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1-20. (canceled). 21. A method for transmitting data from a sender to at least two receivers, the method comprising the steps of: providing a point-to-multipoint service as an extension to a broadcast service in a multilayer protocol system by at least one of a multimedia transmission and a multicast service; and using the point-to-multipoint service provided as an extension to a broadcast service for at least one of (a) planning of use of system resources and use of discontinuous reception, and (b) allocation of use of system resources and use of discontinuous reception. 22. A method for transmitting data from a sender to at least two receivers as claimed in claim 21, wherein the point-to-multipoint service provided as an extension to a broadcast service is a multimedia broadcast/multicast service. 23. A method for transmitting data from a sender to at least two receivers as claimed in claim 21, wherein the planning is carried out in two stages. 24. A method for transmitting data from a sender to at least two receivers as claimed in claim 23, wherein an MC DRX level 1 message is used to signal where, how many and when resources are assigned for transmission of planning information. 25. A method for transmitting data from a sender to at least two receivers as claimed in claim 24, wherein an MC DRX level 1 message is used to transmit information elements regarding one of which resources of transport channels and which frames of physical channels are respectively reserved or assigned. 26. A method for transmitting data from a sender to at least two receivers as claimed in claim 25, wherein a recipient is notified, via one of scheduling messages and planning messages, of planning regarding at least one of which physical channels, which transport channels, which frames and which resources for multicast services are made available, and when, as well as when the respective physical channels, transport channels, frames and resources for the multicast services actually transport multicast messages. 27. A method for transmitting data from a sender to at least two receivers as claimed in claim 25, wherein a common traffic channel is mapped, based on a requirement by the sender, onto transport channels other than a forward access channel and onto physical channels other than a secondary common control physical channel. 28. A method for transmitting data from a sender to at least two receivers as claimed in claim 21, wherein various protocol layers are configured based on planning messages from discontinuous reception via a radio resource monitoring unit in a receiver. 29. A method for transmitting data from a sender to at least two receivers as claimed in claim 21, wherein notification is provided at a physical level regarding the resources in which one of data in a multicast message and further planning messages can be expected. 30. A method for transmitting data from a sender to at least two receivers as claimed in claim 21, wherein information about a respective multicast group is attached to messages regarding at least one of planning and allocation of resources. 31. A method for transmitting data from a sender to at least two receivers as claimed in claim 30, wherein multicast groups are indicated by one of a multicast group address and a multicast group identity. 32. A method for transmitting data from a sender to at least two receivers as claimed in claim 30, wherein further information in a message is identified in a monitoring layer for deciding whether a multicast message with payload data should be received. 33. A method for transmitting data from a sender to at least two receivers as claimed in claim 32, wherein the further information is signaled via an MC DRX level 2 message. 34. A method for transmitting data from a sender to at least two receivers as claimed in claim 33, wherein an MC DRX level 2 message is used to signal the resources to which multicast messages actually can be transmitted as physical channels and transport channels. 35. A method for transmitting data from a sender to at least two receivers as claimed in claim 34, wherein previously assigned indices are used as a basis for one of (a) assigning resources of physical channels and transport channels, and (b) notifying when multicast messages are actually transmitted to resources of physical channels and transport channels. 36. A method for transmitting data from a sender to at least two receivers as claimed in claim 35, wherein at least one of an offset with respect to a first frame which is used for a multicast transmission is indicated and a cell broadcast service planning period is indicated. 37. A method for transmitting data from a sender to at least two receivers as claimed in claim 25, wherein an information element is transmitted in order to decide on reserved resources with respect to one of broadcast services and multicast services. 38. A unit for at least one of transmitting and receiving data, the unit being used in connection with a method for transmitting data from a sender to at least two receivers, the unit comprising parts for communicating with a point to multi-point service provided as an extension to a broadcast service in a multilayer protocol system by at least one of a multimedia transmission and a multicast service, for at least one of (a) planning of use of system resources and use of discontinuous reception and (b) allocation of use of system resources and use of discontinuous reception, wherein the unit represents one of the at least two receivers. 39. A unit for at least one of transmitting and receiving data as claimed in claim 38, wherein the point to multi-point service provided as an extension to a broadcast service is a multimedia broadcast/multicast service. 40. A unit for at least one of transmitting and receiving data as claimed in claim 38, wherein the unit is a mobile telephone. 41. A unit for at least one of transmitting and receiving data as claimed in claim 38, wherein the unit is designed for at least one of sending and receiving multimedia messages. 42. A communications system, comprising: a point to multi-point service provided as an extension to a broadcast service in the communications system by at least one of a multimedia transmission and a multicast service, for at least one of (a) planning of use of system resources and use of discontinuous reception and (b) allocation of use of system resources and use of discontinuous reception, wherein the communications system has a multi-layer protocol architecture; and a unit for at least one of transmitting and receiving data, the unit communicating with the point to multi-point service provided as an extension to a broadcast service, wherein the unit represents one of the at least two receivers to which the sender transmits data. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to a method for transmitting of data from a sender to two or more recipients, to a transmitting and/or receiving unit, and to a communications system. In the case of many services and applications which are offered in modern mobile radio systems, the aim is to transmit messages not just to one mobile radio subscriber but to two or more mobile radio subscribers. Examples of services and applications such as these include news groups, video conferences, video-on-demand, distributing applications, etc. Where messages are being transmitted to the various subscribers, it is possible to send each recipient a copy of the data separately. Although this technique can be implemented easily, it is not suitable for large groups, however. Since the same message is transmitted to a total of N recipients via individual connections or unicast connections, and is transmitted a number of times in the process over common connecting paths, this method requires a very wide bandwidth. A better option is offered by multicast transmission. In this case, the various subscribers to which the same message is intended to be transmitted are combined to form a multicast group, which is allocated a multicast address. The data to be transmitted is then sent only once to this multicast address. The MC message is in the ideal case sent only once from the sender to the recipients via common connecting paths. The sender does not need to know where and how many recipients are concealed behind the multicast address. In the case of broadcast, messages are sent to all the subscribers within a geographical region. A region such as this may, for example, be defined by a part of the overall network. As in the case of multicast, the broadcast message is ideally sent only once via common connecting paths from the sender to the recipients. Each subscriber has to carry out enabling settings on their respective terminal if he/she subsequently wishes to evaluate broadcast packets from a corresponding broadcast group. The subscriber can then determine whether he/she wishes to receive or reject all of the broadcast messages, or to receive only specific messages. In the course of a known method for data transmission, a specific number of frames are typically always interchanged between a network and a mobile radio within a specific time. A frame is in this case a time structure on which, for example, in the case of UMTS, all of the signal processing and data transmission is based, see also [1]. If all of the frames are transmitted and received by the mobile radio continuously, this is referred to as continuous transmission or continuous reception. However, it is also possible, for transmission, to use interrupted reception or so-called discontinuous reception DRX in order, for example, to reduce the energy requirement of the mobile radios. When using DRX, the frames are not transmitted and received by the mobile radio continuously, but rather specific frames are omitted. In this mode, however, at least one specific subset of all of the frames or a subset of the possible frames must be transmitted in order to maintain the connection. The present invention is, therefore, directed toward a method, a transmitting and/or receiving unit and a communications system for efficient, resource-saving and energy-saving transmission of data to a group of recipients on a point-to-multipoint service. In particular, is the present invention seeks to allow use for the purposes of a multimedia broadcast/multicast service MBMS. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, a method according to the present invention is distinguished in that a point-to-multipoint service is provided in a system with a multilayer protocol architecture as an extension to a broadcast service CBS by multimedia transmission and/or a multicast service, preferably in the form of a multimedia broadcast/multicast service MBMS, for allocation and/or planning of use of system resources and use of discontinuous reception DRX. Information is thus sent in an efficient form via the point-to-multipoint service, and is transmitted only once in the process. In this case, for the purposes of the present invention, the expression “information” also refers to information which is basically commercial or is sent without being requested; that is to say, in particular, an offer, a commercial or an advertisement for a new product, and consumer information in some other form. In the case of relatively complex, multilayer protocol architectures, such as the protocol stack in the Universal Mobile Telecommunications System UMTS, no functions have yet been included for group transmission or point-to-multipoint transmissions which either are not defined or are defined not only regionally. Since UMTS forms an essential field of use for the present invention, the following text uses the description of an exemplary embodiment with reference to the figures of the drawing to describe the protocol structure of UMTS, although the present invention is not restricted to such application. The planning for a method according to the present invention is advantageously carried out in two stages: a first message is used to signal where, how many and when resources are assigned for the transmission of multicast messages. Accordingly, this message advantageously may be very short. The first message is preferably used to transmit information elements with details about what resources of the transport channels or which frames of the physical channels are reserved or assigned for the transmission of messages. Signaling therefore does not take place until the planning for the transmission of a message, thus defining which physical channels and transport channels are used for the transmission of messages. The method according to the present invention thus can be adapted in a very flexible manner. In the case of UMTS, a common traffic channel CTCH is mapped in one embodiment of the present invention, on the basis of a requirement by the sender, onto other transport channels than the forward access channel FACH, and onto other physical channels than the secondary common control physical channel S-CCPCH. Various protocol layers are configured on the basis of discontinuous reception DRX planning messages by the radio resource monitoring unit RRC; that is to say, by the RRC of a sender for unidirectional connections. Notification therefore is provided at a physical level of a recipient as to the resources in which data can be expected in an MC message or further planning messages. In this case, the messages about planning and/or assignment of resources include, in one embodiment of the present invention, information about a respective multicast group, so that entire groups of recipients are informed. Groups such as these, particularly multicast groups, are preferably indicated by an MC group address or an MC group identity. Further information in a message is identified in a particularly advantageous manner in a monitoring layer in a recipient in order to decide whether an MC message with payload data should be received. Thus, for example, the only subscribers who are accessed are those who wish to receive sports messages so that, by using this group identity, information and data are effectively prevented from being read unnecessarily by subscribers who have no interest in messages in the corresponding group. A first planning stage, MC DRX level 1 , is used to signal which physical channels and transport channels will be used for the transmission of MC messages. In other words, the resources which are used or reserved for transmission of point-to-multipoint services, particularly the MBMS service, are signaled and/or notified for the transmission of messages and/or signaling data. This is preferably done in the DRX level 1 message, and allows the subscriber terminal to be informed of when messages and/or signaling data, particularly the DRX level 2 messages, actually will be transmitted. This is also used to signal where and on what channels these messages will be transmitted. In one embodiment, a basic specification of the messages and/or signaling data is also produced in order to decide whether this is a CBS, multimedia broadcast or multicast. The advantages of the respective indication, which is linked to a message, about the transmission channels and the fundamental classification of the information which can be expected will be described in more detail in the following text. However, even when using UMTS, it is possible for the CTCH to be mapped, on the basis of a requirement by the sender, onto other transport channels than the FACH and onto other physical channels than the S-CCPCH. On the basis of the discontinuous reception DRX planning messages, various protocol layers are configured via the radio resource monitoring unit RRC, in particular by the RRC in a receiver. In this case, a notification is provided at a physical level as to the resources in which data in an MC message or further planning messages can be expected. These messages about planning and/or assignment of resources include information about a respective multicast group. This further information in a message, inter alia relating to a group association, is identified in a monitoring layer BMC in order to decide whether an MC message with payload data should be received. This information is preferably signaled in the course of an MC DRX level 2 message, which includes information about the physical channels and transport channels on which MC messages actually will be transmitted as payload data. Alternatively, payload data contents also are signaled in the course of an MC DRX level 2 message itself with details about resources via which a multicast message subsequently will be actually transmitted. In one preferred embodiment of the present invention, previously assigned indices are used as the basis for assigning or notifying when MC messages are actually transmitted to resources of physical channels and transport channels, such as frames, in which case an offset with respect to a first frame which is used for an MC transmission, and/or a length of the CBS planning period, can be indicated. Preferably, an information element also is transmitted in order to decide on reserved resources in resources for broadcast or multicast services, so that the method according to the present invention can be used for both services. Owing to the progress in miniaturization, the method according to the present invention is implemented in a mobile telephone as a transmitting and/or receiving unit, with a mobile unit preferably being designed to send and/or receive multimedia messages. A corresponding communications system also can cope with the relatively large amounts of data for multimedia message by virtue of the flexibility explained above. Additional features and advantages of the present invention are described in, and will be apparent from, the following Detailed Description of the Invention and the Figures. |
Vibration isolated table for a charged particle beam apparatus provided with a shock protection element and shock protection element |
A vibration isolated table for a charged particle beam apparatus is provided with a shock protection element (5). The vibration isolated table (1) has a frame (2) and a load plate (3) being connected to the frame through vibration dampers (4). The shock protection element is connected to the frame (2) and extends over the load plate (3). There is free space (6) between a top plate (7) and the load plate (3), so that shock impacts are transferred to the frame and no longer to the load plate on which the charged particle beam is mounted. |
1. Vibration isolated table for a charged particle beam apparatus, the table having a frame and a load plate being connected to the frame through vibration dampers, characterized in that a shock protection element is connected to the frame and extends over the load plate. 2. Vibration isolated table as recited in claim 1, characterized in that there is a space between the shock protection element and the load plate. 3. Vibration isolated table as recited in claim 1, characterized in that the shock protection element comprises a plate having an opening. 4. Vibration isolated table as recited in claim 1, characterized in that the plate is positioned substantially perpendicular to the frame. 5. Vibration isolated table as recited in claim 3, characterized in that the opening in the plate is larger than an opening in the load plate. 6. Vibration isolated table as recited in claim 1, characterized in that the charged beam apparatus is positioned through the opening of the plate and rests on the load plate. 7. Vibration isolated table as recited in claim 3, in which the charged particle beam apparatus further comprises a pumping system suspended from a specimen chamber of the charged particle beam apparatus, characterized in that the charged beam apparatus and the pumping system are aligned substantially perpendicular to the plate. 8. Vibration isolated table as recited in claim 3, characterized in that the plate extends substantially parallel to the load plate. 9. Vibration isolated table as recited in claim 1, characterized in that the shock protection element comprises a folded plate. 10. Vibration isolated table as recited in claim 1, characterized in that the plate follows an edge of the load plate. 11. Vibration isolated table as recited in claim 7, in which the sample chamber comprises a door, characterized in that there is a spacing between the door and the plate. 12. Vibration isolated table as recited in claim 11, characterized in that the spacing between the plate and the load plate is less than 10 mm. 13. Vibration isolated table as recited in claim 1, characterized in that the plate of the shock protection element is a strip. 14. Shock protection element for a vibration isolated table comprising a folded plate. 15. Shock protection element as claimed in claim 14, characterized in that the material of the folded plate is a metal. |
Cellular virus receptors and methods of use |
Methods, reagents and compositions for the treatment, prevention and diagnotic of virus infections in vertebrates and more paticularly in human and animals are described. The invention provides evidence that the CCR1, CCR2, CCR3, CCR4, CCR5 and CCR8 receptors are involved in human respiratory syncytial virus (RSV) infections. Therefore, the present invention describes methods for modulation of cellular viral infection by modulating a binding interaction between a CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8 receptor and a surface protein of the virus. The invention also profits of such a binding interaction for 10 providing methods for reducing viral infection of a cell; methods of attenuating the ability of a pneumovirus to bind a mammalian cell; methods for reducing the initiation or spread of a respiratory tract disease due to human RSV; methods for detecting the presence of a pneumovirus in a biological sample; gene therapy methods, and methods for identifying novel antiviral and anti-inflammatory 15 compounds. |
1-85. (canceled) 86. A method for modulating viral infection of a cell, comprising modulating a binding interaction between a cell chemokine-receptor and a surface protein of said virus, said cell chemokines-receptor comprising an amino acid sequence having at least 38% identity with SEQ ID NO:6, with the proviso that said virus is not HIV. 87. The method of claim 86, wherein said cell chemokine-receptor is selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8. 88. The method of claim 87, wherein said cell chemokine-receptor consists of CCR3. 89. A method of modulating a pneumovirus infection of a cell, comprising modulating a binding interaction between at least one chemokine-receptor of said cell and a surface protein of said pneumovirus, wherein said cell chemokine-receptor is selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8. 90. The method of claim 89, comprising the step of contacting said cell with a CCR-ligand that recognizes at least one of said cell chemokine-receptor, said contacting step being carried out under conditions sufficient for said CCR-ligand to bind at least one of said cell chemokine-receptor, whereby the ability of said pneumovirus to subsequently bind said cell is attenuated. 91. The method of claim 90, wherein said CCR-ligand is selected form the group consisting of: eotaxin I, eotaxin 2, eotaxin 3, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, MCP-4, MCP-5, MIP-1α, MIP-1β, I-309, regulated on activation normal T-cell expressed and secreted (RANTES), TARC, antibodies and fragments thereof which specifically recognize said cell receptor(s), and polypeptides having a binding activity to an extracellular domain of said receptor(s). 92. The method of claim 91, comprising the step of reducing intracellular levels of at least one of said cell chemokine-receptor with antisense molecules introduced or expressed into said cell, thereby limiting pneumovirus ability to infect said cell. 93. The method of claim 89, comprising the step of contacting said pneumovirus with a virus-ligand that recognizes a surface protein of said pneumovirus under conditions sufficient for said virus-ligand to bind said pneumovirus surface protein and subsequently attenuates binding of said pneumovirus to said cell chemokine-receptor(s). 94. The method of claim 93, wherein said virus-ligand is selected from the group consisting of: a. an antibody or fragment thereof which specifically recognizes said virus surface protein; and b. a CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8 receptor or a functional fragment thereof. 95. The method of claim 94, wherein said antibody or fragment thereof specifically binds to a RSV-G or RSV-F protein. 96. The method of claim 95, wherein said virus consists of the Human Respiratory Syncytial Virus (HRSV). 97. A method of reducing the initiation or spread of a respiratory tract disease due to human RSV, comprising administering to a human an antiviral agent comprising a virus-ligand which exhibits the ability to bind to HRSV and reduce infectivity thereof, said virus-ligand exhibiting the ability to bind to a HRSV surface protein involved in binding of the HRSV to a cell chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8. 98. A method for detecting the presence of a pneumovirus in a biological sample, comprising the steps of: a. contacting the biological sample with a cell expressing at least one cell chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8, said contacting step being carried out under conditions sufficient for pneumovirus(es) contained in said sample to infect said cell; and b. detecting the presence of pneumovirus(es) in said cell. 99. The method of claim 98, wherein said cell is selected from the group consisting of: Hep-2 cells, A549 cells, and GHOST cells transfected with the CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8 receptor(s). 100. The method of claim 99, wherein said cell has been pretreated with agent(s) capable of increasing or permitting the expression of said chemokine-receptor(s) on the cell surface. 101. A method for selecting an antiviral compound that is capable of reducing viral infection of a cell by a pneumovirus, the cell expressing at least one cell chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5 and CCR8, the method comprising: a. contacting a functional virus-ligand and a surface protein of a virus in the presence of a potential antiviral compound, said surface protein being involved in binding of the virus to at least one of the chemokine-receptor expressed by the cell; b. measuring a binding interaction between said virus-ligand and said viral surface protein; whereby an antiviral compound is selected when said binding interaction is measurably reduced in presence of said potential antiviral compound. 102. The method of claim 101, wherein said virus-ligand is selected from the group consisting of: a. an antibody or a fragment thereof which specifically recognizes said pneumovirus surface protein; and b. a CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8 receptor or a functional fragment thereof. 103. The method of claim 102, wherein said pneumovirus consists of the Human Respiratory Syncytial Virus (HRSV). 104. A composition for treating and/or preventing infection by a pneumovirus, said composition comprising a CCR-ligand and a pharmaceutically acceptable carrier, said CCR-ligand exhibiting the ability to bind to at least one chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR, CCR4, CCR5, and CCR8, and thereby reduce infectivity of the pneumovirus. 105. The composition of claim 104, wherein said composition consists of a spray for application to airway tissues susceptible to infection by HRSV. 106. A method of attenuating the ability of a pneumovirus to infect a mammalian cell expressing at least one chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8, the method comprising exposing said cell to a CCR-ligand that recognizes at least one of said cell chemokine-receptor, said exposition being carried out under conditions sufficient for said CCR-ligand to bind said at least one of said cell chemokine-receptor, whereby the ability of said pneumovirus to subsequently infect said cell is attenuated. 107. The method of claim 106, wherein said CCR-ligand is selected from the group consisting of: eotaxin 1, eotaxin 2, eotaxin 3, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, MCP-4, MCP-5, MIP-1α, MIP-1β, I-309, regulated on activation normal T-cell expressed and secreted (RANTES), TARC, antibodies and fragments thereof which specifically recognize said cell receptor(s), polypeptides having a binding activity to an extracellular domain of said receptor(s). 108. A method of attenuating the ability of a pneumovirus to bind a mammalian cell, comprising a step selected from the group consisting of: a. exposing said cell to a CCR-ligand that recognizes at least one cell chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8, said exposition being carried out under conditions sufficient for said CCR-ligand to bind said cell receptor; b. exposing said virus to a virus-ligand that recognizes a surface protein of the pneumovirus, said exposition being carried out under conditions sufficient for said virus-ligand to bind said pneumovirus surface protein and subsequently attenuates binding of pneumovirus to at least one cell chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8; and c. reducing intracellular levels of at least one cell chemokine-receptor selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8; thereby limiting the pneumovirus ability to bind said mammalian cell. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. (a) Field of the Invention The invention relates to methods, reagents and compositions for treating or preventing respiratory virus infections in vertebrates, and more particularly, respiratory syncytial virus (RSV) infections in human and animals. The invention also relates to methods for modulating viral infection of cells by modulating a binding interaction between a CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8 receptor and a surface protein of the virus. The invention also profits of such a binding interaction in methods for reducing viral infection of a cell; in methods of attenuating the ability of a pneumovirus to bind a mammalian cell; methods for reducing the initiation or spread of a respiratory tract disease due to human RSV; in methods for detecting the presence of a pneumovirus in a biological sample; in gene therapy methods, and in methods for identifying novel antiviral compounds. 2. (a) Brief Description of the Prior Art Human Respiratory Syncytial Virus (HRSV) is a non-segmented, negative-strand virus in the pneumovirus subfamily of Paramyxoviridae. The virus has been described in detail by Collins, P. et al. in the textbook by Fields , B. N. et al., (1996) Fields Virology , pp 1313-1351 (Raven Press, N.Y). The virus is ubiquitous in the human population and approximately 100% of infants are infected by the age of 3. HRSV infection is the leading cause of serious lower respiratory tract disease in infants and children: HRSV is responsible for at least 50% of bronchiolitis hospitalizations, 25% of pneumonia hospitalizations, and 2% mortality rate among hospitalized infants annually. Approximately 50% of bronchiolitis patients develop asthma. In adults 60 years or older, HRSV causes symptoms similar to the common cold or flu, however it may also cause pneumonia, bronchitis, and death. Although HRSV is thought to account for over 1 million deaths per year worldwide, there is no effective and safe HRSV vaccine currently available. The World Health Organization and National Institutes of Allergy and Infectious Diseases vaccine advisory committees have ranked HRSV second to HIV for vaccine development. Viruses infect cells by interacting with one or more specific cellular receptor proteins that function as coreceptors for the virus (also called virus receptors), as a portal of entry for the virus to gain entry into the target host cells. It is known that HRSV specifically infects alveolar cell types including macrophages and epithelial cells of the respiratory system. The G- and the F-glycoproteins are the two major proteins of the HRSV envelope that are known to be involved in HRSV infection, the attachment (G) glycoprotein being responsible in part for the entry of the virus into the host cells. Recently, it has been demonstrated that HRSV binds the receptor CX3CR1 (the specific receptor for the chemokine fraktalkine) and that this binding facilitates RSV infection of cells (Tripp et al. (2001) Nature Immunology, 8:732-738). The present invention discloses additional cell receptors (CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8) which recognize and bind the RSV-G protein, these additional receptors being involved in HRSV entry into the cell. Several vertebrate cell receptors play a critical role in the pathogenesis of certain viral, bacterial and parasite infections, and have been termed coreceptors (or co-receptors). For example, chemokine receptors CCR2b, CCR3, CCR5, and CXCR4, and others, are involved in HIV infection and their corresponding ligands (chemokines) can also inhibit virus entry and infection (Pelchen-Mathews et al., (1999), Immunological Reviews 168: 3349; Springer et al. (2001) J of Virol 75: 3779-90; and PCT patent application WO 99/06561). Other types of cell receptors also function as coreceptors/viral receptors. For example, the ICAM-1 receptor involved in cellular adhesion is also a coreceptor for human rhinovirus (U.S. Pat. No. 5,589,453). Although the CCR1, CCR2, CCR3, CCR4, CCR5 and CCR8 receptors are well known and have been described in detail previously, they have never been identified up to date as the host cell receptor for RSV, nor for any other virus of the same order (Mononegavirales). In view of the above, there is a need for identifying the viral cell receptor(s) of viruses of the Mononegavirales order, and more particularly for Pneumoviruses such as the human RSV. There is also a long felt need for safe and effective RSV vaccines and compositions for modulating viral cellular infection. There is also a need for methods, reagents and compositions for treating or preventing pneumovirus infections in vertebrates and more particularly respiratory syncytial virus infections in mammals. There is also a need for methods for identifying novel antiviral compounds for viruses of the Mononegavirales order, and more particularly Pneumoviruses such as the human RSV. The present invention fulfils these needs and also other needs which will be apparent to those skilled in the art upon reading the following description. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides methods, compositions and kits for treating, preventing and/or detecting respiratory infections from viruses, and more particularly Pneumoviruses such as the human RSV. The invention further provides methods and tools for identifying/screening in vitro, in vivo and ex vivo, novel antiviral compounds, drugs and vaccine, The present invention also provides gene therapy and transfection methods wherein viruses are used as a delivery vehicle for transferring an exogenous gene in CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8-positive cells. According to a first aspect, the invention relates to a method for modulating viral infection of a cell, comprising modulating a binding interaction between a cell chemokine-receptor and a surface protein of the virus, the cell chemokine-receptor comprising an amino acid sequence having at least 38% identity with SEQ ID NO:6. More preferably, the cell chemokine-receptor consists of the CCR1, CCR2, CCR3, CCR4, CCR5, and/or CCR8. According to another aspect, the invention relates to a method for modulating viral infection of a cell, comprising modulating a binding interaction between a cell chemokine-receptor and a surface protein of said virus. According to the invention, the cell chemokine-receptor is the CCR1, CCR2, CCR3, CCR4, CCR5, and/or the CCR8 and the virus is not HIV. According to a further aspect, the invention relates to a method for increasing viral infection of a cell comprising permitting or increasing a binding interaction between at least one chemokine-receptor of the cell and a surface protein of the virus. According to a related aspect, the invention relates to a method for reducing viral infection of a cell, comprising interfering with a binding interaction between at least one chemokine-receptor of the cell and a surface protein of the virus. In both cases, the chemokine-receptor is selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8. Preferably, the virus consists of a virus of the order Mononegavirales. More preferably, the virus consists of a virus of the order the family Paramyxoviridae. Even more preferably, the virus consists of a virus of the Pneumovirinae subfamily, or a virus of the Pneumoviruses species. In most preferred embodiments, the virus consists of the Human Respiratory Syncytial Virus (HRSV) the viral protein consists of the HRSV G-glycoprotein. In more specific aspects, the invention concerns: a method for reducing pneumoviral infection of a CCR1-positive cell, comprising interfering with binding of a pneumovirus to CCR1 receptor(s) of the cell; a method for reducing pneumoviral infection of a CCR2-positive cell, comprising interfering with binding of a pneumovirus to CCR2 receptor(s) of the cell; a method for reducing pneumoviral infection of a CCR3-positive cell, comprising interfering with binding of a pneumovirus to CCR3 receptor(s) of the cell; a method for reducing pneumoviral infection of a CCR4-positive cell, comprising interfering with binding of a pneumovirus to CCR4 receptor(s) of the cell; a method for reducing pneumoviral infection of a CCR5-positive cell, comprising interfering with binding of a pneumovirus to CCR5 receptor(s) of the cell; and a method for reducing pneumoviral infection of a CCR8-positive cell, comprising interfering with binding of a pneumovirus to CCR8 receptor(s) of the cell. In another specific aspect, the invention concerns a method for modulating a pneumovirus infection of a cell, comprising modulating a binding interaction between a cell CCR1, CCR2, CCR3, CCR4, CCR5, and/or CCR8 receptor and a surface protein of the pneumovirus. Therefore, the present invention describes methods for modulation of viral infection of cell by modulating a binding interaction between a CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8 receptor and a surface protein of the virus. The invention also profits of the binding interaction between the CCR1, CCR2, CCR3, CCR4, CCR5 and/or CCR8 receptor and surface protein(s) of viruses for providing methods for reducing viral infection of a cell; methods of attenuating the ability of a pneumovirus to bind a mammalian cell; methods for reducing the initiation or spread of a respiratory tract disease due to human RSV; methods for detecting the presence of a pneumovirus in a biological sample; gene therapy methods, and methods for identifying novel antiviral compounds. Identification of the CCR1, CCR2, CCR3, CCR4, CCR5 and CCR8 as being coreceptors for HRSV has numerous advantages since it is known that it is the cell receptor expression which determines the tropism of a virus and hence plays a key role in determining virus pathogenicity. Furthermore, the characterization of virus cell receptor(s) facilitates the design and identification of vaccines and antiviral therapeutic agents that may prevent the infection and even treat the infection. Other objects and advantages of the present invention will be apparent upon reading the following non-restrictive description of several preferred embodiments made with reference to the accompanying drawings. |
Fluoro linkers and their use as linkers for enzyme-activated drug conjugates |
The present invention provides compounds or formula (1) R1—HN—CH2—CF2—(CH2)l—CR3R4—CO—R2, wherein: l is 0, 1 or 2, R1 is a labile amino protecting group, R2 is hydroxy group or the residue or an activated ester or halogen atom; R3 and R4 are independently hydrogen atom or C1-C4 alkyl chain. There are also provided their preparation and the water-soluble conjugates based on these linkers, endowed with selective anticancer activity. |
1. A compound of formula (1) R1—HN—CH2—CF2—(CH2)l—CR3R4—CO—R2 (1) wherein: l is 0, 1 or 2; R1 is a labile amino protecting group; R2 is hydroxy, the residue of an activated ester or a halogen atom; and R3 and R4 which are the same or different, are independently hydrogen or C1-C4 alkyl. 2. A compound according to claim 1 wherein l is 1, R3 and R4 are hydrogen atoms, R1 is selected from tert-butoxycarbonyl, 9-fluorenyl methoxycarbonyl, triphenylsilyl, diphenylmethylene and triphenylmethyl group, and R2 is p-nitrophenol or N hydroxysuccinimido residue or chlorine atom. 3. A compound of formula (2: W—[—HN—Y—CO—]p—S0—HN—CH2—CF2—(CH2)l—CR3R4—CO-D (2) wherein: D is the residue of a drug bearing secondary or tertiary hydroxyl groups linked through an ester bond; R3 and R4, which are the same or different, are independently hydrogen or C1-C4 alkyl l is 0, 1 or 2; S0 is a peptide capable of being selectively cleaved at a tumor site by enzymes there expressed in an active form; Y is C2-C12 linear or branched alkylene chain which is unsubstituted or substituted by hydroxyl, p is 0 or 1, and W is a water-soluble polymer or a water-soluble low molecular weight compound. 4. A compound according to claim 3 wherein Y represents —(CH2)5—, p is 1 and W represents a polypyrrolecarboxamidonaphthalene derivative, polyglutamic acid, acarboxylated dextrane, carboxylated polyethylenglycol or a polymer based on hydroxypropylmethacryloylamide. 5. A compound according to claim 3 wherein W is a water soluble polymer based on N-(2-hydroxypropyl) methacryloylamide. 6. A compound according to claim 3 in which the peptide S0 comprises sequences from four to five natural or synthetic amino acids. 7. A compound according to claim 3 wherein S0 represents a sequence of formula: Met(O)-Gly-Cys(Bn)-Leu, Met(O)-Gly-Cys(Bn)-Gly, Met(O)-Gly-Cys (Bn)-Gly-Leu, Met(O)-Gly-Cys(Bn)-Trp-Gly, Met(O)-Gly-Cys(Bn) pFF-Gly, Met (O)-Gly-Cys(Bn)-Gly-Gly, Met(O)-Gly-Cys(Bn)-Leu-Gly, Smc-Gly-Cys(Bn)-Leu, Smc-Gly-Cys(Bn)-Trp, Smc-Gly-Cys(Bn)-pFF, Smc-Gly-Cys(Bn)-Gly, Smc-Gly-Cys(Bn)-Trp-Gly, Smc-Gly-Cys(Bn)-pFF Gly, Smc-Gly-Cys(Bn)-Gly-Gly, Smc-Gly-Cys(Bn)-Leu-Gly, Smc-Gly Leu-Trp, Smc-Gly-Tha-Trp, Smc-Gly-Met-Trp, Smc-Gly-Tha-Trp-Gly, Smc-Gly-Met-Trp-Gly, Leu-Gly-Cys(Bn)-Leu, Leu-Gly-Cys(Bn)-Gly, Leu-Gly-Cys(Bn)-Leu-Gly, Leu-Gly-Cys(Bn)-Gly-Gly, Leu-Gly-Leu-Leu, Leu-Gly-Leu-Trp, Leu-Gly-Leu-Leu-Gly or Leu-Gly-Leu-Trp-Gly. 8. A compound according to claim 3 wherein S0 represents a sequence of formula: Met(O)-Gly-Cys(Bn)-Leu, Met(O)-Gly-Cys (Bn)-Gly, Met(O)-Gly-Cys(Bn)-Gly-Gly, Met(O)-Gly-Cys(Bn) Leu-Gly, Smc-Gly-Cys(Bn)-Leu, Smc-Gly-Cys(Bn)-Gly, Smc-Gly Cys(Bn)-Gly-Gly, Smc-Gly-Cys(Bn)-Leu-Gly, Leu-Gly-Cys(Bn)-Leu, Leu-Gly-Cys(Bn)-Gly, Leu-Gly-Cys(Bn)-Leu-Gly, Leu-Gly-Cys(Bn)-Gly Gly, Leu-Gly-Leu-Leu or Leu-Gly-Leu-Leu-Gly. 9. A compound according any claim 3 wherein the antitumor agent D is a cytotoxic agent belonging to the class of camptothecins, anthracyclines, taxanes, vinca alkaloids, cytotoxic nucleosides or podophyllotoxins. 10. A compound according to claim 9 wherein the antitumor agent D is camptothecin, 7-ethyl-10-hydroxy-camptothecin, 9-aminocamptothecin, doxorubicin, daunorubicin, 4′-epidoxorubicin, 4-demethoxydaunorubicin, 3′-(2-methoxymorpholino) doxorubicin, 4-deacetylvinblastine, 4-deacetyl-vincristine, vindesine, paclitaxel, docetaxel or, etoposide. 11. A process for preparing a compound of formula (1) as defined in claim 1, which process comprises reacting a compound of formula II R′1—HN—CH2—CH2—(CH2)l—CR3R4—COOR′2 II wherein R3 and R4 are the same or different, and are independently hydrogen or C1-C4 alkyl, l is 0, 1 or 2, R′1 is an N protecting group and R′2 is C1-C4 alkyl, phenyl or phenyl-C1-C4 alkyl, with a fluorinating agent, then removing the N-protecting group and the ester residue from the resultant compound of formula III R′1—HN—CH2—CF2—(CH2)l—CR3R4—COOR′2 III wherein R3 and R4 and l are as defined in claim 1, R′1 is an N protecting group and R′2 is C1-C4 alkyl, phenyl or phenyl-C1-C4 alkyl; and then introducing a labile N-protecting group R1, and optionally the activating ester residue R2 is hydroxy the residue of an activated ester or a halogen atom, into the resultant amino acid derivative of formula IV H2N—CH2—CF2—(CH2)l—CR3R4—COOH IV wherein R3 and R4 are the same or different, and are independently hydrogen or C1-C4 alkyl and l is 0, 1 or 2, to give a desired compound of the formula (1). 12. A process according to claim 11 in which the N-protecting group R′1 is a phthaloyl protecting group and the fluorinating agent is DAST. 13. A process for preparing a compound of formula (2) as defined in claim 3, which process comprises reacting a compound of formula (18) H—[—HN—Y—CO—]p—S0—HN—CH2—CF2—(CH2)l—CR3R4—CO-D (18) wherein Y, p, S0, l, R3, R4 and D are as defined in claim 3, with a polymer or water soluble molecule W bearing suitable functional groups for the coupling with a compound (18). 14. A process according to claim 13 in which the suitable functional groups on polymer W for the attachment to compounds (18) comprise carboxyl groups or activated carboxyl groups. 15. An antitumor derivative of formula (18) as claimed in claim 13 or a corresponding salt derivative of formula (18′). 16. A process for preparing a compound of formula (18) or salt (18′) as defined in claim 15, which process comprises: removing under acidic conditions the N-protecting group from a derivative of formula (16); R1—[—HN—Y—CO—]p—S0—HN—CH2—CF2—(CH2)l—CR3R4—CO-D (16) wherein R1, Y, p, S0, l, R3, R4 and D are as defined in claim 3, and optionally converting a resultant compound of general formula (18′) into the corresponding free amino derivative (18) by mild basic treatment. 17. A process according to claim 16 in which the N-protecting group R1 represents tert-butoxycarbonyl, 9-fluorenyl methoxycarbonyl, triphenylsilyl, diphenylmethylene or triphenylmethyl group. 18. A compound according to claim 3 which is a drug conjugate consisting of: (i) from 85 to 97 mol % of N-(2-hydroxypropyl) methacryloylamide units represented by formula (26) (ii) from 3 to 15 mol % of units represented by formula (27) in which Y, p, l, S0, R3, R4 and D and are as defined in claim 3, and (iii) from 0 to 12 mol % of N-methacryloyl-glycine or N-(2-hydroxypropyl) methacryloyl glycinamide units represented by formula (28) wherein R6 represents a hydroxy group or a residue of formula —NH—CH2—CH(OH)—CH3. 19. A process for preparing a drug-conjugate as defined in claim 18, which process comprises reacting a compound of formula (18) or a salt thereof with an activated water soluble polymer (W′) consisting essentially of: activated polymer W′ consisting essentially of: (i) from 85 to 97 mol % of N-(2-hydroxypropyl) methacryloylamide units represented by formula (26) as defined in claim 18, and (ii) from 3 to 15 mol % of N-methacryloyl-glycyl units represented by formula (29) wherein R7 is the residue of an active ester, and optionally displacing the remaining active ester groups with 1-amino-2-propanol. 20. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as active ingredient, a polymeric conjugate as defined in claim 3. 21. (canceled) 22. (canceled) 23. (canceled) 24. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as active ingredient, a compound of formula (18) or (18′) as defined in claim 15. 25. A method of treating for leukemia or a solid tumor in a human or an animal comprising administering the polymeric conjugate of claim 3 to the human or an animal wherein the leukemia or solid tumor is treated. 26. The method of claim 25, wherein the solid tumor is a colon, colo-rectal, ovarian, mammary, prostate, lung or kidney tumor or a melanoma. 27. A method of treating for leukemia or a solid tumor in a human or an animal comprising administering the compound of formula (18) or (18′) as defined in claim 15 to the human or an animal, wherein the leukemia or solid tumor is treated. 28. The method of claim 27, wherein the solid tumor is a colon, colo-rectal, ovarian, mammary, prostate, lung or kidney tumor or a melanoma. |
System which enables a mobile telephone to be used to locate goods or services |
A system which enables a mobile telephone to be used to locate goods or services, comprising the following elements: (a) a communications network to allow a mobile telephone operator to receive, from the mobile telephone, criteria defining the goods or services required; (b) a searching system connected to receive the criteria and perform automated searches against those criteria using resources provided by suppliers of the goods or services and to send results over the communications network to the mobile telephone; (c) an electronic commerce and billing engine operating to allow the user of the mobile telephone to order goods or services from the operator and not the supplier. |
1. A system which enables a mobile telephone to be used to locate goods or services, comprising the following elements: (a) a communications network to allow a mobile telephone operator to receive, from the mobile telephone, criteria defining the goods or services required; (b) a searching system connected to receive the criteria and perform automated searches against those criteria using resources provided by suppliers of the goods or services and to send results over the communications network to the mobile telephone; (c) an electronic commerce and billing engine operating to allow the user of the mobile telephone to order goods or services from the operator and not the supplier. 2. The system of claim 1 in which the searching system uses business logic defined by the operator to prioritise or filter search results according to predefined rules set by the operator. 3. The system of claim 1 in which the searching system automatically interrogates web based resources from suppliers to allow a user of the mobile telephone to compare similar goods or services from different suppliers without those suppliers needing to provide wireless protocol specific data. 4. The system of claim 1 in which the searching system automates user defined processes, enabling the user to delegate tasks to the searching system without the need for continued real time connection to the Internet. 5. The system of claim 1 in which the searching system can be modified by user defined preferences or profiles. 6. The system of claim 1 in which the searching system can supply data records defining the details of the process used by customers to look for goods or services to purchase. 7. A method of enabling a mobile telephone to be used to locate goods or services, comprising the following steps: (a) a mobile telephone operator receiving, from the mobile telephone, criteria defining the goods or services required; (b) the mobile telephone operator then (i) directly or indirectly obtaining from a supplier information describing one or more goods or services meeting the criteria and providing that information to the mobile telephone and (ii) allowing the user of the mobile telephone to order goods or services directly from it and not the supplier. 8. The method of claim 7 in which the user of the mobile telephone can make a purchase by sending a request to the operator, who in turn completes the purchase transaction with an applicable supplier. 9. The method of claim 7 in which the costs of goods or services purchased are added to a regular bill which includes costs of voice services supplied by the mobile operator to the user of the mobile telephone. 10. The method of claim 7 in which the mobile telephone user sends a request for goods and services using a protocol which is device and bearer agnostic. 11. The method of claim 10 in which the request is directed to the operator, who then routes it through to a server which initiates a web based search through web based resources from appropriate suppliers. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention This invention relates to a system which enables a mobile telephone to be used to locate goods or services. 2. Description of the Prior Art Mobile telephone operators, such as Vodafone plc, currently carry voice and data traffic from and to mobile telephones. The business of carrying voice and data traffic is however open to commoditisation as operators increasingly find it difficult to differentiate on meaningful quality comparisons, such as extent of coverage and voice quality. One of the key lessons apparent from many successful internet business models is that, where previously customers dealt directly with a source of goods or services or with an existing intermediary, it can be more efficient to instead deal with a new, on-line intermediary. For example, many people previously bought airline tickets directly from an airline of choice or by visiting a travel agent. But over the past few years, many on-line travel services have been set up, such as Expedia.com, which act as new intermediaries. Expedia will locate airline tickets, holidays etc., which meet a user's criteria and will source these from many different suppliers. The basic relationship of trust, fundamental to a commercial relationship, becomes primarily between consumer and the new intermediary, with the brand importance of the ultimate service or goods supplier being diminished. Mobile telephone operators have addressed the possibility of commoditisation of their services primarily through the mechanism of adding new data services for their customers in an attempt to maintain a relationship with their customers. This is a costly and uncertain process however. The objective of the present invention is to demonstrate an alternative and potentially far more potent strategy for mobile telephone operators. |
<SOH> SUMMARY OF THE PRESENT INVENTION <EOH>In a first aspect of the present invention, there is a system which enables a mobile telephone to be used to locate goods or services, comprising the following elements: (a) a communications network to allow a mobile telephone operator to receive, from the mobile telephone, criteria defining the goods or services required; (b) a searching system connected to receive the criteria and perform automated searches against those criteria using resources provided by suppliers of the goods or services and to send results over the communications network to the mobile telephone; (c) an electronic commerce and billing engine operating to allow the user of the mobile telephone to order goods or services from the operator and not the supplier. Hence, the present invention envisages a technical infrastructure in which the mobile telephone operator is the trusted intermediary and supplier in commercial transactions. This has many practical advantages: first, it uses the mobile telephone operator's existing communication infrastructure with its customers; infrastructure re-use is especially important for 3G networks, which have to deliver very high useage in order to justify the costs incurred in developing them and obtaining spectrum. Secondly, it allows mobile telephone operators to make greater use of their computerised billing systems and associated regular billing relationship with customers, allowing those customers to buy goods etc. and to have these costs added to the regular telephone bill. The mobile telephone operator may become in effect a credit source in the same way a major credit card company like America Express offers credit to consumers and routes payments to suppliers. Thirdly, it allows the mobile telephone operators to become a trusted brand, extending that brand far beyond potentially commoditisable data and voice carrying and into a trusted source of a large range goods and services. It also allows the mobile telephone operator to secure competitive pricing and other commercial advantages by leveraging its huge customer base as a potential customer source. So, a mobile telephone operator using an implementation of the present invention further increases consumer reliance by becoming a trusted and effective supplier of goods and services, reduces the threat of commoditisation, gains leverage over a large number of suppliers and develops a new source of revenue based on fees relating to transactions (e.g. 2% of the costs of goods etc.) and charges to consumers (e.g. interest on unpaid balances). The term ‘mobile telephone operator’ used in this specification covers any entity whose primary role has historically been to carry voice or data traffic. It hence covers traditional mobile telephone operators, such as Vodafone, and also Internet Service Providers, such as Worldcom. The term ‘mobile telephone’ covers any device which can send data and/or voice over a long range wireless communication system, such as GSM, GPRS or 3G. It covers such devices in any form factor, including conventional telephones, PDAs, laptop computers, smart phones and communicators. In a second aspect, there is a method of enabling a mobile telephone to be used to locate goods or services, comprising the following steps: (a) a mobile telephone operator receives, from the mobile telephone, criteria defining the goods or services required; (b) the mobile telephone operator then (i) directly or indirectly obtains from a supplier information describing one or more goods or services meeting the criteria and provides that information to the mobile telephone and (ii) allows the user of the mobile telephone to order goods or services directly from it and not the supplier. In one implementation, a mobile telephone user sends a request for goods and services using a protocol which is device and bearer agnostic (i.e. is not specific to any one kind of device or bearer) over the wireless network operated by the operator (e.g. GSM, GPRS or 3G). The request is directed to the operator, who then routes it through to a server (typically operated by an independent company specializing in designing the software running on such servers, such as Cellectivity Limited), which initiates a search through appropriate suppliers (e.g. by using a web search agent). The search may depend on business logic set by the operator—e.g. it may be limited to suppliers who have entered into commercial arrangements with the operator. The relevant information is then returned over the wireless network operated by the operator to the consumer; the objective is for the consumer experience to be a highly simplified one, using predefined user preferences in order to make sure that the goods/services offered to the consumer are highly likely to appeal. When the consumer is presented with goods/services, which are acceptable, he can initiate the purchase from the operator and not the supplier using the mobile telephone by sending a request to the operator over the wireless network operated by the operator. The applicable costs will be added to his monthly telephone bill. |
Thermostable uvra, uvrb, and uvrc polypeptides and methods of use |
The present invention provides thermostabile UvrA, UvrB and UvrC polypeptides and the polynucleotides that encode the polypeptides of the present invention. The invention also includes compositions and kits containing the UvrA, UvrB, and UvrC polypeptides of the present invention. Also provided by the invention are methods of detecting DNA damage using the UvrA and UvrB polypeptides and methods of incising DNA using the UvrA, UvrB and UvrC polypeptides of the present invention. |
1-26. (Canceled) 27. An isolated polynucleotide wherein the complement of the polynucleotide hybridizes to SEQ ID NO:5 under standard hybridization conditions, wherein the polynucleotide encodes a polypeptide that in a mixture at about 50° C. to about 80° C. incises a BPDE-DNA substrate, wherein the mixture comprises the polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, a UvrB polypeptide comprising SEQ ID NO:4, and the BPDE-DNA substrate. 28. The isolated polynucleotide of claim 27, wherein the polynucleotide comprises SEQ ID NO:5 29. An isolated polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:6, wherein the polypeptide in a mixture at about 50° C. to about 80° C. incises a BPDE-DNA substrate, wherein the mixture comprises the isolated polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, a UvrB polypeptide comprising SEQ ID NO:4, and the BPDE-DNA substrate. 30. The isolated polypeptide of claim 29 comprising SEQ ID NO:6. 31. A composition comprising the isolated polypeptide of claim 29. 32. The composition of claim 31 further comprising; an isolated second polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, wherein the second polypeptide forms a complex at about 50° C. to about 80° C., the complex comprising the second polypeptide, a UvrB polypeptide comprising SEQ ID NO:4, and a BPDE-DNA substrate; and an isolated third polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, wherein the third polypeptide forms complex at about 50° C. to about 80° C., the complex comprising the third polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, and a BPDE-DNA substrate. 33. A kit for detecting DNA damage, comprising: as one component, a first isolated polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, wherein the first polypeptide forms a complex at about 50° C. to about 80° C., the complex comprising the first polypeptide, a UvrB polypeptide comprising SEQ ID NO:4, and a BPDE-DNA substrate; as a second component, a second isolated polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, wherein the second polypeptide forms complex at about 50° C. to about 80° C., the complex comprising the second polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, and a BPDE-DNA substrate; and as a third component, a third isolated polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:6, wherein the third polypeptide, when in a mixture at about 50° C. to about 80° C., incises a BPDE-DNA substrate, wherein the mixture comprises the third polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, a UvrB polypeptide comprising SEQ ID NO:4, and the BPDE-DNA substrate. 34. The kit of claim 33, wherein the first isolated polypeptide comprises SEQ ID NO:2. 35. The kit of claim 33, wherein the second isolated polypeptide comprises SEQ ID NO:4. 36. The kit of claim 33, wherein the third polypeptide comprises SEQ ID NO:6. 37. A kit for UvrABC endonuclease excision comprising: as one component, a first isolated polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, wherein the first polypeptide forms a complex at about 50° C. to about 80° C., the complex comprising the first polypeptide, a UvrB polypeptide comprising SEQ ID NO:4, and a BPDE-DNA substrate; as a second component, a second isolated polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, wherein the second polypeptide forms complex at about 50° C. to about 80° C., the complex comprising the second polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, and a BPDE-DNA substrate; and as a third component, a third isolated polypeptide comprising an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:6, wherein the third polypeptide, when in a mixture at about 50° C. to about 80° C., incises a BPDE-DNA substrate, wherein the mixture comprises the third polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, a UvrB polypeptide comprising SEQ ID NO:4, and the BPDE-DNA substrate. 38. The kit of claim 37, wherein the first isolated polypeptide comprises SEQ ID NO:2. 39. The kit of claim 37, wherein the second isolated polypeptide comprises SEQ ID NO:4. 40. The kit of claim 37, wherein the third polypeptide comprises SEQ ID NO:6. 41. A method for detecting DNA damage, the method comprising: combining a first polypeptide, a second polypeptide, third polypeptide, and a double stranded DNA to form a mixture; wherein the first polypeptide is encoded by a first polynucleotide, wherein the complement of the first polynucleotide hybridizes to SEQ ID NO:1 under standard hybridization conditions, and wherein the first polypeptide forms a complex at about 50° C. to about 80° C., the complex comprising the first polypeptide, a UvrB polypeptide comprising SEQ ID NO:4, and a BPDE-DNA substrate; wherein the second polypeptide is encoded by a second polynucleotide, wherein the complement of the second polynucleotide hybridizes to SEQ ID NO:3 under standard hybridization conditions and wherein the second polypeptide forms a complex at about 50° C. to about 80° C., the complex comprising the second polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, and a BPDE-DNA substrate; wherein the third polypeptide is encoded by a third polynucleotide, wherein the complement of the third polynucleotide hybridizes to SEQ ID NO:5 under standard hybridization conditions and wherein the third polypeptide, in a mixture at about 50° C. to about 80° C., incises a BPDE-DNA substrate, wherein the mixture comprises the third polypeptide, a UvrA polypeptide comprising SEQ ID NO:2, a UvrB polypeptide comprising SEQ ID NO:4, and a BPDE-DNA substrate; incubating the mixture; detecting an incised polynucleotide, wherein the presence of an incised polynucleotide indicates the presence of DNA damage. 42. The method of claim 41, wherein the first polypeptide comprises SEQ ID NO:2. 43. The method of claim 41, wherein the second polypeptide comprises SEQ ID NO:4. 44. The method of claim 41, wherein the third polypeptide comprises SEQ ID NO:6. 45. The method of claim 41, wherein the double stranded DNA is from a subject. 46. The method of claim 45, wherein the subject is undergoing treatment for cancer. 47. The method of claim 46, wherein the treatment comprises chemotherapy. 48. The method of claim 47, wherein the double stranded DNA is obtained from the subject either before, during, or after treatment. 49. The method of claim 45, wherein the subject has been exposed to a genotoxin. 50. The method of claim 49, wherein the double stranded DNA sample is obtained from the subject either before, during, or exposure to a genotoxin. |
<SOH> BACKGROUND <EOH>DNA repair provides a major defense mechanism against DNA lesions and their potential consequences, including mutagenesis, carcinogenesis, or cell death. The nucleotide excision repair (NER) pathway is a general repair process that removes a remarkably diverse array of structurally unrelated lesions, ranging from UV-induced photoproducts, chemical adducts, abasic sites to certain types of cross-links (Van Houten, Microbiol. Rev. 54, 18-51 (1990)). The mechanism of NER is best studied in the bacterium Escherichia coli . This pathway, consisting of five steps: damage recognition, incision, excision, DNA repair synthesis and ligation, is error-free and leads to restoration of the integrity of the genetic information. The NER in bacterial cells is initiated by a combined action of three proteins, a UvrA protein, a UvrB protein, and a UvrC protein, leading to recognition and incision of damaged DNA. The three proteins, which are also referred to as UvrABC endouclease, are typically not stable. For instance, E. coli UvrA protein has been shown to be heat labile, especially in dilute concentrations with a t 1/2 of less than five minutes at 37° C. (Zou et al., J. Biol. Chem. 273, 12887-12892 (1998)). The UvrA protein, which has a moderate affinity for damaged DNA (Van Houten, Microbiol. Rev. 54, 18-51 (1990); Seeberg et al., Proc. Natl. Acad. Sci. USA 79, 988-992 (1982); Claassen et al., J. Biol. Chem. 266, 11388-11394 (1991)), associates with the UvrB protein to form a UvrA 2 UvrB complex that tracks along DNA (Koo et al., Proc. Natl. Acad. Sci. USA 88, 1212-1216 (1991)) and delivers UvrB to the damaged site. UvrA, in an ATP-dependent reaction, dissociates from this complex at the damaged site and a very stable UvrB-DNA complex is formed (Orren et al., Proc. Natl. Acad. Sci. USA 86, 5237-5241 (1989); Orren et al., J. Biol. Chem. 265, 15796-15803 (1990)). This complex constitutes a high affinity binding site for the UvrC protein, which upon binding to a UvrB-DNA complex, triggers incision at the 4th to the 7th phosphodiester bonds 3′ to the damaged site (Lin et al., J. Biol. Chem. 267, 17693-17700 (1992); Moolenaar et al., J. Biol. Chem. 270, 30508-30515 (1995)). Immediately after the 3′ incision, 5′ incision occurs at the 8th phosphate group 5′ to the DNA lesion (Lin et al. J. Biol. Chem. 267, 17688-17692 (1992); Zou et al., Biochemistry 34, 13582-13593 (1995)). Prokaryotic NER leads to the excision of lesions as oligomers 12-15 nucleotides in length. Within this reaction cascade the UvrB protein plays a central role since it interacts with all the components of excision repair, namely UvrA, UvrC, UvrD (helicase II), DNA polymerase I and DNA (Sancar and Sancar (1988) Annu. Rev. Biochem., 57, 29-67; Orren et al. (1992) J. Biol. Chem., 267, 780-788). Sequence comparisons have identified six helicase motifs throughout the sequence of UvrB (Gorbalenya et al. (1989) Nucleic Acids Res., 17, 4713-4730) indicating that UvrB is a member of the helicase II superfamily, like the helicases Rad3 and XPD involved in eukaryotic NER (Sung et al. (1987) Proc. Natl Acad. Sci. USA, 84, 8951-8955; Sung et al. (1993) Nature, 365, 852-855). In complex with UvrA, UvrB has been shown to have helicase-like activity in a reaction requiring the hydrolysis of ATP (Oh and Grossman (1987) Proc. Natl Acad. Sci . USA, 84, 3638-3642; Oh and Grossman (1989) J. Biol. Chem., 264, 1336-1343). In addition to its possible role of tracking along the DNA, UvrB alters the affinity of the UvrA 2 B complex towards more bulky adducts compared with UvrA alone (Snowden and Van Houten (1991) J. Mol. Biol., 220, 19-33; Visse et al. (1991) J. Biol. Chem., 266, 7609-7617; Visse et al. (1994) Biochemistry, 33, 1804-1811). The UvrA dimer is sufficient in recognizing damaged DNA, but it is the UvrA 2 B complex that binds to damaged sites with increased specificity and allows efficient DNA damage recognition in vivo. Furthermore, this damage processing, which involves bending and unwinding of the DNA (Lin et al. (1992) J. Biol. Chem., 267, 17693-17700; Visse et al. (1994) Biochemistry, 33, 9881-9888; Zou and Van Houten (1999) EMBO J., 18, 4889-4901), leads to a stable UvrB-DNA pre-incision complex serving as a scaffold for the binding of UvrC. Genetic and biochemical data show the prokaryotic pattern of NER to be present in more than 30 different eubacterial species, including three thermophilic microorganisms, Thermus thermophilus (Yamamoto et al., Gene 171, 103-106 (1996)), Aquifex aeolicus (Deckert et al., Nature 392, 353-358 (1998)), and Thermotoga maritima (Nelson et al., Nature 399, 323-329 (1999)). Sequence analyses indicate a high level of amino acid sequence similarity between Uvr proteins from different, even phylogenetically very distant bacterial species. Furthermore, it has been shown that the UvrA and UvrB proteins from E. coli , a gram-negative bacterium, can be complemented both in vitro and in vivo with the UvrC protein from gram-positive bacterium, Bacillus subtilis (Lin et al., J. Biol. Cheni. 265,21337-21341 (1990)) indicating a significant evolutionary conservation of the NER system among Eubacteria . More recently, homologues of uvrA, uvrB, and uvrC genes have been found in the genome of Methanococcus thermoautotrophicum (Smith et al., J. Bacteriol. 179, 7135-7155 (1997)), a member of the third kingdom of organisms, Archaea . In contrast, the genome sequences of archaeal Methanococcus janaschii (Bult et al., Science 273, 1058-1073 (1996)) and Archaeoglobus fulgidus (Kienk et al., Nature 310, 364-370 (1997)) do not contain uvr gene homologues, suggesting the presence of a novel pattern of NER pathway at least in some archaeal species. |
<SOH> SUMMARY OF THE INVENTION <EOH>One in four people in the US will be diagnosed with cancer in their lifetime. It has been estimated that as much as 90% of all cancers are due to exposure to agents in the environment that directly or indirectly damages DNA. One of the most important problems in cancer biology is linking exposure of an individual to DNA damaging agents with mutations in critical genes (oncogenes) which lead to cancer. The ability to accurately and routinely measure DNA damage in people who may have been exposed to environmental pollutants would more readily allow analysis of the relationship between DNA damaging agents and mutations. Moreover, in the treatment of cancer, chemotherapeutic drugs are often used which cause DNA damage. Knowing the amount of damage produced in the tumor target versus collateral damage in surrounding normal tissue in patients undergoing chemotherapy would help in increasing the effectiveness of the drug treatment. While several biomarkers of exposure to DNA damaging agents have been developed, such as antibodies to specific DNA lesions, no rapid and easy approach is available to quantify DNA lesions. The present invention represents a significant advance in the art of detecting damaged DNA. With the present invention, the coding regions of the UvrA, UvrB and UvrC polypeptides of the thermophilic microbe Bacillus caldotenax have been cloned, sequenced, produced, and isolated. B. caldotenax is a thermophilic gram-positive eubacterium, with an optimal growth temperature about 65° C. Several thermostable proteins with optimal activity between 65° C. to 70° C., including Bca DNA polymerase have been cloned and characterized from this thermophilic microorganism. Unlike previously characterized UvrA, UvrB, and UvrC proteins, the proteins of the present invention advantagously are more stable at higher temperatures for longer periods of time. The present invention provides polynucleotides wherein the complement of the polynucleotide hybridizes to SEQ ID NO:1 under standard hybridization conditions, and the polynucleotide encodes a polypeptide with ATPase activity. The ATPase activity of the polypeptide is increased by at least about 200% in the presence of a double stranded DNA polynucleotide compared to the ATPase activity of the polypeptide in the absence of the double stranded DNA polynucleotide. The polynucleotide may have the nucleotide sequence of SEQ ID NO:1. The present invention further provides a polypeptide with an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, with an ATPase activity that is increased by at least about 200% in the presence of a double stranded DNA polynucleotide when compared to the ATPase activity of the polypeptide in the absence of the double stranded DNA polynucleotide. Also included in the present invention are compositions including this polypeptide. The polypeptide may have the amino acid sequence of SEQ ID NO:2. The present invention provides a polynucleotide wherein the complement of the polynucleotide hybridizes to SEQ ID NO:3 under standard hybridization conditions, the polynucleotide encoding a polypeptide that forms a complex at about 50° C. to about 80° C. with a UvrA polypeptide of SEQ ID NO:2 and a BPDE-DNA substrate. In other aspects of the present invention, the polynucleotide may encode a polypeptide with ATPase activity in the presence of a UvrA polypeptide having SEQ ID NO:2. This ATPase activity is present after preincubation of the isolated polypeptide at 50° C. to about 80° C. for about 10 minutes. The polynucleotide may have the sequence of SEQ ID NO:3. The present invention also provides a composition of a first polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, the first polypeptide forming a complex at about 50° C. to about 80° C. with a UvrB polypeptide having SEQ ID NO:4, and a BPDE-DNA substrate; and a second polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, the second polypeptide forming a complex at about 50° C. to about 80° C. with a UvrA polypeptide having SEQ ID NO:2, and a BPDE-DNA substrate. In another aspect, the present invention provides a polynucleotide having SEQ ID NO:5. The present invention provides a kit for detecting DNA damage. The kit includes a first and a second component. One component is a first polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, the first polypeptide forming a complex at about 50° C. to about 80° C. with a UvrB polypeptide having SEQ ID NO:4 and a BPDE-DNA substrate. The second component is second polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, the second polypeptide forming a complex at about 50° C. to about 80° C. with a UvrA polypeptide having SEQ ID NO:2 and a BPDE-DNA substrate. Included are kits in which the first polypeptide may have an amino acid of SEQ ID NO:2 and kits in which the second polypeptide may have an amino acid sequence of SEQ ID NO:4. Also included are kits that may have an additional component of an antibody that binds to a polypeptide having the amino acid sequence SEQ ID NO:2 and kits that may have an additional component of an antibody that binds to a polypeptide having the amino acid sequence SEQ ID NO:4. In another aspect, the present invention includes a method for detecting DNA damage. The method includes combining a first polypeptide, a second polypeptide and a double stranded DNA to form a mixture; incubating the mixture such that a complex forms of the first polypeptide, the second polypeptide, and the double stranded DNA and detecting the complex, where the presence of a complex indicates the presence of DNA damage. The first polypeptide is encoded by a polynucleotide, where the complement of the first polynucleotide hybridizes to SEQ ID NO:1 under standard hybridization conditions, and the first polypeptide forms a complex at about 50° C. to about 80° C., with a UvrB polypeptide having SEQ ID NO:4 and a BPDE-DNA substrate. The second polypeptide is encoded by a polynucleotide where the complement of the polynucleotide hybridizes to SEQ ID NO:3 under standard hybridization conditions, and where the second polypeptide forms a complex at about 50° C. to about 80° C. with a UvrA polypeptide having SEQ ID NO:2 and a BPDE-DNA substrate. In some aspects of the present invention are methods in which the complex may be detected by detecting the presence of the second polypeptide; this may include detecting the presence of the second polypeptide with an antibody that binds to the second polypeptide. Also included are methods where the first polypeptide may have an amino acid sequence including SEQ ID NO:2 and methods where the second polypeptide may have an amino acid sequence including SEQ ID NO:4. Also included are methods where the double stranded DNA may be from a subject, including subjects undergoing treatment for cancer or subjects that have been exposed to a genotoxin. The double stranded DNA may be obtained from the subject either before, during, or after treatment or exposure to the genotoxin. The treatment for cancer may include chemotherapy. The present invention is further directed to a polynucleotide where the complement of the polynucleotide hybridizes to SEQ ID NO:5 under standard hybridization conditions and the polynucleotide encodes a polypeptide that in a mixture at about 50° C. to about 80° C. incises a BPDE-DNA substrate. This mixture includes the polypeptide, a UvrA polypeptide having SEQ ID NO:2, a UvrB polypeptide having SEQ ID NO:4, and the BPDE-DNA substrate. The polynucleotide of the present invention may have the sequence of SEQ ID NO:5. Also included in the present invention is a polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:6, where the polypeptide in a mixture at about 50° C. to about 80° C. incises a BPDE-DNA substrate. This mixture includes the polypeptide, a UvrA polypeptide having SEQ ID NO:2, a UvrB polypeptide having SEQ ID NO:4, and the BPDE-DNA substrate. In some aspects, the polypeptide may have the amino acid sequence of SEQ IDNO:6. In some aspects of the present invention are compositions including the polypeptide of claim. These compositions may also include a second polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, the second polypeptide forming a complex at about 50° C. to about 80° C. with a UvrB polypeptide having SEQ ID NO:4, and a BPDE-DNA substrate; and a third polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, the third polypeptide forming a complex at about 50° C. to about 80° C. with a UvrA polypeptide having SEQ ID NO:2 and a BPDE-DNA substrate. Included in another aspect of the present invention is a kit for detecting DNA damage. The kit includes three components. The first component is a first polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, where the first polypeptide forms a complex at about 50° C. to about 80° C. with a UvrB polypeptide having SEQ ID NO:4 and a BPDE-DNA substrate. The second component is a second polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, where the second polypeptide forms complex at about 50° C. to about 80° C. with a UvrA polypeptide having SEQ ID NO:2 and a BPDE-DNA substrate. The third component is a third polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:6, where the third polypeptide, when in a mixture at about 50° C. to about 80° C., incises a BPDE-DNA substrate. The mixture includes the third polypeptide, a UvrA polypeptide having SEQ ID NO:2, a UvrB polypeptide having SEQ ID NO:4, and the BPDE-DNA substrate. Included in some aspect of the present invention are kits in which the first polypeptide may have SEQ ID NO:2; kits in which the second polypeptide may have SEQ ID NO:4; and kits in which the third polypeptide may have SEQ ID NO:6. Included in the present invention is a kit for UvrABC endonuclease excision. The kit includes three components. The first component is a first polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:2, where the first polypeptide forms a complex at about 50° C. to about 80° C. with a UvrB polypeptide having SEQ ID NO:4 and a BPDE-DNA substrate. The second component is a second polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:4, where the second polypeptide forms complex at about 50° C. to about 80° C. with a UvrA polypeptide having SEQ ID NO:2 and a BPDE-DNA substrate. The third component is a third polypeptide having an amino acid sequence having a structural similarity of at least about 65% with SEQ ID NO:6, where the third polypeptide, when in a mixture at about 50° C. to about 80° C., incises a BPDE-DNA substrate. The mixture includes the third polypeptide, a UvrA polypeptide having SEQ ID NO:2, a UvrB polypeptide having SEQ ID NO:4, and the BPDE-DNA substrate. Included in some aspect of the present invention are kits in which the first polypeptide may have SEQ ID NO:2; kits in which the second polypeptide may have SEQ ID NO:4; and kits in which the third polypeptide may have SEQ ID NO:6. Another aspect of the present invention includes a method for detecting DNA damage. The method includes combining a first polypeptide, a second polypeptide, third polypeptide, and a double stranded DNA to form a mixture; incubating the mixture; and detecting an incised polynucleotide, where the presence of an incised polynucleotide indicates the presence of DNA damage. The first polypeptide is encoded by a first polynucleotide, where the complement of the first polynucleotide hybridizes to SEQ ID NO:1 under standard hybridization conditions, the first polypeptide forms a complex at about 50° C. to about 80° C., with a UvrB polypeptide having SEQ ID NO:4 and a BPDE-DNA substrate. The second polypeptide is encoded by a second polynucleotide, where the complement of the second polynucleotide hybridizes to SEQ ID NO:3 under standard hybridization conditions and where the second polypeptide forms a complex at about 50° C. to about 80° C. with a UvrA polypeptide having SEQ ID NO:2 and a BPDE-DNA substrate. The third polypeptide is encoded by a third polynucleotide, where the complement of the third polynucleotide hybridizes to SEQ ID NO:5 under standard hybridization conditions and the third polypeptide, in a mixture at about 50° C. to about 80° C., incises a BPDE-DNA substrate; the mixture including the third polypeptide, a UvrA polypeptide having SEQ ID NO:2, a UvrB polypeptide having SEQ ID NO:4, and a BPDE-DNA substrate. Included in some aspects of the present invention are methods where the first polypeptide may have SEQ ID NO:2; methods where the second polypeptide may have SEQ ID NO:4; and methods where the third polypeptide may have SEQ ID NO:6. The double stranded DNA may be from a subject; including a subject undergoing treatment for cancer and a subject who has been exposed to a genotoxin. The treatment for cancer may include chemotherapy. The double stranded DNA may be obtained from the subject either before, during, or after treatment. |
Method for determiming boutes and rekated navigation system |
A method for ascertaining routes in a route network is provided, in which an optimal route to a target of a certain category can be determined. A route is calculated from a point of origin to an optimal target point from a plurality of spatially separated target points that are allocated to at least one directed segment and/or to at least one node. The method includes defining the target points from entries of addresses, map targets, target memory entries given by an index of a given category, such as, for instance, post office, gas stations. The respective route to the target point is optimized as a sequence of the directed segments having nodes situated between the directed segments such that the sum of all resistances of the sequence to the respective target point becomes a minimum. A list of the respective routes to the respective target point is then drawn up. |
1-27 (canceled) 28. A method for calculating an optimal route from a point of origin to an optimal target point selected from a plurality of spatially separated target points that are allocated in each case to at least one of a directed segment and a node, in a route network mapped in a memory unit as directed segments and nodes situated between the directed segments, the method comprising: allocating a resistance value to each directed segment and each node; defining target points by at least one of an index and a category; optimizing the respective route to each of the target points as a sequence of directed segments using a stepwise backwards iterating route search algorithm, wherein in each iteration step, a route to each of the target points is optimized such that the respective resistance sum for each route representing the sum of resistances of the sequence of directed segments to the respective target point becomes a minimum; and drawing up a list of the respective routes to the respective target point. 29. The method of claim 28, further comprising: displaying a route having the minimum sum of resistances as the optimal route, after drawing up the list of the respective routes to the respective target point. 30. The method of claim 28, wherein the step of defining target points by at least one of an index and a category includes the steps of: initiating a MultiDest List; selecting a certain target using at least one of an address, a map target, and a target memory entry; copying a description of this target into the MultiDest List; determining whether at least one additional target has been added; and wherein if at least one additional target has been added, then a certain target is again selected, and if at least one additional target has not been added, then the step ends. 31. The method of claim 28, wherein the step of defining target points by at least one of an index and a category includes the steps of: selecting the category; determining whether the list of the category has been assigned as the MultiDest List; if the list has been assigned as the MultiDest List, then: initiating the MultiDest List; copying target descriptions into the MultiDest List; and processing at least a selected number of the targets; if the list has not been assigned as the MultiDest List, selecting a target. 32. The method of claim 28, wherein the target points are defined with at least one of: i) user-specified manual input; and ii) automatic input from entries including at least one of addresses, map targets, and target memory entries given by at least one index. 33. The method of claim 32, further comprising: in the case of the automatic input, automatically determining a respective current location of the vehicle. 34. The method of claim 28, wherein each route to a respective target point is calculated iteratively starting from a segment allocated to the respective target point. 35. The method of claim 28, wherein the step of optimizing the respective route to each target point includes: (1) setting up a route table, wherein for each directed segment, both in forward and backward direction, a resistance value and a successor segment is entered; (2) setting all the resistance values of the route table to infinity and deleting all of the successor segments; (3) setting the resistance values of segments allocated to the respective target points to zero; (4) storing segments allocated to the respective target points in a first list for the segments that have already been optimized; (5) setting up an empty second list for segments to be optimized in the next step; (6) determining whether the first list is empty, wherein if the list is empty, ending the step of optimizing the respective route; (7) if the first list is not empty, setting a segment from the first list as an actual segment; (8) determining all the segments interconnected with the actual segment as arriver segments; (9) determining for a respective arriver segment, whether an optimization condition is satisfied, wherein: if the optimization condition is satisfied: I) entering the respective arriver segment in the second list; II) setting the resistance value of the respective arriver segment in the route table to a sum of a section resistance of the arriver segment and a resistance of the actual segment; and III) entering the actual segment as the successor segment of the respective arriver segment; if the optimization condition is not satisfied, discarding the arriver segment; (10) determining whether all arriver segments have been processed, wherein: if not all the arriver segments have been processed, then setting another segment from the first list as the actual segment and performing step (8); and if all arriver segments have been processed, performing step (11); (11) determining whether all segments from the first list have been processed: if all segments from the first list have not yet been processed, performing step (7); and if all segments from the first list have been processed, performing step (12); (12) exchanging the first list with the second list, emptying the second list and performing step (6). 36. The method of claim 28, further comprising: after ascertaining the route from the point of origin to the respective target point, at least one of the following is performed: retaining the current target point and discarding other possible target points; discarding the current target point and determining a route to one of the other possible target points; and maintaining all target points, and deriving a better route when deviating from the calculated route to another target point. 37. The method of 28, further comprising: testing the calculated route for presence of factors influencing the route network by user-specified input or by telematics. 38. The method of claim 37, wherein the calculated route is modified by least one traffic-related event, the traffic-related event including one of a road closing, a traffic jam, traffic coming to a stop, and a traffic accident. 39. The method of claim 28, further comprising: importing the drawn up list of respective routes to the respective target point into at least one navigation system with the aid of traffic telematics. 40. The method of claim 39, wherein the traffic telematics include at least one of GPRS, GSM, UMTS, and an online service provider. 41. The method of claim 28, wherein the method is performed in at least one of a vehicle, a software-based route search application of an electronic data processing system, and an electronic data processing system of a service provider. 42. A navigation system of a vehicle, comprising: at least one processing unit for determining an optimal route from a point of origin to an optimal target point selected from a plurality of spatially separated target points that are allocated in each case to at least one of a directed segment and a nodes, the processing unit performing: allocating a resistance value to each directed segment and each node; defining target points by at least one of an index and a category; optimizing the respective route to each of the target points as a sequence of directed segments using a stepwise backwards iterating route search algorithm, wherein in each iteration step, a route to each of the target points is optimized such that the respective resistance sum for each route representing the sum of resistances of the sequence of directed segments to the respective target point becomes a minimum; and drawing up a list of the respective routes to the respective target point. |
<SOH> BACKGROUND INFORMATION <EOH>In currently-deployed navigation systems, the driver of a vehicle, such as a motor vehicle, can influence the route traveled in various ways, e.g., as described in published European patent document EP 0 979 987. For instance, the driver may select different optimizing criteria, such as “short route”, “fast route”, “avoid expressways” or the like, and/or can influence route sections, determined manually or using traffic telematics, which are then favored or avoided in the route calculation. The driver may also define one or more intermediate targets, which are then approached in sequence leading to a final target. However, before searching for the route, the driver has to commit himself to an intermediate target which has to be a firm intermediate target. Thus, the intermediate targets or targets may essentially be divided into the following categories: a road target given by one or more road sections that are connected to one another;. road crossing target given by a target point which is established by the crossing of roads having different names; directed point target or non-directed point target given by a target point which is mapped onto an orthopole on a nearby road section. However, the various target types mentioned above have in common that all the targets relate spatially to one enclosed region. In some cases, there may be a desire on the part of the driver to be offered an optimum route to any one of several targets. For example, a driver may be looking for the nearest parking lot in a town that is unknown to him or may need a route to the nearest gas station, because his tank contents are low; alternatively, the route to the nearest branch of a fast food chain may be desired. In the current navigation systems, the various applicable targets are shown in an index with a brief description. The user of the navigation system then can select one of these targets from the index and have a route determined. The index list in some conventional navigation systems, besides having a simple description, may also include a pertinent linear distance, and is sorted according to this linear distance. In such cases, the nearest target from the current position can be very simply determined using the criterion of linear distance. However, in actual topography examples may be found in which these targets are not easy to reach from the current location of the means of locomotion, or rather, there are equivalent or even better alternative targets. Consequently, “nearest . . . ” does not necessarily mean the nearest target, but the target that is most easily reached. In such current navigation system, the optimal target is ascertained by consecutive calculations of routes to all the targets offered in the index and by comparison of the same; this is a time-consuming and difficult process even when only the nearest three targets with regard to linear distances are to be considered. After the user of a navigation system has decided on a target, then, this target is maintained. If it is not possible to follow the suggested route to the selected target, whether because of simply departing from the route and/or on account of road closings, the driver continues with the old target despite the fact that there may be a better target. This may lead to inefficient results. For example, it is possible that a route to a selected gas station may directly pass another possible gas station, which, at the start of the navigation, had seemed less favorable. In order to implement a method according to the type described above a route network, such as a road network, is mapped by a digital map. According to an example implementation, a route-search algorithm according to Ford and Moore may be used. For this algorithm, the following criteria for imaging the route network may be used: A route network, in particular a road network, can be depicted using a route-search algorithm as a graph having segments and having nodes. In this connection, the segments represent the routes and the nodes represent the interconnection points of the route network. Since in an actual road network traffic flow has direction, a segment is described with a vector having direction (See FIG. 1 which depicts an exemplary route network as a network of directed segments and of nodes situated between the directed segments). stances, or “segment resistances”, are allocated to As, where each segment resistance represents a measured variable for the effort of getting from one node in the network to another node in the network. In the simplest case, the length of the segment can be used directly as the segment resistance. Alternatively, making the assumption of an average traffic speed, the travel time on a segment may be regarded as its segment resistance; however, configurations are also conceivable in which travel time, length and other variables are linked with one another, in order to view the segment resistance of a map in a graph. In addition, it may be noted at this point, that a resistance may also be allocated to the nodes. All optimal path algorithms determine a route between a starting segment and a target segment in the directed graph having the property that the sum of all segment resistances allocated to the segments has a minimum. An algorithm for route calculation may build upon known optimal method algorithms according to Ford and Moore taken from graph theory; in this connection, these algorithms are adapted to the requirements for use in autonomous vehicle navigation systems. The algorithm according to Ford and Moore is reverse-iterating, i.e., “visits” all the segments in the graph and evaluates the segments with respect to their favorable resistance to the target segment. This means, in other words, that, starting from a target segment, in each iterative step, the most favorable path is sought with respect to resistance, to the segments cited in a list and optimized in the previous iterative step. As a result, the method supplies the optimal route to the target segment from each segment in the graph. To represent the calculation results, a route table is installed in the memory unit, which may appear as follows for an exemplary network according to FIG. 1 : Segment +Resistance +Successor −Resistance −Successor k1 ∞ − ∞ − k2 ∞ − ∞ − k3 ∞ − ∞ − k4 ∞ − ∞ − k5 ∞ − ∞ − k6 ∞ − ∞ − k7 ∞ − ∞ − k8 ∞ − ∞ − k9 ∞ − ∞ − For each segment k 1 through k 9 in the graph, in this table, the resistance up to the target segment and the successor segment (=“successor”) in the target direction is stated. As an initial value, the resistance is set to “infinity”(∞) and the successor segment is set to “indefinite”(−), that is, the successor is deleted; a positive sign (“+”) in the resistance column and the successor column stands for viewing the segment in its arrow direction, and a negative sign (“−”) stands for viewing the segment counter to its arrow direction. Before the start of the iterative optimization, the target segment in the above route table is initially given a resistance value of “zero”; in addition, the target segment is entered in the list of the already optimized segments, denoted as “first list” below. A “second list” is used for storing the segments to be tested in the next optimization step; at the beginning of the iterative optimization, the second list is empty. After the initiation, the optimization method may begin. The segments shown in the first list are regarded as being the “actual” position of the vehicle, and all the segments interconnected with this actual segment, the so-called “arriver segments”, are submitted to an optimization test (designated by an O below). This yields the scenario illustrated in FIG. 2 . It is now assumed for the purposes of optimization that the vehicle is located on one of arriver segments, having a travel direction towards the actual segment. It is then tested as optimization condition whether the previous available route of the arriver segment is worse than the new route while using the actual segment; if the route via the actual segment proves to be better, an optimization is carried out. Corresponding to the configuration shown in FIG. 2 , the following optimization relationships are derived: Optimization Actual Segment Arriver Segment O1a +k1 −k1 O1b +k1 +k2 O1c +k1 −k3 For each actual arriver relationship according to the above table, there takes place the optimization testing which is shown by the example of arriver segment +k 2 (→optimization O 1 b ; see FIG. 2 ). In the optimization testing, the previous route table resistance of the arriver segment +k 2 to the target is compared to the resistance which the arriver segment would have if it led to the target via the actual segment. Optimization takes place if the so-called (resistance) optimization condition in-line-formulae description="In-line Formulae" end="lead"? R RT,actual(+k1) +R segment,Ank(+k2) <R RT(Alt) ,Ank(+k2) in-line-formulae description="In-line Formulae" end="tail"? is satisfied, where in-line-formulae description="In-line Formulae" end="lead"? R RT,actual(+k1) =resistance (from route table RT) of actual segment +k 1 to the target; in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? R segment,Ank(+k2) =segment resistance of arriver segment +k 2 ; in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? R RT(Alt),Ak(+k2) =resistance (from route table RT) of arriver segment +k 2 to the target. in-line-formulae description="In-line Formulae" end="tail"? The above optimization condition thus means, in other words, that the new resistance of the arriver segment is less than the previous resistance of the arriver segment. The resistance of the arriver segment is then replaced by the new, lower value in the route table, the actual segment is entered as the successor segment, and the optimized arriver segment is taken up into the second list. If, in this manner, all the segments from the first list have been processed, the first list and the second list are exchanged; this means that the starting point for the next optimization is the segments optimized in the last method step. The method is ended when the first list is found to be empty, that is, when there are no longer any segments optimized in the previous pass. We shall now explain the problem of a suboptimal route to the next target, in the light of an example: The exemplary network to be considered is shown in FIG. 1 . The assumption is made that segments k 1 , k 3 , k 4 , k 6 as well as k 9 each have the resistance value 10, and segments k 2 , k 5 , k 7 as well as k 8 each have the resistance value 20. At the time of consideration, the vehicle is located on segment +k 8 , i.e. the travel direction corresponds to the preferential direction. The driver of the vehicle, starting from his actual position, would now like to have calculated for him the optimal route to a target of a certain category (this could be, for example, the first post office that comes along, or the first gas station, when the tank reserve of gasoline has already been activated). For this the driver of the vehicle calls up the index of the corresponding category (post offices, gas stations, . . . ) and receives the following list of the particular targets of that category that are located close to the actual position of the vehicle: >20 target A 30 target B This list does not indicate which of the two targets A or B the better route is derived; on this matter, the linear distance between the actual position of the vehicle and individual targets, contained in the index list does not indicate this either. In the exemplary network of FIG. 1 , target A is mapped on segment k 1 and target B is mapped on segment k 4 , as may be seen in FIG. 3 in the light of a double arrow, one in each case. On the basis of the above list, an initial preference would be for target A which is closer to the actual position of the vehicle. By applying the best path algorithm according to Ford and Moore, as well as by applying the corresponding optimization condition with respect to the resistance, there is derived, as shown in FIG. 4 , the route to target A marked by the direction of the arrow, the overall resistance of the route to target A being exactly 50 units. When determining the route from the actual position of the vehicle to target B, that lies at a greater distance from it, the actual difficulty becomes clear because, for this target B, the route shown in FIG. 5 , marked by the direction of the arrows, has a total resistance of 40. When comparing the two routes to target A and to target B, it becomes clear that the route to the nearest-lying target A does not produce the optimal route; the optimal route, in this example, is to the second-nearest target B. It is particularly a problem, in this connection, that the question as to which target produces the optimal route can be determined, using the conventional methods, only by successive calculations of the routes to all targets. |
<SOH> SUMMARY <EOH>Regarding the disadvantages and shortcomings named above, an object of the present invention is to provide a user of a navigation system both the possibility of calculating a route from a starting point to a single target point and also to determine an optimal route to a target of a certain category. In this connection, one of ordinary skill in the field of traffic telematics will particularly appreciate that, according to the teachings of the present invention, no sequential determination of the routes to the various possibilities takes place, but rather, within the scope of a so-called “Multi-Destination Route Search” the simultaneous consideration of all targets that come into consideration takes place, so that the optimal route to the best target is ascertained as the result. In this connection, the targets considered in the so-called “multi-destination route search” are assumed to have an equal chance to be selected. In the case of these targets, the various entries of the index of a certain category of special targets, such as post offices, gas stations or the like may be involved; however, alternatively, or in addition, it is also possible to use various targets, which do not originate from a definite index category, for the MultiDestination Route Search. Thus, for example, addresses, map targets or entries from at least one target memory may be used. According to one embodiment of the present invention, in the MultiDestination Route Search, several targets that are not spatially connected may be used as having equal rights for the route search. In this connection, the driver of the vehicle does not have to ponder which of the targets is easiest to reach, because the route determination from the current actual position to the targets takes place in such a way that the optimal route is ascertained while the selected criteria, such as, for example, “short route”, “fast route”, or the like, are considered. After determination of the optimal route to a target, the driver of the vehicle has the choice of maintaining the target, of specifying it, or rather discarding the other possible targets; of discarding the current target and determining a route to another target; of leaving all targets active, so that a better route is derived when departing from the suggested route to another target. Besides the selected criteria explained above, in the ascertainment of the route according to the present invention, network influences by telematics or by user-specified manipulations may be considered, such as, for example, a “traffic jam ahead” road closing. For the MultiDestination Route Searches, besides adaptations in the route search itself, expansions in the interface unit of the processing unit of the navigation system according to the present invention and/or in the index for the definition of the equally entitled targets to be used are provided. In this connection, besides data on the starting position required for a normal route search, which may be known to the route search with the aid of the position-finding unit of the navigation system, in the so-called MultiDestination Route Search the various targets having equal parameters are to be specified. According to an exemplary embodiment of the navigation system of the present invention, input may be manual and/or automatic input. The automatic input may be based on an automatic determination of the current position of the vehicle. For example, one may work with the still available residual distance in view of the current tank charge, so that then, within the scope of the so-called MultiDestination Route Search (RS) one or more possible routes from the starting point (for example, the current position of the vehicle) to a plurality or multiplicity of equally entitled, spatially separated target points (for example, the gas stations that may still be reached with the current tank charge) may be calculated. Thus, the actual MultiDestination RS may take place after the definition, described below, (manual or automatic) of a “MultiDestination List” (also called “MultiDest List” below): The partial targets, also denoted as so-called “subdestinations” (abbreviated as SD), of the so-called MultiDestination RS, may, for example, be targets from the target memory, addresses, location targets or point targets. In the case of this type of target, the user calls up the various targets and stores them manually via a menu option, instead of beginning the route calculation, in the MultiDest List. According to one example embodiment, the procedure of generating the MultiDest List from the individual targets has the following method steps (shown in FIG. 6 ): (A. 1 ) starting; (A. 2 ) initiating the “MultiDest List”; (A. 3 ) selecting a certain target, such as an address, map target, target memory entry or the like; (A. 4 ) copying the description of these targets into the “MultiDest List” (in the graph); (A. 5 ) adding at least one further target: if at least one additional target is added (+), then return to before step (A. 3 ); if no additional target is added (−), continue to step (A. 6 ) (A. 6 ) end of the method. An alternative or supplementary possibility may be to fill the MultiDest List with the entries of the list of special targets of the desired category (post offices, gas stations or the like) near the actual position of the vehicle; in doing this, the number of entries of the MultiDest List is only limited by the finiteness of the working memory of the navigation system. In this case, the user does not select a certain target from the list, but specifies all entries as partial targets; however, it is also possible to add single entries to the list of a MultiDest List. According to another embodiment, the procedure of generating the MultiDest List from a special target list has the following method steps (as shown in FIG. 7 ): (A. 11 ) starting; (A. 12 ) selecting the category, especially the special target category; (A. 13 ) taking over the list as the MultiDest List: if the list has been taken over as the MultiDest List (+), go to step (A. 14 ): initiate the so-called “MultiDest List”; if the list has not been taken over as the MultiDest List (−), go to step (A. 17 ): select a certain target; (A. 15 ) copying-the target description into the MultiDest List (in the graph); (A. 16 ) processing all targets or a certain number of targets: if all targets or the certain number of targets have been processed (+), go to step (A. 18 ); if not yet all targets or not yet the certain number of targets have been processed (−), go ahead of step (A. 15 ); (A. 18 ) end of method. After all partial targets have been defined in this manner, the subsequently described MultiDestination RS may be started using the desired criteria. In this connection, the general sequence of the MultiDestination RS may be subdivided, in an expedient manner, into the following sections shown in FIG. 8 and FIG. 9 using the route search algorithm according to Ford and Moore: (R. 1 ) starting; (R. 2 ) determining the MultiDest List specifying two partial targets A and B; (R. 3 ) initiating: (R. 3 . 1 ) initiating route table: basic initiation of the route table; in this connection, the resistance is set to infinity (¢) and the successor is deleted (−); (R. 3 . 2 ) initiate the segments of the partial targets described in the MultiDest List. After the basic initiation of the route table, all segments of the partial targets to be considered are initiated in the route table; for this purpose, in the route table the resistance is set to “zero” and the successor is set to the initiation value (no successor: “−”) of the segments entered in a MultiDest Description List; in addition, the processed segments are taken up into the second list, i.e., into the list of segments that are still to be optimized. (R. 4 ) Optimization of the segments of the graph: After the initiation of the route tables and of the MultiDest Description List. The actual route search takes place; in the light of the optimization conditions or optimization rules shown below, optimization of the route is performed, as may be seen in FIG. 10 . (R. 4 . 1 ) starting of the segment optimization; (R. 4 . 2 ) determining whether R RT(new),Ank <R RT(Alt),Ank where R RT(new),Ank +R segment,Ank +R RT,actual if the condition R RT(new),Ank <R RT(Alt),Ank is satisfied (+), go to step (R. 4 . 3 ): update entry in the route table: update the resistance value of the arriver segment in the route table and enter the actual segment as successor; if the condition R RT(new),Ank <R RT(Alt),Ank is not satisfied (−), go to step (R.4.4): end segment optimization. The sufficient condition for the optimization is demonstrated by the formula R segment,Ank +R RT,actual <R RT(Alt),Ank , i.e., the segment must be optimized if the sum of the path resistance of the arriver segment and the resistance of the actual segment that is entered in the route table is less than the previous resistance of the arriver segment that is entered in the route table. Upon satisfaction of this condition, the need for an optimization arises; the new properties of the arriver segment are entered in the route table and as successor the actual segment. If all the segments from the first list used for storing the already optimized segments have been processed in the method described, the first list of the already optimized segments and a second list needed to store the segments to be tested in the next optimization step are exchanged, that is, the point of departure for the next optimizations is the segments optimized in the last method step. The method is terminated when the first list is found to be empty. (R. 5 ) Drawing up the route list: After the completed optimization, the route list is generated from the route table. Starting from the segment of the current position of the vehicle, the segments are written into the route list corresponding to the successor concatenation in the route table. With the aid of the last segment in this route list, the current partial target may be determined via the MultiDest Description List, and may be characterized in a MultiDest Index List for possible location. (R. 6 ) end of the method. According to an embodiment of the present invention, in the case of the MultiDestination-RS, based on the optimal path algorithm according to Ford and Moore, at least one route table gets to be used for describing the characteristics of the segments of the graph. Such a route table includes the description of the characteristics of all segments of the route network with respect to a section of the route to the target; each segment is mapped by an entry which includes the characteristics of the segment both in the direction of the arrow and counter to the direction of the arrow. In the so-called MultiDestination-RS, the optimal route to the best possible target is described in a single route table, the construction of a basically initiated route table being expediently as follows: Segment +Resistance +Successor −Resistance −Successor k1 ∞ − ∞ − k2 ∞ − ∞ − k3 ∞ − ∞ − . . . ∞ − ∞ − k(M − 1) ∞ − ∞ − kM ∞ − ∞ − According to one embodiment of the present invention, the description of the partial targets and the linkage with the appertaining segments in the graph are combined with the aid of the MultiDest Index List and the MultiDest Description List that are linked to each other, which is also denoted as a MultiDest List. In this context, all the partial targets are included in the MultiDest Index List. This MultiDest Index List includes no sorting, and is used only to make possible a simple access to the list of the segments that describe the partial target, as may be seen from the exemplary construction of the so-called MultiDest Index List shown below: MultiDest Index Status/Description 1 /name of partial target 2 /name of partial target 3 /name of partial target . . . /name of partial target N − 1 /name of partial target For each partial target (so-called subdestination SD), in the so-called MultiDest Index List illustrated at the top left of FIG. 11 , a reference to the list of segments K appertaining to the respective subdestinations SD (shown in FIG. 11 , bottom right, in the MultiDest Description List) is stored; FIG. 11 , therefore, illustrates the connection between the MultiDest Index List and the MultiDest Description List. A first list of the already optimized segments may be used for storing the already optimized segments. A second list is used for storing the segments to be tested in the next optimization step, and accordingly it expediently includes the segments to be tested in the next optimization step; at the beginning of the iterative optimization, the second list is empty. In this connection, the segments are derived that are to be tested in the next optimization step, as in already-discussed optimization relationships, beginning from an actual segment, all arriver segments are tested again. In summary, one may determine that the present invention makes it possible to ascertain the optimal route from an actual position to one of a plurality of targets that are not connected and have equal rights. In this case, there is no sequential determination to the individual, possible targets; rather, the route is ascertained as the optimal route within the scope of the so-called MultiDestination RS method, taking into consideration all targets that come into consideration. This yields the advantage that the driver of the vehicle achieves the best target point with the aid of optimal route guidance. That is, unfavorable route guidances, that are able to appear in the case of the exclusive choice of the nearest target, are avoided, because all targets are considered. In addition, with regard to the present invention, one skilled in the art will appreciate that it is not limited to the use of one particular route search algorithm; to be sure, the above exemplified route search algorithm according to Ford and Moore is distinctly suitable for the present invention, but the method may also be implemented using other mathematically exact methods to ascertain the “best path” stemming from graph theory. As was explained before, in the method introduced here, all targets are considered simultaneously, so that the determination of the optimal route to the best target takes place at one time, which, in turn, brings with it a more rapid calculation of the route than would be true in the sequential ascertainment. In this connection, a permanent optimization of the route and the best target from the current actual position takes place, that is, when one leaves the route, a new optimal route to the best target is automatically determined. Since, in this renewed determination of the route, all targets are given consideration, the best target for this current actual position prevails; in this connection, the new target does not have to correspond to the previously utilized target. Since, in the so-called MultiDestination RS, all targets are considered that come into consideration, the optimal route to the optimal target is always available. Consequently, at every point in time, the respective distance to the current target as well as the remaining travel time or even the estimated arrival time may be stated. Independently of, or in conjunction with this, a combination having various route criteria can be made; thus the method according to the present invention may be used while considering the most varied optimization criteria, such as “short route” or “fast route”. Besides the optimization criteria, the method may also be combined with various network manipulations, such as, for instance, telematics or manual blockages. It should also be pointed out that the present method of the so-called MultiDestination RS may quite simply be integrated into intermediate target or so-called “ViaArea” route search methods, so that the specific characteristics of these intermediate area or “ViaArea” route search methods can be used; thus, for example, one could cite in this connection the complete description of the route to the actual target via “ViaArea”. In addition, according to the present invention, telematics service providers may dynamically inject targets in order, for example, to steer the traffic flow. In this connection, the navigation system in the vehicle remains fully autonomous, and is able to react autonomously and rapidly to the departure of the driver of the vehicle from the route. In contrast to this, such rapid reaction times cannot be achieved using methods in which a telematics service provider fully takes over the route calculation and downloads the route course into the vehicle. Finally, the present invention relates to the use of the method explained above in a vehicle, especially in a navigation system of a vehicle. Alternatively, or in addition, the above-explained method may also be used in a particularly software-based route search application of an electronic data processing set-up, particularly of a personal computer (PC) as a PC tool. Thereby the user of the electronic data processing set-up is put in the position, for instance, of testing the advised route for at least one traffic-related event, such as at least one road blockage, at least one traffic jam or traffic coming to a stop and/or at least one traffic accident. If necessary, the user of the electronic data processing set-up may have an alternative route or an evasive route determined and displayed for himself. The use of the above-explained method is also possible to the effect that a service provider calculates an expediently optimized route, when requested by the user, with the aid of an electronic data processing set-up, and transmits the route thus ascertained by remote data transmission to the vehicle, especially to the motor vehicle of the user. |
Data certification method and apparatus |
An apparatus and method for signing electronic data with a digital signature in which a central server comprises a signature server (110) and a authentication server (120). The signature server (110) securely stores the private cryptographic keys of a number of users (102). The user (102) contacts the central server using a workstation (101) through a secure tunnel which is setup for the purpose. The user (102) supplies a password or other token (190), based on information previously supplied to the user by the authentication server (120) through a separate authentication channel. The authentication server provides the signature server with a derived version of the same information through a permanent see tunnel between the servers, which is compared with the one supplied by the user (102). If they match, data received from the user (102) is signed with the user's private key. |
1. A method of certifying electronic data supplied by a user, the method comprising: receiving the data to be certified at a certifying apparatus from a source device; certifying the data at the certifying apparatus with one or more elements of information secure to the certifying apparatus, said elements being unique to the user; and outputting the data so certified from the certifying apparatus, for passing to a recipient device; wherein the elements of secure information certify that the supplier of the data is the user. 2. A method according to claim 1, wherein the private key of a public key/private key pair specific to the user defines a said element unique to the user. 3. A method according to claim 1 or 2, wherein a digital signature specific to the user defines a said element unique to the user. 4. A method according to any preceding claim, wherein the recipient device is the source device. 5. A method according to claim 1, 2 or 3, wherein the recipient device is a third party device. 6. A method according to any preceding claim, wherein a hash value of a message to be certified is generated at the source device, the hash value being the data to be certified by the certifying apparatus. 7. A method according to any preceding claim, wherein the certifying apparatus can receive data from many different source devices. 8. A method of certifying electronic data supplied by a user, the method comprising: establishing a secure connection between a source device and a certifying apparatus; sending the data from the source device to be received by the certifying apparatus; and receiving a version of the data from the certifying apparatus certified as originating from the user, using information unique to the user. 9. A method according to claim 8, further comprising the step of incorporating a certified version of the data into further data to be sent to a third party device. 10. A method according to claim 8 or 9, wherein the certifying apparatus holds information unique to the user to carry out the certification. 11. A method according to claim 10, wherein the unique information is the private key of a public key/private key pair specific to the user. 12. A method according to claim 10 or 11, wherein the unique information is a digital signature specific to the user. 13. A method according to any of claims 8 to 12, wherein the data to be certified is a hash value of a message. 14. A method according to any preceding claim, wherein the certifying apparatus comprises a signature server. 15. A method according to any preceding claim, wherein the certifying apparatus comprises a plurality of signature servers using secret sharing to store individual portions of a private key of a user, and wherein the signature is generated based on individual portions of a private key of a user stored on some or all of the signature servers. 16. A method according to claim 14 or 15, wherein the certifying apparats further comprises one or several authentication servers. 17. A method according to any preceding claim, wherein the source device comprises a workstation. 18. A method according to any preceding claim, wherein the source device comprises an interactive television. 19. A method according to any preceding claim, wherein the source device and certifying apparatus establish authenticated individual connections between the source device and one or several servers of the certifying apparatus before and during transfer of the data to be certified. 20. A method according to claim 19, wherein the connection is encrypted. 21. A method according to claim 19 or 20, wherein the source device supplies a token to the certifying apparatus for authentication. 22. A method according to claim 21, wherein the token is supplied to the user or source device by the certifying apparatus via an alternate channel to the authenticated connection. 23. A method according to claim 22, wherein the alternate channel is a mobile telephone network. 24. A method according to claim 23, wherein the token is distributed as a Short Message Service message. 25. A method according to claim 21 or 22, wherein the token is a fixed password. 26. A method according to any of claims 21 to 24, wherein the token is a one-time password. 27. A method according to claim 21 or 22, wherein the token is unique to a transaction. 28. A method according to claim 21 or 22, wherein the token is stored on a portable device. 29. A method according to any of claims 21 to 28, wherein more than one type of token may authenticate the user or source device to one or several servers at the certifying apparatus. 30. A method according to claim 29, wherein the method operates with one level of security reached by authenticating the user regardless of the source, and another, higher, level of security reached by authenticating the user and the source device. 31. A method according to claim 21 or 22, wherein the certifying apparatus certifies the data with different unique elements, dependent upon the type of token used to authenticate the user or source device of security, as well as the data. 32. A method according to any preceding claim, wherein validation data for validating the user is received from a remote device before the data is certified. 33. A method according to any preceding claim, wherein validation data for validating the data to be certified is received from a remote device before the data is certified. 34. A method according to any preceding claim, wherein the certifying apparatus additionally sends a request to a remote device instructing the remote device to send identification data to the user. 35. A method according to any of claims 32 to 34, further comprising the certifying apparatus sending the request to the remote device after receiving a request to certify data. 36. A method according to any of claims 32 to 35, further comprising receiving data derived from the identification data from the remote device. 37. A method according to claim 36, further comprising the certifying device receiving further user data from the user, comparing the further user data with the data derived from the identification data, and certifying the data to be certified if the further user data corresponds to the data derived from the identification data. 38. A method according to any of claims 32 to 37 further comprising establishing a communication channel between the workstation and the remote device. 39. A method for use in data certification, comprising: receiving a request from a remote device to supply a user with identification data; supplying said identification data to a user; and supplying a derived version of the identification data to the remote device. 40. A method according to claim 39, wherein the identification data is a one-time password. 41. A method according to claim 39 or 40, wherein the request and derived version of the identification are transferred via a different communication method to the identification data. 42. A method according to any of claims 39 to 41, further comprising the method of any of claims 1 to 31. 43. A computer apparatus for use in data certification, the apparatus comprising: a program memory storing instructions for controlling a processor; and a processor for reading and implementing the instructions stored in the program memory; wherein the program instructions stored in the program memory comprise instructions for controlling the processor to carry out the method of claim 1 to claim 38. 44. A carrier medium cog computer readable code for controlling a computer to carry out the method of claim 1 to claim 38. 45. A computer apparatus for certifying data as originating from a user, the apparatus comprising: a program memory storing instructions for controlling a processor, and a processor for reading and implementing the instructions stored in the program memory; wherein the program instructions stored in the program memory comprise instructions for controlling the processor to carry out the method of claim 39 to claim 42. 46. A carrier medium carrying computer readable code for controlling a computer to carry out the method of claim 39 to claim 42. 47. A data certifying apparatus, comprising: a signing device adapted to certify electronic data received from a remote source device as originating from a user, wherein the certifying apparatus is arranged to receive data from the souse device, certify the data as belonging to the user, using information stored in the certifying apparatus and cryptographic techniques, said information being unique to the user, and send the certified data to a recipient device. 48. A certifying apparatus according to claim 47, where the recipient device is the source device. 49. A certifying apparatus according to claim 48, wherein the recipient device is a third party device. 50. A data certifying apparatus according to any of claims 47 to 49, wherein the source device and certifying apparatus are arranged to establish an authenticated connection between them before and during transfer of the data to be certified. 51. A data certifying apparatus according to claim 50, wherein the source device and certifying apparatus are arranged such that the connection between them is encrypted. 52. A data certifying apparatus according to claim 50 or 51, wherein the source device is arranged to supply a token to the certifying apparatus for authentication. 53. A data certifying apparatus according to claim 52, wherein the authentication device is arranged to supply the token to the user or source via an alternate channel to the authenticated connection. 54. A data certifying apparatus according to claim 52 or 53, wherein the token is a fixed password. 55. A data certifying apparatus according to claim 52 or 53, wherein the token is a one-time password. 56. A data certifying apparatus according to claim 52 or 53, wherein wherein the authentication device is arranged to supply the token to the user or source device via a mobile telephone network. 57. A certifying apparatus according to claim 55 or 56, wherein wherein the authentication device is arranged to supply the token to the user or source device via a Short Message Service message. 58. A certifying apparatus according to claim 52 or 53, wherein authentication device is arranged to supply a unique token for each transaction. 59. A data certifying apparatus according to claim 52 or 53, wherein the token is stored on a portable device. 60. A data certifying apparatus according to any of claims 52 to 59, wherein the certifying apparatus is arranged to use more than one type of token to authenticate the user or source device. 61. A data certifying apparatus according to claim 60, wherein the data certifying apparatus is arranged to operate with one level of security reached by authenticating the user regardless of the source device, and another, higher, level of security reached by authenticating the user and the source device. 62. The data certifying apparatus according to claim 52 or 53, wherein the certifying apparatus is arranged to certify the data with different unique elements, dependent upon the type of token used to authenticate the user or source device. 63. A data certifying apparatus according to claims 47 to 62, wherein the certifying apparatus comprises a signature server. 64. A data certifying apparatus according to claim 63, wherein the certifying apparatus comprises a plurality of signature servers, each signature server being arranged to use secret sharing to store individual shares of a private key of a user, wherein, the signature generated. 65. A data certifying apparatus according to claims 63 or 64, wherein the certifying apparatus further comprises an authentication server. 66. A data certifying apparatus according to any of claims 47 to 65, wherein the source device comprises a workstation. 67. A data certifying apparatus according to any of claims 47 to 65, wherein the source device comprises an interactive television. 68. A data certifying apparatus according to any of claims 47 to 67, further comprising instructing means for sending a request to a remote device instructing the remote device to send identification data to the user. 69. A data certifying apparatus according to any of claims 47 to 68, further comprising receiving means for receiving data derived from the identification data from the remote device. 70. A data certifying apparatus according to any of claims 47 to 68, wherein the receiving means is arranged to receive further user data from the user, the apparatus further comprising: comparing means for comparing the further user data with the data derived from the identification data, and certifying means for certifying the data to be certified if the further user data corresponds to the data derived from the identification data. 71. An apparatus for use in data certification, comprising: receiving means for receiving a request from a remote device to supply a user with identification data; supplying means for supplying said identification data to a user; and further supplying means for supplying a derived version of the identification data to the remote device. 72. An apparatus according to claim 71, further comprising password generating means for generating a one-time password to be supplied with the supplying means. 73. An apparatus according to claim 71 or 72, wherein the receiving means and further supplying means are arranged to operate via a different communication method to the supplying means. 74. An apparatus according to claim 73, further comprising an apparatus according to any of claims 47 to 70. |
Compounds effecting glucokinase |
The invention relates to the use of a compound of Formula (I) or a salt, solvate or prodrug thereof, wherein R1, R2, R3, n and m are as described in the specification, in the preparation of a medicament for the treatment or prevention of a disease condition mediated through glucokinase (GLK), such as type 2 diabetes. The invention also relates to a novel group of compounds of Formula (I) and to methods for preparing compounds of Formula (I). |
1. A method for the treatment or prevention of a disease or medical condition mediated through GLK, comprising administering a compound of Formula (I) or a salt, solvate, or prodrug thereof, wherein m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and n+m>0; each R1 is independently selected from OH, —(CH2)1-4OH, —CH3-aFa, —(CH2)1-4CH3-aFa, —OCH3-aFa, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, NH2, —NH—C1-4alkyl, —N-di-(C1-4alkyl), CN, formyl, phenyl, or heterocyclyl optionally substituted with C1-6alkyl; each R2 is the group Y—X—; R3 is selected from phenyl or a heterocyclyl, and R3 is optionally substituted with one or more R7 groups; each R4 is independently selected from halo, —CN3-aFa, CN, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, or phenyl optionally substituted with C1-6alkyl or —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen, C1-6alkyl, —CH3-a, phenyl, naphthyl, heterocyclyl or C3-7cycloalkyl; and R5 is optionally substituted by one or more substituents independently selected from: halo, C1-6alkyl, —OC1-6alkyl, —CH3-aFa, CN, OH, NH2, COOH, or —C(O)OC1-6alkyl; R6 is independently selected from hydrogen, C1-6alkyl, or —C2-4alkyl-O—C1-4alkyl; R6a is independently selected from hydrogen, halo, C1-6alkyl, or —C2-4alkyl-O—C1-4alkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alknyl, (CH2)0-3aryl, (CH2)0-3-heterocyclyl, (CH2)0-3C3-7cycloalkyl, OH, C1-6alkyl-OH, halo, C1-6alkyl-halo, OC1-6alkyl, (CH2)0-3S(O)0-2R8, SH, SO3, thioxo, NH2, CN, (CH2)0-3NHSO2R8, (CH2)0-3COOH, (CH2)0-3-O—O(CH2)0-3R8, (CH2)0-3C(O)(CH2)0-3R8, (CH2)0-3C(O)OR8, (CH2)0-3C(O)NH2, (CH2)0-3C(O)NH(CH2)0-3R8, (CH2)0-3NH(CH2)0-3R8, (CH2)0-3NHC(O)(CH2)0-3R8; (CH2)0-3C(O)NHSO2—R8, and (CH2)0-3SO2NHC(O)—R8, and any alkyl chain, cycloalkyl ring, or heterocyclyl ring is optionally substituted with one or more substituents independently selected from: C1-4alkyl, OH, halo, CN, NH2, N-C1-4alkylamino, N,N-di-C1-4alkylamino, and OC1-4alkyl; R8 is selected from hydrogen, C1-6alkyl, aryl, heterocyclyl, C3-7cycloalkyl, OH, C1-6alkyl-OH, COOH, C(O)OC1-6alkyl, N(R6)C1-6alkyl, OC1-6alkyl, C0-6alkylOC(O)C1-6alkyl, and C(OH)(C1-6alkyl)C1-6alkyl; and any alkyl chain or aryl, heterocyclyl or cycloalkyl ring is optionally substituted with one or more substituents independently selected from: C1-4alkyl, OH, halo, CN, NH2, —NH—C1-4alkyl, —N-di-(C1-4alkyl, and OC1-4alkyl; each X and X1 is independently a linker independently selected from: —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R6)-Z-, —N(R6)SO2-Z-, —SO2N(R6)-Z-, —(CH2)1-4—, —CH═CH-Z-, —C≡C-Z-, —N(R6)CO-Z-, —CON(R6)-Z-, —C(O)N(R6)S(O)2-Z-, —S(O)2N(R6)C(O)-Z-, —C(O)-Z-, -Z-, —C(O)-Z-O-Z-, —N(R6)-C(O)-Z-O-Z-, —O-Z-N(R6)-Z-, —O—C(O)-Z-O-Z-, or a direct bond; each Y is independently selected from aryl-Z1-, heterocyclyl-Z1-, C3-7cycloalkyl-Z1-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)1-4CH3-aFa, or —CH(OH)CH3-aFa, and is independently optionally substituted with up to three R4 groups each Z is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R6a)2—(CH2)q—; each Z1 is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R6a)2—(CH2)q—; each a is independently 1, 2, or 3; p is an integer between 0 and 3; q is an integer between 0 and 3; and p+q<4. provided that when R3 is 2-pyridyl and X is other than -Z-, —C(O)-Z-O-Z-, —N((R6)—C(O)-Z-O-Z- or —O-Z-N(R6)-Z-, then R3 cannot be mono-substituted at the 5-position with an R7 group selected from COOH or C(O)OC1-6alkyl. 2. A method of claim 1, wherein a compound of Formula (I) or a salt, solvate, or prodrug thereof is administered as a pharmaceutical composition, together with a pharmaceutically-acceptable diluent or carrier 3. A compound of Formula (Ib) or a salt, solvate, or prodrug thereof, wherein m is 0, 1, or 2; n is 1, 2, or 3; and n+m is 2 or 3; each R1 is independently selected from OH, —(CH2)1-4OH, —CH3-aFa, —(CH2)1-4CH3-aFa, —OCH3-aFa, halo, OCH3, C2H5O, CH3C(O)O—, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —NH—C1-4alkyl, —N-di-(C1-4alkyl), CN, formyl, phenyl, or heterocyclyl optionally substituted with C1-6alkyl; each R2 is the group Y—X— R3 is heterocyclyl, wherein the atom at the 2-position of the heterocyclyl ring relative to the amide group, to which R3 is attached, is a heteroatom, and when the atom at the 2-position of the heterocyclyl ring relative to the amide group is nitrogen it is sp hybridized, and R3 is optionally substituted with up to 2 R7 groups; each R4 is independently selected from halo, —CH3-aFa, CN, NH2, C1-4alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, phenyl optionally substituted with C1-6alkyl or —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen, C1-6alkyl, —CH3-aFa, phenyl, naphthyl, heterocyclyl, or C3-7cycloalkyl; and R5 is optionally substituted with one or more substituents independently selected from: halo, C1-6alkyl, —OC1-6alkyl, —CH3-aFa, CN, OH, NH2, COOH, or —C(O)OC1-6alkyl; R6 is independently selected from hydrogen. C1-6alkyl, or —C2-4alkyl-O—C1-4alkyl; R6a is independently selected from hydrogen, halo, C1-6alkyl or —C2-4alkyl-O—C1-4alkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6-alkynyl, (CH2)0-3aryl, (CH2)0-3heterocyclyl, (CH2)0-3C3-7cycloalkyl, OH, C1-6alkyl-OH, halo, C1-6alkyl-halo, OC1-6alkyl, (CH2)0-3S(O)0-2R8, SH, SO3, thioxo, NH2, CN, (CH2)0-3NHSO2R8, (CH2)0-3COOH, (CH2)0-3—O—(CH2)0-3R8, (CH2)0-3C(O)(CH2)0-3R8, (CH2)0-3C(O)OR8, (CH2)0-3C(O)NH2, (CH2)0-3C(O)NH(CH2)0-3R8, (CH2)0-3NH(CH2)0-3R8, (CH2)0-3NHC(O)(CH2)0-3R8; (CH2)0-3C(O)NHSO2—R8, and (CH2)0-3SO2NHC(O)—R8. and any alkyl chain, cycloalkyl ring, or heterocyclyl is optionally substituted with one or more substituents independently selected from: C1-4alkyl, OH, halo, CN, NH2, N—C1-4alkylamino, N,N-di-C1-4-alkylamino, and OC1-4alkyl; R8 is selected from hydrogen. C1-6alkyl, aryl, heterocyclyl, C3-7cycloalkyl, OH, C1-6alkyl-OH, COOH, C(O)OC1-6alkyl, N(R6)C1-6alkyl, OC1-6alkyl, C0-6alkylOC(O)C1-6alkyl, C(OH)(C1-6alkyl)C1-6alkyl and any alkyl chain or aryl, heterocyclyl or cycloalkyl ring is optionally substituted with one or more substituents independently selected from: C1-4alkyl, OH, halo, CN, NH2, —NH—C1-4alkyl, —N-di-(C1-4alkyl), and OC1-4alkyl: each X and X1 is independently a linker selected from —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R6)-Z-, —N(R6)SO2-Z-, —SO2N(R6)-Z-, —CH═CH-Z-, —C—C-Z-, —N(R6)CO-Z-, —CON(R6)-Z-, —C(O)N(R6)S(O)2-Z-, —S(O)2N(R6)C(O)-Z-, —C(O)-Z-, -Z-, —C(O)-Z-O-Z-, —N(R6)—C(O)-Z-O-Z-, —O-Z-N(R6)-Z-, —O—C(O)-Z-O-Z-, or a direct bond except when Z is C, alkyl each Y is independently selected from aryl-Z1-, heterocyclyl-Z1-, C3-7cycloalkyl-Z1-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)1-4CH3-aFa, or —CH(OH)CH3-aFa, and is independently optionally substituted with up to three R4 groups; with the proviso that Y—X— cannot be CH3O, C2H5O or CH3C(O)O—; each Z is independently a direct bond, C2-6alkenylene or a group of the formula —(CH2)p—C(R6a)2—(CH2)q—; each Z1 is independently a direct bond, C2-6alkenylene or a group of the formula —(CH2)p—C(R6a)2—(CH2)q—; each a is independently 1, 2, or 3; p is an integer between 0 and 3; q is an integer between 0 and 3; and and p+q<4 provided that (i) when R3 is 2-pyridyl and X is other than -Z-, —C(O)-Z-O-Z-, —N((R6)—C(O)-Z-O-Z-, or —O-Z-N(R6)-Z-, then R3 cannot be mono-substituted at the 5-position with an R7 group selected from COOH or C(O)OC1-6alkyl; (ii) positions 3 and 5 on the phenyl ring (to which R1 and R2 are attached) relative to the amide bond are substituted, wherein at least one of the substituents is an R2 group; (iii) an unbranched, unsubstituted C1-6alkyl chain cannot exceed C6alkyl in length; (iv) when n is 2 or 3, then only one X group can be —NHC(O)—; (v) when R3 is pyridyl and R7 is halo or methyl, then the phenyl ring to which R2 is attached cannot be substituted with an R2 group at the 2-position relative to the amide bond, wherein X is —C(O)NH— and Y is optionally substituted phenyl, optionally substituted thienyl, or optionally substituted pyridyl; (vi) when n+m is 2, m is 0 or m is 1, and R1 is OH, n is 1 and X is —NHC(O)— or n is 2 and X is independently selected from —C(O)NH—, —NHC(O)—, —O—, —S(O2)NH—, or a direct bond, wherein one X group is —NHC(O)—, Y is selected from phenyl, cyclohexyl, 4,5-dihydro-5-oxo-pyrazolyl, thienyl, 1,3-dihydro-1,3-dioxo-isoindolinyl, 2-oxo-1-benzopyran, or pyridyl, and Y is optionally substituted with R4, then R3 cannot be unsubstituted thiazole, 4,5-dihydro-5-oxo-pyrazolyl substituted with trichlorophenyl, 4,5,6,7-tetrahydro-benzo[b]thiophene substituted with ethoxycarbonyl, or pyridyl optionally independently mono or di-substituted with methyl, ethoxy, or propylcarbonylamino; and (vii) when n+m is 3, m is 0 or 2, R1 is independently selected from methyl, methoxy, or hydroxy, n is 1, 2, or 3, X is independently selected from —O—, —S(O2)NH—, —C(O)—, —S(O2)—, —CH2—, or a direct bond, Y is selected from pyrrolidinyl, morpholino, phenyl, tetrazolyl, or propyl, wherein Y is optionally substituted with R4, and R4 is selected from di-hydroxy, methoxy, C1-4alkyl, then R3 cannot be unsubstituted tetrazolyl, unsubstituted thiazolyl, or thiazolyl substituted with ethoxycarbonylmethyl. 4. A compound according to claim 3, or salt, solvate, or prodrug thereof, wherein each R1 is independently selected from OH, formyl, CH3-aFa, OCH3-aFa, halo, C1-6alkyl, NH2, CN, (CH2)1-4OH, or a heterocyclyl optionally substituted with C1-6alkyl. 5. A compound according to claim 3, or salt, solvate, or prodrug thereof, wherein each R2 is the group Y—X—, each X is independently selected from -Z-, —CH═CH-Z-, —O-Z-, —C(O)-Z-, —C(O)O-Z-, —OC(O)-Z-, ,—C(O)-Z-O-Z-, —O—C(O)-Z-O-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R6)-Z-, —N(R6)CO-Z-, —CON(R6)-Z-, —N(R6)—C(O)-Z-O-Z-, —SO2N(R6)-Z-, —N(R6)SO2-Z- or —O-Z-N(R6)-Z-, each Y is independently selected from C1-6alkyl, C2-6alkenyl, aryl-Z1-, heterocyclyl-Z1-, C3-7cycloalkyl(CH2)0-2, —(CH2)1-4CH3-aFa, and each Y is independently optionally subs with R4. 6. A compound according to claim 3, or salt, solvate, or prodrug thereof, wherein each R4 is independently selected from halo, CH3-aFa, OCH3-aFa, CN, C1-6alkyl, OC1-6alkyl, COOH, C(O)OC1-6alkyl, (CH2)0-3COOH, O(CH2)0-3COOH, CO-phenyl, CONH2, CONH-phenyl, SO2NH2, SO2C1-6alkyl, OH, or phenyl optionally substituted with one or more R5 groups wherein R5 is selected from hydrogen, C1-6alkyl, or C(O)OC1-6alkyl. 7. A compound according to claim 3, or salt, solvate, or prodrug thereof, wherein R3 is a nitrogen-containing heterocyclyl, optionally substituted with one or more R7 groups. 8. A compound according to claim 7, or a salt, solvate, or prodrug thereof, wherein R3 is selected from thiazole, benzothiazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrazole, imidazole, pyrimidine, oxazole, and indole. 9. A compound according to claim 3, or salt, solvate, or prodrug thereof, wherein R3 is unsubstituted or is substituted with one R7 group. 10. A compound according to claim 3, or salt, solvate, or prodrug thereof, wherein each R7 is independently selected from OH, CN, NH2, SO3, thioxo, halo, C1-4alkyl, C1-4alkyl-OH, O—C1-4alkyl, C1-4alkyl-halo, (CH2)0-1COOH, (CH2)0-1C(O)OR8, (CH2)0-1NH(CH2)0-2R8, (CH2)0-1NHC(O)(CH2)0-2R8, (CH2)0-1C(O)NH(CH2)0-2R8, —(CH2)0-2S(O)0-2R8, —(CH2)0-1N(R6)SO2R8, (CH2)0-1C(O)N(R6)S(O)2R8, or (CH2)0-1heterocyclyl. 11. A compound according to claim 3, or salt, solvate or prodrug thereof, wherein Y is phenyl-Z1- optionally substituted by halo or C1-6alkyl. 12. A compound according to claim 3, or salt, solvate or prodrug thereof, wherein each R2 is the group Y—X—, Z within the definition of X is a direct bond and Z1 within the definition of Y is a group of the formula —(CH2)p—C(R6a)2—(CH2)q—. 13. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a compound according to claim 3, or a salt, solvate, or prodrug thereof. 14. A method for the treatment or prevention of diabetes and obesity comprising administering a compound of claim 1, or a salt, solvate or prodrug thereof. 15. A process for the preparation of a compound of claim 1 or salt, solvate, or prodruf thereof, which comprises: (a) reaction of a compound of Formula (IIIa) with a compound of Formula (IIIb), wherein X1 is a leaving group (b) for compounds of Formula (I) wherein R3 is hydrogen, deprotection of a compound of Formula (IIIc), wherein P1 is a protecting group; (c) for compounds of Formula (I) wherein n is 1, 2, 3, or 4, reaction of a compound of Formula (IIId) with a compound of Formula (IIIe), Y—X″ Formula (IIId) wherein X′ and X″ comprise groups which, when reacted together, form the group X; (d) for a compound of Formula (I) wherein n is 1, 2, 3, or 4 and X or X1 is —SO-Z- or —SO2-Z-, oxidation of the corresponding compound of Formula (I) wherein X or X1 respectively is —S-Z-; (e) reaction of a compound of Formula (IIIf) with a compound of Formula (IIIg), wherein X2 is a leaving group; and thereafter, if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; iii) forming a salt, prodrug or solvate thereof. |
Pteridinone derivatives as modulators of chemokine receptor activity |
The invention provides certain pteridinone compounds of formula (I), processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy. |
1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof: in which: R1 represents a C3-C7 carbocyclic, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR4, —NR5R6, —CONR5R6, —COOR7, —NR8COR9, —SR10, —SO2R10, —SO2NR5R6, —NR8SO2R9, an aryl or heteroaryl group, which last two may themselves be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR4, —NR5R6, —CONR5R6, —COOR7, —NR8COR9, —SR10, —SO2R10, —SO2NR5R6, —NR8SO2R9, C1-C6 alkyl or trifluoromethyl groups; R2 and R3 each independently represent a hydrogen atom, or a C3-C7 carbocyclic, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from: (a) halogen atoms, —OR4, —NR5R6—CONR5R6, —COOR7, —NR8COR9, —SR10, —SO2R10, —SO2NR5R6, —NR8SO2R9; (b) a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR8 and itself optionally substituted by C1-C3-alkyl or halogen; or (c) an aryl group or heteroaryl group each of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR4, —NR5R6, -—CONR5R6, —NR8COR9, —SO2NR5R6, —NR8SO2R9, C1-C6 alkyl and trifluoromethyl groups; R4 represents hydrogen or a C1-C6 alkyl group which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR11, —NR5R6, or an aryl group or heteroaryl group either of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR11, —NR5R6, —CONR5R6, —NR8COR9, —SO2NR5R6, —NR8SO2R9, C1-C6 alkyl and trifluoromethyl groups; or R4 represents a halogen atom, —OR11, —NR5R6, or an aryl group or heteroaryl group either of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR11, —NR5R6, —CONR5R6, —NR8COR9, —SO2NR5R6, —NR8SO2R9, C1-C6 alkyl and trifluoromethyl groups; R5 and R6 independently represent a hydrogen atom or a C1-C6 alkyl or phenyl group or heteroaryl group the latter three of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR14 and —NR15R16, —CONR15R16, —NR15COR16, —SONR15R16, NR15SO2R16 or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR14, —COOR14, —NR15R16, —CONR15R16, —NR15COR16, —SONR15R16, —NR15SO2R16 or C1-C6 alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR15R16 and —OR17 groups;R10 represents a C1-C6-alkyl or a phenyl group, either of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR17 and —NR15R16, Y is NR20R21, OR4, SR4, a heteroaryl group or NR5R6 where R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR14, —COOR14, —NR15R16, —CONR15R16, —NR15COR16, —SONR15R16, NR15SO2R16 or C1-C6 alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and -NR15R16 and —OR17 groups; each of R7, R8, R9, R11, R15, R16and R17 independently represents a hydrogen atom or a C1-C6, alkyl, or a phenyl group; and R20 and R21 are defined as for R2 and R3. 2. A compound according to claim 1, wherein R1 represents an optionally substituted benzyl group. 3. A compound according to claim 2, wherein R1 represents benzyl substituted by two halogen atoms. 4. A compound according to claim 1, wherein one of R2 and R3 is hydrogen and the other is C3-C4 alkyl substituted by one or more hydroxy groups. 5. A compound according to claim 1 wherein one of R2 and R3 is hydrogen and the other is CH(CH3)CH2OH, CH(Et)CH2OH, C(CH3)2CH2OH or CH(CH2OH)2. 6. A compound according to claim 1 wherein one of R2 and R3 is hydrogen and the other is CH(CH3)CH2OH. 7. A compound according to claim 6 in the form of the (R) isomer. 8. A compound according to claim 1 wherein Y is —NR20R21, —OR4, —SR4, a heteroaryl group or —NR5R6 where R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from —OH, —NH2 or C1-C4 alkyl. 9. A compound according to claim 1 selected from: 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(phenylmethyl)amino]-7(8H)-pteridinone; 2-[[(2,3-Difluorophenyl)methyl]thio-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6,7-pteridinedione; 6-amino-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1H-imidazol-1-yl)-7(8H)-pteridinone; 2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(1-methyl-1H-imidazol-2-yl)thio]-7(8H)-pteridinone; 2-[[2,3-difluorophenyl)methyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-methoxy-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3-pyridinylmethyl)amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(5-methyl-2-furanyl)methyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[methyl[(3-methyl-5-isoxazolyl)methyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[2-(2-pyrimidinylamino)ethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(4-morpholinyl)-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[2-(4-morpholinyl)ethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(2-methoxyethyl)amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-furanylmethyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 6-(1-azetidinyl)-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[5-methylpyrazinyl)methyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[[2-(2-furanyl)ethyl]amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[3-(4-morpholinyl)propyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(3-methyl-5-isoxazolyl)methyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3S)-3-hydroxy-1-pyrrolidinyl]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-furanylmethyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(2-hydroxypropyl)amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[[2-(dimethylamino)ethyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[[(2S)-2-hydroxypropyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3-hydroxypropyl)amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-hydroxyethyl)methylamino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(5-hydroxy-4-methyl-4H-1,2,4-triazol-3-yl)thio]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[(4-hydroxycyclohexyl)amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(1,3,4-thiadiazol-2-ylthio)-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(1S,4R)-4-hydroxy-2-cyclopenten-1-yl]amino]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-7(8H)-pteridinone; 2-[[(2,3-difluorophenyl)methyl]thio]-6-(3-hydroxy-3-methyl-1-azetidinyl)-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; 6-[(3S)-3-amino-1-pyrrolidinyl]-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone; and 6-[(2-aminoethyl)thio]-2-[[(2,3-difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone. 10. A process for the preparation of: (a) a compound of formula (I) as defined in claim 1 where Y is NR20R21 which comprises treatment of a compound of formula (IIA): where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof and L is a leaving group such as bromo with an amine HNR20R21, or (b) a compound of formula (I) as defined in claim 1 where Y is OR4 which comprises treatment of a compound of formula (IIA) where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof and L is a leaving group such as bromo with an alcohol R4OH, or (c) a compound of formula (I) as defined in claim 1 where Y is SR4 which comprises treatment of a compound of formula (IIA) where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof and L is a leaving group such as bromo with a thiol R4SH, or (d) a compound of formula (I) where Y is NR5R6which comprises treatment of a compound of formula (IIA) where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof and L is a leaving group such as bromo with an amine H NR5R6, or (e) a compound of formula (I) where Y is a heteroaryl group which comprises treatment of a compound of formula (IIA) where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof and L is a leaving group such as bromo with a heteroarene, or (f) a compound of formula (I) as defined in claim 1 where Y is OH which comprises treatment of a compound of formula (IIB): where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof with diethyl oxalate, or (g) a compound of formula (I) as defined in claim 1 where Y is NH2 which comprises treatment of a compound of formula (IIB) where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof with iminomethoxy-acetic acid, methyl ester hydrochloride, and optionally thereafter process (a), (b), (c), (d) or (e) and in any order: removing any protecting groups forming a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester. 11. An intermediate compound of formula (IIA) as defined in claim 10. 12. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, as claimed claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 13. A process for the preparation of a pharmaceutical composition as claimed in claim 12 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, as claimed in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier. 14. A compound of formula (I), or a pharmaceutically-acceptable salt, solvate or in vivo hydrolysable ester thereof, as claimed in claim 1 for use in therapy. 15.-16. (Cancelled). 17. A method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, as claimed in claim 1. 18. A method according to claim 17 in which the chemokine receptor belongs to the CXC chemokine receptor subfamily. 19. A method according to claim 17 in which the chemokine receptor is the CXCR2 receptor. 20. A method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, as claimed in claim 1. 21. A method according to claim 20, wherein the disease is psoriasis, rheumatoid arthritis, a disease in which angiogenesis is associated with raised CXCR2 chemokine levels, or COPD. 22. A method according to claim 20, wherein the disease is rheumatoid arthritis. 23. A method according to claim 20, wherein the disease is COPD. |
Method, system and network element for addressing a cell related server |
The present invention relates to a method, system and network element for addressing a server related to a cell in a radio access network. A server identification identifying said server is added to a setup response message transmitted from a drift controller functionality to serving controller functionality. The server identification is then used at the serving controller functionality to derive the address of the server. Thus, the correct server can be addressed and dynamic network configurations can be allowed at reduced delay and processing requirements. |
1. A method for addressing a server related to a cell in a radio access network, said method comprising the steps of: initiating a setup between a serving controller functionality in charge of controlling a mobile terminal located in said cell, and a drift controller functionality in charge of controlling said cell; adding a server identification identifying said server to a setup response message transmitted from said drift controller functionality to said serving controller functionality; and using said server identification at said serving controller functionality (10) to derive the address of said server. 2. A method according to claim 1, wherein said setup is initiated by an lur user plane setup procedure. 3. A method according to claim 2, wherein said setup procedure comprises a common transport channel resources initialization, a radio link setup procedure, or a radio link addition procedure. 4. A method according to claim 1, wherein said setup procedure is selected according to an operating state of said mobile terminal. 5. A method according to claim 1, wherein said response message is a common channel setup response, a radio link setup response, or a radio link addition response. 6. A method according to claim 1, wherein said server identification comprises an identifier or signaling address of said server. 7. A-method according-to any one of claims 1, wherein said server identification comprises at least one SCCP address, identification assigned by the network operator, DNS address or identification, or IP address and port number, based on which said address of said server is derived. 8. A method according to claim 1, wherein said server identification is used to derive the addresses of two servers each controlling a respective cell. 9. A method according to any one of claims 1, wherein said server identification is used to derive the address of a server to be used for the setup connection if a soft handover is performed. 10. A system for addressing a server related to a cell in a radio access network, said system comprising: a serving controller functionality in charge of controlling a mobile terminal located in said cell, for initiating a setup to a drift controller functionality in charge of controlling said cell; wherein said drift controller functionality is arranged to add a server identification identifying said server to a setup response message transmitted to said serving controller functionality; and wherein said serving controller functionality is arranged to use said server identification to derive the address of said server. 11. A system according to claim 10, wherein said serving controller functionality and said drift controller functionality is provided in a corresponding radio network controller or base transceiver station or base station controller. 12. A system according to claim 10, wherein said drift controller functionality is arranged to return its own address or no address, if it is provided in a network element having also the function of said cell related server. 13. A system according to claim 10, wherein said drift controller functionality is arranged to add more than one server identification to said response message, and said serving controller functionality is arranged to select one server identification. 14. A system according to claim 10, wherein said server is associated to a controller functionality of said radio access network. 15. A system according to claim 10, wherein said server comprises a common radio resource management functionality and/or a common position calculation functionality. 16. A network element for addressing a server related to a cell in a radio access network, said network element comprising: signaling means for initiating a setup procedure to a drift controller functionality in charge of controlling said cell; and address generating means for deriving the address of said server from a response message received from said drift controller functionality. 17. A network element according to claim 16, wherein said network element is a base transceiver station or a radio network controller or base station controller. 18. A network element having a drift controller functionality in charge of controlling a cell in a radio access network, comprising: means for adding a server identification of a server, related to said cell, to a setup response message in response to the receipt of a setup request; and means for transmitting said response message to a serving controller functionality from which said setup request has been received. 19. A network element according to claim 18, wherein said network element is a base transceiver station or a radio network controller or base station controller. |
<SOH> BACKGROUND OF THE INVENTION <EOH>As the Internet has grown in popularity and mobile Internet for text-based information and picture messaging is already a reality, the industry has turned its focus on engineering the most cost efficient network for more demanding multimedia services. IP-based networks are considered by many the best way forward and networking technology research and development is by and large centered around IP-technologies. The development of an IP-based radio access network will bring together a number of radio access network technologies including second generation (2G), third generation (3G) and Wireless Local Area Networks (WLANs). Network operators are shifting from a circuit-switched to a packet-switched technology, while IP-based networks need to expand radio access rapidly, flexibly and cost efficiently. IP-based radio access networks can be introduced as a smooth evolution from existing GSM (Global System for Mobile communications), EDGE (Enhanced Data Rates for GSM Evolution) and WCDMA (Wideband Code Division Multiple Access) networks. Key benefits of such IP-based radio access networks are distributed architecture with a separation of user and control planes (offering infinite scalability and no bottlenecks), integration of different radio interface technologies into a single radio access network, common radio resource management for optimum use of radio resources, quality of service (QoS) control, and network automaton, open interfaces for multi-vendor networks, and compatibility to existing transmission networks. In such new radio access networks the standardisation body (i.e. 3GPP (3rd Generation Partnership Project)) is introducing some control plane ‘servers’ that have RAN only functions, e.g. a Serving mobile Location Centre (SMLC) for performing the positioning functions for the mobile station (MS) or user equipment (UE) in the radio access network, and a Common Radio Resource Manager (CRRM) or Common Resource Manager Server (CRMS) for performing radio resource management algorithms based on dynamic status information of cells that do not belong to the same base transceiver station (BTS) or radio network controller (RNC). The SMLC and CRMS are associated to a certain area, where they have the control of a location measurement unit and the radio resource of the cells, respectively. A Serving RNC (SRNC) controlling a UE may use the SMLC for the calculation of the position of the UE, or the CRRM for the prioritisation of the handover target cell(s) to be performed by the UE (or any other operation affecting the radio resources used by the UE). In doing so, the SRNC need to contact the SMLC and CRMS associated to the cell(s) used by the UE. However, the UE may use cells that are not controlled by the SRNC. This is the case if a cell used by the UE is controlled by a Drift RNC (DRNC) which is any RNC, other than the SRNC, that controls cells used by the UE by providing only resources and radio layer 1 (L 1 ) functions for the UE connection so as to route data transparently between the interface (e.g. lu interface) connecting the radio access network to a core network (CN) and the interface (e.g. lur interface) connecting the DRNC to the SRNC. It is noted that one SRNC may use any of the other RNCs as DRNC. Thus, if the SRNC wishes to contact the SMLC or the CRMS associated or related to the current cell used by the UE (e.g. for mobile location, for prioritisation of the handover candidate, or other related operations), the problem arises that the address of the CRMS or SMLC controlling the drift cell Is not available at the SRNC. This problem is unknown, since such common servers (CRMS and SMLC) are not yet specified in 3GPP. Discussion on the SMLC standardisation has been up to now focused on a positioning method that does not require the SMLC to receive measurement from the location measurement unit (LMU), thus without facing this problem. This problem may be solved by pre-configuring the CRMSs and/or SMLCs controlling each own and each possible drift cell (or each possible drift RNC) in the RNC. However, this requires a configuration table which is difficult to manage and reconfigure when the network configuration is changed. Alternatively, the problem may be solved in that the SRNC sends the request for service (location, handover candidate) to a (or one of) predefined SMLC/CRMS, that takes care of forwarding the data to the relevant CRMS/SMLC. Nevertheless, a configuration table defining the predefined CRMS(s)/SMLC(s) is still required. Finally, the SRNC may forward the location/handover priority to the DRNC via the lur interface. The DRNC is then using the SMLC and the CRMS for the evaluation. However, this leads to delay and extra processing of the DRNC and thus to a reduced Quality of Service (QoS). The problem was described above for a UTRAN environment. In the IP-RAN environment the problem is even bigger since the number of IP-BTSs (IP-Base Transceiver Stations) is greater than the number of RNCs. In IP-RAN, the IP-BTS acts in many aspects like an RNC, so that the number of Drift-BTSs (DBTSs) may become very large. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is therefore an object of the present invention to provide an addressing procedure by means of which the correct server in the radio access network can be addressed, especially in case the connection is handled by one or more DRNCs or DBTSs. This object is achieved by a method for addressing a server related to a cell in a radio access network, said method comprising the steps of: initiating a setup between a serving controller functionality in charge of controlling a mobile terminal located in said cell, and a drift controller functionality in charge of controlling said cell; adding a server identification identifying said server to a setup response message transmitted from said drift controller functionality to said serving controller functionality; and using said server identification at said serving controller functionality to derive the address of said server. Furthermore, the above object is achieved by a system for addressing a server related to a cell in a radio access network, said system comprising: a serving controller functionality in charge of controlling a mobile terminal located in said cell, for initiating a setup to a drift controller functionality in charge of controlling said cell; wherein said drift controller functionality is arranged to add a server identification identifying said server to a setup response message transmitted to said serving controller functionality; and wherein said serving controller functionality is arranged to use said server identification to derive the address of said server. Additionally, the above object is achieved by a network element for addressing a server related to a cell in a radio access network, said network element comprising: signaling means for initiating a setup procedure to a drift controller functionality in charge of controlling said cell; and address generating means for deriving the address of said server from a response message received from said drift controller functionality. In addition thereto, the above object is achieved by a network element having a drift controller functionality in charge of controlling a cell in a radio access network, comprising: means for adding a server identification of a server, related to said cell, to a setup response message in response to the receipt of a setup request; and means for transmitting said response message to a serving controller functionality from which said setup request has been received. Accordingly, the correct server is always addressed based on the server identification given in the response message received from the drift controller functionality. A configuration table and the associated difficulty to manage and reconfigure it when the configuration of the network is changed can thus be avoided. Furthermore, dynamic configurations, fault resilience, etc. are allowed. Due to the fact that the serving controller can directly contact the server (SMLC/CRMS), delay and extra processing at the drift cell can be avoided. The setup may be initiated by an lur user plane setup procedure. It may comprise a common transport channel resources initialization, a radio link setup procedure, or a radio link addition procedure. Preferably, the setup procedure is selected according to an operating state of the mobile terminal. The response message may be a common channel setup response, a radio link setup response, or a radio link addition response. The server identification may comprise an identifier or signaling address of the server. Alternatively, the server identification may comprise an SCCP address, an identification assigned by the network operator, a DNS address or identification, or an IP address and port number, based on which the address of the server is derived. The server identification may comprise also several identifiers or signaling addresses of the server. Alternatively, the server identification may comprise SCCP addresses, identifications assigned by the network operator, DNS addresses or identifications, or IP addresses and port numbers, based on which the address of the servers is derived. In this case, the network element having a serving controller functionality may choose which server to use. If a soft handover is performed, the server identification may either be used to derive the addresses of two servers each controlling a respective cell if a soft handover between the respective cells of said servers is performed, or the server identification may be used to derive the address of a server to be used for the setup connection. The network element having a serving controller functionality may choose which server to use. Alternatively, the drift controller functionality may choose which server should be used. In this case, the drift controller functionality may send only the chosen server identification to the serving controller functionality. Preferably, the serving controller functionality and the drift controller functionality is provided in a corresponding radio network controller or base transceiver station. Furthermore, the drift controller functionality may be arranged to return its own address or no address, if it is provided in a network element having also the function of the cell related server. According to a advantageous modification, the drift controller functionality may be arranged to add more than one server identification to the response message, and the serving controller functionality may be arranged to select one server identification. According to another advantageous modification, the server may be associated to a controller functionality of said radio access network. In particular, the server may comprise a common radio resource management functionality and/or a common position calculation functionality. |
Method of extended culture for antigen-specific cytotoxic lumphocytes |
The present invention is a method for inducing cytotoxic T cell having an antigen-specific cytotoxic activity, a method for maintaining the cell, a method for continuously culturing the cell or a method for expanding the cell, comprising the step of culturing a cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) a substance having a binding activity to CD44; (B) a substance capable of regulating a signal emitted by binding a CD44 ligand to CD44; (C) a substance capable of inhibiting binding of a growth factor to a growth factor receptor; (D) a substance capable of regulating a signal emitted by binding of a growth factor to a growth factor receptor; and (E) fibronectin, a fragment thereof or a mixture thereof. |
1. A method for inducing cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of incubating a precursor cell capable of differentiating to cytotoxic T cell with an antigen presenting cell in the presence of at least one substance selected from the group consisting of: (A) a substance having a binding activity to CD44; (B) a substance capable of regulating a signal emitted by binding a CD44 ligand to CD44; (C) a substance capable of inhibiting binding of a growth factor to a growth factor receptor; (D) a substance capable of regulating a signal emitted by binding of a growth factor to a growth factor receptor; and (E) fibronectin, a fragment thereof or a mixture thereof. 2. The method according to claim 1, wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody. 3. The method according to claim 2, wherein the CD44 ligand is hyaluronic acid. 4. The method according to claim 1, wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor. 5. The method according to claim 4, wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody. 6. The method according to any one of claims 1, 4 and 5, wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2. 7. The method according to claim 1, wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain. 8. A method for maintaining cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of continuously culturing the cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) to (E) of claim 1. 9. The method according to claim 8, wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody. 10. The method according to claim 9, wherein the CD44 ligand is hyaluronic acid. 11. The method according to claim 8, wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor. 12. The method according to claim 11, wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody. 13. The method according to any one of claims 8, 11 and 12, wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2. 14. The method according to claim 8, wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain. 15. A method for expanding cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of incubating the cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) to (E) of claim 1. 16. The method according to claim 15, wherein the cytotoxic T cell is incubated further in the presence of anti-CD3 antibody in said step. 17. The method according to claim 15 or 16, wherein the cytotoxic T cell is incubated together with a feeder cell in said step. 18. The method according to claim 17, wherein the feeder cell is a non-virus-infected cell. 19. The method according to claim 15, wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody. 20. The method according to claim 19, wherein the CD44 ligand is hyaluronic acid. 21. The method according to claim 15, wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor. 22. The method according to claim 21, wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody. 23. The method according to claim 15, wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2. 24. The method according to claim 15, wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain. 25. A method for collecting cytotoxic T cell, comprising the step of selecting a cell population rich in cytotoxic T cell having an antigen-specific cytotoxic activity from a culture containing the cytotoxic T cell obtained by the method of any one of claims 1, 8 and 15. 26. A cytotoxic T cell having an antigen-specific cytotoxic activity prepared by the method of any one of claims 1, 8 and 15. 27. A therapeutic agent, characterized in that the therapeutic agent comprises the cytotoxic T cell of claim 26 as an effective ingredient. |
<SOH> BACKGROUND ART <EOH>A living body is protected from foreign substances mainly by an immune response, and an immune system has been established by various cells and the soluble factors produced thereby. Among them, leukocytes, especially lymphocytes, play a key role. The lymphocytes are classified in two major types, B lymphocyte (which may be hereinafter referred to as B cell) and T lymphocyte (which may be hereinafter referred to as T cell), both of which specifically recognize an antigen and act on the antigen to protect the living body. T cell is subclassified to helper T cell having CD(Cluster Designation)4 marker (hereinafter referred to as T H ), mainly involved in assisting in antibody production and induction of various immune responses, and cytotoxic T cell having CD8 marker (T c : cytotoxic T lymphocyte, also referred to as killer T cell, which may be hereinafter referred to as CTL), mainly exhibiting a cytotoxic activity. CTL, which plays the most important role in recognizing, destroying and eliminating tumor cell, virus-infected cell or the like, does not produce an antibody specifically reacting with an antigen like in B cell, but directly recognizes and acts on antigens (antigenic peptide) from a target cell which is associated with major histocompatibility complex (MHC, which may be also referred to as human leukocyte antigen (HLA) in human) Class I molecules existing on the surface of the target cell membrane. At this time, T cell receptor (hereinafter referred to as TCR) existing on the surface of the CTL membrane specifically recognizes the above-mentioned antigenic peptides and MHC Class I molecules, and determines whether the antigenic peptide is derived from itself or nonself. Target cell which has been determined to be from nonself is then specifically destroyed and eliminated by CTL. Recent years, a therapy which would cause a heavier physical burden on a patient, such as pharmacotherapy and radiotherapy, has been reconsidered, and an interest has increased in an immunotherapy with a lighter physical burden on a patient. Especially, there has been remarked an effectiveness of adoptive immunotherapy in which CTL capable of specifically reacting with an antigen of interest is induced in vitro from CTL or T cell derived from a human having normal immune function, and then transferred to a patient. For instance, it has been suggested that adoptive immunotherapy using an animal model is an effective therapy for virus infection and tumor (authored by Greenberg, P. D., Advances in Immunology , published in 1992). Further, use of CTL to a patient with congenital, acquired or iatrogenic T cell immunodeficiency has been remarked, from the fact that administration of CTL to a patient with immunodeficiency results in reconstruction of specific CTL response, by which cytomegalovirus is rapidly and persistently eliminated without showing toxicity [Reusser P., et al., Blood, 78(5), 1373-1380 (1991)] and the like. In this therapy, it is important to maintain or increase the cell number with maintaining or enhancing the antigen-specific cytotoxic activity of the CTL. Also, as to maintenance and increase of the cell number of CTL, if an effective cell number in adoptive immunotherapy for human is deduced on the basis of the studies on an animal model, it is thought that 10 9 to 10 10 antigen-specific T cells are necessary (authored by Greenberg, P. D., Advances in Immunology, published in 1992). In other words, in adoptive immunotherapy, it can be said that it is a major problem to obtain the above cell number in vitro in a short period of time. As to maintenance and enhancement of an antigen-specific cytotoxic activity of CTL, there has been generally employed a method of repeating stimulation with an antigen of interest when a specific response to an antigen for CTL is induced. However, in this method, the cell number may temporarily be increased, but the cell number is eventually decreased, and necessary cell number cannot be obtained. As its countermeasure, there are no other means in the current situation but to lyophilize the cells in an earlier stage during repeat of stimulation with an antigen, or to obtain antigen-specific CTL clones, lyophilize a part of the clones, and repeat antigen stimulation to the lyophilized cells after thawing if the cell number or antigen-specific cytotoxic activity of the CTL clones is lowered due to a long-term culture. A method for establishing T cell by a long-term culture using mouse T cell has been reported [Paul W. E. et al., Nature, 294(5843), 697-699 (1981)], which is a method for isolating T cell and establishing a cell strain therewith. However, it is impossible to proliferate T cell to 10 9 to 10 10 cells by this method. Next, U.S. Pat. No. 5,057,423 discloses a method comprising inducing lymphokine-activated killer (LAK) cell using a large amount of interleukin 2 (IL-2) in a high concentration, thereby increasing the cell number in 100 folds in 3 to 4 days. This cell number is enormous, considering that it usually takes about 24 hours for a single cell to be divided and proliferated into two cells. In addition, adoptive immunotherapy has been tried by inducing tumor-infiltrating lymphocyte (TIL) using IL-2 in a high concentration as above [Rosenberg S. A. et al, New Engl. J. Med., 313(23), 1485-1492 (1985); Rosenberg S. A. et al, New Engl. J. Med., 319(25), 1676-1680 (1988); Ho M. et al., Blood, 81(8), 2093-2101 (1993)]. However, the former is a method for obtaining T cell which is non-specific for an antigen, and in the latter, antigen specificity is very low, if any, because activated polyclonal lymphocyte population is used. Further, in both of the above-mentioned methods, IL-2 is used in a high concentration in order to promote cell proliferation. It is reported that apoptosis (cell death) may occur when T cell treated with IL-2 in a high concentration is stimulated with a specific antigen in the absence of IL-2 [Lenardo M. J. et al., Nature, 353(6347), 858-861 (1991); Boehme S. A. et al., Eur. J. Immunol., 23(7), 1552-1560 (1993)]. Therefore, the effectiveness of LAK cell or TIL obtained by the above-mentioned methods is problematic. In addition, when T cell is cultured at a low density (5×10 3 to 1×10 4 cells/ml) in the presence of T-cell growth factor and IL-2, T cell rapidly proliferates over a period of 7 days, and eventually proliferates to a saturation density of 3 to 5×10 5 cells/ml. However, it is also reported that the cell always dies once the cell reaches the saturation density [Gillis S. et al., Immunol. Rev., 54, 81-109 (1981)]. Therefore, LAK cell, TIL and the method for culturing T cell at a low density are problematic in both aspects of actual use and usefulness. Next, regarding the antigen-specific CTL, there are reported adoptive immunotherapy in which allogenic cytomegalovirus(CMV)-specific CTL is cultured in vitro for 5 to 12 weeks to proliferate CTL, and then administered intravenously to a patient with immunodeficiency [Riddell S. A. et al., Science, 257(5067), 238-240 (1992)]; and a method for isolating and expanding a CMV-specific CTL clone using self-CMV infected fibroblast and IL-2 [Riddell S. A. et al., J. Immunol., 146(8), 2795-2804 (1991)] or using anti-CD3 monoclonal antibody (anti-CD3 mAb) and IL-2 [Riddell S. A. et al., J. Immunol. Methods, 128(2), 189-201 (1990)]. However, there is a serious problem in these methods. Specifically, it takes about 3 months to obtain 1×10 9 cells/ml of antigen-specific CTLs, during which time the symptoms of the patient advance, so that it is difficult to appropriately treat the disease depending on the situation. As a method of solving the above-mentioned problem, WO 96/06929 discloses an REM method (rapid expansion method). This REM method is a method for expanding a primary T cell population containing antigen-specific CTL and T H in a short period of time. In other words, this method is characterized in that a large amount of T cell can be provided by expanding individual T cell clones. However, there is a problem as described below. In the REM method, antigen-specific CTL is expanded using anti-CD3 antibody, IL-2, and PBMC (peripheral blood mononuclear cell) made deficient in an ability for proliferation by irradiation, and Epstein-Barr virus (hereinafter simply referred to as EBV)-infected cells. However, there are problems that risk of admixing EBV-transformed B cell (EBV-B cell) into T cell is not deniable (problem in safety); that a large amount of PBMC (PBMC in an amount of about 40 times the number of antigen-specific CTL required) is required as feeder cell; that the antigen-specific cytotoxic activity of the expanded CTL cannot be sufficiently satisfactory; that the antigen-specific cytotoxic activity possessed by T cell is decreased with the cell proliferation when CTL is allowed to proliferate using a T cell population other than the T cell clone; and the like. In other words, in a conventional method for preparing antigen-specific CTL, there have not been solved the problems essential to adoptive immunotherapy in which CTL having an antigen-specific cytotoxic activity effectively used in the treatment, is prepared in a sufficient amount for a short period of time. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a graph showing an activity of hyaluronic acid to inhibit binding of a soluble CD44 and a soluble CD44-recognizing antibody. FIG. 2 is a graph showing a binding activity of FL-labeled hyaluronic acid and CD44 on CTL cell surface. FIG. 3 is a graph showing a binding activity of a soluble CD44-recognizing antibody and a soluble CD44 in a medium. FIG. 4 is a graph showing a binding activity of an HA Non-Blocking anti-CD44 antibody and a soluble CD44 in a medium. FIG. 5 is a graph showing a binding activity of an HA Non-Blocking anti-CD44 antibody and CD44 on CTL cell surface. FIG. 6 is a graph showing a binding of an HA Non-Blocking anti-CD44 antibody on cell surface of CTL after expansion of CTL in which the antibody is added to a medium. detailed-description description="Detailed Description" end="lead"? |
Document analysis system and method |
A document mapping system including a set of element classes, each element class having an associated set of documents elements and an associated set of format and mapping rules, identifying means for identifying one or more document elements within an original document, and mapping means for creating and displaying a map of document sections linked by labels representing the respective documents elements associated with those document sections. |
1. A document analysis system including a set of element classes, each element class having an associated set of document elements and an associated set of element class rules, identifying means for identifying one or more document elements within an original document, said identified document elements dividing the document into a plurality of document sections associated with one or more document elements, and storing means for storing the document sections in a database wherein said document sections are linked according to the element class rules of the document elements associated with a document section. 2. A document analysis system according to claim 1 wherein said document elements are text strings representing grammatical construct elements. 3. A document analysis system according to claim 1 wherein said grammatical construct elements are logical operators. 4. A document analysis system according to claim 1 wherein said document sections are requirements of a clause of said document. 5. A document analysis system according to claim 4 wherein a requirement record is created for a requirement, said requirement record including a requirement field, wherein text of a requirement is stored in said requirement field. 6. A document analysis system according to claim 5 wherein a requirement record further includes a compliance status field. 7. A document analysis system according to claim 4 wherein an element record is created for an identified document element, said element record containing links to the requirement records to which the document element is related. 8. A document analysis system according to claim 7 wherein an element record includes an element class field for storing the element class of a document element. 9. A document analysis method including the steps of: identifying one or more document elements within an original document, classifying identified elements into one or more of a plurality of element classes, dividing the document into a plurality of document sections linked by the document elements in accordance with a set of rules associated with the element classes to which the identified document elements belong, and storing the document sections in a database. 10. A document mapping system including a set of element classes, each element class having an associated set of document elements and an associated set of format and mapping rules, identifying means for identifying one or more document elements within an original document, and mapping means for creating and displaying a map of document sections linked by labels representing the respective documents elements associated with those document sections. 11. A document mapping system according to claim 10 wherein an element class includes one or more graphical display symbols for displaying an identified document element belonging to that class and document sections associated with an identified document element. 12. A document mapping system according to claim 11 wherein a graphical display symbol includes one or more text boxes for receiving text of a document section. 13. A document mapping system according to claim 10 wherein said mapping means further includes means for graphically linking two or more element symbols. 14. A document analysis system according to claim 11 wherein an element record is created in a system database when a graphical display symbol is added to said document map, said element record containing an element class field. 15. A document analysis system according to claim 14 wherein a section record is created in said system database when a graphical display symbol is added to said map, said section record including a text section field for receiving text of a document section associated with a document element. 16. A document analysis system according to claim 15 wherein an element record further includes one or more fields containing links to associated section records and/or a section record contains one or more fields containing links to an element record. 17. A document analysis system according to claim 16 further including graphical link means for creating and displaying a graphical link between two or more element symbols or components of said symbols, wherein the creation of a graphical link between two element symbols creates a database link between the respective element and/or section records. 18. A document analysis system according to claim 10 further including validation means for indicating on said document map a validation status of a document section. 19. A document analysis system according to claim 18 wherein said validation means further includes display means for indicating on said document map a global validation status pertaining to two or more related document sections. 20. A document analysis system according to claim 19 wherein a global validation status is automatically determined from the validation status of the two or more related document sections. 21. A document analysis system according to claim 20 wherein an element class further includes an associated set of validation rules, and wherein a global validation status is automatically determined using the validation rules of the element class or classes associated with said two or more related document sections. 22. A document analysis method including the steps of: identifying one or more document elements within an original document, classifying identified elements into one or more element classes, dividing the document into a plurality of document sections in accordance with a set of rules associated with the element class of the identified document elements, and representing the original document as a map of document sections linked by labels representing the respective document elements pertaining to those document sections. 23. An interface for creating a map of a document having a plurality of document sections linked by associated document elements, said document elements belonging to one or more of a plurality of element classes, said interface including a menu of graphic display symbols, each display symbol representing one or more element classes, and a mapping display, wherein one or more display symbols include a text area for receiving text of a document section, wherein a user may select a symbol to display in said mapping section, wherein a user can link two or more symbols. 24. A mapping interface according to claim 23 wherein linking two or more symbols creates a logical link between the respective document sections of associated with said symbols. 25. A system for constructing a document from a document map, said document map including a plurality of logically linked graphical symbols of one or more classes and containing a plurality of text sections, said system including a database storing a plurality of document construction rules for said one or more classes, wherein said system converts said document map into a plain language document according to the document construction rules pertaining to the classes of said graphical symbols of said document map. 26. A system according to claim 25 wherein said system creates said plain language document by placing said text sections in an order determined by said document construction rules and linking said text sections with a text string specified by said construction rules. 27. A document analysis system including a set of element classes, each element class having an associated set of document elements and an associated set of format rules, and identifying means for identifying one or more document elements within an original document, wherein the system creates a representation of the original document formatted in accordance with the format rules for the element class of the document elements identified in the original document. 28. A document analysis method including the steps of: identifying one or more document elements within an original document, classifying identified document elements into one or more of a plurality of element classes and creating a representation of the original document formatted in accordance with a set of format rules associated with the element classes to which the identified document elements belong. |
<SOH> FIELD OF THE INVENTION <EOH>This invention relates to a system for analysing, processing and navigating through documents, and in particular documents of a structured nature for example legal and semi-legal documents such as contracts, warranties, policies, legislation etc. |
<SOH> SUMMARY OF THE INVENTION <EOH>In a first aspect, the invention resides in a document analysis system including a set of element classes, each element class having an associated set of document elements and an associated set of format rules, and identifying means for identifying one or more document elements within an original document, wherein the system creates a representation of the original document formatted in accordance with the format rules for the element class of the document elements identified in the original document. In a second aspect, the invention resides in a document analysis method including the steps of: identifying one or more document elements within an original document, classifying identified document elements into one or more of a plurality of element classes and creating a representation of the original document formatted in accordance with a set of format rules associated with the element classes to which the identified document elements belong. In a third aspect, the invention resides in a document analysis system including a set of element classes, each element class having an associated set of document elements and an associated set of document dividing rules, identifying means for identifying one or more document elements within an original document, said identified document elements dividing the document into a plurality of sections according to the dividing rules for the element classes of the identified document elements, said document sections being linked by the document elements and storing means for storing the document sections in a database. In a fourth aspect, the invention resides in a document analysis method including the steps of: identifying one or more document elements within an original document, classifying identified elements into one or more of a plurality of element classes, dividing the document into a plurality of document sections linked by the document elements in accordance with a set of rules associated with the element classes to which the identified document elements belong, and storing the document sections in a database. In a fifth aspect, the invention resides in a document mapping system including a set of element classes, each element class having an associated set of document elements and an associated set of format and mapping rules, identifying means for identifying one or more document elements within an original document, dividing means for dividing the document into a plurality of document sections in accordance with the set of rules for the element class of the identified document elements and mapping means for creating a map of document sections linked by labels representing the respective documents elements pertaining to those document sections. In a sixth aspect, the invention resides in a document analysis method including the steps of: identifying one or more document elements within an original document, classifying identified elements into one or more element classes, dividing the document into a plurality of document sections in accordance with a set of rules associated with the element class of the identified document elements, and representing the original document as a map of document sections linked by labels representing the respective document elements pertaining to those document sections. Preferably the document elements are link element linking sections of document subject matter. More preferably, the document elements are grammatical construct elements, that is words or phrases, linking sections of textual subject matter of the original document. The element classes may further include punctuation that assists in identifying the grammatical construct elements for that class. Preferably, the format and mapping rules for one or more element classes include graphic elements for displaying the document sections pertaining to the respective document element. In one embodiment, the system creates an amended version of the original document containing highlights in accordance with the format rules for the identified document elements. Preferably, the system and method of the invention are embodied in computer software. |
Saddle backing |
The aim of the invention is to configure a saddle backing (1) for a riding animal that is as anatomically compatible as possible. To achieve this, two lateral sections (3), e.g. consisting of lambskin (7) are interconnected by means of a web element (4), in which a recess (6) in the shape of a longitudinal groove is fashioned, said recess extending along the vertebral column (5) of the riding animal, in such a way that no pressure is exerted on said vertebral column (5). The weight of a rider is thus distributed over a large surface area on the lateral sections (3) lying on the flanks of the riding animal. |
1. Saddle pad (1) for laying on the back (2) of a riding animal, characterized in that a recess (6) in the shape of a lengthwise groove is made in the saddle pad (1) in the region lying over the spine (5) of the riding animal, so that the panels (3) resting on the flanks of the riding animal have a greater thickness than the web (4) connecting the two panels (3) to one another over the spine. 2. Saddle pad according to claim 1, characterized in that there is a bulge (10) at the front and/or rear end of the web (4). 3. Saddle pad according to claim 1 or 2, characterized in that at the front and/or rear end of each panel (3) there is in each case a device (11) for fastening a saddlecloth (20). 4. Saddle pad according to claim 3, characterized in that at the front and/or rear end of each panel (3) there is in each case a slit (11) through which a strap (40) is passed. 5. Saddle pad according to claim 4, characterized in that a saddlecloth (20) is fastenable under the saddle pad by straps (40) that can be passed through the slits (11) of the panels (3). 6. Saddle pad according to one of the foregoing claims, characterized in that the panels (3) of the saddlecloth (1) are made of lambskin, to the skin side of which a textile fabric is sewed. 7. Saddle pad according to claim 6, characterized in that the web (4) consists of the textile fabric (8). 8. Saddle pad according to claim 6 or 7, characterized in that the textile fabric (8) is quilted. 9. Saddle pad according to one of claims 1 to 8, characterized in that the saddle pad (1) is covered with lambskin in the region of the undersides of its panels (3). |
Process for screening fungitoxic compounds |
Methods for identifying fungitoxic compounds are disclosed based on inhibition of the enzyme Δ-9 fatty acid de-saturase. |
1. A method for identifying potential fungitoxic compounds which comprises (a) evaluating candidate compounds for the ability to bind to a Δ-9 fatty acid desaturase enzyme, and (b) measuring a significant reduction of enzyme activity. 2. The method according to claim 1 wherein the compounds that inhibit the Δ-9 fatty acid desaturase enzyme are subjected to one or more tests to confirm fungicidal activity. 3. The method according to claim 1 which includes assaying the activity of Δ-9 fatty acid desaturase in a microsomal preparation from fungi in the absence and presence of candidate compounds. 4. The method according to claim 1 wherein activity of Δ-9 fatty acid desaturase is determined by measuring the conversion of a saturated fatty acyl-coenzyme A substrate to an unsaturated fatty acid product. 5. The method according to claim 1 wherein the fungitoxic compound is effective against classes of fungi selected from the group consisting of Ascomycete, Basidiomycete, Deuteromycete, Oomycete and combinations thereof. 6. The method according to claim 1 wherein the assay detects the inhibition of Δ-9 fatty acid desaturase activity in whole cells or cell extracts from plant pathogenic fungi selected from the group consisting of Colletotrichum spp., Magnaporthe spp., Botrytis spp., Fusarium spp., Alternaria spp., Helminthosporium spp., Venturia spp., Cercospora spp., Septoria spp., Mycosphaerella spp., Monilinia spp., Sclerotinia spp., Puccinia spp., Phytophthora spp., Pythium spp., Erysiphe spp., Penicillium spp. and Puccinia spp. and combinations thereof 7. The method according to claim 1 wherein the assay detects the inhibition of Δ-9 fatty acid desaturase activity in whole cells or cell extracts from a fungal pathogen of mammals selected from the group consisting of Candida spp., Aspergillus spp., Fusarium spp., Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Microsporum spp., and Tricophyton spp. 8. The method according to claim 1 wherein the assay detects the inhibition of Δ-9 fatty acid desaturase in whole cells or cell extracts from Saccharomyces cerevisiae or other fungi which may serve as suitable model systems for plant or mammalian fungal pathogens. 9. The method according to claim 1 wherein compounds determined to inhibit Δ-9 fatty acid desaturase enzyme activity are used to prepare fungitoxic compositions and formulations. 10. A method for identifying fungitoxic compounds which comprises (a) screening at least one candidate compound for fungitoxic in the presence and absence of an exogenous supply of (i) an unsaturated fatty acid and (ii) a saturated fatty acid; and (b) identifying inhibitors of Δ-9 fatty acid desaturase activity by demonstrating reduced fungitoxicity in the presence of the exogenous supply of unsaturated fatty acid and no reduction in fungitoxicity in the presence of the exogenous supply of saturated fatty acid. 11. A method for controlling fungal growth on a plant, animal or substrate which comprises testing candidate compounds in an assay which detects the inhibition of Δ-9 fatty acid desaturase activity and applying compounds which inhibit Δ-9 fatty acid desaturase activity to a locus on the plant, animal or substrate. 12. The method according to claim 11 wherein the substrate is selected from the group consisting of wood, leather, concrete, paints, plastics, metals and surfaces having a protective coating. 13. A fungitoxic composition comprising at least one A-9 fatty acid desaturase inhibitor as the active ingredient in combination with one or more carriers. 14. The fungitoxic composition of claim 13 wherein the composition includes one or more saturated fatty acids selected from the group consisting of fatty acids, fatty esters, fatty ethers and compounds having a formula CH3 (CH2)nCO2 X, wherein X is selected from H, alkali metals and C1-C8 alkyl and wherein n is an integer selected from 8-22. 15. The fungitoxic composition of claim 13 excluding pyridazinones of the type selected from the group consisting of 6-(4-chlorophenyl)-2-(2′-pentyn-4′-ene-1-yl)-3(2H)-pyridazinone; 6-(4-chlorophenyl)-2-(2′-pentynyl)-3(2H)-pyridazinone; 6-(4-chlorophenyl)-2-(5′-pentoxy-2′-butynyl)-3(2H)-pyridazi-none; 6-(4-chloro-phenyl)-2-(4′-fluoro-2′-butynyl)-3(2H)-pyridazinone; 6-(2-pyridyl)-2-(2′-nonynyl)-3(2H)-pyridazinone; 7-chloro-2,4,4a,5-tetrahydro-2-(2′-pentyn-yl)-indeno[1,2-c]-pyridazin-3-one; 6-(4-chlorophenyl)-2-(2′-pentynyl)-3(2H)-4,5-dihydropyridazinone; 6-(2-napthyl)-2-(2′-pentynyl)-3(2H)-pyridazi-none; 6-(4-chlorophenyl)-2-(2′-decynyl)-3(2H)-pyridazinone and combinations thereof. 16. The fungitoxic composition of claim 13 wherein the carrier is selected from organic solvents selected from the group consisting of water, acetone, methanol, ethanol, dimethylformamide, pyridine and dimethyl sulfoxide and finely divided solids selected from the group consisting of clays, inorganic silicates and carbonates, and silicas. 17. A fungitoxic formulation comprising; (a) at least one Δ-9 fatty acid desaturase inhibitor (b) at least one fungicide that is not a Δ-9 fatty acid desaturase inhibitor; (c) optionally one or more carriers; and (d) optionally one or more additives or stabilizers. 18. The fungitoxic formulation according to claim 17 wherein the formulation includes one or more saturated fatty acids selected from the group consisting of fatty acids, fatty esters, fatty ethers and compounds having a formula CH3 (CH2)nCO2 X, wherein X is selected from H, alkali metals and C1-C8 alkyl and wherein n is an integer selected from 8-22. 19. A method for controlling growth of fungi on plants, mammals or substrates which comprises testing candidate compounds in an assay which detects the inhibition of Δ-9 fatty acid desaturase activity and applying the fungitoxic formulation of claim 18 to a locus wherein control of fungal growth is desired. 20. The method according to claim 19 wherein the substrate is selected from the group consisting of paint, wood, leather, concrete, metal, plastics and animal skin. |
Optical csma/cd technique |
An optical network (10) comprising a plurality of optical network units (12), an optical line terminal unit, and a first optical combiner unit (20), wherein the optical network units (12) are optically connected to the first optical combiner unit (20) via respective optical connections in a manner such that optical transmissions from the optical network units (12) are combined onto one optical line connection to the optical line terminal unit, a redirection unit (24) for redirecting a portion of a transmission signal on the optical line connection towards the first combiner unit (20) each optical network unit (12) comprising an optical transmitter unit (14) for transmitting an optical signal to the optical line terminal unit, and a CSMA/CD unit (16) arranged, in use, to tap off at least a portion of the redirected portion of the transmission signal from the optical connection between the optical network unit (12) and the first combiner unit (20), wherein the CSMA/CD unit (16) is further arranged to control the transmitter unit (14) based on the tapped off portion of the redirected portion of the transmission signal. |
1. An optical network comprising: a plurality of optical network units, an optical line terminal unit, and a first optical combiner unit, wherein the optical network units are optically connected to the first optical combiner unit via respective optical connections in a manner such that optical transmissions from the optical network units are combined onto one optical line connection to the optical line terminal unit, a redirection unit for redirecting a portion of a transmission signal on the optical line connection towards the first combiner unit, each optical network unit comprising: an optical transmitter unit for transmitting an optical signal to the optical line terminal unit, and a dedicated CSMA/CD unit associated with the optical transmitter unit and arranged, in use, to tap oft at least a portion of the redirected portion of the transmission signal from the optical connection between the optical network unit and the first combiner unit, wherein the CSMA/CD unit is further arranged to control the transmitter unit based on the tapped off portion of the redirected portion of the transmission signal. 2. An optical network as claimed in claim 1, wherein the first optical combiner unit comprises an optical star coupler. 3. An optical network as claimed in claim 1, wherein the redirection unit comprises a reflection grating for reflecting the portion of the transmission signal. 4. An optical network as claimed in claim 3, wherein the reflection grating comprises a Bragg reflection grating. 5. An optical network as claimed in claim 1, wherein the redirection unit comprises: a tap unit for tapping off the portion of the transmission signal, a second optical combiner unit, and an optical redirecting connection disposed between the tap unit and the second optical combiner unit for redirecting the tapped off portion of the transmission signal towards the first optical combiner unit. 6. An optical network as claimed in claim 5, wherein the first and second combiner units are implemented as one combiner unit. 7. An optical network as claimed in claim 1, wherein the redirection unit and the first optical combiner unit are implemented as a 3×N optical combiner, wherein two of the, in use, upstream ports are interconnected for, in use, effecting the redirecting. 8. An optical network as claimed in claim 1, wherein the optical transmitter unit comprises a light emitting diode or a laser source. 9. An optical network as claimed in claim 1, wherein the optical network comprises an access network. 10. An optical network as claimed in claim 1, wherein the CSMA/CD unit is arranged to control the transmitter unit based on the intensity of the tapped off portion of the redirected portion of the transmission signal. 11. An optical network as claimed in claim 10, wherein the CSMA/CD is arranged to effect stopping transmission from the transmitter unit when the intensity of the tapped off portion is equal to or exceeds a predetermined threshold value. 12. An optical network as claimed in claim 1, wherein the CSMA/CD unit is arranged to effect restarting of the transmission from the transmitter unit after a predetermined delay period. 13. An optical network as claimed in claim 12, wherein the CSMA/CD units of the respective optical network units are arranged to restart the transmission from the respective transmitter units after different delay periods. 14. An optical network as claimed in claim 1, wherein the CSMA/CD unit comprises an optical tap unit for tapping off the portion of the redirected transmission signal. 15. An optical network as claimed in claim 1, wherein the CSMA/CD unit comprises an optical circulator for tapping off the redirected transmission signal. 16. An optical network as claimed in claim 1, wherein the redirected portion of the transmission signal is a dedicated portion for the redirecting process as opposed to other portions carrying data intended for transmission to the optical line terminal unit. 17. An optical network as claimed in claim 1, wherein the redirection unit further comprises means for jamming of the redirected portion of the transmission signal. 18. An optical network as claimed in claim 17, wherein the means for jamming the redirected signal comprises means for combining copies of the redirected portion of the transmission signal, wherein, in use, an optical delay is imposed on one of the copies prior to the combining. 19. An optical network as claimed in claims 17, wherein the means for effecting the jamming of the redirected portion of the transmission signal comprises an electronic circuit for manipulating the redirected portion of the transmission signal. 20. An optical network unit for use in an optical network comprising a plurality of optical network units, an optical line terminal unit, and a first optical combiner unit, the optical network units being optically connected to the first optical combiner unit via respective optical connections in a manner such that optical transmissions from the optical network units are combined onto one optical line connection to the optical line terminal unit, and a redirection unit for redirecting a portion of a transmission signal on the optical line connection towards the first combiner unit, the optical network unit comprising: an optical transmitter unit for, in use, transmitting an optical signal towards the optical line terminal unit, and a dedicated CSMA/CD unit associated with the optical transmitter unit and arranged, in use, to tap off at least a portion of the redirected portion of the transmission signal from the optical connection between the optical network unit and the first combiner unit, wherein the CSMA/CD unit is further arranged to control the transmitter unit based on the tapped off portion of the redirected portion of the transmission signal. 21. An optical network unit as claimed in claim 20, wherein the optical transmitter unit comprises a light emitting diode or a laser source. 22. An optical network unit as claimed in claim 20, wherein the CSMA/CD unit is arranged to control the transmitter unit based on the intensity of the tapped off portion of the redirected portion of the transmission signal. 23. An optical network unit as claimed in claim 22, wherein the CSMA/CD unit is arranged to effect stopping transmission from the transmitter unit when the intensity of the tapped off portion is equal to or exceeds a predetermined threshold value. 24. An optical network unit as claimed in claim 20, wherein the CSMA/CD unit is arranged to effect restarting of the transmission from the transmitter unit after a predetermined delay period. 25. A optical network unit as claimed in claim 20, wherein the optical network comprises an optical access network. 26. An optical combiner unit for use in an optical network comprising a plurality of optical network units, an optical line terminal unit, the optical network units being optically connected to the optical combiner unit via respective optical connections in a manner such that optical transmissions from the optical network units are combined onto one optical line connection to the optical line terminal unit, the optical combiner unit comprising: a redirection unit for, in use, redirecting a portion of a transmission signal on the optical line connection to each optical network unit, wherein the redirected portion is chosen in a manner which provides, in use, that the redirected portion of the transmission signal functions as a reference signal in a CSMA/CD technique conducted at the optical network units, and wherein the optical combiner unit further comprises means for jamming of the redirected portion of the transmission signal. 27. An optical combiner unit as claimed in claim 26, wherein the means for jamming the redirected portion of the transmission signal comprises means for combining copies of the redirected portion of the transmission signal, wherein, in use, an optical delay is imposed on one copy prior to the combining. 28. An optical combiner unit as claimed in claim 26, wherein the means for effecting the jamming of the redirected portion of the transmission signal comprises an electronic circuit for manipulating the redirected portion of the transmission signal. 29. An optical combined unit wherein the optical network comprises an optical access network. 30. A method of conducting upstream transmissions from optical network units in an optical network, the method comprising: combining optical transmissions from the optical network units onto one optical line connection, redirecting a portion of a transmission signal on the optical line connection back towards to the network units, tapping off at least a portion of the redirected portion of the transmission signal at each optical network unit utilising a dedicated CSMA/CD unit, and controlling transmissions from the optical network units based on the tapped off portions of the redirected portion of the transmission signal. 31. A method as claimed in claim 30, wherein the step of controlling the transmissions from the optical network units comprises determining the intensities of the tapped off portions of the redirected portion of the transmission signal. 32. A method as claimed in claim 31, wherein the step of controlling comprises effecting stopping transmissions from individual optical network units when the respective intensities of the tapped off portions are equal to or exceed predetermined threshold values. 33. A method as claimed in claim 30, wherein the step of controlling comprises restarting of the transmission from the individual optical network units after predetermined delay periods. 34. A method as claimed in claim 33, wherein the step of controlling the respective optical network units comprises restarting the transmissions from the respective optical network units after different delay periods. 35. A method as claimed in claim 30, wherein the method further comprises the step of jamming the redirected portion of the transmission signal. 36. A method as claimed in claim 35, wherein the jamming of the redirected portion of the transmission signal comprises combining copies of the redirected portion of the transmission signal, wherein an optical delay is imposed on one of the copies prior to the combining. 37. A method as claimed in claim 35, wherein the jamming of the redirected portion of the transmission signal comprises utilising an electronic circuit. 38. A method as claimed in claim 30 wherein the optical network comprises an optical access network. |
<SOH> BACKGROUND OF THE INVENTION <EOH>It has been proposed to transport Ethernet frames over a passive optical network between a central office/server and individual subscribers. This proposal is particularly relevant to Access networks, i.e. the “last mile” in distributing data to individual subscribers. In the Access environment, an emphasis must be placed on providing inexpensive solutions, which is why other proposals such as implementing wavelength division multiplexed (WDM) based optical access networks may not be preferred. In the electrical domain such as in the majority of current internet traffic at the Access level, a “carrier sense multiple access with collision detection” (CSMA/CD) protocol is often used. In the electrical domain, the CSMA/CD technique involves both the electrical line terminal (i.e. at the central office/server) and the electrical network units, i.e. subscribers, to determine whether a collision has occurred between upstream transmissions from individual electrical network units to the electrical line terminal. In the event of a collision having occurred, the transmission of individual electrical network units is stopped and a retry transmission is conducted after predetermined delay periods. In other words, the CSMA/CD technique is substantially a cruel protocol based on retries until a successful transmission, i.e. without collision occurs, rather than relying on a complex synchronisation protocol. However, when applying the CSMA/CD technique to passive optical networks, it is very inefficient to involve both an optical line terminal and the optical network units in the CSMA/CD process analogous to its use in the electrical domain. The inefficiencies are caused by the long distance between the optical line terminal and optical coupler elements used for the last mile distribution to the individual optical network units on the one hand, and the short distance between the optical network units and the optical coupler element on the other. The inefficiency is related to the relatively short packet transmission time in the optical domain. The limiting factor in the application of the CSMA/CD protocol in high-speed passive optical networks is thus the low packet transmission time/propagation delay ratio. At least preferred embodiments of the present invention therefore seek to provide an application of the CSMA/CD technique to passive optical networks which can address the above mentioned inefficiency. |
<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with a first aspect of the present invention there is provided an optical network comprising a plurality of optical network units, an optical line terminal unit, and a first optical combiner unit, wherein the optical network units are optically connected to the first optical combiner unit via respective optical connections in a manner such that optical transmissions from the optical network units are combined onto one optical line connection to the optical line terminal unit, a redirection unit for redirecting a portion of a transmission signal on the optical line connection towards the first combiner unit, each optical network unit comprising an optical transmitter unit for transmitting an optical signal to the optical line terminal unit, and a dedicated CSMA/CD unit associated with the optical transmitter unit and arranged, in use, to tap off at least a portion of the redirected portion of the transmission signal from the optical connection between the optical network unit and the first combiner unit, wherein the CSMA/CD unit is further arranged to control the transmitter unit based on the tapped off portion of the redirected portion of the transmission signal. Preferably, the first optical combiner unit comprises an optical star coupler. In one embodiment, the redirection unit comprises a reflection grating for reflecting the portion of the transmission signal. The reflection grating advantageously comprises a Bragg reflection grating. In another embodiment, the redirection unit comprises a tap unit for tapping off the portion of the transmission signal, a second optical combine unit, and an optical redirecting connection disposed between the tap unit and the second optical combiner unit for redirecting the tapped off portion of the transmission signal towards the first optical combiner unit. The first and second combiner units may be implemented as one combiner unit. In another embodiment, the redirection unit and the first optical combiner unit are implemented as a 3×N optical combiner, wherein two of the, in use, upstream ports are interconnected for, in use, effecting the redirecting. The two upstream ports may be interconnected through an optical isolator, depending on the type of transmitter used. The optical transmitter unit may comprise a light emitting diode or a laser source or any other suitable light source. The optical network may comprise an optical access network. In one embodiment, the CSMA/CD unit is arranged to control the transmitter unit based on the intensity of the tapped off portion of the redirected portion of the transmission signal. Advantageously, the CSMA/CD is arranged to effect stopping transmission from the transmitter unit when the intensity of the tapped off portion is equal to or exceeds a predetermined threshold value. The CSMA/CD unit may be arranged to effect restarting of the transmission from the transmitter unit after a predetermined delay period. In such an embodiment, the CSMA/CD units of the respective optical network units may be arranged to restart the transmission from the respective transmitter units after different delay periods. Accordingly, a hierarchy or preference scheme may be implemented. The CSMA/CD unit may comprise an optical tap unit for tapping off the portion of the redirected transmission signal. The CSMA/CD unit may comprise an optical circulator for tapping off the redirected transmission signal. In a preferred embodiment, the redirected portion of the transmission signal is a dedicated portion for the redirecting process as opposed to other portions carrying data intended for transmission to the optical line terminal unit. The redirection unit may further comprise means for jamming of the redirected portion of the transmission signal. The means for jamming the redirected signal may comprise means for combining copies of the redirected portion of the transmission signal, wherein, in use, an optical delay is imposed on one of the copies prior to the combining. Alternatively or additionally, the means for effecting the jamming of the redirected portion of the transmission signal may comprise an electronic circuit for manipulating the redirected signal. In accordance with a second aspect of the present invention there is provided an optical network unit for use in an optical network comprising a plurality of optical network units, an optical line terminal unit, and a first optical combiner unit, the optical network units being optically connected to the first optical combiner unit via respective optical connections in a manner such that optical transmissions from the optical network units are combined onto one optical line connection to the optical line terminal unit, and a redirection unit for redirecting a portion of a transmission signal on the optical line connection towards the first combiner unit, the optical network unit comprising an optical transmitter unit for, in use, transmitting an optical signal towards the optical line terminal unit, and a dedicated CSMA/CD unit associated with the optical transmitter unit and arranged, in use, to tap off at least a portion of the redirected portion of the transmission signal from the optical connection between the optical network unit and the first combiner unit, wherein the CSMA/CD unit is further arranged to control the transmitter unit based on the tapped off portion of the redirected portion of the transmission signal. The optical transmitter unit may comprise a light emitting diode or a laser source or any other suitable light source. In one embodiment, the CSMA/CD unit is arranged to control the transmitter unit based on the intensity of the tapped off portion of the redirected portion of the transmission signal. Advantageously, the CSMA/CD is arranged to effect stopping transmission from the transmitter unit when the intensity of the tapped off portion is equal to or exceeds a predetermined threshold value. The CSMA/CD unit may be arranged to effect restarting of the transmission from the transmitter unit after a predetermined delay period. The optical network may comprise an optical access network. In accordance with a third aspect of the present invention there is provided an optical combiner unit for use in an optical network comprising a plurality of optical network units, an optical line terminal unit, the optical network units being optically connected to the optical combiner unit via respective optical connections in a manner such that optical transmissions from the optical network units are combined onto one optical line connection to the optical line terminal unit, the optical combiner unit comprising a redirection unit for, in use, redirecting a portion of a transmission signal on the optical line connection to each optical network unit, wherein the redirected portion is chosen in a manner which provides, in use, that the redirected portion of the transmission signal functions as a reference signal in a CSMA/CD technique conducted at the optical network units, and means for jamming of the redirected portion of the transmission signal. The means for jamming the redirected portion of the transmission signal may comprise means for combining copies of the redirected portion of the transmission signal, wherein, in use, an optical delay is imposed on one copy prior to the combining. Alternatively or additionally, the means for effecting the jamming of the redirected portion of the transmission signal may comprise an electronic circuit for manipulating the redirected signal. The optical network may comprise an optical access network. In accordance with a fourth aspect of the present invention there is provided a method of conducting upstream transmissions from optical network units in an optical network the method comprising the steps of combining optical transmissions from the optical network units onto one optical line connection, redirecting a portion of a transmission signal on the optical line connection back towards to the network units, tapping off at least a portion of the redirected portion of the transmission signal at each optical network unit utilising a dedicated CSMA/CD unit, and controlling transmissions from the optical network units based on the tapped off portion of the redirected portion of the transmission signal. In one embodiment, the step of controlling the transmissions from the optical network units comprises determining the intensities of the tapped off portions of the redirected portion of the transmission signal. Advantageously, the step of controlling comprises effecting stopping transmissions from individual optical network units when the respective intensity of the tapped off portion is equal to or exceeds predetermined threshold values. The step of controlling may further comprise restarting of the transmission from the individual optical network units after predetermined delay periods. In such an embodiment, the step of controlling the respective optical network units may comprise restarting the transmissions from the respective optical network units after different delay periods. The method may further comprise the step of jamming the redirected portion of the transmission signal. The jamming of the redirected portion of the transmission signal may comprise combining copies of the redirected portion of the transmission signal, wherein an optical delay is imposed on one of the copies prior to the combining. Alternatively or additionally, the jamming of the redirected portion of the transmission signal may comprise utilising an electronic circuit. The optical network may comprise an optical access network. |
Electrical filters |
An active filter adapted to filter a line containing an electrical waveform, includes an amplifier, a control system, a waveform measuring device and a coupling circuit. The waveform measuring device, in use, provides an input signal to the control system, the control system controlling the amplifier in response to the input signal and the coupling circuit connecting the amplifier to the system to be filtered. The coupling circuit comprises a passive circuit arranged in a four terminal network of restricted form having no poles in its frequency response within its useful bandwidth. Generally, the four terminal network is provided as a ladder circuit, and a primary use of the filter is to filter ac or dc supplies in electrical power systems. |
1-16. (Canceled) 17. An active filter for filtering an electrical line containing an electrical waveform, the active filter comprising: an amplifier, a control system, a waveform measuring device, and a coupling circuit, the waveform measuring device being operative for obtaining a measure of at least one noise frequency in the electrical waveform and for supplying the measure of the at least one noise frequency to an input of the control system, the control system being operative for controlling the amplifier in response to the input signal, and the coupling circuit connecting the amplifier to the line thereby to control the at least one noise frequency, the coupling circuit comprising a four terminal network of passive components in a ladder circuit configuration arranged such that it does not have any poles in its frequency response within its useful bandwidth. 18. The active filter according to claim 17, in which the ladder circuit configuration is arranged such that it has at least one zero occurring at or close to the at least one noise frequency. 19. The active filter according to claim 17, in which the ladder circuit configuration comprises at least three series arms and at least three shunt arms, wherein: a) each series arm of said ladder circuit configuration consists of at least one capacitor, or at least one inductor, or a series combination of at least one capacitor and at least one inductor, and b) each shunt arm of said ladder circuit configuration consists of at least one capacitor, or at least one inductor, or a parallel combination of at least one capacitor and at least one inductor, and c) there is at least one inductor in at least one series arm, and at least one inductor in at least one shunt arm, and at least one capacitor in at least one series arm, and at least one capacitor in at least one shunt arm. 20. The active filter according to claim 17, in which the waveform measuring device is a current transformer connected in series with said line which measures electrical current in said line. 21. The active filter according to claim 17, in which the waveform measuring device is a voltage transformer connected to shunt to said line which measures electrical voltage across said line. 22. The active filter according to claim 17, in which said coupling circuit contains an air-cored transformer. 23. The active filter according to claim 17, in which said coupling circuit contains an iron-cored transformer. 24. The active filter according to claim 17, in which the filter has at least three zeros in its frequency response within the useful bandwidth. 25. The active filter according to claim 17, in which the line is part of a power supply system. 26. The active filter according to claim 25, in which the line carries at least one ac voltage. 27. The active filter according to claim 25, in which the line carries at least one dc voltage. 28. A power supply system including an active filter for filtering an electrical line containing an electrical waveform, the active filter comprising: an amplifier, a control system, a waveform measuring device, and a coupling circuit, the waveform measuring device being operative for obtaining a measure of at least one noise frequency in the electrical waveform and for supplying the measure of the at least one noise frequency to an input of the control system, the control system being operative for controlling the amplifier in response to the input signal, and the coupling circuit connecting the amplifier to the line thereby to control the at least one noise frequency, the coupling circuit comprising a four terminal network of passive components in a ladder circuit configuration arranged such that it does not have any poles in its frequency response within its useful bandwidth. 29. The power supply system according to claim 28, in which the power supply system has multiple phases, and in which the active filter is provided for each phase. 30. The power supply system according to claim 28, including an ac-dc converter. 31. The power supply system according to claim 30, in which the active filter has a useful bandwidth which corresponds to noise frequencies in a range of a fifth harmonic to a forty-ninth harmonic on the ac side of the converter. 32. The power supply system according to claim 30, in which the active filter has a useful bandwidth which corresponds to noise frequencies in a range of a sixth harmonic to a forty-eighth harmonic on the dc side of the converter. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Many devices are connected to ac and dc power systems and often such devices generate distortion in the voltages and currents in the power system. Unless corrected such distortion is liable to cause interference with other equipment in the power system. Possible the largest interfering devices are HVDC converters, at ratings of the order of 100 MW to 2000 MW or more. Other devices having lower ratings include converters associated with industrial equipment such as mine-winders and rolling mills. A method commonly used to reduce interference is to arrange shunt-connected filters at the interfering source between a line and the return of that line. (The return would usually be grounded but need not be). Most of those used at present are in the form of passive filters, that is containing inductors and capacitors, sometimes with added resistors. Passive filters may be connected in shunt to the ac or dc system and usually comprise series inductor-capacitor tuned arms, tuned to the largest interfering harmonics, and sometimes other relatively broad-band (‘damped’) filter arms (usually with added resistors) to filter higher frequencies. The main function of such a passive filter is to present a low (ideally zero) shunt impedance at interfering frequencies, such that substantially all of the interfering current components are diverted through the filter. Such prior art passive filters have the disadvantage that the de-tuning effect of ac system frequency changes, typically of several percent, can cause inadequate filtering. Broad-band (damped) filter arms are less affected by frequency changes, but give relatively weak filtering effect and relatively large losses (and loss capitalisation). These effects become worse if the total fundamental frequency reactive power (or total capacitance) of the filter is required to be small. The cost of passive filters is relatively high. Active filters are known in which an electronic amplifier is connected to the ac or dc line via a passive coupling circuit, the amplifier being controlled in a closed-loop manner via a measurement of the voltage or current distortion in the ac or dc line, such that the distortion in the ac or dc line is reduced to a small (ideally zero) value. FIG. 1 shows in a diagrammatic form an example of a known arrangement for one phase of an active ac filter. The interfering source is assumed to be a 12-pulse converter 1 , drawing a current IC from an ac system 2 (shown as an EMF at fundamental frequency only, behind an impedance Z). The converter 1 generates a dc voltage on to dc supply rails C, C. Current I C is initially assumed to contain the wanted fundamental current plus harmonics of orders 11 , 13 , 23 , 25 . . . . In the absence of a filter, these harmonic currents cause finite harmonic voltages on the ac system due to the finite impedance Z, which may interfere with supplies to other consumers on the ac system (not shown). A typical active filter 3 is shown connected in shunt to the ac system supply rails A-A. Active filter 3 includes a control system 4 , an amplifier 5 , a coupling filter 6 and a sensing means in the form of a measuring current transformer CT provided in association with one of the ac supply rails. The sensing means CT is provided to detect the harmonic currents produced by the dc converter 1 and provides an input to a control system 4 which is, in turn, connected to an amplifier 5 . The output of the amplifier drives the two input terminals B, B of a coupling network 6 . An output terminal of the network 6 is connected to each of the ac supply rails A, A. The control system 4 and the amplifier 5 are each of a type known in active filter practice. For simplicity, only one phase is shown; for a 3-phase system, three such circuits will normally be required. The control system is assumed to control the amplifier in response to the measured current I S in the ac system such that the harmonics in I S are reduced (ideally) to zero. In this condition, the harmonic current IF delivered to the line by the active filter is equal to the harmonic component in I C . The connection from the amplifier 5 to the ac line is shown in this example as being via a passive coupling filter 6 . Other forms of connection are known, such as a single inductor or capacitor, or even a direct connection, but these all require a large output voltage rating of the amplifier, hence a high amplifier cost, which is generally prohibitive. A known arrangement of the passive coupling filter 6 is shown in FIG. 2 , which includes two passive inductor-capacitor filter arms IC 1 , IC 2 connected in parallel, tuned respectively to the two largest ac harmonic currents (11 th and 13 th harmonics for a 12-pulse converter). If the tuning of these is exact, including exact ac system frequency, the amplifier voltage required at 11 th and 13 th harmonics is then in theory zero or, in practice, small. These frequencies are known as the “zeros” of the coupling impedance. FIG. 3 shows a graph of the impedance against frequency (in terms of harmonic order) for a typical arrangement. For normal de-tuning effects (principally due to ac system frequency changes) the amplifier voltage required (hence its rating) will clearly increase but amplifier cost may still be acceptable. Nevertheless, the simple coupling filter shown in FIG. 2 will have an impedance which increases relatively rapidly for harmonic frequencies much smaller or larger than 11 th or 13 th ; filtering of such frequencies, for example orders 23 , 25 or higher, may then require excessive amplifier voltage, hence amplifier cost. At a frequency between the two zeros (at about 12 th harmonic in the example) the coupling shown exhibits a “pole”, that is a frequency at which its theoretical impedance is infinity, or in practice very large, making filtering impracticable in this frequency region. It is possible to increase the number of harmonics filtered by increasing the number of parallel arms in the coupling filter. This is not shown but if, for example, the number of parallel branches in the coupling filter of FIG. 2 is increased to four, these may be tuned to harmonic orders 11 , 13 , 23 , 25 . The required amplifier voltage at harmonic orders 11 , 13 , 23 , 25 may then be reasonably low. However, frequencies which are not close to these frequencies will again require excessive amplifier voltage. In addition, this arrangement would exhibit further poles in its impedance characteristic, between each pair of zeros so that, for example, filtering of harmonic currents of intermediate orders such as 17 or 19 (which may occur due to various converter unbalances) may also require excessive amplifier voltage, even if these harmonic currents are small. The coupling circuit as described so far is effectively a two-terminal circuit. It is also known to use a four-terminal coupling circuit in the form of a ladder circuit including both series and shunt elements, for example, where most series elements of the ladder circuit are inductors and most shunt elements are capacitors, and in which at least one series element is an inductor connected in parallel to a capacitor, or at least one shunt element is an inductor connected in series with a capacitor. Specific examples of such arrangements are given in for example Patent WO 89/06879 A1 (Dan), but all of these have at least one pole in their transfer function. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention there is provided an active filter adapted to filter an electrical line containing an electrical waveform, the active filter comprising an amplifier, a control system, a waveform measuring device, and a coupling circuit, the waveform measuring device being adapted to obtain a measure of at least one noise frequency in the electrical waveform and supply the measure of the noise frequency to an input of the control system, the control system being arranged to control the amplifier in response to the input signal, and the coupling circuit connecting the amplifier to the line thereby to control the at least one noise frequency; wherein the coupling circuit comprises a four terminal network of passive components in a ladder circuit configuration arranged such that it does not have any poles in its frequency response within its useful bandwidth. The ladder circuit configuration is preferably arranged such that it does have at least one zero adapted to occur at or close to the at least one noise frequency. The ladder circuit configuration can comprise at least three series arms and at least three shunt arms, wherein: each series arm of said ladder consists of at least one capacitor, or at least one inductor, or a series combination of at least one capacitor and at least one inductor, and each shunt arm of said ladder circuit consists of at least one capacitor, or at least one inductor, or a parallel combination of at least one capacitor and at least one inductor, and there is at least one inductor in at least one series arm and at least one inductor in at least one shunt arm and at least one capacitor in at least one series arm and at least one capacitor in at least one shunt arm. A four-terminal coupling filter in this form is advantageous because the frequency response of the filter is finite within its operating frequency region, hence the required amplifier voltage and current are finite over the whole operating frequency region. As such, the filter can provide more optimum filtering of the system to which it is connected substantially over the bandwidth of the operating region, with an amplifier relatively of low rating. Coupling arrangements containing a parallel combination of an inductor and a capacitor in a series arm, or a series combination of an inductor and a capacitor in a shunt arm are here excluded because either of these would cause the existence of one or more poles in the coupling filter frequency response. The line may be part of a power supply system. The power supply system may be an ac or dc power supply system and may be a multiple phase power supply system. Typically the power system to be filtered will be a three phase ac power system. A control system, a waveform measuring device, and a coupling circuit is provided for each phase of the power system being filtered. The waveform measuring device may be a current transformer providing a convenient way of detecting the signal within the signal line. Alternatively the waveform measuring device may be a voltage transformer arranged in a shunt configuration with the line; such a voltage transformer may be advantageous in that it will cause the filter to reduce the effect of harmonics originating in the ac system EMF on the busbar voltage, as well as the effect of local load current. The coupling circuit may further include a transformer, which is advantageous because it provides galvanic isolation of the amplifier from the line which can help to protect the amplifier from electrical surges. Any transformer provided in the coupling circuit may have an iron core or may have an air core. The two input terminals of the four terminal network are connected to the amplifier. The two output terminals of the four terminal networks are connected between the line and its return conductor. The return conductor may be grounded, or not grounded. The skilled person will appreciate that as with any filter, the filter according to the present invention will have a useful bandwidth within which useful filtering is obtained and outside which the filter will be relatively ineffective. The filter according to the present invention is characterised in that it does not have any poles in the frequency response of its transfer function within at least the useful bandwidth. This is advantageous, because as the skilled person will appreciate, in theory an infinite (or in practice a very large) voltage would be required from the amplifier to drive the filter at the frequency of the a pole in order to produce filter action. Therefore, it is clearly advantageous to ensure that no poles are present within the frequency response of the useful bandwidth. Preferably, the filter may have three or more zeros in its frequency response within the useful bandwidth. The filter may of course have any number of zeros; possibly the filter may have 3, 4, 5, 6, 7, 8, 9, 10, or more zeros. For minimum filter cost the optimum number of zeros within the useful bandwidth will be governed in part by the total filter bandwidth required and the expected amplitude distribution of power line harmonics within the bandwidth. The filter may be provided in association with a switching device which switches at a predetermined frequency. The predetermined frequency may be a multiple of an ac supply frequency. The switching device may be an AC-DC converter. The skilled person will appreciate that noise will be generated by the switching device at harmonics of its switching frequency. The filter according to the present invention may be designed to remove such harmonics from the line. Where the line is an ac power supply system driving a 12-pulse dc converter, the filter may be adapted to remove the principal ac harmonics of orders 11 , 13 , 23 , 25 , . . . . Where the line is a dc power system (the waveform comprising a dc bias with noise thereon) driven by a 12-pulse dc converter the filter may be adapted to remove the principal dc harmonics of orders 12 , 24 , 36 . . . . The skilled person will appreciate that in either case other intermediate harmonics may be present, caused by various unbalances in the dc converter and in the ac system, and may also be required to be filtered. The filter according to the present invention may be adapted to filter harmonics typically in the range of the 5 th harmonic to 49 th harmonic for use on the ac side of a converter, or from about 6 th to 48 th on its dc side. These ranges of harmonics over which the filter may work may correspond to the useful bandwidth referred to herein. The zeros of the filter may be adapted to occur at approximately the frequencies corresponding to those of the largest harmonic currents caused by the interfering device. Such an arrangement is advantageous because it means that the amplifier voltage required at the frequencies of each such harmonic is therefore small, giving a more efficient amplifier design. It has the further advantage that if the amplifier should fail then the coupling circuit may continue to provide a moderate filtering action, effectively providing passive filters centred on the zeros of the transfer function, since these are the same as the zeros of the coupling output impedance. The line may be a power supply line and may be at voltages of about the order of tens of volts, hundreds of volts, thousands of volts, tens of thousands of volts, or hundreds of thousands of volts. However, it is envisaged that the filter is particularly suitable for filtering lines at a potential of the order of hundreds of thousands of volts. According to a second aspect of the invention there is provided a method of filtering a line having a waveform distortion thereon comprising providing an active filter including an amplifier coupled to the line via a passive circuit arranged in a four terminal network, the method comprising detecting a signal on the line and controlling the amplifier to tend to remove unwanted components of the signal present on the line. Such a method tends to remove the unwanted component of the signal present on the line more efficiently than prior art methods. The line may carry an ac or a dc supply voltage. Further, the unwanted component may be noise on the line. In particular, the noise may be harmonics on the power supply line. The method may comprise providing the coupling filter with a frequency response whose transfer functions do not contain any poles within its useful bandwidth. Such a method is advantageous because it reduces the voltage that must be produced by the amplifier in order to remove the unwanted component. According to a third aspect of the invention there is provided a power supply system fitted with a filter according to the first aspect of the invention. The power supply may be an ac or dc supply and may be at voltages of about the order of tens of volts, hundreds of volts, thousands of volts, tens of thousands of volts or hundreds of thousands of volts. |
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