WO2002014546A1 - Use of microbial dna sequences for the identification of human diseases - Google Patents
Use of microbial dna sequences for the identification of human diseases Download PDFInfo
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- WO2002014546A1 WO2002014546A1 PCT/IB2001/000189 IB0100189W WO0214546A1 WO 2002014546 A1 WO2002014546 A1 WO 2002014546A1 IB 0100189 W IB0100189 W IB 0100189W WO 0214546 A1 WO0214546 A1 WO 0214546A1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- the present invention relates to the use of a DNA sequence comprising a fragment of a nucleic acid encoding a microbial virulence factor as means for the identification of a disease or a genetic predisposition thereof as well as its use for the development of disease animal models .
- virulence factor stems preferably from a intracellular microorgansim and is located on a linear or circular chromosome or a plasmid, more preferably said virulence factor stems from a microorganism which is selected from the group consisting of Borrelia species, Chlamydia sp., Escherichia sp., Plasmo- dium sp. and Rickettsia.
- nucleic acid encoding a virulence factor is selected from the group consisting of Seq. Id. No. 1 to Seq. Id. No. 17.
- Virulence factors stemmming from non-intracellular microorganisms which are part of a cluster shared by intracellular microonganisms are as well suitable for the use in the present invention.
- Another object of the present invention is a method for the identification of a disease or a genetic predisposition thereof, which comprises in a tissue or blood sample of a subject or in a fetal neuro-graft a mutation within a nucleic acid sequence selected from the group consisting of Seq. Id. No. 1 to Seq. Id. No.
- said sequence is inserted in a gene of said subject.
- said sequence is inserted in the 3'UTR of said gene and said mutation is found in the polyadenylation signal of said gene and said mutation preferably affects the expression of the protein encoded by said gene.
- transgenic non-human animals which comprise in their ge- no e a partial or complete inactive endogenous gene which is selected from the group consisting of cannabinoid receptor 1 gene, MAP 2C gene, apolipoprotein E gene, prese- nelin 2 gene, integral membrane protein 2B gene, alpha synuclein gene, oligophrenin 1 gene and myotonin protein kinase gene.
- the gene is inactivated due to at least one mutation in its 3' untranslated region (3' UTR) and said mutation leads to an inhibition or suppression of protein expression.
- the term mutation as used herein encompasses any nucleotide change, insertion or deletion independent of their length that influences the activity, expression or regulation of a gene.
- any mutation in the 3'UTR region leading to an inhi- bition or suppression of protein expression e.g. CBl protein expression
- Any mutation in the polyadenylation signal sequence leading to an inactivation of said signal can be used.
- the mutation can e.g.be caused by a sequence of the same or a different microbial species e.g. by gene conversion or recombination.
- the polyadenylation signal in eukaryotes has the following conserved sequence: AATAAA.
- any non-human mammal can be used.
- rodents e.g. mice or rats, which preferably harbor a homozygous or heterozygous CBl gene inactivation in their genome.
- Another object of the present invention is the use of the transgenic animals of the present invention for the identification of compounds that have an effect on the activity, expression or regulation of the gene encoded protein.
- the animals of the present inven- tion allow the identification of compounds which have a direct or indirect effect on CBl protein, MAP 2C protein, Apolipoprotein E, presenilin 2 protein, integral membrane
- Figure 1 shows genetic exposure triggering gene conversion and further infectious recombination
- Figure 2a shows genetic exposure leading to multiple translocations into the human genome
- Figure 2b shows genetic exposure leading to multiple translocations into the human genome .
- a gene construct for the production of a transgenic animal of the present invention which comprises in its genome a partially or completely inactivated gene, can be prepared using standard genetic engi- neering technologies known in the art, such as described in Maniatis et al . , Molecular cloning: A Laboratory Manual, Cold Spring Laboratory, Cold Springs Harbor, N.Y.
- the starting material for said construct can be a portion of e.g. the genomic or cDNA CBl nucleotide sequence.
- In- troduction of the wanted mutation in e.g. the CBl sequence can be done by methods known to a person skilled in the art e.g. by site directed mutagenesis.
- the term mutation as used herein encompasses any nucleotide change, insertion or deletion independent of their length that influence the activity, expression or regulation of a gene .
- a transgenic animal in accordance with the present invention can be made using generally known methods in the field. See, for example, Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986), Knock-out mouse models used to study neurobiological systems, Critical Reviews in rt ⁇ - ⁇ J tr ⁇ rt o ⁇ - CO rt Hi > ⁇ ! rt O ⁇ rt rt 0 3 rt tr 3 OJ to us Pi en ⁇ OJ en Hi tQ TJ g
- the present invention also concerns methods for the identification of a disease caused by bacterial mutations or a genetic predisposition thereof.
- Said methods comprise detecting the presence in a tissue-or blood sample of a subject a muta- tion within a nucleic acid sequence selected from the group consisting of Seq. Id. No .1 to Seq. Id. No. 17 and said sequence is part of a gene of said subject.
- the method of the present invention is e.g. suitable for the identification of one of the above mentioned diseases.
- Suitable methods for the identification of said diseases or a genetic predisposition thereof in humans are for example PCR techniques, DNA or gene chips, hybridisation techniques and Ligases chain reaction (LCR) .
- said method comprises the following steps:
- the sequencing step allows the identification of mutations present in the insertion sequence of interest.
- the design of the oligonucleotide primers is known to those skilled in the art and can be done using standard software. Examples
- Microbial sequences in 3'UTR polyadenylation regions of schizophrenia and dementia genes harbour microbial virulence factors and plasmids
- DNA from Borrelia burgdorferi , Chlamydia and other intracellular microbes has inserted into ancestral 3 ' polyadenylation sites of the following candidate neu- rological genes: The central cannabinoid receptor gene (CBl) , Alzheimer disease and other dementia genes, Parkinson disease and myotonic dystrophy (see Seq. Id. No. 1 to 17 and Table 1A to IE) . Most insertions originate from microbial virulence factors, transposable elements and plasmids .
- CBl and 5HT1E contain related insertions from B. burgdorferi .
- the human CBl gene is located at 6ql4, which has been reported as a candidate region for schizophrenia involving a translocation break-point co- segregating with schizophrenia, immediately adjacent to the 5-hydroxytryptamine (5HT1E) gene.
- the spirochaetal insertion into 5HT1E originated from a B . burgdorferi virulence factor, the flagellar basal-body rod protein (fbrp) , responsible for chemotaxis, locomotion and a sy- ringe mechanism for injection into cells. Through infectious recombination, B .
- burgdorferi introduced another nucleotide sequence containing pll5 and a polyadenylation site into our ancestral genome.
- pll5 overlaps with fbrp.
- the fbrp section on the CBl gene originates from an ancient 5HT1E receptor already containing the spirochaetal insertion and not from a direct transposition of B . burgdorferi onto 6ql4, because the first three nucleotides of the overlapping sequence (see Table 1A) are on 5HT1E, and not on fbrp of B . burgdorferi .
- Gene conversion is the most likely explanation since CBl and human 5HT1E, on which fbrp is absent, are both located in tandem on 6ql4. OJ OJ t to I- 1 I- 1
- the transition of the parasite from arthropod vector to human host is accompanied by significant changes in gene expression, which has practical relevance for prevention, as well.
- the recently approved vaccine against Lyme disease consists of an immunogenic Osp A, that is expressed by the spirochaetal parasite while in the tick gut, turned off on entry into humans and then expressed again at a late chronic stage. After attachment of an infected tick and initiation of a blood meal, anti-OspA antibodies enter the tick gut and mediate killing of B . burgdorferi .
- pll5 thus introduced the code for the translation and actual genetic ex-pression of CBl.
- B. burgdorferi appears to be excluded from the benefits of the extensive lateral gene transfer between micro-organisms, however, as an intracellular parasite with an incomplete genome B. burgdorferi has a direct access to host genes, which it exploits for replication, and not to be recognised as foreign, the spirochete depends on its own sequences within the human genome.
- B. burgdorferi might, for example, dispose of a protective shield at the DNA and protein level, respectively.
- Dissimilarity and mismatch mutations between B . burgdorferi and its pre-inserted human templates may nevertheless occur, resulting from genetically induced variability by virulence factor operons, osp A and B, or, alternatively, from a genomic decay in plasmids (Casjens et al., Mol. Microbiol. 2000, 35, 490-516) borrelia reinfection causing putative mutations in AATAAA. Intrigu- ingly, by a single frame-shift mutation within the original translocase, the same process of genomic decay has apparently incapacitated B . burgdorferi to translocate further genetic templates into its hosts (Casjens et al . , Mol. Microbiol.
- Dissimilarity and infectious recombination between protein coding sequences of the human chromosome associated protein hCAP and borrelia P115 could, on the other hand, account for the altered leukocyte chromatin ultra-structure reported in schizophrenic patients.
- homologous proteins comprise G-protein coupled receptors that receive information from outside the cell, such as olfaction or vision.
- D2 dopamine 2 receptor
- D2 dopamine 2 receptor
- Identities 19/19 (100%) .
- the circumscribed homology between CBl and the D2 receptor which is an important phar acol- ogical target for the treatment of schizophrenia, encodes the seventh transmembrane loop which is known for its inhibitory-mode (i-mode) of metabotropic action.
- i-mode inhibitory-mode
- this homologous nucleotide sequence can be found an all sequenced primate (Macaca mulatta, Cercopithecus aethiops, H. sapiens; OMIM, 2000) and rodent (Mus muscu- lus) D2 receptor genes.
- dementia praecox schizophrenia
- syphilitic de- mentia The difference between dementia praecox (schizophrenia) and syphilitic de- mentia is that without memory hallucinations are lost, and that the thoughts of schizophrenics are flooded with fixed hallucinations, expanding into overt delusions.
- CBl knock-out mice do show reduced exploratory, goal-directed behaviours (Steiner et al . Proc. Natl. Acad. Sci. USA, 2000, 96, 5786-5790); symptoms that appear to be among the most robust indices in schizophrenia. Without time-bridging working memory, no creative speech and no logical thinking would be possible.
- the phylogenetic traces of microbial insertions into the human genome were investigated and the gene- tic mechanism were analysed, by which bacterial virulence factors and mobile elements from intracellular parasites could disrupt candidate genes for schizophrenia and dementia. This was done by co-incident DNA homology BLAST searches between neurotropic microorganisms, the central cannabinoid receptor CBl, and other known dementia genes, whose complete sequences with 3'UTR and polyadenylation signals are entered on Gene-Bank databases. Several such genes have now been characterised including those of ApoE4 Alzheimer Disease type II (AD2) and presenilin 2 (AD 4) .
- AD2 ApoE4 Alzheimer Disease type II
- AD 4 presenilin 2
- Positional cloning and sequencing has also been carried out in other dementias including Familial British Dementia (with mutations in the gene for integral membra- ne protein 2A) , Hereditary Multi-infarct Dementia (Notch- 3 gene) , primary X-linked mental retardation (oligo- phrenin 1 gene) , Frontotemporal Lobe Dementia, Autosomal Dominant Parkinson Lewy-Body Dementia and Familial Par- kinson disease type I (with mutations in the alpha synuclein gene) .
- the genomic facilities used are accessible at Online Mendelian Inheritance of Man (OMIM) and very much recommended to anybody interested in applied medical genetics . While there are shown and described presently preferred embodiments of the invention, it is to be distinctly understood that the invention is not limited thereto but may be otherwise variously embodied and practiced within the scope of the following claims.
- Chlamydia integration into ancestral rodent CBl Chlamydia (8221) TTACCTGGACTCAAATAAAAGT(8242) 3 ' 20
- Chlamydia (8219) AGTTACCTGGACTCAAATAAA ( 8240 ) 3 ' 2
- AMYLOID PRECURSOR PROTEIN Alzheimer's disease type 1 (protease nexin-II)
- Plasmodium chromosome 3 (79642) TTTTCATGTAAATAAATA (79625)5' 6
- FAMILIAL BRITISH DEMENTIA (xntegral membrane protexn 2B gene) Borrelxa burgdorferi Ixnear plasmxds lp25, lp36 and Plasmodium fal ⁇ iparum major merozoite surface & receptor binding protein
- Oligophrenin 1 Oligophrenin 1
- OPHN 1 (6648) CAAATAAAGTAGTAAAAGA (6666) 3 V 56
- FRONTOTEMPORAL LOBE DEMENTIA gene for microtubule associated protein tau
- Escherichia (pilus protein) (860) AATAATAAAAATCATGCTT(878) 3 ' 11
- Mt-PK human myotonxn protein kinase
- Chlamydia (3551) GCGAATAAAAGGCCCT (3536) 5 ' 14
- Rickettsia (232700) AATAAAAAACATTTAT (232685) 5 ' 15 Borrelia (oppAIV) (1143) ATGTATTTAAAT (1132) 5' 41
- Borrelia burgdorferi (pll5) : related to human chromosome associated protein responsible for DNA and intracellular movement .
- lipoprotein P homologous sequences on plasmids, i.e. Ip38, anti-genetic surface protein.
- Borrelia b. (comp. loc) competence locus with multiple homologous copies throughout genome.
- Borrelia b. (sgp) stability governing protein for stabilisation of membrane.
- Borrelia b. (ospC) outer surface protein C; 18 base pair distant from 3' poly-A cleavage site of (globin. Target of Borrelia vaccine.
- Chlamydia muridarum (ibp) within CBl iron binding protein to overcome host barriers of low iron levels .
- Chlamydia m. within Mt-Pk phosphocarrier protein.
- Chlamydia pneumonae hypothetical protein.
- Clostridium beijerinckii small subunit of coenzyme A transferase.
- Escherichia coli pilus protein responsible for cellular adherence and infection.
- Plasmodium bergei within globin series: phosphoprotein mRNA.
- Plasmodium falciparum within CBl rhoptry associated protein (264) ATCAAATAAAAGTTCTA ( 280 ) 3 ' for erythrocyte penetration.
- Plasmodium f . within amyloid precursor protein several sequences form chromosome 3 including hypothetical pro- teins .
- Plasmodium f. (mmsp) major merozoite surface protein, expressed during sexual stage.
- Plasmodium f. Plasmodium falciparum-encoded protein on the surface of infected erythrocytes mediates receptor binding.
- Plasmodium f . in thalassaemia (globin: RNA polymerase III. Rickettsia prowazekii in (globin: proline-betaine transporter for the reduction of osmotic stress in host environment .
- Vibrio cholerae (ntno) Na+-translocating NADH-ubiquinone oxidoreductase enzyme complex involved in flagella rotation.
- Microbial virulence factors within the 3' genetic hotspot of human disease Base pairs originating form the late- ral gene transfer of microbial nucleotides are indicated in upper case, and non-microbial nucleotides in lower case letters. There are normally no point mutations on the polyadenylation signal, whose non-redundant code protects the microbial inclusions from mutations. Homologous recombination between B. burgdorferi pll5 and the bor- relia template fbrp originating from ancestral 5HT1E has introduced the polyadenylation signal AATAAA into CBl. Note that recombinational mismatch-repair has inserted an additional adenine into CBl.
- a point mutation from A to G has through a reduction of the adenine content led to a shortening of the 3' polyadenylation tail of the rat.
- human CBl and rat CBl almost identical, but independent insertions of C. muridarium nucleotides must have occurred twice. This reoccurrence emphasises the attraction CBl and its polyadenylation signal exerts on microbi- al DNA to recombine .
- dissimilarity i.e. AATATA
- mismatch repair mutations might, in analogy to the genetic knock-out of globin in thalassaemia, result in a knock out of CBl and other neurological candidate genes .
- Microtubule associated protein 2C (MAP2C)
- AD2 Alzheimer's diease type 2
Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU2001230448A AU2001230448A1 (en) | 2000-08-16 | 2001-02-15 | Use of microbial DNA sequences for the identification of human diseases |
US10/344,124 US20040101867A1 (en) | 2001-02-15 | 2001-02-15 | Use of microbial dna sequences for the identification of human diseases |
CA002418087A CA2418087A1 (en) | 2000-08-16 | 2001-02-15 | Use of microbial dna sequences for the identification of human diseases |
JP2002519671A JP2004506429A (en) | 2000-08-16 | 2001-02-15 | Use of microbial DNA sequences to identify human diseases |
EP01902591A EP1309722A1 (en) | 2000-08-16 | 2001-02-15 | Use of microbial dna sequences for the identification of human diseases |
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IBPCT/IB00/01127 | 2000-08-16 | ||
IB0001127 | 2000-08-16 |
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JP (1) | JP2004506429A (en) |
AU (1) | AU2001230448A1 (en) |
CA (1) | CA2418087A1 (en) |
WO (1) | WO2002014546A1 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998058943A1 (en) * | 1997-06-20 | 1998-12-30 | Human Genome Sciences, Inc. | Borrelia burgdorferi polynucleotides and sequences |
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US5986054A (en) * | 1995-04-28 | 1999-11-16 | The Hospital For Sick Children, Hsc Research And Development Limited Partnership | Genetic sequences and proteins related to alzheimer's disease |
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2001
- 2001-02-15 EP EP01902591A patent/EP1309722A1/en not_active Withdrawn
- 2001-02-15 JP JP2002519671A patent/JP2004506429A/en not_active Withdrawn
- 2001-02-15 AU AU2001230448A patent/AU2001230448A1/en not_active Abandoned
- 2001-02-15 CA CA002418087A patent/CA2418087A1/en not_active Abandoned
- 2001-02-15 WO PCT/IB2001/000189 patent/WO2002014546A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998058943A1 (en) * | 1997-06-20 | 1998-12-30 | Human Genome Sciences, Inc. | Borrelia burgdorferi polynucleotides and sequences |
Non-Patent Citations (8)
Title |
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C.M. FRASER ET AL.: "Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi et al.", NATURE, vol. 390, 11 December 1997 (1997-12-11), pages 580 - 586, XP002125758 * |
GADZICKI D ET AL: "A FREQUENT POLYMORPHISM IN THE CODING EXON OF THE HUMAN CANNABINOIDRECEPTOR (CNR1) GENE", MOLECULAR AND CELLULAR PROBES,ACADEMIC PRESS, LONDON,GB, vol. 13, no. 4, 1999, pages 321 - 323, XP000982865, ISSN: 0890-8508 * |
HOEHE M R ET AL: "GENETIC AND PHYSICAL MAPPING OF THE HUMAN CANNABINOID RECEPTOR GENE TO CHROMOSOME 6Q14-Q15", THE NEW BIOLOGIST,PHILADELPHIA,PA,US, vol. 3, no. 9, September 1991 (1991-09-01), pages 880 - 885, XP000991359, ISSN: 1043-4674 * |
K.A. CONWAY ET AL.: "Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid.", BIOCHEMISTRY, vol. 39, no. 10, 14 March 2000 (2000-03-14), pages 2552 - 2563, XP001002067 * |
MORROW J A ET AL: "Functional characterization of apolipoprotein E isoforms overexpressed in Escherichia coli.", PROTEIN EXPRESSION AND PURIFICATION, (1999 JUL) 16 (2) 224-30., XP001002071 * |
N. KALCHEVA ET AL.: "Survey for CAG repeat polymorphisms in the human MAP-2 gene.", PSYCHIATRIC GENETICS, vol. 9, no. 1, March 1999 (1999-03-01), pages 43 - 46, XP001004458 * |
NAKAI T. ET AL: "Membrane topology of Alzheimer 's disease-related presenilin 1. Evidence for the existence of a molecular species with a seven membrane-spanning and one membrane-embedded structure.", JOURNAL OF BIOLOGICAL CHEMISTRY, (13 AUG 1999) 274/33 (23647-23658)., XP001002063 * |
See also references of EP1309722A1 * |
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JP2004506429A (en) | 2004-03-04 |
AU2001230448A1 (en) | 2002-02-25 |
CA2418087A1 (en) | 2002-02-21 |
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