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Polymeric bioresorbable composites containing an amorphous calcium phosphate polymer ceramic for bone repair and replacement |
A bioresorbable composite of a non-crystalline calcium phosphate ceramic synthesized within an encapsulating microspheres of bioresorbable polymeric material for use in bone repair and replacement is provided. Also provides are methods for producing these composites as well as porous, 3-dimensional scaffold produced by sintering together microspheres of this bioresorbable composite. |
1. A bioresorbable composite comprising a non-crystalline calcium phosphate ceramic synthesized within an encapsulating microsphere of bioresorbable polymeric material. 2. A method for producing the bioresorbable composite of claim 1 comprising synthesizing the calcium phosphate ceramic within the encapsulating microspheres of the bioresorbable polymeric material. 3. A porous, 3-dimensional scaffold produced by sintering together microspheres of the bioresorbable composite of claim 1. |
<SOH> BACKGROUND OF THE INVENTION <EOH>With demographics shifting towards an older population and with more people living more active lifestyles, the number of orthopaedic injuries and disorders continues to rise. In the United States alone, there were more than 6 million fractures each year from 1992 to 1994 (Praemer et al. American Academy of Orthopaedic Surgeons 1999 182). In 1995, there were 216,000 total knee replacements, 134,000 total hip replacements, and close to 100,000 bone grafting procedures performed. Traditionally, autografts and allografts have been used by orthopaedic surgeons to repair fractures and other bone defects. However, limitations including donor-site morbidity, risk of disease transfer, potential immunogenicity, and insufficient supply has led investigators to search for alternative bone repair materials. Since the main mineral component of bone is a complex calcium phosphate system called apatite, hydroxyapatite and other materials within the calcium phosphate family have been and continue to be extensively investigated (DeMaeyer et al. J. Biomed. Mater. Res. 2000 52:95-106; Keller, L. and Dollase, W. A. J. Biomed. Mater. Res. 2000 49:244-249; Zeng et al. Biomaterials 1999 20:443-451; Ma et al. J. Biomed. Mater. Res. 2001 54:284-293; and Duracan, C. and Brown, P. W. J. Biomed. Mater. Res. 2000 51:726-734). Further, calcium phosphate ceramics have been reported to be osteoconductive and to directly bond to bone (Jarcho, M. Clin. Orthop. Rel. Res. 1981 157:259-278; Kitsugi et al. Clin. Orthop. Rel. Res. 1988 234:280-290). In addition, calcium phosphate ceramics are believed to serve as precursors to bone apatite formation in vivo. Accordingly, the good bone compatibility of calcium phosphate ceramics is indicative of their suitability for repair or replacement of damaged or diseased bone. However, the brittleness of these materials limits their widespread use in orthopaedics, particularly in load-bearing applications. Accordingly, various attempts has been made to overcome this limitation. One example has been to prepare composities of these ceramics with bioresorbable polymeric materials such as collagen and polymers of lactic acid and glycolic acid (TenHuisen et al. J. Biomed. Mater. Res. 1995 29:803-810; Yasunaga et al. J. Biomed. Mater. Res. 1999 47:412-419; Zhang et al. J. Biomed. Mater. Res. 1999 45:285-293; Devin et al. J. Biomater. Sci. Polyner Edn. 1996 7:661-669; Boeree et al. Biomaterials 1993 14:793-796). In general, these composites are made porous in order to create a 3-dimensional scaffold that allows the ingrowth of new bone and the eventual replacement of the scaffold with new skeletal tissue (Zhang et al. J. Biomed. Mater. Res. 1999 45:285-293; Devin et al. J. Biomater. Sci. Polymer. End. 1996 7:661-669). In these composites, the ceramic typically comprises a calcium phosphate compound with moderate to high crystallinity (TenHuisen et al. J. Biomed. Mater. Res. 1995 29:803-810; Yasunaga et al. J. Biomed. Mater. Res. 1999 47:412-419; Zhang et al. J. Biomed. Mater. Res. 1999 45:285-293; Devin et al. J. Biomater. Sci. Polymer. Edn. 1999 7:661-669; Boeree et al. Biomaterials 1993 14:793-796). In contrast, bone apatite is poorly crystalline and non-stoichiometric due to the presence of other ions such as magnesium and carbonate ions (Posner, A.S. and Betts, F. Acc. Chem. Res. 1975 8:274-281; Bigi et al. Calcif. Tissue Int. 1992 50:439-444). Further, crystalline forms of hydroxyapatite have been shown to resorb at a slower rate than that of new bone formation. In fact, the rate of new bone formation coincides more closely with the resorption rate of poorly crystalline or amorphous calcium phosphate ceramics (Frayssinet et al. Biomaterials 1993 14:423-429; Klein et al. J. Biomed. Mater. Res. 1983 17:769-784; Knaack et al. J. Biomed. Mater. Res. (Appl. Biomater.) 1998 43:399-409). In the present invention, crystalline hydroxyapatite is replaced with a poorly crystalline or amorphous calcium phosphate ceramic believed to resorb concurrently with new bone growth. Also, the degradation of the amorphous calcium phosphate forms alkali products that serve to buffer the acidic degradation product of either lactic or glycolic acid in a composite of the two materials. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object of the present invention is to provide a bioresorbable composite for use in bone repair and replacement which comprises a non-crystalline or amorphous calcium phosphate ceramic synthesized within encapsulating microspheres of a bioresorbable polymeric material. Another object of the present invention is to provide a method for producing a bioresorbable composite which comprises a bioresorbable polymeric material and a non-crystalline or amorphous calcium phosphate ceramic for use in bone repair and replacement wherein the method comprises synthesizing the calcium phosphate ceramic within encapsulating microspheres of the bioresorbable polymeric material. Yet another object of the present invention is to provide porous, 3-dimensional scaffolds with uniform composition throughout the scaffold, wherein said scaffolds are produced by sintering together microspheres of a non-crystalline or amorphous calcium phosphate ceramic synthesized within encapsulating microspheres of a bioresorbable polymeric material. |
Purification materials and method of filtering using the same |
The invention relates to a purification material (1) comprising filtration particulate matter aggregated with a first binder and further processed with a second binder to generate a porous fluid filtration material or a non-pourous coating, a filtering device comprising a housing (11) and the purification material (1), and a method of filtering and/or purifying a fluid including water or other solutions containing chemical and microbiological contaminants, such as fluids containing heavy metals, pesticides, by products of oxidation chemicals and including cysts, bacteria and/or viruses, where the fluid is passed through ot made to contact a surface of the purification material (1). |
1. A purification material for fluids, wherein the material comprises insoluble filtration particles aggregated with a first binder and combined into the form of a porous block, porous sheet, porous coating or a non-porous coating using a second binder. 2. The purification material of claim 1, wherein the material is in the form of a porous block. 3. The purification material of claim 2, wherein the porous block is rigid. 4. The purification material of claim 2, wherein the porous block is flexible. 5. The purification material of claim 1, wherein the material is in the form of a porous sheet. 6. The purification material of claim 5, wherein the porous sheet is rigid. 7. The purification material of claim 5, wherein the porous sheet is flexible. 8. The purification material of claim 1, wherein the material is in the form of a porous coating. 9. The purification material of claim 8, wherein the porous coating is contained on a substrate which is rigid. 10. The purification material of claim 8, wherein the porous coating is contained on a substrate which is flexible. 11. The purification material of claim 1, wherein the material is in the form of a non-porous coating. 12. The purification material of claim 11, wherein the non-porous coating is contained on a substrate which is rigid. 13. The purification material of claim 11, wherein the non-porous coating is contained on a substrate which is flexible. 14. The purification material of claim 1, wherein at least a portion of said insoluble filter material is carbon in a form selected from particles, fibers, or a combination thereof. 15. The purification material of claim 1, wherein at least a portion of said insoluble filtration material is derived from minerals containing apatites, phosphates, silicates, hydroxides, oxides or combinations thereof. 16. The purification material of claim 1, wherein the first binder is a polymer material. 17. The purification material of claim 16, wherein the first binder is a polymer material containing positive charges, negative charges, hydrogen bonding sites, or a combination thereof. 18. The purification material of claim 17, wherein the first binder is a polyelectrolyte material derived from natural polymers or modified natural polymers. 19. The purification material of claim 18, wherein the first binder is a polyelectrolyte material known as cationic starch. 20. The purification material of claim 17, wherein the first binder is a polyelectrolyte material selected from the group consisting of polyamines, polyamides, polyalcohols, polysaacharides, polyacrylamides, polyacrylates, humic acids, proteins, poly(DADMAC), Poly-DADM, polyamine-poly(DADMAC) blends, polyquartenary amines, inorganic-polyamine blends, and inorganic Poly(DADMAC) blends, cationic starch, cationic polymethylmethacrylates, copolymers of vinylimidazolium methochloride and vinylpyrrolidone, quarternized vinylpyrrolidone/dimethyl-aminoethyl-methacrylate copolymer, and polyethyleneimine. 21. The purification material of claim 1, wherein the first binder is selected from the group consisting of metal hydroxides and oxides. 22. The purification material of claim 21, wherein the first binder is selected from the group containing aluminum, calcium, magnesium, iron, polyaluminum sulfates, polyaluminum chlorides, polyorganozirconates, polyorganoaluminates, polysiloxanes, polysilanes, polysilazanes, polycarbosilanes, polyborosilanes, zirconium dimethacrulate, zirconium tetramethacrylate, zirconium 2-ethylhexanoate, aluminum butoxides, aluminum diisopropoxide ethylacetoacetate, tetramethyldisiloxanes and derivatives thereof, tristrimethylsilylphosphate, and tristrimethylsiloxyboron. 23. The purification material of claim 21, wherein the first binder is a metal oxide or hydroxide derived from aluminum, calcium, magnesium, or iron. 24. The purification material of claim 1, wherein the second binder is a polymer material. 25. The purification material of claim 24, wherein the binder is a polymer melting between about 50° C. and about 500° C. 26. The purification material of claim 24, wherein the polymer is stable under sterilization conditions. 27. The purification material of claim 24, wherein said binder is selected from the group consisting of thermoplastics, polyethylene glycols or a derivative thereof, polyvinyl alcohols, polyvinylacetate, and polylactic acids. 28. The purification material of claim 24, wherein the polymer material is a thermoplastic is selected from the group consisting of nylon, polyethylene, polyvinylchloride, fluorocarbon resins, polystyrene, polypropylene, cellulosic resins, and acrylic resins. 29. The purification material of claim 24, wherein the polymer material comprises a naturally occurring polymer. 30. The purification material of claim 29, wherein the naturally occurring polymer is selected from the group consisting of natural and synthetically modified celluloses, collagens, and organic acids. 31. The composite purification material of claim 29, wherein the naturally occurring polymer is selected from the group consisting of natural and synthetically modified celluloses, collagens, and organic acids. 32. The composite purification material of claim 29, wherein the naturally occurring polymer is a biodegradable polymer selected from the group consisting of a polyethyleneglycol, a polylactic acid, a polyvinylalcohol, a co-polylactideglycolide, cellulose, alginic acids, carrageenans isolated from seaweeds, polysaccharides, pectins, xanthans, starch, and combinations thereof. 33. The purification material of claim 24, wherein the polymer material comprises an electrically conductive polymer. 34. The purification material of claim 24, wherein the polymer material comprises a biodegradable polymer. 35. The purification material of claim 34, wherein the biodegradable polymer is a polyethyleneglycol, a polylactic acid, a polyvinylalcohol, or a co-polylactideglycolide. 36. The purification material of claim 24, wherein said binder is selected from the group consisting of gelling or absorbent materials. 37. The purification material of claim 36, wherein said binder is selected from the group consisting of superabsorbents. 38. The composite purification material of claim 37, wherein said superabsorbent comprises a material selected from polyacrylic acids, polyacrylamides, poly-alcohols, polyamines, polyethylene oxides, cellulose, chitins, gelatins. starch, polyvinyl alcohols and polyacrylic acid, polyacrylonitrile, carboxymethyl cellulose, alginic acids, carrageenans isolated from seaweeds, polysaccharides, pectins, xanthans, poly-(diallyldimethylammonium chloride), poly-vinylpyridine, poly-vinylbenzyltrimethylammonium salts, polyvinylacetates, polylactic acids or a combination thereof. 39. The composite purification material of claim 37, wherein the superabsorbent material comprises an ionically charged surface. 40. The composite purification material of claim 37, wherein the superabsorbent material comprises a biodegradable polymer. 41. The purification material of claim 37, wherein said binder is selected from the group consisting polylactic acids, polyacrylamides or combinations of the polymers thereof. 42. The composite purification material of claim 37, wherein the absorbent material comprises a clay or aluminosilicate material. 43. The composite purification material of claim 42, wherein the absorbent material comprises is bentonite. 44. The composite purification material of claim 24, wherein the superabsorbent comprises a material selected from the group consisting of resins obtained by polymerizing acrylic acid and resins obtained by polymerizing acrylamide. 45. The composite purification material of claim 24, wherein the polymer material comprises a naturally occurring polymer, cellulose, alginic acids, carrageenans isolated from seaweeds, polysaccharides, pectins, xanthans, starch, or combinations thereof. 46. The composite purification material of claim 24, wherein the superabsorbent material comprises an ionically charged surface ranging from 1-100% of the material surface. 47. The purification material of claim 6, wherein the purification material is in the form of a sheet and is disposed on a woven web. 48. The purification material of claim 6, wherein the purification material is in the form of a sheet and is disposed on a nonwoven web. 49. The purification material of claim 7, wherein the purification material is in the form of a sheet and is disposed on a woven web. 50. The purification material of claim 7, wherein the purification material is in the form of a sheet and is disposed on a nonwoven web. 51. The purification material of claim 8, wherein the purification material is in the form of a coated substrate and the substrate is rigid. 52. The purification material of claim 51, wherein the substrate is a metal. 53. The purification material of claim 52, wherein the substrate is a coinage metal. 54. The purification material of claim 52, wherein the substrate contains iron. 55. The purification material of claim 51, wherein the substrate is a polymer. 56. The purification material of claim 24, wherein the polymer is derived from synthetic sources. 57. The purification material of claim 56, wherein the synthetic source produces a woven substrate. 58. The purification material of claim 24, wherein the synthetic source produces a non-woven substrate. 59. The purification material of claim 24, wherein the polymer is derived from natural sources. 60. The purification material of claim 59, wherein the natural source produces a woven substrate. 61. The purification material of claim 59, wherein the natural source produces a non-woven substrate. 62. The purification material of claim 8, wherein the purification material is in the form of a coated substrate and the substrate is flexible. 63. The purification material of claim 62, wherein the polymer is derived from synthetic sources. 64. The purification material of claim 63, wherein the synthetic source produces a woven substrate. 65. The purification material of claim 63, wherein the synthetic source produces a non-woven substrate. 66. The purification material of claim 62, wherein the polymer is derived from natural sources. 67. The purification material of claim 66, wherein the natural source produces a woven substrate. 68. The purification material of claim 66, wherein the natural source produces a non-woven substrate. 69. The purification material of claim 51, wherein the substrate conducts electricity. 70. The purification material of claim 62, wherein the substrate conducts electricity. 71. The purification material of claim 1, wherein the binders are present in an amount ranging from about 1 wt % and about 99.9 wt % of the total weight of the purification material. 72. The purification material of claim 1, further comprising one or more additional non-carbon adsorptive materials. 73. The purification material of claim 72, wherein said additional adsorptive material comprises a calcium or magnesium containing phosphate or a calcium or magnesium containing silicate. 74. The purification material of claim 72, wherein said adsorptive material comprises apatite obtained from bone char. 75. The purification material of claim 72, wherein said adsorptive material comprises an aluminum containing silicate, oxide, or hydroxide. 76. The purification material of claim 72, wherein said adsorptive material comprises a magnesium containing hydroxide, oxide, or silicate. 77. The purification material of claim 72, wherein said additional adsorbent material and said insoluble filtration particles are present in approximately equal amounts, further wherein the insoluble filtration particles comprise granulated activated carbon. 78. The purification material of claim 77, wherein said additional adsorbent material and said granulated activated charcoal are each present in amounts of about 42.5 wt %, and said binders are present in an amount of about 15 wt %, based upon the total weight of said purification material. 79. The purification material of claim 72, wherein said additional adsorptive material comprises an ion-binding material selected from the group consisting of synthetic ion exchange resins, zeolites, and phosphate minerals. 80. The purification material of claim 79, wherein the phosphate minerals are members of the phosphate class of minerals. 81. The purification material of claim 79, wherein the phosphate minerals are members of the aluminosilicate group of minerals. 82. The purification material of claim 79, wherein the synthetic ion exchange resins are functionalized styrenes, vinylchlorides, divinyl benzenes, methacrylates, acrylates, and mixtures, copolymers, and blends thereof. 83. The purification material of claim 79 wherein the natural or synthetic zeolites are silicate containing minerals known as clinoptilolite. 84. The purification material of claim 1, further comprising one or more materials that undergo an chemical oxidation or a chemical reduction in the presence of water or aqueous fluid. 85. A device for filtering microbiological contaminants from water or aqueous fluid, comprising: a housing; and a porous block of the purification material of claim 1. 86. The device according to claim 85, wherein the housing comprises an inlet, an outlet, and a contacting chamber therebetween, and wherein said porous block is disposed within the contacting chamber, such that fluid can flow into the housing from the inlet passes through the porous block and then can flow out of the housing through the outlet. 87. A method for filtering a fluid to remove any microorganisms therefrom, comprising causing the fluid to flow through the purification material of claim 1, thereby obtaining filtered fluid. 88. The method of claim 87, wherein said fluid is water. 89. The method of claim 89, wherein the filtered water is potable. 90. The method of claim 87, wherein said fluid is an aqueous solution. 91. The method of claim 90, wherein said aqueous solution is blood. 92. The method of claim 90, wherein said aqueous solution is a fermentation broth. 93. The method of claim 90, wherein said aqueous solution is a recycled stream in a chemical or biological process. 94. The method of claim 90, wherein the aqueous solution is a recycled stream in a cell culturing process. 95. The method of claim 90, wherein the aqueous solution has been used in a surgical procedure. 96. The method of claim 87, wherein the fluid comprises breathable air. 97. The method of claim 87, wherein the fluid comprises a purge gas. 98. The method of claim 97, wherein the purge gas is selected from the group consisting of O2, CO2, N2, or Ar. 99. The method of claim 87, wherein the fluid is an anesthetic gas. 100. The method of claim 99, wherein the anesthetic gas comprises nitrous oxide. 101. The method of claim 87, further comprising regenerating said purification material by sterilization. 102. The method of claim 101, wherein said sterilization comprises exposing the purification material to elevated temperature, pressure, radiation levels, or chemical oxidants or reductants, or a combination thereof. 103. The method of claim 101, wherein said sterilization comprises autoclaving. 104. The method of claim 101, wherein said sterilization comprises electrochemical treatment. 105. The method of claim 101, wherein said sterilization comprises a combination of chemical oxidation and autoclaving. 106. The method of claim 87, wherein said fluid is a gaseous mixture. 107. The method of claim 106, wherein the filtered gas is air. 108. The method of claim 87, wherein said fluid is a chemically unreactive gas. 109. The method of claim 87, wherein said gas is oxygen, carbon dioxide, nitrogen, argon, or nitrogen oxides. 110. The method of claim 87, wherein said gas is used to pressurize a chamber. 111. The method of claim 87, wherein said gas is used to sparge or purge an aqueous solution for the purpose of increasing the concentration of the sparging gas in the solution. 112. The method of claim 87, wherein said gas is used to sparge or purge an aqueous solution for the purpose of decreasing the concentration of the gases initially present in the solution. 113. The method of claim 87, wherein said gas is used to remove particulate material from surfaces. 114. An immobilization and contacting medium for microorganisms, comprising magnesium containing mineral and a binder therefor, the medium in the form of a rigid, porous block or a sheet. 115. The immobilization and contacting medium of claim 114, further comprising one or more microorganisms disposed within the pores thereof. 116. The regeneration of the material of claim 1 through the use of solutions comprising salt, acid, or caustic. 117. A method for filtering a fluid to remove any microorganisms therefrom, comprising causing the fluid to flow over the purification material of claim 11, thereby obtaining filtered fluid. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Purification or filtration of water or other aqueous solutions is necessary for many applications, from the provision of safe or potable drinking water to biotechnology applications including fermentation processing and separation of components from biological fluids. Similarly, the removal of microbial organisms from breathable air in hospitals and clean rooms, where ultrapurified air is required, and in environments where the air will be recirculated, such as aircraft or spacecraft, is also an important application for filtration media. In recent years, the need for air filtration and purification in the home has become more recognized, and the competing concerns of energy efficiency and indoor air quality have lead to numerous air filtration products, such as HEPA filters and the like, that purport to remove small particles, allergens, and even microorganisms from the air. There are many well-known methods currently used for water purification, such as distillation, ion-exchange, chemical adsorption, filtering or retention, which is the physical occlusion of particulates. Particle filtration may be completed through the use of membranes or layers of granular materials, however in each case the pore size of the material and the space between the granular materials controls the particle size retained. Additional purification media include materials that undergo chemical reactions, which alter the state or identity of chemical species in the fluid to be purified. In most cases a combination of techniques are required in order to completely purify fluids, such as water. Combinations of technologies may be implemented by combining functions in a single device or using several devices in series where each performs a distinct function. Examples of this practice include the use of mixed resins that remove both negative and positively charged chemical species as well as species without charge. Many of these fluid purification techniques and practices are costly, energy inefficient and/or require significant technical know-how and sophistication. Traditional means of reducing these complications require extensive processing or specially designed apparatus. Unfortunately, development of low cost techniques do not adequately address the removal of harmful chemical and biological contaminates, such as, bacteria and viruses. For example, simple point-of-use purification devices, such as filters attached to in-house water supply conduits or portable units for campers and hikers, cannot sufficiently remove bacteria and viruses unless relatively costly membrane technology or strong chemical oxidizers, such as halogens or reactive oxygen species, are utilized. The Environmental Protection Agency (EPA) has set forth minimum standards for acceptance of a device proposed for use as a microbiological water purifier. Common coliforms, represented by the bacteria E. coli and Klebsiella terrigena , must show a minimum 6-log reduction, 99.9999% of organisms removed, from an influent concentration of 1×10 7 /100 ml. Common viruses, represented by poliovirus 1 (LSc) and rotavirus (Wa or SA-11), which show resistance to many treatment processes, must show a minimum 4 log reduction, 99.99% of organisms removed, from an influent concentration of 1×10 7 /L. Cysts, such as those represented by Giardia muris or Giardia lamblia , are widespread, disease-inducing, and resistant to chemical disinfection. Devices that claim cyst removal must show a minimum 3 log reduction, 99.9% of cysts removed, from an influent concentration of 1×10 6 /L or 1×10 7 /L, respectively. The EPA has accepted the use of other particles in the appropriate size range as a means of testing devices that claim this function. Materials that are highly efficient at removing and immobilizing microbial organisms have numerous applications, but a particular area of application is in the biotechnology and fermentation industries. Not only would such materials be useful in the processing of fermentation broth for recycling or reuse, they also would have utility as microbial immobilization materials for the microbes of interest to the fermentation process. It is well known to use granular, particulate, or fibers of natural or synthetic materials for fluid treatment. These materials are commonly used singularly and in mixtures. In some cases a material which immobilizes the individual particles or fibers together, referred to as a binder, is used. Techniques for generating porous blocks of carbon using a polymer binder is described in prior art by companies such as KX Industries, Amway Corporation, and Cuno. Natural materials used in filter applications include carbonaceous materials such as activated carbon and minerals such as apatites, oxides, hydroxides, phosphates, and silicates and combinations thereof. Synthetic materials used in filter applications include hydrocarbon polymers, and mineral species such as apatites, oxides, hydroxides, phosphates, and silicates and combinations thereof. The particle size of the filtration material used in filtration devices controls many of the technical specifications and successful application of a filtration device. Particle sizes commonly used include those in a range between 80 and 325 mesh. Grinding and milling of both natural and synthetic materials can be required to generate particles in this size range. Although particle sizes outside this range can be used they present practical problems. As example, small particles such as those smaller than 325 mesh are difficult to retain in the filtration device while particles larger than 80 mesh lack the needed surface area for many applications. The grinding and milling of natural and synthetic materials often produces particles of varying size and distribution. Particles size distributions and mixtures of distributions are modified by sieving, particle collection, and recombination. Particle sizes that are too small for use in filtration devices often go to waste or must be left for other applications. It is also common for synthetic materials to be synthesized in particle sizes that are too small for use in many filtration devices. The use of soluble treatment chemicals for increasing particulate matter size in water and waste water treatment is well known. It is commonly understood that inorganic and organic materials can be used to flocculate, coagulate, and aggregate small particulate material found in a water stream. The resulting larger particles are now able to be filtered or to be removed from the water system through standard sedimentation and clarification methods. It is also well understood that many particulates in the water stream carry positive or negative charges and that this characteristic may be used to aggregate the small particles into larger species. Accordingly, there remains a need in the art of fluid filtration for an uncomplicated, safe, inexpensive fluid purification and filtration method and device incorporating insoluble small filtration particles (<325 mesh) and soluble water treatment chemicals. It is the intention of this invention and art to generate filtration particulate material and filtration devices through the use of multiple different chemical binders. Furthermore it is the intention of this invention and method to permit the simultaneous use of activated carbon, silicates, oxides, metal hydroxides, and phosphates in the forms which are readily available and commonly found or synthesized by a variety of different methods. There is also a need in the art for a method and device that can address the EPA requirements for designation as chemical and microbiological water purifiers, such that the device is more than suitable for consumer and industry point-of-use and point-of-entry applications. |
<SOH> SUMMARY OF THE INVENTION <EOH>To this end, the present inventors have discovered that a significant problem in the known use of small particulate inorganic and organic materials, called fines, incorporated into filter devices is that the particles are difficult to contain thus requiring very small pore size containers which increases the back pressure of devices. Small particles also tend to plug devices which leads to short product lifetimes. Loss of particulate material decreases or inhibits product performance, can cause illness, and presents a general annoyance for devices users. Finally, as with all particulate containing devices, grinding of particles as a result of particle movement generates even smaller particles. Additionally, the present inventors have discovered that there also exists a significant problem in the known binding methods used to generate filter devices. As the size of the filtration particles decreases an increase in the amount of polymer binder is required in order to retain and immobilize the particles. The increase in binder levels required often generates filtration blocks with small pores which increases device backpressure. The invention disclosed provides a means for using small filtration particulate matter (<325 mesh), material fines, generated from the processing of natural or synthetic materials or from the synthesis of materials for the generation of porous blocks suitable for fluid filtration. The invention in general involves the use of multiple organic and/or inorganic binders to first increase the particulate matter size, and subsequently to generate porous blocks or sheets or coatings. Non-flow through coated surfaces which function by contact filtration are also considered an important material that may be used in the invention. The method of the invention involves two steps. The first step involves taking small particles or fines in the size range between 10 nanometers and 200 microns and aggregating or agglomerating them into larger particles through the use of positively charged, negatively charged, and/or uncharged organic or inorganic polymers, and/or compounds such as oxides, hydroxides, phosphates, and silicates. Examples of suitable binders include, polyelectrolytes such as polyamines, polyalcohols, polysaacharides, polyacrylates, polyacrylamides and derivitized natural and synthetic polymers, oxides of magnesium and calcium, and hydroxides of calcium, magnesium, aluminum, and iron. Additionally, precipitation of hydroxide and phosphate compounds may be used. This first processing step may also include mechanical steps, such as mixing, spraying, dripping or fluidic processing. This step may also include heat treatment, including digestion, calcining, sintering, and firing. The chemical and physical processing of this step may be repeated until the particles are of appropriate size, which is usually greater than 325 mesh. It should be understood that during the first step of the invention, the binder may be partially or fully removed by the various processing methods. The second step in the invention involves taking the particulate material generated in step 1 , particles of significantly greater size, and combining them with a second binder, of different type, which immobilizes the particles into a porous block. This second step may utilize standard techniques such as extrusion, molding, and pressure. The invention and method provides an efficient means of using small particles which are difficult to implement in the generation of filtration devices. There are numerous advantageous to the method of this invention. First, the initial starting particles have very large surface areas which increases the filtration efficiency of the filtration device when they are included as components of larger particles which are now retained in the device. Second, the invention provides the ability to simultaneously use a mixture or agglomeration of different filtration particle types. As an example, carbon, apatite, silicate, metal oxide, hydroxide, and/or sulfur containing particles may be agglomerated to generate a mixed composition particle. Third, the method provides a means of producing insoluble water treatment polymer materials from previously soluble polymeric compounds and retaining them in the filtration device. As an example, high molecular weight charged water treatment polymers have a plethora of active binding sites. By using some of the active binding sites to bind particulate material the polymer is rendered insoluble. Since only some of the many active binding sites are used for particle binding there still remains many active binding sites which are now available for participating in the fluid stream filtration, for the removal of chemical and biological contaminants. Fourth, the method allows the use of materials that are hazardous in larger sizes such as magnesium containing silicates in asbestos form to be used in safer smaller particulate sizes. Fifth, the method provides a means for utilizing nanometer size particles of metals and metal oxides that are of interest in fluid catalysis and chemical stream processing. It should be understood that the present invention may also be used for generating particles in a size range greater than 100 mesh. Unfortunately, the effectiveness of filters generated with larger materials with or without a binder is compromised by channeling and by-pass effects caused by the pressure of fluid, in particular, water and aqueous solutions, flowing through the filter media as well as particle erosion and aggregation. Because many chemicals, viruses and bacteria are removed by intimate contact with the adsorption material, even relatively small channels or pathways in the granular material formed over time by water pressure, water flow, particle erosion, or particle aggregation are easily sufficient to allow passage of the undesirable chemical and microbiological contaminants through the filter. For example, taking water as an exemplary fluid and using the material of the invention as a filtration medium for microbial organisms, calculations based on a virus influent concentration of 1×10 6 /L show that where a 4-log reduction is to be expected, only a 3.7 log reduction actually occurs if only 0.01% of the water bypasses treatment by passing through channels formed in the filter media during filtration. If 0.1% of the water passes through untreated, then only a 3 log reduction occurs. If 1% passes through untreated, only a 2 log reduction occurs, and if 10% passes untreated, only a 1 log reduction occurs. Where a 6-log reduction is expected, the detrimental results of channeling are even more dramatic, with only a 4-log reduction actually occurring when 0.01% of the water bypasses treatment. This invention solves this problem by providing a method and device for removing contaminants, including chemicals, bacteria and viruses, where very small particulate filtration materials and device adsorptive filter media are immobilized with multiple chemical binders material to form a porous filter material that eliminates the possibility of channeling and active material by-pass. This invention is, in general, a device and method for the purification and filtration of aqueous fluids, in particular water (such as drinking water or swimming or bathing water), or other aqueous solutions (such as fermentation broths and solutions used in cell culture), or gases and mixtures of gases, such as breathable air, found in clean rooms, hospitals, diving equipment homes, aircraft, or spacecraft, and gases used to sparge, purge, or remove particulate matter from surfaces. The use of the device and method of the invention results in the removal of an extremely high percentage of microbiological contaminants, including bacteria and viruses and components thereof as well as chemical contaminants such as heavy metals, pesticides and by products of chemical treatment processes. In particular, the use of the device and method of the invention results in purification of water to a level that addresses the EPA standards for chemical or microbiological water purification. In one embodiment, the invention relates to a purification material for fluids that contains particulate carbon that is in the form of a porous block as the result of employing multiple binders. Typically, at least a portion of this carbon is activated and from natural sources. In another embodiment, the invention relates to a purification material for fluids that contains particulate apatite minerals that is in the form of a porous block as the result of the presence of the multiple binders. Apatites are commonly mined, prepared from natural sources (bone char), or synthesized from calcium and phosphorus containing compounds. In another embodiment, the invention relates to a purification material for fluids that contains particulate oxide and hydroxide minerals that are in the form of a porous block as the result of the presence of the multiple binders. Aluminum, iron, and magnesium oxides are commonly mined and purified from natural sources (alumina/bauxite, chlorides), or synthesized from aluminum, magnesium containing minerals, or generated from synthetic sources such as the mixing of aluminum, iron, and magnesium containing compounds. In another embodiment, the invention relates to a purification material for fluids that contains particulate silicate minerals that are in the form of a porous block as the result of the presence of the multiple binders. Aluminum, calcium, iron, magnesium, sodium, and potassium containing silicates are commonly mined and purified from natural sources, or synthesized from aluminum, calcium, iron, magnesium, sodium, or potassium containing compounds. In another embodiment, the invention relates to a purification material for fluids that contains particulate metals important in catalysis that are in the form of a porous block as the result of the presence of the multiple binders. Platinum group metals, such as platinum, rhodium, and palladium, as well as coinage metals, such as gold, silver, copper, and nickel, as well as heavy metals, such as cadmium and chromium, are commonly mined and purified from natural sources, or reclaimed from spent electronic components. In another embodiment, the invention relates to a purification material for fluids that contains a mixture of the particulate filtration materials described in the individual embodiments of this invention that are in the form of a porous block as the result of the presence of the multiple binders. The mixtures included in this embodiment can vary dramatically with individual components included varying from less than 1% through greater than 99%. In yet another embodiment, the invention relates to a purification material for fluids that contains a mixture of particulate filtration materials generated by combining particulate material generated by a method consistent with the first step of this invention with materials that have been generated through traditional methods, such as grinding and or milling. The mixture of particles is then processed into the form of a porous block as the result of the presence of the binders and method consistent with the second step of the method. The mixtures of particles generated in the different processes included in this embodiment can vary dramatically with individual components included varying from less than 1% through greater than 99%. Also typically, the binders used are inorganic or organic compounds including polymeric or oligomeric materials that are capable of maintaining the particulate material in a particulate form (first binder) and in block structure form (second binder). This allows the purification material to be extruded, molded or pressed into any desired shape, e.g., a shape suitable for inclusion into the housing of a filtration device, which provides for fluid inflow and outflow, and which filtration device has one or more chambers for contact of the fluid with the purification material. Such a device forms another embodiment of the invention. In addition to maintaining the filtration particles immobilized in a unitary block, the polymeric binders also provide desirable physical characteristics to the filter material, e.g., rendering it rigid or flexible, depending upon the type and amount of polymeric binders used. In another embodiment, the invention relates to a purification material for fluids that is in the form of a self-supporting sheet or membrane containing the particulate filtration immobilized with the binders. In another embodiment, the invention relates to a purification material for fluids that is in the form of a porous coating supported by a porous substrate containing the particulate filtration immobilized with the binders. In another embodiment, the invention relates to a purification material for fluids that is in the form of a nonporous coating supported by a porous or nonporous substrate containing the particulate filtration immobilized with the binders. Here the fluid is filtered by surface contact. The invention also relates to methods of filtering fluids, such as water, aqueous solutions, and gases, to remove a large proportion of one or more types of chemicals, microorganisms contained therein, by contacting the fluid with the purification material of the invention. In a particular aspect of this embodiment of the invention, this contacting occurs within the device described above, with the unfiltered fluid flowing through an inlet, contacting the purification material in one or more chambers, and the filtered fluid flowing out of the chamber through an outlet. The purification material of the invention can be used to purify drinking water, to purify water used for potable and/or recreational purposes, such as in swimming pools, hot tubs, and spas, to purify process water, e.g. water used in cooling towers, to purify aqueous solutions, including, but not limited to, blood, fermentation broths, and cell culture solutions (e.g., for solution recycling in fermentation or other cell culture processes) and aqueous fluids used in surgical procedures for recycle or reuse, and to purify gases and mixtures of gases such as breathable air, for example, air used to ventilate hospital or industrial clean rooms, air used in diving equipment, or air that is recycled, e.g., in airplanes or spacecraft, and gases used to sparge, purge or remove volatile or particulate matter from surfaces, containers, or vessels. The purification material of the invention has the additional advantage of making use of readily available filtration materials and more especially small particulate materials, including those obtained from natural and synthetic sources, while still maintaining high purification efficiency. In yet another embodiment of the invention, the materials of the invention, namely small filtration particulate matter and optionally other adsorptive materials with a multiple binder matrix and which is formed into a block or sheet or coating, can be used as an immobilization medium for microorganisms used in biotechnology applications such as fermentation processes and cell culture. In this embodiment, biological process fluids, such as nutrient broths, substrate solutions, and the like, are passed through or over the immobilization material of the invention in a manner that allows the fluids to come into contact with the microorganisms immobilized therein and thereon, and effluent removed from the material and further processed as needed. |
Texturing method and apparatus |
A method and apparatus is disclosed for conveying and applying texturing instructions within a very speed, or bandwidth environment, or where storage capacity is limited; the invention and of particular use in image displaying mobile telephones (16), but also applies to image data storage (184, 186, 188, 190, 192) and use on the Internet. Image texturing is defined by a texture string (198) defining a seed number (200) for pseudo random generation of z axis displacement of pixels from an initial surface, a roughness value (202) for the surface, warp function values (204, 206), distortion function values (208, 210), texturing cell style and size data (212, 214) colour information (216, 218, 220, 222, 224, 226) and indication of where the texture is to be used (228). Cells (20) tile and wrap. |
1-27 (cancelled) 28: A method of generating a surface texture in an image, said method comprising the steps of: providing a texture field of pixels; allocating a random value for each of said pixels in the field; moving said pixels; dividing said texture field into wrappable cells; and allocating a color to each of said pixels. 29. A method, according to claim 28, wherein said step of allocating a random value for each of said pixels comprises controlling a roughness of said random value. 30. A method, according to any one of the preceding claims, wherein said step of moving said pixels comprise one of warping said pixels and distorting said pixels 31. A method, according to claim 28 or claim 29, wherein the step of dividing said texture field into wrappable cells comprises at least one of the step of selecting a shape of said cells and the step of selecting a size of said cells. 32. A method, according to claim 30, wherein the step of dividing said texture field into wrappable cells comprises at least one of the step of selecting a shape of said cells and the step of selecting a size of said cells. 33. A method, according to claim 28 or claim 29, wherein said step of allocating a color to each of said pixels comprises at least one of the step of taking account of a position of the pixel, the step of taking account of a movement of the pixel and, the step of providing a selected range of colors and of taking allocation from within the selected range of colors. 34. A method, according to claim 30, wherein said step of allocating a color to each of said pixels comprises at least one of the step of taking account of a position of the pixel, the step of taking account of a movement of the pixel and, the step of providing a selected range of colors and of taking allocation from within the selected range of colors. 35. A method, according to claim 31, wherein said step of allocating a color to each of said pixels comprises at least one of the step of taking account of a position of the pixel, the step of taking account of a movement of the pixel and, the step of providing a selected range of colors and of taking allocation from within the selected range of colors. 36. A method, according to claim 32, wherein said step of allocating a color to each of said pixels comprises at least one of the step of taking account of a position of the pixel, the step of taking account of a movement of the pixel and, the step of providing a selected range of colors and of taking allocation from within the selected range of colors. 37. A method, according to claim 28 or claim 29, comprising at least one of the step of using a computer program to generate the surface texture and the step of using a texture data string to generate the surface texture. 38. A method, according to claim 30, comprising the step of generating the surface texture by using a computer program which utilizes a texture data string. 39. A method, according to claim 31, comprising the step of generating the surface texture by using a computer program which utilizes a texture data string. 40. A method, according to claim 32, comprising the step of generating the surface texture by using a computer program which utilizes a texture data string. 41. A method, according to claim 33, comprising the step of generating the surface texture by using a computer program which utilizes a texture data string. 42. A method, according to claim 34, comprising the step of generating the surface texture by using a computer program which utilizes a texture data string. 43. An apparatus for generating a surface texture in an image, said apparatus comprising: means for generating a texture field of pixels; means for allocating a random value for each pixel in the field; means for moving the pixels; means for dividing said texture field into wrappable cells; and means for allocating a colour to each pixel. 44. An apparatus, according to claim 43, wherein said means for allocating a random value to each pixel includes means for controlling a roughness of said random values. 45. An apparatus, according to claim 43 or claim 44, wherein said means for moving said pixels comprises at least one of means for warping said pixels and means for distorting said pixels. 46. An apparatus, according to claim 43 or claim 44, wherein said means for dividing said texture field into wrappable cells comprises at least one of means for selecting a shape of said cells and means for selecting a size of said cells. 47. An apparatus, according to claim 45, wherein said means for dividing said texture field into wrappable cells comprises at least one of means for selecting a shape of said cells and means for selecting a size of said cells. 48. An apparatus, according to claim 43 or claim 44, wherein said means for allocating a color to each pixel comprises at least one of means for responding to a position of the pixel, means for responding to a movement of the pixel and, means for providing a selected range of colors and for allocating a color from within said selected range of colors. 49. An apparatus, according to claim 45, wherein said means for allocating a color to each pixel comprises at least one of means responsive to a position of the pixel, means for responding to a movement of the pixel and, means for providing a selected range of colors and for allocating a color from within said selected range of colors. 50. An apparatus, according to claim 46, wherein said means for allocating a colour to each pixel comprises at least one of means responsive to a position of the pixel, means for responding to a movement of the pixel and, means for providing a selected range of colors and for allocating a color from within said selected range of colors. 51. An apparatus, according to claim 47, wherein said means for allocating a colour to each pixel comprises at least one of means responsive to a position of the pixel, means for responding to a movement of the pixel and, means for providing a selected range of colors and for allocating a color from within said selected range of colors. 52. An apparatus, according to claim 43 or claim 44 comprising a computer program which utilizes a texture data string for generating the surface texture. 53. An apparatus, according to claim 45 comprising a computer program which utilizes a texture data string for generating the surface texture. 54. An apparatus, according to claim 46 comprising a computer program which utilizes a texture data string for generating the surface texture. 55. An apparatus, according to claim 47 comprising a computer program which utilizes a texture data string for generating the surface texture. 56. An apparatus, according to claim 48 comprising a computer program which utilizes a texture data string for generating the surface texture. 57. An apparatus, according to claim 49 comprising a computer program which utilizes a texture data string for generating the surface texture. 58. An apparatus, according to claim 50 comprising a computer program which utilizes a texture data string for generating the surface texture. 59. An apparatus, according to claim 51 comprising a computer program which utilizes a texture data string for generating the surface texture. 60. An apparatus, according to claim 52 comprising a computer program which utilizes a texture data string for generating the surface texture. 61. A computer program comprising an instruction set for generating a surface texture in an image by employing a texture field of pixels; allocating a random value for each of said pixels in the field; moving said pixels; dividing said texture field into wrappable cells; and allocating a color to each of said pixels. 62. A memory device, bearing a copy of a computer program, said computer program comprising an instruction set for generating a surface texture in an image by the steps of employing a texture field of pixels; allocating a random value for each of said pixels in the field; moving said pixels; dividing said texture field into wrappable cells; and allocating a color to each of said pixels. 63. A computer device programmed to generating a surface texture in an image by performing the steps of employing a texture field of pixels; allocating a random value for each of said pixels in the field; moving said pixels; dividing said texture field into wrappable cells; and allocating a color to each of said pixels. 64. A texture string message for generating a surface texture in an image by the steps of: employing a texture field of pixels; allocating a random value for each of said pixels in the field; moving said pixels; dividing said texture field into wrappable cells; and allocating a color to each of said pixels, wherein a texture data string is used to generate the surface texture 65. A computer programmed to generate a surface texture in an image by using a texture data string, by the steps of: providing a texture field of pixels; allocating a random value for each of said pixels in the field; moving said pixels; dividing said texture field into wrappable cells; and allocating a color to each of said pixels. |
Self-foaming or foamy preparations comprising particulate hydrophobic and/or hydrophobized and/or oil-absorbent solid substances |
Self-foaming and/or foam-like cosmetic or dermatological preparations which comprise I. an emulsifier system which consists of A. at least one emulsifier A chosen from the group of wholly neutralized, partially neutralized or unneutralized branched and/or unbranched, saturated and/or unsaturated fatty acids having a chain length of from 10 to 40 carbon atoms, B. at least one emulsifier B chosen from the group of polyethoxylated fatty acid esters having a chain length of from 10 to 40 carbon atoms and a degree of ethoxylation of from 5 to 100 and C. at least one coemulsifier C chosen from the group of saturated and/or unsaturated, branched and/or unbranched fatty alcohols having a chain length of from 10 to 40 carbon atoms, II. up to 30% by weight—based on the total weight of the preparation—of a lipid phase, III. 1 to 90% by volume, based on the total volume of the preparation, of at least one gas chosen from the group consisting of air, oxygen, nitrogen, helium, argon, nitrous oxide (N2O) and carbon dioxide (CO2) IV. 0.01-10% by weight of one or more particulate hydrophobic and/or hydro-phobicized and/or oil-absorbing solid-body substances. |
1-12. (canceled) 13. A cosmetic or dermatological composition which is at least one of self-foaming and foam-like, wherein the composition comprises: I. an emulsifier system comprising A. an emulsifier A comprising one or more C10-40 fatty acids and salts thereof, B. an emulsifier B comprising one or more polyethoxylated C10-40 fatty acid esters having a degree of ethoxylation of from 5 to 100, and C. a coemulsifier C comprising one or more C10-40 fatty alcohols, II. up to 30% by weight of a lipid phase, III. from 1% to 90% by volume of a gas comprising at least one of air, oxygen, nitrogen, helium, argon, nitrous oxide (N2O) and carbon dioxide, IV. from 0.01% to 10% by weight of one or more particulate solid substances which are at least one of hydrophobic, hydrophobicized and oil-absorbing. 14. The composition of claim 13, wherein emulsifier A, emulsifier B and coemulsifier C are present in weight ratios of a:b:c, where a, b and c independently are rational numbers of from 1 to 5. 15. The composition of claim 14, wherein a, b and c independently are rational numbers of from 1 to 3. 16. The composition of claim 14, wherein a:b:c is 1:1:1. 17. The composition of claim 13, wherein emulsifier A, emulsifier B and coemulsifier C are present in a total concentration of from 2% to 20% by weight. 18. The composition of claim 15, wherein emulsifier A, emulsifier B and coemulsifier C are present in a total concentration of from 5% to 15% by weight. 19. The composition of claim 14, wherein emulsifier A comprises at least one of stearic acid, isostearic acid, palmitic acid, myristic acid and salts thereof. 20. The composition of claim 14, wherein emulsifier B comprises at least one of PEG-9 stearate, PEG-8 distearate, PEG-20 stearate, PEG-8 stearate, PEG-8 oleate, PEG-25 glyceryl trioleate, PEG-40 sorbitan lanolate, PEG-15 glyceryl ricinoleate, PEG-20 glyceryl stearate, PEG-20 glyceryl isostearate, PEG-20 glyceryl oleate, PEG-20 stearate, PEG-20 methylglucose sesquistearate, PEG-30 glyceryl isostearate, PEG-20 glyceryl laurate, PEG-30 stearate, PEG-30 glyceryl stearate, PEG-40 stearate, PEG-30 glyceryl laurate, PEG-50 stearate, PEG-100 stearate, and PEG-150 laurate. 21. The composition of claim 19, wherein emulsifier B comprises at least one polyethoxylated stearic ester. 22. The composition of claim 14, wherein coemulsifier C comprises at least one of butyloctanol, butyldecanol, hexyloctanol, hexyldecanol, octyldodecanol, behenyl alcohol, cetearyl alcohol, and lanolin alcohols. 23. The composition of claim 19, wherein coemulsifier C comprises at least one of cetyl alcohol and cetearyl alcohol. 24. The composition of claim 13, wherein the composition further comprises one or more hydrophilic emulsifiers. 25. The composition of claim 24, wherein the one or more hydrophilic emulsifiers comprise at least one of a mono-, di-, and tri-fatty acid ester of sorbitol. 26. The composition of claim 24, wherein the one or more hydrophilic emulsifiers are present in a total concentration of less than 5% by weight. 27. The composition of claim 13, wherein the composition is free of mono- and diglyceryl fatty acid esters. 28. The composition of claim 13, wherein the lipid phase II comprises nonpolar lipids having a polarity of at least 30 mN/m. 29. The composition of claim 14, wherein the composition comprises at least 2.5% by weight of the lipid phase II. 30. The composition of claim 17, wherein the composition comprises from 5% to 15% by weight of the lipid phase II. 31. The composition of claim 13, wherein the composition comprises from 10% to 80% by volume of the gas III. 32. The composition of claim 31, wherein the gas III comprises carbon dioxide. 33. The composition of claim 13, wherein the one or more particulate solid substances IV are selected from modified and unmodified phyllosilicates, modified carbohydrate derivatives, inorganic fillers, inorganic pigments based on metal oxides, metal compounds which are insoluble or sparingly soluble in water, inorganic pigments based on silicon oxides, silicate derivatives, and microspherical particles based on crosslinked polymethyl methacrylates. 34. The composition of claim 33, wherein the one or more particulate solid substances IV comprise at least one of cellulose and derivatives thereof, microcrystalline cellulose, starch and derivatives thereof, talc, kaolin, a zeolite, boron nitride, an oxide of titanium, zinc, iron, manganese, aluminium or cerium, a sodium silicoaluminate, a magnesium silicate, a sodium magnesium silicate, a magnesium aluminum silicate, a fluoromagnesium silicate, a calcium aluminum borosilicate, and a silica dimethyl silylate. 35. The composition of claim 34, wherein the one or more particulate solid substances IV comprise at least one of wheat starch, corn starch, rice starch, manioc starch, hydroxypropyl starch phosphate, distarch phosphate, sodium corn starch octenyl succinate, and aluminum starch octenyl succinate. 36. The composition of claim 13, wherein the one or more particulate solid substances IV comprise at least one of talc, silica, titanium dioxide, kaolin, alumina, aluminum starch ocentyl succinate, a zeolite, distarch phosphate, boron nitride and a silica dimethyl silylate. 37. The composition of claim 13, wherein the composition further comprises one or more moisturizers. 38. The composition of claim 13, wherein the composition further comprises at least one antioxidant. 39. The composition of claim 38, wherein the at least one antioxidant comprises at least one of vitamin E, vitamin A and derivatives thereof. 40. A skin care product which comprises the composition of claim 13. 41. A cosmetic or dermatological composition which is at least one of self-foaming and foam-like, wherein the composition comprises: I. from 8% to 13% by weight of an emulsifier system comprising A. an emulsifier A comprising one or more C10-40 fatty acids and salts thereof, wherein the C10-40 fatty acids comprises at least one of stearic acid, isostearic acid, palmitic acid and myristic acid, B. an emulsifier B comprising one or more polyethoxylated C10-40 fatty acid esters having a degree of ethoxylation of from 5 to 100, wherein the polyethoxylated C10-40 fatty acid esters comprise at least one of PEG-9 stearate, PEG-8 distearate, PEG-20 stearate, PEG-8 stearate, PEG-8 oleate, PEG-25 glyceryl trioleate, PEG-40 sorbitan lanolate, PEG-15 glyceryl ricinoleate, PEG-20 glyceryl stearate, PEG-20 glyceryl isostearate, PEG-20 glyceryl oleate, PEG-20 stearate, PEG-20 methylglucose sesquistearate, PEG-30 glyceryl isostearate, PEG-20 glyceryl laurate, PEG-30 stearate, PEG-30 glyceryl stearate, PEG-40 stearate, PEG-30 glyceryl laurate, PEG-50 stearate, PEG-100 stearate, and PEG-150 laurate, C. a coemulsifier C comprising one or more C10-40 fatty alcohols which comprise at least one of butyloctanol, butyldecanol, hexyloctanol, hexyldecanol, octyldodecanol, behenyl alcohol, cetyl alcohol, cetearyl alcohol, and lanolin alcohols, wherein emulsifier A, emulsifier B and coemulsifier C are present in weight ratios of a:b:c, where a, b and c independently are rational numbers of from 1 to 3, II. from 5% to 15% by weight of a lipid phase which comprises nonpolar lipids having a polarity of at least 30 mN/m, III. from 30% to 80% by volume of a gas which comprises carbon dioxide, IV. from 0.01% to 10% by weight of one or more particulate solid substances which are at least one of hydrophobic, hydrophobicized and oil-absorbing and comprise at least one of modified and unmodified phyllosilicates, modified carbohydrate derivatives, inorganic fillers, inorganic pigments based on metal oxides, metal compounds which are insoluble or sparingly soluble in water, inorganic pigments based on silicon oxides, silicate derivatives, and microspherical particles based on crosslinked polymethyl methacrylates. 42. A cosmetic or dermatological base composition for gaseous active ingredients which comprises: I. an emulsifier system comprising A. an emulsifier A comprising one or more C10-40 fatty acids and salts thereof, B. an emulsifier B comprising one or more polyethoxylated C10-40 fatty acid esters having a degree of ethoxylation of from 5 to 100, and C. a coemulsifier C comprising one or more C10-40 fatty alcohols, II. up to 30% by weight of a lipid phase, III. from 0.01% to 10% by weight of one or more particulate solid substances which are at least one of hydrophobic, hydrophobicized and oil-absorbing. 43. The composition of claim 42, wherein emulsifier A, emulsifier B and coemulsifier C are present in weight ratios of a:b:c, where a, b and c independently are rational numbers of from 1 to 5. 44. The composition of claim 43, wherein emulsifier A, emulsifier B and coemulsifier C are present in a total concentration of from 2 to 20% by weight. 45. The composition of claim 44, wherein emulsifier A comprises at least one of stearic acid, isostearic acid, palmitic acid, myristic acid and salts thereof. 46. The composition of claim 42, wherein emulsifier B comprises at least one polyethoxylated stearic ester. 47. The composition of claim 43, wherein coemulsifier C comprises at least one of butyloctanol, butyldecanol, hexyloctanol, hexyldecanol, octyldodecanol, behenyl alcohol, cetyl alcohol, cetearyl alcohol, and lanolin alcohols. 48. The composition of claim 44, wherein the lipid phase II comprises nonpolar lipids having a polarity of at least 30 mN/m. 49. The composition of claim 43, wherein the composition comprises at least 2.5% by weight of the lipid phase II. 50. The composition of claim 42, wherein the composition comprises from 5% to 15% by weight of the lipid phase II. 51. The composition of claim 50, wherein the of one or more particulate solid substances comprise at least one of talc, silica, titanium dioxide, kaolin, alumina, aluminum starch ocentyl succinate, a zeolite, distarch phosphate, boron nitride and a silica dimethyl silylate. 52. The composition of claim 42, wherein the composition comprises: I. from 2% to 20% by weight of an emulsifier system comprising A. an emulsifier A comprising one or more C10-40 fatty acids and salts thereof, wherein the C10-40 fatty acids comprises at least one of stearic acid, isostearic acid, palmitic acid and myristic acid, B. an emulsifier B comprising one or more polyethoxylated C10-40 fatty acid esters having a degree of ethoxylation of from 5 to 100, wherein the polyethoxylated C10-40 fatty acid esters comprise at least one of PEG-9 stearate, PEG-8 distearate, PEG-20 stearate, PEG-8 stearate, PEG-8 oleate, PEG-25 glyceryl trioleate, PEG-40 sorbitan lanolate, PEG-15 glyceryl ricinoleate, PEG-20 glyceryl stearate, PEG-20 glyceryl isostearate, PEG-20 glyceryl oleate, PEG-20 stearate, PEG-20 methylglucose sesquistearate, PEG-30 glyceryl isostearate, PEG-20 glyceryl laurate, PEG-30 stearate, PEG-30 glyceryl stearate, PEG-40 stearate, PEG-30 glyceryl laurate, PEG-50 stearate, PEG-100 stearate, and PEG-150 laurate, C. a coemulsifier C comprising one or more C10-40 fatty alcohols which comprise at least one of butyloctanol, butyldecanol, hexyloctanol, hexyldecanol, octyldodecanol, behenyl alcohol, cetyl alcohol, cetearyl alcohol, and lanolin alcohols, II. from 5% to 15% by weight of a lipid phase, III. from 0.01% to 10% by weight of one or more particulate solid substances which are at least one of hydrophobic, hydrophobicized and oil-absorbing and comprise at least one of cellulose and derivatives thereof, microcrystalline cellulose, starch and derivatives thereof, talc, kaolin, a zeolite, boron nitride, an oxide of titanium, zinc, iron, manganese, aluminium or cerium, a sodium silicoaluminate, a magnesium silicate, a sodium magnesium silicate, a magnesium aluminum silicate, a fluoromagnesium silicate, a calcium aluminum borosilicate, and a silica dimethyl silylate. |
Method for the detection of nucleic acid molecules |
There is provided a method of simultaneously detecting at least two mutually different nucleic acid molecules in a sample, wherein in a first step a multiplex-PCR and in a second step a hybridizing reaction is carried out with probes immobilized on a microarray, whereupon the hybridized PCR products are detected and optionally quantitated, wherein the probes employed for the hybridizing reaction which in each case will hybridize specifically with the mutually different nucleic acid molecules have melting temperatures which differ from each other by 2° C. at the most, preferably by 1° C. at the most. |
1-27. (canceled) 28. A method of simultaneously detecting mutually different nucleic acid molecules in a sample comprising: obtaining a sample comprising at least two mutually different nucleic acid molecules each with a mutually different nucleic acid sequence; amplifying the at least two mutually different nucleic acid molecules in a multiplex-PCR reaction to obtain at least two mutually different amplified nucleic molecules, each comprising an amplified portion having the nucleic acid sequence of one of the at least two mutually different nucleic acid molecules; hybridizing the amplified portions of the at least two mutually different amplified nucleic acid molecules with at least two mutually different probes immobilized on a microarray to obtain at least two mutually different hybridized amplified nucleic acid molecules with melting temperatures that differ by at most 2° C.; and detecting the at least two mutually different hybridized nucleic acid molecules. 29. The method of claim 28, further comprising quantifying the mutually different hybridized nucleic acid molecules. 30. The method of claim 28, wherein each of the at least two mutually different probes comprises a hybridizing sequence adapted to hybridize, during use, to the amplified portion of one of the at least two mutually different amplified nucleic acid molecules to produce a hybridized amplified nucleic acid molecule having a melting temperature which differs from the melting temperature of one or more other hybridized amplified nucleic acid molecules by at most 2° C. 31. The method of claim 28, wherein the at least two mutually different hybridized amplified nucleic acid molecules have melting temperatures which differ by at most 1° C. 32. The method of claim 28, wherein at least six mutually different nucleic acid molecules are simultaneously detected in the sample. 33. The method of claim 32, wherein at least eight mutually different nucleic acid molecules are simultaneously detected in the sample. 34. The method of claim 33, wherein at least twelve mutually different nucleic acid molecules are simultaneously detected in the sample. 35. The method of claim 28, wherein the mutually different nucleic acid molecules are comprised in at least two antibiotic resistance genes. 36. The method of claim 35, wherein at least one of the antibiotic resistance genes is the gene for beta-lactamase blaZ, chloramphenicol acetyltransferase, fosB protein, adenin methylase ermC, aacA-aphD aminoglycoside resistance, 3′5′-aminoglycoside phosphotransferase aphA-3, mecR, penicillin binding protein PBP2′, aminoglycoside-3′-adenyltransferase aadA, tetracycline-resistance protein tetC, DHFR DfrA, or D-Ala:D-Ala ligase vanB. 37. The method of claim 28, wherein the hybridizing reaction is carried out at 30-80° C. 38. The method of claim 37, wherein the hybridizing reaction is carried out at 40-70° C. 39. The method of claim 28, wherein the hybridizing reaction is carried out at 55-65° C. 40. The method of claim 28, wherein the hybridizing reaction is carried out under highly stringent conditions. 41. The method of claim 28, wherein the multiplex PCR is carried out with labeled probes. 25332285.1 42. The method of claim 28, further comprising the separation of “+” and “−” individual strands of the at least two mutually different amplified nucleic acid molecules prior to the hybridizing step. 43. The method of claim 42, wherein “+” individual strands of the at least two mutually different amplified nucleic acid molecules that have sequences identical to the probes are separated after the amplifying step. 44. The method of claim 43, wherein primers employed for the elongation of the “+” individual strands are coupled to a substance that ensures the separation of the “+” individual strands. 45. The method of claim 44, wherein the primers are coupled to the substance at their 5′ termini. 46. The method of claim 44, wherein the substance is at least one biotin molecule. 47. The method of claim 46, wherein the “+” individual strands are separated by means of streptavidin bound to beads. 48. The method of claim 28, further comprising purifying the at least two mutually different amplified nucleic acid molecules before the hybridizing step. 49. The method of claim 48, wherein the purification step occurs before separation of “+” and “−” individual strands of the at least two mutually different amplified nucleic acid molecules. 50. The method of claim 48, wherein the purification step occurs after separation of “+” and “−” individual strands of the at least two mutually different amplified nucleic acid molecules. 51. A microarray adapted to, during use, hybridize to amplified portions of at least two mutually different amplified nucleic acid molecules, the microarray comprising at least two mutually different probes immobilized on the microarray, wherein each probe comprises a hybridizing sequence adapted to hybridize, during use, to the amplified portion of one of at least two mutually different amplified nucleic acid molecules to produce a mutually different hybridized amplified nucleic acid molecule having a melting temperature which differs from the melting temperature of one or more other mutually different hybridized amplified nucleic acid molecules by at most 2° C. 52. The microarray of claim 51, wherein each probe comprises a hybridizing sequence adapted to hybridize, during use, to the amplified portion of one of the at least two mutually different amplified nucleic acid molecules to produce a hybridized amplified nucleic acid molecule having a melting temperature which differs from the melting temperature of one or more other hybridized amplified nucleic acid molecule by at most 1° C. 53. The microarray of claim 51, further defined as comprising at least six probes. 54. The microarray of claim 53, further defined as comprising at least twelve probes 55. The microarray of claim 51, wherein the probes are adapted to hybridize to amplified portions of mutually different nucleic acid molecules comprised in at least two antibiotic resistance genes. 56. The microarray of claim 55, wherein at least one of the antibiotic resistance genes is the gene for beta-lactamase blaZ, chloramphenicol acetyltransferase, fosB protein, adenin methylase ermC, aacA-aphD aminoglycoside resistance, 3′5′-aminoglycoside phosphotransferase aphA-3, mecR, penicillin binding protein PBP2′, aminoglycoside-3′-adenyltransferase aadA, tetracycline-resistance protein tetC, DHFR DfrA, or D-Ala:D-Ala ligase vanB. 57. The microarray of claim 51, wherein the probes are bound to the surface of the microarray in spots having a diameter of from 100 to 500 μm. 58. The microarray of claim 57, wherein the probes are bound to the surface of the microarray in spots having a diameter of from 200 to 300 μm. 59. The microarray of claim 58, wherein the probes are bound to the surface of the microarray in spots having a diameter of about 240 μm. 60. The microarray of claim 57, wherein the spots are from 100 to 500 μm apart. 61. The microarray of claim 60, wherein the spots are from 200 to 300 μm apart. 62. The microarray of claim 61, wherein the spots are 280 μm apart. 63. The microarray of claim 51, further defined as made of glass, a synthetic material, or a membrane. 64. The microarray of claim 51, wherein the probes are covalently bound to the surface of the microarray. 65. The microarray of claim 51, wherein the hybridizing sequences comprise 15 to 25 nucleotides. 66. The microarray of claim 65, wherein the hybridizing sequences comprise 20 nucleotides. 67. The microarray of claim 51, wherein the probes are bound to the microarray via dT sequences at their 5′ termini. 68. The microarray of claim 51, wherein the hybridizing sequence of at least one probe comprises a sequence of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, or SEQ ID NO:36. 69. The microarray of claim 68, wherein the hybridizing sequence of each probe comprises a sequence of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, or SEQ ID NO:36. 70. A probe set comprising at least two mutually different probes, wherein each probe comprises a hybridizing sequence adapted to hybridize, during use, to an amplified portion of one of at least two mutually different amplified nucleic acid molecules to produce a hybridized amplified nucleic acid molecule having a melting temperature which differs from the melting temperature of one or more other mutually different hybridized amplified nucleic acid molecule by at most 2° C. 71. The probe set of claim 70, further defined as comprising at least six probes. 72. The probe set of claim 71, further defined as comprising at least twelve probes. 73. The probe set of claim 70, wherein the hybridizing sequences comprise 15 to 25 nucleotides. 74. The probe set of claim 70, wherein the hybridizing sequences comprise 20 nucleotides. 75. The probe set of claim 70, wherein the probes comprise dT sequences at their 5′ termini. 76. The probe set of claim 70, wherein the hybridizing sequence of at least one probe comprises a sequence of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, or SEQ ID NO:36. 77. The probe set of claim 76, wherein the hybridizing sequence of each probe comprises a sequence of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, or SEQ ID NO:36. 78. The probe set of claim 70, wherein the probes are adapted to hybridize to amplified portions of mutually different nucleic acid molecules comprised in at least two antibiotic resistance genes. 79. The probe set of claim 78, wherein at least one of the antibiotic resistance genes is the gene for beta-lactamase blaZ, chloramphenicol acetyltransferase, fosB protein, adenin methylase ermC, aacA-aphD aminoglycoside resistance, 3′5′-aminoglycoside phosphotransferase aphA-3, mecR, penicillin binding protein PBP2′, aminoglycoside-3′-adenyltransferase aadA, tetracycline-resistance protein tetC, DHFR DfrA, or D-Ala:D-Ala ligase vanB. 80. A kit for simultaneously detecting at least two mutually different nucleic acid molecules in a sample, wherein the kit comprises: a microarray adapted to, during use, hybridize to amplified portions of at least two mutually different amplified nucleic acid molecules, the microarray comprising at least two mutually different probes immobilized on the microarray, wherein each probe comprises a hybridizing sequence adapted to hybridize, during use, to the amplified portion of one of at least two mutually different amplified nucleic acid molecules to produce a mutually different hybridized amplified nucleic acid molecule having a melting temperature which differs from the melting temperature of one or more other mutually different hybridized amplified nucleic acid molecules by at most 2° C.; and at least one container with primers for the specific amplification of nucleic acid molecules to be detected via multiplex-PCR during use. 81. The kit of claim 80, further comprising a probe set comprising at least two mutually different probes, wherein each probe comprises a hybridizing sequence adapted to hybridize, during use, to an amplified portion of one of at least two mutually different amplified nucleic acid molecules to produce a hybridized amplified nucleic acid molecule having a melting temperature which differs from the melting temperature of one or more other mutually different hybridized amplified nucleic acid molecule by at most 2° C. 82. The kit of claim 80, further comprising at least one container comprising at least one nucleic acid molecule to be detected as a positive sample. 83. The kit of claim 80, further comprising a container comprising streptavidin bound to beads. |
Ligand sensing fluorescent acetylcholinesterase for detection of organophosphate activity |
Disclosed are methods for the preparation and use of labeled AChE and labeled AChE inhibitory conjugate compositions for detecting accumulation of toxic materials such as organophosphates, insecticides, and other nerve agents. Also disclosed are methods for the use of labeled AChE and labeled AChE inhibitory conjugate compositions in a variety of areas, including the detecting of toxic materials in biological samples, in the area of food and water analysis, in environmental monitoring, and in industrial settings. |
1. An in vitro method for identifying an acetylcholinesterase (AChE) cognate partner comprising; a) contacting a sample suspected of containing a cognate partner with a labeled AChE and b) measuring accumulation of a conjugate between the AChE and the partner, wherein detection of the conjugate is indicative of the presence of the cognate partner. 2. The method of claim 1, wherein the cognate partner is selected from the group consisting of a ligand, a modulator and an inhibitor of AChE. 3. The method of claim 2, wherein the inhibitor is a carbamylating inhibitor or a phosphorylating inhibitor. 4. The method of claim 3, wherein the inhibitor is a nerve toxin. 5. The method of claim 4, wherein the inhibitor is selected from the group consisting of insecticides and organophosphates. 6. The method of claim 1, wherein the AChE is labeled with a fluorophore. 7. The method of claim 6, wherein AChE comprises at least one fluorophore. 8. The method of claim 7, wherein at least one label is peripheral to the active center of the AChE. 9. The method of claim 6, wherein the fluorophore shows a Stokes' shift upon binding of ligand, modulator or inhibitor to the labeled enzyme. 10. The method of claim 1, further comprising measuring the ratio of conjugated to unconjugated AChE. 11. The method of claim 10, wherein the measuring is by chromatography or spectroscopy. 12. The method of claim 11, wherein chromatography comprises separation of conjugated and unconjugated AChE by capillary electrophoresis. 13. The method of claim 11, wherein spectroscopy comprises detecting conjugated and unconjugated AChE by fluorescence. 14. The method of claim 6, wherein the fluorophore is selected a dimethoxyphosphoryl compound or a diethoxyphosphoryl compound. 15. A device for measuring accumulation of a conjugate between acetylcholinesterase (AChE) and a cognate partner comprising labeled AChE, wherein at least one site of the AChE is labeled peripheral to the active site of the enzyme. 16. The device of claim 15, wherein the cognate partner is selected from the group consisting of a ligand, a modulator and an inhibitor of AChE. 17. The device of claim 15, wherein the label is a fluorophore. 18. The device of claim 17, wherein the fluorophore shows a Stokes' shift upon binding of a ligand, modulator or inhibitor to AChE. 19. The device of claim 15, wherein the AChE is compartmentalized in a mobile or stationary phase. 20. The device of claim 19, wherein the mobile phase is a suspension. 21. The device of claim 19, wherein the stationary phase is a chip. 22. The device of claim 21, wherein the AChE is covalently or non-covalently immobilized on the stationary phase. 23. The device of claim 15, wherein the AChE can detect multiple AChE cognate partners. 24. The device of claim 15, wherein the cognate partner is a nerve toxin. 25. The device of claim 24, wherein the nerve toxin is selected from the group consisting of insecticides and organophosphates. 26. A labeled acetylcholinesterase (AChE) molecule comprising at least one fluorophore present at the periphery of the active site of AChE, wherein the at least one site is selected from the group consisting of residues 76, 81, 84, 124, 262 and 287 of AChE or equivalents thereof. 27. The labeled AChE of claim 26, wherein the fluorophore shows a Stokes' shift upon binding of a ligand to the labeled enzyme. 28. The labeled AChE of claim 26, wherein the enzyme is recombinantly produced. 29. The labeled AChE of claim 28, modified by mutagenesis or evolution methods, wherein the modification comprises substitution of one or more selected amino acid residues with cysteine residues. 30. The labeled AChE of claim 26, wherein the fluorophore is a dimethoxyphosphoryl compound or a diethoxyphosphoryl compound. 31. The labeled AChE of claim 30, wherein the enzyme is conjugated to an inhibitor. 32. The labeled AChE of claim 31, wherein the conjugate is detectable by antibody. 33. A conjugate comprising a labeled acetylcholinesterase (AChE) molecule, an inhibitor of AChE and an antibody. 34. A method for evaluating the presence of an inhibitor of acetylcholinesterase (AChE), wherein the inhibitor is selected from the group consisting of carbamates and organophosphates, comprising the steps of: a) providing a biological sample; b) contacting the sample with a labeled AChE molecule comprising at least one fluorophore present at the periphery of the active site of the enzyme under conditions sufficient for binding of an inhibitor to the enzyme; and c) measuring accumulation of a conjugate between the AChE and the inhibitor. 35. The method of claim 34, wherein the biological sample is selected from the group consisting of an integumentary system sample, sputum, feces, blood, urine, plasma, lacrimal secretions, cerumen, and semen. 36. The method of claim 35, wherein the inhibitor is a carbamylating inhibitor. 37. The method of claim 35, wherein the inhibitor is a phosphorylating inhibitor. 38. The method of claim 34, wherein the inhibitor is a nerve toxin. 39. The method of claim 34, wherein in the fluorophore shows a Stokes' shift upon binding of a ligand, modulator or inhibitor to the labeled enzyme. 40. The method of claim 34, further comprising measuring the ratio of conjugated to unconjugated AChE. 41. The method of claim 40, wherein the measuring is by chromatography or spectroscopy. 42. The method of claim 41, wherein chromatography comprises separation of conjugated and unconjugated AChE by capillary electrophoresis. 43. The method of claim 41, wherein spectroscopy comprises detecting conjugated and unconjugated AChE by fluorescence. 44. The method of claim 34, comprising a labeled AChE, wherein the fluorophore is a dimethoxyphosphoryl compound or a diethoxyphosphoryl compound. 45. A method for evaluating the presence of an inhibitor of acetylcholinesterase (AChE), wherein the inhibitor is selected from the group consisting of carbamates and organophosphates, comprising the steps of: a) providing a non-biological sample; b) contacting the sample with a labeled AChE molecule comprising at least one fluorophore present at the periphery of the active site of the enzyme under conditions sufficient for binding of an inhibitor to the enzyme; and c) measuring accumulation of a conjugate between the AChE and the inhibitor. 46. The method of claim 45, wherein the non-biological sample is selected from the group consisting of soil, water, air and non-biological surfaces. 47. The method of claim 46, wherein the inhibitor is a carbamylating inhibitor. 48. The method of claim 46, wherein the inhibitor is a phosphorylating inhibitor. 49. The method of claim 45, wherein the inhibitor is a nerve toxin. 50. The method of claim 45, wherein in the fluorophore shows a Stokes' shift upon binding of an inhibitor to the labeled enzyme. 51. The method of claim 45, comprising measuring the ratio of conjugated to unconjugated AChE. 52. The method of claim 51, wherein the measuring is by chromatography or spectroscopy. 53. The method of claim 52, wherein chromatography comprises separation of conjugated and unconjugated AChE by capillary electrophoresis. 54. The method of claim 52, wherein the spectroscopy comprises detecting conjugated and unconjugated AChE by fluorescence. 55. The method of claim 45, wherein the fluorophore is a dimethoxyphosphoryl compound or a diethoxyphosphoryl compound. 56. A kit comprising: a) a labeled acetylcholinesterase (AChE) molecule comprising at least one fluorophore present at the periphery of the active site of AChE and b) a container comprising the labeled enzyme. 57. The kit of claim 56, wherein the container is selected from the group consisting of a glass vial, a glass jar, a plastic pack, a plastic tube, glass tube, a metal tube, a foil pouch and a plastic pouch. 58. The kit of claim 56, wherein the labeled AChE is immobilized on a microtitre plate or a chip. 59. The kit of claim 56, further comprising: c) a control sample. 60. The kit of claim 59, wherein the control sample is a negative control sample. 61. The kit of claim 59, wherein the control sample is a positive control sample. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention This invention relates generally to the field of detecting hazardous chemicals and chemical analysis, to include portable automatic sensing devices. More particularly, the present invention relates to methods, compositions, devices and kits thereof useful in the detection of chemical agents, insecticides and other acetylcholinesterase (AChE) inhibitors, modifiers and ligands. 2. Background Information Acetylcholinesterase (AChE), a serine hydrolase in the α/β-fold hydrolase protein superfamily, terminates nerve signals by catalyzing hydrolysis of the neurotransmitter acetylcholinesterase at a diffusion-limited rate. A number of nerve toxins, including insecticides and organophosphates, act through binding to and inhibiting AChE. Organophosphorus and organosulfur compounds, are used extensively in insecticides and are highly toxic to many organisms including humans. Insecticide residues are found in soil and groundwater, and the detection of these residues is important for their elimination from the environment and to protect the health of both humans and animals. Organophosphorus compounds are also used in nerve agents, such as sarin, phosphine, soman, and tabun, for chemical warfare purposes. These agents are some of the most potent toxic agents and are specific inhibitors of acetylcholinesterase (AChE). Acetylcholine is an essential neurotransmitter that affects parasympathetic synapses (autonomic and CNS), sympathetic preganglionic synapses, and the neuromuscular junction (see, e.g., Taylor et al., in Basic Neurochemistry, 5th ed., 1993, (Siegal et al., eds.), Chapter 11, pp. 231-260, Raven Press, New York, N.Y.). Hydrolysis of acetylcholine by acetylcholinesterase, present in nervous tissue, normally limits the duration of action function. Organophosphate (e.g., Malathion, Parathion, Diasinon, Dursban) and carbamate (e.g., Sevin, Furadan) insecticides exert their toxicity by inhibiting the action of acetylcholinesterase and thereby causing a pronounced cholinergic response (Arron et al., Insecticides: Organophosphate and Carbamates in Goldfrank's Toxicologic Emergencies, 1994, (Goldfrank et al., eds.), Appleton & Lange, Norwalk, Conn.). Enzyme inhibition is the consequence of phosphorylation (organophosphates) or carbamylation (carbamates) of the cholinesterase-active site serine residue. The resulting phosphoroyl-serine bond is stable; therefore, enzyme inhibition is physiologically irreversible, whereas the carbamyl-serine bond undergoes spontaneous hydrolysis with regeneration of enzyme activity (24-48 h). For this reason and because of poor CNS penetration, carbamate insecticide neurotoxicity is less severe and of shorter duration than that for the organophosphates ( Tietz Textbook of Clinical Chemistry, 1999, (Burtis et al., eds.), W. B. Saunders Company, Philadelphia, Pa.). Excess synaptic acetylcholine stimulates muscarinic receptors (peripheral and CNS) and stimulates but then depresses and paralyzes nicotinic receptors. The CNS neurotoxic effects include restlessness, agitation, lethargy, confusion, slurred speech, seizures, coma, cardiorespiratory depression, or death. The need for the reliable determination of these cholinesterase inhibitors has led to the development of a number of sophisticated instrumental methods, mostly involving the use of gas and liquid chromatography and mass spectrometry. Also a number of liquid phase chemiluminescence procedures have been developed for the determination of inorganic and organic species mostly utilizing the luminol and peroxyoxalate reactions. See Robards K. and Worsfold P. J., Anal Chem Acta (1992) 266:147. These traditional methods are not practical for individual use as the methods are time consuming and complicated and the instruments utilized are expensive, non-portable and require high maintenance. Additionally, the measurement of nerve agents in mixtures with these traditional methods requires cumbersome extraction and manipulation procedures. Thus, biosensors were developed as an alternative to the traditional gas and liquid chromatography and mass spectrometry technology. Generally, biosensors include those which are enzyme-based and bioaffinity-based. An enzymatic biosensor uses an enzymatic or metabolic process to detect a reaction product which occurs between an incoming substrate and an immobilized enzyme. A bioaffinity sensor relies on a biological binding event of a target substance. Many existing methods for the detection of organophosphates and cumulative inhibition of cholinesterases lack sensitivity since they are based on inhibition of basal activities rather than accumulation of the inhibitory conjugate. Basal activities vary substantially between subjects resulting in inconsistency in present assays. Existing monitoring methods routinely require expensive laboratory procedures involving sample transport or preparations of samples for assay. Rapid analysis of toxic materials in the areas of food and water analysis, environmental monitoring, and in industrial settings is a problem that continues to exist and is currently addressed by time-consuming, expensive methods or by techniques that may be described as inadequate. Many problems associated with exposure to toxic materials could be avoided or minimized by a detection procedure which gives near “real-time” indication of the presence of toxic gases. Equally important are the characteristics of economy, small size, and ease of use for the successful application of such devices. Accordingly, there is a need for a method of detecting, quantifying, and evaluating hazards which provides for early detection and which can detect low levels of toxic materials. The present invention satisfies this need, as well as others. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention overcomes one or more of the drawbacks in the prior art by providing compositions and methods for their use in the detection of specific inhibitors, modifiers, or ligands of acetylcholinesterase (AChE). Disclosed are methods for the preparation and use of labeled AChE and labeled AChE inhibitory conjugate compositions which are useful in detecting accumulation of toxic materials, which include but are not limited to, organophosphates, insecticides, nerve agents, such as sarin, phosphine, soman, and tabun, and other materials used for chemical warfare purposes. Also disclosed are methods for the use of labeled AChE and labeled AChE inhibitory conjugate compositions in a variety of areas, including the detecting of toxic materials in biological samples, the areas of food and water analysis, environmental monitoring, and in industrial settings. Embodiments are disclosed which describe methods for making and using labeled AChE and labeled AChE inhibitory conjugate compositions comprising fluorescing compounds, including but not limited to, dimethoxyphosphoryl and diethoxyphosphoryl labels. In one embodiment of the invention, methods are disclosed for measuring accumulation of inhibitory conjugates comprising labeled AChE and an inhibitor, modulator or ligand (i.e., cognate partner). In a related aspect, such methods may comprise contacting a sample suspected of containing such cognate partners with labeled AChE in order for labeled AChE binding to occur between cognate partners in the sample and the enzyme. In a further related aspect, conjugated and unconjugated AChE may be separated by chromatographic methods. For example, such chromatographic methods may include, but are not limited to, capillary electrophoresis. In another embodiment, the conjugated and unconjugated, labeled AChE are detected and differentiated by fluorochromic emission shift, where conjugated AChE shows a detectable shift in emission signal. In a related aspect, the shift in emission is a Stokes' shift upon conjugate formation. In a related aspect, the cognate partner is an inhibitor, where the inhibitor may be designated as a carbamylating inhibitor or a phosphorylating inhibitor. In a further related aspect, the inhibitor may be an insecticide or an organophosphate. In another related aspect, the presence of the cognate partner is estimated by determining the ratio of conjugated to unconjugated AChE. In another embodiment, the sample may be obtained from the atmosphere, soil, water, industrial sites or environmental sites. Further, the sample may be biological or non-biological. In a related aspect, a biological sample may include, but is not limited to, the integumentary system, sputum, feces, blood, urine, plasma, lacrimal secretions, cerumen, and semen. In one embodiment, the AChE is labeled on at least one site. In a related aspect, the AChE is labeled at multiple sites. In a further related aspect, the at least one label is peripheral to the active center of the AChE. In one embodiment, a device comprising AChE is envisaged, where the AChE is compartmentalized in a mobile or stationary phase. In a related aspect, the stationary phase is a chip. In another related aspect, the mobile phase is a suspension. In one embodiment, the device is a biosensor for analyzing a sample for at least one organophosphorous, nerve agent and/or insecticide, where at least one enzyme is immobilized on or within the device. In a related aspect, the immobilized enzyme is either covalently or non-covalently bound to the device. In a further related aspect, the biosensor is divided into multiple zones, where each zone differentiates between one or more organophosphorous, nerve and/or insecticide agents. In another embodiment, the present invention also provides kits which contain the present labeled AChE for use in the present identification method. In another embodiment, a labeled AChE composition comprising at least one fluorophore located peripherally to the active center of the AChE, where the at least one fluorophore possesses an emission signal that shows a Stokes' shift upon conjugate formation. In a related aspect, the fluorophore comprises a dimethoxyphosphoryl label or a diethoxyphosphoryl label. In another embodiment, a labeled AChE molecule comprises at least one fluorophore on at least one site present at the periphery of the active site of the enzyme, wherein the at least one site is selected from the group consisting of residues 76, 81, 84, 124, 262 and 287 of AChE or equivalents thereof. Exemplary methods and compositions according to this invention, are described in greater detail below. |
Information processing apparatus and method, and storage medium |
A secure connection between the main unit of a portable information device and a peripheral device via a wireless network is ensured by using an electronic seal that makes it possible to transmit an encryption key to the portable information terminal and the peripheral device thereof by an operation which is analogous to “seal affixing” by a user confirmed as an authorized user. For example, user confirmation is performed by an authentication technology using biometric information, such as “fingerprint authentication”. After the portable information terminal and the peripheral device thereof perform mutual recognition, they can perform secure mutual communication via a wireless network, etc., by using the encryption key provided via the electronic seal. |
1. An information processing apparatus for outputting an encryption key to an authorized user, said information processing apparatus comprising: biometric information input means for inputting biometric information of a user; encryption key generation means for generating an encryption key in response to an input of biometric information; encryption key registration means for storing the encryption key so as to be associated with the biometric information of a user; and encryption key output means for permitting an output of the encryption key as a result of the input biometric information matching the registered biometric information of a user. 2. An information processing apparatus according to claim 1, wherein said biometric information is a fingerprint of the user. 3. An information processing apparatus according to claim 1, wherein said encryption key output means extracts the encryption key from said encryption key registration means and outputs the encryption key in response to a seal-affixing operation of contacting an output target device. 4. An information processing apparatus according to claim 1, further comprising encryption key re-registration means for permitting generation of the encryption key and a re-registration thereof in said encryption key registration means. 5. An information processing apparatus for securely performing data communication with another device, said information processing apparatus comprising: private key receiving means for receiving a private key authenticated based on biometric information of a user; mutual recognition means for performing mutual recognition of whether another device with which communication is performed possesses the same private key; and data communication means for performing data communication, which is encrypted using the mutually recognized private key. 6. An information processing apparatus according to claim 5, wherein said private key receiving means receives the private key in response to a seal-affixing operation of contacting a device on a private key output side. 7. An information processing apparatus according to claim 5, wherein said mutual recognition means performs mutual recognition by a technique of confirming the private key possessed by the other device without knowing the key itself. 8. An information processing method for outputting an encryption key to an authorized user, said information processing method comprising: a biometric information input step of inputting biometric information of a user; an encryption key generation step of generating an encryption key in response to an input of biometric information; an encryption key registration step of storing the encryption key so as to be associated with the biometric information; and an encryption key output step of permitting output of the encryption key as a result of the input biometric information matching the registered biometric information. 9. An information processing method according to claim 8, wherein said biometric information is a fingerprint of the user. 10. An information processing method according to claim 8, wherein, in said encryption key output step, the encryption key stored in said encryption key registration step is output in response to a seal-affixing operation of contacting an output target device. 11. An information processing method according to claim 8, further comprising an encryption key re-registration step of permitting generation of the encryption key and re-registration thereof as a result of the input biometric information matching the registered biometric information. 12. An information processing method for securely performing data communication with another device, said information processing method comprising: a private key receiving step of receiving a private key authenticated based on biometric information of a user; a mutual recognition step of performing mutual recognition of whether another device with which communication is performed possesses the same private key; and a data communication step of performing data communication, which is encrypted using the mutually recognized private key and. 13. An information processing method according to claim 12, wherein, in said private key receiving step, the private key is received in response to a seal-affixing operation of contacting a device on a private key output side. 14. An information processing method according to claim 12, wherein, in said mutual recognition step, mutual recognition is performed by a technique of confirming the private key possessed by the other device without knowing the key itself. 15. A storage medium having stored thereon in a computer-readable form, computer software described so as to execute processing for outputting an encryption key to an authorized user on a computer system, said computer software comprising: a biometric information input step of inputting biometric information of a user; an encryption key generation step of generating an encryption key in response to an input of biometric information; an encryption key registration step of storing the encryption key so as to be associated with the biometric information; and an encryption key output step of permitting output of the encryption key as a result of the input biometric information matching the registered biometric information. 16. A storage medium having stored thereon in a computer-readable form, computer software described so as to execute processing for securely performing data communication with another device on a computer system, said computer software comprising: a private key receiving step of receiving a private key authenticated based on the biometric information of a user; a mutually recognizing step of performing mutual recognition of whether a device of a communication party possesses the same private key; and a data communication step of performing data communication, which is encrypted using the mutually recognized private key. |
<SOH> BACKGROUND ART <EOH>Along with improvements in semiconductor manufacturing technology, electronic devices have become increasingly smaller, and various types of portable information devices, such as notebook computers, PDAs (Personal Digital Assistants), and cellular phones have appeared. These types of portable information device are driven by the supply of electricity from a battery incorporated in the main unit of the device, and are used in a mobile environment, that is, outdoors or at the location of the user. There has been an increasing demand for portable information devices to be equipped with various peripheral devices (for example, a position detecting device such as GPS (Global Positioning System), and user input/output devices such as a microphone, a speaker, a head set, and a keyboard) so as to expand the functions. Hitherto, it has been common practice to meet such needs for expanding the functionality of the main unit of the device by providing the main unit of the device with a space for housing and connecting peripheral devices, such as an expansion slot and a card slot. However, in order to maintain the portability, which is the most striking feature of portable information devices, the occupied volume, the weight, the power consumption, etc., of a device connected to the slot must be strictly limited. For this reason, the number of devices which can be connected to the main unit of the device is greatly limited, and thus it is not possible to satisfactorily meet the function expansion demanded by the user. In order to avoid such a limitation, recently, it has been proposed that the expansion of functions be realized by the main unit of the device communicating with a peripheral device via a wireless network. When devices are wirelessly connected to one another, there are secondary effects, for example, there is no need to use cables and therefore the desktop remains tidy, and there is no mechanical damage of connectors due to the mounting/removal of devices. When compared to a case in which connection among devices is made using cables, in a case where connection is made by a wireless network, the relationships regarding which portable information device corresponds to which peripheral device becomes difficult to keep track of. In particular, in a working environment where a plurality of portable information devices are clustered together, in order to maintain a normal operation in each information device even if a plurality of users come close to one another, a scheme whereby individual peripheral devices are capable of specifying the portable information device which is currently connected or the user thereof is necessary. Though the portable information device has a high economic value due to its high-function computing performance, since it can be easily carried, the risk of encountering loss or theft is high. Therefore, sufficient care must be paid so that the security of the entire system is tot degraded considerably. In a working environment in which devices are connected to one another by a wireless network, including the case in which the functions of an information device are expanded, such user specification is required often. For example, in order that the information device is used as part of a cellular phone system, various technologies having functions for specifying a user while eliminating various types of abuse, including wiretapping, have already been proposed; however, their development is still in progress. However, most existing techniques regarding the security of devices are presupposed on the intervention of special devices which provide network functions, for example, communication devices disposed in a base station. Due to such presupposed conditions, it is not possible to apply the above-described wireless network technology to security on a network which includes not only simple peripheral devices which simply operate in accordance with instructions from a portable information device, but also active devices capable of issuing instructions to another type of expansion device or portable information device. When data communication is performed between two or more information devices, encryption technology is generally used. That is, a device on the transmission side sends transmission data after encrypting the data, and a device on the receiving side decrypts the received data, and thereafter, uses the data for further processing. However, in order to use the encryption method, an encryption key must be shared between both devices. In a usage environment where the connection relationship between devices is fixed and stationary, secure data communication can be realized relatively easily by providing an encryption key to be shared, to both devices at the transmission and receiving sides and by providing the encryption key securely at a place which is protected by means of hardware. In contrast, the connection relationship between devices is not fixed, as with a portable information device and peripheral devices which expand the functions thereof, and for example, each time the user of the device moves, the connection relationship with the peripheral device varies dynamically. In such a usage environment where the connection relationship is dynamic and variable, the encryption key provided to the portable information device and the peripheral devices thereof (or the encryption key shared between the devices) is merely temporary, that is, it can be used only while the connection relationship continues, and when the next connection relationship is established, a new encryption key must be provided. In a case where the encryption key is made to be valid in any connection relationship between devices, it is difficult to crack down on re-use of the encryption key, and the encryption key can no longer function as an encryption key. Furthermore, if an unauthorized person can provide an encryption key to both a portable information device and a peripheral device for which a connection relationship is newly established, commonly called “posing” is permitted, and security on the wireless network is lost. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a block diagram schematically showing the functional configuration of an information processing apparatus 10 according to an embodiment of the present invention, which is capable of functioning as an “electronic seal”. FIG. 2 is a block diagram schematically showing the functional configuration of a portable information device 30 for which seal affixing by an electronic seal is to be received, and a peripheral device 50 which expands the functions thereof. FIG. 3 is a flowchart showing a series of processing procedures for registering a user of the electronic seal and for generating a key for the user. FIG. 4 is a flowchart showing a series of processing procedures for re-registering a user of the electronic seal and for generating a key for the user. FIG. 5 is a flowchart showing a series of processing procedures which is executed between the information processing apparatus 10 and another device (the portable information device 30 , the peripheral device 50 , etc.), for performing a seal-affixing procedure. FIG. 6 is a flowchart showing a processing procedure for examining the matching of a private key by Fiat-Shamir recognition. detailed-description description="Detailed Description" end="lead"? |
Chain branching agent and polyamide composition containing the same |
The invention relates to a chain branching agent containing anhydride groups, which chain branching agent contains. (a) 5-75 mass % of a copolymer of at least an unsaturated dicarboxylic acid or a derivative thereof and a vinyl aromatic monomer; (b) 5-75 mass % of a copolymer of acrylonitrile and a vinyl aromatic monomer, (c) 0-80 mass % of an inert processing aid; and (d) 0-10 mass % customary additives; and in which (a) and (b) are miscible, the ratio (a)/(b) is from 1/3 to 3/1, and the total of (a)+(b)+(c)+(d) is 100%. Advantages of this chain branching agent in the preparation of, for instance, a polyamide composition with non-Newtonian melt flow behaviour include better reproducibility and strongly decreased formation of gel particles. The invention also relates to processes for the preparation of a chain branching agent and of a polyamide composition with non-Newtonian melt flow behaviour as well as to the use of such a polyamide composition for the manufacture of moulding articles. |
1. Chain branching agent containing anhydride groups, characterized in that the chain branching agent consists of (a) 5-75 mass % of a copolymer of at least an unsaturated dicarboxylic acid or a derivative thereof and a vinyl aromatic monomer; (b) 5-75 mass % of a copolymer of acrylonitrile and a vinyl aromatic monomer; (c) 10-80 mass % of a homo- or copolymer of ethylene or propylene; and (d) 0-10 mass % customary additives; and in which (a) and (b) are miscible, the ratio (a)/(b) is from 1/3 to 3/1, and the total of (a)+(b)+(c)+(d) is 100%. 2. Chain branching agent according to claim 1, in which (a) is a copolymer of maleic anhydride and styrene and (b) is a copolymer of acrylonitrile and styrene. 3. Chain branching agent according to claim 1, which contains 40-80 mass % (c). 4. Chain branching agent according to claim 1, which contains 10-30 mass % (a) and 10-30 mass % (b). 5. Chain branching agent according to claim 1, in which (a) and (b) contain 10-35 mass % maleic anhydride and acrylonitrile, respectively. 6. Chain branching agent according to claim 1, in which (a) and (b) contain 20-30 mass % maleic anhydride and acrylonitrile, respectively. 7. Chain branching agent according to claim 1, in which the ratio (a)/(b) lies between 2/1 and 1/2. 8. Chain branching agent according to claim 1, in which the inert processing aid is a thermoplastic polyolefin. 9. Chain branching agent according to claim 8, in which the processing aid is a low-density polyethylene. 10. Process for preparing a chain branching agent according to claim 1, in which the components (a)-(d) are melt mixed and then formed into a granulate. 11. Process for preparing a polyamide composition with non-Newtonian melt flow behaviour, which comprises melt mixing a polyamide having a lower viscosity and substantially Newtonian melt flow behaviour is melt mixed with a chain branching agent containing anhydride groups according to claim 1, and optionally other additives. 12. Process according to claim 11, wherein the polyamide is a PA 6, PA 66, PA 46 or a copolyamide thereof. 13. Process according to claim 11, wherein the polyamide has an amine groups content of at least 20 meq/kg. 14. Process according to claim 11, wherein an amount of chain branching agent is used such that the polyamide composition has a content of component (a) of 0.01-6 mass % (relative to the polyamide). 15. Process according to claim 11, which further comprises melt-mixing at least 15-40 mass % glass fibre as additive. 16. Polyamide composition obtainable with a process according to claim 11. 17. Polyamide composition with non-Newtonian melt flow behaviour containing a polyamide, such an amount of chain branching agent according to claim 1 that the content of component (a) is 0.01-6 mass % (relative to the polyamide), and 0-60 mass % other additives. 18. A method for the manufacture of a part or moulded article comprising injection moulding or extruding a polyamide composition according to claim 16. 19. A method according to claim 18, which comprises forming said part by extrusion blow moulding said polyamide composition. 20. Process for the preparation of a moulded article in which at least two parts are bonded together by means of a welding technique, wherein at least one of the parts substantially consists, at least at the location of a surface to be welded, of said polyamide composition. 21. Process according to claim 20, in which all parts substantially consist of said polyamide composition. 22. Process according to claim 20, wherein vibration welding is used as the welding technique. 23. A molded article obtainable with the process according to claim 20. 24. A molded article according to claim 23 for use in the automotive industry, such as a convoluted tube, a bellows, a liquid container, a component of the fuel system, an air-inlet manifold or an air duct. |
Mobile advertising methods and improvements |
Mobile advertising methods and improvements, for instance, the adding of global positioning satellite tracking devices to mobile advertising platforms for purposes of verification of location, travel routes, mileage, etc. Incorporation of the Internet, Intranet, peer-to-peer and/or other networking systems and associated software for improving business methods, account access, and the interface between the advertiser or client, the ad agency or administration, and those persons or entities associated with the mobile platforms. Providing wireless communication systems for mobile advertising platforms for enabling real-time messages and for real-time interaction and/or for connecting central or distributed service operations. Providing improved compensation particularity to those persons or entities associated most closely with the mobile platforms. Incorporation of video and/or still e-cameras and/or audio equipment into the mobile advertising platform. |
1. Improved method of advertising via non-common carrier automobiles by providing adequate compensation to the persons or entities associated with the vehicles, whereby for example only, ideally a person or person and car, etc., in a desired target market, which also conforms with possible other client/sponsor or agency desired parameters, might list him/herself as available, might request, be requested, or might even bid to contract to provide advertising via their vehicle, and in exchange receive adequate compensation in one or more forms. 2. Improved method of advertising via automobiles by providing an onboard or portable location device, such as a GPS device, whereby for example only, a global positioning satellite system device (“GPS” device) might either communicate various related data in real-time and/or record such data for down loading periodically. 3. Improved method of advertising via automobiles by providing one or more onboard or portable wireless communication systems or devices for improved up-dating of the ad message, spot location advertising, and for other communication purposes, whereby for example only, such wireless device may be used to update, on a real-time, live or down loadable basis, the advertising media or other information in order to for instance change to a new ad as the vehicle approaches a client's store, or for instance to issue a warning to other drivers of an accident ahead, and such communication system may be integrated or not integrated or associated with the GPS system. 4. Improved method of advertising via automobiles by providing an Internet, Intranet, peer-to-peer, or other networking and software systems, as an significant communication and business interface between the ad agency and the persons associated with the vehicles, whereby for example only, a comprehensive business tool consisting of computer hardware, mobile and stationary devices and appropriate software so that, for instance persons interested in signing up as potential ad drivers may review criteria, contracts and other information, potential clients may review advertising plans and rates, and data from various sources may be entered, such as when the car is fueled and the GPS data, payments, etc., and established clients and ad drivers may access their accounts. 5. Improved method of advertising via automobiles by providing one or more onboard or portable video or still cameras, with or without an audio pickup, whereby for example only, such camera captured data may be recorded and stored and/or be transmitted in real-time or by streaming video for various purposes, for instance traffic updates, accidents, and route, parking, delivery/location verification, special events, etc. 6. A comprehensive method of advertising via automobiles, the method comprising the following steps: a) providing adequate compensation to the person associated with the vehicle; b) providing an onboard or portable vehicle location device. 7. A comprehensive method of advertising via automobiles, the method comprising the following steps: a) providing adequate compensation to the person associated with the vehicle; b) providing the Internet, Intranet, or other such networking system as a communication and/or business interface between the ad agency and persons. 8. A comprehensive system regarding the business methods of providing advertising via automobiles, the methods comprising the following steps: a) providing the Internet, Intranet, or other networking system as a communication and/or business interface between the ad agency and persons. b) providing adequate compensation to the person associated with the vehicle. 9. Improved method of advertising via mobile platforms by providing adequate compensation to the person associated with the platform, whereby for example only, ideally a person or person carried platform, etc., in a desired target market, whom/which also conforms with other client/sponsor or agency desired parameters, might list him/herself as available, might request, be requested, or might even bid to contract to provide advertising via their body or personally carried platform, and in exchange receive adequate compensation in one or more forms. 10. Improved method of advertising via mobile platforms, by providing an onboard or portable location device, whereby for example only, said location device, such as a global positioning satellite system device (“GPS” device) might either communicate various related data in real-time and/or record such data for down-loading periodically. 11. Improved method of advertising via mobile platforms by providing one or more wireless communication systems or devices, whereby for example only, such wireless device may be used to update, on a real-time, streaming or down loadable basis, the advertising media or other information in order to, for instance, change ad copy/messages as the mobile platform approaches a client's store, or for instance, to issue a warning to others of some hazard, and such communication system may be integrated or not integrated or associated with other systems. 12. Improved method of advertising via mobile platforms, by providing the Internet, Intranet, peer-to-peer or other networking and software systems as an significant communication and business interface between the ad agency and persons, whereby for example only, a comprehensive business tool consisting of computer hardware, mobile and stationary devices and appropriate software so that, for instance, persons interested in signing up as potential mobile platform carriers, etc., may review criteria, contracts and other information, potential clients may review advertising plans and rates, and data from various sources may be entered, such as when the platform is delivering its message, GPS data, payments, etc., and established clients and ad persons may gain access to their private access account information, etc. 13. Improved method of advertising via mobile platforms, by providing one or more onboard or video and/or still cameras, with or without an audio pickup, whereby for example only, such camera captured data may be recorded and stored and/or be transmitted in real-time or by streaming video for various purposes, for foot traffic updates, store coverage, and routes, delivery and location verification, special events, etc. 14. A comprehensive method of advertising via mobile platforms, the method comprising the following steps: a) providing adequate compensation to the person associated with the platform; b) providing an onboard or portable platform location device, such as a GPS device. 15. A comprehensive method of advertising via mobile platforms, the method comprising the following steps: a) providing adequate compensation to the person associated with the platform; b) providing the Internet, Intranet, or other networking system as a communication and/or business interface between the ad agency, etc. and platform persons. 16. A comprehensive system regarding the business methods of providing advertising media via mobile platforms, the methods comprising the following steps: a) providing the Internet, Intranet, peer-to-peer or other networking system as a communication and/or business interface between the ad agency and/or other administrative organization and the platform persons; b) providing adequate compensation to the persons associated with the platforms. |
<SOH> BACKGROUND <EOH>1. Field of Invention This invention relates generally to new or improved methods relating to advertising on mobile platform mobile advertising and mobile information business and methods (together, herein meaning “advertising”, “advertisements”, “ads” or “adverts”). The word “method” herein will generally be used in place of one or more of the following terms: advertising services, business services, business concepts, mobile advertising processes, business method, business model, etc. These improvements and new methods are accomplished through the inventive integration and/or mixing and matching of various new and existing mobile platforms, the Internet, software, wireless devices, incentives, compensation, communication systems, location technology such as GPS, and methods and/or by the inventive overcoming of serious limitations related to the prior art of mobile advertising. Although this application will primarily apply to mobile advertising platforms, other platforms and methods are included when the inventive combinations and/or new methods herein proposed are applicable. 2. Description of Prior Art Although not so limited, this invention generally relates to mobile platforms used for advertising, such as automobiles (herein, the word “car” may refer to vehicles, trucks, motorcycles, scooters, etc.) boats, planes, bikes, skateboards, signs, phones, PDAs, game and gaming platforms, appliances, computers, living beings, articles of clothing, toys, etc. (these and other related mobile platforms, herein may be referred to as simply “mobile platforms”). Examples of prior art are taxi and bus ads, signs on company owned cars, airplanes pulling ad banners, bumper stickers, license plate frames, dealership logos, race and other cars with sponsorship ads, hats, clothing, etc. These examples represent three common financial models of mobile platform advertising: a. volunteer, i.e., wearing your favorite baseball team's cap, branded shoes, a civic ad (“give blood”, etc.) on a tee shirt, etc.; b. sponsored ads, i.e., race cars, etc.; c. paid mobile platform advertising, i.e., taxi ads, moving billboards, etc. A paid example that will be used herein, is commuter cars whose owners contract with advertising firms, etc. to use their car as a mobile advertising platform in exchange for significant valuable compensation. The general concept of actually paying money to car owners for placing advertisements on their cars may not be new. Reportedly, starting in 1972, a company named Beetleboards paid VW bug car owners about $20 USD per month to place advertising on their Volkswagen cars. In addition to the low monetary compensation, the VW bug owners apparently also benefited from an exclusive “bug club” or Beetleboard membership effect that encouraged them to sport the third partly advertising arranged by the Beetleboard’ company. Apparently, the belonging to the bug ad club effect did not spread to other makes of cars. As the popularity of owning VW bugs died off so did the Beetleboard advertising business. Herein, the “prior art” means, the prior art, prior to the inventor's press publications, related articles, Website and his provisional patent filing. Although not intended to list all the disadvantages related to the prior art, generally the prior art advertising methods and/or platforms present one or more of the following disadvantages or limitations: a) low or too little monetary or other compensation to the platform owner, i.e., “free” bumper stickers, printed tee shirts, antenna balls, hats, etc.; b) no tracking of the amount of public exposure (herein may mean the target audience, etc.) i.e., a bumper sticker could be removed within hours or days, and a tee shirt may never be worn, and a taxi could be in the shop for repairs, etc.; c) no location tracking for mobile platforms, i.e., lack of GPS, etc., enabled mobile platforms; d) limited real-time interactive advertising; e) no or limited automatic inventory and/or automatic and/or interactive replacement ordering platforms or systems; f) no or limited live or real-time updates and live or down loadable changes to the ad copy; g) mostly visual ads; h) limited video and streaming video; i) a very limited variety of platforms; j) no interactive shopping handheld or basket attached PDAs to provide in store or in mall or in car specials, ads, suggestions, recipes, reminders for additional related items, etc.; k) no or limited use of RF and IR technologies; l) no physical interaction technology; m) no or limited artificial intelligence (“AI”) technology used; n) little or no instant public or target audience feedback to the advertising message; o) limited to the use of two of the five human senses. |
<SOH> SUMMARY <EOH>In accordance with the present invention, improvements, various methods and various combinations of apparatus and/or technology for mobile advertising are disclosed. Herein, the proposed improvements, combination of improvements, various methods, models, concepts and combinations of such and combinations of apparatus and/or technology, may be referred to simply as “methods”. detailed-description description="Detailed Description" end="lead"? |
Peptide-chelate conjugates |
A peptide-chelate with affinity for the ST receptor is disclosed, wherein the chelate is tetradentate. The peptide-chelate conjugate of the invention may be labelled with a radiometal to provide a metal complex. A radiopharmaccutical composition comprising the metal complex is provided, which is suitable for the diagnostic imaging of colorectal cancer. Also provided for in the invention is a kit for the preparation of the radiopharmaceutical preparation. |
1) A peptide-chelate conjugate comprising a peptide having affinity for the ST receptor conjugated to a tetradentate chelating agent, wherein the peptide having affinity for the ST receptor comprises 10 to 25 amino acids. 2) The peptide-chelate conjugate of claim 1 wherein the peptide having affinity for the ST receptor comprises 13 to 19 amino acids. 3) The peptide-chelate conjugate of claim 1 where the tetradentate chelating agent is chosen from diaminedioximes, N3S ligands, N4 ligands, diaminediphenols and N2S2 ligands. 4) The peptide-chelate conjugate of claim 1 where the tetradentate chelating agent is chosen from diaminedioximes and N3S ligands. 5) The peptide-chelate conjugate of claim 1 where the tetradentate chelating agent comprises ligands which deprotonate at basic pH to allow binding of 99mTc. 6) The peptide-chelate conjugate of claim 1 where the tetradentate chelating agent is of formula A: where R1-R6 are all CH3 and Q is —(CH2)2NR(CH2)2— and wherein R is an R group as defined for Formula (A) in claim 1. 7) The peptide-chelate conjugate of claim 1 where the tetradentate chelating agent is of formula B: where R1 and R2 are both H and X is a thiol protecting group. 8) The peptide-chelate conjugate of claim 1 where the peptide is chosen from SEQ ID Nos. 1 to 6 and FF—(CH2)5-SEQ ID No. 7. 9) The peptide-chelate conjugate of claim 1 where the conjugation is either at the N-terminus or at the C-terminus of the peptide. 10) The peptide-chelate conjugate of claim 1 which further comprises a linker group between the peptide and the tetradentate chelating agent. 11) The peptide-chelate conjugate of claim 10 where the linker group comprises a peptide sequence of 5 to 9 amino acids. 12) The peptide-chelate conjugate of claim 10 where the linker group is selected from -poly-Lys-, -poly-Glu-, -(Gly)2-Glu-(Lys)3-, (Gly)2-Glu-Lys-Glu-Lys-, (Phe)2-(CH2)5-, (Lys)6-Gly-, -(Gly)3-(DGlu)3- and -(Gly)3-(aminocaproic acid)2-. 13) A metal complex which comprises a radiometal complexed to the tetradentate chelating agent of the peptide-chelate conjugate of claim 1. 14) The metal complex of claim 13 where the radiometal is chosen from 64Cu, 65Cu and 99mTc. 15) The metal complex of claim 13 where the radiometal is 99mTc. 16) A radiopharmaceutical composition in a form suitable for human administration, which comprises the metal complex of claim 13. 17) The radiopharmaceutical composition of claim 16, where the radiometal is 99mTc. 18) Use of the radiopharmaceutical composition of claim 16 for imaging cancer of colorectal origin. 19) A kit for the preparation of the radiopharmaceutical composition of claim 16 which comprises: i) the peptide-chelate conjugate of claim 1 ii) a reducing agent. 20) The kit of claim 19 where the reducing agent is a stannous salt. 21) The kit of claim 19 further comprising one or more of stabilisers; antioxidants; bulking agents for lyophilisation; |
<SOH> BACKGROUND ART <EOH>Colorectal carcinoma (CRC) is the fourth most common malignancy worldwide following cancers of the lung, breast and prostate. Metastases of CRC origin are the main cause of death in patients diagnosed with colorectal primary tumours. Approximately 150,000 to 200,000 new cases are diagnosed annually in the USA and around 50,000 deaths are attributed to this disease. Many patients die due to the metastatic spread of the disease with 60-80% of cases developing liver lesions during the illness. The positive identification of liver metastasis is therefore a clear indication of latent disease. Although much less common, other possible sites of spread include lung, brain and occasionally bone. Due to the strong correlation between extent of liver involvement (number and location of metastasis) and resectability, the appropriate evaluation of patients regarding suitability for surgery is becoming more important (Liver Metastasis: Biology, diagnosis and treatment. Garden O. J., Gereghty J. G., Nagorney D. M. eds. 1998). The need for an agent capable of detecting metastasis of small size (<1 cm) will have a profound impact on the treatment and management of CRC patients. There is a need to specifically detect small (<1 cm) metastatic lesions in the liver. The early detection of number and location of metastatic lesions is critical. There is also a need to characterise and specifically identify the origin of the tumour with no interference from other possible lesions (e.g. cysts, benign lesions, non-treatable tumours). A low-molecular weight heat-stable toxin is produced by enterotoxic strains of E. coli. This toxin, known as ST peptide, mediates acute diarrheal disease by binding to its receptor on colorectal cells and stimulating guanylate cyclase. Synthetic ST peptides that bind to the ST receptor without mediating acute diarrheal disease are disclosed in U.S. Pat. No. 4,545,931 and U.S. Pat. No. 4,886,663. These synthetically produced peptides are suitable for human administration for therapeutic and diagnostic purposes. Targeted ligands directed towards receptors that are expressed selectively on tumour cells of colorectal origin are a means to specifically detect the presence of cancers of colorectal origin. Thus, the ST receptor is a potential target mechanism. Gastrointestinal mucosal cells specifically express the ST receptor and the expression persists after colonic and rectal mucosal cells undergo malignant neoplasic transformation. No ST peptide has been found in any other extra-intestinal tissues, therefore specificity of ligands to tissue of gastrointestinal origin is maintained. Similar levels of expression have been found in human primary and metastatic colorectal tissues with different grades of differentiation and location. A specific ligand for the ST receptor will only bind to metastatic disease, as access to the apical side of intestinal cells will be avoided if the compound is injected intravenously. Radiolabelled ST peptides for CRC imaging and diagnosis have been previously documented. U.S. Pat. No. 5,518,888 claims radiodiagnostic agents based on ST peptides. In one embodiment of that invention, the peptides may be linked to a radioactive imaging agent, such as radioactive iodine, 111 In or 99m Tc. 99m Tc is chelated by DTPA, which is converted to an anhydride and reacted with an ST peptide. No other chelates are disclosed in U.S. Pat. No. 5,518,888. Radiolabelling thus renders the peptides suitable for use in radioimaging metastasized colorectal cancers. U.S. Pat. No. 6,060,037 discloses a method of radioimaging metastatic CRC using such radiolabelled ST peptides. The detection of localised accumulation or aggregation of radioactivity following administration of radiolabelled ST peptide is indicative of the presence of cells with ST receptors. WO 99/21587 and WO 99/39748 also disclose radiolabelled ST peptides for diagnostic imaging. In WO 99/21587 the preferred classes of radiometal complexing agents are terpyridines and phenanthrolines. In WO 99/39748 the complexing agents comprise a macrocyclic oligo-2,6-pyridine-containing ring which is a derivative of a terpyridine, quaterpyridine, quinpyridine, or sexipyridine. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows the effect of pH 8.0, 8.5 and 9.0 in the radiolabelling reaction on the formation of Species 2 (CA-ST 5-18 ). FIG. 2 shows the effect of varying the temperature of the radiolabelling reaction on the formation of Species 2 (CA-ST 5-18 ). The temperatures evaluated were 40° C., 60° C. and 70° C. FIG. 3 shows the effect of compound mass on the percent formation of Species 2 (CA-ST 5-18 ), tested at 12.5 μg, 25 μg, 50 μg and 100 μg compound. FIG. 4 shows SPECT images of mice bearing T84 tumours subcutaneously. The images are planar posterior static images with LEUHR collimator using BPLC purified 99m Tc-labelled CA1-ST 5-18 at 20 MBq per animal. Tumour to liver ratios were; 1.1 at 15 minutes, 2 at 60 minutes and 4 at 120 minutes. Image quality was comparable when crude preparations were used. FIG. 5 shows the relative retention of CA1-ST 5-18 versus the negative control, CA1-ST 5-18(cys-ala) . FIG. 6 shows a comparison of HPLC purified 99m Tc-labelled CA1-ST 5-18 and CA1-ST 5-18(cys-ala) uptake in CD-1 nude mice bearing subcutaneous T84 tumours. Planar posterior static imaging with LEUHR collimator using HPLC purified CA1-ST 5-18 at 20 MBq per animal. FIG. 7 shows the biodistribution of purified CA1-ST 5-18 at 2 MBq per animal in RNU/mu nude rats and mice bearing T84 liver tumours. The data is expressed in as relative retention (RR) and ratios of tumour to liver and tumour to muscle. FIG. 8 shows an image of an RNU/rnu nude rat bearing T84 liver tumours. It is a planar posterior static image at 120 minutes post-injection (p.i.) using HPLC purified CA1-ST 5-18 at 20 MBq with LEUHR collimator. The image is a whole body image with background counts removed and kidneys masked. Image tumour:liver ratio was typically 2.5. FIG. 9 shows an image of RNU/rnu nude mice bearing T84 liver tumours in the presence and absence of excess peptide. The images are planar posterior static images 120 minutes p.i. of BPLC purified CA1-ST 5-18 at 20 MBq per animal with LEUHR collimator. FIG. 10 shows the receptor density (RD) of two human and four xenograft human cell line CRC tumours (nd=receptor density data not detected). detailed-description description="Detailed Description" end="lead"? |
Telecommunications networks |
A first multi protocol label switching (MPLS) enabled Internet Protocol (IP) data network is able to transmit data to a second MPLS enabled IP network via a legacy optical network, which would not otherwise be able to handle the user network interface (UNI) protocols required to be used within an MPLS network environment, by means of configuring the legacy optical network and its traditional network management system (TNMS) so that they simulate or emulate an MPLS enabled optical network. The simulation/emulation of an MPLS network is performed as follows: when a first legacy network element (NE) receives a connection request (a UNI request) from the MPLS network under a UNI protocol, the UNI request is passed to the TNMS, which then sets the required connection across the legacy network via a second edge NE to an NE of the second IP network. Once the connection has been set, the TNMS instructs the edge NE to send a return signal to the requesting network indicating that the connection has been successfully set. Data packets may then be transmitted across the network. |
1-12. (Canceled) 13. A method of operating a connection-oriented first communications network having a plurality of first network elements in which connections across the first network elements are established by a network management system, the first network being connectable to a second communications network by an edge network element, the second network having a plurality of second network elements each operative for making connections or routing data across the second network in accordance with a connection request received by the edge network element, the connection request being in accordance with a predetermined protocol, the method being performed to establish a connection across the connection-oriented first network in response to the connection request from the second network, and comprising the steps of: a) upon the edge network element receiving the connection request from the second network, sending to the network management system information relating to the connection request; b) sending signals by the network management system to set the connection in response to said information received from the edge network element; and c) causing the edge network element by the network management system to send a return signal according to the predetermined protocol to the second network indicating a status of a setting of the connection. 14: The method according to claim 13, wherein the connection-oriented first network is further connectable to a third communications network by a further edge network element, the third network having a plurality of third network elements each operative for making connections or routing data across the third network in accordance with a connection request received by the further edge network element, the method further comprising the step of: causing the further edge network element by the network management system to send a connection request according to the predetermined protocol to the third network, thereby enabling a connection of the second and third networks via the connection-oriented first network. 15. The method according to claim 13, and comprising the step of operating the connection-oriented first network such that, in use, topology information relating to the first network is not made available outside the first network. 16: The method according to claim 13, wherein the predetermined protocol is a user network interface (UNI) protocol. 17: A connection-oriented first communications network, comprising: a plurality of first network elements in which connections across the first network elements are established by a network management system, the first communications network being interoperable with a second communications network by an edge network element, the second network having a plurality of second network elements each operative for making connections or routing data across the second network in accordance with a connection request received by the edge network element, the connection request being in accordance with a predetermined protocol, the edge network element upon receiving the connection request from the second network, being operative for sending to the network management system information relating to the connection request, the network management system being operative for sending signals to the first network elements to set a connection in response to said information received from the edge network element, and the network management system being operative for causing the edge network element to send a return signal according to the predetermined protocol to the second network indicating a status of a setting of the connection. 18. The connection-oriented first communications network according to claim 17, and further comprising a further edge network element for connecting the first network to a third communications network having a plurality of third network elements each operative for making connections or routing data across the third network in accordance with a connection request received by the further edge network element, the network management system being configured to cause the further edge network element to send the connection request according to the predetermined protocol to the third network, thereby enabling the connection of the second and third networks via the first network. 19. The connection-oriented first communications network according to claim 17, wherein the first network is operated such that, in use, topology information relating to the first network is not made available outside the first network. 20: The connection-oriented first communications network according to claim 17, wherein the predetermined protocol is a user network interface (UNI) protocol. 21. The connection-oriented first communications network according to claim 17, wherein the first network is an optical communications network. 22. The connection-oriented first communications network according to claim 17, wherein the second network elements of the second network are operative for establishing connections or routing data in accordance with multi-protocol label switching (MPLS). 23. An edge network element for use in a connection-oriented first communications network according to claim 17. 24. A network management system for use in a connection-oriented first communications network according to claim 17. |
Communications network |
A communications network determines for itself its own network topology, that is, the identity and interconnection of nodes comprising the network. The network comprises a plurality of nodes each having at least one port. The ports are interconnected in accordance with the network topology in which communication traffic is conveyed over the network via the interconnected ports. Each port is arranged to transmit first information within the communication traffic including the identity of the port (Section trace identity) from which the communication traffic originates. Second information is transmitted between nodes identifying which first information identity relates to which node and which port. A processor is operative for determining for each node from the first and second information the identity of adjacent nodes and the identity of the ports to which its ports are connected. |
1-16. (Canceled). 17. A communications network, comprising: a plurality of nodes each having at least one port, the ports being interconnected in accordance with a network topology in which communication traffic is conveyed over the network via the interconnected ports, each port having associated with it a unique port identifier, each node having associated with it a unique node identifier, each port being operative for transmitting within the communication traffic its respective port identifier identifying the port from which the communication traffic originates, means for transmitting to each node second information, including for each node ofthe network, the node identifier and the port identifier for each port associated with the node, and processing means for determining for each node from the received port identifier and the second information, an identity of an adjacent node and an identity of the port to which its ports are connected. 18. The communications network according to claim 17, in which the processing means is operative for determining the topology of the network from the interconnection of the adjacent nodes. 19. The communications network according to claim 17, in which the second information is transmitted to the nodes over connections which are physically separate to those interconnecting the nodes and carrying the communication traffic. 20. The communications network according to claim 19, in which the second information is transmitted as part of control signaling information. 21. The communications network according to claim 17, in which the processing means is distributed among the nodes of the network. 22. The communications network according to claim 17, in which the nodes include storage means for storing pre-loaded check information, the check information including the port identifiers that can be expected to be received on respective ports of the node, and means for comparing the port identifiers received at its ports with the check information for validating an integrity of the connection of the ports of the nodes. 23. The communications network according to claim 17, in which the port identifier is transmitted as a part of an overhead part of the communication traffic. 24. The communications network according to claim 17, in which the second information includes a modified internet protocol. 25. The communications network according to claim 17, in which the network is an optical communications network in which the communication traffic is transmitted between the nodes as optical radiation modulated with the communication traffic, and in which the radiation is conveyed by radiation guiding means interconnecting the nodes. 26. The communications network according to claim 17, in which the network comprises a synchronous digital hierarchy (SDH) network. 27. The communications network according to claim 17, in which the network comprises a synchronous optical network (SONET). 28. The communications network according to claim 26, in which the port identifier comprises a section trace identifier which is carried within section overhead. 29. The communications network according to claim 26, in which the second information is transmitted within a data communications channel (DCC). 30. The communications network according to claim 17, in which the network comprises a wavelength division multiplex (WDM) network. 31. The communications network according to claim 30, in which the second information is transmitted within an optical supervisory channel (OSC). 32. A method of operating a communications network comprising a plurality of nodes each having at least one port, the ports being interconnected in accordance with a network topology in which communication traffic is conveyed over the network via the interconnected nodes, each port having associated with it a unique port identifier, each node having associated with it a unique node identifier, each port transmitting its respective port identifier within the communication traffic identifying the port from which the communication traffic originates, the method being performed for determining the network topology and comprising the steps of: a) transmitting to each node second information which includes for each node of the network the node identifier and the port identifier for each port associated with the node; and b) determining for each node from the received port identifier and the second information, an identity of an adjacent node and an identity of the port interconnecting the adjacent nodes. |
Evolutionary programming of configurable logic devices |
A configurable hardware logic device is configured to implement a complete evolutionary algorithm in hardware. The configured hardware logic device produces an initial population of individuals, carries out fitness tests on the initial population of individuals, selects an individual or individuals of the initial population on the basis of results of the fitness tests, breeds a further population of individuals from the selected individual or individuals, and provides a single preferred selected individual from the further population of individuals. |
1-24. (Canceled) 25: An uncommitted configurable hardware logic device when configured to implement a complete evolutionary algorithm in hardware, the configured hardware logic device comprising: a) population producing means having an output, and operative for producing an initial population of individuals at the output; b) fitness evaluating means having an input and first and second ouputs, the output of the population producing means being connected to the input of the fitness evaluating means, and the fitness evaluating means being operative for carrying out fitness tests on the initial population of individuals, and for providing results of the fitness tests and the respective individuals at the first output of the fitness evaluating means; c) selector means having an input and an output, and operative for selecting at least one individual of the initial population on the basis of the results of the fitness tests and the respective individuals connected from the output of the fitness evaluating means to the input of the selector means, and for providing the selected at least one individual at the output of the selector means; d) breeding means having an input connected to the output of the selector means, and operative for breeding a further population of individuals from the selected at least one individual, and having an output connecting the further population of individuals to the input of the fitness evaluating means; and e) the fitness evaluating means being further operative for providing a single preferred selected individual from the further population of individuals at the second output of the fitness evaluating means. 26: The uncommitted configurable hardware logic device when configured as claimed in claim 25, wherein the evolutionary algorithm is genetic programming. 27: The uncommitted configurable hardware logic device when configured as claimed in claim 25, wherein the uncommitted configurable hardware logic device is a field programmable gate array (FPGA). 28: The uncommitted configurable hardware logic device when configured as claimed in claim 25, which is configured to perform a selected step or steps each in a plurality of parallel steps. 29: The uncommitted configurable hardware logic device when configured as claimed in claim 25, wherein a configuration is by means of a high-level language to hardware compilation system. 30: The uncommitted configurable hardware logic device when configured as claimed in claim 29, wherein the high-level language to hardware compilation system is Handel-C. 31: The uncommitted configurable hardware logic device when configured as claimed in claim 25, wherein the uncommitted configurable hardware logic device is reconfigurable. 32: The uncommitted configurable hardware logic device when configured as claimed in claim 25, and a random access memory included or connected to the device. 33: The uncommitted configurable hardware logic device when configured as claimed in claim 25, and a random number generator configured from a part of the device. 34: The uncommitted configurable hardware logic device when configured as claimed in claim 25, when configured to operate on scalar data. 35: The uncommitted configurable hardware logic device when configured as claimed in claim 25, when configured to operate on vector data. 36: The uncommitted configurable hardware logic device when configured as claimed in claim 25, when configured to operate on sub-machine-code. 37: A method of implementing a complete evolutionary algorithm in hardware by configuring an uncommitted configurable hardware logic device to carry out the steps of: a) creating an initial population of individuals; b) evaluating a fitness of the initial population of individuals; c) selecting at least one individual from the initial population of individuals; d) breeding a further population of individuals from the selected at least one individual; e) evaluating a fitness of the further population of individuals; and f) selecting a preferred one of the further population of individuals based on the fitness of the further population of individuals. 38: The method of claim 37, wherein the evolutionary algorithm is genetic programming. 39: The method of claim 37, wherein the uncommitted hardware logic device is a field programmable gate array (FPGA). 40: The method of claim 37, wherein at least one of the steps is performed in a plurality of parallel steps. 41: The method of claim 37, wherein the configuring is performed by a high-level language to hardware compilation system 42: The method of claim 41, wherein the high-level language to hardware compilation system is Handel-C. 43: The method of claim 37, wherein the uncommitted configurable hardware logic device is reconfigurable. 44: The method of claim 37, and the step of storing data in a random access memory. 45: The method of claim 37, and the step of configuring a random number generator. 46: The method of claim 37, and the step of operating on scalar data. 47: The method of claim 37, and the step of operating on vector data. 48: The method of claim 37, and the step of operating on sub-machine code. |
Method of modulating the proliferation of medullary thyroid carcinoma cells |
The present invention is directed to a method of decreasing the rate of proliferation of medullary thyroid carcinoma cells which comprises contacting medullary thyroid carcinoma cells with one or more SSTR2 agonist. |
1. A method of modulating the rate of proliferation of medullary thyroid carcinoma cells which comprises contacting MTC cells with one or more SSTR2 agonist and one or more SSTR5 agonist, wherein said SSTR2 agonist reduces the rate of proliferation of the MTC cells and said SSTR5 agonist attenuates the SSTR-2 agonist-induced reduction in cellular proliferation rate. 2. A method according to claim 1 wherein said SSTR-5 agonist is D-Phe-Phe-Trp-D-Trp-Lys-Thr-Phe-Thr-NH2 (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof. 3. A method of decreasing the rate of proliferation of medullary thyroid carcinoma cells which comprises contacting said medullary thyroid carcinoma cells with one or more SSTR2 agonist or a pharmaceutically acceptable salt thereof. 4. A method according to claim 3 wherein said SSTR-2 agonist is a SSTR-2 selective agonist or a pharmaceutically acceptable salt thereof. 5. A method according to claim 3 wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 2 times higher than it has for SSTR-2. 6. A method according to claim 3 wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 5 times higher than it has for SSTR-2. 7. A method according to claim 3 wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 10 times higher than it has for SSTR-2. 8. A method according to claim 3 wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value of less than 5. 9. A method according to claim 3 wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value of less than 1. 10. A method according to claim 3 wherein said SSTR-2 selective agonist is a compound selected from the list consisting of: D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (SEQ ID NO:2); cyclo[Tic-Tyr-D-Trp-Lys-Abu-Phe] (SEQ ID NO:3); 4-(2-Hydroxyethyl)-1-piperazinylacetyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2 (SEQ ID NO:4); and 4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2 (SEQ ID NO:5); or a pharmaceutically acceptable salt thereof. 11. A method of treating medullary thyroid carcinoma which comprises administering to a patient in need thereof an effective amount of a SSTR2 agonist or a pharmaceutically acceptable salt thereof. 12. A method according to claim 11 wherein said SSTR2 agonist comprises an SSTR2 selective agonist, or a pharmaceutically acceptable salt thereof. 18. A method according to claim 11 wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof is a compound selected from the list consisting of: D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (SEQ ID NO:2); cyclo[Tic-Tyr-D-Trp-Lys-Abu-Phe] (SEQ ID NO:3); 4-(2-Hydroxyethyl)-1-piperazinylacetyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2 (SEQ ID NO:4); and 4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2 (SEQ ID NO:5); or a pharmaceutically acceptable salt thereof. 19. A method according to claim 11, wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof comprises a Tyr(I) residue, wherein the iodine atom of said Tyr(I) residue comprises a radioactive iodine isotope. 20. A method according to claim 11 or claim 19, wherein said medullary thyroid carcinoma cells have formed metastases outside the thyroid. 21. A method according to claim 20, wherein said metastases are present in the lymph, the lung, the liver, the brain, or in bone. 22. A method of claim 21, wherein said iodine is 125I, 127 I or 131I. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Somatostatin (SS), a tetradecapeptide discovered by Brazeau et al., has been shown to have potent inhibitory effects on various secretory processes in tissues such as pituitary, pancreas and gastrointestinal tract. SS also acts as a neuromodulator in the central nervous system. These biological effects of SS, all inhibitory in nature, are elicited through a series of G protein coupled receptors, of which five different subtypes have been characterized (SSTR1-SSTR5) (Reubi J C, et al., Cancer Res 47: 551-558, Reisine T, et al., Endocrine Review 16: 427-442, Lamberts S W, et al., Endocr Rev 12: 450-482, 4 Patel Y C, 1999 Front Neuroendocrinology 20: 157-198). These five subtypes have similar affinities for the endogenous SS ligands but have differing distribution in various tissues. Somatostatin binds to the five distinct receptor (SSTR) subtypes with relatively high and equal affinity for each subtype. There is evidence that SS regulates cell proliferation by arresting cell growth via SSTR1, 2, 4, and 5 subtypes (Buscail L, et al., 1995 Proc Natl Acad Sci USA 92: 1580-1584; Buscail L, et al., 1994 Proc Natl Acad Sci USA 91: 2315-2319; Florio T, et al., 1999 Mol Endocrinol 13: 24-37; Sharma K, et al., 1999 Mol Endocrinol 13: 82-90), or by inducing apoptosis via SSTR3 subtype (Sharma K, et al., 1996 Mol Endocrinol 10: 1688-1696). SS and various analogues have been shown to inhibit normal and neoplastic cell proliferation in vitro and vivo (Lamberts S W, et al., Endocr Rev 12: 450-482) via specific SS receptors (SSTR's) (Patel Y C, 1999 Front Neuroendocrinology 20: 157-198) and possibly different postreceptor actions (Weckbecker G, et al., Pharmacol Ther 60: 245-264; Bell G I, Reisine T 1993 Trends Neurosci 16: 34-38; Patel Y C, et al., Biochem Biophys Res Commun 198: 605-612; Law S F, et al., Cell Signal 7:1-8). In addition, there is evidence that distinct SSTR subtypes are expressed in normal and neoplastic human tissues (Virgolini I, et al., Eur J Clin Invest 27: 645-647), conferring different tissue affinities for various SS analogues and variable clinical response to their therapeutic effects. Binding to the different types of somatostatin receptor subtypes has been associated with the treatment of various conditions and/or diseases. For example, the inhibition of growth hormone has been attributed to the somatostatin type-2 receptor (“SSTR2”) (Raynor, et al., Molecular Pharmacol. 43:838 (1993); Lloyd, et al., Am. J. Physiol. 268: G 102 (1995)) while the inhibition of insulin has been attributed to the somatostatin type-5 receptor (“SSTR5”) (Coy, et al. 197:366-371 (1993)). Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin receptor subtypes include inhibition of insulin and/or glucagon for treating diabetes mellitus, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis; treatment of inflammatory disorders such as arthritis; retinopathy; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. It is preferred to have an analog which is selective for the specific somatostatin receptor subtype or subtypes responsible for the desired biological response, thus, reducing interaction with other receptor subtypes which could lead to undesirable side effects. Somatostatin (SS) and its receptors (SSTR1 to SSTR5) are expressed in normal human parafollicular C cells and medullary thyroid carcinoma (MTC) cells. MTC is a tumor originating from thyroid parafollicular C cells that produces calcitonin (CT), somatostatin, as well as several other peptides (Moreau J P, et al., Metabolism 45 (8 Suppl 1): 24-26). Recently, Mato et al. showed that SS and SSTR's are expressed in human MTC (Mato E, et al., J Clin Endocrinol Metab 83: 2417-2420). It has been documented that SS and its analogues induce a decrease in plasma CT levels and a symptomatic improvement in MTC patients. However, until now the antiproliferative activity of SS analogues on tumor cells had not been clearly demonstrated (Mahler C, et al., Clin Endocrinol 33: 261-9; Lupoli G, et al., Cancer 78: 1114-8; Smid W M, et al., Neth J Med 40: 240-243). Thus, development and assessment of SSTR subtype analogues selective on MTC cell growth provides a useful tool for clinical application. Until now, no data concerning specific SSTR subtype involvement in MTC cell growth regulation have been reported. The present invention relates to the discovery that the human MTC cell line TT, which displays MTC cell characteristics (Zabel M, et al., 1992 Histochemistry 102: 323-327, 2 Gagel R F, et al., 1986 Endocrinology 118: 1643-1651, Liu J L, et al., 1995 Endocrinology 136: 2389-2396) and which stably expresses all the SSTR subtypes, responds to SSTR2 and SSTR5 activation by subtype selective agonists with two different patterns in terms of [ 3 H]thy incorporation and cell number. SSTR2 preferential agonists significantly suppress [ 3 H]thy incorporation, i.e., inhibit DNA synthesis, and reduce cell proliferation. SSTR5 selective agonists significantly increase [ 3 H]thy incorporation in TT cells, i.e., increase DNA synthesis, but alone fail to influence cell proliferation. Further, SSTR2 antagonists counteract the action of SSTR2 preferential agonists on TT cells. Further still, increasing concentrations of an SSTR5 selective agonist dose-dependently prevents the suppression of TT cell [ 3 H]thy incorporation and proliferation produced by an SSTR2 preferential agonist, and vice versa, showing an antagonism between such agonists. Hetero- and homodimeric interactions between subtypes of the opiate (Jordan B A, et al., 1999 Nature 399:697-700.) and SS (Rocheville M, et al., 2000 J. Biol. Chem. 275:7862-7869) receptor families have been recently demonstrated. Studies in cultured pituitary adenoma cells have demonstrated that SSTR subtype 2 and 5 act synergistically in the suppression of growth hormone and prolactin secretion (Shimon I, et al., 1997 J. Clinical Invest. 100:2386-2392, Jaquet P, et al., 2000 J Clin Endocrinol Metab. 85:781-792). The finding that SSTR5 activation reduces the antiproliferative activity mediated by SSTR2 differs from results in other tissues (Patel Y C, 1999 Front Neuroendocrinology 20: 157-198, Buscail L, et al., 1995 Proc Natl Acad Sci USA 92: 1580-1584, Buscail L, et al., 1994 Proc Natl Acad Sci USA 91: 2315-2319, Sharma K, et al., 1996 Mol Endocrinol 10: 1688-1696). This is the first demonstration that SSTR subtypes 2 and 5 can act antagonistically in regulating cell growth. Thus, SSTR2 and SSTR5 preferential agonists exert differential effects on proliferation of human medullary thyroid TT cell line in vitro, according to their specific SSTR selectivity. Proliferation of the TT cell line can be reduced by SSTR2 selective agonists, but not by SSTR5 agonists, and an SSTR5 agonist can prevent SSTR2 mediated antiproliferative effects. The key inhibitory role of SSTR2 on MTC cell proliferation demonstrates that analogues with enhanced SSTR2 affinity and selectivity versus SSTR5 would be useful as antiproliferative agents in MTC treatment. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is based on the discovery that somatostatin agonists selective for SSTR-2 are effective in reducing the rate of proliferation of medullary thyroid carcinoma cells, and that somatostatin agonists selective for SSTR-5 are effective in attenuating this SSTR-2 agonist-induced reduction in rate of proliferation. In one aspect, the present invention is directed to a method of modulating the rate of proliferation of MTC cells which comprises contacting MTC cells with one or more SSTR2 agonist and one or more SSTR5 agonist, wherein said SSTR2 agonist serves to reduce the rate of proliferation of the MTC cells and said SSTR5 agonist serves to attenuate the SSTR-2 agonist-induced reduction in proliferation rate. In one embodiment, the invention is directed to the immediately foregoing method wherein said SSTR-5 agonist is D-Phe-Phe-Trp-D-Trp-Lys-Thr-Phe-Thr-NH 2 or a pharmaceutically acceptable salt thereof. In another embodiment the invention is directed to a method of decreasing the rate of proliferation of medullary thyroid carcinoma cells which comprises contacting medullary thyroid carcinoma cells with one or more SSTR2 agonist or a pharmaceutically acceptable salt thereof. In a preferred example of the immediately foregoing embodiment the SSTR-2 agonist is a SSTR-2 selective agonist. In a more preferred example, the SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 2 times higher than it has for SSTR-2, more preferably at least 5 times higher than it has for SSTR-2, more preferably still at least 10 times higher than it has for SSTR-2. In another preferred example of the foregoing embodiment the SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value of less than 5 nM, more preferably less than 1 nM. In another preferred example of the foregoing embodiment, the SSTR-2 selective agonist is a compound selected from the list consisting of D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH 2 , cyclo [Tic-Tyr-D-Trp-Lys-Abu-Phe], 4-(2-Hydroxyethyl)-1-piperazinylacetyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2 , and 4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2 ; or a pharmaceutically acceptable salt thereof, wherein “4-(2-Hydroxyethyl)-1-piperazinylacetyl” denotes the structure: and “4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-” denotes the structure: In a third embodiment, the invention is directed to a method of treating medullary thyroid carcinoma which comprises administering to a patient in need thereof an effective amount of a SSTR2 agonist. In a preferred example of the third embodiment the SSTR-2 agonist is a SSTR-2 selective agonist. In a more preferred example, the SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 2 times higher than it has for SSTR-2, more preferably at least 5 times higher than it has for SSTR-2, more preferably still at least 10 times higher than it has for SSTR-2. In another preferred example of the third embodiment the SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value of less than 5 nM, more preferably less than 1 nM. In yet another preferred example of the third embodiment, the SSTR-2 selective agonist is a compound selected from the list consisting of D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH 2 , cyclo[Tic-Tyr-D-Trp-Lys-Abu-Phe], 4-(2-Hydroxyethyl)-1-piperazinylacetyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2 , and 4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2 ; or a pharmaceutically acceptable salt thereof, wherein “4-(2-Hydroxyethyl)-1-piperazinylacetyl” and “4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-” are as previously defined. Importantly, as is well known in the art, standard radioactive iodine therapy, e.g., administration of a radioactive iodine salt to a patient, is not available for the treatment of medullary thyroid carcinoma since parafollicular cells do not take up iodine. Thus in another aspect the invention provides a method of treating medullary thyroid carcinoma patient comprising administering to a patient in need thereof an effective amount of a SSTR2 agonist or a pharmaceutically acceptable salt thereof, wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof comprises a Tyr(I) residue, wherein the iodine atom of said Tyr(I) residue comprises a radioactive iodine isotope. Preferably said iodine isotope comprises 125 I, 127 I or 131 I. In one embodiment of said medullary thyroid carcinoma cells have formed metastases outside the thyroid. In a further embodiment said metastases are present in the lymph, the lung, the liver, the brain, or in bone. |
Projector |
Projector (1) enabling a remarkable flexibility of use and a marked reduction of the dimensions thereof, comprising: a main body (2) housing light generating means and heat disposal means; and a secondary body (3), removably associable to said main body (2), housing means (40) for holding and sliding a film (F), means (30) for cooling said film (F) and an optical projection group (4), |
1. A projector (1), comprising: a main body (2), housing light generating means and heat disposal means; and a secondary body (3), removably associable to said main body (2), housing means (40) for holding and sliding a film (F) and an optical projection group (4), characterised in that said secondary body houses means (30) for cooling said film (F) having a fan (12), located at the bottom edge of the film (F), so as to generate a cooling flow tangential to both the surfaces of said film (f). 2. The projector (1) according to claim 1, wherein said means (40) for holding and sliding a film (F) comprises a film wind shaft (41) about which a film (F) initially wound on a start spool (7a) is wound, and a film rewind shaft (42), about which a take-up spool (7b) gradually winds up as the projection goes on, each shaft (41, 42) having a length such as to house films of different sizes. 3. The projector (1) according to claim 1, wherein said shafts (41, 42) comprise, at a respective end, presser members 43, each kept pressed onto the top edge of the film (F) by a respective spring (44), the presser members keeping the film (F) in the projection position. 4. The projector (1) according to claim 2, wherein the means (40) for holding and sliding comprises auxiliary motor drives (8) connected to said spools (7a, 7b) for the rewinding and the unwinding of the film. 5. The projector (1) according to claim 2, wherein the means (40) for holding and sliding comprises a step-by-step motor drive (9) connected to a motor wheel (10) cooperating with an idle wheel (17), both gripping the film (F) for the sliding thereof, the step-by-step motor drive (9) being apt to determine the shifting rate and accuracy of the film (F). 6. The projector (1) according to claim 1, comprising a first plate (13) constrainable to the secondary body (3) located parallel to the film section at a projection area (6) and orthogonal to an axis of projection (A-A) so as to form, when said first plate (13) is constrained to said secondary body (3), a wall thereof facing the projection optics (4) and so as to face a projection lamp inserted in the main body (2) when the secondary body (3) is constrained to said main body; said first plate being apt, when constrained to the secondary body (3), to keep the film (F) pressed between two idle wheels (15) and the corresponding wheels (10) and (17) of the secondary body (3) and it being apt, when released from said secondary body, to ease the mounting and the dismounting of the film (F) therefrom according to a direction substantially corresponding to the axis of projection (A-A). 7. The projector (1) according to claim 1, wherein to the secondary body (3) a first plate (13), interchangeable with a second plate (20) bearing a device (21) for applying marks (33), is constrainable. 8. Projector (1) according to claim 6, wherein the first plate (13) has an opening (14) which, when said first plate is constrained to the secondary body (3), is centered with respect to the axis of projection (A-A) and has dimensions not smaller than those of the frames impressed onto the film (F); onto the surface of said first plate (13) facing the inside of the secondary body (3) the at least two idle wheels (15) and a film pressure frame (18) are constrained. 9. The projector (1) according to claim 8, wherein said idle wheels (15) have the respective axes of rotation mutually parallel and positioned orthogonal to the sliding direction of the film (F); the idle wheels (15) are constrained to the first plate (13) in a position such as to be capable of cooperating, when said first plate is constrained to the secondary body (3), with the corresponding wheels (10, 17); the idle wheels (15) have supports (16) thereof constrained to the first plate (13) in an elastically yielding way, said elastic compliance being apt to ensure steadiness of pressure between said idle wheels (15) and the wheels (10, 17), said pressure being apt to ensure the normal unwinding of the film (6) between the idle wheels (15) and the wheels (10, 17); all the wheels (15, 17, 10) are coated with friction material, e.g. gummy material. 10. The projector (1) according to claim 9, wherein the film pressure frame (18) is substantially made of a frame enclosing an opening (19), true with respect to the axis of projection (A-A) and having dimensions not smaller than those of the frames impressed on the film (F); said frame (18) being constrained to the first plate (13) by elastic supports apt to give to said film pressure frame (18) a second compliance, it also of elastic type. 11. The projector (1) according to claim 10, wherein the edges of the frame making the film pressure frame (18) have the surface thereof facing the inside of the secondary body (3) provided with a plurality of inserts (35) of a non-stick material, e.g. PTFE. 12. The projector (1) according to claim 11, wherein the bottom edge of the film pressure frame (18) is provided with a plurality of nicks (31) oriented as the axes of rotation of the idle wheels (15); jointly to the scanty thickness of the film pressure frame (18), said nicks being apt to ease the air flow for cooling the film (6) outletted from the fan (12); the reduced thickness of the film pressure frame (18) being also apt to offer the least drag to the cooling air flow outletted from said fan. 13. The projector (1) according to claim 6, wherein the first plate (13) is provided with fastening members (28) apt to enable the mere upturning thereof with respect to the sliding plane of the film (F) as well as the complete releasing of said first plate from the secondary body (3). 14. The projector (1) according to claim 7, wherein said second plate (20) has shapes and dimensions identical to those of the first plate (13) and it is provided with identical idle wheels (15) and identical fastening means (28); the device (21) for applying marks (33) is apt to the applying, onto the film (6), of a plurality of said marks, said applying being viable solely when the second plate (20) is constrained to the secondary body (3) in lieu of the first plate (13); said marks being apt to form finder members aimed at restoring the synchronism of the frames in the case wherein the auxiliary drive motors, the motor drive (9) and/or the wheels (15, 17, 10) cause deviations in the sliding of the film (F). 15. The projector (1) according to claim 14, wherein the applying device (21) comprises a shelf (29) to which there are constrained: one idle spool (22) housing a strip (23) which supports a plurality of the marks (33); a plurality of gripping members (25) apt to grip and to shift the strip (23); shifting means (26) apt to shift said gripping members, said shifting being connected to at least one of the idle wheels (15), said connection being apt, when the second plate (20) is constrained to the secondary body (3), to drive the motion of the motor wheel (10) to the strip (23) eliminating the need of a dedicated motor drive. 16. The projector (1) according to claim 14, wherein onto the second plate (20), in lieu of the film pressure frame (18), there is constrained a plate (27) of the film (F) lacking in any opening; said pressure plate being constrained to the second plate (20) in an elastically yielding way; said pressure plate having a surface destined to contact said film coated with a layer of a non-stick material, e.g. PTFE. |
Methods and devices for treating and processing data |
A data processing unit (VPU) is described, having a field of clocked logic cells (PAEs) which is operable in different configuration states and a clock preselecting means for preselecting logic cell clocking. It is provided here that the clock preselecting means is designed in such a way that, depending on the state, a first clock is preselected at least at a first cell (PAE) and an additional clock is preselected at least at an additional cell. |
1. A data processing unit (VPU) comprising a field of clocked logic cells (PAES) which is operable in different configuration states and a clock preselecting means for preselecting logic cell clocking, wherein the clock preselecting means is designed in such a way that, depending on the state, a first clock is preselected at least at a first cell (PAE) and an additional clock is preselected at least at an additional cell. 2. The data processing unit as recited in the preceding claim, wherein the clock preselecting means is designed in such a way that it receives the setpoint clock for at least one first cell from a unit preselecting configuration states. 3. The data processing unit as recited in the preceding claim, wherein the unit preselecting the configuration states includes a compiling unit and/or a cell configuration preselecting unit. 4. The data processing unit as recited in one of the preceding claims, wherein the clock preselecting means is designed in such a way that it receives the setpoint clock from a logic cell. 5. The data processing unit as recited in one of the preceding claims, wherein the clock preselecting means includes at least one central clock preselecting unit and at least one local clock generating unit for generating the local clock from the preselected central clock, in particular one time synchronizing clock generating unit per cell. 6. The data processing unit as recited in one of the preceding claims, wherein at least a portion of the logic cells includes at last one ALU and/or is formed by such. 7. The data processing unit as recited in one of the preceding claims, wherein at least one memory and/or register is assigned to at least a portion of the logic cells. 8. The data processing unit as recited in one of the preceding claims, wherein a plurality of identical logic cells is provided. 9. The data processing unit as recited in one of the preceding claims, wherein all logic cells are identical. 10. A method for operating a field of clocked logic cells which are settable into different configuration states, wherein a first state is determined, at least temporarily, for at least one first cell, a clock which is to be assigned to the first cell being determined dependent on the first state and the cell being operated using this clock; a second state is determined for at least one additional cell, a second clock which is to be assigned to the second cell being determined dependent on the second state and the second cell being operated using this second clock, which differs from the first clock. 11. The method as recited in the preceding claim, wherein the clock is preselected for at least one first cell, either together with or determined by its configuration. 12. The method as recited in one of the preceding method claims, where a group of cells is jointly configured for executing algebraic and/or other operations which require a different number of clock cycles and where at least one cell, executing an operation which requires fewer clock cells than that operation requiring the most clock cycles within the group, is clocked slower than at least one other cell. 13. The method as recited in one of the preceding method claims, wherein cells of at least one group are configured for sequential data processing. 14. The method as recited in one of the preceding method claims, wherein the field in at least two cell groups is configured for executing at least two different tasks which are assigned different priorities, and the cell group appointed for executing the task having the lower priority is clocked using a lower clock frequency. 15. The method as recited in one of the preceding method claims, wherein the condition of a voltage supply source and/or a temperature is determined and the cell clock is determined as a function of the voltage and/or temperature condition thus determined. 16. A method for operating a system of reconfigurable logic elements which are operable in different configurations, wherein a still permissible frequency, in particular the still executable maximum frequency, is determined for a plurality of possible configurations, in particular such that are simultaneously configured into the field, a plurality of cells being operated using this frequency; the plurality of cells is larger than the plurality which is assigned for executing this so-called slowest configuration and the plurality is able, in particular, to include the entire field of the configurable elements. 17. The method for operating a system of reconfigurable logic elements which are operable in different configurations, wherein configurations are selected such that, by taking signal transmissions via bus lines into account, maximum frequencies are maintained during transmissions via bus systems. |
Tube clamp |
For obtaining a hose clamp which has a continuously smooth inner surface free of gaps and which requires an as short as possible length of band material, the inner band end portion is provided with a tongue the length of which is approximately half the amount by which the hose clamp is narrowed during tightening. During the first half of the tightening movement, the tongue is guided transversely to the band longitudinal direction by a projection which engages a slot provided in the outer band portion. The slot at its end is continued by a window which starts at a step, and the tongue, during the second half of the tightening movement, passes through the window which then takes over the guidance of the tongue. |
1-10. (canceled) 11. A hose clamp made of an open band having an inner band portion with an inner band end, an outer band portion with an outer band end overlapping said inner band portion, the clamp being adapted to be transferred from a closed condition in which said outer band end is connected to said inner band portion, to a tightened condition in which the clamp has a reduced inner dimension, the clamp comprising a tongue formed at said inner band end, the tongue having a length which is substantially smaller than the difference between the inner dimension of the clamp in said closed condition and the reduced inner dimension of the clamp in said tightened condition, an aperture provided in said outer band portion for receiving said tongue in said tightened condition, a step projecting inwardly, as seen from said outer band end, extending transversely to the band longitudinal direction within an area of an end of the aperture nearer to said outer band end, and having a height corresponding to the thickness of the band material, and guide means provided in said outer band portion between said outer band end and said aperture for laterally guiding said tongue prior to its entry into said aperture: 12. The clamp of claim 11 wherein said aperture is a window for said tongue to pass in said tightened condition. 13. The clamp of claim 11 wherein said guide means includes beads formed in said outer band portion on both sides of said tongue. 14. The clamp of claim 13 wherein said inner band portion has two beads in an area adjacent said tongue in the band longitudinal direction, which beads are engaged, in said tightened condition, by said two beads formed in said outer band portion. 15. The clamp of claim 13 wherein the width of each bead is ¼ to 1/10 of the band width. 16. The clamp of claim 11, comprising a point-shaped embossment provided near the free end of said tongue, said embossment facing said outer band portion. 17. The clamp of claim 11 wherein said guide means includes a slot continuous with said aperture in said outer band portion and a projection formed on an outer side of said tongue for engaging said slot. 18. The clamp of claim 17 wherein said projection is a nose punched out of said tongue. 19. The clamp of claim 11 comprising ear-type tightening means provided between said guide means and said outer band end. 20. The clamp of claim 11 comprising an undulation provided between said guide means and said outer band end. |
<SOH> BACKGROUND OF THE INVENTION <EOH>U.S. Pat. No. 4,299,012 discloses a hose clamp which consists of an open band with overlapping band ends and which is adapted to be transferred from a closed condition in which the outer band end is connected to the inner band portion, to a tightened condition having a reduced inner dimension, comprising a tongue formed at the inner band end, an aperture provided in the outer band portion for receiving the tongue in the tightened condition, and a step which projects inwardly as seen from the outer band end, which extends transversely to the band longitudinal direction within the area of the end of the aperture nearer to the outer band end, and which has a height corresponding to the thickness of the band material. This hose clamp has proved suitable for fixing even thin, hard hoses to pipe nipples due to the fact that, in the tightened condition, the inner surface of the clamp is free of gaps and steps and therefore supports the hose at all circumferential positions. For tightening the known hose clamp, a so-called “Oetiker ear” provided in the outer band section is narrowed by means of a pair of grippers. A tongue provided at the inner band end serves to bridge the gap remaining underneath the ear, the tongue cooperating with a tongue channel provided in the outer band portion. The channel is formed by two parallel cuts extending in the longitudinal direction of the band, wherein the two band portions outside these cuts are offset inwardly at their ends close to the outer band end, and the central portion situated between the cuts is offset inwardly at its end remote from the outer band end, each offset corresponding to the thickness of the band material. In the closed but not yet tightened condition of the hose clamp, hooks provided at the inner band end are inserted in openings near the outer band end. The tongue and the tongue channel are so arranged and dimensioned in the circumferential direction of the hose clamp in such a way that, in this closed condition, the free end of the tongue just reaches the channel and the portion of full band width adjacent the tongue bridges the spacing between the legs of the ear. In tightening, the tongue moves completely into the tongue channel until its end comes to lie close to the offset of the centre band portion between the two cuts, and the portion of full band width adjacent the tongue comes to lie close to the offset at the other end of the tongue channel. In this tightened condition, while gaps occur near the offsets, these gaps at no location extend across the full band width so that the hose is supported even in these regions by at least part of the band width, and tightness between the hose and the nipple is ensured over the entire circumference. In the hose clamp known from EP 0 570 742 A1, the tongue during tightening enters a space between two beads formed in the inner surface of the outer band section, which beads project inwardly by an amount corresponding to the thickness of the band material and terminate in a step of the same height. In order to make sure that the tongue is laterally guided throughout the tightening process, the tongue and beads have such a length in the circumferential direction of the hose clamp that the tongue reaches the space between the beads already in the closed condition of the hose clamp. U.S. Pat. No. 4,315,348 describes a hose clamp having a separate insert portion bridging the ear, with two tongue-type ends extending through windows provided in the outer band section. The invention is based on the object to remove at least in part such disadvantages as occur with comparable hose clamps of the prior art. A more specific object may be seen in providing a hose clamp which requires an as small as possible length of band material at a given clamp diameter. The solution of this object in accordance with the invention which consists of an open band with overlapping band ends and which is adapted to be transferred from a closed condition in which the outer band end is connected to the inner band portion, to a tightened condition having a reduced inner dimension, comprising a tongue formed at the inner band end, an aperture provided in the outer band portion for receiving the tongue in the tightened condition, and a step which projects inwardly as seen from the outer band end, which extends transversely to the band longitudinal direction within the area of the end of the aperture nearer to the outer band end, and which has a height corresponding to the thickness of the band material, that the length of the tongue is substantially shorter than the difference between the inner dimension of the hose clamp in its closed condition and that of the hose clamp in its tightened condition, and that the outer band portion in the region between its outer band end and the aperture has means for laterally guiding the tongue prior to its entry into the aperture. The tongue provided at the inner band end is guided during tightening of the hose clamp consecutively by two different measures wherein, during the first part of the tightening movement, the tongue is remote from the aperture and only in the second portion enters the aperture and is guided by it. The tongue can thus be shorter by roughly one half than in the prior art, which results in a corresponding saving in band material length. The embodiment wherein the aperture is a window for the tongue to pass in the tightened condition of the hose clamp leads to a specifically safe guiding and retaining of the central band section transverse to the band. An easily obtained possibility of guiding the tongue in the first part of the tightening movement is obtainable wherein the guiding means includes beads formed in the outer band portion on both sides of the tongue clamp of claim 3 and wherein the inner band end portion has two beads in the area adjacent the tongue in the band longitudinal direction, which beads are engaged, in the tightened condition of the hose clamp, by the two beads in the outer band portion and wherein the width of each bead is ¼ to 1/10 of the band width. For reducing the friction which occurs between the tongue and the outer band portion during tightening of the hose clamp a point-shaped embossment facing the outer band portion is provided near the free end of the tongue. A specifically safe guidance of the tongue transverse to the band longitudinal direction in the first part of the tightening movement is provided when the guiding means includes a slot continuous with the aperture in the outer band portion and a projection on the outer side of the tongue for engaging the slot and wherein the projection is a nose punched out of the tongue. The invention is adapted for use with hose clamps with and without ear-like tightening means wherein an ear-type tightening means is provided between the guiding means and the outer band end and wherein an undulation is provided between the guiding means and the outer band end. Advantageous embodiments will now be explained in more detail with reference to the drawings. In the drawings, |
Subsets and Splits