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Methods and compositions based on protein interactions with mastermind |
The invention is directed to methods of modulating Notch signal transduction and to complexes of the protein Mastermind with proteins identified as interacting with Mastermind by a two-hybrid screen as well as a complex of Mastermind (Mam) with Mip1, or a complex of Mam with Mip30, or a complex of Mam with Mip6. Methods of screening the complexes for efficacy in treating and/or preventing certain diseases and disorders, particularly hyperproliferative and cancerous conditions are also provided. The invention includes nucleic acid and amino acid sequences of Mip30 or Mip6, as well as fragments and derivatives thereof. |
1. A method of inhibiting Notch signal transduction in a cell comprising contacting the cell with an antagonist of sumolation in an amount sufficient to inhibit Notch signal transduction. 2. A method of agonizing Notch signal transduction in a cell comprising contacting the cell with an agonist of sumolation in an amount sufficient to agonize Notch signal transduction. 3. The method according to claim 1 in which the antagonist is a dominant negative form of Mip1. 4. The method according to claim 3 in which the dominant negative form of Mip1 contains a mutated ADP binding site such that the dominant negative form of Mip1 does not bind ADP. 5. The method according to claim 1 in which the antagonist is an antisense nucleic acid to Mip1, or an antibody to Mip1 or the binding domain of an antibody to Mip1. 6. A method of identifying a molecule that alters Notch signal transduction in a cell comprising the following steps in the order stated: (a) contacting the cell with one or more candidate molecules; and (b) measuring the amount of sumolation in the cell, wherein an increase or decrease in the amount of sumolation relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter Notch signal transduction. 7. (canceled) 8. (canceled) 9. A method of identifying a molecule that alters sumolation activity in a cell comprising the following steps in the order stated: (a) contacting the cell with one or more candidate molecules; and (b) measuring the amount of Notch signal transduction in the cell, wherein an increase or decrease in the amount of Notch signal transduction relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter sumolation activity. 10. (canceled) 11. (canceled) 12. A method of inhibiting sumolation activity in a cell comprising contacting the cell with an antagonist of Notch signal transduction in an amount sufficient to inhibit sumolation activity. 13. A method of agonizing sumolation activity in a cell comprising contacting the cell with an agonist of Notch signal transduction in an amount sufficient to agonize sumolation activity. 14. The method according to claim 12 in which the antagonist is a dominant negative form of Notch. 15. The method according to claim 12 in which the antagonist is an antibody to Notch or a fragment of the antibody containing the binding domain of the antibody. 16. The method according to claim 13 in which the agonist is an dominant active form of Notch. 17. The method according to claim 13 in which the agonist is a Delta or Serrate protein or a fragment of Delta or Serrate that binds to Notch. 18. The method according to claim 13 in which the agonist is the soluble extracellular domain of Delta. 19. (canceled) 20. A purified complex of Mam and Mip1, or a purified complex of Mam and Mip30, or a purified complex of Mam and Mip6. 21. (canceled) 22. A purified complex selected from the group consisting of a complex of a derivative of Mam and Mip1, a complex of Mam and a derivative of Mip1, and a complex of a derivative of Mam and a derivative of Mip1; in which the derivative of Mam is able to form a complex with a wild-type Mip1 and the derivative of Mip1 is able to form a complex with wild-type Mam. 23. (canceled) 24. (canceled) 25. (canceled) 26. A chimeric protein comprising a fragment of Mam consisting of at least 6 amino acids fused via a covalent bond to a fragment of Mip1 consisting of at least 6 amino acids. 27. (canceled) 28. (canceled) 29. (canceled) 30. (canceled) 31. (canceled) 32. (canceled) 33. (canceled) 34. (canceled) 35. An antibody which immunospecifically binds the complex according to claim 20 or a fragment or derivative of said antibody containing the binding domain thereof. 36. The antibody according to claim 35 which does not immunospecifically bind Mam, Mip1, Mip30 or Mip6 that is not part of a Mam:Mip1, Mam:Mip30 or Mam:Mip6 complex, respectively. 37. An isolated nucleic acid or an isolated combination of nucleic acids comprising (a) a nucleotide sequence encoding Mam and a nucleotide sequence encoding Mip1, (b) a nucleotide sequence encoding Mam and a nucleotide sequence encoding Mip30, (c) a nucleotide sequence encoding Mam and a nucleotide sequence encoding Mip6, (d) a nucleotide sequence encoding Mip30, or (e) a nucleotide sequence encoding Mip6. 38. (canceled) 39. (canceled) 40. (canceled) 41. (canceled) 42. (canceled) 43. (canceled) 44. (canceled) 45. (canceled) 46. (canceled) 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) 51. (canceled) 52. (canceled) 53. (canceled) 54. (canceled) 55. (canceled) 56. A method of diagnosing or screening for the presence of or a predisposition for developing a disease or disorder characterized by an aberrant level of a complex of Mam and Mip1, Mam and Mip30 or Mam and Mip6, in a subject comprising measuring the level of said complex, RNA encoding Mam and Mip1, Mam and Mip30 or Mam and Mip6, or functional activity of said complex in a sample derived from the subject, in which an increase or decrease in the level of said complex, said RNA encoding Mam and Mip1, Mam and Mip30 or Mam and Mip6, or functional activity of said complex in the sample, relative to the level of said complex, said RNA encoding Mam and Mip1, Mam and Mip30 or Mam and Mip6 or functional activity of said complex found in an analogous sample not having the disease or disorder or a predisposition for developing the disease or disorder, indicates the presence of the disease or disorder or a predisposition for developing the disease or disorder. 57. (canceled) 58. (canceled) 59. (canceled) 60. (canceled) 61. (canceled) 62. (canceled) 63. (canceled) 64. (canceled) 65. A method of treating or preventing a disease or disorder involving an aberrant level of Mip1, Mip30 or Mip6 in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a molecule that modulates the function of Mip1, Mip30 or Mip6, respectively. 66. (canceled) 67. (canceled) 68. (canceled) 69. (canceled) 70. (canceled) 71. (canceled) 72. A method of treating or preventing a disease or disorder involving an aberrant level of Mam in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a molecule that modulates the function of Mam. 73. (canceled) 74. (canceled) 75. (canceled) 76. (canceled) 77. (canceled) 78. (canceled) 79. A recombinant non-human animal in which both an endogenous Mam gene and an endogenous Mip1 have been deleted or inactivated by recombination or insertional mutagenesis of said animal or an ancestor thereof. 80. (canceled) 81. (canceled) 82. (canceled) 83. (canceled) 84. (canceled) 85. (canceled) 86. (canceled) 87. (canceled) 88. (canceled) 89. (canceled) 90. (canceled) 91. (canceled) 92. (canceled) 93. (canceled) 94. (canceled) 95. (canceled) 96. (canceled) 97. (canceled) 98. (canceled) 99. (canceled) 100. (canceled) 101. (canceled) 102. (canceled) 103. (canceled) 104. (canceled) 105. (canceled) 106. (canceled) 107. (canceled) 108. A method of monitoring the efficacy of a treatment of a disease or disorder characterized by an aberrant level of a complex of Mam and Mip1 in a subject administered said treatment for said disease or disorder comprising measuring the level of said complex, RNA encoding Mam and Mip1, or functional activity of said complex in a sample derived from said subject wherein said sample is taken from said subject after the administration of said treatment and compared to (a) said level in a sample taken from said subject prior to the administration of the treatment or (b) a standard level associated with the pretreatment stage of the disease or disorder, in which the change, or lack of change in the level of said complex, said RNA encoding Mam and Mip1, or functional activity of said complex in said sample taken after the administration of said treatment relative to the level of said complex, said RNA encoding Mam and Mip1 or functional activity of said complex in said sample taken before the administration of said treatment or to said standard level indicates whether said administration is effective for treating said disease or disorder. 109. (canceled) 110. (canceled) 111. A purified protein selected from the group consisting of Mip30 and Mip6. 112. (canceled) 113. (canceled) 114. (canceled) 115. (canceled) 116. A purified fragment of a Mip30 protein comprising a domain of the protein selected from the group consisting of the C2H2-type zinc finger domain, the HMG-1 and HMG-Y DNA-binding domain (A+T-hook), and the bipartite nuclear localization signal. 117. (canceled) 118. (canceled) 119. (canceled) 120. (canceled) 121. A chimeric protein comprising a fragment of a Mip6 protein consisting of at least 20 amino acids fused via a covalent bond to an amino acid sequence of a second protein, in which the second protein is not the Mip6 protein. 122. (canceled) 123. (canceled) 124. (canceled) 125. (canceled) 126. An antibody which is capable of binding the Mip30 protein of claim 111. 127. An antibody which is capable of binding the Mip6 protein of claim 111. 128. (canceled) 129. (canceled) 130. (canceled) 131. (canceled) 132. (canceled) 133. (canceled) 134. (canceled) 135. (canceled) 136. (canceled) 137. (canceled) 138. (canceled) 139. (canceled) 140. A method of treating or preventing a disease or disorder in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a Mip30 or Mip6 protein or derivative thereof which is able to bind to a Mam protein. 141. (canceled) 142. (canceled) 143. A method of treating or preventing a disease or disorder in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a molecule, in which the molecule is an oligonucleotide which (a) consists of at least six nucleotides; (b) comprises a sequence complementary to at least a portion of an RNA transcript of a Mip30 or a Mip6 gene; and (c) is specifically hybridizable to the RNA transcript. 144. (canceled) 145. An isolated oligonucleotide consisting of at least six nucleotides, and comprising a sequence complementary to at least a portion of an RNA transcript of a Mip30 or Mip6 gene, which oligonucleotide is specifically hybridizable to the RNA transcript. 146. (canceled) 147. (canceled) |
<SOH> 2. BACKGROUND OF THE INVENTION <EOH>2.1 Notch Signal Transduction Genetic and molecular studies have led to the identification of a group of genes which define distinct elements of the Notch signaling pathway. While the identification of these various elements has come exclusively from Drosophila using genetic tools as the initial guide, subsequent analyses have lead to the identification of homologous proteins in vertebrate species including humans. See, generally, Artavanis-Tsakonas et al., 1995, Science 268:225-232. The Drosophila Notch gene encodes an ˜300 kD transmembrane protein that acts as a receptor in a cell-cell signaling mechanism controlling cell fate decisions throughout development (reviewed, e.g., in Artavanis-Tsakonas et al., 1995, Science 268:225-232). Closely related homologs of Drosophila Notch have been isolated from a number of vertebrate species, including humans, with multiple paralogs representing the single Drosophila gene in vertebrate genomes. The isolation of cDNA clones encoding the C-terminus of a human Notch paralog, originally termed h N, has been reported (Stifani et al., 1992, Nature Genetics 2:119-127). The encoded protein is designated human Notch2 because of its close relationship to the Notch2 proteins found in other species (Weinmaster et al., 1992, Development 116:931-941). The hallmark Notch2 structures are common to all the Notch-related proteins, including, in the extracellular domain, a stretch of 34 to 36 tandem Epidermal Growth Factor-like (EGF) repeats (fewer EGF repeats in Notch 3 and 4) and three Lin-12/Notch repeats (LN repeats), and, in the intracellular domain, 6 Ankyrin repeats and a PEST-containing region. Like Drosophila Notch and the related C. elegans genes lin-12 and glp-1 (Sternberg, 1993, Current Biology 3:763-765; Greenwald, 1994, Current Opinion in Genetics and Development 4:556-562), the vertebrate Notch homologs play a role in a variety of developmental processes by controlling cell fate decisions (reviewed, e.g., in Blaumueller and Artavanis-Tsakonas, 1997, Persp. on Dev. Neurobiol. 4:325-343). For further human Notch sequences, see International Publication WO 92/19734 and WO 99/04746. The extracellular domain of Notch generally carries 36 Epidermal Growth Factor-like (EGF) repeats, two of which (repeats 11 and 12) have been implicated in interactions with the Notch ligands Serrate and Delta. Delta and Serrate are membrane bound ligands with EGF homologous extracellular domains, which interact physically with Notch on adjacent cells to trigger signaling. Functional analyses involving the expression of truncated forms of the Notch receptor have indicated that receptor activation depends on the six cdc10/ankyrin repeats in the intracellular domain. Deltex and Suppressor of Hairless, whose over-expression results in an apparent activation of the pathway, associate with those repeats. Deltex is a cytoplasmic protein which contains a ring zinc finger. Suppressor of Hairless on the other hand, is the Drosophila homolog of CBF1, a mammalian DNA binding protein involved in the Epstein-Barr virus-induced immortalization of B cells. It has been demonstrated that, at least in cultured cells, Suppressor of Hairless associates with the cdc10/ankyrin repeats in the cytoplasm and translocates into the nucleus upon the interaction of the Notch receptor with its ligand Delta on adjacent cells (Fortini and Artavanis, 1994, Cell 79:273-282). The association of Hairless, a novel nuclear protein, with Suppressor of Hairless has been documented using the yeast two hybrid system; therefore, it is believed that the involvement of Suppressor of Hairless in transcription is modulated by Hairless (Brou et al., 1994, Genes Dev. 8:2491; Knust et al. 1992, Genetics 129:803). Finally, it is known that Notch signaling results in the activation of at least certain basic helix-loop-helix (bHLH) genes within the Enhancer of Split complex (Delidakis et al., 1991, Genetics 129:803). The generality of the Notch pathway manifests itself at different levels. At the genetic level, many mutations exist which affect the development of a very broad spectrum of cell types in Drosophila . Knockout mutations in mice are embryonic lethals consistent with a fundamental role for Notch function (Swiatek et al., 1994, Genes Dev. 8:707). Mutations in the Notch pathway in the hematopoietic system in humans are associated with lymphoblastic leukemia (Ellison et al., 1991, Cell 66:649-661). Finally the expression of mutant forms of Notch in developing Xenopus embryos interferes profoundly with normal development (Coffman et al., 1993, Cell 73:659). Increased level of Notch expression is found in some malignant tissue in humans (International Publication WO 94/07474). The expression patterns of Notch in the Drosophila embryo are complex and dynamic. The Notch protein is broadly expressed in the early embryo, and subsequently becomes restricted to uncommitted or proliferative groups of cells as development proceeds. In the adult, expression persists in the regenerating tissues of the ovaries and testes (reviewed in Fortini et al., 1993, Cell 75:1245-1247; Jan et al., 1993, Proc. Natl. Acad. Sci. USA 90:8305-8307; Sternberg, 1993, Curr. Biol. 3:763-765; Greenwald, 1994, Curr. Opin. Genet. Dev. 4:556-562; Artavanis-Tsakonas et al., 1995, Science 268:225-232). Studies of the expression of Notch1, one of three known vertebrate homologs of Notch, in zebrafish and Xenopus , have shown that the general patterns are similar; with Notch expression associated in general with non-terminally differentiated, proliferative cell populations. Tissues with high expression levels include the developing brain, eye and neural tube (Coffman et al., 1990, Science 249:1438-1441; Bierkamp et al., 1993, Mech. Dev. 43:87-100). While studies in mammals have shown the expression of the corresponding Notch homologs to begin later in development, the proteins are expressed in dynamic patterns in tissues undergoing cell fate determination or rapid proliferation (Weinmaster et al., 1991, Development 113:199-205; Reaume et al., 1992, Dev. Biol. 154:377-387; Stifani et al., 1992, Nature Genet. 2:119-127; Weinmaster et al., 1992, Development 116:931-941; Kopan et al., 1993, J. Cell Biol. 121:631-641; Lardelli et al., 1993, Exp. Cell Res. 204:364-372; Lardelli et al., 1994, Mech. Dev. 46:123-136; Henrique et al., 1995, Nature 375:787-790; Horvitz et al., 1991, Nature 351:535-541; Franco del Amo et al., 1992, Development 115:737-744). Among the tissues in which mammalian Notch homologs are first expressed are the pre-somitic mesoderm and the developing neuroepithelium of the embryo. In the pre-somitic mesoderm, expression of Notch1 is seen in all of the migrated mesoderm, and a particularly dense band is seen at the anterior edge of pre-somitic mesoderm. This expression has been shown to decrease once the somites have formed, indicating a role for Notch in the differentiation of somatic precursor cells (Reaume et al., 1992, Dev. Biol. 154:377-387; Horvitz et al., 1991, Nature 351:535-541). Similar expression patterns are seen for mouse Delta (Simske et al., 1995, Nature 375:142-145). Within the developing mammalian nervous system, expression patterns of Notch homologs have been shown to be prominent in particular regions of the ventricular zone of the spinal cord, as well as in components of the peripheral nervous system, in an overlapping but non-identical pattern. Notch expression in the nervous system appears to be limited to regions of cellular proliferation, and is absent from nearby populations of recently differentiated cells (Weinmaster et al., 1991, Development 113:199-205; Reaume et al., 1992, Dev. Biol. 154:377-387; Weinmaster et al., 1992, Development 116:931-941; Kopan et al., 1993, J. Cell Biol. 121:631-641; Lardelli et al., 1993, Exp. Cell Res. 204:364-372; Lardelli et al., 1994, Mech. Dev. 46:123-136; Henrique et al., 1995, Nature 375:787-790; Horvitz et al., 1991, Nature 351:535-541). A rat Notch ligand is also expressed within the developing spinal cord, in distinct bands of the ventricular zone that overlap with the expression domains of the Notch genes. The spatio-temporal expression pattern of this ligand correlates well with the patterns of cells committing to spinal cord neuronal fates, which demonstrates the usefulness of Notch as a marker of populations of cells for neuronal fates (Henrique et al., 1995, Nature 375:787-790). This has also been suggested for vertebrate Delta homologues, whose expression domains also overlap with those of Notch1 (Larsson et al., 1994, Genomics 24:253-258; Fortini et al., 1993, Nature 365:555-557; Simske et al., 1995, Nature 375:142-145). In the cases of the Xenopus and chicken homologues, Delta is actually expressed only in scattered cells within the Notch1 expression domain, as would be expected from the lateral specification model, and these patterns “foreshadow” future patterns of neuronal differentiation (Larsson et al., 1994, Genomics 24:253-258; Fortini et al., 1993, Nature 365:555-557). Other vertebrate studies of particular interest have focused on the expression of Notch homologs in developing sensory structures, including the retina, hair follicles and tooth buds. In the case of the Xenopus retina, Notch1 is expressed in the undifferentiated cells of the central marginal zone and central retina (Coffman et al., 1990, Science 249:1439-1441; Mango et al., 1991, Nature 352:811-815). Studies in the rat have also demonstrated an association of Notch1 with differentiating cells in the developing retina have been interpreted to suggest that Notch1 plays a role in successive cell fate choices in this tissue (Lyman et al., 1993, Proc. Natl. Acad. Sci. USA 90:10395-10399). A detailed analysis of mouse Notch1 expression in the regenerating matrix cells of hair follicles was undertaken to examine the potential participation of Notch proteins in epithelial/mesenchymal inductive interactions (Franco del Amo et al., 1992, Development 115:737-744). Such a role had originally been suggested for Notch1 based on the its expression in rat whiskers and tooth buds (Weinmaster et al., 1991, Development 113:199-205). Notch1 expression was instead found to be limited to subsets of non-mitotic, differentiating cells that are not subject to epithelial/mesenchymal interactions, a finding that is consistent with Notch expression elsewhere. Expression studies of Notch proteins in human tissue and cell lines have also been reported. The aberrant expression of a truncated Notch1 RNA in human T-cell leukemia results from a translocation with a breakpoint in Notch1 (Ellisen et al., 1991, Cell 66:649-661). A study of human Notch1 expression during hematopoiesis has suggested a role for Notch1 in the early differentiation of T-cell precursors (Mango et al., 1994, Development 120:2305-2315). Additional studies of human Notch1 and Notch2 expression have been performed on adult tissue sections including both normal and neoplastic cervical and colon tissue. Notch1 and Notch2 appear to be expressed in overlapping patterns in differentiating populations of cells within squamous epithelia of normal tissues that have been examined and are clearly not expressed in normal columnar epithelia, except in some of the precursor cells. Both proteins are expressed in neoplasias, in cases ranging from relatively benign squamous metaplasias to cancerous invasive adenocarcinomas in which columnar epithelia are replaced by these tumors (Mello et al., 1994, Cell 77:95-106). Insight into the developmental role and the general nature of Notch signaling has emerged from studies with truncated, constitutively activated forms of Notch in several species. These recombinantly engineered Notch forms, which lack extracellular ligand-binding domains, resemble the naturally occurring oncogenic variants of mammalian Notch proteins and are constitutively activated using phenotypic criteria (Greenwald, 1994, Curr. Opin. Genet. Dev. 4:556; Fortini et al., 1993, Nature 365:555-557; Coffman et al., 1993, Cell 73:659-671; Struhl et al., 1993, Cell 69:1073; Rebay et al., 1993, Genes Dev. 7:1949; Kopan et al., 1994, Development 120:2385; Roehl et al., 1993, Nature 364:632). Ubiquitous expression of activated Notch in the Drosophila embryo suppresses neuroblast segregation without impairing epidermal differentiation (Struhl et al., 1993, Cell 69:331; Rebay et al., 1993, Genes Dev. 7:1949). Persistent expression of activated Notch in developing imaginal epithelia likewise results in an overproduction of epidermis at the expense of neural structures (Struhl et al., 1993, Cell 69:331). Neuroblast segregation occurs in temporal waves that are delayed but not prevented by transient expression of activated Notch in the embryo (Struhl et al., 1993, Cell 69:331). Transient expression in well-defined cells of the Drosophila eye imaginal disc causes the cells to ignore their normal inductive cues and to adopt alternative cell fates (Fortini et al., 1993, Nature 365:555-557). Studies utilizing transient expression of activated Notch in either the Drosophila embryo or the eye disc indicate that once Notch signaling activity has subsided, cells may recover and differentiate properly or respond to later developmental cues (Fortini et al., 1993, Nature 365:555-557; Struhl et al., 1993, Cell 69:331). For a general review on the Notch pathway and Notch signaling, see Artavanis-Tsakonas et al., 1995, Science 268:225-232. Ligands, cytoplasmic effectors and nuclear elements of Notch signaling have been identified in Drosophila , and vertebrate counterparts have also been cloned (reviewed in Artavanis-Tsakonas et al., 1995, Science 268:225-232). While protein interactions between the various elements have been documented, the biochemical nature of Notch signaling remains elusive. Expression of truncated forms of Notch reveal that Notch proteins without transmembrane and extracellular domains are translocated to the nucleus both in transgenic flies and in transfected mammalian or Drosophila cells (Lieber et al., 1993, Genes and Development 7:1949-1965; Fortini et al., 1993, Nature 365:555-557; Ahmad et al., 1995, Mechanisms of Development 53:78-85; Zagouras et al., 1995, Proc. Natl. Acad. Sci. USA 92:6414-6418). Sequence comparisons between mammalian and Drosophila Notch molecules, along with deletion analysis, have found two nuclear localization sequences that reside on either side of the ankyrin repeats (Stifani et al., 1992, Nature Genetics 2:119-127; Lieber et al., 1993, Genes and Development 7:1949-1965; Kopan et al., 1994, Development 120:2385-2396). These findings prompted the speculation that Notch may be directly participating in nuclear events by means of a proteolytic cleavage and subsequent translocation of the intracellular fragment into the nucleus. However, conclusive functional evidence for such a hypothesis remains elusive (Artavanis-Tsakonas et al., 1995, Science 268:225-232). 2.2 Mam Mastermind encodes a novel ubiquitous nuclear protein involved in the Notch pathway as shown by genetic analysis (Smoller et al., 1990, Genes Dev. 4:1688). Two human homologs of Mastermind have been cloned, MAML1 and MAML2 (Wu et al., 2000, Nature Genetics 26:484-489; see FIGS. 1-6 ). Mastermind contains an amino-terminal basic domain and two acid domains, one of which is in the carboxy terminus, and has been shown to localize to nuclear bodies. FIG. 5 is a schematic of the Mastermind domains and their location. Drosophila Mastermind is 1596 amino acids in length and has an unusually large number of homopolymer repeats (glutamine, glycine and asparagine) that are separated by regions of charged amino acids, an arrangement similar to nuclear regulatory proteins. Mastermind has been shown to bind to the ankyrin repeat domain of all four known mammalian Notch proteins and its expression has been shown to amplify Notch-induced transcription, and thus, Mastermind functions as a transcriptional co-activator for Notch signal transduction (Wu et al., 2000, Nature Genetics 26:484-489). 2.3 SUMO Conjugation SUMO (small ubiquitin-related modifier) is the best characterized member of a growing family of ubiquitin-related proteins. It resembles ubiquitin in its structure, its ability to be ligated to other proteins, as well as in the mechanism of ligation. However, in contrast to ubiquitinization, often the first step on a one-way road to protein degradation, sumolation does not seem to mark proteins for degradation. In fact, sumolation may even function as an antagonist of ubiquitin in the degradation of selected proteins. The SUMO conjugation machinery is evolutionarily conserved and has been described in organisms ranging from yeast to man. SUMO first undergoes an ATP-dependent activation by a heterodimeric complex (Uba2p/Aos1p) and is conjugated to Aos1p (activating enzyme) through a thioester bond. The SUMO protein is then transferred, through another thioester bond, to a SUMO-conjugating enzyme, Ubc9. Additional components of the SUMO conjugation pathway have not been identified, and it is likely that SUMO is conjugated to a protein substrate through direct transfer from Ubc9. The types of proteins known to date that are modified by SUMO participate in a wide spectrum of nuclear processes, including nuclear transport, kinetochore and centromere function, recombination, transcription and nuclear body structure. Consequently, any protein or signaling pathway that can influence SUMO conjugation could have a profound effect on nuclear functions. For a general review of the SUMO conjugation pathway, see Melchior, 2000, Ann. Rev. Cell Dev. Biol. 16:591-526. 2.4 Mip1/Uba2p Drosophila Uba2p (Mip1) is one of two subunits that comprise the activating enzyme for SUMO. Homologs of the Uba2p gene have been cloned from several species, including humans. See FIG. 8 for an amino acid comparison of different homologs of Uba2p. Citation or identification of any reference in Section 2 or any other section of this application shall not be construed as an admission that such reference is available as prior art to the present invention. |
<SOH> 3. SUMMARY OF THE INVENTION <EOH>The present invention is based, in part, on the discovery of interactions of Mastermind (Mam) with the Mip1, Mip30 and Mip6 proteins, as well as the isolation of Mip30 and Mip6 nucleic and amino acid sequences. The present invention is also based, in part, on the novel observation that an increase in Notch signal transduction results in an increase in sumolation in a cell, thus demonstrating the interdependence of the Notch signal transduction pathway and SUMO conjugation. Mastermind is a member of the Notch family of proteins and is involved in the regulation of cell fate and differentiation through Notch signaling. As described in Section 2.2, supra, Mastermind binds to the ankyrin repeat domain of Notch. Mastermind also binds Mip1, Mip30 and Mip6. Mip1, also called Uba2p, which, as discussed in Sections 2.3 and 2.4, supra, is part of the SUMO conjugation machinery, in particular, one of two subunits that comprise the SUMO activating enzyme. Sumolation of cellular proteins has been shown to alter their subcellular localization and result in longer half-lives, i.e., stabilization of the proteins. Mutations resulting in aberrant sumolation, e.g., disruption of the gene encoding SUMO, leads to severe growth defects in yeast and phenotypes such as aberrant mitosis, increase in telomere length, and defects in chromosomal segregation. It is well known that the centrosome is involved in mitosis and fidelity of chromosome segregation and that malfunctioning centrosomes can lead to missegregation of the chromosomes during mitosis, which appears to be involved in tumorigenesis, i.e. cancer formation. See, e.g., Doxsey, 1998, Nat. Genet. 20:104-106. Thus, the compositions and methods of the present invention are useful in studying cell fate and differentiation and tumorigenesis, and in studying telomere regulation and chromosome segregation and for identifying modulators of cell fate and differentiation and tumorigenesis, and in identifying modulators of telomere regulation and chromosome segregation. The present invention is directed to methods of identifying a molecule that alters Notch signal transduction in a cell comprising contacting the cell with one or more candidate molecules; and measuring the amount of sumolation in the cell, wherein an increase or decrease in the amount of sumolation relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter Notch signal transduction. The present invention is also directed to methods of identifying a molecule that alters Notch signal transduction in a cell comprising recombinantly expressing within the cell one or more candidate molecules; and measuring the amount of sumolation in the cell, wherein an increase or decrease in the amount of sumolation relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter Notch signal transduction. The present invention is also directed to methods of identifying a molecule that alters Notch signal transduction in a cell comprising microinjecting into the cell one or more candidate molecules; and measuring the amount of sumolation in the cell, wherein an increase or decrease in the amount of sumolation relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter Notch signal transduction. Sumolation, or SUMO conjugation activity, can be measured, e.g., by an increase or decrease in the conjugation of SUMO to target proteins. The total cellular complement of protein targets or specific protein targets can be analyzed. The SUMO protein can be introduced as a transgene in either an epitope-tagged form or an un-tagged form. Alternatively, the extent of endogenous SUMO conjugation activity can be assessed, e.g., using anti-SUMO antibodies, or by Western blot analysis in which the results would be amenable to quantification by densitometry. Further, since SUMO conjugation of a protein often influences the intracellular localization of the protein, an assay based upon the localization of a specific target protein can be used. Also, since SUMO conjugation of a protein often stabilizes the protein since SUMO competes with the same target lysine as ubiquitin, sumolation can be measured by measuring the stability, i.e., half-life, of the target protein, e.g., by Western blot analysis. The present invention is directed to methods of identifying a molecule that alters sumolation activity in a cell comprising contacting the cell with one or more candidate molecules; and measuring the amount of Notch signal transduction in the cell, wherein an increase or decrease in the amount of Notch signal transduction relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter sumolation activity. Another method of identifying a molecule that alters sumolation in a cell comprises recombinantly expressing within the cell one or more candidate molecules; and measuring the amount of Notch signal transduction in the cell, wherein an increase or decrease in the amount of Notch signal transduction relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter sumolation activity. Yet another method of identifying a molecule that alters sumolation activity in a cell comprises microinjecting into the cell one or more candidate molecules; and measuring the amount of Notch signal transduction in the cell, wherein an increase or decrease in the amount of Notch signal transduction relative to said amount in a cell not so contacted with one or more of the candidate molecules indicates that the candidate molecules alter sumolation activity. Notch signal transduction or Notch function can be measured using assays commonly known in the art, e.g., by the ability of Notch to activate transcription of a gene in the Enhancer of split complex, e.g., mγ, mδ, m5; or to activate transcription of vestigial, cut, or the HES1 gene. An in vitro transcription assay utilizing HES1 has been described (Wu et al., 2000, Nature Genetics 26:484-489; Jarriault et al., 1995, Nature 377:355-358). Thus, increased levels of mγ, mδ, m5, vestigial, cut or HES1 mRNA or protein indicates an increased level of Notch signal transduction or Notch function. Conversely, decreased levels of mγ, mδ, m5, vestigial, cut or HES1 mRNA or protein indicates a decreased level of Notch signal transduction or Notch function. Further, activation of Notch signal transduction results in the inhibition of differentiation of precursor cells. See, U.S. Pat. No. 5,780,300. Thus, Notch signal transduction can also be measured by assaying for differentiation of precursor cells. Maintenance of the differentiation state of the precursor cell indicates active Notch signal transduction. A change in the differentiation state of the precursor cell indicates inactive Notch signal transduction. Additionally, reporter constructs with a reporter gene under the control of a promoter containing a Notch-responsive promoter element can also be used to detect Notch signal transduction. For example, the EBNA2 response element from the TP-1 promoter can be used in such a reporter construct. The present invention is also directed to methods of inhibiting Notch signal transduction in a cell comprising contacting the cell with an antagonist of sumolation in an amount sufficient to inhibit Notch signal transduction. Further, the present invention is directed to methods of agonizing Notch signal transduction in a cell comprising contacting the cell with an agonist of sumolation in an amount sufficient to agonize Notch signal transduction. The present invention is also directed to methods of inhibiting sumolation activity in a cell comprising contacting the cell with an antagonist of Notch signal transduction in an amount sufficient to inhibit sumolation activity, as well as, methods of agonizing sumolation activity in a cell comprising contacting the cell with an agonist of Notch signal transduction in an amount sufficient to agonize sumolation activity. Agonists and antagonists of both sumolation and Notch signal transduction are well known in the art, and can also be identified using the methods of the present invention, infra. The present invention is directed to certain compositions comprising and methods for production of protein complexes of Mam with a protein that interacts with (i.e., binds to) Mam. As used herein, “Mam-IP” refers to a Mam-interacting protein, e.g. Mip1, Mip30, Mip6. Specifically, the invention is directed to complexes of Mam, and derivatives, fragments and analogs of Mam, with Mip1, Mip30 or Mip6, and their derivatives, fragments and analogs (a complex of Mam and Mip1 or Mam and Mip30 or Mam and Mip6 is designated as Mam:Mip1 or Mam:Mip30 or Mam:Mip6, respectively, herein). The present invention is further directed to methods of screening for proteins that interact with Mam and/or Mip1, Mip30, or Mip6, or with derivatives, fragments or analogs of Mam and/or Mip1, Mip30 or Mip6. The present invention is also directed to Mip30 and Mip6 proteins, fragments and derivatives, and their encoding nucleic acids, as well as antibodies to the proteins, fragments and derivatives of Mip30 and Mip6. Methods for production of the Mam:Mip1, Mam:Mip30 and Mam:Mip6 complexes, and derivatives and analogs of the complexes and/or individual proteins, e.g., by recombinant means, are also provided. Pharmaceutical compositions are also provided. The invention is further directed to methods for modulating (i.e., inhibiting or enhancing) the activity of a Mam:Mip1, Mam:Mip30 or Mam:Mip6 complex, and/or Mip30 or Mip6. The protein components of a Mam:Mip1, Mam:Mip30 and Mam:Mip6 complexes have been implicated in physiological processes including, but not limited to, disease and disorders of cell fate and differentiation and aberrant mitotic events, such as defects in chromosome segregation. Accordingly, the present invention is directed to methods for screening Mam:Mip1, Mam:Mip30 or Mam:Mip6 complexes or Mip30 or Mip6, as well as derivatives and analogs of the complexes or Mip30 or Mip6, for the ability to alter a cell function, particularly a cell function in which Mam, Mip1, Mip30 and/or Mip6 has been implicated, as non-exclusively listed, supra. The present invention is also directed to therapeutic and prophylactic, as well as diagnostic, prognostic, and screening methods and compositions based upon the Mam:Mip1, Mam:Mip30 or Mam:Mip6 complexes (and the nucleic acids encoding the individual proteins that participate in the complex). Therapeutic compounds of the invention include, but are not limited to, Mam:Mip1, Mam:Mip30 or Mam:Mip6 complexes, and a complex where one or both members of the complex is a derivative, fragment, homolog or analog of Mam, Mip1, Mip30 or Mip6; antibodies to and nucleic acids encoding the foregoing; and antisense nucleic acids to the nucleotide sequences encoding the complex components. Diagnostic, prognostic and screening kits are also provided. Animal models and methods of screening for modulators (i.e., agonists, and antagonists) of the activity of Mam:Mip1, Mam:Mip30 or Mam:Mip6 complexes and/or the individual proteins are also provided. Methods of identifying molecules that inhibit, or alternatively, that increase formation of a Mam:Mip1, Mam:Mip30 or Mam:Mip6 complex are also provided. The methods of the present invention can be carried out either in vitro or in vivo. |
Liposomal encapsulation of glycosaminoglycans for the treatment of arthritic joints |
In a preferred embodiemnt the present invention features a composition and method of delivery comprising Glycosaminoglycans encapsulated in a liposomal delivery system for intraarticular administration for the treatment of osteoarthritis In a more preferred embodiemnt the present invention features a composition and method of delivery comprising hyaluronic acid encapsulated in a liposomal delivery system for intraarticular administration for the treatment of osteoarthritis. |
1. A composition useful for the treatment of arthritic joints comprising at least one glycosaminoglycan, at least part of which are encapsulated in at least one liposome. 2. The composition of claim 1, in which the glycosaminoglycan is selected from the group consisting of: chondroitin sulphate, keratinsulphate, heparin, heparin sulphate and dermatan sulphate. 3. The composition of claim 1, wherein the glycosaminoglycan is hyaluronic acid. 4. The Composition of claim 1, wherein the glycosaminoglycan is of greater than 500 kDa molecular weight. 5. The Composition of claim 1, wherein at least 10% by volume of the glycosaminoglycan is encapsulated in at least one liposome. 6. The composition of claim 1, wherein the concentration of glycosaminoglycan is greater than 1 mg/ml. 7. The composition of claim 1, wherein the liposome is made from a bilayer-forming phospholipid. 8. The composition of claim 8, wherein the phospholipid is dipalmitoylphosphatidylcholine. 9. The composition of claim 1, which additionally includes a further benefit agent for the treatment of osteoarthritis 10. The composition of claim 1, wherein the lipid concentration is greater than 10 mg/ml. 11. A liposomal delivery vehicle which encapsulates one or more glycosaminoglycans. 12. The liposomal delivery vehicle of claim 11, which is spherical or rod-shaped in structure. 13. The liposomal delivery system of claim 11 which has a diameter of greater than 0.1 μm. 14. A method for the treatment of arthritic joints, The method comprising the steps of: a) preparing the composition of claim 1 and b) administering the composition in a pharmaceutically appropriate dosage. 15. The method of claim 14, wherein the condition treated is osteoarthritis. 16. A method of claim 14, wherein the method of administration is by intra-articular injection of the composition into the arthritic joint. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Glycosaminoglycans (GAGS) are biopolymers consisting of repeating polysaccharide units, and are present on the cell surface as well as in the extracellular matrix of animals. GAGS are long unbranched polysaccharides containing a repeating disaccharide unit. The disaccharide units contain either of two modified sugars, N-acetylgalactosamine or N-acetylglucosamine and a uronic acid such as glucuronate or iduronate. GAGS are highly negatively charged molecules, with extended conformation that imparts high viscosity to the solution. GAGS are located primarily on the surface of cells or in the extracellular matrix. Along with the high viscosity of GAGS comes low compressibility, which makes these molecules ideal for a lubricating fluids in the joints. At the same time, their rigidity provides structural integrity to cells and provides passageways between cells allowing for cell migration. Common naturally occurring GAGs include, but are not limited to, chondroitin sulphate, keratan sulphate, heparin, heparan sulphate, dermatan sulphate and hyaluronate (commonly referred to as hyaluronic acid, HA). GAGs play an important role in articulating joints, being constituents both of synovial fluid, and of the surface layers of articular cartilage when covalently linked with proteins to form proteoglycans. Hyaluronic acid (HA) is a high molecular weight polysaccharide of N-acetyl glucosamine and glucuronic acid molecules that is naturally occurring in all mammals in a variety of tissues and some bacterial species. HA is unique among the GAGS in that it does not contain any sulphate and is not found covalently attached to proteins as a proteoglycan. HA polymers are very large with molecular weights of between about 100,000-10,000,000, and can displace a large volume of water. The chemical structure of hyaluronic acid is: The highest concentrations are found in connective tissue such as synovial membrane and synovial fluid. Hyaluronic acid forms highly viscoelastic solutions, and is synthesized in the plasma membrane of fibroblasts and other cells by addition of sugars to the reducing end of the polymer, whereas the nonreducing end protrudes into the pericellular space. The polysaccharide is catabolized locally or carried by lymph to lymph nodes or the general circulation, from where it is cleared by the endothelial cells of the liver sinusoids. The overall turnover rate is surprisingly rapid for a connective tissue matrix component (t 1/2 =0.5 to a few days). Methods to prepare pure samples, which are non-inflammatory, are well known in the art. For example, EP 0239335, U.S. Pat. No. 4,879,375, U.S. Pat. No. 4,141,973 disclose methods to prepare highly pure fractions of hyaluronic acid, which purport to be non-inflammatory. Hyaluronic acid is critical for the homeostasis of the joint, in part, because it provides the rheological properties (viscosity and elasticity) of the synovial fluid. It contributes to joint lubrication, buffers load transmission across articular surfaces, provides a renewed source of HA to joint tissues, and imparts anti-inflammatory properties to synovial fluid. In osteoarthritis, the molecular weight and concentration of HA in synovial fluid are diminished and this impairs the ability of synovial fluid to function effectively. The above observations have led to the development of viscosupplementation by means of intra-articular injections of hyaluronic acid for treatment of osteoarthritis of the knee. This treatment involves removal of pathologic osteoarthritic synovial fluid and replacement with HA-based products that restore the molecular weight and concentration of HA toward normal levels that can have beneficial therapeutic effects. Scientific publications describing the use of hyaluronic acid for treatment of articular conditions are well known in the art examples of which are Adams, 1993, 1996; Adams et al., 1995; Baker, 1997; Balazs, 1968, 1982; Balazs & Denlinger, 1985, 1989, 1993; Balazs & Gibbs, 1970; Band et al., 1995; Denlinger, 1982, 1996; Dickson &Hosle,1998; Estey, 1998; Gibbs et al., 1968; Moreland et al., 1993; Peyron, 1993a,1993b,1999; Rydell et al., 1970; Scale et al., 1994; Weiss et al., 1981; and Weiss & Balaz 1987. In the patent literature hyaluronic acid preparations for treatment of arthritic joints have been described. Examples of which are U.S. Pat. No. 5,914,322, described in U.S. Pat. No. 4,801,619. Several preparations of HA, e.g. Hyalgan (Fidia S.p.A) and Synvisc (Biomatrix, Inc.), are commercially available as treatments applied via intra-articular injection into the diseased joint. Such treatments have been found to provide significant pain relief, e.g. Peyron and Balazs, 1974; Adams 1993; Adams et al 1995;;; Huskisson and Donnelly 1999, Kotz and Kolarz 1999, by supplementing the synovial fluid with HA which is chemically and mechanically more closely representative of the HA found in young, healthy articular joints. Although the use of such treatments were reported as early as 1974 [1], the mechanism of action remains poorly understood. While evidence supports several roles of HA within the joint such as viscosupplementation and lubrication, Balazs and Denlinger 1984, protection of the cartilage surfaces, Balazs and Denlinger 1984, and suppression of pain-stimulating mediators such as IL-1α, Balazs and Darrzynkiewicz 1973; Forrester and Balzas 1980; Darzynkiewicz and Balazs, 1971, it is also known that HA molecules are removed from the joint over time through the process of enzymatic breakdown and lymphatic clearance [FDA PMA-Hyalgan 1997; FDA PMA-Hylan G-F 20, 1997; Levick et al 2000. Therefore the longer-term effects of such treatments are limited. Attempts to increase the residence time of HA within the joint have largely focused on modifying the HA molecule by cross-linking FDA PMA-Hylan G-F 2, 1997 [U.S. Pat. No. 5,827,937, WO99/10385], and while this delays clearance of HA there is little evidence to suggest that any additional long-term benefits are derived from such treatments, and concerns remain associated with the altering of the molecular structure, and in some cases the presence of chemical cross-linking agents. Lipids are also present in joint synovial fluid, and certain phospholipids (in particular dipalmitoylphosphatidylcholine (DPPC)) have been implicated in the lubrication of cartilage surfaces Hills 1995, 2000; Hills and Monds, 1998, and shown to reduce osteoarthritic pain by intra-articular injection into the knee joint Vecchio et al 1999. Liposomes were first described in 1965 by Bangham (Bangham, A. D., Standish, M. M. and Watkins, J. C. 1965. “Diffusion of Univalent Ions across the lamellae of swollen phospholipid,” J. Mol. Biol., 13: 238-252). Liposomes are classified by size, number of bilayers and hydrophobicity of the core. A conventional liposome is composed of lipid bilayers surrounding a hydrophilic core. The lipids of the lipid bilayers can have conjugating groups such as proteins, antibody polymers, and cationic polyelectrolytes on the surface of the liposomes and will act as targeting surface agents. Lipid vesicles are often classified into three groups by size and structure; multilamellar vesicles (MLVs), large unilamellar vesicles (LUVs), small unilamellar vesicles (SUVs), and paucilamellar (PLVs) vesicles. MLVs are onion-like structures having a series of substantially spherical shells formed of lipid bilayers interspersed with aqueous layers. LUVs have a diameter greater than 1 μm and are formed of a single lipid bilayer surrounding a large hydrophilic core phase. SUVs are similar in structure to LUVs except their diameter is less than an LUV, e.g., less than 100 nm. PLVs are vesicles that have an internal hydrophobic core surrounded by bilayers. See, e.g., Callow and McGrath, Cryobiology, 1985 22(3) pp. 251-267. Liposomes were initially used as models for studying biological membranes. However, in the last 15 years liposomal delivery systems have been designed as advanced delivery vehicles of drugs and other benefits agents into biological tissues. See, e.g., Gregoriadis, G., ed. 1988. Liposomes as Drug Carriers, New York: John Wiley, pp. 3-18). Traditionally, the thin-film method was used to manufacture liposomes. In this method, the bilayer-forming elements are mixed with a volatile organic solvent (such as chloroform, ether, ethanol, or a combination of these) in a mixing vessel (such as a round bottom flask). The predominant bilayer-forming element used to form conventional phospholipid vesicles is usually a neutral phospholipid such as phosphatidylcholine. Cholesterol is also often included to provide greater stability of the liposome in biological fluids. A charged species such as phosphatidylserine may also be added to prevent aggregation, and other elements such as natural acidic lipids and antioxidants, may also be included. The lipid-solvent solution is then placed under specified surrounding conditions (e.g., pressure and temperature) such that the volatile solvent is removed by evaporation (e.g., using a rotary evaporator) resulting in the formation of a dry lipid film. This film is then hydrated with aqueous medium containing dissolved solutes, including buffers, salts, and hydrophilic compounds, that are to be entrapped in the lipid vesicles. The hydration steps used influence the type of liposomes formed (e.g., the number of bilayers formed, vesicle size, and entrapment volume). If desirable, non-encapsulated drug or active can be removed from the mixture by a variety of techniques such as centrifugation, dialysis or diafiltration and recovered. Combinations of lipids and HA have been variously referenced in the literature. WO-A-91/12026 patented the combination of HA and phospholipid for the treatment of rheumatic joints. It was postulated that by combining HA and DPPC, both of which provide joint lubrication, improved lubrication could be imparted to the cartilage surfaces. A mixture of DPPC liposomes and HA has been shown to remove reduce surgical adhesions post-operatively. In both of these cases the lipid component and the HA component are combined in mixture; therefore no effect on the residence time of the HA molecules would be expected. Chemical interactions between lipids and GAGs have been described which show hexagonal shaped structures [18,19] or display acid amide bonding between the two ingredients (Aoki et. Al., U.S. Pat. No. 5,470,578, Antirheumatic Composition). Buttle et. Al. (WO 00/74662 A2, Arthritis Treatment) showed that catechins could be beneficial in the treatment of osteoarthritis and proposed their combination with HA. A liposomal delivery vehicle was mentioned for such a treatment; however, the method for achieving this was unclear as liposomes are generally less than 200 nm in diameter, while the diameter of HA molecules is typically around 200-300 nm [6]. The above prior art does not address the issue of insufficient residence time of HA in vivo. The present invention does address the issue by encapsulating GAG molecules within a liposome, such that these molecules were released over an appropriate time period to provide a treatment with longer-term effects. Accordingly, the object of the present invention is directed to novel compositions of liposomes and GAGs, which specifically include a liposome of sufficient size to encapsulate the GAG molecules. |
<SOH> SUMMARY OF THE INVENTION <EOH>In a preferred embodiement the present invention features a composition and method of delivery comprising Glycosaminoglycans encapsulated in a liposomal delivery system for intraarticular administration for the treatment of osteoarthritis. In a more preferred embodiemnt the present invention features a composition and method of delivery comprising hyaluronic acid encapsulated in a liposomal delivery system for intraarticular administration for the treatment of osteoarthritis. detailed-description description="Detailed Description" end="lead"? |
Method for locating sensors mounted each on a vehicle wheel |
Each sensor is provided with an emitter and the vehicle is provided with a corresponding receiver adapted to receive signals emitted by each sensor. The receiver is provided with at least one antenna disposed such that it is not located substantially equidistantly from the sensors, the antennas being located on a same side of the vehicle. The location of the sensors is carried out by analyzing the power of the field received by the receiver of each antenna for each sensor, the field power received by one antenna being the greater, the nearer to the antenna is the sensor that emitted the corresponding signal. |
1. Process for locating sensors (100, 101, 110, 111) mounted each on one wheel (4) of a vehicle, each sensor being provided with an emitter and the vehicle (2) being provided with a corresponding receiver (6) adapted to receive signals emitted by each sensor (100, 101, 110, 111), characterized in that the receiver (6) is provided with an antenna (12), so disposed that it is not located substantially equidistant from any two sensors (100, 101, 110, 111), and in that the location of the sensors (100, 101, 110, 111) is carried out by analyzing the field power received by the receiver (6) by means of the antenna (12) for each sensor, the power of the field received by the antenna being greater, the nearer to the detector is the sensor that emitted the corresponding signal. 2. Process for locating sensors (100, 101, 110, 111) each mounted on a vehicle wheel (4), each sensor being provided with an emitter and the vehicle (2) being provided with a corresponding receiver (6) adapted to receive the signals emitted by each sensor (100, 101, 110, 111), characterized in that the receiver (6) is provided with two separate antennas (12, 14), separated from each other and disposed such that neither antenna is located substantially equidistantly from the sensors (100, 101, 110, 111), the two antennas (12, 14) being located on the same side of the vehicle, and in that the location of the sensors (100, 101, 110, 111) is carried out by analyzing the field power received by the receiver (6) by means of each antenna (12, 14) for each sensor, the power of the field received by one antenna being the greater, the nearer to the antenna is the sensor that emitted the corresponding signal. 3. Process for location according to claim 2 for a vehicle having four wheels (4), characterized in that it comprises the following steps: a) analysis of the power of the signals received by the two antennas (12, 14) so as to distinguish the two sensors (100, 101) located on the side of the antennas from the other two sensors (110, 111), the signals received from these two sensors being the less attenuated, b) one antenna being inactivated and the other being activated, analysis of the power of the signals received by the two sensors (100, 101) located on the same side as the antennas so as to determine which sensor is the nearer the antenna that is still activated, c) one antenna being inactivated and the other being activated, analysis of the power of the signals received from the two sensors (110, 111) located on the side opposite the antennas (12, 14) so as to determine which sensor is nearer to the antenna that is still activated. 4. Process for location according to claim 3, characterized in that step a) is carried out as follows: adjustment of the receiver (6) to a predetermined sensitivity to receive all the signals emitted by the four sensors (100, 101, 110, 111) with the two antennas (12, 14), and adjustment of the receiver (6) to a lesser sensitivity such that, for the two antennas (12, 14), the signals emitted by the sensors (100, 101) located on the same side as the antennas will be received whilst the signals emitted by the other sensors (110, 111) are not received. 5. Process for location according to claim 3, characterized in that in step b) and/or step c), the power analysis is carried out by adjusting the sensitivity of the receiver (6) such that the signal power received by the sensor to be identified and located near the inactive antenna will be weak, whilst the power of the signal received by the sensor to be identified and located near the active antenna will be substantially stronger, and in that the analysis of the power levels received is made so as to detect the position of the two sensors whose signals are analyzed. 6. Process for location according to claim 3, characterized in that in step b) and/or step c), the power analysis is carried out by decreasing the sensitivity of the receiver (6) until a single signal emitted by the sensors to be identified will still be received by the receiver (6), and in that a determination of the position of the two sensors to be identified is thus carried out. 7. Process for location according to claim 3, characterized in that step b) and/or c) is carried out twice in succession, once with the first antenna active and the second antenna inactive and the second time with the first antenna inactive and the second antenna active, and in that a step of correlation is provided to compare the results obtained in the course of these two analyses. 8. Process for location according to claim 3, characterized in that step c) is carried out several times in a repetitive manner and in that a statistical analysis of the results is carried out. 9. Process for location according to claim 2, characterized in that the two antennas (12, 14) are integrated into the instrument panel of a vehicle, one antenna being located in the right portion and the other in the left portion of this instrument panel. 10. Process for location according to claim 9, characterized in that one antenna (12) is integrated into an electronic housing integrating the receiver (6) whilst the other antenna (14) is an antenna external to this housing. 11. Process for location according to claim 1, characterized in that it is carried out several times in a repetitive manner and in that a statistical analysis of the results is carried out. 12. Device for location to practice a process according to claim 2, characterized in that it comprises a receiver (6), two antennas (12, 14), a switch with two inputs insulated from each other and one output, mounted such that the receiver (6) is connected to one or the other of the antennas, as well as a computer (8) for the control and management of the device. 13. Device for location according to claim 12, characterized in that the receiver (6) is integrated into the computer (8). 14. Device for location according to claim 12, characterized in that one antenna (12) is integrated into the computer (8) and in that the other antenna (14) is an external antenna. |
Atopy |
The present invention relates to isolated nucleic acid sequences of ANGE, CLLD8 and CLLD7 or sequences complementary or substantially homologous thereto or fragments thereof. Also provided are sequences comprising hybrid nucleic add sequences from two or more of the genes. Also provided are nucleic acid expression vectors, polypeptides, antibodies to the polypeptides, host cells, non-human transgenic animals and pharmaceutical compositions and agents. Also provided is the use of the nucleic acid sequence and/or protein in medicine and research, methods for diagnosing or determining predisposition to disease or severity of disease, methods for preventing or treating disease, and kits for use in the methods and the use of the nucleic acid sequence and protein in treating or preventing IgE mediated diseases and non-atopic asthma, and in screens for identifying new agents for use in the methods. |
1. An isolated or recombinant nucleic acid sequence comprising an ANGE mRNA sequence or a sequence complementary or substantially homologous thereto, or a fragment thereof. 2. An isolated or recombinant nucleic acid sequence comprising a CLLD8 mRNA sequence or a sequence complementary or substantially homologous thereto, or a fragment thereof. 3. An isolated or recombinant nucleic acid sequence comprising a CLLD7 mRNA sequence or a sequence complementary or substantially homologous thereto, or a fragment thereof. 4. An isolated or recombinant nucleic acid sequence comprising an ANGE CLLD8 hybrid mRNA sequence or a sequence complementary or substantially homologous thereto, or a fragment thereof. 5. An isolated or recombinant nucleic acid sequence comprising an ANGE CLLD7 hybrid mRNA sequence or a sequence complementary or substantially homologous thereto, or a fragment thereof. 6. An isolated or recombinant nucleic acid sequence comprising a CLLD7-CLLD8 hybrid mRNA sequence or a sequence complementary or substantially homologous thereto, or a fragment thereof. 7. An isolated or recombinant nucleic acid sequence comprising an ANGE-CLLD8-CLLD7 hybrid mRNA sequence or a sequence complementary or substantially homologous thereto, or a fragment thereof. 8-86. (canceled) |
Method and device for transmitting information |
The invention relates to a method and a device for transmitting information from a transmitter to a receiver. According to the invention, a symbol (image) is selected on the transmitter side; a character string assigned to the symbol is determined on the transmitter side; the character string assigned to the symbol is transmitted to the receiver, the character string is converted into the corresponding symbol on the receiver side; the symbol is shown on a display device and at least one sound sequence assigned to the symbol is acoustically reproduced at the same time. |
1. Method for transmitting information from a transmitter to at least one receiver, characterized in that on the transmitter side a symbol (image) is selected, that on the transmitter side a character string associated with the symbol is determined, that the character string associated with the symbol is transmitted to the receiver, and that on the receiver side the character string is converted to the associated symbol, that the symbol is displayed on a display device and that simultaneously at least one audio sequence associated with the symbol is acoustically reproduced. 2. Method according to claim 1, characterized in that on the transmitter side the symbol is selected from a table of symbols. 3. Method according to one of the preceding claims claim 1, characterized in that on the transmitter side the symbol is fetched from a memory, in which memory the symbol was stored before being fetched. 4. Method according to claims 2 and 3, characterized in that on the transmitter side the table of symbols was previously stored in the memory. 5. Method according to claim 1, characterized in that on the transmitter side the symbol is selected using a microprocessor which is controlled by an input unit. 6. Method according to claim 1, characterized in that on the transmitter side the character string associated with the symbol is determined using a microprocessor. 7. Method according to claim 6, characterized in that on the transmitter side the character string is determined by the microprocessor using an algorithm that was previously stored in a memory. 8. Method according to claim 1, characterized in that on the transmitter side the character string is determined by using a table of symbols and associated character strings. 9. Method according to claim 6, characterized in that the table is fetched from memory by the microprocessor. 10. Method according to claim 1, characterized in that the character string associated with the symbol is a character string that corresponds to and/or identifies the symbol. 11. Method according to claim 1, characterized in that on the transmitter side an identification character is added before the character string is sent, which identification character designates the character string as a coded symbol, wherein the identification character is transmitted together with the character string. 12. Method according to claim 1, characterized in that on the receiver side the symbol associated with the received character string and the associated audio sequences is determined based on a table of character strings and associated symbols and audio sequences. 13. Method according to claim 1, characterized in that on the receiver side the symbol associated with the received character string and the audio sequence is fetched from a memory, in which memory they were stored together with the character string before being fetched. 14. Method according to claim 12, characterized in that on the receiver side the table that contains the character strings and associated symbols and audio sequences was previously stored in the memory. 15. Method according to claim 1, characterized in that on the receiver side the symbol associated with the received character string and the associated audio sequence are automatically determined by a microprocessor. 16. Method according to claim 15, characterized in that on the receiver side the symbol associated with the received character string and the audio sequence are determined by the microprocessor by using an algorithm previously stored in a memory. 17. Method according to claims 15, characterized in that on the receiver side an associated symbol and associated audio sequence are determined only for those received character strings that include an identification character, which identification character identifies the character string as a coded signal. 18. Method according to claim 1, characterized in that on the receiver side the determined symbol is displayed on a display. 19. Method according to claim 1, characterized in that on the receiver side the at least one audio sequence associated with the symbol is fixedly associated therewith. 20. Method according to claim 1, characterized in that the audio sequence reproduced on the receiver side can be affected from the transmitter side. 21. Method according to claim 1, characterized in that several audio sequences are stored on the receiver side, wherein at least one of the audio sequences can be called up from the transmitter side. 22. Device for transmitting information from a transmitter to at least one receiver, characterized in that a microprocessor, which cooperates with at least one memory means, is associated with the transmitter and the at least one receiver, and that a plurality of symbols (images) together with their respective associated character strings as well as at least one audio sequence associated with a symbol are stored in the at least one memory means, and with a display device for displaying the symbols and with an acoustic reproduction unit for reproducing the at least one audio sequence and with a transmitter and receiver device for transmitting the character strings. 23. Mobile telephone, characterized by a device according to claim 22. |
Powder inhaler |
An inhaler device includes an air conduit including a mouthpiece and a dosing means adapted to provide a dose of powder to the air conduit for entrainment in the stream of air. In the area downstream from the dosing means the wall of the air conduit is provided with a secondary air inlet extending to the direction of the mouthpiece such that the entry of secondary air occurs over an extended length of the air conduit downstream from the dosing means. |
1. An inhaler for administering powder by inhalation, comprising an air conduit defined by a wall, a stream of air being drawn through the air conduit upon inhalation by a user, the air conduit including a mouthpiece; a dosing means adapted to provide a dose of powder to the air conduit for entrainment in the stream of air; wherein, in the area downstream from the dosing means, the wall of the air conduit is provided with a secondary air inlet extending to the direction of the mouthpiece such that the entry of secondary air occurs over an extended length of the air conduit downstream from the dosing means. 2. An inhaler according to claim 1, wherein the secondary air inlet is in the form of an elongate slot. 3. An inhaler according to claim 1, wherein the secondary air inlet is in the form of a series of openings. 4. An inhaler according to claim 2, wherein the length of the secondary air inlet is at least 10% of the length of the air conduit downstream from the dosing means. 5. An inhaler according to claim 2, wherein the width of the secondary air inlet is about 1-60% of the inner diameter of the air conduit. 6. An inhaler according to claim 1, wherein the secondary air inlet is positioned adjacent to the dosing means. 7. An inhaler according to claim 2, wherein the length of the secondary air inlet is at least 20% of the length of the air conduit downstream from the dosing means. 8. An inhaler according to claim 2, wherein the length of the secondary air inlet is at least 30% of the length of the air conduit downstream from the dosing means. 9. An inhaler according to claim 2, wherein the width of the secondary air inlet is about 5-40% of the inner diameter of the air conduit. 10. An inhaler according to claim 2, wherein the width of the secondary air inlet is about 10-30% of the inner diameter of the air conduit. 11. An inhaler according to claim 4, wherein the width of the secondary air inlet is about 1-60% of the inner diameter of the air conduit. 12. An inhaler according to claim 4, wherein the width of the secondary air inlet is about 5-40% of the inner diameter of the air conduit. 13. An inhaler according to claim 4, wherein the width of the secondary air inlet is about 10-30% of the inner diameter of the air conduit. 14. An inhaler according to claim 2, wherein the secondary air inlet is positioned adjacent to the dosing means. 15. An inhaler according to claim 3, wherein the secondary air inlet is positioned adjacent to the dosing means. 16. An inhaler according to claim 4, wherein the secondary air inlet is positioned adjacent to the dosing means. 17. An inhaler according to claim 5, wherein the secondary air inlet is positioned adjacent to the dosing means. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to a device for dispensing of a powdered drug preparation by inhalation. In particular it relates to an inhaler device for aerosolizing a dose of powdered medicament for pulmonary delivery by inhalation. The device of the invention is useful, for example, in the treatment of asthma. Several types of dry powder inhalers (DPIs) have been developed, in which the inhalation air of the patient is used for dispersing the drug particles. The powdered medicament is arranged as unit dose containers, e.g. blister packs, cartridges or peelable strips, which are opened in an opening station of the device. Alternatively, the unit dose is measured from a powder reservoir by means of a dosing member, e.g. a dosing cup. Reservoir type powder inhalers comprising a medicament container and a dosing member for measuring and dispensing a unit dose are described e.g. in patent publications WO 92/00771 and WO 92/09322. In these devices, a series of dosing recesses are notched into the surface of a cylindrical or a conical metering member. When the metering member is rotated, the dosing recesses in turn will move first to a position in alignment with the powder container for being filled with a dose of powder falling from the powder container. Thereafter the filled dosing recess is moved to a position in alignment with the inhalation channel and the dose is inhaled directly from the dosing recess by a patient. To increase flowability and dosing accuracy of the powdered medicament, the fine drug particles of respirable size are typically mixed with coarser carrier particles to form an ordered mixture, wherein fine drug particles are attached to the larger carrier particles. This technique complicates the powder aerosolization process and, in particular, necessitates the break-up of the drug/carrier agglomerates before they enter the patient's mouth and throat, where individual large particles and agglomerated large and small particles tend to deposit. Effective aerosolization and deagglomeration of the powder requires that forces exerted on particles (e.g. forces between particles and surfaces of the device, between drug particles and carrier particles or between drug particles themselves) must be overcome such that high fine particle dose (FPD) of particles in the respirable size range is obtained. Various techniques have been used in DPIs to improve aerosolization and deagglomeration of drug powder during inhalation. These include turbines and impellers (U.S. Pat. No. 4,524,769 and U.S. Pat. No. 3,831,606) or other mechanical means (WO 98/26828), compressed gas (U.S. Pat. No. 5,349,947), cyclones (U.S. Pat. No. 5,301,666), electrostatic suspension or piezoelectric vibration (U.S. Pat. No. 3,948,264), venturis (WO 92/00771) and impactors (U.S. Pat. No. 5,724,959). In general, these DPIs have become more complicated and expensive. DPIs having a spot-like secondary air inlet in the air channel are described in U.S. Pat. No. 2,587,215, U.S. Pat. No. 5,383,850, EP 1106196, WO 94/08552, WO 94/11044 and U.S. Pat. No. 5,113,855. However, such secondary air inlets are not adapted to provide efficient deagglomeration of the drug powder during inhalation. Even though various DPIs have been described in the art, their ability to effectively aerosolize and deagglomerate the drug particles into a respirable particle size range is often limited or they use complicated techniques for increasing fine particle dose. Thus, there is a need for a dry powder inhaler, which is simple but capable of providing more efficient aerosolization and deagglomeration of particles. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides an inhaler for administering powder by inhalation, comprising an air conduit defined by a wall a stream of air being drawn through the air conduit upon inhalation by a user, the air conduit including a mouthpiece; a dosing means adapted to provide a dose of powder to the air conduit for entrainment in the stream of air; wherein in the area downstream from the dosing means the wall of the air conduit is provided with a secondary air inlet extending to the direction of the mouthpiece such that the entry of secondary air occurs over an extended length of the air conduit downstream from the dosing means. It has been found that the amount of fine drug particles dispersed from an inhaler and entering deeply into the lungs can be significantly increased, if the air conduit wall, downstream from the dosing means, is equipped with a secondary air inlet which extends longitudinally along the air conduit wall. The secondary air inlet typically is a longitudinal slot in the air conduit wall, extending parallel to the longitudinal axis of the air conduit. The entry of secondary air provides additional turbulence at the area of air entry resulting in more efficient deagglomeration of particles. Furthermore, as the inlet of secondary air is designed to extend over a significant portion of the air conduit length downstream from the dosing means, the dispersed powder is subjected to powerful turbulence longer, preferably over the whole length of the air conduit between the dosing means and the outlet (mouthpiece). The longitudinal slot is preferably positioned adjacent to the dosing means. |
Placing device and method for placing objects onto substrates |
A placing device and a method for placing objects onto substrates are suited for obtaining both very small as well as very large placement forces of the object exerted on the substrate. To this end, a gripper, by way of which the object can be picked up, is pretensioned with regard to a holder in a direction of placement. The pretensioning ensues via a first coupling element provided on the holder and via a second coupling element provided on the gripper. An electrical and/or magnetic field is generated between the first and the second coupling element and effects an action of force between the holder and the gripper. This enables a predetermined placement force to be attained when using the gripper to place the object. |
1. Placing device for placing objects on substrates, comprising: a moving holder; a gripper having a linear guided movement in a placing direction between two ends of a range of movement on the holder, wherein the gripper is adapted to lift the objects and move the objects to a substrate by moving the holder, wherein with the holder includes a first coupling element and the gripper includes a second coupling element and wherein at least one of an electrical and magnetic force is generated by at least one of an electrical and magnetic field acting between the first coupling element and second coupling element, such that the gripper is pretensioned in the placing direction against one of the ends of the range of movement. 2. Placing device in accordance with claim 1, wherein the first coupling element includes a coil through which an electric current flows, the second coupling element includes a permanent magnet and the placing force acting on the substrate when the object is being placed is controlled by controlling the strength of the current. 3. Placing device in accordance with claim 1, wherein the first coupling element includes a permanent magnet, the second coupling element includes a coil through which an electric current flows and the placing force acting on the substrate when the object is being placed is controlled by controlling the strength of the current. 4. Placing device in accordance with claim 1, wherein the first coupling element includes a first coil through which a first current flows, the second coupling element includes a second coil through which a second current flows and the placing force acting on the substrate when the object is being placed is controlled by controlling at least one of the strength of the current and the strength of the second current. 5. Placing device in accordance with claims 2, wherein the first coupling element and the second coupling element form a linear motor. 6. Placing device in accordance with claims 1, wherein the holder and the gripper are arranged coaxially relative to each other in the placing direction. 7. Placing device in accordance with claim 1, wherein a stop piece is fitted at each end of the range of movement, so that the gripper is provided with a guided movement between the stop pieces on the holder by way of a guiding device. 8. Placing device in accordance with claim 7, wherein a damping element is arranged at least one of at each stop piece and at each end area of the guiding device between the stop piece and the guiding device. 9. Placing device in accordance with claim 1, wherein each coupling element is designed in the form of a hollow cylinder. 10. Method for placing objects on substrates using a gripper and a holder moving in a placing device, comprising: linearly guiding the gripper on the holder in the placing direction using a guiding device between two ends of a range of movement, wherein the gripper projects from the holder in the placing direction; and pretensioning the gripper against one of the two ends of the range of movement, whereby a predetermined placing force is specified that acts on the gripper when placing the object, wherein control of the pretension of the gripper relative to the holder is effected by at least one of a controlled magnetic and an electrical field, and wherein the magnitude of the pretension is set corresponding to a preset value by controlling the at least one magnetic and electrical field; moving the holder in the placing direction onto at least one of the object and substrate for placing the gripper; and exerting a predetermined placing force, from the gripper, on the object when being placed on the at least one of the object and the substrate, while the gripper is moved against the placing direction relative to the holder until the holder is stopped. 11. Method in accordance with claim 10, wherein the controlled at least one of magnetic and electrical field is generated by coupling elements mounted on the holder and gripper, wherein at least one of permanent magnets and coils through which currents flow are used as coupling elements and wherein a coil through which current flows is used as at least one of the coupling elements. 12. Method in accordance with claims 10, wherein the placing force is selectively predetermined relative to the properties of the object. 13. Method in accordance with claim 12, wherein the guiding device of the gripper is placed against a stop piece formed at the proximal end of the range of movement before the placing on the object and wherein the placing force of the gripper on the object is being predetermined, in that the application is carried out using a force corresponding to the required placing force. 14. Method in accordance with claim 12, wherein the guiding device of the gripper is placed against a stop piece formed on the holder at the distal end of the range of movement before the placing of the object and wherein the placing force with which the holder is moved onto the object is specified by predetermining the drive force. 15. Method for lifting the objects from substrates by use of a gripper, wherein the gripper includes a linearly guided movement in a lifting direction on a holder by way of a guiding device between the two ends of a range of movement, and wherein the gripper projects from the holder against the lifting direction, the method comprising: moving the gripper to the distal end of the range of movement relative to the holder before lifting; a moving the holder from the substrate in the lifting direction to lift the object from the substrates; moving the gripper to the proximal end of the range of movement relative to the holder when lifting, with the acceleration occurring on the object equalized. 16. Placing device for placing objects on substrates, comprising: gripping means, movable in a placing direction among a range of movement on a holder, for moving the objects to a substrate in conjunction with the holder, wherein with the holder includes a first coupling element and the gripper includes a second coupling element; and means for generating at least one of an electrical and magnetic force by at least one of an electrical and magnetic field acting between the first coupling element and second coupling element, so as to pretension the gripper in a direction against an end of the range of movement. 17. Placing device in accordance with claim 16, wherein the first coupling element includes a coil through which an electric current flows, the second coupling element includes a permanent magnet and a force acting on the substrate when the object is being placed is controlled by controlling the strength of the current. 18. Placing device in accordance with claim 16, wherein the first coupling element includes a permanent magnet, the second coupling element includes a coil through which an electric current flows and a force acting on the substrate when the object is being placed is controlled by controlling the strength of the current. 19. Placing device in accordance with claim 16, wherein the first coupling element includes a first coil through which a first current flows, the second coupling element includes a second coil through which a second current flows and a force acting on the substrate when the object is being placed is controlled by controlling at least one of the strength of the current and the strength of the second current. 20. Placing device for placing objects on substrates, comprising: gripping means, movable in a placing direction among a range of movement on a holder, for moving the objects to a substrate in conjunction with the holder, wherein with the holder includes a first coupling element and the gripper includes a second coupling element; and means for pretensioning the gripper in a direction against an end of the range of movement, the means including at least one of an electrical and magnetic force acting between the first coupling element and second coupling element. 21. Placing device in accordance with claim 20, wherein the first coupling element includes a coil through which an electric current flows, the second coupling element includes a permanent magnet and a force acting on the substrate when the object is being placed is controlled by controlling the strength of the current. 22. Placing device in accordance with claim 20, wherein the first coupling element includes a permanent magnet, the second coupling element includes a coil through which an electric current flows and a force acting on the substrate when the object is being placed is controlled by controlling the strength of the current. 23. Placing device in accordance with claim 20, wherein the first coupling element includes a first coil through which a first current flows, the second coupling element includes a second coil through which a second current flows and a force acting on the substrate when the object is being placed is controlled by controlling at least one of the strength of the current and the strength of the second current. 24. Placing device in accordance with claim 3, wherein the first coupling element and the second coupling element form a linear motor. 25. Placing device in accordance with claim 4, wherein the first coupling element and the second coupling element form a linear motor. 26. Method in accordance with claim 11, wherein the placing force is selectively predetermined relative to the properties of the object. 27. Method in accordance with claim 26, wherein the guiding device of the gripper is placed against a stop piece formed at the proximal end of the range of movement before the placing on the object and wherein the placing force of the gripper on the object is predetermined, in that the application is carried out using a force corresponding to the required placing force. 28. Method in accordance with claim 26, wherein the guiding device of the gripper is placed against a stop piece formed on the holder at the distal end of the range of movement before the placing of the object and wherein the placing force with which the holder is moved onto the object is specified by predetermining the drive force. |
<SOH> BACKGROUND OF THE INVENTION <EOH>A known placing device, however, has a disadvantage that a variable force control of the placing force is possible only by determining that force with which the holder moves to the substrate. However, conventional drives for holders of this kind, and also the holders, have a large mass and therefore a large mass moment of inertia. The placing therefore does not take place at the placing force preset by the spring but instead by a considerably higher force that is exerted on the object and therefore also on the substrate. In addition to the mass moment of inertia of the holder, of the gripper and of the drive of the holder, the moment of inertia of the drive of the holder also has a negative effect in this case. Particularly when fitting electrical components on substrates, it is necessary to have available low placing forces for placing the components on the substrates with high accuracy. This is not possible with conventional devices or with a conventional method. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object of an embodiment of the invention is therefore to provide a placing device and a method for placing objects onto substrates by which very small placing forces can be attained at high accuracy. The object may be achieved by a placing device and/or by a placing method. By use of a placing device in accordance with an embodiment of the invention, it is possible to achieve a controlled dynamic effect between a holder and a gripper moving relative to the holder by use of an electrical, magnetic and/or electromagnetic field. By controlling the field it is possible to predetermine the force very accurately. The predetermined placing force is in this case also independent of the distance covered by the gripper relative to the holder when placing the objects onto the substrates. The controllable dynamic effect enables the placing force to be largely independent of the inertia effects of the placing device. During placing, only the moment of inertia of the gripper acts on the placing force. The moment of inertia of the holder and of the remaining placing device does not act on the placing force. Different embodiments of the invention are shown. In one case, it is possible to use electromagnets and/or permanent magnets as coupling elements that interact with each other to generate a dynamic force by way of a field between the gripper and holder of a placing device. At least one of the coupling elements in accordance with an embodiment of the invention is in this case an electromagnet, for example a coil through which electric current flows. By controlling current flowing through the coil, the placing force of the object onto the substrate can be directly controlled. If the relevant coupling element at the gripper is designed as an electromagnet, it is also possible to attain an even lower mass of the gripper. This effectively prevents peaks in the placing force. By this, it is also possible to control the force pattern not only statically but also dynamically corresponding to a required and predetermined force pattern. Furthermore, a damping element can be positioned in each case between a guiding device of the gripper that guides the gripper on the holder and between stop pieces provided on the holder. Thus, for example, before placing an object on a substrate this enables the gripper to be pretensioned against one of the damping elements by way of both coupling elements in such a way that the placing force or pattern of the placing force is determined only by the characteristic of the damping element. With the method for placing a gripper on objects on a substrate in accordance with an embodiment of the invention, the pattern of the placing force during the placing of the object on the substrate can be determined in advance with regard to both the static and dynamic time characteristics of the placing force. By controlling the magnetic and/or electrical fields, by which the dynamic effect between the holder and gripper that determines the placing force is attained, variable placing forces are possible over a large force range. By the method in accordance with an embodiment of the invention, it is possible both when placing objects on substrates to achieve predetermined placing forces, and also when lifting objects from substrates to effectively reduce acceleration peaks that act on the object. For this purpose, the gripper is moved to the holder before lifting objects from the substrates. In this position, the complete holder together with the gripper is lowered onto the object on the substrate and the object is lifted from the substrate by means of the gripper. During lifting, the gripper is moved against the direction of lift relative to the holder. This reduces the acceleration when lifting the object from the substrate. |
Diamine derivatives |
A compound represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2) -T1-Q4 (1) wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing. |
1. A compound represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 (1) wherein R1 and R2, independently of each other, represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; Q1 represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; Q2 represents a single bond, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic fused heterocyclic group which may be substituted; Q3 represents the following group: in which Q5 means an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, or a group —(CH2)—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or an integer of 1-3, and A means an oxygen atom, nitrogen atom, sulfur atom, —SO—, —SO2—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO2—NH—, and R3 and R4 are substituents on carbon atom(s), nitrogen atom(s) or a sulfur atom(s) of a ring comprising Q5 and are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3- to 6-membered heterocyclic carbonylalkyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may be substituted, N-alkylaminoacyl group, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group(s), alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group, or R3 and R4, together with each other, denote an alkylene group having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5 carbon atoms or carbonyldioxy group; Q4 represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; T0 represents a carbonyl or thiocarbonyl group; and T1 represents a carbonyl group, sulfonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)-A1-N(R′)—, in which A1 means an alkylene group having 1 to 5 carbon atoms, which may be substituted, and R″ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A2-C(═O)—, in which A2 means a single bond or alkylene group having 1 to 5 carbon atoms, group —C(═O)-A3-C(═O)—NH—, in which A3 means an alkylene group having 1 to 5 carbon atoms, group —C(═O)—C(═NORa)—N(Rb)—, group —C(═S)—C(═NORa)—N(Rb)—, in which Ra means a hydrogen atom, alkyl group or alkanoyl group, and Rb means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—N═N—, group —C(═S)—N═N—, group —C(═NORc)—C(═O)—N(Rd)—, in which Rc means a hydrogen atom, alkyl group, alkanoyl group, aryl group or aralkyl group, and Rd means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═N—N(Re)(Rf))—C(═O)—N(Rg)—, in which Re and Rf, independently of each other, mean a hydrogen atom, alkyl group, alkanoyl group or alkyl(thiocarbonyl) group, and Rg means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, or thiocarbonyl group; a salt thereof, a solvate thereof, or an N-oxide thereof. 2. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1, wherein the group Q4 in the formula (1) is a group selected from the group consisting of a phenyl group which may be substituted, a naphthyl group which may be substituted, an anthryl group which may be substituted, a phenanthryl group which may be substituted, a styryl group which may be substituted, a phenylethynyl group which may be substituted, a pyridyl group which may be substituted, a pyridazinyl group which may be substituted, a pyradinyl group which may be substituted, a furyl group which may be substituted, a thienyl group which may be substituted, a pyrrolyl group which may be substituted, a thiazolyl group which may be substituted, an oxazolyl group which may be substituted, a pyrimidinyl group which may be substituted, a tetrazolyl group which may be substituted, a thienylethenyl group which may be substituted, a pyridylethenyl group which may be substituted, an indenyl group which may be substituted, an indanyl group which may be substituted, a tetrahydronaphthyl group which may be substituted, a benzofuryl group which may be substituted, an isobenzofuryl group which may be substituted, a benzothienyl group which may be substituted, an indolyl group which may be substituted, an indolinyl group which may be substituted, an isoindolyl group which may be substituted, an isoindolinyl group which may be substituted, an indazolyl group which may be substituted, a quinolyl group which may be substituted, a dihydroquinolyl group which may be substituted, a 4-oxodihydroquinolyl group (dihydroquinolin-4-on) which may be substituted, a tetrahydroquinolyl group which may be substituted, an isoquinolyl group which may be substituted, a tetrahydroisoquinolyl group which may be substituted, a chromenyl group which may be substituted, a chromanyl group which may be substituted, an isochromanyl group which may be substituted, a 4H-4-oxobenzopyranyl group which may be substituted, a 3,4-dihydro-4H-4-oxobenzopyranyl group which may be substituted, a 4H-quinolizinyl group which may be substituted, a quinazolinyl group which may be substituted, a dihydroquinazolinyl group which may be substituted, a tetrahydroquinazolinyl group which may be substituted, a quinoxalinyl group which may be substituted, a tetrahydroquinoxalinyl group which may be substituted, a cinnolinyl group which may be substituted, a tetrahydrocinnolinyl group which may be substituted, an indolizinyl group which may be substituted, a tetrahydroindolizinyl group which may be substituted, a benzothiazolyl group which may be substituted, a tetrahydrobenzothiazolyl group which may be substituted, a benzoxazolyl group which may be substituted, a benzoisothiazolyl group which may be substituted, a benzoisoxazolyl group which may be substituted, a benzimidazolyl group which may be substituted, a naphthyridinyl group which may be substituted, a tetrahydronaphthyridinyl group which may be substituted, a thienopyridyl group which may be substituted, a tetrahydrothienopyridyl group which may be substituted, a thiazolopyridyl group which may be substituted, a tetrahydrothiazolopyridyl group which may be substituted, a thiazolopyridazinyl group which may be substituted, a tetrahydrothiazolopyridazinyl group which may be substituted, a pyrrolopyridyl group which may be substituted, a dihydropyrrolopyridyl group which may be substituted, a tetrahydropyrrolopyridyl group which may be substituted, a pyrrolopyrimidinyl group which may be substituted, a dihydropyrrolopyrimidinyl group which may be substituted, a pyridoquinazolinyl group which may be substituted, a dihydropyridoquinazolinyl group which may be substituted, a pyridopyrimidinyl group which may be substituted, a tetrahydropyridopyrimidinyl group which may be substituted, a pyranothiazolyl group which may be substituted,a dihydropyranothiazolyl group which may be substituted, a furopyridyl group which may be substituted, a tetrahydrofuropyridyl group which may be substituted, an oxazolopyridyl group which may be substituted, a tetrahydrooxazolopyridyl group which may be substituted, an oxazolopyridazinyl group which may be substituted, a tetrahydrooxazolopyridazinyl group which may be substituted, a pyrrolothiazolyl group which may be substituted, a dihydropyrrolothiazolyl group which may be substituted, a pyrrolooxazolyl group which may be substituted, a dihydropyrrolooxazolyl group which may be substituted, a thienopyrrolyl group which may be substituted, a thiazolopyrimidinyl group which may be substituted, a 4-oxo-tetrahydrocinnolinyl group which may be substituted, a 1,2,4-benzothiadiazinyl group which may be substituted, a 1,1-dioxy-2H-1,2,4-benzothiadiazinyl group which may be substituted, a 1,2,4-benzoxadiazinyl group which may be substituted, a cyclopentapyranyl group which may be substituted, a thienofuranyl group which may be substituted, a furopyranyl group which may be substituted, a pyridoxazinyl group which may be substituted, a pyrazoloxazolyl group which may be substituted, an imidazothiazolyl group which may be substituted, an imidazopyridyl group which may be substituted, a tetrahydroimidazopyridyl group which may be substituted, a pyrazinopyridazinyl group which may be substituted, a benzoisoquinolyl group which may be substituted, a furocinnolyl group which may be substituted, a pyrazolothiazolopyridazinyl group which may be substituted, a tetrahydropyrazolothiazolopyridazinyl group which may be substituted, a hexahydrothiazolopyridazinopyridazinyl group which may be substituted, an imidazotriazinyl group which may be substituted, an oxazolopyridyl group which may be substituted, a benzoxepinyl group which may be substituted, a benzoazepinyl group which may be substituted, a tetrahydrobenzoazepinyl group which may be substituted, a benzodiazepinyl group which may be substituted, a benzotriazepinyl group which may be substituted, a thienoazepinyl group which may be substituted, a tetrahydrothienoazepinyl group which may be substituted, a thienodiazepinyl group which may be substituted, a thienotriazepinyl group which may be substituted, a thiazoloazepinyl group which may be substituted, a tetrahydrothiazoloazepinyl group which may be substituted, a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, and a 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 3. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1 or 2, wherein the substituent(s) on the group Q4 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, aminoalkyl groups, a nitro group, hydroxyalkyl groups, alkoxyalkyl groups, a carboxyl group, carboxyalkyl groups, alkoxycarbonylalkyl groups, acyl groups, an amidino group, a hydroxyamidino group, linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, amidino groups substituted by a linear, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms, linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, linear or branched alkynyl groups having 2 to 6 carbon atoms, linear, branched or cyclic alkoxycarbonyl groups having 2 to 6 carbon atoms, a carbamoyl group, mono- or di-alkylcarbamoyl groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms on the nitrogen atom, mono- or di-alkylamino groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- or 6-membered nitrogen-containing heterocyclic groups. 4. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1, wherein the group Q4 represents any of the following groups: wherein R5 and R6, independently of each other, represent a hydrogen atom, cyano group, halogen atom, alkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, or phenyl group which may be substituted by a cyano group, hydroxyl group, halogen atom, alkyl group or alkoxy group, and R7 and R8, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R9 and R10, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R11, R12 and R13, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X1 represents CH2, CH, NH, NOH, N, O or S, and R14, R15 and R16, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X2 represents NH, N, O or S, X3 represents N, C or CH, X4 represents N, C or CH, and R17 and R18, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, and R19, R20 and R21, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5-Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 and R23, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, and R24 represents a hydrogen atom or alkyl group; wherein X6 represents O or S, and R25 and R26, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R27 and R28, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein E1 and E2, independently of each other, represent N or CH, and R29 and R30, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein Y1 represents CH or N, Y2 represents —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, and R31 and R32, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; and wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, and R34, R35 and R36, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. 5. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 1, wherein the group Q4 represents any of the following groups: wherein R5 and R6, independently of each other, represent a hydrogen atom or alkyl group, R7 represents a hydrogen atom, and R8 represents a hydrogen-atom, halogen atom, alkyl group or alkynyl group; wherein R9 represents a hydrogen atom, and R10 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R11 are R12 both represent hydrogen atoms, and R13 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X1 represents NH, NOH, N, O or S, R14 represents a hydrogen atom, halogen atom, acyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group or alkyl group, R15 represents a hydrogen atom or halogen atom, and R16 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X2 represents NH, O or S, X3 represents N, C or CH, X4 represents N, C or CH, R17 represents a hydrogen atom, and R18 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, R19 and R20 both represent hydrogen atoms, and R21 represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5-Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 represents a hydrogen atom, R23 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, and R24 represents a hydrogen atom; wherein X6 represents O, R25 represents a hydrogen atom, and R26 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R27 represents a hydrogen atom or halogen atom, and R28 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein E1 and E2, independently of each other, represent N or CH, R29 represents a hydrogen atom or halogen atom, and R30 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein Y1 represents CH or N, Y2 represents —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, R31 represents a hydrogen atom or halogen atom, and R32 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; and wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, R34 represents a hydrogen atom or halogen atom, R35 represents a hydrogen atom or halogen atom, and R36 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group. 6. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 3, wherein the group Q4 in the formula (1) is a 4-chlorostyryl, 4-fluorostyryl, 4-bromostyryl, 4-ethynylstyryl, 4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl, 4-ethynylphenylethynyl, 6-chloro-2-naphthyl, 6-fluoro-2-naphthyl, 6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo-2-naphthyl, 7-ethynyl-2-naphthyl, 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 7-ethynylcinnolin-3-yl, 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl, 7-ethynyl-2H-chromen-3-yl, 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl, 6-bromo-4-oxo-1,4-dihydroquinolin-2-yl, 6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl, 6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl, 6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl, 6-bromo-4-oxo-1,4-dihydro-quinazolin-2-yl, 6-ethynyl- 4-oxo-1,4-dihydroquinazolin-2-yl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromo-phenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 4-chloro-3-methylphenyl, 4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl, 4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-bromo-2-methylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dibromophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 6-chloro-3-pyridazinyl, 6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl, 6-ethynyl-3-pyridazinyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl, 5-ethynyl-2-thiazolyl, 2-chlorothieno[2,3-b]pyrrol-5-yl, 2-fluorothieno[2,3-b]pyrrol-5-yl, 2-bromothieno[2,3-b]-pyrrol-5-yl or 2-ethynylthieno[2,3-blpyrrol-5-yl group. 7. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 6, wherein the group Q1 in the formula (1) is a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted. 8. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 6, wherein the group Q1 in the formula (1) is a thienopyridyl group which may be substituted, tetrahydrothienopyridyl group which may be substituted, thiazolopyridyl group which may be substituted, tetrahydrothiazolopyridyl group which may be substituted, thiazolopyridazinyl group which may be substituted, tetrahydrothiazolopyridazinyl group which may be substituted, pyranothiazolyl group which may be substituted, dihydropyranothiazolyl group which may be substituted, furopyridyl group which may be substituted, tetrahydrofuropyridyl group which may be substituted, oxazolopyridyl group which may be substituted, tetrahydrooxazolopyridyl group which may be substituted, pyrrolopyridyl group which may be substituted, dihydropyrrolopyridyl group which may be substituted, tetrahydropyrrolopyridyl group which may be substituted, pyrrolopyrimidinyl group which may be substituted, dihydropyrrolopyrimidinyl group which may be substituted, oxazolopyridazinyl group which may be substituted, tetrahydrooxazolopyridazinyl group which may be substituted, pyrrolothiazolyl group which may be substituted, dihydropyrrolothiazolyl group which may be substituted, pyrrolooxazolyl group which may be substituted, dihydropyrrolooxazolyl group which may be substituted, benzothiazolyl group which may be substituted, tetrahydrobenzothiazolyl group which may be substituted, thiazolopyrimidinyl group which may be substituted, dihydrothiazolopyrimidinyl group which may be substituted, benzoazepinyl group which may be substituted, tetrahydrobenzoazepinyl group which may be substituted, thiazoloazepinyl group which may be substituted, tetrahydrothiazoloazepinyl group which may be substituted, thienoazepinyl group which may be substituted, tetrahydrothienoazepinyl group which may be substituted, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 9. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 8, wherein the substituent(s) on the group Q1 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, an amidino group, a hydroxyamidino group, C1-C6 alkyl groups, C3-C6 cycloalkyl C1-C6 alkyl groups, hydroxy-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxy C1-C6 alkyl group, a carboxyl group, C2-C6 carboxyalkyl groups, C2-C6 alkoxycarbonyl C1-C6 alkyl groups, amidino groups substituted by a C2-C6 alkoxycarbonyl group, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C2-C6 alkoxycarbonyl groups, amino C1-C6 alkyl groups, C1-C6 alkylamino C1-C6 alkyl groups, di(C1-C6 alkyl)amino C1-C6 alkyl groups, C2-C6 alkoxycarbonylamino-C1-C6 alkyl groups, C1-C6 alkanoyl groups, C1-C6 alkanoylamino C1-C6 alkyl groups, C1-C6 alkylsulfonyl groups, C1-C6 alkylsulfonylamino C1-C6 alkyl groups, a carbamoyl group, C1-C6 alkylcarbamoyl groups, N,N-di(C1-C6 alkyl)carbamoyl groups, C1-C6 alkylamino groups, di(C1-C6 alkyl)amino groups, 5- or 6-membered heterocyclic groups containing one of nitrogen, oxygen and sulfur or the same or different two atoms thereof, 5- or 6-membered heterocyclic-C1-C4 alkyl group, and 5- or 6-membered heterocyclic-amino C1-C4 alkyl group. 10. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 9, wherein the group T1 in the formula (1) is a carbonyl group, group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group. 11. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 9, wherein the group T1 in the formula (1) is a group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group. 12. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 3 to 6 carbon atoms or a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group. 13. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group. 14. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 3 to 6 carbon atoms, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group. 15. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s). 16. The compound, the salt thereof, the solvate thereof, or the. N-oxide thereof according to any one of claims 1 to 11, wherein the group Q3 in the formula (1) is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dimethylcarbamoyl group. 17. The compound according to claim 1, which is represented by the general formula (1): Q1 -Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 (1) wherein R1 and R2, independently of each other, represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; Q1 represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; Q2 represents a single bond, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic fused heterocyclic group which may be substituted; Q3 represents the following group: in which Q5 means a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or an integer of 1-3, and A means an oxygen atom, nitrogen atom, sulfur atom, —SO—, —SO2—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO2—NH—, and R3 and R4 are substituents on carbon atom(s), nitrogen atom(s) or a sulfur atom(s) of a ring comprising Q5 and are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a-substituent on the alkyl group(s), carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3- to 6-membered heterocyclic carbonylalkyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may be substituted, N-alkylaminoacyl group, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group(s), alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group, or R3 and R4, together with each other, denote an alkylene group having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5 carbon atoms or carbonyldioxy group; Q4 represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; T0 represents a carbonyl or thiocarbonyl group; and T1 represents a carbonyl group, sulfonyl group or thiocarbonyl group; a salt thereof, a solvate thereof, or an N-oxide thereof. 18. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 17, wherein the group Q1 is a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q2 is a single bond. 19. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 17 or 18, wherein the group Q1 is a thienopyridyl group which may be substituted, tetrahydrothienopyridyl group which may be substituted, thiazolopyridyl group which may be substituted, tetrahydrothiazolopyridyl group which may be substituted, thiazolopyridazinyl group which may be substituted, tetrahydrothiazolopyridazinyl group which may be substituted, pyranothiazolyl group which may be substituted, dihydropyranothiazolyl group which may be substituted, furopyridyl group which may be substituted, tetrahydrofuropyridyl group which may be substituted, oxazolopyridyl group which may be substituted, tetrahydrooxazolopyridyl group which may be substituted, pyrrolopyridyl group which may be substituted, dihydropyrrolopyridyl group which may be substituted, tetrahydropyrrolopyridyl group which may be substituted, pyrrolopyrimidinyl group which may be substituted, dihydropyrrolopyrimidinyl group which may be substituted, oxazolopyridazinyl group which may be substituted, tetrahydrooxazolopyridazinyl group which may be substituted, pyrrolothiazolyl group which may be substituted, dihydropyrrolothiazolyl group which may be substituted, pyrrolooxazolyl group which may be substituted, dihydropyrrolooxazolyl group which may be substituted, benzothiazolyl group which may be substituted, tetrahydrobenzothiazolyl group which may be substituted, thiazolopyrimidinyl group which may be substituted, dihydrothiazolopyrimidinyl group which may be substituted, benzoazepinyl group which may be substituted, tetrahydrobenzoazepinyl group which may be substituted, thiazoloazepinyl group which may be substituted, tetrahydrothiazoloazepinyl group which may be substituted, thienoazepinyl group which may be substituted, tetrahydrothienoazepinyl group which may be substituted, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 20. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 19, wherein the substituent(s) on the group Q1 are 1 to 3 substituent(s) selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, an amidino group, a hydroxyamidino group, C1-C6 alkyl groups, C3-C6 cycloalkyl C1-C6 alkyl groups, hydroxy-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxy C1-C6 alkyl groups, a carboxyl group; C2-C6 carboxyalkyl groups, C2-C6 alkoxycarbonyl-C1-C6 alkyl groups, amidino groups substituted by a C2-C6 alkoxycarbonyl group, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C2-C6 alkoxycarbonyl groups, amino C1-C6 alkyl groups, C1-C6 alkylamino C1-C6 alkyl groups, di(C1-C6 alkyl)amino C1-C6 alkyl groups, C2-C6 alkoxycarbonylamino C1-C6 alkyl groups, C1-C6 alkanoyl groups, C1-C6 alkanoylamino C1-C6 alkyl groups, C1-C6 alkylsulfonyl groups, C1-C6 alkylsulfonylamino C1-C6 alkyl groups, a carbamoyl group, C1-C6 alkylcarbamoyl groups, N,N-di(C1-C6 alkyl)carbamoyl groups, C1-C6 alkylamino groups, di(C1-C6 alkyl)amino groups, 5- or 6-membered heterocyclic groups containing one of nitrogen, oxygen and sulfur or the same or different two atoms thereof, 5- or 6-membered heterocyclic-C1-C4 alkyl group, and 5- or 6-membered heterocyclic-amino C1-C4 alkyl group. 21. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 20, wherein the group Q3 in the formula (1) is wherein Q5 means a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group. 22. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 in the formula (1) is a group selected from the group consisting of a naphthyl group which may be substituted, an anthryl group which may be substituted, a phenanthryl group which may be substituted, a styryl group which may be substituted, a phenylethynyl group which may be substituted, a thienylethenyl group which may be substituted, a pyridylethenyl group which may be substituted, an indenyl group which may be substituted, an indanyl group which may be substituted, a tetrahydronaphthyl group which may be substituted, a benzofuryl group which may be substituted, an isobenzofuryl group which may be substituted, a benzothienyl group which may be substituted, an indolyl group which may be substituted, an indolinyl group which may be substituted, an isoindolyl group which may be substituted, an isoindolinyl group which may be substituted, an indazolyl group which may be substituted, a quinolyl group which may be substituted, a dihydroquinolyl group which may be substituted, a 4-oxo-dihydroquinolyl group (dihydroquinolin-4-on) which may be substituted, a tetrahydroquinolyl group which may be substituted, an isoquinolyl group which may be substituted, a tetrahydroisoquinolyl group which may be substituted, a chromenyl group which may be substituted, a chromanyl group which may be substituted, an isochromanyl group which may be substituted, a 4H-4-oxobenzopyranyl group which may be substituted, a 3,4-dihydro-4H-4-oxobenzopyranyl group which may be substituted, a 4H-quinolizinyl group which may be substituted, a quinazolinyl group which may be substituted, a dihydroquinazolinyl group which may be substituted, a tetrahydroquinazolinyl group which may be substituted, a quinoxalinyl group which may be substituted, a tetrahydroquinoxalinyl group which may be substituted, a cinnolinyl group which may be substituted, a tetrahydrocinnolinyl group which may be substituted, an indolizinyl group which may be substituted, a tetrahydroindolizinyl group which may be substituted, a benzothiazolyl group which may be substituted, a tetrahydrobenzothiazolyl group which may be substituted, a benzoxazolyl group which may be substituted, a benzoisothiazolyl group which may be substituted, a benzoisoxazolyl group which may be substituted, a benzimidazolyl group which may be substituted, a naphthyridinyl group which may be substituted, a tetrahydronaphthyridinyl group which may be substituted, a thienopyridyl group which may be substituted, a tetrahydrothienopyridyl group which may be substituted, a thiazolopyridyl group which may be substituted, a tetrahydrothiazolopyridyl group which may be substituted, a thiazolopyridazinyl group which may be substituted, a tetrahydrothiazolopyridazinyl group which may be substituted, a pyrrolopyridyl group which may be substituted, a dihydropyrrolopyridyl group which may be substituted, a tetrahydropyrrolopyridyl group which may be substituted, a pyrrolopyrimidinyl group which may be substituted, a dihydropyrrolopyrimidinyl group which may be substituted, a pyridoquinazolinyl group which may be substituted, a dihydropyridoquinazolinyl group which may be substituted, a pyridopyrimidinyl group which may be substituted, a tetrahydropyridopyrimidinyl group which may be substituted, a pyranothiazolyl group which may be substituted,a dihydropyranothiazolyl group which may be substituted, a furopyridyl group which may be substituted, a tetrahydrofuropyridyl group which may be substituted, an oxazolopyridyl group which may be substituted, a tetrahydrooxazolopyridyl group which may be substituted, an oxazolopyridazinyl group which may be substituted, a tetrahydrooxazolopyridazinyl group which may be substituted, a pyrrolothiazolyl group which may be substituted, a dihydropyrrolothiazolyl group which may be substituted, a pyrrolooxazolyl group which may be substituted, a dihydropyrrolooxazolyl group which may be substituted, a thienopyrrolyl group which may be substituted, a thiazolopyrimidinyl group which may be substituted, a 4-oxo-tetrahydrocinnolinyl group which may be substituted, a 1,2,4-benzothiadiazinyl group which may be substituted, a 1,1-dioxy-2H-1,2,4-benzothiadiazinyl group which may be substituted, a 1,2,4-benzoxadiazinyl group which may be substituted, a cyclopentapyranyl group which may be substituted, a thienofuranyl group which may be substituted, a furopyranyl group which may be substituted, a pyridoxazinyl group which may be substituted, a pyrazoloxazolyl group which may be substituted, an imidazothiazolyl group which may be substituted, an imidazopyridyl group which may be substituted, a tetrahydroimidazopyridyl group which may be substituted, a pyrazinopyridazinyl group which may be substituted, a benzisoquinolyl group which may be substituted, a furocinnolyl group which may be substituted, a pyrazolothiazolopyridazinyl group which may be substituted, a tetrahydropyrazolothiazolopyridazinyl group which may be substituted, a hexahydrothiazolopyridazinopyridazinyl group which may be substituted, an imidazotriazinyl group which may be substituted, an oxazolopyridyl group which may be substituted, a benzoxepinyl group which may be substituted, a benzoazepinyl group which may be substituted, a tetrahydrobenzoazepinyl group which may be substituted, a benzodiazepinyl group which may be substituted, a benzotriazepinyl group which may be substituted, a thienoazepinyl group which may be substituted, a tetrahydrothienoazepinyl group which may be substituted, a thienodiazepinyl group which may be substituted, a thienotriazepinyl group which may be substituted, a thiazoloazepinyl group which may be substituted, a tetrahydrothiazoloazepinyl group which may be substituted, a 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, and a 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 23. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the substituent(s) on the group Q4 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, aminoalkyl groups, a nitro group, hydroxyalkyl groups, alkoxyalkyl groups, a carboxyl group, carboxyalkyl groups, alkoxycarbonylalkyl groups, acyl groups, an amidino group, a hydroxyamidino group, linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, amidino groups substituted by an linear, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms, linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, linear or branched alkynyl groups having 2 to 6 carbon atoms, linear, branched or cyclic alkoxycarbonyl groups having 2 to 6 carbon atoms, a carbamoyl group, mono- or di-alkylcarbamoyl groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms on the nitrogen atom(s), mono- or di-alkylamino groups substituted by linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- or 6-membered nitrogen-containing heterocyclic groups. 24. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 is wherein R5 and R6, independently of each other, represent a hydrogen atom, cyano group, halogen atom, alkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, or phenyl group which may be substituted by a cyano group, hydroxyl group, halogen atom, alkyl group or alkoxy group, and R7 and R8, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R9 and R10, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein R11, R12 and R13, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X1 represents CH2, CH, NH, NOH, N, O or S, and R14, R15 and R16, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X2 represents NH, N, O or S, X3 represents N, C or CH, X4 represents N, C or CH, and R17 and R18, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, and R19, R20 and R21, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5-Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 and R23, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, and R24 represents a hydrogen atom or alkyl group; wherein X6 represents O or S, and R25 and R26, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; or wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, and R34, R35 and R36, independently of one another, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. 25. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 represents any of the following groups: wherein R5 and R6, independently of each other, represent a hydrogen atom or alkyl group, R7 represents a hydrogen atom, and R8 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R9 represents a hydrogen atom, and R10 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein R11 are R12 both represent hydrogen atoms, and R13 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X1 represents NH, NOH, N, O or S, R14 represents a hydrogen atom, halogen atom, acyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group or alkyl group, R15 represents a hydrogen atom or halogen atom, and R16 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein X2 represents NH, O or S, X3 represents N, C or CH, X4 represents N, C or CH, R17 represents a hydrogen atom, and R18 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, excluding the cases where X3 and X4 are combinations of C and CH, and are both C or CH; wherein N indicates that 1 or 2 carbon atoms of the ring substituted by R19 have been substituted by a nitrogen atom, R19 and R20 both represent hydrogen atoms, and R21 represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group; wherein X5 represents CH2, CH, N or NH, Z1 represents N, NH or O, Z2 represents CH2, CH, C or N, Z3 represents CH2, CH, S, SO2 or C═O, X5- Z2 indicates that X5 and Z2 are bonded to each other by a single bond or double bond, R22 represents a hydrogen atom, R23 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group, and R24 represents a hydrogen atom; wherein X6 represents O, R25 represents a hydrogen atom, and R26 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group; or wherein numerals 1 to 8 indicate positions, each N indicates that any one of carbon atoms of positions 1 to 4 and any one of carbon atoms of positions 5 to 8 has been substituted by a nitrogen atom, R34 represents a hydrogen atom or halogen atom, R35 represents a hydrogen atom or halogen atom, and R36 represents a hydrogen atom, halogen atom, alkyl group or alkynyl group. 26. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 21, wherein the group Q4 is a 4-chlorostyryl, 4-fluorostyryl, 4-bromostyryl, 4-ethynylstyryl, 4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl, 4-ethynylphenylethynyl, 6-chloro-2-naphthyl, 6-fluoro-2-naphthyl, 6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo-2-naphthyl, 7-ethynyl-2-naphthyl, 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-fluoro-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-bromo-3-(N,N-dimethylcarbamoyl)indol-2-yl, 5-ethynyl-3-(N,N-dimethylcarbamoyl)indol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6- ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 7-ethynylcinnolin-3-yl, 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl, 7-ethynyl-2H-chromen-3-yl, 6-chloro-4-oxo-1,4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1,4-dihydroquinolin-2-yl, 6-bromo-4-oxo-1,4-dihydroquinolin-2-yl, 6-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl, 6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl, 6-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl, 6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl, 6-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl, 2-chlorothieno[2,3-b]pyrrol-5-yl, 2-fluorothieno[2,3-b]pyrrol-5-yl, 2-bromothieno[2,3-b]-pyrrol-5-yl or 2-ethynylthieno[2,3-b]pyrrol-5-yl group. 27. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 17 to 26, wherein T1 is a carbonyl group. 28. The compound according to claim 1, which is represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 (1) wherein R1 and R2, independently of each other, represent a hydrogen atom, hydroxyl group, alkyl group or alkoxy group; Q1 represents a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered heterocyclic group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; Q2 represents a single bond, a saturated or unsaturated, 5- or 6-membered divalent cyclic hydrocarbon group which may be substituted, a saturated or unsaturated, 5- to 7-membered divalent heterocyclic group which may be substituted, a saturated or unsaturated, divalent bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, divalent bicyclic or tricyclic fused heterocyclic group which may be substituted; Q3 represents the following group: in which Q5 means an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or an integer of 1-3, and A means an oxygen atom, nitrogen atom, sulfur atom, —SO—, —SO2—, —NH—, —O—NH—, —NH—NH—, —S—NH—, —SO—NH— or —SO2—NH—, and R3 and R4 are substituents on carbon atom(s) of a ring comprising Q5 and are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, cyano group, cyanoalkyl group, amino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, alkoxyimino group, hydroxyimino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylamino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, carbamoylalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, 3- to 6-membered heterocyclic carbonylalkyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminoalkyl group, alkylsulfonylaminocarbonyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkyloxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkyloxycarbonyl group, hydroxyacyl group, alkoxyacyl group, halogenoacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may be substituted, N-alkylaminoacyl group, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group(s), alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group, or R3 and R4, together with each other, denote an alkylene group having 1 to 5 carbon atoms, alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group having 1 to 5 carbon atoms or carbonyldioxy group; Q4 represents an aryl group which may be substituted, an arylalkenyl group which may be substituted, an arylalkynyl group which may be substituted, a heteroaryl group which may be substituted, a heteroarylalkenyl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; T0 represents a carbonyl or thiocarbonyl group; and T1 represents group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)—, group —C(═S)—C(═S)—N(R′)—, in which R′ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)-A1-N(R′)—, in which A1 means an alkylene group having 1 to 5 carbon atoms, which may be substituted, and R″ means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—NH—, group —C(═S)—NH—, group —C(═O)—NH—NH—, group —C(═O)-A2-C(═O)—, in which A2 means a single bond or alkylene group having 1 to 5 carbon atoms, group —C(═O)-A3-C(═O)—NH—, in which A3 means an alkylene group having 1 to 5 carbon atoms, group —C(═O)—C(═NORa)—N(Rb)—, group —C(═S)—C(═NORa)—N(Rb)—, in which Ra means a hydrogen atom, alkyl group or alkanoyl group, and Rb means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═O)—N═N—, group —C(═S)—N═N—, group —C(═NORc)—C(═O)—N(Rd)—, in which Rc means a hydrogen atom, alkyl group, alkanoyl group, aryl group or aralkyl group, and Rd means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, group —C(═N—N(Re)(Rf))—C(═O)—N(Rg)—, in which Re and Rf, independently of each other, mean a hydrogen atom, alkyl group, alkanoyl or alkyl(thiocarbonyl) group, and Rg means a hydrogen atom, hydroxyl group, alkyl group or alkoxy group, or thiocarbonyl group, a salt thereof, a solvate thereof, or an N-oxide thereof. 29. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 28, wherein the group Q1 is a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q2 is a single bond. 30. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to claim 28 or 29, wherein the group Q1 is a thienopyridyl group which may be substituted, tetrahydrothienopyridyl group which may be substituted, thiazolopyridyl group which may be substituted, tetrahydrothiazolopyridyl group which may be substituted, thiazolopyridazinyl group which may be substituted, tetrahydrothiazolopyridazinyl group which may be substituted, pyranothiazolyl group which may be substituted, dihydropyranothiazolyl group which may be substituted, furopyridyl group which may be substituted, tetrahydrofuropyridyl group which may be substituted, oxazolopyridyl group which may be substituted, tetrahydrooxazolopyridyl group which may be substituted, pyrrolopyridyl group which may be substituted, dihydropyrrolopyridyl group which may be substituted, tetrahydropyrrolopyridyl group which may be substituted, pyrrolopyrimidinyl group which may be substituted, dihydropyrrolopyrimidinyl group which may be substituted, oxazolopyridazinyl group which may be substituted, tetrahydrooxazolopyridazinyl group which may be substituted, pyrrolothiazolyl group which may be substituted, dihydropyrrolothiazolyl group which may be substituted, pyrrolooxazolyl group which may be substituted, dihydropyrrolooxazolyl group which may be substituted, benzothiazolyl group which may be substituted, tetrahydrobenzothiazolyl group which may be substituted, thiazolopyrimidinyl group which may be substituted, dihydrothiazolopyrimidinyl group which may be substituted, benzoazepinyl group which may be substituted, tetrahydrobenzoazepinyl group which may be substituted, thiazoloazepinyl group which may be substituted, tetrahydrothiazoloazepinyl group which may be substituted, thienoazepinyl group which may be substituted, tetrahydrothienoazepinyl group which may be substituted, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl group which may be substituted, or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl group which may be substituted. 31. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 30, wherein the substituent(s) on the group Q1 are 1 to 3 substituent(s) selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, an amidino group, a hydroxyamidino group, C1-C6 alkyl groups, C3-C6 cycloalkyl C1-C6 alkyl groups, hydroxy C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkoxy C1-C6 alkyl groups, a carboxyl group, C2-C6 carboxyalkyl groups, C2-C6 alkoxycarbonyl C1-C6 alkyl groups, amidino groups substituted by a C2-C6 alkoxycarbonyl group, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C2-C6 alkoxycarbonyl groups, amino C1-C6 alkyl groups, C1-C6 alkylamino C1-C6 alkyl groups, di(C1-C6 alkyl)amino C1-C6 alkyl groups, C2-C6 alkoxycarbonylamino-C1-C6 alkyl groups, C1-C6 alkanoyl groups, C1-C6 alkanoylamino C1-C6 alkyl groups, C1-C6 alkylsulfonyl groups, C1-C6 alkylsulfonylamino C1-C6 alkyl groups, a carbamoyl group, C1-C6 alkylcarbamoyl groups, N,N-di(C1-C6 alkyl)carbamoyl groups, C1-C6 alkylamino groups, di(C1-C6 alkyl)amino groups, 5- or 6-membered heterocyclic groups containing one of nitrogen, oxygen and sulfur or the same or different two atoms thereof, 5- or 6-membered heterocyclic-Cl-C4 alkyl group, and 5- or 6-membered heterocyclic-amino-C1-C4 alkyl group. 32. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 31, wherein the group Q3 is wherein Q5 means an alkylene group having 3 to 6 carbon atoms or a group —(CH2)m—CH2-A-CH2—(CH2)n—, in which m and n are independently of each other 0 or 1, and A has the same meaning as defined above, and R3 and R4 are independently of each other a hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, halogenoalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, acylalkyl group, acylamino group which may be substituted, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s), N-alkenylcarbamoyl group, N-alkenylcarbamoylalkyl group, N-alkenyl-N-alkylcarbamoyl group, N-alkenyl-N-alkylcarbamoylalkyl group, N-alkoxycarbamoyl group, N-alkyl-N-alkoxycarbamoyl group, N-alkoxycarbamoylalkyl group, N-alkyl-N-alkoxycarbamoylalkyl group, carbazoyl group which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3- to 6-membered heterocyclic carbonyl group which may be substituted, 3- to 6-membered heterocyclic carbonyloxyalkyl group which may be substituted, carbamoylalkyl group, carbamoyloxyalkyl group, N-alkylcarbamoyloxyalkyl group, N,N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), N,N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group(s), alkylsulfonylamino group, alkylsulfonylaminoalkyl group, oxo group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkyloxycarbonyl group, halogenoacyl group, N,N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N,N-dialkylcarbamoylacyl group, N,N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, aminocarbothioyl group, N-alkylaminocarbothioyl group, N,N-dialkylaminocarbothioyl group or alkoxyalkyl(thiocarbonyl) group. 33. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 31, wherein the group Q3 is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group(s). 34. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 31, wherein the group Q3 is wherein Q5 means an alkylene group having 4 carbon atoms, R3 is a hydrogen atom, and R4 is an N,N-dimethylcarbamoyl group. 35. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is a group selected from a phenyl group which may be substituted, a pyridyl group which may be substituted, a pyridazinyl group which may be substituted, a pyrazinyl group which may be substituted, a furyl group which may be substituted, a thienyl group which may be substituted, a pyrrolyl group which may be substituted, a thiazolyl group which may be substituted, an oxazolyl group which may be substituted, a pyrimidinyl group which may be substituted and a tetrazolyl group which may be substituted, 36. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 35, wherein the substituent(s) on the group Q4 are 1 to 3 substituents selected from a hydroxyl group, halogen atoms, halogenoalkyl groups, an amino group, a cyano group, aminoalkyl groups, a nitro group, hydroxyalkyl groups, alkoxyalkyl groups, a carboxyl group, carboxyalkyl groups, alkoxycarbonylalkyl groups, acyl groups, an amidino group, a hydroxyamidino group, linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, amidino groups substituted by a linear, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms, linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms, linear or branched alkynyl groups having 2 to 6 carbon atoms, linear, branched or cyclic alkoxycarbonyl groups having 2 to 6 carbon atoms, a carbamoyl group, mono- or di-alkylcarbamoyl groups substituted by a linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms on the nitrogen atom(s), mono- or di-alkylamino groups substituted by linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, and 5- or 6-membered nitrogen-containing heterocyclic groups. 37. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is wherein R27 and R28, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; wherein E1 and E2, independently of each other, represent N or CH, and R29 and R30, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group; or wherein Y1 represents CH or N, Y2 represents —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, and R31 and R32, independently of each other, represent a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group. 38. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is wherein R27 is a hydrogen atom or halogen atom, and R28 is a hydrogen atom, halogen atom, alkyl group or alkynyl group; wherein E1 and E2, independently of each other, represent N or CH, R29 is a hydrogen atom or halogen atom, and R30 is a hydrogen atom, halogen atom, alkyl group or alkynyl group; or wherein Y1 is CH or N, Y2 is —N(R33)—, in which R33 means a hydrogen atom or alkyl group having 1 to 6 carbon atoms, O or S, and R31 is a hydrogen atom or halogen atom and R32 is a hydrogen atom, halogen atom, alkyl group or alkynyl group. 39. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 34, wherein the group Q4 is a phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 4-chloro-3-methylphenyl, 4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl, 4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-bromo-2-methylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dibromophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 6-chloro-3-pyridazinyl, 6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl, 6-ethynyl-3-pyridazinyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl or 5-ethynyl-2-thiazolyl. 40. The compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 28 to 39, wherein the group T1 is a group —C(═O)—C(═O)—N(R′)—, group —C(═S)—C(═O)—N(R′)—, group —C(═O)—C(═S)—N(R′)— or group —C(═S)—C(═S)—N(R′)—. 41. A medicine comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 42. An activated blood coagulation factor X inhibitor comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 43. An anticoagulant comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 44. An agent for preventing and/or treating thrombosis or embolism, comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 45. An agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 46. A medicinal composition comprising the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40, and a pharmaceutically acceptable carrier. 47. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of a medicine. 48. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an activated blood coagulation factor X inhibitor. 49. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an anticoagulant. 50. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an agent for preventing and/or treating thrombosis or embolism. 51. Use of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40 for preparation of an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing. 52. A method for treating thrombosis or embolism, which comprises administering an effective amount of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 53. A method for treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing, which comprises administering an effective amount of the compound, the salt thereof, the solvate thereof, or the N-oxide thereof according to any one of claims 1 to 40. 54. A compound represented by the following general formula (4): HN(R1)-Q3-N(R2)-T1-Q4 (4) wherein R1, R2 and T1 have the same meanings as defined in claim 1, Q3 represents the following group: wherein Q5, R3 and R4 have the same meanings as defined in claim 1, and Q4 represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; a salt thereof, a solvate thereof, or an N-oxide thereof. 55. A compound represented by the following general formula (9): Q1-Q2-C(═O)—N(R1)-Q3-NHR2 (9) wherein Q2, R1 and R2 have the same meanings as defined in claim 1, Q1 represents a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q3 represents the following group: in which Q5, R3 and R4 have the same meanings as defined in claim 1, a salt thereof, a solvate thereof, or an N-oxide thereof. 56. A compound represented by the following general formula (4): HN(R1)-Q3-N(R2)-T1-Q4 (4) wherein R1, R2 and T1 have the same meanings as defined in claim 17, Q3 represents the following group: wherein Q5, R3 and R4 have the same meanings as defined in claim 17, and Q4 represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; and a salt thereof, a solvate thereof, or an N-oxide thereof. 57. A compound represented by the following general formula (9): Q1-Q2-C(═O)—N(R1)-Q3-NHR2 (9) wherein Q2, R1 and R2 have the same meanings as defined in claim 17, Q1 represents a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q3 represents the following group: in which Q5, R3 and R4 have the same meanings as defined in claim 17, a salt thereof, a solvate thereof, or an N-oxide thereof. 58. A compound represented by the following general formula (4): HN(R1)-Q3-N(R2)-T1-Q4 (4) wherein R1, R2 and T1 have the same meanings as defined in claim 28, Q3 represents the following group: wherein Q5, R3 and R4 have the same meanings as defined in claim 28, and Q4 represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a saturated or unsaturated, bicyclic or tricyclic fused hydrocarbon group which may be substituted, or a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted; and a salt thereof, a solvate thereof, or an N-oxide thereof. 59. A compound represented by the following general formula (9): Q1-Q2-C(═O)—N(R1)-Q3-NHR2 (9) wherein Q2, R1 and R2 have the same meanings as defined in claim 28, Q1 represents a saturated or unsaturated, bicyclic or tricyclic fused heterocyclic group which may be substituted, and Q3 represents the following group: in which Q5, R3 and R4 have the same meanings as defined in claim 28, a salt thereof, a solvate thereof, or an N-oxide thereof. |
<SOH> BACKGROUND ART <EOH>In unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after angioplasty and thrombus formation during extracorporeal circulation, hypercoagulable state is a pivotal factor. Therefore, there is a demand for development of excellent anticoagulants which have good dose responsiveness, long duration, low risk of hemorrhage and little side effects and fast onset of sufficient effects even by oral administration (Thrombosis Research, Vol. 68, pp. 507-512, 1992). Based on the research of anticoagulants worked through various mechanism of action, it is suggested that FXa inhibitors are promising anticoagulants. A blood coagulation system comprises a series of reactions that a great amount of thrombin is produced through an amplification process by multi-stage enzyme reactions to form insoluble fibrin. In an endogenous system, activated factor IX activates into factor X on a phospholipid membrane in the presence of activated factor VIII and calcium ions after multi-stage reactions subsequent to activation of a contact factor. In an exogenous system, activated factor VII activates factor X in the presence of a tissue factor. More specifically, the activation of the factor X into FXa in the coagulation system is a crucial reaction in the formation of thrombin. The activated factor X (FXa) limitedly decomposes prothrombin to produce thrombin in the both systems. Since the produced thrombin activates coagulation factors in the upper stream, the formation of thrombin is more amplified. As described above, since the coagulation system in the upper stream of FXa is divided into the endogenous system and the exogenous system, production of FXa cannot be sufficiently inhibited by inhibiting enzymes in the coagulation system in the upper stream of FXa, leading to production of thrombin. Since the coagulation system comprises self-amplification reactions, inhibition of the coagulation system can be more efficiently achieved by inhibiting FXa in the upper stream of thrombin than the inhibition of thrombin (Thrombosis Research, Vol. 15, pp. 617-629, 1979). An another excellent point of FXa inhibitors is a great difference between an effective dose in a thrombosis model and a dose elongating bleeding time in an experimental hemorrhagic model. From this experimental result, FXa inhibitors are considered to be anticoagulants having low risk of hemorrhage. Various compounds have been reported as FXa inhibitors. It is known that antithrombin III and antithrombin III dependent pentasacchrides can generally not inhibit prothrombinase complexes which play a practical role in the thrombus formation in a living body (Thrombosis Research, Vol. 68, pp. 507-512, 1992; Journal of Clinical Investigation, Vol. 71, pp. 1383-1389, 1983; Mebio, Vol. 14, the August number, pp. 92-97). In addition, they do not exhibit effectiveness by oral administration. Tick anticoagulant peptide (TAP) (Science, Vol. 248, pp. 593-596, 1990) and antistasin (AST) (Journal of Biological Chemistry, Vol. 263, pp. 10162-10167, 1988) isolated from mites or leeches, which are bloodsuckers, also inhibit Fxa and exhibit anti-thrombotic effects against venous thrombosis and arterial thrombosis. However, these compounds are high-molecular weight peptides and unavailable in oral administration. As described above, development of antithrombin III independent low-molecular weight FXa inhibitors which directly inhibit coagulation factors has been conducted. It is therefore an object of the present invention to provide a novel compound which has a potent FXa-inhibiting effect and exhibits an anti-thrombotic effect quickly, sufficiently and persistently by oral administration. |
Antigenic product displaying multiple copies of an epitope of a deposit-forming polypeptide involved in plaque-forming diseases and methods of using same |
The present invention relates to an antigenic product for inducing an immune response to a deposit-forming polypeptide, such as amyloid ss, which antigenic product is a multiple antigenic peptide (MAP) that contains multiple copies of an epitope of a deposit-forming polypeptide involved in a plaque-forming disease. This antigenic product can be formulated into an immunizing composition and used to elicit an immune response against a deposit-forming polypeptide involved in a plaque-forming disease or disorder. |
1. An antigenic product, comprising a dendritic polymer, built on a core molecule which is at least difunctional so as to provide branching and containing up to 16 terminal functional groups to which an antigenic peptide, that comprises an epitope of a deposit-forming polypeptide involved in plaque-forming disease or disorder, is joined by covalent bonds. 2. The antigenic product of claim 1, wherein said dendritic polymer contains eight terminal functional groups to which an antigenic peptide is joined. 3. The antigenic product of claim 1, wherein said dendritic polymer contains four terminal functional groups to which an antigenic peptide is joined. 4. The antigenic product of claim 1, wherein said dendritic polymer contains 16 terminal functional groups to which an antigenic peptide is joined. 5. The antigenic product of claim 1, wherein said deposit-forming polypeptide involved in a plaque-forming disease or disorder is amyloid β. 6. The antigenic product of claim 5, wherein the epitope of said amyloid β depositing-forming polypeptide comprises the amino acid sequence of SEQ ID NO:5. 7. The antigenic product of claim 5, wherein said antigenic peptide comprises the amino acid sequence of SEQ ID NO:1. 8. The antigenic product of claim 1, wherein said depositing-forming polypeptide involved in a plaque-forming disease or disorder is an abnormally folded form of prion protein PrP. 9. The antigenic product of claim 8, wherein said antigenic peptide comprises the amino acid sequence of SEQ ID NO:6. 10. The antigenic product of claim 1, wherein said core molecule is lysine. 11. The antigenic product of claim 1, wherein said core molecule is selected from the group consisting of aspartic acid and glutamic acid. 12. The antigenic product of claim 1, wherein said core molecule has the formula: wherein x, y and z are integers from 0 to 10 and at least one of x, y or z is 1. 13. The antigenic product of claim 12, wherein the integers x, y, and z sums up to a total in a range from 2 to 6 and the amino groups are separated by at least two methylene groups. 14. The antigenic product of claim 12, wherein said core molecule is selected from the group consisting of ornithine, nor-lysine, and amino alanine. 15. The antigenic product of claim 1, wherein said core molecule has the formula: H2N—CH2—(CH2)n—CH2—NH2 wherein n is an integer from 0 to 10. 16. The antigenic product of claim 1, wherein the antigenic peptide comprises two epitopes of said deposit-forming polypeptide. 17. The antigenic product of claim 16, wherein said two epitopes are identical. 18. The antigenic product of claim 17, wherein the antigenic peptide comprises the amino acid sequence of SEQ ID NO:4. 19. The antigenic product of claim 1, further comprising an avidin or streptavidin molecule, wherein one to four of said dendritic polymer are each bound to said avidin or streptavidin molecule via a biotin molecule conjugated to said dendritic polymer to form a complex with said avidin or streptavidin molecule. 20. The antigenic product of claim 19, wherein two or three of said dendritic polymer are bound to said avidin or streptavidin molecule. 21. The antigenic product of claim 1, further comprising a molecule having adjuvant properties joined to said dendritic polymer. 22. The antigenic product of claim 1, which is encapsulated in a liposome. 23. An immunizing composition, comprising the antigenic product of claim 1 and a pharmaceutically acceptable carrier, excipient, adjuvant, or auxiliary agent. 24. A method for eliciting an immune response against a deposit-forming polypeptide involved in a plaque-forming disease or disorder, comprising administering an immunizing effective amount of the antigenic product of claim 1 to a subject in need thereof. 25. The method of claim 24, wherein the occurrence, symptoms, or progression of said plaque-forming disease is treated or inhibited. 26. The method of claim 25, wherein said plaque-forming disease is Alzheimer's disease. 27. The method of claim 25, wherein said plaque-forming disease is selected from the group consisting of early onset Alzheimer's disease, late onset Alzheimer's disease, presymptomatic Alzheimer's disease, SAA amyloidosis, hereditary Icelandic syndrome, senility, and multiple myeloma. 28. The method of claim 25, wherein said plaque-forming disease is Creutzfeldt-Jakob disease. 29. The method of claim 25, wherein said plaque-forming disease is selected from the group consisting of Kuru, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia. 30. The method of claim 25, wherein said plaque-forming disease is selected from the group consisting of scrapie and bovine spongiform encephalitis. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to an antigenic product displaying antigenic peptides for inducing an immune response effective for prevention or reabsorption of deposits of a plaque-forming disease, such as against Aβ in Alzheimer's Disease. 2. Description of the Related Art The pathology of Alzheimer's disease (AD), the most studied conformational disease, is characterized primarily by extracellular amyloid plaques and intracellular neurofibrillary tangles (Price et al., 1993). The relationship between these lesions and the disease process has long been debated. The current dominant theory of AD etiology and pathogenesis is related to the amyloid cascade hypothesis (Hardy and Allsop, 1991; Selkoe, 1996; Hardy, 1997) which states that overproduction of amyloid β peptide (AβP or Aβ), or failure to clear this peptide, leads to AD primarily through amyloid deposition which is involved in the formation of neurofibrillary tangles. These lesions are then associated with cell death which is reflected in memory impairment, the hallmarks of this dementia (Goate, 1991; Hardy et al., 1998). Over a number of years the amyloid cascade hypothesis has gained strength through the observation that AD-causing mutations were identified in the amyloid-β-precursor protein (APP) and in the presenilin genes (Sherrington, et al, 1995; Levy-Lahad, et al., 1995). Many investigators have studied the propensity of AβP or its fragments to assemble into insoluble aggregates (for review see Maggio and Mantyh, 1996). Whereas the hydrophobic segment in the C-terminal domain of AβP develops a β-strand structure in aqueous solutions, independently of pH or temperature conditions, the N-terminal region can exhibit different conformations and solubility properties depending on environmental conditions (Hollossi et al., 1989, Soto et al., 1995; Barrow and Zagorsky, 1991). The N-terminal region seems to provide the means for interfibrillary contacts, as well as for interactions between a filament and other proteins or cellular structures that are often associated with β-amyloid depositions (Fraser et al., 1993). The N-terminal domain contains sequences that permit the existence of a dynamic equilibrium between the α-helix and the β-strand conformations. The perturbations of the equilibrium of various conformational states of the β-amyloid peptide can be caused by local pH changes, alterations of environmental hydrophobicity, or binding of other proteins (Soto et al., 1995; Kirschenbaum and Daggett, 1995). In Vitro Disaggregation and Prevention of Fibrillar β-Amylloid Amyloid filaments, similar to those found in amyloid plaques and cerebrovascular amyloid, can be assembled from chemically synthesized β-peptide under well-defined experimental conditions in vitro, and the effect on neural cells may be neurotoxic or neurotrophic, depending on the β-amyloid fibrillar state (Lorenzo and Yanker, 1990; Howlett et al., 1995). In vitro amyloid formation is a complex kinetic and thermodynamic process and the reversibility of amyloid plaque growth in vitro suggests a steady-state equilibrium between AβP in plaques and in solution (Maggio and Mantyh, 1996). The dependence of AβP polymerization on peptide-peptide interactions to form a β-pleated sheet fibril and the stimulatory influence of other proteins on the reaction suggest that amyloid formation may be subject to modulation. The essential question is how to prevent or, better, how to reverse the conformational changes that result in the formation of the β-sheet rich pathological protein conformer. Based on the conformational mimicry paradigm, it was hypothesized that short synthetic peptides, “minichaperones”, could be designed to specifically interact with the protein fragment that is undergoing the conformational changes and would be useful in stabilizing a desired conformation by adding specific residues that favor or disfavor the adoption of a particular structural motif (Soto, 1999). Recently, the immunological approach in the treatment of conformational diseases gained more attention. Antibody-antigen interactions involve conformational changes in both antibody and antigen that can range from insignificant to considerable. Binding of high affinity monoclonal antibodies (mAbs) to regions of high flexibility and antigenicity may alter the molecular dynamics of the whole antigen (Frauenfelder et al., 1979; Karplus and Petsko, 1990). Appropriate mAbs interact with strategic sites where protein unfolding is initiated, thereby stabilizing the protein and preventing further precipitation (Solomon and Balas, 1991; Katzav-Gozansky et al., 1996). Monoclonal antibodies were found to stabilize the conformation of an antigen against incorrect folding and recognize an incompletely folded epitope, inducing native conformation in a partially unfolded protein (Blond & Goldberg, 1987; Carlson. and Yarmush., 1992; Solomon & Schwartz, 1995). The laboratory of the present inventors investigated a large panel of mAbs against various regions of AβP and found that only site-directed mAbs toward the N-terminal regions of the β-peptide exhibit anti-aggregating properties, being able to prevent amyloid formation and dissolve already formed aggregates. Mabs 6C6 and 10D5 raised against the N-terminal region of the AβP (residues 1-28) can disaggregate Aβ fibrils and restore the peptide solubility. Binding of such antibodies interfered with noncovalent interactions between the amyloid fibrils and led to deterioration of amyloid fibrillar assembly into an amorphous form, even at molar ratios Ab/peptide 1:10-100. The prevention of peptide aggregation, as well as the solubilization of already formed aggregates, required an equimolar ratio of Ab/peptide, indicating the molecular level of these interactions (Solomon et al., 1996; Hanan and Solomon, 1996; Solomon et al., 1997). The neurotoxicity effect was found to correlate with the formation of Aβ aggregates and with the extent of the β-sheet structure (Pike et al., 1995). The effects of Aβ on MTT reduction on PC 12 cells are known to occur at concentrations below those that result in cell death (Sladowsky et al., 1993) and represent early markers of the metabolic compromise that ultimately leads to cellular degeneration. Binding of mAb 6C6 to fibrillar β-amyloid prevents the neurotoxicity of Aβ, as measured by MTT assay, due to disaggregation of β-amyloid fibrils. Antibody engineering methods were applied to minimize the size of mAbs (135-900 kDa) while maintaining their biological activity (Winter et al., 1994). These technologies and the application of the PCR technology to create large antibody gene repertoires make antibody phage display a versatile tool for isolation and characterization of single chain Fv (scFv) antibodies (Hoogenboom et al., 1998). The scFvs can be displayed on the surface of the phage for further manipulation or may be released as a soluble scFv (˜25 kd) fragment. The laboratory of the present inventors engineered an scFv which exhibits anti-aggregating properties similar to the parental IgM molecule (Frenkel et al., 2000a). For scFv construction, the antibody genes from the anti-APP IgM 508 hybridoma were cloned. The secreted antibody showed specific activity toward the AβP molecule in preventing its toxic effects on cultured PC 12 cells. Site-directed single-chain Fv antibodies are the first step towards targeting therapeutic antibodies into the brain via intracellular or extracellular approaches. The ability of single chain antibody 508F(Fv) to dissolve already formed βA fibrils suggests that only the antigen binding site of the antibodies is involved in modulation of β-amyloid conformation. N-Terminal EFRH Sequence of β-Amyloid Peptide is the Epitope of Anti-Aggregating Antibodies The existence of sequences that are kinetically involved in the folding process has previously been suggested in other systems and has been demonstrated by in vitro denaturation-renaturation experiments (Silen and Agard, 1989). Such sequences, which may play a role in the folding pathway, suggest the possibility that they serve not only for the folding process but may also contribute to conformational stability. Identifying the “aggregating epitopes” as sequences that are related to the sites where protein aggregation is initiated, and preparing monoclonal antibodies against these regions, facilitates understanding and prevention of the protein aggregation processes. The disaggregation as well as the prevention of amyloid was found to be dependent on the location of the epitopes on the β-amyloid and the binding characteristics of the mAbs (Solomon et al., 1997; Hanan and Solomon, 1996). The N-terminal region of the β-peptide was suggested to be the immunodominant site in AβP. Mabs raised against AβP fragments comprising amino acids 1-16 in the laboratory of the present inventors demonstrated that this region exhibits increased antigenic characteristics compared with the rest of the β-amyloid peptide. Using the phage-peptide library, composed of filamentous phage displaying random combinatorial peptides, the EFRH residues (SEQ ID NO:5) located at positions 3-6 of the N-terminal AβP were defined as the epitope of anti-aggregating antibodies within βAP (Frenkel et al., 1998). The EFRH (SEQ ID NO:5) epitope is available for antibody binding when β-amyloid peptide is either in solution or is an aggregate, and locking of this epitope by antibodies affects the dynamics of all the molecules, preventing self-aggregation as well as enabling resolubilization of already formed aggregates. Identification of the epitope of mAb 2H3, which cannot affect β-amyloid formation despite the fact that it binds to the N-terminal of β-amyloid peptide, shed light on the importance of this specific sequence region, defined as an anti-aggregating epitope, on the behavior of the whole APP molecule (Frenkel et al., 1999). Immunization Against β-Amyloid with EFRH Phage as Antigen Locking of the EFRH (SEQ ID NO:5) epitope by site-directed antibodies was found to modulate the dynamics of aggregation as well as resolubilization of already formed aggregates. However, such small synthetic peptides, consisting of antibody epitopes, are generally poor antigens requiring the chemical synthesis of a peptide and need to be coupled to a large carrier, but even then they may induce a low affinity immune response. A novel immunization procedure for raising anti-AβP antibodies, using as antigen the filamentous phages displaying only EFRH (SEQ ID NO:5) peptide, was developed in the laboratory of the present inventors. Filamentous bacteriophages have been used extensively in recent years for the ‘display’ on their surface of large repertoires of peptides generated by cloning random oligonucleotides at the 5′ end of the genes coding for the phage coat protein (Scott and Smith, 1990; Scott, 1992). As recently reported, filamentous bacteriophages are excellent vehicles for the expression and presentation of foreig peptides in a variety of biologicals (Greenwood et al., 1993; Medynski, 1994). Administration of filamentous phages induces a strong immunological response to the phage effects systems (Willis et al., 1993; Meola et al., 1995). Phage coat proteins pIII and pVIII are proteins that have been often used for phage display. The recombinant filamentous phage approach for obtaining specific peptide antigens has a major advantage over chemical synthesis, as the products obtained are the result of the biological fidelity of translational machinery and are not subject to the 70-94% purity levels common in the solid-phase synthesis of peptides. The phage presents an easily renewable source of antigen, as additional material can be obtained by growth of bacterial cultures. Immunization with the EFRH (SEQ ID NO:5) displaying phage may, in a short period of time, raise the high concentration of high affinity (IgG) antibodies able to prevent the formation of β-amyloid and to minimize further toxic effects. The level of antibody in the sera was found to be related to the number of peptide copies per phage (Frenkel et al., 2000b). The antibodies resulting from EFRH (SEQ ID NO:5) phage immunization are similar regarding their immunological properties to antibodies raised by direct injection with whole β-amyloid (Table 1). These antibodies recognize the full length β-peptide (1-40) and exhibit anti-aggregating properties as antibodies raised against whole Aβ peptide and/or β-amyloid (Frenkel et al., 2000b, 2001). The high immunogenicity of filamentous phages enables the raising of antibodies against self-antigens. Immunization of guinea pigs with EFRH (SEQ ID NO:5) phage as an antigen, in which the AβP sequence is identical to that in humans, resulted in the production of self-antibodies (Frenkel et al., 2001). TABLE 1 Competitive inhibition by various peptides within βAP of serum antibody raised against f88-EFRH compared to amyloid anti-aggregating antibody*. anti- MICE aggregating PEPTIDE RESIDUES SERUM antibody*. FRH (residues 4-6 of AβP) ˜10 −3 M 3 × 10 −3 M EFRH (residues 3-6 of AβP) and 6.0 × 10 −6 M 3 × 10 −6 M (SEQ ID NO: 5) DAEFRH (residues 1-6 of AβP) and 3.0 × 10 −6 M 8 × 10 −7 M (residues 1-6 of SEQ ID NO: 2) DAEFRHD (residues 1-7 of AβP) and 5.0 × 10 −6 M 9 × 10 −7 M (residues 1-7 of SEQ ID NO: 2) DAEFRHDSG (residues 1-9 of AβP) and 5.0 × 10 −6 M 1 × 10 −6 M (SEQ ID NO: 2) βAP(1-40) 3.0 × 10 −6 M 8 × 10 −7 M WVLD (SEQ ID NO: 3) Nd** Nd** *Frenkel et. al. 1998 **IC 50 value of less than 10 −2 M which cannot be detected by ELISA assay. The above data demonstrated that a recombinant bacteriophage displaying a self-epitope can be used as a vaccine to induce autoantibodies for disease treatment. Filamentous phages are normally grown using a laboratory strain of E. coli , and although the naturally occurring strain may be different, it is reasonable to assume that delivery of phage into the gut will result in infection of the natural intestinal flora. The laboratory of the present inventors has found that UV inactivated phages are as immunogenic as their infective counterparts. There is evidence of long lasting filamentous phages in the guts of the immunized animals that may explain the long lasting immune response found in pIII immunized mice (Zuercher et al., 2000). Due to the high antigenicity of the phage, administration can be given by the intranasal route, which is the easiest way for immunization without any use of adjuvant. As olfactory changes are proposed to play a role in Alzheimer's disease (Murphy, 1999) mucosal immunization is an effective induction of specific APP IgA antibodies for preventing local pathologic effect of the disease. The efficacy of phage-EFRH antigen in raising anti-aggregating β-amyloid antibodies (Solomon and Frenkel, 2000) versus whole β-amyloid shows that: a. the high immunogenicity of the phage enables production of high titer of IgG antibodies in a short period of weeks without need of adjuvant administration; b. self-expression of the antigen led to long-lasting immunization; c. the key role of the EFRH epitope in β-amyloid formation and its high immunogenicity led to anti-aggregating antibodies which recognize whole β-amyloid peptide, substituting the use of β-amyloid fibrils. Performance of Anti-β-Amyloid Antibodies in Transgenic Mice Model of AD Several laboratories have bred transgenic mice that produce Aβ and develop plaques and neuron damage in their brains (reviewed in Van Leuven, 2000). Although they do not develop the widespread neuron death and severe dementia seen in the human disease they are used as models for the study of Alzheimer's disease. Production of anti-β-amyloid antibodies, by immunization with the fibrillar Aβ of the mouse model of AD, led to inhibition of the formation of amyloid plaques and the associated dystrophic neurites in the mouse brain (Schenk et al., 1999), and raises the feasibility of vaccination against AD. However, because of the low immunogenicity of the Aβ fibrils, repeated antigen administration in the presence of adjuvant is required to obtain the anti-AβP antibodies necessary to affect plaque formation. Moreover, immunizing with toxic fibrils may induce more accumulation of the toxic amyloid itself. Another set of experiments showed that peripheral administration of antibodies against amyloid β-peptide was sufficient to reduce amyloid burden in the affected mice brains (Bard et al., 2000). Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of prexisting amyloid. Small amounts of such antibodies that cross the blood-brain barrier (0.1% of serum levels) might be sufficient to attenuate the further aggregation of these species into fibrillar Aβ dense-cored plaques. Because this pool of Aβ is small, and because antibodies to this form of Aβ might need only inhibit assembly of Aβ fibrils to have a functional effect, these antibodies need not necessarily cause large changes in total cerebral Aβ. These antibodies convert Aβ, the dense-cored plaques, to diffuse Aβ deposits. By comparison, of the antibodies tested only mAbs 10D5, 3D6 and PabAβ 1 - 42 , directed to the N-terminal regions of AβP demonstrated efficacy in vivo. In contrast, mAbs16C11, 21F12 and the control antibody TM2a, directed to other regions of AβP, were inactive. This result is consistent with the inability of these two antibodies to decorate plaques after in vivo administration and explains their inability to trigger plaque clearance (Bard et al., 2000). These in vivo data confirm the previous in vitro data (Solomon et al., 1996; 1997) that only antibodies directed to strategic epitopes, such as EFRH (SEQ ID NO:5), exhibit so-called ‘chaperone-like’ properties in dissolving the plaques and preventing their formation. These data also confirm that only a small amount of antibodies is necessary to interfere with non-covalent interactions between AβP fibrils to disaggregate them into an amorphous non-toxic configuration. Appropriate animal models were used to test the effects of anti-β-amyloid antibodies on both brain damage and the cognitive losses caused by Alzheimer's disease. Indeed, immunization with β-amyloid peptide improves learning and memory, as well as diminishing brain damage in mouse models (Janus et al., 2000; Morgan et al., 2000; Chen et al., 2000). The results support a previously observed reduction in the formation of amyloid deposits but they go further to show that immunization also offered the mice some protection from the ‘spatial’ learning deficits that normally accompany plaque formation. Both groups suggest that either a small or selective reduction in β-amyloid deposition may be sufficient to protect against dementia. Each group used different tests of spatial memory, in which mice had to swim to and mount a platform located invisibly beneath the surface of a pool of water. It is remarkable that both groups find that immunization with β-amyloid peptide offers significant protection from the age- and amyloid-dependent performance deficits seen in non-immunized controls. Evidence of learning defects that depend on age (and are associated with increasing accumulation of β-amyloid peptide) was proved in one of the main mouse models of Alzheimer's disease (Chen et al. 2000). The authors show that these defects can be distinguished from age-independent deficits, but only by careful experimental design and analysis. These findings indicate that Aβ overexpression and/or Aβ plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioral assays of the progressive cognitive deficits associated with Alzheimer's disease type pathologies. The mechanism by which anti-β-amyloid antibodies blocks learning and memory deficits is not understood. One possibility is that the antibodies neutralize Aβ in some restricted compartment or deplete a non-deposited form of Aβ (for example, a soluble form) that is responsible for the memory loss observed (Morgan et al., 2000). Recently, soluble Aβ has been proposed as the cause of synapse loss in APP transgenic mice, as some transgenic lines develop reductions in synaptophysin immunoreactivity in dentate gyrus without developing Aβ deposits. A second possibility is that microglia activated by the antibodies can clear the deposited Aβ, thereby permitting normal cognitive function. An alternative explanation is that immunization affects Aβ in a particular conformation, like β-sheet forms in protofibrils. The former is more likely because of oligomeric assemblies of Aβ in β-sheets (‘protofibrils’) as an immunogen, and the resultant antisera preferentially recognized β-sheet forms of Aβ. This is significant because monoclonal antibodies raised to Aβ epitopes that initiate fibril aggregation inhibit assembly of synthetic Aβ oligomeric protofibrils in vitro (Solomon et al., 1996). It is possible, therefore, that the antibodies induced in the transgenic mice may bind to β-sheet oligomeric aggregates and inhibit further assembly. This Aβ species is especially neurotoxic, a critical intermediary in fibrillogenesis and an accurate predictor of neurodegeneration. It is conceivable, however, that immunization might modulate Aβ metabolism through several distinct mechanisms, including destruction of Aβ by microglial phagocytosis (Schenk et al., 1999) or by effectory function of the antibody to activate Fc receptors able to remove the whole immunocomplex of fibrillar Aβ with site-directed antibodies. Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to applicant at the time of filing and does not constitute an admission as to the correctness of such a statement. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides an antigenic product that includes a multiple antigenic peptide (MAP) containing a plurality of an epitope of a deposit-forming polypeptide involved in a plaque-forming disease or disorder such as Alzheimer's disease. This MAP is based on a dendritic polymer built on a core molecule which is at least bifunctional/difunctional and containing up to 16 terminal functional groups to which an antigenic peptide having an epitope of a deposit-forming polypeptide is joined by covalent bonds. The present invention also provides an immunizing composition which contains the antigenic product according to of the present invention as an immunogen. Another aspect of the present invention further provides a method for inducing an immune response against a deposit-forming polypeptide involved in a plaque-forming disease by administering the antigenic product of the present invention. The immune response induced is effective for prevention, inhibition of formation, and/or reabsorption of deposits of a plaque-forming disease, such as against Aβ in Alzheimer's Disease. |
Convertible seat intended to accomodate an aircraft passenger |
A convertible seat to accommodate an aircraft passenger. The seat includes a frame, a sitting portion borne by the frame, a back, and a jointed footrest along the transverse edge of the sitting portion. The seat can change from a so-called seated position in which the back forms an angle with the sitting portion and its base is close to the rear transverse edge of the sitting portion to a so-called lying-down position in which it has a more or less level surface intended to accommodate a passenger in the lying down position. The frame is a fixed frame. At most two of the elements of the whole constituted by the sitting portion, the back, and the footrest form the more or less level surface of the seat in lying-down position. At least one additional berth is provided to cooperate with the sitting portion and/or the back and/or the footrest to form the more or less level surface intended to accommodate a passenger in the lying-down position. |
1-35. (Canceled). 36. A convertible seat configured to accommodate an aircraft passenger, comprising: a frame; a sitting portion borne by the frame; and a back, wherein the seat is configured to change from a seated position in which the back forms an angle with a horizontal sitting portion to a lying-down position in which the back has a more or less level surface configured to accommodate the passenger in the lying-down position, wherein the frame is a fixed frame, and the seat further comprises guiding means for changing the back from its seated position to a more or less horizontal position, and at least one additional berth cooperating with the back to form the more or less level surface configured to accommodate the passenger in the lying-down position. 37. A convertible seat according to claim 36, wherein the back has a base and a free end, and the guiding means for the seat comprises translatory guiding means for the base of the back. 38. A convertible seat configured to accommodate an aircraft passenger, comprising: a frame; a sitting portion borne by the frame; a back having a base and a free end; and a jointed footrest along a transverse edge of the sitting portion between a position more or less perpendicular to the sitting portion and a position in which a plane of the sitting portion and a plane of the footrest form an obtuse or straight angle, wherein the seat is configured to change from a seated position in which the back forms an angle with the sitting portion and its base is close to a rear transverse edge of the sitting portion, to a lying-down position in which the back has a more or less level surface configured to accommodate the passenger in the lying-down position, wherein the frame is a fixed frame, at most two of the sitting portion, the back, and the footrest form the more or less level surface of the seat in the lying-down position, and at least one additional berth is provided to cooperate with at least one of the sitting portion, the back, and the footrest to form the more or less level surface configured to accommodate the passenger in the lying-down position. 39. A convertible seat according to claim 38, wherein the back is a component element of the level surface configured to accommodate the passenger in the lying-down position. 40. A convertible seat according to claim 39, further comprising guiding means for guiding, at a time of changeover of the seat from the seated position to the lying-down position, the back such that the back in the lying-down position comes to cover most of a position of the sitting portion in the seated position. 41. A convertible seat according to claim 40, wherein the back in the lying-down position covers the sitting portion, and a selected edge of the back in the lying-down position comprising the base of the back and its free end is more or less superposed on one edge of the sitting portion. 42. A convertible seat according to claim 40, wherein the guiding means makes it possible, at the time of changeover of the seat from the seated position to the lying-down position, to guide the back according to a movement that is a combination of a longitudinal translation and a rotation around a more or less transverse horizontal axis. 43. A convertible seat according to claim 40, wherein the guiding means comprises on both sides of the frame at least one guiding rail to guide the base of the back, at the time of changeover from the seated position to the lying-down position, from a position corresponding to a rear of the sitting portion in the seated position to a position corresponding to a front of the sitting portion in the seated position. 44. A convertible seat according to claim 40, wherein the guiding means comprises on both sides of the frame at least one guiding rail to guide the base of the back, at the time of changeover from the seated position to the lying-down position, from a position corresponding to a rear of the sitting portion in the seated position to a drawn-back position such that when the base of the back is in the drawn-back position, a free end of the back is in a position corresponding to a front of the sitting portion in the seated position. 45. A convertible seat according to claim 36, wherein the back is joined to a fixed part of the seat by two levers located on both sides of the sitting portion, each lever is assembled pivoting around an axis more or less horizontal and transverse in relation to the sitting portion, and the back is assembled pivoting around a more or less horizontal transverse axis between the two levers. 46. A convertible seat according to claim 45, wherein the sitting portion is fastened to the frame, and the levers are assembled on lateral sides of the sitting position. 47. A convertible seat according to claim 45, wherein the levers are joined by a plate. 48. A convertible seat according to claim 45, wherein for each lever a distance between the axis of pivoting of the lever in relation to the sitting portion and the axis of pivoting of the back ranges between one-half and three-quarters of a length of the sitting portion, in a longitudinal direction. 49. A convertible seat according to claim 36, wherein the at least one of clamping and locking means holds the back in a turned-up position when the seat is in the seated position. 50. A convertible seat according to claim 36, wherein the additional berth cooperating with the back to form a level surface comprises a shelf configured to move between a more or less horizontal position as a continuation of the back toward a front when the seat is in the lying-down position and a more or less lateral vertical position in the seated position. 51. A convertible seat according to claim 50, wherein the more or less level bedding surface is made up of the back in the more or less horizontal position and the movable shelf. 52. A convertible seat according to claim 50, wherein in the lying-down position, the movable shelf cooperates with the back and a unit arranged facing and at a distance from the frame and a height of which corresponds more or less to that of the sitting portion of the seat. 53. A convertible seat according to claim 36, wherein the sitting portion is assembled pivoting around a transverse axis located close to its front edge to be configured to pivot approximately 180° and then be more or less a continuation of the back in the lying-down position. 54. A convertible seat according to claim 53, wherein the guiding means cooperating with the back to form a level surface comprises the pivoted sitting portion and a unit arranged facing and at a distance from the frame and a height of which corresponds more or less to that of the sitting portion of the seat. 55. A convertible seat according to claim 36, further comprising a footrest assembled pivoting around a transverse axis located close to its front edge to be configured to pivot approximately 90° and then be more or less a continuation of the back in the lying-down position. 56. A convertible seat according to claim 55, wherein the guiding means cooperating with the back to form a level surface comprises the pivoted footrest and a unit arranged facing and at a distance from the frame and a height of which corresponds more or less to that of the sitting portion of the seat. 57. A convertible seat according to claim 54, wherein the unit comprises a movable flap configured to pivot approximately 180° around a more or less transverse horizontal axis to form an additional berth. 58. A convertible seat according to claim 36, wherein the back incorporates an additional berth. 59. A convertible seat according to claim 58, wherein the additional berth incorporated into the back is assembled sliding in relation to the back. 60. A convertible seat according to claim 58, wherein the additional berth incorporated into the back is assembled pivoting in relation to the back. 61. A convertible seat according to claim 37, further comprising guiding means for making it possible, at a time of changeover of the seat from the seated position to the lying-down position, to guide the back according to a movement that is a combination of a longitudinal translation and a rotation around a more or less transverse horizontal axis such that the back and the sitting portion are a continuation of one another, the base of the back being situated facing a front transverse edge of the sitting portion. 62. Convertible seat according to claim 61, wherein the additional berth is a fixed portion assembled on the frame at the rear of the sitting portion and a continuation thereof. 63. Convertible seat according to claim 38, wherein the guiding means makes it possible, at a time of changeover of the seat from the seated position to the lying-down position, to guide the back according to a movement that is a combination of a longitudinal translation toward a rear and a rotation around a more or less transverse horizontal axis such that the back in the lying-down position of the seat is more or less perpendicular to a plane of the sitting portion of the seat. 64. Convertible seat according to claim 63, wherein the level surface configured to accommodate a passenger in lying-down position comprises the sitting portion of the seat, a fixed portion assembled on the frame at the rear of the sitting portion and as a continuation of the frame, and a shelf configured to move between a more or less horizontal position as a continuation toward the front of the sitting portion in the lying-down position and a more or less lateral vertical position in the seated position. 65. Convertible seat according to claim 36, further comprising a lateral wall surrounding a back of the seat. 66. Convertible seat according to claim 65, wherein a luggage compartment is provided between the lateral wall and the frame of the seat. 67. Convertible seat according to claim 66, wherein the luggage compartment comprises a lateral door. 68. Convertible seat according to claim 67, wherein the lateral door is a sliding door in a more or less vertical plane with aid of a more or less horizontal guiding rail borne by the lateral wall. 69. Module comprising a seat and a wall surrounding the seat at least partially, wherein the seat is a seat according to claim 36. 70. Aircraft for transport of passengers, comprising at least one convertible seat according to claim 36. |
Flexible wall for containing a fluid under pressure pipe comprising samd and use thereof |
A flexible hose having a wall comprising at least one interlayer (3, 4), to ensure mechanical strength, and two sealing layers (1, 2) lying one on each side of the interlayer. The wall includes an intermediate ply (5) of wires made of a shape-memory material that are arranged and oriented so that their contraction, when the temperature rises, opposes the mechanical deformation of the wall under the effect of pressure. |
1. A flexible wall for containing a pressurized fluid in a volume, this wall comprising at least one interlayer (3, 4), to ensure mechanical strength, and two sealing layers (1, 2) lying one on each side of the interlayer, characterized in that it includes an intermediate ply (5) of wires made of a shape-memory material that are arranged and oriented so that their contraction, when the temperature rises, opposes the mechanical deformation of the wall under the effect of pressure. 2. The wall according to claim 1, characterized in that the intermediate ply of wires made of a shape-memory material consists of a braid (5). 3. The wall according to claim 2, characterized in that electrical couplers (6, 10) are provided on opposed edges of the braid (5) in order to allow an electrical current to flow therein. 4. A hose, in particular for a hydraulic circuit, having a wall according to claims 1. 5. The hose according to claim 4, characterized in that the intermediate ply (5) of wires made of a shape-memory material comprises wires that are inclined with respect to the generatrices of the hose so as to have a component in the hoop direction. 6. The hose according to claim 5, characterized in that the intermediate ply of wires made of a shape-memory material consists of a braid (5). 7. The hose according to claim 6, characterized in that it includes an external layer (2) and an internal layer (1) made of an elastomer, especially a rubber, to ensure sealing. 8. The hose according to claim 6, characterized in that the braid (5) of wires made of a shape-memory material is between two layers (3, 4) ensuring mechanical strength, these being formed in particular by braids made of nylon yarn. 9. The hose according to claims 8, characterized in that it is provided at each end with a hydraulic and electrical coupler (6, 10) electrically connected with the corresponding end of the braid (5) made of a shape-memory material. 10. The hose according to claim 9, characterized in that the hydraulic and electrical coupler (6, 10) includes a prismatic extension (8) in which a housing (9) is provided, the end of the hose (T) passing through the said housing, and a connector (10) designed to fit into the housing (9), this connector comprising a metal blade (10a) having a recess (11) with flanks having cutting edges suitable for cutting layers (2, 4) of the hose (T) in order to come into contact with the braid (5). 11. The hose according to claim 10, characterized in that it is connected at each end to a terminal of an electrical power supply and in that the intensity of the electrical current flowing through the shape-memory braid is adjusted and controlled according to the absorption law desired for the hose. 12. A use of a hose according to claims 11, in a motor-vehicle braking system. 13. The use of a hose according to claims 11 in a calibrated-drop delivery system, characterized in that the delivery system (12) comprises, at the top, a reservoir (13) of pressurized liquid, in that a line (15) leaves the bottom of the reservoir in order to conduct the liquid into a closed volume (16), the cylindrical wall of which consists of a length of hose (T), a cover (17) and a bottom (18) closing off the ends of the volume (16), a solenoid valve (19) being mounted on the line (15) which runs through the cover (17) and a tubing (20) going from the bottom (18) as far as a nozzle (21), the axial ends of the braid made of a shape-memory material of the hose (T) being electrically connected to the terminals of an electrical power supply. 14. The use of a flexible wall according to one of claims 3 in a hydraulic accumulator, characterized in that the hydraulic accumulator (23) is bounded by a flexible wall (24) and in that opposed edges (24a, 24b) of the ply of wires made of a shape-memory material of this wall are connected to the terminals of an electrical power supply. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The invention relates more particularly, but not exclusively, to a flexible wall for containing a pressurized liquid in a motor-vehicle braking system. When a fluid, in particular a pressurized liquid, is imprisoned in a container, the wall defining this container is subjected to deformations due to the pressure of the fluid. These deformations cause variations in the internal volume of the container. For some applications, it is desirable to limit or control such volume variations. For example, in a hydraulic braking system, the volume deformation of the lines due to the pressure causes a liquid absorption phenomenon and less effective braking control. It is furthermore desirable to be able to estimate the value of the internal pressure from the deformation of the wall. |
<SOH> SUMMARY OF THE INVENTION <EOH>The object of the invention is, above all, to provide a wall composed of several layers which, while being more pressure-resistant, makes it possible to act against this deformation. According to the invention, a flexible wall for containing a pressurized fluid, especially for a motor-vehicle braking system, comprising at least one interlayer, to ensure mechanical strength, and two sealing layers lying one on each side of the interlayer, is characterized in that it includes an intermediate ply of wires made of a shape-memory material that are arranged and oriented so that their contraction, when the temperature rises, opposes the mechanical deformation of the wall under the effect of pressure. Preferably, the intermediate ply of wires made of a shape-memory material consists of a braid. Advantageously, electrical couplers are provided on opposed edges of the braid in order to allow an electrical current to flow therein for the purpose of heating it. The invention also relates to a hose, in particular for a hydraulic circuit, the wall of which is as defined above. The intermediate ply of wires made of a shape-memory material comprises wires that are inclined with respect to the generatrices of the hose so as to have a component in the hoop direction. This intermediate ply advantageously consists of a braid. Preferably, the hose includes an external layer and an internal layer made of an elastomer, especially a rubber, to ensure sealing. The ply of wires made of a shape-memory material may be between two layers ensuring mechanical strength, these being formed in particular by braids made of nylon yarn. A length of hose may be provided at; each end with a hydraulic coupler and with an electrical coupler electrically connected to the corresponding end of the braid made of a shape-memory material. Advantageously, the intensity of the electrical current flowing through the shape-memory braid is adjusted and controlled according to the absorption law desired for the hose. A calibrated-drop delivery system may be produced with such a hose. The delivery system comprises a reservoir of pressurized liquid placed above a length of hose whose braid made of a shape-memory material is connected, at each of its ends, to a terminal of an electrical voltage source; the lower end of the length of hose is connected to a drop delivery nozzle. By adjusting the intensity of the current flowing through the braid it is possible to vary the size of the drops delivered. A hydraulic accumulator may be bounded by a flexible wall according to the invention, the deformations of which are controlled by the intensity of the electrical current flowing through the layer made of a shape-memory material. The invention consists, apart from the arrangements mentioned above, of a number of other arrangements which will be explained in greater detail below with regard to illustrative examples which are described with reference to the drawings appended hereto. |
Hypoglycaemic peptides and methods of use thereof |
A peptide of the formula (Xaa)n1-Xaa1-His-Thr-Asp(Xaa)n2, wherein Xaa is any amino acid; Xaa1 is a hydrophobic amino acid, preferably Gly or Val; n1 is 0-10; and n2 is 0-10; and use thereof in regulating in vivo blood glucose levels in a human or other mammal, particularly in the treatment of Type 2 diabetes in a human. Preferably, the peptide is a tetrapeptide selected from Gly-His-Thr-Asp and Val-His-Thr-Asp. These hypoglycaemic peptides are isolated from human urine and they also have been chemically synthesized. |
1. A peptide of the formula: (Xaa)n1-Xaa1-His-Thr-Asp-(Xaa)n2 (SEQ ID NO:2) wherein Xaa is any amino acid; Xaa1 is a hydrophobic amino acid; n1 is 0-10; and n2 is 0-10. 2. A peptide according to claim 1, wherein the hydrophobic amino acid is selected from the group consisting of Gly, Ala, Leu, lie, Phe and Val. 3. A peptide according to claim 1, of the formula: (Xaa)n1-Gly-His-Thr-Asp-(Xaa)n2 or (SEQ ID NO: 3) (Xaa)n1-Val-His-Thr-Asp-(Xaa)n2 (SEQ ID NO: 4) wherein Xaa, n1, and n2 are as defined in claim 1. 4. A peptide according to claim 1, selected from: Gly-His-Thr-Asp; and (SEO ID NO: 5) Val-His-Thr-Asp. (SEO ID NO: 6) 5. A peptide according to any of claims 1 to 4, wherein the amino acids are in the L-form. 6. The isolated tetrapeptide Gly-His-Thr-Asp (SEQ ID NO:5), in substantially purified form. 7. A method of regulating in vivo blood glucose levels in a human or other mammal, which comprises administration to said human or other mammal of an effective amount of a peptide of the formula: (Xaa)n1-Xaa1-His-Thr-Asp-(Xaa)n2 (SEQ ID NO:2) wherein Xaa is any amino acid; Xaal is a hydrophobic amino acid; n1 is 0-10; and n2 is 0-10. 8. A method according to claim 7, wherein the peptide is a peptide of the formula: (Xaa)n1-Gly-His-Thr-Asp-(Xaa)n2 or (SEQ ID NO: 3) (Xaa)n1-Val-His-Thr-Asp-(Xaa)n2 (SEQ ID NO: 4) wherein Xaa, n1 and n2 are as defined in claim 7. 9. A method according to claim 7, wherein the peptide is selected from: Gly-His-Thr-Asp; and (SEQ ID NO: 5) Val-His-Thr-Asp. (SEQ ID NO: 6) 10. A method according to claim 7, wherein the regulation of in vivo blood glucose levels is for treatment of diabetes, particularly Type 2 diabetes, in a human. 11. Use of a peptide of the formula: (Xaa)n1-Xaa1-His-Thr-Asp-(Xaa)n2 (SEQ ID NO:2) wherein Xaa is any amino acid; Xaal is a hydrophobic amino acid; n1 is 0-10;and n2 is 0-10, in the manufacture of a composition for regulating in vivo blood glucose levels in a human or other mammal. 12. Use according to claim 11, wherein the peptide is a peptide of the formula: (Xaa)n1-Gly-His-Thr-Asp-(Xaa)n2 or (SEQ ID NO: 3) (Xaa)n1-Val-His-Thr-Asp-(Xaa)n2 (SEQ ID NO: 4) wherein Xaa, n1, and n2 are as defined in claim 11. 13. Use according to claim 11, wherein the peptide is selected from: Gly-His-Thr-Asp; and (SEQ ID NO: 5) Val-His-Thr-Asp. (SEQ ID NO: 6) 14. Use according to claim 11, wherein the composition is for treatment of diabetes, particularly Type 2 diabetes, in a human. 15. A pharmaceutical composition for regulating in vivo blood glucose levels in a human or other mammal, which comprises the peptide of the formula: (Xaa)n1-Xaa1-His-Thr-Asp-(Xaa)n2 (SEQ ID NO:2) wherein Xaa is any amino acid; Xaal is a hydrophobic amino acid; n1 is 0-10; and n2 is 0-10, together with one or more pharmaceutically acceptable carriers and/or diluents. 16. A composition according to claim 15, wherein the peptide is a peptide of the formula: (Xaa)n1-Gly-His-Thr-Asp-(Xaa)n2 or (SEQ ID NO: 3) (Xaa)n1-Val-His-Thr-Asp-(Xaa)n2 (SEQ ID NO: 4) wherein Xaa, n,1 and n2 are as defined in claim 15. 17. A composition according to claim 15, wherein the peptide is selected from: Gly-His-Thr-Asp; and (SEQ ID NO: 5) Val-His-Thr-Asp. (SEQ ID NO: 6) |
<SOH> BACKGROUND OF THE INVENTION. <EOH>Bibliographic details of the publications referred to hereinafter in this specification are collected at the end of the description. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia. Type 2 diabetes results in chronic hyperglycaemia, hyperinsulinemia, insulin resistance, impaired insulin secretion and the risk of cardiovascular complications (1-4). A recent report (5) showed that there are more than 150 million people worldwide who suffer from diabetes mellitus, among which over 90% of the people have Type 2 diabetes. Currently, apart from insulin, no molecule of biological origin has been found useful for the treatment and management of Type 2 diabetes without further aggravating hyperinsulinemia which is believed to be a potential cause for the development of diabetes complications. The isolation of a peptdic factor from human pituitary growth hormone extracts which accelerated glucose uptake in isolated rat hemi-diaphragms has been reported (6,7,8). The structure studies demonstrated that the molecule was a fragment of the amino terminal sequence of the growth hormone molecule. The amino-terminal region of human growth hormone (hGH) containing the amino acid sequence Leu-Ser-Arg-Leu-Phe-Asp-Asn-Ala (hGH 1-15) was found to enhance the actions of insulin in vitro and in vivo (9). This human growth hormone peptide was used for used for comparison in the course of the work on the urinary peptide factors. Hypoglycaemic action of a semi-purified fraction of human urine has also been observed (10,11). This urinary fraction acted only in the presence of insulin in enhancing glucose uptake, glycogen synthesis, and glycogen synthetase conversion to the active form in vitro and in vivo. The similar in vitro or in vivo biological effects of this urinary fraction led to the assumption that it was the hGH (6-13) fragment of human growth hormone, although no unequivocal evidence was obtained to establish its identity. Studies with ultrafiltration, ion exchange and gel filtration chromatography indicated that the isolate from human urine was a peptidic compound (11). In work leading to the present invention, the hypoglycaemic peptide in human urine has been isolated and purified, and its structure determined. In addition, this peptide has been chemically synthesised. The activity of both the isolated peptide and the chemically synthesised peptide have been examined in vitro and in vivo to demonstrate its insulin-potentiating effects by enhanced glucose uptake and glycogen synthesis in vitro and lowered blood glucose levels in vivo. In addition, peptide analogues of this isolated peptide have also been chemically synthesised, and certain of these analogues have also been shown to have significant biological effects on glucose metabolism both in vitro and in vivo. |
<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, the present invention provides a peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Xaa 1 -His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa is any amino acid; Xaa 1 is a hydrophobic amino acid; n 1 is 0-10; and n 2 is 0-10. In a preferred embodiment of this aspect of the invention, the present invention provides a peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Gly-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? or in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Val-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa, n 1 and n 2 are as defined above. Preferably, the peptide is a tetrapeptide selected from: Gly-His-Thr-Asp (hereinafter identified as UP-401); and Val-His-Thr-Asp (hereinafter identified as UP-402). In another aspect, the present invention provides the isolated tetrapeptide Gly-His-Thr-Asp, in substantially purified form. In a further aspect, the present invention provides a method of regulating in vivo blood glucose levels in a human or other mammal, which comprises administration to said human or other mammal of an effective amount of a peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Xaa 1 -His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa is any amino acid; Xaa 1 is a hydrophobic amino acid; n 1 is 0-10; and n 2 is 0-10. In preferred embodiments of this aspect of the invention, the peptide is a peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Gly-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? or in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Val-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa, n 1 and n 2 are as defined above. Preferably, in this aspect of the invention, the peptide is a tetrapeptide selected from: Gly-His-Thr-Asp (UP-401); and Val-His-Thr-Asp (UP-402). In yet another aspect, the present invention provides use of a peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Xaa 1 -His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa is any amino acid; Xaa 1 is a hydrophobic amino acid; n 1 is 0-10; and n 2 is 0-10, in the manufacture of a composition for regulating in vivo blood glucose levels in a human or other mammal. In preferred embodiments of this aspect of the invention, the peptide is a peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Gly-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? or in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Val-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa, n 1 and n 2 are as defined above. Preferably, in this aspect of the invention, the peptide is a tetrapeptide selected from: Gly-His-Thr-Asp (UP-401); and Val-His-Thr-Asp (UP-402). The present invention also provides a pharmaceutical composition for regulating in vivo blood glucose levels in a human or other mammal, which comprises the peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Xaa 1 -His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa is any amino acid; Xaa 1 is a hydrophobic amino acid; n 1 is 0-10; and n 2 is 0-10, together with one or more pharmaceutically acceptable carriers and/or diluents. In preferred embodiments of this aspect of the invention, the peptide is a peptide of the formula: in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Gly-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? or in-line-formulae description="In-line Formulae" end="lead"? (Xaa) n1 -Val-His-Thr-Asp-(Xaa) n2 in-line-formulae description="In-line Formulae" end="tail"? wherein Xaa, n 1 and n 2 are as defined above. Preferably, in this aspect of the invention, the peptide is a tetrapeptide selected from: Gly-His-Thr-Asp (UP-401); and Val-His-Thr-Asp (UP-402). Preferably, in the peptides of this invention the amino acids are in the L-form, however the present invention also extends to peptides in which one or more of the amino acids are in the D-, α- or β-form. Throughout this specification, unless the context requires otherwise, the word “comprise”, and or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. |
Peptoid compounds |
The invention relates to new peptoid compounds of formula (I), as well as their use in the treatment of bacterial infections, such as those caused by vancomycin resistant microorganisms, and to compositions thereof. |
1. A compound of the formula (I): wherein A is an aromatic or heteroaromatic ring system or partially or fully reduced derivatives thereof; Q is hydrogen, C1-C12 straight chain, branched or cyclic alkyl substituted with one or more hydroxy groups, or a mono- or di-saccharide moiety; Z is —CR10R11—, —NR12—, —C(O)O—, —C(O)NR12— or —O—, where R10 and R11 are independently selected from hydrogen, hydroxy, C1-C6 alkyl, C6-C10 aryl, C1-C6 alkoxy and —N(R13)2 and where each R13 is independently selected from hydrogen and C1-C6 alkyl, and where R12 is selected from hydrogen and C1-C6 alkyl; R1 is selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —N(R13)2 and —N(R12)—COR14; where R12 and R13 are as defined above, and where R14 is selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy and —NR12; R2 is selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —N(R13)2 and —N(R12)—COCHR2aR2b; where R2a and R2b are selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —N(R13)2 and —N(R12)—COR14; where R12, R13 and R14 are as defined above; R3, R4 and R5 are independently selected from hydrogen, C1-C6 alkyl and α side chains of α-amino acids or their enantiomers or their derivatives; R6 is —CO2R15, —CONHR16, —CONHOR16, —CONHNHR16, —SO2N(R16)2, —SO2R17 or —P(O)(OR18)(OR18) where each R15, R16, R17 and R18 is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl and C7-C10 arylalkyl; B is an α-amino acid residue, a β-amino acid residue or an α,α-disubstituted amino acid residue, such residue forming amide linkages with the adjacent molecules; W is —O— or CR10R11 where R10 and R11 are as defined above; Y is an optionally substituted amino group, a moiety containing an optionally substituted amino group or a salt thereof; is a single or double bond; R7 and R8a are hydrogen or are absent if is a double bond; and R8b and R9 are hydrogen, and X is selected from (CR10R11)u, —(CR10R11)u—CH═CH—, —NR12(CR10R11)u—, —(CR10R11)uNR12, —O(CR10R11)u—, —(CR10R11)uO— or —O(CR10R11)CH═CH— where R10, R11 and R12 are as defined above; or R8b and R9 together form a covalent bond between X and the carbon to which R8b is attached, and X is selected from (CR10R11)x, —NR12(CR10R11)x—, —(CR10R11)xNR12—, —O(CR10R11)x— or —(CR10R11)xO—, where R10, R11 and R12 are as defined above; n, m, r and t are independently selected from 0 or 1; s is an integer selected from 0 to 3; p is an integer selected from 0 to 6, provided that when W is —O—, p is at least 1; and u, x and q are independently selected from 0 to 4; and salts and pharmaceutically acceptable derivatives thereof. 2. A compound according to claim 1 having the formula (1A): wherein A, Q, Z, R2a, R2b, R3, B, W, Y, R4, R5, R6, R7, R8a, R8b, R9, X, r, s, n, m, p, q and t are as defined above. 3. A compound according to claim 1 wherein A is an optionally substituted monoaryl group or an optionally substituted fused di- or poly aryl or heteroaryl group wherein the optional substituents are selected from one or more of C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, C1-C6 dialkylamino, halo, C1-C6 haloalkyl (for example trifluoromethyl) nitro, nitrile, sulfonylsulfonamide, alkylsulfonyl, arylsulfonyl, or carboxy groups. 4. A compound according to claim 3 wherein A is optionally substituted phenyl, fluorene, phenanthrene, indole, indazole, benzimidazole, carbazole, quinoline, isoquinoline, dibenzazepine and dibenzazocine. 5. A compound according to claim 4 wherein A is optionally substituted 1,4-linked phenyl, 1,3-linked fluorene or 3,6-linked 9H carbazole, 6. A compound according to claim 1 wherein A is an optionally substituted bridged or bonded di- or poly aryl or heteroaryl group or their atropisomers wherein the optional substituents are selected from one or more of C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, C1-C6 dialkylamino, halo, C1-C6 haloalkyl (for example trifluoromethyl) nitro, nitrile, sulfonylsulfonamide, alkylsulfonyl, arylsulfonyl, or carboxy groups. 7. A compound according to claim 6 wherein A is optionally substituted bi-phenyl or bi-naphthyl or their atropisomers. 8. A compound according to claim 7 wherein A is a 3,3′-linked 2,2′-dimethoxy-1,1′-binaphthyl group or a 2,2′-linked 1,1′-binaphthyl group. 9. A compound according to claim 1 wherein Q is hydrogen. 10. A compound according to claim 1 wherein Z is —CH2— or —O—. 11. A compound according to claim 1 wherein s is 0, 1 or 2 and each R1 is independently selected from hydrogen or hydroxy. 12. A compound according to claim 1 wherein R2 is hydrogen, hydroxy or N(R12)COR2aR2b. 13. A compound according to claim 1 wherein R3 is hydrogen. 14. A compound according to claim 1 wherein B is absent or a D- or L-alanyl residue, a D-lysinyl residue, a D-arginyl residue or a D-homoarginyl residue. 15. A compound according to claim 1 wherein Y is selected from a group consisting of:—N(R13)2, —N(R12)—COR14, —NR13C(═NR13)N(R13)2, —C(═NR13)N(R13)2, —NR13C(═O)N(R13)2, —N═NC(═NR13)N(R13)2, NR13NR13C(═O)NHN(R13)2, —NR13C(═)NHN(R13)2, wherein R12 and each R13 is independently selected from hydrogen and C1-C6 alkyl and R14 is selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy and NR12; and a 3-8-membered N-containing cyclogroup. 16. A compound according to claim 15 wherein Y is an unsubstituted amino group or a guanidino group, or their hydrochloride salts. 17. A compound according to claim 1 wherein R6 is CO2R15 where R15 is C1-C6alkyl or C7-C10arylalkyl. 18. A compound according to claim 17 wherein R15 is methyl or benzyl. 19. A compound according to claim 1 wherein R8b and R9 are hydrogen and X is —(CR10R11)u—, —O(CH2)u—, —CH═CH—, —O(CR10R11)CH═CH— or —CR10R11—CH═CH— where R10 and R11 are hydrogen and u is an integer selected from 2 or 3. 20. A compound according to claim 1 wherein R8b and R9 together form a covalent bond between X and the carbon to which R8b is attached and X is —(CR10R11)x— or —O(CH2)x— wherein R10 and R11 are hydrogen and x is an integer from 1 to 4. 21. A compound according to claim 1 selected from benzyl (aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononanoate (aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene hydrochloride (aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane hydrochloride (aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(tert-butoxy)carbonyl]amino}butyl)-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene methyl (aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoate hydrochloride (aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene hydrochloride (aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene hydrochloride (aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane hydrochloride Methyl (2S,5S,8R/S)-8-acetamido-2-allyl-9-[6-allyl-9-tert-butoxycarbonyl-9H-carbazol-3-yl]-3,6-diaza-5-{3-[(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-guanidino]propyl}-4,7-dioxononanoate 6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S) 6-Acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) 6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) 6-Acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S) 6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9S,12S) Methyl (2S,5S,8R/S)-8-Acetamido-5-(4-aminobutyl)-3,6-diaza-9-{9-[(4-methoxyphenyl)methyl]-6-propyl-9H-carbazol-3-yl}-4,7-dioxo-2-propylnonanoate hydrochloride 6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl (9R,12S) methyl (aR/S,2S,5R)-2-allyl-5-[2-({[(2′-allyloxy-1,1′-binaphthoxymethyl]carbonyl}amino)-3-aza-9-guanidino-4-oxononanoate hydrochloride (aR/S,7R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-10-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-ene hydrochloride methyl (aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-5-(4-aminobutyl)-3,6-diaza-4,7-dioxodecanoate hydrochloride methyl (aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-3,6-diaza-5-(4-guanidinobutyl)-4,7-dioxodecanoate hydrochloride (aR/S,9R,12S)-8,11-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-ene hydrochloride 22. A composition comprising a compound of formula (I), salts or pharmaceutically acceptable derivatives thereof according to claim 1 together with one or more pharmaceutically acceptable carriers or adjuvants. 23. A method of treating a bacterial infection in a mammal comprising administering an effective amount of a compound of formula (I), salts or pharmaceutically acceptable derivatives thereof according to claim 1. 24. A method according to claim 24 where the mammal is a human. 25. A method according to claim 24 wherein the bacterial infection is caused by Gram positive bacteria. 26. A method according to claim 26 wherein the bacterial infection is caused, by vancomycin resistant Staphylococcus aureas. 27. The use of a compound of formula (I) according to claim 1 in the manufacture of a medicament for treating bacterial infections. |
Body with improved surface properties |
The invention describes surfaces as well as combinations of surfaces which possess at least two different structure implementations. These structure formations can consist of any combinations of directed and non-directed structures, with their main formation dimensions being in the micro-meter range. By means of combinations of the surface structuring it is possible both, to improve the benefits of the individual structures and to fulfil new tasks. |
1. Body, with a plurality of surfaces, which get in contact with different media, wherein a first surface is provided with a first surface structuring in the micrometer range and/or in the nanometer range, wherein the first surface structuring is adapted to a first medium which gets in contact with the first surface, wherein a second surface is provided with a second surface structuring in the micrometer range and/or in the nanometer range, wherein the second surface structuring is adapted to a second medium which gets in contact with the second surface. 2. Body in accordance with claim 1, where the first surface structuring is developed as a direction-controlled surface structuring. 3. Body in accordance with claim 2, where the direction-controlled surface structuring possesses protrusions in the shape of ribs and recesses, wherein the protrusions are essentially aligned parallel to each other, and wherein the recesses are essentially aligned parallel to each other. 4. Body in accordance with one of the claims 1 to 3, where the first surface structuring possesses scale-shaped protrusions. 5. Body in accordance with claim 3 or 4, where at least a part of the surface of the protrusions and/or at least a part of the surface of the recesses is hydrophobic. 6. Body in accordance with one of the claims 1 to 5, where the second surface structuring is developed as a non-direction controlled surface structuring, by which the second surface structuring provides a self-cleaning function for the second surface. 7. Body in accordance with claim 6, where the non-direction controlled surface structuring possesses burl-shaped protrusions. 8. Body in accordance with one of the claims 6 or 7, where at least a part of the second surface structuring is hydrophobic to ultraphobic. 9. Body in accordance with one of the claims 2 to 8, where the first surface possesses a first surface section and at least one additional surface section, wherein the first surface section possesses the first surface structuring, and wherein the additional surface section possesses a direction-controlled additional surface structuring in the micrometer range, wherein the directional orientation of the additional surface structuring is inclined at a given angle with respect to the directional orientation of the first surface structuring. 10. Body in accordance with one of the claims 1 to 9, where the first surface structuring and/or the second surface structuring possess/possesses structures of different structure dimensions. 11. Body in accordance with one of the claims 1 to 10, where the first surface structuring and/or the second surface structuring possess/possesses flexible protrusions. 12. Body in accordance with one of the claims 1 to 10, where the second surface additionally possesses a surface structuring where the structure dimension is larger compared to the structure dimension of the second surface structuring. 13. Body in accordance with claim 12, here the additional surface structuring of the second surface possesses a structure dimension in the micrometer range. 14. Body in accordance with claim 12 or 13, where the additional surface structuring of the second surface is developed as a direction-controlled surface structuring. 15. Body in accordance with one of the claims 1 to 14, where the structure dimension of the first surface structuring is between approx. 10_m and approx. 1 mm. 16. Body in accordance with one of the claims 1 to 15, where the structure dimension of the second surface structuring is between approx. 0.5_m and approx. 1 mm. 17. Body in accordance with one of the claims 1 to 16, where the second surface structuring is adapted to the second medium, wherein the second medium is a different medium compared to the first medium. 18. Body in accordance with one of the claims 1 to 17, where the first surface and the second surface form a combined surface, where the first surface structuring and the second surface structuring are arranged. 19. Body in accordance with one of the claims 1 to 18, developed as one of the following devices: sliding element carrier, sliding element box, vehicle bicycle carrier, vehicle load carrier, sports device, especially ball striking device and/or ball. 20. Body in accordance with on of the claims 1 to 18, developed as sliding element. 21. Body in accordance with claim 20, where at least one additional device is attached to the sliding element, which (one additional device) possesses on its surface at least partially the second surface structuring. 22. Body in accordance with claim 21, where the additional device is one of the following devices: sliding element brake, sliding element binding, sliding element binding elevation plate, or sliding element shoes. |
Building module and the method of erecting walls of building with the application of the modules |
The building module and method for erecting walls is composed of the supporting construction provided with the carrying ribs (1), placed at the settled distance one from another, to the above supporting construction at the lateral side of it one or two mantles (2) profiled on the outside surface and composed of at least one profile (3) placed simultaneously lengthwise and crosswise the carrying ribs are fixed. On the opposite side of the mantle, the flat mantle (2a) is fixed to the supporting construction, if necessary. On the top and at the bottom of the mantles there are preferably joint ends (8 and 8a) acting jointly which serve to join the adjacent modules whereas at the corners of buildings erected with their application they are provided with overlapping cruciform recesses (9 and 9a) made on the top and at the bottom of them. The carrying ribs have the uniform or segmented construction composed of cubes (1a) and attachments (1b) which are combined in a rigid way with the mantle profiles. In order to fix stable vertical supporting construction, the ports (14) earmarked for introducing threaded fasteners provided with the bolt have been made in the carrying posts (1). |
1. (canceled) 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. (canceled) 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. (canceled) 15. (canceled) 16. (canceled) 17. (canceled) 18. (canceled) 19. (canceled) 20. Building module earmarked for erecting building walls and consisting of the supporting construction, characterised in that to the supporting construction provided with carrying ribs /1/ placed at the settled distance one from another, at the lateral side of the above construction—the mantle /2/ profiled on the outside surface and composed of at least one profile placed simultaneously both lengthwise and crosswise the carrying ribs—is fixed. 21. The module according to the claim 1 and characterised in that mantles /2 and 2a / situated at the corners of walls erected with their application are preferably provided with overlapping cruciform recesses /9 and 9a / made on the top and at the bottom of them. 22. The module according to the claim 2 and characterised in that recesses /9 and 9a / made in mantles /2 and 2a / have a depth equal approximately to ½ of their height. 23. The module according to the claim 1 and characterised with that the mantle /2/ profiled on the outside surface and composed of at least two profiles /3/ is provided with the tongue-groove joint with a stiffening tongue /7/ which is situated at the point of frontal profiles adhesion. 24. The module according to the claim 1 and characterised with that the carrying ribs /1/ have a segmented construction composed of cubes /1a /and attachments /1b I which are combined in a rigid way with profiles /3/ of the mantle /2/. 25. The module according to the claim 5 and characterised in that the carrying ribs /1/ are provided in their central part with vertically made ports /14/ envisaged for introducing of threaded fasteners. 26. The module according to the claim 5 and characterised in that the cubes /1a / and attachments /1b / are combined one with another by means of the frontal tongue-groove joint /13/. 27. The module according to the claim 5 and characterised in that the attachment /16/ in order to combine, has led arms /25/, embracing the cube /1a / from the top and from the bottom. 28. The module according to the claim 1 and characterised in that at the ends of the module, plugs /11/ shaped to fit the inside contour of the module transverse section are fixed in respective holes. 29. The module according to the claim 9 and characterised in that the plug /11/ on its frontal side is provided with a flanged offset /12/ which is shaped to fit the outside contour of a transverse section of the module. 30. The module according to the claim 1 and characterised in that on the top and at the bottom of the mantle /2/ profiled on the outside surface there are, if necessary, suitable joint ends /8/ acting jointly which serve to join the adjacent modules. 31. The module according to the claim 1 and characterised in that the mantle /2/ profiled on the outside surface, is fixed to the supporting construction provided with the carrying ribs /1/ on one of its lateral sides. 32. The module according to the claim 12 and characterised in that mantles /2 and 2a / situated at the corners of walls erected with their application are preferably provided with overlapping cruciform recesses /9 and 9a / made on the top and at the bottom of them. 33. The module according to the claim 13 and characterised in that recesses /9 and 9a / made in mantles /2 and 2a / have a depth equal approximately to ½ of their height. 34. The module according to the claim 12 and characterised with that the mantle /2/ profiled on the outside surface and composed of at least two profiles /3/ is provided with the tongue-groove joint with a stiffening tongue /7/ which is situated at the point of frontal profiles adhesion. 35. The module according to the claim 12 and characterised with that the carrying ribs /1/ have a segmented construction composed of cubes /1a / and attachments /1bI which are combined in a rigid way with profiles /3/ of the mantle /2/. 36. The module according to the claim 16 and characterised in that the carrying ribs /1/ are provided in their central part with vertically made ports /14/ envisaged for introducing of threaded fasteners. 37. The module according to the claim 16 and characterised in that the cubes /1a / and attachments /1b / are combined one with another by means of the frontal tongue-groove joint /13/. 38. The module according to the claim 16 and characterised in that the attachment /16/ in order to combine, has led arms /25/, embracing the cube /1a / from the top and from the bottom. 39. The module according to the claim 1 and characterised in that it is provided with mantles /2/ profiled on outside surfaces and fixed to the supporting construction with carrying ribs /I/ on both its lateral sides. 40. The module according to the claim 20 and characterised in that mantles /2 and 2a / situated at the corners of walls erected with their application are preferably provided with overlapping cruciform recesses /9 and 9a / made on the top and at the bottom of them. 41. The module according to the claim 21 and characterised in that recesses /9 and 9a / made in mantles /2 and 2a / have a depth equal approximately to ½ of their height. 42. The module according to the claim 20 and characterised with that the mantle /2/ profiled on the outside surface and composed of at least two profiles /3/ is provided with the tongue-groove joint with a stiffening tongue /7/ which is situated at the point of frontal profiles adhesion. 43. The module according to the claim 20 and characterised with that the carrying ribs /1/ have a segmented construction composed of cubes /1a / and attachments /1b I which are combined in a rigid way with profiles /3/ of the mantle /2/. 44. The module according to the claim 24 and characterised in that the carrying ribs /1/ are provided in their central part with vertically made ports /14/ envisaged for introducing of threaded fasteners. 45. The module according to the claim 24 and characterised in that the cubes /1a / and attachments /1b / are combined one with another by means of the frontal tongue-groove joint /13/. 46. The module according to claim 24 and characterised in that the attachment /16/ in order to combine, has led arms /25/, embracing the cube /1a / from the top and from the bottom. 47. The module according to the claim 1 and characterised in that the mantle /2/ profiled on outside surface is fixed to the supporting construction provided with carrying ribs /1/ on one of its lateral sides, whereas the flat mantle /2a/ is fixed to the opposite lateral side of supporting construction, which is situated simultaneously lengthwise and crosswise in relation to the carrying ribs. 48. The module according to the claim 28 and characterised in that mantles /2 and 2a / situated at the corners of walls erected with their application are preferably provided with overlapping cruciform recesses /9 and 9a / made on the top and at the bottom of them. 49. The module according to the claim 29 and characterised in that recesses /9 and 9a / made in mantles /2 and 2a / have a depth equal approximately to ½ of their height. 50. The module according to the claim 28 and characterised with that the mantle /2/ profiled on the outside surface and composed of at least two profiles /3/ is provided with the tongue-groove joint with a stiffening tongue /7/ which is situated at the point of frontal profiles adhesion. 51. The module according to the claim 28 and characterised with that the carrying ribs /1/ have a segmented construction composed of cubes /1a / and attachments /1b I which are combined in a rigid way with profiles /3/ of the mantle /2/. 52. The module according to the claim 28 and characterised in that the carrying ribs /1/ are provided in their central part with vertically made ports /14/ envisaged for introducing of threaded fasteners. 53. The module according to the claim 28 and characterised in that the cubes /1a / and attachments /1b / are combined one with another by means of the frontal tongue-groove joint /13/. 54. The module according to claim 28 and characterised in that the attachment /16/ in order to combine, has led arms /25/, embracing the cube /1a / from the top and from the bottom. 55. The module according to the claim 28 and characterised in that on the top and at the bottom of it, the flat mantle /2—a/ is provided with joint ends /8a/ acting jointly which serve to join the adjacent modules. 56. The method of erecting building walls with the application of building modules which are composed of the supporting constructions provided with the carrying ribs, to one side or both lateral sides of which the mantles are fixed and characterised in that the first wall module is placed on the ground-sill and then band elastic seals /23/ are put on the mantle 12 I ends; next—the successive modules are laid with a simultaneous positioning of the carrying ribs /1/ which are to meet each other; in the end—into the contact point, preferably glue is introduced in order to fix stable vertical supporting construction on the top of which the carrying beam is laid; in the case of erecting corner walls—the modules situated at the corners are laid alternately in a cruciform way and they are fastened on the top and at the bottom one to another with recesses /9 and 9a / that were made in them beforehand. 57. The method according to the claim 37 and characterised in that in order to fix stable vertical supporting construction, the successive modules laid on another are joined with the preceding threaded fasteners which are passed through vertical ports /14/ made beforehand in the carrying ribs /1/. 58. The method according to the claim 37 and characterised in that the modules before the assembly are filled with the thermo insulation material. 59. The method according to the claim 37 and characterised in that the modules during the process of assembly are filled with the thermo insulation material. |
Method for high sensitivity detection of cytosine-methylation |
A method is described for the detection of cytosine methylation in DNA samples, which permits the analysis of DNA to be investigated in the presence of large quantities of background DNA of the same individual. In the first step, a genomic DNA is chemically treated, preferably with a bisulfite (=disulfite, hydrogen sulfite), in such a way that cytosine is converted into a base that is different in its base pairing behavior in the DNA duplex, while 5-methylcytosine remains unchanged. Then segments of the sample DNA are amplified by means of a polymerase reaction. The amplificates are cleaved selectively by enzymes at those position which have a methylation state in the DNA sample that is not characteristic for the DNA to be investigated further, but which is characteristic for background DNA. The DNA that is not cleaved by enzymes is now amplified in another polymerase reaction, and in this way, the DNA to be investigated is concentrated relative to the background DNA that is present. The amplificate is finally investigated with respect to its sequence properties and the methylation state in the DNA to be investigated in the genomic DNA sample is concluded therefrom. |
1. A method for the detection of cytosine methylation in DNA samples is hereby characterized in that the following method steps are conducted: a genomic DNA is chemically treated, preferably with a bisulfite (=disulfite, hydrogen sulfite), in such a way that cytosine is converted into a base that is different in its base pairing behavior in the DNA duplex, while 5-methylcytosine remains unchanged, segments of the sample DNA are amplified by means of a polymerase reaction, the DNA is cleaved selectively by enzymes at those position which have a methylation state in the DNA sample, which is not characteristic for the DNA to be investigated further, but which is characteristic for background DNA, the DNA that is not cleaved by enzymes is amplified in another polymerase reaction, by which means the DNA to be investigated is concentrated relative to the background DNA that is present, the amplificate is investigated with respect to its sequence and the methylation state in the DNA to be investigated in the genomic DNA sample is concluded therefrom. 2. The method according to claim 1, further characterized in that the DNA samples are obtained from serum or other body fluids of an individual. 3. The method according to claim 1, further characterized in that the DNA samples are obtained from cell lines, blood, sputum, stool, urine, serum, cerebrospinal fluid, tissue embedded in paraffin, for example, tissue from eyes, intestine, kidney, brain, heart, prostate, lung, breast or liver, histological slides and all possible combinations thereof. 4. The method according to claim 1, further characterized in that the chemical treatment is conducted with a bisulfite (=disulfite, hydrogen sulfite). 5. The method according to claim 4, further characterized in that the chemical treatment is conducted after embedding the DNA in agarose. 6. The method according to claim 4, further characterized in that, in the chemical treatment, a reagent that denatures the DNA duplex and/or a radical trap is present. 7. The method according to claim 1, further characterized in that the amplification of several fragments is conducted in one reaction vessel in the form of a multiplex PCR. 8. The method according to claim 1, further characterized in that the primers utilized in the amplification amplify the DNA which has been chemically converted with bisulfite, but not the corresponding unconverted genomic sequence. 9. The method according to claim 1, further characterized in that the enzymatic cleavage is produced by means of a restriction endonuclease. 10. The method according to claim 9, further characterized in that the restriction endonucleases include Mae II, Psp 1406 I, Ast II, Ssp 5230 I, Bbr P I, Bsa AI, Sna B I, Cfo I, Hin P1 I, Eco 47 III, NAR I, Ehe I, Kas I, Bbe I, Hae II, Acy I, Ban I, Hgi CI, Aos I, Avi II, Hpa II, Msp I, Pin AI, Age I, Eco 56 I, Nae I, Cfr10I, SgrAI, Fse I, XmaCI, Sma I, Srf I, Ava I, Bse AI, Mro I, Taq I, Cla I, Sal I, Hind III, Acc I, Xho I, Sfu I, BstBI, Hinf I, Sau 96 I, Dra II, PssI, Ita I, Dsa V, Scr F I, Mae III, Bst E II, Dde I, Cel II, Esp I or Aoc I. 11. The method according to claim 9, further characterized in that several restriction endonucleases are applied. 12. The method according to claim 11, further characterized in that several different restriction endonucleases are applied in one reaction vessel. 13. The method according to claim 1, further characterized in that, in the restriction step, at least 90% of all fragments produced in the previous amplification are cleaved. 14. The method according to claim 1, further characterized in that the same primers are used in the second amplification step as in the first amplification step. 15. The method according to claim 1, further characterized in that, in the second amplification step, additional or exclusive primers are used, which hybridize to the amplificates of the first step, but are essentially not identical to the primers of the first step or hybridize with them (nested PCR). 16. The method according to claim 1, further characterized in that the second amplification step is conducted as a multiplex PCR. 17. The method according to claim 1, further characterized in that primers of the second amplification step overlap with the cleavage sites of the restriction endonuclease(s) utilized in the preceding step. 18. The method according to claim 1, further characterized in that the background DNA is present in 100× the concentration in comparison to the DNA to be investigated. 19. The method according to claim 1, further characterized in that the background DNA is present in 1000× the concentration in comparison to the DNA to be investigated. 20. The method according to claim 1, further characterized in that the analysis of the sequence properties of the amplificates is made by means of hybridization to oligomer arrays, whereby the oligomers can be nucleic acids or molecules such as PNAs that are similar in their hybridization properties. 21. The method according to claim 20, further characterized in that the oligomers hybridize to the DNA to be analyzed over a 12-22 base long segment and comprise a CG, TG or CA dinucleotide. 22. The method according to one of claims 20 or 21, further characterized in that the methylation state is detected for more than 10 methylation positions of the DNA to be analyzed in one experiment. 23. The method according to one of claims 20 or 21, further characterized in that the methylation state is detected for more than 60 methylation positions of the DNA to be analyzed in one experiment. 24. The method according to claim 1, further characterized in that the analysis is conducted by measuring the length of the amplified DNA to be investigated, whereby methods for length measurement comprise gel electrophoresis, capillary gel electrophoresis, chromatography (e.g. HPLC), mass spectrometry and other suitable methods. 25. The method according to claim 1, further characterized in that the analysis is conducted by sequencing, whereby methods for sequencing comprise the Sanger method, the Maxam-Gilbert method, and other methods such as sequencing by hybridization (SBH). 26. The method according to claim 25, further characterized in that the sequencing is carried out for each CpG position or a small group of CpG positions, each with a separate primer oligonucleotide and the extension of the primer makes up only one or just a few bases and the methylation state of the respective positions in the DNA to be investigated is concluded from the type of primer extension. 27. The method according to claim 1, further characterized in that a conclusion is made on the presence of a disease or another medical condition of the patient from the methylation degree of the different CpG positions investigated. 28. The method according to claim 1, further characterized in that the amplificates themselves are provided with at least one detectable label for the detection, which label is introduced either by labeling of the primers or the nucleotides during the amplification. 29. The method according to claim 28, further characterized in that the labels are fluorescent labels. 30. The method according to claim 28, further characterized in that the labels are radionuclides. 31. The method according to claim 28, further characterized in that the labels are removable mass labels which are detected in a mass spectrometer. 32. The method according to claim 1, further characterized in that, in at least one of the amplifications, one of the respective primers is bound to a solid phase. 33. The method according to 1, further characterized in that all of the amplificates are detected in the mass spectrometer and are thus clearly characterized by their mass. 34. The method according to claim 1, further characterized in that the formation of specific fragments during the amplification is observed with the use of reporter oligonucleotides, which change their fluorescent properties by interaction with the amplificate and/or the polymerase. 35. The method according to claim 34, further characterized in that, in addition to the reporter oligonucleotide, another oligomer which is labeled with a fluorescent dye is used, which hybridizes to the amplificate right next to the reporter oligonucleotide and this hybridization can be detected by means of fluorescence resonance energy transfer. 36. The method according to one of claims 34 or 35, further characterized in that a Taqman assay is conducted. 37. The method according to one of claims 34 or 35, further characterized in that a LightCycler assay is conducted. 38. The method according to claim 34, further characterized in that the reporter oligonucleotides bear at least one fluorescent label. 39. The method according to claim 34, further characterized in that the reporter molecules indicate the amplification either by an increase or a decrease of the fluorescence. 40. The method according to claim 39, further characterized in that the increase or the decrease in the fluorescence is used directly for the analysis and a conclusion on the methylation state of the DNA to be analyzed is made from the fluorescent signal. 41. Use of a method according to claim 1 for the diagnosis and/or prognosis of adverse events for patients or individuals, whereby these adverse events belong to at least one of the following categories: undesired drug interactions; cancer diseases; CNS malfunctions, damage or disease; symptoms of aggression or behavioral disturbances; clinical, psychological and social consequences of brain damage; psychotic disturbances and personality disorders; dementia and/or associated syndromes; cardiovascular disease, malfunction and damage; malfunction, damage or disease of the gastrointestinal tract; malfunction, damage or disease of the respiratory system; lesion, inflammation, infection, immunity and/or convalescence; malfunction, damage or disease of the body as a consequence of an abnormality in the development process; malfunction, damage or disorder of the skin, the muscles, the connective tissue or the bones; endocrine and metabolic malfunction, damage or disease; headaches or sexual malfunction. 42. Use of a method according to claim 1 for the differentiation of cell types or tissues or for the investigation of cell differentiation. 43. A kit, consisting of a reagent containing bisulfite, primers for the production of amplificates, as well as, optionally, instructions for conducting an assay according to claim 1. |
Extracellular Messengers |
Various embodiments of the invention provide human extracellular messengers (EXMES) and polynucleotides which identify and encode EXMES. Embodiments of the invention also provide expression vectors, host cells, antibodies, agonists, and antagonists. Other embodiments provide methods for diagnosing, treating, or preventing disorders associated with aberrant expression of EXMES. |
1. An isolated polypeptide selected from the group consisting of: a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:2-7, SEQ ID NO:9, SEQ ID NO:16, and SEQ ID NO:19-21, c) a polypeptide comprising a naturally occurring amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO:1, d) a polypeptide comprising a naturally occurring amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:22, e) a polypeptide consisting essentially of a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:17-18, f) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and g) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. 2. An isolated polypeptide of claim 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. 3. An isolated polynucleotide encoding a polypeptide of claim 1. 4. An isolated polynucleotide encoding a polypeptide of claim 2. 5. An isolated polynucleotide of claim 4 comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44. 6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim 3. 7. A cell transformed with a recombinant polynucleotide of claim 6. 8. (canceled) 9. A method of producing a polypeptide of claim 1, the method comprising: a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and b) recovering the polypeptide so expressed. 10. A method of claim 9, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. 11. An isolated antibody which specifically binds to a polypeptide of claim 1. 12. An isolated polynucleotide selected from the group consisting of: a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-30 and SEQ ID NO:32-42, c) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 96% identical to the polynucleotide sequence of SEQ ID NO:31, d) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 94% identical to the polynucleotide sequence of SEQ ID NO:43, e) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 91% identical to the polynucleotide sequence of SEQ ID NO:44, f) a polynucleotide complementary to a polynucleotide of a), g) a polynucleotide complementary to a polynucleotide of b), h) a polynucleotide complementary to a polynucleotide of c), i) a polynucleotide complementary to a polynucleotide of d), j) a polynucleotide complementary to a polynucleotide of e), and k) an RNA equivalent of a)-j). 13. (canceled) 14. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof. 15. (cenceled) 16. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof. 17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient. 18. A composition of claim 17, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. 19. (canceled) 20. A method of screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample. 21. (canceled) 22. (canceled) 23. A method of screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample. 24. (canceled) 25. (canceled) 26. A method of screening for a compound that specifically binds to the polypeptide of claim 1, the method comprising: a) combining the polypeptide of claim 1 with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide of claim 1 to the test compound, thereby identifying a compound that specifically binds to the polypeptide of claim 1. 27. (canceled) 28. A method of screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence of claim 5, the method comprising: a) exposing a sample comprising the target polynucleotide to a compound, under conditions suitable for the expression of the target polynucleotide, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound. 29. A method of assessing toxicity of a test compound, the method comprising: a) treating a biological sample containing nucleic acids with the test compound, b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 12 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 12 or fragment thereof, c) quantifying the amount of hybridization complex, and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound. 30-99. (canceled) |
<SOH> BACKGROUND OF THE INVENTION <EOH>Intercellular communication is essential for the growth and survival of multicellular organisms, and in particular, for the function of the endocrine, nervous, and immune systems. In addition, intercellular communication is critical for developmental processes such as tissue construction and organogenesis, in which cell proliferation, cell differentiation, and morphogenesis must be spatially and temporally regulated in a precise and coordinated manner. Cells communicate with one another through the secretion and uptake of diverse types of signaling molecules such as hormones, growth factors, neuropeptides, and cytokines. Hormones Hormones are signaling molecules that coordinately regulate basic physiological processes from embryogenesis throughout adulthood. These processes include metabolism, respiration, reproduction, excretion, fetal tissue differentiation and organogenesis, growth and development, homeostasis, and the stress response. Hormonal secretions and the nervousss are tightly integrated and interdependent. Hormones are secreted by endocrine glands, primarily the hypothalamus and pituitary, the thyroid and parathyroid, the pancreas, the adrenal glands, and the ovaries and testes. The secretion of hormones into the circulation is tightly controlled. Hormones are often secreted in diurnal, pulsatile, and cyclic patterns. Hormone secretion is regulated by perturbations in blood biochemistry, by other upstream-acting hormones, by neural impulses, and by negative feedback loops. Blood hormone concentrations are constantly monitored and adjusted to maintain optimal, steady-state levels. Once secreted, hormones act only on those target cells that express specific receptors. Most disorders of the endocrine system are caused by either hyposecretion or hypersecretion of hormones. Hyposecretion often occurs when a hormone's gland of origin is damaged or otherwise impaired. Hypersecretion often results from the proliferation of tumors derived from hormone-secreting cells. Inappropriate hormone levels may also be caused by defects in regulatory feedback loops or in the processing of hormone precursors. Endocrine malfunction may also occur when the target cell fails to respond to the hormone. Hormones can be classified biochemically as polypeptides, steroids, eicosanoids, or amines. Polypeptides, which include diverse hormones such as insulin and growth hormone, vary in size and function and are often synthesized as inactive precursors that are processed intracellularly into mature, active forms. Amines, which include epinephrine and dopamine, are amino acid derivatives that function in neuroendocrine signaling. Steroids, which include the cholesterol-derived hormones estrogen and testosterone, function in sexual development and reproduction. Eicosanoids, which include prostaglandins and prostacyclins, are fatty acid derivatives that function in a variety of processes. Most polypeptides and some amines are soluble in the circulation where they are highly susceptible to proteolytic degradation within seconds after their secretion. Steroids and lipids are insoluble and must be transported in the circulation by carrier proteins. The following discussion will focus primarily on polypeptide hormones. Hormones secreted by the hypothalamus and pituitary gland play a critical role in endocrine function by regulating hormonal secretions from other endocrine glands in response to neural signals. Hypothalamic hormones include thyrotropin-releasing hormone, gonadotropin-releasing hormone, somatostatin, growth-hormone releasing factor, corticotropin-releasing hormone, substance P, dopamine, and prolactin-releasing hormone. These hormones directly regulate the secretion of hormones from the anterior lobe of the pituitary. Hormones secreted by the anterior pituitary include adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone, somatotropic hormones such as growth hormone and prolactin, glycoprotein hormones such as thyroid-stimulating hormone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), β-lipotropin, and β endorphins. These hormones regulate hormonal secretions from the thyroid, pancreas, and adrenal glands, and act directly on the reproductive organs to stimulate ovulation and spermatogenesis. The posterior pituitary synthesizes and secretes antidiuretic hormone (ADH, vasopressin) and oxytocin. Disorders of the hypothalamus and pituitary often result from lesions such as primary brain tumors, adenomas, infarction associated with pregnancy, hypophysectomy, aneurysms, vascular malformations, thrombosis, infections, immunological disorders, and complications due to head trauma. Such disorders have profound effects on the function of other endocrine glands. Disorders associated with hypopituitarism include hypogonadism, Sheehan syndrome, diabetes insipidus, Kallman's disease, Hand-Schuller-Christian disease, Letterer-Siwe disease, sarcoidosis, empty sella syndrome, and dwarfism. Disorders associated with hyperpituitarism include acromegaly, giantism, and syndrome of inappropriate ADH secretion (SIADH), often caused by benign adenomas. Hormones secreted by the thyroid and parathyroid primarily control metabolic rates and the regulation of serum calcium levels, respectively. Thyroid hormones include calcitonin, somatostatin, and thyroid hormone. The parathyroid secretes parathyroid hormone. Disorders associated with hypothyroidism include goiter, myxedema, acute thyroiditis associated with bacterial infection, subacute thyroiditis associated with viral infection, autoimmune thyroiditis (Hashimoto's disease), and cretinism. Disorders associated with hyperthyroidism include thyrotoxicosis and its various forms, Grave's disease, pretibial myxedema, toxic multinodular goiter, thyroid carcinoma, and Plummer's disease. Disorders associated with hyperparathyroidism include Conn disease (chronic hypercalemia) leading to bone resorption and parathyroid hyperplasia. Hormones secreted by the pancreas regulate blood glucose levels by modulating the rates of carbohydrate, fat, and protein metabolism. Pancreatic hormones include insulin, glucagon, amylin, γ-aminobutyric acid, gastrin, somatostatin, and pancreatic polypeptide. The principal disorder associated with pancreatic dysfunction is diabetes mellitus caused by insufficient insulin activity. Diabetes mellitus is generally classified as either Type I (insulin-dependent, juvenile diabetes) or Type II (non-insulin-dependent, adult diabetes). The treatment of both forms by insulin replacement therapy is well known. Diabetes mellitus often leads to acute complications such as hypoglycemia (insulin shock), coma, diabetic ketoacidosis, lactic acidosis, and chronic complications leading to disorders of the eye, kidney, skin, bone, joint, cardiovascular system, nervous system, and to decreased resistance to infection. The anatomy, physiology, and diseases related to hormonal function are reviewed in McCance, K. L. and S. E. Huether (1994) Pathophysiology: The Biological Basis for Disease in Adults and Children, Mosby-Year Book, Inc., St. Louis, Mo.; Greenspan, F. S. and J. D. Baxter (1994) Basic and Clinical Endocrinology, Appleton and Lange, East Norwalk, Conn. Growth Factors Growth factors are secreted proteins that mediate intercellular communication. Unlike hormones, which travel great distances via the circulatory system, most growth factors are primarily local mediators that act on neighboring cells. Most growth factors contain a hydrophobic N-terminal signal peptide sequence which directs the growth factor into the secretory pathway. Most growth factors also undergo post-translational modifications within the secretory pathway. These modifications can include proteolysis, glycosylation, phosphorylation, and intramolecular disulfide bond formation. Once secreted, growth factors bind to specific receptors on the surfaces of neighboring target cells, and the bound receptors trigger intracellular signal transduction pathways. These signal transduction pathways elicit specific cellular responses in the target cells. These responses can include the modulation of gene expression and the stimulation or inhibition of cell division, cell differentiation, and cell motility. Growth factors fall into at least two broad and overlapping classes. The broadest class includes the large polypeptide growth factors, which are wide-ranging in their effects. These factors include epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor-β (TGF-β), insulin-like growth factor (IGF), nerve growth factor (NGO), and platelet-derived growth factor (PDGF), each defining a family of numerous related factors. The large polypeptide growth factors, with the exception of NGF, act as mitogens on diverse cell types to stimulate wound healing, bone synthesis and remodeling, extracellular matrix synthesis, and proliferation of epithelial, epidermal, and connective tissues. Members of the TGF-β, EGF, and FGF families also function as inductive signals in the differentiation of embryonic tissue. NGF functions specifically as a neurotrophic factor, promoting neuronal growth and differentiation. Some of the large polypeptide growth factors carry out specific functions on a restricted set of target tissues. For example, mouse growth/differentiation factor 9 (GDF-9) is a TGF-β family member that is expressed solely in the ovary (McPherron, A. C. and S.-J. Lee (1993) J. Biol. Chem. 268:3444-3449). NGF functions specifically as a neurotrophic factor, promoting neuronal growth and differentiation. Scubel (signal peptide-CUB domain-EGF-related 1) may play roles in the development of several organ systems. The protein, which contains ten EGF repeats and a CUB domain, is expressed in the developing central nervous system, gonads, somites, surface ectoderm, and limb buds (Grimmond et al. (2000) Genomics 70:74-81). Hepatocyte growth factor (HGF) promotes cell growth, cell motility and mophogenesis in various target tissues (Michalopoulos, G. K. and Zarnegar, R. (1992) Hepatology 15:149-155; Michalopoulos and DeFrances, M. C. (1997) Science 276:60-66). HGF is required for liver and placental development in mice, and stimulates the renewal of cells in adult organs, including liver, lung, and kidney (Schmidt, C. et al. (1995) Nature 373:699-702). HGF contains four kringle domains followed by a serine protease-like domain, and mediates its effects through binding and activation of c-met, a tyrosine kinase receptor. Follistatin (FS) is a protein that specifically binds and inhibits activin, a member of the transforming growth factor-β family of growth and differentiation factors. Activin performs a variety of functions associated with growth and differentiation, including induction of mesoderm in the developing embryo and regulation of female sex hormone secretion in the adult (de Krester, D. M. (1998) J. Reprod. Immunol. 39:1-12). Both activin and FS are found in many types of cells. The interaction of FS and activin influences a variety of cellular processes in the gonadal tissues, the pituitary gland, membranes associated with pregnancy, the vascular tissues, and the liver (reviewed in Phillips, D. J. and D. M. de Krester (1998) Front. Neuroendocrinol. 19:287-322). FS may also play a direct role in the neuralization of embryonic tissue (Hemnmati-Brivanlou et al. (1994) Cell 77:283-295). FS is conserved among diverse species such as frog, chicken, and human. Variants of human FS include a 288 amino acid and a 315 amino acid isoform (McConnell, D. S. et al. (1998) J. Clin. Endocrinol. Metab. 83:851-858). Most follistatins contain a conserved domain with ten regularly spaced cysteine residues. These residues are likely involved in disulfide bond formation and the binding of cations. Similar domains are observed in Kazal protease inhibitors and osteonectin (also called SPARC or BM-40), an extracellular matrix-associated glycoprotein expressed in a variety of tissues during embryogenesis and repair (reviewed in Lane, T. F. and E. H. Sage (1994) FASEB J. 8:163-173). Osteonectin contains not only an FS-like polycysteine domain, but also other modular domains that can function independently to bind cells and matrix components and can change cell shape by selectively disrupting cellular contacts with matrix. High levels of osteonectin are associated with developing bones and teeth, principally osteoblasts, odontoblasts, and perichondrial fibroblasts of embryos. Osteonectin modulation of cell adhesion and proliferation may also function in tissue remodeling and angiogenesis (Kupprion et al. (1998) J. Biol. Chem. 45:29635-29640). FS is associated with a variety of cell proliferative, reproductive, and developmental disorders. Transgenic mice lacking FS have multiple musculoskeletal defects and die shortly after birth (Matzuk, M. M. et al. (1995) Nature 374:360-363). Abnormal expression and localization of FS have been implicated in benign prostatic hyperplasia and prostate cancer (Thomas, T. Z. et al. (1998) Prostate 34:3443). The Follistatin-Related Gene, which encodes a protein with a FS-like polycysteine domain, is associated with chromosomal translocations that may play a role in leukemogenesis (Hayette, S. (1998) Oncogene 16:2949-2954). In the inflammatory response, FS increases the macrophage foam cell formation characteristic of early atherosclerosis (Kozaki, K. et al. (1997) Arterioscler. Thromb. Vasc. Biol. 17:2389-2394). The bone morphogenetic proteins (BMPs) are bone-derived factors capable of inducing ectopic bone formation (Wozney, J. M. et al. (1988) Science 242:1528-1534). BMPs are hydrophobic glycoproteins involved in bone generation and regeneration, several of which are related to the TGF-beta superfamily. BMP-1, for example, appears to have a regulatory role in bone formation and is characterized by procollagen C-proteinase activity and the presence of an extracellular “CUB” domain. The CUB domain is composed of some 110 residues containing four cysteines which probably form two disulfide bridges, and is found in a variety of functionally diverse, mostly developmentally regulated proteins (ExPASy PROSHIE document PR00908). Another class of growth factors includes the hematopoietic growth factors, which are narrow in their target specificity. These factors stimulate the proliferation and differentiation of blood cells such as B-lymphocytes, T-lymphocytes, erythrocytes, platelets, eosinophils, basophils, neutrophils, macrophages, and their stem cell precursors. These factors include the colony-stimulating factors (G-CSF, M-CSF, GM-CSF, and CSF1-3), erythropoietin, and the cytokines. The cytokines are specialized hematopoietic factors secreted by cells of the immune system and are discussed in detail below. Growth factors play critical roles in neoplastic transformation of cells in vitro and in tumor progression in vivo. Overexpression of the large polypeptide growth factors promotes the proliferation and transformation of cells in culture. Inappropriate expression of these growth factors by tumor cells in vivo may contribute to tumor vascularization and metastasis. Inappropriate activity of hematopoietic growth factors can result in anemias, leukemias, and lymphomas. Moreover, growth factors are both structurally and functionally related to oncoproteins, the potentially cancer-causing products of proto-oncogenes. Certain FGF and PDGF family members are themselves homologous to oncoproteins, whereas receptors for some members of the EGF, NGF, and FGF families are encoded by proto-oncogenes. Growth factors also affect the transcriptional regulation of both proto-oncogenes and oncosuppressor genes. (Reviewed in Pimentel, E. (1994) Handbook of Growth Factors, CRC Press, Ann Arbor, Mich.; McKay, I. and I. Leigh, eds. (1993) Growth Factors: A Practical Approach, Oxford University Press, New York, N.Y.; Habenicht, A., ed. (1990) Growth Factors, Differentiation Factors, and Cytokines, Springer-Verlag, New York, N.Y.) In addition, some of the large polypeptide growth factors play crucial roles in the induction of the primordial germ layers in the developing embryo. This induction ultimately results in the formation of the embryonic mesoderm, ectoderm, and endoderm which in turn provide the framework for the entire adult body plan. Disruption of this inductive process would be catastrophic to embryonic development. Small Pevtide Factors—Neuropeptides and Vasomediators Neuropeptides and vasomediators (NP/VM) comprise a family of small peptide factors, typically of 20 amino acids or less. These factors generally function in neuronal excitation and inhibition of vasoconstriction/vasodilation, muscle contraction, and hormonal secretions from the brain and other endocrine tissues. Included in this family are neuropeptides and neuropeptide hormones such as bombesin, neuropeptide Y, neurotensin, neuromedin N, melanocortins, opioids, galanin, somatostatin, tachykinins, urotensin II and related peptides involved in smooth muscle stimulation, vasopressin, vasoactive intestinal peptide, and circulatory system-borne signaling molecules such as angiotensin, complement, calcitonin, endothelins, formyl-methionyl peptides, glucagon, cholecystokinin, gastrin, and many of the peptide hormones discussed above. NP/VMs can transduce signals directly, modulate the activity or release of other neurotransmitters and hormones, and act as catalytic enzymes in signaling cascades. The effects of NP/VMs range from extremely brief to long-lasting. (Reviewed in Martin, C. R. et al. (1985) Endocrine Physiology, Oxford University Press, New York, N.Y., pp. 57-62.) Cytokines Cytokines comprise a family of signaling molecules that modulate the immune system and the inflammatory response. Cytokines are usually secreted by leukocytes, or white blood cells, in response to injury or infection. Cytokines function as growth and differentiation factors that act primarily on cells of the immune system such as B- and T-lymphocytes, monocytes, macrophages, and granulocytes. Like other signaling molecules, cytokines bind to specific plasma membrane receptors and trigger intracellular signal transduction pathways which alter gene expression patterns. There is considerable potential for the use of cytokines in the treatment of inflammation and immune system disorders. Cytokine structure and function have been extensively characterized in vitro. Most cytokines are small polypeptides of about 30 kilodaltons or less. Over 50 cytokines have been identified from human and rodent sources. Examples of cytoline subfamilies include the interferons (IFN-α, -β, and -γ), the interleukins (IL1-IL13), the tumor necrosis factors (TNF-α and -β), and the chemokines. Many cytokines have been produced using recombinant DNA techniques, and the activities of individual cytokines have been determined in vitro. These activities include regulation of leukocyte proliferation, differentiation, and motility. Cytokines interact with a target through receptors expressed on the surface of the responsive cell. Cytokines bind with hemopoietin receptors, receptor kinases, and tumor necrosis factor (TNF)/nerve growth factor (NGF) receptors by bringing together two receptor subunits. This dimerization of receptor subunits transmits a signal through the plasma membrane to the cell cytoplasm. In the case of protein kinase receptors, such as the receptors for epidermal growth factor (EGF) and insulin, the juxtaposition of the two receptor subunit cytoplasmic domains activates their intrinsic tyrosine kinase activity. As a result, the subunits phosphorylate each other. The resulting phosphorylated tyrosine residues then interact with cytoplasmic proteins containing src homology 2 (SH2) domains. SH2-containing proteins that interact with phosphorylated receptor molecules include phosphatidylinositol 3′-kinase, src kinase family members, GRB2, and shc. These SH2 containing proteins are often associated with other cytoplasmic proteins, such as members of the small, monomeric GTP-binding protein families Ras and Rho, and phosphatases, such as the phosphotyrosine phosphatase SHP-2. The signaling complexes formed by these interactions can initiate signal cascades, such as the kinase cascade involving raf and mitogen activated protein (MAP) kinase, which result in transcriptional regulation and cytoskeleton reorganization. Hemopoietin and TNF/NGF receptors, though they have no intrinsic kinase activity, still activate many of the same signal cascades within responding cells. Many of the kinases involved in cytokine signaling cascades were first identified as products of oncogenes in cancer cells in which kinase activation was no longer subject to normal cellular controls. In fact, about one third of the known oncogenes encode protein kinases. Furthermore, cellular transformation (oncogenesis) is often accompanied by increased tyrosine phosphorylation activity (Charbonneau, H. and N. K. Tonks (1992) Annu. Rev. Cell Biol. 8:463-493). Thus, the cell must have regulatory systems which keep the cytokine signaling cascades under appropriate control. Eps8 is a protein which associates with and is phosphorylated by the EGF receptor. Human tumor cell lines contain high constitutive levels of tyrosine-phosphorylated Eps8, and overexpression of Eps8 in NIH3T3 cells expressing the EGF receptor (EGFR) leads to an enhanced mitogenic response and cell overgrowth (Provenzano, C. et al. (1998) Exp. Cell Res. 242:186-200). A family of molecules, which include ABI (Ab1 interactor protein)-1 and ABI-2/e3B1, interact with tyrosine kinases, such as the src-like kinase Ab1, and Eps8. Overexpression of ABI-2/e3B1 in NIH3T3 cells expressing EGFR inhibits the mitogenic response and cell growth. Thus, the ABI family of proteins function as negative regulators of cytokine signaling (Ziemnicka-Kotula, D. et al. (1998) J. Biol. Chem. 273:13681-13692). The SH2-containing phosphotyrosine phosphatases, SHP-1 and SHP-2, are involved in cytokine signaling. SHP-1, the hemopoietic cell phosphatase, is a potent inhibitor of signaling, whereas SHP-2 is a positive signal transducer for several cytokines. A family of transmembrane glycoproteins, called SIRPs (signal regulatory proteins), are substrates of tyrosine kinases. Phosphorylated SIRPs bind to SHP-2 and have a negative effect on cell response induced by cytokines, including an inhibition of growth factor-induced DNA synthesis. This inhibition correlates with reduced MAP kinase activation in SIRP-transfected NIH3T3 cells stimulated with insulin or EGF. SIRP overexpression also suppressed transformation of NIH3T3 cells by a retrovirus carrying the v-fms oncogene (Kharitonenkov, A. et al. (1997) Nature 386:181-186). The activity of an individual cytokine in vitro may not reflect the full scope of that cytokine's activity in vivo. Cytokines are not expressed individually in vivo but are instead expressed in combination with a multitude of other cytokines when the organism is challenged with a stimulus. Together, these cytokines collectively modulate the immune response in a manner appropriate for that particular stimulus. Therefore, the physiological activity of a cytokine is determined by the stimulus itself and by complex interactive networks among co-expressed cytokines which may demonstrate both synergistic and antagonistic relationships. Recently, a unique cytokine has been isolated that appears to have anti-tumor activity in vitro (Ridge, R. J. and N. J. Sloane (1996) Cytokine 8:1-5). This cytokine, anti-neoplastic urinary protein (ANUP), was originally purified as a dimer from human urine. ANUP was later classified as a cytokine when localization studies demonstrated that it was expressed in human granulocytes. ANUP inhibits the growth of cell lines derived from tumors of the breast, skin, lung, bladder, pancreas, and cervix. However, ANUP does not affect the growth of human non-tumor cell lines. The N-terminal 22 amino acids of ANUP comprise a signal peptide which is cleaved from the mature protein. The first nine amino acids of the mature protein retain about 10% of the anti-tumor activity. In addition, ANUP contains a Ly-6/u-PAR sequence motif that is typical of certain cell surface glycoproteins. This motif is characterized by a distinct pattern of six cysteine residues within a 50-residue consensus sequence. The Ly-6/u-PAR motif is found in the Ly-6 T-lymphocyte surface antigen and in the receptor (u-PAR) for urokinase-type plasminogen activator, an extracellular serine protease. Chemokines comprise a cytokine subfamily with over 30 members. (Reviewed in Wells, T. N. C. and M. C. Peitsch (1997) J. Leukoc. Biol. 61:545-550.) Chemokines were initially identified as chemotactic proteins that recruit monocytes and macrophages to sites of inflammation. Recent evidence indicates that chemokines may also play key roles in hematopoiesis and HIV-1 infection. Chemokines are small proteins which range from about 6-15 kilodaltons in molecular weight. Chemokines are further classified as C, CC, CXC, or CX 3 C based on the number and position of certain cysteine residues. The CC chemokines, for example, each contain a conserved motif consisting of two consecutive cysteines followed by two additional cysteines which occur downstream at 24- and 16-residue intervals, respectively (ExPASy PROSITE database, documents PS00472 and PDOC00434). The presence and spacing of these four cysteine residues are highly conserved, whereas the intervening residues diverge significantly. However, a conserved tyrosine located about 15 residues downstream of the cysteine doublet seems to be important for chemotactic activity. Most of the human genes encoding CC chemokines are clustered on chromosome 17, although there are a few examples of CC chemokine genes that map elsewhere. Other chemokines include lymphotactin (C chemokine); macrophage chemotactic and activating factor (MCAF/MCP-1; CC chemokine); platelet factor 4 and IL-8 (CXC chemokines); and fractalkine and neurotractin (CX 3 C chemokines). (Reviewed in Luster, A. D. (1998) N. Engl. J. Med. 338:436-445.) Recently, a novel CC chemokine has been identified in mouse and human thymus (Vicari, A. P. et al. (1997) Immunity 7:291-301). This protein, called thymus-expressed chemokine (TECK), is also expressed at lower levels in the small intestine. TECK likely plays a role in T-lymphocyte development for two reasons. First, TECK is most abundantly expressed in the thymus, which is the major lymphoid organ where T-lymphocyte maturation occurs. Second, the primary source of TECK in the thymus is dendritic cells, which are leukocytic cells that help establish self-tolerance in developing T-lymphocytes. In addition, TECK demonstrates chemotactic activity for activated macrophages, dendritic cells, and thymic T-lymphocytes. The cDNA encoding human TECK (hTECK) contains an open reading frame of 453 base pairs which predicts a protein of 151 amino acids. hTECK retains the conserved features of CC chemokines described above, including four conserved cysteines at C30, C31, C58, and C75. However, the spacing between C31 and C58 is increased by three residues, and the spacing between C58 and C75 is increased by one residue. In addition, hTECK lacks the conserved tyrosine found in most CC chemokines. Chromogranins and secretogranins are acidic proteins present in the secretory granules of endocrine and neuro-endocrine cells (Huttner, W. B. et al. (1991) Trends Biochem. Sci. 16 27-30) (Simon, J.-P. et al. (1989) Biochem.J. 262 1-13.) Granins may be precursors of biologically-active peptides, or they may be helper proteins in the packaging of peptide hormones and neuropeptides—their precise role is unclear. Alzheimer's disease (AD) is a progressive dementia characterized neuropathologically by the presence of amyloid β-peptide-containing plaques and neurofibrillary tangles in specific brain regions. In addition, neurons and synapses are lost and inflammatory responses are activated in microglia and astrocytes. Human Suppressors of Cvtokine Signaling (SOCS) Homologs Signal transduction is a general process in which cells respond to extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.) through a cascade of biochemical reactions beginning with the binding of the signal molecule to a cell membrane receptor and ending with an effect on an intracellular target molecule. Intermediate steps in this process involve the activation of various cytoplasmic proteins by phosphorylation via protein kinases and the translocation of some of these activated proteins to the cell nucleus, where the transcription of specific genes is affected. The signal transduction process regulates all types of cell functions, including cell proliferation, differentiation, and gene transcription. Many of the cytokine receptors, including those for the growth factors EGF, PDGF, and FGF exhibit intrinsic protein kinase activity. Binding of the cytokine to its receptor triggers the autophosphorylation of a tyrosine residue on the receptor. It is believed that these phosphorylated residues are recognition sites for the binding of other cytoplasmic signaling proteins which link the initial receptor activation at the cell surface to the activation of a specific intracellular target molecule. These signaling proteins contain a src homology 2 (SH2) domain that is a recognition and binding site for the phosphotyrosine residue. SH2 domains are found in a variety of signaling molecules and oncogenic proteins, such as phospholipase C-g, Ras GTP-ase activating protein, and GRB2 (Lowenstein, E. J. et al. (1992) Cell 70:431-442). While much is known about key events in the activation of signaling pathways, less is known about how they are switched off. Recently, several SH2-containing proteins have been identified that are induced in murine lymphoid cells by various cytokines, including IL-2, IL-3, IL-6, Interferon-γ, and EPO (Yoshimura, A. et al. (1995) EMBO Journal 14:2816-2826; Starr, R. et al. (1997) Nature 387:917-921; and Naka, T. et al. (1997) Nature 387:924-929). A common property of these proteins is the ability to suppress growth and differentiation in murine cells. The induction of these SH2-containing proteins in cytokine stimulated cells suggests that they may function as negative regulators of cytokine signaling. Transcription of the genes encoding four of these proteins, CIS (cytokine-inducible SH2-containing protein), and SOCS-1, -2, and -3 (suppressor of cytokine signaling), is induced by IL-6 both in vitro and in vivo (Starr et al., supra). The four proteins share little sequence homology in their N-termiinal regions, but all contain a central SH2 domain and a conserved C-terminal region designated the “SOCS box.” The function of the SOCS box is unknown. However, a conserved core triplet sequence (K/R) (D/E) (Y/F) within the SOCS box is similar to the tyrosine phosphorylation site recognized by the JAK kinase family. This similarity suggests that the SOCS box may provide a site for interaction with, and inhibition of, JAK kinases. The finding that SOCS-1 interacts with the catalytic region of JAK kinases supports this hypothesis (Endo, T. A. et al. (1997) Nature 387:921-24). Constitutive expression of SOCS-1 in M1 murine lymphoid cells also inhibits the phosphorylation of certain cell signaling components (gp130 and Stat3) in response to IL-6 (Starr et al., supra). CIS binds to tyrosine-phosphorylated residues in the beta-chain of the IL-3 and EPO receptors and provides another possible mechanism for suppressing cell signaling by preventing the binding of other signaling proteins (Yoshimura et al., supra). Recently, sixteen additional proteins have been identified containing the SOCS box domain (Hilton, D. J. et al. (1998) Proc. Natl. Acad. Sci. USA 95:114-119). Like the SH2-containing proteins described above, each of the proteins contains a C-terminal SOCS box and a distinctive motif N-terminal of the SOCS box. In addition to four new SOCS proteins containing the SH2 domain, three additional classes of SOCS proteins were found containing WD40 repeats (WSB-1 and -2), SPRY domains (SSB-1 to -3), or ankyrin repeats (ASB-1 to -3). A class of small GTPases (Rar proteins) that contain the SOCS box were also identified. The function of WSB, SSB, and ASB proteins are as yet unknown. However, like SH2 domains, WD-40 repeats, ankyrin repeats, and SPRY domains have been implicated in protein-protein interactions (Hilton et al., supra). Defects or alterations in the activity of signaling proteins such as CIS may play a role in the development of various proliferative disorders and diseases such as cancer. Loss or rearrangement of the putative human gene encoding CIS is associated with the development of renal cell carcinomas and lung cancer (Yoshimura et al., supra). This association suggests that CIS may function as a tumor suppressor gene. Expression Profiling Microarrays are analytical tools used in bioanalysis. A microarray has a plurality of molecules spatially distributed over, and stably associated with, the surface of a solid support. Microarrays of polypeptides, polynucleotides, and/or antibodies have been developed and find use in a variety of applications, such as gene sequencing, monitoring gene expression, gene mapping, bacterial identification, drug discovery, and combinatorial chemistry. One area in particular in which microarrays find use is in gene expression analysis. Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants. When an expression profile is examined, arrays provide a platform for identifying genes that are tissue specific, are affected by a substance being tested in a toxicology assay, are part of a signaling cascade, carry out housekeeping functions, or are specifically related to a particular genetic predisposition, condition, disease, or disorder. Culture medium and other growth conditions can influence epithelial cell phenotypes including expression of the cytokeratin markers. In most cases, primary human mammary epithelial cells (HMECs) and immortalized breast cell lines have been grown in monolayer culture on plastic in media containing serum or pituitary extract. The undefined growth factors and hormones contained in serum and pituitary extract can have profound effects on gene expression patterns and cell morphology. Since epithelial cells under physiological conditions are never exposed to serum, these artifact conditions are not ideal for studying the cell biology of normal and malignant cells. MDA-mb-231 is a breast tumor cell line isolated from the pleural effusion of a 51-year old female. It forms poorly differentiated adenocarcinoma in nude mice and ALS treated BALB/c mice. It also expresses the Wnt3 oncogene, EGF, and tumor necrosis factor alpha (TGF-α). Human aortic endothelial cells (HAECs) are primary cells derived from the endothelium of a human aorta. Human umbilical artery endothelial cells (HUAECs) are primary cells derived from the endothelium of an umbilical artery. HAECs and HUAECs have been used as an experimental model for investigating the role of the endothelium in human vascular biology in vitro. Activation of the vascular endothelium is considered to be a central event in a wide range of both physiological and pathophysiological processes, such as vascular tone regulation, coagulation and thrombosis, atherosclerosis, inflammation, and some infectious diseases. TNF-α is a pleiotropic cytokine that is known to play a central role in the mediation of inflammatory responses through activation of multiple signal transduction pathways. TNF-α is produced by activated lymphocytes, macrophages, and other white blood cells, and is known to activate endothelial cells. Lung cancer is the leading cause of cancer death for men and the second leading cause of cancer death for women in the U.S. The vast majority of lung cancer cases are attributed to smoking tobacco, and increased use of tobacco products in third world countries is projected to lead to an epidemic of lung cancer in these countries. Exposure of the bronchial epithelium to tobacco smoke appears to result in changes in tissue morphology, which are thought to be precursors of cancer. Lung cancers are divided into four histopathologically distinct groups. Three groups (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are classified as non-small cell lung cancers (NSCLCs). The fourth group of cancers is referred to as small cell lung cancer (SCLC). Collectively, NSCLCs account for ˜70% of cases while SCLCs account for ˜18% of cases. The molecular and cellular biology underlying the development and progression of lung cancer are incompletely understood. Deletions on chromosome 3 are common in this disease and are thought to indicate the presence of a tumor suppressor gene in this region. Activating mutations in K-ras are commonly found in lung cancer and are the basis of one of the mouse models for the disease. Most normal eukaryotic cells, after a certain number of divisions, enter a state of senescence in which cells remain viable and metabolically active but no longer replicate. A number of phenotypic changes such as increased cell size and pH-dependent beta-galactosidase activity, and molecular changes such as the upregulation of particular genes, occur in senescent cells (Shelton (1999) Current Biology 9:939-945). When senescent cells are exposed to mitogens, a number of genes are upregulated, but the cells do not proliferate. Evidence indicates that senescent cells accumulate with age in vivo, contributing to the aging of an organism. In addition, senescence suppresses tumorigenesis, and many genes necessary for senescence also function as tumor suppressor genes, such as p53 and the retinoblastoma susceptibility gene. Most tumors contain cells that have surpassed their replicative limit, i.e. they are immortalized. Many oncogenes immortalize cells as a first step toward tumor formation. A variety of challenges, such as oxidative stress, radiation, activated oncoproteins, and cell cycle inhibitors, induce a senescent phenotype, indicating that senescence is influenced by a number of proliferative and anti-proliferative signals (Shelton supra). Senescence is correlated with the progressive shortening of telomeres that occurs with each cell division. Expression of the catalytic component of telomerase in cells prevents telomere shortening and imnmortalizes cells such as fibroblasts and epithelial cells, but not other types of cells, such as CD8+ T cells (Migliaccio et al. (2000) J Immmunol 165:4978-4984). Thus, senescence is controlled by telomere shortening as well as other mechanisms depending on the type of cell. A number of genes that are differentially expressed between senescent and presenescent cells have been identified as part of ongoing studies to understand the role of senescence in aging and tumorigenesis. Most senescent cells are growth arrested in the G1 stage of the cell cycle. While expression of many cell cycle genes is similar in senescent and presenescent cells (Cristofalo (1992) Ann N Y Acad Sci 663:187-194), expression of others genes such as cyclin-dependent kinases p21 and p16, which inhibit proliferation, and cyclins D1 and E is elevated in senescent cells. Other genes that are not directly involved in the cell cycle are also upregulated such as extracellular matrix proteins fibronectin, procollagen, and osteonectin; and proteases such as collagenase, stromelysin, and cathepsin B (Chen (2000) Ann NY Acad Sci 908:111-125). Genes underexpressed in senescent cells include those that encode heat shock proteins, c-fos, and cdc-2 (Chen supra). The potential application of gene expression profiling is particularly relevant to measuring the toxic response to potential therapeutic compounds and of the metabolic response to therapeutic agents. Diseases treated with steroids and disorders caused by the metabolic response to treatment with steroids include adenomatosis, cholestasis, cirrhosis, hemangioma, Henoch-Scbonlein purpura, hepatitis, hepatocellular and metastatic carcinomas, idiopathic thrombocytopenic purpura, porphyria, sarcoidosis, and Wilson disease. Response may be measured by comparing both the levels and sequences expressed in tissues from subjects exposed to or treated with steroid compounds such as mifepristone, progesterone, beclomethasone, medroxyprogesterone, budesonide, prednisone, dexamethasone, betamethasone, or danazol with the levels and sequences expressed in normal untreated tissue. Steroids are a class of lipid-soluble molecules, including cholesterol, bile acids, vitamin D, and hormones, that share a common four-ring structure based on cyclopentanoperhydrophenanthrene and that carrry out a wide variety of functions. Corticosteroids are used to relieve inflammation and to suppress the immune response. They inhibit eosinophil, basophil, and airway epithelial cell function by regulation of cytolines that mediate the inflanmmatory response. They inhibit leukocyte infiltration at the site of inflammation, interfere in the function of mediators of the inflammatory response, and suppress the humoral immune response. Corticosteroids are used to treat allergies, asthma, arthritis, and skin conditions. Dexamethasone is a synthetic glucocorticoid used in anti-inflammatory or immunosuppressive compositions. It is also used in inhalants to prevent symptoms of asthma. Due to its greater ability to reach the central nervous system, dexamethasone is usually the treatment of choice to control cerebral edema. Dexamethasone is approximately 20-30 times more potent than hydrocortisone and 5-7 times more potent than prednisone. The anti-inflammatory actions of corticosteroids are thought to involve phospholipase A 2 inhibitory proteins, collectively called lipocortins. Lipocortins, in turn, control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid. Proposed mechanisms of action include decreased IgE synthesis, increased number of β-adrenergic receptors on leukocytes, and decreased arachidonic acid metabolism. During an immediate allergic reaction, such as in chronic bronchial asthma, allergens bridge the IgE antibodies on the surface of mast cells, which triggers these cells to release chemotactic substances. Mast cell influx and activation, therefore, is partially responsible for the inflammation and hyperirritability of the oral mucosa in asthmatic patients. This inflammation can be retarded by administration of corticosteroids. The effects upon liver metabolism and hormone clearance mechanisms are important to understand the pharmacodynamics of a drug. The human C3A cell line is a clonal derivative of HepG2/C3 (hepatoma cell line, isolated from a 15-year-old male with liver tumor), which was selected for strong contact inhibition of growth. The use of a clonal population enhances the reproducibility of the cells. C3A cells have many characteristics of primary human hepatocytes in culture: i) expression of insulin receptor and insulin-like growth factor II receptor; ii) secretion of a high ratio of serum albumnin compared with α-fetoprotein iii) conversion of ammonia to urea and glutamine; iv) metabolize aromatic amino acids; and v) proliferate in glucose-free and insulin-free medium. The C3A cell line is now well established as an in vitro model of the mature human liver (Mickelson et al. (1995) Hepatology 22:866-875; Nagendra et al. (1997) Am J Physiol 272:G408-G416). Ovarian cancer is the leading cause of death from a gynecologic cancer. The majority of ovarian can-cers are derived from epithelial cells, and 70% of patients with epithelial ovarian cancers present with late-stage disease. As a result, the long-term survival rates for this disease is very low. Identification of early-stage markers for ovarian cancer would significantly increase the survival rate. Genetic variations involved in ovarian cancer development include mutation of p53 and microsatellite instability. Gene expression patterns likely vary when normal ovary is compared to ovarian tumors. There is a need in the art for new compositions, including nucleic acids and proteins, for the diagnosis, prevention, and treatment of autoimmune/inflammatory disorders, neurological disorders; endocrine disorders; developmental disorders; cell proliferative disorders including cancer; reproductive disorders; cardiovascular disorders; and infections. |
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