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Method for protecting personal data read in a terminal station by a server |
The invention concerns a method enabling a server manager to prove subsequently that the server was authorised to read a user's personal data in a terminal station (ST), comprising: transmitting server policy data (PS) to the station; comparing the server policy data with private policy data (PP) pre-stored in the station; determining a signature (SGST) of server policy data received in the station; and transmitting the signature with the personal data (DP) read in the station to the server when the compared policy data (PS, PP) are compatible. |
1. A method of protecting personal data read from a user terminal station (TS) by a server (SE), said method including transmitting (S1) server policy data (SP) from the server to the station, and comparing (S2) the server policy data (SP) with private policy data (PP) pre-stored in the station, said method being characterized by determining (S5) a signature (SGTS) for signing the server policy data (SP) received in the station (TS) and by transmitting (S6) the signature (SGTS) with personal data (PD) read from the station to the server from the station when the server policy data (SP) is compatible with the private policy data (PP). 2. A method according to claim 1, in which the comparing (S2), the determining (S5) of the signature (SGTS) for signing the server policy data (SP), and the transmitting (S6) of the personal data (PD) and of the signature (SGTS) are automatic (S41) in the terminal station (TS) without the user having to intervene. 3. A method according to claim 2, in which the received server policy data (SP) is converted into a form that is viewed in the terminal station (TS) and that is filled in automatically with the read personal data (PD). 4. A method according to any one of claims 1 to 3, in which the terminal station (TS) determines (S5) the signature (SGTS) also as a function of time-stamping data (TSDT). 5. A method according to claim 4, in which the terminal station (TS) stores the signature (SGTS) and preferably the time-stamping data (TSDT). 6. A method according to any one of claims 1 to 5, including transmitting (S1) a signature (SGSE) of the server policy data (SP) with the server policy data from the server (SE) to the terminal station (TS), and storing (S1) said signature (SGSE) in the terminal station, preferably with time-stamping data (TSDR). 7. A method according to any one of claims 1 to 6, including providing means (MD) in the terminal station (TS) for modifying private policy data (PP). 8. A method according to any one of claims 1 to 7, in which the terminal station (TS1, TS2) includes a central processing unit (CPU1, CPU2) and a smart card (SC1, SC2) that is in communication with the central processing unit and that has pre-stored said private policy data (PP) and the personal data (PD). 9. A method according to claim 8, in which the smart card (SC1, SC2) contains an algorithm (ALT) for signing the received server policy data (SP) and preferably time-stamping data. 10. A method according to claim 6 and claim 8 or 9, in which the smart card (SC1, SC2) records the signature (SGSE) of the server policy data (SP) transmitted by the server, preferably with time-stamping data. 11. A method according to any one of claims 1 to 7, in which the terminal station (TS1, TS2) includes a central processing unit (CPU1, CPU2) that has pre-stored said private policy data (PP) and the personal data (PD), and a smart card (CPU1, CPU2) in communication with the central processing unit, and containing an algorithm (ALT) for signing the received server policy data (SP) and preferably time-stamping data. 12. A method according to any one of claims 8 to 11, in which the smart card (SC1, SC2) itself compares the server policy data (SP) with private policy data (PP). |
Chromatin segmentation |
A method of segmenting chromatin particles in a nucleus of a cell by locating regional minima in an image, computing a zone of influence (ZOI) around each regional minimum, and segmenting a single chromatin blob within each ZOI using a region growing procedure. The method can be used as the basis of a method of qualitatively characterizing the distribution of nuclear chromatin by computing features for individual chromatin particles. Chromatin features can be synthesized from the features of individual particles and particle features can be synthesized into nucleus features and slide features. The method is useful for detecting malignancy associated changes and changes during neoplasia. The method may also be used more generally to assess chromatin patterns in living cells during the cell life cycle. This makes it possible to measure alternations in the evolving patterns that result from pathological or environmental influences. |
1. A method of segmenting chromatin particles in the nucleus of a cell including the following steps of: (i) locating regional minima in an image; (ii) computing a zone of influence (ZOI) around each regional minimum; and (iii) segmenting a single chromatin blob within each ZOI using a region growing procedure. 2. The method of claim 1 wherein the image is a two-dimensional gray-scale image comprising only those pixels that define the nucleus of a cell. 3. The method of claim 1 wherein the image is a three-dimensional image. 4. The method of claim 1 wherein the image is a multi-valued image. 5. The method of claim 1 further including the step of evaluating the contrast of each regional minimum and discarding those regional minima that do not satisfy a priori specified contrast criteria. 6. The method of claim 1 further including a preliminary step of pre-processing the image to correct for degradations. 7. The method of claim 6 wherein the pre-processing step removes degradations such as noise and blurring. 8. The method of claim 6 wherein the pre-processed image is up-sampled. 9. The method of claim 1 wherein the regional minima are regions of constant gray-value that are surrounded by pixels of strictly higher (lighter) gray-value, to identify dark blobs. 10. The method of claim 1 wherein the step of computing a zone of influence is performed by means of region growing or the computation of influence zones (IZs). 11. The method of claim 1 wherein the segmentation step is performed by means of one of a watershed transform or a seeded region growing algorithm. 12. A method of quantitatively characterizing the distribution of nuclear chromatin including the steps of: (i) obtaining an image of a cell nucleus showing chromatin texture; (ii) locating regional minima in the image; (iii) computing a zone of influence (ZOI) around each regional minimum; (iv) segmenting a single chromatin blob within each ZOI using a region growing procedure; and (v) computing features for individual chromatin blobs. 13. The method of claim 12 further including the step of: (vi) synthesizing chromatin texture features from the features computed for individual chromatin blob features. 14. The method of claim 13 including the further step of repeating steps (ii) to (v) for the negative of the image of step (i) and using the computed features in step (vi). 15. The method of claim 12 further including the step of evaluating the contrast of each regional minimum in the image of the cell nucleus and discarding those regional minima that do not satisfy a priori specified contrast criteria. 16. The method of claim 12 wherein the image of the cell nucleus is a gray-scale image. 17. The method of claim 12 wherein the computed features are selected from morphometric features, densitometric features, texture features, and contextual features. 18. The method of claim 17 wherein the morphometric features include one or more of: area; perimeter; and G factor. 19. The method of claim 17 wherein the densitometric features include one or more of: volume; mean gray value; and dynamics. 20. The method of claim 17 wherein the contextual features include one or more of: distance to nucleus boundary; number of dark particle neighbors a dark particle has; mean distance between a dark particle and its dark particle neighbors; number of light particle neighbors a light particle has; mean distance between a light particle and its light particle neighbors; number of dark particle neighbors; mean distance to dark particles; number of light particle neighbors; mean distance to light particles; number of particle neighbors; and mean distance to particle neighbors. 21. The method of claim 17 wherein the synthesized features are selected from nucleus features, slide features derived from nucleus features, and slide features derived from particle features. 22. The method of claim 21 wherein the nucleus features include one or more of: mean of each particle feature except dynamics; standard deviation of each particle feature except dynamics; median dynamics; interquartile range of dynamics; number of dark particles; number of light particles; mean of the histogram obtained from the Euclidean distance transform of the nucleus background between the dark particles; standard deviation of the histogram obtained from the Euclidean distance transform of the nucleus background between the dark particles; mean of the histogram obtained from the Euclidean distance transform of the nucleus background between the light particles; standard deviation of the histogram obtained from the Euclidean distance transform of the nucleus background between the light particles; mean of the histogram obtained from the Euclidean distance transform of the nucleus background between both the light and dark particles; standard deviation of the histogram obtained from the Euclidean distance transform of the nucleus background between both the light and dark particles; contrast; and energy computed from the co-occurrence matrix obtained from the neighborhood graph defined on the dark particles, using the particle feature area. |
<SOH> BACKGROUND TO THE INVENTION <EOH>The distribution of the chromosomes or DNA in the nuclei of cells can be quantitatively measured using a computer and image analysis techniques. Moreover, these measurements or features can be used to detect both malignancy associated changes (MACs), and changes during neoplasia. The features that appear to have the most discriminatory power are texture features. Such features quantitatively describe the intensity variation of the chromatin (the substance that constitutes the chromosomes or DNA and is readily visualized by staining) in the nucleus of a cell. The most widely used chromatin texture features are based on a statistical or probabilistic assessment of the gray-levels (intensity levels or optical density levels) in the cell nucleus. Unfortunately these features are difficult to relate to the terms and adjectives (e.g. granularity, compaction, margination, clumping, chromatin particles, condensation) used by cytologists to describe chromatin texture. Moreover they are usually defined at the pixel level and therefore fail to take into account the structural aspect of the chromatin distribution; e.g. this is true of all but the discrete texture features described in the United States Patent of Palcic et al. [System and method for automatically detecting malignant cells and cells having malignancy-associated changes; U.S. Pat. No. 6,026,174 dated Feb. 15, 2000]. Therefore their efficacy in relation to quantifying chromatin distribution is questionable. An alternative approach to computing chromatin texture features is to segment the chromatin into aggregates and then to synthesize chromatin features from quantitative features computed for these aggregates. This approach has two advantages: (i) the segmentation step introduces structural information, and (ii) the synthesized features can be related to qualitative descriptions of chromatin texture made by cytologists. The key to this approach is the segmentation step. Several different methods of chromatin segmentation have been published in the literature. A characteristic they have in common is that they require the a priori specification of one or more operational parameters such as threshold values and region merging criteria. Moreover these parameters need to be tuned to the particular application. As a consequence these methods are not robust to changes in, or non-uniformity of, illumination and staining. The quality of the segmentations produced is arguably poor. This in turn affects the quality of the chromatin features that are computed from such segmentations. This is likely one of the major reasons that such features, with the exception of those of Young, Verbeek, and Mayall [Characterization of chromatin distribution in cell nuclei; Cytometry; vol. 7; 1986; pp. 467-474 ], have not found widespread use. Another possible reason is that the software implementation of the segmentation step is complicated. Three existing methods of chromatin segmentation deserve special attention. The first is the method of Young, Verbeek, and Mayall because it is the basis of the discrete texture features detailed in the aforementioned United States Patent of Palcic et al. The second is the method of Wolf, Beil, and Guski [Chromatin structure analysis based on a hierarchic texture model; Analytical and Quantitative Cytology and Histology; vol. 17; no. 1; 1995; pp. 25-34] because it utilizes the watershed transform as does the preferred embodiment of the present invention. The third is the method of Kondo and Taniguchi [Evaluation of the chromatin for cell images; Systems and Computers in Japan; vol. 17; no. 9; 1986; pp. 11-19] because it represents the closest known prior art to the present invention. The Young, Verbeek, and Mayall (YVM) method of chromatin segmentation takes as input a digitized image of a cell nucleus visualized by light microscopy. Young, Verbeek, and Mayall illustrate their method on images obtained from foam cells in human nipple aspirate fluid, and rat urothelial cells. The method of staining is unspecified. The YVM chromatin segmentation method involves nothing more than partitioning the gray-level histogram of the nucleus image into three parts (i.e. choosing two gray levels), and then using this division to label each nucleus pixel. The result is a segmentation comprising regions of low, medium, and high optical density. The manner in which the partition points (threshold values) are determined must be a priori specified. Although the YVM segmentation method is simple (hence its relative popularity) the quality of the segmentation is questionable for the following two reasons. Firstly, the method of segmentation utilizes only the intensity histogram and does not take into account any spatial information. Secondly, the method requires the specification of two threshold values. The manner in which these are chosen must be a priori specified. Moreover they must be tuned to the particular application. The Wolf, Beil, and Guski (WBG) method of chromatin segmentation takes as input a digitized image of a cell nucleus, visualized by light microscopy, from a cervical tissue section obtained by colposcopic biopsy and stained by the Feulgen method. The WBG method consists of two steps. The first step involves determining the watershed of the gradient of the input image. This is done using a modification of the classic watershed algorithm of Vincent and Soille [Watersheds in digital spaces: an efficient algorithm based on immersion simulations; IEEE Transactions on Pattern Analysis and Machine Intelligence; vol. 13; no. 6; 1991; pp. 583-598]. The result is an oversegmentation; i.e. too many regions are delineated and as a consequence the result does not correspond very well to the chromatin patches in the original image. The second step involves selectively merging the regions segmented in the first step. Specifically, this step involves fitting a plane to each segmented region using standard least-squares techniques and then iteratively merging neighboring regions based on merging criteria related to the standard deviation of gray-levels in the regions. The decision to merge two regions is based on the evaluation of a single parameter that is then compared to a threshold value. This is a drawback of the method because the manner in which this threshold value is determined must be a priori specified. The Kondo and Taniguchi (KT) method of chromatin segmentation represents the closest known prior art to the present invention. The method takes as input a digitized image of a cell nucleus, visualized by light microscopy, from a Pap smear. The method comprises three steps: (i) local maxima (with respect to optical density) are located in the input image (these correspond to local minima of intensity), (ii) the input image is partitioned into sub-images (regions), each containing a single maximum, and (iii) a chromatin granule (densely stained blob of chromatin) is segmented from each region in turn using local adaptive thresholding. Kondo and Taniguchi propose three different methods for the partitioning step: (i) partitioning using a Voronoi neighborhood, (ii) region partitioning by directed tree, and (iii) area expansion by difference direction. A drawback of the Voronoi neighborhood method is that it does not use the topography of the input image to determine a region around each minimum. Consequently it is possible that the region determined around a minimum cuts through one or more adjacent chromatin particles. A drawback of the directed tree method is that it is necessary to a priori select a sensitivity parameter to control growth. A drawback of the density difference method is that the growth is not prescribed by geodesic distance (i.e. if the image is viewed as a landscape then the growth is not prescribed by the topography of the landscape). The local adaptive thresholding method of segmenting a granule from each region has several potential drawbacks including sensitivity to noise and non-uniform illumination, and the need to prescribe the manner in which the threshold value is determined. The present invention is specifically designed for the purpose of segmenting chromatin particles in the nucleus of a cell. The method takes as input an image of the nucleus of a cell. Consequently the task of segmenting a cell from a field of cells and the task of segmenting the nucleus from a single cell, are not the subjects of this invention. Indeed details of these tasks are described in International Patent Application number PCT/AU01/00787 (WO 02/03331) and co-pending International Patent Application number PCT/AU99/00231 (WO 99/52074) respectively. |
<SOH> SUMMARY OF THE INVENTION <EOH>In one form, although it need not be the only, or indeed the broadest form, the invention resides in a method of segmenting chromatin particles in the nucleus of a cell including the following steps of: (i) locating regional minima in the image; (ii) computing a zone of influence (ZOI) around each regional minimum; and (iii) segmenting a single chromatin blob within each ZOI using a region growing procedure. The input image is preferably a two-dimensional gray-scale image comprising only those pixels that define the nucleus of a cell. It will be appreciated that the method is not limited to two-dimensional gray-scale images. The method can be applied to three-dimensional images in which case regional minima will be sets of voxels rather than pixels. The method can also be applied to multi-valued (including multispectral) images. The method may further include the step of evaluating the contrast of each regional minimum and discarding those regional minima that do not satisfy a priori specified contrast criteria. The method may also include a preliminary step of pre-processing the input image to correct for degradations. The pre-processing step suitably removes degradations such as noise and blurring. The pre-processed image may optionally be up-sampled. The regional minima are suitably regions of constant gray-value that are surrounded by pixels of strictly higher (lighter) gray-value. Each regional minimum identifies the location of a dark blob. The method may also be applied to the photographic negative of an image to identify the locations of light blobs. This is equivalent to identifying regional maxima in the original (positive) image. In preference, the step of computing a zone of influence is performed by means of seeded region growing, or catchment basins determined by the watershed transform, or influence zones (IZs) with respect to an a priori specified metric. The segmentation step is suitably performed by means of either a watershed transform or a seeded region growing algorithm. In a further form, the invention resides in a method of quantitatively characterizing the structure of nuclear chromatin including-the steps of: (i) obtaining an image of a cell nucleus showing chromatin texture; (ii) locating regional minima in the image; (iii) computing a zone of influence (ZOI) around each regional minimum; (iv) segmenting a single chromatin blob within each ZOI using a region growing procedure; and (v) computing features for individual chromatin blobs. The method may further include the step of: (vi) synthesizing chromatin features from the features computed for individual chromatin blobs. The method may suitably include the further step of repeating steps (ii) to (v) for the negative of the image of step (i) and using the computed features in step (vi). The method may further include the step of evaluating the contrast of each regional minimum in the image of the cell nucleus and discarding those regional minima that do not satisfy a priori specified contrast criteria. The image of a cell nucleus may be a suitable gray-scale image. |
Device for stacking sheets, especially sheets of paper or cardboard transported by a stream feeder, onto pallets |
In order to stack sheets of paper or cardboard (11) transported by a stream feeder onto pallets (4), devices arm known which comprise a stacking platform (5) which can be raised and lowered, and on which the piles (3) are formed. During the stacking process, the longitudinal edge of a sheet (1) is guided by a separating plate (12) which is suspended on a holding element fixed in the machine frame, and is connected to a vibrator (13) in the form of a shaking element. According to the invention, in order to improve the shaking effect of the separating plate (12), a holding plate (18) is fixed, by means of rubber elements (19), to the holding element fixed in the machine frame, in such a way that it is decoupled from vibrations, the separating plate (12) and vibrator (13) being suspended from the holding plate in a rigid manner. |
1. A device for stacking sheets transported by a stream feeders onto pallets, the device comprising: (a) a stacking platform capable of being raised or lowered on which a stack of sheets is formed, and (b) at least one separating plate capable of guiding the longitudinal edges of a sheet during the stacking, the plate being suspended on a holder attached to a machine frame and and attached to a shaking element, wherein the holder comprises a holding plate attached to the machine frame via rubber elements so as to be vibration-uncoupled and wherein the separating plate and shaking element are rigidly suspended. 2. The device of 1, wherein the separating plate is detachably attached to the holding plate. 3. The device of 1, wherein the holder comprises a holding plate mounted in the machine frame and the holding plate is capable of being raised and lowered. 4. The device of 3, wherein an ejection roll and a separating shoe are additionally attached to the holding plate. 5. The device of claim 1, wherein the shaking element is a vibrator. |
<SOH> TECHNICAL FIELD <EOH>The invention relates to a device for stacking sheets, especially sheets of paper or cardboard transported by a stream feeder, onto pallets, with a stacking platform that can be raised or lowered on which the stacks are formed, and with at least one separating plate that guides the longitudinal edge of a sheet during the stacking, that is suspended on a holder attached to the machine frame and with a vibrator as a shaking element. |
<SOH> BRIEF DESCRIPTION OF THE DRAWING <EOH>The drawing serves to explain the invention with respect to an embodiment depicted in a simplified manner: FIG. 1 —is a schematic representation of the side view of a stacking device. FIG. 2 —is an enlarged representation of the side view of the stack-forming elements acting on the longitudinal edges of the sheet. FIG. 3 —is a view of the stack-forming elements opposite from the sheet-travel direction. FIG. 4 —is a schematic view of the suspension of a separating plate with the appertaining vibrator. detailed-description description="Detailed Description" end="lead"? |
Error concealment for image information |
Method and apparatus for error concealment in an image allowing to conceal an error area in the image with estimated pixels. A first boundary section and a second boundary section adjacent to the error area is determined and correspondences between the boundary elements of the boundary sections are established using non-linear alignment operations. After establishing the correspondences pixels between respective boundary elements of the first boundary section and the second boundary section are estimated. The non-linear alignment operations may include dynamic programming techniques, including Needleman-Wunsch techniques, wherein a similarity measure is used for a matrix fill operation. |
1. Method for error concealment in an image, comprising the steps of: detecting an error area in image data of an image consisting of pixels; determining a first boundary section and a second boundary section of the error area, the boundary sections including boundary elements being defined based on pixels with image information close to the error area; aligning the boundary elements of the first boundary section and the second boundary section using alignment operations to establish correspondences between respective boundary elements of the first boundary section and the second boundary section; and estimating pixels of the error area based on the established correspondences between respective boundary elements of the first boundary section and the second boundary section. 2. Method of claim 1, wherein the alignment operations include non-linear alignment operations including dynamic programming techniques. 3. Method of claim 1, wherein the alignment operations include Needleman-Wunsch techniques. 4. Method of claim 1, wherein a boundary element similarity measure is used for a matrix fill operation. 5. Method of claim 1, wherein the boundary element similarity measure includes classifying the boundary elements into a plurality of ranges of pixel parameters, a pixel parameter being constituted by at least one of grey level values and colour values. 6. Method of claim 5, wherein the width of the individual ranges corresponds to a distribution of the parameter values. 7. Method of claim 1, wherein the first and second boundary section each include an array of pixels adjacent to the error area and are located at opposing sides of the error area. 8. Method of claim 1, wherein the boundary elements are each determined based on at least one image pixel. 9. Method of claim 1, wherein the first and second boundary section include different numbers of boundary elements. 10. Method of claim 1, wherein the establishing of correspondences includes a correspondence from a boundary element of the first boundary section to no boundary element or at least one boundary element of the second boundary section. 11. Method of claim 1, wherein the error area is constituted by missing parts of rows of the image information and the first and second boundary section are constituted by row sections of rows of error free pixels of the image. 12. Method of claim 1, wherein the pixels of the error area are estimated using an interpolation technique. 13. Method of claim 1, wherein the image forms an image of a video sequence of images transmitted in uncompressed or compressed form over a packet network. 14. Method of claim 1, wherein the image is a first image of a sequence of images and the estimated pixels are used for displaying at least one second image of the sequence, the second image following or preceding the first image. 15-17. (Cancelled) 18. Apparatus for error concealment in an image, comprising: a detecting unit for detecting an error area in image data of an image consisting of pixels; a determining unit for determining a first boundary section and a second boundary section of the error area, the boundary sections including boundary elements being defined based on pixels with image information close to the error area; an aligning unit for aligning the boundary elements of the first boundary section and the second boundary section using non-linear alignment operations to establish correspondences between respective boundary elements of the first boundary section and the second boundary section; and an estimating unit for estimating pixels of the error area based on the established correspondences between respective boundary elements of the first boundary section and the second boundary section. 19. Apparatus of claim 18, wherein the alignment operations include non-linear alignment operations including dynamic programming techniques. 20. Apparatus of claim 18, wherein the alignment operations include Needleman-Wunsch techniques. 21. Apparatus of claim 18, wherein a boundary element similarity measure is used for a matrix fill operation. 22. Apparatus of claim 18, wherein the boundary element similarity measure includes classifying the boundary elements into a plurality of ranges of pixel parameters, a pixel parameter being constituted by at least one of grey level values and colour values. 23. Apparatus of claim 22, wherein the width of the individual ranges corresponds to a distribution of the parameter values. 24. Apparatus of claim 18, wherein the first and second boundary section each include an array of pixels adjacent to the error area and located at opposing sides of the error area. 25. Apparatus of claim 18, wherein the boundary elements are each determined based on at least one image pixel. 26. Apparatus of claim 18, wherein the first and second boundary section include different numbers of boundary elements. 27. Apparatus of claim 18, wherein the aligning unit establishes of correspondences from a boundary element of the first boundary section to no boundary element or at least one boundary element of the second boundary section. 28. Apparatus of claim 18, wherein the error area is constituted by missing parts of rows of the image information and the first and second boundary section are constituted by row sections of rows of error free pixels of the image. 29. Apparatus of claim 18, wherein the estimating unit is adapted to estimate the pixels of the error area using an interpolation technique. 30. Apparatus of claim 18, wherein the image forms an image of a video sequence of images transmitted in uncompressed or compressed form over a packet network. 31. Apparatus of claim 18, wherein the image is a first image of a sequence of images and the estimated pixels are used for displaying at least one second image of the sequence, the second image following or preceding the first image. |
<SOH> TECHNOLOGICAL BACKGROUND <EOH>With increased processing capabilities of data processing devices, a growing number of applications makes use of sophisticated graphics and/or video information in providing services for a user. For example, an application may require the display of a single image or a sequence of images on a display. In this case the image information may be retrieved from a local or remote source or storage unit, subjected to further processing, if necessary, and then displayed on a display accessed by a data processing device. Digital representations of images generally consist of a large number of pixels representing the image information, for example grayscale information, color information and similar. When displaying the image pixels on a display, they generate a representation of the original image. As images and particularly sequences of images of a video stream may include large amounts of data, it may be desired to compress the image information in order to reduce the amount of data representing the image. For example, an image can be compressed according to some compression algorithm and then stored on a storage device, requiring less storage space as compared to storing the image in an uncompressed format. If the image is then to be displayed, a corresponding decompression algorithm can be used to decompress the compressed image information prior to displaying it on the display. Compressing the image information can significantly reduce the required amount of information for representing an image or a sequence of images, and thus allows to save storage space. Further, if a source of an image or image sequence is located remote from a data processing device used for displaying the image or sequence of images, compressing the image information can lead to the further advantage of reducing a data rate requirement for transmitting the image information from a storage location or any other source of image information, such as a camera or similar, to the device for actual display. Thus, not only storage space requirements can be reduced, but also bandwidth requirements for transmitting image or video information. Several international standards for image/video compression and/or for transmission of compressed video information over packet networks like the Internet or mobile networks exist. An example thereof is the MPEG-4 (Moving Pictures Experts Group) video compression, combined with RTP(Realtime Transport Protocol)/UDP(User Datagram Protocol) packetization and transmission. Compressed image or video information can be transmitted between data processing devices over any kinds of networks or communication links between data processing devices, including packet switched networks. Packet switched networks are widely used and include wide area networks such as the Internet or local area networks such as company-wide intranets or mobile packet switched networks and similar. Information to be transmitted in packet switched transmission networks is generally divided into information packets which are individually transmitted over the network to a recipient. At the recipient the information included in a plurality of packets is combined and further processed. However, when transmitting packets over packet switched networks, particularly when using unreliable protocols, typically some packet loss occurs, i.e. some packets can be lost or delayed beyond a threshold allowing processing during transmission. Thus, parts of the information scheduled for transmission does not arrive at the recipient, leading to incomplete data for further processing. Typically, information loss when transmitting and/or retrieving images or video sequences of images affects part of a single or a plurality of images. For example, an information loss may affect a region within an image to be displayed, which therefore will be perceived as incomplete or distorted by a viewer unless error concealment is applied. Further, information loss or corruption can occur when retrieving and/or transmitting image data in compressed or uncompressed form due to various other reasons. For example in packets with bit errors delivered for an application or in a bit stream (circuit switched) with bit errors part of the image information is still present in an area. It is therefore desired to conceal the missing or corrupted region of an image such that a viewer does not readily notice the missing part of the image. Several techniques for concealment in video and image transmission exist. Some of these methods perform an error concealment based on available information of the image, and thus estimate and conceal the lost pixels only from the remaining pixels of a picture. Such methods are called intra-frame concealment methods. Others try to estimate and conceal the lost pixels from pixels of previous and/or from the remaining pixels in the picture and possibly also following frames of a video sequence. Such methods are called inter-frame concealment methods, as for example outlined in “Error control and concealment for video communication: A review”, Yao Wang and Qin-Fan Zhu, Proceedings of the IEEE, Vol. 86, No. 5, May 1998. Intra-frame concealment methods may simply apply by linear interpolation between corresponding pixels on two sides of a missing region, more advanced methods use block-based interpolation by looking for dominant edges and attempting to continue the edges. Other methods try to interpolate the block-based coefficient domain. However, all of the above methods fail to provide good error concealment in all possible situations, including characteristics of the images to be handled. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is therefore an object of the invention to provide for an improved method for error concealment allowing a more flexible and efficient error concealment in an image. This object of the invention is solved by a method for error concealment in an image, including: detecting an error area in image data of an image consisting of pixels; determining a first boundary section and a second boundary section of the error area, the boundary sections including boundary elements being defined based on pixels with image information close or adjacent to the error area; aligning the boundary elements of the first boundary section and the second boundary section using alignment operations to establish correspondences between respective boundary elements of the first boundary section and the second boundary section; and estimating pixels of the error area based on the established correspondences between respective boundary elements of the first boundary section and the second boundary section. Accordingly, the invention allows, by aligning the boundary elements using alignment operations, to provide improved correspondences between the boundary elements and thus allows to estimate error concealment information between the established correspondences more closely resembling missing or corrupted image information. Accordingly, the concealment of errors in the image can be improved, both in terms of similarity to the lost information and in terms of visibility for an observer. The alignment operations may include non-linear alignment operations including dynamic programming techniques. The alignment operations may include Needleman-Wunsch techniques. The alignment operations may allow to establish correspondences between respective boundary elements of the boundary sections at reduced computational complexity. Preferably, a similarity measure may be used in the alignment operation. For example, a boundary element similarity measure may be used for a matrix fill operation. By providing a similarity measure, computational requirements can be further reduced, as boundary elements having certain similar values can be grouped together, for example into ranges of values not showing a significant perceptual difference for a viewer. Further, sensitivity to minor variations can be reduced, e.g., noise, artifacts, illumination, variations in the object itself, etc. The similarity measure may include classifying the boundary elements into a plurality of ranges of pixel parameters, a pixel parameter being constituted by at least one of gray level values and color values. By providing a plurality of ranges for the pixel parameters, a classification of the boundary elements using the similarity measure can be effected at reduced computational requirements. Advantageously, the width of the individual ranges may correspond to a distribution of the parameter values. This allows to adapt the similarity measure, i.e., the ranges, to particular image characteristics, for example if certain parameter values of the boundary pixels are encountered less frequently, e.g. if the boundary sections are generally dark or bright, the adapted width of the ranges allows an improved establishment of correspondences between boundary pixels. The first and second boundary section may each include an array of pixels lying adjacent to the error area located at opposing sides of the error area. The arrays of pixels may be either continuous or discontinuous. Each of the boundary elements may be based on at least one image pixel. The first and second boundary sections may include different numbers of boundary elements, allowing a more flexible definition of boundary sections, for example depending on the size of the error area. The establishing of correspondences between boundary elements may include establishing a correspondence from a boundary element of the first boundary to no boundary element or at least one boundary element of the second boundary section. Thus, a particular boundary element may be defined to correspond to one or a plurality of boundary elements or may be defined to not correspond to any boundary element of the second boundary section, allowing further flexibility in establishing the correspondences. The error area may be constituted by missing parts of rows of the image information and the first and second boundary section may be constituted by row sections of rows of error free pixels of the image. Thus, particularly when applying the invention to compressed image information where often blocks of row sections are missing, e.g. due to packet switched transmission losses, the boundary sections can directly be defined as row sections adjacent to the missing row sections. The pixels of the error area may be estimated using an interpolation technique. The image may form an image of a video sequence of images transmitted in uncompressed or compressed form over a packet network. The image may be a first image of a sequence of images and the estimated pixels may be used for displaying at least one second image of the sequence of images, the second image following or preceding the first image. Accordingly, an inter-image error estimation may be applied using estimated missing pixels of a single image, for example in combination with known techniques for inter-image error concealment. A program may have instructions adapted to carry out the above operations. Further, a computer-readable medium may have a program embodied therein, wherein the program is to make a computer execute the above method operations. A computer program product may comprise the computer-readable medium. Further, according to another example, an apparatus for error concealment in an image includes: a detecting unit for detecting an error area in image data of an image consisting of pixels; a determining unit for determining a first boundary section and a second boundary section of the error area, the boundary sections including boundary elements being defined based on pixels with image information close or adjacent to the error area; an aligning unit for aligning the boundary elements of the first boundary section and the second boundary section using non-linear alignment operation to establish correspondences between the respective boundary elements of the first boundary section and the second boundary section; and an estimating unit for estimating pixels of the error area based on the established correspondences between respective boundary elements of the first boundary section and the second boundary section. Further advantageous features of the invention are described in further dependent claims. |
Information processing system and method, information processing device and method, recording medium, and program |
The present invention pertains to an information processing system and method, an information processing apparatus and method, a recording medium, and a program designed such that a service provider can enhance the efficiency and security of its authentication when authenticating a user. A first cryptographic key and a second cryptographic key to be paired with the first cryptographic key which are utilized when a service provider terminal 13 authenticates a key holding apparatus 22 of a user apparatus 11 based on a predetermined authentication technique, are generated by a key allotter terminal 12, and the first cryptographic key is sent to the service provider terminal 13 via a network 14, and the second cryptographic key is sent to the key holding apparatus 22 via the network 14 and a user terminal 21. The present invention is applicable to a system in which each of a plurality of service providers authenticates a user when each of the plurality of service providers provides a corresponding service to the user via communication such as the Internet. |
1. In an information processing system configured of first to third information processing apparatuses, said information processing system is characterized in that: said first information processing apparatus generates a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique, sends said generated first cryptographic key to said second information processing apparatus, and also sends said generated second cryptographic key to said third information processing apparatus; said second information processing apparatus receives said first cryptographic key sent by said first information processing apparatus, and holds; said third information processing apparatus receives said second cryptographic key sent by said first information processing apparatus, and holds; and said second information processing apparatus authenticates said third information processing apparatus by utilizing said held first cryptographic key and said second cryptographic key held by said third information processing apparatus, based on said authentication technique. 2. The information processing system according to claim 1, characterized in that: said authentication technique is common key authentication; and said first cryptographic key and said second cryptographic key are identical cryptographic keys. 3. The information processing system according to claim 1, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key are different cryptographic keys. 4. In an information processing method for an information processing system configured of first to third information processing apparatuses, said information processing method is characterized in that: said first information processing apparatus generates a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique, sends said generated first cryptographic key to said second information processing apparatus, and sends said generated second cryptographic key to said third information processing apparatus; said second information processing apparatus receives said first cryptographic key sent by said first information processing apparatus, and holds; said third information processing apparatus receives said second cryptographic key sent by said first information processing apparatus, and holds; and said second information processing apparatus authenticates said third information processing apparatus by utilizing said held first cryptographic key and said second cryptographic key held by said third information processing apparatus. 5. An information processing apparatus characterized by comprising: generation means for generating a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates another second information processing apparatus based on a predetermined authentication technique; and sending means for sending said first cryptographic key generated by said generation means to said another first information processing apparatus, and sending said second cryptographic key generated by said generation means to said another second information processing apparatus. 6. The information processing apparatus according to claim 5, characterized in that: said authentication technique is common key, authentication; and said first cryptographic key and said second cryptographic key generated by said generation means are identical cryptographic keys. 7. The information processing apparatus according to claim 5, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key generated by said generation means are different cryptographic keys. 8. The information processing apparatus according to claim 5, characterized by further comprising identification means for identifying, when information for authentication is inputted or a predetermined apparatus utilized for authentication is connected, to said another second information processing apparatus, a user who inputs said information or said connected apparatus, wherein said generation means generates said first and said second cryptographic keys when said user who inputs said information to said another second information processing apparatus or said apparatus connected to said another second information processing apparatus is identified by said identification means. 9. The information processing apparatus according to claim 8, characterized in that said identification means identifies said user who inputs said information to said another second information processing apparatus or said apparatus connected to said another second information processing apparatus, by using SSL (Secure Socket Layer), or TLS (Transport Layer Security). 10. The information processing apparatus according to claim 5, characterized by further comprising billing means for fixing a fee for a service provided to said another second information processing apparatus to be authenticated by said another first information processing apparatus, which is other party to whom said first cryptographic key is sent by said sending means, by utilizing said first and said second keys when said first and said second cryptographic keys are generated by said generation means, and billing said user who inputs said information to said another second information processing apparatus, identified by said identification means, or a user identified by said apparatus connected to said another second information processing apparatus, identified by said identification means, for said fee for said service. 11. The information processing apparatus according to claim 10, characterized in that said billing means bills said another second information processing apparatus for said fee for said service, and further, for a fee for said first and said second cryptographic keys generated by said generation means. 12. In an information processing method for an information processing apparatus, said information processing method is characterized by comprising: a generation step of generating a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates another second information processing apparatus based on a predetermined authentication technique; and a sending step of sending said first cryptographic key generated by said generation step to said another first information processing apparatus, and sending said second cryptographic key generated by said generation means to said another second information processing apparatus. 13. A recording medium being recorded therein a computer-readable program, said program for a computer that controls an information processing apparatus is characterized by comprising: a generation step of generating a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates another second information processing apparatus based on a predetermined authentication technique; and a sending step of sending said first cryptographic key generated by said generation step to said another first information processing apparatus, and further sending said second cryptographic key generated by said generation means to said another second information processing apparatus. 14. A program characterized by causing a computer that controls an information processing apparatus to execute: a generation step of generating a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates another second information processing apparatus based on a predetermined authentication technique; and a sending step of sending said first cryptographic key generated by said generation step to said another first information processing apparatus, and sending said second cryptographic key generated by said generation means to said another second information processing apparatus. 15. An information processing apparatus characterized by comprising: receiving means for receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said first cryptographic key; holding means for holding said first cryptographic key received by said receiving means; and authentication means for authenticating said another second information processing apparatus by utilizing said first cryptographic key held by said holding means and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 16. The information processing apparatus according to claim 15, characterized in that: said authentication technique is common key authentication; and said first cryptographic key and said second cryptographic key are identical cryptographic keys. 17. The information processing apparatus according to claim 15, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key are different cryptographic keys. 18. In an information processing method for an information processing apparatus, said information processing method is characterized by comprising: a receiving step of receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said first cryptographic key; a holding step of holding said first cryptographic key received by said receiving step; and an authentication step of authenticating said another second information processing apparatus by utilizing said first cryptographic key held by said holding step and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 19. A recording medium being recorded therein a computer-readable program, said program for a computer that controls an information processing apparatus is characterized by comprising: a receiving step of receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said first cryptographic key; a holding step of holding said first cryptographic key received by said receiving step; and an authentication step of authenticating said another second information processing apparatus by utilizing said first cryptographic key held by said holding step and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 20. A program characterized by causing a computer that controls an information processing apparatus to execute: a receiving step of receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said first cryptographic key; a holding step of holding said first cryptographic key received by said receiving step; and an authentication step of authenticating said another second information processing apparatus by utilizing said first cryptographic key held by said holding step and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 21. An information processing apparatus characterized by comprising: receiving means for receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said second cryptographic key; holding means for holding said second cryptographic key received by said receiving means; and response means for sending a predetermined response to another second information processing apparatus by utilizing said second cryptographic key held by said holding means, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said first cryptographic key, based on said authentication technique. 22. The information processing apparatus according to claim 21, characterized in that: said authentication technique is common key authentication; and said first cryptographic key and said second cryptographic key are identical cryptographic keys. 23. The information processing apparatus according to claim 21, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key are different cryptographic keys. 24. The information processing apparatus according to claim 21, characterized by further comprising input means for inputting information for authentication by said another second information processing. 25. The information processing apparatus according to claim 21, characterized by further comprising connection means for connecting a predetermined apparatus which is utilized when authenticated by said another second information processing apparatus. 26. The information processing apparatus according to claim 21, characterized in that said apparatus connected to said connection means is an IC card. 27. The information processing apparatus according to claim 21, characterized in that said holding means is tamper-proof. 28. In an information processing method for an information processing apparatus, said information processing method is characterized by comprising: a receiving step of receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said second cryptographic key; a holding control step of controlling holding of said second cryptographic key received by said receiving step; and a response step of sending a predetermined response to another second information processing apparatus by utilizing said second cryptographic key, holding of which is controlled by said holding control step, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said first cryptographic key, based on said authentication technique. 29. A recording medium being recorded therein a computer-readable program, said program for a computer that controls an information processing apparatus is characterized by comprising: a receiving step of receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said second cryptographic key; a holding control step of controlling holding of said second cryptographic key received by said receiving step; and a response step of sending a predetermined response to another second information processing apparatus by utilizing said second cryptographic key, holding of which is controlled by said holding control step, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said first cryptographic key, based on said authentication technique. 30. A program characterized by causing a computer that controls an information processing apparatus to execute: a receiving step of receiving, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are sent by another first information processing apparatus and which can be utilized by a predetermined authentication technique, at least said first cryptographic key; a holding control step of controlling holding of said second cryptographic key received by said receiving step; and a response step of sending a predetermined response to another second information processing apparatus by utilizing said second cryptographic key, holding of which is controlled by said holding control step, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said first cryptographic key, based on said authentication technique. 31. In an information processing system configured of first to third information processing apparatuses, said information processing system is characterized in that: said first information processing apparatus generates request information for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique, for sending to said second information processing apparatus; said second information processing apparatus generates, when receiving said request information from said first information processing apparatus, each of said first cryptographic key and said second cryptographic key, sends said generated first cryptographic key to said third information processing apparatus, and holds said generated second cryptographic key; said third information processing apparatus receives said first cryptographic key sent by said second information processing apparatus, and holds; and said third information processing apparatus authenticates said second information processing apparatus by utilizing said held first cryptographic key and said second cryptographic key held by said second information processing apparatus, based on said authentication technique. 32. The information processing apparatus according to claim 31, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key are different cryptographic keys. 33. In an information processing method for an information processing system configured of first to third information processing apparatuses, said information processing method is characterized in that: said first information processing apparatus generates request information for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique, for sending to said second information processing apparatus; said second information processing apparatus generates, when receiving said request information from said first information processing apparatus, each of said first cryptographic key and said second cryptographic key, sends said generated first cryptographic key to said third information processing apparatus, and holds said generated second cryptographic key; said third information processing apparatus receives said first cryptographic key sent by said second information processing apparatus, and holds; and said third information processing apparatus authenticates said second information processing apparatus by utilizing said held first cryptographic key and said second cryptographic key held by said second information processing apparatus, based on said authentication technique. 34. An information processing apparatus characterized by comprising: generation means for generating request information for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates another second information processing apparatus based on a predetermined authentication technique; and sending means for sending said request information generated by said generation means to said another second information processing apparatus. 35. The information processing apparatus according to claim 34, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key generated by said generation means are different cryptographic keys. 36. The information processing apparatus according to claim 34, characterized by further comprising identification means for identifying, when information for authentication is inputted or a predetermined apparatus utilized for authentication is connected, to said another second information processing apparatus, a user who inputs said information or said connected apparatus, wherein said generation means generates said request information when said user who inputs said information to said another second information processing apparatus or said apparatus connected to said another second information processing apparatus is identified. 37. The information processing apparatus according to claim 36, characterized in that said identification means identifies said user who inputs said information to said another second information processing apparatus or said apparatus connected to said another second information processing apparatus, by using SSL (Secure Socket Layer), or TLS (Transport Layer Security). 38. The information processing apparatus according to claim 34, characterized by further comprising billing means for fixing a fee for a service provided to said another second information processing apparatus to be authenticated by said another first information processing apparatus by utilizing said first key and said second key when said request information is sent to said another second information processing apparatus by said sending means, and billing said user who inputs said information to said another second information processing apparatus, identified by said identification means, or a user identified by said apparatus connected to said another second information processing apparatus, identified by said identification means, for said fee for said service. 39. The information processing apparatus according to claim 38, characterized in that said billing means bills said another second information processing apparatus for said fee for said service, and further, for a fee for said first and said second cryptographic keys generated by said another second information processing apparatus in response to said request information sent to said another second information processing apparatus by said sending means. 40. In an information processing method for an information processing apparatus, said information processing method is characterized by comprising: a generation step of generating request information for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates another second information processing apparatus based on a predetermined authentication technique; and a sending step of sending said request information generated by said generation step to said another second information processing apparatus. 41. A recording medium being recorded therein a computer-readable program, said program for a computer that controls an information processing apparatus is characterized by comprising a generation step of generating request information for requesting another second information processing apparatus to generate a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates said another second information processing apparatus based on a predetermined authentication technique. 42. A program characterized by causing a computer that controls an information processing apparatus to execute a generation step of generating request information for requesting another second information processing apparatus to generate a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which are utilized when another first information processing apparatus authenticates said another second information processing apparatus based on a predetermined authentication technique. 43. An information processing apparatus characterized by comprising: receiving means for receiving, when another second processing apparatus generates a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique and sends said generated first cryptographic key at a request of another first information processing apparatus, said first cryptographic key; holding means for holding said first cryptographic key received by said receiving means; and authentication means for authenticating said another second information processing apparatus by utilizing said first cryptographic key held by said holding means and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 44. The information processing apparatus according to claim 43, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key are different cryptographic keys. 45. In an information processing method for an information processing apparatus, said information processing method is characterized by comprising: a receiving step of receiving, when another second processing apparatus generates a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique and sends said generated first cryptographic key at a request of another first information processing apparatus, said first cryptographic key; a holding step of holding said first cryptographic key received by said receiving step; and an authentication step of authenticating said another second information processing apparatus by utilizing said first cryptographic key held by said holding step and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 46. A recording medium being recorded therein a computer-readable program, said program for a computer that controls an information processing apparatus is characterized by comprising an authentication step of authenticating another second information processing apparatus by utilizing, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined technique and which are generated by said another second information processing apparatus based on a request by another first information processing apparatus, said first cryptographic key held by said information processing apparatus itself and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 47. A program characterized by causing a computer that controls an information processing apparatus to execute an authentication step of authenticating another second information processing apparatus by utilizing, of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined technique and which are generated by said another second information processing apparatus based on a request by another first information processing apparatus, said first cryptographic key held by said information processing apparatus itself and said second cryptographic key held by said another second information processing apparatus, based on said authentication technique. 48. An information processing apparatus characterized by comprising: receiving means for receiving request information, sent by another first information processing apparatus, for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique; key generation means for generating said first cryptographic key and said second cryptographic key based on said request information received by said receiving means; sending means for sending said first cryptographic key of said first cryptographic key and said second cryptographic key generated by said key generation means, to another second information processing apparatus; holding means for holding said second cryptographic key of said first cryptographic key and said second cryptographic key generated by said key generation means; and response means for generating a predetermined response by utilizing said second cryptographic key held by said holding means, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said first cryptographic key sent by said sending means based on said authentication technique, wherein said sending means sends said response generated by said response generation means to said another second information processing apparatus. 49. The information processing apparatus according to claim 48, characterized in that: said authentication technique is public key authentication; and said first cryptographic key and said second cryptographic key are different cryptographic keys. 50. The information processing apparatus according to claim 48, characterized in that said key generation means newly generates said first cryptographic key and said second cryptographic key after said request information is received by said receiving means. 51. The information processing apparatus according to claim 48, characterized in that: said holding means holds a plurality of first cryptographic key candidates and a plurality of second cryptographic key candidates to be paired respectively with said plurality of first cryptographic key candidates beforehand; and said key generation means extracts a predetermined first cryptographic key candidate and a second cryptographic key candidate to be paired therewith, of said plurality of first cryptographic key candidates and plurality of second cryptographic key candidates held by said holding means beforehand, to make said extracted first cryptographic key candidate said first cryptographic key and make said extracted second cryptographic key candidate said second cryptographic key, whereby to generate said first cryptographic key and said second cryptographic key. 52. The information processing apparatus according to claim 51, characterized in that said key generation means generates said plurality of first cryptographic key candidates and said plurality of second cryptographic key candidates. 53. The information processing apparatus according to claim 48, characterized by further comprising input means for inputting information for authentication by said another second information processing apparatus. 54. The information processing apparatus according to claim 48, characterized by further comprising connection means for connecting a predetermined apparatus which is utilized when authenticated by said another second information processing apparatus. 55. The information processing apparatus according to claim 54, characterized in that said apparatus connected to said connection means is an IC card. 56. The information processing apparatus according to claim 48, characterized in that said holding means is tamper-proof. 57. In an information processing method for an information processing apparatus, said information processing method is characterized by comprising: a receiving step of receiving request information, sent by another first information processing apparatus, for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique; a key generation step of generating said first cryptographic key and said second cryptographic key based on said request information received by said receiving step; a key sending step of sending said first cryptographic key of said first cryptographic key and said second cryptographic key generated by said key generation step, to another second information processing apparatus; a holding step of holding said second cryptographic key of said first cryptographic key and said second cryptographic key generated by said key generation step; a response generation step of generating a predetermined response by utilizing said second cryptographic key held by said holding step, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said first cryptographic key sent by said key sending step, based on said authentication technique; and a response sending step of sending said response generated by said response step, to said another second information processing apparatus. 58. A recording medium being recorded therein a computer-readable program, said program for a computer that controls an information processing apparatus is characterized by comprising: a key generation step of generating, based on request information sent from another second information processing apparatus to said information processing apparatus for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique, said first cryptographic key to be transmitted to another second information processing apparatus, and said second cryptographic key to be held by said information processing apparatus; and a response generation step of generating a predetermined response by utilizing said second cryptographic key held by said information processing apparatus, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said transmitted first cryptographic key, based on said authentication technique. 59. A program characterized by causing a computer that controls an information processing apparatus to execute: a key generation step of generating, based on request information sent from another second information processing apparatus to said information processing apparatus for requesting generation of a first cryptographic key and a second cryptographic key to be paired with said first cryptographic key which can be utilized by a predetermined authentication technique, said first cryptographic key to be transmitted to another second information processing apparatus, and said second cryptographic key to be held by said information processing apparatus; and a response generation step of generating a predetermined response by utilizing said second cryptographic key held by said information processing apparatus, when said information processing apparatus is authenticated by said another second information processing apparatus which holds said transmitted first cryptographic key, based on said authentication technique. |
<SOH> BACKGROUND ART <EOH>Generally, a person who provides a pay service collects its charge from the other party to whom he/she provides the service. For instance, a person who provides a service to the other party face-to-face with the party often collects cash from the other party at the time when he/she provides the service. By contrast, a person who provides a pay service via communication such as the Internet often provides the service either by collecting the charge of the service later as a “credit” to the other party or after checking that the other party acquires the right to utilize the service by paying the charge, since electronic cash exchangeable via communication has not yet been commercialized. Therefore, the person who provides a pay service via communication needs to identify, i.e., to authenticate the other party to whom he/she provides the service, before providing the service. When this authentication is performed, the authenticating party and the party to be authenticated need to have mutually corresponding information. Note that when such authentication is performed, the party who has such mutually corresponding information and identifies the other party will be called as a verifier, whereas the party who is identified will be called as a certifier, hereinafter. Further, a technique used to have the certifier authenticated by the verifier will be called as an authentication technique. Conventionally, password authentication, common key authentication, and public key authentication are known as authentication techniques. Each of these authentication techniques, i.e., the password authentication, the common key authentication, and the public key authentication will be described below respectively. (Password Authentication) First, the password authentication will be described. In the password authentication, a certifier registers a login name unique to each certifier, with a verifier beforehand, to fix his/her password. Further, the certifier and the verifier exchanges an agreement not to leak the password to anyone except themselves. In this case, the person who knows the correspondence between the specific login name and the password is limited only to the certifier authenticated by that login name and the verifier, in principle. Therefore, the verifier judges that the person who is able to show the specific login name and the password corresponding thereto is the certifier who has made registration under that login name. That is, the password authentication is a system in which the authentication is performed by the certifier directly showing the verifier the knowledge which only the verifier and the certifier know. Therefore, it has a shortcoming that the password is susceptible to leakage at the time of authentication, but the login name and the password can be memorized directly by a person (certifier), and thus has a feature that no special apparatus is required for authentication. Hence, the password authentication is widely utilized. In the password authentication, the verifier and the certifier have the same information, and thus it is possible to exchange their roles between the verifier and the certifier. Such authentication will hereinafter be called as bidirectional authentication. Provided that, in the password authentication, the bidirectional property is not usually used. (Common Key Authentication) Next, the common key authentication will be described. Note that “Challenge & Response authentication” using common key cryptography will herein be called as common key authentication. The common key cryptography is also called as symmetric cryptography, and is a cryptographic algorithm having a property that a cryptographic key for use in encrypting data and a cryptographic key for use in decryption are identical (or a property that even when the cryptographic keys are different, one of the cryptographic keys can be easily calculated from the other cryptographic key). As the common key cryptography, the DES(Data Encryption Standard) and the Triple DES adopted by the National Institute of Standards and Technology of the U.S. Department of Commerce, and FEAL(Fast Data Encipherment Algorithm) developed by NTT(Nippon Telegraph and Telephone Corporation (trade name)), and the like are known. The common key authentication is a technique by which when each of a verifier and a certifier in authentication has an identical cryptographic key K n for common key cryptography, the verifier checks that the certifier has the cryptographic key K n without leaking that cryptographic key K n to anybody other than the two parties having the cryptographic keys K n . A basic, specific example of the common key authentication will be described. First, the verifier generates a random number r, and sends to the certifier (this step will hereinafter be written also as Challenge). The certifier encrypts this random number r with a cryptographic key K n , computes a value R=E(K n , r) (wherein the E(K n , r) means encryption of the random number r utilizing the key K n ), and returns to the verifier (this step will hereinafter be also written as Response). The verifier decrypts the value R with the cryptographic key K n , for comparison with the original random number r, and if the cryptographic key K n matches with the original random number r, judges that the certifier has the cryptographic key K n . Therefore, when a person having a specific cryptographic key K n is identified to be only one certifier other than the verifier, authentication of that certifier becomes possible by the cryptographic key K n . For such common key authentication, a standard technique is defined in, for instance, ISO(International Organization for Standardization)/IEC(International Electro technical Commission) 9798-2. In the common key authentication, the verifier and the certifier have the same information, and thus the common key authentication is a bidirectional authentication technique. In the above-mentioned password authentication, the password kept secret only to the verifier and the certifier is directly compared, and thus has the shortcoming that the password is susceptible to leakage at the time of authentication as mentioned above. By contrast, in the common key authentication, the cryptographic key(s) for the common key cryptography is used in the Challenge & Response authentication as mentioned above, and thus has a feature that the cryptographic key(s) is hard to leak out. Therefore, the common key authentication is superior in terms of security than the password authentication. Provided that, in the common key authentication, it would be difficult for a person to perform calculations necessary for the Challenge & Response authentication, and thus the cryptographic key is usually held by a special apparatus called an IC(Integrated Circuit) card. Note that the IC card holding the cryptographic key for common key cryptography will be written as a CKC-IC card whenever appropriate in order to distinguish it from an IC card holding keys for public key cryptography to be described later. The CKC-IC card internally has a function of performing calculations necessary for the common key authentication. Thus, as long as the common key authentication is performed by the CKC-IC card, there is only little possibility that the cryptographic key(s) will leak out. However, there is a possibility that the cryptographic key(s) will leak due to the CKC-IC card having been physically or logically analyzed, and there is also a possibility that the CKC-IC card itself will be stolen for abuse. (Public Key Authentication) Next, the public key authentication will be described. Note that Challenge & Response authentication utilizing the public key cryptography will herein be called as public key authentication. The public key cryptography is also called as asymmetric cryptography, and is an algorithm in which a cryptographic key for use in encrypting data (hereinafter called as a public key whenever appropriate) and a cryptographic key for use in decrypting (hereinafter called as a private key whenever appropriate) are different, and which has a property that it is very difficult to calculate one cryptographic key-from the other cryptographic key (to calculate the private key from the public key, or to calculate the public key from the private key). The public key authentication is a technique by which when a certifier has a private key S k and a verifier has a public key P k paired with the private key S k , the verifier can check that the certifier owns the private key S k without knowledge of the private key S k itself. A specific example of a basic public key authentication technique will be described. First, the verifier generates a random number r, encrypts it with a public key P k , computes a value R=E(P k , r) (wherein the E(P k , r) means encryption of the r utilizing the public key P k ), and sends to the certifier (Challenge) The certifier computes decrypted r′=D(S k , R) of the value R (wherein the D(S k , R) means decryption of the value R utilizing the private key S k ), and returns to the verifier (Response). The verifier compares the random number r with the decrypted r′ of the value R, and when the random number r matches with those, judges that the certifier has the private key S k . Therefore, if a person having a specific private key S k is identified to be one certifier, the verifier can perform the authentication of that certifier by the above-mentioned procedure. As to the common key cryptography, a standard technique is defined in, for instance, the IEEE(The Institute of Electrical and Electronic, Inc)-P1363. Further, as to the public key authentication, a standard technique is defined in, for instance, the ISO/IEC9798-3. The public key authentication has a feature that an indefinite number of verifiers could exist as will be described later (as will be described by a public key authentication infrastructure to be described later). Further, in the public key authentication, each of the verifier and the certifier has different information, and their roles are not exchangeable, and thus it is not authentication having bidirectionality. Such an authentication technique will hereinafter be called as unidirectional authentication as compared to bidirectional authentication. The public key authentication can keep a private key which a certifier has cryptographically secure, similarly to the common key authentication. Therefore, the public key authentication is also superior to the password authentication in terms of security. Provided that, in the public key authentication, it would be difficult for a person to perform calculations necessary for the Challenge & Response authentication, and thus the cryptographic keys for the public key cryptography are usually held by a special apparatus called as an IC card. Note that the IC card holding the cryptographic keys for the public key cryptography will be written as a PKC-IC card whenever appropriate in order to distinguish it from the above-mentioned CKC-IC card (IC card holding the key for the common key cryptography). The PKC-IC card internally has a function of performing calculations necessary for the public key authentication. Thus, as long as the public key authentication is performed by the PKC-IC card, there is only a remote possibility that the cryptographic keys will leak out. However, there is a possibility that the encryption keys will leak due to the PKC-IC card having been physically or logically analyzed, and there is also a possibility that the PKC-IC card itself will be stolen for abuse. In the authentication technique such as mentioned above, in order to perform authentication of many certifiers efficiently and securely, a technique is needed in which information necessary for authentication is arranged beforehand and managed. Such a technique will hereinafter be called as an authentication infrastructure. Further, a person identified by an authentication infrastructure will be called as a user; a person who manages the authentication infrastructure will be called as a manager; and a person who identifies the user by utilizing the authentication infrastructure and provides a service to the identified user will be called as a service provider, hereinafter. Conventionally, an individual account system, a general-purpose account system, and a public key authentication infrastructure are known as the authentication infrastructures. However, each of these authentication infrastructures, i.e., the individual account system, the general-purpose account system, and the public key authentication infrastructure has the following problems. (Problems of Individual Account System) First, an outline of the individual account system and problems thereof will be described. Among the authentication infrastructures, the most widely used conventionally is the individual account system. In the individual account system, authentication infrastructure is built for each service provider. That is, a user makes an agreement on an authentication technique which he will utilize with the service provider either after registering information necessary for identifying and billing the user (e.g., information including his/her address, name, or credit card number) with the service provider, or having paid for a service to be provided, before receiving the service from the service provider. Note that the authentication technique agreed between the service provider and the user and various information (information about the service provider and the user who are identified based on the authentication) utilized by the authentication technique will hereinafter be called as an account. In this case, the service provider is a manager of this authentication infrastructure and a verifier for authentication of the user. As the authentication techniques, all the above-mentioned three authentication techniques (the password authentication, the common key authentication, and the public key authentication) are applicable. For instance, in a Suica (trademark) system of JR East Japan Railway Company (trade name), the common key authentication is utilized as the authentication technique. Provided that, when a technique other than the password authentication is applied, an IC card or the like for holding the authentication information is needed, and thus costs for developing an authentication infrastructure would increase. For this reason, when service provision via communication is intended, the password authentication is typically utilized. In the individual account system, user authentication could only be initiated on condition that correspondence between a user and a password, a common key, or a public key which the service provider knows is correct (here is neither erroneous recognition nor leakage). Since the individual account system can be implemented by the service provider's own operation, and thus can easily be introduced. However, the individual account system has the following three problems. A first problem is that a user needs to register information for identifying himself/herself with each service provider in order to prepare his/her account. Therefore, the user must spend time and labor in registration, and must also register information susceptible to abuse, such as his/her credit card number, even with an untrustworthy service provider. A second problem is that when one user prepares an account with each of many service providers, management of many accounts (management, such as the user having to memorize many passwords or holding many IC cards) burdens the user. A third problem is that it costs the service provider much to manage authentication information and personal information. That is, the authentication information and personal information need to be updated continuously. Particularly, credit card numbers, passwords, or cryptographic keys need to be handled carefully so as not to be leaked out. (Problems of the General-Purpose Account System) Next, an outline of the general-purpose account system and problems thereof will be described. In order to solve the above-mentioned problems of the individual account system, a system in which each of many service providers performs user authentication by a single general-purpose account, i.e., a general-purpose account system is proposed. As the general-purpose account system, for instance, a Kerberos system RFC1510 and the like are known. The Kerberos is the name of a project conducted by Massachusetts Institute of Technology of the United States of America, and its standard is made open to the public as No. 1510 of the standard series called as RFC(Request For Comment). Note that the RFCs are provided by the IETF(Internet Engineering Task Force). In the general-purpose account system, a person other than a service provider becomes a manager (such a manger will hereinafter be called as a general-purpose account manager) When a service provider identifies a user, first, the general-purpose account manager authenticates the user, and the service provider authenticates the general-purpose account manager. And the general-purpose account manager notifies the service provider of a result of the user authentication (identification of the user). Thus, in the general-purpose account system, the service provider is not a verifier for user authentication, unlike in the individual account system. For this reason, it is based on the following three points. That is, as a first point, the service provider can authenticate the general-purpose account manager; as a second point, the general-purpose account manager is reliable (the authentication result to be notified is correct); and as a third point, the general-purpose account manager can authenticate the user. In the general-purpose account system, the user is required to register his general-purpose account only once. Further, the account information is managed collectively by the general-purpose account manager. Therefore, the general-purpose account system can solve the above-mentioned problems of the individual account system. However, the general-purpose account system has the following two problems, which are different from the above-mentioned problems of the individual account system. That is, a first problem is that the importance of one authentication technique and the frequency of its use become excessive. As a result, chances for leakage of passwords and keys increase, and damage is likely to aggravate in case of their leakage. A second problem is that authentication response deteriorates due to communication, since the communication with the general-purpose account manager needs to be involved at the time of authentication. (Problems of the Public Key Authentication Infrastructure) Next, an outline of the public key authentication infrastructure and problems thereof will be described. As mentioned above, in the password authentication and the common key authentication, the verifier is related to the certifier on a one-to-one basis, but in the public key authentication, anyone can be a verifier since it is quite difficult for the verifier to guess a private key which the certifier has from a public key which he/she has himself/herself. A combination of the property of such public key authentication with a method of obtaining a correspondence relation between a user and a public key is called as a public key authentication infrastructure. Therefore, in the public key authentication infrastructure, the correspondence relation between a user and a public key can be obtained, and thus a service provider himself/herself can become a verifier, thereby making it possible to solve the above-mentioned second problem of the general-purpose account system. It is generally considered that a manager who distributes a public key-incorporated IC card to the user knows the correspondence relation between a user and a public key. Note that the manager will hereinafter be called as an authentication center. The authentication center issues a certificate that guarantees a relation between a user and a public key to a person who desires to obtain the correspondence relation between the user and the public key without inquiry to the authentication center (a person who desires to become verifiers). Here, information that identifies the public key and the user (such as an ID and a name) and digital data including its expiration date, to which a digital signature is added by the authentication center are called as a certificate. The digital signature is a kind of an application of public key cryptography. Therefore, the digital signature will be described so as to be corresponded to the above-mentioned public key cryptography. For instance, when holding digital data M, the authentication center computes a signature SG(M)=E(S k , h(M)) utilizing a private key S k which the authentication center holds itself. Note that a function h( ) is supposed to be a unidirectional function, and is supposed to be a function having a property that it is very hard to know an input value from an output value. For instance, as the functions h( ), functions called as MD5 and SHA-1 in ISO/IEC10118, FIPS180-1, and the like could be applied. The authentication center sends a set of data (M, SG(M)) to a verifier. When holding a public key P k paired with the private key S k which the authentication center holds, the verifier checks whether or not h(M)=D(P k , SG(M)) is satisfied, whereby to check that the digital data M is not tampered, that the signature SG(M) is added by the owner of the private key S k (authentication center). Note that such a verifier's procedure will hereinafter be called as authentication of a digital signature. In this way, the verifier in authentication verifies a digital signature added by the authentication center, and obtains a relation between the user and the public key from its certificate. As to the digital signature, a standard technique is defined in, for instance, IEEE-P1363. The verifier, if he/she knows the public key of the authentication center correctly and once he/she succeeds in verifying its digital signature, can obtain a relation between the user and the public key from the certificate. When the scale of the authentication infrastructure increases, it would be difficult for one authentication center to know the relation covering all users and public keys. In such a case, a hierarchical structure is built among a plurality of authentication centers. The verifier has a certificate issued independently from each of the authentication centers, but as to the public keys, he/she handles only public keys which a small number of authentication centers called as root authentication centers have, whereby he/she verifies all the certificates. In this way, the public key authentication infrastructure is a system in which correspondence between many users and public keys can be obtained, and is specified in ITU(International Telecommunication Union)-T Recommendation X.509. The public key authentication infrastructure can manage information for user authentication in a distributed manner, and thus is an authentication method adapted for environments where user management is not intensive such as for the Internet. However, the relation between the user and the public key changes with time due to, for instance, the user losing the IC card, or being disqualified. That is, invalidation of an issued certificate occurs. As a result, the public key authentication utilizing certificates operates in the following four assumptions. That is, as a first point, the service provider can verify a digital signature (including those traced from root authentication centers) of an authentication center in a certificate; as a second point, a certificate (including those traced from the root authentication centers) is not revoked; as a third point, an authentication center is reliable (the content of a certificate is correct); and as a fourth point, the correspondence between a user and a public key which an authentication center knows is correct (there are neither erroneous recognition nor leakage). A person who best knows the invalidation status of a certificate is an authentication center which distributes a card to the user and issues the certificate. As a result, the verifier may query the authentication center about it when verifying the certificate in order to obtain the latest invalidation status. A communication protocol for such a query is specified as OSCP in RFC(Request For Comments) 2560. However, in this case, the verifier needs to query the authentication center when authenticating the user. That is, the same problem as the second problem of the general-purpose account system occurs. For this reason, a method of terminating use of a revoked certificate is known in which the authentication center issues data called as a certificate invalidation list to users of certificates (such as service providers), and a user of a certificate terminates use of the certificate when the certificate is found revoked by comparison with the certificate invalidation list. The certificate invalidation list is specified by ITU-T Recommendation X.509. Provided that, since it is difficult to predict where in the distributed environments the certificate is used, it would be difficult for the authentication center to publicly announce the invalidation to the user of the certificate even when the certificate is revoked. Particularly, in order to accommodate abrupt invalidation of a certificate, the user of the certificate needs to collect related certificate invalidation lists constantly. From the foregoing, the public key authentication infrastructure has the following two problems. That is, a first problem is that the importance of one authentication technique increases excessively as in the general-purpose account system. A second problem is that handling of invalidation information increases authentication costs, or decreases response. This is because the verifier (e.g., a service provider) needs to be able to verify invalidation or non-invalidation by gathering related certificate invalidation lists or query about the invalidation status via OSCP. In this way, each of the individual account system, the general-purpose account system, and the public key authentication infrastructure has its peculiar problems. That is, the individual account system, due to having the above-mentioned three problems, finds difficulty developing itself into a large-scale authentication infrastructure. The general-purpose account system has many applications and thus can be easily developed as mentioned above, but since a service provider is not a direct verifier for user authentication, it has a problem that authentication response is decreased. This problem becomes conspicuous in situations where authentication is performed frequently. In the public key authentication infrastructure, the verifier gathers the invalidation status of certificates related to the authentication in order to secure reliability of authentication as mentioned above, or queries to an authentication center at the time of authentication, and thus it has a problem that its authentication costs or response deteriorate. This problem would also become conspicuous in situations where authentication is performed frequently. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a diagram illustrating a first example of a business model supported by an authentication key allotment system to which the present invention is applied. FIG. 2 is a diagram illustrating a second example of the business model supported by the authentication key allotment system to which the present invention is applied. FIG. 3 is a diagram illustrating a third example of the business model supported by the authentication key allotment system to which the present invention is applied. FIG. 4 is a block diagram showing an exemplary configuration of the authentication key allotment system to which the present invention is applied. FIG. 5 is a diagram showing an example of a key allotment table. FIG. 6 is a diagram showing an example of a service provider key table. FIG. 7 is a diagram showing an example of a key holding apparatus key table. FIG. 8 is a diagram showing an example of key allotter account information. FIG. 9 is a diagram showing an example of an authentication information table. FIG. 10 is a diagram showing an example of service provider unique information. FIG. 11 is a diagram showing an example of a certifying key table. FIG. 12 is a diagram showing an example of a service information table. FIG. 13 is a diagram showing an example of key holding apparatus unique information. FIG. 14 is a diagram showing an example of user count information. FIG. 15 is a block diagram showing an exemplary configuration of a user terminal of the authentication key allotment system of FIG. 14 . FIG. 16 is a block diagram showing an exemplary configuration of a key holding apparatus of the authentication key allotment system of FIG. 14 . FIG. 17 is a block diagram showing an exemplary configuration of an IC card of the authentication key allotment system of FIG. 14 . FIG. 18 is a block diagram showing an exemplary configuration of a key allotter terminal of the authentication key allotment system of FIG. 14 . FIG. 19 is a block diagram showing an exemplary configuration of a service provider terminal of the authentication key allotment system of FIG. 14 . FIG. 20 is a block diagram showing an exemplary configuration of a general-purpose account manager terminal of the authentication key allotment system of FIG. 14 . FIG. 21 is a diagram showing an example of an account management table. FIG. 22 is a diagram showing an example of an account manager unique key. FIG. 23 is a flowchart illustrating an example of processing by the authentication key system to which the present invention is applied. FIG. 24 is a flowchart illustrating an example of a service selection/key allotment process by a user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 , and the IC card of FIG. 17 . FIG. 25 is a flowchart illustrating an example of a service selection/key allotment process by the key allotter terminal of FIG. 18 . FIG. 26 is a flowchart illustrating an example of a service selection/key allotment process by the service provider terminal of FIG. 19 . FIG. 27 is an arrow chart showing a relation among the service selection/key allotment processes by the user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 and the IC card of FIG. 17 , the key allotter terminal of FIG. 18 , and the service provider terminal of FIG. 19 . FIG. 28 is a diagram showing an example of a key allotment application. FIG. 29 is a diagram showing an example of a key allotment report. FIG. 30 is a flowchart illustrating an example of a key use/service provision process by the user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 , and the IC card of FIG. 17 . FIG. 31 is a flowchart illustrating an example of a key use/service provision process by the service provider terminal of FIG. 19 . FIG. 32 is an arrow chart showing an exemplary relation between a by-purpose authentication verification process in the key use/service provision process by the user apparatus of FIG. 29 and a by-purpose authentication response process in the key use/service provision process by the service provider terminal of FIG. 30 . FIG. 33 is an arrow chart showing another exemplary relation between the by-purpose authentication verification process in the key use/service provision process by the user apparatus of FIG. 29 and the by-purpose authentication response process in the key use/service provision process by the service provider terminal of FIG. 30 . FIG. 34 is an arrow chart showing an exemplary relation between a service utilization process in the key use/service provision process by the user apparatus of FIG. 29 and a service provision process in the key use/service provision process by the service provider terminal of FIG. 30 . FIG. 35 is an arrow chart showing another exemplary relation between the service utilization process in the key use/service provision process by the user apparatus of FIG. 29 and the service provision process in the key use/service provision process by the service provider terminal of FIG. 30 . FIG. 36 is a diagram showing an example of a service request. FIG. 37 is a flowchart illustrating an example of a key deletion process by the user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 , and the IC card of FIG. 17 . FIG. 38 is a flowchart illustrating an example of a key deletion process by the key allotter terminal of FIG. 18 . FIG. 39 is a flowchart illustrating an example of a key deletion process by the service provider terminal of FIG. 19 . FIG. 40 is a flowchart illustrating an example of a key use termination process by the key allotter terminal of FIG. 18 . FIG. 41 is a flowchart illustrating an example of a key use termination process by the service provider terminal of FIG. 19 . FIG. 42 is a diagram showing an example of a key use termination request. FIG. 43 is a diagram showing another example of the key use termination request. FIG. 44 is a block diagram showing another exemplary configuration of the authentication key allotment system to which the present invention is applied. FIG. 45 is a block diagram showing an exemplary configuration of an authentication center terminal of the authentication key allotment system of FIG. 43 . FIG. 46 is a diagram showing an example of a key allotment table. FIG. 47 is a diagram showing an example of a service provider key table. FIG. 48 is a diagram showing an example of a key holding apparatus key table. FIG. 49 is a diagram showing an example of key allotter PKI information. FIG. 50 is a diagram showing an example of CA public key information. FIG. 51 is a diagram showing an example of a key allotment application. FIG. 52 is a diagram showing an example of a key allotment report. FIG. 53 is a diagram showing an example of an authentication information table. FIG. 54 is a diagram showing an example of service provider unique information. FIG. 55 is a diagram showing an example of a invalidation key table. FIG. 56 is a diagram showing an example of service provider PKI information. FIG. 57 is a diagram showing an example of key sharing parameters. FIG. 58 is a diagram showing an example of CA public key information. FIG. 59 is a diagram showing an example of a certifying key table. FIG. 60 is a diagram showing an example of an authentication information table. FIG. 61 is a diagram showing an example of key holding apparatus unique information. FIG. 62 is a diagram showing an example of user PKI information. FIG. 63 is a diagram showing an example of CA public key information. FIG. 64 is a diagram showing an example of a certificate table. FIG. 65 is a diagram showing an example of CA key information. FIG. 66 is a diagram showing an example of a certificate. FIG. 67 is an arrow chart showing a relation between a user recognition response process by a user apparatus and a key holding apparatus user authentication process by a key allotter terminal, in a service selection/key allotment process between the user apparatus and the key allotter terminal of the authentication key allotment system of FIG. 43 . FIG. 68 is a flowchart illustrating an example of a key use/service provision process by the user apparatus of the authentication key allotment system of FIG. 43 . FIG. 69 is a flowchart illustrating an example of a key use/service provision process by a service provider terminal of the authentication key allotment system of FIG. 43 . FIG. 70 is an arrow chart showing an exemplary relation between a by-purpose authentication verification process in the key use/service provision process by the user apparatus of FIG. 67 and a by-purpose authentication response process in the key use/service provision process by the service provider terminal of FIG. 68 . FIG. 71 is an arrow chart showing another exemplary relation between the by-purpose authentication verification process in the key use/service provision process by the user apparatus of FIG. 67 and the by-purpose authentication response process in the key use/service provision process by the service provider terminal of FIG. 68 . FIG. 72 is a diagram showing still another configuration of the authentication key allotment system to which the present invention is applied. FIG. 73 is a diagram showing an example of a key allotment table. FIG. 74 is a diagram showing an example of a service provider key table. FIG. 75 is a diagram showing an example of a key holding apparatus key table. FIG. 76 is a diagram showing an example of key allotter account information. FIG. 77 is a diagram showing an example of CA public key information. FIG. 78 is a diagram showing an example of a document of title. FIG. 79 is a diagram showing an example of a key allotment application. FIG. 80 is a diagram showing an example of a key allotment report. FIG. 81 is a diagram showing an example of an authentication information table. FIG. 82 is a diagram showing an example of service provider unique information. FIG. 83 is a diagram showing an example of a invalidation key table. FIG. 84 is a diagram showing an example of service provider PKI information. FIG. 85 is a diagram showing an example of key sharing parameters. FIG. 86 is a diagram showing an example of CA public key information. FIG. 87 is a diagram showing an example of a certifying key table. FIG. 88 is a diagram showing an example of an authentication information table. FIG. 89 is a diagram showing an example of key holding apparatus unique information. FIG. 90 is a diagram showing an example of user count information. FIG. 91 is a diagram showing an example of CA public key information. FIG. 92 is a flowchart illustrating an example of a service selection/key allotment process by a user apparatus of the authentication key allotment system of FIG. 71 . FIG. 93 is a flowchart illustrating an example of a service selection/key allotment process by a key allotter terminal of the authentication key allotment system of FIG. 71 . FIG. 94 is a diagram showing an example of a service selection/key allotment process by a service provider terminal of the authentication key allotment system of FIG. 71 . FIG. 95 is an arrow chart showing a relation among the service selection/key allotment processes by the user apparatus, the key allotter terminal, and the service provider terminal of the authentication key allotment system of FIG. 71 . FIG. 96 is a flowchart illustrating an example of a key use/service provision process by the user apparatus of the authentication key allotment system of FIG. 71 . FIG. 97 is a flowchart illustrating an example of a key use/service provision process by the service provider terminal of the authentication key allotment system of FIG. 71 . FIG. 98 is a diagram showing an example of a key allotment table. FIG. 99 is a diagram showing an example of a service provider key table. FIG. 100 is a diagram showing an example of a key holding apparatus key table. FIG. 101 is a diagram showing an example of key allotter PK information. FIG. 102 is a diagram showing an example of CA public key information. FIG. 103 is a diagram showing an example of a document of title. FIG. 104 is a diagram showing an example of a key allotment application. FIG. 105 is a diagram showing an example of service provider unique information. FIG. 106 is a diagram showing an example of a invalidation key table. FIG. 107 is a diagram showing an example of key sharing parameters. FIG. 108 is a diagram showing an example of CA public key information. FIG. 109 is a diagram showing an example of a certifying key table. FIG. 110 is a diagram showing an example of an authentication information table. FIG. 111 is a diagram showing an example of key holding apparatus unique information. FIG. 112 is a diagram showing an example of user count information. FIG. 113 is a diagram showing an example of CA public key information. FIG. 114 is a flowchart illustrating an example of a service selection/key allotment process by the user apparatus of the authentication key allotment system of FIG. 98 . FIG. 115 is a flowchart illustrating an example of a service selection/key allotment process by the key allotter terminal of the authentication key allotment system of FIG. 98 . FIG. 116 is a flowchart illustrating an example of a service selection/key allotment process by the service provider terminal of the authentication key allotment system of FIG. 98 . FIG. 117 is an arrow chart showing a relation among the service selection/key allotment processes by the user apparatus, the key allotter terminal, and the service provider terminal of the authentication key allotment system of FIG. 98 . FIG. 118 is a block diagram representing another exemplary configuration of the key holding apparatus. FIG. 119 is a diagram showing an example of a key allotment table. FIG. 120 is a diagram showing an example of key holding apparatus PKI information. FIG. 121 is a diagram showing an example of a temporal holding key table. FIG. 122 is a diagram showing an example of an authenticating key table. FIG. 123 is a flowchart illustrating another example of the service selection/key allotment process by the user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 or 118 and the IC card of FIG. 17 . FIG. 124 is a flowchart illustrating an example of a service selection/key allotment process by the key allotter terminal of FIG. 18 , corresponding to the flowchart of FIG. 123 . FIG. 125 is a flowchart illustrating an example of a service selection/key allotment process by the service provider terminal of FIG. 19 , corresponding to the flowchart of FIG. 123 . FIG. 126 is an arrow chart corresponding to the flowcharts of FIGS. 123 to 125 and showing a relation among the service selection/key allotment processes by the user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 or 118 and the IC card of FIG. 17 , the key allotter terminal of FIG. 18 , and the service provider terminal of FIG. 19 . FIG. 127 is an arrow chart showing details of a relation between a “new key request and reception process” in step S 524 and a “new key generation and sending process” in step S 506 , shown by the arrow chart of FIG. 126 . FIG. 128 is a diagram showing a protocol stack involved when SSL, TLS are utilized. FIG. 129 is an arrow chart showing details of a relation between a “mutual authentication+key sharing process with the key holding apparatus” in step S 522 and a “mutual authentication+key sharing process with the key allotter terminal” in step S 504 , shown by the arrow chart of FIG. 126 performed when SSL, TLS are utilized. FIG. 130 is a diagram showing an example of a key allotment table. FIG. 131 is a flowchart illustrating still another example of the service selection/key allotment process by the user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 or 118 , and the IC card of FIG. 17 . FIG. 132 is a flowchart illustrating an example of a service selection/key allotment process by the key allotter terminal of FIG. 18 , corresponding to the flowchart of FIG. 131 . FIG. 133 is a flowchart illustrating an example of a service selection/key allotment process by the service provider terminal of FIG. 19 , corresponding to the flowchart of FIG. 131 . FIG. 134 is an arrow chart corresponding to the flowcharts of FIGS. 131 to 133 and showing a relation among the service selection/key allotment processes by the user apparatus constituted by the user terminal of FIG. 15 , the key holding apparatus of FIG. 16 or 118 and the IC card of FIG. 17 , the key allotter terminal of FIG. 18 , and the service provider terminal of FIG. 19 . FIG. 135 is an arrow chart showing details of a relation between a “new key request and reception process” in step S 524 and a “new key generation and sending process” in step S 506 , shown by the arrow chart of FIG. 134 . detailed-description description="Detailed Description" end="lead"? |
Cylinder-head gasket comprising an edge-to-edge stop ring |
The invention concerns a head-cylinder gasket with at least an opening (14) corresponding to a combustion chamber, comprising a so-called outer plate (12) including a circular rib (16), surrounding the opening (14), arranged at a distance d from the edge of said opening (14), and a support plate (18) arranged against the surface of the outer plate (12) bearing the rib (16) in projection, including an opening with a diameter larger than the opening (14) of the outer plate so as to define a space wherein is arranged a stop ring (20) in the form of an annular wedge with an internal diameter corresponding to that of the opening (14) and an external diameter substantially adjusted to the opening of the support plate so as to be arranged edge-to-edge. The invention is characterised in that it comprises an element (24) interposed between the stop ring (20) and the support plate maintaining said stop ring. |
1. Cylinder head gasket with at least one opening (14) corresponding to a combustion chamber and comprising, on the one hand, a sheet (12) referred to as the external sheet and comprising a circular rib (16) that surrounds the opening (14) and is disposed at a distance from the edge of said opening (14) and, on the other hand, a support sheet (18) disposed against the face of the external sheet (12) bearing the protruding rib (16) and comprising an opening of diameter greater than the opening (14) of the external sheet so as to define a space within which is disposed a stopper (20) in the form of an annular lining having an internal diameter that corresponds to that of the opening (14) and an external diameter approximately adjusted to the opening of the support sheet so as to be disposed from edge to edge, characterized in that said cylinder head gasket comprises an element (24) that is interposed between the stopper (20) and the support sheet ensuring the support of said stopper. 2. Cylinder head gasket with at least one opening (14) corresponding to a combustion chamber and comprising, on the one hand, at least two sheets (12) referred to as the external sheets at least one of which comprises a circular rib (16) that surrounds the opening (14) and is disposed at a distance from the edge of said opening (14) and, on the other hand, a support sheet (18) disposed between the external sheets (12) and comprising an opening of a diameter greater than the opening (14) of the external sheets so as to define a space wherein is disposed a stopper (20) in the form of an annular lining having an internal diameter that corresponds to that of the opening (14) and an external diameter approximately adjusted to the opening of the support sheet so as to be disposed from edge to edge, characterized in that said cylinder head gasket comprises an element (24) that is interposed between the stopper (20) and the support sheet ensuring the support of said stopper. 3. Cylinder head gasket according to claim 1 or 2, characterized in that the element (24) interposed between the stopper (20) and the support sheet (18) is in the form of a rivet comprising at each end a rim (26) folded against the faces of the support sheet (18) and the stopper (20) so as to grip them and to limit their relative movements. 4. Cylinder head gasket according to claim 3, characterized in that an aperture (28) is provided at the level of the external sheet or sheets (12) opposite each rivet (24). 5. Cylinder head gasket according to claim 3 or 4, characterized in that the thickness of the rivet (24) is less than the total thickness of the cylinder head gasket. 6. Cylinder head gasket according to any one of claims 1 to 5, characterized in that the stopper (18) [sic—“(20)” seems to be meant—Translator] comprises at the periphery thereof at least one tab (26′) at the level of which is disposed the support element (24). 7. Cylinder head gasket according to claim 1 or 2, characterized in that a forced-in pin is interposed between the stopper (20) and the support sheet (18). |
Switching circuit for producing an adjustable output characteristic |
The invention relates to a circuit to generate an output characteristic, having a constant voltage control circuit which receives a voltage supply and generates a constant output voltage; a current reduction section, which receives a control voltage and, depending on this, generates a control current which produces a change in the output voltage; and a limiter section which receives a lower and an upper limit voltage and optionally blocks or activates the current reduction section. The invention also relates to a corresponding method to generate an output characteristic. |
1. A circuit for generating an adjustable output comprising: a constant voltage control circuit (1) which receives a voltage supply (VSUPPLY) and generates a constant output voltage (VOUT); a current reduction section (2) which receives a control voltage (VCONTROL) and, generates a control current (IC) which produces a change in the output voltage (VOUT); and a limiter section (3) which receives a lower and an upper limit voltage (VLIMIT1, VLIMIT2) and optionally blocks or activates the current reduction section (2). 2. The circuit according to claim 1, wherein the constant voltage control circuit (1) further comprises a programmable reference voltage generator (10) whose output voltage (VOUT) can be adjusted via a voltage divider (13, 14, 15). 3. The circuit according to claim 2, wherein the voltage divider (13, 14, 15) includes a first ohmic section with two resistors (13, 14) and a second ohmic section with one resistor (15). 4. The circuit according to claim 3, wherein the current reduction section (2) further comprises a resistor (23) which is connected in series to one (13) of the two resistors in the first ohmic section so that the control current (IC) flows through the one resistor (23) of the current reduction section and through one (13) of the two resistors in the first ohmic section in order to superimpose a voltage (IC.R1) proportional to the control current (IC) on the output voltage (VOUT). 5. The circuit according to claim 1, wherein the current reduction section (2) further comprises a first switching element (22) which optionally activates or blocks the control current (IC). 6. The circuit according to claim 1, wherein the limiter section (3) comprises a comparator (30, 31) which receives the lower and the upper limit voltage (VLIMIT1, VLIMIT2) as well as the control voltage (VCONTROL), and generates a comparator output signal. 7. The circuit according to claim 6, wherein the limiter section (3) blocks or activates the current reduction section (2) as a function of the comparator output signal. 8. The circuit according to claim 7, wherein the comparator output signal of the limiter section (3) is connected to the first switching element (22) of the current reduction section (2) to activate or block the control current (IC). 9. The circuit according to claim 8, wherein the comparator output signal is connected to the first switching element (22) via at least one diode (34). 10. The circuit according to claim 8, wherein the first switching element (22) blocks the control current (IC) when the control voltage (VCONTROL) is less than the lower limit voltage (VLIMIT1) or greater than the upper limit voltage (VLIMIT2). 11. The circuit according to claim 7, wherein the limiter section (3) further comprises a second switching element (32) which receives the comparator output signal and optionally activates the bypass circuit (32, 33). 12. The circuit according to claims 11, wherein the bypass circuit (32, 33) comprises a resistor (33) which is connected in parallel to one (13) of the two resistors in the first ohmic section via the second switching element (32). 13. The circuit according to claim 12, wherein the second switching element (32) activates the bypass circuit (32, 33) when the control voltage (VCONTROL) is less than the lower limit voltage (VLIMIT1) or greater than the upper limit voltage (VLIMIT2). 14. A method for generating an output characteristic comprising the following steps: generating a constant output voltage as a function of a voltage supply and of a reference voltage; generating a control current depending on a control voltage and changing the output voltage as a function of the control current; and optionally activating or blocking the control current depending on whether the control voltage lies within or without an interval between a lower and an upper limit voltage. 15. The method of claim 14, wherein the output characteristics is a variable output voltage. 16. The circuit according to claim 6, wherein the limiter section (3) activates a bypass circuit (32, 33) to generate a voltage drop in the output voltage (VOUT). 17. The circuit according to claim 8, wherein the first switching element (22) activates the control current (IC) when the control voltage (VCONTROL) is substantially between the lower limit voltage (VLIMIT1) and the upper limit voltage (VLIMIT2). 18. The circuit according to claims 3 wherein the bypass circuit (32, 33) comprises a resistor (33) which is connected in parallel to one (13) of the two resistors in the first ohmic section via the second switching element (32). |
<SOH> BACKGROUND OF THE INVENTION <EOH>In the prior art, programmable or adjustable precision reference voltage generators are known, such as the AS 2431 from ASTEC Semiconductor, a division of Emerson Electric Company, Saint Louis, Mo., USA. A programmable reference voltage generator can supply an adjustable, constant output voltage largely independent of voltage supply fluctuations, whereby such a reference voltage generator preferably has a low temperature coefficient, a precise turn-on characteristic and low output impedance. To achieve the required input voltage, the reference voltage generator is connected to external components, in particular resistors. An example of a programmable reference voltage generator is illustrated in FIG. 1 . The reference voltage generator U shown in FIG. 1 is connected to a voltage supply V SUPPLY via a multiplier R V . A bridge circuit consisting of two resistors R B1 , R B2 is connected in parallel to the reference voltage generator U. The bridge circuit comprising the resistors R B1 , R B2 generates a defined reference voltage V REF , adjustable via the resistors, which is applied to a reference input of the reference voltage generator U, so that a very precise, stable constant output voltage V OUT is produced at its cathode K or output. Whereas a stable, constant output voltage is required for many applications, there are other applications which need programmable or adjustable rising or falling voltage characteristics. An example of a voltage characteristic, which, for instance, is needed in power supplies for telecommunications facilities, is shown in FIG. 2 . With an increasing control voltage V CONTROL , the output characteristic illustrated in FIG. 2 rises steadily and monotonously; see the continuous line in FIG. 2 . Provision can also be made for the output characteristic V OUT for control voltage values V CONTROL lying below a lower limit voltage V LIMIT1 or above an upper limit voltage V LIMIT2 to be cut off and restricted to a defined, low output voltage value. This results in an output voltage V OUT which has a constant, low value up to the lower limit voltage V LIMIT1 , which rises to a defined higher value on exceeding V LIMIT1 , rises steadily and monotonously between the lower and upper limit voltage V LIMIT1 and V LIMIT2 and then when the control voltage V CONTROL exceeds the upper limit voltage V LIMIT2 again falls to a constant, low value, which can be the same as or different to the constant low output voltage value on turning on the control voltage V CONTROL . Such a characteristic can be used, for example, in power supplies to charge batteries, in particular, in telecommunications systems. We would like to point out that the characteristic in FIG. 2 is only one example of an adjustable output voltage characteristic and that there are numerous applications for various adjustable output voltage characteristics in all sectors of the electrical industry. It is thus the object of the invention to provide a device and a method to generate an adjustable, exceedingly precise output characteristic, based on a constant voltage generator. The output characteristic should be particularly suitable for power supplies, battery charging units and suchlike, and even more particularly for application in telecommunications facilities. |
<SOH> SUMMARY OF THE INVENTION <EOH>The above-mentioned object has been achieved by means of a circuit having the characteristics outlined in claim 1 as well as a method having the characteristics outlined in claim 14 . In accordance with the invention, a circuit to generate an output characteristic is provided that has a constant voltage control circuit which receives a voltage supply and generates a constant output voltage. This constant voltage control circuit can essentially correspond to the programmable reference voltage generator shown in FIG. 1 . Moreover, the invention provides for the constant voltage control circuit to be connected to a current reduction section which receives a control voltage and, depending on this, generates a control current which produces a change in the output voltage, to produce, in particular, a monotonous, steady rise or fall in the output voltage. The invention additionally provides a limiter section, connected to the current reduction section, which receives a lower and an upper limit voltage and, depending on this, can optionally block or activate the current reduction section. The limiter section thus makes it possible to optionally switch on or off the influence on the output voltage of the constant voltage control circuit by the current reduction section. The invention provides a simple solution in terms of design and circuitry which can be largely integrated and realized at low-cost to generate a specified, adjustable output characteristic with great accuracy and stability. The invention achieves this by using a stable, programmable reference voltage generator which generates a fixed, constant output voltage and by adding a variable current reduction circuit to make the output voltage characteristic adjustable, as well as a limiter in order to achieve a further means of influence, in particular, a cut off of the out-put characteristic. While the supply voltage of the circuit presented in the invention can have strong fluctuations e.g. in the region of 20%, according to the invention, an output characteristic with an accuracy of +/−0.1% to 5% can be achieved, depending on the accuracy of the components used. According to the invention, in the constant voltage control circuit a programmable reference voltage generator is preferably used whose output voltage is adjustable using a voltage divider. For instance, the above-mentioned shunt regulator AS 2431 from ASTEC Semiconductor or a suitable component from Alpha Semiconductor or Texas Instruments, for example, can be used as a reference voltage generator. It is clear that the invention is not restricted to a specific component. In the constant voltage control circuit of the present invention, the voltage divider is preferably divided into a first ohmic section with two resistors and a second ohmic section with one resistor to allow the adjustable output characteristic to be to be influenced with particular ease, as described below. In a preferred embodiment, the current reduction section has a resistor which is connected in series to one of the two. resistors in the first ohmic section so that the control current of the current reduction section flows through these two resistors connected in series in order to superimpose a voltage proportional to the control current on the output voltage. Depending on the design of the current reduction section, this can result in an increase or decrease in the output voltage. The current reduction section is preferably activated via a first switching element which is contained therein in order to optionally activate or block the control current. This switching element is preferably activated via the limiter section. For this purpose, in a preferred embodiment, the limiter section can have a comparator which receives the lower and the upper limit voltage as well as the control voltage, and generates a comparator output signal. This comparator output signal activates or deactivates the current reduction section via the first switching element. In addition, the limiter section can include a bypass circuit which is also activated or blocked depending on the comparator output signal. The limiter section is preferably designed in such a way that it deactivates the current reduction section when the control voltage is less than the lower limit voltage or greater than the upper limit voltage, and otherwise activates it. Moreover, the limiter section can have a second switching element which also receives the comparator output signal and optionally activates or blocks the bypass circuit. In a particularly beneficial embodiment, the bypass circuit has a resistor which is connected in parallel to one of the two resistors in the first ohmic section of the voltage divider of the constant voltage control circuit. The bypass circuit is activated when the control voltage is less than the lower limit voltage or greater than the upper limit voltage, and is otherwise blocked. This means that, for control voltages which lie outside the interval between the lower and the upper limit voltage, the output characteristic of the circuit can be lowered to a defined constant voltage value. Of course, it is possible through an appropriate modification of the limiter circuit, by providing, for example, a series connection instead of the parallel connection of the bypass circuit, to raise the output voltage of the circuit to a defined constant value. The invention also provides a method to generate an output characteristic with the following procedural steps: generating a constant output voltage depending on a voltage supply and a reference voltage; generating a control current depending on a control voltage and changing the output voltage depending on the control current; and optionally activating or blocking the control current depending on whether the control voltage lies within or without an interval between a lower and an upper limit voltage. The invention is explained in more detail below based on a preferred embodiment and with reference to the drawings. In reading the following description, the technician will easily recognize that numerous modifications can be made to the illustrated circuit, particularly to generate a different characteristic to the one illustrated in FIG. 2 , without departing from the scope of the invention. The figures show: |
Non-natural carbon-linked nucleotides and dinucleotides |
Nucleotide derivatives of formula (1) are described, wherein: G is a hydrogen atom or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, polycycloaliphatic, aromatic or heteroaromatic group or a non natural carbon-linked nucleoside as defined herein; G′ is a non-natural carbon-linked nucleoside as defined herein; n is zero, or the integer 1 or 2; m is zero or the integer 1 or 2; and the salts, solvates, hydrates and N-oxides thereof. The compounds are P2Y receptor agonists and are of use in the prophylaxis and treatment of diseases and disorders involving abnormal secretory mechanisms such as inadequate functioning of mucociliary clearance mechanisms or abnormal tear secretion or in the treatment of diseases involving inappropriate cellular glucose uptake. |
1. A compound useful for modulating P2Y receptor activity of formula (1): wherein: G is a hydrogen atom or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, heteropolycyclo-aliphatic, aromatic or heteroaromatic group or a group of formula: Y and Z are each independently a hydrogen or halogen atom or a hydroxyl (—OH), alkoxy, azido (—N3), amino (—NH2), alkylamino or dialkylamino group; b represents the point of attachment to the remainder of the compound of formula (1); B is an optionally substituted carbon-linked bicyclic heteroaromatic group; G′ is a group of formula: B′ is an optionally substituted carbon-linked bicyclic heteroaromatic group; Z′ and Y′ are each independently a hydrogen or halogen atom or a hydroxyl (—OH), alkoxy, azido (—N3), amino (—NH2), alkylamino or dialkylamino group; b represents the point of attachment to the remainder of the compound of formula (1); n is zero, or the integer 1 or 2; m is zero or the integer 1 or 2; and the salts, solvates, hydrates and N-oxides thereof. 2. A compound of formula (1c): wherein: G is a hydrogen atom or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, heteropolycycloaliphatic, aromatic or heteroaromatic group or a group of formula: Y and Z are each independently a hydrogen or halogen atom or a hydroxyl (—OH), alkoxy, azido (—N3), amino (—NH2), alkylamino or dialkylamino group; b represents the point of attachment to the remainder of the compound of formula (1); B is an optionally substituted carbon-linked bicyclic heteroaromatic group; G′ is a group of formula: B′ is an optionally substituted carbon-linked bicyclic heteroaromatic group; Z′ and Y′ are each independently a hydrogen or halogen atom or a hydroxyl (—OH), alkoxy, azido (—N3), amino (—NH2), alkylamino or dialkylamino group; b represents the point of attachment to the remainder of the compound of formula (1); n is zero, or the integer 1 or 2; m is zero or the integer 1 or 2; provided that: 1) when n and m are each zero, G is a hydrogen atom and G′ is a group of formula (1b) in which Y′ and Z′ are each a hydroxyl (—OH) group, then B′ is other than a 7H-pyrazolo[4,3-d]pyrimidine-7-one-3-yl, 7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl, 4H-pyrrolo[3,2-d]pyrimidin-4-one-7-yl or 4-amino-4H-pyrrolo[3,2-d]pyrimidin-7-yl group; 2) when one of n and m is the integer 1 and the other is zero, G is a hydrogen atom and G′ is a group of formula (1b) in which Y′ and Z′ are each a hydroxyl (—OH) group, then B′ is other than a 7H-pyrazolo[4,3-d]pyrimidine-7-one-3-yl, 5-amino-7H-pyrazolo[4,3-d]pyrimidine-7-one-3-yl, 7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl, 2-amino-4H-pyrrolo[3,2-d]pyrimidin-4-one-7-yl, 4H-pyrrolo[3,2-d]pyrimidin-4-one-7-yl, 2-amino-4H-pyrrolo[3,2-d]pyrimidin-4-one-7-yl, 4-aminothieno[3,2-d]pyrimidin-7-yl, 4-amino-4H-pyrrolo[3,2-d]pyrimidin-7-yl or 4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl group; 3) when n and m are each zero, G′ is a group of formula (1b) in which Y′ and Z′ are each a hydroxyl (—OH) group, B′ is a 7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl group and G is a group of formula (1a) in which Y′ and Z′ are each a hydroxyl (—OH) group, then B is other than a 7-amino-1H-pyrazolo[4,3-d]pyrimidin-3-yl group; and the salts, solvates, hydrates and N-oxides thereof. 3. A compound according to claim 1 in which G′ has the formula (1b) in which the furanose sugar has the β-configuration. 4. A compound according to claim 3 in which G′ has the β-D-configuration. 5. A compound according to claim 4 in which G′ has the β-D-ribofuranose configuration. 6. A compound according to claim 1 of formula (2a): wherein: D, E and F are each a carbon or nitrogen atom provided that no more than two of D, E and F are a nitrogen atom; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugar is of a natural β-D configuration as shown; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent that may be on any available carbon atom of the heterocyclic ring B′; and the salts, solvates, hydrates and N-oxides thereof. 7. A compound according to claim 6 in which D and E are each a carbon atom and F is a nitrogen atom. 8. A compound according to claim 6 in which D and F are each a carbon atom and E is a nitrogen atom. 9. A compound according to claim 6 in which E and F are each a carbon atom and D is a nitrogen atom. 10. A compound according to claim 6 in which E and F are each a nitrogen atom and D is a carbon atom. 11. A compound according to claim 1 of formula (2b): wherein: Q is a N atom or a CH or C(R 13) group; M is an oxygen or sulphur atom or an NH or N(R13) group; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugar is of a natural β-D configuration as shown; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent which may be on any available carbon or nitrogen atom of the heterocyclic ring B′; and the salts, solvates, hydrates and N-oxides thereof. 12. A compound according to claim 11 in which M is an oxygen atom and Q is a CH or C(R13) group. 13. A compound according to claim 11 in which M is a sulphur atom and Q is a CH or C(R13) group. 14. A compound according to claim 11 in which M is an NH or N(R13) group and Q is a CH or C(R13) group. 15. A compound according to claim 11 in which Q is a N atom and M is an oxygen or sulphur or NH or N(R13) group. 16. A compound according to claim 11 in which R13 is a —CH3 group. 17. A compound according to claim 1 in which G is a hydrogen atom or an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, polycycloaliphatic, aromatic or heteroaromatic group or a group of formula (1a). 18. A compound according to claim 1 in which G is a group of formula (2c): in which b indicates the point of attachment to the remainder of the compound of formula (1). 19. A compound according to claim 18 in which B is a group of formula (2d): wherein: c represents the point of attachment to the molecule of formula (2c); D, E and F are each a carbon or nitrogen atom provided that no more than two of D, E and F are a nitrogen atom; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugar is of a natural β-D configuration as shown; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent that may be on any available carbon atom of the heterocyclic ring B′. 20. A compound according to claim 18 in which B is a group of formula (2e): wherein: c represents the point of attachment to the molecule of formula (2c); Q is a N atom or a CH or C(R13) group; M is an oxygen or sulphur atom or an NH or N(R13) group; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugar is of a natural β-D configuration as shown; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent which may be on any available carbon or nitrogen atom of the heterocyclic ring B′. 21. A compound according to claim 1 in which G is a group of formula (1a) and G′ is a group of formula (1b) in which B and B′ are each a group of formula (2d): wherein: c represents the point of attachment to the molecules of formulas (1a) and (1b); D, E and F are each a carbon or nitrogen atom provided that no more than two of D, E and F are a nitrogen atom; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugars are of a natural β-D configuration ; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent that may be on any available carbon atom of the heterocyclic ring of formula (2d); or B and B′ are each a group of formula (2e): wherein: c represents the point of attachment to the molecule of formula (2c); Q is a N atom or a CH or C(R13) group; M is an oxygen or sulphur atom or an NH or N(R13) group; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugars are of a natural β-D configuration; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent which may be on any available carbon or nitrogen atom of the heterocyclic ring B′. 22. A compound according to claim 6 in which G is a group of formula (2c): wherein: b indicates the point of attachment to the remainder of the compound of formula (2a); and B is a group of formula (2d): wherein: c represents the point of attachment to the molecule of formula (2c); D, E and F are each a carbon or nitrogen atom provided that no more than two of D, E and F are a nitrogen atom; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugar is of natural β-D configuration as shown; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent that may be on any available carbon atom of the heterocyclic ring of formula (2d). 23. A compound according to claim 6 in which G is a group of formula (2c): wherein: b indicates the point of attachment to the remainder of the compound of formula (2a); and B is a group of formula (2e): wherein: c represents the point of attachment to the molecule of formula (2c); Q is a N atom or a CH or C(R13) group; M is an oxygen or sulphur atom or an NH or N(R13) group; Z′ is a hydroxyl (—OH), amino (—NH2) or azido (—N3) group; the ribose sugar is of natural β-D configuration as shown; h is zero or the integer 1, 2, 3 or 4; R13 is an optional substituent which may be on any available carbon or nitrogen atom of the heterocyclic ring of formula (2e). 24. A compound according to claim 22 in which B and B′ are identical. 25. A compound according claim 1 in which G is a hydrogen atom. 26. A compound according to claim 25 in which m is the integer 1 and n is zero. 27. A compound which is (2R,3S,4R,5R)-3,4-Dihydroxy-5-benzothiazol-2-yl-tetrahydrofuran-2-ylmethyl triphosphate tris-ammonium salt; (2R,3S,4R,5R)-3,4-Dihydroxy-5-(5-trifluoromethyl-benzothiazol-2-yl)-tetrahydrofuran-2-ylmethyl triphosphate tris-ammonium salt; and the free acid, other pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof. 28. A compound which is: (2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-chlorobenzothiazol-2-yl)-tetrahydrofuran-2-ylmethyl triphosphate tris-ammonium salt; (2R,3 S,4R,5R)-3,4-Dihydroxy-5-(5-fluorobenzothiazol-2-yl)-tetrahydrofuran-2-ylmethyl triphosphate tris-triethylammonium salt; (2R,3 S,4R,5R)-5-(6-Chloro-4-fluorobenzothiazol-2-yl)-3,4-dihydroxy-tetrahydrofuran-2-ylmethyl triphosphate tris-triethylammonium salt; and the free acid, other pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof. 29. A pharmaceutical composition comprising a compound according to claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents. 30. (canceled) 31. A method for the treatment of a lung disorder involving inadequate functioning of mucociliary clearance mechanisms comprising administering to a mammal suffering from such a disorder a therapeutically effective amount of a compound of claim 1. 32. The method of claim 31 wherein the disorder is chronic bronchitis, primary ciliary dyskinesia, cystic fibrosis, sinusitis, otitis media, post-operative mucous retention, nasolacrimal duct obstructions, or female infertility or irritation. |
Methods for improved treatment of cancer with irinotecan based on mrp1 |
The present invention relates to the use of irinotecan or derivative thereof for the preparation of a pharmaceutical composition for treating cancer, especially, colorectal cancer, cervical cancer, gastric cancer, lung cancer, malignant glioma, ovarian cancer, and pancreatic cancer in a patient having a genotype with a variant allele which comprises a polynucleotide in accordance with the present invention. Preferably, a nucleotide deletion, addition and/or substitution comprised by said polynucleotide results in an altered expression of a variant allele compared to the corresponding wild type allele or an altered activity of the polypeptide encoded by the variant allele compared to the polypeptide encoded by the corresponding wild type allele. Finally, the present invention relates to a method for selecting a suitable therapy for a subject suffering from colorectal cancer, cervical cancer, gastric cancer, lung cancer, malignant glioma, ovarian cancer, and pancreatic cancer. |
1. A method of using irinotecan to treat a patient suffering from cancer which comprises: (1) determining if the patient has one or more variant alleles of the MRP1 gene in the cancerous tissue; (2) in a patient having one or more of such variant alleles, administering to the patient an amount of irinotecan which is sufficient to treat a patient having such variant alleles which amount is increased or decreased in comparison to the amount that is administered without regard to the patient's alleles in the MRP1 gene. 2. The method of claim 1, wherein the cancer is colorectal cancer, cervical cancer, gastric cancer, lung cancer, malignant glioma, ovarian cancer, or pancreatic cancer. 3. The method of claim 2 in which: (1) the one or more variant alleles result in the patient expressing low amounts of the MRP1 gene product, whereby the amount of irinotecan administered to the patient is decreased to avoid toxicity; or (2) the one or more variant alleles result in the patient expressing high amounts of the MRP1 gene product, whereby the amount of irinotecan administered to the patient is increased to enhance efficacy. 4. The method of claim 3, wherein the one or more variant alleles are in the promoter region of the MRP1 gene. 5. The method of claim 3, wherein the one or more variant alleles are in the coding region of the MRP1 gene. 6. The method of claim 3, wherein the one or more variant alleles are not in either the promoter region or the coding region of the MRP1 gene. 7. The method of claim 3, wherein the one or more variant alleles are in both the promoter region and the coding region of the MRP1 gene. 8. The method of claim 3, wherein the one or more variant alleles comprises a polynucleotide selected from the group consisting of: (a) a polynucleotide having the nucleic acid sequence of any one of SEQ ID NOs:169, 170, 173, 174, 177, 178, 181, 182, 185, 186, 189, 190, 193, 194, 197, 198, 201, 202, 205, 206, 209, 210, 213, 214, 217, 218, 221, 222, 225, 226, 229, 230, 233, 234, 237, 238, 241, 242, 245, 246, 249, 250, 253, 254, 257, 258, 261, 262, 265, 266, 269, 270, 273, 274, 277, 278, 281, 282, 285, 286, 289, 290, 293, 294, 297, 298, 301, 302, 305, 306, 309, 310, 313, 314, 317, 318, 321, 322, 325, 326, 329, 330, 333 and/or 334; (b) a polynucleotide encoding a polypeptide having the amino acid sequence of any one of SEQ ID NOs: 600, 602 and/or 604; (c) a polynucleotide capable of hybridizing to a Multidrug Resistance Protein 1 (MRP1) gene, wherein said polynucleotide is having at a position corresponding to positions 57998, 57853, 53282, and/or 39508 of the MRP1 gene (Accession No: GI:7209451), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 137667, 137647, 137710, 124667, and/or 38646 of the MRP1 gene (Accession No: AC026452), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 27258, 27159, 34218, 34215, 55472, and/or 34206 to 34207 of the MRP1 gene (Accession No: AC003026), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 21133, 14008, 18067, 17970, 17900, and/or 18195 of the MRP1 gene (Accession No: U91318), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 79, 88, and/or 249 of the MRP1 gene (Accession No: AF022830), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 95 and/or 259 of the MRP1 gene (Accession No: AF022831), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 150727 and/or 33551 of the MRP1 gene (Accession No: AC025277), a substitution or deletion of at least one nucleotide or at a position corresponding to position 174 of the MRP1 gene (Accession No: AF022828), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 248 and/or 258 of the MRP1 gene (Accession No: AF022829), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 1884, 1625, 1163, 381, 233, 189, 440, and/or 1720 to 1723 of the MRP1 gene (Accession No: U07050), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 926927 and/or 437/438 of the MRP1 gene (Accession No: U07050) a insertion of at least one nucleotide or at a position corresponding to position 55156/55157 of the MRP1 gene (Accession No: AC003026) a insertion of at least one nucleotide; (d) a polynucleotide capable of hybridizing to a MRP1 gene, wherein said polynucleotide is having at a position corresponding to position 21133, 14008 and/or 18195 of the MRP1 gene (Accession No: U91318) or at a position corresponding to position 27258 and/or 34218 of the MRP1 gene (Accession No: AC003026) or at a position corresponding to position 79 of the MRP1 gene (Accession No: AF022830) or at a position corresponding to position 57998, and/or 57853 of the MRP1 gene (Accession No: GI:7209451) or at a position corresponding to position 137667 and/or 137647 of the MRP1 gene (Accession No: AC026452) or at a position corresponding to position 150727 and/or 33551 of the MRP1 gene (Accession No: AC025277) or at a position corresponding to position 248 of the MRP1 gene (Accession No: AF022829) or at a position corresponding to position 1884, 1625, 233, and/or 189 of the MRP1 gene (Accession No: U07050) an A, at a position corresponding to position 39508 of the MRP1 gene (Accession No: GI:7209451) or at a position corresponding to position 17900, 18067 and/or 18195 of the MRP1 gene (Accession No: U91318) or at a position corresponding to position 174 of the MRP1 gene (Accession No: AF022828) or at a position corresponding to position 440 and/or 1163 of the MRP1 gene (Accession No: U07050) a T, at a position corresponding to position 88 of the MRP1 gene (Accession No: AF022830) or at a position corresponding to position 95 of the MRP1 gene (Accession No: AF022831) or at a position corresponding to position 27159, 55472 and/or 34215 of the MRP1 gene (Accession No: AC003026) or at a position corresponding to position 124667 and/or 38646 of the MRP1 gene (Accession No: AC026452) or at a position corresponding to position 53282 of the MRP1 gene (Accession No: GI:7209451) or at a position corresponding to position 137710 of the MRP1 gene (Accession No: AC026452) a C, at a position corresponding to position 249 of the MRP1 gene (Accession No: AF022830) or at a position corresponding to position 258 of the MRP1 gene (Accession No: AF022829) or at a position corresponding to position 259 of the MRP1 gene (Accession No: AF022831) or at a position corresponding to position 381 of the MRP1 gene (Accession No: U07050) a G, at a position corresponding to position 17970 of the MRP1 gene (Accession No: U91318) a deletion of a T or at a position corresponding to position 34206 to 34207 of the MRP1 gene (Accession No: AC003026) a deletion of a AT or at a position corresponding to position 1720 to 1723 of the MRP1 gene (Accession No: U07050) a deletion of GGTA, at a position corresponding to position 926/927 a insertion of a T and/or 437/438 of the MRP1 gene (Accession No: U07050) a insertion of a TCCTTCC, at a position corresponding to position 55156/55157 of the MRP1 gene (Accession No: AC003026) a insertion of TGGGGC; (e) a polynucleotide encoding an MRP1 polypeptide or fragment thereof, wherein said polypeptide comprises an amino acid substitution at a position corresponding to positions 600, 602, and/or 604 of the MRP1 polypeptide (Accession No: G2828206); (f) a polynucleotide encoding an MRP1 polypeptide or fragment thereof, wherein said polypeptide comprises an amino acid substitution of Phe to Cys at a position corresponding to position 239 of the MRP1 polypeptide (Accession No: G2828206) or/and Arg to Ser at a position corresponding to position 433 of the MRP1 polypeptide (Accession No: G2828206) or/and Arg to Gin at a position corresponding to position 723 of the MRP1 polypeptide (Accession No: G2828206). 9. The method of claim 8, wherein the one or more variant alleles comprises a polynucleotide selected from the group consisting of: (a) a polynucleotide having the nucleic acid sequence of any one of SEQ ID NO: 181, 209, 217, 205, 277, 281, 301, 325, 229, 193, 313, 293 or 253; (b) a polynucleotid encoding a polypeptide having the amino acid sequence of SEQ ID NO: 600; (c) a polynucleotide capable of hybridizing to a MRP1 gene, wherein said polynucleotide is having a substitution at a position corresponding to position 137647 of the MRP1 gene (Accession No: AC026452), 95 of the MRP1 gene (Accession No: AF022831), 53282 of the MRP1 gene (Accession No: GI:7209451), 249 of the MRP1 gene (Accession No: AF022830), 259 of the MRP1 gene (Accession No: AF022831), 124667 of the MRP1 gene (Accession No: AC026452), 381, 440, 1625 of the MRP1 gene (Accession No: U07050), 34218 of the MRP1 gene (Accession No: AC003026), 18067 or 17900 of the MRP1 gene (Accession No: U91318) or an insertion of at least one nucleotide at a position corresponding to position 926/927 of the MRP1 gene (Accession No: U07050); (d) a polynucleotide capable of hybridizing to a MRP1 gene, wherein said polynucleotide is having a T at a position corresponding to position 137647 of the MRP1 gene (Accession No: AC026452), 18067 or 17900 of the MRP1 gene (Accession No: U91318), 440 of the MRP1 gene (Accession No: U07050), a C at a position corresponding toposition 95 of the MRP1 gene (Accession No: AF022831),124667 of the MRP1 gene (Accession No: AC026452), a G at a position corresponding to position 53282 of the MRP1 gene (Accession No: GI:7209451), 249 of the MRP1 gene (Accession No: AF022830), 259 of the MRP1 gene (Accession No: AF022831), 381 of the MRP1 gene (Accession No: U07050), or an A at a position corresponding to position 34218 of the MRP1 gene (Accession No: AC003026) or 1625 of the MRP1 gene (Accession No: U07050) or an insertion of a T at a position corresponding to position 926/927 of the MRP1 gene (Accession No: U07050); (e) a polynucleotide encoding an MRP1 polypeptide or fragment thereof, wherein said polypeptide comprises an amino acid substitution at a position corresponding to position 329 of the MRP1 polypeptide (Accession No: G2828206); and (d) a polynucleotide encoding an MRP1 polypeptide or fragment thereof, wherein said polypeptide comprises an amino acid substitution of Phe to Cys at a position corresponding to position 329 of the MRP1 polypeptide (Accession No: G2828206). 10. The method of claim 8, in which the one or more variant alleles results in the patient expressing low amounts of the MRP1 gene product, whereby the amount of ironotecan administered to the patient is decreased. 11. The method of claim 8, in which the one or more variant alleles results in the patient expressing high amounts of the MRP1 gene product, whereby the amount of irinotecan administered to the patient is increased. 12. The method of claim 9, in which the one or more variant alleles results in the patient expressing low amounts of the MRP1 gene product, whereby the amount of irinotecan administered to the patient is decreased. 13. The method of claim 9, in which the one or more variant alleles results in the patient expressing high amounts of the MRP1 gene product, whereby the amount of irinotecan administered to the patient is increased. 14. A method for determining whether a patient is at risk for a toxic reaction to treatment with irinotecan which comprises determining if the patient has one or more variant alleles of the MRP1 gene. 15. The method of claim 14, which further comprises administering to the patient reduced amounts of irinotecan. 16. A method for determining the optimum treatment regimen for administering irinotecan to a patient suffering from cancer which comprises: (1) determining if the patient has one or more variant alleles of the MRP1 gene; (2) in a patient having one or more of such alleles increasing or decreasing the amount of irinotecan in comparison to the amount that is administered without regard to the patient's alleles in the MRP1 gene. 17. A method of treating cancer in a patient having one or more variant alleles of the MRP1 gene such that expression levels of the MRP1 gene product are lower than in the general population and so indicates high sensitivity to irinotecan which comprises administering to the patient a decreased amount of irinotecan. 18. A method of treating cancer in a patient having one or more variant alleles of the MRP1 gene such that expression levels of the MRP1 gene product are higher than in the and so indicates resistance or predisposition to resistance to irinotecan which comprises administering to the patient an increased amount of irinotecan. 19. The method of claim 18, in which patients that have a variant allele that indicates resistance or predisposition to resistance are treated with an MRP1 inhibitor. 20. The method of claim 19, wherein the MRP1 inhibitor is selected from the group consisting of SDZ-PSC 833, SDZ 280-446, MK571, MS209(quinolone derivative), PAK-104p, Verapamil, Benzbromarone, Dipyridamole, Furosemide, Gamma-GS(naphtyl)cysteinyl-glycine diethyl ester, Genistein, Quinidine, Rifampicin, RU 486, Sulfinpyrazone. 21. The method of claim 17, which further comprises monitoring the patient during treatment by assaying for changes in expression levels of the MRP1 gene product in the cancerous cells whereby an increase in the expression level of the MRP1 gene product is compensated for by an increase in the amount of irinotecan administered to the patient. 22. A method of treating cancer in a patient which comprises internally administering to the patient an effective amount of irinotecan, wherein the treatment regimen is modified based upon the genotype of the patient's MRP1 gene. 23. A method of treating a population of patients suffering from cancer which comprises: (1) determining, on a patient by patient basis, if the patient has one or more variant alleles of the MRP1 gene; (2) in a patient having one or more of such variant alleles, administering to the patient an amount of irinotecan which is sufficient to treat a patient having such variant alleles which amount is increased or decreased in comparison to the amount that is administered without regard to the patient's alleles in the MRP1 gene. 24. A method for predicting sensitivity to irinotecan in a patient suffering from cancer which comprises determining if the patient has one or more variant alleles of the MRP1 gene, which alleles indicate that the cancerous cells express low or high amounts of the MRP1 gene product, whereby low expression indicates high sensitivity to irinotecan and high expression indicates resistance or predisposition to resistance to irinotecan. 25. The method of claim 24, in which patients that have a genotype that indicates resistance or predisposition to resistance are treated with a MRP1 inhibitor. 26. The method of claim 25, wherein the MRP1 inhibitor is selected from the group consisting of SDZ-PSC 833, SDZ 280-446, MK571, MS209 (quinolone derivative), PAK-104p, Verapamil, Benzbromarone, Dipyridamole, Furosemide, Gamma-GS(naphtyl)cysteinyl-glycine diethyl ester, Genistein, Quinidine, Rifampicin, RU 486, Sulfinpyrazone. 27. The method of claim 26, wherein the patients that have a genotype that indicates resistance or predisposition to resistance are monitored during treatment by assaying for expression levels of the MRP1 gene product in the cancerous cells. 28. Use of irinotecan or a derivative thereof for the preparation of a pharmaceutical composition for treating colorectal cancer, cervical cancer, gastric cancer, lung cancer, malignant glioma, ovarian cancer, and pancreatic cancer in a subject having a genome with a variant allele which comprises a polynucleotide selected from the group consisting of: (a) a polynucleotide having the nucleic acid sequence of any one of SEQ ID NOs: 169, 170, 173, 174, 177, 178, 181, 182, 185, 186, 189, 190, 193, 194, 197, 198, 201, 202, 205, 206, 209, 210, 213, 214, 217, 218, 221, 222, 225, 226, 229, 230, 233, 234, 237, 238, 241, 242, 245, 246, 249, 250, 253, 254; 257, 258, 261, 262, 265, 266, 269, 270, 273, 274, 277, 278, 281, 282, 285, 286, 289, 290, 293, 294, 297, 298, 301, 302, 305, 306, 309, 310, 313, 314, 317, 318, 321, 322, 325, 326, 329, 330, 333 and/or 334; (b) a polynucleotide encoding a polypeptide having the amino acid sequence of any one of SEQ ID NOs: 600, 602 and/or 604; (c) a polynucleotide capable of hybridizing to a Multidrug Resistance Protein 1 (MRP1) gene, wherein said polynucleotide is having at a position corresponding to positions 57998, 57853, 53282, and/or 39508 of the MRP1 gene (Accession No: GI: 7209451), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 137667, 137647, 137710, 124667, and/or 38646 of the MRP1 gene (Accession No: AC026452), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 27258, 27159, 34218, 34215, 55472, and/or 34206 to 34207 of the MRP1 gene (Accession No: AC003026), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 21133, 14008, 18067, 17970, 17900, and/or 18195 of the MRP1 gene (Accession No: U91318), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 79, 88, and/or 249 of the MRP1 gene (Accession No: AF022830), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 95 and/or 259 of the MRP1 gene (Accession No: AF02283 1), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 150727 and/or 33551 of the MRP1 gene (Accession No: AC025277), a substitution or deletion of at least one nucleotide or at a position corresponding to position 174 of the MRP1 gene (Accession No: AF022828), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 248 and/or 258 of the MRP1 gene (Accession No: AF022829), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 1884, 1625, 1163, 381, 233, 189, 440, and/or 1720 to 1723 of the MRP1 gene (Accession No: U07050), a substitution or deletion of at least one nucleotide or at a position corresponding to positions 926927 and/or 437/438 of the MRP1 gene (Accession No: U07050) a insertion of at least one nucleotide or at a position corresponding to position 55156/55157 of the MRP1 gene (Accession No: AC003026) a insertion of at least one nucleotide; (d) a polynucleotide capable of hybridizing to a MRP1 gene, wherein said polynucleotide is having at a position corresponding to position 21133, 14008 and/or 18195 of the MRP1 gene (Accession No: U91318) or at a position corresponding to position 27258 and/or 34218 of the MRP1 gene (Accession No: AC003026) or at a position corresponding to position 79 of the MRP1 gene (Accession No: AF022830) or at a position corresponding to position 57998, and/or 57853 of the MRP1 gene (Accession No: GI:7209451) or at a position corresponding to position 137667 and/or 137647 of the MRP1 gene (Accession No: AC026452) or at a position corresponding to position 150727 and/or 33551 of the MRP1 gene (Accession No: AC025277) or at a position corresponding to position 248 of the MRP1 gene (Accession No: AF022829) or at a position corresponding to position 1884, 1625, 233, and/or 189 of the MRP1 gene (Accession No: U07050) an A, at a position corresponding to position 39508 of the MRP1 gene (Accession No: GI:7209451) or at a position corresponding to position 17900, 18067 and/or 18195 of the MRP1 gene (Accession No: U91318) or at a position corresponding to position 174 of the MRP1 gene (Accession No: AF022828) or at a position corresponding to position 440 and/or 1163 of the MRP1 gene (Accession No: U07050) a T, at a position corresponding to position 88 of the MRP1 gene (Accession No: AF022830) or at a position corresponding to position 95 of the MRP1 gene (Accession No: AF02283 1) or at a position corresponding to position 27159, 55472 and/or 34215 of the MRP1 gene (Accession No: AC003026) or at a position corresponding to position 124667 and/or 38646 of the MRP1 gene (Accession No: AC026452) or at a position corresponding to position 53282 of the MRP1 gene (Accession No: GI:7209451) or at a position corresponding to position 137710 of the MRP1 gene (Accession No: AC026452) a C, at a position corresponding to position 249 of the MRP1 gene (Accession No: AF022830) or at a position corresponding to position 258 of the MRP1 gene (Accession No: AF022829) or at a position corresponding to position 259 of the MRP1 gene (Accession No: AF02283 1) or at a position corresponding to position 381 of the MRP1 gene (Accession No: U07050) a G, at a position corresponding to position 17970 of the MRP1 gene (Accession No: U91318) a deletion of a T or at a position corresponding to position 34206 to 34207 of the MRP1 gene (Accession No: AC003026) a deletion of a AT or at a position corresponding to position 1720 to 1723 of the MRP1 gene (Accession No: U07050) a deletion of GGTA, at a position corresponding to position 926/927 a insertion of a T and/or 437/438 of the MRP1 gene (Accession No: U07050) a insertion of a TCCTTCC, at a position corresponding to position 55156/55157 of the MRP1 gene (Accession No: AC003026) a insertion of TGGGGC; (e) a polynucleotide encoding an MRP1 polypeptide or fragment thereof, wherein said polypeptide comprises an amino acid substitution at a position corresponding to positions 600, 602, and/or 604 of the MRP1 polypeptide (Accession No: G2828206); (f) a polynucleotide encoding an MRP1 polypeptide or fragment thereof, wherein said polypeptide comprises an amino acid substitution of Phe to Cys at a position corresponding to position 239 of the MRP1 polypeptide (Accession No: G2828206) or/and Arg to Ser at a position corresponding to position 433 of the MRP1 polypeptide (Accession No: G2828206) or/and Arg to Gin at a position corresponding to position 723 of the MRP1 polypeptide (Accession No: G2828206). 29. The use of claim 28, wherein a nucleotide deletion, addition and/or substitution comprised by said polynucleotide results in an altered expression of the variant allele compared to the corresponding wild type alleles. 30. The use of claim 29, wherein said altered expression is decreased or increased expression. 31. The use of claim 28, wherein a nucleotide deletion, addition and/or substitution comprised by said polynucleotide results in an altered activity of the polypeptide encoded by the variant allele compared to the polypeptide encoded by the corresponding wild type allele. 32. The use of claim 31, wherein said altered activity is decreased or increased activity. 33. The use of claim 28, wherein said subject is an animal. 34. The use of claim 33, wherein said subject is a mouse. 35. The use of claim 28, wherein said subject is a human. 36. The use of claim 35, wherein said human is African or Asian. 37. A method for selecting a suitable therapy for a subject suffering from colorectal cancer, cervical cancer, gastric cancer, lung cancer, malignant glioma, ovarian cancer, and pancreatic cancer, wherein said method comprises: (a) determining the presence or absence of a variant allele as specified in claim 28 in the genome of a subject in a sample obtained from said subject; and (b) selecting a suitable therapy for said subject based on the results obtained in (a). |
Semiconductor device |
A semiconductor device includes a plurality of nonvolatile memory cells (1). Each of the nonvolatile memory cells comprises a MOS type first transistor section (3) used for information storage, and a MOS type second transistor section (4) which selects the first transistor section. The second transistor section has a bit line electrode (16) connected to a bit line, and a control gate electrode (18) connected to a control gate control line. The first transistor section has a source line electrode (10) connected to a source line, a memory gate electrode (14) connected to a memory gate control line, and a charge storage region (11) disposed directly below the memory gate electrode. A gate withstand voltage of the second transistor section is lower than that of the first transistor section. Assuming that the thickness of a gate insulating film of the second transistor section is defined as tc and the thickness of a gate insulating film of the first transistor section is defined as tm, they have a relationship of tc<tm. |
1. A semiconductor device comprising: a plurality of nonvolatile memory cells each including, a MOS type first transistor section used for information storage, and a MOS type second transistor section which selects the first transistor section, wherein the first transistor section and the second transistor section are formed with an insulating region between gate electrodes thereof and adjacent to each other, wherein a channel region connected to channel regions of the first transistor section and the second transistor section is provided below the insulating region, wherein the second transistor section has a bit line electrode connected to a bit line, and a control gate electrode connected to a control gate control line, wherein the first transistor section has a source line electrode connected to a source line, a memory gate electrode connected to a memory gate control line, and a charge storage region disposed directly below the memory gate electrode, wherein a gate withstand voltage of the second transistor section is lower than a gate withstand voltage of the first transistor section, and wherein a gate withstand voltage of a drive MOS transistor connected to the control gate control line is lower than a gate withstand voltage of the first transistor section. 2. A semiconductor device comprising: a plurality of nonvolatile memory cells each including, a MOS type first transistor section used for information storage, and a MOS type second transistor section which selects the first transistor section, wherein the first transistor section and the second transistor section are formed with an insulating region between gate electrodes thereof and adjacent to each other, wherein a channel region connected to channel regions of the first transistor section and the second transistor section is provided below the insulating region, wherein the second transistor section has a bit line electrode connected to a bit line, and a control gate electrode connected to a control gate control line, wherein the first transistor section has a source line electrode connected to a source line, a memory gate electrode connected to a memory gate control line, and a charge storage region disposed directly below the memory gate electrode, wherein when the thickness of a gate insulating film of the control gate electrode of the second transistor section is defined as tc, and the thickness of a gate insulating film of the memory gate electrode of the first transistor section is defined as tm, a relationship of tc<tm is established therebetween, and wherein a gate insulating film of a drive MOS transistor connected to the control gate control line is thinner than said tm. 3. A semiconductor device according to claim 2, wherein when the thickness of an insulating film between the control gate electrode and the charge storage region is defined as ti, a relationship of tm<ti is established. 4. A semiconductor device according to claim 1, wherein the bit line electrode and the source line electrode are formed in a well region in which a high-density impurity region is not formed therebetween. 5. A semiconductor device according to claim 4, wherein the high-density impurity region is a diffused region of an impurity. 6. A semiconductor device according to claim 1, wherein the charge storage region is a conductive floating gate electrode covered with an insulating film. 7. A semiconductor device according to claim 1, wherein the charge storage region is a charge trap insulating film covered with an insulating film. 8. A semiconductor device according to claim 1, wherein the charge storage region is a conductive fine particle layer covered with an insulating film. 9. A semiconductor device according to claim 1, further including: switch MOS transistors each capable of connecting the bit line to a global bit line, wherein the thickness of a gate oxide film of the switch MOS transistor is thinner than the thickness of a gate oxide film of the first transistor section. 10. A semiconductor device according to claim 9, further including: a first driver which has the drive MOS transistor and drives the control gate control line; a second driver which drives the memory gate control line; a third driver which drives the switch MOS transistor to an on state; and a fourth driver which drives the source line, wherein the first driver and the third driver use a first voltage as an operating power supply, and the second driver and the fourth driver use a voltage higher than the first voltage as an operating power supply. 11. A semiconductor device according to claim 10, further including: a control circuit which sets an operating power supply of the first driver to a first voltage, sets an operating power supply of the fourth driver to a second voltage higher than the first voltage, and sets an operating power supply of the second driver to a third voltage greater than or equal to the second voltage when a threshold voltage of the first transistor section is rendered high, thereby enabling injection of hot electrons into the charge storage region from the bit line electrode side. 12. A semiconductor device according to claim 11, wherein the control circuit sets the operating power supply of the second driver to a fourth voltage greater than or equal to the third voltage when the threshold voltage of the first transistor section is rendered low, thereby ejecting electrons from the charge storage region to the corresponding memory gate electrode. 13. A semiconductor device according to claim 12, wherein the first transistor section whose threshold voltage is made low, is set to a depletion type, and the first transistor section whose threshold voltage is made high, is set to an enhancement type. 14. A semiconductor device according to claim 11, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the first driver to a first voltage and sets the memory gate electrode and the source line electrode to a circuit's ground potential. 15. A semiconductor device according to claim 11, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the first driver to a first voltage and sets the memory gate electrode and the bit line electrode to a circuit's ground potential. 16. A semiconductor device according to claim 10, further including a logic operation unit which performs a logical operation with the first voltage as an operating power supply. 17. A semiconductor device according to claim 13, wherein each of the first driver and the third driver receives an address decode signal so that an operation thereof is selected, and each of the second driver and the fourth driver receives the output of the first driver so that an operation thereof is selected. 18. A semiconductor device according to claim 17, wherein the first driver and the third driver are disposed on one side and the second driver and the fourth driver are disposed on the other side, with an array of the nonvolatile memory cells being interposed therebetween. 19. A semiconductor device according to claim 18, wherein in the array of the nonvolatile memory cells, memory gate control lines are formed integrally with memory gate electrodes, and low resistance metal layers are laminated over polysilicon layers respectively. 20. A semiconductor device according to claim 18, wherein discharge MOS transistors for causing the memory gate control lines to be conducted to a circuit's ground potential in response to a read operation are provided at different positions of the memory gate control lines. 21. A semiconductor device according to claim 9, wherein each of the switch MOS transistors is a p channel type MOS transistor. 22. A semiconductor device according to claim 21, wherein n channel type discharge MOS transistors switch-operated complementarily to the switch MOS transistors are provided at their corresponding bit lines. 23. A semiconductor device according to claim 9, wherein the switch MOS transistors are mutually parallel-connected n channel type MOS transistors and p channel type MOS transistors which constitute CMOS transfer gates. 24. A semiconductor device comprising: nonvolatile memory cells disposed over a semiconductor substrate in matrix form, wherein said each nonvolatile memory cell includes in the semiconductor substrate a source line electrode connected to a source line, a bit line electrode connected to a bit line, and channel regions interposed between the source line electrode and the bit line electrode, and includes over the channel regions a control gate electrode disposed near the bit line electrode via a first insulating film and connected to a control gate control line, and a memory gate electrode disposed via a second insulating film and a charge storage region, electrically separated from the control gate electrode and connected to a memory gate control line, wherein the channel regions extend continuously below a region interposed between the control gate electrode and the memory gate electrode, wherein a withstand voltage of the first insulating film is lower than a withstand voltage of the second insulating film, and wherein a withstand voltage of a gate insulating film of a drive MOS transistor connected to the control gate control line is lower than the withstand voltage of the second insulating film. 25. A semiconductor device according to claim 24, further comprising control gate drivers each of which has the drive MOS transistor and drives the control gate control line, memory gate drivers each of which drives the memory gate control line, and source drivers each of which drives the source line, wherein the control gate driver uses a first voltage as an operating power supply, and each of the memory gate driver and the source driver uses a voltage higher than the first voltage as an operating power supply. 26. A semiconductor device according to claim 25, further comprising a control circuit which sets an operating power supply of the control gate driver to a first voltage, sets an operating power supply of the source driver to a second voltage higher than the first voltage, and sets an operating power supply of the memory gate driver to a third voltage greater than or equal to the second voltage when a threshold voltage of the nonvolatile memory cell as viewed from the memory gate electrode is rendered high, thereby enabling injection of electrons into the charge storage region from the bit line electrode side. 27. A semiconductor device according to claim 26, wherein the control circuit sets the operating power supply of the memory gate driver to a fourth voltage greater than or equal to the third voltage when the threshold voltage of the nonvolatile memory cell as viewed from the memory gate electrode is rendered low, thereby ejecting electrons from the charge storage region to the corresponding memory gate electrode. 28. A semiconductor device according to claim 25, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the control gate driver to a first voltage and sets the memory gate electrode and the source line electrode to a circuit's ground potential. 29. A semiconductor device according to claim 25, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the control gate driver to a first voltage and sets the memory gate electrode and the bit line electrode to a circuit's ground potential. 30. A semiconductor device according to claim 24, further including a logic operation unit which performs a logical operation with the first voltage as an operating power supply. 31. A semiconductor device according to claim 25, wherein the control gate driver receives an address decode signal so that an operation thereof is selected, and each of the memory gate driver and the source driver is based on the output of the control gate driver so that an operation thereof is selected. 32. A semiconductor device according to claim 31, wherein the control gate drivers are disposed on one side and the memory gate drivers and the source drivers are disposed on the other side, with an array of the nonvolatile memory cells being interposed therebetween. 33. A semiconductor device according to claim 32, wherein in the array of the nonvolatile memory cells, memory gate control lines are formed integrally with memory gate electrodes, and low resistance metal layers are laminated over polysilicon layers respectively. 34. A semiconductor device according to claim 25, wherein in the array of the nonvolatile memory cells, the memory gate drivers are shared in plural units of the memory gate control lines paired with the control gate control lines and the source drivers are shared in plural units of the source lines paired with the control gate control lines, and the number of the memory gate control lines shared by the corresponding memory gate driver is less than or equal to the number of the source lines shared by the corresponding source driver. 35. A semiconductor device according to claim 34, wherein the memory gate driver and the source driver are driven based on the output of an OR circuit which forms the OR of selected states with respect to their corresponding plural control gate control lines, and wherein an input stage of the OR circuit is provided with transistors using extended portions of the control gate control lines as gate electrodes thereof. 36. A semiconductor device according to claim 24, wherein a plurality of charge MOS transistors for respectively causing the memory gate control lines to be conducted to the first power supply voltage in response to a read operation are provided at different positions of the memory gate control lines. 37. A semiconductor device according to claim 24, further comprising discharge MOS transistors for respectively causing the source lines to be conductive to a circuit's ground potential in response to a read operation, and coupling MOS transistors for respectively performing connection between the source lines in response to the conduction of the discharge MOS transistors to the ground potential. 38. A semiconductor device according to claim 25, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the control gate driver to a first voltage, sets the source line electrode to a circuit's ground potential, and sets the memory gate electrode to a voltage higher than the ground potential. 39. A semiconductor device according to claim 25, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the control gate driver to a first voltage, sets the bit line electrode to a circuit's ground potential, and sets the memory gate electrode to a voltage higher than the ground potential. 40-91. (canceled) 92. A semiconductor device according to claim 2, wherein the bit line electrode and the source line electrode are formed in a well region in which a high-density impurity region is not formed therebetween. 93. A semiconductor device according to claim 92, wherein the high-density impurity region is a diffused region of an impurity. 94. A semiconductor device according to claim 2, wherein the charge storage region is a conductive floating gate electrode covered with an insulating film. 95. A semiconductor device according to claim 2, wherein the charge storage region is a charge trap insulating film covered with an insulating film. 96. A semiconductor device according to claim 2, wherein the charge storage region is a conductive fine particle layer covered with an insulating film. 97. A semiconductor device according to claim 2, further including: switch MOS transistors each capable of connecting the bit line to a global bit line, wherein the thickness of a gate oxide film of the switch MOS transistor is thinner than the thickness of a gate oxide film of the first transistor section. 98. A semiconductor device according to claim 97, further including: a first driver which has the drive MOS transistor and drives the control gate control line; a second driver which drives the memory gate control line; a third driver which drives the switch MOS transistor to an on state; and a fourth driver which drives the source line, wherein the first driver and the third driver use a first voltage as an operating power supply, and the second driver and the fourth driver use a voltage higher than the first voltage as an operating power supply. 99. A semiconductor device according to claim 98, further including: a control circuit which sets an operating power supply of the first driver to a first voltage, sets an operating power supply of the fourth driver to a second voltage higher than the first voltage, and sets an operating power supply of the second driver to a third voltage greater than or equal to the second voltage when a threshold voltage of the first transistor section is rendered high, thereby enabling injection of hot electrons into the charge storage region from the bit line electrode side. 100. A semiconductor device according to claim 99, wherein the control circuit sets the operating power supply of the second driver to a fourth voltage greater than or equal to the third voltage when the threshold voltage of the first transistor section is rendered low, thereby ejecting electrons from the charge storage region to the corresponding memory gate electrode. 101. A semiconductor device according to claim 100, wherein the first transistor section whose threshold voltage is made low, is set to a depletion type, and the first transistor section whose threshold voltage is made high, is set to an enhancement type. 102. A semiconductor device according to claim 99, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the first driver to a first voltage and sets the memory gate electrode and the source line electrode to a circuit's ground potential. 103. A semiconductor device according to claim 99, wherein when information stored in the nonvolatile memory cell is read, the control circuit sets the operating power supply of the first driver to a first voltage and sets the memory gate electrode and the bit line electrode to a circuit's ground potential. 104. A semiconductor device according to claim 98, further including a logic operation unit which performs a logical operation with the first voltage as an operating power supply. 105. A semiconductor device according to claim 101, wherein each of the first driver and the third driver receives an address decode signal so that an operation thereof is selected, and each of the second driver and the fourth driver receives the output of the first driver so that an operation thereof is selected. 106. A semiconductor device according to claim 105, wherein the first driver and the third driver are disposed on one side and the second driver and the fourth driver are disposed on the other side, with an array of the nonvolatile memory cells being interposed therebetween. 107. A semiconductor device according to claim 106, wherein in the array of the nonvolatile memory cells, memory gate control lines are formed integrally with memory gate electrodes, and low resistance metal layers are laminated over polysilicon layers respectively. 108. A semiconductor device according to claim 106, wherein discharge MOS transistors for causing the memory gate control lines to be conducted to a circuit's ground potential in response to a read operation are provided at different positions of the memory gate control lines. 109. A semiconductor device according to claim 97, wherein each of the switch MOS transistors is a p channel type MOS transistor. 110. A semiconductor device according to claim 109, wherein n channel type discharge MOS transistors switch-operated complementarily to the switch MOS transistors are provided at their corresponding bit lines. 111. A semiconductor device according to claim 97, wherein the switch MOS transistors are mutually parallel-connected n channel type MOS transistors and p channel type MOS transistors which constitute CMOS transfer gates. |
<SOH> BACKGROUND ART <EOH>As nonvolatile memory cells, may be mentioned, a split gate type memory cell and a stack gate type memory cell. The split gate type memory cell comprises two transistors of a memory MOS type transistor that constitutes a memory section, and a selection MOS type transistor for selecting its memory section to thereby fetch information therefrom. As a known document, there is known a technology described in 1994—Proceedings of IEEE, VLSI, Technology Symposium, pp 71-72. A structure and operation of a memory cell described therein will be explained in brief. This split gate type memory cell comprises a source, a drain, a floating gate and a control gate. As the injection of electrical charges into the floating gate, may be mentioned a source side injection system using the generation of hot electrons. The charges stored in the floating gate are ejected from a pointed end of the floating gate to the control gate. At this time, there is a need to apply a high voltage of 12 volts to the control gate. The control gate that functions as a charge ejection electrode, serves even as a gate electrode of a reading selection MOS type transistor. A gate oxide film for a selection MOS type transistor section is a deposited oxide film, which functions even as a film for electrically isolating the floating gate and a gate electrode of the selection MOS type transistor. As other known technologies related to the split gate type memory cell, there are known, for example, U.S. Pat. Nos. 4,659,828 and 5,408,115, Japanese Unexamined Patent Publication No. Hei 5(1993)-136422, etc. The stack gate type memory cell comprises a source, a drain, and a floating gate and a control gate stacked on a channel forming region. The generation of hot electrons is used for the injection of electrical charges into the floating gate. The electrical charges stored in the floating gate are ejected toward a substrate. At this time, there is a need to apply a negative high voltage of −10 volts to the control gate. Reading is performed by applying a read voltage like 3.3 volts to the control gate. The stack gate type memory cell has been described in Japanese Unexamined Patent Publication No. Hei 11(1999)-232886, etc. In terms of the speeding up of data processing, the speeding up of a read operation of a nonvolatile memory device becomes important even to the nonvolatile memory device. In the split gate type memory cell, the gate electrode of the selection MOS transistor is configured so as to function even as an erase electrode. Therefore, a gate insulating film had no other choice but to set its thickness to the same thickness as that of a write/erase-voltage control high-voltage MOS transistor in order to ensure a withstand voltage therefor. Thus, Gm (mutual conductance defined as current supply capacity) of the selection MOS transistor becomes small, so the split gate type memory cell is hardly a structure wherein a read current can be obtained sufficiently. If nothing is done, then the split gate type memory cell is not fit for a high-speed operation under a low voltage. Since a thick gate oxide film for realizing a high withstand voltage is adopted for the control gate to which a high voltage is applied upon write/erase operations, it reduces Gm at a read operation, so the stack gate type cell is hardly a structure wherein a read current can be ensured sufficiently. U.S. Pat. Nos. 4,659,828 and 5,408,115 of the known documents respectively describe the invention related to the write/erase operations but do not refer to an improvement in the performance of the read operation. Further, although Japanese Unexamined Patent Publication No. Hei 5(1993)-136422 of the known document discloses a shape most analogous to that of the present invention, it shows the invention related to a method of insulating two gate electrodes adjacent to each other, and does not disclose read performance. A nonvolatile memory device unprovided for the prior art is needed which is adapted to a logical operation device brought to high performance. A structure has been adopted wherein bit lines are hierarchized into main and sub bit lines, only a sub bit line connected with a memory cell to be operated and selected is selected and connected to its corresponding main bit line, and the parasitic capacity of the bit line by the memory cell is apparently reduced, whereby a high-speed read operation is realized. However, it has been found out by the present inventors that there is a fear that where it is necessary to apply a high voltage even to a bit line upon writing as in the stack gate type memory cell, a MOS transistor for selectively connecting a sub bit line to its corresponding main bit line must be brought to high withstanding, whereby Gm of a read path is further reduced and the speeding up by a hierarchized bit line structure based on the main/sub bit lines will not function sufficiently. An object of the present invention is to eliminate a thick-film high-voltage MOS transistor that impairs speeding up, from a memory information read path. Another object of the present invention is to provide a semiconductor device capable of reading memory information from a nonvolatile memory cell at high speed. The above, other objects and novel features of the present invention will become apparent from the description of the present Specification and the accompanying drawings. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a cross-sectional view showing one example of a nonvolatile memory cell used in the present invention; FIG. 2 is an explanatory view typically depicting characteristics with respect to the nonvolatile memory cell shown in FIG. 1 ; FIG. 3 is an explanatory view illustrating by way of example threshold voltage states where erase and write states of the nonvolatile memory cell are set to depletion and enhancement types; FIG. 4 is an explanatory view illustrating by way of example threshold voltage states where the erase and write states of the nonvolatile memory cell are both set to the enhancement type; FIG. 5 is an explanatory view showing, as comparative examples, several connection forms related to the nonvolatile memory cell shown in FIG. 2 , prior to its optimization; FIG. 6 is an explanatory view illustrating by way of example a device section, operating voltages and a hierarchical bit line structure related to a stack gate type flash memory cell having a floating gate; FIG. 7 is an explanatory view illustrating by way of example a device section, operating voltages and a hierarchical bit line structure related to a split gate type flash memory cell; FIG. 8 is an explanatory view illustrating by way of example a device section, operating voltages and a hierarchical bit line structure related to a MONOS-stack gate type memory cell of one-transistor/one-memory cell; FIG. 9 is an explanatory view illustrating by way of example a device section, operating voltages and a hierarchical bit line structure related to a NONOS type memory cell of two-transistor/one-memory cell; FIG. 10 is a cross-sectional view showing a device section where attention is given to a write operation of the nonvolatile memory cell shown in FIG. 2 ; FIG. 11 is a cross-sectional view showing the manner in which a voltage applied state analogous to a write voltage state of FIG. 10 is given to a structure of a nonvolatile memory cell made up of a series circuit of memory holding MONOS and selection MOS transistors; FIG. 12 is a plan view illustrating by way of example a planar configuration of the nonvolatile memory cell shown in FIG. 1 ; FIG. 13 is a plan view illustrating by way of example a planar configuration of each of the nonvolatile memory cells shown in FIGS. 6 and 8 ; FIG. 14 is a plan view illustrating by way of example a planar configuration of the nonvolatile memory cell shown in FIG. 7 ; FIG. 15 is a plan view illustrating by way of example a planar configuration of the nonvolatile memory cell shown in FIG. 9 ; FIG. 16 is a circuit diagram showing one example of a memory cell array which adopts the nonvolatile memory cell shown in FIG. 1 ; FIG. 17 is a circuit diagram depicting one example of a memory cell array in which ZMOSs are constituted by CMOS transfer gates; FIG. 18 is a circuit diagram showing one example of a memory cell array which adopts sub bit line discharge transistors; FIG. 19 is a circuit diagram illustrating by way of example the layout of drivers with respect to the memory cell arrays each of which adopts the nonvolatile memory cell shown in FIG. 1 ; FIG. 20 is a circuit diagram showing one example of a memory cell array; FIG. 21 is a circuit diagram illustrating another example of the memory cell array; FIG. 22 is a circuit diagram showing a further example of the memory cell array; FIG. 23 is a timing chart illustrating by way of example operation timings at the time that the direction of current at a read operation of a nonvolatile memory cell extends from a source line to a bit line; FIG. 24 is a block diagram of a microcomputer in which a nonvolatile memory having adopted the nonvolatile memory cells is provided on-chip; FIG. 25 is a block diagram showing a detailed one example of a flash memory module; FIG. 26 is a circuit diagram illustrating by way of example a form of a forward read operation with respect to a nonvolatile memory cell; FIG. 27 is a timing chart illustrating by way of example main signal waveforms at the forward read operation of FIG. 26 ; FIG. 28 is a circuit diagram illustrating by way of example a form of a backward read operation with respect to a nonvolatile memory cell; FIG. 29 is a timing chart illustrating by way of example main signal waveforms where a read operation is started as the backward read operation of FIG. 28 after a main bit line on the input side of a sense amplifier has been precharged; FIG. 30 is a timing chart illustrating by way of example main signal waveforms where a read operation is started as the backward read operation of FIG. 28 without precharging the main bit line on the input side of the sense amplifier; FIG. 31 is an explanatory view illustrating by way of example other write voltage conditions and the like with respect to the nonvolatile memory cell; FIG. 32 is a circuit diagram showing another example illustrative of the layout of a memory cell array having adopted the nonvolatile memory cells, and drivers; FIG. 33 is a circuit diagram illustrating by way of example a circuit format in which memory gate control lines are individually driven by their corresponding drivers according to the selection of control gate control lines as shown in FIG. 19 ; FIG. 34 is a circuit diagram principally showing a drive format of memory gate control lines corresponding to FIG. 32 ; FIG. 35 is an explanatory view showing in detail a state in which voltages are applied to a memory cell in an allowable disturb state; FIG. 36 is a circuit diagram illustrating by way of example a configuration which needs routing of control gate control lines as a drive form of memory gate control lines; FIG. 37 is a circuit diagram illustrating by way of example a specific configuration of a logic circuit; FIG. 38 is a plan view illustrating by way of example a layout configuration of a NOR gate; FIG. 39 is an explanatory view illustrating by way of example the difference between effects obtained according to whether source-line coupled MOS transistors are adopted; FIG. 40 is a cross-sectional view of a memory cell according to a first embodiment of the present invention; FIG. 41 is a diagram for describing the operation of the memory cell according to the first embodiment of the present invention and voltages applied thereto; FIG. 42 is a cross-sectional view showing a state in which the memory cell according to the first embodiment of the present invention is mixed with other MOS transistors; FIG. 43 is a cross-sectional view of a memory cell according to a second embodiment of the present invention; FIG. 44 is a diagram for describing the operation of the memory cell according to the second embodiment of the present invention and voltages applied thereto; FIG. 45 is a cross-sectional view of a modification of the memory cell according to the second embodiment of the present invention; FIG. 46 is a cross-sectional view showing the difference in channel density in the memory cell according to the second embodiment of the present invention; FIG. 47 is a cross-sectional view of a memory cell according to a third embodiment of the present invention; FIG. 48 is a cross-sectional view of a memory cell according to a fourth embodiment of the present invention; FIG. 49 is a cross-sectional view of a memory cell according to a fifth embodiment of the present invention; FIG. 50 is a first cross-sectional view related to a process for manufacturing a semiconductor integrated circuit in which a memory cell according to the present invention is mixed with other MOS type transistors; FIG. 51 is a second cross-sectional view related to the process for manufacturing the semiconductor integrated circuit in which the memory cell according to the present invention is mixed with other MOS type transistors; FIG. 52 is a third cross-sectional view related to the process for manufacturing the semiconductor integrated circuit in which the memory cell according to the present invention is mixed with other MOS type transistors; FIG. 53 is a fourth cross-sectional view related to the process for manufacturing the semiconductor integrated circuit in which the memory cell according to the present invention is mixed with other MOS type transistors; FIG. 54 is a fifth cross-sectional view related to the process for manufacturing the semiconductor integrated circuit in which the memory cell according to the present invention is mixed with other MOS type transistors; FIG. 55 is a sixth cross-sectional view related to the process for manufacturing the semiconductor integrated circuit in which the memory cell according to the present invention is mixed with other MOS type transistors; FIG. 56 is a seventh cross-sectional view related to the process for manufacturing the semiconductor integrated circuit in which the memory cell according to the present invention is mixed with other MOS type transistors; FIG. 57 is an eighth cross-sectional view related to the process for manufacturing the semiconductor integrated circuit in which the memory cell according to the present invention is mixed with other MOS type transistors; FIG. 58 is a circuit diagram illustrating by way of example a configuration of a memory array to which the memory cells each according to the present invention are applied; FIG. 59 is a cross-sectional view of a memory cell according to a sixth embodiment of the present invention; FIG. 60 is a first cross-sectional view related to a process for manufacturing the memory cell according to the sixth embodiment of the present invention; FIG. 61 is a second cross-sectional view related to the process for manufacturing the memory cell according to the sixth embodiment of the present invention; FIG. 62 is a third cross-sectional view related to the process for manufacturing the memory cell according to the sixth embodiment of the present invention; and FIG. 63 is a cross-sectional view of a memory cell according to a seventh embodiment of the present invention. detailed-description description="Detailed Description" end="lead"? |
System and method for locally sharing subscription of multimedia content |
This invention relates to a method, devices and system for distributing rights to a digital content and for accessing said digital content. Further, the invention relates to a voucher structure defining rights to said digital content. Still further, the invention relates to a digital content structure adapted for arranging the distribution of rights to the digital content. |
1. System for providing a first client family comprising a first parent client and one or more first child clients connected in a second communication network access to a first digital content and comprising: (a) a right of use voucher associated with said first digital content and comprising a first content key and one or more first child vouchers; and (b) a content provider adapted to connect to said first parent client through a first communication network and adapted to communicate said right of use voucher to said first parent client; and wherein said right of use voucher enables said first parent client to communicate said one or more first child vouchers to said one or more first child clients through said second communication network, which one or more first child vouchers enable said one or more first child clients to access said first digital content associated with said right of use voucher. 2. System according to claim 1, wherein said right of use voucher is adapted to enable said first parent client to access said first digital content from said content provider through said first communication network by applying said first content key. 3. System according to claim 1, wherein said first parent client comprising an encryption key adapted to encrypt said first digital content for said one or more first child clients comprising a decryption key associated with said encryption key. 4. System according to claim 1, wherein said first client family comprises a laptop or desktop computer, a personal digital assistant, a mobile or cellular phone, a set-top box, television set, a videophone, or any combination thereof. 5. System according to claim 1, wherein said second communication network comprises a computer network, a wired or wireless telecommunication network, a power-line network, a television network, a proximity terrestrial network such as short range radio or Bluetooth, or any combination thereof. 6. System according to claim 1, wherein said first communication network comprises a wired or wireless telecommunication network, a terrestrial, satellite, or cable television network, a power-line network, a computer network, or any combination thereof. 7. System according to claim 1, wherein said first communication network comprises a physical, tangible carrier comprising a floppy disk, a compact disc, a digital versatile disc, a memory card, a memory stick, or any combination thereof. 8. System according to any of claim 5, wherein said computer network comprises a wired or wireless local area network, metropolitan area network, wide area network, inter-network, or any combination thereof. 9. System according to claim 1, wherein said one or more first child clients comprise a connection to said first communication network and wherein said content provider enables said one or more first child clients having a child voucher through said first communication network to access said first digital content from said content provider. 10. System according to claim 1, wherein said one or more first child vouchers enable said one or more first child clients to access digital content from said first parent client through said second communication network. 11. System according to claim 1, wherein said first digital content comprises graphics, series of graphics, text, series of texts, picture, series of pictures, video, sequences of videos, audio track or series of audio tracks or any combination thereof. 12. System according to claim 1, wherein said right of use voucher further comprises: (a) a first identification tag for identifying a specific first parent client of said first client family owning said right of use voucher; (b) a second identification tag for identifying content provider enabling access for said specific first parent client and one or more first child clients to said first digital content; (c) an authentication key pair operable for authenticating said one or more first child vouchers and comprising a public authentication key and a private authentication key. 13. System according to claim 1, wherein each of said one or more first child vouchers comprises a copy of said first content key operable to enable each of said one or more first child clients access to said first digital content. 14. System according to claim 1, wherein said content provider is adapted to encrypt said right of use voucher by applying a public encryption key of said first parent client. 15. System according to claim 1, wherein said content provider enables said first parent client to authenticate said one or more first child clients having said one or more first client vouchers by communicating a signed child voucher refresher comprising a validity period of associated first child voucher and an identification tag of said associated first child voucher. 16. System according to claim 1, wherein said content provider is adapted to enable said first parent client to transfer said first digital content to reside in a local memory, to view said first digital content at said content provider, to receive a stream of said first digital content from said content provider, or any combination thereof. 17. System according to claim 1, wherein said content provider is adapted to enable said one or more first child clients to view said first digital content at said content provider or said first parent client, to receive a stream of said first digital content from said content provider or said first parent client, or any combination thereof. 18. System according to claim 1, wherein said content provider is adapted to connect to a second client family comprising a second parent client and one or more second child clients connected through a third communication network and wherein said content provider is adapted to enable said one or more second child clients access to a second digital content on the basis of one or more second child vouchers associated with said second digital content and with each of said one or more second child clients. 19. System according to claim 18, wherein said content provider is adapted to enable a first child client of said first client family and a second child client of said second client family to exchange a first child voucher associated with said first digital content and with said first child client and a second child voucher associated with said second digital content and with said second child client. 20. A right of use voucher for enabling a client family access to digital content associated with said right of use voucher and comprising: (a) a first identification tag for identifying a parent client of said client family owning said right of use voucher; (b) a second identification tag for identifying content provider enabling access for said parent client and one or more child clients of said client family to said digital content; (c) one or more child vouchers comprising a content key operable to enable said one or more child clients access to said digital content; and (d) an authentication key pair operable for authenticating said one or more child vouchers and comprising a public authentication key and a private authentication key. 21. A right of use voucher according to claim 20, wherein said right of use voucher is adapted for storage on a carrier such as a floppy disk, a compact disc, a digital versatile disc, a memory card, a memory stick, or any combination thereof, and/or adapted to be forwarded on a communication network such as a wired or wireless telecommunication network, a terrestrial, satellite, or cable television network, a power-line network, a computer network, or any combination thereof. 22. Method for providing access to digital content comprising: (a) connecting to a first parent client by means of a content provider utilising a communication network; (b) communicating a first right of use voucher comprising one or more first child vouchers by means of said content provider to said first parent client; (c) enabling said first parent client to forward said one or more first child vouchers to one or more first child clients through a second communication network; and (d) enabling said one or more first child clients to access said first digital content by means of said one or more first child vouchers provided that the validity of said one or more first child vouchers is authenticated. 23. Method according to claim 22 further comprising (e) enabling said first parent client to access a first digital content provided by said content provider by means of said first right of use voucher. 24. Method according to claim 22 further comprising (f) encrypting said first digital content in accordance with an encryption key by means of said first parent client for said one or more first child clients comprising a decryption key associated with said encryption key. 25. Method according to claim 22 further comprising (g) receiving by means of said content provider a report from said first parent client, which report comprises information on number child vouchers generated by means of a child voucher generating means associated with said right of use voucher. 26. Method according to claim 22 further comprising: (h) enabling said first parent clients to encrypt said one or more first child vouchers with a public encryption key associated with said one or more first child clients before communicating said one or more first child vouchers to said one or more first child clients; (i) enabling said one or more first child clients to decrypt, preferably in a secure mode, said one or more first child vouchers with a private encryption key associated with said one or more first child clients to reveal a content key to enable access to said first digital content. 27. Method according to claim 26, wherein (h) and (i) are performed in a secure mode. 28. Method according to claim 22, further comprising enabling said first parent client to authenticate said one or more first child clients by communicating a signed child voucher refresher including a new validity period for said one or more first child vouchers and an identification tag of said one or more first child vouchers. 29. Method according to claim 22 further comprising: (j) connecting to a second parent client by means of said content provider utilising said communication network; (k) communicating a second right of use voucher including one or more second child vouchers by means of said content provider to said second parent client; (l) enabling said second parent client to access a second digital content provided by said content provider by means of said second right of use voucher; (m) enabling said second parent client to forward said one or more second child vouchers to one or more second child clients through a third communication network; and (n) enabling said one or more second child clients to access said second digital content by means of said one or more second child vouchers provided that the validity of said one or more second child vouchers is authenticated by said second parent client; and (o) enabling said one or more first child clients and said one or more second child clients to exchange said one or more first child vouchers and said one or more second child vouchers. 30. Method according to claim 29, wherein said enabling exchange of said one or more first and second child vouchers between said one or more first and second child clients further comprises: (i) verifying compatibility between one or more first and second child vouchers; (ii) deactivating to-be-exchanged child vouchers by setting stale flags in associated right of use vouchers in said first and second parent client; (iii) enabling a first child client of said one or more first child clients having a second child voucher of said one or more second child vouchers access to said second digital content by means of said second child voucher provided that said first parent client and said second parent client are able to authenticate the validity of said second child voucher; and (iv) enabling a second child client of said one or more second child clients having a first child voucher of said one or more first child vouchers access to said first digital content by means of said first child voucher provided that said first parent client and said second parent client are able to authenticate the validity of said first child voucher. 31. Method according to claim 22, further comprising: (p) enabling access by a basic voucher to a low-resolution stream comprising one or more basic data sets; (q) enabling access by a first enhanced voucher to a first enhancement stream comprising one or more first data sets, which first data sets are based on said basic data sets. 32. Method according to claim 31, further comprising (r) enabling access by a second enhanced voucher to a second enhancement stream comprising one or more second data sets, which second data sets are based on said first data sets. 33. A content provider server for providing a right of use voucher enabling a client family access to digital content associated with said right of use voucher comprising: (a) means for generating a first identification tag for identifying a parent client of said client family owning said right of use voucher; (b) means for generating a second identification tag for identifying content provider enabling access for said parent client and one or more child clients of said client family to said digital content; (c) means for generating one or more child vouchers comprising a content key operable to enable said one or more child clients access to said digital content; and (d) means for generating an authentication key pair operable for authenticating said one or more child vouchers and comprising a public authentication key and a private authentication key. 34. A communication terminal for receiving a right of use voucher enabling access for said communication terminal and one or more designated child terminals to a digital content associated with said right of use voucher according to claim 20, and comprising: (a) means for identifying said first and second identification tag of said right of use voucher; (b) means for distributing one or more child vouchers comprising a content key operable to enable said one or more designated child terminals access to said digital content; and (c) means for processing an authentication key pair operable for authenticating said one or more child vouchers and comprising a public authentication key and a private authentication key. 35. A communication terminal for receiving a child voucher enabling access a digital content associated with a right of use voucher according to claim 20, and comprising: (a) means for revealing a content key from said child voucher operable to enable said client access to a digital content; (b) means for accessing said digital content through a communication network. 36. A communication terminal according to claim 35, wherein said communication terminal is adapted to access said digital content from a content provider, from said parent client, or any combination thereof. 37. A computer program comprising code adapted to perform the following steps when said program is run on a processor: (a) connecting to a first parent client by means of a content provider utilising a communication network; (b) communicating a first right of use voucher comprising one or more first child vouchers by means of said content provider to said first parent client; (c) enabling said first parent client to forward said one or more first child vouchers to one or more first child clients through a second communication network; and (d) enabling said one or more first child clients to access said first digital content by means of said one or more first child vouchers provided that the validity of said one or more first child vouchers is authenticated. 38. A computer program according to claim 37, wherein said processor comprising a content provider, a parent client, a child client, or any combination thereof. |
<SOH> BACKGROUND OF INVENTION <EOH>U.S. patent application Ser. No. US 2002/0013772 and International patent applications no. WO00/58811 and no. WO00/59150 (all emanating from U.S. provisional application 60/126,614) disclose ways of distributing and binding a digital licence to a user device using Digital Rights Management (DRM). A DRM system operates on a computing device when a user requests a digital piece of content to be rendered by the computing device. The system has a license store, a licence evaluator, and a state store, and keeps track of possible content rendering. The digital content is encrypted according to a content key (KD) on a user device having a public key (PU) and a corresponding private key (PR). To render digital content a digital licence corresponding to the content is obtained, where the digital licence includes the content key (KD) therein in an encrypted form. The encrypted content key (KD) from the digital license is decrypted to produce the content key (KD), and the public key (PU) of the user device is obtained there from. The content key (KD) is then encrypted according to the public key (PU) of the user device (PU(KD)), and a sub-license is composed corresponding to and based on the obtained license, where the sub-license includes (PU(KD)). The composed sub-license is then transferred to the user device, wherein the user device can decrypt (PU(KD)) with the private key thereof (PR) to produce the content key (KD), and can render the encrypted content on the user device with the produced content key (KD). The disclosed system requires a separate license for each computing device ordering a particular digital content, thus effectively limiting the fast distribution of content throughout a plurality of computing devices. Hence when a plurality of users request an identical content every user must have a separate licence. International patent application no. WO01/98903 discloses methods and systems for distributing content via a network using distributed conditional access agents to perform DRM. These include a watermarking operation to watermark content distributed to a content consumer. Further, an encryption operation encrypts content using a key associated with the content consumer. The content provider generates a set of session keys, encrypts the content using the set of session keys, and communicates the session keys to a content distributor. The content distributor encrypts the set of session keys using a user key so as to generate a set of encrypted keys, which are subsequently communicated to the content consumer. The content distributor further communicates the user key to the content consumer, which upon receipt decrypts and extracts the set of session keys and uses the set of session keys to decrypt the encrypted content. The set of session keys can be a time-varying sequence of session keys. The process can include authentication and verification of the user credentials against content access criteria. As described above with reference to US 2002/0013772, WO00/58811 and WO00/59150 these systems and methods are directed to one user/one device concept. The patent applications US 2002/0013772, WO00/58811, WO00/59150, and WO01/98903, which patent applications are incorporated by reference in present specification, introduce problems since users want to experience the same right with digital media as with conventional media. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object of the present invention is to provide a flexible distribution of digital content to content users, still protecting the content from unauthorised use or copying. A particular advantage of the present invention is provision of freedom for the content user to use the content in different devices apart from the downloading device. It is further an advantage that a group of users, e.g. a family, can use the content as would be the case with conventional media. Further an advantage is that the content provider can deliver digital content in an attractive and useful way without risking unauthorised use or copying. A particular feature of the present invention relates to the provision of main vouchers defining the content user's rights to the digital content, wherein the main voucher further comprise child vouchers defining use in other devices than the downloading device, or by other users in the proximity of the user having the main voucher. The above object, advantage and feature together with numerous other objects, advantages and features, which will become evident from below detailed description, is obtained according to a first aspect of the present invention by a system for providing a first client family comprising a first parent client and one or more first child clients connected in a second communication network access to a first digital content and comprising: (a) a right of use voucher associated with said first digital content and comprising a first content key and one or more first child vouchers; and (b) a content provider adapted to connect to said first parent client through a first communication network and adapted to communicate said right of use voucher to said first parent client; and wherein said right of use voucher enables said first parent client to communicate said one or more first child vouchers to said one or more first child clients through said second communication network, which one or more first child vouchers enable said one or more first child clients to access said first digital content associated with said right of use voucher. The term “first” and “second” should in this context entirely be construed as term for differentiating between two elements and not be construed as a timing consideration. The right of use voucher according to the first aspect of the present invention may be adapted to enable the first parent client to access the first digital content from the content provider through the first communication network by applying the first content key. Further first parent client may comprise an encryption key adapted to encrypt the first digital content for the one or more first child clients comprising a decryption key associated with the encryption key. The first client family according to the first aspect of the present invention may comprise a laptop or desktop computer, a personal digital assistant, a mobile or cellular phone, a set-top box, television set, a videophone, an accessory thereof, or any combination thereof. That is, a wide variety of electrical gadgets may in fact be connected to the content server. In fact, an oven, fridge or washing machine may connect to the content server and receive particular data from the content provider, for example, enabling the electrical gadget to perform in a different or better way. Alternatively, the device connecting to the content server may be an electronic device dedicated for the purpose of sharing digital content around itself, e.g., a digital subscription module fitted in a private home, an office or a public site. Yet alternatively, the device connecting to the content server may be a virtual arrangement, whereby the device is an non-physical realization in the virtual reality world, and stores links to the content and the vouchers instead of storing them physically. The accessory may comprise MP3 players, smart headphones, video goggles, newspaper or book reading equipment. The first communication network according to the first aspect of the present invention may comprise a wired or wireless telecommunication network, a terrestrial, satellite, or cable television network, a power-line network, a computer network, or any combination thereof. Alternatively, the first communication network may partly or wholly be realized by using physical, tangible carriers like floppy disks, CDs, DVDs, memory cards and sticks or any other transportable media. Yet alternatively, the first network may be realized by a download of content and right of use vouchers over a local connection such as short-range radio or infrared connection. Further, the second communication network may comprise a computer network, a wired or wireless telecommunication network, a power-line network, a television network, a proximity terrestrial network such as short range radio or Bluetooth, or any combination thereof. The second communication network is particularly advantageous when implemented as a short range radio or Bluetooth solution since the parent client in this way may act as a micro transmitter of digital content for child clients in the vicinity. The computer network according to the first aspect of the present invention may comprise a wired or wireless local area network, metropolitan area network, wide area network, inter-network, or any combination thereof. The inter-network such as the Internet provides an ideal solution for the first communication network since digital content may be accessed from any geographical area. Also existing distribution networks for renting or selling digital media such as music CDs and video DVDS may be used for this purpose The one or more first child clients according to the first aspect of the present invention may comprise a connection to the first communication network and the content provider may enable the one or more first child clients having a child voucher to access the first digital content from the content provider through the first communication network. The system thus provides a plurality of access points to the content provider so that the digital content may be easily accessed from a plurality of clients simultaneously during for example a streaming of the digital content. Further, the one or more first child vouchers may enable the one or more first child clients to access digital content from the first parent client through the second communication network. This is particularly beneficiary in situations where the child clients connection to the first communication network is disconnected then the parent client without burden to the first communication network provides a stream of the digital content to the child clients. The first digital content according to the first aspect of the present invention may comprise graphics, series of graphics, text, series of texts, picture, series of pictures, video, sequences of videos, audio track or series of audio tracks or any combination thereof. In fact, the digital content may be control data for electrical gadgets, or music, film, or literary compositions. The right of use voucher according to the first aspect of the present invention may further comprise: (a) a first identification tag for identifying a specific first parent client of said first client family owning said right of use voucher; (b) a second identification tag for identifying content provider enabling access for said specific first parent client and one or more first child clients to said first digital content; (c) an authentication key pair operable for authenticating said one or more child vouchers and comprising a public authentication key and a private authentication key. The first identification tag may be utilised during the periodical authentication of the parent client before the content provider. The parent client may authenticate before the content provider by signing the first and/or second identification tag using the parent client's private key. The content provider according to the first aspect of the present invention may enable the first parent client to authenticate the one or more first child clients having the one or more first client vouchers by communicating a signed child voucher refresher comprising a validity period of associated first child voucher and an identification tag of the associated first child voucher. The authentication key pair may advantageously be utilised by the parent client for authenticating the child clients. The parent client may encrypt and sign the child voucher refresher applying the public authentication key and require the child client to run in a secure mode before the content key may be used for accessing the first digital content. It needs to be noted that the parent client needs not necessarily obtain direct access to the digital content, but may instead act as a holder of the parent voucher as well as a child client using one of the child vouchers contained in the parent voucher. In this way, all devices using the digital content may be treated equally with respect to the access to the digital content. Each of the one or more first child vouchers according to the first aspect of the present invention may comprise a copy of the first content key operable to enable each of the one or more first child clients access to the first digital content. By distributing the delegation of content keys the content provider is freed from recordation of a plurality of clients and instead the content provider only needs to record and authenticate the client families since the parent may authenticate the child clients. The content provider according to the first aspect of the present invention may be adapted to encrypt the right of use voucher by applying a public encryption key of the first parent client. By encrypting the right of use voucher the voucher may be communicated safely across the first communication network. Further, the content provider may be adapted to enable the first parent client to download the first digital content to a local memory, to view the first digital content at the content provider, to receive a stream of the first digital content from the content provider, or any combination thereof. The term “download” should in this context be construed as a transfer of the entire digital content from the content provider to the client, also by using physical memory media, the term “view” should in this context be construed as the content provider executing digital content, i.e. utilising editorial platform, and providing a terminal view of the digital content for the clients from the editorial platform, and finally the term “stream” should in this context be construed as the content provider providing a continuous stream of data from the digital content. The content provider according to the first aspect may further be adapted to enable the one or more first child clients to view the first digital content at the content provider or the first parent client, to receive a stream of the first digital content from the content provider or the first parent client, or any combination thereof. The digital content may thus be provided by the content provider or alternatively or additionally by the parent client. The latter becomes significant whenever the access points to the first communication network are limited, for example, due to costs. The content provider according to the first aspect of the present invention may further be adapted to connect to a second client family comprising a second parent client and one or more second child clients connected through a third communication network and wherein the content provider is adapted to enable the one or more second child clients access to a second digital content on the basis of one or more second child vouchers associated with the second digital content and with each of the one or more second child clients. Obviously, the content provider may connect to a plurality of client families and provide a plurality of digital contents to any of the client families connected to the first communication network. The second parent client, the one or more second child clients and the one or more second child vouchers may incorporate any features of the first parent client, the one or more first child clients and the one or more first child vouchers, respectively. Further, the third communication network may incorporate any features of the second communication network. The content provider according to the first aspect may be adapted to enable a first child client of the first client family and a second child client of the second client family to exchange a first child voucher associated with the first digital content and with the first child client and a second child voucher associated with the second digital content and with the second child client. The enabling of switching child vouchers between two child clients from different client families is particularly flexible compared to prior art since while the digital content cannot be copied the digital content may flow between a plurality of authenticated and validated clients. The exchange of the one or more first and second child vouchers between the one or more first and second child clients may be accomplished by the content provider enabling the first and second parent or one or more child clients to verify the compatibility between the one or more first and second child vouchers; the first and second parent to deactivate exchanged child vouchers by setting stale flags in associated right of use vouchers; a first child client of the one or more first child clients having a second child voucher of the one or more second child vouchers access to the second digital content by means of the second child voucher provided that the first parent client and the second parent client are able to authenticate the validity of the second child voucher; and enabling a second child client of the one or more second child clients having a first child voucher of the one or more first child vouchers access to the first digital content by means of the first child voucher provided that the first parent client and the second parent client are able to authenticate the validity of the first child voucher. The above objects, advantages and features together with numerous other objects, advantages and features, which will become evident from below detailed description, are obtained according to a second aspect of the present invention by a right of use voucher for enabling a client family access to digital content associated with said right of use voucher and comprising: (a) a first identification tag for identifying a parent client of said client family owning said right of use voucher; (b) a second identification tag for identifying content provider enabling access for said parent client and one or more child clients of said client family to said digital content; (c) one or more child vouchers comprising a content key operable to enable said one or more child clients access to said digital content; and (d) an authentication key pair operable for authenticating said one or more child vouchers and comprising a public authentication key and a private authentication key. The right of use voucher according to the second aspect of the present invention may incorporate any features of the system according to the first aspect of the present invention. The above objects, advantages and features together with numerous other objects, advantages and features, which will become evident from below detailed description, are obtained according to a third aspect of the present invention by a method for providing access to digital content comprising: (a) connecting to a first parent client by means of a content provider utilising a communication network; (b) communicating a first right of use voucher comprising one or more first child vouchers by means of said content provider to said first parent client; (c) enabling said first parent client to forward said one or more first child vouchers to one or more first child clients through a second communication network; and (d) enabling said one or more first child clients to access said first digital content by means of said one or more first child vouchers provided that the validity of said one or more first child vouchers is authenticated. The validity of the one or more first child vouchers according to the third aspect of the present invention may be authenticated by the first parent client. The method according to the third aspect of the present invention may further comprise (e) enabling the first parent client to access a first digital content provided by the content provider by means of the first right of use voucher. Further, the method may further comprise (f) encrypting the first digital content in accordance with an encryption key by means of the first parent client for the one or more first child clients comprising a decryption key associated with the encryption key. The one or more first child clients according to the third aspect of the present invention may be enabled to access the first digital content at the content provider. Alternatively, the one or more first child clients may be enabled to access the first digital content at the first parent client. By this approach a highly increased flexibility is given, although unauthorised copying and use of the digital content is prevented. Enabling the one or more first child clients to access the first digital content according to the third aspect of the present invention may comprise downloading the first digital content, viewing the first digital content, streaming the first digital content, or any combination thereof. The preferred access method depends highly on the type of digital content, and on the kind of client apparatus. Thus the present invention provides a beneficiary possibility to enhance the known technology within the state of the art. The method according to the third aspect of the present invention may further comprise (g) receiving by means of the content provider a report from the first parent client, which report comprises information on number child vouchers generated by means of a child voucher generating means associated with the right of use voucher. This makes it possible for the content provider to track redistribution of the digital content, and the received information may be used for a multitude of things, such as statistics, marketing, pricing or for other service development purposes. The method according to the third aspect of the present invention may further comprise: (h) enabling the first parent clients to encrypt the one or more first child vouchers with a public encryption key associated with the one or more first child clients before communicating the one or more first child vouchers to the one or more first child clients; (i) enabling the one or more first child clients to decrypt the one or more first child vouchers with a private encryption key associated with the one or more first child clients to reveal a content key to enable access to the first digital content. In the method according to the third aspect of the present invention (h) and (i) may be performed in a secure mode. The use of encryption and decryption in a secure mode to distribute a digital content encryption key for enabling access to the digital content, effectively prevents unauthorised use of the digital content. On the other hand, the method according to the third aspect of the present invention may enable authorised use in a user-friendly manner. The method according to the third aspect of the present invention may further comprise enabling the first parent client to authenticate the one or more first child clients by communicating a signed child voucher refresher including a new validity period for the one or more first child vouchers and an identification tag of the one or more first child vouchers. The authentication will thus provided a feasible solution for the child client to achieve a right to access limited in time, and to get an update on said right to access. On the other hand, the parent client and the content provider may control the child clients' right to access in a functional manner. The method according to the third aspect of the present invention may further comprise: (j) connecting to a second parent client by means of the content provider utilising the communication network; (k) communicating a second right of use voucher including one or more second child vouchers by means of the content provider to the second parent client; (l) enabling the second parent client to access a second digital content provided by the content provider by means of the second right of use voucher; (m) enabling the second parent client to forward the one or more second child vouchers to one or more second child clients through a third communication network; and (n) enabling the one or more second child clients to access the second digital content by means of the one or more second child vouchers provided that the validity of the one or more second child vouchers is authenticated by the second parent client; and (o) enabling the one or more first child clients and the one or more second child clients to exchange the one or more first child vouchers and the one or more second child vouchers. This provides a solution for more flexible use of digital content across a plurality of devices, while the use cannot be freely copied. The exchange of rights to access digital content between devices will facilitate a user-friendly environment in any situation for consuming the digital content. Enabling exchange of the one or more first and second child vouchers between the one or more first and second child clients according to the third aspect of the present invention may further comprise: (i) verifying compatibility between one or more first and second child vouchers; (ii) deactivating to-be-exchanged child vouchers by setting stale flags in associated right of use vouchers in the first and second parent client; (iii) enabling a first child client of the one or more first child clients having a second child voucher of the one or more second child vouchers access to the second digital content by means of the second child voucher provided that the first parent client and the second parent client are able to authenticate the validity of the second child voucher; and (iv) enabling a second child client of the one or more second child clients having a first child voucher of the one or more first child vouchers access to the first digital content by means of the first child voucher provided that the first parent client and the second parent client are able to authenticate the validity of the first child voucher. The use of a protocol to exchange child vouchers may enable devices of different types to safely exchange and ease handling of vouchers. The method according to the third aspect of the present invention may further comprise: (p) enabling access by a basic voucher to a low-resolution stream comprising one or more basic data sets; (q) enabling access by a first enhanced voucher to a first enhancement stream comprising one or more first data sets, which first data sets are based on the basic data sets. The method according to the third aspect of the present invention may further comprise (r) enabling access by a second enhanced voucher to a second enhancement stream comprising one or more second data sets, which second data sets are based on the first data sets. Providing digital content in this multi-resolution manner further improves the feasibility to provide pre-views, low-resolution content adapted to certain types of clients, extracts from the digital contents or the like by a first voucher, and to provide higher resolution content to other vouchers. The method according to the third aspect of the present invention may incorporate any features of the right of use voucher according to the second aspect of the present invention and the system according to the first aspect of the present invention. The above objects, advantages and features together with numerous other objects, advantages and features, which will become evident from below detailed description, are obtained according to a fourth aspect of the present invention by a content provider server for providing a right of use voucher enabling a client family access to digital content associated with said right of use voucher comprising: (a) means for generating a first identification tag for identifying a parent client of said client family owning said right of use voucher; (b) means for generating a second identification tag for identifying content provider enabling access for said parent client and one more child clients of said client family to said digital content; (c) means for generating one or more child vouchers comprising a content key operable to enable said one or more child clients access to said digital content; and (d) means for generating an authentication key pair operable for authenticating said one or more child vouchers and comprising a public authentication key and a private authentication key. The content provider server according to the fourth aspect of the present invention may incorporate any features of the right of use voucher according to the second aspect of the present invention, the system according to the first aspect of the present invention, and the method according to the third aspect of the present invention. The above objects, advantages and features together with numerous other objects, advantages and features, which will become evident from below detailed description, are obtained according to a fifth aspect of the present invention by a communication terminal for receiving a right of use voucher enabling access for said communication terminal and one or more designated child terminals to a digital content associated with said right of use voucher according to claim 20 , and comprising: (a) means for identifying said first and second identification tag of said right of use voucher; (b) means for distributing one or more child vouchers comprising a content key operable to enable said one or more designated child terminals access to said digital content; and (c) means for processing an authentication key pair operable for authenticating said one or more child vouchers and comprising a public authentication key and a private authentication key. The above objects, advantages and features together with numerous other objects, advantages and features, which will become evident from below detailed description, are obtained according to a sixth aspect of the present invention by a communication terminal for receiving a child voucher enabling access a digital content associated with a right of use voucher according to claim 20 , and comprising: (a) means for revealing a content key from said child voucher operable to enable said client access to a digital content; (b) means for accessing said digital content through a communication network. A communication terminal according to the fifth and sixth aspect of the present invention should in this context be construed as a mobile or cellular phone, a wired phone, a laptop or desktop computer, a personal digital assistant, a set-top box, television set, a videophone, or any combination thereof. The communication terminal according to sixth aspect of the present invention may be adapted to access said digital content from a content provider, from said parent client, or any combination thereof. A communication terminal according to the fifth and sixth aspect of the present invention may incorporate any features from one another and/or from the right of use voucher according to the second aspect of the present invention, the system according to the first aspect of the present invention, the method according to the third aspect of the present invention, and the content provider server according to the fourth aspect of the present invention. The above objects, advantages and features together with numerous other objects, advantages and features, which will become evident from below detailed description, are obtained according to a seventh aspect of the present invention by a computer program comprising code adapted to perform the following steps when said program is run on a processor: (a) connecting to a first parent client by means of a content provider utilising a communication network; (b) communicating a first right of use voucher comprising one or more first child vouchers by means of said content provider to said first parent client; (c) enabling said first parent client to forward said one or more first child vouchers to one or more first child clients through a second communication network; and (d) enabling said one or more first child clients to access said first digital content by means of said one or more first child vouchers provided that the validity of said one or more first child vouchers is authenticated. The processor according to the seventh aspect of the present invention may comprise a content provider, a parent client, a child client, or any combination thereof. A computer program according to the seventh aspect of the present invention may incorporate any features of the right of use voucher according to the second aspect of the present invention, the system according to the first aspect of the present invention, the method according to the third aspect of the present invention, the content provider server according to the fourth aspect of the present invention, and the communication terminal according to the fifth and sixth aspect of the present invention. |
Hair-follicle treatment,in particular against hair loss |
A process for treating hair follicles and their perifollicular region comprising contacting the follicles and the perifollicular region with a composition containing an NK1-receptor antagonist compound. |
1-15. (cancelled). 16. A process for treating hair follicles and their perifollicular region comprising contacting the follicles and the perifollicular region with a composition containing an NK1-receptor antagonist compound. 17. The process of claim 16 wherein the NK1-receptor antagonist compound is a peptide. 18. The process of claim 17 wherein the peptide contains from about 10 to 15 amino acids. 19. The process of claim 16 further comprising contacting the hair follicles and their perifollicular region with an NK1-receptor agonist compound. 20. The process of claim 19 wherein the hair follicles and their perifollicular region are first contacted with the NK1-receptor agonist compound, and are then subsequently contacted with the NK1-receptor antagonist compound. 21. The process of claim 16 wherein the hair follicles and their perifollicular region are treated during a growth stage of the hair follicles. 22. The process of claim 16 wherein the hair follicles and their perifollicular region are treated during a regression stage of the hair follicles. |
<SOH> BACKGROUND ART <EOH>As is known, the life of a hair follicle is characterized by continual and cyclical transition between a growth stage of the follicle (anagen) in which, amongst other things, the development of the hair is observed (by virtue of the activity of the keratinocytes), a subsequent regression stage (catagen) in which the programmed death (apoptosis) of a considerable portion of the cells of the follicle takes place, and a third, quiescence stage (telogen) at the end of which the hair follicle returns to the anagenic stage with the formation of a new hair shaft. The duration of the various stages of the life cycle of the hair follicle depends substantially on its position on the body. For example, whereas in the scalp region, anagen lasts from two to eight years, compared with a period of a few weeks for the catagen stage and a few months for the telogen stage, in the eyebrow region, the anagen stage lasts for only a few months. This time ratio also determines the percentage of hair follicles which are present, on average, in the various stages of the cycle, for each region of the body. The durations of the various stages of the cycle, as well as the transition between one stage and another are regulated by complex biological interactions, the mechanisms of which are not entirely clear, between the various parts of the hair follicle and between the follicle and the surrounding epithelial environment. It is, however, known that these stages are affected by many endogenous and exogenous factors which act, directly or indirectly, on the hair follicle to lengthen or shorten the duration of each individual stage. One of the factors which has been suspected for some time of causing premature catagen of the hair follicle which, in the scalp region, may manifest itself in the form of alopecia or effluvium, giving rise to hair loss, is stress [Paus, R., Peters, E. M., Eichmüller, S., Botchkarev, V. A. (1997): “Neural mechanisms of hair growth control” J. Invest. Dermatol. Symp. Proc. 2, 61-68; Paus, R. “Stress, hair growth control, and the neuro-endocrine-immune connection” J. Allerg. (2001); Ericson M., Gabrielson, A., Worel, S., Lee, W. S., Hordinsky, M. K. (1999) “Substance P (SP) in innervated and non-innervated blood vessels in the skin of patients with symptomatic scalp” Exp. Dermatol. 8, 344-345; Whitlock, F. A. (1976) “Psychophysiological aspects of skin disease” in Rook A. (ed.) Major Problems in Dermatology, Vol. 8; Saunders, London]. Stress which, in the sense used in the present context, is intended to include, in addition to conditions resulting from anxiogenic events, also conditions resulting from chemotherapy or pharmacological treatments, causes a systemic reaction characterized by changes in the blood levels of certain transmitters and hormones. In this connection, some studies have suggested a potentially negative influence of the high level of activity of perifollicular immunocytes (particularly mast cells and macrophages), resulting from the immune response to the stress situation, on the anagen stage of the hair follicle (Maurer, M., Fischer, E., is Handjiski, B., von Stebut, E., Algermissen, B., Bavandi, A., Paus, R. (1997) “Activated skin mast cells are involved in murine hair follicle regression (catagen)” Lab. Invest. 77, 319-332; Eichmüller, S., van der Veen, C., Moll, I., Hermes, B., Hofmann, U., Müller-Röver, S., Paus, R. (1998) “Clusters of. perifollicular macrophages in normal murine skin: physiological degeneration of selected hair follicles by programmed organ deletion” J. Histochem. Cytochem. 46, 361-370; Suzuki, S., Kato, T., Takimoto, H., Masui, S., Oshima, H., Ozava, K., Suzuki, S., Imamura, T. (1998) “Localization of rat FGF-5 protein in skin macrophage-like cells and FGF-5S protein in hair follicle: possible involvement of two Ffg-5 gene products in hair growth cycle regulation” J. Invest. Dermatol. 111, 963-972; Stenn, K. S., Paus, R. “Control of hair cycle” Physiol. Rev. Vol. 81, N. 1, (2001)] Other studies which, however, relate to other fields of research, have shown that the immune response is mediated particularly but not exclusively by the neuropeptide Substance P (SP), a ligand of the NK1 receptor (Zhu, G. F., Chancellor-Freeland, C., Berman, A. S., Kage, R., Leeman, S. E., Beller, D. I., Black P. H. (1996) “Endogenous substance P mediates cold water stress-induced increase in interleukin-6 secretion from peritoneal macrophages” J. Neurosci. 16, 3745-3752; De Felipe, C., Herrero, J. F., O'Brien, J. A., Palmer, J. A., Doyle, C. A., Smith, A. J., Laird, J. M., Belmonte, C., Cervero, F., Hunt, S. P. (1998) “Altered nociception, analgesia and aggression in mice lacking the receptor for substance P” Nature 392, 394-397; Nio, D. A., Moylan, R. N., Roche, J. K. (1993) “Modulation of T lymphocyte function by neuropeptides. Evidence for their role as local immunoregulatory elements.” J. Immunol. 150, 5281-5288]. It is also known that the biological action of substance P can be blocked, or at least limited, by the administration of NK1-receptor antagonist substances. NK1-receptor antagonist substances are currently used in the production of medicaments for the treatment of pathological conditions of the central nervous system (in particular as antidepressants), and respiratory, allergic, cardiovascular, ophthalmic, dermatological and rheumatic pathological conditions in which substance P is thought to be directly involved. A second use of NK1-receptor antagonist substances as angiogenesis-inhibiting agents, for a hair-growth inhibition treatment, is indicated in U.S. Pat. No. 6,093,748. Interference of substance P with the normal cyclical behaviour of the hair follicle has also been observed [Paus, R., Heinzelmann, T., Schultz, K. D., Furkert, J., Fechner, K., Czametzki, B. M. (1994) “Hair growth induction by substance P” Lab. Invest 71, 134-140]. In fact, when subjected to treatment with substance P during the telogen stage, the hair follicle is induced to go on to the subsequent anagen stage. However, it is not possible to infer from these results any positive teaching for the preventive treatment of hair follicles which are subject to premature catagen. detailed-description description="Detailed Description" end="lead"? |
Electrolytic cell and electrodes for use in electrochemical processes |
An electrolytic cell with an anode and cathode for the electrolysis of hydrochloric acid and brine is provided. The anodes and cathodes of the present invention are made of a bulk ceramic or intermetallic material. |
1. An electrolytic cell comprising a cathode and an anode wherein the cathode comprises a cathodic bulk ceramic or intermetallic material. 2. The electrolytic cell of claim 1 wherein the cathodic bulk ceramic or intermetallic material of the cathode comprises a composition Mn+1AXn, wherein M is a metal of group IIIB, IVB, VB, VIB or VIII of the periodic table of elements or a mixture thereof; wherein A is an element of group IIIA, IVA, VA or VIA of the periodic table of elements or a mixture thereof; and wherein X is carbon, nitrogen, or carbon and nitrogen. 3. The electrolytic cell of claim 1 wherein the cathodic bulk ceramic or intermetallic material of the cathode comprises Ti3SiC2. 4. An electrolytic cell comprising a cathode of a material suitable for formation of a cathode coated with a material comprising composition Mn+1AXn, wherein M is a metal of group IIIB, IVB, VB, VIB or VIII of the periodic table of elements or a mixture thereof; wherein A is an element of group IIIA, IVA, VA or VIA of the periodic table of elements or a mixture thereof; and wherein X is carbon, nitrogen or carbon and nitrogen. 5. An electrolytic cell comprising a cathode and an anode wherein the cathode is coated with a ceramic or intermetallic material. 6. The electrolytic cell of claim 5 wherein the ceramic or intermetallic material comprises Ti3SiC2. 7. The electrolytic cell of claim 1 wherein the anode comprises a bulk ceramic or intermetallic material of a composition Mn+1AXn, wherein M is a metal of group IIIB, IVB, VB, VIB or VIII of the periodic table of elements or a mixture thereof; wherein A is an element of group IIIA, IVA, VA or VIA of the periodic table of elements or a mixture thereof; and wherein X is carbon, nitrogen or carbon and nitrogen activated by a catalytic thermally prepared coating containing a mixture of TiO2 and RuO2 or a mixture of TiO2, RuO2 and IrO2. 8. The electrolytic cell of claim 1 wherein the anode comprises a bulk ceramic or intermetallic material of composition Tin+1AXn, wherein A is an element of group IIIA, IVA, VA or VIA of the periodic table of elements or a mixture thereof; and wherein X is carbon, nitrogen or carbon and nitrogen activated by addition of Ru, or Ru and Ir in the bulk ceramic material during processing and subjected to subsequent oxidation. 9. The electrolytic cell of claim 8 wherein the bulk ceramic or intermetallic material of the anode comprises Ti3SiC2 and Ru or Ru and Ir. 10. An anode for use in an electrolytic cell for the electrolysis of hydrochloric acid solutions comprising a bulk ceramic or intermetallic material of composition Mn+1AXn, wherein M is a metal of group IIIB, IVB, VB, VIB or VIII of the periodic table of elements or a mixture thereof; wherein A is an element of group IIIA, IVA, VA or VIA of the periodic table of elements or a mixture thereof; and wherein X is carbon, nitrogen or carbon and nitrogen activated by a catalytic thermally prepared coating containing a mixture of TiO2 and RuO2, or TiO2, RuO2 and IrO2. 11. The anode of claim 10 wherein the bulk ceramic or intermetallic material comprises composition Tin+1AXn, wherein A is an element of group IIIA, IVA, VA or VIA of the periodic table of elements or a mixture thereof; and wherein X is carbon, nitrogen or carbon and nitrogen activated by addition of Ru or Ru and Ir in the bulk ceramic or intermetallic material during processing and subjected to subsequent oxidation. 12. A cathode for use in an electrolytic cell for the electrolysis of hydrochloric acid solutions comprising a bulk ceramic or intermetallic material of the composition Mn+1AXn, wherein M is a metal of group IIIB, IVB, VB, VIB or VIII of the periodic table of elements or a mixture thereof; wherein A is an element of group IIIA, IVA, VA or VIA of the periodic table of elements or a mixture thereof; and wherein X is carbon, nitrogen or carbon and nitrogen. 13. A cathode for use in an electrolytic cell for the electrolysis of hydrochloric acid solutions comprising Ti3SiC2. |
<SOH> BACKGROUND <EOH>In certain industrial operations hydrochloric acid is formed as a by-product of chlorination. There is usually no immediate market for the hydrochloric acid. The lack of a market makes hydrochloric acid production problematic in that it cannot be dumped into sewers and wastewater outlets without costly neutralization. It has been customary in industry to utilize electrolysis of hydrochloric acid to overcome disposal issues. Electrolysis of brines and hydrochloric acid are completed within an electrolytic cell with an anode and a cathode. An electrical potential is established between the anode and the cathode whereby the negatively charged chloride ions are attracted to the anode. Monoatomic chlorine atoms combine at the anode to form diatomic chlorine molecules. In such chlorine production the chlorine molecules form gas bubbles on the surface of the anode and chlorine is recovered as a gas. Monoatomic hydrogen atoms combine at the cathode to form diatomic hydrogen molecules as gas bubbles on the surface of the cathode and hydrogen is also recovered as a gas. As a consequence of the significant increases in energy costs and the increased scarcity of industrial fuel supplies, intensive research in the field of electrolysis has been performed in order to reduce the amount of power used in industrial electrolysis processes. The cost of electrolysis is proportional to the voltage at which the electrolysis is effected. Thus, it is desirable to reduce the amount of voltage at which a solution is electrolyzed to as low of a value as possible. Methods and apparatuses described in the prior art for achieving a low hydrogen over-voltage include the following: U.S. Pat. No. 1,915,473 and U.S. Pat. No. 4,116,804 describe various methods for producing “Raney nickel”, an active porous nickel which provided one of the first alternative cathodic materials to mild steel. This alternative material is used to produce exceptionally low over-voltage as compared to steel cathodes. U.S. Pat. No. 4,401,529 describes an improved hydrogen evolution cathode of the same type as “Raney nickel” with addition of molybdenum to produce NiMo “Raney nickel” surface. U.S. Pat. No. 4,425,203, U.S. Pat. No. 4,430,186 and U.S. Pat. No. 4,466,868 describe the addition of small amounts of from 1 to 5 percent of Ti to NiMo alloy which was found to reduce over-voltage for hydrogen evolution in alkaline solutions in comparison with that of the NiMo alloy in Raney nickel. U.S. Pat. No. 4,975,161 describes hydrogen evolution cathodes produced by thermal decomposition of a mixture of elements of the groups IB, IIB, IIIA, IVA, VA, VIA, VIB and VIII of the Periodic Table. U.S. Pat. No. 5,395,422 describes the process of producing nanocrystalline metallic powders containing Ni, Co, and Fe or mixtures thereof while the alloying element is one or more transition metals such as Mo, W or V, to be used as catalytic materials for hydrogen evolution. U.S. Pat. No. 5,324,395 and U.S. Pat. No. 5,492,732 describe plasma spray techniques for obtaining durable low hydrogen over-voltage cathodes bearing a coating which has an outer layer with at least 10 percent of cerium oxide and at least one non-noble Group VIII metal. U.S. Pat. No. 5,433,797 describes another type of cathode for hydrogen evolution, the design of which is based on the use of nanocrystalline metals of average grain size and less than about 11 nanometers of tertiary and quaternary NiFeCr and NiFeCrMn alloys. This cathode is obtained by electrodeposition using pulsating direct current regimes. U.S. Pat. No. 3,616,445, describes electrodes made of titanium, known as “dimensionally stable anodes” (DSA). The introduction of DSA into the processes of chlorine, chlorate and hypochlorite production by the electrolysis of brine has led to significant decreases in energy costs. DSA are made of titanium coated with a thermally prepared mixture of TiO 2 and RuO 2 DSA are corrosion resistant, selective to chloride ion oxidation and exhibit a high catalytic activity. However, the coating must be routinely replaced. U.S. Pat. No. 3,950,240 describes a procedure of obtaining a catalytic coating of tin oxide with niobium and a relatively small amount of noble metal oxides. This procedure is advantageous over DSA as smaller amounts of expensive noble metal oxides are required. U.S. Pat. No. 4,511,442, U.S. Pat. No. 4,107,025 and U.S. Pat. No. 4,007,107 describe metal coated anodes. U.S. Pat. No. 5,587,058 describes electrodes with better corrosion resistance than DSA in the process of chlorine production. U.S. Pat. Nos. 3,486,994 and 4,210,501 describe production of chlorine by electrolysis of hydrochloric acid in an electrolytic cell having anolyte and catholyte chambers. U.S. Pat. No. 3,242,065 describes production of chlorine from hydrochloric acid using an electrolytic cell with the graphite cathode attached to the frame of the cell. U.S. Pat. No. 5,770,035 describes a method for the production of chlorine from hydrochloric acid in a electrolytic cell, with a cathode compartment equipped with a gas diffusion cathode fed with air, enriched air or oxygen. U.S. Pat. No. 4,959,132 describes a process of fabrication of thin, electronically conductive, high-surface area film formed on both sides of a membrane to form a bipolar structure useful for electrolysis of hydrochloric acid. U.S. Pat. No. 5,580,437 describes a particular anode for conversion of hydrochloric acid into chlorine gas using an electrochemically active material of tin, germanium or lead, or mixtures thereof. U.S. Pat. No. 6,066,248 describes a process for the electrolysis of aqueous hydrochloric acid solution in an electrochemical flow reactor with a solid polymer electrolyte membrane, a platinum-based anode, a cathode and backings. A number of commercial processes of electrolysis of hydrochloric acid for production of chlorine have been developed (see e.g. F. R. Minz, “HCl—electrolysis—Technology for Recycling Chlorine”, Bayer AG, Conference on Electrochemical Processing, Innovation & Progress, Glasgow, Scotland, UK Apr. 21-23, 1993). A currently employed commercial electrochemical process is known as the Uhde process. In this process aqueous HCl solution of approximately 22 percent is fed at 65 to 70 degrees Celsius into an electrochemical cell into both the anodic and cathodic compartments which are divided by a diaphragm made of special type of PVC cloth. Graphite is used as electrode material for both, anode and cathode (bipolar electrode). Exposure to a direct current in the cell results in an electrochemical reaction and a decrease in HCl concentration of up to 17 percent with the production of chlorine gas in the anodic compartment and hydrogen in the cathodic compartment. Both the anode and cathode side of a graphite bipolar electrode, undergo severe destruction after operating for some time in a cell for hydrochloric acid electrolysis (F. M. Berkey, “Electrolysis of Hydrochloric Acid Solutions”, Ch. 7 in “Chlorine its Manufacture, Properties and Uses”, Ed. J. S. Sconce, New York, Reinhold Publishing Corp., 1962). The use of DSA in this process is not recommended since the titanium substrate undergoes significant corrosion in concentrated HCl at high temperatures and the electrode becomes unusable after a short operating time. Other materials stable in hydrochloric acid like platinum group metals are excessively expensive. The present invention provides an electrolytic cell which utilizes electrodes exhibiting high stability in acidic media, particularly in concentrated hydrochloric acid. The electrodes have a corrosion rate of less than 2 im per year. The electrodes also exhibit low over-voltage for hydrogen and chlorine evolution. Methods of their use as cathodes and anodes in production of chlorine by electrolysis of hydrochloric acid and brine are also provided. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object of the present invention is to provide an electrolytic cell with a cathode and an anode, wherein the cathode is made of a bulk ceramic or intermetallic material. Another object of the present invention is to provide an electrolytic cell with a cathode and an anode, wherein the cathode comprises a layer of ceramic or intermetallic material thermally sprayed on a material suitable for formation of a cathode. Another object of the present invention is to provide an electrolytic cell anode for the electrolysis of hydrochloric acid solutions wherein the electrolytic cell anode comprises a bulk ceramic or intermetallic material activated by a thin layer of a thermally prepared mixture of TiO 2 and RuO 2 , or TiO 2 , RuO 2 and IrO 2 . Another object of the present invention is to provide an electrolytic cell anode for the electrolysis of hydrochloric acid solutions wherein the electrolytic cell anode comprises a bulk ceramic or intermetallic material containing Ti and activated upon addition of Ru, or Ru and Ir. Another object of the present invention is to provide an electrolytic cell cathode for the electrolysis of hydrochloric acid solutions wherein the electrolytic cell cathode comprises a bulk ceramic or intermetallic material. Another object of the present invention is to provide an electrolytic cell cathode for the electrolysis of hydrochloric acid solutions wherein the electrolytic cell cathode comprises a layer of ceramic or intermetallic material thermally sprayed on a material suitable for formation of a cathode. Another object of the present invention is to provide a method for electrolysis of hydrochloric acid solutions, alkaline solutions and alkali metal halide solutions using the electrolytic cell of this invention. |
Integrated unit with antenna and switch |
Integrated unit (1) having a connector (3) mounted on a printed circuit (2), the connector having a support (4) in which are placed a first blade (5) and a second blade (10) linked to the printed circuit, the first blade having on an upper side (8) of the support, an extension (7) forming an antenna (6). This first blade is preferably formed by the metallisation of the plastic support. The second blade comes into contact with the first blade. The support has a cavity (18) to receive a coaxial plug (25) and thus to switch the connection between the first and second blades, for a new connection between this second blade and the coaxial plug. |
1. Unit comprising a printed circuit, an insulating support, a first antenna, a switchable coaxial connector, the connector having at least one first contact blade and a second contact blade allowing to switch the origin of a signal received by the printed circuit between a signal received from the first antenna or a signal received from a coaxial plug, characterised in that the first blade and the first antenna placed on the support are formed in continuity by metallisation. 2. Unit according to claim 1 characterised in that the support has a cavity in which the coaxial plug can be introduced, and in that the second blade is inserted from the lower side. 3. Unit according to claim 1, characterised in such that the first antenna covers the upper side of the support. 4. Unit according to claim 1, characterised in that the second blade has a flexible portion crossing the cavity to come into to contact with an arm or with a zone of the first blade. 5. Unit according to claim 1, characterised in that the second blade has at least one flexible portion to insure connection between the printed circuit and the first blade, in the absence of the coaxial plug. 6. Unit according to claim 5, characterised in that the flexible portion insures connection between the printed circuit and the coaxial plug, in the presence of the said coaxial plug. 7. Cancel. 8. Unit according to claim 1, characterised in that the first antenna has a crenellated linear pattern and has two portions opposite each other, the pattern being preferably of the folded rake type. 9. Unit according to claim 1, characterised in that the first antenna is an internal antenna of a cell phone, and that the coaxial plug is a plug for an external cell phone antenna. 10. Unit according to claim 1, characterised in that the connector has an earth blade placed on the circumference of a cavity of the support, the coaxial plug having a pin to be connected to the second blade of the connector placed inside this cavity, and an external envelope to be connected to the earth blade. 11. Manufacturing procedure of a unit according to claim 1, The support is moulded The support is selectively metallised to make the first blade The second blade is cut out and modelled to be pushed into a cavity of the support, from the lower side The support is mounted on a printed circuit board. |
Optical frequency comb generator |
An optical frequency comb generator includes an oscillator (117) for oscillating modulating signals of a preset frequency, and an optical resonator (110) formed by an incident side reflecting mirror (112) and an outgoing side reflecting mirror (113), arranged parallel to each other. The optical resonator causes resonation in light incident via the incident side reflecting mirror (112). The optical frequency comb generator also includes an optical phase modulation unit (111) arranged between the incident side reflecting mirror (112) and the outgoing side reflecting mirror (113) for phase modulating the light, resonated by the optical resonator (110), by the modulating signals supplied from the oscillator (117), and for generating a plurality of sidebands centered about the frequency of the incident light at a frequency interval of the modulating signal. The outgoing side reflecting mirror (113) sets the transmittance from one frequency to another responsive to the light intensity of the generated sidebands. |
1. An optical frequency comb generator comprising oscillation means for oscillating modulating signals of a preset frequency, resonation means formed by an incident side reflecting mirror and an outgoing side reflecting mirror, arranged parallel to each other, said resonation means causing resonation in light incident via said incident side reflecting mirror, and optical modulation means arranged between said incident side reflecting mirror and said outgoing side reflecting mirror for phase modulating the light resonated in said resonation means by said modulating signals supplied from said oscillation means, and for generating a plurality of sidebands centered about the frequency of the incident light at a frequency interval of said modulating signal; the transmittance for said outgoing side reflecting mirror being set from one frequency to another responsive to the light intensity of the generated sidebands. 2. An optical frequency comb generator comprising oscillation means for oscillating modulating signals of a preset frequency, resonation means formed by an incident side reflecting mirror and an outgoing side reflecting mirror, arranged parallel to each other, said resonation means causing resonation in light incident via said incident side reflecting mirror, and optical modulation means arranged between said incident side reflecting mirror and said outgoing side reflecting mirror for phase modulating the light resonated by said resonation means by said modulating signals supplied from said oscillation means, and for generating a plurality of sidebands centered about the frequency of the incident light at a frequency interval of said modulating signal; said incident side reflecting mirror having the maximum transmittance at the frequency of the incident light. 3. The optical frequency comb generator according to claim 2 further comprising a filter on which said generated sidebands are incident via said outgoing side reflecting mirror; said filter having the smallest transmittance at the frequency of said incident light. 4. An optical frequency comb generator comprising oscillation means for oscillating modulating signals of a preset frequency, resonation means formed by an incident side reflecting mirror and an outgoing side reflecting mirror, arranged parallel to each other, said resonation means causing resonation in light incident via said incident side reflecting mirror, and optical modulation means arranged between said incident side reflecting mirror and said outgoing side reflecting mirror for phase modulating the light resonated by said resonation means by said modulating signals supplied from said oscillation means, and for generating a plurality of sidebands centered about the frequency of the incident light at a frequency interval of said modulating signal; wherein said incident side reflecting mirror having the maximum transmittance at the frequency of the incident light and the transmittance for said outgoing side reflecting mirror being set from one frequency to another responsive to the light intensity of the generated sidebands. 5. The optical frequency comb generator according to claim 4 wherein the transmittance for said outgoing side reflecting mirror is set from one frequency to another based on the rate of change of the light intensity of the generated sidebands with respect to the frequency. 6. The optical frequency comb generator according to claim 4 wherein said optical modulation means is a bulk crystal changed in the refractive index on application of an electrical field. 7. The optical frequency comb generator according to claim 6 wherein said incident side reflecting mirror is a high reflecting film formed on the light incident side of said optical modulation means and wherein said outgoing side reflecting mirror is a movable mirror carrying a high reflecting film and arranged on the light radiating side of said optical modulation means for movement by electro-mechanical transducer means. 8. The optical frequency comb generator according to claim 6 further comprising a cavity modulating signal resonator having said optical modulation means enclosed therein; a cavity of said cavity modulating signal resonator resonated with said modulating signals being U-shaped; the length of said cavity ahead and in rear of said optical modulator being set to one-fourth the wavelength of the resonation frequency. 9. The optical frequency comb generator according to claim 6 further comprising a cavity modulating signal resonator having said optical modulation means enclosed therein; a cavity of said cavity modulating signal resonator resonated with said modulating signals being of a closed-loop shape. 10. The optical frequency comb generator according to claim 4 wherein said optical modulation means is a waveguide channel propagating the light. 11. The optical frequency comb generator according to claim 10 wherein said incident side reflecting mirror and the outgoing side reflecting mirror are reflecting films formed on an incident side end face and/or an outgoing side end face of said optical modulation means. 12. The optical frequency comb generator according to claim 10 wherein said incident side reflecting mirror is a reflecting mirror formed on an end face of an incident side optical fiber for transmitting light to said resonation means and wherein the outgoing side reflecting mirror is a reflecting film formed on an end face of an outgoing side optical fiber for receiving the sidebands generated by said optical modulation means. 13. The optical frequency comb generator according to claim 12 wherein the end face of said incident side optical fiber and/or the end face of said outgoing side optical fiber come into contact with end faces of said waveguide channel. 14. The optical frequency comb generator according to claim 12 wherein said reflecting films are dielectric multi-layer films having a plurality of materials of different refractive indices layered together. 15. The optical frequency comb generator according to claim 10 wherein said incident light is radiated from an optical fiber carrying a reflecting film on an end face thereof and resonated between said reflecting film and another reflecting film arranged on the incident side end face of said optical fiber. 16. The optical frequency comb generator according to claim 10 further comprising an electrode arranged parallel to said optical modulating means and including a broad-width area and a narrow-width area, said electrode applying an electrical field to said optical modulation means based on modulating signals oscillated by said oscillation means; said electrode including said broadband areas at a period corresponding to one half wavelength of said modulating signal oscillated by said oscillation means. 17. The optical frequency comb generator according to claim 16 wherein said optical modulation means modulates the phase of the light resonated by said resonation means based on the wavelength of said modulating signal. 18. The optical frequency comb generator according to claim 16 wherein said area is provided in an area where there flows a large current and where a low voltage is applied. |
<SOH> BACKGROUND ART <EOH>If, in heterodyne detection, the light frequency is to be measured to a high frequency, the light to be measured is caused to interfere with other light and an electrical signal of the optical beat frequency generated is detected. The bandwidth of laser light that may be measured in this heterodyne detection is limited to the band of the light receiving element used in the detection system, and is generally on the order of tens of GHz. On the other hand, the bandwidth of light that may be measured needs to be increased further in order to measure the frequency of absorption lines, distributed over a wide range, or in order to control laser light for frequency division multiplex communication, in keeping up with the development in the domain of optoelectronics in recent years. With a view to responding to the demand for enlarging the measurable bandwidth of light, a broadband heterodyne detection system, employing an optical frequency comb generator, was already devised. This optical frequency comb generator generates a number of comb-shaped sidebands, arranged at an equal interval on the frequency axis. The frequency stability of the sidebands is substantially equivalent to the frequency stability of the incident light. The generated sidebands and the light being measured are heterodyne-detected to construct a broadband heterodyne detection system extending over several THz. FIG. 1 shows the topical structure of a conventional optical frequency comb generator 9 . This optical frequency comb generator 9 includes an optical resonator 90 , made up of an optical phase modulator 91 and reflecting mirrors 92 , 93 arranged facing each other with the optical phase modulator 91 in-between. The optical resonator 90 causes light resonation of light Lin, incident via reflecting mirror 92 with a low transmittance, in a space between the reflecting mirrors 92 , 93 , while radiating a fraction Lout of the incident light via reflecting mirror 93 . The optical phase modulator 91 is formed by an electro-optical crystal for optical phase modulation, which is changed in refractive index on application of an electrical field thereto. The light traversing this optical resonator 90 is phase-modulated responsive to an electrical signal of the modulation frequency fm, supplied to an electrode 96 . By introducing an electrical signal, synchronized with the time of a round trip of light through the optical resonator 90 , from the electrode 96 to the optical phase modulator 91 for driving, it is possible with this optical frequency comb generator 9 to apply phase modulation deeper tens of times than in case of light traveling only once through the optical phase modulator 91 . Thus, the optical frequency comb generator 9 is able to generate hundreds of higher order sidebands. The frequency interval fm between the neighboring sidebands is equivalent the modulating frequency fm of the input electrical signals. Meanwhile, in determining the frequency of the light under measurement based on the large number of the optical frequency combs generated, the optical frequency comb generator 9 modulates the incident light with the frequency ν 1 , with the frequency fm, by the optical phase modulator 91 , to generate optical frequency combs composed of the sidebands with the frequency interval fm. These optical frequency combs are superposed on the light under measurement, with the frequency ν 2 , and the beat frequency Δν with respect to the Nth sideband generated as the optical frequency comb is measured to determine |ν 1 −ν 2 |. Ultimately, the frequency ν 2 of the light under measurement is measured. The light intensity distribution of the so generated sidebands is flattened out to render the sensitivity of the optical frequency combs constant for the entire frequency range, such that it becomes possible to measure the frequency of the light under measurement accurately such as to relieve the designing load in the downstream side circuitry used for detecting the generated sidebands. However, in the conventional optical frequency comb generator 9 , the light intensity of the sidebands is decreased with increase in the absolute value of Δν, in other words, with increase in the frequency deviation from the frequency of the incident light. In particular, the light intensity of the sidebands is exponentially decreased for a band which appreciably differs from the frequency of the incident light. The result is that the light intensity distribution of the sidebands is not uniform and susceptible to variations. On the other hand, the optical frequency comb generator 9 has to use a reflecting mirror of high reflectance in order to suppress loss of light to be resonated. However, the reflecting mirror of high reflectance also reflects the light supplied from an external light source, thus increasing the light loss at the time of light incidence. Thus, for accurately measuring the light under measurement, an optical frequency comb generator capable of suppressing the light loss to a minimum, as it is attempted to flatten out the light intensity distribution in the generated sidebands, needs to be realized. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 illustrates a specified illustrative structure of a conventional optical frequency comb generator. FIG. 2 shows the band-based light intensity distribution of the radiated light in the conventional optical frequency comb generator. FIG. 3 shows a specified illustrative structure of a bulk type optical frequency comb generator. FIGS. 4A to 4 C show the transmittance and the reflectance of an incident side reflecting mirror. FIG. 5 shows the ratio of the light intensity of the outgoing light (P out ) and the light intensity of the incident light (P in ) in each band. FIG. 6 shows setting examples of the transmittance of the outgoing side reflecting mirror. FIG. 7 shows the light intensity distribution for each frequency of the outgoing light relative to the incident light. FIG. 8 shows the relationship between the transmittance of the outgoing side reflecting mirror and the standardized frequency difference of the transmittance. FIG. 9 shows transmittance characteristics of the outgoing side reflecting mirror with respect to the frequency difference Δf. FIG. 10 shows the light intensity distribution of the outgoing light relative to the incident light in case of selecting the reflecting mirror having the characteristics of FIG. 9 as an outgoing side reflecting mirror. FIG. 11 shows a bulk type optical frequency comb generator in which a preset transmittance is set only for the incident side reflecting mirror. FIG. 12 shows an example of the reflectance set to the outgoing side reflecting mirror for diminishing the loss of the resonant light. FIG. 13 shows a bulk type optical frequency comb generator in which a filter for passing only a preset band is provided on the outgoing side. FIG. 14 shows the transmittance of the filter to each frequency. FIG. 15 shows the light intensity distribution for each frequency of the light radiated from the filter. FIG. 16 shows a bulk type optical frequency comb generator in which a preset transmittance is set only for the outgoing side reflecting mirror. FIG. 17 shows the structure of a semi-monolithic bulk type optical frequency comb generator. FIG. 18 schematically shows an example of the overall structure of a semi-monolithic bulk type optical frequency comb generator. FIG. 19 shows a structure of a controller of an optical frequency comb generator. FIGS. 20A and 20B show a structure of a U-shaped bulk type optical frequency comb generator. FIG. 21 shows a modification of a U-shaped bulk type optical frequency comb generator. FIGS. 22A and 22B show another structure of a U-shaped bulk type optical frequency comb generator. FIG. 23 shows the structure of a waveguide channel type optical frequency comb generator. FIG. 24 shows an incident side coupling system of the waveguide channel type optical frequency comb generator to which is incident the Fabry-Perot resonated light. FIGS. 25A and 25B show the relationship of the reflectance and the transmittance on an incident side reflecting film of the incident light with the frequency ν 1 with respect to a gap between the incident side reflecting film and the fiber reflecting film. FIGS. 26A and 26B show the relationship of the reflectance and the transmittance for each frequency on the light incident side reflecting film when the length of a gap between the incident side reflecting film and the fiber reflecting film is equal to a. FIG. 27 shows an example of application of a waveguide channel type optical frequency comb generator. FIG. 28 shows the surface of a multi-layer dielectric film polished to a convex shape. FIG. 29 illustrates the shape of the distal end of the incident side optical fiber where a multi-layer dielectric film is formed. FIG. 30 illustrates a case where scars or damages are produced at a corner portion of the multi-layer dielectric film. FIG. 31 shows the structure of an optical frequency comb generator including a broad-with area and a narrow-width area. FIGS. 32A to 32 D show the losses of the micro-wave propagated in the electrode of an optical frequency comb generator including a broad-width area and a narrow-width area. FIG. 33 shows changes in the microwave losses and the modulation efficiency on the electrode of an optical frequency comb generator including a broad-width area and a narrow-width area. FIG. 34 shows the modulation efficiency in the optical frequency comb generator including a broad-width area and a narrow-width area, with the power being constant. FIGS. 35A to 35 D show the exemplary shape of an electrode in the optical frequency comb generator including a broad-width area and a narrow-width area. detailed-description description="Detailed Description" end="lead"? |
Method and device for data exchange and processing |
A method and a device are proposed for the exchange and the processing in common of object data between sensors and a processing unit, position data and/or speed data and/or additional object attributes (size, identification, markings) of sensor objects and fusion objects being transmitted and processed. |
1-13. (Canceled) 14. A method for processing sensor data to fusion data, comprising: causing at least one sensor to generate the sensor data; performing an association step in which one of the following is performed: assigning sensor data to existing fusion data, and in the case that no assignment takes place, generating new fusion data; performing a subsequent fusion step in which the fusion data is formed from associated data; and performing a merging step in which a fusion is performed out of a first fusion piece of data with a second fusion piece of data. 15. The method as recited in claim 14, further comprising: in the subsequent fusion step, weighting the sensor data as a function of a quality measure of the sensor data. 16. The method as recited in claim 15, wherein: for the weighting of the sensor data, one of a statistical standard deviation and a statistical variance thereof is used. 17. The method as recited in claim 14, wherein: in the merging step, the fusing performed if a difference between the first fusion piece of data and the second fusion piece of data undershoots at least one threshold value. 18. The method as recited in Claim 14, further comprising: performing an evaluation step in which a plausibility measure is assigned to one of the first fusion piece of data and the second fusion piece of data. 19. The method as recited in claim 14, further comprising: performing an evaluation step in which a priority measure is assigned to one of the first fusion piece of data and the second fusion piece of data. 20. The method as recited in claim 14, further comprising: performing a processing step in which for one of the first fusion piece of data and the second fusion piece of data an object size attribute is calculated, the object size attribute representing a size of a detected object. 21. The method as recited in claim 14, further comprising: performing a processing step in which, on the basis of at least one of the first fusion piece of data and the second fusion piece of data, at least one of the following is recognized: that an object is moving out of a detection range of the at least one sensor into a detection gap, that the object is present in the detection gap, and that the object is moving out of the detection gap into a detection range of the at least one sensor. 22. A method for exchanging data between a first sensor and a processing unit and between a second sensor and the processing unit, comprising: transmitting the sensor data to the processing unit; causing the processing unit to transmit acknowledgment data to at least one of the first sensor and the second sensor, wherein: the sensor data includes at least one of position data and speed data of an object relative to the first sensor and the second sensor, and the acknowledgment data includes information proportions of at least one of the sensor data and fusion data. 23. The method as recited in claim 22, wherein: the sensor data includes sensor objects and time data. 24. The method as recited in claim 22, wherein: the acknowledgment data is used for at least one of alertness control and a preconditioning of the first sensor, the second sensor, and a third sensor. 25. A device for processing sensor data to fusion data, comprising: a plurality of sensors for generating sensor data; and a processing unit for receiving the sensor data, the processing unit: performing an association step in which one of the following is performed: assigning sensor data to existing fusion data, and in the case that no assignment takes place, generating new fusion data, performing a subsequent fusion step in which the fusion data is formed from associated data, and performing a merging step in which a fusion is performed out of a first fusion piece of data with a second fusion piece of data. |
<SOH> BACKGROUND INFORMATION <EOH>Current vehicle guidance functions such as ACC (Adaptive Cruise Control) are based on the editing and processing of the data from only one environmental sensor, such as a 77 GHz-FMCW radar. An exchange of information between various environmental sensors and a common processing of sensor data of different origins is not possible. The bidirectional exchange of information between various environmental sensors and a central unit is not known as yet. |
<SOH> SUMMARY OF THE INVENTION <EOH>By contrast, the method according to the present invention and the device according to the present invention have the advantage that the power of detection, i.e. the quality of the sensor signals, the detection rate and the response of individual sensors or of sensor clusters is improved, the false alarm rate is reduced and the cases of sensor failure or of sensor blindness are able to be diagnosed more simply and more reliably. For this purpose, from a central processing module, for example, an information platform IP or a sensor data merging unit SDF, object data from the individual sensors are processed and edited in a targeted way, and are distributed to the individual sensors. According to the present invention, it is of particular advantage that data from the central processing module are distributed back to the individual sensors or to the sensor clusters. This contains, for example, the assignment in time of the data of the fusion objects to the sensor objects, and in reverse, the identification of like objects in the processing module and in the individual sensors as well as a prediction of the object movements. If the information that has flown back to the individual sensors, such as the information that an object threatens to intrude upon the recording range of another sensor, is used by the sensors for preconditioning —for example, for lowering detection thresholds and/or for initializing filter parameters—then, overall, a greater detection performance and detection security, as well as an improved response in object detection is achieved. In response to overlapping the detection ranges of various sensors, use may be made of the different quality of individual, compatible sensor signals, in which, for example, the generally more accurate resolution of the lateral deviation during the object detection of a video sensor for supporting its angular position is used by an object detected by a 77 GHz radar. Furthermore, the higher degree of the networked data exchange may be used to reduce the false alarm rate of the individual sensors and to assist in diagnosing and interpreting sensor failures or sensor blindness. Furthermore, according to the present invention, it is advantageously possible that data from various environmental sensors, such as radar, lidar and video are processed in common and condensed. This makes possible object information that is more comprehensive, more reliable, more rapid and at an average time qualitatively of greater value, starting from the measured data supplied by the sensors, than would be possible using a single sensor. In addition, tracking and identifying objects by the different sensing regions of the sensors is continually possible. The edited and condensed data on objects in the vehicle's environment may be made available to driving functions such as vehicle guidance systems or vehicle safety systems. Particularly advantageous is the use of an algorithmic method which permits assigning actual objects, such as sensor objects, to historical objects, such as fusion objects or so-called “tracks”, i.e. histories of measured values. According to the present invention, this assignment is denoted as data association. Additional processing steps of the algorithm according to the present invention include the steps of fusing fusion objects, which in the following is also denoted as merging, and generating new merger objects, particularly for the consideration of object hypotheses. In the method described, these tasks are carried out with great efficiency. For the association, a computing effort is required, for example, that is proportional to the product n*m, n denoting the number of fusion objects and m denoting the number of sensor objects. The computing effort for the merging step is proportional to n*n. Furthermore, according to the present invention, it is of advantage that the method according to the present invention is carried out using a delayed decision logic, which permits, in the case of a conflict, making the decision, as to which measuring object, i.e. sensor object, is allocated to which object hypothesis, final only in following measuring cycles. Because of the processing steps of the method according to the present invention, the aims named above, of a more inclusive, more reliable, quicker and on average time qualitatively higher valued object information, and the tracking and identifying of objects beyond the different sensing regions of the sensors become possible. |
Proteins associated with cell growth, differentiation, and death |
Various embodiments of the invention provide human proteins associated with cell growth, differentiation, and death (CGDD) and polynucleotides which identify and encode CGDD. Embodiments of the invention also provide expression vectors, host cells, antibodies, agonists, and antagonists. Other embodiments provide methods for diagnosing, treating, or preventing disorders associated with aberrant expression of CGDD. |
1. An isolated polypeptide selected from the group consisting of: a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-18, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-9 and SEQ ID NO:11-18, c) a polypeptide comprising a naturally occurring amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:10, d) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-18, and e) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-18. 2. An isolated polypeptide of claim 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-18. 3. An isolated polynucleotide encoding a polypeptide of claim 1. 4. An isolated polynucleotide encoding a polypeptide of claim 2. 5. An isolated polynucleotide of claim 4 comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:19-36. 6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim 3. 7. A cell transformed with a recombinant polynucleotide of claim 6. 8. (canceled) 9. A method of producing a polypeptide of claim 1, the method comprising: a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and recovering the polypeptide so expressed. 10. (canceled) 11. An isolated antibody which specifically binds to a polypeptide of claim 1. 12. An isolated polynucleotide selected from the group consisting of: a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:19-36, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:19-36, c) a polynucleotide complementary to a polynucleotide of a), d) a polynucleotide complementary to a polynucleotide of b), and e) an RNA equivalent of a)-d). 13. An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim 12. 14. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof. 15. A method of claim 14, wherein the probe comprises at least 60 contiguous nucleotides. 16. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof. 17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient. 18.-19. (canceled) 20. A method of screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample. 21.-22. (canceled) 23. A method of screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample. 24.-26. (canceled) 27. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, the method comprising: a) combining the polypeptide of claim 1 with at least one test compound under conditions permissive for the activity of the polypeptide of claim 1, b) assessing the activity of the polypeptide of claim 1 in the presence of the test compound, and c) comparing the activity of the polypeptide of claim 1 in the presence of the test compound with the activity of the polypeptide of claim 1 in the absence of the test compound, wherein a change in the activity of the polypeptide of claim 1 in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide of claim 1. 28. (canceled) 29. A method of assessing toxicity of a test compound, the method comprising: a) treating a biological sample containing nucleic acids with the test compound, b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 12 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 12 or fragment thereof, c) quantifying the amount of hybridization complex, and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound. 30.-45. (canceled) 46. A microarray wherein at least one element of the microarray is a polynucleotide of claim 13. 47.-91. (canceled) |
<SOH> BACKGROUND OF THE INVENTION <EOH>Human growth and development requires the spatial and temporal regulation of cell differentiation, cell proliferation, and apoptosis. These processes coordinately control reproduction, aging, embryogenesis, morphogenesis, organogenesis, and tissue repair and maintenance. At the cellular level, growth and development is governed by the cell's decision to enter into or exit from the cell division cycle and by the cell's commitment to a terminally differentiated state. These decisions are made by the cell in response to extracellular signals and other environmental cues it receives. The following discussion focuses on the molecular mechanisms of cell division, embryogenesis, cell differentiation and proliferation, and apoptosis, as well as disease states such as cancer which can result from disruption of these mechanisms. Cell Cycle Cell division is the fundamental process by which all living things grow and reproduce. In unicellular organisms such as yeast and bacteria, each cell division doubles the number of organisms. In multicellular species many rounds of cell division are required to replace cells lost by wear or by programmed cell death, and for cell differentiation to produce a new tissue or organ. Progression through the cell cycle is governed by the intricate interactions of protein complexes. This regulation depends upon the appropriate expression of proteins which control cell cycle progression in response to extracellular signals, such as growth factors and other mitogens, and intracellular cues, such as DNA damage or nutrient starvation. Molecules which directly or indirectly modulate cell cycle progression fall into several categories, including cyclins, cyclin-dependent protein kinases, growth factors and their receptors, second messenger and signal transduction proteins, oncogene products, and tumor-suppressor proteins. Details of the cell division cycle may vary, but the basic process consists of three principle events. The first event, interphase, involves preparations for cell division, replication of the DNA, and production of essential proteins. In the second event, mitosis, the nuclear material is divided and separates to opposite sides of the cell. The final event, cytokinesis, is division and fission of the cell cytoplasm. The sequence and timing of cell cycle transitions is under the control of the cell cycle regulation system which controls the process by positive or negative regulatory circuits at various check points. Mitosis marks the end of interphase and concludes with the onset of cytokinesis. There are four stages in mitosis, occurring in the following order: prophase, metaphase, anaphase and telophase. Prophase includes the formation of bi-polar mitotic spindles, composed of microtubules and associated proteins such as dynein, which originate from polar mitotic centers. During metaphase, the nuclear material condenses and develops kinetochore fibers which aid in its physical attachment to the mitotic spindles. The ensuing movement of the nuclear material to opposite poles along the mitotic spindles occurs during anaphase. Telophase includes the disappearance of the mitotic spindles and kinetochore fibers from the nuclear material. Mitosis depends on the interaction of numerous proteins. For example, centromere-associated proteins such as CENP-A, -B, and -C, play structural roles in kinetochore formation and assembly (Saffery, R. et al. (2000) Human Mol. Gen. 9:175-185). During the M phase of eukaryotic cell cycling, structural rearrangements occur ensuring appropriate distribution of cellular components between daughter cells. Breakdown of interphase structures into smaller subunits is common. The nuclear envelope breaks into vesicles, and nuclear lamins are disassembled. Subsequent phosphorylation of these lamins occurs and is maintained until telophase, at which time the nuclear lamina structure is reformed. cDNAs responsible for encoding M phase phosphorylation (MPPs) are components of U3 small nucleolar ribonucleoprotein (snoRNP), and relocalize to the nucleolus once mitosis is complete (Westendorf, J. M. et al. (1998) J. Biol. Chem. 9:437-449). U3 snoRNPs are essential mediators of RNA processing events. Proteins involved in the regulation of cellular processes such as mitosis include the Ser/Thr-protein phosphatases type 1 (PP-1). PP-1s act by dephosphorylation of key proteins involved in the metaphase-anaphase transition. The gene PP1R7 encodes the regulatory polypeptide sds22, having at least six splice variants (Ceulemans, H. et al. (1999) Eur. J. Biochem. 262:36-42). Sds22 modulates the activity of the catalytic subunit of PP-1s, and enhances the PP-1-dependent dephosphorylation of mitotic substrates. Cell cycle regulatory proteins play an important role in cell proliferation and cancer. For example, failures in the proper execution and timing of cell cycle events can lead to chromosome segregation defects resulting in aneuploidy or polyploidy. This genomic instability is characteristic of transformed cells (Luca, F. C. and M. Winey (1998) Mol. Biol. Cell. 9:29-46). A recently identified protein, mMOB1, is the mammalian homolog of yeast MOB1, an essential yeast gene required for completion of mitosis and maintenance of ploidy. The mammalian mMOB1 is a member of protein complexes including protein phosphatase 2A (PP2A), and its phosphorylation appears to be regulated by PP2A (Moreno, C. S. et al. (2001) J. Biol. Chem. 276:24253-24260). PP2A has been implicated in the development of human cancers, including lung and colon cancers and leukemias. Cell cycle regulation involves numerous proteins interacting in a sequential manner. The eukaryotic cell cycle consists of several highly controlled events whose precise order ensures successful DNA replication and cell division. Cells maintain the order of these events by making later events dependent on the successful completion of earlier events. This dependency is enforced by cellular mechanisms called checkpoints. Examples of additional cell cycle regulatory proteins include the histone deacetylases (HDACs). HDACs are involved in cell cycle regulation, and modulate chromatin structure. Human HDAC1 has been found to interact in vitro with the human Hus1 gene product, whose Schizosaccharomyces pombe homolog has been implicated in G 2 /M checkpoint control (Cai, R. L. et al. (2000) J. Biol. Chem. 275:27909-27916). DNA damage (G 2 ) and DNA replication (S-phase) checkpoints arrest eukaryotic cells at the G 2 /M transition. This arrest provides time for DNA repair or DNA replication to occur before entry into mitosis. Thus, the G 2 /M checkpoint ensures that mitosis only occurs upon completion of DNA replication and in the absence of chromosomal damage. The Hus1 gene of Schizosaccharomyces pombe is a cell cycle checkpoint gene, as are the rad family of genes (e.g., rad1 and rad9) (Volkmer, E. and L. M. Karnitz (1999) J. Biol. Chem. 274:567-570; Kostrub C. F. et al. (1998) EMBO J. 17:2055-2066). These genes are involved in the mitotic checkpoint, and are induced by either DNA damage or blockage of replication. Induction of DNA damage or replication block leads to loss of function of the Hus1 gene and subsequent cell death. Human homologs have been identified for most of the rad genes, including ATM and ATR, the human homologs of rad3p. Mutations in the ATM gene are correlated with the severe congenital disease ataxia-telagiectasia (Savitsky, K. et al. (1995) Science 268:1749-1753). The human Hus1 protein has been shown to act in a complex with rad1 protein which interacts with rad9, making them central components of a DNA damage-responsive protein complex of human cells (Volkmer and Karnitz, supra). The entry and exit of a cell from mitosis is regulated by the synthesis and destruction of a family of activating proteins called cyclins. Cyclins act by binding to and activating a group of cyclin-dependent protein kinases (Cdks) which then phosphorylate and activate selected proteins involved in the mitotic process. Cyclins are characterized by a large region of shared homology that is approximately 180 amino acids in length and referred to as the “cyclin box” (Chapman, D. L. and D. J. Wolgemuth (1993) Development 118:229-240). In addition, cyclins contain a conserved 9 amino acid sequence in the N-terminal region of the molecule called the “destruction box.” This sequence is believed to be a recognition code that triggers ubiquitin-mediated degradation of cyclin B (Hunt, T. (1991) Nature 349:100-101). Several types of cyclins exist (Ciechanover, A. (1994) Cell 79:13-21). Progression through G1 and S phase is driven by the G1 cyclins and their catalytic subunits, including Cdk2-cyclin A, Cdk2-cyclin E, Cdk4-cyclin D and Cdk6-cyclin D. Progression through the G2-M transition is driven by the activation of mitotic CDK-cyclin complexes such as Cdc2-cyclin A, Cdc2-cyclin B1 and Cdc2-cyclin B2 complexes (reviewed in Yang, J. and S. Kornbluth (1999) Trends Cell Biol. 9:207-210). Cyclins are degraded through the ubiquitin conjugation system (UCS), a major pathway for the degradation of cellular proteins in eukaroytic cells and in some bacteria. The UCS mediates the elimination of abnormal proteins and regulates the half-lives of important regulatory proteins that control cellular processes such as gene transcription and cell cycle progression. The UCS is implicated in the degradation of mitotic cyclin kinases, oncoproteins, tumor suppressor genes such as p53, viral proteins, cell surface receptors associated with signal transduction, transcriptional regulators, and mutated or damaged proteins (Ciechanover, supra). The process of ubiquitin conjugation and protein degradation occurs in five principle steps (Jentsch, S. (1992) Annu. Rev. Genet. 26:179-207). First ubiquitin (Ub), a small, heat stable protein is activated by a ubiquitin-activating enzyme (E1) in an ATP dependent reaction which binds the C-terminus of Ub to the thiol group of an internal cysteine residue in E1. Second, activated Ub is transferred to one of several Ub-conjugating enzymes (E2). Different ubiquitin-dependent proteolytic pathways employ structurally similar, but distinct ubiquitin-conjugating enzymes that are associated with recognition subunits which direct them to proteins carrying a particular degradation signal. Third, E2 transfers the Ub molecule through its C-terminal glycine to a member of the ubiquitin-protein ligase family, E3. Fourth, E3 transfers the Ub molecule to the target protein. Additional Ub molecules may be added to the target protein forming a multi-Ub chain structure. Fifth, the ubiquinated protein is then recognized and degraded by the proteasome, a large, multisubunit proteolytic enzyme complex, and Ub is released for re-utilization. Prior to activation, Ub is usually expressed as a fusion protein composed of an N-terminal ubiquitin and a C-terminal extension protein (CEP) or as a polyubiquitin protein with Ub monomers attached head to tail. CEPs have characteristics of a variety of regulatory proteins; most are highly basic, contain up to 30% lysine and arginine residues, and have nucleic acid-binding domains (Monia, B. P. et al. (1989) J. Biol. Chem. 264:4093-4103). The fusion protein is an important intermediate which appears to mediate co-regulation of the cell's translational and protein degradation activities, as well as localization of the inactive enzyme to specific cellular sites. Once delivered, C-terminal hydrolases cleave the fusion protein to release a functional Ub (Monia et al., supra). Ub-conjugating enzymes (E2s) are important for substrate specificity in different UCS pathways. All E2s have a conserved domain of approximately 16 kDa called the UBC domain that is at least 35% identical in all E2s and contains a centrally located cysteine residue required for ubiquitin-enzyme thiolester formation (Jentsch, supra). A well conserved proline-rich element is located N-terminal to the active cysteine residue. Structural variations beyond this conserved domain are used to classify the E2 enzymes. Class I E2s consist almost exclusively of the conserved UBC domain. Class II E2s have various unrelated C-terminal extensions that contribute to substrate specificity and cellular localization. Class III E2s have unique N-terminal extensions which are believed to be involved in enzyme regulation or substrate specificity. A mitotic cyclin-specific E2 (E2-C) is characterized by the conserved UBC domain, an N-terminal extension of 30 amino acids not found in other E2s, and a 7 amino acid unique sequence adjacent to this extension. These characteristics together with the high affinity of E2-C for cyclin identify it as a new class of E2 (Aristarkhov, A. et al. (1996) Proc. Natl. Acad. Sci. 93:4294-99). Ubiquitin-protein ligases (E3s) catalyze the last step in the ubiquitin conjugation process, covalent attachment of ubiquitin to the substrate. E3 plays a key role in determining the specificity of the process. Only a few E3s have been identified so far. One type of E3 ligases is the HECT (homologous to E6-AP C-terminus) domain protein family. One member of the family, E6-AP (E6-associated protein) is required, along with the human papillomavirus (HPV) E6 oncoprotein, for the ubiquitination and degradation of p53 (Scheffner, M. et al. (1993) Cell 75:495-505). The C-terminal domain of HECT proteins contains the highly conserved ubiquitin-binding cysteine residue. The N-terminal region of the various HECT proteins is variable and is believed to be involved in specific substrate recognition (Huibregtse, J. M. et al. (1997) Proc. Natl. Acad. Sci. USA 94:3656-3661). The SCF (Skp1-Cdc53/Cullin-F box receptor) family of proteins comprise another group of ubiquitin ligases (Deshaies, R. (1999) Annu. Rev. Dev. Biol. 15:435-467). Multiple proteins are recruited into the SCF complex, including Skp1, cullin, and an F box domain containing protein. The F box protein binds the substrate for the ubiquitination reaction and may play roles in determining substrate specificity and orienting the substrate for reaction. Skp1 interacts with both the F box protein and cullin and may be involved in positioning the F box protein and cullin in the complex for transfer of ubiquitin from the E2 enzyme to the protein substrate. Substrates of SCF ligases include proteins involved in regulation of CDK activity, activation of transcription, signal transduction, assembly of kinetochores, and DNA replication. Sgt1 was identified in a screen for genes in yeast that suppress defects in kinetochore function caused by mutations in Skp1 (Kitagawa, K. et al. (1999) Mol. Cell 4:21-33). Sgt1 interacts with Skp1 and associates with SCF ubiquitin ligase. Defects in Sgt1 cause arrest of cells at either G1 or G2 stages of the cell cycle. A yeast Sgt1 null mutant can be rescued by human Sgt1, an indication of the conservation of Sgt1 function across species. Sgt1 is required for assembly of kinetochore complexes in yeast. Abnormal activities of the UCS are implicated in a number of diseases and disorders. These include, e.g., cachexia (Llovera, M. et al. (1995) Int. J. Cancer 61:138-141), degradation of the tumor-suppressor protein, p53 (Ciechanover, supra), and neurodegeneration such as observed in Alzheimer's disease (Gregori, L. et al. (1994) Biochem. Biophys. Res. Commun. 203:1731-1738). Since ubiquitin conjugation is a rate-limiting step in antigen presentation, the ubiquitin degradation pathway may also have a critical role in the immune response (Grant, E. P. et al. (1995) J. Immunol. 155:3750-3758). Certain cell proliferation disorders can be identified by changes in the protein complexes that normally control progression through the cell cycle. A primary treatment strategy involves reestablishing control over cell cycle progression by manipulation of the proteins involved in cell cycle regulation (Nigg, E. A. (1995) BioEssays 17:471-480). Embryogenesis Mammalian embryogenesis is a process which encompasses the first few weeks of development following conception. During this period, embryogenesis proceeds from a single fertilized egg to the formation of the three embryonic tissues, then to an embryo which has most of its internal organs and all of its external features. The normal course of mammalian embryogenesis depends on the correct temporal and spatial regulation of a large number of genes and tissues. These regulation processes have been intensely studied in mouse. An essential process that is still poorly understood is the activation of the embryonic genome after fertilization. As mouse oocytes grow, they accumulate transcripts that are either translated directly into proteins or stored for later activation by regulated polyadenylation. During subsequent meiotic maturation and ovulation, the maternal genome is transcriptionally inert, and most maternal transcripts are deadenylated and/or degraded prior to, or together with, the activation of the zygotic genes at the two-cell stage (Stutz, A. et al. (1998) Genes Dev. 12:2535-2548). The maternal to embryonic transition involves the degradation of oocyte, but not zygotic transcripts, the activation of the embryonic genome, and the induction of cell cycle progression to accommodate early development. MATER (Maternal Antigen That Embryos Require) was initially identified as a target of antibodies from mice with ovarian immunity (Tong, Z-B. and L. M. Nelson (1999) Endocrinology 140:3720-3726). Expression of the gene encoding MATER is restricted to the oocyte, making it one of a limited number of known maternal-effect genes in mammals (Tong, Z-B. et al. (2000) Mamm. Genome 11:281-287). The MATER protein is required for embryonic development beyond two cells, based upon preliminary results from mice in which this gene has been inactivated. The 1111-amino acid MATER protein contains a hydrophilic repeat region in the amino terminus, and a region containing 14 leucine-rich repeats in the carboxyl terminus. These repeats resemble the sequence found in porcine ribonuclease inhibitor that is critical for protein-protein interactions. The degradation of maternal transcripts during meiotic maturation and ovulation may involve the activation of a ribonuclease just prior to ovulation. Thus the function of MATER may be to bind to the maternal ribonuclease and prevent degradation of zygotic transcripts (Tong et al., supra). In addition to its role in oocyte development and embryogenesis, MATER may also be relevant to the pathogenesis of ovarian immunity, as it is a target of autoantibodies in mice with autoimmune oophoritis (Tong and Nelson, supra). The maternal mRNA D7 is a moderately abundant transcript in Xenopus laevis whose expression is highest in, and perhaps restricted to, oogenesis and early embryogenesis. The D7 protein is absent from oocytes and first begins to accumulate during oocyte maturation. Its levels are highest during the first day of embryonic development and then they decrease. The loss of D7 protein affects the maturation process itself, significantly delaying the time course of germinal vesicle breakdown. Thus, D7 is a newly described protein involved in oocyte maturation (Smith, R. C. et al. (1988) Genes Dev. 2(10):1296-306.) Many other genes are involved in subsequent stages of embryogenesis. After fertilization, the oocyte is guided by fimbria at the distal end of each fallopian tube into and through the fallopian tube and thence into the uterus. Changes in the uterine endometrium prepare the tissue to support the implantation and embryonic development of a fertilized ovum. Several stages of division have occurred before the dividing ovum, now a blastocyst with about 100 cells, enters the uterus. Upon reaching the uterus, the developing blastocyst usually remains in the uterine cavity an additional two to four days before implanting in the endometrium, the inner lining of the uterus. Implantation results from the action of trophoblast cells that develop over the surface of the blastocyst. These cells secrete proteolytic enzymes that digest and liquefy the cells of the endometrium. The invasive process is reviewed in Fisher, S. J. and C. H. Damsky (1993; Semin Cell Biol 4:183-188) and Graham, C. H. and P. K. Lala (1992; Biochem Cell Biol 70:867-874). Once implantation has taken place, the trophoblast and other sublying cells proliferate rapidly, forming the placenta and the various membranes of pregnancy. (See Guyton, A. C. (1991) Textbook of Medical Physiology, 8 th ed. W.B. Saunders Company, Philadelphia Pa., pp. 915-919.) The placenta has an essential role in protecting and nourishing the developing fetus. In most species the syncytiotrophoblast layer is present on the outside of the placenta at the fetal-maternal interface. This is a continuous structure, one cell deep, formed by the fusion of the constituent trophoblast cells. The syncytiotrophoblast cells play important roles in maternal-fetal exchange, in tissue remodeling during fetal development, and in protecting the developing fetus from the maternal immune response (Stoye, J. P. and J. M. Coffin (2000) Nature 403:715-717). A gene called syncytin is the envelope gene of a human endogenous defective provirus. Syncytin is expressed in high levels in placenta, and more weakly in testis, but is not detected in any other tissues (Mi, S. et al. (2000) Nature 403:785-789). Syncytin expression in the placenta is restricted to the syncytiotrophoblasts. Since retroviral env proteins are often involved in promoting cell fusion events, it was thought that syncytin might be involved in regulating the fusion of trophoblast cells into the syncytiotrophoblast layer. Experiments demonstrated that syncytin can mediate cell fusion in vitro, and that anti-syncytin antibodies can inhibit the fusion of placental cytotrophoblasts (Mi et al., supra). In addition, a conserved immunosuppressive domain present in retroviral envelope proteins, and found in syncytin at amino acid residues 373-397, might be involved in preventing maternal immune responses against the developing embryo. Syncytin may also be involved in regulating trophoblast invasiveness by inducing trophoblast fusion and terminal differentiation (Mi et al., supra). Insufficient trophoblast infiltration of the uterine wall is associated with placental disorders such as preeclampsia, or pregnancy induced hypertension, while uncontrolled trophoblast invasion is observed in choriocarcinoma and other gestational trophoblastic diseases. Thus syncytin function may be involved in these diseases. Cell Differentiation Multicellular organisms are comprised of diverse cell types that differ dramatically both in structure and function, despite the fact that each cell is like the others in its hereditary endowment. Cell differentiation is the process by which cells come to differ in their structure and physiological function. The cells of a multicellular organism all arise from mitotic divisions of a single-celled zygote. The zygote is totipotent, meaning that it has the ability to give rise to every type of cell in the adult body. During development the cellular descendants of the zygote lose their totipotency and become determined. Once its prospective fate is achieved, a cell is said to have differentiated. All descendants of this cell will be of the same type. Human growth and development requires the spatial and temporal regulation of cell differentiation, along with cell proliferation and regulated cell death. These processes coordinate to control reproduction, aging, embryogenesis, morphogenesis, organogenesis, and tissue repair and maintenance. The processes involved in cell differentiation are also relevant to disease states such as cancer, in which case the factors regulating normal cell differentiation have been altered, allowing the cancerous cells to proliferate in an anaplastic, or undifferentiated, state. The mechanisms of differentiation involve cell-specific regulation of transcription and translation, so that different genes are selectively expressed at different times in different cells. Genetic experiments using the fruit fly Drosophila melanogaster have identified regulated cascades of transcription factors which control pattern formation during development and differentiation. These include the homeotic genes, which encode transcription factors containing homeobox motifs. The products of homeotic genes determine how the insect's imaginal discs develop from masses of undifferentiated cells to specific segments containing complex organs. Many genes found to be involved in cell differentiation and development in Drosophila have homologs in mammals. Some human genes have equivalent developmental roles to their Drosophila homologs. The human homolog of the Drosophila eyes absent gene (eya) underlies branchio-oto-renal syndrome, a developmental disorder affecting the ears and kidneys (Abdelhak, S. et al. (1997) Nat. Genet. 15:157-164). The Drosophila slit gene encodes a secreted leucine-rich repeat containing protein expressed by the midline glial cells and required for normal neural development. At the cellular level, growth and development are governed by the cell's decision to enter into or exit from the cell cycle and by the cell's commitment to a terminally differentiated state. Differential gene expression within cells is triggered in response to extracellular signals and other environmental cues. Such signals include growth factors and other mitogens such as retinoic acid; cell-cell and cell-matrix contacts; and environmental factors such as nutritional signals, toxic substances, and heat shock. Candidate genes that may play a role in differentiation can be identified by altered expression patterns upon induction of cell differentiation in vitro. The final step in cell differentiation results in a specialization that is characterized by the production of particular proteins, such as contractile proteins in muscle cells, serum proteins in liver cells and globins in red blood cell precursors. The expression of these specialized proteins depends at least in part on cell-specific transcription factors. For example, the homeobox-containing transcription factor PAX-6 is essential for early eye determination, specification of ocular tissues, and normal eye development in vertebrates. In the case of epidermal differentiation, the induction of differentiation-specific genes occurs either together with or following growth arrest and is believed to be linked to the molecular events that control irreversible growth arrest. Irreversible growth arrest is an early event which occurs when cells transit from the basal to the innermost suprabasal layer of the skin and begin expressing squamous-specific genes. These genes include those involved in the formation of the cross-linked envelope, such as transglutaminase I and III, involucrin, loricin, and small proline-rich repeat (SPRR) proteins. The SPRR proteins are 8-10 kDa in molecular mass, rich in proline, glutamine, and cysteine, and contain similar repeating sequence elements. The SPRR proteins may be structural proteins with a strong secondary structure or metal-binding proteins such as metallothioneins. (Jetten, A. M. and B. L. Harvat (1997) J. Dermatol. 24:711-725; PRINTS Entry PR00021 PRORICH Small proline-rich protein signature.) The Wnt gene family of secreted signaling molecules is highly conserved throughout eukaryotic cells. Members of the Wnt family are involved in regulating chondrocyte differentiation within the cartilage template. Wnt-5a, Wnt-5b and Wnt-4 genes are expressed in chondrogenic regions of the chicken limb, Wnt-5a being expressed in the perichondrium (mesenchymal cells immediately surrounding the early cartilage template). Wnt-5a misexpression delays the maturation of chondrocytes and the onset of bone collar formation in chicken limb (Hartmann, C. and C. J. Tabin (2000) Development 127:3141-3159). Glypicans are a family of cell surface heparan sulfate proteoglycans that play an important role in cellular growth control and differentiation. Cerebroglycan, a heparan sulfate proteoglycan expressed in the nervous system, is involved with the motile behavior of developing neurons (Stipp, C. S. et al. (1994) J. Cell Biol. 124:149-160). Notch plays an active role in the differentiation of glial cells, and influences the length and organization of neuronal processes (for a review, see Frisen, J. and U. Lendahl (2001) Bioessays 23:3-7). The Notch receptor signaling pathway is important for morphogenesis and development of many organs and tissues in multicellular species. Drosophila fringe proteins modulate the activation of the Notch signal transduction pathway at the dorsal-ventral boundary of the wing imaginal disc. Mammalian fringe-related family members participate in boundary determination during segmentation (Johnston, S. H. et al. (1997) Development 124:2245-2254). Recently a number of proteins have been found to contain a conserved cysteine-rich domain of about 60 amino-acid residues called the LIM domain (for Lin-11 Isl-1 Mec-3) (Freyd, G. et al. (1990) Nature 344:876-879; Baltz, R. et al. (1992) Plant Cell 4:1465-1466). In the LIM domain, there are seven conserved cysteine residues and a histidine. The LIM domain binds two zinc ions (Michelsen, J. W. et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:4404-4408). LIM does not bind DNA; rather, it seems to act as an interface for protein-protein interaction. Apoptosis Apoptosis is the genetically controlled process by which unneeded or defective cells undergo programmed cell death. Selective elimination of cells is as important for morphogenesis and tissue remodeling as is cell proliferation and differentiation. Lack of apoptosis may result in hyperplasia and other disorders associated with increased cell proliferation. Apoptosis is also a critical component of the immune response. Immune cells such as cytotoxic T-cells and natural killer cells prevent the spread of disease by inducing apoptosis in tumor cells and virus-infected cells. In addition, immune cells that fail to distinguish self molecules from foreign molecules must be eliminated by apoptosis to avoid an autoimmune response. Apoptotic cells undergo distinct morphological changes. Hallmarks of apoptosis include cell shrinkage, nuclear and cytoplasmic condensation, and alterations in plasma membrane topology. Biochemically, apoptotic cells are characterized by increased intracellular calcium concentration, fragmentation of chromosomal DNA, and expression of novel cell surface components. The molecular mechanisms of apoptosis are highly conserved, and many of the key protein regulators and effectors of apoptosis have been identified. Apoptosis generally proceeds in response to a signal which is transduced intracellularly and results in altered patterns of gene expression and protein activity. Signaling molecules such as hormones and cytokines are known both to stimulate and to inhibit apoptosis through interactions with cell surface receptors. Transcription factors also play an important role in the onset of apoptosis. A number of downstream effector molecules, especially proteases, have been implicated in the degradation of cellular components and the proteolytic activation of other apoptotic effectors. The phenomenon of apoptosis involves genes expressed specifically for just such an event. For example, the rat Rp8 gene is transiently expressed and thought to be involved in programmed cell death (Owens, G. P. and J. J. Cohen, (1992) Cancer Metastasis Rev. 11: 149-156.) The human homolog to Rp8, PDCD2, contains an open reading frame of 1,032 bp, encoding 344 amino acids. PDCD2 shares 81% identity at the DNA level and 83% identity at the polypeptide level with rat Rp8, and, is expressed in all tissues examined (Kawakami, T. et al. (1995) Cytogenet. Cell Genet. 71:41-43.) Apoptosis activation also occurs as a result of the induction of gene expression in response to a stimulus. The use of all-trans retinoic acid (ATRA) in the myloid cell line P39, derived from a patient with myelodysplastic syndrome (MDS), stimulates apoptosis. ATRA-induced apoptosis was mediated through the caspase pathway. The use of retinoic acid as a stimulant of apoptosis in human apoptotic HL-60 cells also detected an apoptosis related protein, APR-1 (Zhu, F. et al. (1999), GenBank Accession No. AF143225.2.) The Bcl-2 family of proteins, as well as other cytoplasmic proteins, are key regulators of apoptosis. There are at least 15 Bcl-2 family members within 3 subfamilies. These proteins have been identified in mammalian cells and in viruses, and each possesses at least one of four Bcl-2 homology domains (BH1 to BH4), which are highly conserved. Bcl-2 family proteins contain the BH1 and BH2 domains, which are found in members of the pro-survival subfamily, while those proteins which are most similar to Bcl-2 have all four conserved domains, enabling inhibition of apoptosis following encounters with a variety of cytotoxic challenges. Members of the pro-survival subfamily include Bcl-2, Bcl-x L , Bcl-w, Mcl-1, and A1 in mammals; NF-13 (chicken); CED-9 ( Caenorhabditis elegans ); and viral proteins BHRF1, LMW5-HL, ORF16, KS-Bcl-2, and E1B-19K. The BH3 domain is essential for the function of pro-apoptosis subfamily proteins. The two pro-apoptosis subfamilies, Bax and BH3, include Bax, Bak, and Bok (also called Mtd); and Bik, Blk, Hrk, BNIP3, Bim L , Bad, Bid, and Egl-1 ( C. elegans ); respectively. Members of the Bax subfamily contain the BH1, BH2, and BH3 domains, and resemble Bcl-2 rather closely. In contrast, members of the BH3 subfamily have only the 9-16 residue BH3 domain, being otherwise unrelated to any known protein, and only Bik and Blk share sequence similarity. The proteins of the two pro-apoptosis subfamilies may be the antagonists of pro-survival subfamily proteins. This is illustrated in C. elegans where Egl-1, which is required for apoptosis, binds to and acts via CED-9 (for review, see Adams, J. M. and S. Cory (1998) Science 281:1322-1326). Heterodimerization between pro-apoptosis and anti-apoptosis subfamily proteins seems to have a titrating effect on the functions of these protein subfamilies, which suggests that relative concentrations of the members of each subfamily may act to regulate apoptosis. Heterodimerization is not required for a pro-survival protein; however, it is essential in the BH3 subfamily, and less so in the Bax subfamily. The Bcl-2 protein has 2 isoforms, alpha and beta, which are formed by alternative splicing. It forms homodimers and heterodimers with Bax and Bak proteins and the Bcl-X isoform Bcl-x S . Heterodimerization with Bax requires intact BH1 and BH2 domains, and is necessary for pro-survival activity. The BH4 domain seems to be involved in pro-survival activity as well. Bcl-2 is located within the inner and outer mitochondrial membranes, as well as within the nuclear envelope and endoplasmic reticulum, and is expressed in a variety of tissues. Its involvement in follicular lymphoma (type II chronic lymphatic leukemia) is seen in a chromosomal translocation T(14;18) (q32;q21) and involves immunoglobulin gene regions. The Bcl-x protein is a dominant regulator of apoptotic cell death. Alternative splicing results in three isoforms, Bcl-xB, a long isoform, and a short isoform. The long isoform exhibits cell death repressor activity, while the short isoform promotes apoptosis. Bcl-xL forms heterodimers with Bax and Bak, although heterodimerization with Bax does not seem to be necessary for pro-survival (anti-apoptosis) activity. Bcl-xS forms heterodimers with Bcl-2. Bcl-x is found in mitochondrial membranes and the perinuclear envelope. Bcl-xS is expressed at high levels in developing lymphocytes and other cells undergoing a high rate of turnover. Bcl-xL is found in adult brain and in other tissues' long-lived post-mitotic cells. As with Bcl-2, the BH1, BH2, and BH4 domains are involved in pro-survival activity. The Bcl-w protein is found within the cytoplasm of almost all myeloid cell lines and in numerous tissues, with the highest levels of expression in brain, colon, and salivary gland. This protein is expressed in low levels in testis, liver, heart, stomach, skeletal muscle, and placenta, and a few lymphoid cell lines. Bcl-w contains the BH1, BH2, and BH4 domains, all of which are needed for its cell survival promotion activity. Although mice in which Bcl-w gene function was disrupted by homologous recombination were viable, healthy, and normal in appearance, and adult females had normal reproductive function, the adult males were infertile. In these males, the initial, prepuberty stage of spermatogenesis was largely unaffected and the testes developed normally. However, the seminiferous tubules were disorganized, contained numerous apoptotic cells, and were incapable of producing mature sperm. This mouse model may be applicable to some cases of human male sterility and suggests that alteration of programmed cell death in the testes may be useful in modulating fertility (Print, C. G. et al. (1998) Proc. Natl. Acad. Sci. USA 95:12424-12431). Studies in rat ischemic brain found Bcl-w to be overexpressed relative to its normal low constitutive level of expression in nonischemic brain. Furthermore, in vitro studies to examine the mechanism of action of Bcl-w revealed that isolated rat brain mitochondria were unable to respond to an addition of recombinant Bax or high concentrations of calcium when Bcl-w was also present. The normal response would be the release of cytochrome c from the mitochondria. Additionally, recombinant Bcl-w protein was found to inhibit calcium-induced loss of mitochondrial transmembrane potential, which is indicative of permeability transition. Together these findings suggest that Bcl-w may be a neuro-protectant against ischemic neuronal death and may achieve this protection via the mitochondrial death-regulatory pathway (Yan, C. et al. (2000) J. Cereb. Blood Flow Metab. 20:620-630). The bfl-1 gene is an additional member of the Bcl-2 family, and is also a suppressor of apoptosis. The Bfl-1 protein has 175 amino acids, and contains the BH1, BH2, and BH3 conserved domains found in Bcl-2 family members. It also contains a Gln-rich NH2-terminal region and lacks an NH domain 1, unlike other Bcl-2 family members. The mouse A1 protein shares high sequence homology with Bfl-1 and has the 3 conserved domains found in Bfl-1. Apoptosis induced by the p53 tumor suppressor protein is suppressed by Bfl-1, similar to the action of Bcl-2, Bcl-xL, and EBV-BHRF1 (D'Sa-Eipper, C. et al. (1996) Cancer Res. 56:3879-3882). Bfl-1 is found intracellularly, with the highest expression in the hematopoietic compartment, i.e. blood, spleen, and bone marrow; moderate expression in lung, small intestine, and testis; and minimal expression in other tissues. It is also found in vascular smooth muscle cells and hematopoietic malignancies. A correlation has been noted between the expression level of bfl-1 and the development of stomach cancer, suggesting that the Bfl-1 protein is involved in the development of stomach cancer, either in the promotion of cancerous cell survival or in cancer (Choi, S. S. et al. (1995) Oncogene 11: 1693-1698). Cancers are characterized by continuous or uncontrolled cell proliferation. Some cancers are associated with suppression of normal apoptotic cell death. Strategies for treatment may involve either reestablishing control over cell cycle progression, or selectively stimulating apoptosis in cancerous cells (Nigg, E. A. (1995) BioEssays 17:471-480). Immunological defenses against cancer include induction of apoptosis in mutant cells by tumor suppressors, and the recognition of tumor antigens by T lymphocytes. Response to mitogenic stresses is frequently controlled at the level of transcription and is coordinated by various transcription factors. For example, the Rel/NF-kappa B family of vertebrate transcription factors plays a pivotal role in inflammatory and immune responses to radiation. The NF-kappa B family includes p50, p52, RelA, RelB, cRel, and other DNA-binding proteins. The p52 protein induces apoptosis, upregulates the transcription factor c-Jun, and activates c-Jun N-terminal kinase 1 (JNK1) (Sun, L. et al. (1998) Gene 208:157-166). Most NF-kappa B proteins form DNA-binding homodimers or heterodimers. Dimerization of many transcription factors is mediated by a conserved sequence known as the bZIP domain, characterized by a basic region followed by a leucine zipper. The Fas/Apo-1 receptor (FAS) is a member of the tumor necrosis factor (TNF) receptor family. Upon binding its ligand (Fas ligand), the membrane-spanning FAS induces apoptosis by recruiting several cytoplasmic proteins that transmit the death signal. One such protein, termed FAS-associated protein factor 1 (FAF1), was isolated from mice, and it was demonstrated that expression of FAF1 in L cells potentiated FAS-induced apoptosis (Chu, K. et al. (1995) Proc. Natl. Acad. Sci. USA 92:11894-11898). Subsequently, FAS-associated factors have been isolated from numerous other species, including fruit fly and quail (Frohlich, T. et al. (1998) J. Cell Sci. 111:2353-2363). Another cytoplasmic protein that functions in the transmittal of the death signal from Fas is the Fas-associated death domain protein, also known as FADD. FADD transmits the death signal in both FAS-mediated and TNF receptor-mediated apoptotic pathways by activating caspase-8 (Bang, S. et al. (2000) J. Biol. Chem. 275:36217-36222). Fragmentation of chromosomal DNA is one of the hallmarks of apoptosis. Nucleolus fragmentation in the yeast Saccharomyces cerevisiae is characteristic of cellular aging, and leads to senescence and cell death. The longevity assurance protein 1 (LAG1) of Saccharomyces cerevisiae was the first longevity gene to be identified (D'mello, N. P. et al. (1994) J. Biol. Chem. 269:15451-15459.) The LAG1 gene, when deleted in haploid cells of Saccharomyces cerevisiae , resulted in a pronounced increase in both mean and maximum life span (approximately 50%) of the yeast mother cell. These results indicate that LAG1 is involved in determination of yeast longevity (D'mello, supra). The gene for a human (LAG1Hs) and Caenorhabditis elegans (LAG1Ce-1) homolog of LAG1 has been cloned (Jiang, J. C. et al. (1998) Genome Res. 8:1259-1272.) Both homologs are able to functionally complement the lethality of a lag1 double deletion mutant. LAG1Hs was able to restore the life span of the double deletion mutant, indicating its function in establishing the longevity phenotype. Expression studies found LAG1Hs expressed in only 3 tissues: brain, skeletal muscle, and testis. Although both the human and C. elegans proteins have low sequence identity to the yeast LAG1, these two proteins share with the yeast protein a short sequence, the Lag 1 motif, and similar transmembrane domain profiles. The expression pattern and ability to complement a yeast lag1 double deletion mutant suggests that LAG1Hs may have a role in human aging (Jaing, supra). DNA fragmentation factor (DFF) is a protein composed of two subunits, a 40-kDa caspase-activated nuclease termed DFF40/CAD, and its 45-kDa inhibitor DFF45/ICAD. Two mouse homologs of DFF45/ICAD, termed CIDE-A and CIDE-B, have recently been described (Inohara, N. et al. (1998) EMBO J. 17:2526-2533). CIDE-A and CIDE-B expression in mammalian cells activated apoptosis, while expression of CIDE-A alone induced DNA fragmentation. In addition, FAS-mediated apoptosis was enhanced by CIDE-A and CIDE-B, further implicating these proteins as effectors that mediate apoptosis. Transcription factors play an important role in the onset of apoptosis. A number of downstream effector molecules, particularly proteases such as the cysteine proteases called caspases, are involved in the initiation and execution phases of apoptosis. The activation of the caspases results from the competitive action of the pro-survival and pro-apoptosis Bcl-2-related proteins (Print, C. G. et al. (1998) Proc. Natl. Acad. Sci. USA 95:12424-12431). A pro-apoptotic signal can activate initiator caspases that trigger a proteolytic caspase cascade, leading to the hydrolysis of target proteins and the classic apoptotic death of the cell. Two active site residues, a cysteine and a histidine, have been implicated in the catalytic mechanism. Caspases are among the most specific endopeptidases, cleaving after aspartate residues. The caspase pathway is an example of the use of a signal transduction pathway as an effector arm of the apoptotic program. Caspases are a family of cysteine proteases related to the Caenorhabditis elegans CED-3 protein (Alnemri, E. S. et al. (1996) Cell 87:171.) To date, more than 10 caspases have been identified and partially characterized. Many have been implicated in the induction of apoptosis. Caspases are synthesized as inactive zymogens consisting of one large (p20) and one small (p10) subunit separated by a small spacer region, and a variable N-terminal prodomain. This prodomain interacts with cofactors that can positively or negatively affect apoptosis. An activating signal causes autoproteolytic cleavage of a specific aspartate residue (D297 in the caspase-1 numbering convention) and removal of the spacer and prodomain, leaving a p10/p20 heterodimer. Two of these heterodimers interact via their small subunits to form the catalytically active tetramer. The long prodomains of some caspase family members have been shown to promote dimerization and auto-processing of procaspases. Some caspases contain a “death effector domain” in their prodomain by which they can be recruited into self-activating complexes with other caspases and FADD protein-associated death receptors or the TNF receptor complex. In addition, two dimers from different caspase family members can associate, changing the substrate specificity of the resultant tetramer. Tumor necrosis factor (TNF) and related cytokines induce apoptosis in lymphoid cells. (Reviewed in Nagata, S. (1997) Cell 88:355-365.) Binding of TNF to its receptor triggers a signal transduction pathway that results in the activation of a proteolytic caspase cascade. One such caspase, ICE (Interleukin-1β converting enzyme), is a cysteine protease comprised of two large and two small subunits generated by ICE auto-cleavage (Dinarello, C. A. (1994) FASEB J. 8:1314-1325). ICE is expressed primarily in monocytes. ICE processes the cytokine precursor, interleukin-1β, into its active form, which plays a central role in acute and chronic inflammation, bone resorption, myelogenous leukemia, and other pathological processes. ICE and related caspases cause apoptosis when overexpressed in transfected cell lines. A caspase recruitment domain (CARD) is found within the prodomain of several apical caspases and is conserved in several apoptosis regulatory molecules such as Apaf-2, RAIDD, and cellular inhibitors of apoptosis proteins (IAPs) (Hofmann, K. et al. (1997) Trends Biochem. Sci. 22:155-157). The regulatory role of CARD in apoptosis may be to allow proteins such as Apaf-1 to associate with caspase-9 (Li, P. et al. (1997) Cell 91:479-489). A human cDNA encoding an apoptosis repressor with a CARD (ARC) which is expressed in both skeletal and cardiac muscle has been identified and characterized. ARC functions as an inhibitor of apoptosis and interacts selectively with caspases (Koseki, T. et al. (1998) Proc. Natl. Acad. Sci. USA 95:5156-5160). All of these interactions have clear effects on the control of apoptosis (reviewed in Chan S. L. and M. P. Mattson (1999) J. Neurosci. Res. 58:167-190; Salveson, G. S. and V. M. Dixit (1999) Proc. Natl. Acad. Sci. USA 96:10964-10967). ES18 was identified as a potential regulator of apoptosis in mouse T-cells (Park, E. J. et al. (1999) Nuc. Acid. Res. 27:1524-1530). ES18 is 428 amino acids in length, contains an N-terminal proline-rich region, an acidic glutamic acid-rich domain, and a putative LXXLL nuclear receptor binding motif. The protein is preferentially expressed in lymph nodes and thymus. The level of ES18 expression increases in T-cell thymoma S49.1 in response to treatment with dexamethasone, staurosporine, or C2-ceramide, which induce apoptosis. ES18 may play a role in stimulating apoptotic cell death in T-cells. The rat ventral prostate (RVP) is a model system for the study of hormone-regulated apoptosis. RVP epithelial cells undergo apoptosis in response to androgen deprivation. Messenger RNA (mRNA) transcripts that are up-regulated in the apoptotic RVP have been identified (Briehl, M. M. and R. L. Miesfeld (1991) Mol. Endocrinol. 5:1381-1388). One such transcript encodes RVP.1, the precise role of which in apoptosis has not been determined. The human homolog of RVP.1, hRVP1, is 89% identical to the rat protein (Katahira, J. et al. (1997) J. Biol. Chem. 272:26652-26658). hRVP1 is 220 amino acids in length and contains four transmembrane domains. hRVP1 is highly expressed in the lung, intestine, and liver. Interestingly, hRVP1 functions as a low affinity receptor for the Clostridium perfringens enterotoxin, a causative agent of diarrhea in humans and other animals. Cytokine-mediated apoptosis plays an important role in hematopoiesis and the immune response. Myeloid cells, which are the stem cell progenitors of macrophages, neutrophils, erythrocytes, and other blood cells, proliferate in response to specific cytokines such as granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin-3 (IL-3). When deprived of GM-CSF or IL-3, myeloid cells undergo apoptosis. The murine requiem (req) gene encodes a putative transcription factor required for this apoptotic response in the myeloid cell line FDCP-1 (Gabig, T. G. et al. (1994) J. Biol. Chem. 269:29515-29519). The Req protein is 371 amino acids in length and contains a nuclear localization signal, a single Kruppel-type zinc finger, an acidic domain, and a cluster of four unique zinc-finger motifs enriched in cysteine and histidine residues involved in metal binding. Expression of req is not myeloid- or apoptosis-specific, suggesting that additional factors regulate Req activity in myeloid cell apoptosis. Dysregulation of apoptosis has recently been recognized as a significant factor in the pathogenesis of many human diseases. For example, excessive cell survival caused by decreased apoptosis can contribute to disorders related to cell proliferation and the immune response. Such disorders include cancer, autoimmune diseases, viral infections, and inflammation. In contrast, excessive cell death caused by increased apoptosis can lead to degenerative and immunodeficiency disorders such as AIDS, neurodegenerative diseases, and myelodysplastic syndromes. (Thompson, C. B. (1995) Science 267:1456-1462.) Impaired regulation of apoptosis is also associated with loss of neurons in Alzheimer's disease. Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by the formation of senile plaques and neurofibrillary tangles containing amyloid beta peptide. These plaques are found in limbic and association-cortices of the brain, including hippocampus, temporal cortices, cingulate cortex, amygdala, nucleus basalis and locus caeruleus. B-amyloid peptide participates in signaling pathways that induce apoptosis and lead to the death of neurons (Kajkowski, C. et al. (2001) J. Biol. Chem. 276:18748-18756). Early in Alzheimer's pathology, physiological changes are visible in the cingulate cortex (Minoshima, S. et al. (1997) Annals of Neurology 42:85-94). In subjects with advanced Alzheimer's disease, accumulating plaques damage the neuronal architecture in limbic areas and eventually cripple the memory process. Cancer Cancers are characterized by continuous or uncontrolled cell proliferation. Some cancers are associated with suppression of normal apoptotic cell death. Understanding of the neoplastic process can be aided by the identification of molecular markers of prognostic and diagnostic importance. Cancers are associated with oncoproteins which are capable of transforming normal cells into malignant cells. Some oncoproteins are mutant isoforms of the normal protein while others are abnormally expressed with respect to location or level of expression. Normal cell proliferation begins with binding of a growth factor to its receptor on the cell membrane, resulting in activation of a signal system that induces and activates nuclear regulatory factors to initiate DNA transcription, subsequently leading to cell division. Classes of oncoproteins known to affect the cell cycle controls include growth factors, growth factor receptors, intracellular signal transducers, nuclear transcription factors, and cell-cycle control proteins. Several types of cancer-specific genetic markers, such as tumor antigens and tumor suppressors, have also been identified. Oncogenes Oncoproteins are encoded by genes, called oncogenes, that are derived from genes that normally control cell growth and development. Many oncogenes have been identified and characterized. These include growth factors such as sis, receptors such as erbA, erbB, neu, and ros, intracellular receptors such as src, yes, fps, abl, and met, protein-serine/threonine kinases such as mos and raf, nuclear transcription factors such as jun, fos, myc, N-myc, myb, ski, and rel, cell cycle control proteins such as RB and p53, mutated tumor-suppressor genes such as mdm2, Cip1, p16, and cyclin D, ras, set, can, sec, and gag R10. Viral oncogenes are integrated into the human genome after infection of human cells by certain viruses. Examples of viral oncogenes include v-src, v-abl, and v-fps. Transformation of normal genes to oncogenes may also occur by chromosomal translocation. The Philadelphia chromosome, characteristic of chronic myeloid leukemia and a subset of acute lymphoblastic leukemias, results from a reciprocal translocation between chromosomes 9 and 22 that moves a truncated portion of the proto-oncogene c-abl to the breakpoint cluster region (bcr) on chromosome 22. The hybrid c-abl-bcr gene encodes a chimeric protein that has tyrosine kinase activity. In chronic myeloid leukemia, the chimeric protein has a molecular weight of 210 kd, whereas in acute leukemias a more active 180 kd tyrosine kinase is formed (Robbins, S. L. et al. (1994) Pathologic Basis of Disease , W.B. Saunders Co., Philadelphia Pa.). The Ras superfamily of small GTPases is involved in the regulation of a wide range of cellular signaling pathways. Ras family proteins are membrane-associated proteins acting as molecular switches that bind GTP and GDP, hydrolyzing GTP to GDP. In the active GTP-bound state Ras family proteins interact with a variety of cellular targets to activate downstream signaling pathways. For example, members of the Ras subfamily are essential in transducing signals from receptor tyrosine kinases (RTKs) to a series of serine/threonine kinases which control cell growth and differentiation. Activated Ras genes were initially found in human cancers and subsequent studies confirmed that Ras function is critical in the determination of whether cells continue to grow or become terminally differentiated (Barbacid, M. (1987) Annu. Rev. Biochem. 56:779-827; Treisman, R. (1994) Curr. Opin. Genet. Dev. 4:96-98). Mutant Ras proteins, which bind but can not hydrolyze GTP, are permanently activated, and cause continuous cell proliferation or cancer. Activation of Ras family proteins is catalyzed by guanine nucleotide exchange factors (GEFs) which catalyze the dissociation of bound GDP and subsequent binding of GTP. A recently discovered RalGEF-like protein, RGL3, interacts with both Ras and the related protein Rit. Constitutively active Rit, like Ras, can induce oncogenic transformation, although since Rit fails to interact with most known Ras effector proteins, novel cellular targets may be involved in Rit transforming activity. RGL3 interacts with both Ras and Rit, and thus may act as a downstream effector for these proteins (Shao, H. and D. A. Andres (2000) J. Biol. Chem. 275:26914-26924). Tumor Antigens Tumor antigens are cell surface molecules that are differentially expressed in tumor cells relative to non-tumor tissues. Tumor antigens make tumor cells immunologically distinct from normal cells and are potential diagnostics for human cancers. Several monoclonal antibodies have been identified which react specifically with cancerous cells such as T-cell acute lymphoblastic leukemia and neuroblastoma (Minegishi, M. et al. (1989) Leukemia Res. 13:43-51; Takagi, S. et al. (1995) Int. J. Cancer 61:706-715). In addition, the discovery of high level expression of the HER2 gene in breast tumors has led to the development of therapeutic treatments (Liu, E. et al. (1992) Oncogene 7: 1027-1032; Kern, J. A. (1993) Am. J. Respir. Cell Mol. Biol. 9:448-454). Tumor antigens are found on the cell surface and have been characterized either as membrane proteins or glycoproteins. For example, MAGE genes encode a family of tumor antigens recognized on melanoma cell surfaces by autologous cytolytic T lymphocytes. Among the 12 human MAGE genes isolated, half are differentially expressed in tumors of various histological types (De Plaen, E. et al. (1994) Immunogenetics 40:360-369). None of the 12 MAGE genes, however, is expressed in healthy tissues except testis and placenta. Tumor Suppressors Tumor suppressor genes are generally defined as genetic elements whose loss or inactivation contributes to the deregulation of cell proliferation and the pathogenesis and progression of cancer. Tumor suppressor genes normally function to control or inhibit cell growth in response to stress and to limit the proliferative life span of the cell. Several tumor suppressor genes have been identified including the genes encoding the retinoblastoma (Rb) protein, p53, and the breast cancer 1 and 2 proteins (BRCA1 and BRCA2). Mutations in these genes are associated with acquired and inherited genetic predisposition to the development of certain cancers. The role of p53 in the pathogenesis of cancer has been extensively studied. (Reviewed in Aggarwal, M. L. et al. (1998) J. Biol. Chem. 273:14; Levine, A. (1997) Cell 88:323-331.) About 50% of all human cancers contain mutations in the p53 gene. These mutations result in either the absence of functional p53 or, more commonly, a defective form of p53 which is overexpressed. p53 is a transcription factor that contains a central core domain required for DNA binding. Most cancer-associated mutations in p53 localize to this domain. In normal proliferating cells, p53 is expressed at low levels and is rapidly degraded. p53 expression and activity is induced in response to DNA damage, abortive mitosis, and other stressful stimuli. In these instances, p53 induces apoptosis or arrests cell growth until the stress is removed. Downstream effectors of p53 activity include apoptosis-specific proteins and cell cycle regulatory proteins, including Rb, oncogene products, cyclins, and cell cycle-dependent kinases. The metastasis-suppressor gene KAI1 (CD82) has been reported to be related to the tumor suppressor gene p53. KAI1 is involved in the progression of human prostatic cancer and possibly lung and breast cancers when expression is decreased. KAI1 encodes a member of a structurally distinct family of leukocyte surface glycoproteins. The family is known as either the tetraspan transmembrane protein family or transmembrane 4 superfamily (TM4SF) as the members of this family span the plasma membrane four times. The family is composed of integral membrane proteins having a N-terminal membrane-anchoring domain which functions as both a membrane anchor and a translocation signal during protein biosynthesis. The N-terminal membrane-anchoring domain is not cleaved during biosynthesis. TM4SF proteins have three additional transmembrane regions, seven or more conserved cysteine residues, are similar in size (218 to 284 residues), and all have a large extracellular hydrophilic domain with three potential N-glycosylation sites. The promoter region contains many putative binding motifs for various transcription factors, including five AP2 sites and nine SpI sites. Gene structure comparisons of KAI1 and seven other members of the TM4SF indicate that the splicing sites relative to the different structural domains of the predicted proteins are conserved. This suggests that these genes are related evolutionarily and arose through gene duplication and divergent evolution (Levy, S. et al. (1991) J. Biol. Chem. 266:14597-14602; Dong, J. T. et al. (1995) Science 268:884-886; Dong, J. T. et al., (1997) Genomics 41:25-32). The Leucine-rich gene-Glioma Inactivated (LGI1) protein shares homology with a number of transmembrane and extracellular proteins which function as receptors and adhesion proteins. LGI1 is encoded by an LLR (leucine-rich, repeat-containing) gene and maps to 10q24. LGI1 has four LLRs which are flanked by cysteine-rich regions and one transmembrane domain (Somerville, R. P. et al. (2000) Mamm. Genome 11:622-627). LGI1 expression is seen predominantly in neural tissues, especially brain. The loss of tumor suppressor activity is seen in the inactivation of the LGI1 protein which occurs during the transition from low to high-grade tumors in malignant gliomas. The reduction of LGI1 expression in low grade brain tumors and its significant reduction or absence of expression in malignant gliomas suggests that it could be used for diagnosis of glial tumor progression (Chernova, O. B. et al. (1998) Oncogene 17:2873-2881). The ST13 tumor suppressor was identified in a screen for factors related to colorectal carcinomas by subtractive hybridization between cDNA of normal mucosal tissues and mRNA of colorectal carcinoma tissues (Cao, J. et al. (1997) J. Cancer Res. Clin. Oncol. 123:447451). ST13 is down-regulated in human colorectal carcinomas. Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are associated with retinal and central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas (Hoffman, M. et al. (2001) Hum. Mol. Genet. 10:1019-1027; Kamada, M. (2001) Cancer Res. 61:4184-4189). Tumor progression is linked to defects or inactivation of the VHL gene. VHL regulates the expression of transforming growth factor-α, the GLUT-1 glucose transporter and vascular endothelial growth factor. The VHL protein associates with elongin B, elongin C, Cul2 and Rbx1 to form a complex that regulates the transcriptional activator hypoxia-inducible factor (HIF). HIF induces genes involved in angiogenesis such as vascular endothelial growth factor and platelet-derived growth factor B. Loss of control of HIF caused by defects in VHL results in the excessive production of angiogenic peptides. VHL may play roles in inhibition of angiogenesis, cell cycle control, fibronectin matrix assembly, cell adhesion, and proteolysis. Mutations in tumor suppressor genes are a common feature of many cancers and often appear to affect a critical step in the pathogenesis and progression of tumors. Accordingly, Chang, F. et al. (1995; J. Clin. Oncol. 13:1009-1022) suggest that it may be possible to use either the gene or an antibody to the expressed protein 1) to screen patients at increased risk for cancer, 2) to aid in diagnosis made by traditional methods, and 3) to assess the prognosis of individual cancer patients. In addition, Hamada, K. et al. (1996; Cancer Res. 56:3047-3054) are investigating the introduction of p53 into cervical cancer cells via an adenoviral vector as an experimental therapy for cervical cancer. The PR-domain genes were recently recognized as playing a role in human tumorigenesis. PR-domain genes normally produce two protein products: the PR-plus product, which contains the PR domain, and the PR-minus product which lacks this domain. In cancer cells, PR-plus is disrupted or overexpressed, while PR-minus is present or overexpressed. The imbalance in the amount of these two proteins appears to be an important cause of malignancy (Jiang, G. L. and S. Huang (2000) Histol. Histopathol. 15:109-117). Many neoplastic disorders in humans can be attributed to inappropriate gene transcription. Malignant cell growth may result from either excessive expression of tumor promoting genes or insufficient expression of tumor suppressor genes (Cleary, M. L. (1992) Cancer Surv. 15:89-104). Chromosomal translocations may also produce chimeric loci which fuse the coding sequence of one gene with the regulatory regions of a second unrelated gene. An important class of transcriptional regulators are the zinc finger proteins. The zinc finger motif, which binds zinc ions, generally contains tandem repeats of about 30 amino acids consisting of periodically spaced cysteine and histidine residues. Examples of this sequence pattern include the C2H2-type, C4-type, and C3HC4-type zinc fingers, and the PHD domain (Lewin, B. (1990) Genes IV , Oxford University Press, New York, N.Y., and Cell Press, Cambridge, Mass., pp. 554-570; Aasland, R., et al. (1995) Trends Biochem. Sci. 20:56-59). One clinically relevant zinc-finger protein is WT1, a tumor-suppressor protein that is inactivated in children with Wilm's tumor. The oncogene bcl-6, which plays an important role in large-cell lymphoma, is also a zinc-finger protein (Papavassiliou, A. G. (1995) N. Engl. J. Med. 332:45-47). ERM proteins are responsible for the cross-linking of actin filaments to the plasma membrane. FERM domains, located at the N-terminal regions of ERM proteins, regulate interactions between the cytoplasmic domains of the integrated membrane proteins with the membrane itself. The Protein 4.1 family of molecules are responsible for linking the actin cytoskeleton to cell surface glycoproteins. For example, the neurofibromatosis 2 (NF2) tumor suppressor is a member of the Protein 4.1 family. NF2 proteins participate in suppression of cell growth, and retard other cytoskeletal-dependent functions including cell spreading, attachment and motility (Gutmann, D. H. et al. (2001) Neurobiol. Dis. 8:266-278). Recently, a novel putative tumor suppressor gene and member of the NF2/ERM/4.1 superfamily, possessing homology to SEQ ID NO:13, has been observed to retard the growth of non-small cell lung carcinoma cells (Tran, Y. K. et al. (1999) Cancer Res. 59:35-43). Tumor Responsive Proteins Cancers, also called neoplasias, are characterized by continuous and uncontrolled cell proliferation. They can be divided into three categories: carcinomas, sarcomas, and leukemias. Carcinomas are malignant growths of soft epithelial cells that may infiltrate surrounding tissues and give rise to metastatic tumors. Sarcomas may be of epithelial origin or arise from connective tissue. Leukemias are progressive malignancies of blood-forming tissue characterized by proliferation of leukocytes and their precursors, and may be classified as myelogenous (granulocyte- or monocyte-derived) or lymphocytic (lymphocyte-derived). Tumorigenesis refers to the progression of a tumor's growth from its inception. Malignant cells may be quite similar to normal cells within the tissue of origin or may be undifferentiated (anaplastic). Tumor cells may possess few nuclei or one large polymorphic nucleus. Anaplastic cells may grow in a disorganized mass that is poorly vascularized and as a result contains large areas of ischemic necrosis. Differentiated neoplastic cells may secrete the same proteins as the tissue of origin. Cancers grow, infiltrate, invade, and destroy the surrounding tissue through direct seeding of body cavities or surfaces, through lymphatic spread, or through hematogenous spread. Cancer remains a major public health concern and current preventative measures and treatments do not match the needs of most patients. Understanding of the neoplastic process of tumorigenesis can be aided by the identification of molecular markers of prognostic and diagnostic importance. Current forms of cancer treatment include the use of immunosuppressive drugs (Morisaki, T. et al. (2000) Anticancer Res. 20:3363-3373; Geoerger, B. et al. (2001) Cancer Res. 61:1527-1532). The identification of proteins involved in cell signaling, and specifically proteins that act as receptors for immunosuppressant drugs, may facilitate the development of anti-tumor agents. For example, immunophilins are a family of conserved proteins found in both prokaryotes and eukaryotes that bind to immunosuppressive drugs with varying degrees of specificity. One such group of immunophilic proteins is the peptidyl-prolyl cis-trans isomerase (EC 5.2.1.8) family (PPIase, rotamase). These enzymes, first isolated from porcine kidney cortex, accelerate protein folding by catalyzing the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (Fischer, G. and F. X. Schmid (1990) Biochemistry 29:2205-2212). Included within the immunophilin family are the cyclophilins (e.g., peptidyl-prolyl isomerase A or PPIA) and FK-binding protein (e.g., FKBP) subfamilies. Cyclophilins are multifunctional receptor proteins which participate in signal transduction activities, including those mediated by cyclosporin (or cyclosporine). The PPIase domain of each family is highly conserved between species. Although structurally distinct, these multifunctional receptor proteins are involved in numerous signal transduction pathways, and have been implicated in folding and trafficking events. The immunophilin protein cyclophilin binds to the immunosuppressant drug cyclosporin A. FKBP, another immunophilin, binds to FK506 (or rapamycin). Rapamycin is an immunosuppressant agent that arrests cells in the G 1 phase of growth, inducing apoptosis. Like cyclophilin, this macrolide antibiotic (produced by Streptomyces tsukubaensis ) acts by binding to ubiquitous, predominantly cytosolic immunophilin receptors. These immunophilin/immunosuppressant complexes (e.g., cyclophilin A/cyclosporin A (CypA/CsA) and FKBP12/FK506) achieve their therapeutic results through inhibition of the phosphatase calcineurin, a calcium/calmodulin-dependent protein kinase that participates in T-cell activation (Hamilton, G. S. and J. P. Steiner (1998) J. Med. Chem. 41: 5119-5143). The murine fkbp51 gene is abundantly expressed in immunological tissues, including the thymus and T lymphocytes (Baughman, G. et al. (1995) Molec. Cell. Biol. 15: 4395-4402). FKBP12/rapamycin-directed immunosuppression occurs through binding to TOR (yeast) or FRAP (FKBP12-rapamycin-associated protein, in mammalian cells), the kinase target of rapamycin essential for maintaining normal cellular growth patterns. Dysfunctional TOR signaling has been linked to various human disorders including cancer (Metcalfe, S. M. et al. (1997) Oncogene 15:1635-1642; Emami, S. et al. (2001) FASEB J. 15:351-361), and autoimmunity (Damoiseaux, J. G. et al. (1996) Transplantation 62:994-1001). Several cyclophilin isozymes have been identified, including cyclophilin B, cyclophilin C, mitochondrial matrix cyclophilin, bacterial cytosolic and periplasmic PPIases, and natural-killer cell cyclophilin-related protein possessing a cyclophilin-type PPIase domain, a putative tumor-recognition complex involved in the function of natural killer (NK) cells. These cells participate in the innate cellular immune response by lysing virally-infected cells or transformed cells. NK cells specifically target cells that have lost their expression of major histocompatibility complex (MHC) class I genes (common during tumorigenesis), endowing them with the potential for attenuating tumor growth. A 150-kDa molecule has been identified on the surface of human NK cells that possesses a domain which is highly homologous to cyclophilin/peptidyl-prolyl cis-trans isomerase. This cyclophilin-type protein may be a component of a putative tumor-recognition complex, a NK tumor recognition sequence (NK-TR) (Anderson, S. K. et al. (1993) Proc. Natl. Acad. Sci. USA 90:542-546). The NKTR tumor recognition sequence mediates recognition between tumor cells and large granular lymphocytes (LGLs), a subpopulation of white blood cells (comprised of activated cytotoxic T cells and natural killer cells) capable of destroying tumor targets. The protein product of the NKTR gene presents on the surface of LGLs and facilitates binding to tumor targets. More recently, a mouse Nktr gene and promoter region have been located on chromosome 9. The gene encodes a NK-cell-specific 150-kDa protein (NK-TR) that is homologous to cyclophilin and other tumor-responsive proteins (Simons-Evelyn, M. et al. (1997) Genomics 40:94-100). Other proteins that interact with tumorigenic tissue include cytokines such as tumor necrosis factor (TNF). The TNF family of cytokines are produced by lymphocytes and macrophages, and can cause the lysis of transformed (tumor) endothelial cells. Endothelial protein 1 (Edp1) has been identified as a human gene activated transcriptionally by TNF-alpha in endothelial cells, and a TNF-alpha inducible Edp1 gene has been identified in the mouse (Swift, S. et al. (1998) Biochim. Biophys. Acta 1442:394-398). Claudins are a multi-gene family of integral membrane proteins that have four predicted transmembrane domains (Morita, K. et al. (1999) Proc. Natl. Acad. Sci. USA 96:511-516). Several members of the claudin family have been found associated with tight junctions (TJs) in various tissues. For example, human claudin-1 is a hydrophobic protein of 211 residues that incorporates into TJ strands. TJs are located at the most apical region of polarized epithelial and endothelial cells where they form a network of strands within plasma membranes and surround cells with a belt-like structure. The network of TJ strands within membranes creates a permeability barrier to the lateral diffusion of lipids and proteins between apical and basolateral membrane domains and maintains cellular polarity. In the region between adjacent cells where two apposing membranes come close together, each tight junction strand associates with that in the apposing membrane to form a paired strand. The formation of paired TJ strands between adjacent cells creates a permeablity barrier for the diffusion of solutes through the paracellular pathway. Claudin-1 plays a role at tight junction strands in maintaining and controlling cell polarity and permeability. It belongs to a superfamily of epithelial membrane proteins (EMPs) known to carry out functions in cell growth, differentiation, and apoptosis (Lobsiger, C. S. et al. (1996) Genomics 36:379-387). Aberrant expression of EMPs is associated with tumorigenesis (Ben-Porath, I. and Benvenisty, N. (1996) Gene 183:69-75). Expression Profiling Microarrays are analytical tools used in bioanalysis. A microarray has a plurality of molecules spatially distributed over, and stably associated with, the surface of a solid support. Microarrays of polypeptides, polynucleotides, and/or antibodies have been developed and find use in a variety of applications, such as gene sequencing, monitoring gene expression, gene mapping, bacterial identification, drug discovery, and combinatorial chemistry. One area in particular in which microarrays find use is in gene expression analysis. Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants. When an expression profile is examined, arrays provide a platform for identifying genes that are tissue specific, are affected by a substance being tested in a toxicology assay, are part of a signaling cascade, carry out housekeeping functions, or are specifically related to a particular genetic predisposition, condition, disease, or disorder. Colon cancer is causally related to both genes and the environment. Several molecular pathways have been linked to the development of colon cancer, and the expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. There is a particular need to identify genes for which changes in expression may provide an early indicator of colon cancer or a predisposition for the development of colon cancer. For example, it is well known that abnormal patterns of DNA methylation occur consistently in human tumors and include, simultaneously, widespread genomic hypomethylation and localized areas of increased methylation. In colon cancer in particular, it has been found that these changes occur early in tumor progression such as in premalignant polyps that precede colon cancer. Indeed, DNA methyltransferase, the enzyme that performs DNA methylation, is significantly increased in histologically normal mucosa from patients with colon cancer or the benign polyps that precede cancer, and this increase continues during the progression of colonic neoplasms (Wafik, S. et al. (1991) Proc. Natl. Acad. Sci. USA 88:3470-3474). Increased DNA methylation occurs in G+C rich areas of genomic DNA termed “CpG islands” that are important for maintenance of an “open” transcriptional conformation around genes, and that hypermethylation of these regions results in a “closed” conformation that silences gene transcription. It has been suggested that the silencing or downregulation of differentiation genes by such abnormal methylation of CpG islands may prevent differentiation in immortalized cells (Antequera, F. et al. (1990) Cell 62:503-514). Familial Adenomatous Polyposis (FAP) is a rare autosomal dominant syndrome that precedes colon cancer and is caused by an inherited mutation in the adenomatous polyposis coli (APC) gene. FAP is characterized by the early development of multiple colorectal adenomas that progress to cancer at a mean age of 44 years. The APC gene is a part of the APC-β-catenin-Tcf (T-cell factor) pathway. Impairment of this pathway results in the loss of orderly replication, adhesion, and migration of colonic epithelial cells that results in the growth of polyps. A series of other genetic changes follow activation of the APC-β-catenin-Tcf pathway and accompanies the transition from normal colonic mucosa to metastatic carcinoma. These changes include mutation of the K-Ras proto-oncogene, changes in methylation patterns, and mutation or loss of the tumor suppressor genes p53 and Smad4/DPC4. While the inheritance of a mutated APC gene is a rare event, the loss or mutation of APC and the consequent effects on the APC-β-catenin-Tcf pathway is believed to be central to the majority of colon cancers in the general population. Hereditary nonpolyposis Colorectal Cancer (HNPCC) is another inherited autosomal dominant syndrome with a less well defined phenotype than FAP. HNPCC, which accounts for about 2% of colorectal cancer cases, is distinguished by the tendency to early onset of cancer and the development of other cancers, particularly those involving the endometrium, urinary tract, stomach and biliary system. HNPCC results from the mutation of one or more genes in the DNA mis-match repair (MMR) pathway. Mutations in two human MMR genes, MSH2 and MLH1, are found in a large majority of HNPCC families identified to date. The DNA MMR pathway identifies and repairs errors that result from the activity of DNA polymerase during replication. Furthermore, loss of MMR activity contributes to cancer progression through accumulation of other gene mutations and deletions, such as loss of the BAX gene which controls apoptosis, and the TGFβ receptor II gene which controls cell growth. Because of the potential for irreparable damage to DNA in an individual with a DNA MMR defect, progression to carcinoma is more rapid than usual. Although ulcerative colitis is a minor contributor to colon cancer, affected individuals have about a 20-fold increase in risk for developing cancer. Progression is characterized by loss of the p53 gene which may occur early, appearing even in histologically normal tissue. The progression of the disease from ulcerative colitis to dysplasia/carcinoma without an intermediate polyp state suggests a high degree of mutagenic activity resulting from the exposure of proliferating cells in the colonic mucosa to the colonic contents. Almost all colon cancers arise from cells in which the estrogen receptor (ER) gene has been silenced. The silencing of ER gene transcription is age related and linked to hypermethylation of the ER gene (Issa, J-P. J. et al. (1994) Nature Genetics 7:536-540). Introduction of an exogenous ER gene into cultured colon carcinoma cells results in marked growth suppression. The connection between loss of the ER protein in colonic epithelial cells and the consequent development of cancer has not been established. There is a need in the art for new compositions, including nucleic acids and proteins, for the diagnosis, prevention, and treatment of cell proliferative disorders including cancer, developmental disorders, neurological disorders, autoimmune/inflammatory disorders, metabolic disorders, reproductive disorders, and disorders of the placenta. |
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