatccccg aaaatgccgc gtactgggcg cagcagataa tcaccgacag 39060 aacacccaac tggtccgagg tctcgatagt ttattacaac tacgtctaca aggatgagtt 39120 gcataagcta ctgtcatcag aacgtgagcg cctcggacgt aactacccta acgaatattg 39180 gctgcaggat ttcagcggca ctaccgatat tgagtggatc cagaacgcaa tggactgggt 39240 gcatgatgct ggtggcgggt ggttgatact gtcatcggat tatgtgaaga aacagttcat 39300 catctccgaa gcggttatcc accgtagcaa tgtgtgggta gttctcgatg gtgtcgagat 39360 taaactgcag gatggcgtgc atgacaatct gtttcgtgct gccggggtta ttgtcaatcc 39420 tgacgacccg tttggtctgt gcctcgatct tgagataacc gacaacgttc gtctgattgg 39480 tacgggatat ccgaagttaa gtggtgccga tgtgccatat tatgccgata tccccgcagg 39540 aaccgggcca cgctactgga tcggcgacga atatggatgg cgaggtacgg ggctgattta 39600 ttatggtacg cagaattttg agatcggtgg ttttaaactc cagaacgtaa aaaactgggg 39660 tactgatttc gggtacggtt ctaaaaatgg ctatatccac gatatcgacc tgtggcagcc 39720 gaacaaaaac ggcgacggca tccacttcac taacggggcc agtcatatgc gcgtccgtca 39780 gattttcggc tatgcgcgcg atgactgcct agctatggtt aatagcgacg actccctggt 39840 ttacggcccg gacaaagtcc cgacaccggg gtcaattcgc cagtggatct accctacatg 39900 tccattctgg tatggttggg cgggaaatga ggccgtgggg accagtaacg acatccacga 39960 tatcgttgct acgaatatcg ggttaaccgg taacgagcag gtcagcacca ttctgaccac 40020 gcagtttaaa atctacaacg tgacaatcag cggtatcagc agcgtcaact atatgactcc 40080 aggccggggc tgggatgaag ttaatgcgat tctgaaatcg tatgcggcat ttggtgacgg 40140 ctccaggtat caggcaggaa atgtcagtaa catccgcatt aataacatca ttgagtgcgc 40200 atcaaaaaat tacagtatcg atataacgct ggaagggcgg gatatccgca tcaaccggta 40260 tatgaaactg gacacccgtg cgaaaacaaa aggcgcgctg aagatcagca gctcggcggc 40320 cccgtatgtg acaacctcta acatcgtgga ataagcagat gactatattg attcaggatt 40380 cattacgtcg cgccgttgaa gcggcctccc gcggtgcgca gactgtgctt tacacccggt 40440 cgggcgaccc gtcgtttgtg aatatcatcc ccaagtttga cgtcagcacg attgatgcct 40500 cgttggggtc tggaacgcat ccggcattta tcgttaacgg caccgaggtt agtcagattt 40560 tcgtcggcac ctaccccggc tgtattgtta acggccaact gctgtccctt ccggaccgga 40620 tacccgccac gtcggtggcc tatgatacgg gcatcggtct cgcccgggcg gccggcatcg 40680 gctggcacgc catgacaaac gcggaatggg cggcaatcgc tttgttgtgc tatgcacagg 40740 ggcaatcacc gcgcggcaat accaaccggg ggctgtcatc ggataacccc agcgagaagg 40800 ggcggcgggc agacgggctg gccgccggga ccgaatccgg aacgggtctg acgctgaccg 40860 gctccggtcc tgtcagctgg cggcacaacc gcgactatgc aggcattgca gacctggcag 40920 gcaacatttg ggagaccgtt accggggtcc gtttctgcgg tggcgagctg cagataatgg 40980 tcaataacga cgccgcgctt tacaccaccg accacacgtt atcctcaacg gcatggaaag 41040 ccgttagtgg tgtggatggg tctcttctta cgccgactgg caccggaacg ccgggaacag 41100 gttcatatgt tccaaccaca cctaactcag ttcgtatcgg cctttcgggg accgggaatt 41160 acacactgat ttatggtgaa aatacgctgt tcaccagtgc cacgaacccc ggggctacgc 41220 cggtatccga tgtcgcgcta agggtgctgc gccgactgat gttgttcccg ctgccgggtc 41280 tgatttccga cgacgcctta tcgtataaag cgggcgggga ggtcatgaca ctccgcggcg 41340 gggcgtatac caacggggct ggcgggggca tcaacgcgct actcgctaac cgtggacgta 41400 cttcagttgg tcgatctaac tctggtgtcc gtcctgttta ctacaagcct tgacattaat 41460 gcgccatacg gcgcatttct ttcctctttc ccggcgtggt gacagaagat gtttatgagg 41520 attagcttta aaaagtcgaa atggtccctc ttgttattta ttaaactgat caccgtggca 41580 gtattgacgc atttgttcgg tatcgggtgg gggcttctgg ctgtcgcggt ggtggagtct 41640 cttccatcca tcgagattaa gaggtcgatg tgaccgccgg gggtaagggg gccgccagac 41700 aaggcgcggg acccggtttt ttgttgacat caatagtgga actttccacc ggaaatgtcc 41760 agaatagtcc gaagcgatcc gctaccccga ctacaggaat attcatatga ctgaaccagt 41820 tatcaccggt accacgttga cgactgcggc tgccgtggtt ggcgccaccg gctggtgggc 41880 cggacttgac ccgggagtcg ctatcggggc tttctggggg gctatcttct ttgtcctgtc 41940 ttccaaggaa ttaacattaa ttgcgaaaac cggattcggg ggagtaagtt tctttttcgg 42000 aattatctgc gcgaattggg cggctgaatt gctaacatgg ggcgtacata agtttgcgtc 42060 aggcgccagc gatgcacccg ccgcaatggg ggccttcatt gcggccgccg tggcgatcca 42120 aaccctcatg gccatcacga cgaaagattt caccaaggcg ttgctcgacc ggttcctggc 42180 atggctgaaa agcgcgctgg tgaagactga tatcggagga ccgaaataat gtctgccttc 42240 gcattttcgg ataccatcat cacgaccttg ccggatagcc cggcattcct tttcatcacc 42300 catacattcg ctattttcaa cgttcttctc tgcctgtcta tcgtgtggcg gctgttcact 42360 ttccagcgga aaggggcgcg ccaccgttta gcaggcggcg tgatcgccat gttgctgatg 42420 gtcttttaca tgtggacacc gttccagttc gtgctgggac gcgtggccat tgtggactgg 42480 gcgaccgtcg gtattaactg catcgtcttc atcgcgatat tccgggcgcg gggaaatgtg 42540 atgcaactat tcaagtcgtg agggggcagc actatgtcgc tatcggatga cgagtaccag 42600 aaggccgcgg cgaagatcgg aatcagtgta cctgcgctgc gggcattcgc ggaagtggaa 42660 agcaatggca gcggctttat cgatggcaaa cggccaaaag ttcagtatga gccgcatgtg 42720 atgtatcagc ggctgaaaga gaacctcggg gttagcgttg ctaatggtgc gctgcggaaa 42780 tggcctgacc tggtggctac caaacccggc agctatcagt cgctgaacaa ggaagatcag 42840 gacatggacc gggcggccaa agagattgac cgcacaagcg cactggaggc cgccagctgg 42900 ggggcgtttc agattatggg ctaccactgg aagacttgcg gatacccggt gctgcaggca 42960 ttcgttaacg cgcaatactc cgaggctggg cagctggaca cactggtccg gttcctgcgt 43020 gcatcgccgg ccatcgtatc tgcggtcaaa agcaagaact ggtcgaaggc ggcgcagctg 43080 tacaatggcc cggcgtataa gaaaaacgcg tacgacgata aactggcgaa ggcatataaa 43140 aaatacgggg gtgtgtgatg cttacgccta ccgttaaaac tgtagtggcg gctatcatgg 43200 ccgccgctgt tatcttcgcc ctggtgtggc tgcataactc gctggccgag cgccactacc 43260 agcctaccat cgatagcctg aataaaacgc ttggcagcgt gaagcagcac aatgccggtc 43320 tgactgccca gctgcaggcg caaaacgctg ccatcgcgtc tatggcggta cagagcgaga 43380 aagataagca acgtatcgcc gaactggaga aagccgcgca gcggggcgct ggcgaggaat 43440 acggcagggc caatgaagtc ctgcaggaac gcaccaccgg ttccgacgtc tgccgggcgg 43500 ccagtgatgc cttcgacgcc gagctgcgga aggagcgggc aaaatgagaa agctgatcgt 43560 gaccatggtc atgctgcttg tcggctgttc cgcccgaacc gaaacgccgc cggccgtcgt 43620 ggaagtcaaa gtgccggtgc tgcagaagtg cgatatccgc cagcctgacg cgccggcgtt 43680 cccggtggac gcattacctg tcggtgcgcc gatcgatgcc cagatgcgcg ccctgcgagc 43740 ggaacggcac caacggcagg ggtacgagat attactgcga gccgagatag acaagtgcaa 43800 aaagtaagcc cgggaaaccg ggctttttcg ttactggggt ttgcgtttac gccgctggcg 43860 catccggtat ttgaactcgt cccatcccca ctggattaag accagcatta tcgccagcgg 43920 ccaaaagata accgcgaaga accgaccgac tgactcgtcc tctgacgtta tgccggccat 43980 gagcgccata cccagaatcc agaccaccac taacatgatg tcattcagca ttctttaccc 44040 tccacgcgcc gcataacgac tttgaaaatt tcagcgtagt ggtagcgttc ggatgtaccg 44100 ttagcccagt tcaacttaat gattagacca tcaagctgtt cggtgctgtt aacgacatcg 44160 ccgctactta acacgtcgcc cgggcgcagg ttaactgcgg cgacaggggt ttcagttaat 44220 gtcgccagta cacggtcttc cagtttggag aattcatgta cggtcaaagg cccatcggta 44280 tcccacgcct tacctgcgcc cggagacatt tgcatgaaac gccggtgggt ttcttcttcg 44340 ttacggcgca ggagttcata cattccctgt agtccggtac ggtccgggag gatcagctga 44400 atcggcagac ggacgacctg gttttgctgc gcggcccggc gtaacgcgtc aaaactgcgg 44460 tatacctgga tgcccagctg gtacgcgcgg tggacttccg cctttgtgcc ggtgcttacg 44520 acgtccgcgt ttggcatggt tagcagtacg gcgtcgcaac gttccagcat ggccatcgtt 44580 ccgtccaaga aatactggtc gtcgttttgc ttcgcctgat tttcgaagtc ccgggtattg 44640 agatgcggca ccaccgggaa cagtccgaga tggccaagcg tatctaccag gtgaacggcg 44700 gtaagttcgg cgatgctgat attatgggca gtatcgacta acgcgccgca ggcgttggtg 44760 taagggcggt acggcccggc aatgtagatc agtttcattg gctttcccca ttaattcgtt 44820 tcgaacttaa ctttgtccat gtacttgtcg cggaaaggtc cattgcgcac agttcgtctt 44880 cgttgtttaa aaacagaacc cagttacgtt ccgccatttc agcagatatt tcggcgatga 44940 attcgtcggt gatctttaat cgtccggata tatcccgtag ggtattccgg gagaatttat 45000 atcggtttat ctcgcgccct ttctctgtgc cgtatgcatc cgcgttggaa attatcagat 45060 tggcaacgtg acgcgcgccc ctgaccgcca tcatttcata cctttgaagt ttttaggatg 45120 gccgatgtta ctctgaacat cgatagtaat ttcatccatg aagcagggca cgcggacccg 45180 caccagtgtt tttgcgttta ccatgtccac caggcaagtc gtttgcccgg ccactgctgc 45240 gttaacccgt tcatgccctt tcgccttcgc taactcgcta tacgccgcaa ccgtatcggc 45300 gaccatattg gccatgaagt cccactgggc ctcgtttatc ttccgctgga tgtcgtgggg 45360 gatgaccgct ttattcgctt tgaacatatt atttcctccc catggggcga tgtgagccga 45420 tccctttctg gtggccgatg tggatcttgc cgcacagttt gcagtggtag gcatccatcg 45480 gcccgctgta cccgtacgtc cgcttgatat accggatgcc tgccagagcg gccgggatgt 45540 ccggataacg ttgcttcccc tcgcatgact tccggcgcag tctgcgctta ctggccatcg 45600 ttacaggctc cagttaggca ggatgcccat ggcggccagg atggctgcga tgacgaacag 45660 cgcagacagc aggcagcaga taaatccggt gcggcggttc gtcttgtcgc cctccagcgg 45720 caacgactcg atatactctt ccgccttctt acggcctgcc tcccagcgcc agtatgcccg 45780 gcatttcgcc ccggtaccgt tagttgggtc gctgtacggg ttgctttttt cggtggcgcc 45840 ctgcaggccc gccagcacac cttctgcttc ttccagagta cgggccggga tgaattcatg 45900 cgcgccgggt accggtactt cgtagccttt ctcgctttct ttgatcatgg gttaaccctc 45960 gtagttcatg ttaaaggtga tgcgtattac tgacttaata cccaggtgat cggtaatcgc 46020 caggtaattt ggtggctcgc tcatcatggc gaattctttt accgccatat acccgggact 46080 taacggtctc cccctggctt tcatcccggt ttcataggcg gagacgaacg ctttggcgct 46140 gacgacctta cggtccagca caaatcccca ttccatgagc aaggggtaac gcggtggtgc 46200 agttttggcc gttggcttat cagcgaatct acggctgctg cgataaatgc cctgcgggat 46260 ggggtacacc cgacaaaccc cgtgatagcg ccccagttct tccagcccat agaaggtgtt 46320 gcagcggata tcgtattcgc gttcgccgtc cattaatgcg gcaactgcgg ctttcagttc 46380 gtagtaatac tggaaccact ggtggtggcg gttgaccacg cccgaaatga tctgctggtc 46440 aatccggtga acaatctggc tcataatgaa aaactcccgt cgttgccttc gggagtaata 46500 ttagttgcac acgaatcgta tgtcaaacag ttttttaagt tattcaggtt caggttttag 46560 ccgcgggaat ctttccagcc agccgtgatc gataatcacc atatacgcct ggcggtaggc 46620 atcccgtatg gcagtgtgtt gcgctaacgg gcagcgcgct tccgcctgtg cgtcagcgag 46680 ttcccacagg ccgccttctc ccggacggag acggtcccac cgcttcatta gcgtgcgggt 46740 atcgttctca tcccgaaagt cccacggacc ttttccctct ccgccaaaca gcccgttttc 46800 cagttggata atatccacgc gtggtgcatg cccccaaacc tgcgggcgga attcttccca 46860 tgcttgatag aggcccatgt aacccagttc atcctgaccc ggggagcaca tgtattcttt 46920 aagcgcctgg tgtacccagc tcatgaaggt gatacgagcg tcatcgatcg aaaccggttc 46980 agcatcttcc ttcgcgaaaa acgcttccat tgcggcttcc gggttttgca tcgcctgact 47040 gacccaccac ttaaccgttt cagggtcaat gtcgccccgg cggcgacgac cggcaccctt 47100 ggctaacgta acgctgaact cgcggaacca gccttcgtcc gcgtggaaca tgacgcacgc 47160 gaatgacaga aggtagccgt cggtcttgca tgacaggttt tccacgtcga atacgaggtg 47220 gattttgccg atgtgttctg gttttgctct cataggtgtt cctcttcttt ggtccattct 47280 ccgctgccgt cggcgcgggt cactttaata atttcgtctt tttccacgtg catcaccggc 47340 agcggtggaa atgctacggt accgtcggtg tggcataccc gcacttccac ccgccagggc 47400 ttccagaaaa cgggtatcca gtcgcaatgc tcaatcacga tgccggagta ttcccggcca 47460 ttgcatttat cccggaagcg gaccatgtcc ccgtagagcg ggtaatcagg gtccggcggg 47520 agggcggcat atttatccgc aattgatctg caaacgtcat acattgacat attaatcccc 47580 cataaaaggt tcgcagctcg ccgcgcaacc ttcgtaatct tccggagcgt cttcacgaac 47640 cggcactgtc aggtcgaaac tggcgatcag ctgctgcgta tttcggtatc cccggaagaa 47700 gacccgtggg tcgtctacct ttaccccttt gaccatgttg tcgccaacgc ggccatagcg 47760 ttcttccatc tcccgcgtcc actcgaagaa gtccagcacg tccagcttgt cagtcgggaa 47820 ccagtcgatc agcgggtaca cgcggacctg gcccgtctga cggctaaccg tggtcttctt 47880 acgctgcagt tcgtccgtac gaatgccgat cgccgtctgg taggtgccgc gcttccagcc 47940 gatggaccgc atgtacgagt ggatcacgtt ctccttcaat tcccgggtgc aatggatgta 48000 gtttttgttc gggatgccgt actttttgag catctcttcg aacaccctgc cttcccggtc 48060 cgccgtctcg tacgagatga cccgatgggt acagccgcgc tttttgccgt ggtgaacaac 48120 cgcttccagc cataccgtgt tgaagccgaa gtgctggtcg cagtctcgta cgaagtccag 48180 cgtttccgga ttctcacggc cggtattggc gaagcacacg ataatctcgt acttatcggc 48240 gtactctttc aggatccggt aggtcatgta agcggaggtg cgccccccgc tgaacagcac 48300 cagtaagcgc ggctttgcca ttagaaatcc ccgtctaact cgcccaggtc atcggcacgg 48360 ccatacagct cttcgaacag gatcatcgct gcggcgtaca ccagcgtccc gcgaagttcg 48420 ttgatccggg cctgtttagt cggcagcgtg cgggcctcaa tggttttctt gataacctgc 48480 tgcgccaggc cggcgtcgct gtccagcata tgcgccatgg tcagaatcgg ctgttcgata 48540 aacggcaggt cattggcgtg acgctcacgg cctttaccgt acgccgcctg ttccagcgcg 48600 ccgaggaagg tgcgcagcag cggcaggtag tcatcacggt ctttctcgtt tttgaaccgg 48660 aacaaggtcg accggatgcc ggaatcatcg gcgaccatag tcaggtccag gtcgtcatta 48720 gtatccgtgg ttgatgggcg taactccgga gcgaactttt catactctat gccctggcaa 48780 tcctctgctg ccttatcgta cgcagaagcc aggccactcc atttcagttc ttcaaccgca 48840 cctactggca gtgtcacgtg aggccatttt gcaccagcct taatcttgat gcgttgttcc 48900 ggaaacaggt ccggagcggc ttcgtttttg atagtcacgg tatttttagc atgagtgttt 48960 ctacccgcat cggcggactg gcgggcttcc ggttccactg gccggggggc gacgagcgta 49020 tcgatcgctg acaggatgct ttcgtctgac gattcgaaat caagttttaa cgtcgctgca 49080 atcgtttcca aggttgtttg gtgttcaaac gcctgcgcat tcacagcgcc taccatggcc 49140 agcatttcgt cccagctgcg gcctgtaaca cccagcgcgt tcgccagctg gtcacgcatt 49200 tgcgaatcaa tgctgaccgg ttcgtcaatg gacgggttac gcagcgaaag gagtttatgc 49260 ccgttgagat gcgcgaacat gagatagttc atcgcgtcga tcaacttacc cttggccagc 49320 gaatcgcgaa tgcaggtacg gcattcatgc tcggtcagtt ctttccatgg ttcagcggtc 49380 gcccagcctt tgcgcttatc cgcgccgtag taaagacgac caagcatctc atcgaagacg 49440 cctttaactg aggtcaggaa cgcttcattc aataaattgc tatggaaggg cggccagcgg 49500 agttcggttc tcgggtgaac gattctgttt ttggccggca tttctttatt ctctgacatg 49560 gtatatctcc gggttgtttt gttgttcgat tagaatacta gctgcacacg ttttgtgtgt 49620 caaacgtttt ctagaaaatc tacagttccc accataaagt ttcggatgaa ctgggcgccg 49680 acttgaggga cgattgcatt gccgtatccg cgcagtcgca ccactcgggc gggtacccca 49740 ttagccaacg ggaaaacgcc ggatccaacg ggcctgaact tcccatcccg gcatagcagc 49800 cagtcagcat ttgaccacgg gccgtgatcc tgatcgggaa gtcgggggca ggcgtacact 49860 tctccatgcc cttccggtag ctccccgata gctgccccct cgatgccggc gagtccggta 49920 ctgtcagcgg tgtcgggtag ctggcgagac gaaccgcgcc gcccagggtc gtcgaccgat 49980 ccggatggcc cgctgcgccc gcctccccgc gtacctgatt gttgtcgatc gtcgtcaccg 50040 ttggccaggt cgccagctgc gccgccacgt ccagccggtc gacggatagt ttgccattcc 50100 ttatccgccc acccgcgtag ccgcctttcc agtccgtcgc tgacgaggtc ggccaggtcg 50160 atagcgccaa agaaaaggcg atctctttta tgcggggcgc cgacgctgca cgctggcaat 50220 actgccgacc cgcaggcgta accttcttct tccagctcaa cgaatagagc atcgagccac 50280 aattctttaa ttgctgcgct aacctgttcg ccaaaaataa ctggaggtcg cagctctgcg 50340 atgaggtcga gaaaggccgg agccaggtga cgggagtcgt cccgcccgcc tcgttttcca 50400 gccacactaa aaggctggca cggcggactt cccgtacaca ctggcgcata cgccggccat 50460 ccggcgagtt taagggccag cggccatccc ccgataccgg cgaagaagtg ccactgacgg 50520 aaaccccgga ggtcttccgg ggcgacttcg gtgattgatc gttcatcgac aattccatct 50580 ggcaggtggc cgcgcctgat tagttcacga agccacgctg cggttttagc gtcccactcg 50640 ttgtagtagt ggaacggttt agagccgttt atgtatgcca ttctgcgcct tcttctcttc 50700 gcgtcttttg accgcacaat cggcatggat cgtagtccac gttccggacg cagacctttc 50760 aagatacccg gcgccggccg gcactggctt tttgcagtag caacacatag ccacgtattt 50820 atttctggcc atctttgacc ctcgcgaaac aggcatacgg gccatcgaat tccgtcggcg 50880 ccgtatacag gagaaaccag ccggacccgt taagcgacgt cgggcgcggc atccaggtac 50940 gcagcacaga ggcgcgcatc tcgtccgtct tcgcgttgtc gtacgccacc cgcagcggca 51000 cttccagcgc tcgcggatag ccttcgccca ggtagaatcc ctcgcactcc aggttgtatg 51060 catccagcag cgcgtcgaga ttggacccat catagttatt actggcgtgg aagaagacgg 51120 gatggtagta ccaggcgtcc gggtcatacc cgtccgccag gcttacctgc tcgccaatta 51180 cgccatcgtt atacacgttt ggctttggca ttcttccctt cctcttcggc aactgaccag 51240 acgacctcgg tgaacgggtc agggttgatc gtcttcccga ccttattctg gtcgaggtac 51300 cagtcgtcgc cgcaccacag tttgacgccg tgggcatccc ggcggacttc aacgtcgaac 51360 gttttcactt cggtgatctt gccgttacgg gttacagttt tggttaattt catggtcttg 51420 gcctcacgtt tatgaacacg aacctgtttc atgggtcatt ccccgaggta attcatggcg 51480 ccgcaatccc ggcatacaac ttcacgcggt ttcccttccc acgtccattc cgtcacatcg 51540 cattgatagt gactacagct atcctgaatg cgctgcgttt cctgccgttg cgcttcgtat 51600 ttagcgtcct gctcggcgcg gcgttcatcc cgtaaacgct gcttgcgttg ttttgatgat 51660 tcgaatgtca ttgctatacc tcgtcccact gggcgatcca cttctcgcgg acgtcctgca 51720 tgatgttggc catgggcagt ccgatgtcca tgagcgcttc ccgggagatg tactccgggg 51780 catgtttttc ttcgtcttcc ggatcgaaga tgactatcgc ggcgccgaag cccgcggacg 51840 ttgcacctgc ggcgcccgtc ttcgctttga accataccgg cggttcgaaa ccgatacgcc 51900 ctttgatgaa tatggtgcgc gtggcgatgg tatctggcca ccatgtttca gcggtagccg 51960 ctttgatcac ccagaccgta cccgcgcctt tcttccgttc ctcttccgcc ttggccatga 52020 tgttgaccat gccggtcagc ggcacttcca cagcacggtt acggctgtat ggcgggttgc 52080 cgaaacccca tacccgccga acgtggtcgg cgacatcgta cacttccgcc tcggcctcca 52140 gttccgcctg tatccttttc agccggcccg cccagtcctg gcgcagcgcg ttgtcctcgg 52200 cggtgtaata gcgcgtgcat ttggcgttct ggccatcggt gaacaggtcg agcaccagcg 52260 ggccgaacag cttgtccagc gcgaagaaca gccagtcggg tgttcgccac tggtcgccta 52320 tctctttcag gtcatgcgct tcccgggctt tcagcgcgat gaggttgtca acgtattcac 52380 tcacaaatta gcctccatgt atggacttgg tcgccctggg tgatgagatt cacaatgata 52440 aagccgcctt ctttttccat tcgcgcttta tccgcgaatg ccggaattgc ggcaaggaag 52500 tctttccatg gcagggggtt aaacgcgcca atggctaccg agatttccag gtttttattc 52560 ccaccggcct tgtgggaaac gcagcaaagg ctggttccgg ttttatcccg cagccaacgg 52620 tctacgctcc ggaggaattt cccgtctccg gcggttaaaa tgtcgcactg gacaacgata 52680 tttgtcacgt cactcatggc cttttctccg ctaaaaattc gcgtaatacc ttttccatgg 52740 ccaattcgtt tgccgcagcg ccaggccatt taccgagaag ccgcgcatta ttcggtacgg 52800 tctgcatttc cacaagacag actttgttac ccaactcatt gcgagaatgg ttgatactca 52860 ggctgtaaat gctgacgtcg tccgggccat cccataggtc ttttcggata ttaagatatg 52920 cctgaatatt acctgcatcc gggatcgcac ctgcgctcat aatatctacg cacatttcct 52980 ggatgacctt ttggtcgtta attacgtttt tcatttccgt ttttccttct gtcgtgacac 53040 gaactggact ggggtgacga cctcaccgaa attcgggtaa cggctgcgca ccagctcaag 53100 ggtcagcggg ttgatctccg cacgcggcgt cttcacgtcg tacgcgcggt ccgggatgtc 53160 gatgcggcgc atgtacgtcg gtcgcatccc gacgcgtacg gcgtagttat acgcttcctt 53220 cgggccgttc gcccagacca cgaagccgac cccgcggcgc tgcagataat atgcctgcgc 53280 cgtattggag tcatcgcgag gcagattttg tggtatcgcg ggaaaacggg cgctacttcc 53340 tttcacggtt cctgtatacc aattggtcga agcatggcgt tcttccgaac actccggcgg 53400 gtacgggtca ttgatatccc acgtctttcc gcaccaggaa cagaacacct ggtccgattg 53460 ctggatagcg tttttgtggc cgttagtttc catcggtgtc ctccatcatc caggacggcc 53520 atacgccatc gcggatcatc tggcgctggg ccttccagtc ggcctgcgcg agttctttaa 53580 ctcgggtccg gatgacagcg tcgggcataa acgccgtcat tactttcgtc aggaaaactt 53640 tgttgtaggg gtcctccacg cggcagttta acgcccgggc gcaggactgg atcgccgcct 53700 tatcattgcc gtgttctttc atgcacagca tgagcgtaac gatcatgtct atcgcctcgg 53760 cgatatcccg gcacgctttc ttttctggcc cgtggacctc aatggaaata ctggtcgccg 53820 ggaataacag gtggtctttg tacgggcgca gccagtccgc tttcgcccgg tcttctgcgc 53880 tggtggtcat acttcgatgt cctcttcccg gatcagctgc agggcgttgc cgttcactgc 53940 ccacggttgc cacacgtcca ccaccagcgc cgcacggaat gaccggttga agcagttctc 54000 gatcatcgcc cagttatcgt ccggacggtc tgacgcaatg ccattgcgtt cccagtgcca 54060 ctggcgaggc gcctgggcca gctcgcggag gggcgggcgg gggtgtgagt agggattgca 54120 caggccggaa cgcagcaggc cacgctggag ccatgagcgc tgccaccaga ggtcacagcg 54180 ggtcgacccg acggcgtatt cctcttccag catgccgcac atgatcagcg cgcacacagt 54240 atcgcgtggc gccggcgcac cgatgaggtc gaaatcctcc agcctcttcg ccaggcggtc 54300 ggcggaccct tcgtcctgcc cgttgccgtc ggtacggtca tgcagaatta catcgaggat 54360 gatggccgga aaaacgactt gtttgccgtt gcgggtaaag cgggggtccg gctcattgaa 54420 gagggcgtga tacagccgcc cgaaccactc cgacaggtca ggcacgaagt cggcgatatc 54480 cggccagctg cgttcctctg tgttgtggat gcgcacggac gtctcttcct ctatcgggtc 54540 gtactcgacg cggacgatgc agcgcgggcc gtgcgggagg ggaaaaatgt agatggtctg 54600 tttgccgatt cgattctggt caaagcggcc aaacgacatt agatgcttct tcatgggatg 54660 ttcctttttg tggactccca agaaatgtag ctgaacacga ttcgtgtgtc aaacgctttc 54720 tgcaggcaaa aaagaagccc ggacaaagcg tgccgggctt taatgtcagt ggaacaccga 54780 gcatgaagat ttcatcccat gtcccgatca ctatacgtca ggattgcgat aaatcaaatc 54840 ccagtaggtg aatgtttcca ggtcgacttc cgtccagtcc gggtcgtcca ggtacgacag 54900 gcaggtgccg gcatcctcgg cgcagacctg cccggcggcc gcattatgca gcaggcggac 54960 ttcccggaaa tagatgaacc actcgcggca tggcgtatag gactcgggct gacgggtctt 55020 gatgatctgg cccgtctttt tgtcctgcca gtacgccgtc cgtttcttcg ccaggtagcc 55080 catatcagcc caccctcatg acgcgggatc ccatgcggcc gtaaatcggg tcgcgcagca 55140 cccagcggat agccagctta taccccaact ggtaccccag gcgccgcacg tagcccaggt 55200 ccgcaggccg cttgccgctc acgaagaagg actcgccgac agccatagcg ccaagcaggc 55260 gtttatgctc ggcgatatgg gggttcggtt tagcgtgttt acggcctgcc atgtcacacc 55320 tcgtcgtcgt cttccagctg cgcgtcgacc tcaaccgtga tgtccatctt atcgcggaag 55380 acgtcaatga cgtcctgcag cgacagcacc gtctggaaca ggttggccat gtaggtcagg 55440 aacgtaccgc tgtcattgtt gtagcgctcc agcgtggctt cgtagttggc gtcaacatcc 55500 gcctcgccga tgtggatccc ggagatgatc gccttgtcgg taaggcggaa gaacacgttg 55560 cccacgcccg ggcgcatctc gccttcgtcg attcgcatgt tcagcgcccg aaccgtgtaa 55620 tgccgcgcca ggtagtcgag gaccacttcg tccttgtgga tgtcaatgtc cttgaacttc 55680 acgtcatcgc catcgtcgtg cttgatgtgg atgaagtcct cgccggtgac accctcgatg 55740 tcgccgcgta cgaccttctc cattgactga cgcagcacga agtcattgat cagcaggtgt 55800 tccactggcc aggtaccgaa cgcggcacgc agtagggagt taatctcttc ggcggtcctg 55860 gcgctggtgg tgaacacgta gacgtacggg acggcgatga tcacgttgta gcgggtcggg 55920 cggataggcg cggttttcag catttcggct tcaacatcgt ctttcagctg cgcccagtct 55980 ttccgggtcg gctcccagcc ttcaatctct ttctcgcgcc aggtgtccat acgcttcgtc 56040 acttcgttgc gcacgctgac gccgggcagc acgcgttcac gcttttcggc ctgcagcacg 56100 atggcgttag tacccgggat gcccatggca aacttgccgc ccacgtagtc cgcgtacggc 56160 gcaaagccaa tcgtcttata gccgatcggg tctttcactt catgcttcgc cagcagatcg 56220 ctcacacggc cggcggcgaa ttcatggacc gacatttcgt ccatgttcgg cgtgttcagc 56280 agcgtgcggt ggaaactttt taccgacttc tcgccagcgt ttgcggcgcc aaagagcgcg 56340 ccgagatgca gaatgatgac tttctcaaag cctttaactt tcattggggg tatctccgtt 56400 tgcaaacaga ttcaggaatg gcgcacgcac aagggcggcg gttagatggg ccagcagcac 56460 acggttcgtc tcccgggcgc tacgcaggtc tgccgccatt tcggcatact ctttatcgac 56520 tttgacaaag gcaccttcgt cagcgtcagg gtcgaccatc gtgttgccga ggacttcggt 56580 atacacccgg gtcgcttcat cctcgatgtc ggcgataatg ctgttcagga tggcgatctt 56640 actgcgtacc tggtcgagcc ggtcagcgcg ggtcgtcgcg tacgctttca gcagttcagt 56700 gttcatccgc gtgctctctt ttcgttacgg cggcgctggc gctcatcctt gcgcttctcc 56760 acctgtgcat tccagcggtc gcgttcctct gactccgccc ggttcttgag ccagagttcc 56820 tcccgttcgc caagcgcttt actgaccgca ccgtcaataa cttccgtggc ccggaccagc 56880 tcgtcttccg tcatttcagc ggcagagcac ttcccgatct ccgtctgcag caaacggaca 56940 acggcagaga tgccgatcgc gtcgatggcg atacgggcct tttgcgcata cagcagtctt 57000 tggttaaccg gcatcatttc acccccgttg tcaggacgac atagaggacc gccacgcagg 57060 cgaccagctc gatcagcacc atgaacagga tggacgccag cagcagtttc gcaaatgacg 57120 gcaggtatgg agtaaggcgt atgcgagcat gaccgtccag ctctttgtgc ttcattggtc 57180 ggcggttacg tttggtccag cggcgtatcc agttttcgcc gcggcggtgt acgaggctat 57240 cattcatcac ggttccctcg catggcatcg cgcaggtctt tcggcgggta gattttattg 57300 acgccatcac cttcacgcag gaaacggatt aacatggcca gggtctgcac gatctcttct 57360 tcgacatgga cccaggtatc acggcgctcc gcgtaatgca ctgctgcctt gatcacctcg 57420 ccggcctctt ccgagaattt cagcatggtg taattcggct gcgggtattt ttcgatagcc 57480 cgggccgatt cggctcgtgc ctggtcgacg aggatatcga aataatcggc cttcgcttcc 57540 gcctgcgaat tcatctgcag gtaaaagatg gccagcgtcg tgaggaattc cgggctggcg 57600 cgcgctttc tctctgaact cattttcatt tgacatgggg tttccttctt agtgtttttc gccagcaatc 57720 tccgccagta cggcagcgac ttccggcgtt ggcatgtggg tgttagccca gtacagcagc 57780 ccgatgatgt agtggatcat ctgaccgacc tctgccgcgc cgcgggcttt tccgcctttg 57840 gctttcgcat aatcgccttc gctgaacagc actttgccgg taccgcggta gccaacaatg 57900 gccgaaccgg tatgcgtgac gtaaatggcc acggcgtatt tgtcttccag ggatcgaaac 57960 gccgggccag cgtcgagtcg tttgcgcggc gccgcaacgc ggttcaccgc cagcgcgaca 58020 ttactcggtg tcgggttttc cattgagcgg ctctccgttc agggtgtaga tgacgacgcc 58080 cggcacgctg acgtcgatcg acagcgatgg cacaaagccg gacatgacgt tctgcggggt 58140 gatggtggcg cgtttcaggc cgttctcgta catgatgttc gcgatgcctg ccatgacgga 58200 cttctccacg atgttctggt tcgtctcttc gcgcatggtc agcagctgtt tcaactcttc 58260 gacttcattt ggaatgtcaa aggtatgctg taacatccgg ataagcgtaa tggcatcatc 58320 acgggtgatc ggggtcagta gctgggcata agcagggtca atatggtcga tcatgatctc 58380 gccatcctgc tgtcctggct tacggtaggt atgcaggact cgcgctaact cagggtagcc 58440 gggcataatt tccgacgttt tcctttggtc atcatatgac atagggtgtc tccgggtgaa 58500 aagggtggta cggcaaaaaa gaggtgccgc gtcctacagg attaaacttc gtcgtcttcc 58560 ggtgtgccgg cgccgtcatc aacgcgcttg atcgccacct ggataaacgc acggcccgac 58620 gggtacatga ccagcgccgt ttccagtgag aactgactat tgcaggcccg tttggcgtta 58680 cgcagggaag acgacacgcc gttacgcatt ttgtagcgca gcgccgtggc ttcggtctgc 58740 aggtctgcca gcgccttgct gctgtccagc tcctgcgcat aaacgtagac ctcgcccggc 58800 ttgaggccga tcaggttgcc agtgatactg ttagcccgga tacctgacgg cagttccacg 58860 tccgtctcca tggtcatcat ggccggcgtc aggtcatcca ggataatcgc gtcgttcatc 58920 ggtattctcc gtcgttaaat ttgcgtatct gtcacgctga aagatagttg catacgttcc 58980 gtgtgtcaat cgttttcact gaacgacaac ctgccagctt tttcaagtaa gaaatttcag 59040 ccggctaact ttttgaagta agacccgaac cgctatggcg ccggccatgg ttattacggg 59100 59100 <210> 2 <211> 333 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15 / 11 / N54_KPN_BP ORF 48 <400> 2 atgtctgcct tcgcattttc ggataccatc atcacgacct tgccggatag cccggcattc 60 cttttcatca cccatacatt cgctattttc aacgttcttc tctgcctgtc tatcgtgtgg 120 cggctgttca ctttccagcg gaaaggggcg cgccaccgtt tagcaggcgg cgtgatcgcc 180 atgttgctga tggtctttta catgtggaca ccgttccagt tcgtgctggg acgcgtggcc 240 attgtggact gggcgaccgt cggtattaac tgcatcgtct tcatcgcgat attccgggcg 300 cggggaaatg tgatgcaact attcaagtcg tga 333 <210> 3 <211> 585 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15 / 11 / N54_KPN_BP ORF 49 <400> 3 atgtcgctat cggatgacga gtaccagaag gccgcggcga agatcggaat cagtgtacct 60 gcgctgcggg cattcgcgga agtggaaagc aatggcagcg gctttatcga tggcaaacgg 120 ccaaaagttc agtatgagcc gcatgtgatg tatcagcggc tgaaagagaa cctcggggtt 180 agcgttgcta atggtgcgct gcggaaatgg cctgacctgg tggctaccaa acccggcagc 240 tatcagtcgc tgaacaagga agatcaggac atggaccggg cggccaaaga gattgaccgc 300 acaagcgcac tggaggccgc cagctggggg gcgtttcaga ttatgggcta ccactggaag 360 acttgcggat acccggtgct gcaggcattc gttaacgcgc aatactccga ggctgggcag 420 ctggacacac tggtccggtt cctgcgtgca tcgccggcca tcgtatctgc ggtcaaaagc 480 aagaactggt cgaaggcggc gcagctgtac aatggcccgg cgtataagaa aaacgcgtac 540 gacgataaac tggcgaaggc atataaaaaa tacgggggtg tgtga 585
Claims (15)
상기 박테리오파지는 서열번호 1로 표시되는 유전체로 이루어진 것인, 박테리오파지.The method according to claim 1,
Wherein the bacteriophage is composed of the genome of SEQ ID NO: 1.
상기 클렙시엘라속 균은 클렙시엘라 뉴모니아(Klebsiella pneumoniae), 클렙시엘라 옥시토카(Klebsiella oxytoca), 클렙시엘라 플란티콜라(Klebsiella planticola) 및 클렙시엘라 테리게나(Klebsiella terrigena)로 구성된 군으로부터 선택되는 1종 이상인 것인, 박테리오파지.The method according to claim 1,
The Klebsiella spp. Is composed of Klebsiella pneumoniae , Klebsiella oxytoca , Klebsiella planticola and Klebsiella terrigena . Lt; RTI ID = 0.0 > bacteriophage < / RTI >
상기 클렙시엘라속 균은 클렙시엘라 뉴모니아(Klebsiella pneumoniae)인, 박테리오파지.The method of claim 3,
Wherein the Klebsiella sp. Is Klebsiella pneumoniae .
상기 박테리오파지의 명칭은 YMC15/11/N54_KPN_BP이고, 기탁번호는 [KCTC18572P]인 것인, 박테리오파지.The method according to claim 1,
Wherein the bacteriophage is named YMC15 / 11 / N54_KPN_BP and the deposit number is [KCTC18572P].
상기 박테리오파지는 형태학상 정이십면체의 머리(isometric capsid) 및 수축성이 없는 꼬리(long non-contractile tail)로 구성된 형태형(morphotype) 시포비리데(Siphoviridae)에 속하며, 전체 게놈 크기가 59087bp인, 박테리오파지.The method according to claim 1,
The bacteriophage is a bacteriophage, belonging to the morphotype Siphoviridae, consisting of a morphological isomeric capsid and a long non-contractile tail, with a total genome size of 59087 bp, .
상기 항생제는 카바페넴(Carbapenem)인, 박테리오파지.The method according to claim 1,
The antibiotic is Carbapenem, a bacteriophage.
상기 박테리오파지는 서열번호 1로 표시되는 유전체를 포함하는 것인, 약학 조성물.9. The method of claim 8,
Wherein the bacteriophage comprises the genome of SEQ ID < RTI ID = 0.0 > 1. ≪ / RTI >
상기 형태학상 정이십면체의 머리(isometric capsid) 및 수축성이 없는 꼬리(long non-contractile tail)로 구성된 형태형(morphotype) 시포비리데(Siphoviridae)에 속하며, 전체 게놈 크기가 59087bp인, 약학 조성물.9. The method of claim 8,
Wherein the total genome size is 59087 bp, belonging to the morphotype Siphoviridae consisting of the isometric capsid and the long non-contractile tail of the morphological shape.
상기 박테리오파지의 명칭은 YMC15/11/N54_KPN_BP이고, 기탁번호는 [KCTC18572P]인 것인, 약학 조성물.9. The method of claim 8,
Wherein the name of the bacteriophage is YMC15 / 11 / N54_KPN_BP, and the deposit number is [KCTC18572P].
상기 항생제 내성 클렙시엘라속 균 유발성 질환은 패혈증, 폐렴 및 폐기종으로 이루어진 군에서 선택되는 어느 하나인 것인, 약학 조성물.9. The method of claim 8,
Wherein the antibiotic-resistant Klebsiella spp. -Induced disease is any one selected from the group consisting of sepsis, pneumonia, and emphysema.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170077538A KR102011956B1 (en) | 2017-06-19 | 2017-06-19 | Lytic bacteriophage specific for klebsiella genus resistant to antibiotics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170077538A KR102011956B1 (en) | 2017-06-19 | 2017-06-19 | Lytic bacteriophage specific for klebsiella genus resistant to antibiotics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20180137813A true KR20180137813A (en) | 2018-12-28 |
| KR102011956B1 KR102011956B1 (en) | 2019-08-19 |
Family
ID=65008883
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170077538A KR102011956B1 (en) | 2017-06-19 | 2017-06-19 | Lytic bacteriophage specific for klebsiella genus resistant to antibiotics |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR102011956B1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000508322A (en) * | 1996-04-15 | 2000-07-04 | エヌワイエムオーエックス コーポレーション | Compositions containing bacteriophages and methods of using bacteriophages to treat infectious diseases |
| KR20040111357A (en) * | 2002-02-13 | 2004-12-31 | 이뮤놀로지 래보러토리스 인코포레이티드 | Compositions and methods for treatment of microbial infections |
| JP2015523850A (en) * | 2012-05-04 | 2015-08-20 | バイオコントロール リミテッドＢｉｏｃｏｎｔｒｏｌ Ｌｉｍｉｔｅｄ | Therapeutic bacteriophage composition |
| WO2017081709A1 (en) * | 2015-11-09 | 2017-05-18 | Universita' Degli Studi Di Siena | Bacteriophage able to lyse klebsiella pneumoniae expressing a cpskkbo-4 capsular polysaccharide and related medical uses thereof |
-
2017
- 2017-06-19 KR KR1020170077538A patent/KR102011956B1/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000508322A (en) * | 1996-04-15 | 2000-07-04 | エヌワイエムオーエックス コーポレーション | Compositions containing bacteriophages and methods of using bacteriophages to treat infectious diseases |
| KR20040111357A (en) * | 2002-02-13 | 2004-12-31 | 이뮤놀로지 래보러토리스 인코포레이티드 | Compositions and methods for treatment of microbial infections |
| JP2015523850A (en) * | 2012-05-04 | 2015-08-20 | バイオコントロール リミテッドＢｉｏｃｏｎｔｒｏｌ Ｌｉｍｉｔｅｄ | Therapeutic bacteriophage composition |
| WO2017081709A1 (en) * | 2015-11-09 | 2017-05-18 | Universita' Degli Studi Di Siena | Bacteriophage able to lyse klebsiella pneumoniae expressing a cpskkbo-4 capsular polysaccharide and related medical uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR102011956B1 (en) | 2019-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10953053B2 (en) | Methods and compositions for preventing infection by a Vibrio species | |
| KR101261873B1 (en) | Bacteriophage having bacteriocidal effect on Salmonella spp., the cause of sitotoxism | |
| KR101822812B1 (en) | Novel Enterococcus faecium bacteriophage Ent-FAP-4 and its use for preventing proliferation of Enterococcus faecium | |
| KR20130087118A (en) | Podoviridae bacteriophage having killing activity specific to gram negative bacteria | |
| KR101915486B1 (en) | Novel Vibrio parahaemolyticus bacteriophage Vib-PAP-7 and its use for preventing proliferation of Vibrio parahaemolyticus | |
| US20210163897A1 (en) | Novel streptococcus suis bacteriophage str-sup-2, and use thereof for inhibiting proliferation of streptococcus suis strains | |
| US20210161977A1 (en) | Novel streptococcus suis bacteriophage str-sup-1 and use thereof in inhibiting streptococcus suis bacterium proliferation | |
| KR101859973B1 (en) | Novel Aeromonas hydrophila bacteriophage Aer-HYP-1 and its use for preventing proliferation of Aeromonas hydrophila | |
| KR20180137814A (en) | Lytic bacteriophage specific for klebsiella genus resistant to antibiotics | |
| KR101940019B1 (en) | Lytic bacteriophage specific for klebsiella genus resistant to antibiotics | |
| KR102041109B1 (en) | Novel Salmonella Heidelberg bacteriophage Sal-HEP-1 and its use for preventing proliferation of Salmonella Heidelberg | |
| US20210161978A1 (en) | Novel streptococcus suis bacteriophage str-sup-3, and use thereof for inhibiting proliferation of streptococcus suis strains | |
| KR102011956B1 (en) | Lytic bacteriophage specific for klebsiella genus resistant to antibiotics | |
| KR102011965B1 (en) | Lytic bacteriophage specific for klebsiella genus resistant to antibiotics | |
| KR101789877B1 (en) | Lytic bacteriophage specific for Pseudomonas genus resistant to antibiotics | |
| KR101824778B1 (en) | Lytic bacteriophage specific for Pseudomonas genus resistant to antibiotics | |
| KR102193101B1 (en) | Novel bacteriophage specific for Klebsiella genus bacteria resistant to antibiotics | |
| KR101788401B1 (en) | Lytic bacteriophage specific for Pseudomonas genus resistant to antibiotics | |
| KR101915493B1 (en) | Novel Vibrio parahaemolyticus bacteriophage Vib-PAP-8 and its use for preventing proliferation of Vibrio parahaemolyticus | |
| Sorour et al. | Virulence Range and New Pathological Pictures of Salmonella enteridits and Salmonella typhimurium Isolated from Ducklings in Experimental Infected Chicks | |
| WO2023063453A1 (en) | Bacteriophage specific to pseudomonas having antibiotic resistance | |
| US20240287468A1 (en) | Bacteriophages against vancomycin-resistant enterococci | |
| KR102269089B1 (en) | Novel bacteriophage specific for Acinetobacter genus bacteria resistant to antibiotics | |
| Feng et al. | Characterization of novel phage pK3–24 targeting multidrug-resistant Klebsiella pneumoniae and its therapeutic efficacy in Galleria mellonella larvae | |
| KR20230159558A (en) | Compositions and methods for inhibiting the growth of enterotoxigenic Bacteroides fragilis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |