LOCUS       NM_138554              12677 bp    mRNA    linear   PRI 15-OCT-2024
DEFINITION  Homo sapiens toll like receptor 4 (TLR4), transcript variant 1,
            mRNA.
ACCESSION   NM_138554
VERSION     NM_138554.5
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 12677)
  AUTHORS   Wang,C., Huang,C., Li,Y., Bai,J., Zhao,K., Fang,Z. and Chen,J.
  TITLE     Hepatitis B surface antigen impairs TLR4 signaling by upregulating
            A20 expression in monocytes
  JOURNAL   Microbiol Spectr 12 (10), e0090924 (2024)
   PUBMED   39248482
  REMARK    GeneRIF: Hepatitis B surface antigen impairs TLR4 signaling by
            upregulating A20 expression in monocytes.
REFERENCE   2  (bases 1 to 12677)
  AUTHORS   Geng,X., Xia,X., Liang,Z., Li,S., Yue,Z., Zhang,H., Guo,L., Ma,S.,
            Jiang,S., Lian,X., Zhou,J., Sung,L.A., Wang,X. and Yao,W.
  TITLE     Tropomodulin1 exacerbates inflammatory response in macrophages by
            negatively regulating LPS-induced TLR4 endocytosis
  JOURNAL   Cell Mol Life Sci 81 (1), 402 (2024)
   PUBMED   39276234
  REMARK    GeneRIF: Tropomodulin1 exacerbates inflammatory response in
            macrophages by negatively regulating LPS-induced TLR4 endocytosis.
            Publication Status: Online-Only
REFERENCE   3  (bases 1 to 12677)
  AUTHORS   Ozbay Kurt,F.G., Cicortas,B.A., Balzasch,B.M., De la Torre,C.,
            Ast,V., Tavukcuoglu,E., Ak,C., Wohlfeil,S.A., Cerwenka,A.,
            Utikal,J. and Umansky,V.
  TITLE     S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in
            melanoma through TLR4 signaling
  JOURNAL   J Immunother Cancer 12 (9), e009552 (2024)
   PUBMED   39266214
  REMARK    GeneRIF: S100A9 and HMGB1 orchestrate MDSC-mediated
            immunosuppression in melanoma through TLR4 signaling.
            Publication Status: Online-Only
REFERENCE   4  (bases 1 to 12677)
  AUTHORS   Ning,F., Wang,H., Liang,Z. and Lan,J.
  TITLE     TNFAIP3 Overexpression Inhibits Diffuse Large B-Cell Lymphoma
            Progression by Promoting Autophagy through TLR4/MyD88/NF-kappaB
            Signaling Pathway
  JOURNAL   Discov Med 36 (187), 1627-1640 (2024)
   PUBMED   39190378
  REMARK    GeneRIF: TNFAIP3 Overexpression Inhibits Diffuse Large B-Cell
            Lymphoma Progression by Promoting Autophagy through
            TLR4/MyD88/NF-kappaB Signaling Pathway.
REFERENCE   5  (bases 1 to 12677)
  AUTHORS   Dinice,L., Esposito,G., Cacciamani,A., Balzamino,B.O., Cosimi,P.,
            Cafiero,C., Ripandelli,G. and Micera,A.
  TITLE     TLR2 and TLR4 Are Expressed in Epiretinal Membranes: Possible Links
            with Vitreous Levels of Complement Fragments and DAMP-Related
            Proteins
  JOURNAL   Int J Mol Sci 25 (14), 7732 (2024)
   PUBMED   39062973
  REMARK    GeneRIF: TLR2 and TLR4 Are Expressed in Epiretinal Membranes:
            Possible Links with Vitreous Levels of Complement Fragments and
            DAMP-Related Proteins.
            Publication Status: Online-Only
REFERENCE   6  (bases 1 to 12677)
  AUTHORS   Zareparsi,S., Buraczynska,M., Branham,K.E., Shah,S., Eng,D., Li,M.,
            Pawar,H., Yashar,B.M., Moroi,S.E., Lichter,P.R., Petty,H.R.,
            Richards,J.E., Abecasis,G.R., Elner,V.M. and Swaroop,A.
  TITLE     Toll-like receptor 4 variant D299G is associated with
            susceptibility to age-related macular degeneration
  JOURNAL   Hum Mol Genet 14 (11), 1449-1455 (2005)
   PUBMED   15829498
  REMARK    GeneRIF: examination of a variant as candidate gene for age related
            macular degeneration susceptibility
            GeneRIF: Observational study of gene-disease association and
            gene-gene interaction. (HuGE Navigator)
REFERENCE   7  (bases 1 to 12677)
  AUTHORS   Chow,J.C., Young,D.W., Golenbock,D.T., Christ,W.J. and Gusovsky,F.
  TITLE     Toll-like receptor-4 mediates lipopolysaccharide-induced signal
            transduction
  JOURNAL   J Biol Chem 274 (16), 10689-10692 (1999)
   PUBMED   10196138
REFERENCE   8  (bases 1 to 12677)
  AUTHORS   Muzio,M., Natoli,G., Saccani,S., Levrero,M. and Mantovani,A.
  TITLE     The human toll signaling pathway: divergence of nuclear factor
            kappaB and JNK/SAPK activation upstream of tumor necrosis factor
            receptor-associated factor 6 (TRAF6)
  JOURNAL   J Exp Med 187 (12), 2097-2101 (1998)
   PUBMED   9625770
REFERENCE   9  (bases 1 to 12677)
  AUTHORS   Rock,F.L., Hardiman,G., Timans,J.C., Kastelein,R.A. and Bazan,J.F.
  TITLE     A family of human receptors structurally related to Drosophila Toll
  JOURNAL   Proc Natl Acad Sci U S A 95 (2), 588-593 (1998)
   PUBMED   9435236
REFERENCE   10 (bases 1 to 12677)
  AUTHORS   Medzhitov,R., Preston-Hurlburt,P. and Janeway,C.A. Jr.
  TITLE     A human homologue of the Drosophila Toll protein signals activation
            of adaptive immunity
  JOURNAL   Nature 388 (6640), 394-397 (1997)
   PUBMED   9237759
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from DA187988.1, BC117422.1,
            AK226155.1, BG622357.1, DA218006.1 and AL160272.16.
            This sequence is a reference standard in the RefSeqGene project.
            
            On Nov 22, 2018 this sequence version replaced NM_138554.4.
            
            Summary: The protein encoded by this gene is a member of the
            Toll-like receptor (TLR) family which plays a fundamental role in
            pathogen recognition and activation of innate immunity. TLRs are
            highly conserved from Drosophila to humans and share structural and
            functional similarities. They recognize pathogen-associated
            molecular patterns that are expressed on infectious agents, and
            mediate the production of cytokines necessary for the development
            of effective immunity. The various TLRs exhibit different patterns
            of expression. In silico studies have found a particularly strong
            binding of surface TLR4 with the spike protein of severe acute
            respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative
            agent of Coronavirus disease-2019 (COVID-19). This receptor has
            also been implicated in signal transduction events induced by
            lipopolysaccharide (LPS) found in most gram-negative bacteria.
            Mutations in this gene have been associated with differences in LPS
            responsiveness, and with susceptibility to age-related macular
            degeneration. Multiple transcript variants encoding different
            isoforms have been found for this gene. [provided by RefSeq, Aug
            2020].
            
            Transcript Variant: This variant (1) encodes the longest isoform
            (A).
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: U93091.1, SRR14038192.402779.1
                                           [ECO:0000332]
            RNAseq introns              :: single sample supports all introns
                                           SAMEA1965299, SAMEA1966682
                                           [ECO:0000348]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            coronavirus related    :: relevant for COVID-19 treatment
            MANE Ensembl match     :: ENST00000355622.8/ ENSP00000363089.5
            RefSeq Select criteria :: based on conservation, expression,
                                      longest protein
            ##RefSeq-Attributes-END##
            COMPLETENESS: full length.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-50                DA187988.1         229-278
            51-2632             BC117422.1         1-2582
            2633-4813           AK226155.1         2736-4916
            4814-5260           BG622357.1         121-567
            5261-5433           DA218006.1         386-558
            5434-12677          AL160272.16        26075-33318
FEATURES             Location/Qualifiers
     source          1..12677
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="9"
                     /map="9q33.1"
     gene            1..12677
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="toll like receptor 4"
                     /db_xref="GeneID:7099"
                     /db_xref="HGNC:HGNC:11850"
                     /db_xref="MIM:603030"
     exon            1..163
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /inference="alignment:Splign:2.1.0"
     CDS             71..2590
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /EC_number="3.2.2.6"
                     /note="isoform A precursor is encoded by transcript
                     variant 1; homolog of Drosophila toll; hToll; toll like
                     receptor 4 protein"
                     /codon_start=1
                     /product="toll-like receptor 4 isoform A precursor"
                     /protein_id="NP_612564.1"
                     /db_xref="CCDS:CCDS6818.1"
                     /db_xref="GeneID:7099"
                     /db_xref="HGNC:HGNC:11850"
                     /db_xref="MIM:603030"
                     /translation="MMSASRLAGTLIPAMAFLSCVRPESWEPCVEVVPNITYQCMELN
                     FYKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLS
                     HLSTLILTGNPIQSLALGAFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHN
                     LIQSFKLPEYFSNLTNLEHLDLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFI
                     QPGAFKEIRLHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSA
                     LEGLCNLTIEEFRLAYLDYYLDDIIDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQH
                     LELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCS
                     QSDFGTTSLKYLDLSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSLRNLI
                     YLDISHTHTRVAFNGIFNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQCQL
                     EQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTSKKQELQH
                     FPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLVEVERMECATPSDKQGMPVLSLN
                     ITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLMLLAGCIKYGRGENIYDAFVIYSS
                     QDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIHEGFHKSRKVIVVVSQH
                     FIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLRQQVELYRLLSRNTYLEWE
                     DSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI"
     exon            164..330
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /inference="alignment:Splign:2.1.0"
     exon            331..12677
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /inference="alignment:Splign:2.1.0"
     regulatory      4789..4794
                     /regulatory_class="polyA_signal_sequence"
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="hexamer: AATATA"
     polyA_site      4813
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="major polyA site"
     regulatory      5387..5392
                     /regulatory_class="polyA_signal_sequence"
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="hexamer: AATAAA"
     polyA_site      5408
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="major polyA site"
     regulatory      8498..8503
                     /regulatory_class="polyA_signal_sequence"
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="hexamer: AATAAA"
     polyA_site      8516
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="major polyA site"
     regulatory      10111..10116
                     /regulatory_class="polyA_signal_sequence"
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="hexamer: AGTAAA"
     polyA_site      10127
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
     regulatory      10822..10827
                     /regulatory_class="polyA_signal_sequence"
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="hexamer: AATAAA"
     polyA_site      10846
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
     regulatory      12646..12651
                     /regulatory_class="polyA_signal_sequence"
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
                     /note="hexamer: AATAAA"
     polyA_site      12672
                     /gene="TLR4"
                     /gene_synonym="ARMD10; CD284; TLR-4; TOLL"
ORIGIN      
        1 agacggtgat agcgagccac gcattcacag ggccactgct gctcacagaa gcagtgagga
       61 tgatgccagg atgatgtctg cctcgcgcct ggctgggact ctgatcccag ccatggcctt
      121 cctctcctgc gtgagaccag aaagctggga gccctgcgtg gaggtggttc ctaatattac
      181 ttatcaatgc atggagctga atttctacaa aatccccgac aacctcccct tctcaaccaa
      241 gaacctggac ctgagcttta atcccctgag gcatttaggc agctatagct tcttcagttt
      301 cccagaactg caggtgctgg atttatccag gtgtgaaatc cagacaattg aagatggggc
      361 atatcagagc ctaagccacc tctctacctt aatattgaca ggaaacccca tccagagttt
      421 agccctggga gccttttctg gactatcaag tttacagaag ctggtggctg tggagacaaa
      481 tctagcatct ctagagaact tccccattgg acatctcaaa actttgaaag aacttaatgt
      541 ggctcacaat cttatccaat ctttcaaatt acctgagtat ttttctaatc tgaccaatct
      601 agagcacttg gacctttcca gcaacaagat tcaaagtatt tattgcacag acttgcgggt
      661 tctacatcaa atgcccctac tcaatctctc tttagacctg tccctgaacc ctatgaactt
      721 tatccaacca ggtgcattta aagaaattag gcttcataag ctgactttaa gaaataattt
      781 tgatagttta aatgtaatga aaacttgtat tcaaggtctg gctggtttag aagtccatcg
      841 tttggttctg ggagaattta gaaatgaagg aaacttggaa aagtttgaca aatctgctct
      901 agagggcctg tgcaatttga ccattgaaga attccgatta gcatacttag actactacct
      961 cgatgatatt attgacttat ttaattgttt gacaaatgtt tcttcatttt ccctggtgag
     1021 tgtgactatt gaaagggtaa aagacttttc ttataatttc ggatggcaac atttagaatt
     1081 agttaactgt aaatttggac agtttcccac attgaaactc aaatctctca aaaggcttac
     1141 tttcacttcc aacaaaggtg ggaatgcttt ttcagaagtt gatctaccaa gccttgagtt
     1201 tctagatctc agtagaaatg gcttgagttt caaaggttgc tgttctcaaa gtgattttgg
     1261 gacaaccagc ctaaagtatt tagatctgag cttcaatggt gttattacca tgagttcaaa
     1321 cttcttgggc ttagaacaac tagaacatct ggatttccag cattccaatt tgaaacaaat
     1381 gagtgagttt tcagtattcc tatcactcag aaacctcatt taccttgaca tttctcatac
     1441 tcacaccaga gttgctttca atggcatctt caatggcttg tccagtctcg aagtcttgaa
     1501 aatggctggc aattctttcc aggaaaactt ccttccagat atcttcacag agctgagaaa
     1561 cttgaccttc ctggacctct ctcagtgtca actggagcag ttgtctccaa cagcatttaa
     1621 ctcactctcc agtcttcagg tactaaatat gagccacaac aacttctttt cattggatac
     1681 gtttccttat aagtgtctga actccctcca ggttcttgat tacagtctca atcacataat
     1741 gacttccaaa aaacaggaac tacagcattt tccaagtagt ctagctttct taaatcttac
     1801 tcagaatgac tttgcttgta cttgtgaaca ccagagtttc ctgcaatgga tcaaggacca
     1861 gaggcagctc ttggtggaag ttgaacgaat ggaatgtgca acaccttcag ataagcaggg
     1921 catgcctgtg ctgagtttga atatcacctg tcagatgaat aagaccatca ttggtgtgtc
     1981 ggtcctcagt gtgcttgtag tatctgttgt agcagttctg gtctataagt tctattttca
     2041 cctgatgctt cttgctggct gcataaagta tggtagaggt gaaaacatct atgatgcctt
     2101 tgttatctac tcaagccagg atgaggactg ggtaaggaat gagctagtaa agaatttaga
     2161 agaaggggtg cctccatttc agctctgcct tcactacaga gactttattc ccggtgtggc
     2221 cattgctgcc aacatcatcc atgaaggttt ccataaaagc cgaaaggtga ttgttgtggt
     2281 gtcccagcac ttcatccaga gccgctggtg tatctttgaa tatgagattg ctcagacctg
     2341 gcagtttctg agcagtcgtg ctggtatcat cttcattgtc ctgcagaagg tggagaagac
     2401 cctgctcagg cagcaggtgg agctgtaccg ccttctcagc aggaacactt acctggagtg
     2461 ggaggacagt gtcctggggc ggcacatctt ctggagacga ctcagaaaag ccctgctgga
     2521 tggtaaatca tggaatccag aaggaacagt gggtacagga tgcaattggc aggaagcaac
     2581 atctatctga agaggaaaaa taaaaacctc ctgaggcatt tcttgcccag ctgggtccaa
     2641 cacttgttca gttaataagt attaaatgct gccacatgtc aggccttatg ctaagggtga
     2701 gtaattccat ggtgcactag atatgcaggg ctgctaatct caaggagctt ccagtgcaga
     2761 gggaataaat gctagactaa aatacagagt cttccaggtg ggcatttcaa ccaactcagt
     2821 caaggaaccc atgacaaaga aagtcatttc aactcttacc tcatcaagtt gaataaagac
     2881 agagaaaaca gaaagagaca ttgttctttt cctgagtctt ttgaatggaa attgtattat
     2941 gttatagcca tcataaaacc attttggtag ttttgactga actgggtgtt cactttttcc
     3001 tttttgattg aatacaattt aaattctact tgatgactgc agtcgtcaag gggctcctga
     3061 tgcaagatgc cccttccatt ttaagtctgt ctccttacag aggttaaagt ctagtggcta
     3121 attcctaagg aaacctgatt aacacatgct cacaaccatc ctggtcattc tcgagcatgt
     3181 tctatttttt aactaatcac ccctgatata tttttatttt tatatatcca gttttcattt
     3241 ttttacgtct tgcctataag ctaatatcat aaataaggtt gtttaagacg tgcttcaaat
     3301 atccatatta accactattt ttcaaggaag tatggaaaag tacactctgt cactttgtca
     3361 ctcgatgtca ttccaaagtt attgcctact aagtaatgac tgtcatgaaa gcagcattga
     3421 aataatttgt ttaaaggggg cactctttta aacgggaaga aaatttccgc ttcctggtct
     3481 tatcatggac aatttgggct agaggcagga aggaagtggg atgacctcag gaggtcacct
     3541 tttcttgatt ccagaaacat atgggctgat aaacccgggg tgacctcatg aaatgagttg
     3601 cagcagaagt ttattttttt cagaacaagt gatgtttgat ggacctctga atctctttag
     3661 ggagacacag atggctggga tccctcccct gtacccttct cactgccagg agaactacgt
     3721 gtgaaggtat tcaaggcagg gagtatacat tgctgtttcc tgttgggcaa tgctccttga
     3781 ccacattttg ggaagagtgg atgttatcat tgagaaaaca atgtgtctgg aattaatggg
     3841 gttcttataa agaaggttcc cagaaaagaa tgttcatcca gcctcctcag aaacagaaca
     3901 ttcaagaaaa ggacaatcag gatgtcatca gggaaatgaa aataaaaacc acaatgagat
     3961 atcaccttat accaggtaga atggctacta taaaaaaatg aagtgtcatc aaggatatag
     4021 agaaattgga acccttcttc actgctggag ggaatggaaa atggtgtagc cgttatgaaa
     4081 aacagtacgg aggtttctca aaaattaaaa atagaactgc tatatgatcc agcaatctca
     4141 cttctgtata tatacccaaa ataattgaaa tcagaatttc aagaaaatat ttacactccc
     4201 atgttcattg tggcactctt cacaatcact gtttccaaag ttatggaaac aacccaaatt
     4261 tccattgaaa aataaatgga caaagaaaat gtgcatatac gtacaatggg atattattca
     4321 gcctaaaaaa agggggaatc ctgttattta tgacaacatg aataaacccg gaggccatta
     4381 tgctatgtaa aatgagcaag taacagaaag acaaatactg cctgatttca tttatatgag
     4441 gttctaaaat agtcaaactc atagaagcag agaatagaac agtggttcct agggaaaagg
     4501 aggaagggag aaatgaggaa atagggagtt gtctaattgg tataaaatta tagtatgcaa
     4561 gatgaattag ctctaaagat cagctgtata gcagagttcg tataatgaac aatactgtat
     4621 tatgcactta acattttgtt aagagggtac ctctcatgtt aagtgttctt accatataca
     4681 tatacacaag gaagcttttg gaggtgatgg atatatttat taccttgatt gtggtgatgg
     4741 tttgacaggt atgtgactat gtctaaactc atcaaattgt atacattaaa tatatgcagt
     4801 tttataatat caattatgtc tgaatgaagc tataaaaaag aaaagacaac aaaattcagt
     4861 tgtcaaaact ggaaatatga ccacagtcag aagtgtttgt tactgagtgt ttcagagtgt
     4921 gtttggtttg agcaggtcta gggtgattga acatccctgg gtgtgtttcc atgtctcatg
     4981 tactagtgaa agtagatgtg tgcatttgtg cacatatccc tatgtatccc tatcagggct
     5041 gtgtgtattt gaaagtgtgt gtgtccgcat gatcatatct gtatagaaga gagtgtgatt
     5101 atatttcttg aagaatacat ccatttgaaa tggatgtcta tggctgtttg agatgagttc
     5161 tctactcttg tgcttgtaca gtagtctccc cttatccctt atgcttggtg gatacgttct
     5221 tagaccccaa gtggatctct gagaccgcag atggtaccaa acctcatata tgcaatattt
     5281 tttcctatac ataaatacct aagataaagt tcatcttctg aattaggcac agtaagagat
     5341 taacaataac taacaataaa attgaatagt tataataata tattgtaata aaagttatgt
     5401 gaatgtgatc tctttctttc tctctctcaa aatatcttac tgtactgtac tcacctattt
     5461 tcagaccata actgaccatg aaacctggga aagtgaaact gtggataagt gaggaactaa
     5521 catacataca tgattgttta tctacagatg tatgcctcag tttcttagta tgcttgaaaa
     5581 tgtatgattt tgtgtatatc cgtgctacat gtaagtgtgg ttctattcat atttgaatat
     5641 gaattctgca taagtgtgtt tattcaagca aatgtacaag gctctgagaa ggaagatcaa
     5701 catacaactt ggaatatttc aaggccgaaa tattcaaggc tgacattggc ctccttccta
     5761 tcagttccct ctcccagatg gaaattctag aaatggcagg tgaggtggac aagcagggaa
     5821 agaaattata tgcatagaac agaaggagaa gaaagagtaa agtcaggcct cagccagcct
     5881 ctttttagct ctttaaatcc tctggattta agagggataa agggtggaat aaggataaat
     5941 taatgccaat tgtaatgcct taaatttgtg tgatacctta caacttgaaa catattcaca
     6001 aaactatata tttgaatatc tcattagctg agtaaggtag caaatcataa ttaacttttt
     6061 ccattttatt gatgggaaag ctgaagttca atgaagtaaa tttttcaata gcccacagag
     6121 taggaaagtg acaaaacctg agcctgggcc tccaggtcac tcaaggacac tttctttctt
     6181 ccacacccaa ttgcttcatg cttaaagttg gcaaaacagg aagtgaaact cctgcagttt
     6241 tctgtgtggt tgacactagc aagggtttct cagttgaagc catgaatcat taagccaata
     6301 catatgcata tatgttatac ataccaaatg atttatttat aaccctatct ttccataaag
     6361 gacttgaagg agcttcaaac aaaggatatg tgaacaatag ggttaatcaa taataagtag
     6421 aaaatctgga catagaataa aaagaggaga gaaagacacc gagaatgagc gttaatacag
     6481 tgctttccat ttttctggtg ttttgagtag cgtggctttt ggagaaagcc aaaactcaaa
     6541 ttcactcctt atcaactgtg tgccttgggc tccatttctc tgagagtcta cttagctcca
     6601 atgtaaaata agaatagaac tatgactttg taaggttgct ctaaggattg aaaatcatgt
     6661 attatgttca atacggggac actgtcctta tgggtgagta ctcccctaag actttattaa
     6721 gagggcacta ggagaagcac tgggaggtct tctcagtaac aacactaaag taattgctat
     6781 ttttccagcc tgtggaacca cagaagtgac tgtaactaaa attagacatt tctttctgat
     6841 tcattctcta ctcacgggat tgtcagaccc cagtcttctt ctggactcta taaacttttt
     6901 agaaatcatc agcaggctcc tggagaagct taaatgaact cacacaatat gtgacagtga
     6961 actccctggg agagtgaaaa ccaaagtcta agccagtgtc tccatttact tgtgtgattg
     7021 tgggcaagtc attcaagtgc tttgaggctc aggtcttaat tcatgaaatg gaggtaataa
     7081 taccttgttg gcagacctca cttggttaaa atgataatgt tgatagttac aatagttaca
     7141 tttaattgat caattgtttt atgcaagggc tttatttgtg ctatctcagt ttgtcacatc
     7201 aatgaattag aaagatacga aagtatttcc aatttacaaa tgaggagtct gagtctggga
     7261 gtcattctgt catgtgtcca ctgtcacctg ctcattggtg gcagcactga gattaggatc
     7321 taagtccact tcaccgcaga agcagggctt ctaaatactg ttctatggca agagcaccct
     7381 gctctcacaa aatgcataaa acttcctatc tcaccattat aattttgact gatattaaac
     7441 aaagagaagt attattatta ttacttgttt ttatttatat tacagctgta agagccagga
     7501 aaaatgtgat ctaagttatg tgatcaaaga ttttttaaca gtgaacaaat caggcccact
     7561 agatgatggc ctttctttga acaacatgcc tagggttgct ctatcatgtc tacagttggt
     7621 ctgacttcct gacgggcatc acagacttgt gattaaacac agaggttatg ggggaagttc
     7681 caaaagctta ggactttcca gatggttgga ataagatcac acactctggc tgcccttatg
     7741 gagatcaccg aacttttcaa ctcaaagtaa aatctgtgga gtaaatggtc gatcaaaagg
     7801 aaccaactat attgagcacc atgcgtgatc atctgatcgt tactgctacc ttgtgagtta
     7861 aaggctactc ttctcatttt agaaatgaga aaagagatgc ccagagagga cgagtaactt
     7921 gccttaggtc acacagctta tattaatcac aataacattt gccgcacctt ctgtattttt
     7981 tttaagttgc taagcttttg gtgcatgtct ggcaccgttt tagttgtata ttatttcatt
     8041 taattgttaa aatgaccttc tgatgcaggt atttgtagct ttgccattcc acagatgaag
     8101 aaacagatga aaggactgaa ttgttcaata ggaaggagca gaatcaggat atgaacttgg
     8161 gttggcctga ttcttggggc tgcattcttt ccataacata attgcttgct gtgatgtcct
     8221 gggctactct gccaggggtg gttagtggag tgaatggaga ataatttaga caaggtcagt
     8281 aactcccatg ccatctagaa attaaaagtt taaaaggcag agtctgcaac tctccttgat
     8341 ttctacagaa ataaagatga tccctcctgt gacagtgcta agtgacaatt ctgagtgtaa
     8401 atgcgctttt tggcacaaat tgtcctgtcc taatagtctt gattataatt ataaaataat
     8461 gggtttctga aaggctgcaa gcagttctgg gaatggcaat aaaggtttag aaatgacgtg
     8521 atgtttatga gagaagtgtt ttgttgaaaa ttaaactcac gtttaggaga aaggattgtg
     8581 ttgtatgctc ctaggaaact atctcactat gtaattaaat caaaaccagc cagttaccaa
     8641 tttgagctct tgactcatac taacaacacc ccatttccca tgggccaagc aaggcaggac
     8701 tgacctgaaa taacccagcc tgactctatc cacagccacc ccaggacctt gcccctccgt
     8761 cttcctaggg ctcggccgtg agatgctagt gcatgaccct tcctcttcct gggactgtcc
     8821 ttgtctttcc ctttggactc tgggaggtct gttctcctcc tcagaaagga ataaacactc
     8881 tttctatttg tgggattccc taggagacac tatataaaaa tatagagtta aaaaaactat
     8941 ttaaaaaaaa gacaacttca tgtctctact ctgacttcat tctttttaag atgggtaaca
     9001 aagactctct tcaaggttag aaaattttat tttaattttt atagatttag agagtgcaaa
     9061 tgcagttttg ttacatgaat atattgcata atggtttagt ctgggctgtt agcgtaacca
     9121 tcaactgaac agtgtacttt gtacctatta ggtactttct catcccttaa ccccttccca
     9181 cctttctgag tcctcaatgt ctgttatttc attctccatg tccatgtcta caaattattt
     9241 agtttccact cataagtgag agcatggatg gaactggaga agagtatttt ctatcccaag
     9301 atcggttcct tgatcttgtg tctccaaatc acttgctctc tctcttacat cttttctatc
     9361 ttcttctagc ctctttttgc aaacttcatt ttgacaaaga attccaggca gtctacagct
     9421 gattttattt caatacaacg attaaaatgg aaaccatata tgaagatgac aaagttgagc
     9481 aggtcccaaa ctctcacttt taaacaaatg cttggcttaa gaatcactta atgactttca
     9541 ttctgctatc tatgtgtctg tgtatctagg tactaattat ctatctttat gatctttatt
     9601 gctagaaatt ctggttcaat atcagaggtt agtcctaagg aatttatatt ttaaaatatt
     9661 ctcccagttt tcgtgcacag acagatttgg gaattactgt tataatggaa aatggagaat
     9721 aaccacccac atttaatatg gttattggtt ttgttcttga gatttattgc taagattcat
     9781 gatagcccag gcaaggtcag ataatgtatt tttattttac actgtatagt tgattcttct
     9841 caatcccact agatcagact ctttgggata ctaggattgg cctatttgat ggtgagctca
     9901 ctacatccat ttagatgttg tgtccatgca atcattttag ttctcctagt ttctacctat
     9961 cacgttgtca ttttcccttc tttatcatcc tgggtagctg agaccccaca taaatatata
    10021 ccagaaaaat gttgtggtct tttctaaact ctctgaggca tctgttgtca atgtgatgtt
    10081 gttttttgtt tccagtccaa aatatatcaa agtaaaattt aactccactt ttgctaagta
    10141 ttcatcttgc cttgagtact aagattccaa aaatgacttt cccctctgaa aaacacagga
    10201 tttccttgcg aaaacttgct gggccactgc caatcttccc agaaactcct ttttccttat
    10261 cgttgagggg aattggggaa gtgatcactg acggttgaaa ttcagtagtt ttggtcttta
    10321 agctgagacc ctgagtcttc tgaggagtct actgctcccc agtgggaaac acctgctgtc
    10381 aaaattttcc tgcttgcaaa gagcactttt gaaattaatg gcaggggatg aatatctggc
    10441 tagtgctgtg ctcagctgag ttattaatag ggccttctga gtcctctcta cacatcatct
    10501 ttggctgaat tagctgtggt ttcagcacct gagagtctag caccactaaa ggcagggaat
    10561 acctttgcca gtttctggca tattaacagc tgagatcaga taagtgaaca gcgatagagg
    10621 tagtgaggtt taggattcag gtctgccacc gggagcgcac ctctgggctc aggtctctca
    10681 tttgtaaaat gggacattta ggtcagatca gcattttcaa aagtgtgaca tgttagtaaa
    10741 taagatgatt ttatgtggtt gacagatgaa tgtattacct ttagtggtta tatgtttatt
    10801 ttcatggtta cttttattta taataaattt tgtgactagc taagaatcaa ttatctcttt
    10861 aaaatatatt taagtttaaa atgtgggcca acttaggaaa aaaacgggat gaaatgaatt
    10921 atataaaagg tatgcagatt tggaaaaatt ttgaaggtgt cacaagaaag attggcagtc
    10981 agaaaggaat gaaccaaacg gctgctgagg gtcaggccag ctctctgaca ttctagcatg
    11041 ttcacatctc cagggctgtt tccttaccta taaattgtgg caattggagt aaatgtccat
    11101 tccaggaatt ctattctatg attagaggtg taacttcatc atccagattt tccagcatcc
    11161 ttaacatgtg gttttagcgt tctaaacctg atgatgctat atcaaaacgg gagactcatt
    11221 cgtcaagtca tgatgtatcc atgtatttat aatatttccc atgttccctc atttctgaaa
    11281 aggattaagc tatcaacccc attgagttat aggtgaaagg ctgtggaaac aagacattga
    11341 tagtgaaatg gctccaccac taacaggctg ttgaacaaag gcaaatctct tgatctcttt
    11401 gctctttggt ctctgtttat ctatgagata acgttatttt tacgctgtct tctgtgaaag
    11461 ttttgagaat gaaatgagac agagcctcca ataaaattta gggaagtgct acataaatgc
    11521 aaggagttat tatgataaca gattgaaaac tcctccaagg aggagtttct cttttgcccc
    11581 atgttataaa ctcaagaata tcttccattt tgcctacata ttccaaaagc ttttaaatta
    11641 agctatatgt cattcttaca ggagtctcct ctatttcagc aatgtgtata cttggtcagt
    11701 tttaattatc ttaaaggaga agaatacagt ttctctaaac tcaagcactt ttgtggacta
    11761 atccttgcaa ttattctttc ttctttccca tacttgacat ttaaagtgat atctcccagg
    11821 ctcctacact gttagtcaca gaggtaccat tcgacccctt gtgcctctta ccatatgtga
    11881 atgcttgtca gttgagagta aactttcttc ataaatttca cagttgtgga ttgataaaaa
    11941 cagagaactc tggttcctca ttccttcctg ctttctttct tgaaatgcca ttcatgatgg
    12001 tcccttatat cactataggg ctgctatcat ccttcatcct tatgccactg caaatagcaa
    12061 ccaacagtgt ccttagtgcc agcactccca ggcatgcccc tttccaagca gcagggtcaa
    12121 gccgctccct tcctgagctg tggcatctgt ctctaaatca tgcttcctcc ttgcctgctg
    12181 caggcccttg tctctgccct ttactttttc tggctcttgc cacggttttg aataaaactc
    12241 ttccaaatat ctgaagctca attctgttgc cattctaagc tctctaaatg tcaccacaat
    12301 cttccttcct ttgcattttc ttattgtgca ctaagttagt tcttgcttag taagtcttgt
    12361 ctttctctct gctttgacct gtcagtattc caacttcctt attttttgat gttcattttc
    12421 tccttgctct ctttcttcct ttcttgtctg tgaactccat taaccgcttc tgcatgtgac
    12481 cattaatgtg cctgtctttc ttctcatgta ttagagagaa caaaagcttt gggaatcaga
    12541 cagatctgtg ttctgatcct gtcttatggt atctgtcttg tttgtctcgg cttaaaatgg
    12601 ggataatatc tacctctcag ttttgttggc agttcagtac acggaaataa agttctcact
    12661 ttcttttttc tccttga
//
