micro-RNA and obesity

Abstract

The present disclosure provides a method of treating or preventing metabolic disorders by administering an agent that inhibits the activity of a microRNA that regulates metabolism.

Description

[0001] priority

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 62 / 642,934, filed March 14, 2018, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to the treatment and prevention of metabolic disorders by administering agents that regulate the activity or expression of microRNAs.

[0004] Instructions for electronically submitted text files

[0005] The contents of the text file submitted electronically are incorporated herein by reference in their entirety: a computer-readable copy of the sequence list (filename: BID-005PC1_ST25.txt; creation date: March 14, 2019; file size: 323,976 bytes). Background Art

[0006] MicroRNAs (miRNAs or miRs) are nucleic acid molecules that regulate the expression of target genes. miRNAs are typically short (usually 18 to 24 nucleotides); and, when the miRNA and its target mRNA are perfectly complementary, the miRNA acts as a repressor by promoting the degradation of the target mRNA, and / or when the miRNA contains mismatches, the miRNA acts as a repressor by inhibiting translation of the target mRNA. Functional analysis of miRNAs has shown that these small non-coding RNAs contribute to various physiological and metabolic processes, including regulating genes associated with metabolic disorders. Metabolic disorders are characterized by one or more abnormalities in metabolic function within the body. Metabolic disorders are also characterized by obesity and weight gain, insufficient insulin production, or insufficient insulin sensitivity. Some metabolic disorders are associated with defects in glucose use, leading to abnormally high blood sugar levels. Metabolic disorders affect millions of people worldwide and can be life-threatening conditions. With the rising prevalence of obesity in the United States, there is an urgent need to develop more effective therapies to reduce health risks and alleviate symptoms associated with obesity, overeating, excessive weight gain, or excessive fat accumulation. Therefore, methods and compositions are needed to treat, prevent, or delay the onset of metabolic disorders. SUMMARY OF THE INVENTION

[0008] This disclosure provides a novel method for treating or preventing metabolic disorders by applying agents that regulate the activity or expression of microRNAs, for example, by inhibiting the expression and / or activity of microRNAs. This inhibition can be mediated by sequence-specific chemically modified oligonucleotides, including, for example, locked nucleic acids (LNAs). LNA-based inhibitors offer an effective method for treating or preventing metabolic disorders when targeting miRNAs of metabolic regulatory genes disclosed herein.

[0009] In one aspect, this disclosure provides a method for treating or preventing metabolic disorders, the method comprising administering an effective amount of an inhibitor of miR-22 to a subject in need of such treatment.

[0010] In some implementations, the expression and / or activity of miR-22 are reduced in subjects after administration of the inhibitor.

[0011] In some embodiments, the miR-22 inhibitor is an oligonucleotide-based inhibitor. In some embodiments, the oligonucleotide-based inhibitor comprises a sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% complementary to the mature sequence of miR-22. In some embodiments, the oligonucleotide-based inhibitor comprises a deoxynucleotide or a ribonucleotide. In some embodiments, the oligonucleotide-based inhibitor is single-stranded. In some embodiments, the oligonucleotide-based inhibitor is double-stranded.

[0012] In some embodiments, oligonucleotide-based inhibitors comprise one or more chemically modified nucleotides.

[0013] In some embodiments, the chemically modified nucleotide is a locked nucleotide (LNA).

[0014] In some embodiments, the oligonucleotide-based inhibitor comprises about 25, about 20, about 15, about 10, about 9, about 8, about 7, about 6, or about 5 or fewer nucleotides. In some embodiments, the oligonucleotide-based inhibitor binds to one or more N-acetylgalactosamine (GalNAc) moieties.

[0015] In some embodiments, the oligonucleotide-based inhibitor is an antisense oligonucleotide inhibitor. In some embodiments, the oligonucleotide-based inhibitor is a small interfering RNA (siRNA). In some embodiments, the oligonucleotide-based inhibitor is an aptamer.

[0016] In some embodiments, miR-22 inhibitors are peptide-based or protein-based inhibitors. In some embodiments, protein-based inhibitors are antibodies or their antigen-binding moieties. In some embodiments, miR-22 inhibitors are small-molecule-based inhibitors.

[0017] In some embodiments, the metabolic disorder is obesity.

[0018] In some embodiments, the subject has Prader-Willi Syndrome.

[0019] In some implementation schemes, the subjects had hypercholesterolemia.

[0020] In some embodiments, the subject has a fat mass and obesity-related protein (FTO) variant, and / or displays upregulation of FTO expression and / or activity.

[0021] In some embodiments, the subject is obese and has a body mass index greater than about 30. In some embodiments, the subject is overweight and has a body mass index of about 25-29.9.

[0022] In some embodiments, the method causes weight loss. In some embodiments, the method causes a total weight loss of about 1%, about 5%, about 10%, about 15%, about 20%, or about 25% or more in the subject. In some embodiments, the method prevents weight gain.

[0023] In some embodiments, the method reduces or prevents adipose tissue growth. In some embodiments, the method disrupts adipocyte differentiation.

[0024] In some embodiments, the metabolic disorder is fatty liver disease. In some embodiments, the fatty liver disease is selected from non-alcoholic fatty acid liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the method reduces or prevents hepatic steatosis.

[0025] In some implementations, this method reduces or prevents liver fibrosis.

[0026] In some implementations, the method reduces the activity and / or expression of FTO, ALKB homolog 5 (ALKBH5), CCAAT / enhancer-binding protein α (CEBPα), peroxisome proliferator-activated receptor γ (PPARγ), and / or ATP citrate lyase (ACLY).

[0027] In some implementations, the method increases the activity and / or expression of phosphatases and tensin homologs (PTEN) and / or tet methylcytosine dioxygenase 2 (TET2).

[0028] In some embodiments, the method alters the activity and / or expression of PPARγ coactivator-α (PGC1-α), specificity protein 1 (SP1), fibroblast growth factor 21 (FGF-21), uncoupling protein 1 (UCP1), DNA damage-induced transcript 4 (DDIT-4, REDD1), tumor protein p63 (TP63), fibroblast growth factor 1 (FGF1) and / or methyltransferase-like protein 3 (METTL3). In some embodiments, the method alters the level of DNA or RNA methylation, or affects m6A levels at the RNA level.

[0029] Any aspect or implementation described herein may be combined with any other aspect or implementation disclosed herein.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] This patent or application document contains at least one color drawing. A copy of this patent or application publication with a color drawing will be provided by the Patent Office upon request and payment of the necessary fees.

[0032] Figure 1 The schematic diagram of AC shows the modulation spectrum of miR-22. Figure 1 A schematic diagram shows the location of miR-22 in exon 3 of the non-coding transcript MGC14376. Figure 1 B shows miRNAs targeting PTEN, Figure 1 C showed that miR-22 directly targets PTEN and TET to promote tumorigenesis and metastasis.

[0033] Figure 2 AD showed that overexpression of miR-22 affected the body weight of mice. Figure 2 Photo A shows the feeding protocols for wild-type (WT) and transgenic (Tg) mice. Figure 2 B is immunohistochemical staining of WT liver and miR-22Tg mouse liver. Figure 2 Graph C shows the comparison of the mean weight of WT mice with the mean weight of miR-22Tg mice. Figure 2 The bar chart D shows the mean weight of the WT and miR-22Tg mouse colonies. These data indicate that miR-22 overexpression affects mouse body weight. The right bar (red) in each pair of data represents the data from miR-2Tg mice.

[0034] Figure 3 AC is a pair of bar graphs and a line graph showing that miR-22null mice do not gain weight on a high-fat diet (HFD). Figure 3 A shows the percentage of body weight gain of the entire group after 2 weeks on HFD. Figure 3 B shows the percent body weight gain of the entire group after 4 weeks on HFD. Figure 3 C shows a comparison of the weight changes of KO and WT from week 1 to week 8 of the start of HFD.

[0035] Figure 4 A series of bar graphs from AF showed that miR-22null mice did not gain weight under HFD. Figure 4 A shows the percentage increase in body weight of female mice after 2 weeks under HFD. Figure 4 B shows the percent body weight gain of female mice after 4 weeks on HFD. Figure 4 C shows the percentage increase in body weight of female mice after 8 weeks under HFD. Figure 4 D shows a comparison of weight changes in KO and WT mice after 2 weeks. Figure 4 E shows a comparison of weight changes in KO and WT mice after 4 weeks. Figure 4 F shows a comparison of weight changes in KO mice and WT mice after 8 weeks.

[0036] Figure 5 A series of bar graphs for AD showed that miR-22null mice exhibited different metabolisms compared to WT mice when fed HFD. Figure 5 A shows the fat mass and lean mass of miR-22KO and WT mice before HFD (day 0) and 8 weeks later. Figure 5 B) Percentage (as a percentage of total body weight). After 8 weeks of HFD, the miR-22KO group had statistically significantly lower fat mass compared to WT. The lean body mass of the miR-22KO group was not affected by HFD, in contrast, the top WT group showed an increase in the percentage of fat mass and a decrease in the percentage of lean body mass after HFD. Figure 5 C and 5D show a range of parameters collected from the metabolic cage. At homeostasis, miR-22KO and WT mice exhibited similar metabolism. Once subjected to the HFD challenge, the miR-22KO group did not reduce its energy expenditure, while the WT group did. Although KO mice were less active than WT mice, both VCO2 and VO2 were significantly higher in the miR-22KO group compared to those in the WT group. Figure 5 The data in the right bar (red) of each bar chart in C and 5D are data from miR-22KO mice.

[0037] Figure 6 The bar chart shows that there was no difference in food consumption (HFD) between the WT and KO groups.

[0038] Figure 7AB is a bar graph and Oil Red-O staining, which shows that downregulation of miR-22 disrupts the ability of mouse embryonic fibroblasts (MEF) to differentiate into adipocytes. Figure 7 The bar graph of A shows adipocyte differentiation in MEF, indicating that miR-22- / -MEF shows 27% fewer adipocytes than WT. Figure 7 Oil Red-O staining of B revealed the presence of miR-22 from WT. + / - and miR-22 - / - MEFs were cultured in Adipo-differentiation medium for 5 days.

[0039] Figure 8 The design of anti-miR-22 LNA is shown.

[0040] Figure 9 The plan and conditions for in vivo experiments in miR-22- / - and WT mice under HFD following transfection with vector (VCH), irrational control RNA (SCR), and locked nucleic acid (LNA) are shown.

[0041] Figure 10 The bar graph shows that there was no difference in food consumption between treated and untreated mice for (Δ) mediator, (◇) SCR, and (□) anti-miR-22.

[0042] Figure 11 The line graph of AB shows that pharmacologically, in vivo inhibition of miR-22 prevented obesity in mice. Figure 11 A shows the final percentage of body gain. Figure 11 B shows the silencing of miR-22 in DIO mice. In both figures, at the final time point, the data are arranged from top to bottom as mediator (green), SCR (red), and anti-miR-22 (blue).

[0043] Figure 12 It is a Western blot that shows that in vivo anti-miR-22 treatment can increase the protein levels of the main miR-22 target in the liver.

[0044] Figure 13 AB is a series of bar graphs ( Figure 13 A) and immunohistochemical staining ( Figure 13 B) showed that anti-miR-22 treatment did not affect liver lipid composition, but significantly inhibited hepatic steatosis.

[0045] Figure 14 A series of bar graphs from AB show the relative mRNA levels in the livers of mice treated with VHL, SCR LNA, or LNA anti-miR-22. Figure 14A shows the mRNA expression of TET2 and PTEN. Figure 14 B shows the mRNA expression of FTO, FTO, and CEBPa.

[0046] Figure 15 A series of bar graphs from AC show the relative mRNA levels in brown adipose tissue (BAT) of mice treated with VHL, SCR LNA, or LNA anti-miR-22. Figure 15 A shows the mRNA expression of TET2 and PTEN. Figure 15 B shows the mRNA expression of FTO, CEBPa and PPARg, Figure 15 C shows the mRNA expression of UCP1 and CD36.

[0047] Figure 16 A series of bar graphs from AC show the relative mRNA levels in white adipose tissue (WAT) of mice treated with VHL, SCR LNA, or LNA anti-miR-22. Figure 16 The bar graph in A shows the mRNA expression levels of TET2 and PTEN. Figure 16 The bar chart in section B shows the mRNA expression levels of FTO, CEBPa, and PPARg. Figure 16 The bar graph in C shows the expression levels of UCP1 and CD36.

[0048] Figure 17 Schematic representation of the therapeutic approach showing that miR-22- / - and WT mice on HFD were treated with anti-miR-22-LNA, SCR, and VHL and placed on a second HFD regimen.

[0049] Figure 18 The line graph shows the results of the treatment method, by which mice that were already obese and fed a HFD had a significant reduction in body weight. After 3.5 months of treatment, a significant reduction in body weight was observed in mice that were obese (average weight >40g) and fed a HFD. Mice were sacrificed, tissues were collected, and RNA from the liver was used for RNAseq.

[0050] Figure 19 Three images from AC show that pharmacological inhibition of miR-22 reverts to the obesity phenotype in mice. Figure 19 A shows the fat pads of mice treated with VHL. Figure 19 B shows the fat pads of mice treated with anti-miR-22. Figure 19 C shows the fat pad of SCR-treated mice.

[0051] Figure 20The RNA-seq graph shows a hierarchical clustering analysis of mouse livers that clusters pharmacological inhibition and gene knockout (KO) of miR-22 together, indicating that the treatment was on target and that the KO phenotype could be mimicked using LNA constructs.

[0052] Figure 21 is an RNA-Seq graph showing gene ontology analysis in mouse liver, which revealed that top-down regulated pathways in KO and LNA-treated mice were related to lipid metabolism and biosynthesis.

[0053] Figure 22 This is a Western blot analysis, which shows a significant downregulation of ATP-citrate lyase (ACL) in vivo with anti-miR-22 treatment.

[0054] Figure 23 is Oil Red-O staining, which shows that pharmacological inhibition of miR-22 effectively impaired adipocyte differentiation of MEFs.

[0055] Figure 24 Oil Red O staining ( Figure 24 A) and bar charts ( Figure 24 B), which shows the anti-miR-22 treatment of human primitive mesenchymal cells cultured in Adipo differentiation medium for 2 weeks with or without LNA anti-miR-22. No helper uptake of 500 nM (LNA added every 2 days). Figure 24 In B, the data in the right bar (red) in each bar graph are data for cells treated with LNA#10.

[0056] Figure 25 The bar graph shows that pharmacological inhibition of miR-22 effectively impairs adipocyte differentiation of MEFs. The order of the data in the bar graph, when read from left to right, corresponds to the legend (located on the right of the figure) when read from top to bottom.

[0057] Figure 26 This is a schematic diagram of the metabolic network coordinated by miR-22. miR-22 can simultaneously target multiple metabolic participants (directly or indirectly).

[0058] Figure 27 AB studies showed that during adipogenic differentiation, fat mass and the expression of obesity-related protein (FTO) were significantly downregulated in miR-22-deficient MEFs, but not in WT MEFs. Figure 27 A is a representative diagram of the FTO gene. Figure 27 The bar graph in B shows the FTO mRNA expression levels under steady-state and differentiation medium conditions. Figure 27In B, the data read from left to right in the bar chart is WT (black), miR-22+ / - (gray), and miR-22- / - (blue).

[0059] Figure 28 AD showed that (genetically or pharmacologically) downregulation of miR-22 increased RNA m6A levels. Figure 28 A represents a chemical reaction. Figure 28 B. Figure 28 C and Figure 28 The bar graph in D shows the percentage and relative amount of m6A levels in mice on a HFD.

[0060] Figure 29 This is a series of immunohistochemical images showing that genetic depletion of miR-22 does not affect liver function in 2-month-old mice, n=8.

[0061] Figure 30 is a series of immunohistochemistry images showing that genetic depletion of miR-22 does not affect liver function and that miR-22 KO mice do not display any liver-related disease or dysfunction upon aging.

[0062] Figure 31 A series of immunohistochemistry images showing that anti-miR-22 LNA treatment prevents hepatic steatosis in diet-induced obese mice. Images are at a magnification of 10x.

[0063] Figure 32 This is a series of immunohistochemical images showing the effects of miR-22 overexpression and underexpression on liver fibrosis.

[0064] Figure 33 AC shows that overexpression of miR-22 affects liver function when fed a normal chow diet: WT- mice ( Figure 33 A) and miR-22Tg mice ( Figure 33 Fatty liver and fibrosis in (B) Figure 33 C shows FSP-1 positive cells in the liver of WT and miR-22Tg mice under normal diet.

[0065] Figure 34 AC showed that overexpression of miR-22 affects liver function: WT mice ( Figure 34 A) and miR-22+ / - mice ( Figure 34 Fatty liver and fibrosis in B). Figure 34 C shows FSP-1 positive cells in the liver of WT and miR-22+ / - mice under HFD. Invention Details

[0067] This disclosure is based on the finding that miRNAs, including miR-22, can regulate targets associated with a variety of metabolic disorders, including obesity, Pradwell-Willi syndrome, hypercholesterolemia, fatty liver disease, non-fatty acid liver disease (NAFLD), and / or non-alcoholic steatohepatitis (NASH).

[0068] This disclosure includes targeting miRNAs, including miR-22, with multiple inhibitors to treat and / or prevent diseases whose etiologies can be affected by metabolic regulation, such as metabolic disorders, including obesity, Prader-Willi syndrome, hypercholesterolemia, NAFLD, and / or NASH.

[0069] MiR-22 directly targets phosphatase and tensin homologous protein (PTEN) and tet methylcytosine dioxygenase (TET) to promote tumorigenesis, metastasis and metabolic disorders. More than 60 miRNAs targeting PTEN and no less than 30 new oncogene loci have been studied in human cancers. MiRNAs targeting PTEN are highly evolutionarily conserved among vertebrates and are ubiquitously expressed in various tissues (Lagos-Quintana et al., 2001, 2002; Neely et al., 2006). MiR-22 is associated with metabolism due to its targeting of PTEN, because a decrease or increase in PTEN triggers a Warburg- or anti-Warburg metabolic state, respectively. In some embodiments, the genes targeted by miR-22 regulate metabolism and fatty acid oxidation or biogenesis.

[0070] In one aspect, the methods disclosed herein provide a method for treating or preventing metabolic disorders, the method comprising administering an effective amount of an inhibitor of miR-22 to a subject in need of such treatment.

[0071] For example, such inhibition can be mediated by sequence-specific chemically modified oligonucleotides. An exemplary modification is a locked nucleic acid (LNA), in which the ribose moiety of the nucleic acid is modified with an additional bridge connecting the 2' oxygen and the 4' carbon, which locks the ribose in a 3'-endo conformation. When targeting miRNAs that regulate metabolic genes as disclosed herein, LNA inhibitors are particularly cost-effective agents that can be efficiently delivered and have sufficient bioavailability for the treatment and prevention of various metabolic disorders.

[0072] This disclosure further provides for the use of any of the methods or combinations described herein in the preparation of medicaments for treating diseases. These diseases include, for example, metabolic disorders or diseases affected by regulated metabolism (e.g., lipid-related metabolic and synthetic pathways).

[0073] In some embodiments of the methods disclosed herein, miRNAs, including miR-22, regulate targets and / or genes involved in fat-related metabolic and synthetic pathways. In some embodiments, fat-related metabolic and synthetic genes include fat mass and obesity-associated protein (FTO), CCAAT / enhancer-binding protein α (CEBPα), peroxisome proliferator-activated receptor γ (PPARγ), phosphatase and tensin homolog (PTEN), tet methylcytosine dioxygenase 2 (TET2), ATP citrate lyase (ACLY), bone morphogenetic protein 7 (BMP-7), and / or sirtuin 1 (SIRT-1).

[0074] In some embodiments, fat-related metabolic and synthetic genes include FTO. In some embodiments, the method reduces fat mass and the activity and / or expression of obesity-related proteins (FTO), CEBPα, and / or PPARγ.

[0075] In some embodiments, the method reduces the activity and / or expression of ALKB homolog 5 (ALKBH5). In some embodiments, the method increases the activity and / or expression of PTEN and / or TET2.

[0076] In some embodiments, the method alters the activity and / or expression of PPARγ coactivator-α (PGC1-α), specific protein 1 (SP1), fibroblast growth factor 21 (FGF-21), uncoupling protein 1 (UCP1), DNA damage-inducing transcript 4 (DDIT-4, REDD1), methyltransferase-like protein 3 (METTL3), tumor protein p63 (TP63), and / or fibroblast growth factor 1 (FGF1).

[0077] In some implementations, the method alters the methylation level of DNA or RNA, or affects the m6A level at the RNA level.

[0078] In some embodiments, this disclosure treats or prevents metabolic disorders in subjects by inhibiting miRNAs (non-limiting examples include obesity, Prader-Willi syndrome, hypercholesterolemia, fatty liver disease, NAFLD, and / or NASH). miRNAs are short nucleic acid molecules that regulate the expression of target genes. See review Carrington et al., Science, Vol. 301(5631):336-338, 2003. miRNAs are typically between about 18 and 24 nucleotides in length. When the miRNA and its target mRNA are perfectly complementary, the miRNA acts as a repressor by promoting the degradation of the target mRNA, and / or when the miRNA contains mismatches, the miRNA acts as a repressor by inhibiting translation of the target mRNA.

[0079] Unbound by theory, it is believed that mature miRNAs are produced by pol II or pol III and originate from initial transcripts called pri-miRNAs. These pri-miRNAs are typically several thousand bases long and are thus processed into much shorter mature miRNAs. These pri-miRNAs can be polycistronic and are produced from transcription of several clustered sequences arranged in a manner that can form numerous miRNAs. The process of miRNA production can be two-step. First, pri-miRNAs can be processed in the cell nucleus by RNaseDrosha into hairpin-shaped precursors (pre-miRNAs) of approximately 70 to approximately 100 nucleotides. Then, after translocation to the cytoplasm, the hairpin pre-miRNAs can be further processed by RNase Dicer to produce double-stranded miRNAs. The mature miRNA strands can then be introduced into the RNA-induced silencing complex (RISC), where the mature miRNAs bind to their target mRNAs via base pair complementarity, leading to the inhibition of protein expression. The other strand of the miRNA duplex that is not preferentially selected to enter the RISC silencing complex is the passenger strand, minor miRNA, or the asterisked (*) strand. This strand is degradable. It should be understood that, unless otherwise stated, as used herein, miRNA can refer to pri-miRNA and / or pre-miRNA and / or mature miRNA and / or minor (asterisked) strand and / or the duplex form of miRNA.

[0080] In some implementations, miRNA genes may be located within introns of protein-coding genes or within introns or exons of non-coding transcription units. Expression of intronic miRNAs can occur simultaneously with the expression of host transcription units because they are typically oriented in the same direction and co-expressed with the pre-mRNA they reside in.

[0081] In some embodiments, the miRNA can bind to a sequence within the 3' untranslated region (3'UTR) of the target gene transcript. In some embodiments, the miRNA can bind to a sequence outside the 3'UTR of the target gene transcript. In some embodiments, the miRNA can bind to both sequences within and outside the 3'UTR of the target gene transcript.

[0082] In some embodiments, nucleotide pairing (seed matching) can occur between the second to seventh nucleotides of the miRNA (miRNA seed sequence) and the corresponding sequence along the target 3'UTR for target recognition. Therefore, the binding of the miRNA to the target may involve approximately 5 nucleotide base pairs. Alternatively, the binding of the miRNA to the target may involve more than 5 nucleotide base pairs. In some embodiments, the binding of the miRNA to the gene it regulates can be mediated by the miRNA binding to up to 2, 4, 6, 8, or 10 positions on the target nucleic acid.

[0083] The miRNAs disclosed herein can regulate nucleic acids through direct binding, including but not limited to metabolically critical genes, such as genes containing biomarkers associated with metabolic disorders. This binding can be perfectly complementary to the target nucleic acid or contain a mismatch. The effect of this binding can be to promote target degradation and / or inhibit target translation.

[0084] In some embodiments, the present invention treats or prevents metabolic disorders in subjects by inhibiting miRNAs such as miR-22. In some embodiments, the nucleic acid encoding miR-22 comprises or is composed of AAGCGUGCCAGUUGAAGAACUGU (SEQ ID NO:1).

[0085] The predicted miR-22 hairpin precursor is entirely contained within exon 2 of the non-coding transcript C17orf91, and despite the lack of protein-coding potential, the splicing pattern is generally conserved in humans and mice. See Rodriguez et al., Identification of mammalian microRNA host genes and transcription units. Genome Res. Oct 2004; 14(10A):1902-10. Deletion of exon 2 of C17orf91 containing miR-22 in mouse models has suggested that miR-22 may play a role in cardiac hypertrophy and remodeling by targeting SIRT1 (NAD-dependent deacetylase sirtuin-1), HDAC4 (histone deacetylase 4), PURB (purine-rich element-binding protein B), and PTEN. See Gurha et al., Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction. Circulation. 2012 Jun 5;125(22):2751-61; Huang et al., MicroRNA-22 regulates cardiac hypertrophy and remodeling in response to stress. Circ Res. 2013 Apr 26;112(9):1234-43.

[0086] In addition, it has been observed that ART (a downstream target of PTEN) activates mir-22 transcription, suggesting a regulatory loop in the oncogenic PI3K / AKT signaling pathway. See Bar et al., miR-22 forms a regulatory loop in PTEN / AKT pathway and modulates signaling kinetics. PLoS One. 2010; 5(5): e10859.

[0087] In some embodiments, the present invention proves that miR-22 can act as an epigenetic modifier and EMT promoter, which is independent of its ability to target Pten. In some embodiments, the present disclosure includes treating or preventing metabolic disorders in subjects by preventing the increase of fat mass and obesity-related protein (FTO) variants and / or causing them to decrease, and / or the present disclosure shows the downregulation of FTO expression and / or activity. FTO is an enzyme encoded by the FTO gene on chromosome 16 in humans. As a homolog of the AlkB family of proteins, it is the first mRNA demethylase to be identified. Certain variants of the FTO gene are associated with human obesity.

[0088] In some embodiments, the inhibitor's sequence is conserved across species. In some embodiments, the inhibitor's sequence is partially derived from a human transcript. In some embodiments, the inhibitor is selected to reduce the expression and / or activity of a target miRNA (miR-22, as a non-limiting example) in the subject.

[0089] In some implementations, the miRNA inhibitor is an antisense oligonucleotide. The antisense oligonucleotide may include ribonucleotides or deoxyribonucleotides, or combinations thereof. The antisense oligonucleotide may have at least one chemical modification (a non-limiting example is a sugar or backbone modification).

[0090] In some embodiments, the chemical modification is one or more of the following: thiophosphate, 2'-O-methyl, or 2'-O-methoxyethyl, 2'-O-alkyl-RNA unit, 2'-OMe-RNA unit, 2'-amino-DNA unit, 2'-fluoro-DNA unit (including, but not limited to, DNA analogs substituted with fluorine (2'F) at position 2'), LNA unit, PNA unit, HNA unit, INA unit, and 2'MOE RNA unit.

[0091] Suitable antisense oligonucleotides may contain one or more conformationally constrained or bicyclic glycosidic modifications (BSNs) that confer enhanced thermostability to the complex formed between the BSN-containing oligonucleotide and their complementary miRNA target strand. For example, in one embodiment, the antisense oligonucleotide contains at least one locked nucleic acid. The locked nucleic acid (LNA) contains 2'-O,4'-C-methylene ribonucleoside (structure A), wherein the ribose moiety is in a locked conformation. In another embodiment, the antisense oligonucleotide contains at least one 2',4'-C-bridged 2'-deoxyribonucleoside (cDNA, structure B). See, for example, U.S. Patent No. 6,403,566 and Wang et al., (1999) Bioorganic and Medicinal Chemistry Letters, Vol. 9: 1147-1150, both of which are incorporated herein by reference in their entirety. In yet another embodiment, the antisense oligonucleotide contains at least one nucleotide with a modification having the structure shown in structure C. Antisense oligonucleotides targeting miRNAs that regulate metabolic and synthetic pathways related to fat may contain BSNs (LNA, cDNA, etc.) or other modified nucleotides and combinations of ribonucleotides or deoxyribonucleotides.

[0092]

[0093] Additionally, the antisense oligonucleotide may comprise a peptide nucleic acid (PNA) containing a peptide-based backbone rather than a sugar-phosphate backbone. Other modifications to the antisense oligonucleotide, such as sugar or phosphodiester modifications, are also considered. Other chemical modifications may include, in non-limiting examples, 2'-o-alkyl (e.g., 2'-O-methyl, 2'-o-methoxyethyl), 2'-fluoro, and 4'-thio modifications, as well as backbone modifications such as one or more thiophosphate, morpholino, or phosphonocarboxylic acid ester bonds (see, for example, U.S. Patents 6,693,187 and 7,067,641, which are incorporated herein by reference in their entirety). In one embodiment, the antisense oligonucleotide targeting the oncogenic miRNA contains a 2'-O-methyl sugar modification at each base, linked by a thiophosphate bond. Antisense oligonucleotides, particularly those of shorter length (e.g., less than 16 nucleotides, 7 to 8 nucleotides), may contain one or more affinity-enhancing modifications, such as, but not limited to, LNA, dicyclic nucleosides, phosphonocarbamates, 2'O-alkyl modifications, etc. In some embodiments, suitable antisense oligonucleotides are 2'-O-methoxyethyl spacers containing 2'-O-methoxyethyl-modified ribonucleotides at both the 5' and 3' ends and having at least ten deoxyribonucleotides at their center. These spacers can trigger RNase H-dependent degradation mechanisms of RNA targets. Other modifications of antisense oligonucleotides that enhance stability and improve efficacy, such as those described in U.S. Patent No. 6,838,283 (which is incorporated herein by reference in its entirety), are known in the art and are suitable for use in the methods of the present invention. For example, and not intended to be restrictive, to facilitate in vivo delivery and stability, antisense oligonucleotides may be linked at their 3' end to steroid moieties such as cholesterol, vitamins, fatty acids, carbohydrates, or glycosides, peptides, or other small molecule ligands.

[0094] In some embodiments, the length of the antisense oligonucleotides for inhibiting miRNA activity (including, for example, miR-22) is about 5 to about 25 nucleotides, about 10 to about 30 nucleotides, or about 20 to 25 nucleotides. In certain embodiments, the antisense oligonucleotides targeting oncogenic miRNAs are about 8 to about 18 nucleotides in length, about 12 to about 16 nucleotides in length in other embodiments, and about 7 to about 8 nucleotides in length in other embodiments. Any 7-mer or longer sequence complementary to an oncogenic miRNA can be used, i.e., any anti-miR that is complementary to the 5' end of the miRNA and continuous over the entire complementary sequence of the miRNA. By way of non-limiting example, antisense oligonucleotides targeting oncogenic miRNAs, including, for example, miR-22, are about 5, or about 6, or about 7, or about 8, or about 9, or about 10, or about 11, or about 12, or about 13, or about 14, or about 15, or about 16, or about 17, or about 18, or about 19, or about 20, or about 21, or about 22, or about 23, or about 24, or about 25, or about 26, or about 27, or about 28, or about 29, or about 30 nucleotides in length.

[0095] The antisense oligonucleotide may comprise a sequence that is at least partially complementary to a mature or minor (i.e., starred) oncogenic miRNA sequence, for example, at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% complementary to a mature or minor (i.e., starred) oncogenic miRNA sequence. In some embodiments, the antisense oligonucleotide may be substantially complementary to a mature or minor oncogenic miRNA sequence, i.e., at least about 90%, 95%, 96%, 97%, 98%, or 99% complementary to a target polynucleotide sequence. In one embodiment, the antisense oligonucleotide comprises a sequence that is 100% complementary to a mature or minor oncogenic miRNA sequence.

[0096] As used herein, complementarity is essentially defined as the sequence being at least about 95%, 96%, 97%, 98%, 99%, or 100% complementary to the target polynucleotide sequence (non-limiting examples include, for example, mature miRNA, minor miRNA, precursor miRNA, or pri-miRNA sequences of miR-22).

[0097] In some embodiments, the antisense oligonucleotide is antagomir. Antagomir is a single-stranded, chemically modified ribonucleotide that is at least partially complementary to the miRNA, thus silencing it. See, for example, Kriitzfeldt et al., Nature (2005) 438(7068): 685-9. Antagomir may contain one or more modified nucleotides, such as 2'-O-methyl-sugar modifications. In some embodiments, antagomir contains only modified nucleotides. Antagomir may also contain one or more phosphate thioester links, forming a partial or complete phosphate thioester backbone. To facilitate in vivo delivery and stability, antagomir may be linked to cholesterol or other moieties at its 3' end. Suitable lengths for inhibition of antagomir can be about 15 to about 50 nucleotides, about 18 to about 30 nucleotides, and about 20 to about 25 nucleotides. Antagomir is complementary to mature or minor oncogenic miRNA sequences by at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, antagomir is substantially complementary to mature or minor oncogenic miRNA sequences, i.e., complementary to target polynucleotide sequences by at least about 95%, 96%, 97%, 98%, or 99%. In other embodiments, antagomir is 100% complementary to mature or minor oncogenic miRNA sequences.

[0098] The antisense oligonucleotide or antagomir may contain a sequence substantially complementary to the pre-miRNA or primordial miRNA sequence of the oncogenic miRNA. In some embodiments, the antisense oligonucleotide contains a sequence located outside the 3' untranslated region of the target of the miRNA. In some embodiments, the antisense oligonucleotide contains a sequence located within the 3' untranslated region of the target of the miRNA.

[0099] By delivering an expression vector encoding a miRNA inhibitor or agonist to a cell, any inhibitor or agonist of oncogenic miRNA described herein (including but not limited to miR-22) can be delivered to a target cell. A vector is a composition of matter that can be used to deliver a target nucleic acid to the interior of a cell. Many vectors are known in the art, including, but not limited to, linear polynucleotides, polynucleotides connected to ionic compounds or amphipathic compounds, plasmids, and viruses. Therefore, the term vector includes autonomously replicating plasmids or viruses. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated viral vectors, retroviral vectors, and the like. Expression constructs can be replicated in living cells or can be synthesized. For the purposes of this application, the terms expression construct, expression vector, and vector are used interchangeably to demonstrate the application of the present invention in a general illustrative sense and are not intended to limit the present invention.

[0100] In one embodiment, the expression vector for expressing an oncogenic miRNA (e.g., miR-22) inhibitor comprises a promoter operably linked to a polynucleotide encoding an antisense oligonucleotide. The sequence of the expressed antisense oligonucleotide may be partially or completely complementary to the mature or secondary sequence of the oncogenic miRNA. As used herein, the phrase "operably linked to" or "under transcriptional control" means that the promoter is in the correct position and orientation relative to the polynucleotide to control transcription initiation of RNA polymerase and expression of the polynucleotide.

[0101] As used herein, a promoter refers to a DNA sequence that is recognized by the synthetic machinery of the cell or an introduced synthetic machinery and is required to initiate specific transcription of a gene. Suitable promoters include, but are not limited to, RNA pol I, pol II, pol III, and viral promoters (e.g., the human cytomegalovirus (CMV) immediate early gene promoter, the SV40 early promoter, and the Rous sarcoma virus long terminal repeat).

[0102] In certain embodiments, the promoter operably linked to a polynucleotide encoding a miRNA inhibitor or a polynucleotide encoding a miRNA that regulates a metabolic gene and / or a gene for a marker associated with a metabolic etiology targeted by the miRNA can be an inducible promoter. Inducible promoters are known in the art and include, but are not limited to, tetracycline promoters, metallothionein IIA promoters, heat shock promoters, steroid / thyroid hormone / retinoic acid response elements, adenovirus late promoters, and inducible mouse mammary tumor virus LTRs.

[0103] Methods for delivering expression constructs and nucleic acids into cells are known in the art and may be exemplified in a non-limiting manner, including calcium phosphate coprecipitation, electroporation, microinjection, DEAE-dextran, lipofection, transfection using polyamine transfection reagents, cell sonication, gene guns using high-speed microparticles, and receptor-mediated transfection.

[0104] The present invention also includes inhibitors that sweep away or eliminate oncogenic miRNAs after treatment. Scavengers may include isolated nucleic acids complementary to the miRNA inhibitor or to a vector expressing the miRNA inhibitor. Therefore, they can bind to the miRNA inhibitor or the vector expressing the miRNA inhibitor, thereby preventing binding between the miRNA and the target.

[0105] In some embodiments, this disclosure provides a method for treating or preventing metabolic disorders in a subject with such need. In some embodiments, this disclosure provides a method for treating or preventing metabolic disorders in a subject, including obesity, Prader-Willi syndrome, hypercholesterolemia, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), and / or non-alcoholic steatohepatitis (NASH).

[0106] Metabolic disorders

[0107] As used in the context of this invention, the term "metabolic disorder" refers to a disease or condition affected by the presence, level, or activity of brown adipose tissue, blood glucose concentration, plasma insulin levels, and / or body fat content. In some embodiments, metabolic disorders or conditions also include, but are not limited to, metabolic syndrome, impaired glucose tolerance, elevated plasma insulin concentrations and insulin resistance, dyslipidemia, hyperglycemia, hyperlipidemia, hypertension, lipodystrophy, cardiovascular disease, respiratory problems, or conditions. Metabolic disorders of particular interest include obesity, Prader-Willi syndrome, hypercholesterolemia, fatty liver diseases, including non-fatty acid liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH).

[0108] obesity

[0109] In some embodiments, this disclosure relates to obesity. Obesity is a highly prevalent chronic disease in modern society, associated not only with social stigma but also with shortened lifespan and numerous medical problems, including diabetes, insulin resistance, hypertension, hypercholesterolemia, gallstones, osteoarthritis, orthopedic injuries, thromboembolic diseases, cancer, and coronary artery disease. (Rissanen et al., British Medical Journal, 301: 835-837 (1990)). In some embodiments, obesity can be calculated using body mass index (BMI: weight / height (m) squared). In some embodiments, obesity is defined as a subject being otherwise healthy except for having a BMI greater than or equal to 30 kg / m², or a subject with at least one comorbidity having a BMI greater than or equal to 27 kg / m². In some embodiments of the methods of this disclosure, the subject is obese and has a BMI greater than about 30. In some embodiments, the subject is overweight and has a BMI of about 25-29.9. In some embodiments, the method induces weight loss. In some embodiments, the method prevents weight gain. In some implementations, the method prevents adipose tissue growth and disrupts adipocyte differentiation.

[0110] In some embodiments, this disclosure provides a treatment method including administration of an inhibitor of miR-22 (and compounds related to miR-22), and / or the use of miR-22 (and compounds related to miR-22) in the treatment of obesity and overweight and related conditions, or its pharmaceutical use. In some embodiments, this disclosure provides a method for treating or preventing obesity, comprising administering an effective amount of miR-22 (and compounds related to the inhibition of miR-22) to a patient in need. In some aspects, this disclosure provides a method for weight management, comprising administering an effective amount of an inhibitor of miR-22 (and compounds related to the inhibition of miR-22) to induce weight loss and / or prevent weight gain in a patient in need.

[0111] In some embodiments, this disclosure relates to a method for inducing weight loss or preventing weight gain (or treating or preventing obesity or inducing weight loss or preventing weight gain in patients without substantially altering their caloric intake), comprising administering an effective amount of an inhibitor of miR-22 (and miR-22-related compounds) to patients who: have undergone or will undergo surgery on the digestive system; are overweight by about 80-100 pounds; have a BMI greater than about 35; or have health problems related to obesity.

[0112] In some implementations, surgeries of the digestive system are one or more of those classified under ICD-9-CM: surgeries of the digestive system and therefore may include esophageal surgeries; gastric incision and resection; other gastric surgeries; intestinal incision, resection, and anastomosis; other intestinal surgeries; cecal surgeries; surgeries of the rectum, rectosigmoid colon, and perirectal tissues; anal surgeries; liver surgeries; gallbladder and bile duct surgeries; pancreatic surgeries; hernia repair; and other surgeries of the abdominal region.

[0113] In some implementations, the digestive system surgery is one or more restrictive and / or malabsorption-related surgeries, including, for example, vertical banding gastrectomy (VBG, e.g., gastric suture); gastric banding (e.g., LAP-BAND or REALIZE); sleeve gastrectomy; gastric shunt (e.g., Roux-en-Y gastric shunt); bile-pancreatic secretion transfer surgery; and cosmetic surgery (e.g., liposuction, such as suction-assisted liposuction (SAL); ultrasound-assisted liposuction (UAL); power-assisted liposuction (PAL); double-cannula (assisted) liposuction (TCAL or TCL); external ultrasound-assisted liposuction (XUAL or EUAL); water-assisted liposuction (WAL); laser-assisted liposuction; tumescent liposuction; and cryolipolysis).

[0114] In some implementations, obesity-related health problems are selected from cardiovascular diseases (e.g., high cholesterol, hypercholesterolemia, low HDL, high HDL, hypertension, coronary artery disease, heart failure), sleep apnea (including obstructive sleep apnea), osteoarthritis, thyroid problems, dementia, gout, asthma, gastroesophageal reflux disease, and chronic renal failure. In some implementations, obesity-related health problems are heart disease, sleep apnea, or high cholesterol.

[0115] In some aspects, this disclosure provides uses and methods for inducing weight loss or preventing weight gain, comprising administering an effective amount of an inhibitor of miR-22 (and a compound associated with the inhibition of miR-22) to a patient in need, wherein the patient substantially does not alter their caloric intake. In some embodiments, the caloric intake is relatively high compared to guidelines such as those in USDA tables. In some embodiments, the patient's caloric intake is 2000-10000 calories / day, or greater than about 2000 calories / day, or about 2200 calories / day, or about 2400 calories / day, or about 2600 calories / day, or about 2800 calories / day, or about 3000 calories / day, or about 3200 calories / day, or about 3400 calories / day, or about 3600 calories / day, or about 3800 calories / day, or about 4000 calories / day, or about 5000 calories / day, or about 6000 calories / day. In some embodiments, the patient has a high caloric intake and does not gain weight or even loses weight. Therefore, this disclosure provides an effect that often reduces patient adherence (e.g., diet failure) without changing lifestyle. In some embodiments, the patient's calorie intake is restricted to no more than about 20%, or no more than about 10%, or no more than about 5% of the patient's calorie intake at the start of treatment. In some embodiments, a large portion of the patient's calorie intake is "empty calories," i.e., calories from solid fats and / or added sugars. In some embodiments, more than about 15%, or 20%, or 25%, or 30%, or 35%, or 50% of the patient's calorie intake is empty calories. Even in these embodiments, the patient may experience no weight gain or even weight loss.

[0116] In some embodiments, the patients of this disclosure are overweight or obese. In some embodiments, the patients of this disclosure suffer from central obesity. In some embodiments, obesity is one of the following: simple obesity (dietary obesity, typically caused by calorie consumption exceeding the body's available calories), secondary obesity (typically caused by an underlying medical condition such as Cushing's syndrome and polycystic ovary syndrome), and childhood obesity. In some embodiments, obesity is classified as: Category I, which includes a BMI between 30 and 34.99; Category II, which includes a BMI between 35 and 39.99; and Category III, which includes a BMI greater than 40. Furthermore, this disclosure provides that obesity in any of Categories I, II, or III is further classified as severe, pathological, or morbid obesity. In some embodiments, the patient is at risk of further weight gain, as assessed by, for example, daily calorie intake.

[0117] In some implementations, the weight management / weight loss / anti-obesity effects of miR-22 (and miR-22-related compounds) inhibitors can be evaluated using a variety of techniques and indicators. In some implementations, evaluations are performed before, during, and after treatment. In some implementations, body mass index (BMI), a measure of a person's weight that takes into account their height, can be used. In some implementations, the patients described herein have a BMI in the "overweight" category, i.e., 25-29.9, such as about 25, or about 25.5, or about 26, or about 26.5, or about 27, or about 27.5, or about 28, or about 28.5, or about 29, or about 29.5. In some implementations, the patients described herein have a BMI in the "obese" category, i.e., greater than 30, such as about 30, or about 31, or about 32, or about 33, or about 34, or about 35, or about 36, or about 37, or about 38, or about 39, or about 40, or about 50. In some embodiments, the Body Volume Index (BVI) is used. BVI uses 3D software to create a 3D image of a person, thus allowing BVI to distinguish individuals with the same BMI level but different body shapes and weight distributions. BVI measures a person's weight and where fat is located in the body, rather than measuring total weight or total fat percentage, and it focuses on weight around the abdomen, often referred to as central obesity. In some embodiments, whole-body air displacement plethysmography (ADP) is used to assess the weight management / weight loss / anti-obesity effects of miR-22 (and miR-22-related compounds). In some embodiments, simple weighing is used in this invention. In some embodiments, skinfold calipers or "pinch test," bioelectrical impedance analysis, underwater weighing, or dual-energy X-ray absorptiometry (DEXA) may be used.

[0118] In some embodiments, a simple circumference measurement of the body can be used. In some embodiments, the patient of this disclosure has a waist circumference exceeding approximately 35 inches, or approximately 36 inches, or approximately 37 inches, or approximately 38 inches, or approximately 39 inches, or approximately 40 inches, or approximately 41 inches, or approximately 42 inches, or approximately 43 inches, or approximately 44 inches, or approximately 45 inches, or approximately 46 inches, or approximately 47 inches, or approximately 48 inches, or approximately 50 inches, or approximately 55 inches, or approximately 60 inches. In some embodiments, the patient is a male with a waist circumference exceeding 40 inches. In some embodiments, the patient is a female with a waist circumference exceeding 35 inches.

[0119] The methods disclosed herein can be used to treat individuals with a body fat percentage higher than recommended, i.e., at least in the “overweight” or at least in the “obese” range. Body fat percentage will differ between men and women. Specifically, for women, the methods disclosed herein can be used to treat female humans with a body fat percentage of at least about 25%, more than 25%, at least about 32%, or more than 32%. For men, the methods disclosed herein can be used to treat men with a body fat percentage of at least about 14%, more than 14%, at least about 18%, more than 18%, at least about 25%, or more than 25%. Body fat percentage can be assessed using any method accepted in the art, including, for example, near infrared interaction, dual-energy X-ray absorptiometry, body density measurement, bioelectrical impedance analysis, etc.

[0120] The methods disclosed herein can be used to treat male patients who are overweight (over 100 pounds) and / or have a waist circumference greater than 40 inches. The methods disclosed herein can be used to treat female patients who are overweight (over 80 pounds) and / or have a waist circumference greater than 35 inches.

[0121] In some embodiments, this disclosure provides for the use of miR-22 inhibitors (and compounds associated with miR-22 inhibition) to treat and / or prevent certain conditions related to overweight. For example, miR-22 (and compounds associated with miR-22) have been found to be useful for cardiovascular diseases (e.g., high cholesterol, hypercholesterolemia, low HDL, high HDL, hypertension, coronary artery disease, heart failure), sleep apnea (including obstructive sleep apnea), osteoarthritis, thyroid problems, dementia, gout, asthma, gastroesophageal reflux disease, and chronic renal failure.

[0122] In some embodiments, the administration and / or use of an inhibitor of miR-22 (and miR-22-related compounds) inhibits or reduces adipose tissue growth. In some embodiments, miR-22 (and miR-22-related compounds) affects one or more types of white adipose tissue (WAT) and brown adipose tissue (BAT), including, for example, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), or ectopic fat. This effect can be assessed using any of the techniques described herein (e.g., BMI, weight for-stature, skinfold measurement, electrobioimpedance analysis, etc.), and various imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI, including transverse body scans), and dual-energy X-ray absorptiometry (DXA).

[0123] miR-22 (and compounds associated with miR-22) may also be used in combination with diet therapy, behavioral therapy, physical therapy, exercise, and bariatric surgery, or in combination with two or more such therapies. In some embodiments, the subject is on a calorically restricted diet. In some embodiments, the subject is participating in or will participate in a physical exercise or physical therapy program. In some embodiments, the subject has undergone or will undergo weight-loss surgery. In some embodiments, miR-22 inhibitors (and compounds associated with miR-22 inhibition) may be combined with other agents or may be administered to patients undergoing various agent treatments.

[0124] For example, including but not limited to implementation schemes involving obesity and / or weight loss / reduction, other agents may include one or more of the following: orlistat (e.g., ALLI, XENICAL), lorcaserin (e.g., BELVIQ), phentermine-topiramate (e.g., QSYMIA), sibutramine (e.g., REDUCTIL or MERIDIA), rimonabant (ACOMPLIA), exenatide (e.g., BYETTA), pramlintide (e.g., SYMLIN), phentermine, benzphetamine, diethylpropion, phendimetrazine, bupropion, and metformin.

[0125] Agents that interfere with the body's ability to absorb specific nutrients from food fall under the category of other agents, such as orlistat (e.g., ALLI, XENICAL), glucomannan, and guar gum. Appetite suppressants also fall under this category, such as catecholamines and their derivatives (e.g., phentermine and other amphetamine-based drugs), various antidepressants and mood stabilizers (e.g., bupropion and topiramate), and anorexic drugs (e.g., dexedrine sulfate, digoxin). Agents that increase metabolism also fall under this category.

[0126] In some implementations, other agents may be selected from appetite suppressants, neurotransmitter reuptake inhibitors, dopaminergic agonists, serotonergic agonists, GABAergic signaling modulators, anticonvulsants, antidepressants, monoamine oxidase inhibitors, substance P (NK1) receptor antagonists, melanocortin receptor agonists and antagonists, lipase inhibitors, fat absorption inhibitors, energy intake or metabolism modulators, cannabinoid receptor modulators, addiction treatment agents, metabolic syndrome treatment agents, peroxisome proliferator-activated receptor (PPAR) modulators; dipeptidyl peptidase-4 (DPP-4) antagonists, cardiovascular disease treatment agents, agents for treating elevated triglyceride levels, low HDL treatment agents, hypercholesterolemia treatment agents, and hypertension treatment agents. Some agents used for cardiovascular diseases include statins (such as lovastatin, atorvastatin, fluvastatin, rosuvastatin, simvastatin, and pravastatin) and omega-3 agents (such as LOAZA, EPANOVA, VASCEPA, esterified omega-3, which are generally fish oil, krill oil, and algae oil).In some implementation schemes, other reagents may be selected from amphetamines, benzodiazepines, sulfonyl ureas, meglitinides, thiazolidinediones, biguanides, beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, phenlermine, sibutramine, lorcaserin, cetilistat, rimonaban, taranabant, topiramate, gabapentin, valproate, vigabatrin, bupropion, and tiagabine. Sertraline, fluoxetine, trazodone, zonisamide, methylphenidate, varenicline, naltrexone, amphetamine, benzotriazine, repaglinide, nateglinide, glimepiride, metformin, pioglitazone, rosiglilazone, and sitagliptin.

[0127] Prader-Willi syndrome

[0128] In some implementations, the method involves Prad-Willi syndrome. Prad-Willi syndrome is a complex genetic condition that affects many parts of the body. In infancy, the condition is characterized by hypotonia (low muscle tone), feeding difficulties, poor growth, and developmental delays. From childhood, affected individuals develop an insatiable appetite, leading to habitual overeating and obesity. In some implementations, the subject has Prad-Willi syndrome. In some implementations, individuals with Prad-Willi syndrome, particularly those who are obese, also develop type 2 diabetes.

[0129] fatty liver disease

[0130] In some embodiments, the methods of this disclosure relate to fatty liver disease. Fatty liver disease (also known as non-alcoholic steatohepatitis (NASH)) affects a significant portion of the population. NASH is commonly associated with obesity and diabetes. Hepatic steatosis, the presence of triglyceride droplets in hepatocytes, makes the liver susceptible to chronic inflammation (detected as infiltration of inflammatory leukocytes in biopsy samples), which can lead to fibrosis and cirrhosis. Although a definitive diagnosis of fatty liver disease often requires a biopsy, its detection is typically achieved by observing elevated serum levels of liver-specific enzymes (such as transaminases ALT and AST) as indicators of hepatocyte damage, and the presence of symptoms including fatigue and pain in the liver area. The anticipated benefit is a reduction in liver inflammation and fat content, leading to attenuation, cessation, or reversal of the progression of NASH to fibrosis and cirrhosis. In some embodiments, the method reduces or prevents hepatic steatosis. In some embodiments, the method reduces or prevents liver fibrosis.

[0131] In some embodiments, the method is a method of treating NASH by administering an inhibitor of miR-22 as described herein. The NASH patient may be a high-risk NASH patient. "High-risk NASH patient" refers to a patient with one or more of the following characteristics: NAS ≥ 4; baseline fibrosis stage 2 or 3; or baseline fibrosis stage 1 with comorbidity (type 2 diabetes, BMI ≥ 30 kg / m2, or ALT ≥ 60 U / L).

[0132] In some embodiments, an inhibitor of miR-22 reduces one or more of: steatosis, mixed acinar inflammation, and hepatocyte ballooning and / or pericellular fibrosis.

[0133] In some implementations, miR-22 inhibitors reduce one or more types of fatty degeneration.

[0134] In some embodiments, inhibitors of miR-22 treat mild Grade 1 NASH, or moderate Grade 2 NASH, or severe Grade 3 NASH as described in Brunt et al. Am. J. Gastroenterology, Vol. 94, No. 9 (1999), which is incorporated herein by reference in its entirety:

[0135] Mild, grade 1 includes steatosis (predominantly macrovesicular) in up to 66% of biopsies; occasional hepatocytes with ballooning in zones 3; scattered intraacinar neutrophils ± intraacinar lymphocytes; and absent or mild chronic portal inflammation.

[0136] Moderate, Grade 2: Any degree of steatosis; marked hepatocellular ballooning (primarily in zone 3); intraacinar neutrophils noted, which may be associated with pericellular fibrosis in zone 3; mild to moderate portal and intraacinar chronic inflammation noted.

[0137] Severe, grade 3 panacinar steatosis; marked ballooning degeneration and disorder, mainly in zone 3; noteworthy intraacinar inflammation as scattered neutrophils, neutrophils associated with ballooning hepatocytes ± mild chronic inflammation; mild or moderate portal vein chronic inflammation (unmarked).

[0138] In some implementations, miR-22 inhibitor therapy is used to treat NASH in any of the following stages: Stage 0, no fibrosis; Stage 1, localized or extensive zone 3 pericellular / sinusoidal fibrosis; Stage 2, same as Stage 1 plus localized or extensive portal fibrosis; Stage 3, localized or extensive bridging fibrosis; and Stage 4, cirrhosis (+ / - residual pericellular fibrosis).

[0139] In some implementations, miR-22 inhibitors treat NASH of any activity fraction (NAS), as described in Kleiner et al., Hepatology, 2005, 41(6):p.1313-21, the entire contents of which are incorporated herein by reference in their entirety:

[0140]

[0141] *针对 Lobular inflammation, counting the number of lesions at 200x magnification

[0142] ** The small number of ballooning degenerative cells indicates a sparse but definite number of ballooning degenerative hepatocytes and the extent of the diagnostic boundary.

[0143] In some embodiments, miR-22 inhibitors reduce NASH to less than 8, or less than 7, or less than 6, or less than 5, or less than 4, or less than 3, or less than 2, or less than 1. In some embodiments, AP-based inhibitors reduce NASH to about 7, or about 6, or less than 5, or less than 4, or about 3, about 2, or about 1.

[0144] In some implementations, miR-22 inhibitors reduce fatty degeneration by approximately 5%, or approximately 10%, or approximately 15%, or approximately 20%, or approximately 25%, or approximately 30%, or approximately 35%, or approximately 40%, or approximately 45%, or approximately 50%, or approximately 55%, or approximately 60%, or approximately 65%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 85%, or approximately 90%, or approximately 95%.

[0145] In some implementations, miR-22 inhibitors reduce lobular inflammation to at least four lesions, or fewer than three lesions, or fewer than two lesions, or fewer than one lesion.

[0146] In some embodiments, an inhibitor of miR-22 reduces ballooning to a score of 0 or 1 according to the above scoring.

[0147] In some implementations, miR-22 inhibitors treat subjects at risk of NASH, such as those with various acquired metabolic diseases, such as obesity, diabetes (e.g., type 2), hypertriglyceridemia, rapid weight loss, and malnutrition. In some implementations, miR-22 inhibitors treat subjects at risk of NASH, such as those with various inherited metabolic diseases, such as Wilson's disease, hypertyrosinemia, and abeta-lipoproteinemia. In some implementations, miR-22 inhibitors treat subjects at risk of NASH, such as those suffering from multiple other factors, such as lipodystrophy and jejunoileal bypass surgery. In some implementations, miR-22 inhibitors are used to treat subjects at risk of NASH, such as those who have received one or more treatments with amiodarone, chemotherapy agents (e.g., irinotecan), tamoxifen, steroids, estrogens, diethylstilbestrol, methotrexate, or calcium channel blockers (e.g., nifedipine, verapamil, and diltiazem).

[0148] In some embodiments, this disclosure provides methods for reducing or preventing fibrosis. Direct markers of fibrosis include procollagen types (types I, III, and IV), matrix metalloproteinases, cytokines, and chemokines. In some embodiments, the invention provides methods for reducing extracellular matrix synthesis or preventing its enhancement (e.g., through activated stellate cells). In some embodiments, the invention provides methods for regulating TIMP-1 levels. In some embodiments, this disclosure provides methods for reducing or preventing serum hyaluronic acid levels.

[0149] In some implementations, the effectiveness of miR-22 inhibitors is monitored using a combination of one or more assays that monitor hyaluronic acid, tissue inhibitors of metalloproteinase-1 (TIMP-1), and α-2-macroglobulin (e.g., FIBROSpect II).

[0150] In some embodiments, the present invention provides methods for alleviating or preventing cirrhosis.

[0151] In some embodiments, this disclosure provides methods for regulating one or more of platelet counts, prothrombin time, albumin, total bilirubin, and serum aminotransferases. In some embodiments, the invention provides methods for regulating serum fibrosis markers such as hyaluronic acid (HA) and α-2-macroglobulin.

[0152] Hypercholesterolemia

[0153] In some embodiments, the methods of this disclosure relate to hypercholesterolemia. Hypercholesterolemia is a disease characterized by elevated serum cholesterol levels. Elevated serum cholesterol levels affect a significant portion of the population and are a major risk factor for atherosclerosis and myocardial infarction. In addition to the agents of the present invention, cholesterol-lowering drugs such as HMG-CoA reductase inhibitors (statins) may be administered to patients with hypercholesterolemia, optionally in combination with the same drug. In some embodiments, the hypocholesterolemia is on-familial hypercholesterolemia, characterized by elevated serum cholesterol not due to a single gene mutation. In some embodiments, the hypercholesterolemia is polygenic hypercholesterolemia, characterized by elevated cholesterol due to the influence of multiple genetic factors. In some embodiments, dietary lipid intake can exacerbate polygenic hypercholesterolemia. In some embodiments, the hypercholesterolemia is familial hypercholesterolemia (FH), an autosomal dominant metabolic disorder characterized by mutations in the LDL-receptor (LDL-R) gene, significantly elevated LDL-C, and premature onset of atherosclerosis. A diagnosis of familial hypercholesterolemia can be made when an individual meets one or more of the following criteria: genetic testing confirms two mutations in the LDL-receptor gene; genetic testing confirms one mutation in the LDL-receptor gene; a history of untreated serum LDL-cholesterol greater than 500 mg / dL; tendinous xanthoma and / or cutaneous xanthoma before age 10; or both parents have a history of elevated serum LDL-cholesterol before lipid-lowering therapy, consistent with heterozygous familial hypercholesterolemia. In some implementations, the hypercholesterolemia is homozygous familial hypercholesterolemia or HoFH, characterized by mutations in both the maternal and paternal LDL-R genes. In some implementations, the hypercholesterolemia is heterozygous familial hypercholesterolemia or HeFH, characterized by mutations in either the maternal or paternal LDL-R gene.

[0154] In some embodiments of the method disclosed herein, the wild-type human FTO gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001080432.2; SEQ ID NO:13).

[0155] In some embodiments of the method disclosed herein, the wild-type human FTO gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001073901.1; SEQ ID NO:14).

[0156] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_004364.4, transcript variant 1; SEQ ID NO:15).

[0157] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_004355.2, transcript variant 1; SEQ ID NO:16).

[0158] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001285829.1, transcript variant 2; SEQ ID NO:17).

[0159] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NM_001285829.1, transcript variant 2; SEQ ID NO:18).

[0160] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001287424.1, transcript variant 3; SEQ ID NO:19).

[0161] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001274353.1, transcript variant 3; SEQ ID NO:20).

[0162] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001287435.1, transcript variant 4; SEQ ID NO:21).

[0163] In some embodiments of the method disclosed herein, the wild-type human CEBPa gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001274364.1, transcript variant 4; SEQ ID NO:22).

[0164] In some embodiments of the method disclosed herein, the wild-type human PPARg gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_138712.3, transcript variant 1; SEQ ID NO:23).

[0165] In some embodiments of the method disclosed herein, the wild-type human PPARg gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_619726.2, transcript variant 1; SEQ ID NO:24).

[0166] In some embodiments of the method disclosed herein, the wild-type human PPARg gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_015869.4, transcript variant 2; SEQ ID NO:25).

[0167] In some embodiments of the method disclosed herein, the wild-type human PPARg gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_056953.2, transcript variant 2; SEQ ID NO:26).

[0168] In some embodiments of the method disclosed herein, the wild-type human PPARg gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_138711.3, transcript variant 3; SEQ ID NO:27).

[0169] In some embodiments of the methods of the present disclosure, the wild-type human PPARg gene of the present disclosure consists of or comprises the amino acid sequence (Genbank Accession No.: NP_619725.2, transcript variant 3; SEQ ID NO: 28).

[0170] In some embodiments of the method disclosed herein, the wild-type human PPARg gene of this disclosure consists of or contains the nucleic acid sequence (Genbank accession number: NM_005037.5, transcript variant 4; SEQ ID NO:29).

[0171] In some embodiments of the method disclosed herein, the wild-type human PPARg gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_005028.4, transcript variant 4; SEQ ID NO:30).

[0172] In some embodiments of the method disclosed herein, the wild-type human PTEN gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_000314.6, transcript variant 1; SEQ ID NO:31).

[0173] In some embodiments of the method disclosed herein, the wild-type human PTEN gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_000305.3, transcript variant 1; SEQ ID NO:32).

[0174] In some embodiments of the method disclosed herein, the wild-type human PTEN gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001304717.2, transcript variant 1; SEQ ID NO:33).

[0175] In some embodiments of the method disclosed herein, the wild-type human PTEN gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001291646.2, transcript variant 1; SEQ ID NO:34).

[0176] In some embodiments of the method disclosed herein, the wild-type human PTEN gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001304718.1, transcript variant 2; SEQ ID NO:35).

[0177] In some embodiments of the method disclosed herein, the wild-type human PTEN gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001291647.1, transcript variant 2; SEQ ID NO:36).

[0178] In some embodiments of the method disclosed herein, the wild-type human TET2 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001127208.2, transcript variant 1; SEQ ID NO:37).

[0179] In some embodiments of the method disclosed herein, the wild-type human TET2 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001120680.1, transcript variant 1; SEQ ID NO:38).

[0180] In some embodiments of the method disclosed herein, the wild-type human TET2 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_017628.4, transcript variant 2; SEQ ID NO:39).

[0181] In some embodiments of the method disclosed herein, the wild-type human TET2 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_060098.3, transcript variant 2; SEQ ID NO:40).

[0182] In some embodiments of the method disclosed herein, the wild-type human BMP-7 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001719.2, transcript variant 1; SEQ ID NO:41).

[0183] In some embodiments of the method disclosed herein, the wild-type human BMP-7 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001710.1, transcript variant 1; SEQ ID NO:42).

[0184] In some embodiments of the method disclosed herein, the wild-type human SIRT-1 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_012238.4, transcript variant 1; SEQ ID NO:43).

[0185] In some embodiments of the method disclosed herein, the wild-type human SIRT-1 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_036370.2, transcript variant 1; SEQ ID NO:44).

[0186] In some embodiments of the method disclosed herein, the wild-type human SIRT-1 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001142498.1, transcript variant 2; SEQ ID NO:45).

[0187] In some embodiments of the method disclosed herein, the wild-type human SIRT-1 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001135970.1, transcript variant 2; SEQ ID NO:46).

[0188] In some embodiments of the method disclosed herein, the wild-type human SIRT-1 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number: NM_001314049.1, transcript variant 3; SEQ ID NO:47).

[0189] In some embodiments of the method disclosed herein, the wild-type human SIRT-1 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number: NP_001300978.1, transcript variant 3; SEQ ID NO:48).

[0190] In some embodiments of the method disclosed herein, the wild-type human PGC1-α gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_001330751, transcript variant 1; SEQ ID NO:49).

[0191] In some embodiments of the method disclosed herein, the wild-type human PGC1a gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number NP_001317680: transcript variant 2; SEQ ID NO:50).

[0192] In some embodiments of the method disclosed herein, the wild-type human PGC1-α gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_013261, transcript variant 2; SEQ ID NO:51).

[0193] In some embodiments of the method disclosed herein, the wild-type human PGC1a gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number NP_037393: transcript variant 2; SEQ ID NO:52).

[0194] In some embodiments of the methods of the present disclosure, the wild-type human PGC1-α gene of the present disclosure consists of or comprises the nucleic acid sequence (Genbank Accession No. NM_001330752.1, transcript variant 3; SEQ ID NO: 53).

[0195] In some embodiments of the methods of the present disclosure, the wild-type human PGC1a gene of the present disclosure consists of or comprises the amino acid sequence (Genbank Accession No. NP_001317681.1, transcript variant 3; SEQ ID NO: 54).

[0196] In some embodiments of the methods of the present disclosure, the wild-type human PGC1-α gene of the present disclosure consists of or comprises the nucleic acid sequence (Genbank Accession No. NM_001330753.1, transcript variant 4; SEQ ID NO: 55).

[0197] In some embodiments of the method disclosed herein, the wild-type human PGC1a gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number NP_001317682, transcript variant 4; SEQ ID NO:56).

[0198] In some embodiments of the method disclosed herein, the wild-type human SP-1 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_138473.2; SEQ ID NO:57).

[0199] In some embodiments of the methods of the present disclosure, the wild-type human SP-1 gene of the present disclosure consists of or comprises the amino acid sequence (Genbank Accession No. NP_612482; SEQ ID NO: 58).

[0200] In some embodiments of the method disclosed herein, the wild-type human FGF-21 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_019113.3; SEQ ID NO:59).

[0201] In some embodiments of the methods of the present disclosure, the wild-type human FGF-21 gene of the present disclosure consists of or comprises the amino acid sequence (Genbank Accession No. NP 061986.1; SEQ ID NO: 60).

[0202] In some embodiments of the method disclosed herein, the wild-type human UCP1 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_021833.4; SEQ ID NO:61).

[0203] In some embodiments of the methods of the present disclosure, the wild-type human UCPl gene of the present disclosure consists of or comprises the amino acid sequence (Genbank Accession No. NP_068605.1; SEQ ID NO: 62).

[0204] In some embodiments of the methods of the present disclosure, the wild-type human DDIT-4 gene of the present disclosure consists of or comprises the nucleic acid sequence (Genbank Accession No. NM_019058.3; SEQ ID NO: 63).

[0205] In some embodiments of the methods of the present disclosure, the wild-type human DDIT-4 gene of the present disclosure consists of or comprises the amino acid sequence (Genbank Accession No. NP_061931.1; SEQ ID NO: 64).

[0206] In some embodiments of the method disclosed herein, the wild-type human METTL3 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_019852.4; SEQ ID NO:65).

[0207] In some embodiments of the method disclosed herein, the wild-type human METTL3 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number NP_062826.2; SEQ ID NO:66).

[0208] In some embodiments of the method disclosed herein, the wild-type human FGF1 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_000800.4; SEQ ID NO:67).

[0209] In some embodiments of the method disclosed herein, the wild-type human FGF1 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number NP_000791.1; SEQ ID NO:68).

[0210] In some embodiments of the method disclosed herein, the wild-type human TP63 gene of this disclosure consists of or contains a nucleic acid sequence (Genbank accession number NM_001114978.1; SEQ ID NO:69).

[0211] In some embodiments of the method disclosed herein, the wild-type human TP63 gene of this disclosure consists of or contains an amino acid sequence (Genbank accession number NP_001108450.1; SEQ ID NO:70).

[0212] As used herein, the term subject or patient refers to any vertebrate, including but not limited to humans and other primates (e.g., chimpanzees and other apes and monkey species), farm animals (e.g., cattle, sheep, pigs, goats, and horses), domestic animals (e.g., dogs and cats), laboratory animals (e.g., rodents such as mice, rats, and guinea pigs), and birds (e.g., domestic birds, wild birds, and game birds such as chickens, turkeys, and other quail and gallinaceous birds, ducks, geese, etc.). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0213] Another embodiment of the present invention is a pharmaceutical composition or use of a pharmaceutical composition comprising an inhibitor of a miRNA, such as miR-22, and a pharmaceutically acceptable carrier. When considering clinical applications, the pharmaceutical composition can be prepared in a form suitable for the intended application. Typically, this requires preparing a composition that is substantially free of pyrogens and other impurities that may be harmful to humans or animals.

[0214] In one embodiment, the pharmaceutical composition comprises an effective dose of a miRNA inhibitor (in the form of a non-limiting example, an antisense oligonucleotide for miR-22) and a pharmaceutically acceptable carrier. The effective dose is an amount sufficient to produce a beneficial or desired clinical result. The effective dose of the miRNA inhibitor of the present invention may be from about 1 mg / kg to about 100 mg / kg, from about 2.5 mg / kg to about 50 mg / kg, or from about 5 mg / kg to about 25 mg / kg. Accurately determining what is an effective dose can be based on individual factors of each patient, including their body size, age, type of metabolic disorder, and the properties of the inhibitor or agonist (non-limiting examples include antagomir, expression constructs, antisense oligonucleotides, polynucleotide duplexes, etc.). Therefore, a person of ordinary skill in the art can easily determine the dosage from this disclosure and knowledge in the art. For example, the dosage can be determined by reference to Physicians' Desk Reference, 66th edition, PDR Network; 2012 edition (December 27, 2011), the contents of which are incorporated herein by reference in their entirety.

[0215] Beneficial or desired therapeutic outcomes may in particular include a reduction in body mass index, weight loss, or a decrease in markers associated with the presence of metabolic disorders compared to when no inhibitors are administered. Beneficial or desired therapeutic outcomes may also in particular include a reduction or increase in the presence of markers or genes associated with a reduction in metabolic disorders compared to when no inhibitors are administered. In some embodiments, the markers or genes are fat mass and obesity-related protein (FTO), CEBPa and / or PPARγ, ALKBH5, and ACLY. In some embodiments, the activity and / or expression of FTO, CEBPa, PPARγ, ACLY, SP-1, PGC1a, ALKBH5, SIRT-1, TP63, FGF1, and / or DDIT4 are interfered with. In some embodiments, the marker or gene is fat mass and obesity-related protein (FTO).

[0216] Colloidal dispersion systems, such as polymeric complexes, nanocapsules, microspheres, beads, and lipid-based systems (including water-in-oil emulsions, micelles, hybrid micelles, and liposomes), can serve as delivery mediators for delivering oligonucleotide inhibitors of oncogenic miRNAs, polynucleotides encoding miRNA agonists targeting lipid-related metabolic and synthetic pathways, or constructs expressing specific miRNA inhibitors or agonists. Commercially available lipid emulsions suitable for delivering the nucleic acids of this disclosure to adipose tissue (e.g., adipocytes) include INTRALIPIDO, II. III. Nutrilipid and other similar lipid emulsions. Colloidal systems used as in vivo delivery mediators are liposomes (i.e., artificial membrane vesicles). The preparation and use of such systems are well known in the art. Exemplary formulations are also disclosed in US 5,981,505, US 6,217,900, US 6,383,512, US 5,783,565, US 7,202,227, US 6,379,965, US 6,127,170, US 5,837,533, US 6,747,014, and WO 03 / 093449, all of which are incorporated herein by reference in their entirety.

[0217] Suitable salts and buffers are generally preferred to stabilize the delivery medium and allow it to be taken up by target cells. The aqueous compositions of the present invention contain an effective amount of a delivery medium containing an inhibitory oligonucleotide (e.g., liposomes or other complexes or expression vectors) dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. The phrase pharmaceutically acceptable or pharmacologically acceptable means a molecular entity or composition that does not produce an adverse, allergic, or other adverse reaction when administered to animals or humans. As used herein, pharmaceutically acceptable carriers include solvents, buffers, solutions, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents that are acceptable for formulation of pharmaceuticals (such as those suitable for human administration). The use of such media and reagents for pharmaceutically active substances is well known in the art. The use of such media or reagents in therapeutic compositions is contemplated unless any conventional media or reagent is incompatible with the active ingredient of the present invention. Additional active ingredients may also be incorporated into the composition, provided they do not inactivate the carrier or polynucleotide of the composition.

[0218] The active compositions of the present invention may include conventional pharmaceutical formulations. These compositions of the present invention may be administered via any common route, as long as the target tissue is accessible via that route. This includes oral, nasal, or buccal routes. Alternatively, administration may be by intradermal, subcutaneous, intramuscular, intraperitoneal, or intravenous injection, or by direct injection into adipose tissue. The agents disclosed herein may also be administered via catheter systems. Such compositions will generally be administered as pharmaceutically acceptable compositions as described herein.

[0219] The active compounds can also be administered parenterally or intraperitoneally. By way of enumeration, solutions of the active compounds can be prepared in water with a suitable mixture of surfactants (such as hydroxypropyl cellulose) as a free base or a pharmacologically acceptable salt. Dispersion systems can also be prepared in glycerol, liquid polyethylene glycol, mixtures thereof, and in oils. Under normal storage and use conditions, these formulations typically contain preservatives to prevent microbial growth.

[0220] The pharmaceutical form suitable for injection purposes or catheter delivery includes, for example, sterile aqueous solution or dispersion system and sterile powder, for the temporary preparation of sterile injection solution or dispersion system. Generally, these preparations are sterile fluids (to the extent of easy injection). Preparations should be stable under the conditions of production and storage, and should be preserved to avoid microorganisms such as bacteria and fungal contamination. Suitable solvents or dispersion media can include, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.), their suitable mixtures and vegetable oils. Suitable fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of dispersion systems and by using surfactants. By various antibacterial and antifungal agents, such as parahydroxybenzoate, chlorobutanol, phenol, sorbic acid, thimerosal, etc., microbial action can be prevented. In many cases, isotonic agents such as saccharides or sodium chloride are preferably included. By using the reagent (such as aluminum monostearate and gelatin) that delays absorption in the composition, the extended absorption of the injectable composition can be achieved.

[0221] Sterile injectable solutions can be prepared by incorporating an appropriate amount of the active compound into a solvent along with any other ingredients desired (e.g., as listed above) and then sterilizing by filtration. Typically, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other desired ingredients, such as those listed above. With respect to sterile powders for the preparation of sterile injectable solutions, preferred preparation methods include vacuum drying and freeze drying techniques, which produce powders of the active ingredient and any other desired ingredients from their previously sterile filtered solutions.

[0222] Once prepared, the solution can be administered in a manner compatible with the dosage form and in a therapeutically effective amount. The formulation is readily available in various dosage forms, such as injectable solutions, drug-release capsules, etc. For example, for parenteral administration in aqueous solution, the solution is typically appropriately buffered and first made isotonic with, for example, sufficient physiological saline or glucose. Such aqueous solutions can be used for, for example, intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Preferably, a sterile aqueous medium as known to those skilled in the art is used, particularly according to the invention. By way of enumeration, a single dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of subcutaneous infusion fluid or injected at the recommended infusion site (see, for example, Remington Pharmaceutical Sciences, 15th edition, pp. 1035-1038 and 1570-1580, the contents of which are incorporated herein by reference in their entirety). Dosage will inevitably vary depending on the condition of the treated subject. In any case, the person responsible for administration should determine the appropriate dose for the individual subject. In addition, for human use, the formulation should meet the sterility, pyrogen, general safety and purity standards required by the FDA Office of Biologics.

[0223] In some embodiments, this disclosure includes a method for treating or preventing metabolic disorders in a subject with such a need, the method comprising administering to the subject: a first inhibitor of a first miRNA, wherein the miRNA is miR-22, and a second inhibitor of a second miRNA, wherein the miRNA is a regulator of a metabolism-related gene. In some embodiments, the second miRNA is a known miR inhibitor, included by way of non-limiting example, those disclosed in International Patent Publication No. WO 2012 / 142313 (the contents of which are incorporated herein by reference in their entirety). In some embodiments, both the first and second inhibitors may be administered in any order (e.g., first then second, or second then first) or simultaneously.

[0224] In some embodiments, this disclosure includes a method for treating or preventing metabolic disorders in a subject with such need, the method comprising administering to the subject a first reagent and a second reagent, the first reagent being or containing a miR-22 inhibitor, and the second reagent being or containing a biologic, therapeutic, or pharmaceutical product of at least one other metabolic disorder. In some embodiments, the first and second inhibitors may be administered in any order (e.g., first then second, or second then first) or simultaneously.

[0225] The present invention also provides a kit that can simplify the administration of any reagent described herein, such as inhibitors of oncogenic miRNA (including antisense oligonucleotides for miR-22). An exemplary kit of the present invention comprises any composition described herein in unit dosage form. In one embodiment, the unit dosage form is a container, such as a sterile prefilled syringe, which comprises any reagent described herein and a pharmaceutically acceptable carrier, diluent, excipient or vehicle. The kit may further comprise a label or printed instructions indicating the use of any reagent described herein. The kit may also comprise a lid speculum, a local anesthetic and a cleanser for the application site. The kit may further comprise one or more other reagents, such as a second inhibitor of oncogenic miRNA, or a biological product, therapeutic, chemotherapeutic or drug as described herein. In one embodiment, the kit comprises a container containing an effective amount of a composition of the present invention and an effective amount of another composition (such as those described herein). Example

[0226] To facilitate a more effective understanding of the invention disclosed herein, embodiments are provided below. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0227] Example 1: Role of MiR-22 in Obesity

[0228] MiR-22 directly targets PTEN and TET to promote tumorigenesis, metastasis and other metabolic disorders. More than 60 miRNAs targeting PTEN and no less than 30 new oncogene loci have been studied in human cancers. It is highly evolutionarily conserved among vertebrates and is ubiquitously expressed in various tissues (Lagos-Quintana et al., 2001, 2002; Neely et al., 2006). By targeting PTEN, miR-22 remains metabolically relevant because the reduction or increase of PTEN triggers the Warburg- or anti-Warburg metabolic state, respectively. Figure 2 AD showed that overexpression of miR-22 affected the body weight of mice.

[0229] miR-22 knockout method

[0230] To assess whether the effects on mouse body weight and fat accumulation were due to miR-22 overexpression, and to evaluate differences in body weight gain and food consumption during the period, 2-month-old mice (start date), wild-type (Wt), and miR-22 transgenic (Tg) mice were placed on a high-fat (60%) diet. Mouse body weight was monitored twice weekly, and food intake was monitored once weekly. (See [link to original text]) Figure 3 AC and Figure 4AF). Transgenic miR-22 (Tg) mice developed an obese phenotype on a non-diet (ND), whereas miR-22 knockout (KO) mice did not gain weight on an HFD. Mouse embryonic fibroblast (MEF) cells deficient in miR-22 showed an impaired ability to differentiate into adipocytes. This phenotype was associated with differential gene expression of a diverse set of genes involved in adipocyte differentiation and generally in fat metabolism. In addition, the results also demonstrated that the effects of miR-22 on weight gain were independent of leptin (or leptin-like) (see Figure 5 AD and Figure 6 ).

[0231] Example 2: miR-22 inhibition as an obesity therapy

[0232] All LNA anti-miR-22s are available for use in humans and mice. The host gene showed 49% complementarity between humans and mice, and LNA anti-HG-miR-22 primarily functions in humans.

[0233] Design of anti-miR-22 locked nucleic acid (LNA)

[0234] The LNA was designed to cover the seed sequence, containing lengths from 8 to 20 nt, with length-specific LNA portions and the highest possible miR-22 binding affinity.

[0235] The sequence was validated experimentally by optimizing the LNA-assisted uptake protocol (Lipo200 transfection) in adherent cell lines, using FAM-labeled LNA, and the biological effect was confirmed by identifying the most effective anti-miR-22 in adherent cell lines with and without assisted uptake (analysis of miR-22 levels and TET2 activity and protein levels before and after treatment). The goal was to use the anti-miR in a mouse model, where the most effective anti-miR was used for in vivo treatment, and the results were confirmed in Figure 33 AC. In the following sequences, uppercase letters indicate modified LNA, lowercase letters indicate unmodified; miR-22 (SEQ ID NO: 1) and anti-miR-22 oligonucleotides (SEQ ID NO: 2 to SEQ ID NO: 10) are oriented from 5' to 3'. Figure 8 The anti-miR-22 oligonucleotides with orientations from 3' to 5' are shown, as they hybridize with miR-22. The oligonucleotides with orientations from 5' to 3', SEQ ID NO:11 and SEQ ID NO:12, are disordered sequences and do not hybridize with miR-22 (SEQ ID NO:1).

[0236]

[0237]

[0238] In vivo anti-miR-22 therapy

[0239] See also Figure 9 In the in vivo experimental protocol for prophylaxis, 2-month-old miR-22- / - and WT mice under HFD were transfected with vector (VCH), scrambled control RNA (SCR), and locked nucleic acid (LNA) and treated with weekly intraperitoneal injections of 20 mg / kg loading dose (first administration) and 10 mg / kg maintenance dose without auxiliary uptake. There was no difference in food consumption between treated and untreated mice; see [link to relevant documentation]. Figure 10 Pharmacologically, in vivo inhibition of miR-22 prevented obesity in mice, and in vivo anti-miR-22 therapy increased the protein levels of major miR-22 targets in the liver. Anti-miR-22 treatment did not affect liver lipid composition but significantly inhibited hepatic steatosis.

[0240] To assess the potential gene expression related to lipid metabolism, synthesis, and differentiation in treated and untreated mice, RNA was extracted from liver, white adipose tissue (WAT), and brown adipose tissue (BAT) of mice treated with VHL, SCR LNA, or LNA anti-miR-22. The mRNA expression of TET2, PTEN (positive control), FTO, CEBPa, and PPARg, which are involved in lipid-related metabolic and synthetic pathways, as well as the mRNA expression of UCP1 and CD36 (as a brown biomarker) were determined (see [link to relevant documentation]). Figure 12 ).

[0241] In the treatment regimen, miR-22- / - and WT mice under HFD were treated with anti-miR-22-LNA, SCR, and VHL, and these mice were then placed in a second HFD regimen. Significant weight loss was observed in obese (mean weight >40g) mice fed HFD after 3.5 months of treatment. Mice were sacrificed, tissues were collected, and RNA from the liver was used for RNA-seq (…). Figure 16 AC, 17). Pharmacological inhibition of miR-22 was shown to restore the obese phenotype in mice ( Figure 18 ). Figure 19 AC is an RNA-seq graph showing a hierarchical clustering analysis of mouse livers. This analysis clusters pharmacological inhibition and gene knockout (KO) of miR-22 together, indicating that the treatment is targeted and that the KO phenotype can be modeled using LNA constructs; and Figure 20Figure 3 shows an RNA-Seq plot of gene ontology analysis in mouse liver, demonstrating top-down regulation of pathways related to lipid metabolism and biosynthesis in KO and LNA-treated mice. In vivo anti-miR-22 therapy robustly downregulated ACL and demonstrated that pharmacological inhibition of miR-22 was effective in impairing adipocyte differentiation of MEFs.

[0242] The results showed that anti-miR-22 therapy prevented weight gain in mice fed a high-fat diet, reversed the obese phenotype of obese mice fed a high-fat diet, did not affect food consumption, and effectively targeted the liver and WAT in vivo. In addition, anti-miR-22 treatment affected the protein levels of miR-22 target genes and did not affect any specific lipid species, but was able to reduce the total amount of lipids in mice.

[0243] Example 3: miR-22 controls obesity and fat mass and obesity-related protein (FTO).

[0244] miR-22 directly targets PTEN and TET to promote tumorigenesis and metastasis. PTEN, like many other miR-22-targeted genes, is involved in metabolism and fatty acid oxidation or biosynthesis, including, for example, SIRT-1, BMP-7, PPAR-α, PPAR-γ, SP-1, PGC1a, FGF-21, UCP1, methyltransferase-like protein 3, and DDIT4. In miR-22-deficient MEFs, FTO expression was significantly downregulated during induced adipogenic differentiation, but not in WT MEFs ( Figure 26 Furthermore, downregulation of miR-22 (genetically or pharmacologically) increases RNA m6A levels. Figure 27 AB). It was shown that downregulation of mir-22 did not affect liver function or indicate any liver-related diseases or dysfunction in old age ( Figure 28 AB, 29).

[0245] To assess whether overexpression of miR-22 affects liver function, steatosis, and fibrosis, mice aged 8 to 10 months were fed a regular diet. They showed that miR-22 overexpression resulted in steatosis and increased the presence of FSP-1-positive cells. FSP-1 identifies a subset of macrophages in the liver that is associated with fibrosis.

[0246] In summary, miR-22 is an onco-miR (targeting PTEN, MEF conversion, EMT). miR-22 is 100% conserved in humans and mice. Under ND, miR-22 OE induces an obesity phenotype. Under HFD, miR-22 KO mice do not gain weight. Pharmacologically, silencing miR-22 disrupts MEF and human MES differentiation into adipocytes. LNA anti-miR-22 treatment prevents obesity in mice under a preventative setting. LNA anti-miR-22 treatment reverts to the obesity phenotype in obese mice fed with HFD. miR-22 silencing does not show any hepatotoxicity. miR-22 silencing prevents hepatic steatosis and fibrosis. miR-22 can simultaneously target multiple genes involved in metabolism and lipid biogenesis.

[0247] Other implementation plans

[0248] It should be understood that although the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate, rather than limit, the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0249] Incorporated by Reference

[0250] All patents and publications cited in this article are incorporated herein in their entirety by reference.

[0251] The publications discussed herein are provided only because they were published prior to the date of this application. Nothing herein shall be construed as an admission that the invention is not entitled to precedence over these publications by virtue of prior invention.

[0252] As used in this article, all headings are for organizational purposes only and are not intended to restrict public access in any way. Sequence Listing <110> Beth Israel Deacones Medical Center R.PANELLA, Riccardo Pier Paolo, P.P. Pandorfi <120> microRNA and obesity <130> BID-005PC1 <150> US 62 / 642,934 <151> 2018-03-14 <160> 82 <170> PatentIn version 3.5 <210> 1 <211> twenty two <212> RNA <213> Artificial sequence <220> <223> Synthetic polymers <400> 1 aagcugccag uugaagaacu gu 22 <210> 2 <211> 10 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymers <220> <221> misc_feature <222> (1)..(1) <223> N-terminal, no nucleotides <220> <221> misc_feature <222> (2)..(9) <223> Optional LNA <220> <221> misc_feature <222> (10)..(10) <223> C-terminus, no nucleotides <400> 2 ntggcagctn 10 <210> 3 <400> 3 000 <210> 4 <211> 15 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(1) <223> LNA <220> <221> misc_feature <222> (3)..(3) <223> LNA <220> <221> misc_feature <222> (6) (7) <223> LNA <220> <221> misc_feature <222> (10)..(10) <223> LNA <220> <221> misc_feature <222> (12)..(12) <223> LNA <220> <221> misc_feature <222> (14) (15) <223> LNA <400> 4 cttcaactgg cagct 15 <210> 5 <211> 15 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(3) <223> LNA <220> <221> misc_feature <222> (6) (7) <223> LNA <220> <221> misc_feature <222> (10) (12) <223> LNA <220> <221> misc_feature <222> (14) (15) <223> LNA <400> 5 tcgacggtca acttc 15 <210> 6 <211> 16 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(2) <223> LNA <220> <221> misc_feature <222> (4) (6) <223> LNA <220> <221> misc_feature <222> (8) <223> LNA <220> <221> misc_feature <222> (11) (13) <223> LNA <220> <221> misc_feature <222> (15) (16) <223> LNA <400> 6 tcgacggtca acttct 16 <210> 7 <211> 16 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(2) <223> LNA <220> <221> misc_feature <222> (4)..(4) <223> LNA <220> <221> misc_feature <222> (8) <223> LNA <220> <221> misc_feature <222> (10) (13) <223> LNA <220> <221> misc_feature <222> (15) (16) <223> LNA <400> 7 tcgacggtca acttct 16 <210> 8 <211> 16 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(2) <223> LNA <220> <221> misc_feature <222> (4) (6) <223> LNA <220> <221> misc_feature <222> (9)..(9) <223> LNA <220> <221> misc_feature <222> (11) (13) <223> LNA <220> <221> misc_feature <222> (15) (16) <223> LNA <400> 8 tcgacggtca acttct 16 <210> 9 <211> 17 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(2) <223> LNA <220> <221> misc_feature <222> (5)..(7) <223> LNA <220> <221> misc_feature <222> (10)..(10) <223> LNA <220> <221> misc_feature <222> (12) (14) <223> LNA <220> <221> misc_feature <222> (16) (17) <223> LNA <400> 9 tcgacggtca acttctt 17 <210> 10 <211> 18 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(2) <223> LNA <220> <221> misc_feature <222> (6) <223> LNA <220> <221> misc_feature <222> (10)..(10) <223> LNA <220> <221> misc_feature <222> (13)..(14) <223> LNA <220> <221> misc_feature <222> (16)..(18) <223> LNA <400> 10 tcgacggtca acttcttg 18 <210> 11 <211> 16 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(2) <223> LNA <220> <221> misc_feature <222> (4) (6) <223> LNA <220> <221> misc_feature <222> (8) <223> LNA <220> <221> misc_feature <222> (11) (13) <223> LNA <220> <221> misc_feature <222> (15) (16) <223> LNA <400> 11 gcgatgattg ataagc 16 <210> 12 <211> 16 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <220> <221> misc_feature <222> (1)..(2) <223> LNA <220> <221> misc_feature <222> (4) (6) <223> LNA <220> <221> misc_feature <222> (8) <223> LNA <220> <221> misc_feature <222> (11) (13) <223> LNA <220> <221> misc_feature <222> (15) (16) <223> LNA <400> 12 gcgatgattg ataagc 16 <210> 13 <211> 4313 <212> DNA <213> Artificial sequence <220> <223> synthetic polymers <400> 13 ctacgctctt ccagctgtcg gacctgggaa attctcctgt gctaaatccc gtggcgctcg 60 cgggtgtcgc cgcggtgcat cctgggagtt gtagtttttt ctactcagag ggagaatagc 120 tccagacggg agcaggacgc tgagagaact acatgcagga ggcggggtcc agggcgaggg 180 atctacgcag cttgcggtgg cgaaggcggc tttagtggca gcatgaagcg caccccgact 240 gccgaggaac gagagcgcga agctaagaaa ctgaggcttc ttgaagagct tgaagacact 300 tggctccctt atctgacccc caaagatgat gaattctatc agcagtggca gctgaaatat 360 cctaaactaa ttctccgaga agccagcagt gtatctgagg agctccataa agaggttcaa 420 gaagccttc tcacactgca caagcatggc tgcttatttc gggacctggt taggatccaa 480 ggcaaagatc tgctcactcc ggtatctcgc atcctcattg gtaatccagg ctgcacctac 540 aagtacctga acaccaggct ctttacggtc cctggccag tgaaagggtc tatataaaa 600 cacaccgagg ctgaatagc cgctgcttgt gagaccttcc tcaagctcaa tgactacctg 660 cagatagaaa ccatccaggc tttggaagaa cttgctgcca aagagaaggc taatgaggat 720 gctgtgccat tgtgtatgtc tgcagatttc cccaggggttg ggatgggttc atcctacaac 780 ggacagatg aagtggacat tagagcaga gcagcataca acgtacttt gctgaatttc 840 atggatccctc agaaaatgcc atacctgaaa gaggaacctt attttggcat ggggaaatg 900 gcagtgagct ggcatcatga tgaaaatctg gtggacaggt cagcggtggc agtgtacagt 960 tatagctgtg aaggccctga agaggaagt gaggatgact ctcatctcga agghaggt 1020 cctgatattt ggcatgttgg tttagatc tcatgggaca tagagacacc tggttttggg 1080 ataccccttc accaaggaga ctgctatttc atgcttgatg atctcaatgc cacccaccaa 1140 cactgtgttt tggccggttc acaacctcgg tttagttcca cccaccgagt ggcagagtgc 1200 tcacaggaa ccttggatta tattcaa cgctgtcagt tggctctgca gatgtctgt 1260 gacgatgtgg acatgatga tgtctcttg aaatcctttg agcctgcagt ttgaaacaa 1320 ggagaagaaa ttcataatga ggtcgagtttt gagtggctga ggcagtttg gtttcaaggc 1380 aatcgataca gaagtgcac tgactggtgg tgtcaaccca tggctcact ggaagcactg 1440 height tggaggtgt gaaatgct gtgcttcatg agttaaaag height gaggggctc 1500 cccgtggaac aaggaatga aatcttgact gccatccttg cctcgctcac tgcacgccag 1560 aacctgagga gagaatggca tgccaggtgc cagtcacgaa ttgccgaac attackgct 1620 gatcagaagc cagaatgtcg gccatactgg gaaaggatg atgctcgat gcctctgccg 1680 tttgacctca cagacatcgt ttcagactc agaggtcagc ttctggagc aaaaccctag 1740 aaggagcaca agtctcaggc ggaggagaa aagagatcgg ctttctcct ccaacgttgt 1800 catgggctta agcagagca gtggagactt ctcttggccc ctagattgta gcaccccggt 1860 cccaatccaa aacagctagg aaatggtgcc catgaagtttt taaatgtttt aaatgaccc 1920 tgtgttatag tctgatttgg tgttaaacag gaccttctc cccaaaatt gttcagatta 1980 taaaatgtga gccattcagc cccaaggtc caggcaggc gaggaacg agcccaggcgt 2040 gtgacaaagc ctaactact ttcctcttc ccaagctttt tcagagactc tggagtggac 2100 ccagccctct ggggaagac agaacttaga gatacccag ttactcacca cacccatagt 2160 gctgtccaat atggtagcca ctagctagct gtggctactt caatttaaat tcagttttaa 2220 ttttaattaa aaatgcagct cttcagtcgc cctggccaca tttcaagtgc ttaacagcct 2280 catgtggcta gtgactgctg tattggacgg tacagatatg gaacattttc atcatcgaag 2340 aaagtcctat tggacaacac ttctataaaaa agtttgagag caggaattct catttccatt 2400 cgtctgtagc ttctatcccc aaaggcaaag aaactaaaag agaaatgact cattgaagat 2460 tggcctcttt cctttctcta agacaaacct aagtaaaagc ctgagctttg agtcctatgc 2520 tcagcacacg ggaaggagat gttaataatt aaaataaagt tgatatcctg tctttaggga 2580 gttcccttga tctcttgaaa gagacacagc cccatttaca ttatttcgtg gatttcacca 2640 gcatagtata gtttttttct gtaagtccct cattcttatg taataacagg tggaactgag 2700 gtttgaagaa cctcagtggc ccatcctgat gacattggag actcaaagag acaagagaga 2760 gtagggttta aaacctgagc tttaagactc ccactagctt cgtgtccttt ggcatgttaa 2820 cgtgcctcag tttcctcatc tgtataatgg ggatatatga aaggcaccag tcctaaggtg 2880 aacattaagt gagatgattc tagttacaga cttagaacaa tttccagcac atagttaaat 2940 atccaggaaa ttctggtact gttatgtgtg ggtgagctga cctggatgta gatgttttcc 3000 tctctcttgc tgacccctcc gccagttttg tcttgtgatg ccattaacac atctctccct 3060 ttctgacctg gctcctgccc attggtgtcc caagaaatcg tgagaatagt tagccccccg 3120 tctccccagc ctgttgcttt ctcgtgtagt tgttcacagt agttgagaag ttgaagagct 3180 tttgcctatt gaaggtgcac tgagaataaa ctctttcctg ccaccagaat tgcagtggtt 3240 cacggcctgc actcattccc atgaatgcag ttaatagcca cagaaatgtc acattaagca 3300 aagcagccag ggtctcatcg tgttgagact cgagtctctc agaccttgga ttcattccct 3360 ggtgtctttg agcctcagtt tcctcattgg taaaagagaa gtgaagcagt gtctcacagg 3420 gtcattacag agattaaatg aaataaatga aataacatag accaggaggg cgtggtgttt 3480 aaaagtcaca gatggggcac cctcgggcca tccagcccag tgttttcttt agcccctatg 3540 atgttcattt tttgttatat cccattaggt gcccatattt aaaaattggg agatttcaca 3600 taaattaaa aggtctgcat tttcttttt cttttcttttt tttttttt tgagacacag 3660 tctcactctg tcaccaggct agagtgcagt ggcacgatct cagctcactg caacctctgc 3720 ctcccaggtt caagtaattc tcctgcctca gcctcccaag tagctgggac tacaggcacg 3780 tgccaccacg cccagctaat ttttgtattt ttagcagaga tggggtttca ccacattggc 3840 caggatggtc tcgatctcaa cctcgtgatc cacccacctc ggtctcccaa agcgctggga 3900 ttacaggcgt gagccaccgc gccaagccaa ggtctgcatt tttctttaga actcagaaca 3960 cccaatagtc ctaggccccc atcctcgcat ggcagcaagc taaataagca tcttcccact 4020 gcgagttggg gcatgaccca gcctatggtt tgccatactc cctctttttc tccgtttttt 4080 cattaattgt gaacctgacc tgcatcaccc tttcatgtca gtgctctcca aacctgcttg 4140 cttgcacccc tctagtcgaa atattttgtg cttaccccaa tatatgtgtg tgactattga 4200 actctattcg tagactgctt gtactaatgt catttgcatc ataaaatatt catatccaat 4260 aaacatatta aaaggatgag ataagaaacc gaaaaaaaa aaaaaaaaa aaa 4313 <210> 14 <211> 505 <212> PRT <213> artificial sequence <220> <223> synthetic polymers <400> 14 Met Lys Arg Thr Pro Thr Ala Glu Glu Arg Glu Arg Glu Ala Lys Lys 1 5 10 15 Leu Arg Leu Leu Glu Glu Leu Glu Asp Thr Trp Leu Pro Tyr Leu Thr 20 25 30 Pro Lys Asp Asp Glu Phe Tyr Gln Gln Trp Gln Leu Lys Tyr Pro Lys 35 40 45 Leu Ile Leu Arg Glu Ala Ser Ser Val Ser Glu Glu Leu His Lys Glu 50 55 60 Val Gln Glu Ala Phe Leu Thr Leu His Lys His Gly Cys Leu Phe Arg 65 70 75 80 Asp Leu Val Arg Ile Gln Gly Lys Asp Leu Leu Thr Pro Val Ser Arg 85 90 95 Ile Leu Ile Gly Asn Pro Gly Cys Thr Tyr Lys Tyr Leu Asn Thr Arg 100 105 110 Leu Phe Thr Val Pro Trp Pro Val Lys Gly Ser Asn Ile Lys His Thr 115 120 125 Glu Ala Glu Ile Ala Ala Ala Cys Glu Thr Phe Leu Lys Leu Asn Asp 130 135 140 Tyr Leu Gln Ile Glu Thr Ile Gln Ala Leu Glu Glu Leu Ala Ala Lys 145 150 155 160 Glu Lys Ala Asn Glu Asp Ala Val Pro Leu Cys Met Ser Ala Asp Phe 165 170 175 Pro Arg Val Gly Met Gly Ser Ser Tyr Asn Gly Gln Asp Glu Val Asp 180 185 190 Ile Lys Ser Arg Ala Ala Tyr Asn Val Thr Leu Leu Asn Phe Met Asp 195 200 205 Pro Gln Lys Met Pro Tyr Leu Lys Glu Glu Pro Tyr Phe Gly Met Gly 210 215 220 Lys Met Ala Val Ser Trp His His Asp Glu Asn Leu Val Asp Arg Ser 225 230 235 240 Ala Val Ala Val Tyr Ser Tyr Ser Cys Glu Gly Pro Glu Glu Glu Ser 245 250 255 Glu Asp Asp Ser His Leu Glu Gly Arg Asp Pro Asp Ile Trp His Val 260 265 270 Gly Phe Lys Ile Ser Trp Asp Ile Glu Thr Pro Gly Leu Ala Ile Pro 275 280 285 Leu His Gln Gly Asp Cys Tyr Phe Met Leu Asp Asp Leu Asn Ala Thr 290 295 300 His Gln His Cys Val Leu Ala Gly Ser Gln Pro Arg Phe Ser Ser Thr 305 310 315 320 His Arg Val Ala Glu Cys Ser Thr Gly Thr Leu Asp Tyr Ile Leu Gln 325 330 335 Arg Cys Gln Leu Ala Leu Gln Asn Val Cys Asp Asp Val Asp Asn Asp 340 345 350 Asp Val Ser Leu Lys Ser Phe Glu Pro Ala Val Leu Lys Gln Gly Glu 355 360 365 Glu Ile His Asn Glu Val Glu Phe Glu Trp Leu Arg Gln Phe Trp Phe 370 375 380 Gln Gly Asn Arg Tyr Arg Lys Cys Thr Asp Trp Trp Cys Gln Pro Met 385 390 395 400 Ala Gln Leu Glu Ala Leu Trp Lys Lys Met Glu Gly Val Thr Asn Ala 405 410 415 Val Leu His Glu Val Lys Arg Glu Gly Leu Pro Val Glu Gln Arg Asn 420 425 430 Glu Ile Leu Thr Ala Ile Leu Ala Ser Leu Thr Ala Arg Gln Asn Leu 435 440 445 Arg Arg Glu Trp His Ala Arg Cys Gln Ser Arg Ile Ala Arg Thr Leu 450 455 460 Pro Ala Asp Gln Lys Pro Glu Cys Arg Pro Tyr Trp Glu Lys Asp Asp 465 470 475 480 Ala Ser Met Pro Leu Pro Phe Asp Leu Thr Asp Ile Val Ser Glu Leu 485 490 495 Arg Gly Gln Leu Leu Glu Ala Lys Pro 500 505 <210> 15 <211> 2631 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 15 tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60 cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120 tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180 ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240 ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300 ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360 gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420 gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480 gcgcccgcgg gccccggcgg cgccgtcatg cccgggggag cgcacgggcc cccgcccggc 540 tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600 ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660 aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720 cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780 gcgcactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccacg 840 cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900 agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960 gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020 cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080 cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140 ctgagccgcg aactggacac gctgcggggc atcttccgcc agctgccaga gagctccttg 1200 gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt gggaccgccc tgggccagcc 1260 tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320 gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380 ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440 ccctgcgagg aggggagaat tcttggggct gagctgggag cccggcaact ctagtattta 1500 ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtaggggga 1560 gcaaatcgtg ccttgtcatt ttatttggag gtttcctgcc tccttcccga ggctacagca 1620 gacccccatg agagaaggag gggagcaggc ccgtggcagg aggagggctc agggagctga 1680 gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740 aaacataggg acttggggct tggaacctaa ggttgttccc ctagttctac atgaaggtgg 1800 agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860 ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt 1920 gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980 tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040 gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100 gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160 ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220 atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280 tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340 ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400 ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460 tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520 ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580 actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631 <210> 16 <211> 358 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 16 Met Glu Ser Ala Asp Phe Tyr Glu Ala Glu Pro Arg Pro Pro Met Ser 1 5 10 15 Ser His Leu Gln Ser Pro Pro His Ala Pro Ser Ser Ala Ala Phe Gly 20 25 30 Phe Pro Arg Gly Ala Gly Pro Ala Gln Pro Pro Ala Pro Pro Ala Ala 35 40 45 Pro Glu Pro Leu Gly Gly Ile Cys Glu His Glu Thr Ser Ile Asp Ile 50 55 60 Ser Ala Tyr Ile Asp Pro Ala Ala Phe Asn Asp Glu Phe Leu Ala Asp 65 70 75 80 Leu Phe Gln His Ser Arg Gln Gln Glu Lys Ala Lys Ala Ala Val Gly 85 90 95 Pro Thr Gly Gly Gly Gly Gly Gly Asp Phe Asp Tyr Pro Gly Ala Pro 100 105 110 Ala Gly Pro Gly Gly Ala Val Met Pro Gly Gly Ala His Gly Pro Pro 115 120 125 Pro Gly Tyr Gly Cys Ala Ala Ala Gly Tyr Leu Asp Gly Arg Leu Glu 130 135 140 Pro Leu Tyr Glu Arg Val Gly Ala Pro Ala Leu Arg Pro Leu Val Ile 145 150 155 160 Lys Gln Glu Pro Arg Glu Glu Asp Glu Ala Lys Gln Leu Ala Leu Ala 165 170 175 Gly Leu Phe Pro Tyr Gln Pro Pro Pro Pro Pro Pro Pro Ser His Pro 180 185 190 His Pro His Pro Pro Pro Ala His Leu Ala Ala Pro His Leu Gln Phe 195 200 205 Gln Ile Ala His Cys Gly Gln Thr Thr Met His Leu Gln Pro Gly His 210 215 220 Pro Thr Pro Pro Pro Thr Pro Val Pro Ser Pro His Pro Ala Pro Ala 225 230 235 240 Leu Gly Ala Ala Gly Leu Pro Gly Pro Gly Ser Ala Leu Lys Gly Leu 245 250 255 Gly Ala Ala His Pro Asp Leu Arg Ala Ser Gly Gly Ser Gly Ala Gly 260 265 270 Lys Ala Lys Lys Ser Val Asp Lys Asn Ser Asn Glu Tyr Arg Val Arg 275 280 285 Arg Glu Arg Asn Asn Ile Ala Val Arg Lys Ser Arg Asp Lys Ala Lys 290 295 300 Gln Arg Asn Val Glu Thr Gln Gln Lys Val Leu Glu Leu Thr Ser Asp 305 310 315 320 Asn Asp Arg Leu Arg Lys Arg Val Glu Gln Leu Ser Arg Glu Leu Asp 325 330 335 Thr Leu Arg Gly Ile Phe Arg Gln Leu Pro Glu Ser Ser Leu Val Lys 340 345 350 Ala Met Gly Asn Cys Ala 355 <210> 17 <211> 2631 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymer <400> 17 tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60 cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120 tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180 ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240 ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300 ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360 gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420 gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480 gcgcccgcgg gccccggcgg cgccgtcatg cccgggggag cgcacgggcc cccgcccggc 540 tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600 ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660 aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720 cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780 gcgcactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccacg 840 cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900 agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960 gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020 cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080 cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140 ctgagccgcg aactggacac gctgcggggc atcttccgcc agctcccaga gagctccttg 1200 gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt ggggaccgcc tgggccagcc 1260 tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320 gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380 ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440 ccctgcgagg aggggagaat tcttggggct gagctgggag cccggcaact ctagtatta 1500 ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtagggggga 1560 gcaaatcgtg ccttgtcatt ttatttggag gtttcctgcc tccttcccga ggctacagca 1620 gacccccatg agagaaggag gggagcaggc ccgtggcagg aggagggctc agggagctga 1680 gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740 aaacataggg acttggggct tggaacctaa ggttgttccc ctagttctac atgaaggtgg 1800 agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860 ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt 1920 gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980 tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040 gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100 gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160 ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220 atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280 tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340 ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400 ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460 tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520 ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580 actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631 <210> 18 <211> 239 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 18 Met Pro Gly Gly Ala His Gly Pro Pro Pro Gly Tyr Gly Cys Ala Ala 1 5 10 15 Ala Gly Tyr Leu Asp Gly Arg Leu Glu Pro Leu Tyr Glu Arg Val Gly 20 25 30 Ala Pro Ala Leu Arg Pro Leu Val Ile Lys Gln Glu Pro Arg Glu Glu 35 40 45 Asp Glu Ala Lys Gln Leu Ala Leu Ala Gly Leu Phe Pro Tyr Gln Pro 50 55 60 Pro Pro Pro Pro Pro Pro Ser His Pro His Pro His Pro Pro Pro Ala 65 70 75 80 His Leu Ala Ala Pro His Leu Gln Phe Gln Ile Ala His Cys Gly Gln 85 90 95 Thr Thr Met His Leu Gln Pro Gly His Pro Thr Pro Pro Pro Thr Pro 100 105 110 Val Pro Ser Pro His Pro Ala Pro Ala Leu Gly Ala Ala Gly Leu Pro 115 120 125 Gly Pro Gly Ser Ala Leu Lys Gly Leu Gly Ala Ala His Pro Asp Leu 130 135 140 Arg Ala Ser Gly Gly Ser Gly Ala Gly Lys Ala Lys Lys Ser Val Asp 145 150 155 160 Lys Asn Ser Asn Glu Tyr Arg Val Arg Arg Glu Arg Asn Asn Ile Ala 165 170 175 Val Arg Lys Ser Arg Asp Lys Ala Lys Gln Arg Asn Val Glu Thr Gln 180 185 190 Gln Lys Val Leu Glu Leu Thr Ser Asp Asn Asp Arg Leu Arg Lys Arg 195 200 205 Val Glu Gln Leu Ser Arg Glu Leu Asp Thr Leu Arg Gly Ile Phe Arg 210 215 220 Gln Leu Pro Glu Ser Ser Leu Val Lys Ala Met Gly Asn Cys Ala 225 230 235 <210> 19 <211> 2631 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymer <400> 19 tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60 cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120 tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180 ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240 ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300 ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360 gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420 gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480 gcgcccgcgg gccccggcgg cgccgtcatg cccggggag cgcacgggcc cccgcccggc 540 tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600 ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660 aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720 cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780 gcgccactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccag 840 cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900 agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960 gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020 cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080 cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140 ctgagccgcg aactggacac gctgcggggc atcttccgcc agctcccaga gagctccttg 1200 gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt gggaccgccc tgggccagcc 1260 tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320 gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380 ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440 ccctgcgagg aggggagat tcttggggct gagctgggag cccggcaact ctagtattta ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtaggggga gcaaatcgtg ccttgtcatt ttatttggag gttttcctgcc tccttcccga ggctacagca 1620 gacccccatg aggaggag gggagcaggc ccgtggcagg aggagggctc aggagctga 1680. gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740 aaacataggg acttggggct tggacctaa ggttgttccc ctagttctac atgaaggtgg agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860 ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980 tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040 gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100 gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160 ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220 atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280 tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340 ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400 ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460 tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520 ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580 actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631 <210> 20 <211> 393 <212> PRT <213> Artificial sequence <220> <223> Synthetic polymer <400> 20 Met Arg Gly Arg Gly Arg Ala Gly Ser Pro Gly Gly Arg Arg Arg Arg 1 5 10 15 Pro Ala Gln Ala Gly Gly Arg Arg Gly Ser Pro Cys Arg Glu Asn Ser 20 25 30 Asn Ser Pro Met Glu Ser Ala Asp Phe Tyr Glu Ala Glu Pro Arg Pro 35 40 45 Pro Met Ser Ser His Leu Gln Ser Pro Pro His Ala Pro Ser Ser Ala 50 55 60 Ala Phe Gly Phe Pro Arg Gly Ala Gly Pro Ala Gln Pro Pro Ala Pro 65 70 75 80 Pro Ala Ala Pro Glu Pro Leu Gly Gly Ile Cys Glu His Glu Thr Ser 85 90 95 Ile Asp Ile Ser Ala Tyr Ile Asp Pro Ala Ala Phe Asn Asp Glu Phe 100 105 110 Leu Ala Asp Leu Phe Gln His Ser Arg Gln Gln Glu Lys Ala Lys Ala 115 120 125 Ala Val Gly Pro Thr Gly Gly Gly Gly Gly Gly Asp Phe Asp Tyr Pro 130 135 140 Gly Ala Pro Ala Gly Pro Gly Gly Ala Val Met Pro Gly Gly Ala His 145 150 155 160 Gly Pro Pro Pro Gly Tyr Gly Cys Ala Ala Ala Gly Tyr Leu Asp Gly 165 170 175 Arg Leu Glu Pro Leu Tyr Glu Arg Val Gly Ala Pro Ala Leu Arg Pro 180 185 190 Leu Val Ile Lys Gln Glu Pro Arg Glu Glu Asp Glu Ala Lys Gln Leu 195 200 205 Ala Leu Ala Gly Leu Phe Pro Tyr Gln Pro Pro Pro Pro Pro Pro Pro 210 215 220 Ser His Pro His Pro His Pro Pro Pro Ala His Leu Ala Ala Pro His 225 230 235 240 Leu Gln Phe Gln Ile Ala His Cys Gly Gln Thr Thr Met His Leu Gln 245 250 255 Pro Gly His Pro Thr Pro Pro Pro Thr Pro Val Pro Ser Pro His Pro 260 265 270 Ala Pro Ala Leu Gly Ala Ala Gly Leu Pro Gly Pro Gly Ser Ala Leu 275 280 285 Lys Gly Leu Gly Ala Ala His Pro Asp Leu Arg Ala Ser Gly Gly Ser 290 295 300 Gly Ala Gly Lys Ala Lys Lys Ser Val Asp Lys Asn Ser Asn Glu Tyr 305 310 315 320 Arg Val Arg Arg Glu Arg Asn Asn Ile Ala Val Arg Lys Ser Arg Asp 325 330 335 Lys Ala Lys Gln Arg Asn Val Glu Thr Gln Gln Lys Val Leu Glu Leu 340 345 350 Thr Ser Asp Asn Asp Arg Leu Arg Lys Arg Val Glu Gln Leu Ser Arg 355 360 365 Glu Leu Asp Thr Leu Arg Gly Ile Phe Arg Gln Leu Pro Glu Ser Ser 370 375 380 Leu Val Lys Ala Met Gly Asn Cys Ala 385 390 <210> 21 <211> 2631 <212> DNA <213> Synthetic sequence <220> <223> Synthetic polymer <400> 21 tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60 cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120 tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180 ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240 ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300 ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360 gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420 gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480 gcgcccgcgg gccccggcgg cgccgtcatg cccgggggag cgcacgggcc cccgcccggc 540 tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600 ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660 aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720 cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780 gcgcactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccacg 840 cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900 agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960 gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020 cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080 cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140 ctgagccgcg aactggacac gctgcggggc atcttccgcc agctcccaga gagctccttg 1200 gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt ggggaccgcc tgggccagcc 1260 tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320 gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380 ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440 ccctgcgagg aggggagaat tcttggggct gagctgggag cccggcaact ctagtatta 1500 ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtagggggga 1560 gcaaatcgtg ccttgtcatt ttattggag gtttcctgcc tccttccga ggctacagca 1620 gacccccatg agagaaggag gggagcaggc ccgtggcagg aggagggctc agggagctga 1680 gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740 aaacataggg acttggggct tggaacctaa ggttgttccc ctagttctac atgaaggtgg 1800 agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860 ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt 1920 gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980 tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040 gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100 gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160 ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220 atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280 tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340 ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400 ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460 tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520 ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580 actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631 <210> 22 <211> 344 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 22 Met Ser Ser His Leu Gln Ser Pro Pro His Ala Pro Ser Ser Ala Ala 1 5 10 15 Phe Gly Phe Pro Arg Gly Ala Gly Pro Ala Gln Pro Pro Ala Pro Pro 20 25 30 Ala Ala Pro Glu Pro Leu Gly Gly Ile Cys Glu His Glu Thr Ser Ile 35 40 45 Asp Ile Ser Ala Tyr Ile Asp Pro Ala Ala Phe Asn Asp Glu Phe Leu 50 55 60 Ala Asp Leu Phe Gln His Ser Arg Gln Gln Glu Lys Ala Lys Ala Ala 65 70 75 80 Val Gly Pro Thr Gly Gly Gly Gly Gly Gly Asp Phe Asp Tyr Pro Gly 85 90 95 Ala Pro Ala Gly Pro Gly Gly Ala Val Met Pro Gly Gly Ala His Gly 100 105 110 Pro Pro Pro Gly Tyr Gly Cys Ala Ala Ala Gly Tyr Leu Asp Gly Arg 115 120 125 Leu Glu Pro Leu Tyr Glu Arg Val Gly Ala Pro Ala Leu Arg Pro Leu 130 135 140 Val Ile Lys Gln Glu Pro Arg Glu Glu Asp Glu Ala Lys Gln Leu Ala 145 150 155 160 Leu Ala Gly Leu Phe Pro Tyr Gln Pro Pro Pro Pro Pro Pro Pro Ser 165 170 175 His Pro His Pro His Pro Pro Pro Ala His Leu Ala Ala Pro His Leu 180 185 190 Gln Phe Gln Ile Ala His Cys Gly Gln Thr Thr Met His Leu Gln Pro 195 200 205 Gly His Pro Thr Pro Pro Pro Thr Pro Val Pro Ser Pro His Pro Ala 210 215 220 Pro Ala Leu Gly Ala Ala Gly Leu Pro Gly Pro Gly Ser Ala Leu Lys 225 230 235 240 Gly Leu Gly Ala Ala His Pro Asp Leu Arg Ala Ser Gly Gly Ser Gly 245 250 255 Ala Gly Lys Ala Lys Lys Ser Val Asp Lys Asn Ser Asn Glu Tyr Arg 260 265 270 Val Arg Arg Glu Arg Asn Asn Ile Ala Val Arg Lys Ser Arg Asp Lys 275 280 285 Ala Lys Gln Arg Asn Val Glu Thr Gln Gln Lys Val Leu Glu Leu Thr 290 295 300 Ser Asp Asn Asp Arg Leu Arg Lys Arg Val Glu Gln Leu Ser Arg Glu 305 310 315 320 Leu Asp Thr Leu Arg Gly Ile Phe Arg Gln Leu Pro Glu Ser Ser Leu 325 330 335 Val Lys Ala Met Gly Asn Cys Ala 340 <210> 23 <211> 1892 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymer <400> 23 ggcgcccgcg cccgcccccg cgccgggccc ggctcggccc gacccggctc cgccgcgggc 60 aggcggggcc cagcgcactc ggagcccgag cccgagccgc agccgccgcc tggggcgctt 120 gggtcggcct cgaggacacc ggagaggggc gccacgccgc cgtggccgca gatttgaaag 180 aagccaacac taaacaacaa atacaacaa aggccatttt ctcaaacgag agtcagcctt 240 taacgaaatg accatggttg acacagagat gccattctgg cccaccaact ttgggatcag 300 ctccgtggat ctctccgtaa tggaagacca ctcccatcc tttgatatca agcccttcac 360 tactgttgac ttctccagca tttctactcc acattacgaa gacattccat tcaagaac 420 agatccagtg gttgcagatt acaagtatga cctgaaactt caagagtacc aaagtgcaat 480 caaagtggag cctgcatctc caccttatta ttctgagaag actcagctct aaataagcc 540 tcatgaagag ccttccaact ccctcatggc aattgaatgt cgtgtctgtg gagataaagc 600 ttctggattt cactatggag ttcatgcttg tgaaggatgc aagggtttct tccggagaac 660 aatcagattg aagcttatct atgacagatg tgatcttaac tgtcggatcc acaaaaaaaag 720 tagaaataa tgtcagtact gtcggtttca gaaatgcctt gcagtggggga tgtctcataa 780 tgccatcagg ttgggcgga tgccacaggc cgagaggg aagctgttgg cggagatctc 840 cagtgatatc gaccagctga atccagagtc cgctgaccctc cgggccctgg caaacattt 900 gtatgactca tacataagt ccttcccgct gaccaagca aaggcgaggg cgatcttgac 960 aggaaagaca acagacaat caccattcgt tatctatgac atgaatttcct taatgatggg 1020 agaagataa atcaagttca aacacatcac cccctgcag gagcagagca aagaggtggc 1080 catccgcatc ttcaggct gccagttcg ctccgtggag gctgtgcagg agatcacaga 1140 gtatgccaaa agcattcctg gtttgtaaa tcttgacttg aacgaccaag taactctcct 1200 CAatatgga gtccacgaga tcatttacac atgctggcc tccttgatga ataagatgg 1260 ggttctcata tccgaggggcc aaggctcat gataagggag tttctaaaga gcctgcgaaa 1320 gccttttggt gactttatgg agcccaagtt tgagtttgct gtgaagttca atgcactgga 1380 attagatgac agcgacttgg caatttat tgctgtcatt attctcagtg gagaccgccc 1440 aggtttgctg aatgtgaagc ccattgaaga cattcagac aacctgctac aagccctgga 1500 gctccagctg aagctgaacc accctgagtc ctcacagctg tttgccaagc tgctccagaa 1560 aatgacagac ctcagacaga ttgtcacgga acacgtgcag ctactgcagg tgatcaagaa 1620 gacggagaca gacatgagtc ttcacccgct cctgcaggag atctacaagg acttgtacta 1680 gcagagagtc ctgagccact gccaacattt cccttcttcc agttgcacta ttctgaggga 1740 aaatctgaca cctaagaaat ttactgtgaa aaagcatttt aaaaagaaaa ggttttagaa 1800 tatgatctat tttatgcata ttgtttataa agacacattt acaatttact tttaatatta 1860 aaaattacca tattatgaaa ttgctgatag ta 1892 <210> 24 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 24 Met Thr Met Val Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly 1 5 10 15 Ile Ser Ser Val Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe 20 25 30 Asp Ile Lys Pro Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro 35 40 45 His Tyr Glu Asp Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp 50 55 60 Tyr Lys Tyr Asp Leu Lys Leu Gln Glu Tyr Gln Ser Ala Ile Lys Val 65 70 75 80 Glu Pro Ala Ser Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn 85 90 95 Lys Pro His Glu Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg 100 105 110 Val Cys Gly Asp Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys 115 120 125 Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr Ile Arg Leu Lys Leu Ile 130 135 140 Tyr Asp Arg Cys Asp Leu Asn Cys Arg Ile His Lys Ser Arg Asn 145 150 155 160 Lys Cys Gln Tyr Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser 165 170 175 His Asn Ala Ile Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys 180 185 190 Leu Leu Ala Glu Ser Ser Ile Asp Ile Asp Gln Leu Asn Pro Glu Ser 195 200 205 Ala Asp Leu Arg Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys 210 215 220 Ser Phe Pro Leu Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys 225 230 235 240 Thr Thr Asp Lys Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met 245 250 255 Met Gly Glu Asp Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu 260 265 270 Gln Ser Lys Glu Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg 275 280 285 Ser Val Glu Ala Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro 290 295 300 Gly Phe Val Asn Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr 305 310 315 320 Gly Val His Glu Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys 325 330 335 Asp Gly Val Leu Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe 340 345 350 Leu Lys Ser Leu Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe 355 360 365 Glu Phe Ala Val Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu 370 375 380 Ala Ile Phe Ile Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu 385 390 395 400 Leu Asn Val Lys Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala 405 410 415 Leu Glu Leu Gln Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe 420 425 430 Ala Lys Leu Leu Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu 435 440 445 His Val Gln Leu Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser 450 455 460 Leu His Pro Leu Leu Gln Glu Ile Tyr Lys Asp Leu Tyr 465 470 475 <210> 25 <211> 1820 <212> Ms <213> artificial sequence <220> <223> synthetic polymers <400> 25 ttcaagtctt tttcttttaa cggattgatc ttttgctaga tagagacaaa atatcagtgt 60 gaattacagc aaacccctat tccatgctgt tatgggtgaa actctgggag attctcctat 120 tgacccagaa agcgattcct tcactgatac actgtctgca aacatatcac aagaaatgac 180 catggttgac acagagatgc cattctggcc caccaacttt gggatcagct ccgtggatct 240 ctccgtaatg gaagaccact cccactcctt tgatatcaag cccttcacta ctgttgactt 300 ctccagcatt tctactccac attacgaaga cattccattc acaagaacag atccagtggt 360 tgcagattac aagtatgacc tgaaacttca agagtaccaa agtgcaatca aagtggagcc 420 tgcatctcca ccttattatt ctgagaagac tcagctctac aataagcctc atgaagagcc 480 ttccaactcc ctcatggcaa ttgaatgtcg tgtctgtgga gataaagctt ctggatttca 540 ctatggagtt catgcttgtg aaggatgcaa gggtttcttc cggagaacaa tcagattgaa 600 gcttatctat gacagatgtg atcttaactg tcggatccac aaaaaaagta gaaataaatg 660 tcagtactgt cggtttcaga aatgccttgc agtggggatg tctcataatg ccatcaggtt 720 tgggcggatg ccacaggccg agaaggagaa gctgttggcg gagatctcca gtgatatcga 780 ccagctgaat ccagagtccg ctgacctccg ggccctggca aaacatttgt atgactcata 840 cataaagtcc ttcccgctga ccaaagcaaa ggcgagggcg atcttgacag gaaagacaac 900 agacaaatca ccattcgtta tctatgacat gaattcctta atgatgggag aagataaaat 960 caagttcaaa cacatcaccc ccctgcagga gcagagcaaa gaggtggcca tccgcatctt 1020 tcagggctgc cagtttcgct ccgtggaggc tgtgcaggag atcacagagt atgccaaaag 1080 cattcctggt tttgtaaatc ttgacttgaa cgaccaagta actctcctca aatatggagt 1140 ccacgagatc atttacacaa tgctggcctc cttgatgaat aaagatgggg ttctcatatc 1200 cgagggccaa ggcttcatga caagggagtt tctaaagagc ctgcgaaagc cttttggtga 1260 ctttatggag cccaagtttg agtttgctgt gaagttcaat gcactggaat tagatgacag 1320 cgacttggca atatttattg ctgtcattat tctcagtgga gaccgcccag gtttgctgaa 1380 tgtgaagccc attgaagaca ttcaagacaa cctgctacaa gccctggagc tccagctgaa 1440 gctgaaccac cctgagtcct cacagctgtt tgccaagctg ctccagaaaa tgacagacct 1500 cagacagatt gtcacggaac acgtgcagct actgcaggtg atcaagaaga cggagacaga 1560 catgagtctt cacccgctcc tgcaggagat ctacaaggac ttgtactagc agagagtcct 1620 gagccactgc caacatttcc cttcttccag ttgcactatt ctgagggaaa atctgacacc 1680 taagaaattt actgtgaaaa agcattttaa aaagaaaagg ttttagaata tgatctattt 1740 tatgcatatt gtttataaag acacatttac aatttacttt taatattaaa aattaccata 1800 ttatgaaatt gctgatagta 1820 <210> 26 <211> 505 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 26 Met Gly Glu Thr Leu Gly Asp Ser Pro Ile Asp Pro Glu Ser Asp Ser 1 5 10 15 Phe Thr Asp Thr Leu Ser Ala Asn Ile Ser Gln Glu Met Thr Met Val 20 25 30 Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly Ile Ser Ser Val 35 40 45 Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe Asp Ile Lys Pro 50 55 60 Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro His Tyr Glu Asp 65 70 75 80 Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp Tyr Lys Tyr Asp 85 90 95 Leu Lys Leu Gln Glu Tyr Gln Ser Wing Ile Lys Val Pro Glu Wing Ser 100 105 110 Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn Lys Pro His Glu 115 120 125 Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg Val Cys Gly Asp 130 135 140 Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys Glu Gly Cys Lys 145 150 155 160 Gly Phe Phe Arg Thr and Arg Leu Lys Leu and Tyr Asp Arg Cys 165 170 175 Asp Leu Asn Cys Arg Ile His Lys Ser Arg Asn Lys Cys Gln Tyr 180 185 190 Cys Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser His Asn Ala Ile 195 200 205 Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys Leu Leu Ala Glu 210 215 220 Ile Ser Ser Asp Ile Asp Gln Leu Asn Pro Glu Ser Ala Asp Leu Arg 225 230 235 240 Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys Ser Phe Pro Leu 245 250 255 Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys Thr Thr Asp Lys 260 265 270 Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met Met Gly Glu Asp 275 280 285 Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu Gln Ser Lys Glu 290 295 300 Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg Ser Val Glu Ala 305 310 315 320 Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro Gly Phe Val Asn 325 330 335 Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr Gly Val His Glu 340 345 350 Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys Asp Gly Val Leu 355 360 365 Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe Leu Lys Ser Leu 370 375 380 Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe Glu Phe Ala Val 385 390 395 400 Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu Ala Ile Phe Ile 405 410 415 Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu Leu Asn Val Lys 420 425 430 Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala Leu Glu Leu Gln 435 440 445 Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe Ala Lys Leu Leu 450 455 460 Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu His Val Gln Leu 465 470 475 480 Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser Leu His Pro Leu 485 490 495 Leu Gln Glu Ile Tyr Lys Asp Leu Tyr 500 505 <210> 27 <211> 1919 <212> Ms <213> artificial sequence <220> <223> synthetic polymers <400> 27 ttggtggaag gtgggtgtgt agtcgtgta ctttacgcct cggtgtttag ggaggagcct 60 aaggtagga gtcagaaacg gggagtacc gagctgcggc tttataa ggtcagtggt 120 aggtaggaa ggggccttaa cctctgctgg tgaccagaag cctgcatttc tgcattctgc 180 ttaatttccct ttccttagat ttgaagag ccacacta ccacaata 240 ccattttctc aaacgagagt cagccttaa cgaatgacc atggttgaca cagagatgcc 300 attctggccc accactttg ggatcagctc cgtggatctc tccgtaatgg agaccactc 360 ccactccttt gatatcaagc ccttcactac tgttgactc tccagcattt ctactccaca 420 ttacgaagac attccattca ttacgaacaga tccagtggtt gcagattaca agtatgacct 480 gaaacttcaa gagtaccaa gtgcaatcaa agtggagcct gcatctccac cttattattc 540 tgagagact cagctctaca ataagcctca tgagagcct tccactccc tcatggcaat 600 tgaatgtcgt gtctgtggag ataaagcttc tggattcac tatggattc atgcttgtga 660 aggatgcaag gttttcttcc ggagaacaat cagattgaag cttatctatg acgatgtga 720 tcttaactgt cggatccaca aaaaagtag aaataatgt cagtactgtc ggtttcagaa 780 atgccttgca gtggggatgt ctcataatgc catcaggtttt gggcggatgc cacaggccga 840 gaaggagaag ctgttggcgg agatctccag tgatatcgac cagctgaatc cagagtccgc 900 tgacctccgg gccctggcaa aacattgta tgactcatac ataaagtcct tcccgctgac 960 haaagcaag gcgaggggcga tcttgacagg aagacaacac cattcgttat 1020 ctatgacatg aattccttaa tgatgggaga agtaaaatc aagttcaac acatcacccc 1080 cctgcaggag cagagcaag aggtggccat ccgcatctt cagggctgcc agttcgctc 1140 cgtggaggct gtgcaggaga tcacagagta tgccaaagc attcctggtt ttgtaaatct 1200 tgacttgaac gaccaagtaa ctctcctcaa atatggagtc cacgagatca tttacacaat 1260 gctggcctcc ttgatgaata aagatggggt tctcatatcc gagggccaag gcttcatgac 1320 aagggagttt ctaaagagcc tgcgaaagcc ttttggtgac tttatggagc ccaagtttga 1380 gtttgctgtg aagttcaatg cactggaatt agatgacagc gacttggca tattattgc 1440 tgtcattatt ctcagtggag accgcccagg tttgctgaat gtgaagccca ttgaagacat 1500 tcaagacaac ctgctacaag ccctggagct ccagctgaag ctgaaccacc ctgagtcctc 1560 acagctgttt gccaagctgc tccagaaaat gacagacctc agacagattg tcacggaaca 1620 cgtgcagcta ctgcaggtga tcaagaagac ggagacagac atgagtcttc acccgctcct 1680 gcaggagatc tacaaggact tgtactagca gagagtcctg agccactgcc aacatttccc 1740 ttcttccagt tgcactattc tgagggaaaa tctgacacct aagaaattta ctgtgaaaaa 1800 gcattttaaa aagaaaaggt tttagaatat gatctatttt atgcatattg tttataaaga 1860 cacatttaca atttactttt aatattaaaa attaccatat tatgaaattg ctgatagta 1919 <210> 28 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 28 Met Thr Met Val Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly 1 5 10 15 Ile Ser Ser Val Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe 20 25 30 Asp Ile Lys Pro Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro 35 40 45 His Tyr Glu Asp Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp 50 55 60 Tyr Lys Tyr Asp Leu Lys Leu Gln Glu Tyr Gln Ser Ala Ile Lys Val 65 70 75 80 Glu Pro Ala Ser Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn 85 90 95 Lys Pro His Glu Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg 100 105 110 Val Cys Gly Asp Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys 115 120 125 Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr Ile Arg Leu Lys Leu Ile 130 135 140 Tyr Asp Arg Cys Asp Leu Asn Cys Arg Ile His Lys Ser Arg Asn 145 150 155 160 Lys Cys Gln Tyr Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser 165 170 175 His Asn Ala Ile Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys 180 185 190 Leu Leu Ala Glu Ile Ser Ser Asp Ile Asp Gln Leu Asn Pro Glu Ser 195 200 205 Ala Asp Leu Arg Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys 210 215 220 Ser Phe Pro Leu Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys 225 230 235 240 Thr Thr Asp Lys Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met 245 250 255 Met Gly Glu Asp Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu 260 265 270 Gln Ser Lys Glu Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg 275 280 285 Ser Val Glu Ala Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro 290 295 300 Gly Phe Val Asn Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr 305 310 315 320 Gly Val His Glu Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys 325 330 335 Asp Gly Val Leu Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe 340 345 350 Leu Lys Ser Leu Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe 355 360 365 Glu Phe Ala Val Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu 370 375 380 Ala Ile Phe Ile Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu 385 390 395 400 Leu Asn Val Lys Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala 405 410 415 Leu Glu Leu Gln Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe 420 425 430 Ala Lys Leu Leu Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu 435 440 445 His Val Gln Leu Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser 450 455 460 Leu His Pro Leu Leu Gln Glu Ile Tyr Lys Asp Leu Tyr 465 470 475 <210> 29 <211> 1818 <212> Ms <213> artificial sequence <220> <223> synthetic polymers <400> 29 ggcgcccgcg cccgcccccg cgccgggccc ggctcggccc gacccggctc cgccgcgggc 60 aggcggggcc cagcgcactc ggagcccgag cccgagccgc agccgccgcc tggggcgctt 120 gggtcggcct cgaggacacc ggagaggggc gccacgccgc cgtggccgca gaaatgacca 180 tggttgacac agagatgcca ttctggccca ccaactttgg gatcagctcc gtggatctct 240 ccgtaatgga agaccactcc cactcctttg atatcaagcc cttcactact gttgacttct 300 ccagcatttc tactccacat tacgaagaca ttccattcac aagaacagat ccagtggttg 360 cagattacaa gtatgacctg aaacttcaag agtaccaaag tgcaatcaaa gtggagcctg 420 catctccacc ttattattct gagaagactc agctctacaa taagcctcat gaagagcctt 480 ccaactccct catggcaatt gaatgtcgtg tctgtggaga taaagcttct ggatttcact 540 atggagttca tgcttgtgaa ggatgcaagg gtttcttccg gagaacaatc agattgaagc 600 ttatctatga cagatgtgat cttaactgtc ggatccacaa aaaaagtaga aataaatgtc 660 agtactgtcg gtttcagaaa tgccttgcag tggggatgtc tcataatgcc atcaggtttg 720 ggcggatgcc acaggccgag aaggaagc tgttggcgga gatctccagt gatatcgacc 780 agctgaatcc agagtccgct gacctccggg ccctggcaaa acatttgtat gactcataca 840 taaagtcctt cccgctgacc aaagcaaagg cgagggcgat cttgacagga aagacaacag 900 960 agttcaaaca catcacccc ctgcaggagc agagcaaga ggtggccatc cgcatctttc 1020 agggctgcca gtttcgctcc gtggaggctg tgcaggagat cacagagtat gccaaaagca 1080 ttcctggttt tgtaaatctt gacttgaacg accaagtaac tctcctcaaa tatggagtcc 1140 acgagatcat ttacacaatg ctggcctcct tgatgaataa agatggggtt ctcatatccg 1200 agggccaagg cttcatgaca agggagtttc taaagagcct gcgaaagcct tttggtgact 1260 ttatggagcc caagtttgag tttgctgtga agttcaatgc actggaatta gatgacagcg 1320 acttggcaat atttattgct gtcattattc tcagtggaga ccgcccaggt ttgctgaatg 1380 tgaagcccat tgaagacatt caagaacaacc tgctacaagc cctggagctc cagctgaagc 1440 tgaaccaccc tgagtcctca cagctgtttg ccaagctgct ccagaaaatg acagacctca 1500 gacagattgt cacggaacac gtgcagctac tgcaggtgat caagaagacg gagacagaca 1560 tgagtcttca cccgctcctg caggagatct acaaggactt gtactagcag agagtcctga 1620 gccactgcca acatttccct tcttccagtt gcactattct gagggaaaat ctgacaccta 1680 agaaatttac tgtgaaaaag cattttaaaa agaaaaggtt ttagaatatg atctatttta 1740 tgcatattgt ttataaagac acatttacaa tttactttta atattaaaaa ttaccatatt 1800 atgaaattgc tgatagta 1818 <210> 30 <211> 477 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 30 Met Thr Met Val Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly 1 5 10 15 Ile Ser Ser Val Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe 20 25 30 Asp Ile Lys Pro Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro 35 40 45 His Tyr Glu Asp Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp 50 55 60 Tyr Lys Tyr Asp Leu Lys Leu Gln Glu Tyr Gln Ser Ala Ile Lys Val 65 70 75 80 Glu Pro Ala Ser Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn 85 90 95 Lys Pro His Glu Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg 100 105 110 Val Cys Gly Asp Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys 115 120 125 Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr Ile Arg Leu Lys Leu Ile 130 135 140 Tyr Asp Arg Cys Asp Leu Asn Cys Arg Ile His Lys Ser Arg Asn 145 150 155 160 Lys Cys Gln Tyr Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser 165 170 175 His Asn Ala Ile Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys 180 185 190 Leu Leu Ala Glu Ser Ser Ile Asp Ile Asp Gln Leu Asn Pro Glu Ser 195 200 205 Ala Asp Leu Arg Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys 210 215 220 Ser Phe Pro Leu Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys 225 230 235 240 Thr Thr Asp Lys Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met 245 250 255 Met Gly Glu Asp Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu 260 265 270 Gln Ser Lys Glu Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg 275 280 285 Ser Val Glu Ala Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro 290 295 300 Gly Phe Val Asn Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr 305 310 315 320 Gly Val His Glu Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys 325 330 335 Asp Gly Val Leu Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe 340 345 350 Leu Lys Ser Leu Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe 355 360 365 Glu Phe Ala Val Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu 370 375 380 Ala Ile Phe Ile Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu 385 390 395 400 Leu Asn Val Lys Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala 405 410 415 Leu Glu Leu Gln Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe 420 425 430 Ala Lys Leu Leu Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu 435 440 445 His Val Gln Leu Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser 450 455 460 Leu His Pro Leu Leu Gln Glu Ile Tyr Lys Asp Leu Tyr 465 470 475 <210> 31 <211> 8718 <212> Ms <213> artificial sequence <220> <223> synthetic polymers <400> 31 cctcccctcg cccggcgcgg tcccgtccgc ctctcgctcg cctcccgcct cccctcggtc 60 ttccgaggcg cccgggctcc cggcgcggcg gcggaggggg cgggcaggcc ggcggggcggt 120 gatgtggcgg gactctttat gcgctgcggc aggatacgcg ctcggcgctg ggacgcgact 180 gcgctcagtt ctctcctctc gcgctgca gccatgatgg aagtttgaga gttgagccgc 240 tgtgaggcga ggccgggctc aggcgaggga gatgagagac ggcggcggcc gcggcccgga 300 gcccctctca gcgcctgtga gcagccgcgg gggcagcgcc ctcggggagc cggccggcct 360 gcggcggcgg cagcggcggc gtttctcgcc tcctcttcgt cttttctaac cgtgcagcct 420 cttcctcggc ttctcctgaa agggaaggtg gaagccgtgg gctcgggcgg gagccggctg 480 aggcgcggcg gcggcggcgg cacccccgc tcctggagcg ggggggaga gcggcggcgg 540 cggcggccgc ggcggctgca gctccaggga gggggtctga gtcgcctgtc accatttcca 600 gggctgggaa cgccggagag ttggtctctc cccttctact gcctccaaca cggcggcggc 660 ggcggcggca catccaggga cccggggccgg ttttaaacct cccgtccgcc gccgccgcac 720 cccccgtggc ccgggctccg gaggccgccg gcggaggcag ccgttcggag gattattcgt 780 cttctcccca ttccgctgcc gccgctgcca ggctctggc tgctgaggag aagcaggcc 840 agtcgctgca accatccagc agccgccgca gcagccatta cccggctgcg gtccagagcc 900 aagcggcggc agagcgaggg gcatcagcta ccgccaagtc cagagccatt tccatcctgc 960 agaagaagcc ccgccaccag cagctctgc catctctc ctccttttc ttcagccaca 1020 ggctcccaga catgacagcc atcatcaag agatcgttag cagaacaa aggagatc 1080 aagaggatgg attcgactta gacttgacct atatttatcc aacattatt gctatgggat 1140 ttcctgcaga aagacttgaa ggcgtataca ggaacaat tgatgta gtaggtttt 1200 tggattcaa gcataaaaac cattacaaga tatacaatct tgtgctgaa agacattatg 1260 acaccgccaa atttaattgc agagttgcac atatcctttt tgaagaccat aacccaccac 1320 agctagaact tatcaaaccc tttgtgaag atcttgacca atggctaagt gaagagatgaca 1380 atcatgttgc agcattcac tgtaaagctg gaaagggacg aactggtgta atgatatgtg 1440 catatttatt acatcggggc aaatttttaa aggcacaaga ggccctagat ttctatgggg 1500 aagtaggac cagagacaaa aagggagta ctattcccag tcagaggcgc tatgtgtatt 1560 attatagcta cctgttaaag aatcatctgg attatagacc agtgcactg ttgttcaca 1620 nagatgatgtt tgaactatt ccaatgttca gtggcggac ttgcaatcct cagtttgtgg 1680 tctgccagct aaggtgaag atatattcct ccaattcagg acccacacga cgggagaca 1740 agttcatgta ctttgagttc cctcagccgt tacctgtgtg tggtgatatc aaagtagagt 1800 tcttccacaag atgctaaaaa aggacaaat gtttcacttt tggtaata 1860 cattcttcat accaggacca gaggaaacct cagaaaagt agaaaatgga agtctatgtg 1920 atcaagaaat cgatagcatt tgcagtatag agcgtgcaga taatgacaag gatatctag 1980 tacttacttt aaaaaaat gatcttgaca aagcaata agacaagcc aaccgatact 2040 tttctccaaa tttaaggtg aagctgtact tcacaaaac agtagaggag ccgtcaatc 2100 cagaggctag cagttcact tctgtacac cagatgttag tgacaatgaa cctgatcatt 2160 atagatattc tgacaccact gactctgatc cagagaatga accttttgat gagatcagc 2220 atacacaaat tacaaagtc tgaattttttt ttcaaga gggataaac accatgaaaa 2280 taaacttgaa taaactgaaa atggacctttt tttttta tggcaatagg acatgtgtc 2340 agattaccag ttataggaac aattctcttt tcctgaccaa tctgtttta ccctatacat 2400 ccacagggtt ttgacacttg tgtccagtt gaaaaaggt tgtgtagctg tgtcatgtat 2460 attacktttt gtgtcaaag gatacttaa attack gatttaataa gatggcactt 2520 tcccgtttta ttccagtttt aaaaagtg gagacagact gatgtgtata cgtaggaatt 2580 ttttcctttt gtgttctgtc accaactgaa gtggctaaag agctttgtga tatactggtt 2640 cacatcctac ccctttgcac tgtggcac agatagttt gcagttggct aagagaggtt 2700 tccgaagggt ttgctacat tctaatgcat gtattcggt tagggaatg gagggaatgc 2760 tcagaaagga ataatttta tgctggactc tggaccatat accatctcca gctatttaca 2820 cacaccttc tttagcatgc tacagttatt aatctggaca tcgaggaat tggccgctgt 2880 cactgcttgt tgtttgcgca tttttttta aagcatattg gtgctagaaa aggcagctaa 2940 aggaagtgaa tctgtattgg gggtacaggaa tgaaccttct gcacatctt aagatccaca 3000 atgaaggga tataaaaata atgtcatagg windowaacac agcacaatg acttaaccat 3060 aaatgtgg aggctatca caagaatgg gcttgaaca tttaaaaat tgacaatgat 3120 ttattaaata tgttttctca attgtaacga cttctccatc tcctgtgta tcaggccag 3180 tgctaaaatt cagatgctgt tagtacctac atcagtcac aacttacact tattttacta 3240 gttttcaatc ataataccctg ctgtggatgc ttcatgtgct gcctgcaagc ttctttttc 3300 tcattaaata taaaatattt tgtaatgctg cacagaaatt ttcaatttga gattctacag 3360 taagcgtttt ttttctttga agatttatga tgcacttatt caatagctgt cagccgttcc 3420 acccttttga ccttacacat tctattaca tgaatttgc agttttgcac atttttaaa 3480 tgtcattaac tgttaggaa ttttacttga atactgaata catataatgt ttatattaaa 3540 aaggacattt gtgttaaaaa ggaaattaga gttgcagtaa actttcaatg ctgcacacaa 3600 aaaaaagaca tttgatttt cagtagaaat tgtcctacat gtgctttatt gatttgctat 3660 tgaaagaata gggtttttt tttttttttt tttttttt ttaaatgtgc agtgttgaat 3720 cattcttca tagtgctccc ccgagttggg actagggctt caatttcact tcttaaaaaa 3780 aatcatcata tatttgatat gcccagactg catacgattt taagcggagt acaactacta 3840 ttgtaaagct aatgtgaaga tattattaaa aaggtttttt tttccagaaa tttggtgtct 3900 tcaaattata ccttcacctt gacatttgaa tatccagcca ttttgtttct taatggtata 3960 aaattccatt ttcaataact tattggtgct gaaattgttc actagctgtg gtctgaccta 4020 gttaatttac aaatacagat tgaataggac ctactagagc agcatttata gagtttgatg 4080 gcaaatagat taggcagaac ttcatctaaa atattcttag taaataatgt tgacacgttt 4140 tccatacctt gtcagtttca ttcaacaatt tttaaatttt taacaaagct cttaggatttt 4200 acacatttat attaaacat tgatatatag agtattgatt gattgctcat aagttaaatt 4260 ggtaaagtta gagacaacta ttctaacacc tcaccattga aatttatatg ccaccttgtc 4320 tttcataaaa gctgaaaatt gttacctaaa atgaaaatca acttcatgtt ttgaagatag 4380 ttataaatat tgttctttgt tacaatttcg ggcaccgcat attaaaacgt aactttattg 4440 ttccaatatg taacatggag ggccaggtca taaataatga cattataatg ggcttttgca 4500 ctgttattat ttttccttg gaatgtgaag gtctgaatga gggttttgat tttgaatgtt 4560 tcaatgtttt tgagaagcct tgcttacatt tttggtgta gtcattggaa atggaaaaat 4620 ggcattat father father father father father actctcctta ctttatttca 4680 gttaccatcc ccatagaatt tgacaagaat tgctatgact gaaaggtttt cgagtcctaa 4740 ttaaaacttt attatggca gtattcataa ttagcctgaa atgcattctg taggtaatct 4800 ctgagtttct ggaatatttt cttagacttt ttggatgtgc agcagcttac atgtctgaag 4860 ttacttgaag gcatcacttt taagaaagct tacagttggg ccctgtacca tcccaagtcc 4920 tttgtagctc ctcttgaaca tgtttgccat acttttaaaa gggtagttga ataatagca 4980 tcaccattct ttgctgtggc acaggttata aacttaagtg gagtttaccg gcagcatcaa 5040 atgtttcagc tttaaaaaat aaaagtaggg tacaagttta atgtttagtt ctagaaattt 5100 tgtgcaatat gttcataacg atggctgtgg ttgccacaaa gtgcctcgtt tacctttaaa 5160 tactgttaat gtgtcatgca tgcagatgga agggtggaa ctgtgcacta aagtggggc 5220 tttaactgta gtatttggca gagttgcctt ctacctgcca gttcaaagt tcaacctgtt 5280 ttcatataga atatatatac taaaaaattt cagtctgtta aacagcctta ctctgattca 5340 gcctcttcag atactctgt gctgtgcagc agtggctg tgtgtaatg ctagcactg 5400 aggatacaca aaataccaa tatgatgt acaggataat gcctcatccc aatcagatgt 5460 ccatttgtta tgtgtttgt taacaaccct ttatctctta gtgttataaa ctccacttaa 5520 aactgattaa agtctcattc ttgtcattgt gtgggtgttt tattaatga gagtttataa 5580 ttcaattgc ttaagtccat tgaagtttta attaatgggc agccaatgt gatacaag 5640 tttcagtttt ttttttcc tgctgtcctt caaagcctac tgtttaaaa aaaaaaaaaa 5700 aaaaaacatg gcctgagagt aggatatctg tctactcatg tttattag gaaaaacact 5760 tattttagg gctttagtca tcacttcata aattgtataa gcacattaaa tagcgttcta 5820 gtcctgaaaa agtccaagat tcttagaaaa ttgtgcatat ttttattatg acagatgttt 5880 gaagataatt ccccagaatg gatttgatac tttagatttc aattttgtgg cttttgtcta 5940 ttattctgta ctctgccatc agcatatgga aagcttcatt tactcatcat gacttgtgcc 6000 atataaaaat tgatatttcg gaatagtcta aaggactttt tgtacttgaa tttaatcatg 6060 ttgtttctaa tattcttaaa agcttgaaga ctaaagcata tcctttcaac aaagcatagt 6120 aaggtaataa gaaagtgtag tttgtacaag tgttaaaaaa ataaagtaga caatgttaca 6180 gtgggactta ttatttcaag tttacatttt ctccatgtaa ttttttaaaa agtaaatgaa 6240 aaaatgtgca ataatgtaaa atatgaagtg tatgtgtaca cacattttat ttttcggtat 6300 cttgggtata cgtatggttg aaaactatac tggagtctaa aagtattcta atttataaga 6360 agacattttg gtgatgtttg aaaaatagaa atgtgctagt tttgttttta tatcatgtcc 6420 tttgtacgtt gtaatatgag ctggcttggt tcagtaaatg ccatcaccat ttccattgag 6480 aatttaaaac tcaccagtgt ttaatatgca ggcttccaaa ggcttatgaa aaaaatcaag 6540 acccttaaat ctagttaatt tgctgctaac atgaaactct ttggttcttt tatttttgcc 6600 agataattag acacacatct aaagcttagt cttaaatggc ttaagtgtag ctattgatta 6660 gtgctgttgc tagttcagaa agaaatgttt gtgaatggaa acaagaatat tcagtccaaa 6720 ctgttgtaag gacagtacct gaaaaccagg aaacaggata atggaaaaag tcttttaaag 6780 atgaaatgtt ggagccaact ttcttataga attaattgta tgtggctata gaaagcctaa 6840 tgattgttgc ttatttttga gagcatatta ttcttttatg accataatct tgctgttttt 6900 ccatcttcca aaagatcttc cttctaatat gtatatcaga atgtgggtag ccagtcagac 6960 aaattcatat tggttggtag ctttaaaaag tttgtaatgt gaagacagga aaggacaaaa 7020 tagtttgctt tggtggtagt actctggttg ttaagctagg tattttgaga ctacttcccc 7080 atcacaacaa caataaaata atcactcata atcctatcac ctggagacat agccatcgtt 7140 aatatgttag tgactataca atcatgtttt cttctgtata tccatgtata ttctttaaaa 7200 atgaaattta tactgtacct gatctcaaag ctttttagct tagtatatct gtcatgaatt 7260 tgtaggatgt tccattgcat cagaaaacgg acagtgatt gattactttc taatgccaca 7320 gatgcagatt acatgtagtt attgagaatc ctttcgaatt cagtggctta atcatgaatg 7380 tctaaatatt gttgacatta ggatgataca tgtaattaa agttacattt gtttagcata 7440 gandaagctta acattgtaga tgttctctt caaaatcat cttaaactt tgcatttgga 7500 attgtgttaa atagaatgtg tgaacactg tattagtaaa cttcatcacc tttctactc 7560 cttatagttt gaacttttca gttttgtag ttcccaaca gttgctcaat ttagagcaaa 7620 ttaatttaac acctgccaaa aaaagctgc tgttggctta tcagttgtct ttaattchca 7680 atgctcatgt gactttatc acatcaaaa attttcatt atgattcac ctttagctct 7740 gaaaattacc gcgtttagta attatagtgg gcttataaaa acatgcaact ctttttgata 7800 gttattgag aattttggtg aaaaatattt agctgagggc agtatagaac ttataaacca 7860 atatattgat atttttaaaa cattttaca tataagtaaa ctgccatctt tgagcataac 7920 tacatttaa aaagctg catattttta aatcaagtgt ttacaagaa tttatattt 7980 ttatttttta aaattaaaaa taatttatat ttcctctgtt gcatgaggat tctcatctgt 8040 gcttataatg gttagagatt ttattgtgt ggaatgaagt gaggcttgta gtcatggttc 8100 tagtgtttca gtttgccaag tctgtttact gcagtgaaat tcatcaaatg tttcagtgtg 8160 gttttctgta gcctatcatt tactggctat ttttttatgt acacctttag gattttctgc 8220 ctactctatc cagttgtcca aatgatatcc tacattttac aaatgccctt tcagtttcta 8280 ttttcttttt ccattaaatt gccctcatgt cctaatgtgc agtttgtaag tgtgtgtgtg 8340 tgtgtctgtg tgtgtgtgaa tttgattttc aagagtgcta gacttccaat ttgagagatt 8400 aaataattta attcaggcaa acatttttca ttggaatttc acagttcatt gtaatgaaaa 8460 tgttaatcct ggatgacctt tgacatacag taatgaatct tggatattaa tgaatttgtt 8520 agtagcatct tgatgtgtgt tttaatgagt tattttcaaa gttgtgcatt aaaccaaagt 8580 tggcatactg gaagtgttta tatcaagttc catttggcta ctgatggaca aaaaatagaa 8640 atgccttcct atggagagta tttttccttt aaaaaattaa aaaggttaat tattttgact 8700 aaaaaaaaaa aaaaaaaa 8718 <210> 32 <211> 403 <212> PRT <213> Artificial sequence <220> <223> Synthetic polymer <400> 32 Met Thr Ala Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg Arg Tyr 1 5 10 15 Gln Glu Asp Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro Asn Ile 20 25 30 Ile Ala Met Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr Arg Asn 35 40 45 Asn Ile Asp Asp Val Val Arg Phe Leu Asp Ser Lys His Lys Asn His [[ID=三十]]<22> 50 55 60 Tyr Lys Ile Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr Ala Lys 65 70 75 80 Phe Asn Cys Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn Pro Pro 85 90 95 Gln Leu Glu Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln Trp Leu 100 105 110 Ser Glu Asp Asp Asn His Val Ala Ala Ile His Cys Lys Ala Gly Lys 115 120 125 It should be noted that there is an error in the original text where [[ID=三十]] is incorrect. It should probably be . This has been corrected in the translation where applicable. Also, the line breaks and tags are preserved as per the requirements.Gly Arg Thr Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg Gly Lys 130 135 140 Phe Leu Lys Ala Gln Glu Ala Leu Asp Phe Tyr Gly Glu Val Arg Thr 145 150 155 160 Arg Asp Lys Lys Gly Val Thr Ile Pro Ser Gln Arg Arg Tyr Val Tyr 165 170 175 Tyr Tir Ser Tire Leo Lys Asn His Leu Asp Tire Arg Pro Val Ala 180 185 190 Leu Leu Phe His Lys Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly 195 200 205 Gly Thr Cys Asn Pro Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile 210 215 220 Tyr Ser Ser Asn Ser Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr 225 230 235 240 Phe Glu Phe Pro Gln Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu 245 250 255 Phe Phe His Gln Asn Lys Met Leu Lys Lys Asp Lys Met Phe His 260 265 270 Phe Trp Val Asn Thr Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu 275 280 285 Lys Val Glu Asn Gly Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys 290 295 300 Ser Ile Glu Arg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu 305 310 315 320 Thr Lys Asn Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr 325 330 335 Phe Ser Pro Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu 340 345 350 Glu Pro Ser Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp 355 360 365 Val Ser Asp Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp 370 375 380 Ser Asp Pro Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile ;385 390 395 400 Thr Lys Val <210> 33 <211>​​​​​​​​​​​​ttccgaggcg cccgggctcc cggcgcggcg gcggaggggg cgggcaggcc ggcggggcggt 120 gatgtggcgg gactctttat gcgctgcggc aggatacgcg ctcggcgctg ggacgcgact 180 gcgctcagtt ctctcctctc gcgctgca gccatgatgg aagtttgaga gttgagccgc 240 tgtgaggcga ggccgggctc aggcgaggga gatgagagac ggcggcggcc gcggcccgga 300 gcccctctca gcgcctgtga gcagccgcgg gggcagcgcc ctcggggagc cggccggcct 360 gcggcggcgg cagcggcggc gtttctcgcc tcctcttcgt cttttctaac cgtgcagcct 420 cttcctcggc ttctcctgaa agggaaggtg gaagccgtgg gctcgggcgg gagccggctg 480 aggcgcggcg gcggcggcgg cacccccgc tcctggagcg ggggggaga gcggcggcgg 540 cggcggccgc ggcggctgca gctccaggga gggggtctga gtcgcctgtc accatttcca 600 gggctgggaa cgccggagag ttggtctctc cccttctact gcctccaaca cggcggcggc 660 ggcggcggca catccaggga cccggggccgg ttttaaacct cccgtccgcc gccgccgcac 720 cccccgtggc ccgggctccg gaggccgccg gcggaggcag ccgttcggag gattattcgt 780 cttctcccca ttccgctgcc gccgctgcca ggctctggc tgctgaggag aagcaggcc 840 agtcgctgca accatccagc agccgccgca gcagccatta cccggctgcg gtccagagcc 900 aagcggcggc agagcgaggg gcatcagcta ccgccaagtc cagagccatt tccatcctgc 960 agaagaagcc ccgccaccag cagctctgc catctctc ctccttttc ttcagccaca 1020 ggctcccaga catgacagcc atcatcaag agatcgttag cagaacaa aggagatc 1080 aagaggatgg attcgactta gacttgacct atatttatcc aacattatt gctatgggat 1140 ttcctgcaga aagacttgaa ggcgtataca ggaacaat tgatgta gtaggtttt 1200 tggattcaa gcataaaaac cattacaaga tatacaatct tgtgctgaa agacattatg 1260 acaccgccaa atttaattgc agagttgcac atatcctttt tgaagaccat aacccaccac 1320 agctagaact tatcaaaccc tttgtgaag atcttgacca atggctaagt gaagagatgaca 1380 atcatgttgc agcattcac tgtaaagctg gaaagggacg aactggtgta atgatatgtg 1440 catatttatt acatcggggc aaatttttaa aggcacaaga ggccctagat ttctatgggg 1500 aagtaggac cagagacaaa aagggagta ctattcccag tcagaggcgc tatgtgtatt 1560 attatagcta cctgttaaag aatcatctgg attatagacc agtgcactg ttgttcaca 1620 nagatgatgtt tgaactatt ccaatgttca gtggcggac ttgcaatcct cagtttgtgg 1680 tctgccagct aaggtgaag atatattcct ccaattcagg acccacacga cgggagaca 1740 agttcatgta ctttgagttc cctcagccgt tacctgtgtg tggtgatatc aaagtagagt 1800 tcttccacaag atgctaaaaa aggacaaat gtttcacttt tggtaata 1860 cattcttcat accaggacca gaggaaacct cagaaaagt agaaaatgga agtctatgtg 1920 atcaagaaat cgatagcatt tgcagtatag agcgtgcaga taatgacaag gatatctag 1980 tacttacttt aaaaaaat gatcttgaca aagcaata agacaagcc aaccgatact 2040 tttctccaaa tttaaggtg aagctgtact tcacaaaac agtagaggag ccgtcaatc 2100 cagaggctag cagttcact tctgtacac cagatgttag tgacaatgaa cctgatcatt 2160 atagatattc tgacaccact gactctgatc cagagaatga accttttgat gagatcagc 2220 atacacaaat tacaaagtc tgaattttttt ttcaaga gggataaac accatgaaaa 2280 taaacttgaa taaactgaaa atggacctttt tttttta tggcaatagg acatgtgtc 2340 agattaccag ttataggaac aattctcttt tcctgaccaa tctgtttta ccctatacat 2400 ccacagggtt ttgacacttg tgtccagtt gaaaaaggt tgtgtagctg tgtcatgtat 2460 attacktttt gtgtcaaag gatacttaa attack gatttaataa gatggcactt 2520 tcccgtttta ttccagtttt aaaaagtg gagacagact gatgtgtata cgtaggaatt 2580 ttttcctttt gtgttctgtc accaactgaa gtggctaaag agctttgtga tatactggtt 2640 cacatcctac ccctttgcac tgtggcac agatagttt gcagttggct aagagaggtt 2700 tccgaagggt ttgctacat tctaatgcat gtattcggt tagggaatg gagggaatgc 2760 tcagaaagga ataatttta tgctggactc tggaccatat accatctcca gctatttaca 2820 cacaccttc tttagcatgc tacagttatt aatctggaca tcgaggaat tggccgctgt 2880 cactgcttgt tgtttgcgca tttttttta aagcatattg gtgctagaaa aggcagctaa 2940 aggaagtgaa tctgtattgg gggtacaggaa tgaaccttct gcacatctt aagatccaca 3000 atgaaggga tataaaaata atgtcatagg windowaacac agcacaatg acttaaccat 3060 aaatgtgg aggctatca caagaatgg gcttgaaca tttaaaaat tgacaatgat 3120 ttattaaata tgttttctca attgtaacga cttctccatc tcctgtgta tcaggccag 3180 tgctaaaatt cagatgctgt tagtacctac atcagtcac aacttacact tattttacta 3240 gttttcaatc ataataccctg ctgtggatgc ttcatgtgct gcctgcaagc ttctttttc 3300 tcattaaata taaaatattt tgtaatgctg cacagaaatt ttcaatttga gattctacag 3360 taagcgtttt ttttctttga agatttatga tgcacttatt caatagctgt cagccgttcc 3420 acccttttga ccttacacat tctattaca tgaatttgc agttttgcac atttttaaa 3480 tgtcattaac tgttaggaa ttttacttga atactgaata catataatgt ttatattaaa 3540 aaggacattt gtgttaaaaa ggaaattaga gttgcagtaa actttcaatg ctgcacacaa 3600 aaaaaagaca tttgatttt cagtagaaat tgtcctacat gtgctttatt gatttgctat 3660 tgaaagaata gggtttttt tttttttttt tttttttttt ttaaatgtgc agtgttgaat 3720 cattcttca tagtgctccc ccgagttggg actagggctt caatttcact tcttaaaaaa 3780 aatcatcata tatttgatat gcccagactg catacgattt taagcggagt acaactacta 3840 ttgtaaagct aatgtgaaga tattattaaa aaggtttttt tttccagaaa tttggtgtct 3900 tcaaattata ccttcacctt gacatttgaa tatccagcca ttttgtttct taatggtata 3960 aaattccatt ttcaataact tattggtgct gaaattgttc actagctgtg gtctgaccta 4020 gttaatttac aaatacagat tgaataggac ctactagagc agcatttata gagtttgatg 4080 gcaaatagat taggcagaac ttcatctaaa atattcttag taaataatgt tgacacgttt 4140 tccatacctt gtcagtttca ttcaacaatt tttaaatttt taacaaagct cttaggatttt 4200 acacatttat attaaacat tgatatatag agtattgatt gattgctcat aagttaaatt 4260 ggtaaagtta gagacaacta ttctaacacc tcaccattga aatttatatg ccaccttgtc 4320 tttcataaaa gctgaaaatt gttacctaaa atgaaaatca acttcatgtt ttgaagatag 4380 ttataaatat tgttctttgt tacaatttcg ggcaccgcat attaaaacgt aactttattg 4440 ttccaatatg taacatggag ggccaggtca taaataatga cattataatg ggcttttgca 4500 ctgttattat ttttccttg gaatgtgaag gtctgaatga gggttttgat tttgaatgtt 4560 tcaatgtttt tgagaagcct tgcttacatt tttggtgta gtcattggaa atggaaaaat 4620 ggcattat father father father father father actctcctta ctttatttca 4680 gttaccatcc ccatagaatt tgacaagaat tgctatgact gaaaggtttt cgagtcctaa 4740 ttaaaacttt attatggca gtattcataa ttagcctgaa atgcattctg taggtaatct 4800 ctgagtttct ggaatatttt cttagacttt ttggatgtgc agcagcttac atgtctgaag 4860 ttacttgaag gcatcacttt taagaaagct tacagttggg ccctgtacca tcccaagtcc 4920 tttgtagctc ctcttgaaca tgtttgccat acttttaaaa gggtagttga ataatagca 4980 tcaccattct ttgctgtggc acaggttata aacttaagtg gagtttaccg gcagcatcaa 5040 atgtttcagc tttaaaaaat aaaagtaggg tacaagttta atgtttagtt ctagaaattt 5100 tgtgcaatat gttcataacg atggctgtgg ttgccacaaa gtgcctcgtt tacctttaaa 5160 tactgttaat gtgtcatgca tgcagatgga agggtggaa ctgtgcacta aagtggggc 5220 tttaactgta gtatttggca gagttgcctt ctacctgcca gttcaaagt tcaacctgtt 5280 ttcatataga atatatatac taaaaaattt cagtctgtta aacagcctta ctctgattca 5340 gcctcttcag atactctgt gctgtgcagc agtggctg tgtgtaatg ctagcactg 5400 aggatacaca aaataccaa tatgatgt acaggataat gcctcatccc aatcagatgt 5460 ccatttgtta tgtgtttgt taacaaccct ttatctctta gtgttataaa ctccacttaa 5520 aactgattaa agtctcattc ttgtcattgt gtgggtgttt tattaatga gagtttataa 5580 ttcaattgc ttaagtccat tgaagtttta attaatgggc agccaatgt gatacaag 5640 tttcagtttt ttttttcc tgctgtcctt caaagcctac tgtttaaaa aaaaaaaaaa 5700 aaaaaacatg gcctgagagt aggatatctg tctactcatg tttattag gaaaaacact 5760 tattttagg gctttagtca tcacttcata aattgtataa gcacattaaa tagcgttcta 5820 gtcctgaaaa agtccaagat tcttagaaaa ttgtgcatat ttttattatg acagatgttt 5880 gaagataatt ccccagaatg gatttgatac tttagatttc aattttgtgg cttttgtcta 5940 ttattctgta ctctgccatc agcatatgga aagcttcatt tactcatcat gacttgtgcc 6000 atataaaaat tgatatttcg gaatagtcta aaggactttt tgtacttgaa tttaatcatg 6060 ttgtttctaa tattcttaaa agcttgaaga ctaaagcata tcctttcaac aaagcatagt 6120 aaggtaataa gaaagtgtag tttgtacaag tgttaaaaaa ataaagtaga caatgttaca 6180 gtgggactta ttatttcaag tttacatttt ctccatgtaa ttttttaaaa agtaaatgaa 6240 aaaatgtgca ataatgtaaa atatgaagtg tatgtgtaca cacattttat ttttcggtat 6300 cttgggtata cgtatggttg aaaactatac tggagtctaa aagtattcta atttataaga 6360 agacattttg gtgatgtttg aaaaatagaa atgtgctagt tttgttttta tatcatgtcc 6420 tttgtacgtt gtaatatgag ctggcttggt tcagtaaatg ccatcaccat ttccattgag 6480 aatttaaaac tcaccagtgt ttaatatgca ggcttccaaa ggcttatgaa aaaaatcaag 6540 acccttaaat ctagttaatt tgctgctaac atgaaactct ttggttcttt tatttttgcc 6600 agataattag acacacatct aaagcttagt cttaaatggc ttaagtgtag ctattgatta 6660 gtgctgttgc tagttcagaa agaaatgttt gtgaatggaa acaagaatat tcagtccaaa 6720 ctgttgtaag gacagtacct gaaaaccagg aaacaggata atggaaaaag tcttttaaag 6780 atgaaatgtt ggagccaact ttcttataga attaattgta tgtggctata gaaagcctaa 6840 tgattgttgc ttatttttga gagcatatta ttcttttatg accataatct tgctgttttt 6900 ccatcttcca aaagatcttc cttctaatat gtatatcaga atgtgggtag ccagtcagac 6960 aaattcatat tggttggtag ctttaaaaag tttgtaatgt gaagacagga aaggacaaaa 7020 tagtttgctt tggtggtagt actctggttg ttaagctagg tattttgaga ctacttcccc 7080 atcacaacaa caataaaata atcactcata atcctatcac ctggagacat agccatcgtt 7140 aatatgttag tgactataca atcatgtttt cttctgtata tccatgtata ttctttaaaa 7200 atgaaattta tactgtacct gatctcaaag ctttttagct tagtatatct gtcatgaatt 7260 tgtaggatgt tccattgcat cagaaaacgg acagtgatt gattactttc taatgccaca 7320 gatgcagatt acatgtagtt attgagaatc ctttcgaatt cagtggctta atcatgaatg 7380 tctaaatatt gttgacatta ggatgataca tgtaattaa agttacattt gtttagcata 7440 gandaagctta acattgtaga tgttctctt caaaatcat cttaaactt tgcatttgga 7500 attgtgttaa atagaatgtg tgaacactg tattagtaaa cttcatcacc tttctactc 7560 cttatagttt gaacttttca gttttgtag ttcccaaca gttgctcaat ttagagcaaa 7620 ttaatttaac acctgccaaa aaaagctgc tgttggctta tcagttgtct ttaattchca 7680 atgctcatgt gactttatc acatcaaaa attttcatt atgattcac ctttagctct 7740 gaaaattacc gcgtttagta attatagtgg gcttataaaa acatgcaact ctttttgata 7800 gttattgag aattttggtg aaaaatattt agctgagggc agtatagaac ttataaacca 7860 atatattgat atttttaaaa cattttaca tataagtaaa ctgccatctt tgagcataac 7920 tacatttaa aaagctg catattttta aatcaagtgt ttacaagaa tttatattt 7980 ttatttttta aaattaaaaa taatttatat ttcctctgtt gcatgaggat tctcatctgt 8040 gcttataatg gttagagatt ttattgtgt ggaatgaagt gaggcttgta gtcatggttc 8100 tagtgtttca gtttgccaag tctgtttact gcagtgaaat tcatcaaatg tttcagtgtg 8160 gttttctgta gcctatcatt tactggctat ttttttatgt acacctttag gattttctgc 8220 ctactctatc cagttgtcca aatgatatcc tacattttac aaatgccctt tcagtttcta 8280 ttttcttttt ccattaaatt gccctcatgt cctaatgtgc agtttgtaag tgtgtgtgtg 8340 tgtgtctgtg tgtgtgtgaa tttgattttc aagagtgcta gacttccaat ttgagagatt 8400 aaataattta attcaggcaa acatttttca ttggaatttc acagttcatt gtaatgaaaa 8460 tgttaatcct ggatgacctt tgacatacag taatgaatct tggatattaa tgaatttgtt 8520 agtagcatct tgatgtgtgt tttaatgagt tattttcaaa gttgtgcatt aaaccaaagt 8580 tggcatactg gaagtgttta tatcaagttc catttggcta ctgatggaca aaaaatagaa 8640 atgccttcct atggagagta tttttccttt aaaaaattaa aaaggttaat tattttgact 8700 aaaaaaaaaaaaa aaaaaaaaa 8718 <210> 34 <211> 576 <212> PRT <213> artificial sequence <220> <223> synthetic polymers <400> 34 Leu Glu Arg Gly Gly Glu Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala 1 5 10 15 Ala Pro Gly Arg Gly Ser Glu Ser Pro Val Thr Ile Ser Arg Ala Gly 20 25 30 Asn Ala Gly Glu Leu Val Ser Pro Leu Leu Leu Pro Pro Thr Arg Arg 35 40 45 Arg Arg Arg Arg His Ile Gln Gly Pro Gly Pro Val Leu Asn Leu Pro 50 55 60 Ser Ala Ala Ala Ala Pro Pro Val Ala Arg Ala Pro Glu Ala Ala Gly 65 70 75 80 Gly Gly Ser Arg Ser Glu Asp Tyr Ser Ser Ser Pro His Ser Ala Ala 85 90 95 Ala Ala Ala Arg Pro Leu Ala Ala Glu Glu Lys Gln Ala Gln Ser Leu 100 105 110 Gln Pro Ser Ser Ser Arg Arg Ser Ser His Tyr Pro Ala Ala Val Gln 115 120 125 Gln Ser Ser Glu Arg Gly Ser Ser Thr On Lys Ser Arg 130 135 140 Ala Ile Ser Ile Leu Gln Lys Pro Arg His Gln Gln Leu Pro 145 150 155 160 Ser Leu Ser Ser Phe Phe Phe Ser His Arg Leu Pro Asp Met Thr Ala 165 170 175 Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg Tyr Gln Glu Asp 180 185 190 Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro Asn Ile Ala Met 195 200 205 Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr Arg Asn Asn Ile Asp 210 215 220 Asp Val Val Arg Phe Leu Asp Ser Lys Lys Asn His Tyr Lys Ile 225 230 235 240 Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr Ala Lys Phe Asn Cys 245 250 255 Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn Pro Pro Gln Leu Glu 260 265 270 Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln Trp Leu Ser Glu Asp 275 280 285 Asp Asn His Val Ala Ala Ile His Cys Lys Ala Gly Lys Gly Arg Thr 290,295,300 Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg Gly Lys Phe Leu Lys 305 310 315 320 Gln Glu Ala Leu Asp Phe Tyr Gly Glu Val Arg Thr Arg Asp Lys 325 330 335 Lys Gly Val Thr Ile Pro Ser Gln Arg Arg Tyr Val Tyr Tyr Tyr Ser 340 345 350 Tyr Leu Leu Lys Asn His Leu Asp Tyr Arg Pro Val Ala Leu Phe 355 360 365 His Lys Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly Gly Thr Cys 370 375 380 Asn Pro Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile Tyr Ser Ser 385 390 395 400 Asn Ser Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr Phe Glu Phe 405 410 415 Pro Gln Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu Phe Phe His 420 425 430 Lys Gln Asn Lys Met Leu Lys Lys Asp Lys Met Phe His Phe Trp Val 435 440 445 Asn Thr Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu Lys Val Glu 450 455 460 Asn Gly Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys Ser Ile Glu 465 470 475 480 Arg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu Thr Lys Asn 485 490 495 Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr Phe Ser Pro 500 505 510 Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu Glu Pro Ser 515 520 525 Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp Val Ser Asp 530 535 540 Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp Ser Asp Pro 545 550 555 560 Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile Thr Lys Val 565 570 575 <210> 35 <211> 8833 <212> DNA <213> Synthetic sequence <220> <223> Synthetic polymer <400> 35 60. cctcccctcg cccggcgcgg tcccgtccgc ctctcgctcg cctcccgcct cccctcggtc ttccgaggcg cccgggctcc cggcgcggcg gcggaggggg cgggcaggcc ggcggggcggt 120 gatgtggcgg gactctttat gcgctgcggc aggatacgcg ctcggcgctg ggacgcgact 180 gcgctcagtt ctctcctctc gcgctgca gccatgatgg aagtttgaga gttgagccgc 240 tgtgaggcga ggccgggctc aggcgaggga gatgagagac ggcggcggcc gcggcccgga 300 gcccctctca gcgcctgtga gcagccgcgg gggcagcgcc ctcggggagc cggccggcct 360 gcggcggcgg cagcggcggc gtttctcgcc tcctcttcgt cttttctaac cgtgcagcct 420 cttcctcggc ttctcctgaa agggaaggtg gaagccgtgg gctcgggcgg gagccggctg 480 aggcgcggcg gcggcggcgg cacccccgc tcctggagcg ggggggaga gcggcggcgg 540 cggcggccgc ggcggctgca gctccaggga gggggtctga gtcgcctgtc accatttcca 600 gggctgggaa cgccggagag ttggtctctc cccttctact gcctccaaca cggcggcggc 660 ggcggcggca catccaggga cccggggccgg ttttaaacct cccgtccgcc gccgccgcac 720 cccccgtggc ccggctccg gaggccgccg gcggaggcag ccgttcggag gattattcgt 780 cttctcccca ttccgctgcc gccgctgcca ggctctggc tgctgaggag aagcaggcc 840 agtcgctgca accatccagc agccgccgca gcagccatta cccggctgcg gtccagagcc 900 aagcggcggc agagcgaggg gcatcagcta ccgccaagtc cagagccatt tccatcctgc 960 agaagaagcc ccgccaccag cagctctgc catctctc ctccttttc ttcagccaca 1020 ggctcccaga catgacagcc atcatcaag agatcgttag cagaacaa aggagatc 1080 aagaggatgg attcgactta gacttgacct atatttatcc aacattatt gctatgggat 1140 ttcctgcaga aagacttgaa ggcgtataca ggaacaat tgatgta gtaagttgtg 1200 ctgaaagaca ttatgacacc gccaaattta attgcagagt tgcacaat ccttttgaag 1260 accataaccc accacagcta gaacttatca aacccttttg tgagatctt gaccaatggc 1320 taagtgaga tgacaatcat gttgcagcaa ttcactgtaa agctgaaag ggacgaactg 1380 gtgtaatgat atgtgcatat ttattacatc ggggcaaatt tttaaggca caaggcccc 1440 tagattcta tggggaagta aggaccagag acaaaaaggc agatcctaca ggaggtattc 1500 cagataaagg cattattgtc ataggagatg gcagctccat ggatgttatt gccccttaag 1560 accttccagt gggacaagat gtataggtgg aagacagtga tattgatgat cctgaccttg 1620 tagaggccaa ggctaaagga gtaactattc ccagtcagag gcgctatgtg tattattata 1680 gctacctgtt aaagaatcat ctggattata gaccagtggc actgttgttt cacaagatga 1740 tgttgaaac tattccaatg ttcagtggcg gaacttgcaa tcctcagttt gtggtctgcc 1800 agctaaaggt gaagatatat tcctccaatt caggacccac acgacgggaa gacaagttca 1860 tgtactttga gttccctcag ccgttacctg tgtgtggtga tatcaaagta gagttcttcc 1920 acaaacagaa caagatgcta aaaaaggaca aaatgtttca cttttgggta aatacattct 1980 tcataccagg accagaggaa acctcagaaa aagtagaaaa tggaagtcta tgtgatcaag 2040 aaatcgatag catttgcagt atagagcgtg cagataatga caaggaatat ctagtactta 2100 ctttaacaaa aaatgatctt gacaaagcaa ataaagacaa agccaaccga tactttctc 2160 caaattttaa ggtgaagctg tacttcaaa aaacagtaga ggagccgtca aatccagagg 2220 ctagcagttc aacttctgta acaccagatg ttagtgacaa tgaacctgat cattagat 2280 attctgacac cactgactct gatccagaga atgaaccttt tgatgaagat cagcatacac 2340 aaattacaaa agtctgaatt ttttttatc aagagggata aaacaccatg aaaataaact 2400 tgaataact gaaaatggac cttttttttt ttaatggcaa taggacattg tgtcagatta 2460 ccagttatag gaacaattct cttttcctga ccaatcttgt tttaccctat acatccacag 2520 ggttttgaca cttgttgtcc agttgaaaaa aggttgtgta gctgtgtcat gtatatacct 2580 ttttgtgtca aaaggacatt taaaattcaa ttaggattaa taaagatggc actttcccgt 2640 tttattccag ttttataaaa agtggagaca gactgatgtg tatacgtagg aattttttcc 2700 ttttgtgttc tgtcaccaac tgaagtggct aaagagcttt gtgatatact ggttcacatc 2760 ctaccccttt gcacttgtgg caacagataa gtttgcagtt ggctaagaga ggtttccgaa 2820 gggttttgct acattctaat gcatgtattc gggttagggg aatggaggga atgctcagaa 2880 aggaat tttatgctgg actctggacc atataccatc tccagctatt tacacacacc tttctttagc atgctacagt tattaatctg gacattcgag gattggccg ctgtcactgc ttgttgtttg cgcatttttt tttaagcat attggtgcta gaaaaggcag ctaaaggaag tgaatctgta ttggggtaca ggaatgaacc ttctgcaaca tcttaagatc cacaaatgaa gggatataaa aataatgtca taggtaagaa acacagcaac aatgactaa ccatataaat gtggaggcta tcaacaaaga atgggcttga aacattataa aaattgacaa tgatttatta aatatgtttt ctcaattgta acgacttctc catctcctgt gtaatcaagg ccagtgctaa aattcagatg ctgttagtac ctacatcagt caacaactta cacttatttt actagttttc aatcataata cctgctgtgg atgcttcatg tgctgcctgc aagcttcttt tttctcatta 3420 father attttgtaat gctgcacaga father ttgagattct acagtaagcg ttttttttct ttgaagattt atgatgcact tattcaatag ctgtcagccg ttccaccctt 3540. ttgaccttac acattctatt acaatgaatt ttgcagtttt gcacattttt taaatgtcat taactgttag ggaattttac ttgaatactg atacatata atgtttatat taaaaaggac 3660 atttgtgtta aaaaggaaat tagagttgca gtaaactttc aatgctgcac acaaaaaaaa 3720 gatatttgat tttcagtag aaattgtcct acatgtgctt tattgattg ctattgaaag 3780 atagggttttttttttttttttttttttttttaaat gtgcagtgtt gatcatttc 3840 ttcatagtgc tccccgagt tgggactag gctcaattt cactcttaa aaaaaatcat 3900 catatattg attgcccag actgcatacg attttaagcg gagtacaact actattgtaa 3960 agctaatgtg aagatattat taaaaaggtt ttttttcca gaaatttggt gtcttcaaat 4020 tataccttca ccttgacatt tgaatatcca gccattttgt ttcttaatgg tataaaattc 4080 cattttcaat aacttattgg tgctgaatt gttcactagc tgtgtctga cctagttaat 4140 ttachaatc natgaat gacctacta gagcagcatt tatagagttt gatggcaat 4200 agattaggca gaacttcatc taaaatattc ttagtaata atgttgacac gttttccata 4260 ccttgtcagt ttcattcac aatttttaaa ttcacaac agctcttagg atttacacat 4320 ttatatta acattgatat atagagtatt gattgattgc tcatagtta aattggtaaa 4380 gttagagaca actattctaa cacctcacca ttgaaattta tatgccacct tgtctttcat 4440 aaagctgaa attgttacc taaaatgaa atcaacttca tgttttgaag atgttataa 4500 atattgttct ttgttacaat ttcggcacc gcatattaaa acgtacttt attgttccaa 4560 tatgtacat ggaggccag gtcataaata atgacattat atggggcttt tgcactgtta 4620 ttatttttcc tttggaatgt gaagtctga atgaggtttt tgatttga tgttcaatg 4680 ttttgagaa gccttgctta cattttatgg tgtagtcatt ggaatggaa aaatggcatt 4740 atatatatta tatatataaa tatatatta acatactctc cttactttat ttcagttacc 4800 atccccatag aatttgaca gattgctat gactgaaagg tttcgagtc ctaattaaaa 4860 ctttattt ggcagtattc atattagcc tgaaatgcat tctgtaggta atctctgagt 4920 ttctggaata tttcttaga ctttttggat gtgcagcagc ttacatgtct gaagttactt 4980 gaaggcatca cttttaagaa agcttacagt tggccctgt accatchcca gtcctttgta 5040 gctcctcttg aacatgtttg catactttt aaaagggtag ttgaataaat agcatcacca 5100 ttctttgctg tggcacaggt tataaactta agtggagttt accggcagca tcaaatgttt 5160 cagctttaaa aaataaaagt agggtacaag tttaatgttt agttctagaa atttgtgca 5220 atatgttcat aacgatggct gtggttgcca caaagtgcct cgtttacctt taatactgt 5280 taatgtgtca tgcatgcaga tggaaggggt ggaactgtgc actaaagtgg gggctttaac 5340 tgtagtattt ggcagagttg ccttctacct gccagttcaa aagttcaacc tgttttcata 5400 tagaatatat atactaaaaa atttcagtct gttaaacagc cttactctga ttcagcctct 5460 tcagatactc ttgtgctgtg cagcagtggc tctgtgtgta aatgctatgc actgaggata 5520 cacaaaaata ccaatatgat gtgtacagga taatgcctca tcccaatcag atgtccattt 5580 gttattgtgt ttgttaacaa ccctttatct cttagtgtta taaactccac ttaaaactga 5640 ttaaagtctc attcttgtca ttgtgtgggt gttttattaa atgagagttt ataattcaaa 5700 ttgcttaagt ccattgaagt tttaattaat gggcagccaa atgtgaatac aaagttttca 5760 gtttttttt ttcctgctgt ccttcaaagc ctactgttta aaaaaaaaaa aaaaaaaaa 5820 catggcctga gagtagagta tctgtctact catgtttaat taaggaaaaa cacttatttt 5880 tagggcttta gtcatcactt cataaattgt ataagcacat taaatagcgt tctagtcctg 5940 aaaaagtcca agattcttag aaaattgtgc atatttttat tatgacagat gtttgaagat 6000 aattccccag aatggatttg atactttaga tttcaattttt gtggcttttg tctattattc 6060 tgtactctgc catcagcata tggaaagctt catttactca tcatgacttg tgccatataa 6120 aaattgatat ttcggaatag tctaaaggac tttttgtact tgaatttaat catgttgttt 6180 ctaatattct taaaagcttg aagactaaag catatccttt caacaaagca tagtaaggta 6240 ataagaaagt gtagtttgta caagtgttaa aaaaataaag tagacaatgt tacagtggga 6300 cttattattt caagtttaca ttttctccat gtaattttttt aaaaagtaaa tgaaaaaatg 6360 tgcaataatg taaaatatga agtgtatgtg tacacacatt ttatttttcg gtatcttggg 6420 tatacgtatg gttgaaaact atactggagt ctaaaagtat tctaatttat aagaagacat 6480 tttggtgag tttgaaaaat agaaatgtgc tagttttgtt ttatatcat gtcctttgta 6540 cgttgtataa tgagctggct tggttcagta atgccatca ccatttccat tgagaattta 6600 aaactcacca gtgtttaata tgcaggctc caaggctta tgaaaaaat caaccctt 6660 aaatctagtt aatttgctgc taacatgaaa ctctttggtt ctttatttt tgccagataa 6720 ttagacacac atctaaagct tagtcttaaa tggcttaagt gtagctattg attagtgctg 6780 ttgctagttc agaaagaat gttgtgaat ggaaacaaga atttcagtc caaactgttg 6840 taaggacagt acctgaaaac taaggaacag gatatggaa aaagtctttt aagatgaaa 6900 tgttggagcc aactttctta tagattaat tgtatgtggc tatagaagc ctaatgattg 6960 ttgcttattt ttgagagcat attattcttt tatgaccata atcttgctgt ttttccatct 7020 tccaaaagat cttccttcta atatgtatat cagaatgtgg gtagccagtc agacaaatttc 7080 atattggttg gtagctttaa aaagtttgta atgtgagac aggaaggac aaatagttt 7140 gctttggtgg tagtactctg gttgttaagc taggtattt gagactactt cccatcaca 7200 acaacaataa aataatcact cataatccta tcacctggag acatagccat cgttaatatg 7260 ttagtgacta tacaatcatg ttttcttctg tatatccatg tatattcttt aaaaatgaaa 7320 tttatactgt acctgatctc aaagcttttt agcttagtat atctgtcatg aatttgtagg 7380 atgttccatt gcatcagaaa acggacagtg atttgattac tttctaatgc cacagatgca 7440 gattacatgt agttattgag aatcctttcg aattcagtgg cttaatcatg aatgtctaaa 7500 tattgttgac attaggatga tacatgtaaa ttaaagttac atttgtttag catagacaag 7560 cttaacattg tagatgtttc tcttcaaaaa tcatcttaaa catttgcatt tggaattgtg 7620 ttaaatagaa tgtgtgaaac actgtattag taaacttcat cacctttcta cttccttata 7680 gtttgaactt ttcagttttt gtagttccca aacagttgct caatttagag caaattaatt 7740 taacacctgc caaaaaaagg ctgctgttgg cttatcagtt gtctttaaat tcaaatgctc 7800 atgtgacttt tatcacatca aaaaatattt cattaatgat tcacctttag ctctgaaaat 7860 taccgcgttt agtaattata gtgggcttat aaaaacatgc aactcttttt gatagttatt 7920 tgagaatttt ggtgaaaaat atttagctga gggcagtata gaacttataa accaatatat 7980 tgatattttt aaaacatttt tacatataag taaactgcca tctttgagca taactacatt 8040 taaaaataaa gctgcatatt tttaaatcaa gtgtttaaca agaatttata ttttttattt 8100 tttaaaatta aaaataattt atatttcctc tgttgcatga ggattctcat ctgtgcttat 8160 aatggttaga gattttattt gtgtggaatg aagtgaggct tgtagtcatg gttctagtgt 8220 ttcagtttgc caagtctgtt tactgcagtg aaattcatca aatgtttcag tgtggttttc 8280 tgtagcctat catttactgg ctattttttt atgtacacct ttaggatttt ctgcctactc 8340 tatccagttg tccaaatgat atcctacatt ttacaaatgc cctttcagtt tctattttct 8400 ttttccatta aattgccctc atgtcctaat gtgcagtttg taagtgtgtg tgtgtgtgtc 8460 tgtgtgtgtg tgaatttgat tttcaagagt gctagacttc caatttgaga gattaaataa 8520 tttaattcag gcaaacattt ttcattggaa tttcacagtt cattgtaatg aaaatgttaa 8580 tcctggatga cctttgacat acagtaatga atcttggata ttaatgaatt tgttagtagc 8640 atcttgatgt gtgttttaat gagttatttt caaagttgtg cattaaacca aagttggcat 8700 actggaagtg tttatatcaa gttccatttg gctactgatg gacaaaaaat agaaatgcct 8760 tcctatggag agtatttttc ctttaaaaaa ttaaaaaggt taattatttt gactaaaaaa 8820 aaaaaaaaaa aaa 8833 <210> 36 <211> 206 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 36 Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly Gly Thr Cys Asn Pro 1 5 10 15 Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile Tyr Ser Ser Asn Ser 20 25 30 Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr Phe Glu Phe Pro Gln 35 40 45 [[ID=?]]Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu Phe Phe His Lys Gln 50 55 60 Asn Lys Met Leu Lys Lys Asp Lys Met Phe His Phe Trp Val Asn Thr 65 70 75 80 Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu Lys Val Glu Asn Gly It seems there is a possible error in the original text where the tag in line 34 might be incorrect. I've translated it as is but it should be checked for accuracy in the original context.85 90 95 Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys Ser Ile Glu Arg Ala 100 105 110 Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu Thr Lys Asn Asp Leu 115 120 125 Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr Phe Ser Pro Asn Phe 130 135 140 Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu Glu Pro Ser Asn Pro 145 150 155 160 Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp Val Ser Asp Asn Glu 165 170 175 Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp Ser Asp Pro Glu Asn 180 185 190 Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile Thr Lys Val 195 200 205 <210> 37 <211> 9796 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymer <400> 37 ggcagtggca gcggcgagag cttgggcggc cgccgccgcc tcctcgcgag cgccgcgcgc 60 ccggtcccg ctcgcatgca agtcacgtcc gcccctcgg cgcggccgcc ccgagacgcc 120 ggccccgctg agtgatgaga acagacgtca aactgcctta tgaatattga tgcggaggct 180 aggctgcttt cgtagagaag cagaggaag cagatggct gccctttagg atttgttaga 240 aaggagaccc gactgcact gctggattgc tgcaggctg agggacgaga acgaggctgg 300 caaacattca gcagcacacc ctctcaagat tgtttacttg cctttgctcc tgttgagtta 360 caacgcttgg aagcaggaga tgggctcagc agcagccaat aggacatgat ccaggaagg 420 cagtaaggga ctgagctgct gattcact agagggcagc cttgtggatg gccccgaagc 480 aagcctgatg gaacaggata gaaccacca tgttgagggc aacagactaa gtccattcct 540 gataccatca cctcccattt gccagacaga acctctggct acaaagctcc agaatggaag 600 cccactgcct gagagagctc atccagaagt aaatggagac accaagtggc actctttcaa 660 aagttattat ggaataccct gtatgaaggg aagccagaat agtcgtgtga gtcctgactt 720 tacacagaa agtagaggtt attccaagtg ttgcaaat ggaggaataa aacgcacagt 780 tagtgaacct tctctctg ggctccttca gatcaagaaa ttgaacaag accaaaggc 840 taatggagaa agacgtact tcggggtaag ccagaaga aatccaggtg aaagcagtca 900 accaaatgtc tccgatttga gtgataagaa agaatctgtg agttctgtag cccaagaaaa 960 tgcagttaaa gatttcacca gttttcaac acatactgc agtggggcctg aaatccaga 1020 gcttcagatt ctgaatgagc aggaggaa aagtgctaat taccatgaca agaacattgt 1080 attacttaa aaaaggcag tgctaatgcc taatggtgct acagttctg cctcttccgt 1140 ggaacacaca catggtgaac tcctggaaa aacactgtct caatattatc cagattgtgt 1200 ttccattgcg gtgcagaaaa ccacatctca cataaatgcc atttacagtc aggtactaa 1260 tgagttgtcc tgtgagatca ctcacccatc gcatacctca gggcagatca attccgcaca 1320 gacctactaac tctgagctgc ctccaagcc agctgcagtg gtgagtgagg cctgtgatgc 1380 tgatgatgct gataatgcca gtaaactagc tgcaatgcta atacctgtt cctttcagaa 1440 accagaaaa ctacaacaac aaaaatcagt tttgagata tgcccatctc ctgcagaaaaa 1500 1560 caatttgcaa gctcctggtg gcagctctga acggtattta aaacaaaatg aaatgaatgg 1620 tgcttacttc aagcaaagct cagtgttcac taaggattcc tttctgcca ctaccacacc 1680 accaccacca tcacaattgc ttctttctcc ccctcctcct cttccacagg ttcctcagct 1740 tccttcagaa ggaaaaagca ctctgaatgg tggagtttta gaagaacacc accactaccc 1800 caaccaaagt aacacaacac ttttaaggga agtgaaaaata gagggtaaac ctgaggcacc 1860 accttcccag agtcctaatc catctacaca tgtatgcagc ccttctccga tgctttctga 1920 1980 tccattgtgt tctgagaaaa caagaccaat gtcagaacac ctcaagcata acccaccaat 2040 2100 agagattctg aagggtcgag acaggagaca aacacgagat cttgtgcccc caacacagca 2160 ctatctgaaa ccaggatgga ttgaattgaa ggcccctcgt tttcaccaag cggaatccca 2220 tctaaaacgt aatgaggcat cactgccatc aattcttcag tatcaaccca atctctccaa 2280 tcaaatgacc tccaaacaat acactggaaa ttccaacatg cctggggggc tcccaaggca 2340 agcttacacc cagaaaacaa cacagctgga gcacaagtca caaatgtacc aagttgaaat 2400 gaatcaaggg cagtcccaag gtacagtgga ccaacatctc cagttccaaa aaccctcaca 2460 ccaggtgcac ttctccaaaa cagaccattt accaaaagct catgtgcagt cactgtgtgg 2520 cactagattt cattttcaac aaagagcaga ttcccaaact gaaaaactta tgtccccagt 2580 gttgaaacag cacttgaatc aacaggcttc agagactgag ccattttcaa actcacacct 2640 tttgcaacat aagcctcata aacaggcagc acaaacacaa ccatcccaga gttcacatct 2700 ccctcaaaac cagcaacagc agcaaaaatt acaataaag aataagagg aaatactcca 2760 gacttttcct cacccccaaa gcaacaatga tcagcaaga gaaggatcat tctttggcca 2820 gactaaagtg gaagaatgtt ttcatggtga aaatcagtat tcaaaatcaa gcgagttcga 2880 gactcataat gtccaaatgg gactggagga agtacagaat ataaatcgta gaaattcccc 2940 ttatagtcag accatgaaat caagtgcatg caaaatacag gtttcttgtt caaacaatac 3000 acacctagtt tcagagaata aagaacagac tacacatcct gaactttttg caggaaacaa 3060 gacccaaaac ttgcatcaca tgcaatattt tccaaataat gtgatcccaa agcaagatct 3120 tcttcacagg tgctttcaag aacaggagca gaagtcacaa caagcttcag ttctacaggg 3180 atataaaaat agaaaccaag atatgtctgg tcaacaagct gcgcaacttg ctcagcaaag 3240 gtacttgata cataaccatg caaatgtttt tcctgtgcct gaccagggag gaagtcacac 3300 tcagacccct ccccagaagg acactcaaaa gcatgctgct ctaaggtggc atctcttaca 3360 gaagcaagaa cagcagcaaa cacagcaacc ccaaactgag tcttgccata gtcagatgca 3420 caggccaatt aaggtggaac ctggatgcaa gccacatgcc tgtatgcaca cagcaccacc 3480 agaaaacaaa acatggaaaa aggtaactaa gcaagagaat ccacctgcaa gctgtgataa 3540 tgtgcagcaa aagagcatca ttgagaccat ggagcagcat ctgaagcagt ttcacgccaa 3600 gtcgttattt gaccataagg ctcttactct caaatcacag aagcaagtaa aagttgaaat 3660 gtcagggcca gtcacagttt tgactagaca aaccactgct gcagaacttg atagccacac 3720 cccagcttta gagcagcaaa caacttcttc agaaaagaca ccaaccaaaa gaacagctgc 3780 ttctgttctc aataatttta tagagtcacc ttccaaatta ctagatactc ctataaaaaa 3840 tttattggat acacctgtca agactcaata tgatttccca tcttgcagat gtgtagagca 3900 aattattgaa aaagatgaag gtccttttta tacccatcta ggagcaggtc ctaatgtggc 3960 agctattaga gaaatcatgg aagaaaggtt tggacagaag ggtaaagcta ttaggattga 4020 aagagtcatc tatactggta aagaaggcaa aagttctcag ggatgtccta ttgctaagtg 4080 ggtggttcgc agaagcagca gtgaagagaa gctactgtgt ttggtgcggg agcgagctgg 4140 ccacacctgt gaggctgcag tgattgtgat tctcatcctg gtgtgggaag gaatcccgct 4200 gtctctggct gacaaactct actcggagct taccgagacg ctgaggaaat acggcacgct 4260 caccaatcgc cggtgtgcct tgaatgaaga gagaacttgc gcctgtcagg ggctggatcc 4320 agaaacctgt ggtgcctcct tctcttttgg ttgttcatgg agcatgtact acaatggatg 4380 taagttttgcc agaagcaaga tccaggaa gtttaagctg cttgggattg accaaaga 4440 ggaagagaaa ctggagtctc atttgcaaa cctgtccact cttggcac siacatataa 4500 gaaacttgca cctgatgcat ataataatca gattgaat gaacacagag caccagagtg 4560 ccgtctgggt ctgaggaag gccgtccatt ctcaggggtc actgcatgtt tggactctg 4620 tgctcatgcc cacagagact tgcacacat gcagaatggc agcacattgg tatgcactt 4680 cactagagaa gatatcgag aatttggagg aaaacctgag gatgagcagc ttcacgttct 4740 gcctttatac aaagtctctg acgtggatga gtttgggagt gtggaagctc aggaggaa 4800 aaaacggagt gtgccattc aggtactgag ttctttcgg cgaaaagtca ggatgttagc 4860 agagccagtc aagacttgcc gawaaggaa actagaagcc aagaagctg cagctgaaaa 4920 gctttcctcc ctggagaca gctcaataa aaatgaaag gaaagtcag cccatcacg 4980 tacaaaaaaa actgaaaacg caagccaggc taacagttg gcagaacttt tgcgactttc 5040 aggaccagtc atgcagcagt cccagcagcc cccagccta cccagcagc cccacagcc 5100 ccagcagcag cagagacccc agcagcagca gccacatcac cctcagacag agtctgtcaa 5160 ctcttattct gcttctggat ccaccaatcc atacatgaga cggcccaatc cagttagtcc 5220 ttatccaaac tcttcacaca cttcagatat ctatggaagc accagcccta tgaacttcta 5280 ttccacctca tctcaagctg caggttcata tttgaattct tctaatccca tgaaccctta 5340 ccctgggctt ttgaatcaga atacccaata tccatcatat caatgcaatg gaaacctatc 5400 agtggacaac tgctccccat atctgggttc ctattctccc cagtctcagc cgatggatct 5460 gtataggtat ccaagccaag accctctgtc taagctcagt ctaccaccca tccataact 5520 ttaccagcca aggtttggaa atagccagag ttttacatct aaatacttag gttatggaaa 5580 ccaaaatatg cagggagatg gtttcagcag ttgtaccatt agaccaaatg tacatcatgt 5640 agggaaattg cctccttatc ccactcatga gatggatggc cacttcatgg gagccacctc 5700 tagattacca cccaatctga gcaatccaaa catggactat aaaaatggtg aacatcattc 5760 accttctcac ataatccata actacagtgc agctccgggc atgttcaaca gctctcttca 5820 tgccctgcat ctccaaaaca aggagaatga catgctttcc cacacagcta atgggttatc 5880 aagatgctt ccagctctta accatgatag aactgcttgt gtccaaggag gcttacacaa 5940 attaagtgat gctaatggtc aggaaagca gccattggca ctagtccagg gtgtggctc 6000 tggtgcagag vakaacgatg aggtctggtc agacagcgag cagagctttc tggatcctga 6060 cattggggga gtggccgtgg ctccaactca tggtcatt ctcattgagt gtgcaagcg 6120 tgagctgcat gccacaaccc ctttaaagaa tcccaatagg atcacccca ccaggatctc 6180 cctcgtcttt taccagcata agagcatgaa tgagccaaa catggcttgg ctctttggga 6240 agccaaaatg gctgaaaaag cccgtgagaa aggagaag tgtgaaaagt atggcccaga 6300 ctatgtgcct cagaaatccc atggcaaaa agtgaaacgg gagcctgctg agccacatga 6360 aacttcagag cccacttacc tgcgttcat caagtctctt gccgaaagga ccatgtccgt 6420 gaccacagac tccacagta ctacatctcc atatgccttc actcgggtca cagggcctta 6480 cacagatat atatgatatc accccctttt gttggttacc tcacttgaaa agaccacaac 6540 caacctgtca gtagtatagt tctcatgacg tgggcagtgg ggaaaggtca footttcat 6600 gacaaatgtg gtgggaaaaa cctcagctca ccagcaacaa aagaggttat cttaccatag 6660 cacttaattt tcactggctc ccaagtggtc acagatggca tctaggaaaa gaccaaagca 6720 ttctatgcaa aaagaaggtg gggaagaaag tgttccgcaa tttacatttt taaacactgg 6780 ttctattatt ggacgagatg atatgtaaat gtgatcccccc ccccccgctt acaactctac 6840 6900 agtactgtag tattacagtg aaggaatct taaaatacca tctggtgctg aatatatgat 6960 gtactgaaat actggaatta tggctttttg aaatgcagtt tttactgtaa tcttaacttt 7020 7080 gttctaagaa atggtgctaa gaaaatggtg tctttaatag ctaaaaaattt aatgccttta 7140 tatcatcaag atgctatcag tgtactccag tgcccttgaa taataggggt accttttcat 7200 tcaagttttt atcataatta cctattctta caaagctta gttttaaaaa tgtggacatt 7260 ttaaaggcct ctggattttg ctcatccagt gaagtccttg taggacaata aacgtatata 7320 tgtacatata tacacaaaca tgtatatgtg cacacacatg tatatgtata aatattttaa 7380 atggtgtttt agaagcactt tgtctaccta agctttgaca acttgaacaa tgctaaggta 7440 ctgagatgtt taaaaaacaa gtttactttc attttagaat gcaaagttga tttttttaag 7500 gaaacaaaga aagcttttaa aatatttttg cttttagcca tgcatctgct gatgagcaat 7560 tgtgtccatt tttaacacag ccagttaaat ccaccatggg gcttactgga ttcaagggaa 7620 tacgttagtc cacaaaacat gttttctggt gctcatctca catgctatac tgtaaaacag 7680 ttttacaa aattgtatga caagttcatt gctcaaaaat gtacagttt aagaattttc 7740 tattaactgc aggtaataat tagctgcatg ctgcagactc aacaaagcta gttcactgaa 7800 gcctatgcta tttatggat cataggctct tcagagaact gaatggcagt ctgcctttgt 7860 gttgataatt atgtacattg tgacgttgtc atttcttagc ttaagtgtcc tctttaacaa 7920 gaggattgag cagactgatg cctgcataag atgaataaac agggttagtt ccatgtgaat 7980 ctgtcagtta aaaagaaaca aaaacaggca gctggtttgc tgtggtggtt ttaaatcatt 8040 aatttgtata aagaagtgaa agagttgtat agtaaattaa attgtaaaca aaactttttt 8100 aatgcaatgc tttagtattt tagtactgta aaaaaattaa atatatacat atatatatat 8160 atatatatat atatatatat gagtttgaag cagaattcac atcatgatgg tgctactcag 8220 cctgctacaa atatatcata atgtgagcta agaattcatt aaatgtttga gtgatgttcc 8280 tacttgtcat atacctcaac actagtttgg caataggata ttgaactgag agtgaaagca 8340 ttgtgtacca tcattttttt ccaagtcctt ttttttattg ttaaaaaaaa aagcatacct 8400 tttttcaata cttgatttct tagcaagtat aacttgaact tcaacctttt tgttctaaaa 8460 attcagggat atttcagctc atgctctccc tatgccaaca tgtcacctgt gtttatgtaa 8520 aattgttgta ggttaataaa tatattcttt gtcagggatt taacccttt attttgaatc 8580 ccttctattt tacttgtaca tgtgctgatg taactaaaac taattttgta aatctgttgg 8640 ctcttttat tgtaaagaaa agcattttaa aagttttgagg aatcttttga ctgtttcaag 8700 caggaaaaaa aaattacatg aaatagaat gcactgagtt gataaaggga aaaattgtaa 8760 ggcaggagtt tggcaagtgg ctgttggcca gagacttact tgtaactctc taaatgaagt 8820 ttttttgatc ctgtaatcac tgaaggtaca tactccatgt ggacttccct taaacaggca 8880 aacacctaca ggtatggtgt gcaacagatt gtacaattac attttggcct aaatacattt 8940 ttgcttacta gtatttaaaa taaattctta atcagaggag gcctttgggt tttattggtc 9000 aaatctttgt aagctggctt ttgtcttttt aaaaaatttc ttgaatttgt ggttgtgtcc 9060 aatttgcaaa catttccaaa aatgtttgct ttgcttacaa accacatgat tttaatgttt 9120 tttgtatacc ataatatcta gccccaaaca tttgattact acatgtgcat tggtgattttt 9180 gatcatccat tcttaatatt tgattctgt gtcacctact gtcatttgtt aaactgctgg 9240 ccaacaagaa caggaagtat agtttggggg gttggggaga gtttacataa ggaagagaag 9300 aaattgagtg gcatattgta aatatcagat ctataattgt aaatataaaa cctgcctcag 9360 ttagaatgaa tggaaagcag atctacaatt tgctaatata ggaatatcag gttgactata 9420 tagccatact tgaaaatgct tctgagtggt gtcaacttta cttgaatgaa tttttcatct 9480 tgattgacgc acagtgatgt acagttcact tctgaagcta gtggttaact tgtgtaggaa 9540 acttttgcag tttgacacta agataacttc tgtgtgcatt tttctatgct tttttaaaaa 9600 ctagtttcat ttcattttca tgagatgttt ggtttataag atctgaggat ggttataaat 9660 actgtaagta ttgtaatgtt atgaatgcag gttatttgaa agctgtttat tattatatca 9720 ttcctgataa tgctatgtga gtgtttttaa taaaatttat atttatttaa tgcactctaa 9780 aaaaaaaaaa aaaaaa 9796 <210> 38 <211> 2002 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 38 Met Glu Gln Asp Arg Thr Asn His Val Glu Gly Asn Arg Leu Ser Pro 1 5 10 15 Phe Leu Ile Pro Ser Pro Pro Ile Cys Gln Thr Glu Pro Leu Ala Thr 20 25 30 Lys Leu Gln Asn Gly Ser Pro Leu Pro Glu Arg Ala His Pro Glu Val 35 40 45 Asn Gly Asp Thr Lys Trp His Ser Phe Lys Ser Tyr Tyr Gly Ile Pro 50 55 60 Cys Met Lys Gly Ser Gln Asn Ser Arg Val Ser Pro Asp Phe Thr Gln 65 70 75 80 Glu Ser Arg Gly Tyr Ser Lys Cys Leu Gln Asn Gly Gly Ile Lys Arg 85 90 95 Thr Val Ser Glu Pro Ser Leu Ser Gly Leu Leu Gln Ile Lys Lys Leu 100 105 110 Lys Gln Asp Gln Lys Ala Asn Gly Glu Arg Arg Asn Phe Gly Val Ser 115 120 125 Gln Glu Arg Asn Pro Gly Glu Ser Ser Gln Pro Asn Val Ser Asp Leu 130 135 140 Ser Asp Lys Lys Glu Ser Val Ser Ser Val Ala Gln Glu Asn Ala Val 145 150 155 160 Lys Asp Phe Thr Ser Phe Ser Thr His Asn Cys Ser Gly Pro Glu Asn 165 170 175 Pro Glu Leu Gln Ile Leu Asn Glu Gln Glu Gly Lys Ser Ala Asn Tyr 180 185 190 His Asp Lys Asn Ile Val Leu Leu Lys Asn Lys Ala Val Leu Met Pro 195 200 205 Asn Gly Ala Thr Val Ser Ala Ser Ser Val Glu His Thr His Gly Glu 210 215 220 Leu Leu Glu Lys Thr Leu Ser Gln Tyr Tyr Pro Asp Cys Val Ser Ile 225 230 235 240 Ala Val Gln Lys Thr Thr Ser His Ile Asn Ala Ile Asn Ser Gln Ala 245 250 255 Thr Asn Glu Leu Ser Cys Glu Ile Thr His Pro Ser His Thr Ser Gly 260 265 270 Gln Ile Asn Ser Ala Gln Thr Ser Asn Ser Glu Leu Pro Pro Lys Pro 275 280 285 Ala Ala Val Val Ser Glu Ala Cys Asp Ala Asp Asp Ala Asp Asn Ala 290 295 300 Ser Lys Leu Ala Ala Met Leu Asn Thr Cys Ser Phe Gln Lys Pro Glu 305 310 315 320 Gln Leu Gln Gln Gln Lys Ser Val Phe Glu Ile Cys Pro Ser Pro Ala 325 330 335 Glu Asn Asn Ile Gln Gly Thr Thr Lys Leu Ala Ser Gly Glu Glu Phe 340 345 350 Cys Ser Gly Ser Ser Ser Asn Leu Gln Ala Pro Gly Gly Ser Ser Glu 355 360 365 Arg Tyr Leu Lys Gln Asn Glu Met Asn Gly Ala Tyr Phe Lys Gln Ser 370 375 380 Ser Val Phe Thr Lys Asp Ser Phe Ser Ala Thr Thr Thr Pro Pro Pro 385 390 395 400 Pro Ser Gln Leu Leu Leu Ser Pro Pro Pro Pro Leu Pro Gln Val Pro 405 410 415 Gln Leu Pro Ser Glu Gly Lys Ser Thr Leu Asn Gly Gly Val Leu Glu 420 425 430 Glu His His His Tyr Pro Asn Gln Ser Asn Thr Thr Leu Leu Arg Glu 435 440 445 Val Lys Ile Glu Gly Lys Pro Glu Ala Pro Pro Ser Gln Ser Pro Asn 450 455 460 Pro Ser Thr His Val Cys Ser Pro Ser Pro Met Leu Ser Glu Arg Pro 465 470 475 480 Gln Asn Asn Cys Val Asn Arg Asn Asp Ile Gln Thr Ala Gly Thr Met 485 490 495 Thr Val Pro Leu Cys Ser Glu Lys Thr Arg Pro Met Ser Glu His Leu 500 505 510 Lys His Asn Pro Pro Ile Phe Gly Ser Ser Gly Glu Leu Gln Asp Asn 515 520 525 Cys Gln Gln Leu Met Arg Asn Lys Glu Gln Glu Ile Leu Lys Gly Arg 530 535 540 Asp Lys Glu Gln Thr Arg Asp Leu Val Pro Pro Thr Gln His Tyr Leu 545 550 555 560 Lys Pro Gly Trp Ile Glu Leu Lys Ala Pro Arg Phe His Gln Ala Glu 565 570 575 Ser His Leu Lys Arg Asn Glu Ala Ser Leu Pro Ser Ile Leu Gln Tyr 580 585 590 Gln Pro Asn Leu Ser Asn Gln Met Thr Ser Lys Gln Tyr Thr Gly Asn 595 600 605 Ser Asn Met Pro Gly Gly Leu Pro Arg Gln Ala Tyr Thr Gln Lys Thr 610 615 620 Thr Gln Leu Glu His Lys Ser Gln Met Tyr Gln Val Glu Met Asn Gln 625 630 635 640 Gly Gln Ser Gln Gly Thr Val Asp Gln His Leu Gln Phe Gln Lys Pro 645 650 655 Ser His Gln Val His Phe Ser Lys Thr Asp His Leu Pro Lys Ala His 660 665 670 Val Gln Ser Leu Cys Gly Thr Arg Phe His Phe Gln Gln Arg Ala Asp 675 680 685 Ser Gln Thr Glu Lys Leu Met Ser Pro Val Leu Lys Gln His Leu Asn 690 695 700 Gln Gln Ala Ser Glu Thr Glu Pro Phe Ser Asn Ser His Leu Leu Gln 705 710 715 720 His Lys Pro His Lys Gln Ala Ala Gln Thr Gln Pro Ser Gln Ser Ser 725 730 735 His Leu Pro Gln Asn Gln Gln Gln Gln Gln Lys Leu Gln Ile Lys Asn 740 745 750 Lys Glu Glu Ile Leu Gln Thr Phe Pro His Pro Gln Ser Asn Asn Asp 755 760 765 Gln Gln Arg Glu Gly Ser Phe Phe Gly Gln Thr Lys Val Glu Glu Cys 770 775 780 Phe His Gly Glu Asn Gln Tyr Ser Lys Ser Ser Glu Phe Glu Thr His 785 790 795 800 Asn Val Gln Met Gly Leu Glu Glu Val Gln Asn Ile Asn Arg Arg Asn 805 810 815 Ser Pro Tyr Ser Gln Thr Met Lys Ser Ser Ala Cys Lys Ile Gln Val 820 825 830 Ser Cys Ser Asn Asn Thr His Leu Val Ser Glu Asn Lys Glu Gln Thr 835 840 845 Thr His Pro Glu Leu Phe Ala Gly Asn Lys Thr Gln Asn Leu His His 850 855 860 Met Gln Tyr Phe Pro Asn Asn Val Ile Pro Lys Gln Asp Leu Leu His 865 870 875 880 Arg Cys Phe Gln Glu Gln Glu Gln Lys Ser Gln Gln Ala Ser Val Leu 885 890 895 Gln Gly Tyr Lys Asn Arg Asn Gln Asp Met Ser Gly Gln Gln Ala Ala 900 905 910 Gln Leu Ala Gln Gln Arg Tyr Leu Ile His Asn His Ala Asn Val Phe 915 920 925 Pro Val Pro Asp Gln Gly Gly Ser His Thr Gln Thr Pro Pro Gln Lys 930 935 940 Asp Thr Gln Lys His Ala Ala Leu Arg Trp His Leu Leu Gln Lys Gln 945 950 955 960 Glu Gln Gln Gln Thr Gln Gln Pro Gln Thr Glu Ser Cys His Ser Gln 965 970 975 Met His Arg Pro Ile Lys Val Glu Pro Gly Cys Lys Pro His Ala Cys 980 985 990 Met His Thr Ala Pro Pro Glu Asn Lys Thr Trp Lys Lys Val Thr Lys 995 1000 1005 Gln Glu Asn Pro Pro Ala Ser Cys Asp Asn Val Gln Gln Lys Ser 1010 1015 1020 Ile Ile Glu Thr Met Glu Gln His Leu Lys Gln Phe His Ala Lys 1025 1030 1035 Ser Leu Phe Asp His Lys Ala Leu Thr Leu Lys Ser Gln Lys Gln 1040 1045 1050 Val Lys Val Glu Met Ser Gly Pro Val Thr Val Leu Thr Arg Gln 1055 1060 1065 Thr Thr Ala Ala Glu Leu Asp Ser His Thr Pro Ala Leu Glu Gln 1070 1075 1080 Gln Thr Thr Ser Ser Glu Lys Thr Pro Thr Lys Arg Thr Ala Ala 1085 1090 1095 Ser Val Leu Asn Asn Phe Ile Glu Ser Pro Ser Lys Leu Leu Asp 1100 1105 1110 Thr Pro Ile Lys Asn Leu Leu Asp Thr Pro Val Lys Thr Gln Tyr 1115 1120 1125 Asp Phe Pro Ser Cys Arg Cys Val Glu Gln Ile Ile Glu Lys Asp 1130 1135 1140 Glu Gly Pro Phe Tyr Thr His Leu Gly Ala Gly Pro Asn Val Ala 1145 1150 1155 Ala Ile Arg Glu Ile Met Glu Glu Arg Phe Gly Gln Lys Gly Lys 1160 1165 1170 Ala Ile Arg Ile Glu Arg Val Ile Tyr Thr Gly Lys Glu Gly Lys 1175 1180 1185 Ser Ser Gln Gly Cys Pro Ile Ala Lys Trp Val Val Arg Arg Ser 1190 1195 1200 Ser Ser Glu Glu Lys Leu Leu Cys Leu Val Arg Glu Arg Ala Gly 1205 1210 1215 His Thr Cys Glu Ala Ala Val Ile Val Ile Leu Ile Leu Val Trp 1220 1225 1230 Glu Gly Ile Pro Leu Ser Leu Ala Asp Lys Leu Tyr Ser Glu Leu 1235 1240 1245 Thr Glu Thr Leu Arg Lys Tyr Gly Thr Leu Thr Asn Arg Arg Cys 1250 1255 1260 Ala Leu Asn Glu Glu Arg Thr Cys Ala Cys Gln Gly Leu Asp Pro 1265 1270 1275 Glu Thr Cys Gly Ala Ser Phe Ser Phe Gly Cys Ser Trp Ser Met 1280 1285 1290 Tyr Tyr Asn Gly Cys Lys Phe Ala Arg Ser Lys Ile Pro Arg Lys 1295 1300 1305 Phe Lys Leu Leu Gly Asp Asp Pro Lys Glu Glu Glu Lys Leu Glu 1310 1315 1320 Ser His Leu Gln Asn Leu Ser Thr Leu Met Ala Pro Thr Tyr Lys 1325 1330 1335 Lys Leu Ala Pro Asp Ala Tyr Asn Asn Gln Ile Glu Tyr Glu His 1340 1345 1350 Arg Ala Pro Glu Cys Arg Leu Gly Leu Lys Glu Gly Arg Pro Phe 1355 1360 1365 Ser Gly Val Thr Ala Cys Leu Asp Phe Cys Ala His Ala His Arg 1370 1375 1380 Asp Leu His Asn Met Gln Asn Gly Ser Thr Leu Val Cys Thr Leu 1385 1390 1395 Thr Arg Glu Asp Asn Arg Glu Phe Gly Gly Lys Pro Glu Asp Glu 1400 1405 1410 Gln Leu His Val Leu Pro Leu Tyr Lys Val Ser Asp Val Asp Glu 1415 1420 1425 Phe Gly Ser Val Glu Ala Gln Glu Glu Lys Lys Arg Ser Gly Ala 1430 1435 1440 Ile Gln Val Leu Ser Ser Phe Arg Arg Lys Val Arg Met Leu Ala 1445 1450 1455 Glu Pro Val Lys Thr Cys Arg Gln Arg Lys Leu Glu Ala Lys Lys 1460 1465 1470 Ala Ala Ala Glu Lys Leu Ser Ser Leu Glu Asn Ser Ser Asn Lys 1475 1480 1485 Asn Glu Lys Glu Lys Ser Ala Pro Ser Arg Thr Lys Gln Thr Glu 1490 1495 1500 Asn Ala Ser Gln Ala Lys Gln Leu Ala Glu Leu Leu Arg Leu Ser 1505 1510 1515 Gly Pro Val Met Gln Gln Ser Gln Gln Pro Gln Pro Leu Gln Lys 1520 1525 1530 Gln Pro Pro Gln Pro Gln Gln Gln Gln Arg Pro Gln Gln Gln Gln 1535 1540 1545 Pro His His Pro Gln Thr Glu Ser Val Asn Ser Tyr Ser Ala Ser 1550 1555 1560 Gly Ser Thr Asn Pro Tyr Met Arg Arg Pro Asn Pro Val Ser Pro 1565 1570 1575 Tyr Pro Asn Ser Ser His Thr Ser Asp Ile Tyr Gly Ser Thr Ser 1580 1585 1590 Pro Met Asn Phe Tyr Ser Thr Ser Ser Gln Ala Ala Gly Ser Tyr 1595 1600 1605 Leu Asn Ser Ser Asn Pro Met Asn Pro Tyr Pro Gly Leu Leu Asn 1610 1615 1620 Gln Asn Thr Gln Tyr Pro Ser Tyr Gln Cys Asn Gly Asn Leu Ser 1625 1630 1635 Val Asp Asn Cys Ser Pro Tyr Leu Gly Ser Tyr Ser Pro Gln Ser 1640 1645 1650 Gln Pro Met Asp Leu Tyr Arg Tyr Pro Ser Gln Asp Pro Leu Ser 1655 1660 1665 Lys Leu Ser Leu Pro Pro Ile His Thr Leu Tyr Gln Pro Arg Phe 1670 1675 1680 Gly Asn Ser Gln Ser Phe Thr Ser Lys Tyr Leu Gly Tyr Gly Asn 1685 1690 1695 Gln Asn Met Gln Gly Asp Gly Phe Ser Ser Cys Thr Ile Arg Pro 1700 1705 1710 Asn Val His His Val Gly Lys Leu Pro Pro Tyr Pro Thr His Glu 1715 1720 1725 Met Asp Gly His Phe Met Gly Ala Thr Ser Arg Leu Pro Pro Asn 1730 1735 1740 Leu Ser Asn Pro Asn Met Asp Tyr Lys Asn Gly Glu His His Ser 1745 1750 1755 Pro Ser His Ile Ile His Asn Tyr Ser Ala Ala Pro Gly Met Phe 1760 1765 1770 Asn Ser Ser Leu His Ala Leu His Leu Gln Asn Lys Glu Asn Asp 1775 1780 1785 Met Leu Ser His Thr Ala Asn Gly Leu Ser Lys Met Leu Pro Ala 1790 1795 1800 Leu Asn His Asp Arg Thr Ala Cys Val Gln Gly Gly Leu His Lys 1805 1810 1815 Leu Ser Asp Ala Asn Gly Gln Glu Lys Gln Pro Leu Ala Leu Val 1820 1825 1830 Gln Gly Val Ala Ser Gly Ala Glu Asp Asn Asp Glu Val Trp Ser 1835 1840 1845 Asp Ser Glu Gln Ser Phe Leu Asp Pro Asp Ile Gly Gly Val Ala 1850 1855 1860 Val Ala Pro Thr His Gly Ser Ile Leu Ile Glu Cys Ala Lys Arg 1865 1870 1875 Glu Leu His Ala Thr Thr Pro Leu Lys Asn Pro Asn Arg Asn His 1880 1885 1890 Pro Thr Arg Ile Ser Leu Val Phe Tyr Gln His Lys Ser Met Asn 1895 1900 1905 Glu Pro Lys His Gly Leu Ala Leu Trp Glu Ala Lys Met Ala Glu 1910 1915 1920 Lys Ala Arg Glu Lys Glu Glu Glu Cys Glu Lys Tyr Gly Pro Asp 1925 1930 1935 Tyr Val Pro Gln Lys Ser His Gly Lys Lys Val Lys Arg Glu Pro 1940 1945 1950 Ala Glu Pro His Glu Thr Ser Glu Pro Thr Tyr Leu Arg Phe Ile 1955 1960 1965 Lys Ser Leu Ala Glu Arg Thr Met Ser Val Thr Thr Asp Ser Thr 1970 1975 1980 Val Thr Thr Ser Pro Tyr Ala Phe Thr Arg Val Thr Gly Pro Tyr 1985 1990 1995 Asn Arg Tyr Ile 2000 <210> 39 <211> 9236 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 39 aaacagaagg tgggccgggg cggggagaaa cagaactcgg tcaatttccc agtttgtcgg 60 gtctttaaaa atacaggccc ctaaagcact aagggcatgc cctcggtgaa acaggggagc 120 gcttctgctg aatgagatta aagcgacaga aaagggaaag gagagcgcgg gcaacgggat 180 ctaaagggag atagagacgc gggcctctga gggctggcaa acattcagca gcacaccctc 240 tcaagattgt ttacttgcct ttgctcctgt tgagttacaa cgcttggaag caggagatgg 300 gctcagcagc agccaatagg acatgatcca ggaagagcag taagggactg agctgctgaa 360 ttcaactaga gggcagcctt gtggatggcc ccgaagcaag cctgatggaa caggatagaa 420 ccaaccatgt tgagggcaac agactaagtc cattcctgat accatcacct cccatttgcc 480 agacagaacc tctggctaca aagctccaga atggaagccc actgcctgag agagctcatc 540 cagaagtaaa tggagacacc aagtggcact ctttcaaaag ttattatgga ataccctgta 600 tgaagggaag ccagaatagt cgtgtgagtc ctgactttac acaagaaagt agagggtatt 660 ccaagtgttt gcaaaatgga ggaataaaac gcacagttag tgaaccttct ctctctgggc 720 tccttcagat caagaaattg aaacaagacc aaaaggctaa tggagaaaga cgtaacttcg 780 gggtaagcca agaaagaaat ccaggtgaaa gcagtcaacc aaatgtctcc gatttgagtg 840 ataagaaaga atctgtgagt tctgtagccc aagaaaatgc agttaaagat ttcaccagtt 900 tttcaacaca taactgcagt gggcctgaaa atccagagct tcagattctg aatgagcagg 960 aggggaaaag tgctaattac catgacaaga acattgtatt acttaaaaac aaggcagtgc 1020 taatgcctaa tggtgctaca gtttctgcct cttccgtgga acacacacat ggtgaactcc 1080 tggaaaaaac actgtctcaa tattatccag attgtgtttc cattgcggtg cagaaaacca 1140 catctcacat aaatgccatt aacagtcagg ctactaatga gttgtcctgt gagatcactc 1200 acccatcgca tacctcaggg cagatcaatt ccgcacagac ctctaactct gagctgcctc 1260 caaagccagc tgcagtggtg agtgaggcct gtgatgctga tgatgctgat aatgccagta 1320 aactagctgc aatgctaaat acctgttcct ttcagaaacc agaacaacta caacaacaaa 1380 aatcagtttt tgagatatgc ccatctcctg cagaaaataa catccaggga accacaaagc 1440 tagcgtctgg tgaagaattc tgttcaggtt ccagcagcaa tttgcaagct cctggtggca 1500 gctctgaacg gtatttaaaa caaaatgaaa tgaatggtgc ttacttcaag caaagctcag 1560 tgttcactaa ggattccttt tctgccacta ccacaccacc accaccatca caattgcttc 1620 tttctccccc tcctcctctt ccacaggttc ctcagcttcc ttcagaagga aaaagcactc 1680 tgaatggtgg agttttagaa gaacaccacc actaccccaa ccaaagtaac acaacacttt 1740 taagggaagt gaaaatagag ggtaaacctg aggcaccacc ttcccagagt cctaatccat 1800 ctacacatgt atgcagccct tctccgatgc tttctgaaag gcctcagaat aattgtgtga 1860 acaggaatga catacagact gcagggacaa tgactgttcc attgtgttct gagaaaacaa 1920 gaccaatgtc agaacacctc aagcataacc caccaatttt tggtagcagt ggagagctac 1980 aggacaactg ccagcagttg atgagaaaca aagagcaaga gattctgaag ggtcgagaca 2040 aggagcaaac acgagatctt gtgcccccaa cacagcacta tctgaaacca ggatggattg 2100 aattgaaggc ccctcgtttt caccaagcgg aatcccatct aaaacgtaat gaggcatcac 2160 tgccatcaat tcttcagtat caacccaatc tctccaatca aatgacctcc aaacaataca 2220 ctggaaattc caacatgcct ggggggctcc caaggcaagc ttacacccag aaaacaacac 2280 agctggagca caagtcacaa atgtaccaag ttgaaatgaa tcaagggcag tcccaaggta 2340 cagtggacca acatctccag ttccaaaaac cctcacacca ggtgcacttc tccaaaacag 2400 accattacc aaaagctcat gtgcagtcac tgtgtggcac tagatttcat tttcaacaaa 2460 gagcagattc ccaaactgaa aaacttatgt ccccagtgtt gaaacagcac ttgaatcaac 2520 aggcttcaga gactgagcca ttttcaaact cacacctttt gcaacataag cctcataaac 2580 aggcagcaca aacacaacca tcccagagtt cacatctccc tcaaaaccag caacagcagc 2640 aaaaattaca aataaagaat aaagaggaaa tactccagac ttttcctcac ccccaaagca 2700 acaatgatca gcaagagaa ggatcattct ttggccagac taaagtggaa gaatgttttc 2760 atggtgaaaa tcagtattca aaatcaagcg agttcgagac tcataatgtc caaatgggac 2820 tggaggaagt acagaatata aatcgtagaa attcccctta tagtcagacc atgaaatcaa 2880 gtgcatgcaa aatacaggtt tcttgttcaa acaatacaca cctagtttca gagaataaag 2940 aacagactac acatcctgaa ctttttgcag gaagaagac ccaaaacttg catcacatgc 3000 aatattttcc aaataatgtg atcccaaagc aagatcttct tcacaggtgc tttcaagaac 3060 3120 tgtctggtca acaagctgcg caacttgctc agcaaaggta cttgatacat aaccatgcaa 3180 atgtttttcc tgtgcctgac cagggagaa gtcacactca gacccctccc cagaaggaca 3240 ctcaaaagca tgctgctcta aggtggcatc tcttacagaa cgaagaacag cagcaaacac 3300 agcaacccca aactgagtct tgccatagtc agatgcacag gccaattaag gtggaacctg 3360 gatgcaagcc acatgcctgt atgcacacag caccaccaga aaacaaaaca tggaaaaagg 3420 taactaagca agagaatcca cctgcaagct gtgataatgt gcagcaaaag agcatcattg 3480 agaccatgga gcagcatctg aagcagtttc acgccaagtc gttatttgac cataaggctc 3540 3600 ctagacaac cactgctgca gaacttgata gccacacccc agctttagag cagcaacaa 3660 cttcttcaga aaagacacca accaaaagaa cagctgcttc tgttctcaat aattttatag 3720 agtcaccttc caaattacta gatactccta taaaaaattt attggataca cctgtcaaga 3780 ctcaatatga tttcccatct tgcagatgtg taggtaagtg ccagaaatgt actgagacac 3840 atggcgttta tccagaatta gcaaatttat cttcagatat gggattttcc ttcttttttt 3900 aaatcttgag tctggcagca atttgtaaag gctcataaaa atctgaagct tacatttttt 3960 gtcaagttac cgatgcttgt gtcttgtgaa agagaacttc acttacatgc agtttttcca 4020 aaagaattaa ataatcgtgc atgtttattt ttccctctct tcagatcctg taaaatttga 4080 atgtatctgt tttagatcaa ttcgcctatt tagctctttg tatattatct cctggagaga 4140 cagctaggca gcaaaaaaac aatctattaa aatgagaaaa taacgaccat aggcagtcta 4200 atgtacgaac tttaaatatt ttttaattca aggtaaaata tattagtttc acaagatttc 4260 tggctaatag ggaaattat atcttcagtc ttcatgagtt gggggaaatg ataatgctga 4320 cactcttagt gctcctaaag tttccttttc tccatttata catttggaat gttgtgattt 4380 atattcattt tgattccctt ttctctaaaa tttcatcttt ttgattaaaa aatatgatac 4440 aggcatacct cagagatatt gtgggtttgg ctccatacca caataaaatg aatattacaa 4500 taaagcaagt tgtaaggact ttttggttc tcactgtatg taaaagttat ttatatacta 4560 tactgtaaca tactaagtgt gcaatagcat tgtgtctaaa aaatatatac tttaaaaata 4620 atttattgtt aaaaaaatgc caacaattat ctgggccttt agtgagtgct aatctttttg 4680 ctggtggagg gtcgtgcttc agtattgatc gctgtggact gatcatggtg gtagttgctg 4740 aaggttgctg ggatggctgt gtgtgtggca atttcttaaa ataagacaac agtgaagtgc 4800 tgtatcaatt gatttttcca ttcacaaaag atttctctgt agcatgcaat gctgtttgat 4860 agcatttaac ccacagcaga atttctttga aaattggact cagtcctctc aaactgtgct 4920 gctgcttat caactaagtt tttgtaattt tctgaatcct ttgttgtcat ttcagcagtt 4980 tacagcatct tcattggaag tatattccat ctcaaacatt ctttgttcat ccataagaag 5040 caacttctta tcaagttttt tcatgacatt gcagtaactc agccccatct tcaggctcta 5100 cttctaattc tggttctctt gctacatctc cctcatctgc agtgacctct ccacggaagt 5160 cttgaactcc tcaaagtaat ccatgagggt tggaatcaac ttctaaactc ctgttaatgt 5220 tgatatattg accccctccc atgaattatg aatgttctta ataacttcta aatggtgata 5280 cctttccaga aggctttcaa tgtactttgc ccggatccat cagaagacta tcttggcagc 5340 tgtagactaa caatatattt cttaaatgat aagacttgaa agtcaaaagt actccttaat 5400 ccataggctg cagaatcaat gttgtattaa caggcacgaa aacagcatta atcttgtgca 5460 tctccatcgg agctcttggg tgactaggtg ccttgagcag taatattttg aaaggaggtt 5520 ttggttttgt tttttgtttt ttttttttgt tttttagcag taagtctcaa cactgggctt 5580 aaaatattca gtaaactatg ttgtaaaaag atgtgttatc atccagactt tgttgttcca 5640 ttactctaca caagcagggt acacttagca taattcttaa gggccttgga attttcagaa 5700 tggtaaatga gtatgggctt caacttaaaa tcatcaactg cattagcctg taacaagaga 5760 gtcagcctgt cctttgaagc aaggcattga cttctatcta tgaaagtctt agatggcacc 5820 ttgtttcaat agtaggctgt ttagtacagc caccttcatc agtgatctta gctagatctt 5880 ctgcataact tgctgcagct tctacatcag cacttgctgc ctcaccttgt ccttttatgt 5940 tatagagaca gctgcgcttc ttaaacttta taaaccaact tctgctagct tccaacttct 6000 cttctgcagc ttcctcattc tcttcataga actgaaggga gtcaaggcct tgctctgggat 6060 taagctttgg cttaaggaat gttgtggctg acgtgatctt ctatccagac cactaaagcg 6120 ctctccatat cagcaataag gccgttttgc tttcttacct ttcatgtgtt cactggagta 6180 atttccttca agaatttttc ctttacattc acaacttggc taactggcat gcaaggccta 6240 gctttcagcc tgtcttggct tttgacatgc cttctcct tagctcgtca tatctagctt 6300 ttgatttaaa gtggcaggca tacaactctt cctttcactt gaacacttag aggccactgt 6360 agggtatta attggcctaa tttcaatatt gttgtgtttt agggaataga gaggcccagg 6420 gaggaggaga gagcccaaac ggctggttga tagagcaggc agaatgcaca caacattat 6480 cagattatgt ttgcaccatt taccagatta tgggtacggt ttgtggcacc ccccaaaaat 6540 tagaatagta acatcaaaga tcactgatca cagatcgcca taacataaat aataataaac 6600 tttaaaatac tgtgagaatt accaaaatgt gatacagaga catgaagtga gcacatgctg 6660 ttgaaaaaaa tgacactgat agacatactt aacacgtggg attgccacaa accttcagtt 6720 tgtaaaagtc acagtaactg tgactcacaa aagaacaaag cacaataaaa cgaggtatgc 6780 ctgtattttt aaaaaaagct ttttgttaaa attcaggata tgtaataggt ctgtaggaat 6840 agtgaaatat ttttgctgat ggatgtagat atatacgtgg atagagatga agatcttaat 6900 tatagctatg cagcatagat ttagtcaaag acatttgaaa agacaaatgt taaattagtg 6960 tggctaatga cctacccgtg ccatgttttc cctcttgcaa tgagataccc cacactgtgt 7020 agaaggatgg agggaggact cctactgtcc ctctttgcgt gtggttatta agttgcctca 7080 ctgggctaaa acaccacaca tctcatagat aatatttggt aagttgtaat cgtcttcact 7140 cttctcttat cacccacccc tatcttccca cttttccatc tttgttggtt tgcaacagcc 7200 ccttcttttt gcctgactct ccaggatttt ctctcatcat aaattgttct aaagtacata 7260 ctaatatggg tctggattga ctattcttat ttgcaaaaca gcaattaaat gttataggga agtaggaga aaaaggggta tccttgacaa taaccaagc aatattctgg ggttgggata gagcagga ttttattttt aatcttttaa aatccaagta ataggtaggc ttccagttag ctttaaatgt tttttttttc cagctcaaaa aattggattg tagttgatac tacatataat acattctat tccctcactg tattctttgt ttagttttcat tttttggtt taaataatt ttttatccca tatctgaat gtaatatatt tttatccaac aaccagcatg tacatatact father gcacattttc father gtccatcaat ctactcattt taaagaaaaa aaaattttaa agtcactttt agagccctta atgtgtagtt gggggttaag ctttgtggat 7740. gtagccttta tatttagtat aattgaggtc taaataata atcttctatt atctcaacag agcaaattat tgaaaaagat gaaggtcctt tttataccca tctaggagca ggtcctaatg tggcagctat tagagaaatc atggaagaaa ggtaattaac gcaaaggcac agggcagatt aacgtttatc cttttgtata tgtcagaatt tttccagcct tcacacacaa agcagtaaac aattgtaaat tgagtaatta ttagtaggct tagctattct agggttgcca acactacaca 8040 ctgtgctatt caccagagag tcacaatatt tgacaggact aatagtctgc tagctggcac 8100 aggctgccca ctttgcgatg gatgccagaa aacccaggca tgaacaggaa tcggccagcc 8160 aggctgccag ccacaaggta ctggcacagg ctccaacgag aggtcccact ctggctttcc 8220 cacctgataa taaagtgtca aagcagaaag actggtaaag tgtggtataa gaaaagaacc 8280 actgaattaa attcacctag tgttgcaaat gagtacttat ctctaagtttt tcttttacca 8340 taaaaagaga gcaagtgtga tatgttgaat agaaagagaa acatactatt tacagctgcc 8400 tttttttt ttttcgcta tcaatcacag gtatacaagt acttgccttt actcctgcat 8460 gtagaagact cttatgagcg agataatgca gagaaggcct ttcatataaa tttatacagc 8520 tctgagctgt tcttcttcta gggtgccttt tcattaagag gtaggcagta ttattattaa 8580 agtacttagg atacattggg gcagctagga catattcagt atcattcttg ctccatttcc 8640 aaattattca tttctaaatt agcatgtaga agttcactaa ataatcatct agtggcctgg 8700 cagaaatagt gaatttccct aagtgccttt tttttgttgt ttttttgttt tgttttttaa 8760 acaagcagta ggtggtgctt tggtcataag ggaagatata gtctatttct aggactattc 8820 catattttcc atgtggctgg atactacta tttgccagcc tcctttcta aattgtgaga 8880 cattcttgga ggaacagttc taactaaaat ctattatgac tccccaagtt ttaaaatagc 8940 taaatttagt aagggaaaaa atagtttatg ttttagaaga ctgaacttag caaactaacc 9000 tgaattttgt gctttgtgaa attttattc gaaatgagct ttcccatttt cacccacatg 9060 taatttacaa aatagttcat tacaattatc tgtacatttt gatatgagg aaaaacaagg 9120 cttaaaaacc attatccagt ttgcttggcg tagacctgtt taaaaaataa taaaccgttc 9180 atttctcagg atgtggtcat agaataaagt tatgctcaaa tgttcaaata tttaaa 9236 <210> 40 <211> 1165 <212> PRT <213> Artificial sequence <220> <223> Synthetic polymer <400> 40 Met Glu Gln Asp Arg Thr Asn His Val Glu Gly Asn Arg Leu Ser Pro 1 5 10 15 Phe Leu Ile Pro Ser Pro Pro Ile Cys Gln Thr Glu Pro Leu Ala Thr 20 25 30 Lys Leu Gln Asn Gly Ser Pro Leu Pro Glu Arg Ala His Pro Glu Val 35 40 45 Asn Gly Asp Thr Lys Trp His Ser Phe Lys Ser Tyr Tyr Gly Ile Pro 50 55 60 Cys Met Lys Gly Ser Gln Asn Ser Arg Val Ser Pro Asp Phe Thr Gln 65 70 75 80 Glu Ser Arg Gly Tyr Ser Lys Cys Leu Gln Asn Gly Gly Ile Lys Arg 85 90 95 Thr Val Ser Glu Pro Ser Leu Ser Gly Leu Leu Gln Ile Lys Lys Leu 100 105 110 Lys Gln Asp Gln Lys Ala Asn Gly Glu Arg Arg Asn Phe Gly Val Ser 115 120 125 Gln Glu Arg Asn Pro Gly Glu Ser Ser Gln Pro Asn Val Ser Asp Leu 130 135 140 Ser Asp Lys Lys Glu Ser Val Ser Ser Val Ala Gln Glu Asn Ala Val 145 150 155 160 Lys Asp Phe Thr Ser Phe Ser Thr His Asn Cys Ser Gly Pro Glu Asn 165 170 175 Pro Glu Leu Gln Ile Leu Asn Glu Gln Glu Gly Lys Ser Ala Asn Tyr 180 185 190 His Asp Lys Asn Ile Val Leu Leu Lys Asn Lys Ala Val Leu Met Pro 195 200 205 Asn Gly Ala Thr Val Ser Ala Ser Ser Val Glu His Thr His Gly Glu 210 215 220 Leu Leu Glu Lys Thr Leu Ser Gln Tyr Tyr Pro Asp Cys Val Ser Ile 225 230 235 240 Ala Val Gln Lys Thr Thr Ser His Ile Asn Ala Ile Asn Ser Gln Ala 245 250 255 Thr Asn Glu Leu Ser Cys Glu Ile Thr His Pro Ser His Thr Ser Gly 260 265 270 Gln Ile Asn Ser Ala Gln Thr Ser Asn Ser Glu Leu Pro Pro Lys Pro 275 280 285 Ala Ala Val Val Ser Glu Ala Cys Asp Ala Asp Asp Ala Asp Asn Ala 290 295 300 Ser Lys Leu Ala Ala Met Leu Asn Thr Cys Ser Phe Gln Lys Pro Glu 305 310 315 320 Gln Leu Gln Gln Gln Lys Ser Val Phe Glu Ile Cys Pro Ser Pro Ala 325 330 335 Glu Asn Asn Ile Gln Gly Thr Thr Lys Leu Ala Ser Gly Glu Glu Phe 340 345 350 Cys Ser Gly Ser Ser Ser Asn Leu Gln Ala Pro Gly Gly Ser Ser Glu 355 360 365 Arg Tyr Leu Lys Gln Asn Glu Met Asn Gly Ala Tyr Phe Lys Gln Ser 370 375 380 Ser Val Phe Thr Lys Asp Ser Phe Ser Ala Thr Thr Thr Pro Pro Pro 385 390 395 400 Pro Ser Gln Leu Leu Leu Ser Pro Pro Pro Pro Leu Pro Gln Val Pro 405 410 415 Gln Leu Pro Ser Glu Gly Lys Ser Thr Leu Asn Gly Gly Val Leu Glu 420 425 430 Glu His His His Tyr Pro Asn Gln Ser Asn Thr Thr Leu Leu Arg Glu 435 440 445 Val Lys Ile Glu Gly Lys Pro Glu Ala Pro Pro Ser Gln Ser Pro Asn 450 455 460 Pro Ser Thr His Val Cys Ser Pro Ser Pro Met Leu Ser Glu Arg Pro 465 470 475 480 Gln Asn Asn Cys Val Asn Arg Asn Asp Ile Gln Thr Ala Gly Thr Met 485 490 495 Thr Val Pro Leu Cys Ser Glu Lys Thr Arg Pro Met Ser Glu His Leu 500 505 510 Lys His Asn Pro Pro Ile Phe Gly Ser Ser Gly Glu Leu Gln Asp Asn 515 520 525 Cys Gln Gln Leu Met Arg Asn Lys Glu Gln Glu Ile Leu Lys Gly Arg 530 535 540 Asp Lys Glu Gln Thr Arg Asp Leu Val Pro Pro Thr Gln His Tyr Leu 545 550 555 560 Lys Pro Gly Trp Ile Glu Leu Lys Ala Pro Arg Phe His Gln Ala Glu 565 570 575 Ser His Leu Lys Arg Asn Glu Ala Ser Leu Pro Ser Ile Leu Gln Tyr 580 585 590 Gln Pro Asn Leu Ser Asn Gln Met Thr Ser Lys Gln Tyr Thr Gly Asn 595 600 605 Ser Asn Met Pro Gly Gly Leu Pro Arg Gln Ala Tyr Thr Gln Lys Thr 610 615 620 Thr Gln Leu Glu His Lys Ser Gln Met Tyr Gln Val Glu Met Asn Gln 625 630 635 640 Gly Gln Ser Gln Gly Thr Val Asp Gln His Leu Gln Phe Gln Lys Pro 645 650 655 Ser His Gln Val His Phe Ser Lys Thr Asp His Leu Pro Lys Ala His 660 665 670 Val Gln Ser Leu Cys Gly Thr Arg Phe His Phe Gln Gln Arg Ala Asp 675 680 685 Ser Gln Thr Glu Lys Leu Met Ser Pro Val Leu Lys Gln His Leu Asn 690 695 700 Gln Gln Ala Ser Glu Thr Glu Pro Phe Ser Asn Ser His Leu Leu Gln 705 710 715 720 His Lys Pro His Lys Gln Ala Ala Gln Thr Gln Pro Ser Gln Ser Ser 725 730 735 His Leu Pro Gln Asn Gln Gln Gln Gln Gln Lys Leu Gln Ile Lys Asn 740 745 750 Lys Glu Glu Ile Leu Gln Thr Phe Pro His Pro Gln Ser Asn Asn Asp 755 760 765 Gln Gln Arg Glu Gly Ser Phe Phe Gly Gln Thr Lys Val Glu Glu Cys 770 775 780 Phe His Gly Glu Asn Gln Tyr Ser Lys Ser Ser Glu Phe Glu Thr His 785 790 795 800 Asn Val Gln Met Gly Leu Glu Glu Val Gln Asn Ile Asn Arg Arg Asn 805 810 815 Ser Pro Tyr Ser Gln Thr Met Lys Ser Ser Ala Cys Lys Ile Gln Val 820 825 830 Ser Cys Ser Asn Asn Thr His Leu Val Ser Glu Asn Lys Glu Gln Thr 835 840 845 Thr His Pro Glu Leu Phe Ala Gly Asn Lys Thr Gln Asn Leu His His 850 855 860 Met Gln Tyr Phe Pro Asn Asn Val Ile Pro Lys Gln Asp Leu Leu His 865 870 875 880 Arg Cys Phe Gln Glu Gln Glu Gln Lys Ser Gln Gln Ala Ser Val Leu 885 890 895 Gln Gly Tyr Lys Asn Arg Asn Gln Asp Met Ser Gly Gln Gln Ala Ala 900 905 910 Gln Leu Ala Gln Gln Arg Tyr Leu Ile His Asn His Ala Asn Val Phe 915 920 925 Pro Val Pro Asp Gln Gly Gly Ser His Thr Gln Thr Pro Pro Gln Lys 930 935 940 Asp Thr Gln Lys His Ala Ala Leu Arg Trp His Leu Leu Gln Lys Gln 945 950 955 960 Glu Gln Gln Gln Thr Gln Gln Pro Gln Thr Glu Ser Cys His Ser Gln 965 970 975 Met His Arg Pro Ile Lys Val Glu Pro Gly Cys Lys Pro His Ala Cys 980 985 990 Met His Thr Ala Pro Pro Glu Asn Lys Thr Trp Lys Lys Val Thr Lys 995 1000 1005 Gln Glu Asn Pro Pro Ala Ser Cys Asp Asn Val Gln Gln Lys Ser 1010 1015 1020 Ile Ile Glu Thr Met Glu Gln His Leu Lys Gln Phe His Ala Lys 1025 1030 1035 Ser Leu Phe Asp His Lys Ala Leu Thr Leu Lys Ser Gln Lys Gln 1040 1045 1050 Val Lys Val Glu Met Ser Gly Pro Val Thr Val Leu Thr Arg Gln 1055 1060 1065 Thr Thr Ala Ala Glu Leu Asp Ser His Thr Pro Ala Leu Glu Gln 1070 1075 1080 Gln Thr Thr Ser Ser Glu Lys Thr Pro Thr Lys Arg Thr Ala Ala 1085 1090 1095 Ser Val Leu Asn Asn Phe Ile Glu Ser Pro Ser Lys Leu Leu Asp 1100 1105 1110 Thr Pro Ile Lys Asn Leu Leu Asp Thr Pro Val Lys Thr Gln Tyr 1115 1120 1125 Asp Phe Pro Ser Cys Arg Cys Val Gly Lys Cys Gln Lys Cys Thr 1130 1135 1140 Glu Thr His Gly Val Tyr Pro Glu Leu Ala Asn Leu Ser Ser Asp 1145 1150 1155 Met Gly Phe Ser Phe Phe Phe 1160 1165 <210> 41 <211> 4049 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 41 agcgcgtacc actctggcgc tcccgaggcg gcctcttgtg cgatccaggg cgcacaaggc 60 tgggagagcg ccccggggcc cctgctatcc gcgccggagg ttggaagagg gtgggttgcc 120 gccgcccgag ggcgagagcg ccagaggagc gggaagaagg agcgctcgcc cgcccgcctg 180 cctcctcgct gcctccccgg cgttggctct ctggactcct aggcttgctg gctgctcctc 240 ccacccgcgc ccgcctcctc actcgccttt tcgttcgccg gggctgcttt ccaagccctg 300 cggtgcgccc gggcgagtgc ggggcgaggg gcccggggcc agcaccgagc agggggcggg 360 ggtccgggca gagcgcggcc ggccggggag gggccatgtc tggcgcgggc gcagcggggc 420 ccgtctgcag caagtgaccg agcggcgcgg acggccgcct gccccctctg ccacctgggg 480 cggtgcgggc ccggagcccg gagcccgggt agcgcgtaga gccggcgcga tgcacgtgcg 540 ctcactgcga gctgcggcgc cgcacagctt cgtggcgctc tgggcacccc tgttcctgct 600 gcgctccgcc ctggccgact tcagcctgga caacgaggtg cactcgagct tcatccaccg 660 gcgcctccgc agccaggagc ggcgggagat gcagcgcgag atcctctcca ttttgggctt 720 gccccaccgc ccgcgcccgc acctccaggg caagcacaac tcggcaccca tgttcatgct 780 ggacctgtac aacgccatgg cggtggagga gggcggcggg cccggcggcc agggcttctc 840 ctacccctac aaggccgtct tcagtaccca gggcccccct ctggccagcc tgcaagatag 900 ccatttcctc accgacgccg acatggtcat gagcttcgtc aacctcgtgg aacatgacaa 960 ggaattcttc cacccacgct accaccatcg agagttccgg tttgatcttt ccaagatccc 1020 agaaggggaa gctgtcacgg cagccgaatt ccggatctac aaggactaca tccgggaacg 1080 cttcgacaat gagacgttcc ggatcagcgt ttatcaggtg ctccaggagc acttgggcag 1140 ggaatcggat ctcttcctgc tcgacagccg taccctctgg gcctcggagg agggctggct 1200 ggtgtttgac atcacagcca ccagcaacca ctgggtggtc aatccgcggc acaacctggg 1260 cctgcagctc tcggtggaga cgctggatgg gcagagcatc aaccccaagt tggcgggcct 1320 gattgggcgg cacgggcccc agaacaagca gcccttcatg gtggctttct tcaaggccac 1380 ggaggtccac ttccgcagca tccggtccac ggggagcaaa cagcgcagcc agaaccgctc 1440 caagacgccc aagaaccagg aagccctgcg gatggccaac gtggcagaga acagcagcag 1500 cgaccagagg caggcctgta agaagcacga gctgtatgtc agcttccgag acctgggctg 1560 gcaggactgg atcatcgcgc ctgaaggcta cgccgcctac tactgtgagg gggagtgtgc 1620 cttccctctg aactcctaca tgaacgccac caaccacgcc atcgtgcaga cgctggtcca 1680 cttcatcaac ccggaaacgg tgcccaagcc ctgctgtgcg cccacgcagc tcaatgccat 1740 ctccgtcctc tacttcgatg acagctccaa cgtcatcctg aagaaataca gaaacatggt 1800 ggtccgggcc tgtggctgcc actagctcct ccgagaattc agaccctttg gggccaagtt 1860 tttctggatc ctccattgct cgccttggcc aggaaccagc agaccaactg ccttttgtga 1920 gaccttcccc tcctatccc caactttaaa ggtgtgagag tattaggaaa catgagcagc 1980 atatggcttt tgatcagttt ttcagtggca gcatccaatg aacaagatcc tacaagctgt 2040 gcaggcaaaa cctagcagga aaaaaaaaca acgcataaag aaaaatggcc gggccaggtc 2100 attggctggg aagtctcagc catgcacgga ctcgtttcca gaggtaatta tgagcgccta 2160 ccagccaggc cacccagccg tgggaggaag ggggcgtggc aaggggtggg cacattggtg 2220 tctgtgcgaa aggaaaattg acccggaagt tcctgtaata aatgtcacaa taaaacgaat 2280 gaatgaaaat ggttaggacg ttacagatat atttcctaa acaatttatc cccatttctc 2340 ggtttatcct gatgcgtaaa cagaagctgt gtcaagtgga gggcggggag gtccctctcc 2400 attccctaca gttttcatcc tgaggcttgc agaggcccag tgtttaccga ggtttgccca 2460 aatccaagat ctagtgggag gggaaagagc aaatgtctgc tccgaggagg gcggtgtgtt 2520 gatctttgga ggaaaaatat gttctgttgt tcagctggat ttgccgtggc agaaatgaaa 2580 ctaggtgtgt gaaatacccg cagacatttg ggattggct ttcacctcgc cccagtggta 2640 gtaaatccat gtgaaattgc agaggggaca aggacagcaa gtaggatgga acttgcaact 2700 caaccctgtt gttaagaagc accaatgggc cgggcacagt agctcccacc tgtaatccca 2760 gcactttggg aggctgaggt gggcggatca tttgaggtca ggagttcgag accagcctgg 2820 ccaacatggt gaaaccccat ctctactaaa aatacaaaaa ttagccgggc atggtggcac 2880 gcacctgtaa tcccagctac tctggaggct gaggcaggag aattgcttga accccagagg 2940 tggaggttgc agtgagccaa gatcgtccca ctgcactcca gcttgggtga caaaacaaga 3000 ctccatctca aaagaaaaaa aaaacagcac caatgaagcc tagttctcca cgggagtggg 3060 gtgagcagga gcactgcaca tcgccccagt ggaccctctg gtctttgtct gcagtggcat 3120 tccaaggctg ggccctggca agggcaccg tggctgtctc ttcatttgca gaccctgatc 3180 agaagtctct gcaaacaaat ttgctccttg aattaagggg gagatggcat aataggaggt 3240 ctgatgggtg caggatgtgc tggacttaca ttgcaaatag aagccttgtt gagggtgaca 3300 tcctaaccaa gtgtcccgat ttggaggtgg catttctgac gtggctcttg gtgtaagcct 3360 gccttgcctt ggctggtgag tcccataaat agtatgcact cagcctccgg ccacaaacac 3420 aaggcctagg ggagggctag actgtctgca aacgttttct gcatctgtaa agaaaacaag 3480 gtgatcgaaa actgtggcca tgtggaaccc ggtcttgtgg gggactgttt ctccatcttg 3540 actcagacag ttcctggaaa caccggggct ctgtttttat tttctttgat gtttttcttc 3600 tttagtagct tgggctgcag cctccactct ctagtcactg gggaggagta ttttttgtta 3660 tgtttggttt catttgctgg cagagctggg gctttttgtg tgatccctct tggtgtgagt 3720 tttctgaccc aaccagcctc tggttagcat catttgtaca tttaaacctg taaatagttg 3780 ttacaaagca aagagattat ttatttccat ccaaagctct tttgaacacc cccccccctt 3840 taatccctcg ttcaggacga tgagcttgct ttccttcaac ctgtttgttt tcttatttaa 3900 gactatttat taatggttgg accaatgtac tcacagctgt tgcgtcgagc agtccttagt 3960 gaaaattctg tataaataga caaaatgaaa agggtttgac cttgcaataa aaggagacgt 4020 ttggttctgg caaaaaaaaa aaaaaaaaa 4049 <210> 42 <211> 431 <212> PRT <213> Artificial sequence <220> <223> Synthetic polymer <400> 42 Met His Val Arg Ser Leu Arg Ala Ala Ala Pro His Ser Phe Val Ala 1 5 10 15 Leu Trp Ala Pro Leu Phe Leu Leu Arg Ser Ala Leu Ala Asp Phe Ser 20 25 30 Leu Asp Asn Glu Val His Ser Ser Phe Ile His Arg Arg Leu Arg Ser 35 40 45 Gln Glu Arg Arg Glu Met Gln Arg Glu Ile Leu Ser Ile Leu Gly Leu 50 55 60 Pro His Arg Pro Arg Pro His Leu Gln Gly Lys His Asn Ser Ala Pro 65 70 75 80 Met Phe Met Leu Asp Leu Tyr Asn Ala Met Ala Val Glu Glu Gly Gly 85 90 95 Gly Pro Gly Gly Gln Gly Phe Ser Tyr Pro Tyr Lys Ala Val Phe Ser 100 105 110 Thr Gln Gly Pro Pro Leu Ala Ser Leu Gln Asp Ser His Phe Leu Thr 115 120 125 Asp Ala Asp Met Val Met Ser Phe Val Asn Leu Val Glu His Asp Lys 130 135 140 Glu Phe Phe His Pro Arg Tyr His His Arg Glu Phe Arg Phe Asp Leu 145 150 155 160 Ser Lys Ile Pro Glu Gly Glu Ala Val Thr Ala Ala Glu Phe Arg Ile 165 170 175 Tyr Lys Asp Tyr Ile Arg Glu Arg Phe Asp Asn Glu Thr Phe Arg Ile 180 185 190 Ser Val Tyr Gln Val Leu Gln Glu His Leu Gly Arg Glu Ser Asp Leu 195 200 205 Phe Leu Leu Asp Ser Arg Thr Leu Trp Ala Ser Glu Glu Gly Trp Leu 210 215 220 Val Phe Asp Ile Thr Ala Thr Ser Asn His Trp Val Val Asn Pro Arg 225 230 235 240 His Asn Leu Gly Leu Gln Leu Ser Val Glu Thr Leu Asp Gly Gln Ser 245 250 255 Ile Asn Pro Lys Leu Ala Gly Leu Ile Gly Arg His Gly Pro Gln Asn 260 265 270 Lys Gln Pro Phe Met Val Ala Phe Phe Lys Ala Thr Glu Val His Phe 275 280 285 Arg Ser Ile Arg Ser Thr Gly Ser Lys Gln Arg Ser Gln Asn Arg Ser 290 295 300 Lys Thr Pro Lys Asn Gln Glu Ala Leu Arg Met Ala Asn Val Ala Glu 305 310 315 320 Asn Ser Ser Ser Asp Gln Arg Gln Ala Cys Lys Lys His Glu Leu Tyr 325 330 335 Val Ser Phe Arg Asp Leu Gly Trp Gln Asp Trp Ile Ile Ala Pro Glu 340 345 350 Gly Tyr Ala Ala Tyr Tyr Cys Glu Gly Glu Cys Ala Phe Pro Leu Asn 355 360 365 Ser Tyr Met Asn Ala Thr Asn His Ala Ile Val Gln Thr Leu Val His 370 375 380 Phe Ile Asn Pro Glu Thr Val Pro Lys Pro Cys Cys Ala Pro Thr Gln 385 390 395 400 Leu Asn Ala Ile Ser Val Leu Tyr Phe Asp Asp Ser Ser Asn Val Ile 405 410 415 Leu Lys Lys Tyr Arg Asn Met Val Val Arg Ala Cys Gly Cys His 420 425 430 <210> 43 <211> 4110 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymer <400> 43 gtcgagcggg agcagaggag gcgagggagg agggccagag aggcagttgg aagatggcgg 60 acgaggcggc cctcgccctt cagcccggcg gctccccctc ggcggcgggg gccgacaggg 120 aggccgcgtc gtcccccgcc ggggagccgc tccgcaagag gccgcggaga gatggtcccg 180 gcctcgagcg gagcccgggc gagcccggtg gggcggcccc agagcgtgag gtgccggcgg 240 cggccagggg ctgcccgggt gcggcggcgg cggcgctgtg gcgggaggcg gaggcagagg 300 cggcggcggc aggcggggag caagaggccc aggcgactgc ggcggctggg gaaggagaca 360 atgggccggg cctgcagggc ccatctcggg agccaccgct ggccgacaac ttgtacgacg 420 aagacgacga cgacgagggc gaggaggagg aagaggcggc ggcggcggcg attgggtacc 480 gagataacct tctgttcggt gatgaaatta tcactaatgg ttttcattcc tgtgaaagtg 540 atgaggagga tagagcctca catgcaagct ctagtgactg gactccaagg ccacggatag 600 gtccatatac ttttgttcag caacatctta tgattggcac agatcctcga acaattctta 660 aagatttt gccggaaaca atacctccac ctgagttgga tgatatgaca ctgtggcaga 720 ttgttattaa tatcctttca gaaccaccaa aaaggaaaaa aagaaaagat attaatacaa 780 ttgaagatgc tgtgaaatta ctgcaagagt gcaaaaaaat tatagttcta actggagctg 840 gggtgtctgt ttcatgtgga atacctgact tcaggtcaag ggatggtatt tatgctcgcc 900 ttgctgtaga cttcccagat cttccagatc ctcaagcgat gtttgatatt gaatatttca 960 gaaaagatcc aagaccattc ttcaagtttg caaaggaaat atatcctgga caattccagc 1020 catctctctg tcacaaattc atagccttgt cagataagga aggaaaacta cttcgcaact 1080 atacccagaa catagacacg ctggaacagg ttgcgggaat ccaaaggata attcagtgtc 1140 atggttcctt tgcaacagca tcttgcctga tttgtaaata caaagttgac tgtgaagctg 1200 tacgaggaga tatttttaat caggtagttc ctcgatgtcc taggtgccca gctgatgaac 1260 cgcttgctat catgaaacca gagattgtgt tttttggtga aaatttacca gaacagtttc 1320 atagagccat gaagtatgac aaagatgaag ttgacctcct cattgttatt gggtcttccc 1380 tcaaagtaag accagtagca ctaattccaa gttccatacc ccatgaagtg cctcagatat 1440 taattaatag agaacctttg cctcatctgc atttgatgt agagcttctt ggagactgtg 1500 atgtcataat taatgaattg tgtcataggt taggtggtga atatgccaaa ctttgctgta 1560 accctgtaaa gctttcagaa attactgaaa aacctccacg aacacaaaaa gaattggctt 1620 atttgtcaga gttgccacccc acacctcttc atgtttcaga agactcaagt tcaccagaaa 1680 gaacttcacc accagattct tcagtgattg tcacactttt agaccaagca gctaagagta 1740 atgatgattt agatgtgtct gaatcaaaag gttgtatgga agaaaaacca caggaagtac 1800 aaacttctag gaatgttgaa agtattgctg aacagatgga aaatccggat ttgaagaatg 1860 ttggttctag tactggggag aaaaatgaaa gaacttcagt ggctggaaca gtgagaaaat 1920 gctggcctaa tagagtggca aaggagcaga ttagtaggcg gcttgatggt aatcagtatc 1980 tgtttttgcc accaaatcgt tacattttcc atggcgctga ggtatattca gactctgaag 2040 atgacgtctt atcctctagt tcttgtggca gtaacagtga tagtgggaca tgccagagtc 2100 caagtttaga agaacccatg gaggatgaaa gtgaaattga agaattctac aatggcttag 2160 aagatgagcc tgatgttcca gagagagctg gaggagctgg atttgggact gatggagatg 2220 atcaagaggc aattaatgaa gctatatctg tgaaacagga agtaacagac atgaactatc 2280 catcaaacaa atcatagtgt aataattgtg caggtacagg aattgttcca ccagcattag 2340 gaactttagc atgtcaaaat gaatgtttac ttgtgaactc gatagagcaa ggaaaccaga 2400 aaggtgtaat atttataggt tggtaaaata gattgttttt catggataat ttttaacttc 2460 attatttctg tacttgtaca aactcaacac taacttttt ttttttaaaa aaaaaaaggt 2520 actaagtatc ttcaatcagc tgttggtcaa gactaacttt cttttaaagg ttcatttgta 2580 tgataaattc atatgtgtat atataattt ttttgttttg tctagtgagt ttcaacattt 2640 ttaaagtttt caaaaagcca tcggaatgtt aaattaatgt aaagggaaca gctaatctag 2700 accaaagaat ggtattttca cttttctttg taacattgaa tggtttgaag tactcaaaat 2760 ctgttacgct aaacttttga ttctttaaca caattatttt taaacactgg cattttccaa 2820 aactgtggca gctaactttt taaaatctca aatgacatgc agtgtgagta gaaggaagtc 2880 aacaatatgt ggggagagca ctcggttgtc tttactttta aaagtaatac ttggtgctaa 2940 gaatttcagg attattgtat ttacgttcaa atgaagatgg cttttgtact tcctgtggac 3000 atgtagtaat gtctatattg gctcataaaa ctaacctgaa aaacaaataa atgctttgga 3060 aatgtttcag ttgctttaga aacattagtg cctgcctgga tccccttagt tttgaaatat 3120 ttgccattgt tgtttaaata cctatcactg tggtagagct tgcattgatc ttttccacaa 3180 gtattaaact gccaaaatgt gaatatgcaa agcctttctg aatctataat aatggtactt 3240 ctactgggga gagtgtaata ttttggactg ctgttttcca ttaatgagga gagcaacagg 3300 cccctgatta tacagttcca aagtaataag atgttaattg taattcagcc agaaagtaca 3360 tgtctcccat tgggaggatt tggtgttaaa taccaaactg ctagccctag tattatggag 3420 atgaacatga tgatgtaact tgtaatagca gaatagttaa tgaatgaaac tagttcttat 3480 aatttatctt tatttaaaag cttagcctgc cttaaaacta gagatcaact ttctcagctg 3540 caaaagcttc tagtctttca agaagttcat actttatgaa attgcacagt aagcatttat 3600 ttttcagacc atttttgaac atcactccta aattaataaa gtattcctct gttgctttag 3660 tatttattac aataaaaagg gtttgaaata tagctgttct ttatgcataa aacacccagc 3720 taggaccatt actgccagag aaaaaaatcg tattgaatgg ccatttccct acttataaga 3780 tgtctcaatc tgaatttatt tggctacact aaagaatgca gtatatttag ttttccattt 3840 gcatgatgtt tgtgtgctat agatgatatt ttaaattgaa aagtttgttt taaattattt 3900 ttacagtgaa gactgttttc agctcttttt atattgtaca tagtctttta tgtaatttac 3960 tggcatatgt tttgtagact gtttaatgac tggatatctt ccttcaactt ttgaaataca 4020 aaaccagtgt tttttacttg tacactgttt taaagtctat taaaattgtc atttgacttt 4080 tttctgttaa cttaaaaaaa aaaaaaaaaa 4110 <210> 44 <211> 747 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 44 Met Ala Asp Glu Ala Ala Leu Ala Leu Gln Pro Gly Gly Ser Pro Ser 1 5 10 15 Ala Ala Gly Ala Asp Arg Glu Ala Ala Ser Ser Pro Ala Gly Glu Pro 20 25 30 Leu Arg Lys Arg Pro Arg Arg Asp Gly Pro Gly Leu Glu Arg Ser Pro 35 40 45 Gly Glu Pro Gly Gly Ala Ala Pro Glu Arg Glu Val Pro Ala Ala Ala 50 55 60 Arg Gly Cys Pro Gly Ala Ala Ala Ala Leu Trp Arg Glu Ala Glu 65 70 75 80 Ala Glu Ala Ala Ala Gly Gly Glu Gln Glu Ala Gln Ala Thr Ala 85 90 95 Ala Ala Gly Glu Gly Asp Asn Gly Pro Gly Leu Gln Gly Pro Ser Arg 100 105 110 Glu Pro Pro Leu Path Asp Asn Leu Tyr Asp Glu Asp Asp Asp Asp Glu 115 120 125 Gly Glu Glu Glu Glu Glu Ala Ala Ala Ala Ile Gly Tyr Arg Asp 130 135 140 Asn Leu Leu Phe Gly Asp Glu Ile Ile Thr Asn Gly Phe His Ser Cys 145 150 155 160 Glu Ser Asp Glu Glu Asp Arg Ala Ser His Ala Ser Ser Ser Asp Trp 165 170 175 Thr Pro Arg Pro Arg Ile Gly Pro Tyr Thr Phe Val Gln Gln His Leu 180 185 190 Met Ile Gly Thr Asp Pro Arg Thr Ile Leu Lys Asp Leu Leu Pro Glu 195 200 205 Thr Ile Pro Pro Pro Glu Leu Asp Asp Met Thr Leu Trp Gln Ile Val 210 215 220 Ile Asn Ile Leu Ser Glu Pro Pro Lys Arg Lys Lys Arg Lys Asp Ile 225 230 235 240 Asn Thr Ile Glu Asp Ala Val Lys Leu Leu Gln Glu Cys Lys Lys Ile 245 250 255 Ile Val Leu Thr Gly Ala Gly Val Ser Val Ser Cys Gly Ile Pro Asp 260 265 270 Phe Arg Ser Arg Asp Gly Ile Tyr Ala Arg Leu Ala Val Asp Phe Pro 275 280 285 Asp Leu Pro Asp Pro Gln Ala Met Phe Asp Ile Glu Tyr Phe Arg Lys 290 295 300 Asp Pro Arg Pro Phe Phe Lys Phe Ala Lys Glu Ile Tyr Pro Gly Gln 305 310 315 320 Phe Gln Pro Ser Leu Cys His Lys Phe Ile Ala Leu Ser Asp Lys Glu 325 330 335 Gly Lys Leu Leu Arg Asn Tyr Thr Gln Asn Ile Asp Thr Leu Glu Gln 340 345 350 Val Ala Gly Ile Gln Arg Ile Ile Gln Cys His Gly Ser Phe Ala Thr 355 360 365 Ala Ser Cys Leu Ile Cys Lys Tyr Lys Val Asp Cys Glu Ala Val Arg 370 375 380 Gly Asp Ile Phe Asn Gln Val Val Pro Arg Cys Pro Arg Cys Pro Ala 385 390 395 400 Asp Glu Pro Leu Ala Ile Met Lys Pro Glu Ile Val Phe Phe Gly Glu 405 410 415 Asn Leu Pro Glu Gln Phe His Arg Ala Met Lys Tyr Asp Lys Asp Glu 420 425 430 Val Asp Leu Leu Ile Val Ile Gly Ser Ser Leu Lys Val Arg Pro Val 435 440 445 Ala Leu Ile Pro Ser Ser Ile Pro His Glu Val Pro Gln Ile Leu Ile 450 455 460 Asn Arg Glu Pro Leu Pro His Leu His Phe Asp Val Glu Leu Leu Gly 465 470 475 480 Asp Cys Asp Val Ile Ile Asn Glu Leu Cys His Arg Leu Gly Gly Glu 485 490 495 Tyr Ala Lys Leu Cys Cys Asn Pro Val Lys Leu Ser Glu Ile Thr Glu 500 505 510 Lys Pro Pro Arg Thr Gln Lys Glu Leu Ala Tyr Leu Ser Glu Leu Pro 515 520 525 Pro Thr Pro Leu His Val Ser Glu Asp Ser Ser Ser Pro Glu Arg Thr 530 535 540 Ser Pro Pro Asp Ser Ser Val Ile Val Thr Leu Leu Asp Gln Ala Ala 545 550 555 560 Lys Ser Asn Asp Asp Leu Asp Val Ser Glu Ser Lys Gly Cys Met Glu 565 570 575 Glu Lys Pro Gln Glu Val Gln Thr Ser Arg Asn Val Glu Ser Ile Ala 580 585 590 Glu Gln Met Glu Asn Pro Asp Leu Lys Asn Val Gly Ser Ser Thr Gly 595 600 605 Glu Lys Asn Glu Arg Thr Ser Val Ala Gly Thr Val Arg Lys Cys Trp 610 615 620 Pro Asn Arg Val Ala Lys Glu Gln Ile Ser Arg Arg Leu Asp Gly Asn 625 630 635 640 Gln Tyr Leu Phe Leu Pro Pro Asn Arg Tyr Ile Phe His Gly Ala Glu 645 650 655 Val Tyr Ser Asp Ser Glu Asp Asp Val Leu Ser Ser Ser Ser Cys Gly 660 665 670 Ser Asn Ser Asp Ser Gly Thr Cys Gln Ser Pro Ser Leu Glu Glu Pro 675 680 685 Met Glu Asp Glu Ser Glu Ile Glu Glu Phe Tyr Asn Gly Leu Glu Asp 690 695 700 Glu Pro Asp Val Pro Glu Arg Ala Gly Gly Ala Gly Phe Gly Thr Asp 705 71​​​​​​​​​​​​​​​​​​​​​​​gcatctcctc ctccctctcc ccgggctcct actggcctga ggttgagggc ggctgggggc 60 tcggggcagg ctccgcggcg ttcccctccc caccccggcc ctccgttcag ccgcgctcct 120 ccggggctgc ggttcctact gcgcgagctg ccagtggatt cgctcttttc ctccgtccgt 180 ggcccgcctg ggcggccttg ttctttccgc agcagccaga taaccttctg ttcggtgatg 240 aaattatcac taatggtttt cattcctgtg aaagtgatga ggaggataga gcctcacatg 300 caagctctag tgactggact ccaaggccac ggataggtgt ctgtttcatg tggaatacct 360 gacttcaggt caagggatgg tatttatgct cgccttgctg tagacttccc agatcttcca 420 gatcctcaag cgatgtttga tattgaatat ttcagaaaag atccaagacc attcttcaag 480 tttgcaaagg aaatatatcc tggacaattc cagccatctc tctgtcacaa attcatagcc 540 ttgtcagata aggaaggaaa actacttcgc aactataccc agaacataga cacgctggaa 600 caggttgcgg gaatccaaag gataattcag tgtcatggtt cctttgcaac agcatcttgc 660 ctgatttgta aatacaaagt tgactgtgaa gctgtacgag gagatatttt taatcaggta 720 gttcctcgat gtcctaggtg cccagctgat gaaccgcttg ctatcatgaa accagagatt 780 gtgttttttg gtgaaaattt accagaacag tttcatagag ccatgaagta tgacaaagat 840 gaagttgacc tcctcattgt tattgggtct tccctcaaag taagaccagt agcactaatt 900 ccaagttcca taccccatga agtgcctcag atattaatta atagagaacc tttgcctcat 960 ctgcatttg atgtagagct tcttggagac tgtgatgtca taattaatga attgtgtcat 1020 aggttaggtg gtgaatatgc caaactttgc tgtaaccctg taaagctttc agaaattact 1080 gaaaaacctc cacgaacaca aaaagaattg gcttatttgt cagagttgcc acccacacct 1140 cttcatgttt cagaagactc aagttcacca gaaagaactt caccaccaga ttcttcagtg 1200 attgtcacac ttttagacca agcagctaag agtaatgatg atttagatgt gtctgaatca 1260 aaaggttgta tggaagaaaa accacaggaa gtacaaactt ctaggaatgt tgaaagtatt 1320 gctgaacaga tggaaaatcc ggatttgaag aatgttggtt ctagtactgg ggaaaaat 1380 gaaagaactt cagtggctgg aacagtgaga aaatgctggc ctaatagagt ggcaaaggag 1440 cagattagta ggcggcttga tggtaatcag tatctgtttt tgccaccaaa tcgttacatt 1500 ttccatggcg ctgaggtata ttcagactct gaagatgacg tcttatcctc tagttcttgt 1560 ggcagtaaca gtgatagtgg gacatgccag agtccaagtt tagaagaacc catggaggat 1620 gaaagtgaaa ttgaagaatt ctacaatggc ttagaagatg agcctgatgt tccagagaga 1680 gctggaggag ctggatttgg gactgatgga gatgatcaag aggcaattaa tgaagctata 1740 tctgtgaaac aggaagtaac agacatgaac tatccatcaa acaaatcata gtgtaataat 1800 tgtgcaggta caggaattgt tccaccagca ttaggaactt tagcatgtca aaatgaatgt 1860 ttacttgtga actcgataga gcaaggaaac cagaaaggtg tatatttat aggttggtaa 1920 aatagattgt ttttcatgga taatttttaa cttcattatt tctgtacttg tacaaactca 1980 acactaactt tttttttttt aaaaaaaaaa aggtactaag tatcttcaat cagctgttgg 2040 tcaagactaa cttctttta aaggttcatt tgtatgataa attcatatgt gtatatataa 2100 ttttttgtgt tttgtctagt gagtttcaac atttttaaag ttttcaaaaa gccatcggaa 2160 tgttaaatta atgtaaaggg aacagctaat ctagaccaaa gatggtatt ttcactttc 2220 ttgtaacat tgaatggttt gaagtactca aaatctgtta cgctaaactt ttgattctt 2280 aacacaatta tttttaaca ctggcatttt ccaaaactgt ggcagctaac tttttaaaat 2340 ctcaaatgac atgcagtgtg agtagaagga agtcaacaat atgtgggg agcactcggt 2400 tgtctttact tttaaaagta atactggtg ctaagaattt caggattatt gtatttacgt 2460 tcaatgaag atggctttg tacttcctgt ggacatgtag taatgtctat attggctcat 2520 aaaactaacc tgaaaaaaaatgctt tggaatgtt tcagttgctt tagaacatt 2580 agtgcctgcc tggatcccct tagttttgaa atatttgcca ttgttgtttta atacctac 2640 actgtgtag agcttgcatt gatctttcc acagtatta aactgccaaa atgtgaatat 2700 gcaaagcctt tctgaatcta taataatggt acttctactg gggagagtgt atattttgg 2760 actgctgttt tccattaatg aggagagcaa caggcccctg attatacagt tccaagtaa 2820 taagatgtta attgtattc agccagaaag tacatgtctc ccattgggag gatttggtgt 2880 taataccaa actgctagcc ctagtattat ggagatgaac atgatgatgt aacttgtaat 2940 agcagaatag ttaatgaatg aaactagttc ttataattta tctttattta aaagcttagc 3000 ctgccttaaa actagagatc aactttctca gctgcaaaag cttctagtct ttcaagaagt 3060 tcatacttta tgaaattgca cagtaagcat ttattttca gaccattttt gaacatcact 3120 cctaaattaa taaagtattc ctctgttgct ttagtattta ttacaataaa aagggtttga 3180 aatatagctg ttctttatgc ataaaacc cagctaggac cattactgcc agagaaaaaa 3240 atcgtattga atggccattt ccctacttat aagatgtctc aatctgaatt tatttggcta 3300 cactaaagaa tgcagtatat ttagttttcc atttgcatga tgtttgtgtg ctatagatga 3360 tattttaaat tgaaaagttt gttttaaatt atttttacag tgaagactgt tttcagctct 3420 ttttatattg tacatagtct tttatgtaat ttactggcat atgttttgta gactgtttaa 3480 tgactggata tcttccttca acttttgaaa tacaaaacca gtgtttttta cttgtacact 3540 gttttaaagt ctattaaaat tgtcatttga cttttttctg ttaacttaaa aaaaaaaaa 3600 aaaa 3604 <210> 46 <211> 452 <212> PRT <213> Artificial sequence <220> <223> Synthetic polymer <400> 46 Met Phe Asp Ile Glu Tyr Phe Arg Lys Asp Pro Arg Pro Phe Phe Lys 1 5 10 15 Phe Ala Lys Glu Ile Tyr Pro Gly Gln Phe Gln Pro Ser Leu Cys His 20 25 30 Lys Phe Ile Ala Leu Ser Asp Lys Glu Gly Lys Leu Leu Arg Asn Tyr 35 40 45 Thr Gln Asn Ile Asp Thr Leu Glu Gln Val Ala Gly Ile Gln Arg Ile 50 55 60 Ile Gln Cys His Gly Ser Phe Ala Thr Ala Ser Cys Leu Ile Cys Lys 65 70 75 80 Tyr Lys Val Asp Cys Glu Ala Val Arg Gly Asp Ile Phe Asn Gln Val 85 90 95 Val Pro Arg Cys Pro Arg Cys Pro Ala Asp Glu Pro Leu Ala Ile Met 100 105 110 Lys Pro Glu Ile Val Phe Phe Gly Glu Asn Leu Pro Glu Gln Phe His 115 120 125 Arg Ala Met Lys Tyr Asp Lys Asp Glu Val Asp Leu Leu Ile Val Ile 130 135 140 Gly Ser Ser Leu Lys Val Arg Pro Val Ala Leu Ile Pro Ser Ser Ile 145 150 155 160 Pro His Glu Val Pro Gln Ile Leu Ile Asn Arg Glu Pro Leu Pro His 165 170 175 Leu His Phe Asp Val Glu Leu Leu Gly Asp Cys Asp Val Ile Ile Asn 180 185 190 Glu Leu Cys His Arg Leu Gly Gly Glu Tyr Ala Lys Leu Cys Cys Asn 195 200 205 Pro Val Lys Leu Ser Glu Ile Thr Glu Lys Pro Pro Arg Thr Gln Lys 210 215 220 Glu Leu Ala Tyr Leu Ser Glu Leu Pro Pro Thr Pro Leu His Val Ser 225 230 235 240 Glu Asp Ser Ser Ser Pro Glu Arg Thr Ser Pro Pro Asp Ser Ser Val 245 250 255 Ile Val Thr Leu Leu Asp Gln Ala Ala Lys Ser Asn Asp Asp Leu Asp 260 265 270 Val Ser Glu Ser Lys Gly Cys Met Glu Glu Lys Pro Gln Glu Val Gln 275 280 285 Thr Ser Arg Asn Val Glu Ser Ile Ala Glu Gln Met Glu Asn Pro Asp 290 295 300 Leu Lys Asn Val Gly Ser Ser Thr Gly Glu Lys Asn Glu Arg Thr Ser 305 310 315 320 Val Ala Gly Thr Val Arg Lys Cys Trp Pro Asn Arg Val Ala Lys Glu 325 330 335 Gln Ile Ser Arg Arg Leu Asp Gly Asn Gln Tyr Leu Phe Leu Pro Pro 340 345 350 Asn Arg Tyr Ile Phe His Gly Ala Glu Val Tyr Ser Asp Ser Glu Asp 355 360 365 Asp Val Leu Ser Ser Ser Ser Cys Gly Ser Asn Ser Asp Ser Gly Thr 370 375 380 Cys Gln Ser Pro Ser Leu Glu Glu Pro Met Glu Asp Glu Ser Glu Ile 385 390 395 400 Glu Glu Phe Tyr Asn Gly Leu Glu Asp Glu Pro Asp Val Pro Glu Arg 405 410 415 Ala Gly Gly Ala Gly Phe Gly Thr Asp Gly Asp Asp Gln Glu Ala Ile 420 425 430 Asn Glu Ala Ile Ser Val Lys Gln Glu Val Thr Asp Met Asn Tyr Pro 435 440 445 Ser Asn Lys Ser 450 <210> 47 <211> 3393 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 47 gtgtctgttt catgtggaat acctgacttc aggtcaaggg atggtattta tgctcgcctt 60 gctgtagact tcccagatct tccagatcct caagcgatgt ttgatattga atatttcaga 120 aaagatccaa gaccattctt caagtttgca aagaagaaac agcattgaag cattatttgg 180 ggggaaaaac acacacacaa aatccagcaa ctcagcattc atgagcaact ctatactata 240 ccagtatgtg cctgtgcagt ggaaggaaaa caattttgga aatatatcct ggacaattcc 300 agccatctct ctgtcacaaa ttcatagcct tgtcagataa ggaaggaaaa ctacttcgca 360 actataccca gaacatagac acgctggaac aggttgcggg aatccaaagg ataattcagt 420 gtcatggttc ctttgcaaca gcatcttgcc tgatttgtaa atacaaagtt gactgtgaag 480 ctgtacgagg agatattttt aatcaggtag ttcctcgatg tcctaggtgc ccagctgatg 540 aaccgcttgc tatcatgaaa ccagagattg tgttttttgg tgaaaattta ccagaacagt 600 ttcatagagc catgaagtat gacaaagatg aagttgacct cctcattgtt attgggtctt 660 ccctcaaagt aagaccagta gcactaattc caagttccat accccatgaa gtgcctcaga 720 tattaattaa tagagaacct ttgcctcatc tgcatttga tgtagagctt cttggagact 780 gtgatgtcat aattaatgaa ttgtgtcata ggttaggtgg tgaatatgcc aaactttgct 840 gtaaccctgt aaagctttca gaaattactg aaaaacctcc acgaacacaa aaagaattgg 900 cttattgtc agagttgcca cccacacctc ttcatgtttc agaagactca agttcaccag 960 aaagaacttc accaccagat tcttcagtga ttgtcacact tttagaccaa gcagctaaga 1020 gtaatgatga tttagatgtg tctgaatcaa aaggttgtat ggaagaaaaa ccacaggaag 1080 tacaaacttc taggaatgtt gaaagtattg ctgaacagat ggaaaatccg gatttgaaga 1140 atgttggttc tagtactggg gagaaaaatg aaagaacttc agtggctgga acagtgagaa 1200 aatgctggcc tatagagtg gcaaaggagc agattagtag gcggcttgat ggtaatcagt 1260 atctgttttt gccaccaaat cgttacattt tccatggcgc tgaggtatat tcagactctg 1320 aagatgacgt cttatcctct agttcttgtg gcagtaacag tgatagtggg acatgccaga 1380 gtccaagttt agaagaaccc atggaggatg aaagtgaaat tgaagaattc tacaatggct 1440 tagagatga gcctgatgtt ccagagagag ctggaggagc tggatttggg actgatggag 1500 atgatcaaga ggcaattaat gaagctatat ctgtgaaaca ggaagtaaca gacatgaact 1560 atccatcaaa caaatcatag tgtaataatt gtgcaggtac aggaattgtt ccaccagcat 1620 taggaacttt agcatgtcaa aatgaatgtt tacttgtgaa ctcgatagag caaggaaacc 1680 agaaaggtgt aatatttata ggttggtaaa atagattgtt tttcatggat aatttttaac 1740 ttcattattt ctgtacttgt acaaactcaa cactaacttt tttttttta aaaaaaaaaa 1800 ggtactaagt atcttcaatc agctgttggt caagactaac tttctttaa aggttcattt 1860 gtatgataaa ttcatatgtg tatatataat tttttttgtt ttgtctagtg agtttcaaca 1920 ttttaaagt tttcaaaaag ccatcggaat gttaaattaa tgtaaaggga acagctaatc 1980 tagaccaaag aatggtattt tcactttct ttgtaacatt gaatggttg aagtactcaa 2040 aatctgttac gctaaacttt tgattcttta acacaattat ttttaaacac tggcattttc 2100 caaaactgtg gcagctaact ttttaaaatc tcaaatgaca tgcagtgtga gtagaaggaa 2160 gtcaacaata tgtggggaga gcactcggtt gtctttactt ttaaaagtaa tacttggtgc 2220 taagaatttc aggattattg tatttacgtt caaatgaaga tggctttgt acttcctgtg 2280 gacatgtagt aatgtctata ttggctcata aaactaacct gaaaaacaaa taaatgcttt 2340 ggaaatgttt cagttgcttt agaaacatta gtgcctgcct ggatcccctt agttttgaaa 2400 tatttgccat tgttgttaa atacctatca ctgtggtaga gcttgcattg atcttttcca 2460 caagtattaa actgccaaaa tgtgaatatg caaagccttt ctgaatctat aataatggta 2520 cttctactgg ggagagtgta atattttgga ctgctgtttt ccattaatga ggagagcaac 2580 aggcccctga ttatacagtt ccaaagtaat aagatgttaa ttgtaattca gccagaaagt 2640 acatgtctcc cattgggagg atttggtgtt aaataccaaa ctgctagccc tagtattatg 2700 gagatgaaca tgatgatgta acttgtaata gcagaatagt taatgaatga aactagttct 2760 tataatttat ctttatttaa aagcttagcc tgccttaaaa ctagagatca actttctcag 2820 ctgcaaaagc ttctagtctt tcaagaagtt catactttat gaaattgcac agtaagcatt 2880 tatttttcag accatttttg aacatcactc ctaaattaat aaagtattcc tctgttgctt 2940 tagtattt tacaataaaa agggtttgaa atatagctgt tctttatgca taaaacaccc 3000 agctaggacc attactgcca gagaaaaaaa tcgtattgaa tggccatttc cctacttata 3060 agatgtctca atctgaattt atttggctac actaaagaat gcagtatatt tagttttcca 3120 tttgcatgat gtttgtgtgc tatagatgat attttaaatt gaaaagtttg ttttaaatta 3180 tttttacagt gaagactgtt ttcagctctt tttatattgt acatagtctt ttatgtaatt 3240 tactggcata tgttttgtag actgtttaat gactggatat cttccttcaa cttttgaaat 3300 acaaaaccag tgtttttac ttgtacactg ttttaaagtc tattaaaatt gtcatttgac 3360 ttttttctgt taacttaaaa aaaaaaaaaa aaa 3393 <210> 48 <211> 444 <212> PRT <213> Artificial sequence <220> <223> Synthetic polymer <400> 48 Met Cys Leu Cys Ser Gly Arg Lys Thr Ile Leu Glu Ile Tyr Pro Gly 1 5 10 15 Gln Phe Gln Pro Ser Leu Cys His Lys Phe Ile Ala Leu Ser Asp Lys 20 25 30 Glu Gly Lys Leu Leu Arg Asn Tyr Thr Gln Asn Ile Asp Thr Leu Glu 35 40 45 Gln Val Ala Gly Ile Gln Arg Ile Ile Gln Cys His Gly Ser Phe Ala 50 55 60 Thr Ala Ser Cys Leu Ile Cys Lys Tyr Lys Val Asp Cys Glu Ala Val 65 70 75 80 Arg Gly Asp Ile Phe Asn Gln Val Val Pro Arg Cys Pro Arg Cys Pro 85 90 95 Ala Asp Glu Pro Leu Ala Ile Met Lys Pro Glu Ile Val Phe Phe Gly 100 105 110 Glu Asn Leu Pro Glu Gln Phe His Arg Ala Met Lys Tyr Asp Lys Asp 115 120 125 Glu Val Asp Leu Leu Ile Val Ile Gly Ser Ser Leu Lys Val Arg Pro 130 135 140 Val Ala Leu Ile Pro Ser Ser Ile Pro His Glu Val Pro Gln Ile Leu 145 150 155 160 Ile Asn Arg Glu Pro Leu Pro His Leu His Phe Asp Val Glu Leu Leu 165 170 175 Gly Asp Cys Asp Val Ile Ile Asn Glu Leu Cys His Arg Leu Gly Gly 180 185 190 Glu Tyr Ala Lys Leu Cys Cys Asn Pro Val Lys Leu Ser Glu Ile Thr 195 200 205 Glu Lys Pro Pro Arg Thr Gln Lys Glu Leu Ala Tyr Leu Ser Glu Leu 210 215 220 Pro Pro Thr Pro Leu His Val Ser Glu Asp Ser Ser Ser Pro Glu Arg 225 230 235 240 Thr Ser Pro Pro Asp Ser Ser Val Ile Val Thr Leu Leu Asp Gln Ala 245 250 255 Ala Lys Ser Asn Asp Asp Leu Asp Val Ser Glu Ser Lys Gly Cys Met 260 265 270 Glu Glu Lys Pro Gln Glu Val Gln Thr Ser Arg Asn Val Glu Ser Ile 275 280 285 Ala Glu Gln Met Glu Asn Pro Asp Leu Lys Asn Val Gly Ser Ser Thr 290 295 300 Gly Glu Lys Asn Glu Arg Thr Ser Val Ala Gly Thr Val Arg Lys Cys 305 310 315 320 Trp Pro Asn Arg Val Ala Lys Glu Gln Ile Ser Arg Arg Leu Asp Gly 325 330 335 Asn Gln Tyr Leu Phe Leu Pro Pro Asn Arg Tyr Ile Phe His Gly Ala 340 345 350 Glu Val Tyr Ser Asp Ser Glu Asp Asp Val Leu Ser Ser Ser Ser Cys 355 360 365 Gly Ser Asn Ser Asp Ser Gly Thr Cys Gln Ser Pro Ser Leu Glu Glu 370 375 380 Pro Met Glu Asp Glu Ser Glu Ile Glu Glu Phe Tyr Asn Gly Leu Glu 385 390 395 400 Asp Glu Pro Asp Val Pro Glu Arg Ala Gly Gly Ala Gly Phe Gly Thr 405 410 415 Asp Gly Asp Asp Gln Glu Ala Ile Asn Glu Ala Ile Ser Val Lys Gln 420 425 430 Glu Val Thr Asp Met Asn Tyr Pro Ser Asn Lys Ser 435 440 <210> 49 <211> 6849 <212> DNA<00038​​<220> <223> Synthetic polymer <400> 49 gcggtctctc gctctgcgcg cacacaccac acacacgcac acgcacacac acgcgcgcac 60 acacgcagcc ggcacaggcg gcggcggcgg ctgcccaagt caggacgaac ctatctaggt 120 accgtcttga gaaggcggca gcggcggcgg cggcggcggc ggcggcagcc cgagcatccc 180 tcctctcccg gagagggagc accgccgaga gtttccgttc cctttgccat tcccttcccc 240 ctccttttct tttattttcg agagaatttc ttcttggctt attggtttaa tttgattttt 300 aaaattttgg gttgcttttg tgtatgtgtg cttttttttt ctttcctcat tttatttgca 360 tccagagcat ggcgggctgc gggctgtcgg aagacaccct cttctcttcc ttcttttaca 420 actacggctc ctcctgggaa accccttcca accaggtttt ttgcgaaaat cagtgaacta 480 atattggtaa aattggagcc ccatggatga agggtacttt tctgcccctg gactgccctg 540 gctgctgctt tggtaaaagc ttgcaaggag agagagtaac agccgctggc gaatccagtt 600 tgtgcaagca gcatcagcaa tggatgagac ctccccaagg ctggaagaag actggaaaaa 660 agtacttcag cgagaagcag gctggcagtg tgctgctctg gttggtgag accagcctct 720 ttgcccagat cttcctgaac ttgatctttc tgaactagat gtgaacgact tggatacaga cagctttctg ggtggactca agtggtgcag tgaccaatca gaataatat ccaatcagta caacaatgag ccttcaaaca tatttgaga caaacttgct caaacttgct agcagtcctc acagagacac agcagtct ccctgtggat gaagacggat tgccctcatt tgatgcgctg acagatggag acgtgaccac tgacaatgag gctagtcctt cctccatgcc tgacggcacc cctccacccc aggaggcaga agagccgtct ctcttaaga agctcttact 1080 ggcaccagcc aacactcagc tagttataa tgaatgcagt ggtctcagta cccagaacca tgcaaatcac aatcacagga tcagaacaaa ccctgcaatt gttaagactg agaattcatg gcgaagagta tttgtcaaca gcaaaagcca caaagacgtc cctgctcgga gcttctcaaa tatctgacca caacgatga ccctcctcac accaaaccca cagagaacag aaacagcagc agagacaaat gcacctccaa aaagaagtcc cacacacagt cgcagtcaca acacttacaa gccaaaccaa caactttatc tcttcctctg accccagagt caccaaatga 1440 ccccaagggt tccccatttg agaacaagac tattgaacgc accttaagtg tggaactctc 1500 tggaactgca ggcctaactc cacccaccac tcctcctcat aaagccaacc aagataaccc 1560 ttttagggct tctccaaagc tgaagtcctc ttgcaagact gtggtgccac caccatcaaa 1620 gaagcccagg tacagtgagt cttctggtac acaaggcaat aactccacca agaaagggcc 1680 ggagcaatcc gagttgtatg cacaactcag caagtcctca gtcctcactg gtggacacga 1740 ggaaaggaag accaagcggc ccagtctgcg gctgtttggt gaccatgact attgccagtc 1800 aattaattcc aaaacagaaa tactcattaa tatatcacag gagctccaag actctagaca 1860 actagaaaat aaagatgtct cctctgattg gcaggggcag atttgttctt ccacagattc 1920 agaccagtgc tacctgagag agactttgga ggcaagcaag caggtctctc cttgcagcac 1980 aagaaaacag ctccaagacc aggaaatccg agccgagctg aacaagcact tcggtcatcc 2040 cagtcaagct gttttgacg acgaagcaga caagaccggt gaactgaggg acagtgattt 2100 cagtaatgaa caattctcca aactacctat gtttataaat tcaggactag ccatggatgg 2160 cctgtttgat gacagcgaag atgaaagtga taaactgagc tacccttggg atggcacgca 2220 atcctattca ttgttcaatg tgtctccttc ttgttcttct tttaactctc catgtagaga 2280 ttctgtgtca ccacccaaat ccttattttc tcaaagaccc caaaggatgc gctctcgttc 2340 aaggtccttt tctcgacaca ggtcgtgttc ccgatcacca tattccaggt caagatcaag 2400 gtctccaggc agtagatcct cttcaagatc ctgctattac tatgagtcaa gccactacag 2460 acaccgcacg caccgaaatt ctcccttgta tgtgagatca cgttcaagat cgccctacag 2520 ccgtcggccc aggtatgaca gctacgagga atatcagcac gagaggctga agagggaaga 2580 atatcgcaga gagtatgaga agcgagagtc tgagagggcc aagcaaaggg agaggcagag 2640 gcagaaggca attgaagagc gccgtgtgat tttgcggt aaaatcagac ctgacacaac 2700 acggacagaa ctgagggacc gttttgaagt ttttggtgaa attgaggagt gcacagtaaa 2760 tctgcgggat gatggagaca gctatggttt cattacctac cgttatacct gtgatgcttt 2820 tgctgctctt gaaaatggat acactttgcg caggtcaaac gaaactgact ttgagctgta cttttgtgga cgcaagcaat ttttcaagtc taactatgca gacctagtt caaactcaga tgactttgac cctgcttcca ccaagagca gtatgactct ctggattttg atagtttact gaaagaagct cagagaagct tgcgcaggta acatgttccc tagctgagga tgacagaggg atggcgaata cctcatggga cagcgcgtcc ttccctaaag actattgcaa gtcatactta ggaatttctc ctactttaca ctctctgtac aaaaacaaaaa caaaacaaca acaatacaac 3240. aagaacaaca acaacaata caacaatggt ttacatgaac acagctgctg aagaggcaag 3300. 3300. 3300. 3300. 3300. 3300. 3300. 3300 gagtctcttg gtgatggagt gtgcgtgtgt gcatgtatgt gtgtgtgt gtatgtgtgt 3360 ggtgtgtgtg cttggtttag gggaagtatg tgtgggtaca tgtgaggact gggggcacct 3420 3480. cgcaagggca aaccatttca aatggcagca gttccatgaa gacacgctta aaacctagaa cttcaaaatg ttcgtattct attcaaaagg aaatatatat aatatatat atatatatat atatatatat aaattaaaaa ggaaagaaaa ctaacaacca accaaccaac 3600 caaccaacca caaaccaccc taaaatgaca gccgctgatg tctgggcatc agcctttgta 3660 ctctgttttt ttaagaaagt gcagaatcaa cttgaagcaa gctttctctc ataacgtaat 3720 gattatatga caatcctgaa gaaaccacag gttccataga actaatatcc tgtctctctc 3780 tctctctctc tctctctctt ttttttttct ttttcctttt gccatggaat ctgggtggga 3840 gaggatactg cgggcaccag aatgctaaag tttcctaaca ttttgaagtt tctgtagttc 3900 atccttaatc ctgacaccca tgtaaatgtc caaaatgttg atcttccact gcaaatttca 3960 aaagccttgt caatggtcaa gcgtgcagct tgttcagcgg ttctttctga ggagcggaca 4020 ccgggttaca ttactaatga gagttgggta gaactctctg agatgtgttc agatagtgta 4080 attgctacat tctctgatgt agttaagtat ttacagatgt taaatggagt atttttattt 4140 tatgtatata ctatacaaca atgttctttt ttgttacagc tatgcactgt aaatgcagcc 4200 ttcttttcaa aactgctaaa tttttcttaa tcaagaatat tcaaatgtaa ttatgaggtg 4260 aaacaattat tgtacactaa catatttaga agctgaactt actgcttata tatatttgat 4320 tgtaaaaaca aaagacagt gtgtgtgtct gttgagtgca acaagagcaa aatgatgctt 4380 tccgcacatc catcccttag gtgagcttca atctaagcat cttgtcaaga aatatcctag 4440 tcccctaaag gtattaacca cttctgcgat atttttccac atttctttgt cgcttgtttt 4500 tctttgaagt tttatacact ggatttgtta ggggaatgaa attttctcat ctaaaatttt 4560 tctagaagat atcatgattt tatgtaaagt ctctcaatgg gtaaccatta agaaatgttt 4620 ttattttctc tatcaacagt agttttgaaa ctagaagtca aaaatcttttt taaaatgctg 4680 ttttgtttta atttttgtga ttttaatttg atacaaaatg ctgaggtaat attatagta 4740 tgattttac aataattaat gtgtgtctga agactatctt tgaagccagt atttctttcc 4800 cttggcagag tatgacgatg gtatttatct gtatttttta cagttatgca tcctgtataa 4860 atactgatat ttcattcctt tgtttactaa agagacatat tttcagttg cagatagcct 4920 attattata aattatgaga tgatgaaaat aataaagcca gtggaaattt tctacctagg 4980 atgcatgaca attgtcaggt tggagtgtaa gtgcttcatt tgggaaattc agcttttgca 5040 gaagcagtgt ttctacttgc actagcatgg cctctgacgt gaccatggtg ttgttcttga 5100 tgacattgct tctgctaaat ttaataaaaa cttcagaaaa acctccattt tgatcatcag 5160 gatttcatct gagtgtggag tccctggaat ggaattcagt aacatttgga gtgtgtattc 5220 aagtttctaa attgagattc gattactgtt tggctgacat gacttttctg gaagacatga 5280 tacacctact actcaattgt tcttttcctt tctctcgcc aacacgatct tgtaagatgg 5340 atttcacccc caggccaatg cagctaattt tgatagctgc attcatttat caccagcata 5400 ttgtgttctg agtgaatcca ctgtttgtcc tgtcggatgc ttgcttgatt ttttggcttc 5460 ttattctaa gtagatagaa agcaataaaa atactatgaa atgaaagaac ttgttcacag 5520 gttctgcgtt acaacagtaa cacatcttta atccgcctaa ttcttgttgt tctgtaggtt 5580 aaatgcaggt attttaactg tgtgaacgcc aaactaaagt ttacagtctt tctttctgaa 5640 ttttgagtat cttctgttgt agaataataa taaaaagact attaagagca ataaaattat 5700 tttaagaaat cgagatttag taaatcctat tatgtgttca aggaccacat gtgttctcta 5760 ttttgccttt aaatttttgt gaaccaattt taaatacatt ctcctttttg ccctggattg 5820 ttgacatgag tggaatactt ggtttctttt cttacttatc aaaagacagc actacagata 5880 tcatattgag gattaattta tcccccctac ccccagcctg acaaatattg ttaccatgaa 5940 gatagttttc ctcaatggac ttcaaattgc atctagaatt agtggagctt ttgtatcttc 6000 tgcagacact gtgggtagcc catcaaaatg taagctgtgc tcctctcatt tttatttta 6060 tttttttggg agaaatatt tcaaatgaac acgtgcaccc catcatcact ggaggcaaat 6120 ttcagcatag atctgtagga tttttagaag accgtgggcc attgccttca tgccgtggta 6180 agtaccacat ctacaatttt ggtaaccgaa ctggtgcttt agtaatgtgg atttttttct 6240 tttttaaaag agatgtagca gaataattct tccagtgcaa caaaatcaat tttttgctaa 6300 acgactccga gaacaacagt tgggctgtca acattcaaag cagcagagag ggaactttgc 6360 actattgggg tatgatgttt gggtcagttg ataaaaggaa accttttcat gcctttagat 6420 gtgagcttcc agtaggtaat gattatgtgt cctttcttga tggctgtaat gagaacttca 6480 atcactgtag tctaagacct gatctataga tgacctagaa tagccatgta ctataatgtg 6540 atgattctaa atttgtacct atgtgacaga cattttcaat aatgtgaact gctgatttga 6600 tggagctact ttaagatttg taggtgaaag tgtaatactg ttggttgaac tatgctgaag 6660 agggaaagtg agcgattagt tgagcccttg ccgggccttt tttccacctg ccaattctac 6720 atgtattgtt gtggttttat tcattgtatg aaaattcctg tgattttttt taaatgtgca 6780 gtacacatca gcctcactga gctaataaag ggaaacgaat gtttcaaatc taaaaaaaaa 6840 aaaaaaaaa 6849 <210> 50 <211> 803 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polymer <400> 50 Met Asp Glu Thr Ser Pro Arg Leu Glu Glu Asp Trp Lys Lys Val Leu 1 5 10 15 Gln Arg Glu Ala Gly Trp Gln Cys Ala Ala Leu Val Gly Glu Asp Gln 20 25 30 Pro Leu Cys Pro Asp Leu Pro Glu Leu Asp Leu Ser Glu Leu Asp Val 35 40 45 Asn Asp Leu Asp Thr Asp Ser Phe Leu Gly Gly Leu Lys Trp Cys Ser 50 55 60 Asp Gln Ser Glu Ile Ile Ser Asn Gln Tyr Asn Asn Glu Pro Ser Asn 65 70 75 80 Ile Phe Glu Lys Ile Asp Glu Glu Asn Glu Ala Asn Leu Leu Ala Val 85 90 95 Leu Thr Glu Thr Leu Asp Ser Leu Pro Val Asp Glu Asp Gly Leu Pro 100 105 110 Ser Phe Asp Ala Leu Thr Asp Gly Asp Val Thr Thr Asp Asn Glu Ala 115 120 125 Ser Pro Ser Ser Met Pro Asp Gly Thr Pro Pro Pro Gln Glu Ala Glu 130 135 140 Glu Pro Ser Leu Leu Lys Lys Leu Leu Leu Ala Pro Ala Asn Thr Gln 145 150 155 160 Leu Ser Tyr Asn Glu Cys Ser Gly Leu Ser Thr Gln Asn His Ala Asn 165 170 175 His Asn His Arg Ile Arg Thr Asn Pro Ala Ile Val Lys Thr Glu Asn 180 185 190 Ser Trp Ser Asn Lys Ala Lys Ser Ile Cys Gln Gln Gln Lys Pro Gln 195 200 205 Arg Arg Pro Cys Ser Glu Leu Leu Lys Tyr Leu Thr Thr Asn Asp Asp 210 215 220 Pro Pro His Thr Lys Pro Thr Glu Asn Arg Asn Ser Ser Arg Asp Lys 225 230 235 240 Cys Thr Ser Lys Lys Lys Ser His Thr Gln Ser Gln Ser Gln His Leu 245 250 255 Gln Ala Lys Pro Thr Thr Leu Ser Leu Pro Leu Thr Pro Glu Ser Pro 260 265 270 Asn Asp Pro Lys Gly Ser Pro Phe Glu Asn Lys Thr Ile Glu Arg Thr 275 280 285 Leu Ser Val Glu Leu Ser Gly Thr Ala Gly Leu Thr Pro Pro Thr Thr 290 295 300 Pro Pro His Lys Ala Asn Gln Asp Asn Pro Phe Arg Ala Ser Pro Lys 305 310 315 320 Leu Lys Ser Ser Cys Lys Thr Val Val Pro Pro Pro Ser Lys Lys Pro 325 330 335 Arg Tyr Ser Glu Ser Ser Gly Thr Gln Gly Asn Asn Ser Thr Lys Lys 340 345 350 Gly Pro Glu Gln Ser Glu Leu Tyr Ala Gln Leu Ser Lys Ser Ser Val 355 360 365 Leu Thr Gly Gly His Glu Glu Arg Lys Thr Lys Arg Pro Ser Leu Arg 370 375 380 Leu Phe Gly Asp His Asp Tyr Cys Gln Ser Ile Asn Ser Lys Thr Glu 385 390 395 400 Ile Leu Ile Asn Ile Ser Gln Glu Leu Gln Asp Ser Arg Gln Leu Glu 405 410 415 Asn Lys Asp Val Ser Ser Asp Trp Gln Gly Gln Ile Cys Ser Ser Thr 420 425 430 Asp Ser Asp Gln Cys Tyr Leu Arg Glu Thr Leu Glu Ala Ser Lys Gln 435 440 445 Val Ser Pro Cys Ser Thr Arg Lys Gln Leu Gln Asp Gln Glu Ile Arg 450 455 460 Ala Glu Leu Asn Lys His Phe Gly His Pro Ser Gln Ala Val Phe Asp 465 470 475 480 Asp Glu Ala Asp Lys Thr Gly Glu Leu Arg Asp Ser Asp Phe Ser Asn 485 490 495 Glu Gln Phe Ser Lys Leu Pro Met Phe Ile Asn Ser Gly Leu Ala Met 500 505 510 Asp Gly Leu Phe Asp Asp Ser Glu Asp Glu Ser Asp Lys Leu Ser Tyr 515 520 525 Pro Trp Asp Gly Thr Gln Ser Tyr Ser Leu Phe Asn Val Ser Pro Ser 530 535 540 Cys Ser Ser Phe Asn Ser Pro Cys Arg Asp Ser Val Ser Pro Pro Lys 545 550 555 560 Ser Leu Phe Ser Gln Arg Pro Gln Arg Met Arg Ser Arg Ser Arg Ser 565 570 575 Phe Ser Arg His Arg Ser Cys Ser Arg Ser Pro Tyr Ser Arg Ser Arg 580 585 590 Ser Arg Ser Pro Gly Ser Arg Ser Ser Ser Arg Ser Cys Tyr Tyr Tyr 595 600 605 Glu Ser Ser His Tyr Arg His Arg Thr His Arg Asn Ser Pro Leu Tyr 610 615 620 Val Arg Ser Arg Ser Arg Ser Pro Tyr Ser Arg Arg Pro Arg Tyr Asp 625 630 635 640 Ser Tyr Glu Glu Tyr Gln His Glu Arg Leu Lys Arg Glu Glu Tyr Arg 645 650 655 Arg Glu Tyr Glu Lys Arg Glu Ser Glu Arg Ala Lys Gln Arg Glu Arg 660 665 670 Gln Arg Gln Lys Ala Ile Glu Glu Arg Arg Val Ile Tyr Val Gly Lys 675 680 685 Ile Arg Pro Asp Thr Thr Arg Thr Glu Leu Arg Asp Arg Phe Glu Val 690 695 700 Phe Gly Glu Ile Glu Glu Cys Thr Val Asn Leu Arg Asp Asp Gly Asp 705 710 715 720 Ser Tyr Gly Phe Ile Thr Tyr Arg Tyr Thr Cys Asp Ala Phe Ala Ala 725 730 735 Leu Glu Asn Gly Tyr Thr Leu Arg Arg Ser Asn Glu Thr Asp Phe Glu 740 745 750 Leu Tyr Phe Cys Gly Arg Lys Gln Phe Phe Lys Ser Asn Tyr Ala Asp 755 760 765 Leu Asp Ser Asn Ser Asp Asp Phe Asp Pro Ala Ser Thr Lys Ser Lys 770 775 780 Tyr Asp Ser Leu Asp Phe Asp Ser Leu Leu Lys Glu Ala Gln Arg Ser 785 790 795 800 Leu Arg Arg <210> 51 <211> 6335 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymer <400> 51 tagtaagaca ggtgccttca gttcactctc agtaaggggc tggttgcctg catgagtgtg 60 tgctctgtgt cactgtggat tggagttgaa aaagcttgac tggcgtcatt caggagctgg 120 atggcgtggg acatgtgcaa ccaggactct gagtctgtat ggagtgacat cgagtgtgct 180 gctctggttg gtgaagacca gcctctttgc ccagatcttc ctgaacttga tctttctgaa 240 tttctgggtg gactcaagtg gtgcagtgac 300 360 420 gtggatgaag acggattgcc ctcatttgat gcgctgacag atggagacgt gaccactgac 480 aatgaggcta gtccttctc catgcctgac ggcacccctc caccccagga ggcagaagag 540 ccgtctctac ttaagaagct cttactggca ccagccaaca ctcagctaag ttataatgaa 600 tgcagtggtc tcagtaccca gaaccatgca aatcacaatc acaggatcag aacaaaccct 660 gcaattgtta agactgagaa ttcatggagc aataaagcga agagtatttg tcaacagcaa 720 aagccacaaa gacgtccctg ctcggagctt ctcaaatatc tgaccacaaa cgatgaccct 780 cctcacacca aacccacaga gaacagaaac agcagcagag acaaatgcac ctccaaaaag 840 aagtcccaca cacagtcgca gtcacaacac ttacaagcca aaccaacaac tttatctctt 900 cctctgaccc cagagtcacc aaatgacccc aagggttccc catttgagaa caagactatt 960 gaacgcacct taagtgtgga actctctgga actgcaggcc taactccacc caccactcct 1020 cctcataaag ccaaccaaga taaccctttt agggcttctc caaagctgaa gtcctcttgc 1080 aagactgtgg tgccaccacc atcaaagaag cccaggtaca gtgagtcttc tggtacacaa 1140 ggcaataact ccaccaagaa agggccggag caatccgagt tgtatgcaca actcagcaag 1200 tcctcagtcc tcactggtgg acacgaggaa aggaagacca agcggcccag tctgcggctg 1260 tttggtgacc atgactattg ccagtcaatt aattccaaaa cagaaatact cattaatata 1320 tcacaggagc tccaagactc tagacaacta gaaaataaag atgtctcctc tgattggcag 1380 gggcagattt gttcttccac agattcagac cagtgctacc tgagagagac tttggaggca 1440 agcaagcagg tctctccttg cagcacaaga aacagctcc aagaccagga aatccgagcc 1500 gagctgaaca agcactcgg tcatcccagt caagctgttt tgacgacga agcagacaag 1560 accggtgaac tgagggacag tgatttcagt atgaacaat tctccaact acctatgttt 1620 aaattcag gactagccat ggatggcctg tttgatgaca gcgaagatga aagtgataaa 1680 ctgagctacc cttgggatgg cacgcaatcc tattcattgt tcaatgtgtc tccttctgt 1740 tcttcttta actctccatg tagagattct gtgtcaccac ccaatcctt attttcca 1800 agaccccaaa ggatgcgctc tcgttcagg tccttctc gacaggctc gtgttcccga 1860 tcaccatatt ccaggtcag atcaggctct ccaggcagta gatcctctc aagatccctgc 1920 tattactatg agtcaagcca ctacagacac cgcacgcacc gaaatctcc cttgtagtg 1980 agatcacgtt siagatcgcc ctacagccgt cggcccaggt atgacagcta cgaggaat at 2040 cagcacgaga ggctgaagg ggagaat cgcagagagt atgagaagcg agagtctgag 2100 agggccaagc aaagggagag gcagaggcag aaggcaattg aagagcgccg tgtgatttat 2160 gtcggtaaaa tcagacctga cacaacacgg acagaactga gggaccgttt tgaagttttt 2220 ggtgaaattg aggagtgcac agtaaatctg cgggatgatg gagacagcta tggtttcatt 2280 acctaccgtt atacctgtga tgcttttgct gctcttgaaa atggatacac tttgcgcagg 2340 tcaaacgaaa ctgactttga gctgtacttt tgtggacgca agcaatttt caagtctaac 2400 tatgcagacc tagattcaaa ctcagatgac tttgaccctg cttccaccaa gagcaagtat 2460 gactctctgg attttgatag tttactgaaa gaagctcaga gaagcttgcg caggtaacat 2520 gttccctagc tgaggatgac agagggatgg cgaatacctc atgggacagc gcgtccttcc 2580 ctaaagacta ttgcaagtca tacttaggaa tttctcctac tttacactct ctgtacaaaa 2640 acaaaacaaa acaacaacaa tacaacaaga acaacaacaa caataacaac aatggtttac 2700 atgaacacag ctgctgaaga ggcaagagac agaatgatat ccagtaagca catgtttatt 2760 catgggtgtc agctttgctt ttcctggagt ctcttggtga tggagtgtgc gtgtgtgcat 2820 gtatgtgtgt gtgtatgtat gtgtgtggtg tgtgtgcttg gtttagggga agtatgtgtg 2880 ggtacatgtg aggactgggg gcacctgacc agaatgcgca agggcaaacc atttcaaatg 2940 gcagcagttc catgaagaca cgcttaaaac ctagaacttc aaaatgttcg tattctattc 3000 aaaaggaaat atatatatat atatatatat atatatatat atatataaat taaaaaggaa 3060 agaaaactaa caaccaacca accaaccaac caaccacaaa ccaccctaaa atgacagccg 3120 ctgatgtctg ggcatcagcc tttgtactct gtttttttaa gaaagtgcag aatcaacttg 3180 aagcaagctt tctctcataa cgtaatgatt atatgacaat cctgaagaaa ccacaggttc 3240 catagaacta atatcctgtc tctctctctc tctctctctc tctctttttt ttttcttttt 3300 ccttttgcca tggaatctgg gtgggagagg atactgcggg caccagaatg ctaaagtttc 3360 ctaacatttt gaagtttctg tagttcatcc ttaatcctga cacccatgta aatgtccaaa 3420 atgttgatct tccactgcaa atttcaaaag ccttgtcaat ggtcaagcgt gcagcttgtt 3480 cagcggttct ttctgaggag cggacaccgg gttacattac taatgagagt tgggtagaac 3540 tctctgagat gtgttcagat agtgtaattg ctacattctc tgatgtagtt aagtatttac 3600 agatgttaaa tggagtattt ttattttatg tatatactat acaacaatgt tctttttttgt 3660 tacagctatg cactgtaaat gcagccttct tttcaaaact gctaaatttt tcttaatcaa 3720 gaatattcaa atgtaattat gaggtgaaac aattattgta cactaacata tttagaagct 3780 gaacttactg cttatatata tttgattgta aaaaaaaaa gacagtgtgt gtgtctgttg 3840 agtgcaacaa gagcaaaatg atgctttccg cacatccatc ccttaggtga gcttcaatct 3900 aagcatcttg tcaagaaata tcctagtccc ctaaaggtat taaccacttc tgcgatattt 3960 ttccacattt tcttgtcgct tgtttttctt tgaagtttta tacactggat ttgttagggg 4020 aatgaaattt tctcatctaa aatttttcta gaagatatca tgattttatg taaagtctct 4080 caatgggtaa ccattaagaa atgttttat tttctctatc aacagtagtt ttgaaactag 4140 aagtcaaaaa tctttttaaa atgctgtttt gttttaattt ttgtgatttt aatttgatac 4200 aaaatgctga ggtaataatt atagtatgat ttttacaata attaatgtgt gtctgaagac 4260 tatctttgaa gccagtattt ctttcccttg gcagagtatg acgatggtat ttatctgtat 4320 ttttacagt tatgcatcct gtataaatac tgatatttca ttcctttgtt tactaaagag 4380 acatatttat cagttgcaga tagcctattt attaaatt atgagatgat gaaaataata 4440 aagccagtgg aaatttcta cctaggatgc atgacaattg tcaggttgga gtgtaagtgc 4500 ttcatttggg aaattcagct tttgcagaag cagtgtttct acttgcacta gcatggcctc 4560 tgacgtgacc atggtgttgt tcttgatgac attgcttctg ctaaatttaa taaaaacttc 4620 agaaaaacct ccattttgat catcaggatt tcatctgagt gtggagtccc tggaatggaa 4680 ttcagtaaca tttggagtgt gtattcaagt ttctaaattg agattcgatt actgtttggc 4740 tgacatgact tttctggaag acatgataca cctactactc aattgttctt ttcctttctc 4800 tcgcccaaca cgatcttgta agatggattt cacccccagg ccaatgcagc taattttgat 4860 agctgcattc attatcacc agcatattgt gttctgagtg aatccactgt ttgtcctgtc 4920 ggatgcttgc ttgatttttt ggcttcttat ttctaagtag atagaaagca ataaaaatac 4980 tatgaaatga aagaacttgt tcacaggttc tgcgttacaa cagtaacaca tctttaatcc 5040 gcctaattct tgttgttctg taggttaaat gcaggtattt taactgtgtg aacgccaaac 5100 taaagtttac agtctttctt tctgaattttt gagtatcttc tgttgtagaa tataataaa 5160 aagactatta agagcaataa attattttta agaaatcgag atttagtaaa tcctattatg 5220 tgttcaagga ccacatgtgt tctctatttt gcctttaaat ttttgtgaac caattttaaa 5280 tacattctcc ttttgccct ggattgttga catgagtgga atacttggtt tcttttctta 5340 cttatcaaaa gacagcacta cagatatcat attgaggatt aatttatccc ccctaccccc 5400 agcctgacaa atattgttac catgaagata gttttcctca atggacttca aattgcatct 5460 agaattagtg gagctttgtgt atcttctgca gacactgtgg gtagcccatc aaaatgtaag 5520 ctgtgctcct ctcattttta ttttatttt tttgggagag aatatttcaa atgaacacgt 5580 gcaccccatc atcactggag gcaaatttca gcatagatct gtaggatttt tagaagaccg 5640 tgggccattg ccttcatgcc gtggtaagta ccacatctac aatttggta accgaactgg 5700 tgctttagta atgtggatttt ttttcttttt taaaagagat gtagcagaat aattcttcca 5760 gtgcaacaaa atcaattttt tgctaaacga ctccgagaac aacagttggg ctgtcaacat 5820 tcaaagcagc agagagggaa ctttgcacta ttggggtatg atgtttgggt cagttgataa 5880 aaggaaacct tttcatgcct ttagatgtga gcttccagta ggtaatgatt atgtgtcctt 5940 tcttgatggc tgtaatgaga acttcaatca ctgtagtcta agacctgatc tatagatgac 6000 ctagaatagc catgtactat aatgtgatga ttctaaattt gtacctatgt gacagacatt 6060 ttcaataatg tgaactgctg atttgatgga gctactttaa gatttgtagg tgaaagtgta 6120 atactgttgg ttgaactatg ctgaagaggg aaagtgagcg attagttgag cccttgccgg 6180 gccttttttc cacctgccaa ttctacatgt attgttgtgg ttttattcat tgtatgaaaa 6240 ttcctgtgat tttttttaaa tgtgcagtac acatcagcct cactgagcta ataaagggaa 6300 acgaatgttt caaatctaaa aaaaaaaaaa aaaaa 6335 <210> 52 <211> 798 <212> PRT <213> Artificial sequence <220> <223> Synthetic polymer <400> 52 Met Ala Trp Asp Met Cys Asn Gln Asp Ser Glu Ser Val Trp Ser Asp 1 5 10 15 Ile Glu Cys Ala Ala Leu Val Gly Glu Asp Gln Pro Leu Cys Pro Asp 20 25 30 Leu Pro Glu Leu Asp Leu Ser Glu Leu Asp Val Asn Asp Leu Asp Thr 35 40 45 Asp Ser Phe Leu Gly Gly Leu Lys Trp Cys Ser Asp Gln Ser Glu Ile 50 55 60 Ile Ser Asn Gln Tyr Asn Asn Glu Pro Ser Asn Ile Phe Glu Lys Ile 65 70 75 80 Asp Glu Glu Asn Glu Ala Asn Leu Leu Ala Val Leu Thr Glu Thr Leu 85 90 95 Asp Ser Leu Pro Val Asp Glu Asp Gly Leu Pro Ser Phe Asp Ala Leu 100 105 110 Thr Asp Gly Asp Val Thr Thr Asp Asn Glu Ala Ser Pro Ser Ser Met 115 120 125 Pro Asp Gly Thr Pro Pro Pro Gln Glu Ala Glu Glu Pro Ser Leu Leu 130 135 140 Lys Lys Leu Leu Leu Ala Pro Ala Asn Thr Gln Leu Ser Tyr Asn Glu 145 150 155 160 Cys Ser Gly Leu Ser Thr Gln Asn His Ala Asn His Asn His Arg Ile 165 170 175 Arg Thr Asn Pro Ala Ile Val Lys Thr Glu Asn Ser Trp Ser Asn Lys 180 185 190 Ala Lys Ser Ile Cys Gln Gln Gln Lys Pro Gln Arg Arg Pro Cys Ser 195 200 205 Glu Leu Leu Lys Tyr Leu Thr Thr Asn Asp Asp Pro Pro His Thr Lys 210 215 220 Pro Thr Glu Asn Arg Asn Ser Ser Arg Asp Lys Cys Thr Ser Lys Lys 225 230 235 240 Lys Ser His Thr Gln Ser Gln Ser Gln His Leu Gln Ala Lys Pro Thr 245 250 255 Thr Leu Ser Leu Pro Leu Thr Pro Glu Ser Pro Asn Asp Pro Lys Gly 260 265 270 Ser Pro Phe Glu Asn Lys Thr Ile Glu Arg Thr Leu Ser Val Glu Leu 275 280 285 Ser Gly Thr Ala Gly Leu Thr Pro Pro Thr Thr Pro Pro His Lys Ala 290 295 300 Asn Gln Asp Asn Pro Phe Arg Ala Ser Pro Lys Leu Lys Ser Ser Cys 305 310 315 320 Lys Thr Val Val Pro Pro Pro Ser Lys Lys Pro Arg Tyr Ser Glu Ser 325 330 335 Ser Gly Thr Gln Gly Asn Asn Ser Thr Lys Lys Gly Pro Glu Gln Ser 340 345 350 Glu Leu Tyr Ala Gln Leu Ser Lys Ser Ser Val Leu Thr Gly Gly His 355 360 365 Glu Glu Arg Lys Thr Lys Arg Pro Ser Leu Arg Leu Phe Gly Asp His 370 375 380 Asp Tyr Cys Gln Ser Ile Asn Ser Lys Thr Glu Ile Leu Ile Asn Ile 385 390 395 400 Ser Gln Glu Leu Gln Asp Ser Arg Gln Leu Glu Asn Lys Asp Val Ser 405 410 415 Ser Asp Trp Gln Gly Gln Ile Cys Ser Ser Thr Asp Ser Asp Gln Cys 420 425 430 Tyr Leu Arg Glu Thr Leu Glu Ala Ser Lys Gln Val Ser Pro Cys Ser 435 440 445 Thr Arg Lys Gln Leu Gln Asp Gln Glu Ile Arg Ala Glu Leu Asn Lys 450 455 460 His Phe Gly His Pro Ser Gln Ala Val Phe Asp Asp Glu Ala Asp Lys 465 470 475 480 Thr Gly Glu Leu Arg Asp Ser Asp Phe Ser Asn Glu Gln Phe Ser Lys 485 490 495 Leu Pro Met Phe Ile Asn Ser Gly Leu Ala Met Asp Gly Leu Phe Asp 500 505 510 Asp Ser Glu Asp Glu Ser Asp Lys Leu Ser Tyr Pro Trp Asp Gly Thr 515 520 525 Gln Ser Tyr Ser Leu Phe Asn Val Ser Pro Ser Cys Ser Ser Phe Asn 530 535 540 Ser Pro Cys Arg Asp Ser Val Ser Pro Pro Lys Ser Leu Phe Ser Gln 545 550 555 560 Arg Pro Gln Arg Met Arg Ser Arg Ser Arg Ser Phe Ser Arg His Arg 565 570 575 Ser Cys Ser Arg Ser Pro Tyr Ser Arg Ser Arg Ser Arg Ser Pro Gly 580 585 590 Ser Arg Ser Ser Ser Arg Ser Cys Tyr Tyr Tyr Glu Ser Ser His Tyr 595 600 605 Arg His Arg Thr His Arg Asn Ser Pro Leu Tyr Val Arg Ser Arg Ser 610 615 620 Arg Ser Pro Tyr Ser Arg Arg Pro Arg Tyr Asp Ser Tyr Glu Glu Tyr 625 630 635 640 Gln His Glu Arg Leu Lys Arg Glu Glu Tyr Arg Arg Glu Tyr Glu Lys 645 650 655 Arg Glu Ser Glu Arg Ala Lys Gln Arg Glu Arg Gln Arg Gln Lys Ala 660 665 670 Ile Glu Glu Arg Arg Val Ile Tyr Val Gly Lys Ile Arg Pro Asp Thr 675 680 685 Thr Arg Thr Glu Leu Arg Asp Arg Phe Glu Val Phe Gly Glu Ile Glu 690 695 700 Glu Cys Thr Val Asn Leu Arg Asp Asp Gly Asp Ser Tyr Gly Phe Ile 705 710 715 720 Thr Tyr Arg Tyr Thr Cys Asp Ala Phe Ala Ala Leu Glu Asn Gly Tyr 725 730 735 Thr Leu Arg Arg Ser Asn Glu Thr Asp Phe Glu Leu Tyr Phe Cys Gly 740 745 750 Arg Lys Gln Phe Phe Lys Ser Asn Tyr Ala Asp Leu Asp Ser Asn Ser 755 760 765 Asp Asp Phe Asp Pro Ala Ser Thr Lys Ser Lys Tyr Asp Ser Leu Asp 770 775 780 Phe Asp Ser Leu Leu Lys Glu Ala Gln Arg Ser Leu Arg Arg 785 790 795 <210> 53 <211> 6681 <212> DNA <213> Artificial sequence <220> <223> Synthetic polymer <400> 53 gcggtctctc gctctgcgcg cacacaccac acacacgcac acgcacacac acgcgcgcac 60 acacgcagcc ggcacaggcg gcggcggcgg ctgcccaagt caggacgaac ctatctaggt 120 accgtcttga gaaggcggca gcggcggcgg cggcggcggc ggcggcagcc cgagcatccc 180 tcctctcccg gagagggagc accgccgaga gtttccgttc cctttgccat tcccttcccc 240 ctccttttct tttattttcg agagaatttc ttcttggctt attggtttaa tttgattttt 300 aaaattttgg gttgcttttg tgtatgtgtg cttttttttt ctttcctcat tttatttgca 360 tccagagcat ggcgggctgc gggctgtcgg aagacaccct cttctcttcc ttcttttaca 420 actacggctc ctcctgggaa accccttcca accaggtttt ttgcgaaaat cagtgaacta 480 atattggtaa aattggagcc ccatggatga agggtacttt tgtgctgctc tggttggtga 540 agaccagcct ctttgcccag atcttcctga acttgatctt tctgaactag atgtgaacga 600 cttggataca gacagctttc tgggtggact caagtggtgc agtgaccaat cagaaataat 660 atccaatcag tacaacaatg agccttcaaa catatttgag aagatagatg aagagaatga 720 ggcaaacttg ctagcagtcc tcacagagac actagacagt ctccctgtgg atgaagacgg 780 attgccctca tttgatgcgc tgacagatgg agacgtgacc actgacaatg aggctagtcc 840 ttcctccatg cctgacggca cccctccacc ccaggaggca gaagagccgt ctctacttaa 900 gaagctctta ctggcaccag ccaacactca gctaagttat aatgaatgca gtggtctcag 960 tacccagaac catgcaaatc acaatcacag gatcagaaca aaccctgcaa ttgttaagac 1020 tgagaattca tggagcaata aagcgaagag tatttgtcaa cagcaaaagc cacaaagacg 1080 tccctgctcg gagcttctca aatatctgac cacaaacgat gaccctctc acaccaaacc 1140 cacagagaac agaaacagca gcagagacaa atgcacctcc aaaaagaagt cccacacaca 1200 gtcgcagtca caacacttac aagccaaacc aacaacttta tctcttctc tgaccccaga 1260 gtcaccaaat gaccccaagg gttccccatt tgagaacaag actattgaac gcaccttaag 1320 tgtggaactc tctggaactg caggcctaac tccacccacc actcctcctc ataaagccaa 1380 ccaagataac ccttttaggg cttctccaaa gctgaagtcc tcttgcaaga ctgtggtgcc 1440 accaccatca aagaagccca ggtacagtga gtcttctggt acacaaggca ataactccac 1500 caagaaaggg ccggagcaat ccgagttgta tgcacaactc agcaagtcct cagtcctcac 1560 tggtggacac gaggaaagga agaccaagcg gcccagtctg cggctgtttg gtgaccatga 1620 ctattgccag tcaattaatt ccaaaacaga aatactcatt aatatatcac aggagctcca 1680 agactctaga caactagaaa ataaagatgt ctcctctgat tggcaggggc agatttgttc 1740 ttccacagat tcagaccagt gctacctgag agagactttg gaggcaagca agcaggtctc 1800 tccttgcagc acaagaaaac agctccaaga ccaggaaatc cgagccgagc tgaacaagca 1860 cttcggtcat cccagtcaag ctgtttttga cgacgaagca gacaagaccg gtgaactgag 1920 ggacagtgat ttcagtaatg aacaattctc caaactacct atgtttataa attcaggact 1980 agccatggat ggcctgtttg atgacagcga agatgaaagt gataaactga gctacccttg 2040 ggatggcacg caatcctatt cattgttcaa tgtgtctcct tcttgttctt cttttaactc 2100 tccatgtaga gattctgtgt caccacccaa atccttattt tctcaaagac cccaaaggat 2160 gcgctctcgt tcaaggtcct tttctcgaca caggtcgtgt tcccgatcac catattccag 2220 gtcaagatca aggtctccag gcagtagatc ctcttcaaga tcctgctatt actatgagtc 2280 aagccactac agacaccgca cgcaccgaaa ttctcccttg tatgtgagat cacgttcaag 2340 atcgccctac agccgtcggc ccaggtatga cagctacgag gaatatcagc acgagaggct 2400 gaagagggaa gaatatcgca gagagtatga gaagcgagag tctgagaggg ccaagcaaag 2460 ggagaggcag aggcagaagg caattgaaga gcgccgtgtg atttatgtcg gtaaaatcag 2520 acctgacaca acacggacag aactgaggga ccgttttgaa gtttttggtg aaattgagga 2580 gtgcacagta aatctgcggg atgatggaga cagctatggt ttcattacct accgttatac 2640 ctgtgatgct tttgctgctc ttgaaaatgg atacactttg cgcaggtcaa acgaaactga 2700 ctttgagctg tacttttgtg gacgcaagca atttttcaag tctaactatg cagacctaga 2760 ttcaaactca gatgactttg accctgcttc caccaagagc aagtatgact ctctggattt 2820 tgatagttta ctgaaagaag ctcagagaag cttgcgcagg taacatgttc cctagctgag 2880 gatgacagag ggatggcgaa tacctcatgg gacagcgcgt ccttccctaa agactattgc 2940 aagtcatact taggaattc tcctacttta cactctctgt acaaaaacaa aacaaaacaa 3000 caacaataca acaagaacaa caacaacaat aacaacaatg gtttacatga acacagctgc 3060 3120 ttgcttttcc tggagtctct tggtgatgga gtgtgcgtgt gtgcatgtat gtgtgtgtgt 3180 3240 ctggggcac ctgaccagaa tgcgcaaggg caaaccattt caaatggcag cagttccatg 3300 aagacacgct taaaacctag aacttcaaaa tgttcgtatt ctattcaaaa ggaaatat 3360 atatatatat atatatatat atatatat ataaaaaaaaa aaagaaaa aatcaaac 3420 caaccaacca accaaccaac caaaaccac cctaaaatga cagccgctga tgtctgggca 3480 tcagcctttg tactctgttt ttttaagaaa gtgcagaatc aacttgaagc aagctttctc 3540 tcataacgta atgattatat gacaatcctg aagaaaccac aggttccata gaactaatat 3600 cctgtctctc tctctctctc tctctctctc tttttttttt ctttttcctt ttgccatgga 3660 atctgggtgg gagaggatac tgcgggcacc agaatgctaa agtttcctaa cattttgaag 3720 tttctgtagt tcatccttaa tcctgacacc catgtaaatg tccaaaatgt tgatcttcca 3780 ctgcaaattt caaaagcctt gtcaatggtc aagcgtgcag cttgttcagc ggttctttct 3840 gaggagcgga caccgggtta cattactaat gagagttggg tagaactctc tgagatgtgt 3900 tcagatagtg taattgctac attctctgat gtagttaagt atttacagat gttaaatgga 3960 gtatttttat tttatgtata tactatacaa caatgttctt ttttgttaca gctatgcact 4020 gtaaatgcag ccttcttttc aaaactgcta aatttttctt aatcaagaat attcaaatgt 4080 aattatgagg tgaaacaatt attgtacact aacatattta gaagctgaac ttactgctta 4140 tatatatttg attgtaaaaa caaaaagaca gtgtgtgtgt ctgttgagtg caacaagagc 4200 aaaatgatgc ttccgcaca tccatcctt aggtgagctt caatctaagc atcttgtca 4260 gaaatatcct agtcccctaa agttattac cacttctgcg atatttttcc acatttctt 4320 gtcgcttgtt ttcttgaa gttttaca ctggattgt tagggaatg aaatttctc 4380 atctaaaatt tttctagag attcatgat tttgtaaa gtctctcaat gggtaaccat 4440 tagaaatgt ttttattc tctatcaaca gtagttttga actagaagt caaaatctt 4500 tttaaaatgc tgttttgtt taatttttgt gattttaatt tgatacaaaa tgctgaggta 4560 ataattatag tatgattttt acaatatta atgtgtgtct gaagactatc tttgaagcca 4620 gtatttcttt cccttggcag agtatgacga tggtatttat ctgtattttt tacagttatg 4680 catcctgtat aaatactgat atttcattcc tttgtttact aaagagacat atttatcagt 4740 tgcagatagc ctatttatta taaattatga gatgatgaa ataataagc cagtggaat 4800 tttctaccta ggatgcatga caatgtcag gttggagtgt aagtgcttca tttgggaat 4860 tcagctttg cagaagcagt gtttactt gcactagcat ggcctgac gtgaccatgg 4920 tgttgttctt gatgacattg cttctgctaa atttaataaa aacttcagaa aaacctccat 4980 tttgatcatc aggatttcat ctgagtgtgg agtccctgga atggaattca gtaacatttg 5040 gagtgtgtat tcaagtttct aaattgagat tcgattactg tttggctgac atgacttttc 5100 tggaagacat gatacaccta ctactcaatt gttcttttcc tttctctcgc ccaacacgat 5160 cttgtaagat ggatttcacc cccaggccaa tgcagctaat tttgatagct gcattcattt 5220 atcaccagca tattgtgttc tgagtgaatc cactgtttgt cctgtcggat gcttgcttga 5280 ttttttggct tcttatttct aagtatag aaagcaataa aaatactatg aaatgaaaga 5340 acttgttcac aggttctgcg ttacaacagt aacacatctt taatccgcct aattcttgtt 5400 gttctgtagg ttaaatgcag gtattttaac tgtgtgaacg ccaaactaaa gtttacagtc 5460 tttctttctg aattttgagt atcttctgtt gtagaataat aataaaaaga ctattaagag 5520 caataaatta tttttaagaa atcgagattt agtaaatcct attatgtgtt caaggaccac 5580 atgtgttctc tattttgcct ttaaattttt gtgaaccaat tttaaataca ttctccttt 5640 tgccctggat tgttgacatg agtggaatac ttggtttctt ttcttactta tcaaaagaca 5700 gcactacaga tatcatattg aggattaatt tatcccccct acccccagcc tgacaaatat 5760 tgttaccatg aagatagttt tcctcaatgg acttcaaatt gcatctagaa ttagtggagc 5820 ttttgtatct tctgcagaca ctgtgggtag cccatcaaaa tgtaagctgt gctcctctca 5880 ttttttttt tattttttg ggagagaata tttcaaatga acacgtgcac cccatcatca 5940 ctggaggcaa atttcagcat agatctgtag gatttttaga agaccgtggg ccattgcctt 6000 catgccgtgg taagtaccac atctacaatt ttggtaaccg aactggtgct ttagtaatgt 6060 ggattttttt cttttttaaa agagatgtag cagaataatt cttccagtgc aacaaaatca 6120 attttttgct aaacgactcc gagaacaaca gttgggctgt caacattcaa agcagcagag 6180 agggaacttt gcactattgg ggtatgatgt ttgggtcagt tgataaaaagg aaaccttttc 6240 atgcctttag atgtgagctt ccagtaggta atgattatgt gtcctttctt gatggctgta 6300 atgagaactt caatcactgt agtctaagac ctgatctata gatgacctag aatagccatg 6360 tactataatg tgatgattct aaatttgtac ctatgtgaca gacattttca ataatgtgaa 6420 ctgctgattt gatggagcta ctttaagatt tgtaggtgaa agtgtaatac tgttggttga 6480 actatgctga agagggaaag tgagcgatta gttgagccct tgccgggcct tttttccacc 6540 tgccaattct acatgtattg ttgtggtttt attcattgta tgaaaattcc tgtgattttt 6600 tttaaatgtg cagtacacat cagcctcact gagctaataa agggaaacga atgtttcaaa 6660 tctaaaaaaa aaaaaaaaaa a 6681 <210> 54 <211> 786 <212> PRT <213> Artificial sequence [[ID="20"]]<220> <223> Synthetic polymer <400> 54 Met Asp Glu Gly Tyr Phe Cys Ala Ala Leu Val Gly Glu Asp Gln Pro 1 5 10 15 Leu Cys Pro Asp Leu Pro Glu Leu Asp Leu Ser Glu Leu Asp Val Asn 20 25 30 Asp Leu Asp Thr Asp Ser Phe Leu Gly Gly Leu Lys Trp Cys Ser Asp 35 40 45 Gln Ser Glu Ile Ile Ser Asn Gln Tyr Asn Asn Glu Pro Ser Asn Ile 50 55 60 Phe Glu Lys Ile Asp Glu Glu Asn Glu Ala Asn Leu Leu Ala Val Leu 65 70 75 80 Thr Glu Thr Leu Asp Ser Leu Pro Val Asp Glu Asp Gly Leu Pro Ser 85 90 95 Phe Asp Ala Leu Thr Asp Gly Asp Val Thr Thr Asp Asn Glu Ala Ser 10...

Claims

1. Use of an inhibitor of miR-22 in the preparation of a medicament for treating or preventing a metabolic disorder in a subject in need thereof, wherein the inhibitor of miR-22 is an oligonucleotide-based inhibitor comprising one or more chemically modified nucleotides, wherein the chemically modified nucleotides are locked nucleotides (LNAs), wherein the inhibitor results in decreased expression and / or activity of miR-22, and wherein the metabolic disorder is hepatic steatosis, wherein the oligonucleotide-based inhibitor consists of a polynucleotide sequence of CTTcaACtgGCAgCT (SEQ ID NO: 5), wherein capital letters represent LNA-modified nucleotides and lowercase letters represent unmodified nucleotides.

2. The use of claim 1, wherein the oligonucleotide-based inhibitor is conjugated to one or more N-acetylgalactosamine (GalNAc) moieties.

3. The use of claim 1, wherein the subject is obese.

4. The method of claim 3, wherein the subject suffers from Prader-Willi syndrome.

5. The method of claim 3, wherein the subject suffers from hypercholesterolemia.

6. The use according to claim 3, wherein the subject has a fat mass and obesity-related protein (FTO) variant and / or shows upregulation of FTO expression and / or activity.

7. The use according to any one of claims 3 to 6, wherein the subject is obese and has a body mass index greater than 30.

8. The use according to any one of claims 3 to 6, wherein the subject is overweight and has a body mass index of 25-29.

9.

9. The use according to any one of claims 3 to 6, wherein the medicament causes weight loss.

10. The use of claim 9, wherein the medicament causes a total body weight loss of 1%, 5%, 10%, 15%, 20% or 25% or more in the subject.

11. The use according to any one of claims 3 to 6, wherein the medicament prevents weight gain.

12. The use according to any one of claims 3 to 6 and 10, wherein the medicament reduces or prevents adipose tissue growth.

13. The use according to any one of claims 3 to 6 and 10, wherein the medicament disrupts adipocyte differentiation.

14. The use according to any one of claims 1 to 6 and 10, wherein the drug reduces the activity and / or expression of fat mass and obesity-associated protein (FTO), ALKB homolog 5 (ALKBH5), CCAAT / enhancer binding protein alpha (CEBPα), peroxisome proliferator-activated receptor γ (PPARγ), peroxisome proliferator-activated receptor alpha (PPARa), ATP citrate lyase (ACLY), PPARγ coactivator-α (PGC1-α), specificity protein 1 (SP1), fibroblast growth factor 21 (FGF-21), uncoupling protein 1 (UCP1), DNA damage-induced transcript 4 (DDIT-4, REDD1), tumor protein p63 (TP63), fibroblast growth factor 1 (FGF1) and / or methyltransferase-like protein 3 (METTL3).

15. The use according to any one of claims 1 to 6 and 10, wherein the drug increases the activity and / or expression of phosphatase and tensin homologous protein (PTEN) and / or tet methylcytosine dioxygenase 2 (TET2).

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