Datasets:

dheerajpai

/

uspatents

like 0

Mutated aqp, method for detecting cancer using the same, dna chip having oligonucleotides of said mutated aqp sequence

The present invention relates to mutation genes of the AQP(aquaporin), a method for detecting cancer using mutations and expressions of the AQP and a DNA chip possessing oligonucleotides of mutated AQP base sequence. In case of the present method for detecting cancer and DNA chip using the AQP's mutations and expressions, it is highly accurate, rapid and effective in cancer diagnosis.

1. A mutant AQP5 gene, in which at least single base was changed from SEQ ID NO: 1. 2. A method for diagnosing cancer comprising detecting presence or absence of mutation of AQP5 gene in claim 1 and expression of AQP5, AQPL1, AQP3 and/or AQP 4. 3. The method as set forth in claim 2, wherein the cancer comprises lung cancer, stomach cancer, colon cancer, prostatic cancer, and head and neck cancer. 4. The method as set forth in claim 3, wherein the cancer comprises lung cancer. 5. The method as set forth in claim 2, wherein presence or absence of mutation of AQP5 gene is detected by at least one method selected from the group consisting of immunohistochemical study, western blotting, dot blotting, ELISA (enzyme-linked immunosorbent assay), RT-PCR, nucleic acid sequencing, restriction enzyme analysis, nothern blotting, Southern blotting, RNase protection assay, in situ hybridization, SSCP (single strand conformational polymorphism) analysis, MSO hybridization (Mutant specific oligonucleotide-hybridization) assay, ARMS (amplification refractory mutation system) and DNA chip (microarray) analysis. 6. The method as set forth in claim 5, wherein the MSO hybridization assay comprises the steps of: 1) arraying oligonucleotides to nitrocellulose membrane or nylon membrane in parallel; 2) preparing biotin labeled probe DNA by using PCR with oligonucleotide primer labeled by biotin at 5′ end; 3) denaturing biotin labeled probe, followed by hybridization of probe with the membrane in 1) and eliminating unlabelled probe by washing; and 4) treating the washed membrane with alkaline phosphatase-labeled streptavidin, combining the formed biotin labeled hybrid, and inducing the color reaction, in particular comprising the use of strip in hybridization. 7. The method as set forth in claim 5, wherein the DNA chip analysis comprises the steps of: 1) synthesizing oligonucleotide primer for each base of AQP5 cDNA, modifying 5′ end of primers with chemical linker, spotting the primers onto slide treated by special coating and thus producing oligo DNA chip; 2) preparing target DNAs by PCR amplification of coding sequence of AQP5 followed by fragmentation of the PCR products into nucleotides with 50 to 100-bp in length; 3) adding fragmented PCR products of 2), four fluorescence-labelled dideoxynucleotides and DNA polymerase onto the oligo DNA chip in 1), mixing them, and then performing arrayed primer extension reaction; and 4) analyzing automatically the results of arrayed primer extension reaction in 3) by using 4 color fluorescence DNA scanner. 8. A DNA chip comprising one of nucleotide sequences of mutant AQP5 gene in claim 1. 9. An oligonucleotide chip wherein oligonucleotide primers sequences of FIG. 20 are arrayed.

<SOH> BACKGROUND ART <EOH>Neoplastic diseases, including most: particularly the collection of diseases known as cancer, are major cause of mortality and morbidity of human and are the most difficult disease to treat. Although medical science and natural science has recently advanced so much, cancer still remains unresolved problem. In United States of America, cancer is surpassed only by cardiovascular diseases as the primary cause of adult death, one million and three hundred thousands of new cases of cancer develop yearly and five hundred and fifty thousands of men die of cancer every year. This means that one of every 2 or 3 American people falls victim to cancer. The four major cancers in United States of America include lung cancer, colorectal cancer, prostate cancer and breast cancer, and the risk of American people to get these 4 major cancer are shown in Table 1 (Bang Y J et al. Cancer: Current Diagnosis and Therapy. Hanuri Company:Seoul, 1999;69-107) TABLE 1 The risk of American men to get four major cancers (from National Cancer Institute of United States, SEER Data) Risk of getting cancer Risk of dying of Type of cancer Sex (%) cancer(%) Lung cancer Male 8.6 7.1 Female 5.4 4.2 Colorectal Male 6.2 2.6 cancer Female 5.9 2.6 Prostate Male 18.5 3.6 cancer Breast cancer Female 12.6 3.6 The mechanism of development of human cancer is being clarified in more detail owing to advances of molecular biology and genetics; especially human genome project, functional genomics, nanotechnology and bioinformatics. Cancer is genetic disease, ie. Cancer develops secondary to genetic abnormality. Acquired genetic abnormality secondary to chemical carcinogen, UV light, irradiation or virus and hereditary genetic abnormality induces change (ie, mutation) into genetic information (DNA, RNA) of genome. When these mutation activate oncogenes and inactivate tumor suppressor genes, cancers may develop. Oncogene and tumor suppressor genes play key roles in regulation of signal transduction, cell cycle progression, cellular death and survival, accommodation with neighbor cells and angiogenesis is. Oncogenes induce proliferation, survival and escape from death, invasion of adjacent tissues and angiogenesis and thus stimulate development of cancer, whereas, tumor suppressor genes counteract oncogenes and thus inhibit development of cancer (Evan G et al. Matter of life and cell death, Science (1998) 281, 1317-1322; Harrington E A et al. Oncogene and cell death. Curr Opin Genet Dev (1994) 4, 120-129). During the past twenty years, many medical scientists have focused on oncogenes and tumor suppressor genes and have tried to find genetic markers of cancer and tumor markers through investigation of oncogenes and tumor suppressor genes. Through these research, they have found important genes such as p53, Rb, p16 and other CDK inhibitors, which regulate cell cycle and cellular apoptosis (Macleod K et al. Tumor suppressor genes. Curr Opin Genet Dev (2000) 10, 81-93; Adams P D et al. Negative control elements of the cell cycle in human tumors. Curr. Opin. Cell. Biol. (1998); 10, 791-797), BRCA1 and BRCA2 which are closely related with hereditary breast cancer and hereditary ovarian cancer (Miki Y et al. A strong candidate for the breast and ovarian susceptibility gene BRCA1, Science (1994) 266, 66-71); Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature (1995) 378, 789-792), and APC gene which is closely related with hereditary colorectal cancer (Kinzier K, et al, Lessons from hereditary colorectal cancer, Cell(1996) 87, 159-170). These findings, had greatly contributed to progress of cancer research. In addition, these research stimulated establishment of many research centers which tested specific gene mutation on a commercial basis, in particular, BRCA1 and BRCA2 in women with high risk of development of breast cancer and ovarian cancer owing to family history (Levine A J. p53, the cellular gatekeeper for growth and division, Cell(1997), 88, 323-331; Frank T S. Laboratory. identification of hereditary risk of breast and ovarian cancer, Curr. Opin. Biotech. (1999) 10, 289-294). However, ideal genetic marker remains not to be found for acquired solid tumors which constitute most of human cancers. In addition, no molecular marker common to all human cancer has been found so far. It is p53 gene that shows highest frequency of mutation in all forms of human cancer, but even for p53 gene, the frequency of mutation or deletion is only 30 to 50%, which suggests that p53 is inappropriate for use as a molecular diagnostic marker of human cancer in clinical practice (Levine A J et al. p53, the cellular gatekeeper for growth and division, Cell (1997) 88, 323-331). Oligonucleotide DNA chip which detects mutation of p53 gene has recently been tested in patients with lung cancer, but only 40% of the lung cancer tissues showed mutation of p53 gene, which indicates limitation of analysis of mutation of p53 gene as a diagnostic tool of lung cancer (Ahrendt S A et al. Rapid p53 sequence analysis in primary lung cancer using an oligonucleotide probe array, Proc Natl Acad Sci U.S.A(1999) 96, 7382-7387). So far, no marker has been found to be of practical value for the clinical management of lung cancer, stomach cancer, colorectal cancer and breast cancer which form more than 50% of all human cancers. Affymetrix company (www.affymetrix.com) has recently manufactured Human Cancer G110 Array, a new type complementary DNA(cDNA) chip which detects expression of about 100 oncogenes and tumor suppressor genes which have been found so far. However, it is questionable whether this DNA chip pan detect all human cancer, due to the fact that the genes found so far are at most 5-10% of the genes related to all human cancer. Despite progress of surgery, chemotherapy, radiation therapy and immunotherapy, the success rate of treatment of human cancer except some hematologic cancer and childhood malignancies has not been remarkably improved during last several decades. The main reason for the poor treatment outcome of human cancer lies in the delayed diagnosis of cancer in advanced status when it has already metastasized and cure is hard to attain rather than limited efficacy of current therapy for cancer. Nowadays the prevention of cancer takes a key place in clinical science as does treatment of cancer. Primary method of cancer prevention is so called chemoprevention which aims to delay or inhibit multistep development of cancer by change of life style, diet or drugs. The chemoprevention is appropriate in particular for asymptommatic people with high risk of cancer because of family history or past medical history of cancer. For example, a clinical study of chemoprevention is under way to administer retinoic acid to patients in status of long term remission from lung cancer after therapy. However, we still do not exactly know either the etiology of cancer (except smoking) or effective chemopreventive drugs, and we have no reliable marker to identify the efficacy of chemopreventive agents, all of which limit the practical value of chemoprevention of cancer. The secondary method of cancer prevention is early detection or screening of cancer. The fate of individual cancer patient, ie. cure rate and long term survival, is primarily determined by volume and stage of tumor at the time of diagnosis; The cure rate and survival rate is highest among cancers in stage 1 or stage 2. In fact, we can expect cure of cancer only when it is diagnosed in early stage, ie. stage 1 and/or stage 2. Therefore, medical society makes every effort to detect cancer from the general public in early stage. Screening methods of cancer include inspection (skin, oral cavity, external genitalia, uterine, cervix), palpation (breast, oral cavity, thyroid, anus and rectum, prostate, testicle, uterus, lymph nodes), clinical chemistry tests such as, Papanicolaou smear and tumor markers including serum prostate specific antigen (PSA) or α-feto protein, radiologic study such as barium enema study of colon, chest X ray, and endoscopic examination. Table 2 shows the cancer screening methods recommended by American Cancer Society. TABLE 2 Cancer screening methods: Guideline recommended by American Cancer Society (1993). Target Screening Age of screening Screening Cancer method Sex population frequency Prostate Digital rectal Male 50 years or after yearly cancer examination Serum Male 50 years or after Yearly PSA assay Breast Self Female 20 years or after monthly cancer examination Clinical Female 20-40 years/ Every 3 breast 40 years or years/ examination after Yearly Mammography Female 50 years or after Yearly Colorectal Stool occult Male and 50 years or after Yearly cancer blood test female Colonoscopy Male and 50 years or after Every 3 to female 5 years Uterine Pap smear Female 18 years or after Yearly cervix Pelvix Female 18-40 years/ Every 1-3 cancer examination 40 years or after years/ Yearly Endometrial Female Postmenopausal, Depending biopsy High risk women on doctor's recom- mendation Lung Chest X ray Not recommended as a routine study cancer Sputum cytology The cancer screening tests listed in Table 2 have been shown actually to improve the treatment outcome of target cancers. In particular, serum PSA assay is widely used for the screening, diagnosis, follow up after therapy of prostate cancers (Rimer B K et al. Cancer Screening. In DeVita V T Jr, Hellman S, Rosenberg S A. eds. Cancer. Principles and Practice of Oncology. fifth ed., Lippincott-Rave:Philadelphia, 1997; 619-631). Detection of expression of specific gene in blood has recently been used to identify specific cells and diagnosis of specific diseases, especially cancer. For example, detection of benign or malignant prostatic epithelial cells which express PSA or prostate specific membrane antigen (PSMA) from blood by using reverse transcription, polymerase chain reaction (RT-PCR) assay has been shown to be of value for the staging of cancer, ie. detection of metastatic cancer (which has been called molecular staging) as well as diagnosis of prostatic cancer. Presence of cancer cells within blood does not indicate metastasis by itself, but highly suggests metastasis (Katz A E et al. Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay; Israeli R S et als. Sensitive nested reverse transcription polymerase chain reaction detection of circulating prostatic tumor cells: comparison of prostate specific membrane antigen and prostate specific antigen-based assays. Cancer Research(1994) 54: 6306). However, no pan-tumor molecular marker has been found so far which show abnormality in most human cancers and thus is of practical value for the diagnosis and staging of cancer in clinical practice. Lung cancer ranks the first of all human cancers both in the incidence and death rates in United States of America: About 180,000 new cases of lung cancer develop yearly, about 160,000 patients die of lung cancer and overall 5-year survival rate of patients with lung cancer is only around 10%. Most of human lung cancers are bronchogenic carcinomas, which is primarily classified into small cell carcinoma and non-small cell carcinoma. The small cell carcinomas are a single type, while the non-small cell carcinomas consist of adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioalveolar carcinoma. Primary cause of lung cancer is smoking and the amount and duration of smoking is directly correlated with incidence and death rates of lung cancer. The risk of getting lung cancer increases twenty-folds and risk of death of lung cancer becomes 13% on smoking 25 cigarettes daily for 10 years. Of remark is that the risk of lung cancer increases not only in primary or direct smokers but also in secondary or indirect smokers. The screening for lung cancer is indicated both in primary smokers and secondary smokers and also in men who had been exposed to lung carcinogen such as asbestos. Classical methods for the screening of lung cancer include chest radiography (simple X ray) and sputum cytology examination, however the former and the latter has a diagnostic sensitivity for lung cancer of only 30% and 40-60%, respectively. It is hard for these two studies to detect lung cancer in early stage and to significantly improve treatment outcomes of lung cancer, and for this reason these two studies were excepted from a list of recommended screening tests for cancers by American Cancer Society. Owing to lack of effective screening methods, ninety percent of cases of lung cancer are nowadays diagnosed in, advanced status(stage III or IV), in which cases most of the patients die within 2 years after diagnosis and 5 year survival rate is less than five percent despite aggressive chemotherapy and irradiation therapy (Choi S J et al. eds. Lung: neoplasia and cancer. In Current Diagnosis and Therapy. Han-Uri Publishing Co.:Seoul. 1999;323-332). In contrast, if lung cancer can be detected by screening study in occult carcinoma status when patient has no symptoms and radiologic study of the lung shows no cancerous lesion, the cure rate of cancer is more than eighty percent. In fact some reports showed evidence that treatment outcomes of lung cancer are remarkably improved even by limited classical screening study of chest radiography and sputum cytology examination and that there were significant differences in 5 year survival rate between lung cancers detected by screening study (35%) and those diagnosed by lung cancer-related symptoms (13%) (Berlin N I et al. Early lung cancer detection: Summary and conclusions, American Review of respiratory diseases (1984) 30, 565). Diagnostic study and follow up study after therapy of lung cancer leaves much room for improvement. Accurate diagnosis of lung cancer is in reality not easy. It is hard to detect early stage lung cancer by chest X ray and sputum cytology examination and, even after detection of lung mass, it is not easy to differentiate between lung cancer and benign lung mass and between primary lung cancer and metastatic lung cancer. Definitive diagnosis of lung cancer is usually made by bronchoscopic biopsy, brush biopsy, bronchoalveolar lavage cytology examination, percutaneous needle aspiration cytology examination, mediastinoscopic biopsy, lymph node biopsy or pleural biopsy, but sometimes requires even open lung biopsy. The diagnosis is often ambiguous even after radiologic study and biopsy, in particular for solitary pulmonary nodules with diameter of less than 5 mm as being important in clinic (Ginsberg R J et al. Cancer of the lung. Section 2. Non-small cell lung cancer. In DeVita V T Jr. Hellman S, Rosenberg S A. eds. Cancer. Principles and Practice of Oncology, 5th ed., Lippincott-Raven: Philadelphia, 1997; 858-910). The next step after diagnosis of lung cancer is staging work up, ie., study of extent of cancer. The conventional staging methods for lung cancer include: computerized tomography (CT) scan, bronchoscopy, thoracoscopy, mediastinoscopy, and biopsy and cell examination using them, but all of these methods have limited accuracy and endoscopic studies are invasive. Lung cancer commonly invades pleura band and thus induce pleural effusion, in which cases, pleural fluid cytology examination and/or pleural biopsy are performed to identify the cause of pleural effusion, but reveals definitive diagnosis in only about half of the cases. Therefore, staging method for lung cancer definitely leaves much room for improvement. The appropriate follow up study is essential after therapy for lung cancer which can accurately define the results of therapy, detect residual or recurrent cancer in a sensitive and rapid way. The current follow Up study of lung cancer include radiologic study such as CT scan and endoscopic examination, but it is almost impossible to detect microscopic residual or recurrent cancer by these study. Therefore, novel method for follow up of lung cancer is urgently necessary. Appropriate maintenance of membrane water permeability is a fundamental requirement of all living organisms. Aquaporin (AQP) is a family of water channel proteins of membranes through which water are transported into and out of cells. AQP exists in all type of living organisms which include microorganisms, plants, mammalians. Ten types of mammalian AQP, ie., from type 1 to type 10 AQP, have been identified so far, whereas, more than 100 types of AQP exist in plants in which transport of water are more critical for the survival than in mammalians. AQP1 was the first type to be isolated in erythrocytes. Human type AQP1 was cloned for the first time by one of the present inventors (Moon C et als. Cloning of human aquaporin 1 gene, J Biol Chem (1993) 268, 15772-15778). Two functional groups of AQP are now being recognized. The first, including AQP1, AQP2, AQP4, AQP5, AQP6, AQP8 and AQP10 are permeable only to water, as classically defined. A second group, including AQP3, AQP7 and AQP9 are highly permeable to water, but also are permeable by glycerol (King L S et al. Aquaporin in health and disease, Molecular Medicine Today (2000) 6, 60-65). The present inventors have recently found the evidence that AQP also plays important roles in cell cycle regulation, signal transduction, delayed early response to growth factors, and gas exchange in hypoxic condition. AQP proteins exist in cell membranes, and to adapt to water channel function, its structure has six transmembrane domains and five connecting loops (loop A-E). The. Amino terminal (NH2 terminal) and carboxy terminal (COOH terminal) portion of AQP are located inside cytoplasm. Loop B and E of AQP contains signature motif Asn-Pro-Ala, which is called NPA, and adjacent cysteine. Two NPA motifs and cysteine combine to become center of the water channel (Walz T et als. Three-dimensional electron density map of human aquaporin 1 at 6 A resolution. Nature (1997) 387, 624-627; Lee M D et al. The human aquaporine-5 gene. J. Biol. Chem (1996) 271, 8599-8604). Each type of 10 mammalian aquaporins has a distinct tissue and cellular distribution and plays a diverse and specific role depending on the type of tissues and cells where it is located. AQP1 is located in erythrocytes, kidney, lung, eye, choroid plexus, biliary tract, nonfenestrated endothelia. AQP1 is abundant in proximal tubules and descending thin limb of Henle's loop segments, actively reabsorbs most of glomerular, filtrate and thus greatly contributes to concentration of urine. AQP2 is located in collecting duct epithelia of kidney, secreted in response to stimulation of antidiuretic hormone and thus contribute to concentration of urine. Deficiency of AQP2 produces nephrogenic diabetes insipidus which is characterized by failure to concentrate urine. AQP3 is located in renal collecting duct, gastrointestinal tract, airway epithelia, corneal epithelium and brain. AQP4 is abundant in glial cells and ependymal cell of brain tissue, but is also located in retina and airway epithelia. AQP5 is located in salivary gland, lacrimal gland and lung, in which plays an important role in production of saliva, tear and airway secretions. AQP6 is located in proximal tubular epithelia and collecting duct epithelia of kidney and characteristically acts as intracellular water channel and also is involved in regulation of acid base balance. AQP7 and AQP8 are expressed in germ cells and sperms. AQP9 is abundant in adipocytes (Deen P R T et al. Epithelial aquaporins., Current Opinion in Cell Biology.(1999) 10, 435-442; King L S et al. Aquaporin in health and disease, Molecular Medicine Today (2000) 6, 60-65; Agre P. Aquaporin water channels in kidney. J. American Society of Nephrology (2000) 11, 764-777). AQP plays important roles particularly in kidney, lung, brain, eye and eythrocytes. The lung has exceptionally high epithelial and endothelial permeability. Appropriate removal and supply of water in the airway, vascular and interstitial compartments of the lung are essential for normal gas exchange and lung defence. AQP is actively involved in the maintenance of liquid layer of surface of airway epithelia, which is essential for normal mucosal ciliary action, and also involved in appropriate supply of water to airway which prevents dehydration of airway and ensures adequate dehydration of expired air. Four water channels, including AQP1, AQP3, AQP4 and AQP5 have been indentified in the lung of rats and mice. AQP1 (Genebank No. NM-000385) is abundant in apical and basolateral membrane, of microvasculature and pleural membrane. AQP5 (Genebank No. NM-001651) is abundant in apical membrane of type 1 alveolar pneumocytes and secretory cells of airway submucosal gland. AQP3 (Genebank No. NM-004925) and AQP4 (Genebank No. U63623) are expressed in epithelial cells of airway and nasopharynx. AQP is also reported to be involved in CO 2 exchange of alveolar cells, which suggest that AQP may act as a gas channel (Nielsen S et al. Aquaporin in complex tissue II., Cellular and subcellular distribution in respiratory tract and glands of rat., American J. Physiology (1997) 273, 1549-1561; King L S et al. Aquaporin-1 water channel protein in lung: ontogeny, steroid-induced expression, and distribution in rat., J. Clin Invest (1996) 97, 2183-2191). However, distribution and function of each type of AQP in the human lung remain to be indefinite. In addition, role of AQP in human cancer, in particular lung cancer, remains to be indefinite. Considering the prior art up to now, there is a need for the development of new tumor markers, which is useful for screening, diagnosis, and follow-up study after treatment for human cancer including lung cancer.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 illustrates expression of aquaporin (AQP) gene in bronchial and airway tissues of adult human by using in situ hybridization methodology. In A: antisense probe of aquaporin type 1 (AQP1) was used, In B: sense probe of AQP1 was used, In C: antisense probe of aquaporin type 5 (AQP5) was used, In D: sense probe of AQP5 was used, In E: antisense probe of aquaporin type 3 (AQP3) was used, In F: sense probe AQP3 was used, In G: antisense probe of aquaporin type 4 (AQP4) was used, In H: sense probe of AQP4 was used. FIG. 2 illustrates expression of aquaporin (AQP) gene in bronchial and airway tissues of 17-week old male infant by using in situ hybridization methodology. In A and B, antisense probe of AQP1 and sense probe of AQP1 was used for the study of bronchial epithelium and developing bronchiolar structure, respectively, In C and D, antisense probe of AQP1 and sense probe of AQP1 was used for the study of immature alveolar structure, respectively, In E and F, antisense probe of AQP5 and sense probe of AQP5 was used for the study of bronchial epithelium and developing bronchiolar structure, respectively, In G and H, antisense probe of AQP5 and sense probe of AQP5 was used for the study of immature alveolar structure, respectively, FIG. 3 illustrates expression of aquaporin gene family in bronchial tissues of 3 men with history of smoking as analyzed by reverse transcription polymerase chain reaction (RT-PCR) assay. Products of RT-PCR were shown on gel electrophoresis. 1: AQP1 3: AQP3 4: AQP4 5: AQP5 The sample number indicates serial number of man under study. FIG. 4 illustrates expression of AQP1 gene in human head and neck cancer cell lines and human lung cancer cell lines as analyzed by RT-PCR. Products of RT-PCR were identified on gel electrophoresis. FIG. 5 illustrates expression of AQP3 in human head and neck cancer cell lines and human lung cancer cell lines as analyzed by RT-PCR. Products of RT-PCR are shown on gel electrophoresis. FIG. 6 illustrates expression of AQP4 in human head and neck cancer cell lines and human lung cancer cell lines as analyzed by RT-PCR. Products of RT-PCR are shown on gel electrophoresis. FIG. 7 illustrates expression of AQP5 in human head and neck cancer cell lines and human lung cancer cell lines as analyzed by RT-PCR. Products of RT-PCR are shown on gel electrophoresis. FIG. 8 illustrates expression of AQP5 in human lung cancer tissues as analyzed by Nothern blotting. SQC1 and SQC2 indicate tissue of squamous cell carcinoma, ADE1, ADE2 and ADE3 adenocarcinoma, BAC1 bronchioalveolar carcinoma, LAG large-cell carcinoma, and SMC1 small cell carcinoma, respectively. FIG. 9 illustrates expression of AQP gene family in human lung cancer tissues as analyzed by in situ hybridization. In A-1, antisense probe of AQP1 was used in the analysis of a tissue of squamous cell carcinoma, In A-2, sense probe of AQP1 was used in the analysis of a tissue of squamous cell carcinoma, In B-1, antisense probe of AQP1 was used in the analysis of a tissue of brochioalveolar carcinoma, In B-2, sense probe of AQP1 was used in the analysis of a tissue of bronchioalveolar carcinoma, In C, antisense probe of AQP5 was used in the analysis of a tissue of squamous cell carcinoma, In D, antisense probe of AQP5 was used in the analysis of a tissue of bronchioalveolar carcinoma, FIG. 10 illustrates detection of AQP expression in sputum of patients with lung cancer and normal man as analyzed by using RT-PCR. Products of RT-PCR are shown on gel electrophoresis. FIG. 11 illustrates detection of AQP expression in blood of patients with lung cancer and normal man as analyzed by using RT-PCR. Products of RT-PCR were identified on gel electrophoresis. FIG. 12 illustrates the results of nucleic acid sequencing analysis of cDNA of AQP5 which were obtained from normal lung tissues and lung cancer tissues by RT-PCR followed by cloning. FIG. 13 illustrates the results of automated sequencing analysis of cDNA of mutant AQP5 gene which was obtained from bronchoscopic lavage sample of a patient with lung cancer by using RT-PCR followed by cloning. FIG. 14 illustrates the result of automated sequencing analysis of cDNA of mutant AQP5 gene which was obtained by RT-PCR followed by cloning from sputum of a patient with lung cancer. FIG 15 illustrates the frequency of mutation of AQP5 gene, which was found in human lung cancer tissues. In FIG. 15 a, the mutation frequency of AQP5 were analyzed depending on exon number. In FIG. 15 b, the mutation frequency of AQP5 were analyzed depending on codon number, FIG. 16 illustrates an example of detection of mutation of exon 1 of AQP5 by using single strand conformational polymorphism (SSCP) analysis. FIG. 17 illustrates an example of detection of AQP5 mutation by using mutant specific oligonucleotide (MSO) hybridization method. FIG. 18 illustrates an example of detection of mutation of AQP5 by using multiplex PCR. LANE 1: mutant AQP5, LANE 2: wild type AQP5. FIG. 19 illustrates an example of analysis of mutation of AQP5 by using DNA chip of the present invention. FIG. 20 illustrates an list of nucleic acid sequences of sense primer and antisense primer which were arrayed on oligonucleotide chip of the present invention. FIG. 21 illustrates a four-colored image of oligonucleotide chip of AQP5 gene in which each base of adenine (A), cytosine (C), guanine (G) and thymine (T) is shown in different color and thus is easily discriminated. FIG. 22 illustrates an example of test for AQP5 mutation by using oligonucleotide DNA chip and automated nucleic acid sequencing assay. In FIG. 22 a, point mutation of AQP5 was found in the form of heterozygosity of A/G. This point mutation was missed on automated sequencing analysis (ABI Prism) of FIG. 22 b. FIG. 23 . illustrates an example of test for AQP5 point mutation by using oligonucleotide chip of the present invention. A base was changed to T on analysis of both sense strand and antisense strand. detailed-description description="Detailed Description" end="lead"?

Method of culturing mesenchymal stem cells

This invention provides a novel method of culturing mesenchymal stem cells whereby a remarkably larger number of mesenchymal stem cells can be obtained compared with the conventional culture methods. This culture method is characterized by adding to a medium a fibroblast growth factor (FGF) as a substance which stimulates the proliferation potency of the mesenchymal stem cells while retaining the pluripotency thereof and prolongs the life. According to the method, mesenchymal stem cells can be cultured at least over 30 generations and, moreover, about 105 to 106 times as much as cell count in the conventional culture methods can be obtained.

1. A method of culturing mesenchymal stem cells, comprising culturing said mesenchymal stem cells in a medium that contains a substance that stimulates the proliferation of said mesenchymal stem cells. 2. The method of claim 1, wherein the substance is a fibroblast growth factor. 3. The method of claim 2, wherein the fibroblast growth factor is added to the medium at a concentration of 0.04 to 10 ng/ml. 4. The method of claim 3, wherein the fibroblast growth factor is added to the medium at a concentration of 0.1 to 1 ng/ml. 5. The method of claim 11, wherein the mesenchymal stem cells are derived from a human. 6. Mesenchymal stem cells obtained by the method of claim 1 or 2, wherein the mesenchymal stem cells retain their pluripotency. 7. The mesenchymal stem cells of claim 6, wherein the mesenchymal stem cells have the potential to differentiate into chondrocytes. 8. (canceled) 9. The mesenchymal stem cells of claim 6, wherein the mesenchymal stem cells retain their pluripotency in subculture for at least 15 generations. 10. The mesenchymal stem cells of claim 6, wherein the mesenchymal stem cells retain their pluripotency in subculture for at least 16 days. 11. The method of claim 1, wherein the mesenchymal stem cells are derived from a mammal. 12. The method of claim 2, wherein the fibroblast growth factor is fibroblast growth factor 1 or fibroblast growth factor 2. 13. The mesenchymal stem cells of claim 6, wherein the mesenchymal stem cells have the potential to differentiate into osteoblasts.

<SOH> BACKGROUND TECHNOLOGY <EOH>Tissues of a vertebrate, especially mammalian tissues, contain stem cells which have the ability to regenerate cells and tissues in cell regeneration system, for example, to regenerate cells and tissues lost by trauma, disease or aging. Stem cells therefore are found within the tissue or in other tissues that serve as stem cell reservoirs. Bone marrow and periosteum are the major stem cell reservoirs. Bone marrow is the major source of adult hematopoietic stem cells, which are undifferentiated pluripotent cells. It is known that all blood cells (e.g. erythrocyte, leukocyte, lymphocyte, etc.) are differentiated from the hematopoietic stem cells. Many researches have been made on cultivation and differentiation of hematopoietic stem cells, and many substances (growth factors) have been reported which are useful for culturing hematopoietic stem cells and for differentiating and inducing to various blood cells (components). On the other hand, bone marrow, periosteum and the like contain other stem cells than hematopoietic stem cells, i.e. mesenchymal stem cells, which play an important role for regenerating the mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, adipose and stroma. Mesenchymal stem cells proliferate as undifferentiated cells and retain the pluripotency, by which can differentiate into such as adipocytes, chondrocytes or osteoblasts. The stem cells can easily be isolated from adult bone marrow and periosteum, and show a stable phenotypic cell form. For example, the mesenchymal stem cells derived from bone marrow retain the character of monolayer in vitro cultivation (Pittenger M. F. et al., Science 284, 143-147, 1999). It was therefore proposed to culture mesenchymal stem cells in large amounts and to differentiate and induce thus obtained undifferentiated cells into cartilage tissue or bone tissue, which can be used for transplantation therapy. Cultivation of bone marrow-derived mesenchymal stem cells was attempted as the first step. The conventional culture methods however cannot produce sufficient amounts of mesenchymal stem cells because the proliferation of said stem cells stops or becomes extremely slow around 15 th generation. There is further problem that the differentiation potential to chondrocytes or osteoblasts is lost. In order to induce cartilage or bone tissue from the mesenchymal stem cells and to use them for transplantation therapy, large amounts of said stem cells are required as a start material.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 a graph which shows the cell growth in FGF-added group by [cell number/days in culture]. FIG. 2 is a graph which shows the cell growth in FGF-added group by [generation number/days in culture]. FIG. 3 is a microphotograph of the tissue before chondrogenic differentiation by the addition of bFGF. FIG. 4 is a microphotograph of the tissue after chondrogenic differentiation by the addition of bFGF. FIG. 5 contains graphs showing the cell growth of the rabbit mesenchymal stem cells (derived from ilium (I), derived from tibia (T)) (A, B) in the presence of bFGF (1 ng/ml) or absence, and human mesenchymal stem cells (C). FIG. 6 is to illustrate the chondrogenic differentiation potential of the mesenchymal stem cells by FGF, contains a series of microphotographs of cell pellets cultured in the presence of FGF (A-C) and absence (D), after 2 days (A), 4 days (B) and 8 days (C, D) from chondrogenic differentiation, and a series of microphotographs of cell pellets of 3, 6, 9 or 12 generations subcultured in the presence of FGF (E-H). FIG. 7 is to illustrate the chondrogenic differentiation potential of the mesenchymal stem cells subcultured in FGF(+) or FGF(−), and shows the amount of glycosaminoglycan content (A), alkaline phosphatase activity (B) and expression of cartilage specific genes (type II collagen, type X collagen) (C). FIG. 8 is to illustrate the osteogenic differentiation potential of the mesenchymal stem cells which subcultured in FGF(+) or FGF(−), and shows the calcium content of the mesenchymal stem cells seeded at a high density or low density (A, B), alkaline phosphatase activity (C), and expression of bone specific genes (bone sialoprotein (BSP), osteopontin (OP) and osteocalcin (OC)) (D). FIG. 9 is to illustrate the adipogenic differentiation potential of the mesenchymal stem cells subcultured in FGF(+) or FGF(−), and shows microphotographs of the cells differentiated into adipocyte in FGF(+) (A) and FGF(−) (B), and expression of adipocyte specific gene (PPAR-γ2) (C). detailed-description description="Detailed Description" end="tail"?

Arrangement in a distributed control system for increasing the availability of data and/or control commands

There is a need for increasing the availability of data and/or control commands in a distributed control system for one or more machines, vehicles and/or processes. The control system comprises or is controlled by a transmitting node (1) or transmitter unit and has two or more receiving nodes (13, 14, 15, 16). The transmitting nodes and receiving nodes are connected to each other via wire [sic] radio links. The receiving nodes are located at a distance from each other and are connected to a few-wire digital link in a wired system for forwarding of the said data and/or control commands to the executing devices. The control [sic] node transmits the said data and/or the control commands in different directions towards the receiving nodes which are arranged at a distance from each other. Receiving nodes with reception that is essentially not subject to interference are arranged to be able to connect to the few-wire link in parallel and simultaneously with a receiver unit or units which have links that are connected to the few-wire link. In another case, only those receiver unit or units are connected that have reception links that are not subject to interference, while the receiver unit of units with links that are subject to interference do not participate in the transmission of the message on the few-wire link.

1. An arrangement for increasing availability of data and/or control commands (D) in a distributed control system (CAN) for one or more machines (2″) (also vehicles) and/or processes (2″), the control system being influenced by or comprising at least one transmitting node (1) or transmitter unit, and also comprising two or more receiving nodes (13, 14, 15, 16), and where the transmitting node or transmitter unit and the receiving nodes can be connected or are connected to each other via wireless links (radio links 5, 6, 7, 8) and where the receiving nodes are located at a distance (A, B) from each other and are connected to a few wire digital (21) link in a wired system for forwarding the said data and/or control commands to executing devices (41) for, for example, functions, measurements, etc, characterized in that the transmitting node or transmitter unit is arranged to send the said data and/or control commands in parallel and simultaneously in different directions (9, 10, 11, 12) towards the receiving nodes, and that in the event of wireless links that are essentially not subject to interference between the transmitting node or transmitter unit and the receiving nodes, the latter are arranged to connect in parallel and simultaneously for parallel and simultaneous transmission of the said data and/or control commands to the few-wire link and thereby to the executing device or devices (41) concerned, and in the event of wireless link or links that are essentially subject to interference between the transmitting node or transmitter unit and the receiving node or nodes concerned, the latter are prevented from making their connections to the few-wire link, whereby the transmission of the said data and/or control commands to the few-wire link and respective executing device in this case is effected by the remaining receiver devices with wireless link or links that are essentially not subject to interference. 2. An arrangement according to claim 1, characterized in that the transmitting node (1) or transmitter unit sends the said data and/or control commands to the receiving nodes (13, 14, 15, 16) on different frequencies. 3. An arrangement according to claim 2, characterized in that data and/or the control commands are incorporated in or form messages (27, 27′, 27″, 27′″) with system identification (ID, C), data (D) and data length codes and control codes (CRC and CH). 4. An arrangement according to any one of the preceding claims, characterized in that the distributed system (CAN) consists of or comprises a system of the control area system type where the receiving nodes (13, 14, 15, 16) are synchronized with each other or coordinated with the connection or arbitration functions of the few-wire link (21), with the result that they simultaneously obtain access to the few-wire link via messages received from the transmitting node or transmitter unit that are essentially or completely not subject to interference and that in the event of absent coordinated connections on account of messages (27) from the transmitting node (1) or transmitter unit essentially subject to interference or absent, they obtain information from the few-wire link concerning cancelling further attempts to connect to the few-wire link after the receiving node or receiving nodes with link or links that are essentially not subject to interference have completed the transmission of the message on the few-wire link. 5. An arrangement according to any one of the preceding claims, characterized in that, in the event of its message from the transmitting node or transmitter unit being essentially subject to interference or absent, the respective receiving part is arranged to receive or detect all or parts of the message that was transmitted on the few-wire link (21) from the receiving unit or receiving units with received message or messages that are essentially not subject to interference, and that, in the event of such received part of the message or received message, it is arranged to prevent continued attempts to access the few-wire link (21). 6. An arrangement according to any one of the preceding claims, characterized in that, in the event of a predetermined level of interference in its received message, the respective receiving node is arranged to generate an internal cancellation signal (i2) or cancelling which prevents the connection of the receiving node to the few-wire link (21). 7. An arrangement according to any one of the preceding claims, characterized in that, in the event of interference in their received messages above a predetermined value, the receiving nodes are arranged to effect an arrangement between the receiving nodes which selects the receiver unit that at the time of reception has reception which is the least subject to interference, and that only the receiving node thereby selected obtains access to the few-wire link for transmission of its received message on this link. 8. An arrangement according to any one of the preceding claims, characterized in that the transmitting node consists of or comprises a service unit provided with a computer, and that the receiver units are located in a vehicle (2′), with the executing devices in the vehicle controlling function executors, for example in the form of door mirrors, driver's seat, sunroof, etc. 9. An arrangement according to any one of the preceding claims, characterized in that the transmitting node or transmitter unit is fixed, that is allocated a predetermined geographical position. 10. An arrangement according to any one of claims 1-9, characterized in that the transmitting node or transmitter unit is movable and constitutes a mobile unit for example incorporated in the general communication mobile system (GSM). 11. An arrangement according to any one of the preceding claims, characterized in that the nodes or units in the system are arranged for message forms that exist in association with Bluetooth. 12. An arrangement according to any one of the preceding claims, characterized in that the receiving nodes are synchronized with each other with regard to connection and arbitration functions that occur in conventional control area systems. 13. An arrangement according to any one of the preceding claims, characterized in that the receiver units operate with and are synchronized or coordinated with each other by means of time functions incorporated in the control area system (CAN). 14. An arrangement according to any one of the preceding claims, characterized in that the system has two types of link, wireless links and wired links, where by wired links is meant such links as have wires, leads, etc, and/or optical connections comprising opto links. 15. An arrangement according to any one of the preceding claims, characterized in that the system can operate with two, three or more steps, where in a first step a transmission is carried out from wireless transmitter to wireless receiver and from wireless receiver to wired link and in the case with three steps from wired link to wireless transmitter(s), from wireless transmitter to wireless receiver(s) per channel, and from wireless receiver(s) to wired link. 16. An arrangement according to any one of the preceding claims, characterized in that the wireless transmitters each transmit on a separate channel (channel frequency), where a channel is characterized in that when transmitting each transmitter has access to a part of the available bandwidth in the ether which is exclusive to the system. 17. An arrangement according to claim 16, characterized in that the exclusivity can be an allocated frequency in a time interval, for example as in the known Bluetooth protocol, IEEE 802.11 for jumping frequency or a correlation code (as in IEEE 802.11 Direct Sequence Spread Spectrum). 18. An arrangement according to any one of the preceding claims, characterized in that a transmitter and one or more receivers can operate on one and the same channel during one and the same time interval. 19. An arrangement according to any one of the preceding claims, characterized in that units in the form of g-nodes, that is nodes that are connected both to the respective wireless network and the respective wired network, are arranged to operate as gateways, where they receive a complete message on the wireless links in question and ascertain in a known way that it has been correctly received by means of check code, error-correcting code, etc, after which the message is able to be sent on the wired links concerned. 20. An arrangement according to any one of the preceding claims, characterized in that the respective message has an identity in the respective medium which is unique at least at the time of transmission, which identity can be a bit code or can consist of a particular time slot in a scheduled system or a combination of these functions. 21. An arrangement according to claim 19 and 20, characterized in that the identity is the same or different for media involved, where in the case where they are different, respective g-nodes are arranged to know the association between the identifies. 22. An arrangement according to any one of the preceding claims 17-21, characterized in that the Bluetooth protocol is used in a modified form as a protocol, inasmuch as several slaves are allocated the same time slot for the reception in question, that a field bus message (CAN message in the form of LLC data frame) is arranged for generation in a computer (microcomputer) which is equipped with a radio interface of the Bluetooth type. 23. An arrangement according to any one of the preceding claims 17-22, characterized in that a CAN message is arranged for packaging as data in a Bluetooth message which is sent by the computer (microcomputer) and that reception of this message is carried out in two or more g-nodes. 24. An arrangement according to any one of the preceding claims 17-23, characterized in that the g-nodes that received the CAN message [error-]free according to the Bluetooth protocol's error-detection mechanisms are able thereafter to transmit the CAN message on the CAN bus. 25. An arrangement according to any one of the preceding claims 19-24, characterized in that in the case where several g-nodes commence their transmission synchronized to the same frame (Strat of Frame=SOF), simultaneous transmission of the message from the g-nodes takes place bit by bit, which is made possible as the messages are identical. 26. An arrangement according to any one of the preceding claims 19-25, characterized in that in the case where any one or more of the g-nodes can not synchronize with the message that the first g-node transmits, they change over to receiving nodes in accordance with the CAN protocol, which means that the respective g-node concerned will receive a message which is identical to the one the respective g-node was in the process of transmitting on the bus, and that when the respective g-node has ascertained that such is the case, the g-node ceases to send its message in question, which thus means that there is parallel redundancy for signalling from the computer (the microcomputer) to the CAN network. 27. An arrangement according to any one of the preceding claims 19-26, characterized in that in the opposite direction there is serial redundancy where the respective g-nodes are each allocated a time slot for transmission and information about which CAN identifier identifies the CAN message in question which is arranged to be sent to the computer/processor (microcomputer PC), where the respective g-node receives at the same time the message on the CAN bus in accordance with the CAN protocol. 28. An arrangement according to any one of the preceding claims 19-27, characterized in that the respective message which is arranged to be sent to the computer/processor (PC) is arranged for packaging as data in a Bluetooth message and for dispatch in the respective time slot, where the computer (PC) receives one or more identical messages from the CAN system. 29. An arrangement according to any one of the preceding claims 19-28, characterized in that information about which receiver has received the strongest signal is able to be produced, where the radio part or parts of the g-nodes provide a value for the signal strength (signal strength indicator, SSI), for example a measurement value 0-255, that the CAN identifier is divided into at least three fields, where one contains the value 255 minus the SSI value, one field indicates which g-node is sending the message, and one field indicates that it is one (of several) messages from the computer/processor (PC). 30. An arrangement according to any one of the preceding claims 19-29, characterized in that the said SSI value−255 is applied in the CAN identifier, where the g-node that [has] the highest signal strength gains access to the bus if all the anodes commence signalling at the same time, which information about which g-node has the strongest signal and the relevant value of this is thus indicated in the CAN identifier and is thus available to all nodes which require this information. 31. An arrangement according to any one of the preceding claims, characterized in that the signal strength in combination with indication of bit errors can be used together with other measures, for example change of transmitter, and/or amended propagation diagram from the transmitter or transmitters, etc, which can be relevant in the case when the signal comes via several different signal paths (a so-called multipath situation). 32. An arrangement according to any one of the preceding claims, characterized in that in the case with one or more mobile transmitters, in a first position these can have contact with a first number of receivers, for example two receivers, thereafter with a second number of receivers, for example three receivers, and thereafter again with the first number of receivers, for example the said two receivers, that the transmission reliability is thereby able to be ensured by the P-presentation function, where the SSI-presentation provides an indication of where the mobile transmitter is located. 33. An arrangement according to claim 32, characterized in that the combination of a mobile transmitter and a fixed network can consist of a car that is in a garage, a car that is at a service station, an ignition key (or corresponding unit that can comprise a similar function, for example a mobile phone, identity card, etc) for a vehicle. 34. An arrangement according to any one of the preceding claims, characterized in that a unit that is not yet connected (for example a mobile unit) can listen on a fixed frequency on which time messages will appear and on which the unit that is not yet connected is able to synchronize itself to the network on the messages that are still to be sent to maintain the global time in the system, and that the messages can contain identification data for the system in addition to the said messages.

Method and device for the measurement of chemical and/or biological samples

A device for the measurement of chemical and/or biological samples, in particular by means of luminescence spectroscopy, comprises an irradiation unit (12), a sample receiver (10), at least one optical unit (30) and a detector unit (40). Electromagnetic radiation of various wavelength ranges and/or polarizations are led from the sample (10) from the irradiation unit (12). The color marker in the sample (10), which contains at least one color marker, is stimulated into producing luminescence and gives off light. The emitted light is led by means of an optical unit to a detector unit. The light emitted by the color markers is detected by detectors (42, 44, 46, 48) in the detector unit. According to the invention, the measurement results may be improved on the irradiation unit (12) generating a pulsed irradiation. The irradiation unit is thus preferably controlled by a control unit (18) in such a way that the irradiation pulses impinge on the sample (10) in a temporal sequence.

1. A method for measuring chemical and/or biological samples by means of spectroscopic or microscopic methods, in particular using luminescence spectroscopy, wherein: the sample including at least one marker in a measuring volume is irradiated with electromagnetic radiation of at least two different wavelength ranges and/or polarizations, the excited marker emits radiation in an emission wavelength range, and the emitted radiation is detected by at least one detector, characterized in that the electromagnetic radiation used to excite the marker is pulsed in at least two different wavelength ranges and/or polarizations and the radiation pulses of the individual wavelength ranges and/or polarizations impinge on the sample with a temporal offset. 2. The method of claim 1, wherein a relative movement between the measuring volume and the marker, in particular between the measuring volume and a single marker molecule, occurs in a relative movement period and the electromagnetic radiation used to excite the marker is pulsed in at least one wavelength range and/or one polarization such that at least two radiation pulses hit the marker within the relative movement period in which the measuring volume contains the marker. 3. The method of claim 1 or 2, wherein the marker, in particular a single marker molecule, diffuses through the measuring volume during a diffusion period and the electromagnetic radiation used to excite the marker is pulsed in at least one wavelength range and/or one polarization such that at least two radiation pulses hit the marker within the diffusion period. 4. The method of claim 1 or 2, wherein the marker is stationary and a relative movement between the measuring volume and the marker occurs by moving the measuring volume and/or by moving the sample receiver containing the marker. 5. The method of one of claim 1, wherein a radiation pulse is generated only after the excitation of the marker, excited by a previous radiation pulse of a different wavelength range and/or a different polarization, has substantially decayed. 6. The method of one of claims 1-5, wherein the radiation of the individual wavelength ranges and/or polarizations is emitted in repetitive sequence. 7. The method of one of claims 1-6, wherein the sample includes two markers, each marker being excited by one wavelength range and/or one polarization, respectively. 8. The method of one of claims 1-7, wherein a red and/or a green color marker are used together with red and/or green excitation light, the green excitation light has a wavelength range preferably of 480 to 550 nm, more preferred of 485 to 535 nm, and the red excitation light has a wavelength range preferably of 630 to 690 nm, more preferred of 635 to 655 nm. 9. Device for measuring chemical and/or biological samples by means of spectroscopic or microscopic methods, in particular by luminescence spectroscopy, comprising a irradiation unit (12) for generating electromagnetic radiation in at least two different wavelength ranges and/or polarizations, a sample receiver (10) for holding the sample including at least one marker, a detector unit (40) comprising at least one detector (42-48) for detecting the radiation emitted by the sample, and at least one optic unit (30) directing the radiation from the irradiation unit (12) to a measuring volume in the sample receiver (10) and/or directing the radiation emitted by the sample to the detector unit (40), characterized in that the irradiation unit (12) generates radiation pulsed in at least two different wavelength ranges and/or polarizations and the radiation pulses of the individual wavelength ranges and/or polarizations are temporally offset. 10. The device of claim 9, wherein a relative movement between the measuring volume and the marker, in particular between the measuring volume and a single marker molecule, occurs in a relative movement period and the irradiation unit generates radiation that is pulsed such that at least two radiation pulses hit the marker within the relative movement period in which the measuring volume contains the marker. 11. The device of claim 9 or 10, wherein the marker, in particular a single marker molecule, diffuses through the measuring volume during a diffusion period and the irradiation unit (12) generates radiation pulsed in at least one wavelength range and/or one polarization such that at least two radiation pulses hit the marker within the diffusion period. 12. The device of one of claims 9-11, wherein it comprises means for moving the measuring volume and/or the sample receiver containing the marker. 13. The device of at least one of claims 9-12, wherein the irradiation unit is connected to a control unit (18), preferably a mode coupler, for generating the radiation pulses. 14. The device of claim 13, wherein the control unit (18) controls the radiation pulses such that a radiation pulse is generated only after the excitation of the marker, excited by a previous radiation pulse of a different wavelength range and/or a different polarization, has substantially decayed. 15. The device of claims 13 or 14, wherein the control unit (18) controls the radiation pulses such that the radiation pulses of the individual wavelength ranges and/or polarizations are emitted in repetitive sequence. 16. The device of one of claims 9-15, wherein the irradiation unit (12) comprises at least two radiation sources, in particular lasers (14, 16), for generating different wavelength ranges and/or polarizations. 17. The device of claim 12, wherein the irradiation unit (12) comprises a common control unit (18) for all radiation sources (14, 16). 18. The device of claim 17, wherein the control unit (18) is connected to the radiation sources (14, 16) through a respective trigger wire (20, 22), the time interval between the radiation pulses being defined by the length of the trigger wires (20, 22). 19. The device of one of claims 16-18, wherein the irradiation unit (12) comprises two radiation sources (14, 16), one radiation source (14) generating red light and the other (16) generating green light, and wherein the green light has a wavelength range preferably of 480 to 550 nm, more preferred of 485 to 535 nm, and the red light has a wavelength range preferably of 630 to 690 nm, more preferred of 635 to 655 nm. 20. The device of one of claims 9-19, wherein the irradiation unit (12) comprises only one non-polarized pulsed radiation source (14), the irradiation unit (12) additionally comprising (a) a beam splitter and, in each beam path established, a polarizing filter as well as a component for combining the beam paths, or (b) a polarizing beam splitter for establishing two beam paths of different polarizations as well as a component for combining the beam paths, or (c) a rapidly rotating polarizing filter in an unsplit beam path. 21. The device of one of claims 9-20, wherein the irradiation unit (12) comprises two polarized pulsed radiation sources (14, 16) of the same wavelength range but of opposite polarization. 22. The device of one of claims 9-21, wherein the detector unit (40) comprises only one combination detector connected to an evaluating unit (52), the evaluating unit (52) evaluating the radiation emitted by the at least one marker separately due to the time interval. 23. The device of one of claims 9-22, wherein the detector unit (40) comprises two detectors (42, 44), in particular one for detecting the light emitted by red color markers and one for detecting light emitted by green color markers. 24. The device of one of claims 9-23, wherein the detector unit (40) comprises a beam splitter (50), arranged before the detectors (42-48), for generating two beams (54, 56) of different polarization and each beam (54, 56) is detected by at least one detector (42, 44, 46, 48). 25. The device of at least one of claims 9-24, wherein the marker, in particular a single marker molecule, has a characteristic fading time during which only it emits radiation, and the irradiation unit (12) generates radiation that is pulsed in at least one wavelength range and/or polarization such that at least two radiation pulses hit the marker within the fading period. 26. The method of at least one of claims 1-8, wherein the marker, in particular a single marker molecule, has a characteristic fading time during which only it emits radiation, and the electromagnetic radiation used to excite the marker is pulsed in at least one wavelength range and/or one polarization such that at least two radiation pulses impinge on the marker within the fading period.

Method of deinking waste paper using cellulase without lowering paper strength and method of evaluating the same

A deinking method using a cellulase which enables the load upon the environment to be reduced; and an evaluation method whereby a cellulase effective in deinking and the effective addition level of the cellulase can be appropriately determined. By proposing pulp-swelling activity (PSA) that elevates the water-retention value of pulp after pulp is reacted with cellulase, it becomes possible to select an enzyme that is effective in cellulase-deinking treatment without lowering the paper strength and to determine the effective enzyme dosage. Namely, a method of deinking waste paper is provided wherein the selection of an effective cellulase and the optimization of the enzyme dosage with the use of PSA as an indication make it possible to minimize the cellulase addition level and lessen the amount of the deinking agent.

1. A deinking method for waste paper characterized by the use of cellulase exhibiting a pulp-swelling activity (PSA). 2. The method of claim 1, characterized by being conducted with a cellulase of a dosage level wherein the pulp-swelling activity (PSA) is 25 units (25U) or more. 3. The method of claim 1, characterized by being conducted with cellulase of a dosage level wherein the pulp-swelling activity (PSA) exhibits a maximum value. 4. The method of claim 1, in which cellulase is endoglucanase. 5. The method of claim 4, in which endoglucanase is SCE3 derived from Trichoderma genus, NCE4 derived from Humicola genus, or RCEI derived from Rhizopus genus. 6. An evaluation method for obtaining a cellulase enzyme and an enzyme dosage that are effective in deinking of waste paper without lowering the paper strength, characterized in that, after reacting cellulase with pulp, the degree of swelling of the pulp is determined. 7. The method of claim 6, characterized in that, after reacting pulp with cellulase for 60 minutes at an optimal pH and optimal temperature of the enzyme used at a pulp consistency of 1% (w/v), a change in a water retention value (WRV) of the pulp is measured. 8. The method of claim 6 or 7, characterized in that, using 0.5 grams of oven-dried pulp as a substrate, cellulase is reacted for 60 minutes under conditions of an optimal pH and optimal temperature at a pulp consistency of 1% (w/v), and then a pulp-swelling activity (PSA) is determined taking cellulase activity that increases the water retention value (WRV) of pulp by 1% as 10 units (10U). 9. The method of claim 2, characterized by being conducted with cellulase of a dosage level wherein the pulp-swelling activity (PSA) exhibits a maximum value. 10. The method of claim 2, in which cellulase is endoglucanase. 11. The method of claim 3, in which cellulase is endoglucanase. 12. The method of claim 7, characterized in that, using 0.5 grams of oven-dried pulp as a substrate, cellulase is reacted for 60 minutes under conditions of an optimal pH and optimal temperature at a pulp consistency of 1% (w/v), and then a pulp-swelling activity (PSA) is determined taking cellulase activity that increases the water retention value (WRV) of pulp by 1% as 10 units (10U).

<SOH> BACKGROUND ART <EOH>Deforestation is cited as a cause of global warming and the reduction of carbon-dioxide emissions is the focus of attention as a global environmental problem. Forest resources are utilized in contemporary industries in the forms of wood, pulp, and paper. Various methods are being studied to reduce the amount of deforestation in order to prevent global warming. In the field of paper, efforts are being made worldwide to increase the rate of waste paper recycling. Waste paper deinking is largely established as a method of waste paper recycling. In current methods, alkalis such as sodium hydroxide and sodium silicate, oxidative bleaching agents such as hydrogen peroxide, chelating agents, and agents such as surfactants are added to the waste paper to accelerate the release of ink from the pulp fiber. Thereafter, a washing technique and/or flotation technique is used to carry out deinking to separate the pulp and ink. However, due to the variety of raw materials used in waste paper and the variety of printing techniques, deinking by the conventional deinking techniques is becoming problematic. Further, in order to solve problems concerning adhesion of foreign matter (stickies), fiber damage, effluent load and the like, neutral deinking is attracting attention as a deinking method that is kinder to the environment. In order to carry out neutral deinking more effectively, enzymatic treatments utilizing cellulase and the like are being studied. A number of proposals have been put forth concerning deinking methods for waste paper using cellulase derived from fungi or bacteria. Kao Corp. proposes a deinking agent containing cellulase in JP Patent Publication (Unexamined Application) No. 59-9299, however there is no disclosure therein regarding the putative lowering of paper strength due to the action of the cellulase. In JP Patent Publication (Examined Application) No. 3-57235, Honshu Paper Co., Ltd. proposes a deinking technique for waste paper in which enzymatic treatment using alkali-resistant cellulase is performed at the same time as treatment with an alkaline deinking agent or after treatment with the deinking agent. In Japanese Patent No. 2805313, Oji Paper Co., Ltd. discloses a deinking technique in which treatment is conducted with a deinking agent after enzymatic treatment that contains cellulase. Further, in Japanese Patent No. 3042718, Novo Nordisk A/S attempts to find an enzyme component that can perform effective deinking by producing monocomponent cellulase. However, none of the above methods succeeded in providing an effective means for selecting an enzyme that realizes, at a low cost, a deinking effect that reduces the amount of the chemical agents that constitute an environmental burden or lower the strength (intensity) of waste paper in deinking. Although various studies are being conducted, the rate of diffusion of enzymatic deinking is extremely low. Up to now, studies have been conducted on the application of cellulases to areas such as elimination of vessel pick, improvement of paper machine runnability and drainage, and deinking of waste paper. However, because of the high cost of cellulases and the fact that the action and effects of cellulases is not clear, the current situation is that cellulase has not been offered for practical use in areas other than elimination of vessel pick. Furthermore, because cellulase is an enzyme that degrades cellulose fiber, it has been pointed out that a decrease in the yield and the strength (intensity) of waste paper pulp after deinking is prone to occur. Meanwhile, in deinking of waste paper, because the objects of effective deinking involve detachment and saponification of printing ink and pulp swelling, alkaline chemical agents and the like are used that amount to as much as several percent of the dry pulp weight. Further, as pulp is normally treated by being suspended in water of a volume that is equivalent to several dozen times the weight of the dry pulp, a vast amount of alkaline effluent is generated. Thus, because chemical agents are used in the treatment to neutralize the effluent, the recovery treatment is one that involves a heavy environmental burden. There is a need for development of an environmentally friendly deinking method that improves the current deinking technology that creates a heavy environmental burden. Waste paper recycling is technology that indirectly protects forest resources and contributes to conservation of the global environment. It is anticipated that by further improvements such as reducing the environmental burden caused by waste effluent and decreasing the usage amount of chemical agents, the environmental adaptability of waste paper recycling will be enhanced. Thus, it was expected that enzymatic deinking would be applied as a technique to effectively remove ink at a neutral pH. However, its application has been postponed due to problems concerning decreases in the strength (intensity) of waste paper pulp and the cost of enzymes. Accordingly, the object of the present invention is to provide a cellulase deinking method for waste paper without lowering paper strength, that is implemented using an economically feasible enzyme amount that reduces the amount of deinking agents.

Cleaning device and container containing a single dosage of cleaning material

The present invention relates to a cleaning device (1, 1′) especially for cleaning surfaces, as toilet bowls and the like, having a cleaning head (3, 3′) and a handle (2, 2″). The cleaning device further comprises delivering means operable, in use, to deliver a single dosage of cleaning material (17), preferably contained in a small container, into or next to the cleaning head (3, 3′) and to release the cleaning material (17) from the cleaning head (3, 3′). Thereby exactly the amount of cleaning material needed for the cleaning action is dispensed and distributed over the surface by the cleaning head, no overdosing occurs.

1-15. (Cancelled) 16. A cleaning device for cleaning surfaces, the device comprising a cleaning head and a handle wherein the handle is adapted to receive at least one single dosage of cleaning material and by delivering means operable to deliver a single dosage of the cleaning material into the cleaning head and to release the cleaning material from the cleaning head. 17. Cleaning device according to claim 16, adapted to receive a single dosage of cleaning material enclosed in a container made of a water soluble material. 18. Cleaning device according to claim 16, wherein the handle comprises a hollow shaft extending to the cleaning head forming a passage for insertion and delivery of the single dosage of cleaning material. 19. Cleaning device according to claim 17, wherein the handle comprises a hollow shaft extending to the cleaning head forming a passage for insertion and delivery of the single dosage of cleaning material. 20. Cleaning device according to claim 18, wherein the handle further comprises a rod dimensioned to slide within the passage for pushing the single dosage of cleaning material into or next to the cleaning head. 21. Cleaning device according to claim 20, further comprising a spring acting to push the rod to the bottom of the passage. 22. Cleaning device according to claim 20, wherein the length of the rod is about half the length of the shaft. 23. Cleaning device according to claim 21, wherein the length of the rod is about half the length of the shaft. 24. Cleaning device according to claim 18, further comprising a cutting edge located at a bottom end of the passage for cutting or piercing a container inserted into the passage, the container containing the single dosage of cleaning material. 25. Cleaning device according to claim 18, wherein the shaft comprises an insertion opening for feeding the single dosage of cleaning material to the cleaning device, the insertion opening located half way between an upper end and a bottom end of the shaft. 26. Cleaning device according to claim 25, wherein the insertion opening is located at the upper end of the shaft. 27. Cleaning device according to claim 16, wherein the cleaning head comprises at least one outlet opening through which cleaning material can be released. 28. Cleaning device according to claim 16, wherein the cleaning head comprises a plurality of bristles and a plurality of outlet openings between the bristles. 29. A container comprising a single dosage of cleaning material, wherein the container is made of a water soluble foil and contains powder or liquid, non-aqueous material. 30. Container according to claim 29, wherein the water soluble foil comprises a low-temperature dissolving polyvinylalcohol (PVA). 31. Container according to claim 29, wherein the container has a cylindrical shape with a circular cross section. 32. Container according to claim 30, wherein the container has a cylindrical shape with a circular cross section. 33. A method of cleaning surfaces comprising feeding a container comprising a single dosage of a cleaning material to a cleaning device as claimed in claim 16. 34. A method of cleaning surfaces comprising feeding tablet comprising a single dosage of a cleaning material to a cleaning device as claimed in claim 16.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 a - d show a sectional view of an inventive cleaning device and steps of insertion of a container with cleaning material into the device; FIG. 2 a shows a second inventive device in a first position for the insertion of a cartridge; FIG. 2 b shows the second inventive device in a second position, e.g. for storing the device or for cleaning. FIG. 1 a - d show an inventive cleaning device 1 in a sectional view. Four steps of the insertion of a container 15 with cleaning material 17 into the device 1 are depicted. detailed-description description="Detailed Description" end="lead"? The inventive device 1 comprises a cleaning head 3 in the form of a brush with a plurality of bristles 9 . It further comprises a handle 2 having a shaft 2 ′ whose bottom end 2 a comprises the bristles 9 and forms the cleaning head 3 . The upper end 2 b of the shaft 2 ′ comprises a grip portion where the user can grip the handle 2 when cleaning. The shaft is a hollow tube forming a cylindrical passage 4 . The bottom end 5 of the passage 4 is closed. A cutting edge 10 is located at the bottom end 5 for piercing a cartridge-like container 15 inserted into the passage 4 and pushed down to the bottom end 5 . A cylindrical rod 6 fits tightly into the passage 4 and is able to slide up and down. A user can move the rod 6 by moving a slider 13 which is connected to the rod 6 and moves along an axial slit opening 14 in the shaft 2 ′. A preferably weak spring 8 contained at the upper end 2 b of the shaft 2 ′ is compressed when the slider 13 respectively the rod 6 is pulled upward, as shown in FIG. 1 b . The spring 14 helps to push the rod downward when moving the slider 13 downward and to keep the rod in the downward position, as shown in FIGS. 1 a , 1 c and 1 d. FIG. 1 a shows a cleaning device 1 without a container 15 with cleaning material 17 inserted, the rod 6 being in the downward position. When the rod 6 is in the upper position access to the bottom end 5 of the passage 4 can be gained via an introduction opening 12 , which can be additionally closed by a door. Through this introduction opening 12 a container 15 with cleaning material 17 is inserted into the passage 4 , as shown in FIG. 1 b . The cartridge 15 is then pushed down by the rod 6 , as shown in FIG. 1 c . As it contacts an is pressed against the cutting edge 10 , here a spike, the foil forming the container walls is pierced and the cleaning material 17 , e.g. a powder, is released via outlet openings 16 in the walls of the bottom portion 2 a of the shaft, as shown in FIG. 1 d . The container itself is then dissolved by water entering the bottom end 5 of the passage 4 via the outlet openings 16 . The empty cleaning device can then be reused for another cleaning action, i.e. inserting a new container, pushing it down, etc. FIG. 2 a, b show a second inventive device 1 ′ in two positions. The device 1 ′ in a first “open” position for the insertion of a cartridge (not shown) is shown in FIG. 2 a ; the device in a second “closed” position, e.g. for storing the device or for cleaning, is shown in FIG. 2 b. The inventive device 1 ′, here for the use as toilet brush, comprises a handle 2 ″ and a cleaning head 3 ″ connected to or being an integral part of the handle 2 ″. The cleaning head has a plurality of bristles 9 ′ for scrubbing a toilet bowl and the like. The handle comprises a first member 19 and an elongate second member 20 which forms the major part of the handle. First and second member 19 , 20 are movable with respect to each other by a bar 18 which is connected to the first member 19 an is able to slide within the second member 20 in its axial direction. The second member comprises an insertion opening 12 ′ for the cleaning cartridge. The opening 12 ′ is open when the two members 19 , 20 are at maximum distance from each other, as shown in FIG. 2 a . At least in the a region 21 extending from the opening 12 ′ to the cleaning head 3 ′ the second member 20 and the cleaning head 3 ′ are hollow, forming a passage 4 ′ extending from the opening to the bottom 5 ′ of the cleaning head 3 ′ for the insertion and delivery of cleaning material. In the “open” position as shown in FIG. 2 a a cartridge can be inserted into the opening. It is then pushed down to the bottom 5 ′ of the passage 4 ′ by moving the first member 19 towards the second member 20 . Via the bar 18 a rod 6 ′ which is connected to the bar or an integral part of the bar 18 is pushed into the passage, acting to push the cartridge down towards the cleaning head 3 ′. The rod 6 ′ closes the opening 12 ′ by fitting tightly into the passage 4 ′. In FIG. 2 b two members 19 , 20 are snapped onto each other to facilitate handling the device. In use, water enters the cleaning head 3 ′ through openings 16 ′ which are disposed between the bristles 9 ′. Water then dissolves or disintegrates the cartridge with active material or a solid tablet of cleaning material contained inside the head 3 ′. Liquid containing active material is then released via the same openings 16 ′ directly to the place of application. detailed-description description="Detailed Description" end="tail"?

Vaccine against Streptococcus pneumoniae

The present invention relates to the field of bacterial polysaccharide antigen vaccines. In particular, the present invention relates to vaccines comprising a pneumococcal polysaccharide antigen, typically a pneumococcal polysaccharide conjugate antigen from Streptococcus pneumoniae selected from the group consisting of PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133, and optionally a Th1-inducing adjuvant.

1. An immunogenic composition comprising at least one Streptococcus pneumoniae polysaccharide antigen and at least one Streptococcus pneumoniae protein antigen selected from the group consisting of: PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133, or immunologically functional equivalent thereof. 2. The immunogenic composition of claim 1, wherein the polysaccharide antigen is presented in the form of a polysaccharide-protein carrier conjugate. 3. The immunogenic composition of claim 2, wherein the carrier protein is selected from the group consisting of: Diphtheria toxoid, Tetanus toxoid, CRM197, Keyhole Limpet Haemocyanin (KLH), protein derivative of Tuberculin (PPD), and protein D from H. influenzae. 4. An immunogenic composition as claimed in any of claims 1 to 3 wherein the vaccine comprises at least four pneumococcal polysaccharide antigens from different serotypes. 5. An immunogenic composition as claimed herein additionally comprising an adjuvant. 6. An immunogenic composition as claimed in claim 5, wherein the adjuvant comprises an aluminium salt. 7. An immunogenic composition as claimed in claim 5, wherein the adjuvant is a preferential inducer of a TH1 response. 8. An immunogenic composition as claimed in claim 7, wherein the adjuvant comprises at least one of the following: 3D-MPL, a saponin immunostimulant, or an immunostimulatory CpG oligonucleotide. 9. An immunogenic composition as claimed in claim 8, wherein the adjuvant comprises a carrier selected from the group comprising: an oil in water emulsion, liposomes, and an aluminium salt. 10. An immunogenic composition composition as claimed herein for use as a medicament. 11. A vaccine comprising the immunogenic composition of claims 1-9. 12. A method of preventing or ameliorating Streptoccocus pneumoniae infection in a patient over 55 years, comprising administering an effective amount of a vaccine comprising a Streptococcus pneumoniae polysaccharide and at least one Streptococcus pneumoniae protein selected from the group consisting of PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133, and optionally a TH1 inducing adjuvant. 13. Use of a pneumococcal polysaccharide antigen in combination with a Streptoccocus pneumoniae protein antigen selected from the group consisting of PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133, and optionally a TH1 inducing adjuvant, in the manufacture of a medicament for the prevention or treatment of pneumonia in patients over 55 years. 14. Use of a pneumococcal polysaccharide antigen in combination with a Streptoccocus pneumoniae protein antigen selected from the group consisting of PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133, and optionally a TH1 inducing adjuvant, in the manufacture of a medicament for the prevention or treatment of otitis media in infants or toddlers. 15. A method of making an immunogenic composition as claimed herein, comprising the steps of: selecting one or more pneumococcal polysaccharide antigen(s); selecting one or more pneumococcal protein antigen(s) from the group consisting of PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133; and mixing said polysaccharide and protein antigens with a suitable excipient. 16. A method of preventing or ameliorating Otitis media in Infants, comprising administering a safe and effective amount of a vaccine comprising a Streptococcus pneumoniae polysaccharide antigen and a Streptococcus pneumoniae protein antigen selected from the group consisting of PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133, optionally with a TH1 adjuvant, to said Infant.

<SOH> BACKGROUND OF INVENTION <EOH>Streptococcus pneumoniae is a Gram-positive bacteria responsible for considerable morbidity and mortality (particularly in the young and aged), causing invasive diseases such as pneumonia, bacteremia and meningitis, and diseases associated with colonisation, such as acute Otitis media. The rate of pneumococcal pneumonia in the US for persons over 60 years of age is estimated to be 3 to 8 per 100,000. In 20% of cases this leads to bacteremia, and other manifestations such as meningitis, with a mortality rate close to 30% even with antibiotic treatment. Pneumococcus is encapsulated with a chemically linked polysaccharide which confers serotype specificity. There are 90 known serotypes of pneumococci, and the capsule is the principle virulence determinant for pneumococci, as the capsule not only protects the inner surface of the bacteria from complement, but is itself poorly immunogenic. Polysaccharides are T-independent antigens, and can not be processed or presented on MHC molecules to interact with T-cells. They can however, stimulate the immune system through an alternate mechanism which involves cross-linking of surface receptors on B cells. It was shown in several experiments that protection against invasive pneumococci disease is correlated most strongly with antibody specific for the capsule, and the protection is serotype specific. Polysaccharide antigen based vaccines are well known in the art. Four that have been licensed for human use include the Vi polysaccharide of Salmonella typhi, the PRP polysaccharide from Haemophilus influenzae, the tetravalent meningococcal vaccine composed of serotypes A, C, W135 and Y, and the 23-Valent pneumococcal vaccine composed of the polysaccharides corresponding to serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33 (accounting for at least 90% of pneumococcal blood isolates). The latter three vaccines confer protection against bacteria causing respiratory infections resulting in severe morbidity and mortality in infants, yet these vaccines have not been licensed for use in children less than two years of age because they are inadequately immunogenic in this age group [Peltola et al. (1984), N. Engl. J. Med. 310:1561-1566 ]. Streptococcus pneumoniae is the most common cause of invasive bacterial disease and otitis media in infants and young children. Likewise, the elderly mount poor responses to pneumococcal vaccines [Roghmann et al., (1987), J. Gerontol. 42:265-270], hence the increased incidence of bacterial pneumonia in this population [Verghese and Berk, (1983) Medicine (Baltimore) 62:271-285]. Strategies, which have been designed to overcome this lack of immunogenicity in infants, include the linking of the polysaccharide to large immunogenic proteins, which provide bystander T-cell help and which induce immunological memory against the polysaccharide antigen to which it is conjugated. Pneumococcal glycoprotein conjugate vaccines are currently being evaluated for safety, immunogenicity and efficacy in various age groups. The 23-valent unconjugated pneumococcal vaccine has shown a wide variation in clinical efficacy, from 0% to 81% (Fedson et al. (1994) Arch Intern Med. 154: 2531-2535). The efficacy appears to be related to the risk group that is being immunised, such as the elderly, Hodgkin's disease, splenectomy, sickle cell disease and agammaglobulinemics (Fine et al. (1994) Arch Intern Med. 154:2666-2677), and also to the disease manifestation. The 23-valent vaccine does not demonstrate protection against pneumococcal pneumonia (in certain high risk groups such as the elderly) and otitis media diseases. There is therefore a need for improved pneumococcal vaccine compositions, particularly ones which will be more effective in the prevention or amelioration of pneumococcal disease (particularly pneumonia) in the elderly and in young children. The present invention provides such an improved vaccine.

<SOH> SUMMARY OF TIE INVENTION <EOH>Accordingly the present invention provides a vaccine composition, comprising at least one Streptococcus pneumoniae polysaccharide antigen (preferably conjugated to a protein carrier) and a Streptococcus pneumoniae protein antigen selected from the group consisting of: Poly Histidine Triad family (Pht; e.g. PhtA, PhtB, PhtD, or PhtE), Lyt family (e.g. LytA, LytB, or LytC), SpsA, Sp128, Sp130, Sp125, Sp101 and Sp133, or truncate or immunologically functional equivalent thereof, optionally with a Th1 adjuvant (an adjuvant inducing a predominantly Th1 immune response). Preferably both a pneumococcal protein and Th1 adjuvant are included. Advantageous compositions comprising combinations of the above pneumococcal proteins of the invention with each other and with other pneumococcal proteins are also described. The compositions of the invention are particularly suited in the treatment of elderly pneumonia. Pneumococcal polysaccharide vaccines (conjugated or not) may not be able to protect against pneumonia in the elderly population for which the incidence of this disease is very high. The key defense mechanism against the pneumococcus is opsonophagocytosis (a humoral B-cell/neutrophil mediated event caused by the production of antibodies against the pneumococcal polysaccharide, the bacterium eventually becoming phagocytosed), however parts of the involved opsonic mechanisms are impaired in the elderly, i.e. superoxide production by PMN (polymorphonuclear cells), other reactive oxygen species production, mobilization of PMN, apoptosis of PMN, deformability of PMN. Antibody responses may also be impaired in the elderly. Contrary to the normally accepted dogma, normal levels of anti-capsular polysaccharide antibodies may not be effective in complete clearance of bacteria, as pneumococci may invade host cells to evade this branch of the immune system. Surprisingly, the present inventors have found that by simultaneously stimulating the cell mediated branch of the immune system (for instance T-cell meditated immunity) in addition to the humoral brach of the immune system (B-cell mediated), a synergy (or cooperation) may result which is capable of enhancing the clearance of pneumococci from the host. This is a discovery which will aid the prevention (or treatment) of pneumococcal infection in general, but will be particularly important for the prevention (or treatment) of pneumonia in the elderly where polysaccharide based vaccines do not show efficacy. Without wishing to be bound by any theory, the present inventors have found that both arms of the immune system may synergise in this way if a pneumococcal polysaccharide (preferably conjugated to a protein carrier) is administered with a pneumococcal protein selected from the group consisting of: PhtA, PhtD, PhtB, PhtE, SpsA, LytB, LytC, LytA, Sp125, Sp101, Sp128, Sp130 and Sp133 (proteins which can be processed and presented in the context of Class II and MHC class I on the surface of infected mammalian cells). Although one or more of these pneumococcal proteins can trigger cell mediated immunity by itself, the inventors have also found that the presence of a Th1 inducing adjuvant in the vaccine formulation helps this arm of the immune system, and surprisingly further enhances the synergy between both arms of the immune system.

Clothing piece

A garment of a stretch fabric knit in a fine-meshed manner, particularly a pair of cycling pants, comprises a front part (10) and a rear part (12). The front part (10) and the rear part (12) are knit simultaneously. Along at least one connecting edge (14,18), the front part is knit together with the rear part in a seamless manner. Thus, a seamless garment is manufactured. Since the garment does not have any bead-like seams, the occurrence of pressure marks and chafes caused by the seams is avoided.

1. A garment of a stretch fabric knit in a fine-meshed manner, particularly a pair of cycling pants, comprising a front part (10) and a rear part (12) knit independently of each other and simultaneously, the front part (10) and the rear part (12) being knit together in a seamless manner along at least one connecting edge (14,18). 2. The garment according to claim 1, characterized in that the stretch fabric is smooth and free of beads along the connecting edge (14,18) at both sides thereof. 3. The garment according to claim 1 or 2, characterized in that the entire garment is manufactured of the same yarn. 4. The garment according to one of claims 1-3, characterized in that each row of the front part (10) is knit together with a row of the rear part (12) so that an uninterrupted connecting edge (14,18) is produced. 5. The garment according to one of claims 1-4, characterized in that the front part (10) is knit together with the rear part (12) during the knitting of the front (10) and rear parts (12). 6. The garment according to one of claims 1-5, characterized in that knitting together the front part (10) and the rear part (12) is effected by connecting the yarn with which the front part (10) is knit and the yarn with which the rear part (12) is knit. 7. The garment according to one of claims 1-6, characterized in that the mesh width at the connecting edge (14,18) substantially corresponds to the mesh width of the front (10) and rear parts (12). 8. The garment according to one of claims 1-7, characterized in that the front (10) and/or the rear part (12) comprise portions knit in a wide-meshed manner to increase the air permeability. 9. Cycling pants according to one of claims 1-8, characterized in that knit straps (24) are connected with the front part (10) and a substantially closed back part (26) is connected with the rear part (12).

Servo control system and its control method

After a controller #1 has started giving an interpolating instruction, the length on an interpolation line is calculated by a first calculation means in synchronism with a clock signal from a clock synchronous circuit 45, and after having executed a first step for generating a synthetic locus-use frame 100 based upon the calculated value, the synthetic locus-use frame 100 is transmitted to controller #2 so that, after controller #2 has executed a second step for receiving a synthetic locus calculation-use frame from a receiving means, controllers #1, #2 execute a third step for calculating the position on the interpolation line based upon the synthetic locus-use frame 100 by using a second calculation means.

1. A servo-control system, comprising: a first controller which controls a first and third shafts; a second controller which controls a second and fourth shafts; wherein said first controller includes a first storing means in which information used for calculating the length on a first interpolation line is written, a first calculation means for reading the information from said first storing means to calculate the length on said first interpolation line, a transmitting means, and a receiving means, said second controller includes a second storing means in which information used for calculating the length on a second interpolation line is written, a second calculation means for reading the information from said second storing means to calculate the length on said second interpolation line, a transmitting means, and a receiving means, and said first and second controllers transmit or receive mutually the lengths on said first interpolation line and second interpolation line through said transmitting means or receiving means, whereby calculating the positions of said first and second axes based upon the length on the first interpolation line, and calculating the positions of said third and fourth axes based upon the length on the second interpolation line. 2. A servo-control system according to claim 1, wherein the calculation of the length on the first interpolation line by said first calculation means is simultaneously executed with the calculation of the length on the second interpolation line by said second calculation means. 3. A servo-control system according to claim 1, wherein said first and second controllers further comprise a fourth storing means respectively, the fourth storing means in said first controller stores information needed for interpolation instruction for said first and second axes, which includes a current position, a target position, a maximum speed value, an acceleration time, and a deceleration time, the fourth storing means in said second controller stores information needed for interpolation instruction to said third and fourth axes, which includes a current position, a target position, a maximum speed value, an acceleration time, and a deceleration time, the first and second controllers generate respectively respective-axis calculation frame every target position based upon the information from said fourth storing means to transmit or receive mutually the respective axis calculation frame before said target position control starts. 4. A servo-control system according to claim 1, wherein said first and second controllers transmit or receive mutually an in-position instruction and an instruction type, along with the length on the first or second interpolation line, wherein the in-position instruction serves as a reaching instruction that is generated by reaching a predetermined range in the previous positioning instruction position and wherein the instruction type shows a controlled state including a control completion instruction. 5. A servo-control system according to claim 1, wherein said first and second controllers further comprise an upper controller, the upper controller containing information needed for interpolation instruction to the first and second axes, including a current position, a target position, a maximum speed value, an acceleration time, and deceleration time; and information needed for interpolation instruction to the third and fourth axes, including a current position, a target position, a maximum speed value, an acceleration time, and deceleration time; the respective-axis calculation frame being generated based upon said information to transmit to said first and second controllers. 6. A control method of a servo-control system using a first controller which controls a first and third shafts and a second controller which controls a second and fourth shafts, and mutually controlling between said first and second controllers, comprising the steps of: executing simultaneously a synthetic locus calculation needed for respective axes calculation for said first and second axes in said first controller and a synthetic locus calculation needed for respective axes calculation for said third and fourth axes in said second controller, transmitting the result of said synthetic locus calculation in the first controller to the second controller, transmitting the result of said synthetic locus calculation in the second controller to the first controller, and executing respective axes calculation for said first to fourth axes based upon the result of said synthetic locus calculations.

<SOH> BACKGROUND ART <EOH>Referring to FIG. 8 , a conventional servo control system which is disclosed in Japanese Laid-Open Patent Publication No. 9-269811, will be explained. In FIG. 8 , the servo control system is constituted by a host CPU 6 which outputs controlling instructions to the entire system as an upper controlling unit, a plurality of servo-CPUs 8 , 9 which executes the same calculations as the host CPU 6 and serve as lower controlling unit, drivers D 1 to D 3 which are connected to the servo-CPU 8 and also connected to servo motors M 1 to M 3 of an orthogonal-type robot (Cartesian type robot) 15 , and drivers D 4 , D 5 which are connected to the servo-CPU 9 and also connected to servo motors M 4 ,M 5 of a joint-type robot 17 . To the host CPU 6 are connected a key board 10 through which positional data for positioning points, for example, are inputted, an instruction device 11 for giving instructions about positional data as to positioning target points, and an external input-output circuit 13 that allows transmitting and receiving operations to or from an external device. The following description will discuss an operation of the servo-control system having the above-mentioned arrangement shown in FIG. 8 . Upon starting an interpolation controlling process, the host CPU 6 transmits operating instructions for the next target point etc., to the servo-CPUs 8 and 9 , and then the servo-CPUs 8 , 9 execute the same calculations respectively for the synchronous control. Based on the result of the above calculations, the servo-CPUs 8 , 9 execute the position feed-back controlling calculations of the respective servo-motors M 1 to M 3 , M 4 , M 5 to transmit positioning completion instructions to the host CPU 6 . In the above-mentioned servo control system, the respective servo-CPus 8 , 9 to which operating instructions are transmitted from the host CPU 6 can execute the same calculations respectively to carry out the synchronous control among the robots 15 and 17 . Therefore, the above-mentioned system provides an effective control system for synchronous control when the number of controlled axes is comparatively small. However, in a servo control system in which a number of motors are synchronously controlled among the respective servo-CPUs 8 , 9 for interpolation controls, for example, in a servo control system for driving a tire molding machine with a number of control axes, as will be described later, the calculation time required in the respective servo-CPUs 8 , 9 increases as the number of motors to be synchronously controlled increases, when each servo CPUs 8 and 9 need to execute the same calculations. This results in a longer interpolation controlling time. In order to solve this problem, utilization of those servo-CPUs 8 , 9 with a higher processing speed is recommendable, however, there is an inevitable limitation to the processing speed. Here, in the case when respective motors are mutually subjected to an interpolation controlling process, with respect to multiple axes M 1 -M 5 as shown in FIG. 8 , these are simply shown by two axes form, that is, X-axis and Y-axis as shown in FIG. 9 . In FIG. 9 , the interpolation controlling calculations consist of synthetic locus calculations for calculating a length Lt 1 on an interpolation line and respective-axis calculations for calculating positions Xt 1 and Yt 1 of the respective axes based on the length Lt 1 on the interpolation line. Since the synthetic locus calculations are expected to be common to the respective motors, there is no need for the respective servo-CPUs 8 , 9 to execute the same synthetic locus calculations, respectively. Therefore, it is possible that either one of the servo CPU 8 ( 9 ) executes the synthetic locus calculations, and the other respective servo CPUs 8 , 9 execute respective-axis calculations using the resultant value of the synthetic locus calculations. However, the respective servo CPUs 8 , 9 can not execute the respective axis calculations while one of the servo CPU 8 ( 9 ) is executing the synthetic locus calculations, therefore, the total interpolation-control processing time which is the sum of the synthetic locus calculation time and respective axis calculation time is not substantially reduced. The present invention has been made to solve the above-mentioned problem in the servo-control system which carries out an interpolation control of respective axes of motors, and the object of the invention is to provide a servo control system and a control method thereof which can decrease the interpolation-control processing time of this entire system among two or more controllers without using CPU with a higher processing speed.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a schematic front view of the tire molding equipment which is driven and controlled by a servo control system in accordance with one embodiment of this invention; FIG. 2 is a block diagram of the entire servo control system showed in FIG. 1 ; FIG. 3 ( a ) is a block diagram showing the synthetic locus calculation frame which is used in the system shown in FIG. 2 ; FIG. 3 ( b ) is a block diagram of a frame for respective axes calculation; FIG. 4 is an explanatory curve showing an interpolation controlling process which is executed by the servo control system shown in FIG. 1 , in which positioning points P 0 , P 1 , P 2 , P 11 , P 12 are indicated on a plane defined by the X-Y axes; FIG. 5 is a flow chart showing a process in which a target is shifted to positioning points shown in FIG. 4 by using the servo control system of FIG. 1 ; FIG. 6 is a time chart showing a process in which a target is shifted to positioning points, P 0 , P 1 , P 2 , Pl 1 , P 12 shown in FIG. 4 , by using the servo control system of FIG. 1 ; FIG. 7 is a block diagram showing the entire constitution of a servo control system according to another embodiment of this invention; FIG. 8 is a schematic diagram showing the entire constitution of the conventional servo control system; FIG. 9 is a curve showing the positioning points P 0 , P 1 , and P 2 . detailed-description description="Detailed Description" end="lead"?

Deflector devices

A deflector for offsetting a streamer being towed by its lead-in by a seismic survey vessel comprises a wing-shaped body which is coupled to the lead-in and shaped to produce a sideways force which urges the lead-in laterally with respect to the direction of movement of the vessel. A boom extends rearwardly from the wing-shaped body, and forms part of an arrangement by which the angle of the wing-shaped body in the water, and therefore the sideways force produced by it, can be varied. The upper end of the wing-shaped body is directly connected to the underside of an elongate float.

1. A deflector device for use with a tow line between a towing vessel and a tow in water behind the vessel, the device comprising a wing-shaped body adapted to be coupled to the tow line and shaped to produce in use a sideways force which urges the tow line laterally with respect to the direction of movement of the towing vessel, a boom extending rearwardly from the wing-shaped body, the end of the boom remote from the wing-shaped body being adapted to be connected to the tow, and the angle between the boom and the wing-shaped body being remotely adjustable to vary the sideways force produced by the wing-shaped body, and an elongate float member whose underside is directly connected to the upper end of the wing-shaped body, 2. A deflector device as claimed in claim 1, wherein the centre of buoyancy of the float member is near the trailing edge of the wing-shaped body. 3. A deflector device as claimed in claim 1 or claim 2, wherein the angle between the longitudinal axis of the float member and the chord of the wing-shaped body is selected such that, in use, the longitudinal axis of the float member is aligned with the towing direction when the chord of the wing-shaped body is at its mean or normal angle to the towing direction. 4. A deflector device for use with a tow line between a towing vessel and a tow in water behind the vessel, the device comprising a principal wing-shaped body adapted to be coupled to the tow line and shaped to produce in use a sideways force which urges the tow line laterally with respect to the direction of movement of the towing vessel, a boom extending rearwardly from the principal wing-shaped body, an auxiliary wing-shaped body, smaller than the principal wing-shaped body, secured to the end of the boom remote from the principal wing-shaped body and shaped so as to produce in use a sideways force in generally the opposite direction to that produced by the principal wing-shaped body, and an elongate float member whose underside is directly connected to the upper end of the principal wing-shaped body, 5. A deflector device as claimed in claim 4, wherein the angle between the boom and the principal wing-shaped body is remotely adjustable, to vary the sideways force produced by the principal wing-shaped body. 6. A deflector device as claimed in claim 4, wherein the angle between the boom and the principal wing-shaped body is substantially fixed, and further comprising remotely operable means for varying the angle of the auxiliary wing-shaped body to vary the sideways force produced by the auxiliary wing-shaped body, and thereby vary the sideways force produced by the principal wing-shaped body. 7. A deflector device as claimed in any one of claims 4 to 6, wherein the centre of buoyancy of the float member is near the trailing edge of the principal wing-shaped body. 8. A deflector device as claimed in any one of claims 4 to 7, wherein the angle between the longitudinal axis of the float member and the chord of the principal wing-shaped body is selected such that, in use, the longitudinal axis of the float member is aligned with the towing direction when the chord of the principal wing-shaped body is at its mean or normal angle to the towing direction. 9. A deflector device as claimed in any one of claims 4 to 8, wherein the end of the boom remote from the wing-shaped body is adapted to be connected to the tow. 10. A deflector device as claimed in any preceding claim, wherein the or each wing-shaped body is made from titanium. 11. A deflector device as claimed in claim 10, wherein the float member is made from titanium. 12. A deflector device as claimed in any one of claims 1 to 10, wherein the float member is made from a fibre-reinforced composite material. 13. A method of performing a marine seismic survey, the method including towing a plurality of laterally spaced seismic streamers over an area to be surveyed, wherein the lateral position of at least one of the streamers is controlled by a deflector device in accordance with any one of the preceding statements of invention.

Integrated optical transmitter, receiver for free space optical communication and network system and application apparatus thereof

The present invention relates to the optical transmitter, receiver and application apparatus thereof for OWLL (Optical WireLess Link) which transmits and receives the optical signals through the free space and FSON (Free Space Optical Network) system using OWLL. Photonic devices such as laser diode and photo detector and integrated circuits for driving the photonic devices are formed directly into a single chip and the chip is assembled with optical instrument which is manufactured as a standardized optical module. Then, the optical transmitter, receiver and application apparatus thereof becomes small, light, cost-effective, multi-functional and reliable.

1. A transmitter for Free Space Optical Communication comprising: a semiconductor substrate; a light source formed on said substrate; a photo detector formed on said substrate for detecting the light from said light source; a current driver and automatic output controller circuit integrally formed on said substrate for driving said light source using the input signals from the outside and controlling the output power of said light source using the signals from said photo detector; a frame, where said substrate is fixed, having a plurality of pins for electrical connection to the outside; and an optics module formed to be assembled with said frame for receiving the light from said light source and transmitting the received light to the external free space. 2. The transmitter of claim 1, wherein said light source is a laser diode or a light emitting diode. 3. The transmitter of claim 1, wherein said optics module comprises: a lens; and a lens holder being, able to adjust the focal length of said lens. 4. The transmitter of claim 1, wherein said lens is an aspheric lens or a Fresnel lens. 5. The transmitter of claim 1, further comprising: a first screw unit formed to be integrated or assembled with said frame; and a second screw unit formed to be integrated or assembled with said optics module; wherein said frame and said optics module are assembled using said first and second screw units. 6. The transmitter of claim 5, wherein said first and second screw units are standardized whereby various optics modules having lenses of different sizes can be assembled with said frame. 7. The transmitter of claim 1, wherein the light from said transmitter is eye-safe. 8. A receiver for Free Space Optical Communication comprising: a semiconductor substrate having a first and a second faces being opposite to each other; a photo detector formed on said first face of said substrate; an optical receiver circuit integrally formed on said first face of said substrate for transforming and outputting the signals received from said photo detector; a frame, where said substrate is fixed, having a plurality of pins for electrical connection to the outside; and an optics module formed to be assembled with said frame for receiving the light from the external free space and transmitting the received light to said photo detector. 9. The receiver of claim 8, wherein said optical receiver circuit comprises a terminal for monitoring the magnitude of input signal at the outside of said optical receiver circuit. 10. The receiver of claim 9, further comprising: a display unit connected to said terminal via at least one of said plurality of pins of said frame for displaying said magnitude of input signal to the outside of said receiver. 11. The receiver of claim 9, wherein said magnitude of input signal can be transferred to the base station at the outside of said receiver. 12. The receiver of claim 8, wherein said optics module comprises: a lens; and a lens holder being able to adjust the focal length of said lens. 13. The receiver of claim 12, wherein said lens is an aspheric tens or a Fresnel lens. 14. The receiver of claim 8, further comprising: a first screw unit formed to be integrated or assembled with said frame; and a second screw unit formed to be integrated or assembled with said optics module; wherein said frame and said optics module are assembled using said first and second screw, units. 15. The receiver of claim 14, wherein said first and second screw unit are standardized whereby various optics modules having lenses of different sizes can be assembled with said frame. 16. The receiver of claim 8, wherein said optics module is arranged in a row with said optical receiver circuit and said photo detector. 17. The receiver of claim 8, wherein said optics module is arranged parallel to said second face on or above said second face side; and said frame has an aperture exposing a part of said second face opposite to the part of said first face where said light source is formed. 18. The receiver of claim 17, wherein said optics module is a tens formed on said second face of said substrate; and said aperture exposes a part where said lens is formed. 19. The receiver of claim 18, wherein said lens is formed by etching said semiconductor substrate. 20. The receiver of claim 18, wherein said lens is formed by coating. 21. A transceiver for Free Space Optical Communication comprising: a semiconductor substrate; a light source formed on said substrate; a first photo detector formed on said substrate for detecting the light from said light source; a current driver and automatic output controller circuit integrally formed on said substrate for driving said light source using the input signals from the outside and controlling the output power of said light source using the signals from said first photo detector; a second photo detector formed on said substrate; an optical receiver circuit integrally formed on said substrate for transforming and outputting the signals received from said second photo detector; a frame, where said substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with said frame for receiving the light from said light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with said frame for receiving the light from the external free space and transmitting the received light to said second photo detector. 22. The transceiver of claim 21, further comprising: a first screw unit formed to be integrated or assembled with said frame and adjacent with the part of said substrate where said light source is formed; a second screw unit formed to be integrated or assembled with said frame and adjacent with the part of said substrate where said second photo detector is formed; a third screw unit formed to be integrated or assembled with said transmitting optics module; and a fourth screw unit formed to be integrated or assembled with said receiving optics module; wherein said frame and said transmitting optics module are assembled using said first and third screw units; and wherein said frame and said receiving optics module are assembled using said second and fourth screw units. 23. The transceiver of claim 21, wherein said transmitting optics module and said receiving optics module face to the same side. 24. The transceiver of claim 21, wherein said transmitting optics module and said receiving optics module have the same configuration. 25. The transceiver of claim 21, wherein said transmitting optics module and said receiving optics module have different configurations from each other. 26. A transceiver for Free Space Optical Communication comprising: a first semiconductor substrate; a light source formed on said first substrate; a first photo detector formed on said first substrate for detecting the light from said light source; a current driver and automatic output controller circuit integrally formed on said first substrate for driving said light source using the input signals from the outside and controlling the output power of said light source using the signals from said first photo detector; a first frame, where said first substrate is fixed, having a plurality of pins for electrical connection to the outside; a second semiconductor substrate; a second photo detector formed on said second substrate; an optical receiver circuit integrally formed on said second substrate for transforming and outputting the signals received from said second photo detector; a second frame, where said second substrate is fixed, having a plurality of pins for electrical connection to the outside; a printed circuit board where said first and second frames are fixed at a predetermined interval; a transmitting optics module formed to be assembled with said printed circuit board for receiving the light from said light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with said printed circuit board for receiving the light from the external free space and transmitting the received light lo said second photo detector. 27. The transceiver of claim 26, further comprising: a first screw unit formed to be integrated or assembled with said printed circuit board and adjacent with the part of said first substrate where said light source is formed; a second screw unit formed to be integrated or assembled with said printed circuit board and adjacent with the part of said second substrate where said second photo detector is formed; a third screw unit formed to be integrated or assembled with said transmitting optics module; and a fourth screw unit formed to be integrated or assembled with said receiving optics module; wherein said printed circuit board and said transmitting optics module are assembled using said first and third screw units; and wherein said printed circuit board and said receiving optics module are assembled using said second and fourth screw units. 28. A transceiver for Free Space Optical Communication comprising: a semiconductor substrate; a first light source formed on said substrate; a first photo detector formed on said substrate for detecting the light from said first light source; a first current driver and automatic output controller circuit integrally formed on said substrate for driving said first light source using the input signals from the outside and controlling the output power of said first light source using the signals from said first photo detector; a first optical receiver circuit integrally formed on said substrate and connected to said first current driver and automatic output controller circuit for providing said first current driver and automatic output controller circuit with input signals; a second photo detector connected to said first optical receiver circuit for providing said first optical receiver circuit with input signal; a first optical fiber adaptor connected to said second photo detector for connecting said second photo detector to an optical fiber; a third photo detector formed on said substrate; a second optical receiver circuit integrally formed on said substrate for transforming and outputting the signals received from said third photo detector; a second current driver and automatic output controller circuit integrally formed on said substrate for receiving signals from said second optical receiver circuit; a second light source connected to said second current driver and automatic output controller circuit and driven bar said second current driver and automatic output controller circuit; a second optical fiber adaptor connected to said second light source for connecting said second tight source to an optical fiber; a frame, where said substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with said frame for receiving the Light from said first light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with said frame for receiving the light from the external free space and transmitting the received light to said third photo detector. 29. The transceiver of claim 28, wherein said second photo detector and said second light source are packaged in TO-cans respectively. 30. The transceiver of claim 28, wherein said second photo detector and said second light source are formed on said substrate. 31. A transceiver for Free Space Optical Communication comprising: a semiconductor substrate; a light source formed on said substrate; a first photo detector formed on said substrate for detecting the light from said light source; a current driver and automatic output controller circuit integrally formed on said substrate for driving said light source using the input signals from the outside and controlling the output power of said light source using the signals from said first photo detector; a second photo detector formed on said substrate; an optical receiver circuit integrally formed on said substrate for transforming and outputting the signals received from said second photo detector; a frame, where said substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with said frame for receiving the light from said first light source and transmitting the received light to the external free space; a receiving optics module formed to be assembled with said frame for receiving the light from the external free space and transmitting the received light to said second photo detector; and a media converter circuit integrally formed on said substrate and connected to said current driver and automatic output controller circuit and said optical receiver circuit, for transforming the signals transmitted from said optical receiver circuit to Ethernet signals and for transforming Ethernet signals received from the outside to said current driver and automatic output controller circuit and transmitting it, and having UTP (unshielded twisted-pair) port for transmitting and receiving Ethernet signals to and from the outside. 32. A transponder for Free Space Optical Communication comprising: a semiconductor substrate; a light source formed on said substrate; a first photo detector formed on said substrate for detecting the light from said light source; a current driver and automatic output controller circuit integrally formed on said substrate and connected to said light source for driving said light source using the input signals from the outside and controlling the output power of said light source using the signal from said first photo detector; a multiplexer circuit integrally formed on said substrate and connected to said current driver and automatic output controller circuit for multiplexing the input signals from the outside and outputting the multiplexed signals to said current driver and automatic output controller circuit; a second photo detector formed on said substrate; an optical receiver circuit integrally formed on said substrate for transforming and outputting the signals received from said second photo detector; a demultiplexer circuit integrally formed on said substrate and connected to said optical receiver circuit for receiving signals from said optical receiver circuit and outputting demultiplexed signals; a frame, where said substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with said frame for receiving the light from said first light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with said frame for receiving the light from the external free space and transmitting the received light to said second Photo detector. 33. A transponder for Free Space Optical Communication comprising: a first semiconductor substrate; a first photo detector formed on said first substrate; an optical receiver circuit integrally formed on said first substrate for transforming and outputting the signals received from said first photo detector; a demultiplexer circuit, integrally formed on said first substrate, having an input port connected to said optical receiver circuit for receiving signals from said optical receiver circuit, a drop port for distributing a part of demultiplexed signals, and an output port for outputting the rest of said demultiplexed signals; a first frame, where said first substrate is fixed, having a plurality of pills for electrical connection to the outside; a second semiconductor substrate; a light source formed on said second substrate; a second photo detector formed on said substrate for detecting the light from said light source; a current driver and automatic output controller circuit integrally formed on said second substrate and connected to said light source for driving said light source using the input signals from the outside and controlling the output power of said light source using the signals received from said second photo detector; a multiplexer circuit, integrally formed on said second substrate, having an input port for receiving signals from said output port of said demultiplexer, an add port for receiving additional signals from the outside, and an output port for outputting multiplexed signal to said current driver and automatic output controller circuit; a second frame, where said second substrate is fixed, having a plurality of pins for electrical connection for the outside; a printed circuit board where said first and second frames are fixed at a predetermined interval; a transmitting optics module formed to be assembled with said printed circuit board for receiving the light from said first light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with said printed circuit board for receiving the light from the external free space and transmitting the received light to said second photo detector.

<SOH> BACKGROUND OF THE INVENTION <EOH>The 21th century information communication society requires a social environment in which the subscribers can exchange the large amount of information at high speed, and such high speed communication becomes possible due to the improvements of the wireless communication technique of high frequency band and high speed optical communication technique using optical fibers. The study of optical communication which started in 1970s has progressed recent ten and some years to minimize the transmission loss to extend the transmission distance and to transmit a large amount of information at high speed, and now the optical communication system is in the stage of practical use, that is, the band width of the core optical communication network is over 100 Gbps, and it may reach some Tbps by 2000s. However, the technique providing the information at over tens of Mbps speed for the final user or subscriber is not developed so much. Roles of optical communication technique, which secure the high speed, parallelism, and large capacity, are very important to establish very high speed broadband integrated services communication network. The conventional wireless communication system, which transmits data at tens of kbps speed in PCS system of 2 GHz, is not enough to provide wireless multimedia service. In this regard, studies about IMT-2000 having maximum data transmission rate of 2 Mbps, which is called as the third generation wireless communication, are in progress, and now it is in the stage of practical user. However, the next generation multimedia system for very high rate data transmission such as HDTV requires tens to hundreds Mbps rate data transmission for the subscribers, therefore, the IMT-2000 cannot be a final solution. The next generation multimedia is a system and service which make various information such as text, data, audio, graphic, photo, animation, image, etc. to produce, collect, transmit, and process integrally, and the multimedia industry means the industrial field related to those activities. Recently, the multimedia information industry goes in the direction of digitalization, bi-directionization, asynchronization, and integrallization of image, sound, etc. in the content, form, and exchange method due to the development of the technologies in computer and communication fields. The effect of the technology development to the industrial structure is evolutional. For the most important obstacle to the present multimedia service, the performance of the communication network having insufficient capacity is pointed out, and the role of locomotive to progressive reproduction of the next generation multimedia is given to providing the communication network of very high speed and large capacity for individual subscribers economically. It is considered that the only network technology which able to provide the very high speed and large capacity information for individual subscribers is the fiber-to-the-home (“FTTH”), however, in case of the FTTH, the installation is difficult, and the cost of installation is large because additional cost is required to lay the optical fiber underground as well as the communication device. Moreover, it requires additional steps of aligning between the optical fiber and laser diode (“LD”) or photo detector (“PD”) for the optical transmitting/receiving module. The present invention pursues very economical and easily installable optical transmitting/receiving module which enabling FSON which can solve the problems of the FTTH instead of the wireless communication network using coaxial cables and microwave (“MW”) transmitting/receiving device such as high frequency oscillator, modulator, etc. to connect the base station (“BS”) and the central base station (“CBS”) such as mobile service switching center. Until now, the FSON is used as the back-up system for the existing wire network utilizing the advantages that the service can be provided instantly because the installation is easy and fast and that the communication protection is guaranteed physically, or most efforts are concentrated on development of high power transceiver focusing point-to-point connection considering quick installation, therefore, it is not used so practically. Therefore, the present invention suggests economical transmitting/receiving modules for FSON suitable to provide the very high speed and large capacity information for a plurality of users or subscribers stably using OWLL and FSON system using OWLL different from the existing simple point-to-point type.

<SOH> SUMMARY OF THE INVENTION <EOH>The new OWLL and FSON system leaded to resolve the problems and limits of the above described convention technology has differences to the conventional wire/wireless communication network in that they can provide the complex multimedia communication service such as high-speed internet, point-to-point and point-to-multiple point data, audio, and image transmission with very high speed, large capacity, stability, and efficiency preparing the next generation multimedia era. The OWLL and FSON system in which basic blocks are set according to the transmission distance and transmission rate and such blocks are combined in various way to provide very high speed and large capacity information without being affected by the position and distance of the subscriber is the communication system of completely new concept for very high speed and large capacity communication system. The OWLL and FSON system should be robust to the turbulence of the air, temperature gradient, snow, rain, fog, etc. and able to change the intensity and direction of the optical output, bit-rate, etc. adaptively according to the surrounding environments. In addition, it should be constituted as a system able to monitor, control, and operate the transmitting/receiving status integrally. The necessities for OWLL and FSON system are the economical transmitter, receiver, and various application apparatuses thereof enabling the OWLL and FSON system. Therefore, the object of the present invention is to provide the transmitter, receiver, and various application apparatuses thereof for OWLL and FSON. Another object of the present invention is to provide the transmitter, receiver, and various application apparatuses thereof for OWLL, which are small, light, cheap, stable, and reliable. To achieve the above objects, the present invention provides transmitting/receiving apparatuses for providing OWLL and FSON information communication service in which light source(s) such as laser diode, photo-electric device(s) for optical transmission and reception such as photo detector, and related circuit(s) are formed on one printed circuit board, and the printed circuit board and the optics modules are manufactured as standardized modules to be easily assembled with each other. To achieve the above objects, the present invention provides transmitting/receiving apparatuses for providing OWLL and FSON information communication service in which light source(s) such as laser diode, photo-electric device(s) for optical transmission and reception such as photo detector, and related circuit(s) are formed on one printed circuit board, and the printed circuit board and the optics modules are manufactured as standardized modules to be easily assembled with each other. That is, a transmitter for free space optical communication according to the present invention comprises: a semiconductor substrate; a light source formed on the substrate; a photo detector formed on the substrate for detecting the light from the light source; a current driver and automatic output controller circuit integrally formed on the substrate for driving the light source using the input signals from the outside and controlling the output power of the light source using the signals from the photo detector; a frame, where the substrate is fixed, having a plurality of pins for electrical connection to the outside; and an optics module formed to be assembled with the frame for receiving the light from the light source and transmitting the received light to the external free space. Here, the light source is preferably a laser diode or a light emitting diode. The optics module comprises: a lens; and a lens holder being able to adjust the focal length of the lens, and an aspheric lens or a Fresnel lens can be used for the lens. In addition, the transmitter of the present invention further includes a first screw unit formed to be integrated or assembled with the frame; and a second screw unit formed to be integrated or assembled with the optics module to make the frame and the optics module be assembled using the first and second screw units. The light from the transmitter is eye-safe. A receiver for free space optical communication according to the present invention comprises: a semiconductor substrate having a first and a second faces being opposite to each other; a photo detector formed on the first face of the substrate; an optical receiver circuit integrally formed on the first face of the substrate for transforming and outputting the signals received from the photo detector; a frame, where the substrate is fixed, having a plurality of pins for electrical connection to the outside; and an optics module formed to be assembled with the frame for receiving the light from the external free space and transmitting the received light to the photo detector. Here, the optical receiver circuit comprises a terminal for monitoring the magnitude of input signal at the outside of the optical receiver circuit, and it is preferable that the receiver further includes a display unit connected to the terminal via at least one of the plurality of pins of the frame for displaying the magnitude of input signal to the outside of the receiver or the magnitude of input signal can be transferred to the base station at the outside of the receiver. Also, the receiver of the present invention has a first screw unit formed to be integrated or assembled with the frame; and a second screw unit formed to be integrated or assembled with the optics module to make it possible for the frame and the optics module to be assembled using the first and second screw units. On the other hand, the optics module is arranged in a row with the optical receiver circuit and the photo detector or parallel to the second face on or above the second face side. In case of the latter, the frame has an aperture exposing a part of the second face opposite to the part of the first face where the light source is formed, the optics module is a lens formed on the second face of the substrate, and the aperture exposes a part where the lens is formed. The lens can be formed by etching or coating. A transceiver for free space optical communication according to the present invention comprises: a semiconductor substrate; a light source formed on the substrate; a first photo detector formed on the substrate for detecting the light from the light source; a current driver and automatic output controller circuit integrally formed on the substrate for driving the light source using the input signals from the outside and controlling the output power of the light source using the signals from the first photo detector; a second photo detector formed on the substrate; an optical receiver circuit integrally formed on the substrate for transforming and outputting the signals received from the second photo detector; a frame, where the substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with the frame for receiving the light from the light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with the frame for receiving the light from the external free space and transmitting the received light to the second photo detector. Here, the transceiver further includes a first screw unit formed to be integrated or assembled with the frame and adjacent with the part of the substrate where the light source is formed; a second screw unit formed to be integrated or assembled with the frame and adjacent with the part of the substrate where the second photo detector is formed; a third screw unit formed to be integrated or assembled with the transmitting optics module; and a fourth screw unit formed to be integrated or assembled with the receiving optics module, and it is preferable that the frame and the transmitting optics module are assembled using the first and third screw units and the frame and the receiving optics module are assembled using the second and fourth screw units. The transmitting optics module and the receiving optics module can face to the same side, and the transmitting optics module and the receiving optics module have the same configuration or different configurations from each other. Here, it is possible to fix a first and a second frames on one printed circuit board after fixing a first and a second substrates on the first and second frames after forming the light source, first photo detector, current driver and automatic output controller circuit on the first substrate and forming the second photo detector and optical receiver circuit for optical communication on the second substrate. The transceiver of the present invention may provide a connection with an optical fiber link. That is, a transceiver according to another embodiment of the present invention comprises: a semiconductor substrate; a first light source formed on the substrate; a first photo detector formed on the substrate for detecting the light from the first light source; a first current driver and automatic output controller circuit integrally formed on the substrate for driving the first light source using the input signals from the outside and controlling the output power of the first light source using the signals from the first photo detector; a first optical receiver circuit integrally formed on the substrate and connected to the first current driver and automatic output controller circuit for providing the first current driver and automatic output controller circuit with input signals; a second photo detector connected to the first optical receiver circuit for providing the first optical receiver circuit with input signal; a first optical fiber adaptor connected to the second photo detector for connecting the second photo detector to an optical fiber; a third photo detector formed on the substrate; a second optical receiver circuit integrally formed on the substrate for transforming and outputting the signals received from the third photo detector; a second current driver and automatic output controller circuit integrally formed on the substrate for receiving signals from the second optical receiver circuit; a second light source connected to the second current driver and automatic output controller circuit and driven by the second current driver and automatic output controller circuit; a second optical fiber adaptor connected to the second light source for connecting the second light source to an optical fiber; a frame, where the substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with the frame for receiving the light from the first light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with the frame for receiving the light from the external free space and transmitting the received light to the third photo detector. Here, the second photo detector and the second light source may be packaged in TO-cans, respectively, or formed directly on the substrate. Moreover, the transceiver of the present invention provides a connection to the Ethernet using a media converter, and a transceiver of another embodiment for this purpose comprises: a semiconductor substrate; a light source formed on the substrate; a first photo detector formed on the substrate for detecting the light from the light source; a current driver and automatic output controller circuit integrally, formed on the substrate for driving the light source using the input signals from the outside and controlling the output power of the light source using the signals from the first photo detector; a second photo detector formed on the substrate; an optical receiver circuit integrally formed on the substrate for transforming and outputting the signals received from the second photo detector; a frame, where the substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with the frame for receiving the light from the first light source and transmitting the received light to the external free space; a receiving optics module formed to be assembled with the frame for receiving the light from the external free space and transmitting the received light to the second photo detector; and a media converter circuit, integrally formed on the substrate and connected to the current driver and automatic output controller circuit and the optical receiver circuit, for transforming the signals transmitted from the optical receiver circuit to Ethernet signals and for transforming Ethernet signals received from the outside to the current driver and automatic output controller circuit and transmitting it, and having UTP (unshielded twisted-pair) port for transmitting and receiving Ethernet signals to and from the outside. A transponder for free space optical communication according to the present invention comprises a semiconductor substrate; a light source formed on the substrate; a first photo detector formed on the substrate for detecting the light from the tight source; a current driver and automatic output controller circuit integrally formed on the substrate and connected to the light source for driving the light source using the input signals from the outside and controlling the output power of the light source using the signal from the first photo detector; a multiplexer circuit integrally formed on the substrate and connected to the current driver and automatic output controller circuit for multiplexing the input signals from the outside and outputting the multiplexed signals to the current driver and automatic output controller circuit; a second photo detector formed on the substrate; an optical receiver circuit integrally formed on the substrate for transforming and outputting the signals received from the second photo detector; a demultiplexer circuit integrally formed on the substrate and connected to the optical receiver circuit for receiving signals from the optical receiver circuit and outputting demultiplexed signals; a frame, where the substrate is fixed, having a plurality of pins for electrical connection to the outside; a transmitting optics module formed to be assembled with the frame for receiving the light from the first light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with the frame for receiving the light from the external free space and transmitting the received light to the second photo detector. A transponder for free space optical communication according to another embodiment of the present invention comprises: a first semiconductor substrate; a first photo detector formed on the first substrate; an optical receiver circuit integrally formed on the first substrate for transforming and outputting the signals received from the first photo detector; a demultiplexer circuit, integrally formed on the first substrate, having an input port connected to the optical receiver circuit for receiving signals from the optical receiver circuit, a drop port for distributing a part of demultiplexed signals, and an output port for outputting the rest of the demultiplexed signals; a first frame, where the first substrate is fixed, having a plurality of pins for electrical connection to the outside; a second semiconductor substrate; a light source formed on the second substrate; a second photo detector formed on the substrate for detecting the light from the light source; a current driver and automatic output controller circuit integrally formed on the second substrate and connected to the light source for driving the light source using the input signals from the outside and controlling the output power of the light source using the signals received from the second photo detector; a multiplexer circuit, integrally formed on the second substrate, having an input port for receiving signals from the output port of the demultiplexer, an add port for receiving additional signals from the outside, and an output port for outputting multiplexed signal to the current driver and automatic output controller circuit; a second frame, where the second substrate is fixed, having a plurality of pins for electrical connection for the outside; a printed circuit board where the first and second frames are fixed at a predetermined interval; a transmitting optics module formed to be assembled with the printed circuit board for receiving the light from the first light source and transmitting the received light to the external free space; and a receiving optics module formed to be assembled with the printed circuit board for receiving the light from the external free space and transmitting the received light to the second photo detector.

Method for evaluating formation properties

Methods for evaluating the properties of formations surrounding a borehole, include the steps of measuring electrical properties of the formation from within the borehole; deriving a model of parameters of the formation surrounding the borehole; and estimating the properties of the formation using the model to interpret the measured electrical properties. In one aspect of the invention in which the formation includes a series of distributed beds, each bed having specific properties. Another aspect includes grouping similar beds, assigning one or more properties to all of the beds in a group, and using the assigned properties to estimate the properties of the formation for measurements relating to the beds of that group. Another aspect includes making several different measurements of formation electrical properties and simultaneously estimating the formation properties from the different measurements to provide a joint inversion. A still further aspect includes the use of a complex model incorporating electrical properties with other petrophysical information to estimate the properties of the formation from the electrical measurements.

1. A method for evaluating the properties of an underground formation surrounding a borehole, comprising: (i) measuring electrical properties of the formation from within the borehole; (ii) deriving a model of parameters of the formation surrounding the borehole; and (iii) estimating the properties of the formation using the model to interpret the measured electrical properties. 2. A method as claimed in claim 1, characterised in that the formation includes a series of distributed beds, each bed having specific properties, the method comprising estimating the positions of the beds, simulating measurements of the electrical properties using the estimated bed positions, comparing the simulated measurements to the measured electrical properties, and using the comparison to optimise the bed positions and estimate the formation properties from the measured electrical properties. 3. A method as claimed in claim 2, further comprising: (a) determining the variation of the measured electrical properties across the series of beds; (b) analysing the measured properties to obtain a first estimate of the position of each bed in the series; (c) simulating the variation of the measured electrical properties across the series using the model, the specific bed properties and the first estimated positions of the beds; (d) comparing the simulated variation of electrical properties with the determined variation of measured electrical properties; (e) using the comparison to adapt the estimate of the position of the beds such that the estimated variation and the determined variation are substantially the same; and (f) using the adapted estimate of the bed positions in the estimation of the formation properties. 4. A method as claimed in claim 2, wherein the bed position estimated is the bed boundary position. 5. A method as claimed in claim 1, further comprising grouping similar beds, assigning one or more properties to all of the beds in a group, and using the assigned properties to estimate the properties of the formation for measurements relating to the beds of that group. 6. A method as claimed in claim 5, further comprising: (a) identifying sequences of beds that are below the resolution of the electrical measurement; (b) assigning one or more properties to the beds in those sequences; and (c) using the assigned properties to estimate the properties of the formation including those sequences. 7. A method as claimed in claim 1, further comprising making several different measurements of formation electrical properties and simultaneously estimating the formation properties from the different measurements to provide a joint inversion. 8. A method as claimed in claim 7, further comprising: (a) obtaining several measurements of electrical properties of a formation of interest, each measurement being of a different nature; (b) simultaneously estimating the formation properties using the model and the different measurements of electrical properties. 9. A method as claimed in claim 3, wherein the bed position estimated is the bed boundary position. 10. A method as claimed in claim 1, further comprising the use of a complex model incorporating electrical properties with other petrophysical information to estimate the properties of the formation from the electrical measurements.

Oligonucleotides, agents containing these oligonucleotides, and the use thereof

The invention relates to particular oligonucleotides, pharmaceutical agents that contain these oligonucleotides, and to the therapeutic use thereof. The oligonucleotides are, in particular, capable of inhibiting the proliferation of pancreatic tumors. These oligonucleotides thus have a therapeutic potential for the treatment of pancreatic tumors. This can involve, in the broadest sense, an antisense therapy.

1-34. (cancelled) 35. Oligonucleotide, characterized in that more than 40% of the nucleobases are cytosine groups or mimetics thereof, the oligonucleotide has an arrangement of at least 8 consecutive nucleobases of sequence SEQ ID NO:1 and that the oligonucleotide is modified at the 3′ terminal with polyethyleneglycol (MW 1500) or a tocopheryl group and at the 5′ terminal with a tocopheryl group. 36. The oligonucleotide according to claim 35, characterized in that at least a portion of the nucleobases is arranged according to the sequence SEQ ID NO:1. 37. The oligonucleotide according to claim 35, characterized in that the ratio of cytosine, or mimetics thereof, to guanine or mimetics thereof is at least 2:1. 38. The oligonucleotide according to claim 37, characterized in that less than 15% of the nucleobases are adenine or mimetics thereof. 39. The oligonucleotide according to claim 35, characterized in that the oligonucleotide has 8 to 30 nucleobases. 40. The oligonucleotide according claim 35, characterized in that both terminals have a tocopheryl group. 41. The oligonucleotide according to claim 35, namely 5′-tocopheryl-TGC TCC CCC CTG GCT-3′-PEG1500; 5′-tocopheryl-TGC TCC CCC CTG GCT-3′-tocopheryl. 42. Oligonucleotide, characterized in that more than 40% of the nucleobases are cytosine groups, or mimetics thereof, and the oligonucleotide has an arrangement of at least 8 consecutive nucleobases of sequence SEQ ID NO:2. 43. The oligonucleotide according to claim 42, characterized in that at least a portion of the nucleobases are arranged according to the sequence SEQ ID NO:2. 44. The oligonucleotide according to claim 42, characterized in that the ratio of cytosine, or mimetics thereof, to guanine or mimetics thereof is at least 2:1. 45. The oligonucleotide according to claim 44, characterized in that less than 15% of the nucleobases are adenine or mimetics thereof. 46. The oligonucleotide according to claim 42, characterized in that the oligonucleotide has 8 to 30 nucleobases. 47. The oligonucleotide having the sequence SEQ ID NO:2. 48. The oligonucleotide according to claim 42, characterized in that the oligonucleotide has terminal modifications. 49. The oligonucleotide according to claim 48, characterized in that the oligonucleotide is modified at the 3′ and/or 5′ terminal. 50. The oligonucleotide according to claim 49, characterized in that at least one polyalkyleneglycol, a lipophilic group or a peptide is bound terminally. 51. The oligonucleotide according to claim 50, characterized in that the polyalkyleneglycol is a polyethyleneglycol. 52. The oligonucleotide according to claim 51, characterized in that the polyethyleneglycol has a mean molecular weight of 150 to 3000 Daltons. 53. The oligonucleotide according to claim 52, characterized in that the polyethyleneglycol is hexaethyleneglycol. 54. The oligonucleotide according to claim 50, characterized in that the lipophilic group is a fatty acid group, cholesterol, a steroid group, a tocopheryl group, or a derivative of those groups. 55. The oligonucleotide according to claim 54, characterized in that the lipophilic group is α-tocopheryl, preferably D-tocopheryl. 56. The oligonucleotide according to claim 48, characterized in that one terminal has a polyethyleneglycol group and the other terminal has a tocopheryl group. 57. The oligonucleotide according to claim 56, characterized in that the polyethyleneglycol group is bound to the 3′ terminal and the tocopheryl group to the 5′ terminal. 58. The oligonucleotide according to claim 48, characterized in that both terminals have a tocopheryl group. 59. The oligonucleotide according to claim 42, namely 5′-tocopheryl-CCT CGC TTC GCC CGT-3′-PEG; 5′-tocopheryl-CCT CGC TTC GCC CGT-3′-tocopheryl. 60. The oligonucleotide according to claim 35, characterized in that the terminal group is bound through an amide or ester linkage. 61. The oligonucleotide according to claim 35, characterized in that the oligonucleotide has at least one phosphorothioate linkage. 62. The oligonucleotide according to claim 61, characterized in that all nucleosides are linked via phosphorothioates. 63. Pharmaceutical agent containing at least one oligonucleotide according to claim 35, and optionally pharmaceutically acceptable auxiliary agents. 64. Method for the treatment of tumors, in particular human tumors, which comprises administering an oligonucleotide according to claim 35 to a subject in need thereof. 65. The method according to claim 64, in which the treatment is directed towards pancreatic tumors. 66. The method according to claim 64, in which the treatment is adjuvant. 67. The method according to claim 64, wherein the treatment is in combination with at least one cytostatic agent and/or radiation therapy. 68. Method for inhibition of the proliferation of tumor cells, in which at least one oligonucleotide according to claim 35 is allowed to act on tumor cells in vitro or ex vivo. 69. The oligonucleotide according to claim 42, characterized in that the terminal group is bound through an amide or ester linkage. 70. The oligonucleotide according to claim 42, characterized in that the oligonucleotide has at least one phosphorothioate linkage. 71. The oligonucleotide according to claim 70, characterized in that all nucleosides are linked via phosphorothioates. 72. Pharmaceutical agent containing at least one oligonucleotide according to claim 42, and optionally pharmaceutically acceptable auxiliary agents. 73. Method for the treatment of tumors, in particular human tumors, which comprises administering an oligonucleotide according to claim 42 to a subject in need thereof. 74. The method according to claim 73, in which the treatment is directed towards pancreatic tumors. 75. The method according to claim 73, in which the treatment is adjuvant. 76. The method according to claim 73, wherein the treatment is in combination with at least one cytostatic agent and/or radiation therapy. 77. Method for inhibition of the proliferation of tumor cells, in which at least one oligonucleotide according to claim 42 is allowed to act on tumor cells in vitro or ex vivo. 78. Pharmaceutical agent containing at least one oligonucleotide according to claim 47, and optionally pharmaceutically acceptable auxiliary agents.

Moisture management double face woven fabric

A process for manufacturing a differential function, double-face fabric, comprises the steps of a) providing two different yarns, the first yarn exhibiting hydrophilic behavior and the second yarn exhibiting hydrophobic behavior; b) providing a knot yarn; and c) producing a fabric by simultaneously weaving said two yarns, and linking them with said knot yarn.

1. A process for manufacturing a differential function, double-face fabric, comprising the steps of: providing two different yarns, the first yarn exhibiting hydrophilic behavior and the second yarn exhibiting hydrophobic behavior; providing a knot yarn; producing a fabric by simultaneously weaving said two yarns, and linking them with said knot yarn. 2. A process according to claim 1, wherein the weaving is performed in a warp and weft structure. 3. A process according to claim 1, wherein the first of the two different yarns is made from wool alone, or from wool wrapped with a nylon filament or from cellulose alone. 4. A process according to claim 1, wherein the first of the two different yarns is made from wool wrapped with covered elastane or from cellulose with elastane. 5. A process according to claims 3 and 4, wherein the yarn is treated with fluorocarbons selected from fluoroalkanes, fluoroalcohols, fluoroglycols, fluoroanhydrides, fluoroacrylates, fluoroesters, and brominated fluoroalkanes. 6. A process according to claim 1, wherein the second of the two different yarns is made from a polyester selected from polyethyleneterephthalate, polymethyleneterephthalate, polybutyleneterephthalate, modified polyesters, or their mixtures. 7. A process according to claim 5, wherein the yarn is treated with polysiloxanes selected from functional linear or network polysiloxanes. 8. A process according to claims 5 or 7, wherein the treatment is carried out at about 40° C. 9. A process according to claim 5 or 7, wherein the yarns are dyed prior to the chemical treatment. 10. A process according to claim 1, wherein the knot yarn is made from polyamides selected from nylon 66, or polyesters selected from polyethyleneterephthalates. 11. A process according to any one of claims 1 to 10, wherein the fabric comprises a face side of wool or cellulose and a back side of polyester. 12. A process according to claim 11, wherein the back side is hydrophilic and water-absorbent. 13. A process according to claim 11, wherein the face side is hydrophobic and water-repellent. 14. A double-faced fabric, comprising two layers made by simultaneously weaving two different yarns and linking them with a knot yarn. 15. A fabric according to claim 14, wherein one of the two different yarns is a wool or wool-based yarn, or cellulose or cellulose-based yarn. 16. A fabric according to claim 15, wherein the second of the two different yarns is a polyester yarn. 17. A garment made of a fabric according to any one of claims 14 to 16.

<SOH> BACKGROUND OF THE INVENTION <EOH>Clothing fabrics may be produced for various objectives and needs. Traditionally, it is common in the art to provide formal and casual garments for outwear as monofunctional fabrics which have one dominant property, for example; heat retention or wind protection provided by natural or synthetic yarns of weaves and knits. Another traditional approach is to provide fabrics with additive function; to improve the functionality of fabrics by the application of various chemicals/polymers and by adding certain features to the garment, for example: water repellence, antibacterial or UV protection, flame retardancy, shrink-proofing, etc. Another common approach is to modify the fabric properties by coating or lamination by using various polymers. However, fabric that is single-layered, may offer only one function, or additive functions, but not contrasting chemical function such as hydrophobicity and hydrophilicity. A known method used to achieve such result is to provide a multilayer fabric by introducing a membrane between two layers, leading to different functionality of the two sides of the multilayer fabric. U.S. Pat. No. 5,787,503 teaches the joining together of two different layers, one hydrophobic and the other hydrophilic, by knitting, to form a double-layer sweater, wherein the linking between the two layers is a polygonal-shaped quilting stitch pattern forming insulating pockets between the layers. The purpose of this configuration is to manufacture a sweater that keeps the wearer dry as well as warm. A different approach for a double-layered garment is described in U.S. Pat. No. 6,128,783, which teaches the production of a reversible sweater having one layer composed of knit fabric, and the other of micro-fiber fabric. According to this patent, the wearer may select which side of the sweater to wear according to weather conditions. The use of a dual-function garment has been considered also for medical applications. U.S. Pat. No. 6,148,444 discloses the use of a sweater for hemodialysis patients. According to this patent, the sweater is warm and keeps the patient dry at the same time, and contains a series of openings that will allow access to grafts or fistulas, as well as catheters, during medical procedures. It is a purpose of the present invention to provide a combination of desired properties in a garment generating a double-layered fabric, without introducing any membrane between the two layers, choosing two compatible layers, wherein one face of the fabric has a desired property, and the other has a different desirable property, and then superimpose the two layers together. It is another purpose of the present invention to provide an outwear that combines desired properties in a comfortable, economic and simple to manufacture manner. It is still another purpose of the invention to provide a two-layered fabric, comprising an external face, designated as face-side, made from wool alone or wool wrapped with nylon or cellulosic yarn, and an internal layer, designated as back-side, made from polyester. The face-side is water-repellent, and prevents permeability of water droplets inside the fabric while the back-side is hydrophilic, water-absorbent allowing the perspiration to diffuse through the fabric outside, and then to evaporate. It is a further object of the invention to provide a breathable fabric, moving moisture away from the skin. It is a further object of the invention to provide a process for the manufacture of a light clothing or garment possessing the above mentioned properties. Other purposes and advantages of this invention will become apparent as the description proceeds.

<SOH> SUMMARY OF THE INVENTION <EOH>The invention relates to a process of manufacturing a differential function fabric, which can be further used to prepare a breathable garment, which can aid moisture evaporation from the skin. In one aspect, the invention is directed to the preparation of a double face fabric comprising the steps of dyeing, chemically treating two different yarns, simultaneously weaving the yarns in a warp and weft, and linking them by a knot yarn. The knot yarn is preferably—but non limitatively—made from nylon 66. According to a preferred embodiment of the invention, the first of the two yarns is made from wool alone, or from wool wrapped with nylon 66 filament, or cellulosic yarn, or wool wrapped with covered elastane or cellulosic yarn with elastane. In this specification, the term “elastane” (also known as “Spandex”) is used to designate man-made elastic fiber, consisting of polyester diol, or polyether diol with diisocyanate. According to another preferred embodiment, the second yarn is made from spun or filament polyester selected from polyethyleneterephthalate (PET), polymethyleneterephthalate (PTT), or polybutyleneterephthalate (PBT). According to a preferred embodiment of the invention, a double face fabric which has differential functionality is provided, comprising two layers, a face side which is hydrophobic and water-repellent, and a back side which is hydrophilic, and water-absorbent. Preferably, the face side is wool or wool-based or cellulosic-based, and the back face is polyester. According to another aspect of the invention, the wool yarn or cellulosic yarn is treated with fluorocarbons, and the polyester yarn is treated with polysiloxanes. The invention will be further understood through the following illustrative and non-limititative examples.

Method and device for the electrical zero balancing for a micromechanical component

A method for the electrical zero balancing of a micro mechanical component including a first capacitor electrode rigidly suspended over a substrate, a second capacitor electrode rigidly suspended over the substrate, and a third capacitor electrode disposed there between, resiliently and deflectably suspended over the substrate, as well as a differential-capacitance detector for measuring a differential capacitance of the capacitances of the variable capacitors configured in this manner. In this context, a first electric potential is applied to the first capacitor electrode; a second electric potential is applied to the second capacitor electrode; a third electric potential is applied to the third capacitor electrode; and a fourth electric potential is applied to the substrate. The fourth electrical potential applied to the substrate for the electrical zero-point balancing is changed for the operation of the differential-capacitance detector.

1-6. Cancelled 7. A method for electrical zero balancing a micro-mechanical component which includes a first capacitor electrode rigidly suspended over a substrate, a second capacitor electrode rigidly suspended over the substrate, a third capacitor electrode arranged between the first capacitor electrode and the second capacitor electrode and resiliently and deflectably suspended over the substrate, and a differential-capacitance detector for measuring a differential capacitance of the capacitances of a plurality of variable capacitors: applying a first electric potential to the first capacitor electrode; applying a second electric potential to the second capacitor electrode; and applying a third electric potential to the third capacitor electrode; and applying a fourth electric potential to the substrate, wherein the fourth electrical potential applied to the substrate for the electrical zero-point balancing is changed for operation of the differential-capacitance detector. 8. The method of claim 7, wherein the first electric potential, the second electric potential, the third electric potential, and the fourth electric potential required for measuring the differential capacitance are applied in a clocked cycle. 9. The method of claim 7, wherein the micro-mechanical component includes an interdigital capacitor device with movable capacitor electrodes and fixed capacitor electrodes. 10. A device for electrical zero balancing of a micro-mechanical component, which includes a first capacitor electrode rigidly suspended over a substrate, a second capacitor electrode rigidly suspended over the substrate, a third capacitor electrode arranged between the first capacitor electrode and the second capacitor electrode and resiliently and deflectably suspended over the substrate, and a differential-capacitance detector for measuring a differential capacitance of a plurality of capacitances of a plurality of variable capacitors, the device comprising: a potential-supplying device to apply a first electric potential to the first capacitor electrode, to apply a second electric potential to the second capacitor electrode, to apply a third electric potential to the third capacitor electrode, and to apply a fourth electric potential to the substrate, wherein the potential-supplying device is able to vary the fourth electrical potential applied to the substrate for the electrical zero-point balancing for operation of the differential-capacitance detector. 11. The device of claim 10, wherein the first electric potential, the second electric potential, the third electric potential, and the fourth electric potential required for measuring the differential capacitance are applied in a clocked cycle. 12. The device of claim 10, wherein the micro-mechanical component includes an

<SOH> BACKGROUND INFORMATION <EOH>Acceleration sensors in general and micro mechanical acceleration sensors in particular, based on the technology of surface or volume micromechanics, are gaining ever greater market shares in the automotive equipment sector and are increasingly replacing the piezoelectric acceleration sensors that have been standard till now. Micro mechanical acceleration sensors of other systems may function in such a manner that the resiliently supported seismic mass device, which is deflectable in response to an external acceleration in at least one direction, when deflected, effects a change in capacitance at a differential-capacitor device connected thereto, this change is a measure of the acceleration. It is customary for these elements to be structurally formed in polysilicon, e.g., epitaxial polysilicon, over a sacrificial layer of oxide. However, micro mechanical sensor elements are not only generally used to detect linear and rotative accelerations, but also to detect gradients and rotational speeds. In this context, the differential-capacitive measuring principle may apply, according to which the measured quantity, for example the acceleration, causes a positional change in a movable capacitor electrode of a micro mechanical sensor structure, which induces two corresponding fixed capacitor electrodes, positioned on both sides of the movable capacitor electrode, to change their electrical measurement capacitance values in the opposite sense. In other words, the capacitance of the one capacitor increases by a specific amount, and the capacitance of the other capacitor formed in such a manner, decreases by a corresponding value, and, in fact, due to corresponding changes in the capacitor electrode distances. The smallest asymmetries in the zero position of such measuring structures or in the parasitic capacitance components of the micro mechanical sensor element in question lead, in the process, to an electrical offset or an electrical zero-point displacement at the output of the sensor element. Such an offset may be compensated when balancing an individual sensor by adding an appropriate voltage or an appropriate current in the relevant signal path of the differential-capacitance detector. By intervening in this manner in the relevant signal path when balancing the sensor offset, it may happen that other functional parameters are negatively influenced, for example, temperature sensitivities may arise in the offset or the signal amplifications and the sensor sensitivity or the like may change simultaneously. This leads then to further compensation and balancing requirements and substantially increases the outlay for sensor balancing. In addition, the gradation of such an offset balancing is dependent upon the total amplification of the signal path in question, for example upon the nominal sensitivity to be balanced, provided that at least some of the amplification balancing is not performed until after the offset-compensation point.

<SOH> SUMMARY OF THE INVENTION <EOH>The exemplary method according to the present invention for the electrical zero balancing of a micro mechanical component may provide that the offset balancing or the zero-point balancing of a micromechanical, capacitively evaluated sensor element may be performed outside of the sensitive signal path, i.e., independently of amplification factors, and without introducing parasitic signal distortions, caused, for example, by responses to temperature changes. The idea underlying the present invention is that the fourth electrical potential applied to the substrate for the electrical zero-point balancing, is changed for the operation of the differential-capacitance detector. In accordance with an exemplary embodiment, the potentials required for measuring differential capacitance are able to be applied in a clocked cycle. In accordance with another exemplary embodiment, the micro mechanical component includes an interdigital capacitor device including a multiplicity of movable and fixed capacitor electrodes.

Electrical connector module with housings for receiving forwardly-inserted female contacts

The object of the invention is an electrical connector module comprising housings (16) for receiving forwardly-inserted female contacts (18), each contact comprising a forward cage (20) and a rear blade (24) provided with pins (26) to be crimped on a flexible circuit (12). The object of the arrangement according to the present invention is to permit a forward mounting of the contact with an immobilization in its housing.

1. Electrical connector module comprising housings (16) each for receiving a forwardly-inserted female contact (18), characterized in that each housing (16) has the shape of a truncated pyramid with a clearance angle and in that each female contact (18) comprises on its cage bosses (36) for immobilizing and preventing gap, by exerting forces perpendicular to the wall of the said housing. 2. Electrical connector module according to claim 1, characterized in that the truncated pyramid shape of each housing (16) is at a slight clearance angle on only two opposite surfaces which receive the immobilization bosses (36). 3. Electrical connector module according to claim 1, characterized in that each female contact (18) comprises a cage (20) which carries at least one retention catch (38) so as to assure an immobilization in the forward/reverse direction in the housing. 4. Electrical connector module according to claim 3, characterized in that each retention catch (38) is disposed facing parallel opposing surfaces of each housing. 5. Electrical connector module according to claim 4, characterized in that each retention catch (38) is disposed downstream of the said contact. 6. Electrical connector module according to claim 3, characterized in that each female contact (18) comprises in addition to the forward cage (20), a rear blade (24), provided with pins (26) to be crimped on a flexible circuit (12) and means (32) for retaining the flexible circuit (12) when the pins (26) are crimped on the flexible circuit. 7. Electrical connector module according to claim 6, characterized in that the retaining means (32) comprise a flap (28) which is pivotable about an axis (30) with a tongue/groove assembly (32) adapted to generate an offset portion in the flexible circuit (12) and to immobilize this latter upon lowering the flap (28). 8. Electrical connector module according to claim 1, characterized in that it comprises means (44) for snap-locking in a module-carrier.

Self-encoding sensor with microspheres

A micro-sphere-based analytic chemistry system is disclosed in which self-encoding microspheres having distinct characteristic optical response signatures to specific target analytes may be mixed together while the ability is retained to identify the sensor type and location of each sensor in a random dispersion of large numbers of such sensors in a sensor array using an optically interrogatable encoding scheme. An optical fiber bundle sensor is also disclosed in which individual microsphere sensors are disposed in microwells at a distal end of the fiber bundle and are optically coupled to discrete fibers or groups of fibers within the bundle. The identities of the individual sensors in the array are self-encoded by exposing the array to a reference analyte while illuminating the array with excitation light energy. A single sensor array may carry thousands of discrete sensing elements whose combined signal provides for substantial improvements in sensor detection limits, response times and signal-to-noise ratios.

1. A method of detecting a target analyte the method comprising: a. providing a first classifier for the response of a first population of sensors from a first pool of sensors to a first target analyte; b. distributing a second population of sensors from said first pool of sensors on an array; and c. determining the response of said second population of sensors to a sample, wherein the response of said second population resembles said first classifier for the response of said first population to said first target analyte, thereby indicating the presence of said first target analyte in said sample. 2. The method according to claim 1, wherein said sensors are microspheres. 3. The method according to claim 2, wherein said microspheres comprise dyes. 4. The method according to claim 1, 2 or 3, wherein said second population of sensors is distributed on a substrate. 5. The method according to claim 1, 2, 3 or 4, wherein said second population of sensors is distributed on a patterned substrate with wells. 6. The method according to claims 4 or 5, wherein said substrate is a fiber optic bundle. 7. The method according to claim 4 or 5, wherein said substrate is selected from the group consisting of glass and plastic. 8. The method according to claims 1, 2, 3, 4, 5, 6, 7 or 8, further comprising providing a second classifier for the response of a third population of sensors from said first pool of sensors to a second target analyte, wherein at least a second and a third response to said first and second target analytes, respectively, of said third population of sensors from said first pool of sensors is determined, and wherein said response of said third population of sensors from said first pool of sensors resembles at least one of said first and second classifiers for the response to said first and second target analytes, thereby indicating the presence of said at least one of said first and second target analytes. 9. The method according to claims 1, 2, 3, 4, 5, 6, 7 or 8, wherein said response of said first population of sensors to said first target analyte is indicative of the response of at least a second and third population of sensors from said first pool to said first target analyte. 10. A method of detecting a target analyte the method comprising: a. providing a first and second classifier for the response of a first and a second population of sensors from first and second pools of sensors, respectively, to a first target analyte; b. distributing third and fourth populations of sensors from said first and second pools of sensors, respectively, on an array; and c. determining the response of said third and fourth population of sensors to a sample, wherein the response of said third and fourth populations resembles said first and second classifiers for the response of said first and second populations, respectively, to said first target analyte, thereby indicating the presence of said first target analyte in said sample. 11. A method of making an array the method comprising: a. providing a population of microspheres, wherein said microspheres comprise an optical signature; b. contacting said microspheres with a sample comprising a target analyte; c. recording the response of said microspheres to said target analyte, d. generating a classifier for said response of said microspheres to said target analyte; and d. distributing said microspheres on a substrate with a surface comprising discrete sites.

<SOH> BACKGROUND OF THE INVENTION <EOH>The use of optical fibers and optical fiber strands in combination with light absorbing dyes for chemical analytical determinations has undergone rapid development, particularly within the last decade. The use of optical fibers for such purposes and techniques is described by Milanovich et al., “Novel Optical Fiber Techniques For Medical Application”, Proceedings of the SPIE 28th Annual International Technical Symposium On Optics and Electro-Optics, Volume 494, 1980; Seitz, W. R., “Chemical Sensors Based On Immobilized Indicators and Fiber Optics” in C.R.C. Critical Reviews In Analytical Chemistry, Vol. 19, 1988, pp. 135-173; Wolfbeis, O. S., “Fiber Optical Fluorosensors In Analytical Chemistry” in Molecular Luminescence Spectroscopy, Methods and Applications (S. G. Schulman, editor), Wiley & Sons, New York (1988); Angel, S. M., Spectroscopy 2(4):38 (1987); Walt, et al., “Chemical Sensors and Microinstrumentation”, ACS Symposium Series, Vol. 403, 1989, p. 252, and Wolfbeis, O. S., Fiber Optic Chemical Sensors, Ed. CRC Press, Boca Raton, Fla., 1991, 2nd Volume. When using an optical fiber in an in vitrolin vivo sensor, one or more light absorbing dyes are located near its distal end. Typically, light from an appropriate source is used to illuminate the dyes through the fiber's proximal end. The light propagates along the length of the optical fiber; and a portion of this propagated light exits the distal end and is absorbed by the dyes. The light absorbing dye may or may not be immobilized; may or may not be directly attached to the optical fiber itself; may or may not be suspended in a fluid sample containing one or more analytes of interest; and may or may not be retainable for subsequent use in a second optical determination. Once the light has been absorbed by the dye, some light of varying wavelength and intensity returns, conveyed through either the same fiber or collection fiber(s) to a detection system where it is observed and measured. The interactions between the light conveyed by the optical fiber and the properties of the light absorbing dye provide an optical basis for both qualitative and quantitative determinations. Of the many different classes of light absorbing dyes which conventionally are employed with bundles of fiber strands and optical fibers for different analytical purposes are those more common compositions that emit light after absorption termed “fluorophores” and those which absorb light and internally convert the absorbed light to heat, rather than emit it as light, termed “chromophores.” Fluorescence is a physical phenomenon based upon the ability of some molecules to absorb light (photons) at specified wavelengths and then emit light of a longer wavelength and at a lower energy. Substances able to fluoresce share a number of common characteristics: the ability to absorb light energy at one wavelength; reach an excited energy state; and subsequently emit light at another light wavelength. The absorption and fluorescence emission spectra are individual for each fluorophore and are often graphically represented as two separate curves that are slightly overlapping. The same fluorescence emission spectrum is generally observed irrespective of the wavelength of the exciting light and, accordingly, the wavelength and energy of the exciting light may be varied within limits; but the light emitted by the fluorophore will always provide the same emission spectrum. Finally, the strength of the fluorescence signal may be measured as the quantum yield of light emitted. The fluorescence quantum yield is the ratio of the number of photons emitted in comparison to the number of photons initially absorbed by the fluorophore. For more detailed information regarding each of these characteristics, the following references are recommended: Lakowicz, J. R., Principles of Fluorescence Spectroscopy, Plenum Press, New York, 1983; Freifelder, D., Physical Biochemistry, second edition, W. H. Freeman and Company, New York, 1982; “Molecular Luminescence Spectroscopy Methods and Applications: Part I” (S. G. Schulman, editor) in Chemical Analysis, vol. 77, Wiley & Sons, Inc., 1985; The Theory of Luminescence, Stepanov and Gribkovskii, Iliffe Books, Ltd., London, 1968. Many of the recent improvements employing optical fiber sensors in both qualitative and quantitative analytical determinations concern the desirability of depositing and/or immobilizing various light absorbing dyes at the distal end of the optical fiber. In this manner, a variety of different optical fiber chemical sensors and methods have been reported for specific analytical determinations and applications such as pH measurement, oxygen detection, and carbon dioxide analyses. These developments are exemplified by the following publications: Freeman, et al., Anal Chem. 53:98 (1983); Lippitsch et al., Anal. Chem. Acta. 205:1, (1988); Wolfbeis et al., Anal. Chem. 60:2028 (1988); Jordan, et al., Anal. Chem. 59:437 (1987); Lubbers et al., Sens. Actuators 1983; Munkholm et al., Talanta 35:109 (1988); Munkholm et al., Anal. Chem. 58:1427 (1986); Seitz, W. R., Anal. Chem. 56:16A-34A (1984); Peterson, et al., Anal. Chem. 52:864 (1980): Saari, et al., Anal. Chem. 54:821 (1982); Saari, et al., Anal. Chem. 55:667 (1983); Zhujun et al., Anal. Chem. Acta. 160:47 (1984); Schwab, et al., Anal. Chem. 56:2199 (1984); Wolfbeis, O. S., “Fiber Optic Chemical Sensors”, Ed. CRC Press , Boca Raton, Fla., 1991, 2nd Volume; and Pantano, P., Walt, D. R., Anal. Chem., 481A-487A, Vol. 67, (1995). More recently, fiber optic sensors have been constructed that permit the use of multiple dyes with a single, discrete fiber optic bundle. U.S. Pat. Nos. 5,244,636 and 5,250,264 to Walt, et al. disclose systems for affixing multiple, different dyes on the distal end of the bundle, the teachings of each of these patents being incorporated herein by this reference. The disclosed configurations enable separate optical fibers of the bundle to optically access individual dyes. This avoids the problem of deconvolving the separate signals in the returning light from each dye, which arises when the signals from two or more dyes are combined, each dye being sensitive to a different analyte, and there is significant overlap in the dyes' emission spectra. Most recently, fiber optic sensors have been employed in arrays of semi-selective chemical sensors and pattern recognition schemes to discriminate and quantify odors. Such approaches have been useful in implementing the principles of biological olfaction in the design of sensing devices or systems. In this field of biomimetry, various technologies have been applied to the sensor transduction mechanism. For example, surface acoustic wave, conducting polymer, metal oxide sensor field-effect transistor (MOSFET), piezo-electric, and quartz crystal microbalance sensor arrays have been pursued. While such technologies provide inventive approaches utilizing a variety of physical and chemical phenomena to odor sensing, there are a number of limitations to these methods which restrict the efficacy of such devices. Firstly, element-to-element reproducibility both within a single array and between sensor arrays is typically unsatisfactory and thus requires recalibration and network retraining from sensor to sensor. Secondly, most of these methods have a relatively slow response time, frequently requiring several minutes to respond to the presence of an odor. Thirdly, such methods have relatively high detection limits and low sensitivity, typically not functioning at odor levels below 10 ppm. Fourthly, devices which embody such technologies typically require a relatively large inherent size, thereby restricting miniaturization of the sensor array for use in remote sensing applications. Finally, construction of multi-sensor arrays by these methods is complex and involves expensive and tedious preparation and placement of individual sensors within a well-defined array. Most recently, many of these shortcomings have been overcome through the application of fiber optic sensor arrays in an artificial nose sensor device and system. U.S. Pat. Nos. 5,320,814 and 5,512,490 to Walt, et al., the teachings of each of these patents being incorporated herein by reference, disclose a fiber optic array formed of heterogeneous, semi-selective thin films which function as sensing receptor units and are able to detect a variety of different analytes and ligands using spectral recognition patterns. This technology has been applied to a vapor-sensing system which utilizes arrays of polymer-dye combinations which coat the ends of select optical fibers in a fiber optic bundle. These developments are further described in Dickinson, et al, Nature 382:697 (1996) and White, et al, Anal. Chem. 68:2191 (1996). An innovative feature of the four previously referenced patents to Walt, et al., was the placement of multiple chemical functionalities at the end of a single optical fiber bundle sensor. This configuration yielded an analytic chemistry sensor that could be remotely monitored via the typically small bundle. The drawback, however, was the difficulty in applying the various chemistries associated with the chemical functionalities at the sensor's end; the functionalities were built on the sensor's end in a step-wise serial fashion. This was a slow process, and in practice, only tens of functionalities could be applied. U.S. patent application Ser. No. 08/818,199 to Walt, et al, the teachings of which are incorporated herein by this reference, discloses the use of dye infiltrated polymer microspheres as a substitute for polymer-dye coating layers in optical fiber array sensors. With this approach, a fiber optic bundle serves as a substrate for dye-polymer microsphere array which contains a variety of microsphere bead sensors having different chemical and optical responses to the presence of target analytes. One innovative feature of this invention is in providing for a bead-based analytic chemistry system in which beads or microspheres carrying different chemical functionalities may be mixed together while retaining the ability to identify the functionality of each bead using an optically interrogatable encoding scheme. Additionally, this invention provides for an optical fiber bundle sensor in which the separate beads or microspheres may be optically coupled to discrete fibers or groups of fibers within the bundle. While the innovative features of this invention have separate applications, when implemented together, the invention provides for an optical fiber sensor that can support large numbers, thousands or more, of separate chemical sensor elements, which can be incorporated into a chemical sensor array and chemical analysis system. This approach provides for rapid fabrication and assembly of individual sensors and complex sensor arrays containing a multitude of discrete sensor types. The method also provides for a high degree of reproducibility and conformity within a batch of sensors and sensor arrays. Additional advantages are realized due to the ultrafine sizing available in microspheres. The overall size of the sensor array can be substantially reduced to submillimeter scale. This reduction in scale is particularly advantageous for remote sensing arrays. While the method of applying microsphere sensor elements in chemical sensor arrays as taught in U.S. patent application Ser. No. 08/818,199 to Walt, et al, has many innovative features, this method has certain limitations. The method requires a complex multi-step bead encoding process to identify the type and location of bead subpopulations used in the sensor array. Beads are encoded by employing combinations of fluorescent dyes in varying ratio. The choice of encoding dyes is limited to those dyes which emit light at different wavelengths upon exposure to excitation light energy. While combinations of dyes in different ratios provide for encoding subpopulations of beads, the number of dye ratios available for encoding beads with a given dye pair or combination is significantly limited due to crowding the emission spectrum from peak overlap. In addition, a separate reporting dye is necessary for obtaining a unique characteristic optical response signature for a target analyte. Thus, the encoding dye choice is further limited by selecting dyes whose emission wavelengths do not overlap or interfere with the reporting dye which is uniquely responsive to the presence of an analyte. Another limiting feature of this invention is that the process of encoding beads requires a series of measurements which calibrate and train the sensors and the sensor array. Encoding is initially accomplished by first illuminating the beads with excitation light energy and monitoring and recording the type and location of the specific bead subpopulation within the sensor array having a given encoding dye ratio. Next, the array is exposed to an analyte while illuminating the array with excitation light energy in the presence of a reporter dye. Those beads which are responsive to the analyte in the presence of the reporter dye are monitored and mapped on the sensor array. In addition, the characteristic optical response signature is stored in a library. This step is repeated for each analyte of interest in combination with a reporter dye. Once all bead subpopulations are encoded and their response characteristics monitored and recorded, the entire sensor array must be decoded for each analyte by indexing each sensor element with the stored optical response signature for each analyte. This process of decoding individual subpopulations of beads may be require additional steps when a large number of subpopulations are deployed in the array, thereby increasing the training time required for each array. Other alternative approaches to bead encoding, utilizing molecular tagging, capillary gas chromatography and electron capture detection have been disclosed by Still, et al, Acc. Chem. Res. 29:155 (1996). However, such methods are limited in scope and have been applied only to a narrow class of bead materials having specific chemical functionality and molecular tags which are readily analyzable.