text
stringlengths 0
1.67M
|
|---|
1. A screed for a paving machine comprising: a sole plate; a tamper positioned adjacent the sole plate; at least one electrical heating element mounted on the sole plate; and a heat conductor mounted on the sole plate, the heat conductor being arranged to conduct heat from said at least one heating element to the tamper. 2. A screed according to claim 1, in which said at least one heating element is a tubular element arranged such that electrical connectors for connecting said at least one heating element to a power source are central to the sole plate. 3. A screed according to claim 1, in which the heat conductor has a thermal conductivity greater than around 160 W/mK 4. A screed according to claims 3, in which the heat conductor is aluminum. 5. A screed according to claims 3, in which the heat conductor is copper. 6. (Canceled) 7. A method of heating a tamper for a paving screed, said screed including a sole plate having at least one electrical heating element, and a heat conductor positioned between said sole plate and said tamper, comprising the steps of: supplying electrical power to said at least one heating element and heating said sole plate; and heating said tamper by conducting heat from said sole plate to said tamper through said heat conductor. 8. (Canceled) |
Method and device for quenching steel in pressurized air |
The method for quenching a steel charge after carburizing or carbonitriding is carried out at atmospheric pressure and comprises the following steps: the charge is extracted from a treatment furnace (1) at a temperature ranging from 750 ° C. to 1100 ° C.; b) the charge is transferred to a quenching cell (3); c) a quenching fluid is introduced at a pressure which is higher than atmospheric pressure; d) the charge is cooled to a temperature of less than 400 ° C. According to the invention, the fluid is primarily composed of air, and the part is brought to a temperature of at least 400 ° C., whereby an oxide layer preventing decarburization is formed in the time period starting from the moment when the charge exits (1) from the furnace. |
1. Method of quenching of a steel charge after a treatment of carburization or carbonitriding, carried out at atmospheric pressure, comprising the following steps: a. the charge is removed from the treatment furnace (1) at a temperature between 750° C. and 1100° C., b. the charge is transferred to a quenching cell (3), c. a quenching fluid is introduced under a pressure greater than atmospheric pressure and it is put into circulation inside the cell, d. the charge is cooled to a temperature below 400° C., characterized by the fact that the fluid is composed mostly of air, and that the piece is brought to a temperature of at most 400° C. within a time from removal from the furnace (1) during which an oxide layer is formed which prevents decarburization of the steel. 2. Method according to claim 1, characterized by the fact that the transfer is carried out with open air, and the temperature of the charge is lowered to 600° C. in less than forty seconds, preferably in less than twenty seconds. 3. Method according to claim 1 or 2, characterized by the fact that the thickness of the oxide layer formed is less than 12 μm, preferably less than 5 μm. 4. Method according to claim 1, characterized by the fact that the transfer is carried out under a protecting atmosphere. 5. Method according to one of claims 1 to 4, characterized by the fact that the fluid is a mixture of air and of a gas, which modifies its density and/or its thermal conductivity. 6. Method according to one of claims 1 to 4, characterized by the fact that the fluid is a two-phase mixture of air/atomized liquid. 7. Method according to one of the preceding claims, in which the quenching fluid inside the cell is at a pressure between 3 and 40 bars, preferably between 5 and 20 bars. 8. Device for carrying out the method according to one of the preceding claims, characterized by the fact that it comprises a transfer handler and a quenching cell capable of holding the charge between the furnace and the cell at a surface temperature of 600° C. in less than forty seconds. 9. Device according to the preceding claim, characterized by the fact that the handler permits transfer in less than thirty seconds. 10. Device according to claim 8 or 9, characterized by the fact that the quenching cell comprises a turbine which allows lowering of the temperature of the surface of the pieces of the charge to 400° C. in less than 10 seconds. 11. Device according to one of claims 8 to 10, characterized by the fact that it is associated with a continuous furnace, a batch furnace, a bell furnace, a pit furnace operating at atmospheric pressure. |
Method And Apparatus For Video/Image Communication With Watermarking |
A video communication unit (405) includes a video input (415) for receiving an un-watermarked video or image signal transmission having a number of video or image frames (110, 120, 130, 140), wherein each video or image frame includes a number of bit planes, the video input (415) being operably coupled to a processor (410). The processor (410) splits at least one bit plane (116) from each of at least two video or image frames (205, 210) into a first and second portion. The processor combines (235, 242,232,245) a second portion of the at least one bit plane of a first frame with a first portion of the at least one bit plane of a second frame to apply a watermark bit to the video or image signal transmission. A video communication system and methods of detecting a tampered area and visually labelling the tampered area are described. This enables fraudulent tampering of images and video to be detected, and the location of such tampering to be revealed to users of the material. |
1. A video communication unit comprising a video input for receiving an un-watermarked video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the video input being operably coupled to a processor, the video communication unit characterised by said processor: splitting at least one bit plane from each of at least two video or image frames into a first and second portion; and combining a second portion of a bit plane of a first frame with a first portion of a bit plane of a second frame, to apply a watermark bit to the video or image signal transmission. 2. The video communication unit according to claim 1, wherein the combining of at least one bit plane from at least portions of two video or image frames is made between consecutive video or image frames. 3. The video communication unit according to claim 1, wherein the consecutive frames are then arranged such that they include the same watermarked bit plane. 4. The video communication unit according to claim 1, wherein the step of combining portions of at least one bit plane includes the step of discarding the portions that are not used to form the watermarked bit plane to be transmitted. 5. The video communication unit according to claim 1, wherein the combining of at least one bit plane is repeated throughout the video or image signal transmission. 6. The video communication unit according to claim 1, wherein the combining of at least one bit plane includes combining a subset of pixels within a frame. 7. A video communication unit according to claim 1, comprising a video receiver for receiving, from a transmitting video communication unit, a watermarked video signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the receiver being operably coupled to a processor, the video communication unit characterised by said processor comparing at least one bit plane of each of at least two video or image frames to detect any tampering of the watermark. 8. The video communication unit according to claim 7, further characterised by said processor determining whether a frame has been tampered with by comparing the at least one bit plane between the at least two frames, wherein: if said comparison shows equal bit planes, no tampering occurred; or if said comparison shows unequal bit planes, tampering occurred. 9. A video communication unit, in particular according to the video communication unit of claim 7, the video communication unit comprising a processor that detects tampering of an area of an image, the video communication unit characterised by said processor visually labelling, upon detection of said tampering, said area to inform a user viewing the video of said tampering. 10. The video communication unit according to claim 9, wherein said visual labelling includes replacing any or all of the tampered image with a known value such that the tampering is visible, for example black, white, any saturated colour, and/or any non-natural colour. 11. The video communication unit according to claim 9, wherein said visual labelling includes altering only a coloured appearance of a tampered pixel such that the underlying image content remains visible but the tampering is marked. 12. The video communication unit according to claim 9, wherein said visual labelling includes replacing one component of a tampered pixel with a known value in an image format comprising more than one component. 13. The video communication unit according to claim 9, wherein a complete image frame is visually labeled, when any of the pixels within said frame are detected as having been tampered with. 14. The video communication unit according to claim 13, wherein the complete image frame and all subsequent images in the video sequence within and/or following an image frame in which any of the pixels are detected as having been tampered with are visually labelled. 15. The video communication unit according to claim 1, wherein the watermark is applied to at least one of the following image formats: YCbCr, RGB, or any single component of an image format. 16. The video communication unit according to claim 1 wherein the watermark is applied in a restricted area or region of an image, or throughout the entire image. 17. A video transmission system comprising a video communication unit comprising a video input for receiving an un-watermarked video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the video input being operably coupled to a processor, the video communication unit characterised by said processor: splitting at least one bit plane from each of at least two video or image frames into a first and second portion; and combining a second portion of a bit plane of a first frame with a first portion of a bit plane of a second frame, to apply a watermark bit to the video or image signal transmission. 18. A mobile radio device comprising a video communication unit comprising a video input for receiving an un-watermarked video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the video input being operably coupled to a processor, the video communication unit characterised by said processor: splitting at least one bit plane from each of at least two video or image frames into a first and second portion; and combining a second portion of a bit plane of a first frame with a first portion of a bit plane of a second frame, to apply a watermark bit to the video or image signal transmission. 19. The mobile radio device of claim 18, wherein the mobile radio device is a mobile phone, a portable or mobile PMR radio, a personal digital assistant, a lap-top computer or a wirelessly networked PC. 20. A method of watermarking a video signal transmission in a video transmission system, the method comprising the step of: receiving an un-watermarked video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes; the method characterised by the steps of: splitting at least one bit plane from each of at least two video or image frames into a first and second portion; and combining a second portion of a bit plane of a first frame with a first portion of a bit plane of a second frame to apply a watermark bit to the video or image signal transmission. 21. The method of watermarking a video signal transmission according to claim 20, wherein the step of combining includes combining at least one bit plane from at least portions of each of two video or image frames between consecutive video or image frames. 22. The method of watermarking a video signal transmission according to claim 21, wherein the step of combining includes arranging the frames such that they include the same watermarked bit plane. 23. The method of watermarking a video signal transmission according to claim 20, the method further characterised by the step of: discarding the portions of the frames that are not used to form the watermarked bit plane to be transmitted. 24. The method of watermarking a video signal transmission according to claim 20, wherein the step of combining of at least one bit plane is repeated throughout the video or image signal transmission. 25. The method of watermarking a video signal transmission according to claim 20, wherein the step of combining includes the step of: combining a subset of pixels within a frame. 26. A method of detecting tampering of a watermarked digital image, the method comprising the steps of: receiving a digitally watermarked image having a number of video or image frames, wherein each video or image frame includes a number of bit planes, at least one of which is watermarked; the method characterised by the steps of: extracting said watermarked bit plane from each of at least two video or image frames; and comparing said at least one watermarked bit plane between each of said at least two video or image frames to detect any tampering of the watermark. 27. The method of detecting tampering of a watermarked digital image according to claim 26, wherein the step of detecting includes the step of: determining whether a frame has been tampered with by comparing the at least one bit plane between each of the at least two frames, wherein: if said comparison shows equal bit planes, no tampering occurred; or if said comparison shows unequal bit planes, tampering occurred. 28. A method of visually labelling a video sequence containing an attacked watermark, in particular according to the method of detecting tampering of a watermarked digital image of claim 26, the method comprising the step of: detecting tampering of an area of an image; the method characterised by the step of: visually labelling said area to inform a user viewing the video of said tampering. 29. The method of visually labelling a video sequence according to claim 28, the method further characterised by the step of: altering a coloured appearance of a tampered pixel to inform a user viewing the video/image sequence of said tampering. 30. The method of visually labelling a video sequence according to claim 28, wherein said visually labelling step includes the step of: replacing any or all of a tampered image with a known value such that the tampering is visible, for example black, white, any saturated colour, and/or any non-natural colour. 31. The method of visually labelling a video sequence according to claim 28, wherein said visually labelling step includes the step of: altering only a coloured appearance of a tampered pixel such that the underlying image content remains visible but the tampering is marked. 32. The method of visually labelling a video sequence according to claim 28, wherein said visually labelling step includes the step of: replacing one component of a tampered pixel with a known value in an image format comprising more than one component. 33. The method of visually labelling a video/image sequence according to claim 28, wherein said visually labelling step includes the step of: visually labelling a complete image frame within which any of the pixels are detected as having been tampered with. 34. A storage medium storing processor-implementable instructions for controlling one or more processors to carry out the method of watermarking a video signal transmission in a video transmission system, the method comprising the step of receiving an un-watermarked video or image signal transmission having a number of video or image frames, wherein each video or image frame includes a number of bit planes, the method characterised by the steps of: splitting at least one bit plane from each of at least two video or image frames into a first and second portion; and combining a second portion of a bit plane of a first frame with a first portion of a bit plane of a second frame to apply a watermark bit to the video or image signal transmission. 35-39. (canceled) 40. A mobile radio device comprising a video communication unit in accordance with claim 42. 41. The mobile radio device of claim 43, wherein the mobile radio device is a mobile phone, a portable or mobile PMR radio, a personal digital assistant, a lap-top computer or a wirelessly networked PC. 42. A storage medium storing processor-implementable instructions for controlling one or more processors to carry out a method of detecting tampering of a watermarked digital image, the method comprising the steps of receiving a digitally watermarked image having a number of video or image frames, wherein each video or image frame includes a number of bit planes, at least one of which is watermarked, the method characterised by the steps of: extracting said watermarked bit plane from each of at least two video or image frames; and comparing said at least one watermarked bit plane between each of said at least two video or image frames to detect any tampering of the watermark. 43. A storage medium storing processor-implementable instructions for controlling one or more processors to carry out a method of visually labelling a video sequence containing an attacked watermark, comprising the steps of: detecting tampering of an area of an image according to the method of claim 26; and visually labelling said area to inform a user viewing the video of said tampering. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The ability to transmit real-time video and/or image data is a desirable characteristic of many current wireline and wireless communication systems. However, it is known that individual images/pictures, or a series of images say, in a transmitted video stream, may be subjected to ‘attacks’, i.e. the images may have been tampered with. Therefore, a need exists to protect image or video transmissions from such undesirable tampering. One known technique employed to protect still/video images or documents is by the use of “watermarks”. In the context of the present invention, the terms ‘video’ and ‘image’ are used interchangeably, with the term ‘video’ generally used to represent one or more still images. Wolfgang R, Podilchuk C, Delp E “Perceptual watermarks for digital images and video”, SPIE Conference on Security and Watermarking of Multimedia Content, January 1999, describes some state of the art watermarking methods for use with video and images. Protection of digital media (including image and video) has also become a key standardisation topic within the multimedia industry over the last year. Police users have formally stated that they do not envisage using digitally transmitted and processed images for evidential purposes without the existence of reliable tamper detection methods. The European Broadcasting Union has issued a second call for systems that offer watermarking of multimedia transmissions for entertainment applications. In addition, the International Standards Organisation (ISO) has set up a working group known as MPEG-21, whose essential function is to investigate digital rights management including the authentication of multimedia data. In image watermarking, a known binary pattern or signature is embedded into an image at the moment of image acquisition. Such watermarks are termed “robust”, because they are designed to remain intact regardless of any post-processing of the image such as filtering, cropping, etc. While such watermarks do provide a useful degree of protection, they cannot at present be wholly relied on in a court of law. The purpose of these watermarking methods is such that they are not designed to possess the required degree of surety that an image has not been tampered with, in order for the image to be used as evidence. Thus, there exists a need in the field of the present invention to provide a video communication unit and methods, based on a watermarking system, that can be used for testing a video sequence for evidence of tampering, wherein the abovementioned disadvantages may be alleviated. Furthermore, there exists a need for a labelling method to highlight areas of a video sequence that are detected as having been tampered with. Additionally, it would be beneficial to visually label tampered video sequences such that they are rendered unusable, or valueless, to the attacker. Published United States patent applications U.S. Pat. No. 5,875,249 and U.S. Pat. No. 5,734,752 are known. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Exemplary embodiments of the present invention are now described with reference to the accompanying drawings, in which: FIG. 1 shows a watermark embedding method, in accordance with the preferred embodiment of the invention. FIG. 2 shows a random grid-based method using the 5th bit plane of a video sequence, in accordance with the preferred embodiment of the invention. FIG. 3 shows a flowchart of a decision process for determining whether tampering has occurred, in accordance with the preferred embodiment of the invention. FIG. 4 shows a block diagram of a video communication system incorporating a communication unit embedding a watermark, and a communication unit detecting a watermark, in accordance with the preferred embodiment of the invention. detailed-description description="Detailed Description" end="lead"? |
Back-illuminated msm module |
The invention relates to a BIMSM element (M,M′), in which at least the substrate (1,1′), the electrode pair (2) and the photosensitive layer (3) are combined in a monolithic structure. According to the invention, at least one electrode of the electrode pair (2) can be used to induce a modulation voltage, at least one electrode of the electrode pair (2) can be used to decouple a mixed product and the MSM element (M,M′) can be used as an electro-optical mixer. |
1. Back-illuminated MSM element (M, M′), having at least one substrate (1,1′), a electrode pair (2) attached above the substrate (1,1′), at least one light-sensitive layer 3, at least attached to the electrode pair (2), which can be illuminated on the side facing away from the electrode pair (2), characterized in that at least the substrate (1,1′), the electrode pair (2) and the light-sensitive layer (3) are jointly monolithically structured, at least one electrode of the electrode pair (2) can be used for coupling in a modulation voltage, at least one electrode of the electrode pair (2) can be used for decoupling a mixing product, the MSM element (M, M′) can be used as an electrooptical mixer. 2. MSM element (M, M′) according to claim 1, in which the light-sensitive layer (3) is coated with a passivation layer (4). 3. MSM element (M, M′) according to one of claims 1 or 2, in which there is a first insulating layer (6) between the substrate (1,1′) and electrode pair (2). 4. MSM element (M) according to one of claims 1 to 2, in which an electronic component, in particular an ASIC produced in VLSI technology, is integrated in the substrate (1). 5. MSM element (M) according to claim 4, in which the light-sensitive layer (3) is integrated in crystalline form in the electronic component (1). 6. MSM element (M′) according to one of claims 1 to 2, in which the substrate is an insulating layer (1′), in particular of ceramic or glass. 7. MSM element (M) according to one of the previous claims 1-2, in which the light-sensitive layer (3) is applied as an amorphous thin film, in particular with silicon as basic material. 8. MSM element (M, M′) according to one of the previous claims 1-2, the layer thicknesses (a, b, c) of which are chosen such that the permeability of the boundary surface to the light-sensitive layer (3) is wavelength-sensitive, in particular if the layer thicknesses (a, b, c) correspond to a quarter or a multiple of the preferred wavelength. 9. MSM array (MAR), having at least two MSM elements (M,M′) each with integrated evaluation circuits (7), in particular connected to common pixel electronics (8). 10. MSM array (MAR) according to claim 9, in which a readout circuit (7) is individually integrated in each MSM element (M,M′). 11. MSM array (MAR) according to claim 9 or 10, in which the frequency-dependent amplification is chosen such that there is no need for an upstream filter. 12. Process for producing an MSM element (M, M′) in which the substrate (1, 1′) is coated at least with the conductor structure (2), at least the conductor structure (2) is coated so that the semiconductor structure (2) forms thereon. |
Animal healthcare well-being and nutrition |
This invention relates to a method, system and apparatus for the management of comprehensive and cumulative genetic and health assessment databases in relation to animals worldwide. More specifically, the invention is directed to methods and systems that are used to determine animal health care, well-being and nutrition. |
1. A method of managing the health care and well-being of a non-livestock animal comprising the steps of: a) obtaining a database relating to at least one of: i. species of the animal, ii. a selected group of the species; b) obtaining data relating to the animal, the data including laboratory test data relating to the animal; c) relating the database of a) with the data of b) by a computer; and d) determining, based on c), a regimen for the management of the animal. 2. A method of managing the nutrition of a non-livestock animal comprising the steps of: a) obtaining a database relating to at least one of: i. species of the animal, ii. a selected group of the species; b) obtaining data relating to the animal, the data including laboratory test data relating to the animal; c) relating the database of a) with the data of b) by a computer; and d) determining, based on c), a nutritional regimen for the management of the animal. 3. A method of managing the health of a non-livestock animal comprising the steps of: a) obtaining a database relating to at least one of: i. species of the animal, ii. a selected group of the species; b) obtaining data relating to the animal, the data including diagnostic laboratory test data relating to the animal; c) relating the database of a) with the data of b) by a computer; and d) determining, based on c), a therapeutic intervention or maintenance for the management of the animal. 4. The method of claim 1, wherein further comprising obtaining genetic profile data relating the animal. 5. The method of claim 1, wherein the species and animal are canine. 6. The method of claim 1, wherein the species and animal are feline. 7. The method of claim 1, wherein the database of the selected group of the species is at least on of breed, age, sex, size, weight, performance use, or geographical location. 8. The method of claim 2, wherein the nutritional regimen is selected from the group consisting of foodstuffs, treats, drinks, nutritional supplements, holistic treatments and exercise. 9. The method of claim 3, wherein the therapeutic intervention or maintenance is selected from the group consisting of drugs, nutraceuticals, nutritional supplements, holistic treatments and exercise. 10. The method of claim 1 wherein the diagnostic laboratory test data is a comprehensive general health profile and selectively at least one selected diagnostic profile for a selected subject. 11. The method of claim 1 wherein the computer uses at least one of an expert system or interrelationship program or network for determining database and data relationships. 12. The method of claim 1 including the step of reporting the determination on a communications network including the Internet. 13. The method of claim 1 including the step of reporting the determination on a communications network including the Internet, and obtaining payment for the report through the Internet. 14. A method of modulating disease in a non-livestock animal comprising the steps of: a) obtaining a database relating to at least one of: i. a species of the animal ii. a selected group of the species; b) obtaining genotypic data relating to the animal, the genotypic data includes genetic profile data relating to DNA markers associated with the disease. c) relating the database of a) with the data of b) by a computer; and d) determining, based on c), a nutritional regimen to modulate the disease. 15. The method of claim 14, wherein modulating is inhibition of the disease. 16. The method of claim 14, wherein modulating is prevention of the disease. 17. A method of modulating a disease in a non-livestock animal comprising the steps of: a) performing a DNA test to determine a known DNA marker associated with a disease; b) obtaining the data from the DNA test; and c) determining based on b), a nutritional regimen to modulate the disease. |
<SOH> BACKGROUND OF THE INVENTION <EOH>A. Technical Field This invention relates to a method, system and apparatus for the management of comprehensive and cumulative genetic and health assessment databases in relation to animals worldwide. In particular, the invention relates to a bioinformatics system and its implementation in relation to animal biological data. More specifically, the invention is directed to methods and systems that are used to determine animal health care, well-being and nutrition. B. Related Art Substantial investments in time, effort and financial resources are made by breeders, owners, and caregivers of animals, particularly purebred animals, to characterize the animal's health state. This characterization may include determining the animal's genetic background and predicting the animal's morbidity, mortality and longevity. The probability that an individual animal will develop a specific health-related condition in its lifetime is a product of complex interactions between its genetic makeup, environmental influences including diet, and agents of disease (i.e., chemical, physical, or biological) that it encounters. Thus, perhaps the best indicator of overall health of an individual animal or breed is longevity. 1. Phenotype Data Generally, the phenotype is the genetic nature of an organism that is revealed by visible characteristics or measurable performance. Phenotype data or information includes physical descriptive and health assessment profile characteristics. These characteristics, include, for example physiological, pathological, endocrinological, hematological, epidemiological, behavioral, and immunological data from parameters such as phenotype, breed, lifespan, health history, and presence of infectious diseases and metabolic disorders. Blood and other biological samples of a subject animal are analyzed by laboratories having a central database processing resource (CDPR). This is a system for obtaining the phenotypic information. Communication systems are known for connecting these laboratories with veterinary clinics through a telephone and/or fax connection on an automated basis. These systems permit the veterinarian, animal hospital, or other authorized person (collectively or individually termed the “remote user”) to receive the health assessment profile and basic descriptive identifying data, namely phenotypic information, of a subject animal from the CDPR. Until recently, it was not possible for the remote user to access the CDPR directly to obtain this phenotypic information of a subject animal. Typically, a breeder and/or owner of animals obtains health assessments of their animals by submitting blood or other body fluid or tissue samples to a veterinarian or veterinary clinic. The veterinarian or veterinary clinic submits the sample to a laboratory for analysis of the biological, physiological, or pathological condition of the animal. The data (physical health of the animal) are reported to the owner through the veterinarian or veterinary clinic. The data also can be stored on the CDPR of the laboratory. Additionally, for each subject animal, the phenotypic data can be stored on a computer storage system at the veterinary clinic or in a computer storage system of the owner and/or breeder. The retrieval of the data can be electronically, by voice, hard copy, or fax as required. Seeking, obtaining and storing this phenotypic information is driven by the needs of the animal breeder, owner or the agent of the owner and the animal's healthcare provider. This information is sought to resolve the clinical, diagnostic, management, and therapeutic needs of an animal subject when the animal is in need of periodic wellness examination, is ill, or is to be restored to a well condition. 2. Genotype Data A second aspect of data associated with animals is genetic or genotype data or information. The genetic constitution of an organism includes genes without visible effects as well as those revealed by the phenotype. Genetic data are typically used to estimate the presence and prevalence of disease and/or disorder among different breeds or kinds of animals. Genotypic information is most often stored manually in a non-CDPR facility, for example, select clinical research databases, book form, hard copy, or genetic disease registries. Some of the genetic registries are related to specific diseases or disorders, for instance, hip dysplasia, eye conditions, thyroid conditions, and blood conditions. When retained in a genetic disease registry, the data typically list only those animals that are not affected with or carrying the heritable trait in question. These genetic registries are normally the subject of confidential knowledge of a breeder and/or owner, and not the subject of a generally accessible database. These are retained as confidential by the owners either for financial reasons, risk reasons, legal liability reasons, or personal reasons. Thus, genotypic information is transmitted manually to and from persons or local and national genotypic databases maintained for specific disorders, and designed to foster research into diseases and disorders, rather than being readily accessible to users for clinical purposes in the manner of phenotypic data on a CDPR 3. Failings of the Existing Systems There is a need to develop these data in a cumulative, comprehensive, and dynamic system of database management to thereby enhance the health predictability, and longevity of animals. This type of comprehensive and cumulative database on individual or groups of animals needs to be preserved and shared locally, regionally, nationally, and globally. A mechanism to do this is presently not known due to the various constraints surrounding each of the two types of databases. The phenotype database storage, use, and access is fashioned, formed and structured for use by clinical laboratories and veterinarians. The genotype information is fashioned and structured generally for clinical research and breeder/owner uses as opposed to clinical medical uses. There is also a need for a new database management bioinformatics scheme and relational database, together with computerized networks that manage, analyze, and/or integrate comprehensive and cumulative animal health assessment data and genetic identifier, genomic mapping, and genetic assessment data. Current laboratory and research systems and computerization have not achieved this, and nor have communication protocols been used effectively in this technological area to facilitate such a relationship or relational bioinformatics database system for management and dissemination of this comprehensive and cumulative information. More specifically, it is necessary in animal health diagnosis and care that appropriate predictive testing for diseases and disorders of animals be achieved in order to reduce morbidity and mortality, and improve the quality of life and lifespan. Currently, available testing is unnecessarily complex and expensive in relation to the ability to be an accurate predictor of diseases and disorders in animals. The present invention is the first to store and/or present phenotypic information and genotypic information as a comprehensive and cumulative assessment of individual animal subjects, families of subjects, breeds of subjects, or species of animals in a computerized format which is available through computer networking to authorized remote users. |
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>One embodiment of the present invention is a dynamic method and system of managing the health care and well-being of a non-livestock animal subject. Such an animal is preferably a canine subject or a feline subject. This method comprises obtaining a database relating to at least one of the species of the animal or selected group of the species. Next, the method comprises obtaining data relating to the animal, for example laboratory test data relating to the animal. The next step involves relating the database with the data using a computer; and determining a regimen for the management of the animal. A further embodiment of the present invention is a method of managing the nutrition of a non-livestock animal. This method comprises obtaining a database relating to at least one of the species of the animal or selected group of the species. Next, the method comprises obtaining data relating to the animal, for example laboratory test data relating to the animal. The next step involves relating the database with the data using a computer; and determining a nutritional regimen for the management of the animal. The nutritional regimen is at least related to the nutrient or caloric composition, or the food allergies and food intolerances. The therapeutic intervention or maintenance may include drugs, nutraceuticals, vitamins, antioxidants, holistic treatments, exercise or liquid intake. Another embodiment of the present invention is a method of managing the health of a non-livestock animal. This method comprises obtaining a database relating to at least one of the species of the animal or selected group of the species. Next, the method comprises obtaining data relating to the animal, for example laboratory test data relating to the subject. The next step involves relating the database with the data using a computer; and determining a therapeutic intervention or maintenance for the management of the animal. The database of at least one of the species or the group is periodically updated thereby to obtain cumulative data of the species or group. Preferably both these data bases are used, and preferably both are updated to obtain the cumulative data. The data of the animal is periodically updated thereby to obtain cumulative data. Preferably, both the databases are periodically updated. The updating picks up data drift in different populations of the animals, groups and species over time, and thereby allows for the regulation of the database so as to be substantially or essentially current. The invention also includes the step of reporting the determination of the health care, well-being, nutrition or other therapeutic requirements and suggestions or health on a communications network including the Internet. Preferably, there is a payment procedure for the report which is achieved through the Internet. This communication network and structure is described here in further detail. Yet further, another embodiment of the present invention is a method of modulating disease of a non-livestock animal. This method comprises obtaining a database relating to at least one of the species of the animal or selected group of the species. Next, the method comprises obtaining genotypic data relating to the animal, for example genotypic data relating to the animal. The next step involves relating the database with the data using a computer; and determining a nutritional regimen to modulate the disease. Another embodiment of the present invention is a method of modulating a disease in a non-livestock animal comprising performing a DNA test to determine a known DNA marker associated with the disease and determining a nutritional regimen to modulate the disease based on the data obtained from the DNA test. The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the following detailed description of the invention may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only, and is not intended as a definition of the limits of the present invention. |
Polyolefins made by catalyst comprising a noncoordinating anion and articles comprising them |
Polymers made by transition metal catalyst systems comprising a bulky noncoordinating anion (NCA) as cocatalyst component. In comparison to polymers containing a conventional NCA, these polymers show a considerably lower dielectric loss, making them suitable for insulation applications such as for power cable. |
1. An article of manufacture comprising (i) an electrically conductive member comprising at least one electrically conductive substrate and (ii) at least one electrically insulating member comprising at least one polymer based on one or more monomers selected from monoolefins and diolefins, wherein the at least one polymer comprises a residue of a polymerization catalyst, the polymerization catalyst comprising a non-polymeric noncoordinating anion having at least 33 atoms Z that are different from hydrogen and fluorine atoms. 2. The article of claim 1, wherein the electrically conductive member is surrounded by the at least one electrically insulating member. 3. The article of claim 1, wherein the at least one polymer is selected from homo- and copolymers of ethylene. 4. The article of claim 3, wherein the at least one polymer comprises units derived from ethylene and at least one α-olefin having from 3 to 20 carbon atoms. 5. The article of claim 4, wherein the at least one polymer further comprises units derived from at least one diene having 4 to 20 carbon atoms. 6. The article of claim 1, wherein the polymerization catalyst comprises a transition metal complex. 7. The article of claim 6, wherein the transition metal complex comprises a metallocene. 8. The article of claim 7, wherein the metallocene comprises a metal selected from Ti, Zr and Hf. 9. The article of claim 1, wherein the noncoordinating anion comprises at least 37 atoms Z independently selected from Groups 3-17. 10. The article of claim 9, wherein the noncoordinating anion comprises not more than 180 atoms Z. 11. The article of claim 10, wherein the atoms Z are independently selected from B, Al, Ga, C, Si, Ge, N, P, O, Cl, Br, and elements of Groups 3-12. 12. The article of claim 11, wherein the atoms Z comprise C and at least one of B, Al, Si, N and P. 13. The article of claim 12, wherein at least 75% of the atoms Z are carbon atoms. 14. The article of claim 1, wherein the non-coordinating anion comprises: (a) M central core atoms of an element selected from Groups 3-12, 13, 14 and 15 and the lanthanides; and, directly or indirectly bonded thereto, (b) at least (33 minus m) atoms selected from atoms of one or more of Groups 13, 14, 15 and 16, chlorine, bromine and iodine. 15. The article of claim 14, wherein the central core atom(s) comprise(s) at least one of B, Al, Si and P. 16. The article of claim 9, wherein the noncoordinating anion comprises at least one unit of general formula (I): -MR1R2R3 . . . Rn (I) wherein: M is an element selected from Groups 13-15; R1 and R2 are independently selected from (a) radicals comprising a ring system having at least 9 ring members; and (b) radicals comprising a ring having 5 to 8 ring members and at least one substituent group comprising at least 5 atoms selected from carbon, nitrogen, oxygen, silicon, phosphorus, chlorine, and bromine; R3 to Rn are (is) independently selected from the above radicals ,(a) and (b), halogen, and hydrocarbyl; and n equals the valence of M minus 1. 17. The article of claim 16, wherein M is selected from B, Al, Si and P. 18. The article of claim 16, wherein M is selected from B and Al. 19. The article of claim 17, wherein R3 to Rn are (is) independently selected from the radicals (a) and (b), halogen, unsubstituted phenyl and halogen-substituted phenyl. 20. The article of claim 17, wherein at least three of R1 to Rn are identical. 21. The article of claim 16, wherein the ring system having at least 9 ring members is selected from naphthyl, indenyl, fluorenyl, anthracyl, phenanthryl and azulyl. 22. The article of claim 21, wherein the ring system is fluorinated naphthyl. 23. The article of claim 16, wherein the ring comprising 5 to 8 ring members is selected from aromatic and heteroaromatic rings. 24. The article of claim 23, wherein the ring comprises fluorinated phenyl. 25. The article of claim 14, wherein the at least one substituent group comprises at least 6 atoms selected from C, N, O, Si, and Cl. 26. The article of claim 23, wherein the at least one substituent group comprises a fluorinated phenyl group. 27. An electrical cable comprising a metal conductor and at least one electrically insulating member surrounding the conductor, the at least one electrically insulating member comprising at least one polyolefin comprising ethylene units, wherein the at least one polyolefin has been prepared with a catalyst comprising a cationic metallocene species and a noncoordinating anion, the noncoordinating anion having at least 33 atoms Z that are different from hydrogen and fluorine atoms and comprising at least one unit of general formula (II): —BAr1Ar2Ar3 (II) wherein Ar1 to Ar3 are aryl radicals, at least two of the aryl radicals selected from (i) fused aromatic ring systems having at least 10 carbon atoms; and (ii) phenyl groups having at least one substituent selected from phenyl groups, naphthyl groups, hydrocarbylsilyl groups and moieties comprising at least one of these groups. 28. The cable of claim 27, wherein the noncoordinating anion is of the general formula (III): [BAr1Ar2Ar3Ar4]! (III) wherein Ar4 has the meanings given for Ar1 to Ar3. 29. The cable of claim 27, wherein the cable is a medium voltage cable. 30. The cable of claim 28, wherein all of Ar1 to Ar4 are selected from categories (i) and (ii). 31. The cable of claim 27, wherein Ar1 to Ar3 are identical and fluorinated. 32. The cable of claim 27, wherein at least two of Ar1 to Ar3 are selected from naphthyl, anthracyl and phenanthryl. 33. The cable of claim 28, wherein all of Ar1 to Ar4 are perfluorinated fused aromatic ring systems. 34. The cable of claim 27, wherein the hydrocarbylsilyl groups are selected from triarylsilyl and trialkylsilyl groups. 35. The cable of claim 27, wherein the moieties (ii) are selected from aryloxy; aryloxyalkyl; aralkoxy; aryl-trihydrocarbylsilylalkyl; N-alkyl-N-arylamino; N-trihydrocarbylsilyl-N-arylamino; N-alkyl-N-trihydocarbylsilylamino; diarylamino; bis(trihydrocarbylsilyl)amino; aryloxyaryl; aryloxyalkaryl; arylalkoxyaryl; (aryl-trihydrocarbylsilylalkyl)aryl; (N-alkyl-N-arylamino)aryl; (N-trihydrocarbylsilyl-N-arylamino)aryl; (N-alkyl-N-trihydocarbylsilylamino)aryl; diarylaminoaryl; and [bis(trihydrocarbylsilyl)]aminoaryl. 36. The cable of claim 35, wherein the moieties (ii) are selected from phenoxy; naphthoxy; phenoxyalkyl; naphthoxyalkyl; phenylalkoxy; phenyl-trihydrocarbylsilylalkyl; N-alkyl-N-phenylamino; N-trihydrocarbylsilyl-N-phenyl-amino; N-alkyl-N-trihydocarbylsilylamino; diphenylamino; bis(trihydrocarbyl-silyl)amino; N-naphthyl-N-trihydrocarbylsilylamino; phenoxyphenyl; naphthoxy-phenyl; phenoxyalkylphenyl; naphthoxyalkylphenyl; phenylalkoxyphenyl; (phenyl-trihydrocarbylsilylalkyl)phenyl; (N-alkyl-N-phenylamino)phenyl; (N-trihydrocarbylsilyl-N-phenylamino)phenyl; (N-alkyl-N-trihydocarbylsilylamino)-phenyl; diphenylaminophenyl; [bis(trihydrocarbylsilyl)amino]phenyl and (N-naphthyl-N-trihydrocarbylsilylamino)phenyl. 37. The cable of claim 35, wherein the moieties (ii) are selected from fluorophenoxy; fluoronaphthoxy; fluoronaphthoxyalkyl; fluorophenoxyalkyl; fluorophenylalkoxy; fluorophenyl-trialkylsilylalkyl; N-alkyl-N-fluorophenylamino; N-trialkylsilyl-N-fluorophenylamino; N-alkyl-N-trialkylsilylamino; bis(fluorophenyl)amino; bis(trialkylsilyl)amino; N-fluoronaphthyl-N-trialkylsilylamino; fluorophenoxy-fluorophenyl; fluoronaphthoxyfluorophenyl; (fluoronaphthoxyalkyl)-fluorophenyl; (fluorophenoxyalkyl)fluorophenyl; (fluorophenylalkoxy)fluorophenyl; (fluorophenyl-trialkylsilylalkyl)fluorophenyl; (N-alkyl-N-fluorophenylamino)-fluorophenyl; (N-trialkylsilyl-N-fluorophenylamino)fluorophenyl; (N-alkyl-N-trialkylsilylamino)fluorophenyl; [bis(fluorophenyl)amino]fluorophenyl; [bis-(trialkylsilyl)-amino]fluorophenyl and (N-fluoronaphthyl-N-trialkylsilylamino) fluorophenyl. 38. The cable of claim 28, wherein Ar1 to Ar4 are selected from perfluoronaphthyl; perfluorodiphenyl; N-perfluorophenyl-N-tri(C1-C8 alkyl)silylamino-tetrafluoro-phenyl; tris(C3-C8 alkyl)siloxy-tetrafluorophenyl; bis(perfluorophenyl)fluoro-methyltetrafluorophenyl; (perfluoronaphthyl)perfluorophenyl; (perfluoro-diphenyl)perfluorophenyl; [N-perfluorophenyl-N-tri(C1-C8alkyl)silylamino tetrafluorophenyl]perfluorophenyl; [tris(C3-C8alkyl)siloxytetrafluorophenyl]-perfluorophenyl; and [bis(perfluorophenyl)fluoromethyltetrafluorophenyl]-perfluorophenyl. 39. The cable of claim 38, wherein Ar1 to Ar4 are selected from perfluoro-1-naphthyl; perfluoro-2-naphthyl; perfluoro-p-diphenyl; 4-(N-perfluorophenyl-N-trimethylsilyl- amino)tetrafluorophenyl; 4-(N-perfluorophenyl-N-triethylsilylamino)tetrafluoro-phenyl; 4-triisopropylsiloxy-tetrafluorophenyl; and 4-bis(perfluorophenyl)-fluoromethyl-tetrafluorophenyl. 40. The cable of claim 29, wherein the electrically insulating member has a dielectric tan delta after 14 days in water at 90° C., as determined by ASTM D 150-95, of less than 0.02. 41. A method of improving the dielectric loss properties of a polymer made by contacting one or more olefinic monomers under polymerization conditions with a transition metal catalyst comprising a noncoordinating anion, which method comprises using as the noncoordinating anion an anion having at least 33 atoms Z independently selected from B, Al, Ga, C, Si, Ge, N, P, O, Cl, Br, and elements of Groups 3-12. 42. The method of claim 41, wherein the polymer is an ethylene-based polymer. 43. The method of claim 42, wherein the polymer is selected from polyethylenes, EPMs, and EPDMs. 44. The method of claim 41, wherein the atoms Z comprise at least boron and carbon. 45. The method of claim 44, wherein the noncoordinating anion has a molecular weight of at least 900. 46. The method of claim 42, wherein the catalyst comprises a metallocene complex. 47. The method of claim 46, wherein the metallocene complex comprises at least one of Zr and Hf. 48. A process for making an electrical cable comprising the steps of: (a) providing an electrically conductive member comprising a metal conductor; and (b) surrounding the electrically conductive member with at least. one electrically insulating member comprising at least 20 weight-% of at least one olefinic polymer; wherein the at least one olefinic polymer is based on ethylene and one or more olefins selected from a-olefins having from 3 to 20 carbon atoms and non-conjugated dienes having from 4 to 20 carbon atoms, wherein the at least one polymer has been prepared in the presence of a metallocene-based catalyst comprising a noncoordinating anion, the non-coordinating anion comprising at least one unit of general formula (I): -MR1R2R3 (I) wherein: M is B or Al; R1 to R3 are independently selected from (a) fused aromatic ring systems having at least 10 ring members; and (b) phenyl groups having at least one substituent group comprising at least 9 atoms selected from carbon, nitrogen, oxygen, silicon and chlorine. 49. A process for making a polyolefin suitable for use in an electrically insulating composition by polymerizing one or more olefins in the presence of a transition metal catalyst, wherein the process comprises using a catalyst comprising a cationic metallocene species and a noncoordinating anion of the general formula (III): [BAr1Ar2Ar3Ar4]! (III) wherein Ar1 to Ar4 are aryl radicals, at least three of the aryl radicals selected from (i) fused aromatic ring systems having 10 to 30 ring members; and (ii) phenyl groups having at least one substituent selected from phenyl groups, naphthyl groups, trialkylsilyl groups and moieties comprising at least one of these groups. 50. A composition suitable for electrical insulation purposes, the composition comprising at least 30% by weight, based on the composition, of at least one polymer comprising a catalyst residue, the catalyst comprising a non-polymeric noncoordinating anion, wherein the composition shows a dielectric tan delta after 14 days in water at 90° C., as determined by ASTM D 150-95, of less than 0.015. 51. The composition of claim 50, wherein the composition comprises at least one additional polymer not made by a noncoordinating anion containing catalyst. 52. The composition of claim 51, wherein the composition comprises at least 50% by weight of the at least one polymer. 53. The composition of claim 52, wherein the composition shows a dielectric tan delta of less than 0.013. 54. An olefinic polymer comprising a residue of a transition metal catalyst, the catalyst comprising a non-polymeric noncoordinating anion, wherein the polymer has a dielectric tan delta after 14 days in water at 90° C., as determined by ASTM D 150-95, of less than 0.02, based on a catalyst efficiency of 10,000 g polymer/mmol transition metal. 55. An article of manufacture comprising (i) an electrically conductive member comprising at least one electrically conductive substrate and (ii) at least one electrically insulating member comprising at least one polymer based on one or more monomers selected from monoolefins and diolefins, wherein the at least one polymer comprises a residue of a polymerization catalyst, the catalyst comprising a transition metal complex and a non-polymeric noncoordinating anion having at least 33 atoms Z that are different from hydrogen and fluorine atoms wherein the insulating member has a dielectric tan delta values less than 650.64x−0.971, where x=the polymerization activity of the catalyst in grams polymer/mmole transition metal complex, after 14 days in water at 90° C. according to ASTM D-150-95. 56. The article of claim 55, wherein the at least one polymer is selected from homo- and copolymers of ethylene. 57. The article of claim 56, wherein the at least one polymer further comprises units derived from at least one diene having 4 to 20 carbon atoms. 58. The article of claim 55, wherein the transition metal complex comprises a metallocene. 59. The article of claim 1, wherein the noncoordinating anion comprises at least 37 atoms Z independently selected from Groups 3-17. 60. The article of claim 55, wherein the noncoordinating anion comprises not more than 180 atoms Z. 61. The article of claim 55, wherein the atoms Z are independently selected from B, Al, Ga, C, Si, Ge, N, P, O, Cl, Br, and elements of Groups 3-12. 62. The article of claim 55, wherein the atoms Z comprise C and at least one of B, Al, Si, N and P. 63. The article of claim 55, wherein the non-coordinating anion comprises: (a) M central core atoms of an element selected from Groups 3-12, 13, 14 and 15 and the lanthanides; and, directly or indirectly bonded thereto, (b) at least (33 minus m) atoms selected from atoms of one or more of Groups 13, 14, 15 and 16, chlorine, bromine and iodine. 64. The article of claim 63, wherein the central core atom(s) comprise(s) at least one of B, Al, Si and P. 65. An article of manufacture comprising (i) an electrically conductive member comprising at least one electrically conductive substrate and (ii) at least one electrically insulating member comprising at least one polymer based on one or more monomers selected from monoolefins and diolefins, wherein the at least one polymer comprises a residue of a polymerization catalyst, the catalyst comprising a transition metal complex and a non-polymeric noncoordinating anion having at least 33 atoms Z that are different from hydrogen and fluorine atoms wherein the insulating member has a dielectric tan delta values less than 650.64x−0971, where x=the polymerization activity of the catalyst in grams polymer/mmole transition metal complex, after 14 days in water at 90° C. according to ASTM D-150-95n, and wherein the noncoordinating anion comprises at least one unit of general formula (I): -MR1R2R3 . . . Rn (I) wherein: M is an element selected from Groups 13-15; R1 and R2 are independently selected from (a) radicals comprising a ring system having at least 9 ring members; and (b) radicals comprising a ring having 5 to 8 ring members and at least one substituent group comprising at least 5 atoms selected from carbon, nitrogen, oxygen, silicon, phosphorus, chlorine, and bromine; R3 to Rn are (is) independently selected from the above radicals (a) and (b), halogen, and hydrocarbyl; and n equals the valence of M minus 1. 66. The article of claim 65, wherein M is selected from B and Al. 67. The article of claim 65, wherein R3 to Rn are (is) independently selected from the radicals (a) and (b), halogen, unsubstituted phenyl and halogen-substituted phenyl. 68. The article of claim 65, wherein the ring system is fluorinated naphthyl. 69. The article of claim 65, wherein the ring comprises fluorinated phenyl. 70. The article of claim 65, wherein the at least one substituent group comprises a fluorinated phenyl group. 71-91. (canceled) |
<SOH> DISCUSSION OF BACKGROUND <EOH>The term “noncoordinating anion” is now accepted terminology in the field of olefin and vinyl monomer polymerization to indicate an anion that stabilizes (stabilizing anion) a transition metal cation. This cation is generally accepted to be the active site in Ziegler-Natta catalysts. For example, the polymerization may be a coordination, insertion or carbocationic polymerization. See, e.g., EP 0 277 003, EP 0 277 004, U.S. Pat. Nos. 5,198,401 and 5,278,119, and Baird, Michael C., et al, J. Am. Chem. Soc. 1994, 116, 6435-6436, the disclosures of which are expressly incorporated herein by reference in their entireties for purposes of U.S. patent practice. NCAs are described to function as electronic stabilizing cocatalysts, or counterions, for essentially cationic metallocene complexes that are active for polymerization. The term “noncoordinating anion” as used herein applies both to truly noncoordinating anions and coordinating anions that are at most weakly coordinated to the cationic complex so as to be labile to replacement by olefinically or acetylenically unsaturated monomers at the insertion site. In solid insulations, dielectric loss under alternating current (ac) field conditions commonly arises from relaxation processes associated with dipole orientation (polarization) and the movement of free charge carriers such as ions or electrons (conduction). The most commonly used parameter for expressing the dielectric loss of an insulator is the dissipation factor (tan δ). Dielectric tan δ, analagous to dynamic mechanical loss tan δ, is a measure of the ratio of the energy dissipated to the energy stored during a complete cycle of loading and unloading. However, in this case the load is an ac voltage rather than an oscillating mechanical strain. Ion conduction processes can lead to significant power losses in insulating materials if ionic charge carriers are present. Electrical insulation applications are generally divided into low voltage insulation, which are those applications which generally involve less than 1,000 volts (1K volts), medium voltage insulation applications which generally range from 1,000 volts to 35,000 volts, and high voltage insulation applications, generally above 35,000 volts Typical power cables such as those made for medium voltage applications include one or more conductors in a core that is generally surrounded by several layers that can include a first polymeric semi-conducting shield layer, a polymeric insulating layer and a second polymeric semi-conducting shield layer, a metallic tape and a polymeric jacket. A wide variety of polymeric materials have been utilized as electrical insulating and semi-conducting shield materials for power cable (e.g., building wire, electric motor wire, machinery power wire, underground power transmitting cable, and the like) and numerous other electrical applications. In elastomers or elastomer-like polymers often used as one or more of the polymer members in electrical devices such as, e.g., power cables, ethylene/alpha-olefin/non-conjugated diene elastic polymer materials that have come into wide use usually include ethylene, an α-olefin such as, e.g., propylene, and a non-conjugated diene such as, e.g., 5-ethylidene-2-norbornene (ENB), 1,4-hexadiene, 1,6-octadiene, 5-methyl-1,4-hexadiene, 3,7-dimethyl-1,6-octadiene, and the like. Such polymers made with conventional Ziegler-Natta catalysts usually provide a good insulating property for power cables. In comparison to conventional Ziegler-Natta catalysts (such as those based on titanium and vanadium transition metal compounds), metallocene-based catalysts offer a number of advantages that would make the latter appear to be even more suitable for the production of polymers and in particular, polyolefins to be used for electrical devices than the former. For example, due to the usually much higher activity of metallocene-based catalysts, the polyolefin made therewith can be expected to contain much less catalyst (metal) residue (“ash”) than a corresponding Ziegler-catalyzed polyolefin. This reduced ash content translates into a reduced number of metal ions in the final polymer that can contribute to electrical conductivity. Furthermore, in order to reduce the relatively high residual transition metal (e.g., Ti and/or V) content of Ziegler-catalyzed polymers, these polymers are often washed by slurrying them in a suitable aqueous liquid. To make this washing operation effective, slurrying aids such as calcium stearate are added to the aqueous liquid to keep agglomeration of polymer particles at a minimum. As a result thereof the washed polymer, while having a reduced transition metal content, contains ions derived from the slurrying aid (e.g., calcium ions) that adversely affect the insulating properties of the polymer. Since metallocene-based catalysts overcome the above-discussed problems associated with the less active, conventional Ziegler-Natta catalysts, metallocene-catalyzed polyolefins would be expected to exhibit lower dielectric loss and, therefore, even better insulating property than polyolefins made by Ziegler catalysts. However, polyolefins made with catalysts derived from a metallocene catalyst precursor compound and a cocatalyst (activator) compound which includes a typically used NCA such as tetrakis(pentafluorophenyl)borate, B(C 6 F 5 ) 4 − , show a higher dielectric loss than conventional Ziegler-Natta catalyzed polyolefins, making the former less suitable for electrical insulation purposes. In the case of NCA-activated metallocene-catalyzed polyolefins ionic cocatalyst residues are known to be present in the polymers. These ions are believed to be major contributors to the high dielectric loss observed in these polymers. One way to avoid this problem in polymers to be used for electrical devices is to use metallocene cocatalysts that can easily be decomposed into uncharged species upon completion of the polymerization. A typical example of such a cocatalyst is an alumoxane such as methylalumoxane (MAO) which can easily be hydrolyzed to form methane and aluminum hydroxide (see, e.g., U.S. Pat. No. 5,246,783, incorporated herein by reference in its entirety for purposes of U.S. patent practice). However, while with an NCA such as B(C 6 F 5 ) 4 − the molar ratio of metallocene transition metal (e.g., Zr) to NCA can be kept close to 1:1, a relatively large excess of alumoxane Al over the metallocene transition metal (e.g., 10:1 and higher) is needed to achieve high catalyst activity, thereby increasing the amount of catalyst residue (in particular, Al) in the resulting polymer. One of the reasons for the lower amount of NCA needed to activate the metallocene in comparison to an alumoxane is believed to be that the NCA is a stoicheometric activator (1 mole NCA:i mole metallocene). The stability of the NCA causes a problem after completion of the polymerization in that unlike an alumoxane, an NCA such as B(C 6 F 5 ) 4 − is very hard to decompose, i.e., it cannot easily be converted into uncharged species that do not compromise the electrical insulation properties of the polymer containing them. It is thought that the presence of stable anions, even in very low concentrations, cause dielectric loss due to their high mobility within the polymer interfaces. In view of the foregoing, there is a need for an NCA cocatalyst that, while showing a high stability, does not later cause any significant conductivity problems in the finished polymer. It would, thus be desirable to have available polyolefins made by an unsupported, highly active NCA containing catalyst system (such as a metallocene-based catalyst system) which show a dielectric loss that is low enough (i.e., have a sufficiently low tan delta) for making them suitable for use in electrical devices, e.g., for power cable applications. |
<SOH> SUMMARY OF THE INVENTION <EOH>We have discovered that the dielectric loss properties of olefinic polymers made by catalyst systems comprising unsupported NCAs can be improved using selected NCAs, particularly those in which the shielding ligands are sufficiently bulky. Presumably, the bulky nature of these activators reduce their mobility and thereby reduce dielectric loss. In one aspect, the invention provides an article of manufacture which comprises (i) an electrically conductive member comprising at least one electrically conductive substrate and (ii) at least one electrically insulating member comprising at least one polymer based on one or more monomers selected from monoolefins and diolefins. This polymer comprises a residue of a polymerization catalyst which comprises a non-polymeric NCA having at least 33 atoms Z that are different from H and F. (“Residue” in the present context means catalyst-derived material that is left behind in the finished polymer after polymerization and optional further processing). The electrically conductive member usually comprises a metal conductor and is surrounded, at least in part, by the at least one electrically insulating member. Furthermore, the at least one polymer may be selected from homo- and copolymers of ethylene, and in one embodiment it comprises units derived from ethylene and at least one α-olefin having from 3 to 20 carbon atoms. In another embodiment the at least one polymer further comprises units derived from at least one diene having 4 to 20 atoms. In still another aspect, the catalyst further comprises a transition metal complex that comprises a metallocene and sometimes the metallocene comprises Ti, Zr or Hf. In a further aspect, the NCA comprises at least 37 atoms Z independently selected from Groups 3-17. In some embodiments, the NCA comprises not more than 180 atoms Z. In another aspect, the atoms Z may independently be selected from B, Al, Ga, C, Si, Ge, N, P, O, Cl, Br, and elements of Groups 3-12. According to some embodiments, the atoms Z comprise C and at least one of B, Al, Si, N and P. Often at least 75% of the atoms Z will be carbon atoms. In a further aspect, the NCA can comprise (a) one or more central core atoms of elements selected from Groups 3-12, 13, 14 and 15 and the lanthanides; and, directly or indirectly bonded thereto, (b) at least (33-m) atoms selected from atoms of one or more of Groups 13, 14, 15 and 16, chlorine, bromine and iodine, m being the number of central core atoms (a). (“Directly or indirectly bonded thereto” means that an atom (b) is directly bonded to a central core atom (a) through a covalent bond or that the atom (b) is bonded to a central core atom (a) through one or more other atoms (b) with covalent bonds between these atoms and between these atoms and the central core atom (a)). Some embodiments select the central core atom(s) of the NCA from B, Al, Si, and P. In some embodiments of the present invention the NCA comprises at least one unit of general formula (I): in-line-formulae description="In-line Formulae" end="lead"? -MR 1 R 2 R 3 . . . R n (I) in-line-formulae description="In-line Formulae" end="tail"? wherein M is an element selected from Groups 13-15 and R 1 and R 2 are independently selected from radicals comprising a ring system having at least 9 ring members; and radicals comprising a ring having 5 to 8 ring members and at least one substituent group comprising at least 5 atoms selected from carbon, nitrogen, oxygen, silicon, phosphorus, chlorine and bromine. R 3 to R n are (is) independently selected from the above radicals for R 1 and R 2 , halogen, and hydrocarbyl, while n equals the valence of M minus 1. By way of non-limiting, illustrative example, M may be B, Al, Si, and P. In some embodiments, M is B or Al. Also, R 3 to R n may independently be selected from the radicals given for R 1 and R 2 , halogen, unsubstituted phenyl and halogen-substituted phenyl and at least three of R 1 to R n may be identical. Examples of the ring system having at least 9 ring members are naphthyl, indenyl, fluorenyl, anthracyl, phenanthryl and azulyl, e.g., fluorinated naphthyl. In yet another aspect, the ring comprising 5 to 8 ring members is selected from aromatic and heteroaromatic rings. For example, it may be fluorinated phenyl. In some embodiments, the at least one substituent group for the ring comprising 5 to 8 members comprises at least 6 atoms selected from C, N, O, Si, and Cl. Illustratively, this substituent group may comprise a fluorinated phenyl group. According to some aspects, the present invention provides an electrical cable, such as a medium voltage cable, which comprises an electrical conductor and at least one electrically insulating member, the at least one electrically insulating member comprising at least one polyolefin comprising ethylene units and prepared by a catalyst comprising a cationic metallocene species and an NCA, the NCA having at least 33 atoms Z that are different from hydrogen and fluorine atoms and comprising at least one unit of general formula (II): in-line-formulae description="In-line Formulae" end="lead"? —BAr 1 Ar 2 Ar 3 (II) in-line-formulae description="In-line Formulae" end="tail"? wherein Ar 1 to Ar 3 are aryl radicals. At least two of the aryl radicals are selected from (i) fused aromatic ring systems having at least 10 carbon atoms; and (ii) phenyl groups having at least one substituent selected from phenyl groups, naphthyl groups, hydrocarbylsilyl groups and moieties comprising at least one of these groups. In some embodiments, the NCA is of the general formula (III): in-line-formulae description="In-line Formulae" end="lead"? [BAr 1 Ar 2 Ar 3 Ar 4 ] − (III) in-line-formulae description="In-line Formulae" end="tail"? wherein Ar 4 has the same meanings given for Ar 1-3 . According to another aspect, the cable is a medium voltage cable. In another aspect, all of Ar 1 to Ar 4 are selected from the above fused aromatic ring systems and the above phenyl groups. Also, in some embodiments, Ar 1 to Ar 4 are identical and fluorinated. Further, at least two of these or other embodiments, Ar 1 to Ar 3 are selected from naphthyl, anthracyl and phenanthryl. Still further, these or other embodiments all of Ar 1 to Ar 4 may be perfluorinated fused aromatic ring systems. Some embodiments select triarylsilyl and trialkylsilyl groups as the hydrocarbylsilyl groups. According to another aspect, the above moieties (ii) which comprise at least one of a phenyl group, naphthyl group and hydrocarbylsilyl group are selected from aryloxy; aryloxyalkyl; arylalkoxy; aryl-trihydrocarbylsilylalkyl; N-alkyl-N-arylamino; N-trihydrocarbylsilyl-N-arylamino; N-alkyl-N-trihydocarbylsilylamino; diarylamino; bis(trihydrocarbylsilyl)amino; aryloxyaryl; aryloxyalkaryl; arylalkoxyaryl; (aryl-trihydrocarbylsilylalkyl)aryl; (N-alkyl-N-arylamino)aryl; (N-trihydrocarbylsilyl-N-arylamino)aryl; (N-alkyl-N-trihydocarbylsilylamino)aryl; diarylaminoaryl; and [bis(trihydrocarbylsilyl)]aminoaryl; and, in particular, from phenoxy; naphthoxy; phenoxyalkyl; naphthoxyalkyl; phenylalkoxy; phenyltrihydrocarbylsilylalkyl; N-alkyl-N-phenylamino; N-trihydrocarbylsilyl-N-phenylamino; N-alkyl-N-trihydocarbylsilylamino; diphenylamino; bis(trihydrocarbylsilyl)amino; N-naphthyl-N-trihydrocarbylsilylamino; phenoxyphenyl; naphthoxyphenyl; phenoxyalkylphenyl; naphthoxyalkylphenyl; phenylalkoxyphenyl; (phenyltrihydrocarbylsilylalkyl)phenyl; (N-alkyl-N-phenylamino)-phenyl; (N-trihydrocarbylsilyl-N-phenylamino)phenyl; (N-alkyl-N-trihydocarbylsilylamino)phenyl; diphenylaminophenyl; [bis(trihydrocarbylsilyl)-amino]phenyl and (N-naphthyl-N-trihydrocarbylsilylamino)phenyl. Some embodiments select the moieties (ii) from phenyl group, naphthyl and hydrocarbylsilyl fluorophenoxy; fluoronaphthoxy; fluoronaphthoxyalkyl; fluorophenoxyalkyl; fluorophenylalkoxy; fluorophenyl-trialkylsilylalkyl; N-alkyl-N-fluorophenylamino; N-trialkylsilyl-N-fluorophenylamino; N-alkyl-N-trialkylsilylamino; bis(fluorophenyl)amino; bis(trialkylsilyl)amino; N-fluoronaphthyl-N-trialkylsilylamino; fluorophenoxy-fluorophenyl; fluoronaphthoxyfluorophenyl; (fluoronaphthoxyalkyl)-fluorophenyl; (fluorophenoxyalkyl)fluorophenyl; (fluorophenylalkoxy)fluorophenyl; (fluorophenyl-trialkylsilylalkyl)fluorophenyl; (N-alkyl-N-fluorophenylamino)fluoro-phenyl; (N-trialkylsilyl-N-fluorophenylamino)fluorophenyl; (N-alkyl-N-trialkylsilyl-amino)fluorophenyl; [bis(fluorophenyl)amino]fluorophenyl; [bis(trialkylsilyl)-amino]fluorophenyl and (N-fluoronaphthyl-N-trialkylsilylamino)fluorophenyl. In some embodiments for example, Ar 1 to Ar 4 is selected from perfluoronaphthyl; perfluorodiphenyl; N-perfluoro-phenyl-N-tri(C 1 -C 8 alkyl)silylaminotetrafluorophenyl; tris-(C 3 -C 8 alkyl)siloxy-tetrafluorophenyl; bis(perfluorophenyl)fluoromethyltetrafluoro-phenyl; (perfluoronaphthyl)perfluorophenyl; (perfluorodiphenyl)perfluorophenyl; [N-perfluoro-phenyl-N-tri(C 1 -C 8 alkyl)silylamino-tetrafluorophenyl]perfluorophenyl; [tris(C 3 -C 8 alkyl)-siloxytetrafluorophenyl]perfluorophenyl; and [bis(perfluorophenyl)fluoromethyl-tetrafluorophenyl]perfluorophenyl, such as, e.g., perfluoro-1-naphthyl; perfluoro-2-naphthyl; perfluoro-p-diphenyl; 4-(N-perfluorophenyl-N-trimethylsilylamino)-tetrafluorophenyl; 4-(N-perfluorophenyl-N-triethylsilylamino)tetrafluorophenyl; 4-triiso-propylsiloxytetrafluorophenyl; and 4-bis(perfluorophenyl)fluoromethyltetrafluorophenyl. In one aspect, this invention relates to a method of improving the dielectric loss properties of an insulating member of a cable by reducing the concentration of the anion in the insulating member. The anion concentration can be reduced through higher polymerization activity, and thus tan delta is a function of polymerization activity. FIG. 1 defines the present art of tan delta as a function of polymerization activity (anion concentration) using activator A (see Table 10). The relationship is a power law function where x=polymerization activity in grams polymer/mmole metallocene and tan delta (y)=650.64x −0.971 where x=the polymerization activity in grams polymer/mmole transition metal catalyst, after 14 days in water at 90° C. (ASTM D-150-95). The present invention provides a method for producing electrical cables having an insulating member with ionic residue and having dielectric tan delta value after 14 days in water at 90° C. (ASTM D-150-95) that is less than that described for the present art using the above equation. In some embodiments, the electrically insulating member of the above cable has a dielectric tan delta after 14 days in water at 90° C. of less than 0.02 (ASTM D 150-95). According to another aspect, the present invention provides a method of improving the dielectric loss properties of a polymer made by contacting one or more olefinic monomers under polymerization conditions with a transition metal catalyst comprising an NCA. The method comprises using as the NCA an anion having at least 33 atoms Z independently selected from B, Al, Ga, C, Si, Ge, N, P, O, Cl, Br, and elements of Groups 3-12. In some embodiments, the polymer is an ethylene-based polymer. Illustratively, the polymer may be a polyethylene homopolymer or copolymer, EPM or EPDM. According to still another aspect, the atoms Z of the NCA comprise at least boron and carbon. In these or other embodiments, the NCA of the above catalyst has a molecular weight of at least 900. The catalyst may further comprise a metallocene complex, e.g., a metallocene complex of zirconium or hafnium. The present invention also provides a process for making an electrical cable. According to this process, an electrically conductive member comprising a metal conductor (strand) is surrounded with at least one electrically insulating member comprising at least 20 weight-% of at least one polymer ethylene and one or more olefins selected from α-olefins having from 3 to 20 carbon atoms and optionally non-conjugated dienes having from 4 to 20 carbon atoms. This polymer has been prepared in the presence of a metallocene-based catalyst that comprises an NCA, the NCA comprising at least one unit of general formula (I): in-line-formulae description="In-line Formulae" end="lead"? -MR 1 R 2 R 3 (I) in-line-formulae description="In-line Formulae" end="tail"? wherein M is B or Al and R 1 to R 3 are independently selected from fused aromatic ring systems having at least 10 ring members; and phenyl groups having at least one substituent group comprising at least 9 atoms selected from carbon, nitrogen, oxygen, silicon and chlorine. Also provided by the present invention is a process for making a polyolefin suitable for use in an electrically insulating composition by polymerizing one or more olefins in the presence of a transition metal catalyst, this process comprising the use of a catalyst including a cationic metallocene species and an NCA of the general formula (III): in-line-formulae description="In-line Formulae" end="lead"? [BAr 1 Ar 2 Ar 3 Ar 4 ] ! (III) in-line-formulae description="In-line Formulae" end="tail"? Ar 1 to Ar 4 in the above formula are aryl radicals and at least three of these aryl radicals are selected from fused aromatic ring systems having 10 to 30 ring members or phenyl groups having at least one substituent selected from phenyl groups, naphthyl groups, trialkylsilyl groups and moieties comprising at least one of these groups. A composition suitable for electrical insulation purposes constitutes another aspect of the present invention. The composition comprises at least 30% by weight, based on the composition, of at least one polymer containing a catalyst residue comprising an NCA, and shows a dielectric tan delta after 14 days in water at 90° C. of less than 0.015, in some embodiments, less than 0.013 (ASTM D 150-95). In one aspect, the composition comprises at least 50% by weight of the at least one polymer comprising an NCA. Also, it may comprise at least one further polymer not including an NCA. Still further, the present invention provides an olefinic polymer containing a transition metal catalyst residue comprising an NCA and having dielectric tan delta values less than those of the present art as described by the equation; tan delta=650.64x −0971 , where x=the polymerization activity in grams polymer/mmole transition metal catalyst, after 14 days in water at 90° C. (ASTM D-150-95). Still further, the present invention provides an olefinic polymer containing a transition metal catalyst residue comprising an NCA and showing a dielectric tan delta after 14 days in water at 90° C. of less than 0.02 (ASTM D 150-95), based on a catalyst efficiency of 10,000 g polymer/mmol transition metal. |
Adhesive tape especially for packaging purposes |
The invention relates to adhesive tape which is provided with adhesive on one side thereof, said adhesive comprising a) a film based on drawn polyolefins, b) an adhesive layer applied to one side of the film, made of a mixture containing 35 69.5 wt. % natural rubber latex, 20 64.5 wt. % resin dispersion based on a hydrocarbon resin, 0.5-20 wt. % of an additive based on oil. |
1. A unilaterally self-adhesively coated adhesive tape, comprising a. a film based on oriented polyolefins, b. an adhesive layer applied to one side of the film, prepared from a mixture comprising (i) from 35 to 69.5% by weight of a natural rubber latex, (ii) from 20 to 64.5% by weight of a resin dispersion based on a hydrocarbon resin, (iii) from 0.5 to 20% by weight of an oil-based additive 2. The adhesive tape of claim 1, wherein the film is composed of oriented polyolefins and/or has a thickness of between 20 and 50 μm. 3. The adhesive tape of claim 1, wherein the film is composed of monoaxially oriented films based on polypropylene and/or has a thickness of between 25 and 200 μm. 4. The adhesive tape of claim 1, wherein a layer of a primer has been applied between the film and the adhesive layer. 5. The adhesive tape of at claim 1, wherein the application rate of the adhesive layer to the film is from 10 to 45 g/m2. 6. The adhesive tape of claim 1, wherein the adhesive layer comprises: (i) from 0.1 to 5% by weight of an aging inhibitor, (ii) from 0.05 to 5% by weight of a defoamer, (iii) from 0.05% to 20% by weight of at least one color pigment and/or (iv) from 0.05 to 10% by weight of a stabilizer. 7. The adhesive tape of claim 1, wherein a unwind noise at a distance of 25 cm from the adhesive tape is less than 80 dB(A). 8. (Cancel). 9. The adhesive tape of claim 1, wherein the film is composed of monoaxially oriented films based on polypropylene and/or has a thickness of between 40 and 130 μm. 10. A method of sealing a package, comprising applying the adhesive tape of claim 1 to a portion of said package to seal said package. 11. The method according to claim 10, wherein the package comprises paper. 12. The method according to claim 11, wherein the paper is recycled paper. |
Grain oriented electric sheet of metal with an electrically insulating coating |
The invention relates to grain-oriented magnetic steel sheet comprising an electrically insulating coating, made of an amorphous carbon-hydrogen network, which is applied after final annealing in order to ensure electrical insulation of the individual layers of sheet, said grain-oriented magnetic steel sheet being used e.g. in transformers. The invention also relates to a method for producing the grain-oriented magnetic steel sheet comprising an electrically insulating coating made of an amorphous carbon-hydrogen network, which method consists of coating of the strip-shaped sheet substrate taking place in a continuous strip method. The application is to be published without a Figure. |
1. A grain-oriented magnetic steel sheet comprising an electrically insulating coating made of an amorphous carbon-hydrogen network. 2. The grain-oriented magnetic steel sheet according to claim 1, characterised in that the electrically insulating coating is doped with at least one of the elements Si, O, N, B or F. 3. The grain-oriented magnetic steel sheet according to claim 2, characterised in that the doping elements are contained in the electrically insulating coating in a range from 1 to 20 atomic per cent. 4. The grain-oriented magnetic steel sheet according to any one of claims 1 to 3, characterised in that the electrically insulating coating exerts a tensile stress of at least 8 MPa on the sheet substrate. 5. The grain-oriented magnetic steel sheet according to any one of claims 1 to 4, characterised in that at least one adhesion-improving intermediate layer is arranged between the electrically insulating coating and the sheet substrate. 6. The grain-oriented magnetic steel sheet according to claim 5, characterised in that at least one adhesion-improving intermediate layer consists of an Si—C—O—H network. 7. The grain-oriented magnetic steel sheet according to one of claims 5 or 6, characterised in that at least one adhesion-improving intermediate layer consists of an Si—C—H network. 8. The grain-oriented magnetic steel sheet according to any one of claims 5 to 7, characterised in that at least one adhesion-improving intermediate layer consists of titanium or a titaniferous compound. 9. The grain-oriented magnetic steel sheet according to claim 8, characterised in that the titaniferous compound is titanium nitride. 10. The grain-oriented magnetic steel sheet according to any one of claims 1 to 9, characterised in that the layer has a surface insulation resistance of at least 10 Ohm*cm2. 11. The grain-oriented magnetic steel sheet according to any one of claims 1 to 10, characterised in that at a sheet thickness of 0.30 mm, it has a hysteresis loss (at a frequency of 50 Hertz and a polarisation of 1.7 Tesla) of P1.7≦0.90 W/kg; at a sheet thickness of 0.27 mm, of P1.7≦0.80 W/kg; and at a sheet thickness of 0.23 mm, of P1.7≦0.70 W/kg. 12. The grain-oriented magnetic steel sheet according to any one of claims 1 to 11, characterised in that the sheet substrate contains 2.5 weight % to 4.0 weight % silicon, up to 0.20 weight % manganese, up to 0.50 weight % copper, up to 0.065 weight % aluminium, up to 0.0150 weight % nitrogen, and at least 90 weight % iron. 13. The grain-oriented magnetic steel sheet according to claim 12, characterised in that additionally at least one of the elements Cr, Ni, Mo, P, As, Sn, Sb, Se, Te, B or Bi, at up to 0.2 weight % is present. 14. A method for producing grain-oriented magnetic steel sheet with an electrically insulating coating from an amorphous carbon-hydrogen network according to any one of claims 1 to 13, characterised in that coating of the strip-shaped sheet substrate with the electrically insulating coating takes place in a continuous strip method. 15. The method according to claim 14, characterised in that coating of the sheet substrate with adhesion-improving intermediate layers according to claims 5 to 9 takes place in a continuous strip method prior to the application of the electrically insulating coating. 16. The method according to one of claims 14 or 15, characterised in that at least one of the coating steps takes place by means of a CVD (chemical vapour deposition) method. 17. The method according to any one of claims 14 to 16, characterised in that at least one of the coating steps takes place by means of a PVD (physical vapour deposition) method. 18. The method according to claim 17, characterised in that at least one of the coating steps takes place by means of a plasma-activated PVD method. 19. The method according to claim 17 or 18, characterised in that at least one of the coating steps takes place by means of a hollow-cathode glow-discharge method. 20. The method according to any one of claims 14 to 19, characterised in that the surface of the steel substrate prior to coating has a roughness Ra of max. 0.5 μm. |
Optoelectronic component and method for the production thereof |
In order to apply an optical element such as a lens, for example, to an optoelectronic component, the surface (3B), averted from the transmitter or receiver (2), of the filling material (3) is designed directly with a lens profile (7). This is done by filling a defined quantity of the transparent filling material (3) into the recess (1A) of the carrier body (1) for the purpose of embedding the transmitter or receiver (2), and by subsequently impressing a lens profile (7) onto the surface (3B), averted from the transmitter or receiver, of the transparent filling material (3) by means of a punch (8), before the transparent filling material with the lens profile (7) thus impressed is completely cured. |
1. An optoelectronic component, having a carrier body (1) with a recess (1A); an optoelectronic transmitter or receiver (2) arranged in the recess (1A) on the carrier body (1); and a filling (3) which is made from a transparent material and embeds the optoelectronic transmitter or receiver (2) in the recess (1A) of the carrier body (1), characterized in that the surface (3B), averted from the transmitter or receiver (2), of the filling (3) is designed with a lens profile (7). 2. The optoelectronic component as claimed in claim 1, characterized in that the surface (3B), averted from the transmitter or receiver (2), of the filling (3) is substantially aligned with the surface (1B), averted from the transmitter or receiver (2), of the carrier body (1). 3. The optoelectronic component as claimed in claim 1, characterized in that lens profile (7) is designed in the form of a Fresnel lens. 4. The optoelectronic component as claimed in claim 1, characterized in that the material of the filling (3) is a transparent, cationically curable, UV-initiated or light-initiated material. 5. The optoelectronic component as claimed in claim 4, characterized in that the material of the filling (3) contains a cationically curable, UV-initiated or light-initiated epoxy resin. 6. A method for producing an optoelectronic component having a carrier body (1) with a recess (1A) and an optoelectronic transmitter or receiver (2) arranged in the recess (1A) on the carrier body (1), having the following method steps: forming the recess (1A) in the carrier body (1); mounting the transmitter or receiver (2) in the recess (1A) thus formed; filling a defined quantity of a transparent filling material (3) into the recess (1A) for the purpose of embedding the transmitter or receiver (2); impressing a lens profile (7) on the surface (3B), averted from the transmitter or receiver (2), of the transparent filling material (3); and curing the transparent filling material (3) with the surface (3B) having the lens profile (7). 7. The method as claimed in claim 6, characterized in that the lens profile (7) is impressed on the surface (3B), averted from the transmitter or receiver (2), of the transparent filling material (3) by means of a punch (8) which has a punch face (8A) corresponding to the lens profile (7). 8. The method as claimed in claim 7, characterized in that the punch face (8A) of the punch (8) corresponds to the profile of a Fresnel lens. 9. The method as claimed in claim 7, characterized in that the method step of impressing the lens profile (7) has the following substeps: pressing the punch (8) with the punch face (8A) onto the surface (3B) of the transparent filling material (3) to form the lens profile (7) corresponding to the punch face (8A); incipiently curing the transparent filling material (3) with the lens profile (7) thus formed; and lifting the punch (8) off from the incipiently cured transparent filling material (3). 10. The method as claimed in claim 9, characterized in that at least the punch face (8A) of the punch (8) has a coating made from a material that has non-stick properties with reference to the filling material (3). 11. The method as claimed in claim 9, characterized in that the punch (8) comprises a transparent material, and the filling material (3) comprises a transparent, cationically curable, UV-initiated or light-initiated material, and in that the method step of incipiently curing the filling material (3) with lens profile (7) is performed by means of applying UV or light radiation (9) through the punch (8) to the filling material (3). 12. The method as claimed in claim 1, characterized in that the method step of incipiently curing the filling material (3) with lens profile (7) is performed by means of a UV flash. 13. The method as claimed in claim 11, characterized in that the filling material (3) contains a cationically curable, UV-initiated or light-initiated epoxy resin. |
Receiver device comprising an alternating current coupling |
A receiver arrangement with AC coupling is specified in which a filter arrangement (3) is provided in a baseband signal processing chain in a homodyne receiver and can be switched between at least two high-pass filter cut-off frequencies. In this case, a brief changeover is made to a higher cut-off frequency when varying the gain of a low-noise baseband amplifier (2), for example when the received field strength changes, during the reception mode. The described arrangement allows changes to be carried out to the gain in baseband during the normal reception mode. The present receiver is accordingly suitable for code division multiple access methods, such as those which are provided in the UMTS Standard. |
1-10. (canceled) 11. A receiver arrangement with AC coupling, comprising: an input for supplying a radio-frequency signal; a frequency converter which is coupled to the input and produces a baseband signal at its output; a baseband amplifier with variable gain, which is connected to the output of the frequency converter and has a control input for varying the gain; a filter arrangement for AC coupling, with an input which is connected to an output of the baseband amplifier and with a high-pass filter for filtering the baseband signal, with a cut-off frequency which can be switched between at least two values, with the lower of the at least two cut-off frequencies being used during normal operation and with the higher of the at least two cut-off frequencies being used in a changeover mode, and with a control input for varying the cut-off frequency; and a control circuit for activation of the higher cut-off frequency during the changeover mode on the basis of a readjustment of the gain of the baseband amplifier, with an output which is connected to the control inputs of the baseband amplifier and of the filter arrangement. 12. The receiver arrangement as claimed in claim 11, wherein the control circuit is for activating the higher cut-off frequency in the high-pass filter of the filter arrangement during a variable time interval, which starts at the time of the change to the gain of the baseband amplifier on the basis of the readjustment of the gain. 13. The receiver arrangement as claimed in claim 12, wherein the filter arrangement comprises a selectively activatable low-pass filter coupled to the control circuit in order to activate the low-pass filter effect during the changeover mode. 14. The receiver arrangement as claimed in claim 13, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode 15. The receiver arrangement as claimed in claim 12, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode. 16. The receiver arrangement as claimed in claim 11, wherein the filter arrangement comprises a selectively activatable low-pass filter coupled to the control circuit in order to activate the low-pass filter effect during the changeover mode. 17. The receiver arrangement as claimed in claim 16, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode. 18. The receiver arrangement as claimed in claim 11, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode. 19. The receiver arrangement as claimed in claim 18, including a baseband filter for channel selection connected between the filter arrangement and the programmable amplifier. 20. The receiver arrangement as claimed in claim 11, wherein the receiver arrangement is designed for processing balanced signals. 21. The receiver arrangement as claimed in claim 11, wherein the high-pass filter in the filter arrangement comprises a balanced signal path having therein a parallel branch that includes a resistor and a parallel-connected first switch, the balanced signal path including series branches connected upstream of the parallel branch, each said series branch including a capacitance. 22. The receiver arrangement as claimed in claim 21, including a baseband filter for channel selection connected between the filter arrangement and the programmable amplifier. 23. The receiver arrangement as claimed in claim 21, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode. 24. The receiver arrangement as claimed in claim 21, wherein the filter arrangement comprises a selectively activatable low-pass filter coupled to the control circuit in order to activate the low-pass filter effect during the changeover mode. 25. The receiver arrangement as claimed in claim 24, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode. 26. The receiver arrangement as claimed in claim 21, wherein the control circuit is for activating the higher cut-off frequency in the high-pass filter of the filter arrangement during a variable time interval, which starts at the time of the change to the gain of the baseband amplifier on the basis of the readjustment of the gain. 27. The receiver arrangement as claimed in claim 26, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode. 28. The receiver arrangement as claimed in claim 26, wherein the filter arrangement comprises a selectively activatable low-pass filter coupled to the control circuit in order to activate the low-pass filter effect during the changeover mode. 29. The receiver arrangement as claimed in claim 28, including a programmable amplifier coupled to the output of the filter arrangement and connected to the control circuit, in order to set the lowest gain which can be set for the programmable amplifier during the changeover mode. 30. The receiver arrangement as claimed in claim 21, wherein the series branches of the balanced signal path in the filter arrangement each comprise a parallel circuit formed by a resistor and a second switch in order to form with the associated capacitance a low-pass filter, and wherein the parallel circuits are connected upstream of the associated capacitances. 31. The receiver arrangement as claimed in claim 30, wherein the parallel branch includes a further resistor and parallel-connected first switch, connected in series with the first-mentioned resistor and parallel-connected first switch, and wherein the control circuit is operable such that in order to activate the changeover mode, the second switches are first of all opened and the first switches are then closed, and such that, in order to return to the normal mode, the first switches are first of all opened, and the second switches are then closed. 32. The receiver arrangement as claimed in claim 11, wherein the higher cut-off frequency is greater than or equal to 1 Megahertz. |
Nasal and oral cannula apnea detection device |
A cannula (3) defined by a main body (1) having an internal passage (6). The internal passage (6) communicate with a nare (5, 7) and an oral prong or a mouthpiece (9) which is adjustable to provide a desirable signal from a patient's mouth and nose to indicate breathing by the patient. |
1. An improved nasal and oral cannula to facilitate detection of apnea, the cannula comprising: a main body supporting a pair of nares, and each one of the pair of nares communicating with an internal passage of the main body to facilitate communication with a nostril of a user; an oral prong connected to and communicating with the internal passage of the main body, the oral prong extending away from the pair of nares to facilitate insertion of a remote end, having an inlet, of the oral prong adjacent an open between a pair of lips of the user, and the remote end of the oral prong being trimmable to a shortened length so that the oral prong is positioned in the open between a pair of lips of the user, during use, to facilitate receiving a signal from the user indicative of breathing. 2. A method of fitting a nasal and oral cannula to a patient for detection of apnea, the method comprising the steps of: placing at least one nare of a cannula in a nostril of a user; positioning an oral prong of the cannula between lips of the user; trimming a remote end of the oral prong of the cannula to a shortened length so that the remote end is positioned between the lips of a user; and receiving a signal from the user via the cannula, during breathing of the user, to indicate breathing of the user. |
<SOH> BACKGROUND OF THE INVENTION <EOH>This invention relates generally to cannulas adapted for both mouth and nasal use to monitor breathing, in particular, a method of manufacturing a cannula adapted to interconnect with both nasal passages and the mouth for use to monitor breathing, especially for the detection of apnea (the absence of breathing). Nasal cannulas are commonly used to administer gases, such as oxygen, to humans having respiratory problems. Illustrations of nasal cannulas used for this purpose are found in U.S. Pat. No. 3,802,431. Nasal cannulas have been used also for inhalation therapy, made possible by development of inhalation sensors such as described in U.S. Pat. No. 4,745,925. A nasal cannula can be used to monitor breathing and for detection of apnea when connected to an inhalation sensor. Nasal cannulas additionally adapted to communicate with the mouth of humans to permit administration of gaseous fluids or sensing of apnea during periods of mouth breathing or nasal blockage are also known. The Nasal Oral Cannula of the present invention is designed to optimize patient comfort, and at the same time, produce robust nasal and oral signals. The greatest challenge in this design (and the most unique aspect) is the capture of the oral flow signal, particularly the inspiratory oral flow signal. It is well documented that all of the important information relating to the upper airway obstruction lies in the inspiratory flow signal. Current art makes use of large scoops and baffles that hang in front of the mouth in order to capture the oral signal (see U.S. Pat. No. 6,155,986). These designs reduce patient comfort due to their bulk and are only marginally effective. The prior art of dipping a part in a plastisol to create a coating thereof is exemplified by U.S. Pat. Nos. 3,906,071, 4,695,241, 4,800,116 and U.S. pending application Ser. No. 09/754,471 filed Jan. 4, 2001, the disclosures of which are hereby incorporated by reference. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention there is provided a cannula, defining an interior cavity interconnecting an elongate mouthpiece, an elongate main body and at least one nare. |
Method and installation for producing patterned textile labels |
The invention relates to a method for producing patterned textile labels during which a production machine, which is controlled by a pattern device (22), provides labels (E1 to EN)with a pattern (M), which is the same for all labels, and with pattern sections (T1 to TN) that are different from one another. In order to improve production, a virtual label (V) is created from N individual labels E1 to EN)which are distributed over the width (B) and the length (L) of the virtual label (V) and which have N individual pattern sections (T1 to TN) that are different from one another, and then virtual label (V) is then divided into individual labels (E1 to EN). |
1. A method for producing patterned textile labels, the labels (E1 to EN) being provided with a pattern (M) identical for all the labels and with pattern parts (T1 to TN, Z1 to ZN) different from one another by means of a production machine controlled by a pattern device (22), characterized in that a virtual label (V) consisting of N individual labels (E1 to EN) is produced, said individual labels being distributed over the width (B) and the length (L) of the virtual label (V) and having N individual pattern parts (T1 to TN, Z1 to ZN) that differ from one another, and virtual label (V) thus produced is subdivided into individual labels (E1 to EN). 2. The method as claimed in claim 1, characterized in that the width corresponds to a number of warp threads (4) used for a production machine. 3. The method as claimed in claim 1, characterized in that the length (L) of the virtual label (V) is selected according to the cloth web (W) which is capable of being wound on a winding beam of a production machine. 4. The method as claimed in claim 1, characterized in that the number N of labels (E) of the virtual label (V) is selected according to the number of labels capable of being packaged in a packaging unit. 5. The method as claimed in claim 1, characterized in that the labels (E1 to EN) are provided in each case with at least one second pattern part (Z1 to ZN) which is different from label to label. 6. The method as claimed in claim 5, characterized in that a continuous numbering is selected for at least one individual pattern part (T1 to TN, Z1 to ZN) and is distributed continuously, preferably in the longitudinal direction of the virtual label (V), in rows lying next to one another. 7. The method as claimed in claim 5, characterized in that bar codes different from label to label are selected for at least one individual pattern part (T1 to TN, Z1 to ZN). 8. The method as claimed in claim 5, characterized in that counterfeit-proof additional codes which are different from label to label and are preferably generated by means of a random generator are selected for an individual pattern part Z1 to ZN. 9. The method as claimed in claim 5, characterized in that graphic figures, such as images, logos or the like, which are different from label to label are selected for an individual pattern part (T1 to TN, Z1 to ZN). 10. The method as claimed in claim 1, characterized in that the virtual label (V) is provided at the start and at the end with identifying information. 11. The method as claimed in claim 1, characterized in that pattern-free intermediate zones (25) for subdividing the virtual label into individual labels or label webs are arranged in the virtual label (V) between the individual labels in the longitudinal direction and/or in the width direction. 12. The method as claimed in claim 11, characterized in that the intermediate zones are formed by a pattern-free ground fabric part. 13. The method as claimed in claim 11, characterized in that the intermediate zones are formed in the longitudinal direction by fabric-free zones, in that the virtual label is produced in longitudinal strips distributed over the width. 14. The method as claimed in claim 1, characterized in that the virtual label (V) is first prepared in the design mode and is then converted by means of a converter (22b) into a pattern mode capable of being processed by the production machine. 15. The method as claimed in claim 14, characterized in that the individual pattern parts (T1 to TN, Z1 to ZN) are generated manually in the design mode. 16. The method as claimed in claim 14, characterized in that the individual pattern parts (T1 to TN, Z1 to ZN) are generated semiautomatically in the design mode. 17. The method as claimed in claim 14, characterized in that the individual pattern parts (T1 to TN, Z1 to ZN) are generated fully automatically in the design mode. 18. The method as claimed in claim 14, characterized in that a computer-controlled pattern device (22) with a CAD system (23a) having design software and with at least one control means (23b, 23c) for generating the individual pattern parts (T1 to TN, Z1 to ZN) is used for the design mode. 19. The method as claimed in claim 1, characterized in that the pattern device (22) is arranged independently of the production machine and carries out the data transfer to the production machine by means of a data line or preferably by means of a data carrier. 20. The method as claimed in claim 1, characterized in that the production machine used is a printing machine. 21. The method as claimed in claim 1, characterized in that the production machine used is a Jacquard weaving machine. 22. The method as claimed in claim 21, characterized in that the virtual label (V) is woven on a Jacquard broad-weaving machine without fabric-width repeat repetition. 23. The method as claimed in claim 21, characterized in that the virtual label (V) is produced on a multi-section Jacquard needle ribbon weaving machine without fabric-width repeat repetition. 24. The method as claimed in claim 1, characterized in that the virtual label (V) is subdivided at least in the longitudinal direction on the production machine, preferably by thermal cutting. 25. The method as claimed in claim 1, characterized in that the virtual label (V) is subdivided in the width direction on the production machine, preferably by thermal cutting. 26. The method as claimed in claim 1, characterized in that the subdivision of the virtual label (V) is carried out independently of the production machine. 27. The method as claimed in claim 1, characterized in that the virtual label (V) is produced on the production machine which has a production counter (20) for the individual labels which is preferably capable of being loaded with an instruction for the number of labels to be produced. 28. An installation for carrying out the method as claimed in claim 1, with a pattern device (22) and with a production machine, characterized in that the pattern device (22) has control means for generating a virtual label (V) which has N individual labels (E1 to EN) distributed over the width (B) and the length (L) of the virtual label and having N individual pattern parts (T1 to TN, Z1 to ZN) different from one another. 29. The installation as claimed in claim 28, characterized in that the pattern device (22) is arranged independently of the production machine. 30. The installation as claimed in claim 29, characterized in that the pattern device (22) has output means for generating a data carrier for data exchange with the production machine. 31. The installation as claimed in claim 28, characterized in that the production machine has a production counter (20) for detecting the number of individual or single labels produced. 32. The installation as claimed in claim 28, characterized in that the production machine is a printing machine. 33. The installation as claimed in claim 28, characterized in that the production machine is a Jacquard weaving machine. 34. The installation as claimed in claim 33, characterized in that the Jacquard weaving machine is a broad-weaving machine. 35. The installation as claimed in claim 33, characterized in that the Jacquard weaving machine is a multi-section needle ribbon weaving machine. |
<SOH> BACKGROUND <EOH>A method and in installation of the type initially mentioned are known, for example, from DE 36 27 315 A or WO 00/73 559. The labels produced there have, in addition to a regular pattern, individual pattern parts for which spaces provided with basic designs of specific configuration are reserved in a specific region (space holders). Design pattern parts, that is to say finished design parts, are inserted into the space regions automatically from an electronic store. These pattern parts may be variable. The finished design parts already possess all the information for controlling the production machine, for example a Jacquard weaving machine. It is relatively difficult, however, in the case of a continuous production of labels, to provide each label with a markedly different individual pattern part. At all events, the spaces where variable data can be inserted are fixed and limited. A further difficulty is that the pattern parts have to be prefabricated, therefore it is not possible in a simple way to change, for example, the width, the length or another parameter. There has to be a fundamental redesign, thus incurring high costs. Furthermore, the transitions from one pattern part to another must be coordinated exactly with one another in terms of weave, which is difficult to implement. Moreover, there is no safety against wrongly assigning an individual pattern part many times. |
<SOH> SUMMARY OF THE INVENTION <EOH>The object of the invention is to improve a method and an installation of the type initially mentioned in such a way that labels having pattern parts individually different from one another can be produced continuously in a simple and reliable way. Since the virtual label consisting of N individual labels distributed over the width and length of the virtual label and having a pattern and N individual pattern parts different from label to label is produced, and the virtual label thus produced is subdivided into N individual labels, this ensures that the individual labels produced in the batch size N are also actually different from one another. The width of the virtual label corresponds to the number of warp threads used in a production machine, for example a weaving machine. N may be of any desired size. Preferably, a length is used which corresponds to the length of a cloth web capable of being wound on a winding beam. The batch size N may also depend on the labels capable of being packaged in a packaging unit. The labels may in each case be provided with at least one second pattern part which may be a continuous numbering which may be distributed continuously, preferably in the longitudinal direction of the virtual label, in rows lying next to one another. The individual pattern parts may also be a bar code or counterfeit-proof additional code which can be generated by a random generator. Pattern parts may also be various graphic figures, such as images, logos or the like. Other individual pattern parts may also be envisaged, such as various forenames and/or family names. The individual pattern part may also consist of a series of objects, plants, animals or the like. The virtual label is provided at the start and at the end with identifying information, in order, for example, to identify or inscribe a batch size. Pattern-free intermediate zones for subdividing the virtual labeling to individual labels or label webs are provided between the individual labels in the virtual label V in the longitudinal direction and/or in the width direction. These intermediate zones may be formed by a pattern-free ground fabric part. The intermediate zones may also be formed in the longitudinal direction by fabric-free zones, in that the virtual label is produced in longitudinal strips distributed over the width. The virtual label is first produced in the design mode and only then converted by means of a converter into a pattern mode capable of being processed by the production machine. These individual pattern parts may be generated manually, semiautomatically and fully automatically. Particularly in the latter case, it is advantageous if a computer-controlled pattern device with a CAD system having design software and with at least one generator for generating the individual pattern parts is used for the design mode. The pattern device may be arranged independently of the production machine, and data transfer to the production machine may take place by means of a data line or preferably by means of a data carrier. In this case, the pattern device may preferably be arranged advantageously even independently of the user of the production machine, on the premises of the manufacturer. The person operating the production machine can then transmit the desired pattern and the desired individual pattern parts as a model to the operator of the pattern device who then sets up the necessary control program, what is known as the master program, the control signals for the production machine, then determines returns it to the user for controlling the production machine. The production machine may be a printing machine, on which a textile web is printed with the virtual label. It is appreciably more advantageous to use a Jacquard weaving machine for producing the virtual label. The virtual label may be woven with a selvedge on a multi-section Jacquard needle ribbon weaving machine without fabric-width repeat repetition. Higher performances can be achieved by means of a method when the virtual label is produced on a Jacquard broad-weaving machine without fabric-width repeat repetition. The virtual label, then, may be produced continuously on such a production machine as a ribbon or broad web and subdivided into individual labels, independent of the production machine, and at all events also folded to the final shape in a folding machine. However, it is also possible for the virtual label to be cut in the longitudinal and/or width direction during production on the production machine. It is advantageous if the virtual label is produced for a production machine which has a production counter, in order to detect the number of labels produced for the most diverse possible applications, such as a check of the batch size produced for a customer for the labels, and/or for license accounting for the machine and/or software manufacturer. |
Mycobacterial proteins as early antigens for serodiagnosis and vaccines |
In view of the paucity of human material available to study the immunological events occurring after inhalation of virulent bacilli, but prior to development of clinical TB, the present invention is based in part on studies of aerosol infected rabbits. The present inventors reasoned that by 3-5 weeks post-infection, the sera from infected rabbits would contain antibodies to the antigens being expressed by the in vivo bacteria. |
1. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of early antibodies specific for one or more early Mtb antigens which antigens are characterized as being surface or secreted proteins that are (i) reactive with antibodies found in tuberculosis patients who are in a stage of disease prior to the onset of (a) smear-positivity of sputum or other pulmonary associated fluid for acid-fast bacilli and (b) cavitary pulmonary lesions, and (ii) non-reactive with sera from healthy control subjects or healthy subjects with latent inactive tuberculosis wherein the presence of said early antibodies specific for said early antigens is indicative of the presence of said disease or infection. 2. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of antibodies or T lymphocytes specific for or reactive with an early Mtb antigen selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810; (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); (d) MtrA protein encoded by the Mtb gene Rv3246c; and (e) an epitope of any of (a)-(d). 3. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid or cell or tissue sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of one or more early M. tuberculosis early antigens selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810;, (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); (d) MtrA protein encoded by the Mtb gene Rv3246c; and (e) an epitope of any of (a)-(d), using an antiserum or a monoclonal antibody specific for an epitope of said an early antigen, wherein the presence of said one or more early antigens is indicative of the presence of said disease or infection. 4. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of immune complexes consisting of one or more early M. tuberculosis antigens complexed with an antibody specific for said antigen selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810; (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); and (d) MtrA protein encoded by the Mtb gene Rv3246c, (e) an epitope of any of (a)-(d), wherein the presence of said immune complexes is indicative of the presence of said disease or infection. 5. The method of any one of claims 1-4 that further includes performance of a test that detects mycobacterial bacilli in a sample of sputum or other body fluid of said subject. 6. The method of any of claims 1-5 wherein said biological fluid sample is serum, urine or saliva. 7. The method of any of claims 1-6 comprising, prior to said assaying step, the step of removing from said sample antibodies specific for cross-reactive epitopes or antigens of proteins present in M. tuberculosis and in other bacterial genera. 8. The method of any of claims 1-7 wherein said removing is performed by immunoadsorption of said sample with E. coli antigens. 9. The method of any of claims 1-8, wherein said subject is a human. 10. The method of claim 9 wherein said subject is infected with HIV-1 or is at high risk for tuberculosis. 11. The method of any of claims 1-10 which includes assaying said sample for antibodies specific for one or more additional early antigens of M. tuberculosis selected from the group consisting of: (a) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTV NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R (b) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO: 14: APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR; (c) a protein characterized as M. tuberculosis antigen 85C; and (d) a glycoprotein characterized as M. tuberculosis antigen MPT32. 12. A kit useful for early detection of M. tuberculosis disease comprising: (a) an antigenic composition comprising one or more proteins selected from the group consisting of (i) PirG protein encoded by the Mtb gene Rv3810; (ii) PE-PGRS protein encoded by the Mtb gene Rv3367; (iii) PTRP protein encoded by the Mtb gene Rv0538); and (iv) MtrA protein encoded by the Mtb gene Rv3246c, or an epitope of any of (i)-(iv), in combination with (b) reagents necessary for detection of antibodies which bind to said M. tuberculosis protein. 13. The kit of claim 12 further supplemented with one or more additional early antigens of M. tuberculosis selected from the group consisting of: (A) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R (B) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO:14: APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA MNTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA LAAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW VHASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP ASGDNGWGSW APQLGAMSGD IVGAIR (C) a protein characterized as M. tuberculosis antigen 85C; or (D) a glycoprotein characterized as M. tuberculosis antigen MPT32. 14. The kit of claim 12 or claim 13 further supplemented with one or more of the following M. tuberculosis antigenic proteins having an approximate molecular weight as indicated: (i) a 28 kDa protein corresponding to the spot identified as Ref. No. 77 in Table 2. (ii) a 29/30 kDa protein corresponding to the spot identified as Ref. No. 69 or 59 in Table 2; (iii) a 31 kDa protein corresponding to the spot identified as Ref. No. 103 in Table 2; (iv) a 35 kDa protein corresponding to the spot identified as Ref. No. 66 in Table 2 and reacting with monoclonal antibody IT-23; (v) a 42 kDa protein corresponding to the spot identified as Ref. No. 68 or 80 in Table 2; (vi) a 48 kDa protein corresponding to the spot identified as Ref. No. 24 in Table 2; and (vii) a 104 kDa protein corresponding to the spot identified as Ref. No. 111 in Table 2, which spots are obtained by 2-dimensional electrophoretic separation of M. tuberculosis lipoarabinomannan-free culture filtrate proteins as follows: (A) incubating 3 hours at 20° C. in 9M urea, 2% Nonidet P-40, 5% β-mercaptoethanol, and 5% anpholytes at pH 3-10; (B) isoelectric focusing on 6% polyacrylamide isoelectric focusing tube gel of 1.5 mm×6.5 cm, said gel containing 5% ampholytes in a 1:4 ratio of pH 3-10 ampholytes to pH 4-6.5 ampholytes for 3 hours at 1 kV using 10 mM H3PO4 as catholyte and 20 mM NaOH as anolyte, to obtain a focused gel; (C) subjecting the focused gel to SDS PAGE in the second dimension by placement on a preparative SDS-polyacrylamide gel of 7.5×10 cm×1.5 mm containing a 6% stack over a 15% resolving gel and electrophoresing at 20 mA per gel for 0.3 hours followed by 30 mA per gel for 1.8 hours. 15. The kit of any of claims according of claim 12 wherein at least one of said early M. tuberculosis antigens is a recombinant protein or glycoprotein. 16. An antigenic composition useful for early detection of M. tuberculosis disease or infection comprising a onr or a mixture of two or more early M. tuberculosis antigens which antigens are selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810; (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); (d) MtrA protein encoded by the Mtb gene Rv3246c; and (e) an epitope of any of (a)-(d), said composition being substantially free of other M. tuberculosis proteins with which said early M. tuberculosis antigens are natively admixed in a culture of M. tuberculosis. 17. The antigenic composition of claim 16 wherein said other proteins are not early M. tuberculosis antigens. 18. The antigenic composition of claim 16 or 17, further comprising one or more of: (a) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHVHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R; (b) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO:14 APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR; (c) a protein characterized as M. tuberculosis antigen 85C; or (d) a glycoprotein characterized as M. tuberculosis antigen MPT32. 19. The antigenic composition of any of claims 16-18 further comprising one or more of the following M. tuberculosis antigenic proteins having an approximate molecular weight as indicated: (i) a 28 kDa protein corresponding to the spot identified as Ref. No. 77 in Table 2. (ii) a 29/30 kDa protein corresponding to the spot identified as Ref. No. 69 or 59 in Table 2; (iii) a 31 kDa protein corresponding to the spot identified as Ref. No. 103 in Table 2; (iv) a 35 kDa protein corresponding to the spot identified as Ref. No. 66 in Table 2 and reacting with monoclonal antibody IT-23; (v) a 42 kDa protein corresponding to the spot identified as Ref. No. 68 or 80 in Table 2; (vi) a 48 kDa protein corresponding to the spot identified as Ref. No. 24 in Table 2; and (vii) a 104 kDa protein corresponding to the spot identified as Ref. No. 111 in Table 2, which spots are obtained by 2-dimensional electrophoretic separation of M. tuberculosis lipoarabinomannan-free culture filtrate proteins as follows: (A) incubating 3 hours at 20° C. in 9M urea, 2% Nonidet P-40, 5% β-mercaptoethanol, and 5% ampholytes at pH 3-10; (B) isoelectric focusing on 6% polyacrylamide isoelectric focusing tube gel of 1.5 mm×6.5 cm, said gel containing 5% ampholytes in a 1:4 ratio of pH 3-10 ampholytes to pH 4-6.5 ampholytes for 3 hours at 1 kV using 10 mM H3PO4 as catholyte and 20 mM NaOH as anolyte, to obtain a focused gel; (C) subjecting the focused gel to SDS PAGE in the second dimension by placement on a preparative SDS-polyacrylamide gel of 7.5×10 cm×1.5 mm containing a 6% stack over a 15% resolving gel and electrophoresing at 20 mA per gel for 0.3 hours followed by 30 mA per gel for 1.8 hours. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The invention in the fields of microbiology and medicine relates to methods for rapid early detection of mycobacterial disease in humans based on the presence of antibodies to particular “early” mycobacterial antigens which have not been previously recognized for this purpose. Assay of such antibodies on select partially purified or purified mycobacterial preparations containing such early antigens permits diagnosis of TB earlier than has been heretofore possible. Also provided is a surrogate marker for screening populations at risk for TB, in particular subjects infected with human immunodeficiency virus (HIV). The invention is also directed to vaccine compositions and methods useful for preventing or treating TB. 2. Description of the Background Art The incidence of tuberculosis has shown a rapid increase in recent years, not only in the developing countries, but also in crowded urban settings in the US and in specific subsets of our society, including the homeless, IV drug users, HIV-infected individuals, immigrants and refugees from high prevalence endemic countries (Raviglione, M C et al., 1995. JAMA. 273:220-226). Studies show that these populations are at a significantly greater risk of developing tuberculosis, and also serve as the reservoir of infection for the community as a whole Raviglione, M C et al., 1992, Bull World Health Organization. 70:515-526; Raviglione, M C et al., 1995. JAMA. 273:220-226). None of the currently used methods for diagnosis of tuberculosis identify individuals with active but sub-clinical infection, and the disease is generally detected when the individuals are already infectious. Design of new diagnostic assays requires knowledge of antigens expressed by the bacteria during their in vivo survival. Most current studies of antigens of Mycobacterium tuberculosis (Mtb); also abbreviated herein are focused on antigens present in the culture filtrates of bacteria replicating actively in vitro, with the presumption that the same molecules are expressed by the in vivo bacteria. A vast majority of the Mtb infected individuals develop immune responses that arrest progression of infection to clinical TB, and also prevent the latent bacilli from reactivating to cause clinical disease, whereas about 10-15% of the infected individuals progress to developing primary or reactivation TB. Understanding the host-pathogen interactions that occur after infection, but prior to development of clinical TB (pre-clinical TB) is required both for the design of effective vaccines and for development of diagnosis of early disease. Several studies have shown that Mtb adapts to different environments in broth media (Garbe, T R et al., 1999, Infect. Immun. 67:460-465; Lee, B-Y et al., 1995, J. Clin. Invest. 96:245-249; Wong, D K et al., 1999, Infect. Immun. 67:327-336) and during intracellular residence by altering its gene expression (8, 22, 34). Clark-Curtiss, J E et al., 1999, p. 206-210. In Proceedings of Thirty-Fourth Tuberculosis-Leprosy Research Conference, San Francisco, Calif., Jun. 27-30. Lee et al., supra; Smith, I et al., 1998, Tuber. Lung Dis. 79:91-97). Earlier studies from the present inventors' laboratory with cavitary and non-cavitary TB patients have also shown that the in vivo environment in which the bacilli replicate affects the profile of the antigenic proteins expressed by Mtb (Samanich, K M et al., 1998, J. Infect. Dis. 178:1534-1538; Laal et al., U.S. Pat. No. 6,245,331 (2001)). One objective of the present invention was to identify the antigens expressed by inhaled Mtb during the pre-clinical stages of TB. There are no markers to identify non-diseased humans with an active infection with Mtb, but the rabbit model of TB closely resembles TB in immuno-competent humans in that both species are outbred, both are relatively resistant to Mtb, and in both the caseous lesions may liquify and form cavities (Converse, P J et al., 1996, Infect. Immun. 64:4776-4787). Studies have shown that on being inhaled, the bacilli are phagocytosed by (non specifically) activated alveolar macrophages (AM) which either destroy or allow them to multiply. If the bacilli multiply, the AM die and the released bacilli are phagocytosed by non activated monocyte/macrophages that emigrate from the bloodstream. Intracellular replication and host cell death continue for 3-5 weeks, when both cellular and humoral immune responses are elicited (Lurie, M B, 1964. Chapter VIII, p. 192-222, In M. B. Lurie (ed.) Resistance to tuberculosis: experimental studies in native and acquired defensive mechanisms. Harvard University Press, Cambridge, Mass.; Lurie, M B et al., 1965, Bact. Rev. 29:466-476; Dannenberg, A M., Jr., 1991, Immunol. Today. 12:228-233). Lymphocytes and macrophages enter the foci of infection, and if they become activated bacillary replication is controlled, if not, the infection progresses to clinical disease. During these initial stages of bacillary replication and immune stimulation, there are no outward signs of disease except the conversion of cutaneous reactivity to PPD. The antigens of Mtb expressed, and their interaction with the immune system during these pre-clinical stages of TB is not delineated. |
<SOH> SUMMARY OF THE INVENTION <EOH>In view of the paucity of human material available to study the immunological events occurring after inhalation of virulent bacilli, but prior to development of clinical TB, the present invention is based in part on studies of aerosol infected rabbits. The present inventors reasoned that by 3-5 weeks post-infection, the sera from infected rabbits would contain antibodies to the antigens being expressed by the in vivo bacteria. Four antigens of Mtb that are expressed in vivo after aerosol infection, but prior to development of clinical TB, in rabbits were identified by immunoscreening an expression library of Mtb genomic DNA with sera obtained 5 weeks post-infection. Three of the proteins identified, PirG (Rv3810) [SEQ ID NO:1 and 2; nucleotide and amino acid], PE-PGRS (Rv3367) [SEQ ID NO:3 and 4] and PTRP (Rv0538) [SEQ ID NO:5 and 6] have multiple tandem repeats of unique amino-acid sequences, and have characteristics of surface or secreted proteins. The fourth protein, MtrA (Rv3246c) [SEQ ID NO:7 and 8], is a response regulator of a putative two-component signal transduction system, mtrA-mtrB, of Mtb. All four antigens were recognized by pooled sera from TB patients and not from healthy controls, confirming their in vivo expression during active infection in humans. Three of the antigens, (PE-PGRS, PTRP and MtrA) were also recognized by retrospective, pre-clinical TB sera obtained from HIV-TB patients prior to the clinical manifestation of TB, suggesting their utility as diagnostics for active, pre-clinical (“early”) TB. The present invention provides methods, kits and compositions directed to the detection of antibodies or T cell reactivity to any of the above early antigens or to the detection of the antigens themselves in a body fluid of a subject as a means of detecting early mycobacterial disease in the subject. In other embodiments, the invention provides, methods, kits and compositions useful for detecting antibody or T cell reactivity to, in addition to one or more of the above early antigens, to one or more of the following early Mtb antigens: (a) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R (b) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO:14: APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR; (c) a protein characterized as M. tuberculosis antigen 85C; or (d) a glycoprotein characterized as M. tuberculosis antigen MPT32. In yet another embodiment, the invention provides methods, kits and compositions useful for the detection of antibodies or T cell reactivity to any of the above early antigens or to one or more of the following early antigens: (i) a 28 kDa protein corresponding to the spot identified as Ref. No. 77 in Table 2. (ii) a 29/30 kDa protein corresponding to the spot identified as Ref No. 69 or 59 in Table 2; (iii) a 31 kDa protein corresponding to the spot identified as Ref. No. 103 in Table 2; (iv) a 35 kDa protein corresponding to the spot identified as Ref. No. 66 in Table 2 and reacting with monoclonal antibody IT-23; (v) a 42 kDa protein corresponding to the spot identified as Ref. No. 68 or 80 in Table 2; (vi) a 48 kDa protein corresponding to the spot identified as Ref. No. 24 in Table 2; and (vii) a 104 kDa protein corresponding to the spot identified as Ref. No. 111 in Table 2, which spots are obtained by 2-dimensional electrophoretic separation of M. tuberculosis lipoarabinomannan-free culture filtrate proteins as follows: (A) incubating 3 hours at 20° C. in 9M urea, 2% Nonidet P-40, 5% β-mercaptoethanol, and 5% ampholytes at pH 3-10; (B) isoelectric focusing on 6% polyacrylamide isoelectric focusing tube gel of 1.5 mm×6.5 cm, said gel containing 5% ampholytes in a 1:4 ratio of pH 3-10 ampholytes to pH 4-6.5 ampholytes for 3 hours at 1 kV using 10 mM H 3 PO 4 as catholyte and 20 mM NaOH as anolyte, to obtain a focused gel; (C) subjecting the focused gel to SDS PAGE in the second dimension by placement on a preparative SDS-polyacrylamide gel of 7.5×10 cm×1.5 mm containing a 6% stack over a 15% resolving gel and electrophoresing at 20 mA per gel for 0.3 hours followed by 30 mA per gel for 1.8 hours. In yet other embodiments, the present invention provides vaccines compositions and methods for treating or preventing mycobacterial disease in a subject. The vaccine composition may comprise any one or more of the early antigens noted above or an epitope thereof. Preferred vaccine epitopes are T helper epitopes, more preferably T helper epitopes that stimualte Th1 cells. |
Image display apparatus and electronic apparatus |
An image display device of this invention includes image memory (3) which is constructed of SRAM and which does not need any refreshing operation, image memory (3) being composed of MSB division memory (13) for storing MSB data of each pixel data item and lower-order bit division memory (14) for storing lower-order bit data other than the MSB data. In a normal mode MSB division memory (13) and lower-order bit division memory (14) are driven to cause the MSB data and the lower-order bit data to be read/written, whereas in an electric power saving mode only MSB division memory (13) is driven with lower-order bit division memory (14) remaining undriven to cause the MSB data to be read/written. |
1. An image display device comprising: a display section having a plurality of pixels for image display; and image memory which is operative to store pixel data associated with colors to be displayed by the pixels and which does not need any refreshing operation, the image memory having first memory for storing a predetermined bit of the pixel data and second memory for storing bits of the pixel data other than the predetermined bit, the image display device having an arrangement capable of switching between a first mode in which the predetermined bit is read out of the first memory and the display section is caused to display an image in accordance with the predetermined bit thus read out and a second mode in which the predetermined bit and the bits other than the predetermined bit are read out of the first memory and the second memory, respectively, and the display section is caused to display an image in accordance with the predetermined bit and the bits other than the predetermined bit thus read out. 2. The image display device according to claim 1, wherein the pixel data comprises data items indicative of respective gradations of the three primary colors and the predetermined bit of the pixel data comprises a set of respective predetermined bits of the data items indicative of the respective gradations of the three primary colors. 3. The image display device according to claim 2, wherein the predetermined bit of the pixel data comprises a set of respective MSBs of the data items indicative of the respective gradations of the three primary colors. 4. The image display device according to claim 1, wherein in the first mode the predetermined bit is read out of the first memory and the display section is caused to display the image by a frame rate control exercised in accordance with the predetermined bit thus read out. 5. The image display device according to claim 1, wherein in the first mode the predetermined bit is read out of the first memory and the display section is caused to display the image by a duty control based on pulse width modulation in accordance with the predetermined bit thus read out. 6. An image display device comprising: a display section having a plurality of pixels for image display; and image memory which is operative to store pixel data associated with colors to be displayed by the pixels and which does not need any refreshing operation, the image memory having first memory for storing a predetermined bit of the pixel data and second memory for storing bits of the pixel data other than the predetermined bit, the image display device having an arrangement capable of switching between a first mode in which a predetermined bit of pixel data for a predetermined pixel is read out of the first memory and the display section is caused to display an image in accordance with the predetermined bit thus read out and a second mode in which the predetermined bit and the bits other than the predetermined bit of pixel data for each of the pixels are read out of the first memory and the second memory, respectively, and the display section is caused to display an image in accordance with the predetermined bit and the bits other than the predetermined bit thus read out. 7. The image display device according to claim 6, wherein the pixel data comprises data items indicative of respective gradations of the three primary colors and the predetermined bit of the pixel data comprises a set of respective predetermined bits of the data items indicative of the respective gradations of the three primary colors. 8. The image display device according to claim 7, wherein the predetermined bit of the pixel data comprises a set of respective MSBs of the data items indicative of the respective gradations of the three primary colors. 9. The image display device according to claim 6, which has an arrangement capable of changing the predetermined pixel in the first mode. 10. An image display device comprising: a display section having a plurality of pixels for image display, and image memory which is operative to store pixel data associated with colors to be displayed by the pixels and which does not need any refreshing operation, the image memory having first memory for storing a predetermined bit of pixel data for each of the pixels and second memory for storing bits of the pixel data other than the predetermined bit, the image display device having an arrangement capable of switching between a first mode in which: a specific pixel is selected from the plurality of pixels depending on a residual capacity of an electric power supply battery; a predetermined bit of pixel data for the specific pixel thus selected is read out of the first memory or the predetermined bit and the bits other than the predetermined bit of the pixel data for the specific pixel thus selected are read out of the first memory and the second memory, respectively; and the display section is caused to display an image in accordance with the predetermined bit read out or in accordance with the predetermined bit and the bits other than the predetermined bits read out and a second mode in which: a predetermined bit and bits other than the predetermined bit of pixel data for each of the pixels are read out of the first memory and the second memory, respectively; and the display section is caused to display an image in accordance with the predetermined bit and the bits other than the predetermined bit thus read out. 11. The image display device according to claim 10, wherein the pixel data comprises data items indicative of respective gradations of the three primary colors and the predetermined bit of the pixel data comprises a set of respective predetermined bits of the data items indicative of the respective gradations of the three primary colors. 12. The image display device according to claim 11, wherein the predetermined bit of the pixel data comprises a set of respective MSBs of the data items indicative of the respective gradations of the three primary colors. 13. An image display device comprising: a display section having a plurality of pixels for image display; first memory and second memory which are operative to store pixel data associated with colors to be displayed by the pixels and which do not need any refreshing operation; and a control section for switching between a first mode in which pixel data for each of the pixels is written to the first memory and a second mode in which a predetermined bit of the pixel data for each of the pixels is written to the second memory, wherein in the first mode the pixel data for each of the pixels is read out of the first memory and the display section is caused to display an image in accordance with the pixel data thus read out, whereas in the second mode the predetermined bit of the pixel data for each of the pixels is read out of the second memory and the display section is caused to display an image in accordance with the predetermined bit of the pixel data thus read out. 14. The image display device according to claim 13, wherein the pixel data comprises data items indicative of respective gradations of the three primary colors and the predetermined bit of the pixel data comprises a set of respective predetermined bits of the data items indicative of the respective gradations of the three primary colors. 15. The image display device according to claim 14, wherein the predetermined bit of the pixel data comprises a set of respective MSBs of the data items indicative of the respective gradations of the three primary colors. 16. An image display device comprising: a display section having a plurality of pixels for image display; first memory which is operative to store a predetermined bit of pixel data associated with colors to be displayed by the pixels and which does not need any refreshing operation; second memory which is operative to store bits of the pixel data other than the predetermined bit and which does not need any refreshing operation; and third memory which is operative to store fixed data having a bit width equal to the bits of the pixel data other than the predetermined bit and which does not need any refreshing operation, the image display device having an arrangement capable of switching between a first mode in which: the predetermined bit and the bits other than the predetermined bit are read out of the first memory and the second memory, respectively; and the display section is caused to display an image in accordance with the predetermined bit and the bits other than the predetermined bit thus read out and a second mode in which: the predetermined bit and the fixed data are read out of the first memory and the third memory, respectively; and the display section is caused to display an image in accordance with the predetermined bit and the fixed data thus read out. 17. The image display device according to claim 16, wherein the pixel data comprises data items indicative of respective gradations of the three primary colors and the predetermined bit of the pixel data comprises a set of respective predetermined bits of the data items indicative of the respective gradations of the three primary colors. 18. The image display device according to claim 17, wherein the predetermined bit of the pixel data comprises a set of respective MSBs of the data items indicative of the respective gradations of the three primary colors. 19. The image display device according to claim 16, which has an arrangement capable of changing the fixed data. 20. An electronic apparatus comprising: an image display device as recited in claim 1; and an arrangement for outputting pixel data to the image display device. |
<SOH> BACKGROUND ART <EOH>In recent years, image display devices for use in small-sized electronic apparatus such as mobile telephones have their respective display screens with increasing number of pixels and increasing number of displayable colors. An increase in electric power consumption with this trend has been concerned about. As a result, electric power saving has been strongly desired. For example, a mobile telephone has to be capable of displaying all colors using all the pixels in normal use, but minimum display is sufficient for such a mobile telephone in a standby (waiting) state. For this reason the art of providing a non-display area during such a standby state to reduce electric power consumption is becoming known means. For example, Japanese Patent Laid-Open Publication No. HEI 11-184434 discloses a display device configured to allow the user to establish a display area and a non-display area. This display device is configured to display an image only in an area established by the user and not to display any image in other area, as shown in FIGS. 1 ( a ) and 1 ( b ). By thus providing such a non-display area, electric power saving is realized. In FIGS. 1 ( a ) and 1 ( b ), reference characters SP 1 and SP 2 indicate display start positions, while reference characters EP 1 and EP 2 indicate display end positions. In the case of a large-sized image display device of 15 inches or larger, the electric power consumption of the LSI used in the device makes up a relatively small proportion of the electric power consumption required for driving the device. In the case of a small-sized image display device for use in small-sized electronic apparatus, on the other hand, the proportion of the electric power consumption of the LSI is relatively large. In recent years, the electric power consumption of the image memory incorporated in the LSI used in an image display device makes up an increasing proportion of the electric power consumption of the LSI. For this reason, it is an important challenge to reduce the electric power consumption of image memory as much as possible by driving the image memory efficiently in accordance with uses and the like by the user. Conventionally, however, even when a non-display area is provided as described above, it has been necessary to read not only image data for the display area but also image data for the non-display area out of the image memory. Specifically, a system which is configured to read image data items for, for example, one line collectively out of image memory has to read all the image data items for a certain line even when that line contains a non-display area. In this case image data that is not utilized for display is read, which consumes electric power uselessly. In the case of a mobile telephone or the like, the mobile telephone has to display an image constantly even in the standby state despite the need to ensure sufficient time for the device to operate in the standby state. For this reason, such a mobile telephone has to save electric power while displaying an image without providing a non-display area. The present invention has been made in view of the foregoing circumstances and it is an object of the present invention to provide an image display device capable of realizing electric power saving and an electronic apparatus incorporating the image display device. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a view illustrating display states of a conventional display device. FIG. 2 is a block diagram illustrating the configuration of an image display device according to embodiment 1 of the present invention. FIG. 3 is a view illustrating the outward appearance of a mobile telephone provided with the image display device according to embodiment 1 of the present invention as a display section. FIG. 4 is a conceptual illustration of an arrangement of image memory included in the image display device according to embodiment 1 of the present invention; specifically, FIG. 4 ( a ) is an illustration of the arrangement of the image memory in connection with pixels of the display section, while FIG. 4 ( b ) is an illustration of the arrangement of the image memory in terms of a three-dimensional coordinate system. FIG. 5 is a schematic diagram illustrating a specific example of an arrangement of the image memory included in the image display device according to embodiment 1 of the present invention. FIG. 6 is a diagram illustrating an example of a detailed arrangement of the image memory shown in FIG. 5 . FIG. 7 is a diagram illustrating an arrangement of image memory for reading/writing higher-order M bits and lower-order (N-M) bits of pixel data separately. FIG. 8 is a schematic diagram illustrating another specific example of an arrangement of the image memory included in the image display device according to embodiment 1 of the present invention. FIG. 9 is a schematic diagram illustrating yet another specific example of an arrangement of the image memory included in the image display device according to embodiment 1 of the present invention. FIG. 10 is a conceptual illustration of an arrangement of image memory included in an image display device according to embodiment 2 of the present invention in terms of a three-dimensional coordinate system. FIG. 11 is a conceptual illustration of display areas and non-display areas of the image display device according to embodiment 2 of the present invention; specifically, FIGS. 11 ( a ) to 11 ( c ) are illustrations of the display areas and the non-display areas in an electric power saving mode. FIG. 12 is a block diagram illustrating the configuration of an image display device according to embodiment 3 of the present invention. FIG. 13 illustrates display processing in the image display device according to embodiment 3 of the present invention; specifically, FIG. 13 ( a ) is an illustration of an example of correspondence between residual capacity levels of a battery and operations of switches, while FIG. 13 ( b ) is an illustration of an example of correspondence between residual capacity levels of the battery and display patterns. FIG. 14 is a block diagram illustrating the configuration of an image display device according to embodiment 4 of the present invention. FIG. 15 illustrates the configuration of an image display device according to embodiment 5 of the present invention; specifically, FIG. 15 ( a ) is a block diagram illustrating the configuration, while FIG. 15 ( b ) is a diagram illustrating a computation on pixel data performed in the image display device. FIG. 16 illustrates the configuration of an image display device according to embodiment 6 of the present invention; specifically, FIG. 16 ( a ) is a block diagram illustrating the configuration, while FIG. 16 ( b ) is a diagram illustrating a computation on pixel data performed in the image display device. detailed-description description="Detailed Description" end="lead"? |
Thermocycling device and rotor means therefor |
The invention relates to rotor means (5) for centrifuging reaction vessels containing samples in a thermocycling device. The rotor means (5) comprise/-s at least one fan blade (18) which force ambient gas to pass to samples. The intention also, relates to a thermocycling device for centrifuging reaction vessels containing samples comprising said rotor means (5). |
1. Rotor means for centrifuging reaction vessels containing samples in a thermocycling device, characterised in that the rotor means (5) are adapted for centrifuging samples arranged in at least one microtitre plate (12) and comprise/-s at least one fan blade (18), which force ambient gas to pass the samples. 2. Rotor means according to claim 1, wherein at least one gas conducting passage (17) is arranged in the rotor means (5) to conduct the gas to pass the samples. 3. Rotor means according to claim 1, wherein the rotor means (5) comprise/-s a base portion (6) and a lid portion (7), in between which an inner space (17) is formed wherein the fan blade/-s (18) are arranged. 4. Rotor means according to claim 1, wherein the lower region of the rotor means (5) is provided with at least one through hole (19) through which the gas may be drawn. 5. Rotor means according to claim 1, wherein the upper region of the rotor means (5) is provided with at least one through hole (20) through which the gas is let out. 6. Rotor means according to claim 3, wherein the fan blade/-s (18) are arranged at the inside of the base portion (6) of the rotor means (5). 7. Rotor means according to claim 3, wherein the fan blade/-s (18) are arranged at the inside of the lid portion (7) of the rotor means (5). 8. Rotor means according to claim 2, wherein the at least one gas conducting passage is arranged to conduct the gas between the sample-containing wells (15) of the microtitre plate (12). 9. Rotor means according to claim 1, wherein a screen (13) with lateral density differences towards the centre is arranged at the rotor means (5) between the samples and heating means (3) outside of the rotor means (5), for compensating of chord differences in the microtitre plate (12). 10. Rotor means according to claim 1, wherein a plate (11) pervious to IR radiation, is arranged to support the at least one microtitre plate. 11. Rotor means according to claim 10, wherein the plate (11) has indentations corresponding to the apices of the wells of the microtitreplate. 12. Rotor means according to claim 1, wherein the gas is ambient air. 13. Rotor means according to claim 1, wherein cooling means (24) is provided to cool the ambient gas. 14. Thermocycling device for centrifuging reaction vessels containing samples, characterised in that it comprises rotor means (5) according to claim 1. |
<SOH> TECHNICAL BACKGROUND <EOH>The applicant has developed a method and an apparatus for rapid thermocycling of samples, i.e. to repeatedly subject the samples to heating and cooling while the samples are centrifuged. This method and apparatus is described in a previous patent application WO 00/58013 of the present applicant, incorporated herein by reference. When using said apparatus, reaction vessels including the samples, i.e. the complete reaction mixture or a subset of this, are placed in a rotor of a centrifuge with the closed end directed downwards, outwards or otherwise according to standard practice for centrifuging the reaction vessels in question. The centrifuge is then started, i.e. the engine which brings the rotor to spin is switched on. When the rotor has accelerated to the chosen gravitational force, the rotation is kept at constant speed. A heating source is now switched on leading to an increased temperature predominantly at the apices of the reaction vessels. The heat will be transferred through the material of the walls of the reaction vessels, to the most distal portion of the bulk of the samples. Alternatively, the heating acts directly on the samples contained in the reaction vessels. Increased molecular motion due to increased temperature will expand the volume, that is, decrease the density of this heated part of the sample. Due to the forces caused by the gravitation acting on more dense subsets of the samples, the portions with lower density will be forced to move towards the opening end, immediately replaced by sample with higher density. This dense portion will then be heated by means of the same process of heat transfer from the heating source. The density of this portion of the sample will decrease and move towards the opening end and become replaced by cooler sample. In other words, the centrifugal forces render the heat convection much more effective. Thereafter a cooling of the samples in the reaction vessels will take place. The heating source is switched off and the reaction vessels are made accessible to the flow of air or gas, caused by the rotation and/or a cooling gas is supplied to the centrifuge. During the cooling of the reaction vessels, the heat in the walls of the vessels will decrease and the portion of the sample closest to the wall will cool down and become more dense, whereby the cooled sample portion will move towards the closed end, i.e. in the direction of the gravitational force, sliding along the walls, whereby a new portion of the sample will be cooled in the vicinity of the walls. Again, the centrifugal forces increase the effectiveness of convection. In thermocycling processes, for example polymerase chain reactions (PCR), the heating and cooling phases are repeated several times. Of course this take a lot of time, although the apparatus and method of WO 00/58013 has tremendously decreased the process time. Still there is a need of shortening the process time, in particular the transition time between the different process temperatures. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accurate and fast cooling of the samples is important in thermocycling processes. In particular in PCR, it is known that no productive activity occurs in the samples during the cooling phase of the process. Therefore the cooling time should be decreased to a minimum. This insight forms one of the basis of the present invention. The solution to the problem of decreasing the cooling time is provided by novel rotor means having the features according to claim 1 and by a novel a thermocycling device having rotor means according to the present invention. By the provision of at least one fan blade in the rotor means, ambient gas is forced to pass the samples, whereby, for example, a more effective cooling of the samples may be performed since a larger amount of ambient gas will pass the samples than if the samples would only be, subjected to the ambient gas by its rotational speed. The function of the fan blade-/s may be compared with the function of a centrifugal pump. In order to effectively perform the cooling of the samples, the ambient gas could be conducted through a conducting passage. According to a preferred embodiment the rotor means comprises a base portion and a lid portion, forming an inner space between these two portions. Within this inner space the fan blade-/s are provided. Preferably the lower portion of the rotor means, for example but not necessarily the base portion, is provided with at least one through hole to let the gas into the inner space, or more precisely, the gas will be drawn into the inner space by the performance of the rotating fan blade-/s in the inner space. Preferably the upper portion of the rotor means, for example the lid portion but not necessarily, is provided with at least one through hole to let the gas, which is drawn in and forced through the inner space, out of the inner space. The fan blade-/s may for example be arranged on the inside, i.e. the side that faces the inner space, of the lid portion or on the inside of the base portion. In order to increase the throughput of the device and/or process, it would be an advantage to be able to handle more samples at the same time. One way of doing this is to handle samples arranged in a parallel format, for example in at least one microtitre plate. Microtitre plates are available in different formats, such as the traditional 96 well format, and e.g. the more dense 384 well format, as well as the 1536 well format. Using microtitreplates, the benefits of the invention become accentuated. If only the airflow caused by the rotation velocity is used to cool the reaction vessels containing the samples, a problem of non-uniform cooling of the samples will appear. The airflow will hit the row of reaction vessels in the front, in relation to the travelling direction of the microtitre plate, whereafter, due to natural flow, the airflow will be diverted outside the closed ends of the reaction vessels of the microtitre plate towards the back of the plate. Thanks to the present invention it becomes possible to cool all the samples in the microtitre plate by forcing ambient gas to pass in between the wells containing the samples by means of at least one fan blade and at least one gas conducting passage provided in the rotor means. The gas may be ambient air or any gas supplied to the rotor means and its surroundings. The air or gas may be cooled by cooling means. Another problem that arises when centrifuging microtitre plates is that there will be a chord difference between the side edges and the centre in comparison with heating means, e.g. IR sources, provided adjacent outside the rotor means so that the samples arranged closer to the side edges will be closer to the heating means, and thereby more heated, than the samples closer to the centre. According to the present invention this problem is solved by providing a screen with lateral density differences towards the centre between the heating means and the samples, arranged at the rotor means, for compensating of the chord differences. Yet another problem that arises in particular when reaction vessels in the parallel format, e.g. microtitre plates, are used is that of deformation of the reaction vessels. Under the high centrifugal forces and elevated temperatures, the microtitreplates are frequently deformed. According to conventional techniques, this is avoided by the provision of supporting elements shaped as a negative print of the microtitreplate. In other words, the microtitreplate is placed in a solid support having wells corresponding to each reaction vessel or well of the microtitreplate. Due to this arrangement, the reaction vessels or wells are not accessible for analysis, nor for effective heating and cooling. The arrangement according to the present invention provides a highly beneficial solution to the problem of microtitreplate deformation. The base portion of the rotor which together with the lid portion define an inner space through which ambient air is forced, does simultaneously constitute a support for the microtitreplates without obstructing the airflow and thus allowing for efficient cooling. By providing a transparent base plate, the reaction vessels are available for analysis if desired. Optionally, the base plate may be provided with indentations corresponding to the apices of the reaction vessels. It should be noted that the function of the rotor means according to the present invention may be advantageous not only during cooling but also during keeping of temperature in and heating the samples. |
Identification of ses-3 and the uses of the same |
The invention relates to isolated nucleic acid molecules coding for SES-3 proteins or muted SES-3 proteins, and vectors and transgenic organisms containing such nucleic acid molecules. The invention also relates to uses of such nucleic acid molecules or others which are functionally similar, for producing pharmaceuticals and for producing model organisms. The invention further relates to the corresponding SES-3 proteins and muted SES-3 proteins, and the antibodies induced thereby. Finally, the invention relates to the use of substances which increase the expression of human presenilin, for the treatment of Alzheimer's disease, in addition to said substances themselves and pharmaceutical compositions containing the same. |
1-31. (Cancelled). 32. An isolated nucleic acid molecule that encodes SES-3 or a mutated form of SES-3. 33. An isolated nucleic acid as described in claim 32, wherein the mutated form of SES-3 is a protein having at least one of an FAD binding site and an amino oxidase motif. 34. An isolated nucleic acid as described in claim 32, wherein the mutated form is a protein having one or more alterations in activity. 35. An isolated nucleic acid molecule as described in claim 32, which is DNA, cDNA, genomic DNA, or RNA. 36. An isolated nucleic acid molecule as described in claim 32, wherein the SES-3 has an amino acid sequence identical to, or essentially the same as, SEQ ID NO: 1. 37. An isolated nucleic acid molecule as described in claim 32, comprising a nucleotide sequence of SEQ ID NO: 2, or a sequence that is complementary thereto. 38. An isolated nucleic acid molecule, comprising a nucleotide sequence having at least 75% sequence similarity to a nucleotide sequence as described in claim 37, or a sequence complementary thereto. 39. An isolated nucleic acid molecule that hybridizes with an isolated nucleic acid molecule as described in claim 37 under conditions of 0.1×SSC at 68 degrees centigrade. 40. A vector that comprises an isolated nucleic acid molecule or a fragment thereof as described in claim 32. 41. A vector as described in claim 40, which comprises a promoter for expression in a eukaryote cell. 42. A vector as described in claim 40, which is in the form of a plasmid, a cosmid, a bacmid, a virus or a bacteriophage. 43. An SES-3 protein comprising the amino acid sequence of SEQ ID NO: 1, or a fragment thereof. 44. A mutated SES-3 protein, or a fragment thereof. 45. An SES-3 protein as described in claim 43, comprising one or more additions, deletions, or alterations at one or more amino acid positions corresponding to one or more amino acids of SEQ ID NO: 1. 46. An antibody produced against an SES-3 protein as described in claim 43. 47. An antibody as described in claim 46, wherein the antibody is a monoclonal antibody or a polyclonal antibody. 48. A transgenic, nonhuman organism that comprises a nucleic acid molecule as described in claim 32. 49. A transgenic, nonhuman organism as described in claim 48, wherein the organism is C. elegans. 50. A transgenic C. elegans organism as described in claim 49, which expresses an SES-3 allele that decreases, amplifies or eliminates the activity of SES-3. 51. A transgenic C. elegans organism as described in claim 50, which expresses an SES-3 allele that offsets the egg-laying defect phenotype (EgI) in sel-12 C. elegans mutants. 52. A transgenic C. elegans organism as described in claim 50, which expresses an SES-3 allele that increases the activity of hop-1 or sel-12. 53. A transgenic organism that comprises a foreign SES-3 gene homologue. 54. A transgenic organism as described in claim 53, wherein the homologue is human gene KIAA0601 or Drosophila melanogaster ALT1. 55. A method of producing a pharmaceutically active substance useful for treating neurodegenerative disease, comprising expressing an isolated nucleic acid molecule as described in claim 32, or a functionally similar gene, to produce a gene product and then isolating the gene product. 56. A method for preparing a transgenic organism for investigating neurodegenerative disease, comprising incorporating an isolated nucleic acid molecule as described in claim 32 into an organism. 57. A method for discovering substances that alter the activity of SES-3, comprising monitoring SES-3 activity in the presence of a test substance, and identifying or characterizing an effect of the substance on the monitored activity. 58. The method of claim 57, wherein the SES-3 activity is monitored in a transgenic organism or transgenic cell. 59. The method of claim 58, wherein the transgenic organism is E. elegans. 60. A method for evaluation of substances that increase the activity of at least one of hop-1 and sel-12 in a transgenic cell or organism containing a nucleic acid molecule as described in claim 1, comprising monitoring the activity in the presence of a test substance, and identifying or characterizing an effect of the substance on the monitored activity. 61. The method of claim 29, wherein the organism is C. elegans. 62. A method for evaluation of substances that affect the expression of presenilin in a transgenic cell or organism containing a nucleic acid molecule as described in claim 1, comprising monitoring presenilin expression in the presence of a test substance, and identifying or characterizing an effect of the substance on the monitored expression. 63. A method for producing a medicament for treating Alzheimer's disease, comprising providing a substance identified by the method of claim 31, and formulating the substance into a pharmaceutical. 64. A substance that increases the expression of human presenilin I or presenilin 2, comprising a molecule discovered by the method of claim 62. 65. A pharmaceutical composition that comprises a substance as described in claim 64. |
<SOH> BACKGROUND TO THE INVENTION <EOH>Aside from Parkinson's disease, Alzheimer's disease is that neuro-degenerative disease which is most well known. The characteristic feature of Alzheimer's disease is the development of neuronal protein aggregations, what are termed plaques, which are essentially composed of an insoluble peptide, of 4 kDa in size, termed amyloid beta-peptide (Aβ4). Investigations carried out in the last few years indicate that the formation of Aβ4 is causatively involved in the development of the disease. Dominant mutations in three genes give rise to familial forms of the disease (FAD, familial Alzheimer's disease). It has been found that one of the genes concerned encodes amyloid precursor protein (APP), which can be processed by three proteases, resulting in the formation of Aβ4, inter alia. FAD mutations in APP increase the quantity of Aβ42, a 42 amino acid-long variant of Aβ4, which is produced. Molecular genetic investigations of families in which Alzheimer's disease has occurred have led to the identification of the human genes presenilin 1 and presenilin 2 (Rogaev et al. 1995, Nature 376, 775-778; Levy-Lahad, E. et al. 1995, Science 269: 973-977) which, when altered by particular mutations, are causatively involved in the onset of Alzheimer's disease and which also play a key role in the Notch signal transduction pathway during development of the disease. Presenilin proteins are located in the ER-Golgi and possess at least 6 transmembrane domains. It has been found that mutations in PS1 and PS2 influence the formation of Aβ4 and are involved in giving rise to Alzheimer's disease, presumably by means of the formation of amyloid deposits. Members of the presenilin family have been identified in the mouse, in Drosophila melanogaster , in Xenopus laevis and in the threadworm Caenorhabditis elegans , inter alia. Although mutated presenilins influence the processing of APP in humans, their natural function in humans is not known in detail; it has been postulated that they might function as an APP protease (gamma-secretase). Other investigations carried out on human cell cultures have indicated that presenilins play a role in the intracellular proteolysis of Notch-like receptors after they have been activated by ligand binding. It is assumed, therefore, that the presenilins are involved in processing at least two different membrane proteins (APP and Notch). At present, it is a controversial matter as to whether the presenilins themselves are the proteases in this processing or whether they are cofactors of these reactions or influence the proteolysis indirectly (Haass, C. et al. 1999, Science 286 (5441): 916-919). Taking the abovementioned presenilin genes as the starting point, intensive research is being carried out to elucidate the molecular disease processes and to develop pharmaceuticals for treating and preventing Alzheimer's disease. Factors which influence the activity of the presenilin genes are being sought, in particular, particular importance being attached, in this connection, to the search for suppressors of the presenilin mutant phenotype. Suppressors can be mutations in other genes which eliminate the requirement for the presenilin function or they can be substances which modulate the activity of other genes, or of the presenilins, such that the presenilin mutant defect does not have any phenotypic consequences. A nematode, in particular Caenorhabditis elegans , has frequently been employed as a preferred model organism in these investigations. The advantage of a nematode model, in particular of the C. elegans model, lies, in particular, in its suitability for a high-throughput method (HTS; high-throughput screening), the possibility of faster genetic analysis due to a shorter generation time (2-3 days) and detailed knowledge of the molecular and functional properties of the nervous system in C. elegans . Since C. elegans can be kept on microtiter plates, it is possible to use this test system to test, by means of HTS, 10 000 or more substances on the living worm over a short period of time. Three presenilin genes, designated sel-12, hop-1 and spe-4, have thus far been identified in the threadworm C. elegans . Spe-4 is the most divergent member of the family. Mutations in spe-4 lead to a defect in cytoplasmic partitioning during spermatogenesis (L'Hernault, S. W. et al. 1992, J Cell Biol 119: 55-68). While mutations in hop-1 do not have any visible phenotype, they lead, in combination with mutations in sel-12, to a synthetically lethal phenotype (Li, X. et al. 1997, Proc Natl Acad Sci USA 94: 12204-12209). Sel-12 is the gene which most strongly resembles human PS1 and PS2 and is also the best-studied presenilin gene in C. elegans . It has been found that certain sel-12 mutants exhibit an egg-laying defect and also morphological changes in vulva development (Levitan, D. et al. 1995, Nature 377: 3514). Sel-12 is 50% identical with human presenilins, and the egg-laying defect in sel-12 mutants can be offset by transgenically expressing PS1 or PS2 from the sel-12 promoter (Baumeister et al., 1997, Genes and Function 1: 149-159). This demonstrates that PS1 and PS2 exhibit functional homology with sel-12. Sel-12 mutations were initially identified as suppressors of the multivulva phenotype of a gain-of-function mutant in the lin-12 and glp-1 Notch receptor gene. Notch receptors control determination of cell fate in many multicellular organisms. In addition, it has been shown that the phenotype of sel-12 mutants resembles that of weak function-loss mutants of lin-12. In summary, it can be stated that presenilins play an important role in Notch signal transduction in a large number of organisms, including mammals. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present inventors have now found, surprisingly, that certain mutations in another gene, i.e. the C. elegans ses-3 gene, which was first identified by the inventors, are able to suppress a defect, in particular the egg-laying defect of a sel-12 mutant. These mutations are characterized by the fact that they alter, in particular reduce, the expression or activity of ses-3. This means that particular mutations in the ses-3 gene lead, for example, to the egg-laying defect, which is caused by certain sel-12 mutations, being eliminated and the double mutants (sel-12; ses-3) once again exhibiting a normal wild-type phenotype. More detailed investigations have shown that these mutations in the ses-3 gene lead, in the sel-12 mutants, to hop-1 being activated, i.e. the hop-1 presenilin protein takes over the function of the defective sel-12 presenilin protein ( FIG. 1 ). The present inventors have located the novel ses-3 gene on the C. elegans genome and sequenced it. Consequently, the present invention initially relates to an isolated nucleic acid molecule which encodes SES-3 protein and to other nucleic acid molecules which encode mutated SES-3 proteins. In addition to this, the invention relates to a vector which comprises these isolated nucleic acid molecules, or fragments thereof. The invention furthermore relates to the SES-3 proteins and mutated SES-3 proteins, or fragments thereof, which are encoded by the nucleic acid molecules and to antibodies which are generated using these proteins. In addition, the invention relates to a transgenic, nonhuman organism which comprises an isolated nucleic acid molecule which encodes SES-3 protein or mutated SES-3 protein. In particular, the invention relates to transgenic C. elegans organisms which exhibit an ses-3 allele which decreases the activity of ses-3 and, respectively, increases the activity of sel-12 or hop-1. In this connection, transgenic organisms are understood as being those organisms in which the genome has been altered by mutation, and which exhibit a mutated ses-3 gene as a result, or from which the ses-3 gene has been removed. Finally, the invention relates to uses of these nucleic acid molecules for producing a pharmaceutical directed against Alzheimer's disease and for generating model systems for investigating this disease still further. In particular, the invention relates to the use of transgenic C. elegans in a method for identifying and/or characterizing substances which reduce the activity of ses-3 or, respectively, increase the activity of sel-12 or hop-1. The invention furthermore also relates to the use of homologous human genes, homologous Drosophila melanogaster genes or genes which exhibit functional similarity to ses-3 for producing a pharmaceutical which is directed against Alzheimer's disease and for generating model systems for investigating this disease still further. Finally, the invention also relates to the use of substances which increase the expression of human presenilin 1 or 2 for treating Alzheimer's disease and to these substances themselves and to pharmaceutical compositions which comprise these substances. |
Identification of ses-1 and the uses of the same |
The invention relates to isolated nucleic acid molecules coding for SES-1 proteins or muted SES-1 proteins, and vectors and transgenic organisms containing such nucleic acid molecules. The invention also relates to uses of such nucleic acid molecules for producing pharmaceuticals and for producing model organisms. The invention further relates to the corresponding SES-1 proteins and muted SES-1 proteins, and the antibodies induced thereby. Finally, the invention relates to the use of substances which increase the expression of human presenilin, for the treatment of Alzheimer's disease, in addition to said substances themselves and pharmaceutical compositions containing the same. |
1-32. (Cancelled). 33. An isolated nucleic acid molecule that encodes SES-1 or a mutated form of SES-1. 34. An isolated nucleic acid as described in claim 33, wherein the nucleic acid is a DNA with one or more alterations at one or more of positions 1393, 1784, 1481, 3052, 6698, 549, 25042, 27543, and 1163 relative to a starting ATG. 35. An isolated nucleic acid as described in claim 34, wherein the one or more alterations is selected from the group consisting of a C to T conversion at position 1393, a G to A conversion at position 1784, a CAA to AAC conversion at position 1481, a deletion from position 3052 towards position 6698 by a single A base pair insertion, an A removal at position 549, a deletion from the EcoR1 side at position 25042 of F4686 to the Scal side at position 27543, and a T to A conversion at position 1163. 36. An isolated nucleic acid molecule as described in claim 33, which is a DNA molecule, a cDNA molecule, a genomic DNA molecule, or an RNA molecule. 37. An isolated nucleic acid molecule as described in claim 33, wherein the SES-1 has an amino acid sequence identical to, or essentially the same as at least one of SEQ ID NO: 1 and SEQ ID NO:2. 38. An isolated nucleic acid molecule as described in claim 33, comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, or comprising a sequence that is complementary thereto. 39. An isolated nucleic acid molecule as described in claim 33, comprising a nucleotide sequence having at least 75% sequence similarity to a nucleotide sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, or a sequence complementary thereto. 40. An isolated nucleic acid molecule that hybridizes with an isolated nucleic acid molecule as described in claim 33 under conditions of 0.1×SSC at 68 degrees centigrade. 41. A vector that comprises an isolated nucleic acid molecule or a fragment thereof as described in claim 33. 42. A vector as described in claim 41, which comprises a promoter for expression in a cell of the nematode C. elegans. 43. A vector as described in claim 41, which is in the form of a plasmid, a cosmid, a bacmid, a virus or a bacteriophage. 44. An SES-1 protein comprising the amino acid sequence of at least one of SEQ ID NO: 1 and SEQ ID NO: 2, a mutated version thereof, or a fragment thereof. 45. An SES-1 protein as described in claim 44, comprising one or more additions, deletions, or alterations at one or more amino acid positions corresponding to one or more amino acids of at least one of SEQ ID NO: 1 and SEQ ID NO: 2. 46. A mutated protein as described in claim 45, encoded by a nucleic acid molecule comprising one or more mutations at nucleic acid positions 1393, 1784, 1481, 3052, 6698, 549, 25042, 27543, and 1163 relative to a starting ATG. 47. An antibody having binding activity against an SES-1 protein as described in claim 44. 48. An antibody as described in claim 46, comprising a monoclonal antibody or a polyclonal antibody. 49. A transgenic, nonhuman organism or cell that comprises a foreign nucleic acid molecule having a sequence as described in claim 39. 50. A transgenic organism as described in claim 49, wherein the organism is C. elegans. 51. A transgenic C. elegans organism as described in claim 50, which expresses an SES-1 allele that decreases, amplifies or eliminates the activity of SES-1. 52. A transgenic C. elegans organism as described in claim 51, which expresses an SES-1 allele that offsets the egg-laying defect phenotype (Egl) in sel-12 C. elegans mutants. 53. A transgenic C. elegans organism as described in claim 51, which expresses an SES-1 allele that increases the activity of hop-1 or sel-12. 54. A method of producing a pharmaceutical for treating neurodegenerative disease, comprising expressing an isolated nucleic acid molecule as described in claim 33, or a functionally similar gene, to produce a gene product, and isolating the gene product. 55. A method for investigating neurodegenerative disease, comprising generating a transgenic organism by incorporating a nucleic acid molecule as described in claim 33 into the organism, such that the introduced nucleic acid functions to affect the activity of SES-1. 56. A method for investigating neurodegenerative disease, comprising monitoring SES-1 activity in the presence of a test substance, and identifying or characterizing an effect of the substance on the monitored activity. 57. The method of claim 56, wherein the SES-1 activity is monitored in a transgenic organism or cell. 58. The method of claim 57, wherein the transgenic organism is C. elegans. 59. The method of claim 57, wherein a decrease or elimination of SES-1 activity is detected and correlated with the presence or abundance of the test substance. 60. The method of claim 57, wherein an increase in the activity of hop-1 or sel-12 is monitored and correlated with the presence or abundance of the test substance. 61. A method of identifying a compound for treating or preventing Alzheimer's disease, comprising providing a transgenic C. elegans organism as described in claim 50, exposing the organism to the compound, and detecting an effect of that exposure. 62. A method for discovering a medicament for treating Alzheimer's disease, comprising obtaining a substance identified by the method of claim 50, and determining the effect of that substance on the expression of presenilin 1 or presenilin 2. 63. A substance that increases the expression of human presenilin 1 or presenilin 2, comprising a molecule discovered by the method of claim 62. 64. A pharmaceutical composition that comprises a substance as described in claim 63. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Aside from Parkinson's disease, Alzheimer's disease is that neuro-degenerative disease which is most well known. The characteristic feature of Alzheimer's disease is the development of neuronal protein aggregations, what are termed plaques, which are essentially composed of an insoluble peptide, of 4 kDa in size, termed amyloid beta-peptide (Aβ4). Investigations carried out in the last few years indicate that the formation of Aβ4 is causatively involved in the development of the disease. Dominant mutations in three genes give rise to familial forms of the disease (FAD, familial Alzheimer's disease). It has been found that one of the genes concerned encodes amyloid precursor protein (APP), which can be processed by three proteases, resulting in the formation of Aβ4, inter alia. FAD mutations in APP increase the quantity of Aβ42, a 42 amino acid-long variant of Aβ4, which is produced. Molecular genetic investigations of families in which Alzheimer's disease has occurred have led to the identification of the human genes presenilin 1 and presenilin 2 (Rogaev et al. 1995, Nature 376, 775-778; Levy-Lahad, E. et al. 1995, Science 269: 973-977) which, when altered by particular mutations, are causatively involved in the onset of Alzheimer's disease and which also play a key role in the Notch signal transduction pathway during development of the disease. Presenilin proteins are located in the ER-Golgi and possess at least 6 transmembrane domains. It has been found that mutations in PS1 and PS2 influence the formation of Aβ4 and are involved in giving rise to Alzheimer's disease, presumably by means of the formation of amyloid deposits. Members of the presenilin family have been identified in the mouse, in Drosophila melanogaster, in Xenopus laevis and in the threadworm Caenorhabditis elegans, inter alia. Although mutated presenilins influence the processing of APP in humans, their natural function in humans is not known in detail; it has been postulated that they might function as an APP protease (gamma-secretase). Other investigations carried out on human cell cultures have indicated that presenilins play a role in the intracellular proteolysis of Notch-like receptors after they have been activated by ligand binding. It is assumed, therefore, that the presenilins are involved in processing at least two different membrane proteins (APP and Notch). At present, it is a controversial matter as to whether the presenilins themselves are the proteases in this processing or whether they are cofactors of these reactions or influence the proteolysis indirectly (Haass, C. et al. 1999, Science 286 (5441): 916-919). Taking the abovementioned presenilin genes as the starting point, intensive research is being carried out to elucidate the molecular disease processes and to develop pharmaceuticals for treating and preventing Alzheimer's disease. Factors which influence the activity of the presenilin genes are being sought, in particular, particular importance being attached, in this connection, to the search for suppressors of the presenilin mutant phenotype. Suppressors can be mutations in other genes which eliminate the requirement for the presenilin function or they can be substances which modulate the activity of other genes, or of the presenilins, such that the presenilin mutant defect does not have any phenotypic consequences. A nematode, in particular Caenorhabditis elegans, has frequently been employed as a preferred model organism in these investigations. The advantage of a nematode model, in particular of the C. elegans model, lies, in particular, in its suitability for a high-throughput method (HTS; high-throughput screening), the possibility of faster genetic analysis due to a shorter generation time (2-3 days) and detailed knowledge of the molecular and functional properties of the nervous system in C. elegans. Since C. elegans can be kept on microtiter plates, it is possible to use this test system to test, by means of HTS, 10 000 or more substances on the living worm over a short period of time. Three presenilin genes, designated sel-12, hop-1 and spe-4, have thus far been identified in the threadworm C. elegans. Spe-4 is the most divergent member of the family. Mutations in spe-4 lead to a defect in cytoplasmic partitioning during spermatogenesis (L'Hemault, S. W. et al. 1992, J Cell Biol 119: 55-68). While mutations in hop-1 do not have any visible phenotype, they lead, in combination with mutations in sel-12, to a synthetically lethal phenotype (Li, X. et al. 1997, Proc Natl Acad Sci USA 94: 12204-12209). Sel-12 is the gene which most strongly resembles human PS1 and PS2 and is also the best-studied presenilin gene in C. elegans. It has been found that certain sel-12 mutants exhibit an egg-laying defect and also morphological changes in vulva development (Levitan, D. et al. 1995, Nature 377: 35-14). Sel-12 is 50% identical with human presenilins, and the egg-laying defect in sel-12 mutants can be offset by transgenically expressing PS1 or PS2 from the sel-12 promoter (Baumeister et al., 1997, Genes and Function 1: 149-159). This demonstrates that PS1 and PS2 exhibit functional homology with sel-12. Sel-12 mutations were initially identified as suppressors of the multivulva phenotype of a gain-of-function mutant in the lin-12 and glp-1 Notch receptor gene. Notch receptors control determination of cell fate in many multicellular organisms. In addition, it has been shown that the phenotype of sel-12 mutants resembles that of weak function-loss mutants of lin-12. In summary, it can be stated that presenilins play an important role in Notch signal transduction in a large number of organisms, including mammals. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present inventors have now found, surprisingly, that certain mutations, as shown in FIG. 1 for example, in another gene, i.e. the C. elegans ses-1 gene, which was first identified by the inventors, are able to suppress a defect, in particular the egg-laying defect of a sel-12 mutant. This means that particular mutations in the ses-1 gene lead, for example, to the egg-laying defect, which is caused by certain sel-12 mutations, being eliminated and the double mutants (sel-12 − ; ses-1 − ) once again exhibiting a normal wild-type phenotype. More detailed investigations have shown that these mutations in the ses-1 gene lead, in the sel-12 mutants, to hop-1 being activated, i.e. the hop-1 presenilin protein takes over the function of the defective sel-12 presenilin protein. The present inventors have located the novel ses-1 gene on the C. elegans genome and sequenced it. Consequently, the present invention initially relates to an isolated nucleic acid molecule which encodes SES-1 protein and to other nucleic acid molecules which encode mutated SES-1 proteins. In addition to this, the invention relates to a vector which comprises these isolated nucleic acid molecules, or fragments thereof. The invention furthermore relates to the SES-1 proteins and mutated SES-1 proteins, or fragments thereof, which are encoded by the nucleic acid molecules and to antibodies which are generated using these proteins. In addition, the invention relates to a transgenic, nonhuman organism which comprises an isolated nucleic acid molecule which encodes SES-1 protein or mutated SES-1 protein. In particular, the invention relates to transgenic C. elegans organisms which exhibit an ses-1 allele which decreases the activity of ses-1 and, respectively, increases the activity of sel-12 or hop-1. In this connection, transgenic organisms are understood as being those organisms in which the genome has been altered by mutation, and which exhibit a mutated ses-1 gene as a result, or from which the ses-1 gene has been removed. Finally, the invention relates to uses of these nucleic acid molecules for producing a pharmaceutical directed against Alzheimer's disease and for generating model systems for investigating this disease still further. In particular, the invention relates to the use of transgenic C. elegans in a method for identifying and/or characterizing substances which reduce the activity of ses-1 or, respectively, increase the activity of sel-12 or hop-1. The invention furthermore also relates to the use of substances which increase the expression of human presenilin 1 or 2 for treating Alzheimer's disease and to these substances themselves and to pharmaceutical compositions which comprise these substances. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.