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<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 illustrates comparison among a putative amino acid sequence of human chondroitin synthase (Human), and amino acid sequences of homologous proteins of C. elegans (T25233) and Drosophila (AE003499). Those putative amino acid sequences were analyzed by using GENETYX-MAC (version 10) computer program. Respectively, the black boxes indicate that three of them have an identical amino acid, and the gray boxes indicate that two of them have an identical amino acid. The broken lines indicate gaps inserted for attaining highest degree of matching. Surrounded by the rectangular frames are predicted transmembrane domain. A D×D motif that was preserved is indicated by underline. Three sites predicted N-glycosylation sites are marked with star marks. FIG. 2 shows a genome structure of the human chondroitin synthase geneExon regions are indicated by the boxes. The black boxes indicate coding sequences, whereas the white boxes indicate 5′- and 3′-untranslated sequences. The translation initiation codon (ATG) and stop codon (TAA) are shown as well. The black horizontal line indicates introns. FIGS. 3 ( a ) and 3 ( b ) show results of identification of reaction products from human chondroitin synthase reaction. FIG. 3 ( a ): A reaction product of GlcUA transferase collected from a Superdex peptide column was digested by chondroitinase AC-II or β-glucuronidase. The reaction product (black rectangle) that was not digested, the reaction product (black circle) that was digested by chondroitinase AC-II, and the reaction product that was digested by β-glucuronidase, were applied into the Superdex peptide column. Radioactivity of elution fractions of each (0.4 ml each) was analyzed. Arrows indicate elution positions of saturated disaccharide (1, GlcUAβ1-3GalNAc) or isolated GlcUA (2, [ 14 C]GlcUA). FIG. 3 ( b ): A reaction product of GalNAc transferase collected from a Superdex peptide column was digested by chondroitinase AC-II. The reaction product (black rectangle) that was not digested, or the reaction product (black circle) that was digested by chondroitinase AC-II, was applied into the Superdex peptide column. Radioactivity of elution fractions of each (0.4 ml each) was analyzed. Arrows indicate elution positions of saturated disaccharide (1, GlcUAβ1-3GalNAc), or isolated GalNAc (2, [ 3 H]GalNAc). FIG. 4 shows a result of Northern blot analysis (a photograph of gel-electrophoresis) of chondroitin synthase in a human tissue. Hybridization of RNAs derived from various human tissues was carried out by using probes of chondroitin synthase: Lane 1 is brain; Lane 2 is heart; Lane 3 is skeletal muscle; Lane 4 is colon; Lane 5 is thymus; Lane 6 is spleen; Lane 7 is kidney; Lane 8 is liver; Lane 9 is small intestine; Lane 1 is placenta; Lane 11 is lung, and Lane 12 is leukocyte in peripheral blood. detailed-description description="Detailed Description" end="lead"? |
Novel recombinant gene expression method by stop codon suppression |
This invention describes a novel recombinant gene expression method based on a novel recombinant gene expression vector, comprising in the following order a promoter sequence, a gene of interest, a translational stop signal and translationally linked to said gene of interest a selectable marker gene. |
1. A recombinant gene expression vector comprising in the following order a promoter sequence, a gene of interest, a translational stop signal and translationally linked to said gene of interest a selectable marker gene whereby a recombinant gene expression vector is excluded which recombinant gene expression vector contains in the following order a promoter sequence, a gene encoding β-galactosidase, a TGA stop codon, and translationally linked to said β-galactosidase gene a gene encoding luciferase. 2. A recombinant gene expression vector as claimed in claim 1, comprising at least two genes of interest. 3. A recombinant gene expression vector according to claim 1, wherein said selectable marker gene encodes a functional protein for selection of host cells comprising said recombinant gene expression vector and expressing said selectable marker gene. 4. A recombinant gene expression vector according to claim 1, wherein said translational stop signal is at least one stop codon selected from the group of TAA, TGA and TAG. 5. A recombinant gene expression vector according to claim 1, comprising downstream of said selectable marker gene a SECIS element which modulates the expression of said selectable marker gene from the corresponding mRNA. 6. A recombinant gene expression vector, comprising in the following order a promoter sequence, a gene of interest, a translational stop signal and translationally linked to said gene of interest a selectable marker gene wherein the gene of interest encoding a secreted product protein and the selectable marker gene are separated by a translational stop signal and an in frame stop transfer sequence. 7. A host cell comprising a recombinant gene expression vector as claimed in claims 1 to 6, which host cell is capable of expressing both said gene of interest and as a fusion protein said gene of interest and said selectable marker gene. 8. A host cell as claimed in claim 7 which is a host cell line and which is stably maintaining the expressing of said gene of interest during cultivation. 9. A process for producing a host cell clone comprising a recombinant gene expression vector as claimed in claims 1 to 6, which process comprises transforming a host cell with said recombinant gene expression vector as claimed in claims 1 to 6 and selecting a host cell clone comprising said recombinant gene expression vector on the expression of said selectable marker gene. 10. A process for producing a protein encoded by a gene of interest, which process comprises the production of a host cell line comprising a recombinant gene expression vector, the cultivation of said host cell line, stably maintaining the expression of said gene of interest, and recovery of the product of said gene of interest, whereby said recombinant gene expression vector comprises in the following order a promoter sequence, a gene of interest, a translational stop signal and translationally linked to said gene of interest a selectable marker gene, and whereby the production of said host cell line comprises the transformation with said recombinant gene expression vector and the selection of a host cell comprising said recombinant gene expression vector on the expression of said selectable marker gene. 11. A process for producing a secreted product protein encoded by a gene of interest, which process comprises the production of a host cell line comprising a recombinant gene expression vector, the cultivation of said host cell line, stably maintaining the expression of said gene of interest, and recovery of said secreted product protein from the cell's surrounding culture medium, whereby said recombinant gene expression vector comprises in the following order a promoter sequence, a gene of interest encoding a secreted product protein, a translational stop signal, an in frame stop transfer sequence and translationally linked to said gene of interest a selectable marker gene, and whereby the production of said host cell line comprises the transformation with said recombinant gene expression vector and the selection of a host cell comprising said recombinant gene expression vector on the expression of said selectable marker gene. 12. Use of a recombinant gene expression vector as claimed in claims 1 to 6 in a process for efficiently selecting a host cell clone highly expressing a gene of interest. 13. A process of producing a host cell line highly expressing a gene of interest, which process comprises a process for producing a host cell clone as claimed in claim 9 and efficiently selecting a host cell clone highly expresses said gene of interest. |
<SOH> TECHNICAL FIELD <EOH>The present invention relates to the field of recombinant protein expression in host cells, to a new method to obtain and identify cell clones expressing a gene of interest above a threshold level and stably maintaining or increasing expression levels during cultivation and to a process for producing recombinant proteins. |
Formulations of compounds derived from natural sources and their use with irradiation for food preservation |
The present invention provides formulations comprising one or more compounds derived from natural sources that act to reduce the dose of irradiation required to inhibit the growth of micro-organisms in food. The present invention further provides for the use of the formulations in conjunction with low doses of irradiation to increase the safety and prolong the shelf life of food without adversely affecting its organoleptic qualities. The present invention also provides methods of applying the formulations to food products. |
1: A formulation comprising one or more compounds derived from natural sources and substantially purified, wherein application of said formulation to a food product and irradiation of said food product at less than 3 kGy results in a decrease in the number of micro-organisms in said food product when compared to an irradiated control. 2: The formulation according to claim 1, wherein said irradiation takes place under modified atmospheric packaging (MAP) conditions. 3: The formulation according to claim 1, wherein said decrease is at least one log order. 4: The formulation according to claim 3, wherein said decrease is at least two log orders. 5: The formulation according to claim 4, wherein said decrease is at least 3 log orders. 6: The formulation according to claim 4, wherein said decrease is at least 4 log orders. 7: The formulation according to claim 1, wherein said one or more compounds present in the formulation provide a final concentration of between about 0.001% and 10.0% of each compound to the food product. 8: The formulation according to claim 7, wherein said concentration is between about 0.005% to 5.0%. 9: The formulation according to claim 8, wherein said concentration is between about 0.01% and 2.5%. 10: The formulation according to claim 1, wherein one or more of said compounds are GRAS food additives. 11: The formulation according to claim 1, wherein one or more of said compounds are anti-oxidants. 12: The formulation according to claim 1, wherein one or more of said compounds are anti-microbial agents. 13: The formulation according to claim 1, wherein one of said compounds is thymol. 14: The formulation according to claim 1, wherein one of said compounds is trans-cinnamaldehyde. 15: The formulation according to claim 1, wherein one of said compounds is carvacrol. 16: The formulation according to claim 1, wherein one of said compounds is tannic acid. 17: The formulation according to claim 1, wherein one of said compounds is nisin. 18: The formulation according to claim 1 further comprising a carrier. 19: The formulation according to claim 1 further comprising one or more additives selected from the group of: chelating agents, surfactants, herbs, spices, essential oils, thickeners, anti-oxidants, emulsifiers, sequestering agents, colourings, flavourings, vitamins, minerals, and enzymes. 20: The formulation according to claim 19, wherein said additive is a sequestering agent. 21: The formulation according to claim 20, wherein said sequestering agent is tetrasodium pyrophosphate. 22: The formulation according to claim 21, wherein the amount of tetrasodium pyrophosphate in said formulation provides a final concentration of between about 0.003% and 0.1%. 23: A method of inhibiting the growth of a population of micro-organisms in a food product, comprising combining the food product with one or more compounds and exposing to a radiation dose of less than 3 kGy, wherein said compounds are derived from natural sources and are substantially purified. 24: The method according to claim 23, wherein said radiation dose is applied under modified atmosphere packaging (MAP) conditions. 25: The method according to claim 23, wherein said one or more compounds present in the formulation provide a final concentration of between about 0.001% and 10.0% of each compound to the food product. 26: The method according to claim 25, wherein said concentration is between about 0.005% and 5.0%. 27: The method according to claim 26, wherein said concentration is between about 0.01% and 2.5%. 28: The method according to claim 23, wherein one or more of said compounds are GRAS food additives. 29: The method according to claim 23, wherein one or more of said compounds are anti-oxidants. 30: The method according to claim 23, wherein one or more of said compounds are anti-microbial agents. 31: The method according to claim 23, wherein one of said compounds is thymol. 32: The method according to claim 23, wherein one of said compounds is trans-cinnamaldehyde. 33: The method according to claim 23, wherein one of said compounds is carvacrol. 34: The method according to claim 23, wherein one of said compounds is tannic acid. 35: The method according to claim 23, wherein one of said compounds is nisin. 36: The method according to claim 23, wherein said formulation further comprises a carrier. 37: The method according to claim 23, wherein said formulation further comprises one or more additives selected from the group of: chelating agents, surfactants, herbs, spices, essential oils, thickeners, anti-oxidants, emulsifiers, sequestering agents, colourings, flavourings, vitamins, minerals, and enzymes. 38: The method according to claim 37, wherein said additive is a sequestering agent. 39: The method according to claim 38, wherein said sequestering agent is tetrasodium pyrophosphate. 40: The method according to claim 39, wherein the amount of tetrasodium pyrophosphate in said formulation provides a final concentration of between about 0.003% and 0.1%. 41: The method according to claim 23, wherein said formulation is applied to said food product in liquid form. 42: The method according to 41, wherein said liquid formulation is applied to the food product by injection, vacuum tumbling, spraying, painting or dipping. 43: The method according to claim 23, wherein said formulation is applied to said food product in the form of a marinade, a breading, a seasoning rub, a glaze, or a colourant mixture. 44: The method according to claim 23, wherein said radiation dose is between about 0.005 kGY and 2.75 kGy. 45: The method according to claim 44, wherein said radiation dose is between about 0.05 kGy and 2.0 kGy. 46: The method according to claim 45, wherein said radiation dose is between about 0.1 kGy and 0.7 kGy. 47: A method of food preservation comprising the steps of: a) contacting a food product with a formulation comprising one or more compounds, wherein said compounds are derived from natural sources and are substantially purified, and b) exposing said food product to a radiation dose of less than 3 kGy. 48: A method of decreasing the radiation dose required to inhibit the growth of a population of micro-organisms in a food product by at lease one log order comprising contacting said food product with a formulation comprising one or more compounds prior to irradiation with a dose of less than 3 kGy, wherein said compounds are derived from natural sources and are substantially purified. 49: A method of increasing the shelf life of a food product comprising the steps of: a) contacting the food product with a formulation comprising one or more compounds, wherein said compounds are derived from natural sources and are substantially purified, and b) exposing said food product to a radiation dose of less than 3 kGy. 50: A method of preventing spoilage of a food product comprising the steps of: a) contacting the food product with a formulation comprising one or more compounds, wherein said compounds are derived from natural sources and are substantially purified, and b) exposing said food product to a radiation dose of less than 3 kGy. 51: A method of decreasing the off-flavour development associated with irradiation of a food product comprising the steps of: a) contacting the food product with a formulation comprising one or more compounds, wherein said compounds are derived from natural sources and are substantially purified, and b) exposing said food product to a radiation dose of less than 3 kGy. 52: The method according to any one of claims 47-51, wherein exposing said food product to said radiation takes place under modified atmosphere packaging (MAP) conditions. 53: The method according to claim 47, wherein said one or more compounds present in the formulation provide a final concentration of between about 0.001% and 10.0% of each compound to the food product. 54: The method according to claim 53, wherein said concentration is between about 0.005% and 5.0%. 55: The method according to claim 54, wherein said concentration is between about 0.01% and 2.5%. 56: The method according to claim 47, wherein one or more of said compounds are GRAS food additives. 57: The method according to claim 47, wherein one or more of said compounds are anti-oxidants. 58: The method according to claim 48, wherein one or more of said compounds are anti-microbial agents. 59: The method according to claim 47, wherein one of said compounds is thymol. 60: The method according to claim 47, wherein one of said compounds is trans-cinnamaldehyde. 61: The method according to claim 47, wherein one of said compounds is carvacrol. 62: The method according to claim 47, wherein one of said compounds is tannic acid. 63: The method according to claim 47, wherein one of said compounds is nisin. 64: The method according to claim 47, wherein said formulation further comprises a carrier. 65: The method according to claim 47, wherein said formulation further comprises one or more additives selected from the group of: chelating agents, surfactants, herbs, spices, essential oils, thickeners, anti-oxidants, emulsifiers, sequestering agents, colourings, flavourings, vitamins, minerals, and enzymes. 66: The method according to claim 65, wherein said additive is a sequestering agent. 67: The method according to claim 66, wherein said sequestering agent is tetrasodium pyrophosphate. 68: The method according to claim 67, wherein the amount of tetrasodium pyrophosphate in said formulation provides a final concentration of between about 0.003% and 0.1%. 69: The method according to claim 47, wherein said formulation is applied to said food product in liquid form. 70: The method according to claim 69, wherein said liquid formulation is applied to the food product by injection, vacuum tumbling, spraying, painting or dipping. 71: The method according to claim 47, wherein said formulation is applied to said food product in the form of a marinade, a breading, a seasoning rub, a glaze or a colourant mixture. 72: The method according to claim 47, 49, 50 or 51 wherein said radiation dose is between about 0.005 kGy and 2.75 kGy. 73: The method according to claim 72, wherein said radiation dose is between about 0.05 kGy and 2.0 kGy. 74: The method according to claim 73, wherein said radiation dose is between about 0.1 kGy and 0.7 kGy. 75: The method according to claim 48, wherein the growth of the population of micro-organisms in said food product is inhibited by at least two log orders. 76: The method according to claim 75, wherein the growth of the population of micro-organisms in said food product is inhibited by at least 3 log orders. 77: The method according to claim 76, wherein the growth of the population of micro-organisms in said food product is inhibited by at least 4 log orders. 78: An assay to identify a compound for inclusion in the formulation according to claim 1, comprising: a) providing a food product to be treated; b) inoculating said food product with a defined number of micro-organisms; c) contacting said food product with one or more candidate compounds, wherein said candidate compounds are substantially purified and are derived form natural sources; d) exposing said food product to a radiation dose of less than 3 kGy to provide a treated food product; e) evaluating the number of organisms in said treated food product, wherein a lower number of micro-organisms in step e) than in step b) indicates that the compound is suitable for inclusion in the formulation. |
<SOH> BACKGROUND <EOH>The ability of ionising energy to preserve foods by eliminating microbial contamination is well known and documented in the literature. The use of this technology is becoming standard in the food industry due to the increasing number of incidents of food-borne sickness and death caused by food-bone pathogens. Irradiation of meats, for example, is the only current commercially viable technology that can destroy all harmful bacteria on or in a raw product [Thayer, D. W., J. Food Protection, 56: 831-833 (1993)]. During irradiation treatment, energy is transferred into the food product resulting in the formation of high-energy oxidants and reductants. The most important of these in foods that have relatively high water content (such as meats) are the hydroxyl radical and the hydrogen atom, which result from the dissociation of water. Other active species formed in the radiolysis of water include hydrated electrons, hydrogen peroxide, and hydronium ions. These active species are responsible for the anti-microbial action of irradiation, but can also cause adverse chemical effects in the irradiated foods, including organoleptic changes (such as the generation of off-flavours and/or aromas) and a decrease in oxidative stability of the food on subsequent storage. Several methods for reducing objectionable off-odours and flavours associated with irradiated foods have been developed. For example, at an early stage in the development of irradiation as a food preservation technique, freezing and irradiating meat at very low temperatures were determined to reduce radiation-induced off-flavour and odours. Similarly, irradiation in the absence of oxygen, under vacuum or in the presence of an inert atmosphere is known to help decrease undesirable organoleptic changes [Huber, et al., Food Tech. pp. 109-115 1954)]. Addition of a protective substance such as ascorbic acid or its derivatives, which act as free radical acceptors, to decrease the development of radiation-induced off-flavour is also known [U.S. Pat. No. 2,832,689; Hannan, Food Sci. Abs. pp. 121-125 (1954)]. Other compounds reported in the literature as exhibiting flavour protection qualities in irradiated food include certain herbs and spices such as pepper, mace, allspice, turmeric, celery, dill, caraway, thyme, onion and sage or extracts derived therefrom [Huber, et al., Food Tech. pp. 109-115 (1954)]. The anti-oxidant effects of herbs, spices and their extracts are well known [for example, see “ Spices: Flavor Chemistry and Antioxidait Properties ,” S. J. Risch and C -T. Ho, eds., ACS Symposium Series 660, American Chemical Society, Washington, D.C. (1996)] and are generally believed to be responsible for their ability to preserve the flavours in irradiated foods. Mixing ground thyme or ground rosemary with selected commercially available fatty acids (arachidonic, linoleic, myristic, and stearic acids), for example, followed by exposure to gamma-irradiation (3 kGy and 9 kGy doses) significantly reduced the amount of lipidolysis that normally results from the irradiation process [Lacroix, M. et al., Food Res. Int. 30:457-462 (1997)]. There is an increasing demand for natural food additives, for example, from plants and plant extracts to improve the quality of food products. Essential oils isolated from herbs, spices and other plants, in particular from thyme and rosemary, have been found to have antimicrobial activity in addition to their anti-oxidant properties. For example, essential oils have been used effectively against many food-bome bacteria including Escherichia coli [Eloff, J. N., J. Ethnopharmacol., 67:355-360 (1999)], Salmonella typhimurium and Staphylococcus aureus [Juven, et al., J. Appl. Bacteriol., 76 : 626 -631 (1994)], Listeria monocytogenes [Aureli, et al., J. Food Prot., 55:344-348 (1992)] and Vibrio spp. [Koga et al., Microbiol. Res., 154:267-273 (1999)]. Unfortunately, the concentration of essential oils needed to prevent bacterial growth is generally found to be much higher than the concentrations currently being used in the industry (ICMSF, 1980). Furthermore, essential oils tend to lose their inhibitory activity after a certain period of incubation [Ouattara et al., Int. J. Food Microbiol., 37:155-162 (1997)], which can limit their application in the food industry. Some of the active constituents responsible for the anti-microbial activity of essential oils and plant extracts have also been identified, for example thymol [Aktug & Karapinar, Int. J. Food Microbiol., 4:161-166 (1989); Beuchal & Golden, Food Technol., 1:134-142 (1989); Juven, et al., J. Appl. Bacteriol., 76:626-631 (1994)], eugenol, menthol, anethole [Aktug & Karapinar, ibid], carnasol, ursolic acid, rosmanol [Collins & Charles, Food Miciobiol., 4:311-315 (1987)] and proanthocyanidins [Canadian Patent Application No. 2,302,743]. Both the anti-oxidative and anti-microbial properties of essential oils and plant extracts have been investigated with respect to irradiation of foods, particularly meat and meat products. For example, U.S. Pat. No 6,099,879 describes a method for treating meat and meat products with a rosemary extract prior to irradiation. The patent describes the use of rosemary extracts to prevent or reduce lipid peroxidation and oxidation in the meat products. The breakdown of lipids is responsible for the development of the “wet dog, burnt or metallic” off-flavours in meat products which often result fiom the use of gamma-irradiation. U.S. Pat. No 6,099,879 also describes the use of the active anti-oxidant ingredients of rosemary, i.e. carnosic acid, carnosol, and rosmarinic acid, as a replacement for rosemary extract, as well as the use of these ingredients or a rosemary extract together with other anti-oxidant compounds (such as tocopherols, ascorbic acid, citric acid or sodium tripolyphosphate, niacin, mannitol, sodium benzoate, chloride ion, sodium fumarate, monosodium glutamate, ascorbic acid, pepper, mace, turmeric, celery, dill, caraway, thyme, onion, and sage or extracts). Although the rosemary extract and the active anti-oxidant ingredients thereof are described as decreasing,the amount of off-flavour and aroma associated with irradiated meats, the irradiation method described by this patent, however, still relies on doses of irradiation of between 3 and 7 kGy. Mahrour et al. describe the use of thyme and rosemary with lower doses of irradiation (as low as 3 kGy) and the ability of these compounds to decrease fatty acid oxidation and the survival of Salmonella bacteria in irradiated chicken [Mahrour et al., Radiat. Phys. Chem., 52:77-80 (1998); Mahrour et al., Radiat. Phys. Chem., 52:81-84 (1998)]. Chicken legs were marinated in a mixture of lemon juice, thyme and rosemary prior to irradiation at a dose of either 3 kGy or 5 kGy. In comparison to non-marinated controls, a significant decrease in the amount of fatty acid oxidation and the number of Salmonella surviving treatment was observed in the marinated chicken. International Patent Application No. WO01/37683 describes the use of protein and polysaccharide-based food covering materials as a method of food preservation. This patent application also describes the use of these food coverings in conjunction with irradiation (3 kGy). The food covering materials are described as optionally including additives, such as flavourings and anti-bacterial agents (for example, thyme oil and trans-cinnamaldehyde). The use of the food coverings both with and without added anti-bacterial agents in combination with irradiation resulted in a decrease in the number of bacteria surviving treatment when compared to the effects of irradiation alone. Radiation-induced effects on the quality of food (i.e. undesirable changes to the organoleptic qualities) are a major drawback inherent in the use of irradiation as a food preservation technique. Many of these detrimental effects could be eliminated if lower doses of radiation could be used, however, the use of lower doses may compromise the safety of the food. For example, it has been postulated that irradiation doses higher than 2.5 kGy may be required to eliminate Salmonella spp. from chicken [Katta et al., J. Food Sci, 56:371-372 (1991)]. This level of irradiation has been shown to result in off-flavours and odours in poultry [Hanis et al., J. Food Protection, 52:26-29 (1989)]. A need remains, therefore, for improved methods of food preservation that provide safe food, but which also allow the desirable organoleptic qualities of the food product to be maintained. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object of the present invention is to provide formulations of compounds derived from natural sources and their use with irradiation for food preservation. In accordance with an aspect of the present invention, there is provided a formulation comprising one or more compounds derived from natural sources and substantially purified, wherein application of said formulation to a food product and irradiation of said food product at less than 3 kGy inhibits the growth of a population of micro-organisms in said food product by at least one log order. In accordance with another aspect of the present invention, there is provided a use of a formulation comprising one or more compounds in combination with a radiation dose of less than 3 kGy to inhibit the growth of a population of micro-organisms in a food product, wherein said compounds are derived from natural sources and are substantially purified. In accordance with another aspect of the present invention, there is provided a method of food preservation comprising the steps of: (a) contacting a food product with a formulation comprising one or more compounds, wherein said compounds are derived from natural sources and are substantially purified, and (b) exposing said food product to a radiation dose of less than 3 kGy. In accordance with still another aspect of the present invention, there is provided a method of decreasing the radiation dose required to inhibit the growth of a population of micro-organisms in a food product by at least one log order comprising contacting said food product with a formulation comprising one or more compounds prior to irradiation, wherein said compounds are derived from natural sources and are substantially purified. In accordance with still another aspect of the present invention, there is provided a method of increasing the shelf life of a food product comprising the steps of: (a) contacting the food product with a formulation comprising one or more compounds, wherein said compounds are derived from natural sources and are substantially purified, and (b) exposing said food product to a radiation dose of less than 3 kGy. |
Method for transmitting audio-visual programmes proposed by users, terminal and server therefor |
The present invention concerns a method of receiving audiovisual programmes transmitted to terminals. The users of the terminals choose a programme from a catalogue and make a proposition to a server to download it to their terminals. The proposition is accompanied by a price and/or deadline. The server analyses the propositions it receives and, taking account of its profitability constraints, decides whether or not it will transmit the programme. Depending on the case, it sends the acceptance to each user who has made a proposition with profitable parameters for the transmission of the programme and gives the users the means of receiving the programme for viewing. The decision to transmit the programme is determined according to various strategies the common criterion of which is profitability. The invention also concerns a terminal and a server for the implementation of the method. |
1. A method of transmitting audiovisual programmes from a server to at least one terminal comprising a first step of viewing a catalogue of downloadable audiovisual programmes on the terminal, comprising the following chronological steps: at the terminal: a step of selecting at least one audiovisual program; a step of generating a proposition conditioning the reception of the selected program; a step of transmitting the proposition to the server, the proposition comprising at least one of the following parameters: deadline, price; and at the server: a step of analysing the propositions sent by the terminals and of determining a decision to transmit the transmission taking account of the parameters; if the decision to transmit the programme is taken: a step of transmitting the selected programme over a broadcast network, a step of transmitting a code enabling each terminal that has sent a proposition to view the received program, viewing occurring after payment of a minimum price and/or not later than expiry of the determined deadline. 2. The method of transmitting programs as claimed in claim 1, wherein at the server, the analysis step is activated after a determined time from the moment when the programme is placed in the catalogue. 3. The method of transmitting programs as claimed in claim 1, wherein at the server, the analysis step is activated after a determined number of propositions is received. 4. The method of transmitting programs as claimed in claim 1, additionally comprising a step of transmission by the server to at least one terminal of a notification indicating that the server has decided not to transmit the program. 5. The method of transmitting programs as claimed in claim 4, wherein the said notification comprises an indication of the reason for the server's refusal to transmit the program. 6. Method of transmitting programs as claimed in claim 4, wherein the said notification comprises a parameter value such as the price or deadline which, incorporated in a proposition, would enable the user to view the program. 7. The method of transmitting programs as claimed in claim 1, wherein the proposition sent by the terminal comprises an indication determining a subset of programmes in the catalogue and in that, in the course of the analysis and determination step, the server selects from the subset a programme from the catalogue the transmission of which to the terminals satisfies the server's own criteria. 8. The method of transmitting programs as claimed in claim 1, wherein the decision to transmit a programme is taken preferably when many users have proposed that programme. 9. The method of transmitting programs as claimed in claim 1, additionally comprising a step of recording the program within the terminal. 10. An audiovisual terminal comprising a central processor unit, a means of receiving audiovisual programmes from a broadcast network, a means of two-way communication with a second network, a means of displaying a catalogue of available programs and a means of selecting an audiovisual program, comprising a means of generating at least one parameter such as the price and/or deadline, associated with the downloading of at least one selected programme, a first means for transmitting to the second network a proposition comprising at least one program identifier and the parameter entered, and a means of receiving a decision concerning the proposition, to download the programme from the broadcast network according to the previously generated parameter. 11. The audiovisual terminal as claimed in claim 10, additionally comprising a means of receiving a notification of refusal to download, the refusal being displayed on the display means. 12. The audiovisual terminal as claimed in claim 11, additionally comprising a means of receiving a second parameter such as the price or deadline incorporated in the notification of refusal to download, the second parameter being displayed on the display means. 13. The audiovisual terminal as claimed in claim 10, wherein only one of the parameters such as price or deadline is incorporated in the proposition, the agreement to download received from the network is accompanied by a value of the other parameter (deadline or price), and in that it comprises a second means of transmission over the network of a second proposition comprising the two parameters. 14. The audiovisual terminal as claimed in claim 10, wherein the proposition comprises an identifier (TOPIC) of a subset of programs presented in the catalogue, and in that it comprises a means of receiving an identifier of a program likely to be received according to the parameters defined in the proposition. 15. The audiovisual terminal as claimed in claim 10, additionally comprising a means of receiving (5) a channel and network reference (6) to receive the selected programme. 16. The audiovisual terminal as claimed in claim 10, additionally comprising a means of storing the programs received. 17. A server comprising a database containing audiovisual programs, the server having a communication interface for establishing a link (6) with a plurality of terminals, said server additionally comprising: a means of receiving propositions to transmit at least one program contained in the database, the said propositions coming from at least one terminal comprising at least one parameter such as a price or a deadline relating to the transmission of the program from the server to the terminals, a means of analysis of the propositions received, a means of determining a decision to transmit the program taking account of the parameters transmitted over a broadcast network; and a means of transmitting to the terminal a code for viewing at least one selected program. 18. The server as claimed in claim 17, wherein the means of analysis and determination is activated after a determined time from the moment when the programme is accessible to the users of the terminals. 19. The server as claimed in claim 17, wherein the means of analysis and determination is activated after receipt of a determined number of propositions from the terminals. 20. The server as claimed in claim 17, wherein a proposition received from a terminal comprises only one of the parameters from the set: price, deadline; and in that the acceptance sent to that terminal comprises a value of the other parameter in the set. 21. The server as claimed in claim 17, wherein a proposition received from a terminal comprises only one indication determining a subset of programs, the means of analysis and determination also comprises a means of determining a program belonging to that subset, for which the parameters sent in the proposition enable a transmission to that terminal. 22. The server as claimed in claim 17, additionally comprising a means of determining the means of transmission of the program, the notification of acceptance of the transmission to the terminals comprising an identifier of the means of transmission. |
Medium recording method, medium recording device, and information recording medium |
This invention is a recording medium recording method for an optical disc or the like. Every time one VTS is prepared, padding processing is executed to secure a recording area for new TMP_VMGI following that VTS and for VTSI and VTSM VOBS of the subsequent title. As, every time one VTS is prepared, new TMP_VMGI following that VTS is recorded, TMP_VMGI is recorded at the position that is added to the number of VTSs. Therefore, even when the management information becomes unreadable because of update exceeding the rewriting durability of the medium with respect to the recording area of TMP_VMGI on the innermost side, the management information can be read from TMP_VMGI recorded in the other recording areas and the finalizing processing can be executed. |
1. An optical disc recording method for recording a set made up of a file to be recorded and management information of the file into a user area on a rewritable optical disc while conforming to a recording format for a playback-only recording medium including at least a file containing recording information to be reproduced and management information for managing the recording information, and file management information for managing one or plural files, the method comprising: securing a recording area for temporary management information for managing the file recorded in the user area, management information conformable to the recording format of the playback-only recording medium, and management information for managing recording information of the file to be recorded; recording the temporary management information for managing the file to the recording area and subsequently recording the recording information of the file to be recorded to the recording area; recording the management information for managing the recording information of the file to the recording area so as to close the file, then securing a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then recording the temporary management information for managing the file to the recording area, and rewriting the previously recorded temporary management information with the latest temporary management information; and every time a file is recorded, securing a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then recording the temporary management information for managing the file to the recording area, and updating the temporary management information recorded at least on the innermost side. 2. The recording method as claimed in claim 1, wherein every time a file is recorded, a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next is secured, the temporary management information for managing the file is recorded into the recording area, and all the temporary management information that has already been recorded is updated. 3. The recording method as claimed in claim 1, wherein every time a file is recorded, a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next is secured, the temporary management information for managing the file is recorded into the recording area, and only the temporary management information recorded on the innermost side is updated. 4. The recording method as claimed in claim 1, wherein when recording and closing a file, management information for managing recording information of that file is used to overwrite a temporary management information part recorded when closing a previous file, and the temporary management information at two positions, that is, the temporary management information on the innermost side and the temporary management information on the outermost side, are saved. 5. The recording method as claimed in claim 1, wherein as a recording format of the file and the management information, a DVD video format is used for the file, the medium is a DVD-RW (DVD-rewritable), the file is a VTS (video title set) in the DVD video format, the management information for managing recording information of the file is VMGI (video manager information) in the DVD video format, the DVD video file is managed by temporary VMGI (TMP_VMGI), and the DVD video file is recorded using a ROW (restricted overwrite) system. 6. An optical disc recording apparatus for recording a set made up of a file to be recorded and management information of the file into a user area on a rewritable optical disc while conforming to a recording format for a playback-only recording medium including at least a file containing recording information to be reproduced and management information for managing the recording information, and file management information for managing one or plural files, the apparatus comprising: management information generation means for generating management information of a file to be recorded; recording means for recording the set made up of the file and the management information of the file into the user area of the optical disc; and control means for controlling operation of at least the management information generation means and the recording means; wherein the control means secures a recording area for temporary management information for managing the file recorded in the user area, management information conformable to the recording format of the playback-only recording medium, and management information for managing recording information of the file to be recorded, then records the temporary management information for managing the file to the recording area, subsequently records the recording information of the file to be recorded to the recording area, then records the management information for managing the recording information of the file to the recording area so as to close the file, then secures a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then records the temporary management information for managing the file to the recording area, and rewriting the previously recorded temporary management information with the latest temporary management information, and every time a file is recorded, the control means secures a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then records the temporary management information for managing the file to the recording area, and updates the temporary management information recorded at least on the innermost side. 7. The recording apparatus as claimed in claim 6, wherein every time a file is recorded, the control means performs control to secure a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then record the temporary management information for managing the file into the recording area, and update all the temporary management information that has already been recorded. 8. The recording apparatus as claimed in claim 6, wherein every time a file is recorded, the control means performs control to secure a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then record the temporary management information for managing the file into the recording area, and update only the temporary management information recorded on the innermost side. 9. The recording apparatus as claimed in claim 6, wherein when recording and closing a file, the control means performs control to use management information for managing recording information of that file to overwrite a temporary management information part recorded when closing a previous file, and save the temporary management information at two positions, that is, the temporary management information on the innermost side and the temporary management information on the outermost side. 10. The recording apparatus as claimed in claim 9, wherein as a recording format of the file and the management information, a DVD video format is used for the file, the medium is a DVD-RW (DVD-rewritable), the file is a VTS (video title set) in the DVD video format, the management information for managing recording information of the file is VMGI (video manager information) in the DVD video format, and the control means manages the DVD video file by temporary VMGI (TMP_VMGI) and records the DVD video file using a ROW (restricted overwrite) system. 11. An information recording medium having a control program recorded thereon so that the control program is readable by a control computer, the control computer controlling operation of management information generation means for generating management information of a file to be recorded and recording means for recording a set of a file and management information of the file into a user area of an optical disc, the management information generation means and the recording means being provided in an optical disc recording apparatus for recording the set made up of the file to be recorded and the management information of the file into the user area on the optical disc, the control program causing the control computer to function as control means for performing control to secure a recording area for temporary management information for managing the file recorded in the user area, management information conformable to the recording format of the playback-only recording medium, and management information for managing recording information of the file to be recorded, then record the temporary management information for managing the file to the recording area, subsequently record the recording information of the file to be recorded to the recording area, then record the management information for managing the recording information of the file to the recording area so as to close the file, then secure a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then record the temporary management information for managing the file to the recording area, and rewrite the previously recorded temporary management information with the latest temporary management information, and every time a file is recorded, to secure a recording area for the temporary management information for managing the file and management information for managing recording information of a file to be recorded next, then record the temporary management information for managing the file to the recording area, and update the temporary management information recorded at least on the innermost side. |
<SOH> BACKGROUND ART <EOH>Conventionally, as information-writable DVDs (digital versatile discs), which are large-capacity optical discs, DVD-R (DVD-recordable) on which information can be written once, DVD-RW (DVD-rewritable) on which information can be rewritable, and DVD-RAM (DVD-random access memory) are provided. As for DVD-R and DVD-RW of these optical discs, if video data is recorded in a format conformable to the DVD video format, the data can be reproduced by a playback-only optical disc player. This standard enables reading of data recorded on a disc in a computer that processes data, by supporting the standard of universal disk format (UDF). FIGS. 1A to 1 C are views showing a logical format of an optical disc based on the DVD video format. The optical disc based on this format has its information recording surface sectioned into a lead-n area, a data zone, and a lead-out area, from the innermost side, which is the leading side, and desired video data is recorded in the data zone, as shown in FIG. 1A . The data zone is sectioned into, from the lead-in side, a UDF (universal disk format) area A 1 , which is a file system area with a UDF bridge structure described therein, a VMG (video manager) area A 2 , which is a DVD management information area, and a real-time data recording area A 3 . The UDF area and VMG area are management information recording areas for managing files based on video data recorded on this optical disc. Of these UDF area and VMG area, the second management information recording area, that is, the VMG area, is an area corresponding to a file management system proper to the DVD video format, and TOC information as management information for managing the whole video data recorded in the real-time data recording area A 3 is recorded in this area. On the other hand, the first management information recording area, that is, the UDG area A 1 , is an area corresponding to a file management system based on a computer, and management information for managing the whole video data recorded in the real-time data recording area A 3 in a format that realizes compatibility with the file system in the computer is recorded in this area. The real-time data recording area A 3 is a user area for recording actual data, and video data is recorded by each VTS (video title set, hereinafter suitably referred to as title) as a unit in this area, as shown in FIG. 1B . 99 VTSs can be provided at the maximum. This VTS includes, from the leading side, VTSI (video title set information), VTSM VOBS (video object set for the VTSM), VTSTT VOBS (video object set for titles in a VTS), and VTSI BUP (backup of VTSI), as shown in FIG. 1C . In VTSTT VOBS, video data based on the MPEG (Moving Picture Experts Group) 2 format, which is actual data, is recorded. In VTSI, recording position information or the like, which is management information for managing video data based on this actual data, is recorded. In VTSTT VOBS, a title menu of video data is recorded. VTSTT VOBS is optional. VTSI BUP is a backup for VTSI. With an optical disc of this type, when accessing data by using a computer, a desired file can be retrieved and reproduced on the basis of UDF, and when reproducing data by using a DVD player, a desired file can be retrieved and reproduced on the basis of VMG. As a system for writing video data to such an optical disc, an incremental recording system (hereinafter referred to as INC system) or a restricted overwrite system (hereinafter referred to as ROW system) is used. The INC system is a system of sequentially recording video data. The ROW system is a system applied to an optical disc on which data can be overwritten. However, even in the ROW system, when recording data to an non-recorded area, video data is recorded sequentially. In the INC system and the ROW system, processing to the optical disc such as reservation is managed using RMA (recording management area) provided on the inner side of the lead-in area. FIGS. 2A to 2 H show recording procedure based on the INC system. In the INC system, it is defined that data can be written into a maximum of three areas at a time. Each of these areas is called R zone and each R zone is managed using RMA. Specifically, in the case of recording a motion picture in the INC system, R zones are reserved first, as shown in FIG. 2A . In executing the reservation of R zones, an R zone 1 area, which forms a UDF area and a VMG area as a management information recording area, is defined, and then an R zone 2 area, which forms VTSI and VTSM VOBS of the leading VTS, is defined in a non-recorded area, which forms a real-time data recording area. The remaining non-recorded area is defined as an Invisible R zone area. In the INC system, by reserving these R zone 1 and R zone 2 , the management information recording area is secured and the area forming VTSI and VTSM VOBS of the leading VTS is secured. In the INC system, VTSTT VBOS based on actual data is formed by sequentially recording video data from the leading side of the Invisible R zone. Moreover, when recording of actual data for one title is completed by a user's instruction, VTSI BUP is recorded after the recording of this actual data, as shown in FIG. 2B . Then, again from the leading side, VTSI and VTSM VOBS are formed in the R zone 2 , as shown in FIG. 2C , and the R zone 2 is closed. In this manner, one VTS is recorded on the optical disc in the INC system. In the case of continuously recording the next title in the INC system, an R zone 3 is reserved in the remaining non-recorded area to secure VTSI and VTSM VOBS, and the Invisible R zone is defined, as shown in FIG. 2D . Then, after VTSTT VOBS is formed by recording actual data, VTSI BUP is formed, as shown in FIG. 2E , and VTSI and VTSM VOBS are formed in the previously secured area, as shown in FIG. 2F . In this manner, the subsequent VTS is recorded on the optical disc, as shown in FIG. 2G . In the INC system, in the case of recording subsequent titles, the non-recorded area is similarly defined and VTSs are sequentially recorded. In the INC system, on the optical disc on which the real-time data recording area is formed by sequentially recording VTSs in this manner, a UDF area and a VMG area are formed by finalizing processing, and a lead-in area and a lead-out area are formed, as shown in FIG. 2H . This realizes compatibility with a playback-only optical disc. The formation of the UDF area and the VMG area is executed by generating UDF and VMG data from VTSI and VTSM VOBS of each title, then recording the data in the R zone 1 , and closing the R zone 1 . FIGS. 3A to 3 G show recording procedure based on the ROW system. In the ROW system, a recording area for lead-in, UDF, VMG, and VTSI and VTSM VOBS of the leading title is secured in advance by padding, as shown in FIG. 3A . Padding is the processing to secure an area by recording dummy data such as NULL. As these areas are secured in this manner, in the ROW system, VTSTT VOBS based on actual data is formed by sequentially recording video data, as shown in FIG. 3B . As recording of actual data of one title is completed, VTSI BUP is subsequently recorded, as shown in FIG. 3B . Then, to secure a recording area for VTSI and VTSM VOBS of a subsequent title, padding processing is executed. Again from the leading side, VTSI and VTSM VOBS corresponding to the recording of this actual data are formed, as shown in FIG. 3C . In this manner, one VTS is recorded on the optical disc in the ROW system. In the case of continuously recording the next title in the ROW system, VTSTT VOBS and VTSI BUP are formed by recording actual data, following the padding area formed by the VTS that is immediately before, as shown in FIG. 3D . To secure a recording area for VTSI and VTSM VOBS of a subsequent title, padding processing is executed. Next, VTSI and VTSM VOBS are formed, as shown in FIG. 3E , and the subsequent VTS is recorded on the optical disc, as shown in FIG. 3F . In the ROW system, in the case of recording subsequent titles, processing such as padding is similarly executed and VTSs are sequentially recorded. In the ROW system, on the optical disc on which the real-time data recording area is formed by sequentially recording VTSs in this manner, a UDF area and a VMG area are formed by finalizing processing similar to that of the INC system, and a lead-in area and a lead-out area are formed, as shown in FIG. 3G . This realizes compatibility with a playback-only optical disc. Generally, in the case of recording data in the DVD video format to a DVD-RW medium, a file system for managing an intermediate state is necessary. If only recording conformable to the DVD video standard is performed, information managing VTSs is held in the file system for the intermediate state. Therefore, when a VTS is deleted, which LSN (logical sector number) on the medium has become free is managed. By utilizing this information, it is possible to newly record data to this position. For example, JP-A-14-063765 discloses a technique of recording information to a DVD-R along real time in such a manner that the information can also be reproduced by a player for a playback-only DVD where information is recorded irrespective of real time. According to this disclosed technique, in the case of recording information to a DVD-R while conforming to the DVD video standard including at least a VTS containing VOBS to be reproduced and the corresponding VTSI, and VMGI for controlling reproduction of one or plural VTSs, the VTS is recorded to the DVD-R, and after recording the VTS, temporary VMGI is generated as temporary control information corresponding to the recorded VTS and adapted for later forming VMGI and recording the VMGI to the DVD-R. The generated temporary VMGI is recorded to the DVD-R every time a VTS is recorded to the DVD-R. By thus generating temporary control information and temporarily recording the temporary control information to the write-once recording medium when unit recording information is recorded, and by accurately recording original management control information later by using the temporary control information containing the latest contents, even if plural units of recording information are recorded on the write-once recording medium, it is possible to execute information recording to the write-once recording medium along real time in conformity with the recording format for a playback-only recording medium, which is not assumed to record information along real time. Conventionally, in the case of realizing the DVD video format in a video recording apparatus using a rewritable optical disc medium, typically, temporary reproduction management information is recorded at a fixed address and a file system and reproduction information conformable to the DVD video format are recorded at the time of finalizing. In this method, the fixed address is frequently accessed and the rewriting durability of the medium may be exceeded in a short time. Once this management information becomes unreadable, the entire management information of the disc will be lost. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIGS. 1A to 1 C are charts for explaining the DVD video format. FIGS. 2A to 2 H are charts for explaining recording based the INC system. FIGS. 3A to 3 G are charts for recording based on the ROW system. FIG. 4 is a block diagram showing the structure of an optical disc recording/reproducing apparatus to which the present invention is applied. FIG. 5 is a flowchart showing processing procedure executed at the time of turning on power in the optical disc recording/reproducing apparatus according to the present invention. FIG. 6 is a view for explaining image file recording processing based on the ROW system in the optical disc recording/reproducing apparatus according to the present invention. FIGS. 7A to 7 G are views for explaining image file recording processing based on the ROW system. FIGS. 8A to 8 G are view for explaining another example of image file recording processing based on the ROW system. FIG. 9 is a flowchart showing reproduction processing procedure in the optical disc recording/reproducing apparatus according to the present invention. detailed-description description="Detailed Description" end="lead"? |
Wind-energy installation comprising a ring generator |
The present invention concerns a wind power installation having a (ring) generator which has a stator in which grooves are provided at the inner or outer periphery in mutually spaced relationship to receive a stator winding. In order to provide a stator having a winding, in which the susceptibility to trouble as a consequence of the high loading on the generator is substantially reduced, the stator winding is wound without interruption continuously throughout. |
1. A wind power installation having a ring generator which has a stator in which grooves are provided at the inner or outer periphery in mutually spaced relationship to receive a stator winding, wherein the winding is wound without interruption continuously throughout. 2. The wind power installation according to claim 1 characterised by a stator having at least two phase windings which are wound continuously throughout. 3. The wind power installation according to claim 1 wherein only respective windings of a phase are arranged within a groove. 4. The wind power installation according to claim 1 characterised in that groove windings of different phases are arranged in adjacent relationship. 5. The wind power installation according to claim 1 characterised in that the winding of a phase comprises at least one conductor bundle, wherein a conductor bundle comprises a plurality of mutually insulated conductors. 6. The wind power installation according to claim 6 characterised in that at least two conductor bundles are arranged in mutually superposed relationship in a groove. 7. The wind power installation according to claim 7 characterised in that, in grooves in which a plurality of conductor bundles are arranged, the positions of the upper and lower conductor bundles are interchanged in a predetermined order. 8. The wind power installation according to claim 1 characterised in that inserted into each groove are two turns which preferably correspond to the same phase. 9. An apparatus for the production of a stator of a synchronous machine according to claim 1 characterised by a mounting apparatus for the stator, in which the stator is held in a standing position. 10. The apparatus according to claim 9 characterised by at least one drive for rotating the stator in the mounting apparatus in its peripheral direction. 11. The apparatus according to claim 9 characterised by a carrier apparatus for holding at least one drum with winding wire, the carrier apparatus being separate from the mounting apparatus. 12. The apparatus according to claim 11 characterised by a pair-wise arrangement of a plurality of drums, wherein the pairs of drums are arranged in uniformly spaced relationship on a rotational circle. 13. An apparatus according to one of claim 1 characterised by a carrier apparatus arranged at each side of the stator. 14. An apparatus according to one of claim 1 characterised by a number of the pairs of drums, equal to the number of phases to be wound on the stator. 15. The apparatus according to claim 14 characterised in that each of the carrier apparatuses carries the respective half of the drum. 16. An apparatus according to one of claim 1 characterised by a substantially vertically arranged carrier plate and carrier arms extending outwardly from the centre of the carrier plate for receiving the drums. 17. The apparatus according to claim 16 characterised by a rotatable mounting for the carrier plate. 18. The apparatus according to claim 17 characterised by a drive for rotating the carrier plate in the peripheral direction. 19. The apparatus according to claim 16 characterised in that the drums are mounted to a substantially horizontally extending portion of the carrier arms and that the horizontally extending portion is adapted to be rotatable about its longitudinal axis. 20. A synchronous machine comprising a rotor and a stator, wherein the stator has grooves provided in mutually spaced relationship at the inner or outer periphery for receiving a stator winding and wherein the stator winding is of a continuous nature throughout in the grooves. 21. The synchronous machine according to claim 20 characterised in that the stator winding is of an at least phase nature and wherein windings of different phases are disposed in adjacent grooves, wherein each winding comprises at least one conductor bundle having a plurality of conductors, and each winding comprises two conductor bundles which are interchangeable in their arrangement relative to each other within a groove over the stator periphery. 22. Use of a synchronous machine according to claim 20. 23. A ring generator for a wind power installation wherein the stator is secured fixedly to the machine carrier of the wind power installation whereas the rotor of the synchronous machine is coupled to the rotor of the wind power installation. 24. The wind power installation according to claim 1 characterised by a stator having 6-phase windings that are each wound without interruption continuously. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention concerns a wind power installation having a generator which has a stator in which grooves are provided at the inner or outer periphery in mutually spaced relationship to receive a stator winding. Such wind power installations are known and are produced and marketed for example by ENERCON. 2. Description of the Related Art A known process for the production of stator windings in generators includes the use of what are referred to as former-wound coils. Those former-wound coils are individual windings of the stator winding, which are already adapted in respect of their form to the grooves and groove spacings of the stator and which are firstly individually inserted into the grooves and then connected together. It will be appreciated however that wind power installations are always exposed to high levels of loading during operation thereof. With an increasing wind speed the power output of the wind power installation increases but at the same time the mechanical loading also rises. That means that the stress on the wind power installation increases substantially simultaneously, from the mechanical and the electrical point of view. At high wind speeds the mechanical stress on the installation is high and at the same time a great deal of electrical power is generated so that the stress on the electrical components is also high. In that situation, the generator of the wind power installation, which is subjected to mechanical and electrical stresses, is particularly stressed. That combination gives rise to problems if for example, as a consequence of high electric currents generated, the temperature in the region of the generator is also high and, as a consequence of mechanical stress, connections between individual components are subjected to the effect of vibration. If thermal expansion also gives rise to a small amount of play or a loosening effect, the mechanical loadings can here result in a defect or even damage. If that trouble involves the stator winding or a phase thereof, at least that phase is out of commission in terms of energy production. Furthermore this involves an additional asymmetrical loading in the generator as, as a consequence of the interruption, that phase acts as in the no-load mode of operation. In that respect mechanical damage due to released and freely movable components such as connecting sleeves is not even taken into consideration. In the case of a stator, wound in six-phase configuration, of a generator with 72 poles, there are 432 former-wound coils which are connected together by 864 connecting locations. Those connecting locations are usually in the form of screw, clamping or solder connections. Having regard to statistical probabilities (of no matter how small magnitude), the high number of connecting locations and the permanent changes in load mean that, even if the connection between the former-wound coils is carefully made, this involves a serious source of trouble. In that respect only one stator is taken into account in the foregoing considerations. The aspect of mass production clearly reveals the actual probability of such a problem occurring. |
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>Therefore one object of the present invention is to provide a stator having a winding, in which the above-discussed problems are substantially reduced. In a wind power installation of the kind set forth in the opening part of this specification, that object is attained by a stator winding which is of a continuous nature throughout. That arrangement avoids in particular the need for a connector between individual portions of a stator winding. In a preferred embodiment of the invention all phases are respectively wound continuously throughout on the stator. In order to be able to compensate for current-displacement effects in the individual turns, the turns are produced from at least two conductor bundles, wherein a plurality of mutually insulated conductors is present in each conductor bundle. Those conductor bundles are introduced into grooves in the stator in a predetermined sequence and the sequence is altered at also predetermined spacings so that each of the conductor bundles is alternately affected as uniformly as possible by those effects. It is possible to forego compensation measures by virtue of that uniform influence in respect of all conductor bundles of a phase. In order to facilitate handling of the stator during production of the winding and to provide a situation which is favorable in work-physiological terms, the stator is kept in a mounting apparatus in which the grooves are at a favorable working height for production of the winding and which permits rotation of the stator in the peripheral direction by a desired amount. This can preferably be effected using a motor drive. In a particularly preferred development of the invention there is further provided at least one carrier apparatus for carrying at least one coil with winding wire. That carrier apparatus makes it possible to handle the winding wire, for example in the form of conductor bundles, the length of which, in accordance with the invention, is such that the phase can be wound continuously throughout on the stator. The conductor bundle length required for that purpose results in a considerable weight which can no longer be handled manually. In a particularly preferred embodiment two respective drums with winding wire are handled in pairs in order in that way to be able to handle both conductor bundles at the same time and a carrier apparatus carries three pairs of the drums with winding wire so that, using such a carrier apparatus, a three-phase system with two respective conductor bundles per phase can be wound on the stator. In a particularly preferred development of the invention the drums with the winding wire are arranged pivotably about a central axis of rotation of the carrier apparatus. That arrangement makes it possible to compensate for twisting of the conductor bundles, which arises out of the rotation of the stator in the holding apparatus, by virtue of the drums being correspondingly rotationally entrained on the carrier apparatuses. Further advantageous embodiments of the invention are set forth in the appendant claims. |
Road weather prediction system and method |
In one aspect, the present invention relates to a method of determining the sky-view factor at a location. The method comprises the steps of receiving data from at least one global positioning satellite at the location, and comparing the data so obtained with a mathematical function. The function is derived from corresponding data obtained from reference locations at which the sky view factor is known, whereby to arrive at an approximation of the sky view factor at said location. In another aspect, the invention relates to a method for predicting the variation in temperatures over time at locations along a survey route, particularly a road network. The method comprises the steps of establishing a database for the survey route containing location specific geographical parameters, obtaining actual and forecast meteorological data and separately predicting the temperature at each location using energy balance equations. The predicted temperature calculated for each location is dependent upon the meteorological data and the geographical parameters for the location whose temperature is being predicted. The invention also discloses systems which relate to the above methods. |
1. a method of determining the sky-view factor at a location, comprising the steps of: (I) receiving data from at least one global positioning satellite at said location, and (ii) comparing the data so obtained with a mathematical function derived from corresponding data obtained from reference locations at which the sky view factor is known, whereby to arrive at an approximation of the sky view factor at said location. 2. A method as claimed in claim 1, wherein the satellite data is selected from one or more of (I) the number of satellites in line of sight at said location, (ii) the sum of signal strengths of the or each satellite, and (iii) the dilution of precision value at said location. 3. A method as claimed in claim 1, wherein the mathematical function is obtained by plotting for each reference location the actual sky view factor against the satellite data corresponding to that to be received for the location whose sky view factor is to be determined, and fitting a curve through the plots, the mathematical function corresponding to the equation of the fitted curve. 4. A method as claimed in claim 1, wherein said reference locations are selected to be of a similar type to the location whose sky view factor is being determined. 5. A method as claimed in claim 1, wherein locations are classified according to their surroundings. 6. A method as claimed in claim 5, wherein locations are classified as urban, suburban, rural with leaves on trees or rural with leaves off trees. 7. A method as claimed in claim 5 which includes an initial step of receiving data from a user on the type of location at which the sky view factor is being determined, the mathematical function being derived only from reference locations of that same type. 8. A method as claimed in claim 5 in which data on the type of location at which the sky view factor is being determined is received from a database. 9. A method as claimed in claim 8, wherein said database is created from a satellite image. 10. A system for generating an approximate sky view factor at a location, said system comprising: (I) data receiving means for receiving data from GPS satellites, (ii) data storage means, (iii) a processor, and (iv) output means selected from a visual display and/or printer for outputting the calculated sky view factor wherein the data storage means holds a pre-defined mathematical function relating GPS satellite data at a location to the approximate sky view factor at that location, and in use, satellite data received by the data receiving means is transferred to the processor where a sky view factor for that location is calculated from said mathematical function. 11. A system as claimed in claim 10, wherein the data receiving means is adapted to receive satellite data selected from one or more of (I) the number of satellites in line of sight at said location, (ii) the sum of signal strengths of the or each satellite, and (iii) the dilution of precision value at said location. 12. A system as claimed in claim 10, wherein the predetermined mathematical function held in the data storage means is obtained by plotting for a plurality of reference locations the actual sky view factor against the satellite data corresponding to that to be received for the location whose sky view factor is to be determined, and fitting a curve through the plots, the mathematical function corresponding to the equation of the fitted curve. 13. A system as claimed in claim 12, additionally comprising a location classification database, and wherein the data storage means holds a pre defined mathematical function for each location class, such that in use, the appropriate pre-determined mathematical function to be used for a location is determined by the database classification of that location. 14. A system as claimed in claim 13, wherein said classification database is created from a satellite image. 15. (Canceled). 16. A system as claimed in claim 10, wherein the calculated sky view factor is stored on the data storage means, and a data bus is provided for transmitting the calculated sky view factor to an external system. 17. A system as claimed in claim 10, wherein the data receiving means is constituted by a standard GPS receiver unit and the data storage means and processor are constituted by a computer. 18. A system as claimed in claim 10, wherein the data receiving means, the data storage means and the processor are integrated into a single hand-held unit. 19-24. (Canceled). 25. A system for predicting temperatures at locations along a survey route, said system comprising: (I) data storage means containing actual and forecast meteorological data, location specific geographical parameters and pre-defined energy balance equations, (ii) a system for determining the sky view factor at locations along the survey route in accordance with claim 10, and (iii) a processor for calculating the predicted temperature at each location on the survey route based on the meteorological data, sky view factor and location specific parameters input into the energy balance equations. 26. A system as claimed in claim 25, wherein said meteorological data held in the data storage means includes road surface temperature. 27. A system as claimed in claim 25, wherein said meteorological data held in said data storage means includes one or more of air temperature, dew-point, precipitation, cloud cover, cloud type and windspeed. 28. A system as claimed in claim 25, wherein said geographical parameters contained in said database are selected from latitude, longitude, altitude, an empirically derived cold air pooling index, sky view factor, screening, surface construction and landuse. 29-31. (Canceled). |
Method and device for determining the acoustic parameters of fluids in a resonator device |
A method for determining acoustic parameters of a liquid (1) in a resonator arrangement having a resonator chamber (2) includes the following steps: acoustic excitation of the liquid in the resonator chamber (2) in such a way that a sequence of liquid resonances is excited in a frequency range in which the wall material of the resonator chamber (2) and/or associated transducers (6) have natural resonances with amplitude different from zero, and measurement of the associated resonance frequencies of the liquid in the resonator chamber (2); determining an observed deviation of the measured resonance frequencies from ideal resonance frequencies in an ideal resonator corresponding to the resonator chamber (2); calculating a simulation function (yk), which is a function of the acoustic parameters of the liquid (1) and represents calculated deviations of the resonance frequencies from the ideal resonance frequencies; adapting the calculated deviations to the observed deviations through variation of the acoustic parameters of the simulation function (yk); and deriving the acoustic parameters sought from the adapted simulation function (yk). A resonator arrangement for implementing the method is also described. |
1. A method for determining acoustic parameters of a liquid in a resonator arrangement having a resonator chamber, comprising the steps of: acoustic excitation of the liquid in the resonator chamber in such a way that a sequence of liquid resonances is excited in a frequency range in which a wall material of the resonator chamber or associated transducers have natural resonances with an amplitude different from zero, measurement of resonance frequencies of the liquid resonances in the resonator chamber, determining an observed deviation of the measured resonance frequencies from ideal resonance frequencies in an ideal resonator corresponding to the resonator chamber, calculating a simulation function (yk), depending on the acoustic parameters of the liquid, representing calculated deviations of the resonance frequencies from the ideal resonance frequencies, adapting the calculated deviations to the observed deviations through variation of acoustic parameter variables of the simulation function (yk), and deriving the acoustic parameters sought from the adapted simulation function (yk). 2. The method according to claim 1, wherein the acoustic parameters comprise at least one of the speed of sound in the liquid, mass density of the liquid, and viscoelastic properties of the liquid. 3. The method according to claim 1, wherein essentially plane standing soundwave fields are excited in the liquid. 4. The method according to claim 1, wherein the plane soundwave fields are generated using curved transducers, which are excited at high frequencies at a distance from the transducer basic frequency, or using plane transducers. 5. The method according to claim 1, wherein the simulation function (yk) is formed by: y k = c L 2 D { k + 2 π arctan z L z R tan { π f k f R } } for f k < f R and y k = c L 2 D { k - 2 + 2 π arctan z L z R tan { π f k f R } } for f k > f R , where D is layer thickness of the liquid k is harmonic order fk is observed resonance frequency fR is coupled resonance frequency of a reflecting wall structure cL is speed of sound in the liquid zL is acoustic impedance of the liquid zR is acoustic impedance of the reflecting wall structure yk is calculated deviation. 6. The method according to claim 1, wherein the simulation function is empirically determined through measurements using a liquid having known acoustic parameters. 7. The method according to claim 1, wherein the sequence of liquid resonances is formed by multiple sequential resonance frequencies of the liquid which lie in a neighborhood below a predetermined natural frequency of the resonator chamber, and an approximate value of a basic frequency of the liquid is determined from two or more neighboring resonance frequencies, whose difference is smaller than the natural frequency of the resonator chamber, to determine the observed deviation from the ideal resonance frequency. 8. The method according to claim 1, wherein the measurement of the resonance frequencies, the determination of the observed deviations, and the adaptation of the simulation function is performed multiple times and an average value of the particular adapted acoustic parameter is calculated. 9. The method according to claim 1, wherein the acoustic parameters of the liquid are detected while this liquid flows through the resonator chamber. 10. A resonator arrangement for determining acoustic parameters of a liquid in a resonator chamber having at least one sound transducer attached to the resonator chamber and/or in contact with the liquid, the sound transducer being designed for operation at a predetermined excitation frequency, wherein the resonator chamber, at least on its inside, is made of a wall material having a frequency characteristic, which is different from zero in a specific frequency range, containing the excitation frequency of the sound transducer or higher harmonics of the excitation frequency. 11. The resonator arrangement according to claim 10, wherein the resonator chamber has a rectangular cross-section, two diametrically opposite walls of the resonator chamber being formed by two plane sound transducers and the remaining walls being formed by chamber bodies which support the sound transducers at a distance to one another. 12. The resonator arrangement according to claim 10, wherein the resonator chamber has a cylindrical shape and two plane sound transducers are provided as the sound transducers, which are positioned on the faces of the resonator chamber, perpendicularly to the cylinder axis. 13. The resonator arrangement according to claim 12, wherein the resonator chamber is formed in a chamber body, in which a lateral channel is provided for supplying or removing liquid. 14. The resonator arrangement according to claim 10, wherein the resonator chamber is formed by a cylindrical tubular body, on the outside of which two sound transducers are positioned. 15. The resonator arrangement according to claim 14, wherein the tubular body is made of metal and forms a shared ground contact for the sound transducers. 16. The resonator arrangement according to claim 14, wherein the tubular body is made of plastic and has a metallic coating on its outside which forms a shared ground contact for the sound transducers. |
Method and system for valuing intellectual property |
An automated system and method for determining the value of an intangible asset or intellectual property and developing a fair remuneration structure for licensing or purchasing the intangible asset or intellectual property by comparison to a dissected database of prior licensing and sale transactions. Valuation determinants and remuneration structures from prior transactions are extracted, analyzed and weighted and loaded into a knowledge base. Remuneration structures are normalized and used to train predictive algorithms based on a market analysis of previous transactions. The algorithms are able both to learn from previous transactions and to assess the importance of particular valuation determinants in determining the value under particular circumstances. An equitable rate for a new transaction is determined by examining the knowledge base and varying the valuation determinants. An optional expert system and dynamic modeling environment are provided. |
1. A method of valuing intellectual property, the method comprising: compiling a first, transaction database of transaction data corresponding to a plurality of transactions relating to intellectual property; normalizing the remuneration structure of specific transactions in order to extract normalized values thereof and storing said values in a second, market value database; dissecting and analysing the transaction data according to a predetermined scheme and storing the dissected and analysed data in a third, determinants database; evaluating the importance of selected determinants according to predetermined criteria to obtain ratings and weightings corresponding thereto, and storing the ratings and weightings in a fourth, ratings and weightings database; compiling an artificial neural network knowledgebase using information from the ratings and weightings database and other inputs; extracting financial and market data from the transaction data and storing the extracted financial and market data in a fifth, financial database; comparing stored data from the second, third, fourth and fifth databases and the artificial neural network knowledgebase with current transaction data, current market value data, and current financial and market data relating to a transaction under consideration, according to predetermined criteria, to identify similarities between the stored data and the said current data, thereby to generate an initial valuation model for the transaction under consideration; and applying weightings, priorities and/or probabilistic criteria to the valuation model according to criteria related to the transaction under consideration to generate a final valuation model. 2. A method according to claim 1 including the steps of extracting conceptual data from the transaction data and storing the extracted conceptual data in a sixth, concepts database, and comparing stored data from the sixth database with current conceptual data relating to a transaction under consideration, according to predetermined criteria, when generating the initial valuation model. 3. IA method according to claim 1 or claim 2 including the steps of storing data concerning selected valuation methodologies and techniques and facts and rules pertaining thereto, in an expert knowledgebase, and utilising the stored data in generating the initial valuation model. 4. A method according to claim 2 comprising extracting the conceptual data from the transaction data by pattern matching, context analysis and/or concept extraction of noun phrases or concepts in the form of a “conceptual fingerprint” that characterizes similar transactions within the transaction database. 5. A method according to any one of claims 1 to 4 including using the weightings and ratings of the determinants and the normalized values of, the transactions to train algorithms in a software application of an artificial neural network by storing said weightings, ratings and normalized values in the configuration of the nodes of the network and using the application to predict the value of a new transaction. 6. A method according to claim 5 wherein the artificial neural network algorithms compare the ratings, weightings and normalized values assigned to valuation determinants to the normalized market value of a known transaction to predict a value for a transaction under consideration. 7. IA method according to any one of claims 1 to 6 wherein the comparison of stored data from the second, third, fourth and fifth databases and the artificial neural network knowledgebase with current transaction data, current market value data and current financial and market data relating to a transaction under consideration is carried out utilising artificial intelligence software for comparing noun phrases, concepts and/or keywords and tokens in order to search for and compare the stored data with current data relevant to the transaction under consideration. 8. A system for valuing intellectual property, the system comprising: a first, transaction database, comprising transaction data corresponding to a plurality of transactions relating to intellectual property; a second, market value database, comprising data relating to normalized values extracted from the remuneration structure of specific transactions; a third, determinants database comprising dissected and analysed data obtained by dissecting and analysing the transaction data according to a predetermined scheme; a fourth, weightings and ratings database comprising weightings and ratings data obtained by evaluating the importance of selected determinants according to predetermined criteria; an artificial neural network knowledgebase comprising information from the ratings and weightings database and other inputs; a fifth, financial database comprising financial and market data extracted from the transaction data; and a modeling and estimation module comprising an artificial neural network application arranged to compare stored data from the second, third, fourth and fifth databases and the artificial neural network knowledgebase with current transaction data, current market value data and current financial and market data relating to a transaction under consideration, according to predetermined criteria, to identify similarities between the stored data and the said current data, thereby to generate an initial valuation model for the transaction under consideration and further to apply weightings, ratings, priorities and/or probabilistic criteria to the initial valuation model according to criteria related to the transaction under consideration to generate a final valuation model. 9. A system according to claim 8 wherein the first, transaction database contains data of transactions relating to royalty rates, license fees and intellectual property valuations or sales as well as transfers concluded as part of a sale of a business. 10. A system according to claim 8 or claim 9 wherein the weightings and ratings attached to specific transaction determinants are located within the second, determinants database or in a separate database associated with the artificial neural network application. 11. A system according to any one of claims 8 to 10 including artificial intelligence software for comparing noun phrases, concepts and/or keywords and tokens in order to search for and compare the stored data with current data relevant to the transaction under consideration. 12. A system according to claim 11 wherein the artificial intelligence software is operable to develop intelligent agents having a learning capability that can be used to search for similarities between transactions on a conceptual level and to order transactions according to such similarities, and thus to characterize transactions by means of a “conceptual fingerprint”. 13. A system according to any one of claims 8 to 12 including an expert system comprising a knowledge base of facts and rules pertaining to valuation methods and an associated inference engine. 14. A system according to any one of claims 8 to 12 wherein the fifth, financial database contains data relating to relevant economic, industry, business and market information which may influence royalty rates, license fees or the value of intellectual property. 15. A system according to any one of claims 8 to 14 which is implemented as a web service on the Internet. |
<SOH> BACKGROUND OF THE INVENTION <EOH>THIS invention relates to the valuation of intangible assets, including intellectual property, more particularly to an automated system that predicts a fair rate for the sale or licensing of an intellectual property or intangible asset based predominantly on a market assessment of other transactions. The invention relates generally to the field of royalty rate and license fee determination and intangible asset and intellectual property valuation. More specifically, the invention relates to a method and computer-implemented system for accurately determining license fees and royalty rates and for valuing intellectual property. Many organisations and individuals need to calculate license fees and royalty rates or perform intellectual property valuations. Lawyers and accountants need to calculate license fees and royalty rates and value intellectual property in drawing up certain documents and calculating the asset structure of a company. Banks need to be able to value intellectual property as part of organisational intangible assets in order to better calculate net worth and establish lending risk, and thus rate, and borrowing power. Insurers need to perform valuations in order to calculate actuarial values for coverage. A significant amount of skill and effort is required to research and gather the required background information and accurately calculate license fees and royalty rates and value intellectual property. In general, heavy reliance is mad on valuation professionals with direct knowledge of the specific area of application and, sometimes, valuations are simply loose estimates based on heuristics particularly where there is insufficient knowledge of the application domain. The process is complicated by the fact that a particular valuation is often inextricably linked to the organisation or industry in which it appears and the fact that expert understanding of a particular industry is required to perform a fair valuation. There are three generally accepted valuation approaches. The cost approach quantifies the replacement cost of future service capability; the income approach quantifies the income producing capability and the market approach bases the estimation on a consensus of what others perceive the value to be, as indicated by arms length transactions in a free market. Although the market approach is the most direct and easily understood valuation method, it is seldom used as it requires, among others, an active public market and exchange of comparable intangible assets or intellectual property in the same or very similar area of application and these are seldom known (or existent). Valuators often spend a significant amount of time and effort gleaning data from financial statements which, while providing a consistent and reliable framework from which to work, are also unreliable predictors of value. This is mainly because financial statements are generally skewed heavily or exclusively in favor of tangible assets and therefore are unreliable predictors of intangible asset or intellectual property value. In the absence of a counterbalancing force, as in an arms length business negotiation process, appraiser bias may also skew a particular valuation in one or other direction, depending on the purpose for which the valuation will be used. Several companies sell books, professional journals, access to electronic databases, information retrieval or alerting services and software systems, that include algorithmic estimation and modeling applications, to assist with license fee and royalty rate determination and with intellectual property valuation. These are generally based on the cost or income approach. Much of the information regarding licensing transactions is publicly available and, in addition, many organizations maintain private licensing transaction databases. At present, valuators mostly use the income approach to intellectual property valuation and require an extensive information gathering effort before the valuation can be performed. This is expensive, time-consuming and requires specialist skills. Although databases of transaction information do exist, they are generally used as repositories of information and not as the basis for artificial intelligence (AI) techniques such as artificial neural networks, concept matching or expert system analysis. On account of the fact that transaction information is largely incomparable, valuations based on prior transactions are rare, and legal precedents of little value. In addition, there are few valuation standards or generally accepted procedures that result in an objective assessment. As a result, valuations are often the result of a business negotiation process and not necessarily based on an understanding of the actual market value. This issue is increasingly becoming the norm as a result of the emergence of organisations whose main (or even sole) value is in intellectual property, with the consequent increased requirement for licensing transactions and payment of royalties. Information age managers are increasingly becoming aware of the shortfalls of conventional methods for performing valuations and increasingly require techniques that are able to effectively value intangible assets and intellectual property. It is an object of the invention to provide an automated method and system for accurately determining license fees and royalty rates and for valuing intangible assets, and particularly intellectual property. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention there is provided a method of valuing intellectual property, the method comprising: compiling a first, transaction database of transaction data corresponding to a plurality of transactions relating to intellectual property; normalizing the remuneration structure of specific transactions in order to extract normalized values thereof and storing said values in a second, market value database; dissecting and analysing the transaction data according to a predetermined scheme and storing the dissected and analysed data in a third, determinants database; evaluating the importance of selected determinants according to predetermined criteria to obtain ratings and weightings corresponding thereto, and storing the ratings and weightings in a fourth, ratings and weightings database; compiling an artificial neural network knowledgebase using information from the ratings and weightings database and other inputs; extracting financial and market data from the transaction data and storing the extracted financial and market data in a fifth, financial database; comparing stored data from the second, third, fourth and fifth databases and the artificial neural network knowledgebase with current transaction data, current market value data, and current financial and market data relating to a transaction under consideration, according to predetermined criteria, to identify similarities between the stored data and the said current data, thereby to generate an initial valuation model for the transaction under consideration; and applying weightings, priorities and/or probabilistic criteria to the valuation model according to criteria related to the transaction under consideration to generate a final valuation model. The method may include the steps of extracting conceptual data from the transaction data and storing the extracted conceptual data in a sixth, concepts database, and comparing stored data from the sixth database with current conceptual data relating to a transaction under consideration, according to predetermined criteria, when generating the initial valuation model. The method may further include the steps of storing data concerning selected valuation methodologies and techniques, and facts and rules pertaining thereto, in an expert knowledgebase, and utilising the stored data in generating the initial valuation model. Preferably, the method comprises extracting the conceptual data from the transaction data by pattern matching, context analysis and/or concept extraction of noun phrases or concepts in the form of a “conceptual fingerprint” that characterizes similar transactions within the transaction database. The method may include using the weightings and ratings of the determinants and the normalized values of the transactions to train algorithms in a software application of an artificial neural network by storing said weightings, ratings and normalized values in the configuration of the nodes of the network and using the application to predict the value of a new transaction. The artificial neural network algorithms preferably compare the ratings, weightings and normalized values assigned to valuation determinants to the normalized market value of a known transaction to predict a value for a transaction under consideration. The comparison of stored data from the second, third, fourth and fifth databases and the artificial neural network knowledgebase with current transaction data, current market value data and current financial and market data relating to a transaction under consideration is preferably carried out utilising artificial intelligence software for comparing noun phrases, concepts and/or keywords and tokens in order to search for and compare the stored data with current data relevant to the transaction under consideration. Further according to the invention there is provided a system for valuing intellectual property, the system comprising: a first, transaction database, comprising transaction data corresponding to a plurality of transactions relating to intellectual property; a second, market value database, comprising data relating to normalized values extracted from the remuneration structure of specific transactions; a third, determinants database comprising dissected and analysed data obtained by dissecting and analysing the transaction data according to a predetermined scheme; a fourth, ratings and weightings database comprising ratings and weightings data obtained by evaluating the importance of selected determinants according to predetermined criteria; an artificial neural network knowledgebase comprising information from the ratings and weightings database and other inputs; a fifth, financial database comprising financial and market data extracted from the transaction data; and a modeling and estimation module comprising an artificial neural network application arranged to compare stored data from the second, third, fourth and fifth databases and the artificial neural network knowledgebase with current transaction data, current market value data and current financial and market data relating to a transaction under consideration, according to predetermined criteria, to identify similarities between the stored data and the said current data, thereby to generate an initial valuation model for the transaction under consideration and further to apply weightings, priorities and/or probabilistic criteria to the initial valuation model according to criteria related to the transaction under consideration to generate a final valuation model. The first, transaction database preferably contains data of transactions relating to royalty rates, license fees and intellectual property valuations or sales as well as transfers concluded as part of a sale of a business. The weightings and ratings attached to specific transaction determinants are preferably located within the second, determinants database or in a separate database associated with the artificial neural network application. The system may include artificial intelligence software for comparing noun phrases, concepts and/or keywords and tokens in order to search for and compare the stored data with current data relevant to the transaction under consideration. The artificial intelligence software is preferably operable to develop intelligent agents having a learning capability that can be used to search for similarities between transactions on a conceptual level and to order transactions according to such similarities, and thus to characterize transactions by means of a “conceptual fingerprint”. The system may include an expert system comprising a knowledge base of facts and rules pertaining to valuation methods and an associated inference engine. The fifth, financial database preferably contains data relating to relevant economic, industry, business and market information which may influence royalty rates, license fees or the value of intellectual property. The system may be implemented as a web service on the Internet. |
Magnetic resonance angiography with automated vessel segmentation |
A magnetic resonance angiogram (MRA) is acquired using a contrast enhancement method in which a series of NMR images are rapidly acquired during a time resolved phase of the examination in which the contrast bolus makes a first pass through the arteries and veins. Arterial and venous voxels are automatically identified in the images using either of two disclosed methods. The signals from identified arterial voxels are used to produce an arterial contrast enhancement reference curve that is used to segment arterial voxels by a correlation process. Venous voxels are segmented in the same manner using a calculated venous contrast enhancement reference curve. |
1. A method for producing a magnetic resonance angiogram of a patient using an MRI system, the steps comprising: a) injecting the patient with a contrast agent which flows into a region of interest in the patient; b) acquiring NMR image data for a series of NMR time course data sets during a time resolved phase of an examination, during which the contrast agent makes a first passage through the patient's arteries in the region of interest; c) reconstructing a corresponding series of image frames depicting NMR signal magnitude in an array of voxels during the first passage of contrast agent; d) calculating a plurality of arterial contrast enhancement reference curves by: i) dividing the array of voxels into a plurality of regions; ii) identifying a set of arterial voxels in each region; and iii) computing an arterial contrast enhancement reference curve for each region by averaging the signals from identified arterial voxels therein; and e) producing the magnetic resonance angiogram from the acquired NMR image data by segmenting arteries in each region of the angiogram using information contained in the series of NMR time course images and the calculated arterial contrast enhancement curve for the corresponding region. 2. The method as recited in claim 1 in which the arterial voxels are identified in step d)ii) by: producing a mean transit time histogram which indicates the number of image voxel signals that reach a peak magnitude at each time interval during the time resolved phase of the examination; and identifying arterial voxels using information in the mean transit time histogram. 3. The method as recited in claim 2 in which step d)ii) includes locating an arterial peak in the mean transit time histogram and identifying image voxels which have a peak signal at the mean transit time corresponding to this arterial peak. 4. The method as recited in claim 2 which includes eliminating from the mean transit time histogram image voxels whose signal magnitude does not vary significantly in magnitude during the time resolved phase of the examination. 5. The method as recited in claim 2 in step e) is performed by comparing image voxel signals with the arterial enhancement reference curve. 6. The method as recited in claim 2 which includes producing from the NMR time course images a venous contrast enhancement reference curve for each region that indicates the signal enhancement of image voxels depicting veins during the time resolved phase of the examination, and the segmenting of each region in step e) employs the corresponding venous enhancement reference curve to segment veins. 7. The method as recited in claim 6 in which each venous contrast enhancement reference curve is computed by: identifying venous voxels in the region using information in the mean transit time histogram; and computing the venous contrast enhancement reference curve by averaging the signals from identified venous voxels. 8. The method as recited in claim 7 which includes locating a venous peak in the mean transit time histogram and identifying image voxels which have a peak signal at the mean transit time corresponding to this venous peak. 9. The method as recited in claim 1 in which the arterial voxels are identified in step d)ii) by: calculating an arterial contrast arrival time from data in the time course data sets; and calculating a contrast arrival time for each voxel; and selecting as arterial voxels, those voxels which have a contrast arrival time substantially the same as the arterial contrast arrival time. 10. The method as recited in claim 9 in which the arterial contrast arrival time is calculated by: determining from the time course data sets a mean contrast arrival time interval; calculating the slope of each voxel signal during the mean contrast arrival time interval; identifying a voxel with the maximum signal slope; and calculating the contrast arrival time for the identified voxel. 11. The method as recited in claim 1 in which background voxels are excluded from the set of arterial voxels identified in step d)ii) by: calculating the standard deviation of voxel signals; determining the maximum standard deviation of the voxel signals; and excluding voxels having signals with a standard deviation less than a preset percentage of the maximum standard deviation. 12. The method as recited in claim 1 which includes producing from the NMR time course images a venous contrast enhancement reference curve for each region that indicates the signal enhancement of image voxels depicting veins during the time resolved phase of the examination, and the segmenting of each region in step e) employs the corresponding venous enhancement reference curve to segment veins. 13. The method as recited in claim 12 in which each venous enhancement reference curve is computed by: identifying venous voxels in the region using information in the time course data sets; and computing the venous contrast enhancement curve by averaging the signals from identified venous voxels. 14. The method as recited in claim 13 in which the venous voxels are identified by: calculating the contrast arrival time at each of a plurality of candidate voxels; producing a histogram of the calculated contrast arrival times; determining venous contrast arrival time from a peak in the histogram; and selecting a set of venous voxels as those which have a contrast arrival time substantially the same as the venous arrival time. 15. The method as recited in claim 14 in which background voxels are excluded from the set of venous voxels by: calculating the standard deviation of voxel signals; determining the maximum standard deviation of the voxel signals; and excluding voxels having a signal with a standard deviation less than a preset percentage of the maximum standard deviation. 16. The method as recited in claim 14 in which background voxels are excluded from the plurality of candidate voxels by: establishing a voxel signal threshold level; and excluding voxels whose signals do not exceed the signal threshold level. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The field of the invention is magnetic resonance angiography (“MRA”), and particularly, studies of the human vasculature using contrast agents which enhance the NMR signals. Diagnostic studies of the human vasculature have many medical applications. X-ray imaging methods such as digital subtraction angiography (“DSA”) have found wide use in the visualization of the cardiovascular system, including the heart and associated blood vessels. Images showing the circulation of blood in the arteries and veins of the kidneys and the carotid arteries and veins of the neck and head have immense diagnostic utility. Unfortunately, however, these x-ray methods subject the patient to potentially harmful ionizing radiation and often require the use of an invasive catheter to inject a contrast agent into the vasculature to be imaged. One of the advantages of these x-ray techniques is that image data can be acquired at a high rate (i.e. high temporal resolution) so that a sequence of images may be acquired during injection of the contrast agent. Such “dynamic studies” enable one to select the image in which the bolus of contrast agent is flowing through the vasculature of interest. Earlier images in the sequence may not have sufficient contrast in the suspect vasculature, and later images may become difficult to interpret as the contrast agent reaches veins and diffuses into surrounding tissues. Subtractive methods such as that disclosed in U.S. Pat. No. 4,204,225 entitled “Real-Time Digital X-ray Subtraction Imaging” may be used to significantly enhance the diagnostic usefulness of such images. Magnetic resonance angiography (MRA) uses the nuclear magnetic resonance (NMR) phenomenon to produce images of the human vasculature. When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B 0 ), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B 1 ) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, M z , may be rotated, or “tipped”, into the x-y plane to produce a net transverse magnetic moment M t . A signal is emitted by the excited spins, and after the excitation signal B 1 is terminated, this signal may be received and processed to form an image. When utilizing these signals to produce images, magnetic field gradients (G x G y and G z ) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. Each measurement is referred to in the art as a “view” and the number of views determines the resolution of the image. The resulting set of received NMR signals, or views, are digitized and processed to reconstruct the image using one of many well known reconstruction techniques. The total scan time is determined in part by the number of measurement cycles, or views, that are acquired for an image, and therefore, scan time can be reduced at the expense of image resolution by reducing the number of acquired views. MR angiography (MRA) has been an active area of research. Two basic techniques have been proposed and evaluated. The first class, time-of-flight (TOF) techniques, consists of methods which use the motion of the blood relative to the surrounding tissue as a means for differentiating the NMR signal amplitude. The most common approach is to exploit the differences in signal saturation that exist between flowing blood and stationary tissue. Flowing blood, which is moving through the excited region, is continually refreshed by spins experiencing fewer RF excitation pulses and is, therefore, less saturated. The result is the desired image contrast between the high-signal blood and the low-signal stationary tissues. MR methods have also been developed that encode motion into the phase of the acquired NMR signal as disclosed in U.S. Pat. No. Re. 32,701. These form the second class of MRA techniques, which are known as phase contrast (PC) methods. Currently, most PC MRA techniques acquire two images, with each image having a different sensitivity to the same spin motion. Angiographic images are then obtained by forming either the phase difference or complex difference between the pair of velocity-encoded images. Phase contrast MRA techniques have been extended so that they are sensitive to velocity components in all three orthogonal directions. To enhance the diagnostic capability of MRA a contrast agent such as gadolinium can be injected into the patient prior to the MRA scan. As described in U.S. Pat. No. 5,417,213 the trick with this contrast enhanced (CE) MRA method is to acquire the central k-space views at the moment the bolus of contrast agent is flowing through the vasculature of interest. Collection of the central lines of k-space during peak arterial enhancement is key to the success of a CE-MRA exam. If the central lines of k-space are acquired prior to the arrival of contrast, severe image artifacts can limit the diagnostic information in the image. Alternatively, arterial images acquired after the passage of the peak arterial contrast are obscured by the enhancement of veins. In many anatomic regions, such as the carotid or renal arteries, the separation between arterial and venous enhancement can be as short as 6 seconds. The short separation time between arterial and venous enhancement dictates the use of acquisition sequences of either low spatial resolution or very short repetition times (TR). Short TR acquisition sequences severely limit the signal-to-noise ratio (SNR) of the acquired images relative to those exams in which longer TRs are possible. The rapid acquisitions required by first pass CE-MRA methods thus impose an upper limit on either spatial or temporal resolution. An additional detrimental effect of rapid imaging of the first pass of the bolus of contrast is the spurious modulation of k-space data resulting from the shape of the bolus of contrast. Current CE-MRA exams are of immense clinical utility, but due to the temporal-spatial limitations, they still fall short of x-ray DSA, the current “gold standard”. Ideally, angiograms should be acquired with techniques which allow longer scan times, after the first pass of the contrast bolus. For example, intravascular contrast agents can provide significant signal enhancement of the blood pool for over one hour. Images acquired after the first pass of the contrast agent in the so called “steady state” portion of the examination have the advantages of providing SNR and resolution increases limited only by patient motion. Even images acquired using currently available extravascular agents, which show only weak decay of plasma T1 shortening, may be improved by longer acquisitions acquired after the first pass of the bolus. Steady-state images permit excellent vessel delineation, although venous enhancement can severely limit arterial visualization reprojection images. Clearly, an acquisition method which combines the excellent arterial-venous separation seen in first pass CE-MRA with the high resolution, high SNR images acquired in the steady-state is desirable. One approach is to acquire an angiogram without regard for the venous enhancement, and then remove the venous signal as a post-processing step. These venous removal techniques, which are referred to as vessel “segmentation”, have been attempted by several researchers. Current methods of vessel segmentation, however, have proven to be of limited usefulness partially due to the difficulty in determining which voxels are artery and which are vein based solely on a spatial/geometric analysis of the vessels, or an analysis of their signal intensities. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is an automated method for segmenting vessels in time resolved, contrast enhanced magnetic resonance angiography. More specifically, a time course series of images is acquired with an MRI system during the first pass of a contrast agent; the images are divided into regions; arterial and venous contrast enhancement reference curves are automatically calculated for each region; and the voxels in each region are segmented into arterial and venous by comparing their signal over the time course series with the contrast enhancement reference curves. In one embodiment of the invention contrast enhancement reference curves are produced automatically by producing a mean transit time image which indicates the time during the acquisition when each image voxel reaches its peak signal magnitude; producing a histogram from the mean transit time image; locating arterial and venous peaks in the histogram; selecting those image voxels having a mean transit time corresponding to the arterial peak as arterial voxels; and selecting those image voxels having a mean transit time corresponding to the venous peak as venous voxels. In another embodiment of the invention contrast enhancement reference curves are produced by an automatic method in which arterial voxels are first identified as those which have maximum slope in their signals during a contrast arrival time interval; and venous voxels are identified by producing a contrast arrival time histogram and selecting those voxels with the same contrast arrival time as the peak in the histogram. A general object of the invention is to automate the two-dimensional correlation method for segmenting contrast enhanced images. Rather than manually selecting venous and arterial voxels from which contrast enhancement reference curves are computed, these voxels are automatically selected. Another object of the invention is to more accurately produce contrast enhancement reference curves for correlation segmentation of images. The contrast agent arrival time is usually different at different locations in the acquired images. This is particularly true if the field of view is large and encompasses vasculature from widely separated parts of the anatomy. The present invention divides the field of view into a plurality of regions and the contrast enhancement reference curves are automatically produced for each region. This enables a more accurate segmentation of arteries, veins and background tissues in each region. The foregoing and other objects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration a preferred embodiment of the invention. Such embodiment does not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims herein for interpreting the scope of the invention. |
Housing for a mirror actuator |
A housing for a mirror actuator, comprising a first housing member (10), provided with at least one first mounting opening (14′,15′,16′,17′), and a second housing member (50), provided with at least one second mounting opening (74,77), while in a mounted condition of the first and second housing member (10,50) the respective mounting openings (14′,15′,16′17′,74′,77), are in line, and in the mounted condition a connecting means (80) is arranged through the two mounting openings (14′,15′,16′,17′,74′,77), the first housing member (10) being provided with a first edge (11), and the second housing member (50) being provided with a second edge (51), while the first and second edge (11, 51) in mounted condition link up with each other, further provided with a sealing edge (60) which in mounted condition is arranged between the two edges (11,51). |
1. A housing for a mirror actuator, comprising a first housing member (10), provided with at least one first mounting opening (14′, 15′, 16′, 17′), and a second housing member (50), provided with at least one second 6 mounting opening (74, 77), while in a mounted condition of the first and second housing member (10, 50) the respective mounting openings (14′, 15′, 16′, 17′, 74, 77) are in line, and in the mounted condition a connecting means (80) is arranged through the two mounting openings (14′, 15′, 16′, 17′, 74, 77), characterized in that the first housing member (10) is provided with a first edge (11), that the second housing member (50) is provided with a second edge (51), while the first and second edge (11, 51) in mounted condition line up with each other and cooperate to surround an adjusting mechanism to be placed in the housing, and in that the housing is further provided with a sealing edge (60) of elastic design which in mounted condition is arranged between the two edges (11, 51), such that in mounted condition the two housing members (10, 50) are mounted under a mutual bias through the sealing edge (60). 2. A device according to claim 1, wherein the sealing edge (60) is provided on one of the two edges (11). 3. A device according to any one of the preceding claims, wherein the connecting means (80) in mounted condition exerts a spring force directed in a radial sense on the mounting openings (14′, 15′, 16′, 17′). 4. A device according to any one of the preceding claims, wherein the connecting means (80) is a tubular rivet. 5. A device according to claim 4, wherein the tubular rivet (80) in an outwardly sprung condition has an outside diameter greater than an inside diameter of the mounting openings (14′, 15′, 16′, 17′, 74, 77). 6. A device according to any one of the preceding claims, further comprising a driving mechanism mounted in a frame (40), the frame being provided with at least one through opening (41, 42, 43, 44), which through opening (41, 42, 43, 44) is in line with the respective mounting openings (14′, 15′, 16′, 17′, 74, 77), while in the mounted condition the connecting means (80) extends through the through opening (41, 42, 43, 44) of the frame (46). 7. A wing mirror unit for a motor vehicle, provided with a housing (1) for a mirror actuator according to any one of the preceding claims. 8. A method for assembling a housing according to any one of claims 1-6, comprising the steps of aligning respective mounting openings (14′, 15′, 16′, 17′, 74, 77) in a first and a second housing member (10, 50), and arranging a connecting means (80) in the aligned mounting openings (14′, 15′, 16′, 17′, 74, 77) to join the two housing members (10, 50) relative to each other. 9. A method according to claim 9, wherein arranging the connecting means (80) comprises introducing a tubular rivet (80) into the aligned mounting openings (14′, 15′, 16′, 17′, 74, 77), which tubular rivet (80) in outwardly sprung condition has an outside diameter greater than an inside diameter of the mounting openings (14′, 15′, 16′, 17′, 74, 77), while the tubular rivet (80) in mounted condition exerts a spring force directed in a radial sense on the respective mounting openings (14′, 15′, 16′, 17′, 74, 77). |
Inhibitor of dna methylation |
Zebularine has hypomethylating activity, and can be used to inhibit, reverse, and/or reduce DNA methylation in vivo and in vitro. Methods are provided for treating methylation-linked conditions through the application of 2-pyrimidinone derivatives, such as Zebularine. Compositions, including pharmaceutical compositions, comprising such derivatives are also provided. Also provided are kits for use in inhibiting DNA methylation, which kits include an amount of a 2-pyrimidinone derivative. |
1. A method of reducing, preventing or reversing nucleic acid methylation in a cell, omprising administering a hypomethylating effective amount of a 2-pyrimidinone derivative to the cell, thereby reducing, preventing or reversing DNA methylation in the cell. 2. The method of claim 1, wherein the 2-pyrimidinone derivative or a metabolite thereof inhibits a DNA methyltransferase. 3. The method of claim 1, wherein the cell is a bacterial cell, a protist cell, a fungal cell, a plant cell, or an animal cell. 4. The method of claim 1, wherein the cell is known to comprise or suspected of comprising a hypermethylated nucleic acid molecule. 5. The method of claim 4, wherein the known or suspected hypermethylated nucleic acid molecule comprises a CpG dinucleotide. 6. The method of claim 1, wherein the 2-pyrimidinone derivative contains a carbohydrate derivative. 7. The method of claim 6, wherein the 2-pyrimidinone derivative is Zebularine or a Zebularine derivative. 8. The method of claim 7, wherein reducing, preventing or reversing DNA methylation ameliorates a tumorigenic state of the cell. 9. The method of claim 6, wherein the 2-pyrimidinone derivative is incorporated into an oligonucleotide. 10. The method of claim 9, wherein the 2-pyrimidinone derivative is administered to the cell in the oligonucleotide. 11. The method of claim 9, wherein the 2-pyrimidinone derivative is incorporated into RNA. 12. The method of claim 9, wherein the 2-pyrimidinone derivative is incorporated into DNA. 13. The method of claim 9, wherein a nucleic acid in the cell is known to be or is suspected of being hypermethylated. 14. The method of claim 9, wherein the cell is a bacterial cell, a protist cell, a fungal cell, a plant cell, or an animal cell. 15. The method of claim 9, wherein the cell is a hyper-proliferative cell. 16. The method of claim 15, wherein the hyper-proliferative cell is a mammalian tumor cell. 17. The method of claim 1, further comprising pre- or co-administering a cytidine deaminase inhibitor to the cell 18. The method of claim 17, where the cytidine deaminase inhibitor is tetrahydrouridine. 19. The method of claim 1, where the 2-pyrimidinone derivative is a 4,6-difluoropyrimidinone derivative. 20. The method of claim 19, where the 4,6-difluoropyrimidinone derivative is a 4,6-difluoro-Zebularine derivative. 21. A method of treating or ameliorating a hypermethylation-related disease, condition, or disorder in a subject, comprising administering to the subject a hypomethylating effective amount of Zebularine, or an analog or a derivative thereof that retains hypomethylating activity. 22. The method of claim 21, wherein the analog or derivative has a formula: where R groups independently are selected from the group consisting of carboxylic acid esters, phosphoesters and ethers, X is selected from the group consisting of H, F, Cl, Br, alkyl, and groups according to the formula where Y is selected from the group consisting of H, carboxylic acids, carboxylic acid esters, and the halogens. 23. The method of claim 21, wherein the disease is a hyper-proliferative disease. 24. The method of claim 21, wherein the Zebularine is administered in the form of a pharmaceutical composition. 25. The method of claim 21, wherein the Zebularine is incorporated into an oligonucleotide. 26. The method of claim 25, wherein the oligonucleotide is RNA. 27. The method of claim 25, wherein the oligonucleotide is DNA. 28. The method of claim 21, wherein the Zebularine is provided in an oligonucleotide. 29. A method of ameliorating a tumorigenic state of a cell, comprising administering a hypomethylating effective amount of Zebularine to the cell to reduce methylation of cytosine in a CpG dinucleotide in the cell, thereby ameliorating the tumorigenic state of the cell. 30. The method of claim 29, further comprising administering an anti-cancer agent to the cell. 31. The method of claim 30, wherein the anti-cancer agent is selected from the group consisting of ifosamide, cisplatin, methotrexate, procarizine, etoposide, BCNU, vincristine, vinblastine, cyclophosphamide, gemcitabine, 5-fluorouracil, paclitaxel, doxorubicin, and combinations thereof. 32. The method of 29, wherein the Zebularine is provided in the form of a pharmaceutical composition. 33. The method of claim 29, wherein the cell is a cell in a subject. 34. A method of inhibiting methylation of a target sequence, comprising contacting the sequence with a derivatized oligonucleotide complementary to at least a portion of the target sequence, wherein the derivatized oligonucleotide comprises at least one 2-pyrimidinone moiety. 35. The method of claim 34, wherein the oligonucleotide comprises DNA. 36. The method of claim 35, wherein the oligonucleotide comprises RNA. 37. The method of claim 34, wherein the target sequence comprises a CpG dinucleotide. 38. The method of claim 34, wherein the target sequence comprises a regulatory region of a tumor suppressor gene. 39. The method of claim 34, wherein contacting occurs within a cell. 40. The method of claim 39, wherein the cell is a bacterial cell, a protist cell, a fungal cell, a plant cell, or an animal cell. 41. The method of claim 38, wherein the derivatized oligonucleotide, comprises at least one Zebularine residue. 42. A derivative of Zebularine, wherein the derivative retains hypomethylating activity in a biological system relative to Zebularine. 43. The derivative of claim 42, wherein the derivative has greater hypomethylating activity compared to Zebularine. 44. The derivative of claim 42, wherein the derivative is a phosphorylated Zebularine derivative. 45. The derivative of claim 44, wherein the derivative is a 2′-deoxy-Zebularine derivative. 46. The derivative according to claim 44, wherein the derivative has a formula: where R groups independently are selected from the group consisting of carboxylic acid esters, phosphoesters and ethers, X is selected from the group consisting of H, F, Cl, Br, alkyl, and groups according to the formula where Y is selected from the group consisting of H, carboxylic acids, carboxylic acid esters, and the halogens. 47. A kit for reducing, preventing or reversing nucleic acid methylation, comprising: an effective amount of a 2-pyrimidinone derivative. 48. The kit of claim 47, wherein the 2-pyrimidinone derivative is a 4,6-difluoro-Zebularine derivative. 49. The kit of claim 47, which is a kit for treating a hyper-methylation mediated disease or disorder in a subject suspected of needing such inhibition. 50. The kit of claim 47, further comprising instructions. 51. The kit of claim 50, wherein the instructions include directions for administering at least one dose of a therapeutic substance to the subject in need of such treatment. 52. The kit of claim 47, wherein the 2-pyrimidinone derivative is Zebularine. 53. A pharmaceutical composition, comprising a 2-pyrimidinone derivative and tetrahydrouridine. 54. The composition of claim 53 where the 2-pyrimidinone derivative is a Zebularine analog. 55. The composition of claim 54 where the 2-pyrimidinone derivative is Zebularine. |
<SOH> BACKGROUND <EOH>DNA methyltransferases (also referred to as DNA methylases) transfer methyl groups from the universal methyl donor S-adenosyl methionine to specific sites on a DNA molecule. Several biological functions have been attributed to the methylated bases in DNA. The most established biological function is the protection of the DNA from digestion by cognate restriction enzymes. The restriction modification phenomenon has been observed only in bacteria. Mammalian cells possess at least several methyltransferases; one of these (DNMT1) preferentially methylates cytosine residues on the DNA, which are 5′ (upstream) neighbors of guanine (forming the dinucleotide CpG). This methylation has been shown by several lines of evidence to play a role in gene activity, cell differentiation, tumorigenesis, X-chromosome inactivation, genomic imprinting and other major biological processes (Razin and Riggs, eds. in DNA Methylation Biochemistry and Biological Significance, Springer-Verlag, New York, 1984). When most gene sequences contain many methylated cytosines, they are less likely to be expressed (Willson, Trends Genet. 7:107-109, 1991); in particular, if a site in the promoter of the gene is methylated, gene silencing is likely to occur. Hence, if a maternally-inherited copy of a gene is more highly methylated than the paternally-inherited copy, the paternally-inherited copy will be expressed more effectively. Similarly, when a gene is expressed in a tissue-specific manner, that gene often will be unmethylated in the tissues where it is active but highly methylated in the tissues where it is inactive. Incorrect methylation is believed to be the cause of some diseases such as Beckwith-Wiedemann syndrome and Prader-Willi syndrome (Henry et al., Nature 351:665, 1991; Nicholls et al., Nature 342:281, 1989), as well as a contributing factor in many cancers (Laird and Jaenisch, Hum. Mo. Genet. 3 Spec. No.: 1487-1495, 1994). Expression of a tumor suppressor gene can be abolished by de novo DNA methylation of a normally unmethylated 5′ CpG island (Issa et al., Nature Genet., 7:536, 1994; Herman et al., Proc. Natl. Acad. Sci., U.S.A., 91:9700, 1994; Merlo et al., Nature Med., 1:686, 1995; Herman et al., Cancer Res., 56:722, 1996; Graff et al., Cancer Res., 55:5195, 1995; Herman et al., Cancer Res., 55:4525, 1995). Such hypermethylation has now been associated with the loss of expression of VHL, a renal cancer tumor suppressor gene on 3p (Herman et al., Proc. Natl. Acad. Sci. USA, 91:9700-9704, 1994), the estrogen receptor gene on 6q (Ottaviano et al., Cancer Res., 54:2552, 1994) and the H19 gene on 11p (Steenman et al., Nature Genetics, 7:433, 1994). Similarly, a CpG island has been identified at 17p 13.3, which is aberrantly hypermethylated in multiple common types of human cancers (Makos et al., Proc. Natl. Acad. Sci. USA, 89:1929, 1992; Makos et al., Cancer Res., 53:2715, 1993; Makos et al., Cancer Res. 53:2719, 1993). This hypermethylation coincides with the timing and frequency of 17p losses and p53 mutations in brain, colon, and renal cancers. Many effects of methylation are discussed in detail for instance in published International patent application PCT/US00/02530. Both 5-fluorodeoxycytidine (FdCyd) and 5-azacytidine (5-aza-CR) have been shown to inhibit methylation of DNA with resultant effects on gene expression and cell differentiation (Jones and Taylor, Cell 20:85-93, 1980; Osterman et al., Biochemistry 27:5204-5210, 1988). However, these compounds are unstable or produce toxic metabolites in vivo (Santi et al., Proc. Natl. Acad. Sci. USA 91:6993-6997, 1984; Newman et al., Proc. Natl. Acad. Sci. USA 79:6419-6423, 1982). Thus, there exists a need for an effective, stable, and low-toxicity inhibitor of DNA methylation. |
<SOH> SUMMARY <EOH>It has now been discovered that Zebularine is a potent inhibitor of methylation, and that it can specifically reactivate silenced tumor suppressor genes. Zebularine can be used to inhibit methylation and thereby combat certain diseases (including cancers that have been linked to hypermethylation) and activate methylation-silenced genes in plants, fungi, and animals. Substantially more stable than 5-azacytidine, Zebularine can be given orally, which is tremendously beneficial in the clinical setting. This disclosure provides methods of employing the hypomethylating activity of Zebularine (and derivatives, analogs, and mimetics), for instance to reduce or reverse DNA methylation, to inhibit, ameliorate, reverse, reduce or relieve methylation-linked diseases, conditions, and disorders, and to ameliorate or reduce a tumorigenic state of a tumor. The disclosure further provides kits for use in these methods. Also provided are DNA and RNA oligonucleotides comprising Zebularine, 2′-deoxy-Zebularine and derivatives thereof; and pharmaceutical preparations comprising Zebularine and Zebularine derivatives. The foregoing and other features and advantages will become more apparent from the following detailed description of several embodiments, which proceeds with reference to the accompanying figures. |
Printing system and server monitoring printing job |
Disclosed is a printing system suitable for use at photo studio(s) and permitting printing of color photograph(s) as desired by user(s). Client machine(s) 5A, 5B may acquire photo image(s) from digital camera(s) 6 and may carry out editing (retouching and/or print layout/design editing) of photo image(s). At the start of editing, working color profile(s) may be set for photo image(s) editing operations, and color matching may be carried out on photo image(s) using color profile(s) for digital camera(s) 6 and working color profile(s). During editing, such photo image(s) may be displayed at monitor(s), at which time color matching may be carried out on such photo image(s) using monitor color profile(s) and color profile(s) for such photo image(s). After editing is completed, edited photo image(s) and working color profile(s) for same may be sent to print server machine(s) 2. Print server machine(s) 2 may carry out color matching using printer color profile(s) for output printer(s) and working color profile(s) for such photo image(s), may create print image(s) for such photo image(s), and may send such print image(s) to output printer(s) 3A and/or 3B. |
1. A printing system equipped with one or more photo editing means for causing one or more desired editing operations to be carried out on image data, at least one of the photo editing means being capable of causing one or more working color profiles indicating one or more working color spaces for at least one of the editing operation or operations to be automatically set for at least a portion of the image data subject to editing, and capable of causing, after completion of at least one of the editing operation or operations, at least a portion of the edited image data to be output in linked fashion with at least one of the working color profiles or profiles; one or more printers; and one or more print control means for causing print image data to be created using at least a portion of the edited image data and permitting at least one of the printer or printers to be driven using at least a portion of the created print image data, at least one of the print control means having one or more printer color profiles indicating one or more color spaces for at least one of the printer or printers, and color matching being carried out on at least a portion of the edited image data using at least one of the working color profiles or profiles linked to at least a portion of the edited image data and at least one of the printer color profile or profiles when at least one of the print image or images is created. 2. A system according to claim 1 further equipped with one or more display monitors; and one or more display control means for causing at least a portion of the image data subject to editing to be output to at least one of the display monitor or monitors while at least one of the editing operation or operations is being carried out, at least one of the display control means having one or more monitor color profiles indicating one or more monitor color spaces for at least one of the display monitor or monitors, and color matching being carried out on at least a portion of the image data subject to editing using at least one of the working color profiles or profiles and at least one of the monitor color profile or profiles when at least a portion of the image data subject to editing is output to at least one of the display monitor or monitors. 3. A system according to claim 1 or 2 in which at least one of the photo editing means identifies one or more original color profiles that it detects as having been or assumes to have been previously linked to at least a portion of the image data subject to editing, and selects one of (1) through (3), below— (1) at least one of the detected or assumed original color profile or profiles, (2) one or more color profiles substantially corresponding to one or more color profiles for one or more display monitors, (3) one or more user-specified color profiles which it sets as at least one of the working color profiles or profiles. 4. A system according to claim 3 in which at least one of the photo editing means, in the event that at least one of the original color profile or profiles is different from at least one of the working color profile or profiles, carries out color matching on at least a portion of the image data subject to editing using at least one of the original color profile or profiles and at least one of the working color profiles or profiles before beginning at least one of the editing operation or operations. 5. A system according to claim 3 in which, unless otherwise requested by a user, one of (1) or (2), above, is automatically selected as the default setting by at least one of the photo editing means. 6. A system according to claim 3 in which, when at least one of the original color profile or profiles cannot be detected, one of (1) or (2), below— (1) one or more color profiles substantially corresponding to one or more color profiles of at least one of the display monitor or monitors, (2) one or more user-specified color profiles is selected by at least one of the photo editing means and is assumed to be at least one of the original color profiles or profiles. 7. A system according to claim 1 in which at least one of the photo editing means is equipped with (1) one or more image retouching means for causing one or more desired retouching operations to be carried out on at least a portion of the image data subject to editing, at least one of the image retouching means being capable of causing one or more working color profiles for at least one of the retouching operation or operations to be automatically set for at least a portion of the image data subject to retouching, and capable of causing, after completion of at least one of the retouching operation or operations, at least a portion of the retouched image data to be output in linked fashion with at least one of the working color profiles or profiles for at least one of the retouching operation or operations; and (2) one or more layout editing means for causing one or more desired print layout editing operations to be carried out for at least a portion of the image data subject to editing, at least one of the layout editing means being capable of causing one or more working color profiles for at least one of the print layout editing operation or operations to be automatically set for at least a portion of the image data subject to print layout editing, and capable of causing, after completion of at least one of the print layout editing operation or operations, at least a portion of the print-layout-edited image data to be output in linked fashion with at least one of the working color profiles or profiles. 8. A system according to claim 7 in which at least one of the image retouching means identifies one or more original color profiles that it detects as having been or assumes to have been previously linked to at least a portion of the image data subject to photo retouching, and selects one of (1) through (3), below— (1) at least one of the detected or assumed original color profile or profiles, (2) one or more color profiles substantially corresponding to one or more color profiles for one or more display monitors, (3) one or more user-specified color profiles which it sets as at least one of the working color profiles or profiles for at least one of the photo retouching operation or operations. 9. A system according to claim 7 or 8 in which at least one of the print layout editing means identifies one or more original color profiles that it detects as having been or assumes to have been previously linked to at least a portion of the image data subject to print layout editing, and sets at least one of the detected and/or assumed original color profile or profiles as at least one of the working color profiles or profiles for at least one of the print layout editing operation or operations. 10. A system according to claim 1 further equipped with one or more printer color profile update means for updating at least one of the printer color profile or profiles in correspondence to changes occurring in at least one of the printer or printers over time. 11. A printing method comprising one or more steps wherein one or more desired editing operations is or are carried out on image data; one or more steps wherein one or more working color profiles indicating one or more working color spaces for at least one of the editing operation or operations is or are automatically set for at least a portion of the image data subject to editing; one or more steps wherein, after completion of at least one of the editing operation or operations, at least a portion of the edited image data is output in linked fashion with at least one of the working color profiles or profiles; one or more steps wherein print image data is created using at least a portion of the edited image data, at which time color matching is carried out on at least a portion of the edited image data using at least one of the working color profiles or profiles linked to at least a portion of the edited image data and one or more printer color profiles indicating one or more color spaces for at least one of the printer or printers; and one or more steps wherein one or more printers is or are driven using one or more created print images. 12. An image editing apparatus equipped with one or more means for carrying out one or more desired editing operations on image data; one or more means for causing one or more working color profiles indicating one or more working color spaces for at least one of the editing operation or operations to be automatically set for at least a portion of the image data subject to editing; and one or more means for causing, after completion of at least one of the editing operation or operations, at least a portion of the edited image data to be output in linked fashion with at least one of the working color profiles or profiles. 13. A computer program for causing one or more computers to carry out one or more steps wherein one or more desired editing operations is or are carried out on image data; one or more steps wherein one or more working color profiles indicating one or more working color spaces for at least one of the editing operation or operations is or are automatically set for at least a portion of the image data subject to editing; and one or more steps wherein, after completion of at least one of the editing operation or operations, at least a portion of the edited image data is output in linked fashion with at least one of the working color profiles or profiles. 14. A printer control apparatus for controlling one or more printers, the apparatus being equipped with one or more image data acquisition means for acquiring image data and one or more color profiles for one or more devices at which at least a portion of this image data was created and/or edited; one or more means for storing one or more color profiles for at least one of the printer or printers; one or more print image data creating means for creating print image data using at least a portion of the image data, at least one of the print image data creating means being capable, when creating at least a portion of the print image data, of carrying out color matching on at least a portion of the image data using at least one of the printer color profile or profiles and at least one of the device color profile or profiles; and one or more printer drive means for driving one or more printers using at least a portion of the print image data. 15. A printer control apparatus according to claim 14 further equipped with means for updating at least one of the stored color profile or profiles. 16. A printer control method for controlling one or more printers, the method comprising one or more steps wherein image data and one or more color profiles for one or more devices at which at least a portion of this image data was created and/or edited are acquired; one or more steps wherein one or more color profiles for at least one of the printer or printers is or are acquired; one or more steps wherein print image data is created using at least a portion of the image data, at which time color matching is carried out on at least a portion of the image data using at least one of the printer color profile or profiles and at least one of the device color profile or profiles; and one or more steps wherein one or more printers is or are driven using at least a portion of the print image data. 17. A printer control method according to claim 16 further comprising one or more steps wherein at least one of the stored color profile or profiles is updated. 18. A computer program for controlling one or more printers, the computer program being capable of causing one or more computers to carry out one or more steps wherein image data and one or more color profiles for one or more devices at which at least a portion of this image data was created and/or edited are acquired; one or more steps wherein one or more color profiles for at least one of the printer or printers is or are acquired; one or more steps wherein print image data is created using at least a portion of the image data, at which time color matching is carried out on at least a portion of the image data using at least one of the printer color profile or profiles and at least one of the device color profile or profiles; and one or more steps wherein one or more printers is or are driven using at least a portion of the print image data. 19. A computer program according to claim 18 further capable of causing one or more computers to carry out one or more steps wherein at least one of the stored color profile or profiles is updated. 20. A printing system equipped with one or more client systems capable of generating print job data and one or more printers capable of executing one or more print jobs received from at least one of the client system or systems, at least one of the client system or systems having storage capable of storing image data; one or more image retouching programs capable of causing image data to be read as desired from at least a portion of the storage, capable of causing one or more desired retouching operations to be carried out on at least a portion of the read image data, and capable of causing at least a portion of the retouched image data to be stored in at least a portion of the storage; and one or more layout editing programs which is or are computer program or programs independent of at least one of the image retouching program or programs and which is or are capable of causing one or more desired sets of image data to be read from at least a portion of the storage, capable of causing one or more print layout editing operations to be carried out for at least a portion of the read image data, and capable of causing print job data to be created using one or more edited print layout or layouts. 21. A printing system according to claim 20 in which at least one of the client system or systems is equipped with a plurality of client machines connected so as to permit mutual communication such that at least a portion of the storage is shared, at least one of the image retouching program or programs and at least one of the layout editing program or programs being capable of being executed in parallel on respectively different client machines. 22. A printing system according to claim 20 in which at least one of the image retouching program or programs has one or more browsing means for browsing one or more sets of image data present within at least a portion of the storage and selecting desired image data; one or more trimming means for carrying out trimming as desired on one or more images selected using at least one of the browsing means; one or more retouching means for carrying out one or more desired modifications at one or more desired locations on image data selected using at least one of the browsing means; one or more color adjusting means for adjusting color or colors as desired on image data selected using at least one of the browsing means; and one or more guiding means for guiding one or more users to sequentially use at least one of the trimming means, at least one of the retouching means, and at least one of the color adjusting means in at least one prescribed order. 23. A printing system according to claim 20 in which at least one of the client system or systems has one or more photo retouching programs which is or are separate from at least one of the image retouching program or programs; and at least one of the image retouching program or programs has one or more means for launching at least one of the photo retouching program or programs responsive to user request while at least one of the retouching operation or operations is underway, passing at least a portion of image data which is the subject of at least one of the retouching operation or operations to at least one of the photo retouching program or programs, and temporarily halting at least one of the retouching operation or operations; and one or more means for, upon termination of at least one of the photo retouching program or programs, receiving at least a portion of image data which is the subject of at least one of the retouching operation or operations from at least one of the photo retouching program or programs and causing resumption of at least one of the retouching operation or operations. 24. A printing system according to claim 20 in which at least one of the layout editing program or programs has one or more means for displaying one or more thumbnail image lists for one or more sets of image data present within at least a portion of the storage; one or more means for displaying one or more templates representing one or more basic print layouts wherein one or more photo frames of one or more desired sizes is or are arranged on one or more print pages of one or more desired sizes; one or more means for causing, responsive to one or more user operations whereby desired image data is selected from at least one of the list or lists and whereby at least one desired photo frame within at least one of the template or templates is selected, one or more images representing at least a portion of the desired image data to be displayed within at least one of the desired photo frame or frames within at least one of the template or templates, and one or more print layouts to be edited as displayed at at least one of the template or templates; and one or more means for causing, after completion of at least one of the print layout editing operations, print job data to be created in accordance with at least one of the edited print layout or layouts. 25. A printing system according to claim 24 further equipped with one or more template libraries storing a plurality of templates respectively representing a plurality of basic print layouts; at least one of the layout editing program or programs being capable of causing one or more desired templates to be acquired from at least one of the template library or libraries. 26. In the context of a method whereby print job data is created by one or more client systems having at least one image retouching program and at least one layout editing program which are mutually independent, a method for creating print job data comprising one or more steps wherein image data is acquired from one or more external devices and at least a portion of the acquired image data is stored in storage; one or more steps wherein at least one of the image retouching program or programs is used to carry out one or more retouching operations on desired image data present within at least a portion of the storage, and at least a portion of the retouched image data is stored in at least a portion of the storage; and one or more steps wherein at least one of the layout editing program or programs is used to carry out one or more print layout editing operations on one or more desired sets of image data present within at least a portion of the storage, and at least a portion of the edited print layout or layouts is used to create print job data. 27. A method according to claim 26 in which at least one of the client system or systems is equipped with a plurality of client machines connected so as to permit mutual communication such that at least a portion of the storage is shared; at least one of the step or steps wherein at least one of the image retouching program or programs is used being carried out on at least one among the plurality of client machines; and at least one of the step or steps wherein at least one of the layout editing program or programs is used being carried out on at least one other among the plurality of client machines. |
<SOH> TECHNICAL BACKGROUND <EOH>As a result of improvements in digital camera and electronic printer performance, not only amateurs but also photographic industry professionals have begun using digital cameras and electronic printers. Amateurs as well as professionals typically make use of a simple system wherein an electronic printer is connected by way of a dedicated interface cable, LAN, or the like to a personal computer on which a photo retouching program is installed. Use of a sophisticated photo retouching program makes it possible to carry out a diverse variety of retouching and/or color correction operations on photographic images taken with a digital camera, and/or freely vary the size and/or resolution of such images. Inkjet printers are favorably used as such electronic printers, as they permit printed output of high-quality full-color photographs that are as good as silver halide photographs. The typical system described above performs extremely well in terms of its ability to permit each individual photograph to be finished as necessary to achieve a quality print which can then be output. However, at photo studios or other such sites dealing with commercial or professional photographic prints, a variety of other capabilities are required in addition to capabilities related to high-quality print generation. First and foremost, professionals demand the ability to produce printed output having color that is consistent with what they were expecting. One factor which interferes with this ability is the fact that the characteristics affecting color in digital cameras, computer display monitors, printers, and other such image processing devices differ from device to device. For this reason, the color of the original image taken with the camera, the color of the image on the monitor screen, and the color of the image which is printed out will all be different. Despite this, conventional systems do not possess the capability to automatically adjust color to compensate for differences in color characteristics among devices. Unless the user has a good understanding of the color characteristics of each device and manually adjusts color himself or herself in, for example, photo retouching software or the like, the user will be unable to produce printed output having color that is consistent with what the user was expecting. Second, the ability to efficiently process studio business is demanded. For example, as the operation which takes the most time at a photo studio is the retouching of photographs, there is a demand for reduction in the amount of time that must be set aside for same. Conventional photo retouching software is provided with an extremely diverse variety of retouching functionalities so as to also appeal to graphical designers and the like. However, as the retouching carried out most frequently by photo studios is more or less limited to a few particular categories, it is instead more important that they be able to carry those particular categories of retouching quickly and in routine fashion. Furthermore, as there are any number of standard sizes which may be used for printed output of commercial photographs, prior to printing it is necessary to carry out print layout operations wherein photograph size is made to conform to such a standard size and/or multiple numbers of photographs of standard size are arranged on a sheet of media. However, such print layout operations also represent an inconvenience in conventional systems. There is therefore a demand that such print layout operations be made capable of being carried out easily and in routine fashion. There is furthermore a desire to be able to carry out photo retouching operations simultaneously and in parallel fashion with respect to printing of photos which have already been retouched. Third, the ability to manage studio business is demanded. For example, capabilities such as would permit proper management of printer status, execution history, and execution status of a multiplicity of print jobs are demanded. There is demand and desire that such management should allow prevention of interruption to printing operations caused by printer failures or the like, allow supply of consumables to take place as appropriate, allow system maintenance to take place as appropriate, and/or improve efficiency of operations for calculation of charges. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is drawing showing a schematic example of printer and monitor gamuts. FIG. 2 is a block diagram showing the overall constitution of an embodiment of the present invention. FIG. 3 is a block diagram showing constitution, function, and operation at print server machine 2 and client machines 5 A, 5 B in photo studio system 1 . FIG. 4 is a block diagram showing constitution, function, and operation at print server machine 2 and center server machine 8 . FIG. 5 is a drawing showing retoucher main window 110 of special photo retoucher 11 . FIG. 6 is a drawing showing COLOR PROFILE SETUP dialog box 130 of special photo retoucher 11 . FIG. 7 is a flowchart showing flow of processing for setting of working ICC profile(s) at special photo retoucher 11 and for color matching using such working ICC profile(s). FIG. 8 is a drawing showing layout editor main window 140 of layout editor 13 . FIG. 9 is a drawing showing PREFERENCES dialog box 160 of layout editor 13 . FIG. 10 is a drawing showing an example of printer status window 170 of status monitor 14 at a client machine. FIG. 11 is a drawing showing an example of a job list page 180 which might be provided to WWW browser 17 from print server machine 2 . FIG. 12 is a drawing showing an example of a job control page 190 which might be provided to WWW browser 17 from print server machine 2 . FIG. 13 is a drawing showing an example of a printer status page 200 which might be provided to WWW browser 17 from print server machine 2 . FIG. 14 is a drawing showing an example of a paper status page 210 which might be provided to WWW browser 17 from print server machine 2 . FIG. 15 is a drawing showing an example of a user information page 220 which might be provided to WWW browser 17 from print server machine 2 . FIG. 16 is a drawing showing an example of a web page for display of consumable (print media in the present example) usage history or histories at respective photo studio(s) such as might be provided by WWW server 82 of center server machine 8 . FIG. 17 is a drawing showing an example of a web page for display of list(s) of photo studio(s) whose account(s) is or are handled by respective dealer(s) such as might be provided by WWW server 82 of center server machine 8 . FIG. 18 is a drawing showing an example of a web page for display of upload history or histories at photo studio(s) whose account(s) is or are handled by a given dealer or dealers such as might be provided by WWW server 82 of center server machine 8 . FIG. 19 is a block diagram showing functional constitution of print server machine 2 and center server machine 8 for updating printer ICC profile(s). detailed-description description="Detailed Description" end="lead"? |
Hierachical image model adaptation |
The invention relates to a method for processing digitized image data by adapting image adaptation models. Said method involves: furnishing a hierarchical structure graph with nodes respectively representing at least one parametrized image adaptation model; a predetermined amount of superimposed planes, wherein at least one node is located on each plane; edges connecting pairwise predetermined nodes of different planes and defining a father node for each node pair as the node in the lower plane and a son node as the node in the upper plane; applying the structure graphs on the image data by processing at least one node beginning with the lowest plane, wherein processing of a node involves the following steps: adapting its at least one image adaptation model to the image data by varying model parameters; determining a degree of adaptation for every parameter variation as a measure of the quality of image adaptation and determining an evaluation for each parameter variation taking into account the at least one degree of adaptation already determined and wherein the evaluation already determined for each parameter variation is used as a criterion for the processing of a son node of the processed node. If this criterion is met, processing of the son node through predetermined parameters of the father node is started with the initialization of the at least one adaptation model of said son node. |
1. A method of processing digitised picture data by matching of picture matching models, comprising: (i) provision of an hierarchical structure graph comprising: nodes, wherein each node represents at least one parameterised picture matching model, a specified number of levels, arranged one above the other, whereby at least one node is located in each level, edges connecting pairs of predetermined nodes of different levels and defining, for each pair of nodes, a father node as the node in the lower level and a son node as the node in the upper level; (ii) application of the structure graph to the picture data in that, starting with the lowermost level, at least one node is processed, whereby the processing of a node comprises the steps: matching of its at least one picture matching model to the picture data by variation of the model parameters, determination of a matching quantity for each parameter variation as a measure of the quality of the picture match, and determination of an assessment for each parameter variation, taking into account the at least one determined matching quantity, and whereby the assessment found for each parameter variation is applied as a criterion for the processing of a son node of the processed node and, if the criterion is fulfilled, the processing of the son node starts with the initialisation of its at least one matching model through predetermined parameters of the father node. 2. A method according to claim 1, in particular for the recognition of at least one object of a given object class in a picture, whereby the structure graph includes precisely one node in each level, which at least represents one picture matching model and a lower threshold value and/or an upper threshold value is assigned to given nodes, whereby the method is terminated with the result, that no object of the given object class is recognised, if for a node the assessment of each parameter variation lies below the lower threshold value assigned to the node, or that at least one object of the given object class is recognised, if for a node the assessment of at least one parameter variation lies above the upper threshold value assigned to the node or if the end node is reached. 3. A method according to claim 1 for the recognition of the orientation and/or arrangement of elements of an object of an object class in a picture, in particular for estimating the pose, whereby the structure graph for each orientation to be recognised and/or arrangement of elements of the object exhibits at least one node with at least one picture matching model for the orientation to be recognised and/or arrangement of the elements of the object, and an upper and/or lower threshold value for the assessment of the parameter variations is assigned to given nodes, whereby the processing of son nodes of those processed nodes is waived for which the assessment of each parameter variation lies below the lower threshold value assigned to the relevant node with the result that the corresponding orientations and/or arrangements of the elements of the object are not present in the picture, whereby son nodes of those processed nodes are processed for which the assessment of at least one parameter variation lies between the upper and lower threshold values assigned to the node, and whereby processing of son nodes for the parameter variations is waived whose assessment lies above the upper threshold value assigned to the relevant node with the result that the orientation and/or arrangement of the elements of the object is classified as being present in the picture which receives the best assessment on the highest fully processed level. 4. A method according to claim 1 for scene analysis through the recognition of objects of different object classes and the arrangement of the objects in a picture: whereby the structure graph for each object class exhibits at least one node with at least one picture matching model for the object class and a lower and/or upper threshold value is assigned to given nodes for the assessment of the parameter variations, whereby the processing of son nodes of those processed nodes is waived for which the assessment of each parameter variation lies below the lower threshold value assigned to the relevant node with the result that the associated object is classified as not being present in the picture, whereby son nodes of those processed nodes are processed for which the assessment of at least one parameter variation lies between the lower and upper threshold values assigned to the relevant nodes, and whereby the processing of son nodes for the parameter variations is waived whose assessment lies above the upper threshold value assigned to the relevant node with the result that the associated object is classified as being present in the picture. 5. A method according to claim 1, in which a lower threshold value is assigned to each node of the structure graph and the processing of son nodes of a node is waived if each parameter variation produces an assessment below the lower threshold value assigned to the node. 6. A method according to claim 1, in which the lower and/or upper threshold value for given nodes is dynamically adaptable. 7. A method according to claim 1, whereby, at least partially, parameters of the processed father nodes are accepted for the processing of given nodes. 8. A method according to claim 1, whereby the assessment of the father node is taken into account for the assessment of given nodes. 9. A method according to claim 1, in which weightings, which are included in the assessment, are assigned to each picture matching model and/or each edge. 10. A method according to claim 1, in which the picture matching models of the nodes of the uppermost level are based on digitised reference picture data and/or the picture matching models of predetermined nodes are based on the picture matching models of their son nodes. 11. A method according to claim 1, in which the picture matching models comprise graphs of features which are the result of the application of predetermined filters on reference picture data. 12. A method according to claim 11, in which the features include jets, whereby the scaling of the filters from which the features are obtained becomes smaller from the lower levels to the upper levels in the structure graph. 13. A method according to claim 12, in which the matching quantity for the parameter variations is computed according to the formula S(n)=f(n)(Pk(n)j(k,m),Pk(n){tilde over (j)}(k),d(0)(k,m),d(n)(k,m)),k ε K′(n)⊂ K, whereby: j(k,m) is the jet of the picture matching model m on the node k, {tilde under (j)}(k) is the jet of the picture on the position of the node k, d(0)(k, m) is the original position of the node k of the picture matching model m, d(n)(k, m) is the position of the node k of the picture matching model m in step n, f(n)( . . . ) is a functional of the picture matching model jet and the picture jet at corresponding locations, Pk(n) represents an image of the jets j(k, m) or {tilde over (j)}(k), and K′(n) is a subset of the set K of all graph nodes k. 14. A method according to claim 12, in which the features comprise combinations of various types of jet. 15. A method according to claim 2 for picture compression and picture sequence compression, comprising the steps: compressing each recognised object with a compression factor specified for the corresponding object class, whereby the control of the parameters of the compression method is based on the parameters of the results of the scene analysis, and compressing the picture region not occupied by objects using a higher specified compression factor. 16. A method of decompressing a picture which has been compressed according to the method described in claim 15. 17. A method substituting at least one selected object, recognised according to claim 2, by an object representative, in particular by an avatar, comprising the steps: providing reference pictures of the object representatives, substituting the at least one selected recognised object by the object representative, whereby part of the parameters of the picture matching models may be used for the control of the object representative. 18. A method of substituting a picture background by an alternate background, comprising the steps: providing at least one reference picture for the alternate background, positioning of the objects recognised according to claim 2 in the reference picture. 19. A method, comprising: (i) substituting at least one selected object, recognised according to claim 2, by an object representative, in particular by an avatar, comprising the steps: providing reference pictures of the object representatives, substituting the at least one selected recognised object by the object representative, whereby part of the parameters of the picture matching models may be used for the control of the object representative; and (ii) substituting a picture background by an alternate background, comprising the steps: providing at least one reference picture for the alternate background, positioning of the objects recognised according to claim 2 in the reference picture; whereby at least one selected recognised object is substituted by an object representative and the background is substituted by the alternate background. 20. A method of visually displaying scenes processed according to claim 17, comprising the steps: providing a data base with the object representatives and/or the reference pictures for the background. 21. A method according to claim 16, in which the object representatives comprise real objects and/or virtual objects. 22. A method according to claim 1, whereby, for the processing of individual pictures in a picture sequence, the parameters of the picture matching models are assigned initial values which use part of the parameters from the processing of previous pictures. 23. A method according to claim 22, whereby the possible variations of the parameters of the picture matching models, based on a part of the parameters from the processing of previous pictures, are restricted. 24. A method according to claim 13, in which the features comprise combinations of various types of jet. |
Polyvalent vaccine against diseases caused by papilloma viruses, method for the production and the use thereof |
A vaccine against disease caused by papilloma viruses is described in certain embodiments, as well as certain vectors, obtainable by the following methods: (a) one or more expression vectors that contain the DNA code for a structural protein of papilloma viruses or a fragment thereof are injected into mammals, whereby in at least some of the expression vectors randomly generated heterologous sequences are inserted into the DNA code (b) serums are obtained from the mammals and these are tested for the presence of antibodies against particles of various papilloma virus types, and (c) using the serums tested, the structural protein gene clones are identified that code for a polyvalent vaccine, and (d) the vaccine is produced from them. Procedures for producing a vaccine is also described, together with its use for vaccination against diseases caused by papilloma viruses. |
1. A method of making a polyvalent vaccine against a plurality of papilloma virus types, comprising: (a) injecting into at least one mammal at least one expression vector comprising at least one structural protein gene clone to generate particles of papilloma virus from a plurality of structural protein gene clones, wherein each structural protein gene clone comprises DNA that encodes at least a portion of a structural protein of a papilloma virus, and wherein the at least a portion of a structural protein of a papilloma virus comprises at least one randomly generated heterologous sequence; (b) obtaining serum from the at least one mammal, testing the serum to detect antibodies against the particles of papilloma virus, and identifying at least one structural protein gene clone that leads to an antibody response directed against a plurality of papilloma virus types; and (c) producing the polyvalent vaccine using the at least one structural protein gene clone that leads to an antibody response directed against a plurality of papilloma virus types. 2. The method of claim 1, wherein the papilloma virus is a human pathogenic papilloma virus. 3. The method of claim 1, wherein the structural protein is L1. 4. The method of claim 1, wherein the particles of papilloma virus comprise DNA-free virus capsids. 5. The method of claim 1, wherein the particles of papilloma virus comprise capsomeres. 6. The method of claim 1, wherein the vaccine is a DNA vaccine that comprises at least one expression vector containing a DNA code for at least a portion of a structural protein of a papilloma virus, wherein the at least a portion of the structural protein of the papilloma virus comprises at least one of the heterologous sequences. 7. The method of claim 1 wherein the heterologous sequences have a length of between 6 and 200 bases. 8. The method of claim 1 wherein the structural protein is L1 protein, the structural protein gene clone comprises DNA that encodes for a hyper-variable portion of the L1 protein, and wherein the at least one randomly generated heterologous sequence comprises a heterologous sequence inserted into the hyper-variable portion of the L1 protein. 9. The method of claim 1, wherein the number of structural protein gene clones is between 10 and 10,000. 10. The method of claim 1, wherein the number of structural protein gene clones is at least 100. 11. A method of vaccination, the method comprising introducing a vaccine produced by the method of claim 1 into a mammal to vaccinate the mammal against a disease caused by a papilloma virus. 12. The method of claim 11, wherein the disease is a member of the group consisting of warts, papillomas, acanthomas, skin cancers, and cervical cancers. 13. A library of DNA vectors, comprising: a plurality of expression vectors each comprising DNA having a sequence that encodes at least a portion of a structural protein of a papilloma virus, wherein the DNA having the sequence encoding the portion of the structural protein comprises at least one randomly generated heterologous sequence, wherein the randomly generated heterologous sequences encoding the structural protein portions are different from each other. 14. The library of claim 13, further comprising another plurality of expression vectors each comprising DNA having a sequence that encodes at least a portion of a structural protein of a papilloma virus, wherein the DNA having the sequence encoding the portion of the structural protein comprises at least one randomly generated heterologous sequence, wherein the randomly generated heterologous sequences encoding the structural protein portions are not different from each other. 15. The library of claim 13, wherein the structural protein is L1. 16. The library of claim 13, wherein the heterologous sequences have a length of between 6 and 200 bases. 17. The library of claim 13, wherein the number of expression vectors is between 10 and 10,000. 18. The library of claim 13, wherein the number of structural protein gene clones is at least 100. 19. The library of claim 18, wherein the structural protein is L1. 20. The library of claim 19, wherein the at least a portion of the L1 structural protein is a hyper-variable portion of L1 protein. |
<SOH> BACKGROUND <EOH>The invention relates to polyvalent vaccines against diseases caused by papilloma viruses, the production process and application of the vaccines. Papilloma viruses are a sub-family of papovaviruses with considerably more than 80 genotypes. Infection with papilloma viruses can lead to warts, papillomas, acanthomas, and skin and cervical carcinomas. A single illness can be caused by various papilloma virus types. The capsids of the individual types of human pathogenic papilloma viruses (HPV) differ in their antigen characteristics (epitopes), meaning that after immunization with a specific HPV type, neutralizing antibodies cannot be induced against capsids of other HPV types. However such antibodies would be necessary to give comprehensive protection against diseases that can be caused by different HPV types. An example is that infection with one of more than ten different HPV types can lead to cervical cancer. Although the virus particles of the individual types are very similar in their composition, they carry different neutralizing epitopes on their surface and are therefore only recognized by the immune system if there has been either a previous natural infection or vaccination with particles of the same type, and type-specific (neutralizing) antibodies are induced. Vaccines for the effective prevention of diseases caused by HPV must therefore always contain a mixture of various virus types in order to give comprehensive protection. The production of such vaccines is however rendered more difficult owing to the fact described above, namely that one and the same disease can be caused by different HPV types. To date only monovalent HPV vaccines have been developed, in other words vaccines directed against only one HPV type. However these have the serious disadvantage that they only guarantee protection against this one special HPV type, and not against other HPV types. Thus monovalent HPV vaccines do not furnish a comprehensive immune reaction. detailed-description description="Detailed Description" end="lead"? |
<SOH> SUMMARY AND DETAILED DESCRIPTION <EOH>Consequently the present invention is based on making a vaccine and also a process for its simple production available with which an immune response against different HPV types can be obtained. According to the invention this is achieved by a vaccine against diseases caused by papilloma viruses, obtainable by the following method: (a) One or more expression vectors are injected into mammals. These vectors contain the DNA code for a structural protein of papilloma viruses (PV) or a fragment thereof, whereby in the case of at least some of the expression vectors randomly generated heterologous sequences are inserted into the DNA code. (b) serums are obtained from the mammals and these are examined for the presence of antibodies against particles of different papilloma virus types. (c) using the serums examined the structural protein clones, particularly L1 clones, are identified that code for a polyvalent vaccine and (d) the vaccine is produced from them. The expression “fragments thereof,” as used above, indicates that the DNA codes for a protein that is shorter than the wild-type proteins, but which has the characteristics needed for this invention, especially the chemical, physical and/or functional characteristics. When producing the vaccine according to the invention, the gene coding for PV capsids of a specific type, for example L1, can therefore be modified by inserting randomly generated sequences. Without prior production and cleaning of the capsids, for example by expression of the L1 gene using recombinant vectors such as plasmids, serums are produced through immunization with several L1 expression vectors that can be defined as pools of expression vectors, and these serums are then tested for reactivity with capsids of different PV types. Only after this are the pools isolated and in this way the capsids with cross-neutralizing epitopes identified. As can be seen from the above detail the vaccine in accordance with the invention can be either VLPs (virus-like particles) or capsomeres containing modified L1 proteins that may indicate the presence of cross-neutralizing epitopes, in other words which lead to an antibody response directed against various different PV types. Such vaccines can be defined as polyvalent vaccines that can be used against infections with various PV types. As explained above, DNA-free virus capsids, so-called virus-like particles (VLP), which accumulate in eucaryotic cells after the expression of the main structural protein L1, using recombinant vectors, may be suitable for the induction of neutralizing antibodies. VLPs are empty (free of nucleic acid) virus capsids produced using genetic engineering. Substructures of VLPs, too, known as capsomeres, which result from an incomplete assembly, for example when modified L1 molecules are present, contain neutralizing epitopes, which means they are suitable for producing vaccines in accordance with the invention. Epitope is another term for antigen determinants. These are areas on the surface of an antigen where a specific antibody binds using its antigen-binding region. To produce the vaccine according to the invention, a randomly generated heterologous sequence is inserted into a main structural protein, such as the L1 gene, of a specific papilloma virus type, especially into the hyper-variable regions of L1 genes. The expression “insert” in the sense intended in this invention indicates that the randomly generated heterologous sequences could be present in the structural protein gene in addition to the naturally occurring epitopes, and/or that the naturally occurring epitope in the gene for the structural protein may be exchanged for a randomly generated heterologous sequence. As an example the production of an L1 gene cassette will be described below, which enables various randomly generated oligo-nucleotides to be inserted into the hyper-variable areas of the L1 structural protein. For inserting the randomly generated oligo-nucleotides into the DNA sequence of the L1 structural protein, a gene cassette can first be constructed. This gene cassette is characterized by the fact that, for example, the DNA code for the hyper-variable areas of the L1 structural protein is modified such that silent mutations are used to insert monovalent interfaces for restriction endonucleases, where the said interfaces flank these hyper-variable areas. The term ‘silent mutation’ is one used for the introduction of a modified DNA sequence that carries a recognition point for a specific restriction endonuclease without this changing the amino-acid sequence. The term ‘monovalent interface’ means a recognition sequence for a restriction endonuclease that occurs only once in the DNA sequence coding for the target protein. For technical reasons this has to be a recognition sequence for a restriction enzyme that may not be present additionally in the plasmids employed for the production of the variable DNA mixtures. The heterologous, randomly degenerated oligo-nucleotides may be constructed in such a way that they are also flanked by the monovalent interfaces, just as they flank the hyper-variable areas of the L1 DNA sequence. This way the gene cassette (in a cloning plasmid) and oligo-nucleotides can be treated with the same corresponding restriction enzymes. Ligation of the oligo-nucleotides into the gene cassette can then occur. The expression “heterologous sequences”, as used in this invention, refers to any sort of DNA sequence that differs from the coding DNA sequence for the naturally occurring epitope in the structural protein in at least one up to a maximum of all nucleotides. This can be achieved by replacing the nucleotides. Because epitopes usually only consist of a few amino-acids that are of the same size range as oligo-proteins, the heterologous sequences can be produced in the customary way, using the DNA sequences of the known epitopes as the basis, for example by oligo-nucleotide synthesis. For example, if an epitope contains 12 amino acids, the corresponding DNA sequence will consist of 36 nucleotides. For the randomly generated heterologous sequences, one up to a maximum of all of these nucleotides can be substituted. Because one nucleotide can be replaced by a total of three other nucleotides differing from it, when DNA sequences are randomly generated a large number, up to several thousand, of new DNA sequences are created that are heterologous to the original DNA sequence. Because the production of this DNA is not site-specific, such as is the case when for example only one specific nucleotide in a DNA sequence is replaced, it can be defined as a randomly generated DNA sequence A so-called “random library” is an example of a collection of different, heterologous, randomly generated sequences. Therefore in the case of the randomly generated heterologous DNA sequences employed to manufacture the vaccine in accordance with the invention we find they are ones not produced by site-specific mutations; rather, based on known epitope sequences, at least one nucleotide up to a maximum of all nucleotides are replaced in random fashion by one of the three other conceivable nucleotides, which gives rise to a randomly generated collection of a wide variety of DNA sequences. It is advantageous if the randomly generated heterologous DNA sequence is oriented to the naturally occurring epitopes in respect of the number of nucleotides, or ideally has the same number of nucleotides. When manufacturing the randomly generated heterologous DNA sequences the DNA sequence of the wild type epitope is unavoidably obtained again through the random combining of the nucleotides. Examples will be given below to show how randomly generated oligo-nucleotides are obtained. Oligo-nucleotides may be produced using the process of oligo-nucleotide synthesis. In this process the nucleotide sequence is produced linearly, in other words the extension of the chain occurs from the reaction of the already present nucleotide sequence with an active pre-stage of the following nucleotide. But to produce degenerated oligo-nucleotides not only the activated pre-stage of a nucleotide can be deployed; the activated pre-stages of 2, 3 or 4 nucleotides can also be introduced. This gives rise to oligo-nucleotide mixtures coding in this position for several different amino acids. If this process is repeated in subsequent stages of the reaction, a combination of different DNA sequences arises. Here both DNA sequences that do not occur in human pathogen PVs result, as well as the sequences that code for the wild-type epitope. As an example, for the main structural protein L1 the sequence area of amino acid 130 to 152 may apply (sequence numbering of HPV16L1). For the 23 amino acids of this sequence section a DNA sequence codes from 69 nucleotides. By also introducing the monovalent sequences, DNA sequences arise with more than 80 nucleotides. Alternatively the area of amino acids 260-299 or amino acids 349-360 may be selected. With complementary primers, different replenishing reactions with DNA polymerases can be used to synthesize the matching strand. The double-stranded DNA obtained this way can then be modified directly with the corresponding restriction endonucleases and ligated into the L1 gene cassette. To obtain greater efficiency the specialist may firstly ligate the double-stranded DNA sequences, using ‘blunt end’ clonings, into cloning vectors. From these ‘random libraries’ the DNA sequences can then be re-cloned with a high degree of efficiency into the L1 gene cassettes. The randomly generated heterologous DNA sequences are then, as described above, inserted into the gene of the structural proteins of the PV, and in particular into the L1 gene of papilloma viruses of a specific type. HPV, BPV and CRPV are representative types of papilloma viruses. Particularly, insertion into the hyper-variable regions of L1 genes is carried out. The invention has been described here using the preferred structural protein gene L1, but it is not limited to this. The length of the inserted heterologous DNA, in other words the number of nucleotides, is guided, as described above, by the length of the naturally occurring epitope. It is selected with particular care being taken not to interfere with the formation of the capsomeres and VLPs. If the original epitopes of the L1 gene are replaced by the randomly generated heterologous DNA sequences, it may be that only one of the epitopes is replaced. However several, even all of the maximum possible epitopes in the L1 gene may be replaced by randomly generated heterologous sequences. The L1 gene into which the randomly generated heterologous sequences are inserted may subsequently be cloned into eucaryotic expression vectors. In this case many bacterial clones may arise, and from this large number of bacteria clones sub-groups can then be formed. In other words this large number of bacteria clones is split up into pools of a few thousand bacteria clones and deployed for the production of vaccines in accordance with the invention. To produce the vaccine in accordance with the invention one or more than one expression vector(s) are injected into mammals, whereby these vectors can be characterized as described above. The term ‘more than one’ here indicates that a pool of expression vectors can be used, containing up to 10,000, but particularly up to 5,000 expression vectors that differ from each other. The differences in the expression vectors then exist in particular in the randomly generated heterologous DNA cloned into them. As is clear from the above comments on randomly generated heterologous DNA, the expression vectors may also contain DNA sequences that were obtained when randomly generating the DNA sequences, but which—because the generation is also random in this case—are identical with the DNA sequence for the wild-type epitope. Consequently expression vectors are injected into the mammals where at least some, up to a maximum of all, of them contain randomly generated heterologous DNA sequences inserted into the DNA code. These preselected pools are used for a DNA vaccination (genetic immunization). This consists of a recognized immunization procedure in which, unlike conventional immunizations, no antigens are injected; instead the DNA code is injected into a corresponding expression vector. The intramuscular application form has been shown to be favorable for DNA vaccination, because obviously in this case absorption and expression of the gene by the cell takes place before the DNA is broken down. The immune reaction then takes place in response to the expressed protein. One advantage of DNA vaccination can be seen particularly in the fact that the virus particles no longer need to be manufactured and purified, for example by expression of the L1 gene using recombinant vectors. Thus DNA vaccination can be carried out simply and rapidly. This DNA vaccination may be carried out on mammals such as rats, mice, hamsters and guinea pigs. Serums can then be obtained from the test animals in the normal way, which are tested for reactivity with different types of papilloma virus. Testing can be done using ELISA, which are specific for papilloma virus types. The DNA pools deployed for the DNA vaccination that provoke an immune reaction against different papilloma virus types can subsequently be isolated and again analyzed using DNA. In this way clones can be identified that code for VLPs or capsomeres and which contain cross-neutralizing epitopes. These are epitopes that lead to an antibody reaction against various papilloma virus types. After this the corresponding DNA clones can be further examined using the customary procedures of genetic engineering, and, as the case may be, the corresponding virus particles produced, isolated and purified. Additionally L1 molecules, for example, can be expressed, VLPs or capsomeres can be produced and the immunity of the purified particles can be examined. Finally it is possible in this way to obtain the vaccine according to the invention, which is characterized by the fact that immunization against more than one papilloma virus type is possible. The vaccine according to the invention is, therefore, a multivalent vaccine that induces immune protection against diseases caused by different PV types. In a preferred embodiment of the vaccine according to the invention the papilloma virus is a human pathogenic papilloma virus. This makes it possible to treat diseases caused by human pathogenic papilloma viruses with the vaccine according to the invention. In another preferred embodiment the structural protein is L1, because this is particularly well suited for producing the vaccine according to the invention. In another preferred embodiment the structural protein creates DNA-free virus capsids or capsomeres. The object of this invention is also a DNA vaccine comprising one or more expression vector(s) containing the DNA code for a structural protein of papilloma viruses or a fragment thereof, wherein in at least some of the expression vectors randomly generated heterologous sequences are inserted into the DNA code. As regards the structures and manufacture of the DNA vaccine reference should be made to the descriptions given above. When administering the DNA vaccine according to the invention, the structural protein gene is expressed and immunization is carried out against the expressed protein. In this way immunization is achieved with particular ease. The object of this invention is also a procedure to manufacture the vaccine described above, wherein (a) one or more expression vectors that contain the DNA code for a structural protein of papilloma viruses or a fragment thereof are injected into mammals, whereby in at least some of the expression vectors randomly generated heterologous sequences are inserted into the DNA code. (b) serums are obtained from the mammals and these are tested for the presence of antibodies against particles of various papilloma virus types, and (c) using the serums tested, structural protein gene clones, particularly L1 clones, are identified that code for a polyvalent vaccine, and (d) the vaccine is produced from them. The individual steps of the procedure according to the invention have already been described in connection with the vaccine according to the invention, so reference is made to the respective embodiments. The procedure according to the invention is characterized by the fact that the modified genes of the structural protein (insertion of randomly generated heterologous DNA) no longer have to be tested individually before immunization for their capacity to form VLPs or capsomeres. Instead, pools of recombinant DNA expression vectors are used to immunize mammals, in particular mice. The serums obtained are tested for the presence of antibodies against particles of various papilloma virus types, especially HPV types. If the reaction is positive, in other words if cross-neutralizing epitopes can be demonstrated, the pools of expression vectors are isolated and the corresponding proteins analyzed. This procedure according to the invention enables the testing of a large number of variants of papilloma virus particles, especially capsids, for their immunogenic qualities, without having to express and purify the particles individually by expression of the mutated structural protein beforehand. Moreover, the procedure according to the invention enables the production of highly effective, multivalent papilloma virus vaccines quickly, simply and at a low cost. The vaccine according to the invention is best suited as a polyvalent vaccine used in vaccinations against diseases caused by papilloma viruses, particularly diseases that are caused by more than one kind of papilloma virus. Examples of these diseases are warts, papillomas, acanthomas, and skin and cervical cancers. detailed-description description="Detailed Description" end="tail"? |
Photolytic cell for providing physiological gas exchange |
The present invention is directed to a photolytic cell, and to a photolytic artificial lung incorporating such a cell. The photolytic artificial lung converts water to oxygen for blood absorption, regulates pH, the removes carbon dioxide, and co-produces electrical power. The photolytic artificial lung includes a photolytic cell where all of the chemical reactions occur. Additionally, the present invention relates to photolytically sensitive materials for oxygen generation. These materials are useful for gas-free artificial lung fabrication. The photolytic cell disclosed herein can also be used to direct chemical reactions in organs other than the lung. It can also be used to maintain breathing air in confined systems. |
1. A photolytic artificial lung for oxygenating blood comprising: an inlet for receiving at least partially deoxygenated blood and transporting the blood to a photolytic cell; the photolytic cell having a light transparent substrate, an electrically conducting layer, and a photo-reactive surface, said photo-reactive surface having the ability to convert water in the blood to dissolved oxygen upon light activation; a light source for providing light photons to said photolytic cell and activating said photo-reactive surface; and an outlet for transporting oxygenated blood out of said photolytic cell. 2. The photolytic artificial lung of claim 1, wherein said photo-reactive surface comprises a light activated catalyst. 3. The photolytic artificial lung of claim 2, wherein said light activated catalyst is a metal oxide. 4. The photolytic artificial lung of claim 3, wherein said metal oxide comprises anatase (TiO2), WO3 or ZnO, combinations thereof, with or without performance enhancing dopents. 5. The photolytic artificial lung of claim 1, wherein said light source is an ultraviolet laser light emitting in the range at 350-390 nm. 6. The photolytic artificial lung of claim 1, wherein said light source is a UV light emitting in the range at 350-390 nm. 7. The photolytic artificial lung of claim 1, wherein said light source is a UV light emitting in the range at 350-500 nm. 8. The photolytic artificial lung of claim 1, wherein said photo-reactive surface further comprises a disproportionation catalyst. 9. The photolytic artificial lung of claim 8, wherein said disproportionation catalyst comprises MnO2. 10. The photolytic artificial lung of claim 1, wherein said photolytic cell converts water to dissolved oxygen by a series of photochemically initiated reactions. 11. The photolytic artificial lung of claim 1, wherein said photolytic artificial lung further comprises a CO2 gas sorption device connected to said photolytic cell. 12. The photolytic artificial lung of claim 1, wherein said photolytic artificial lung further comprises a CO2 gas permeable degassing material. 13. The photolytic artificial lung of claim 1, wherein said photo-reactive surface comprises a light-activated photolytic catalyst disposed over said light transparent substrate and a disproportionation catalyst disposed over said light-activated photolytic catalyst. 14. The photolytic artificial lung of claim 13, wherein said light-activated photolytic catalyst converts, when photolytically irradiated, water in the blood to hydrogen ions, electrons and active oxygen. 15. The photolytic artificial lung of claim 13, wherein said disproportionation catalyst converts active oxygen to dissolved oxygen. 16. The photolytic artificial lung of claim 1, wherein said photolytic cell simultaneously produces dissolved oxygen from water and carbon dioxide from a bicarbonate ion present in the blood. 17. A photolytic artificial lung for producing oxygen and removing carbon dioxide from the blood of a patient comprising: an inlet for receiving blood from a patient and transporting the blood to a photolytic cell; a photolytic cell having a light activated catalyst, said light activated catalyst having the ability to convert water to dissolved oxygen upon light activation; a light source for providing light photons to said photolytic cell and activating said catalyst to initiate a series of chemical reactions that result in dissolved oxygen generation and carbon dioxide formation; an outlet for transporting oxygenated blood out of said photolytic cell and returning the blood to the patient; and an outlet for removing gaseous CO2 from the blood by gaseous defusing tubing or by sorption into a solid. 18. The photolytic artificial lung of claim 17, wherein said light activated catalyst is anatase (TiO2). 19. The photolytic artificial lung of claim 17, wherein said light source is an ultraviolet laser light at 350-390 nm. 20. The photolytic artificial lung of claim 17, wherein said photolytic artificial lung further comprises a sensor which monitors the reaction chemistry in said photolytic cell. 21. The photolytic artificial lung of claim 17, wherein said lung further comprises a processor for regulating said photolytic cell in response to said sensor. 22. The photolytic artificial lung of claim 17, wherein said photolytic cell converts water to dissolved oxygen by a series of photochemically initiated reactions. 23. The photolytic artificial lung of claim 17, wherein said photolytic artificial lung further comprises a carbon dioxide gas sorption device. 24. A photolytic cell comprising: a transparent substrate; a light-activated photolytic catalyst disposed upon said substrate; and a disproportionation catalyst disposed upon said light-activated photolytic catalyst. 25. The photolytic cell of claim 24, wherein said light-activated photolytic catalyst is a metal oxide. 26. The photolytic cell of claim 25, wherein said metal oxide is selected from the group consisting of TiO2 anatase, WO3, and ZnO. 27. The photolytic cell of claim 24, wherein said disproportionation catalyst includes at least one of FeII, FeIII, CuI, CuII, CoII, CoIII, MnII, MnIII, MnIV, and MnO2. 28. The catalyst of claim 27, wherein said catalyst is MnO2. 29. The photolytic cell of claim 24, wherein said photolytic cell converts water into dissolved oxygen. 30. The photolytic cell of claim 24, wherein said light-activated photolytic catalyst converts water into active oxygen. 31. The photolytic cell of claim 24, wherein said disproportionation catalyst converts active oxygen to dissolved oxygen. 32. A gas sorption device comprising: a coalescence compartment comprising a gas head space and a gas coelescor connected to said gas head space; and a gas sorber connected to said coalescence compartment, wherein gas accumulating in said gas head space moves to said gas sorber, and said gas sorber converts gas to a solution or solid. 33. The gas sorption device of claim 32, wherein said gas sorption device further comprises an entry point connected to said gas head space for entry of hydrogen gas. 34. The gas sorption device of claim 32, wherein said coelescor further comprises an outlet connected to said coelescor for the removal of said solution. 35. A method for delivering oxygen to a solution comprising: providing the solution into a photolytic cell; converting water into dissolved oxygen by a light-activated catalyst in said photolytic cell; binding said dissolved oxygen to said solution; and removing said solution out of said photolytic cell. 36. The method of claim 35, wherein said solution is blood. 37. The method of claim 35, further comprising removing carbon dioxide from said solution in said photolytic cell. 38. The method of claim 35, further comprising producing carbon dioxide from said solution in said photolytic cell; and removing said carbon dioxide from said photolytic cell. 39. A method for oxygenating blood from a patient comprising the steps of: providing blood from a patient into a photolytic cell; converting water present in the blood into dissolved oxygen in said photolytic cell by a series of photochemical reactions; binding the dissolved oxygen to blood hemoglobin; forming carbon dioxide in said photolytic cell; removing carbon dioxide formed in said photolytic cell and blood; and removing oxygenated blood out of said photolytic cell and returning the blood to the patient. 40. A method for producing oxygen and removing carbon dioxide from a patient's blood comprising the steps of: providing deoxygenated blood received from a patient into a photolytic cell, wherein said photolytic cell contains a light-activated catalyst having the ability of converting water to oxygen upon light activation; providing light to said photolytic cell and activating said catalyst wherein water present in the blood is converted into dissolved oxygen and carbon dioxide is formed in said photolytic cell; binding the dissolved oxygen to blood hemoglobin in said photolytic cell; removing the carbon dioxide formed in said photolytic cell; and removing the oxygenated blood out of said photolytic cell and returning the blood to the patient. 41. An artificial pulmonary capillary for oxygenating blood comprising: an inlet for receiving deoxygenated blood and transporting the blood to a photolytic cell; the photolytic cell having a photo-reactive surface, said photo-reactive surface having the ability to convert water in the blood to dissolved oxygen upon light activation; a light source for providing light photons to said photolytic cell and activating said photo-reactive surface; and an outlet for transporting oxygenated blood out of said photolytic cell. 42. The artificial pulmonary capillary of claim 41, wherein said photo-reactive surface comprises a light-activated catalyst. 43. The artificial pulmonary capillary of claim 42, wherein said light activated catalyst is a metal oxide catalyst comprising anatase (TiO2), WO3 or ZnO. 44. The artificial pulmonary capillary of claim 41, wherein said light source is an ultraviolet laser light at 350-390 nm. 45. The artificial pulmonary capillary of claim 41, wherein said capillary has an internal diameter of 10μ or more. 46. The artificial pulmonary capillary of claim 41, wherein the photolytic cell comprises a mesoporous material. 47. An artificial pulmonary capillary for producing oxygenated blood from the venous blood of a patient comprising: an inlet for receiving deoxygenated, venous blood from a patient and transporting the blood to a photolytic cell; a photolytic cell having a light transparent substrate and a photo-reactive surface, said photo-reactive surface comprising a layer of a light activated, photolytic catalyst and a layer of a disproportionation catalyst disposed on said photolytic catalyst and wherein said photo-reactive surface has the ability to convert water in the blood to dissolved oxygen upon light activation; a light source for providing light photons to said light transparent substrate of the photolytic cell and activating said photolytic catalyst to initiate a series of chemical reactions that result in dissolved oxygen generation by the photo-reactive surface of the photolytic cell; and an outlet for transporting oxygenated blood out of said photolytic cell and returning the blood to the patient. 48. The artificial pulmonary capillary of claim 47, wherein said light activated, photolytic catalyst is a metal oxide. 49. The artificial pulmonary capillary of claim 47, wherein said metal oxide comprises TiO2 (anatase), WO3 or ZnO. 50. The artificial pulmonary capillary of claim 47, wherein said light source is an ultraviolet laser light at 350-390 nm. 51. The artificial pulmonary capillary of claim 47, wherein said capillary is constructed from mesoporous materials. |
<SOH> BACKGROUND OF THE INVENTION <EOH>There have been numerous efforts in the past 40 years to achieve artificial lung function. Unfortunately, no new innovative respiratory assist therapy has been developed for patients with severe, life-threatening lung disease. This is largely due to inadequate knowledge of pulmonary pathophysiology, a lack of emerging therapies, and insufficient mechanisms for providing intermediate to long-term respiratory support. The lack of adequate technology for respiratory support for the patient with deteriorating lung function, in particular, has had profound effects on the quality of life for this increasingly large segment of the population. The number of deaths annually from all lung disease is estimated to be approximately 250,000 (150,000 related to acute, potentially reversible respiratory failure and 100,000 related to chronic irreversible respiratory failure) with an estimated economic burden of disease in the range of 72 billion dollars per year. Furthermore, the emotional toll of progressive respiratory failure is profound, particularly as it affects children and adolescents with progressive pulmonary disease. The impact of this public health problem can be conceived in terms of the direct costs for intensive, sub-acute, and long-term health care services, and the indirect costs associated with lost wages and productivity for the patient and the patient's family, and the increased need for support services. While the death rates for cardiovascular disease, cancer, and all other major diseases have recently decreased significantly, the rate of death related to chronic pulmonary lung disease (CPLD) has increased by 54%. Lung disease also represents one of the leading causes of infant mortality, accounting for 48% of all deaths under the age of one. For these patients, respiratory assistance during pulmonary failure has been achieved by employing ventilator therapy, despite the enormous cost and morbidity associated with this modality. Furthermore, it is well accepted that closed, positive-pressure, mechanical ventilation, applied at moderate levels of intensity, for short periods of time, is a somewhat safe and efficient means for improving gas exchange in patients with acute respiratory failure. However, with prolonged duration of intensive respiratory support, serious adverse effects may occur. These effects, including oxygen toxicity, baromtrauma, altered hormone and enzyme systems, and impaired nutrition, may result in further injury to the failing lungs, or add significantly to the morbidity and mortality for these patients. As a result, alternative methods have been sought for augmenting blood gas exchange, where mechanical ventilation is inadequate or cannot be safely applied. In view of the above and other reasons, there has been great interest in developing an artificial means for accomplishing physiological gas exchange directly to the circulating blood and bypassing the diseased lungs. While previous efforts have provided some measure of success, they have been limited in their usefulness or hindered by excessive cost. One approach to artificial lung function has been by gas sparging or diffusion of gas across the membrane surface of hollow fibers placed within the blood supply. Previous efforts have achieved some success, and have taught much to pulmonary physiologists, but gas sparging or diffusion has yet achieved the degree of gas exchanges optimally desired. Furthermore, other methods and artificial lung systems have been developed from introducing gaseous oxygen by air sparging. However, gas sparging is very detrimental to biological tissues such as red blood cells. Also, gas sparging attempts to control the differential pressure across thin gas/liquid membranes such as those found in porous-walled hollow fibers. Another approach to artificial lung function, extracorporeal membrane oxygenation (ECMO), constitutes a mechanism for prolonged pulmonary bypass, which has been developed and optimized over several decades but has limited clinical utility today as a state-of-the-art artificial lung. The ECMO system includes an extra-corporeal pump and membrane system that performs a gas transfer across membranes. Despite the numerous advances in the implementation of ECMO over the years, its core technology is unchanged and continues to face important limitations. The limitations of ECMO include the requirement for a large and complex blood pump and oxygenator system; the necessity for a surgical procedure for cannulation; the need for systemic anticoagulation; a high rate of complications, including bleeding and infection; protein adsorption and platelet adhesion on the surface of oxygenator membranes; labor intensive implementation; and exceedingly high cost. As a result of these limitations, ECMO has become limited in its utility to select cases of neonatal respiratory failure, where reversibility is considered to be highly likely. The development of the intravenous membrane oxygenation (IVOX) also represented a natural extension in the artificial lung art, since it was capable of performing intracorporeal gas exchange across an array of hollow fiber membranes situated within the inferior vena cava but did not require any form of blood pump. The insertion of the IVOX effectively introduced a large amount of gas transfer surface area (up to 6000 cm 2 ) without alteration of systemic hemodynamics. Unfortunately, as with ECMO, the IVOX system has numerous limitations, including only a moderate rate of achievable gas exchange; difficulty in device deployment; a relatively high rate of adverse events; and a significant rate of device malfunctions, including blood-to-gas leaks due to broken hollow fibers. A further approach to treat lung disease, is through the use of lung transplants. The improvement of methods to transplant viable lungs into patients is fundamentally the most significant recent advance in the therapy of chronic lung diseases. The most common indications for lung transplantation are emphysema, pulmonary fibrosis, cystic fibrosis, and pulmonary hypertension. Selection conditions emphasize the presence of irreversible disease localized to the respiratory system, and social and psychological conditions supportive of the ability to go through extended pulmonary rehabilitations. In contrast, the absence of these conditions present relative contraindications to this approach. The donor organ should originate in a relatively healthy, infection free individual, under the age of 65. Following these guidelines, success has been achieved in increasing numbers for patients throughout the United States. Profound limitations in the number of donor organs has made this option unrealistic for the great majority of patients who would benefit the most. While rationing is the standard for all transplantable organs, the need for rationing is particularly acute in the case of the lungs, owing to the following issues: (1) the large discrepancy between donor and recipient numbers (3350 registration for lung transplant in 1999 and only 862 performed); (2) the relatively low yield of usable lungs, with only 5-10% of multiorgan donors yielding lungs acceptable for transplantation; and (3) the absence of effective temporary methods to support blood gas exchange during the waiting period prior to transplantation. The complexity of this problem is increased even further, when considering the inevitable compromise between supplying organs to patients who are the most ill, and who have the most to gain, but for whom outcomes are generally poor, versus relatively healthier patients with no complications, who have less need but for whom outcomes are predictably better. For example, a patient with emphysema is highly likely to achieve a positive outcome from transplantation, but generally will not exhibit improved survival. In contrast, a patient with cystic fibrosis has considerably higher risk of surgery due to the presence of multiorgan involvement of the disease, but for these young patients, successful transplantation optimizes survival. Therefore, a serious need exists for new technology and therapeutic approaches that have the potential to provide intermediate to long-term respiratory support for patients suffering from severe pulmonary failure. Also, the need for an efficient and inexpensive technology to achieve sustained gas exchange in the blood, thereby bypassing the diseased lungs without resorting to chronic ventilation, remains paramount. |
<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, the present invention is directed to a photolytic cell and, more specifically, to a photolytic artificial lung incorporating such a cell. The photolytic artificial lung is capable of facilitating gas exchange in the blood of a patient while bypassing the alveolar-capillary interface. It may be utilized for lung replacement and/or for oxygenation supplementation of the blood stream. Moreover, it is also particularly useful for treating a number of lung afflictions. The photolytic artificial lung is a device, internal or external to the body, that utilizes light, such as a laser or lamp, to achieve physiological and therapeutic gas exchange in the blood stream. In such an exchange, oxygen is dissolved into the blood stream while carbon dioxide is removed and pH is controlled. This is due to the use of photochemistry. The photolytic artificial lung oxygenates blood without the deleterious effect on red blood cells associated with direct gas sparing (i.e. blood cell lysis, pH balance difficulties, etc.), while simultaneously controlling blood pH and carbon dioxide content. More particularly, the photolytic artificial lung includes a photo-electro chemical cell (“photolytic cell” or “photolytic module”) that, in part, operates similar to the photosynthesis process that takes place in green plants. The photolytic artificial lung utilizes the photolytic cell to convert light energy in order to simultaneously generate oxygen from water, useful acidity and electrical energy. The photolytic cell also removes carbon dioxide from the blood stream. One or more photolytic cells can be included in the photolytic artificial lung of the present invention depending on the quantity, quality, etc. of desired gas exchange. The light energy utilized in the present invention is ultraviolet (“UV”) light or visible light, with the laser form being the most preferred. However, the light energy can also be broad-band, received by the way of a “light pipe” fiber optic cable or by the way of an attenuated total reflectance (ATR) link. In the artificial lung, dissolved oxygen is generated from water present in the blood stream by means of the light dependent chemical reactions, photolysis and disproportionation. This is followed by the removal or clearing of carbon dioxide by the reactions of bicarbonate ion protonation and dehydration. Photolysis is the initiation of a chemical reaction as a result of absorbing one or more quanta of radiation. Here, water is converted into oxygen by a light-activated catalyst, such as a semiconducting metal oxide. The metal oxide is utilized as a photo-absorbent material or a photo-absorption element. It is photolytically irradiated to form, from water present in the fluid or blood stream, hydrogen ions, hydrogen peroxide or other forms of oxygen gas precursor (active oxygen, “AO”) and electrons by the absorption of one or more quantra of electromagnetic radiation. The free electrons generated are then electrically conducted away to avoid reversal of the reaction and optionally utilized to drive electrical devices, such as a pump. For example, it has been found that active oxygen is readily generated in the present invention by the use of the anatase form of titania (TiO 2(a) ) as the light absorbent material. The photo energy of light, such as ultraviolet laser light (about 350 nm), selectively excites TiO 2 semiconductor transition (about 350-390 nm band, or about 3.1 eV) with minimal material radiation or transmission. The ultraviolet energy produces charge separation in the anatase form of TiO 2 , which then produces active oxygen (AO) and free electrons. The free electrons are then subsequently electrically conducted away due to the semi-conducting property of the anatase. Alternatively, other suitable light absorbent materials can also be utilized in the present invention at various wavelengths provided that the energy is sufficient to produce active oxygen. Disproportionation is a chemical reaction in which a single compound serves as both oxidizing and reducing agent and is thereby converted into a more oxidized and a more reduced derivative. For example, hydrogen peroxide (active oxygen) produced during photolysis can be converted by means of manganese dioxide (MnO 2 ), or other disproportionation catalytic agents and/or processes, into dissolved oxygen (DO) and water. This reaction produces dissolved oxygen (DO) from water and bypasses the harmful gaseous state. Additionally, in the artificial lung of the present invention, carbon dioxide is removed from the blood stream by the means of the reactions of protonation and dehydration. In essence, the hydrogen ions formed during photolysis react with the bicarbonate (HCO 3 − ) and carbonate (CO 3 = ) ions present in the blood stream causing conversion of these ions into carbonic acid. In the presence of carbonic anhydrase, a blood component, the carbonic acid then quickly dissociates into water and carbon dioxide. The carbon dioxide gas is then subsequently vented into the environment. Alternatively, due to concerns with infection in human lung assistance applications, a novel method and device is also disclosed herein for removing carbon dioxide from the system by molecular absorption. In this embodiment, carbon dioxide is removed from the blood stream by means of a carbon dioxide absorber device (i.e., a sorber), or other similar gaseous removal devices, under sterile conditions. Consequently, the artificial lung of the present invention produces dissolved oxygen directly from water present in the blood stream, omitting the gaseous state which has previously caused pressure, shear, weight, and bulkiness problems with other blood oxygenation technologies. At the same time, the artificial lung also utilizes the hydrogen ions produced from the water to release the carbon dioxide. Additionally, the reactions occurring in the artificial lung do not involve the generation or use of high temperatures or pressures associated with previous devices and/or processes. The photolytic artificial lung is preferably designed to be self-contained and self-regulated. It requires no external gas supply. A brief description of the pertinent reactions involved in the embodiment of the present invention utilizing anatase as the light absorbent material (i.e. as the photolytic catalyst and MnO 2 as the disproportionation catalyst) is provided below: Photolysis: where H 2 O 2 is used to illustrate an “active oxygen” intermediate. Disproportionation: DO=dissolved oxygen in blood, which can readily be converted to gaseous oxygen, O 2 (g), for breathable air maintenance applications. Protonation (H + Ions from Photolysis Reaction): in-line-formulae description="In-line Formulae" end="lead"? H+Na + +HCO − 3 Na + +H 2 CO 3 in-line-formulae description="In-line Formulae" end="tail"? CO 2 Gas Generation: in-line-formulae description="In-line Formulae" end="lead"? H 2 CO 3 H 2 O+CO 2 ↑ in-line-formulae description="In-line Formulae" end="tail"? Catalyzed Dehydration (Optional): CA=carbonic anhydrase (already a blood component) The above information shows the general chemical reactions involved in the photolytic cell to produce dissolved oxygen. Subsequent to this production, the electrons are conducted away, and the dissolved oxygen diffuses from the film surface to oxygenate hemoglobin present in the blood. As a result, the primary function of the photolytic artificial lung of the present invention is to provide respiration assistance in patients with lung disease, both in acute as well as chronic conditions. However, other medical applications are also feasible which also require the photochemical reactions of the present invention and/or the convenience of photolytic power. These include, among others, in-body drug level maintenance and release, and the contribution to the function of other organs such as the kidneys and the liver. In a more particular embodiment, the photolytic artificial lung of the present invention comprises an inlet for receiving blood from the blood stream of a patient. A pump extracts blood from the patient and moves the blood into at least one flow-through photolytic cell via the inlet. The photolytic cell contains a photolytic coating comprising a light-activated photolytic catalyst and a disproportionation catalyst that converts water from the blood into dissolved oxygen, while at the same time removing carbon dioxide as described above. A light supply provides light energy to the photolytic cell. An outlet moves blood out of the photolytic artificial lung and back into a patient. The photolytic cell is compatible with blood and provides high yields of dissolved oxygen to the blood stream. The resulting photolytic artificial lung is capable of use externally or internally by a patient, as well as in a stationary or portable form. Furthermore, the artificial lung is scalable to allow the photo-activated gas exchanges to be accomplished in a small and wearable extra-corporeal device, or in an intra-corporeal device inserted into a patient's venous blood supply. Examples of such microfabricated devices, such as artificial pulmonary capillaries, are discussed in more detail below. In a further aspect, the present invention is also directed to a photolytic cell. The photolytic cell includes a transparent substrate or window. An anode (such as a metal film) is adjacent to the transparent window. A photolytic coating containing a light-activated catalyst and a disproportionation catalyst abuts the anode. A cell flow through area is adjacent to the light activated catalyst. A cation exchange membrane borders the cell flow through area. A catholyte abuts the cation exchange membrane. A cathode is present adjacent to the catholyte and is connected to the anode. In another aspect, the present invention is further directed to a gas absorption or sorption device for collecting and converting a gas, such as carbon dioxide, to a solution or solid. The gas sorption device comprises a coalescence compartment including a gas head space and a coelesor connected thereto, wherein gas accumulates and/or is concentrated in the gas head space. A gas sorber connected to the coalescence compartment allows for the movement of gas from the gas head space to the gas sorber and the gas sorber converts gas to a solution or a solid. The sorber can be disposed or regenerated thereby avoiding the continuous venting of carbon dioxide to the atmosphere. In an additional aspect, the present invention is further directed to a method for delivering oxygen to an aqueous bicarbonate ion solution. The method comprises moving the solution into a photolytic cell wherein light is utilized by a light-activated catalyst to produce oxygen from water, with a small concomitant pH change to cause a release of carbon dioxide, and moving the oxygenated solution out of the photolytic cell. In still another aspect, the present invention is yet further directed to a method for oxygenating blood from a patient. The method includes moving deoxygenated blood into a photolytic cell; converting water to dissolved oxygen in the photolytic cell; binding dissolved oxygen to blood hemoglobin; forming carbon dioxide in the photolytic cell; removing carbon dioxide formed in the photolytic cell; and moving oxygenated blood out of the photolytic cell. This process emulates, to a certain degree, selected portions of the natural process by which plants produce oxygen, namely photosynthesis, and the way the lung eliminates carbon dioxide, namely through a pH drop. This method produces dissolved oxygen directly from water, omitting the gaseous state. It can be utilized to achieve therapeutic gas exchange in patients with respiratory failure. In a further aspect, the present invention relates to the direct photolytic conversion of water to liquid phase oxygen (dissolved oxygen), with commensurate clearance of carbon dioxide. A test flow cell is provided comprising a conductive coating of vacuum-deposited titanium (Ti) metal, adherent TiO 2 (anatase), and MnO 2 , applied as a laminant to a glass substrate. The device was then immersed in Lockes-Ringer solution (synthetic blood serum) and/or blood. Long wavelength (low energy) UV laser light, directed to the transparent glass slide, reproducibly resulted in the generation of H 2 O 2 , an active form of oxygen (active oxygen), which was subsequently converted, by the catalytic action of MnO 2 , to dissolved oxygen The absence of light activation provided an entirely null reaction. Based on these results and other, the photolytic cell or module may be used, employing multiple parallel photolytic surfaces to improve system yield and CO 2 clearance through selective membrane diffusion of gas phase molecules from the dissolved oxygen enriched fluid following photolytic induction. In a still further aspect, the present invention relates to the use of mesoporous materials in the. photolytic artificial lung. The mesoporous materials are used to provide high-surface area photolytically active coatings to photolytically drive chemical changes, photochemical changes, electricity generation, and/or electrochemical changes in fluid streams adjacent to the coating/material, or in the case of electricity, electrical current driven into wires attached to the coatings directly, or via an electrical conducting intermediate material. Preferably, the mesoporous materials are self-assembled monolayers on mesoporous supports (“SAMMS”). A particularly useful material from this technology is known as “mesoporous silica.” Moreover, molecular sieves, such as zeolites with 3-D pore structure (pore size, about 7-100 Å) including zeolite X, Y and B, and silica and/or silica/titania MCM's (pore size, about 20-80 Å) are also beneficial. Similarly, titania (especially anatase versions) is useful in accordance with the present subject matter. Other useful coatings chemistries are based on zinc oxide, tungstates, etc. The photolyzed mesoporous coatings consist of a photoactive material which results in the conversion of water into oxygen, especially dissolved oxygen. Additionally, the bicarbonate ion is converted therein by the hydrogen ions into carbon dioxide gas for venting and/or removal. This embodiment utilizing mesoporous materials represents the next critical technology portion of the photolytic lung (PAL, and more generally, photolytically driven electrochemically conversion, PDEC) technologies—that of organized microscopic architecture of photolytic constructs (OMAPC). The design of the fluid/photo-sensitive coatings/films architecture is critical to controlling the commercial value of the technology by providing small device size (practical ambulatory use, and for implantation into the body), and photolytic conversion efficiency (low cost and low power requirements). The SAMMS technology, and any other micro- or nano-fabricated material of highly ordered structural support, such as these used in integrated circuit fabrication, photo-voltaic cell fabrication, or fiber-optics fabrication for example, represents candidates for commercially viable PDEC technologies for at least three reasons; 1. near UV and/or visible light transparency (silica and metal oxides) 2. high solid-to-liquid surface area with fluids flowing through them 3. organized structure so that optical light guides can be designed into them. Consequently, a further embodiment of the invention is directed to the use of micro-fabricated materials, and the like, to construct (in the case of PAL) artificial pulmonary capillaries. Note that the gross shape of the final device can have any suitable shape to fit the need (e.g. the body lung cavity, a vein, a module to fit into an extra corporeal device, etc.). It's the microstructure and how it relates to controlling the light path to a region adjacent to the fluid (blood, breathing air) that is the key architecture needed from the mesoporous (and the like) material. These and other objects and features of the invention will be apparent from the detailed description set forth below. |
Plate making method for mimeographic printing and plate making device and mimiographic printing machine |
The present invention is a plate-making method for stencil printing in which heat-sensitive stencil plate material for stencil printing consisting of a thermoplastic resin film is melted by heating of a thermal head to perforate an ink permeable openings. Many minute recesses are formed on one side of the film. The thermal head 10 is constituted so that the heater size thereof satisfies HM>0.6 PM and HS>0.7 PS when the arranging pitch of heaters on a main scanning side is set to PM, the length of the heaters on the main scanning side is set to HM, a feed pitch on a sub-scanning side is set to PS and the length of the heaters on the sub-scanning side is set to HS. An opposite side to the minute recess side of the film is heated by heating of the thermal head with an energy output of 35 mili-joule/mm2, so that the heated portion is melted for communication with the recesses to form ink permeable openings. It make it possible to thermally perforating individual ink permeable openings in the film independently without increasing an output of a thermal head, and it realizes stencil printing by using a stencil plate material consisting only of a thermoplastic resin film. |
1. A plate-making method for stencil printing in which a heat-sensitive stencil plate material for stencil printing consisting of an extended thermoplastic resin film with a predetermined thickness is fused or melted by heating of a thermal head to perforate an ink-permeable openings, characterized in that: a tensile stress at the time of extension is internally remains and many minute recesses are formed on one side surface of the above film, an opposite side surface to the minute recess side of the film is heated by the thermal head, an energy output of the thermal head for heating sufficiently satisfies to fuse-penetrate a thin closing portion of the minute recess, but it is restricted to the range which does not fuse-perforate a thick portion except the recess portion of the film, so that said openings are formed by the heated fused portion communicating with the minute recess. 2. A plate-making method for stencil printing according to the claim 1, wherein two or more heaters are arranged in a main scanning direction at one sequence or tier on the thermal head, When a main scanning side array pitch of the heater is set to PM, a main scanning side heater length is set to HM, a sub scanning side delivery pitch is set to PS and a sub scanning side heater length is set to HS, the heater size satisfies HM>0.6PM and HS>0.7PS. 3. A plate-making method for stencil printing according to the claim 1 or claim 2, wherein an impression energy of the thermal head is below into the 35 mili-joule/mm2. 4. A plate-making method for stencil printing according to the claim 1 or 2, wherein said stencil plate material is constituted of an extended polyethylene-terephthalate(PET) film or an extended low melting point film by copolymerizing polyethylene terephthalate(PET) and polybutylene terephthalate(PBT), Many minute recesses are formed on one side surface of the film by templating, when the working temperature is set to t° C. the melting point of the film is set to m° C. and the glass transition point is set to g° C., said templating is performed by P Pa of working pressure force of 104×102(m−t)/(m−g) or more. 5. A plate-making method for stencil printing according to the claim 1 or 2, wherein said recess is a penetrated hole having openings on both sides of the film, a diameter of an opening on the heated side of the film is smaller than a diameter of an opening on the opposite side to said heated side, but is small not to permit ink-permeating. 6. A plate-making method for stencil printing according to the claim 1 or 2, wherein said minute recess is a dent which reduces a thickness of said the film partially and forms a closing thin portion. 7. A plate-making apparatus for stencil printing comprising: a plate feed section which feeds the heat-sensitive stencil plate consisting of an extended thermoplastic resin film with a predetermined thickness, and a heating means to form ink-permeable openings in the film by heating the film, in which an opposite side surface to the minute recess side of the film is heated by the heating means, said heating means is a thermal head, a tensile stress at the time of extension is internally remains in said thermoplastic resin film, an energy output of the thermal head for heating sufficiently satisfies to fuse-penetrate a thin closing portion of the minute recess, but it is restricted to the range which does not fuse-perforate a thick portion except the recess portion of the film, so that said openings are formed by the heated fused portion communicating the minute recess. 8. A plate-making apparatus for stencil printing according to the claim 7, wherein said heating means is a thermal head on which two or more heaters are arranged in the main scanning direction at one sequence or tier, when a main scanning side array pitch of the heater is set to PM, a main scanning side heater length is set to HM, a sub scanning side delivery pitch is set to PS and a sub scanning side heater length is set to HS, the heater size satisfies HM>0.6PM and HS>0.7PS. 9. A plate-making apparatus for stencil printing according to the claim 7 or 8, Wherein impression energy of the thermal head is below into the 35 mili-joule/mm2. 10. A plate-making apparatus for stencil printing according to the claim 7 or 8, wherein the minute recess can be made into a penetrated hole that a diameter of an opening on the heated side of the film is smaller than a diameter of an opening on the opposite side to said heated side, the diameter the opening on the heated side is small not to permit ink-permeating. 11. A plate-making apparatus for stencil printing according the claim 7 or 8, wherein said minute recess is a dent which reduces a thickness of said the film partially and forms a closing thin portion. 12. A stencil printing machine comprising: a plate feed section which feeds the heat-sensitive stencil plate consisting of an extended thermoplastic resin film with a predetermined thickness, and a heating means to form ink-permeable openings in the film by heating the film, in which an opposite side surface to the minute recess side of the film is heated by the heating means, said heating means is a thermal head, a tensile stress at the time of extension is internally remains in said thermoplastic resin film, an energy output of the thermal head for heating sufficiently satisfies to fuse-penetrate a thin closing portion of the minute recess, but it is restricted to the range which does not fuse-perforate a thick portion except the recess portion of the film, so that said openings are formed by the heated fused portion communicating the minute recess. 13. A stencil printing machine according to the claim 12, wherein two or more heaters are arranged in the main scanning direction at one sequence or tier on said thermal head, when a main scanning side array pitch of the heater is set to PM, a main scanning side heater length is set to HM, a sub scanning side delivery pitch is set to PS and a sub scanning side heater length is set to HS, the heater size satisfies HM>0.6PM and HS>0.7PS. 14. A stencil printing machine according to the claim 12 or 13, wherein an impression energy of the thermal head is below into the 35 mili-joule/mm2. 15. A stencil plate printing machine according to the claim 12 or 13, wherein the minute recess is a penetrated hole that a diameter of an opening on the heated side of the film is smaller than a diameter of an opening on the opposite side to said heated side, the diameter the opening on the heated side is small not to permit ink-permeating. 16. A stencil plate printing machine according to the claim 12 or 13, wherein said minute recess is a dent which reduces a thickness of said the film partially and forms a closing thin portion. 17. A plate-making apparatus for stencil printing according to the claim 7 or 8 including; a means to form many minute recesses on one side surface of the film. 18. A stencil printing machine according to the claim 12 or 13 including; a means to form many minute recesses on one side surface of the film. |
<SOH> BACKGROUND ART <EOH>Conventionally, a stencil sheet, which is utilized for a stencil plate in stencil printing, generally comprises an ink-permeable supporter and a thermoplastic resin film which is stuck on the supporter with adhesives. The ink-permeable supporter is made of Japanese paper or nonwoven fabric and the like. The thermoplastic resin film is made from polyester and the like. A thickness of the thermoplastic resin film is 1.5 μm to generally a thickness of the supporter being about 30-40 μm. Printing is performed by taking out ink from a stencil plate which is formed by thermally perforating the film. Said thermal perforation is mainly performed by heating of a thermal head, namely, said stencil sheet is inserted between the thermal head and a platen roller, and then is heated by the thermal head. Respect to stencil printing performed by using such a stencil plate made or engraved by the above mentioned method, from before, various inconveniences or disadvantages of using the stencil plate which is stuck the thermoplastic resin film with adhesives, are mentioned. Meanwhile, various improvement proposals, which constitute a stencil plate only of a thermoplastic resin film without supporters, are proposed. However, none of the proposals has resulted in utilization now, and any proposals must overcome certain technical problems. When the stencil plate particularly is constituted only of a thermoplastic resin film, it is hard to deal with the stencil plate if a thickness of the film is not made to some extent thick. In addition, it is necessary to enlarge an output force of the thermal head in order to carry out thermally perforating at the thick film. That caused various problems and has become the greatest difficulty of utilization. On the other hand, it is preferable that perforations of the stencil plate made in stencil printing are perforated independently for every dot, and for that, it is desirable to make heater size as small as possible to a dot pitch as shown in the Japanese examined patent publication No.2732532. However, corresponding to a size of the heater becoming small, an influence of a heat diffusion which the heater receives from the circumference electrodes becomes large, thereby, a thermal efficiency of the thermal head falls down and a life of the thermal head becomes short. Furthermore, with respect to a thin film type thermal head, since an exothermic portion is dented compared with a surrounding electrode, the stencil sheet will be supported by high electrode sections around of the dented portion according to the size of the heater becoming small. Therefore, a contact state or an adhesion state between the exothermic portion and the stencil sheet becomes bad, and thermal efficiency falls increasingly. Moreover, in order to solve the above-mentioned problem about aggravation of the contact state between the exothermic portion and the stencil sheet by the size of the heater becoming small, the thermal head so called a “partial glaze type” which raises only the exothermic portion by glaze is proposed. However, even if the thermal head is the partial glaze type, since an upheaval of the partial glaze is very smooth, the raising curve also turns into a straight line in approximation. After all, it becomes not impossible to fully solve the problem of the adhesion. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a drawing showing a concept of the plate-making method and the apparatus for according to the present invention. FIG. 2 is a drawing showing a front view of the array state of the heater section of the thermal head. FIG. 3 is a drawing showing a state of the stencil plate which is perforated by making the heater of the position which expresses “1” of a number according to this plate-making method generate heat, and above mentioned process is performed by means of the plate-making method according to the present invention. FIG. 4 is a drawing showing a concept about the structure of the stencil sheet used for the plate-making method and apparatus according to the present invention. FIG. 5 is a drawing showing a concept about the structure of the stencil sheet used for the plate-making method and apparatus according to the present invention. FIG. 6 is a drawing showing an example of a composition for forming minute recesses in the stencil sheet. FIG. 7 is a drawing showing an example of a composition for forming minute recesses in the stencil sheet. FIG. 8 is a drawing showing an example of a composition for forming minute recesses in the stencil sheet. FIG. 9 is a drawing showing an example of a composition for forming minute recesses in the stencil sheet. detailed-description description="Detailed Description" end="lead"? |
Method and device for establishing network communication compatibility of terminal, for example to enable dialogue with a smart card application |
In order to set up a communication channel on a link connecting a client application on a client machine and a service application present on a device dependent on a terminal, the client machine includes a representative of the service application. A formatting module is located at the client machine, downstream of the representative, for formatting the client application messages in a form readable by the service application. A gateway is located at the terminal, for receiving the messages readable by the card and transmitting them to the service application. Typically, the communicating device is a smart card, and the service application is a card application. The link is typically a network, for example of the Internet type. |
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