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Delayed and sustained drug release |
The invention relates to the controlled release of preparations of therapeutic agents, for example a steroid; formulations comprising said preparations; and the use of said formulations to treat diseases such as those diseases which would benefit from steroid treatment. |
1-25. (cancelled) 26. A method of treating adrenal dysfunction in a patient, said method comprising administering to said patient a pharmaceutically effective amount of a combined glucocorticoid and a delivery vehicle, wherein said delivery vehicle provides for delayed and sustained release of said glucorticoid. 27. A method according to claim 26, wherein said glucocorticoid is selected from the group consisting of hydrocortisone, cortisol, cortisone acetate, prednisolone, prednisone, and dexamethasone. 28. A method according to claim 27, wherein said glucocorticoid is hydrocortisone. 29. A method according to claim 26, wherein the adrenal dysfunction is caused by a condition selected from the group consisting of primary and secondary adrenal failure, congenital adrenal hyperplasia, late-onset congenital adrenal hyperplasia, and polycystic ovarian failure. 30. A method according to claim 26, wherein the adrenal dysfunction is a congenital adrenal dysfunction. 31. A method for administering a glucorticoid to an animal, said method comprising the steps of: i) providing a combined preparation of a glucorticoid and a delivery vehicle wherein said vehicle provides for the sustained release of said glucorticoid; ii) administering the combined preparation from (i) to an animal requiring treatment such that the glucorticoid is released in a sustained manner; iii) providing a combined preparation of a glucorticoid and a delivery vehicle wherein said vehicle provides for the delayed and sustained release of the glucorticoid; and iv) administering the combined preparation from (iii) to an animal requiring treatment such that the glucorticoid is released in a delayed and sustained manner. 32. A method according to claim 31, wherein said animal is a human. 33. A method according to claim 31, wherein said glucocorticoid is selected from the group consisting of hydrocortisone, cortisol, cortisone acetate, prednisolone, prednisone, and dexamethasone. 34. A method according to claim 33, wherein said glucocorticoid is hydrocortisone. 35. A method according to claim 31, wherein said sustained release preparation is about 10-100 times slower than an otherwise identical preparation without the delivery vehicle. 36. A method according to claim 35, wherein said sustained release preparation is about 30-80 times slower than an otherwise identical preparation without the delivery vehicle. 37. A method according to claim 36, wherein said sustained release preparation is about 45-50 times slower than an otherwise identical preparation without the delivery vehicle. 38. A method according to claim 31, wherein the sustained release preparation is administered in the morning, between 8:00 am and 12:00 noon. 39. A method according to claim 31, wherein said delayed and sustained release preparation is administered between 8:00 pm and 12:00 midnight. 40. A method of treating congenital adrenal hyperplasia in a patient, said method comprising administering to said patient a pharmaceutically effective amount of a combined preparation comprising cortisol and a delivery vehicle, wherein said delivery vehicle provides for delayed and sustained release of the cortisol. 41. A method of treating Addison's disease in a patient, said method comprising administering to said patient a pharmaceutically effective amount of a combined preparation comprising cortisol and a delivery vehicle, wherein said delivery vehicle provides for delayed and sustained release of the cortisol. |
Communication method and communication module |
The document proposes a method for communication between a plurality of local applications and a diagnostic application in a motor vehicle, where data are transmitted from the local applications to the diagnostic application using a transmission medium, and a corresponding communication module having the steps of event-oriented provision of the data by the local applications, acceptance of the data by a communication module when initiated by the event-oriented provision of the data, management and conditioning of the data by the communication module, and transfer of the conditioned data from the communication module to the central application, with the conditioning of all the data accepted from the local applications, within the communication module, comprising data formatting into a data format which is determined by the central application. The method and the communication module are particularly suitable for performing an onboard system diagnosis in motor vehicles. |
1-14. (Cancelled) 15. A method for communication of data between local applications and a diagnostic application in a motor vehicle, via a transmission medium, said method comprising: event-oriented provision of data by the local applications; acceptance of said data by a communication module when initiated by the event-oriented provision of said data; management and conditioning of the data by the communication module; and transfer of the conditioned data from the communication module to the diagnostic application; wherein conditioning of data accepted from the local applications, within the communication module, comprises data formatting into a data format which is determined by the diagnostic application and is independent of the local applications. 16. A method for communication of data between local applications and a diagnostic application in a motor vehicle, via a transmission medium, said method comprising: aligning a communication module with the local applications in a configuration phase; the local applications, providing data on an event oriented basis; the communication module accepting data when initiated by the event-oriented provision of the data; the communication module managing and conditioning the data; and transferring the conditioned data from the communication module to the diagnostic application; wherein the conditioning of data accepted from the local applications, within the communication module, comprises data formatting into a data format which is determined by the diagnostic application and is independent of the local applications. 17. The method as claimed in claim 16, wherein said alignment comprises stipulation of data management and data conditioning algorithms in the communication module based on the type of the local applications, the type of hardware on which the local applications operate, the versions of the local applications, the version of the hardware on which the local applications operate and/or the configuration of the hardware, to suit a transmission protocol between the local applications and the diagnostic application. 18. The method as claimed in claim 15, wherein at least one of the following is true: the local applications are control unit applications in control units in the motor vehicle; and the method is used for onboard diagnosis. 19. The method as claimed in claim 18, wherein data conditioning comprises a local preliminary diagnosis in at least one control unit. 20. The method as claimed in claim 15, wherein at least one of the following is true: management of the data comprises buffer-storage of the data; data conditioning comprises compression; and data conditioning involves selection of the data. 21. The method as claimed in claim 15, wherein the transfer of the conditioned data from the communication module to the diagnostic application is controlled by the communication module. 22. The method as claimed in claim 15, wherein the data are managed by the communication module such that one of the following is true: data transfer to the diagnostic application can take place in a fixed cycle; data transfer to the diagnostic application takes place only for data in the communication module which have changed with respect to the past cycle. 23. The method as claimed in claim 22, wherein a cycle for data transfer to the diagnostic application is triggered by the local applications. 24. The method as claimed in claim 15, wherein the data comprise one of error state data, input/output state data, internal state data from the local applications, and analog values. 25. A communication module in a motor vehicle for performing the method as claimed in claim 1, said module comprising: data acceptance means for event-oriented acceptance of data from local applications; data conditioning means for managing and conditioning the data; and at least one data transfer interface to a diagnostic application; wherein the data conditioning means format the data accepted from the local applications into a data format which is determined by the diagnostic application and is independent of the local applications. 26. A networked diagnostic system in a motor vehicle for performing the method as claimed in claim 18, said system comprising: control unit applications as local applications; a system diagnosis application as a central application; and a communication module comprising data acceptance means for event-oriented acceptance of data from the control unit applications, data conditioning means for managing and conditioning the data and at least one data transfer interface to the system diagnosis application; wherein the data conditioning means format the data accepted from the control unit applications into a data format which is determined by the system diagnosis application and is independent of the control unit applications. 27. The communication module as claimed in claim 25, wherein at least one of the following is true: the communication module includes means for providing data for the local applications; and the communication module has means for controlling the local applications. 28. The diagnostic system as claimed in claim 26, wherein at least one of the following is true: the communication module includes means for providing data for the local applications; and the communication module has means for controlling the local applications. 29. The diagnostic system as claimed in claim 26, wherein control units are connected to a diagnostic unit by means of a network interconnection; the data acceptance means for the event-oriented acceptance of data from the control unit applications and the data conditioning means for managing and conditioning the data are located in a submodule of the communication module in the control units; the data transfer interface for transferring data to the system diagnosis application is located in the diagnostic unit; and the submodule has means for sending data via the network interconnection to the data transfer interface in the diagnostic unit. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to a communication method and apparatus for distributing data in a motor vehicle in a defined, standardized manner, particularly for overall vehicle diagnosis, such as system diagnosis. The method is applied within a networked system which contains, for example, control units that are networked to a diagnostic unit for system diagnosis in the motor vehicle. In a central application in a complex, networked system, communication and data interchange with subsystems is an important fundamental aspect which affects the diagnostic quality of the application functionality. A central application such as system diagnosis requires process data from individual control unit applications at the time of execution; and in the case of onboard diagnosis, these data must be provided continually, on an event-oriented basis. As used herein, onboard diagnosis is understood to mean the vehicle's product-integrated self-diagnosis, independently of a service station. The diagnostic unit is thus located in the motor vehicle. To achieve a high-quality diagnostic result, precisely defined, standard provision of the data relevant to system diagnosis is required from the control units. The type of data provision thus has a substantial effect on the result of the system diagnosis. German patent document DE 195 41 816 discloses a diagnostic system for a motor vehicle in which data formatting is performed in a communication module for all types of control units that are installed in the vehicle, and have different communication protocols. Thus, vehicle diagnosis can be performed independently of the control units' communication protocols. The system is used for diagnosis in the respective control units, with the communication module being used for communication between a control unit and the vehicle diagnosis. Because the data transmission is initiated by the vehicle diagnosis, the diagnostic system is not suitable for event-oriented vehicle diagnosis. Accordingly, it is not suitable for onboard diagnosis. German patent document DE 44 43 218 discloses a device for storing diagnosis-related data in motor vehicles, including control units that are designed to be able to communicate with one another via a bus, and are configured to recognize errors independently and send requests for setting error codes to the data bus. A bus memory module capable of communicating with the control units is configured to store diagnostic data in response to such a request, so that the data can then be read for later evaluation. However, the system does not reformat data into a data format prescribed by the diagnostic module, and it is thus not possible to perform any data evaluation which is independent of control unit hardware. In addition, the data delivered by the control units are not selected according to diagnostic relevance. The resources of the data bus are therefore not used efficiently, and the system is therefore also not suitable for onboard diagnosis. The diagnostic methods based on the prior art thus share the following restrictions: The system diagnosis uses the offboard information associated with the individual control units, which is not sufficient for a future onboard diagnosis. The different implementations of the communication and of the interfaces between control units and system diagnosis (e.g., with regard to error transmission, setting/resetting the status of errors, designing the specifications) requires an interface in each diagnostic modules, that is individually matched to the associated control unit. The transmission capacity of the transmission protocol underlying the network interconnection is utilized inefficiently as a result of the transmission of data which are unimportant to the diagnosis. Because the data transfer from the control units is initiated by the diagnostic process, so that the control units do not transfer their data until requested to do so, processing of the error setting conditions and the time reference are different. One object of the present invention is to provide a communication module, and an operating method, which avoid the drawbacks of the prior art. Another object of the invention is to provide standardized communication between local applications (such as control unit applications in control units) and a central application (particularly for system diagnosis), in order to facilitate onboard diagnosis. Hereinafter, the central application is referred to as a system diagnosis application, and the local applications are referred to as control unit applications, without restricting the general nature. The local applications can also be any desired application which is able to provide diagnostic data (e.g., external temperature). The network interconnection of the system, and the transmission protocol used for data transmission in the system, are also referred to as a transmission medium below. The local applications are processes which operate within the hardware of, for example, control units. The central application is a process which preferably operates in the hardware of a diagnostic unit. The system diagnostic data (also called process data) are transferred from the control unit application to the communication module on an event-oriented basis, when the value of the data changes. These data are managed and conditioned internally, by reformatting the data (which are available in the data format of the control unit applications' transfer interface) into a format that is prescribed by the diagnostic application, and is independent of the control unit application transfer data formats. Preferably in a defined cycle, the process data are converted into the respective transmission format and are transmitted to the system diagnosis application using a standard transmission protocol. The method can have its parameters adjusted to suit the requirements of the target hardware, using a configuration process. The internal data management, the transmission format and the transmission protocol are stipulated during this configuration phase on the basis of the magnitude of the system diagnosis-related process data. In the method according to the invention, the control unit applications provide data for acceptance by the communication module according to the invention, on an event-oriented basis. (That is, the data are provided when a predetermined event occurs.) The data transfer is thus initiated by the respective control units, which transfer the appropriate data to the communication module when it is established that such an event has occurred. The database relating to whether an event results in data transfer is held in the control unit applications. Such events may be of external or internal type. Which events result in data transfer is specified by the system development process. (External events may be, for example, the occurrence of error states, such as failure of a brake light or a particular coolant temperature reaching of a threshold value, while internal events are, for example, computation errors which occur in a control unit itself.) The data are then immediately accepted by the communication module in the data format set by the control unit application interface. The communication module manages and conditions the data, preferably in two ways: All data are reformatted from the data format of the control unit application interface into a specified data format that is known by the system diagnosis application and is independent of the local applications. (Hereinafter, such reformatting is referred to as data formatting in order to distinguish it from the coding described below.) The data are coded onto a transmission protocol which forms the basis of the data transmission on the network interconnection between the control units and the diagnostic unit (e.g., a CAN bus or MOST). In a preferred embodiment, data compression is also performed, using any known data compression method. During data formatting, the data formatted in accordance with the control unit application interfaces are preferably selected based on a relevance which is prescribed for an envisaged central application (e.g., system diagnosis relevance). Data which are not relevant to this application and are provided by the local applications are not processed further for the data formatting. The relevant data are then rewritten in accordance with the format of the central application's interface, so that they are in a bit format which is known to the system diagnosis application. The diagnosis application therefore does not have to know the interface formatting of the individual control unit applications. This information is held in the communication module. The communication module reorganizes the data provided by the control units according to the data format determined by the diagnosis application. Thus, data are available to the diagnosis application in a structure which is independent of the control unit application interfaces. This allows error-free interpretation of process data by the diagnosis application, without the need to modify the diagnosis application in the event of a change of control unit interfaces (e.g., if a faulty control unit is replaced by another control unit version or if a control unit application is updated). The data conditioned in this manner are formatted in line with the underlying data transmission protocol in order to send them via the network interconnection between control units and diagnostic unit. In one preferred embodiment of the inventive method, a local preliminary diagnosis is also performed. To this end, diagnostic data which complement the data accepted on an event-oriented basis from the local applications are also generated specifically by initiating diagnostic routines in the individual control unit applications. Management of the data in the communication module preferably comprises buffering between the receipt of data by the communication module and data transfer to the central application. Such buffering allows a transition from event-oriented data acceptance from the control unit applications by the communication module to coordination of the timing of data transfer for the conditioned data to the central application. Preferably, the data transfer from the communication module to the central application is initiated by the communication module (e.g., is controlled by the communication module). In this case, the timing of this data transfer can be determined by a timer in the communication module or by the transmission medium. The timer is preferably provided by a local application. The data transfer from the communication module to the central application is preferably performed in a fixed transfer cycle triggered (i.e., set and initiated) by a timer (i.e., a time cycle transmitter in a local application). In this case, the data are preferably transferred only in the event of a data change relative to the preceding transfer cycle. This technique minimizes the computation power requirement and efficiently uses the transmission medium that networks the control units to the diagnostic unit. In another embodiment of the invention, the data are buffer-stored in the communication module. This embodiment is used preferably when the volume of data accepted from the control unit applications exceeds the transmission capacity of the transmission protocol such that it is not possible to transfer all the data accepted from the local application between the communication module and the central application within one transmission cycle. Examples of the system diagnosis of relevant process data are: error states (e.g., no error, error, or no statement possible; input and output states (e.g., active, inactive); and internal states (e.g., switched, not switched analog values, such as measured values for state variables for vehicle components monitored by a control unit). The communication module can handle all data types in a flexible manner. The system diagnosis-related process data must be transferred to the communication module immediately after a change in the values when data are provided on an event-oriented basis. The data interchange between a central application, such as the system diagnosis in a motor vehicle, and local applications which are involved (e.g., control unit applications) is performed efficiently, in standard fashion and independently of the volume of data which are to be interchanged. This likewise applies to the management, conditioning and coding of the data which are to be sent by the individual local applications. In one particular embodiment of the invention, distributed overall vehicle diagnosis is made possible. In this case, the flow of diagnostic routines, particularly error location routines, in the control unit applications is initiated under the control of the communication module. The diagnostic data ascertained directly in the control unit as a result are then transmitted from the communication module to the central application. To this end, the communication module may include, in addition to data conditioning means in the communication module (which are set up to format the data accepted from the local applications into a data format which is determined by the diagnostic application, and is independent of the local applications and/or to select the diagnosis-related data and/or to compress the data), means for controlling the local applications. Alternatively, the control unit applications may access the data in the communication module. Parameters of the communication module can be set in optimum fashion for the respective target hardware during a configuration phase. In this context, the volume of data to be processed is used to determine the functionality of the internal data management, data conditioning and data coding. A plurality of available data coding mechanisms guarantee a high density of information within the network protocol on which the application is based (e.g., the CAN protocol). Specific embodiments of the invention allow intelligent variant handling. The communication module's configuration phase is carried out prior to use of the communication method according to the invention. Configuration of the method proceeds from known data formats for the control unit applications, and the stipulated selection of which of the control unit data are relevant to diagnosis. During this configuration phase, the following adjustments to the communication module to suit the hardware and software (that is, control units, control unit applications and physical network interconnection and also network protocol of the networked system in which the inventive method is used) are preferably made: The transmission format for transmitting data from the local applications to the central application is adjusted to suit the transmission format on which the network interconnection is based. As the selection for the transmission format, it is possible to select between the data protocol MOST or CAN, for example. The types of control units which are in the network are recorded, and used to determine the location of the diagnosis-related data within the data format used by the control unit application in the control unit, for the data selection during the use of the method. For the intelligent variant handling, the software and/or hardware version of the control unit application or of the control units is established. Based on this information, the location of the diagnosis-related data within the data format used by the control unit application is determined for the data selection during the use of the method. A further form of intelligent variant handling makes it possible to take into account different configurations for the control units within the vehicle. The diagnostic relevance of the data from a control unit application in a control unit may depend, for example, on whether the control unit is used in a vehicle with left or right-hand drive. With the system prerequisites established in this way, it is possible to establish in the actual configuration phase whether the method is applied with buffer-storage of the data. The inventive method affords the following advantages, in particular: A standard interface is provided between the local applications and a central application. The communication module is freely configurable for different local applications. Intelligent variant handling is made possible. The communication module is freely configurable for different transmission protocols (e.g., CAN, LIN, MOST). A plurality of methods are provided for internal data management and data coding. It is possible to integrate distributed diagnostic algorithms. High information density for data transmission is assured. The method works independently of the kind (type and volume) of data. Intelligent selection of data which are relevant to the diagnosis and which are provided by the control unit applications minimizes the burden on the transmission system. The flexibility of the communication module minimizes the complexity of integrating new control units into the networked system and allows the use of existing control units for onboard diagnosis. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to a communication method and apparatus for distributing data in a motor vehicle in a defined, standardized manner, particularly for overall vehicle diagnosis, such as system diagnosis. The method is applied within a networked system which contains, for example, control units that are networked to a diagnostic unit for system diagnosis in the motor vehicle. In a central application in a complex, networked system, communication and data interchange with subsystems is an important fundamental aspect which affects the diagnostic quality of the application functionality. A central application such as system diagnosis requires process data from individual control unit applications at the time of execution; and in the case of onboard diagnosis, these data must be provided continually, on an event-oriented basis. As used herein, onboard diagnosis is understood to mean the vehicle's product-integrated self-diagnosis, independently of a service station. The diagnostic unit is thus located in the motor vehicle. To achieve a high-quality diagnostic result, precisely defined, standard provision of the data relevant to system diagnosis is required from the control units. The type of data provision thus has a substantial effect on the result of the system diagnosis. German patent document DE 195 41 816 discloses a diagnostic system for a motor vehicle in which data formatting is performed in a communication module for all types of control units that are installed in the vehicle, and have different communication protocols. Thus, vehicle diagnosis can be performed independently of the control units' communication protocols. The system is used for diagnosis in the respective control units, with the communication module being used for communication between a control unit and the vehicle diagnosis. Because the data transmission is initiated by the vehicle diagnosis, the diagnostic system is not suitable for event-oriented vehicle diagnosis. Accordingly, it is not suitable for onboard diagnosis. German patent document DE 44 43 218 discloses a device for storing diagnosis-related data in motor vehicles, including control units that are designed to be able to communicate with one another via a bus, and are configured to recognize errors independently and send requests for setting error codes to the data bus. A bus memory module capable of communicating with the control units is configured to store diagnostic data in response to such a request, so that the data can then be read for later evaluation. However, the system does not reformat data into a data format prescribed by the diagnostic module, and it is thus not possible to perform any data evaluation which is independent of control unit hardware. In addition, the data delivered by the control units are not selected according to diagnostic relevance. The resources of the data bus are therefore not used efficiently, and the system is therefore also not suitable for onboard diagnosis. The diagnostic methods based on the prior art thus share the following restrictions: The system diagnosis uses the offboard information associated with the individual control units, which is not sufficient for a future onboard diagnosis. The different implementations of the communication and of the interfaces between control units and system diagnosis (e.g., with regard to error transmission, setting/resetting the status of errors, designing the specifications) requires an interface in each diagnostic modules, that is individually matched to the associated control unit. The transmission capacity of the transmission protocol underlying the network interconnection is utilized inefficiently as a result of the transmission of data which are unimportant to the diagnosis. Because the data transfer from the control units is initiated by the diagnostic process, so that the control units do not transfer their data until requested to do so, processing of the error setting conditions and the time reference are different. One object of the present invention is to provide a communication module, and an operating method, which avoid the drawbacks of the prior art. Another object of the invention is to provide standardized communication between local applications (such as control unit applications in control units) and a central application (particularly for system diagnosis), in order to facilitate onboard diagnosis. Hereinafter, the central application is referred to as a system diagnosis application, and the local applications are referred to as control unit applications, without restricting the general nature. The local applications can also be any desired application which is able to provide diagnostic data (e.g., external temperature). The network interconnection of the system, and the transmission protocol used for data transmission in the system, are also referred to as a transmission medium below. The local applications are processes which operate within the hardware of, for example, control units. The central application is a process which preferably operates in the hardware of a diagnostic unit. The system diagnostic data (also called process data) are transferred from the control unit application to the communication module on an event-oriented basis, when the value of the data changes. These data are managed and conditioned internally, by reformatting the data (which are available in the data format of the control unit applications' transfer interface) into a format that is prescribed by the diagnostic application, and is independent of the control unit application transfer data formats. Preferably in a defined cycle, the process data are converted into the respective transmission format and are transmitted to the system diagnosis application using a standard transmission protocol. The method can have its parameters adjusted to suit the requirements of the target hardware, using a configuration process. The internal data management, the transmission format and the transmission protocol are stipulated during this configuration phase on the basis of the magnitude of the system diagnosis-related process data. In the method according to the invention, the control unit applications provide data for acceptance by the communication module according to the invention, on an event-oriented basis. (That is, the data are provided when a predetermined event occurs.) The data transfer is thus initiated by the respective control units, which transfer the appropriate data to the communication module when it is established that such an event has occurred. The database relating to whether an event results in data transfer is held in the control unit applications. Such events may be of external or internal type. Which events result in data transfer is specified by the system development process. (External events may be, for example, the occurrence of error states, such as failure of a brake light or a particular coolant temperature reaching of a threshold value, while internal events are, for example, computation errors which occur in a control unit itself.) The data are then immediately accepted by the communication module in the data format set by the control unit application interface. The communication module manages and conditions the data, preferably in two ways: All data are reformatted from the data format of the control unit application interface into a specified data format that is known by the system diagnosis application and is independent of the local applications. (Hereinafter, such reformatting is referred to as data formatting in order to distinguish it from the coding described below.) The data are coded onto a transmission protocol which forms the basis of the data transmission on the network interconnection between the control units and the diagnostic unit (e.g., a CAN bus or MOST). In a preferred embodiment, data compression is also performed, using any known data compression method. During data formatting, the data formatted in accordance with the control unit application interfaces are preferably selected based on a relevance which is prescribed for an envisaged central application (e.g., system diagnosis relevance). Data which are not relevant to this application and are provided by the local applications are not processed further for the data formatting. The relevant data are then rewritten in accordance with the format of the central application's interface, so that they are in a bit format which is known to the system diagnosis application. The diagnosis application therefore does not have to know the interface formatting of the individual control unit applications. This information is held in the communication module. The communication module reorganizes the data provided by the control units according to the data format determined by the diagnosis application. Thus, data are available to the diagnosis application in a structure which is independent of the control unit application interfaces. This allows error-free interpretation of process data by the diagnosis application, without the need to modify the diagnosis application in the event of a change of control unit interfaces (e.g., if a faulty control unit is replaced by another control unit version or if a control unit application is updated). The data conditioned in this manner are formatted in line with the underlying data transmission protocol in order to send them via the network interconnection between control units and diagnostic unit. In one preferred embodiment of the inventive method, a local preliminary diagnosis is also performed. To this end, diagnostic data which complement the data accepted on an event-oriented basis from the local applications are also generated specifically by initiating diagnostic routines in the individual control unit applications. Management of the data in the communication module preferably comprises buffering between the receipt of data by the communication module and data transfer to the central application. Such buffering allows a transition from event-oriented data acceptance from the control unit applications by the communication module to coordination of the timing of data transfer for the conditioned data to the central application. Preferably, the data transfer from the communication module to the central application is initiated by the communication module (e.g., is controlled by the communication module). In this case, the timing of this data transfer can be determined by a timer in the communication module or by the transmission medium. The timer is preferably provided by a local application. The data transfer from the communication module to the central application is preferably performed in a fixed transfer cycle triggered (i.e., set and initiated) by a timer (i.e., a time cycle transmitter in a local application). In this case, the data are preferably transferred only in the event of a data change relative to the preceding transfer cycle. This technique minimizes the computation power requirement and efficiently uses the transmission medium that networks the control units to the diagnostic unit. In another embodiment of the invention, the data are buffer-stored in the communication module. This embodiment is used preferably when the volume of data accepted from the control unit applications exceeds the transmission capacity of the transmission protocol such that it is not possible to transfer all the data accepted from the local application between the communication module and the central application within one transmission cycle. Examples of the system diagnosis of relevant process data are: error states (e.g., no error, error, or no statement possible; input and output states (e.g., active, inactive); and internal states (e.g., switched, not switched analog values, such as measured values for state variables for vehicle components monitored by a control unit). The communication module can handle all data types in a flexible manner. The system diagnosis-related process data must be transferred to the communication module immediately after a change in the values when data are provided on an event-oriented basis. The data interchange between a central application, such as the system diagnosis in a motor vehicle, and local applications which are involved (e.g., control unit applications) is performed efficiently, in standard fashion and independently of the volume of data which are to be interchanged. This likewise applies to the management, conditioning and coding of the data which are to be sent by the individual local applications. In one particular embodiment of the invention, distributed overall vehicle diagnosis is made possible. In this case, the flow of diagnostic routines, particularly error location routines, in the control unit applications is initiated under the control of the communication module. The diagnostic data ascertained directly in the control unit as a result are then transmitted from the communication module to the central application. To this end, the communication module may include, in addition to data conditioning means in the communication module (which are set up to format the data accepted from the local applications into a data format which is determined by the diagnostic application, and is independent of the local applications and/or to select the diagnosis-related data and/or to compress the data), means for controlling the local applications. Alternatively, the control unit applications may access the data in the communication module. Parameters of the communication module can be set in optimum fashion for the respective target hardware during a configuration phase. In this context, the volume of data to be processed is used to determine the functionality of the internal data management, data conditioning and data coding. A plurality of available data coding mechanisms guarantee a high density of information within the network protocol on which the application is based (e.g., the CAN protocol). Specific embodiments of the invention allow intelligent variant handling. The communication module's configuration phase is carried out prior to use of the communication method according to the invention. Configuration of the method proceeds from known data formats for the control unit applications, and the stipulated selection of which of the control unit data are relevant to diagnosis. During this configuration phase, the following adjustments to the communication module to suit the hardware and software (that is, control units, control unit applications and physical network interconnection and also network protocol of the networked system in which the inventive method is used) are preferably made: The transmission format for transmitting data from the local applications to the central application is adjusted to suit the transmission format on which the network interconnection is based. As the selection for the transmission format, it is possible to select between the data protocol MOST or CAN, for example. The types of control units which are in the network are recorded, and used to determine the location of the diagnosis-related data within the data format used by the control unit application in the control unit, for the data selection during the use of the method. For the intelligent variant handling, the software and/or hardware version of the control unit application or of the control units is established. Based on this information, the location of the diagnosis-related data within the data format used by the control unit application is determined for the data selection during the use of the method. A further form of intelligent variant handling makes it possible to take into account different configurations for the control units within the vehicle. The diagnostic relevance of the data from a control unit application in a control unit may depend, for example, on whether the control unit is used in a vehicle with left or right-hand drive. With the system prerequisites established in this way, it is possible to establish in the actual configuration phase whether the method is applied with buffer-storage of the data. The inventive method affords the following advantages, in particular: A standard interface is provided between the local applications and a central application. The communication module is freely configurable for different local applications. Intelligent variant handling is made possible. The communication module is freely configurable for different transmission protocols (e.g., CAN, LIN, MOST). A plurality of methods are provided for internal data management and data coding. It is possible to integrate distributed diagnostic algorithms. High information density for data transmission is assured. The method works independently of the kind (type and volume) of data. Intelligent selection of data which are relevant to the diagnosis and which are provided by the control unit applications minimizes the burden on the transmission system. The flexibility of the communication module minimizes the complexity of integrating new control units into the networked system and allows the use of existing control units for onboard diagnosis. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings. |
Agonists and antagonists of 5h3-like receptors of invertebrates as pesticides |
The present invention provides compositions and methods for controlling an helminth or arthropod pest. In a preferred embodiment of the invention provided herein, the compositions comprise compounds which alter the 5-HT3 receptor of the pest. Also claimed are various esters of N-methyl 8-azabicyclo[3.2.1]octan-3-ol (tropan-3-yl esters) and an assay for identifying and/or assessing a helminth and/or arthropod control compound by determining the ability of a candidate compound to modulate the activity of a helminth or arthropod 5-HT3 receptor. |
1-48. (canceled) 49. A method for controlling a pest selected from helminths and arthropods, said method comprising exposing said pest to an effective amount of a compound comprising one of the following formulae: in which, X is selected from substituted and unsubstituted cyclic rings, Y is absent or otherwise selected from substituted of unsubstituted alkyl, substituted or unsubstituted alkyloxy, optionally interrupted by one or more heteroatoms, Z is selected from substituted or unsubstituted alkyl, O, N, NH, S and SH, and A is selected from nitrogen-containing substituents; in which, X, Y and A are as defined above, and D is selected from C, CH, CH2, O and N; and in which, A and O are as defined above, R is H or alkyl; with the proviso that said compound is not ondansetron or tropanyl dichlorobenzoate. 50. The method of claim 49, wherein X of formula (I) or (II) is a mono- or bi-cyclic ring. 51. The method of claim 49, wherein X of formula (I) or (II) comprises at least one substituted or unsubstituted aromatic and/or heterocyclic rings which may be fused or non-fused. 52. The method of claim 49, wherein X of formula (I) or (II) is selected from mono-, di- and tri-substituted phenyl. 53. The method of claim 49, wherein Y is absent and X is bonded directly to the carbon of the C═O group. 54. The method of claim 49, wherein Y is a substituted or unsubstituted lower alkyl. 55. The method of claim 49, wherein Y is a substituted or unsubstituted lower alkyloxy. 56. The method of claim 49, wherein Y is a heteroatom selected from the group consisting of: O, N, NH, Sand SH. 57. The method of claim 49, wherein Z of formula (I), Z is O or NH. 58. The method of claim 49, wherein Z of formula (I) is a substituted or unsubstituted lower alkyl. 59. The method of claim 49, wherein A comprises nitrogen-containing substituents with a basic characteristic. 60. The method of claim 49, wherein A comprises an alkylamine. 61. The method of claim 49, where A of formula (III) is a heterocyclic or heterocyclicalkyl. 62. The method of claim 49, wherein O of formula (II) is CH or N. 63. The method of claim 49, wherein R of formula (III) is lower alkyl. 64. The method of claim 49, wherein the compound comprises the following formulae: 65. The method of claim 64, wherein X of formula (IV) is selected from substituted and unsubstituted phenyl, phenoxyalkyl, phenyl alkyl, cubanyl carboxylate, cycloalkyl, cycloalkyl carboxylate, benzylcarboxylate, pyridine carboxylate, indolyl. 66. The method of claim 64, wherein X of formula (IV) is selected from substituted and unsubstituted phenyl, benzylcarboxylate, and indolyl. 67. The method of claim 64, wherein the compound is selected from the group consisting of 3-chloro-benzoic acid tropan-3-yl ester, 3,4-dichloro-benzoic acid tropan-3-yl, 2-fluoro-benzoic acid tropan-3-yl ester, phthalic acid methyl ester tropan-3-yl ester, and 1H-indole-3carboxylic acid tropan-3-yl. 68. A composition for controlling a pest selected from helminths and arthropods, said composition comprising a compound according to claim 49 in combination with a pharmaceutically/veterinary/agriculturally acceptable carrier and/or excipient. 69. A compound of the formulae: in which, X is selected from substituted and unsubstituted cyclic rings, Y is absent or selected from lower alkyl, lower alkyloxy, O, N, NH, S and SH, Z is O, and A is tropanyl, with the proviso that compound is not tropanyl dichlorobenzoate. 70. The compound of claim 69, wherein Y is absent. 71. The compound of claim 69, wherein the compound comprises the following formulae: 72. The compound of claim 71, wherein X of formula (IV) is selected from substituted and unsubstituted phenyl, phenoxyalkyl, phenyl alkyl, cubanyl carboxylate, cycloalkyl, cycloalkyl carboxylate, benzylcarboxylate, pyridine carboxylate, indolyl. 73. The compound of claim 71, wherein X of formula (IV) is selected from substituted and unsubstituted phenyl, benzylcarboxylate, and indolyl. 74. The compound of claim 71, selected from the group consisting of 3chloro-benzoic acid tropan-3-yl ester, 3,4-dichloro-benzoic acid tropan-3-yl ester, 2-fluoro-benzoic acid tropan-3-yl ester, phthalic acid methyl ester tropan-3-yl ester, and 1H-indole-3-carboxylic acid tropan-3-yl. 75. A composition for controlling a pest selected from helminths and arthropods, said composition comprising a compound according to claim 69 in combination with a pharmaceutically/veterinary/agriculturally-acceptable carrier and/or excipient. 76. An assay for identifying and/or assessing an helminth and/or arthropod control compound, the method comprising determining the ability of a candidate compound to modulate the activity of a 5-HT3 receptor of the helminth or arthropod, wherein the candidate compound is a compound as defined in claim 49 or claim 69. 77. The assay of claim 76, wherein the modulation of 5-HT3 activity is determined by measuring changes in cell membrane potential or Ca2+ levels. 78. The assay of claim 76, wherein the 5-HT3 receptor(s) is contacted simultaneously with a serotonergic ligand and the candidate compound, and the modulation of 5-HT3 activity is determined by measuring the amount of bound and/or unbound labelled serotonergic ligand. 79. An helminth and/or arthropod control compound identified by an assay according to claim 76. |
<SOH> BACKGROUND TO THE INVENTION <EOH>Many species of nematodes are parasites of considerable medical, veterinary and agricultural significance. For example, nematodes of the Orders Strongylida, Strongyloides , Ascaradida, Oxyurida and Trichocephalida include many species that cause disease in humans, sheep, cattle, pigs and other species. Further, nematodes of the Orders Tylenchida and Aphelenchida, and others, include species which are parasitic of important crop plants and fungi. It has been conservatively estimated that plant parasitic nematodes cause US $77 billion worth of damage to major food crops annually (Evans and Haydock, 1999). There are, unfortunately, very few control options for plant parasitic nematodes. Fumigants such as methyl bromide are generally being withdrawn from sale and use, because of their detrimental effects on the ozone layer, whilst the remaining available agents are among the most toxic and undesirable pesticides in current use. Animal parasitic nematodes infect humans, companion animals and livestock and cause serious morbidity and economic loss worldwide. This group of parasites includes hookworms and roundworms. They can cause anaemia, loss of weight, hyperimmune reactions and other complications, including death of livestock. There are currently a small number of human and veterinary drugs available for their treatment but, particularly in the veterinary field, the efficacy of a number of existing drugs is reducing because of resistance development. For the reasons described, there is an ongoing need for the identification of new nematicidal compounds. Pharyngeal pumping is the basis of nematode feeding and the ability of nematodes to maintain their “hydrostatic skeleton” (Brownlee et al., 1997). The pharyngeal pump of nematodes is already a well-established target organ for anthelmintics and nematicidal agents. In particular, inhibition of pharyngeal pumping is a major mode of action of ivermectin, an extremely successful modern nematicide and insecticide. Ivermectin acts on inhibitory glutamate receptors present in the pharynx and other tissues of nematodes and insect (Brownlee et al. 1997). Novel compounds that inhibit pumping of the nematode pharynx would have significant potential benefit for the control of plant and animal parasitic nematodes, and other helminth, arthropod and other invertebrate pests. They would also serve as lead molecules to facilitate the discovery process for other nematicidal compounds and insecticidal compounds. The macrocyclic lactone nematicides (avermectins) exemplify the potential utility of nematicides in controlling other invertebrate pests and parasites. Avermectins were originally registered as anthelminthics but these and related compounds are now being used increasingly as insecticides. The damage caused by arthropod pests is better known and characterised than that caused by nematodes. For example, the worldwide market for chemical insecticides is about US $12 billion, mostly in crop protection, but also in animal and public health. The market is growing at about 5% p.a. These costs of control are only a fraction of the economic costs of losses to crops and livestock worldwide. In particular, sucking plant pests such as aphids and plant-hoppers are second only to caterpillars in their economic importance and their value as a market for insecticides. They are particularly important in Europe and Asia. Whilst there are some existing insecticides active against these pests, a number of them are highly toxic and development of resistance is also causing problems. Thus, there is a great need for new classes of insecticides active on these pests. Also, insects with piercing and sucking mouthparts are the main vectors of diseases to humans and livestock. These vectors include mosquitoes (e.g. malaria, Japanese encephalitis, dengue fever etc.), higher flies (e.g. onchocerciasis) and true bugs (e.g. trypanosomiosis). Existing control measures are increasingly reliant on pesticides (e.g. permethrin-treated mosquito nets), because of the absence or failure of drug treatments. Therefore, there is also a need for new classes of insecticides active against these pests. Serotonin (5-Hydroxytryptamine, 5-HT) has a number of profound effects on the behaviour of Caenorhabditis elegans and other nematodes. In C. elegans , exogenously applied 5-HT results in reduced locomotion, increased pharyngeal pumping, increased egg-laying and decreased defaecation. It is also involved in male mating behaviour. These effects of exogenous 5-HT are believed to occur because 5-HT is a natural nematode neurotransmitter that serves these behaviours. For example, two serotonergic neurones (NSM) are located over the pharynx whilst the HSNL and HSNR serotonergic neurones connect with the vulva. It is quite likely, based on the known biology of 5-HT in vertebrates, that each of these behaviours is controlled by serotonin action on different receptors present in different cells. Vertebrate serotonin receptors are known to fall into two distinct multigene superfamilies. One of these, the rhodopsin/β-adrenergic receptor superfamily, includes 7-transmembrane G-protein-linked receptors of the 5-HT 1 , 5-HT 2 , 5-HT 4 , 5-HT 5 , 5-HT 6 , and 5-HT 7 classes. Receptors of the other, 5-HT 3 , class belong to the nicotinic-acetylcholine receptor (nAChR), GABA-, glycine- and glutamate-gated ion channel superfamily and are pentameric, 4-membrane-spanning ligand-gated ion channels. It is generally observed that physiologically expressed pentameric receptors of this family comprise two or more types of subunits, with each type being the product of a distinct gene. While functioning ion channels may be obtained experimentally with a pentamer composed of identical subunits, these do not behave identically with respect to their channel conductance properties, to the heteropentameric ion channel that is present in vivo. In the case of the mammalian 5-HT 3 gated ion-channel, faithful electrophysiology has only been obtained with a heteromeric ion channel containing both 5-HT 3A and 5-HT 3B subunits (Davies et al., 1999). The mammalian 5-HT 3 receptors are known to form channels that gate the passage of cations across the cell membrane and when activated they tend to excite the cell. In this respect, as in many others, their closest relatives are the nicotinic acetylcholine receptors. GABA A -gated, glycine-gated, and the invertebrate-specific glutamate-gated ion channels all gate the passage of anions and their activation generally hyperpolarises the cell membrane. WO 01/6100 (the entire disclosure of which is to be regarded as incorporated herein by reference) is the first disclosure of the cloning of a cationic 5-HT 3 receptor subunit from an invertebrate species. In addition, WO 01/6100 shows that two 5-HT 3 antagonists (tropanyl dichlorobenzoate and ondansetron) profoundly inhibited pharyngeal pumping while the 5-HT 3 specific agonist 2-methyl-5-hydroxytryptamine hydrochloride strongly and specifically stimulated pharyngeal pumping. Moreover, tropanyl dichlorobenzoate caused dose-dependent mortality and other detrimental effects in C. elegans , and tropanyl dichlorobenzoate and ondansetron caused significant detrimental effects, including some mortality, in insects. There is a need for further compounds, compositions and methods for controlling helminth and arthropod populations. |
<SOH> BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES <EOH>FIG. 1 : Structural formulae of compounds used or mentioned in Example 1. FIG. 2 : Log dose responses for bead ingestion by nematodes. Compounds identified as strongly reversing the stimulatory effects of 0.325 mM serotonin on bead ingestion (see Table 3) were tested over a range of doses. The results were plotted as percentage of the fluorescence due to bead ingestion in the presence of 1 mM serotonin alone. Data were fitted to the equation y=a/(1+Exp(b−c*x)) by iterative least squares regresssion in DeltaGraph version 4.05 and 4.5 for the Macintosh (SPSS Australasia Pty Ltd). detailed-description description="Detailed Description" end="lead"? |
Recombinant anti-plasmodium falciparum antibodies |
The present invention relates to a recombinant human antibody comprising an antibodysequence specific for the MSP-3 antigen of Plasmodium falciparum. In particular, the invention relates to a recombinant human antibody which is specific for the MSP-3194-257 antigen. The invention further relates to nucleic acid encoding such antibodies and to uses of these antibodies, in particular in the treatment or prophylaxis of malaria. |
1. A recombinant human antibody comprising an antibody sequence specific for the MSP-3 antigen of Plasmodium falciparum. 2. A recombinant human antibody according to claim 1 which is specific for the MSP-3194-257 antigen. 3. A recombinant human antibody according to claim 2 which is specific for an epitope having the amino acid sequence ILGWEFGGGVP which corresponds to residues 220-230 of the MSP-3 antigen. 4. A recombinant human antibody according to any one of the preceding claims which comprises a CDR sequence selected from: CDR1 of RAM1 VH; CDR2 of RAM1 VH; CDR3 of RAM1 VH; CDR1 of RAM1 VK; CDR2 of RAM1 VK; CDR3 of RAM1 VK; CDR1 of RAM2 VH; CDR2 of RAM2 VH; CDR3 of RAM2 VH; CDR1 of RAM2 VK; CDR2 of RAM2 VK; CDR3 of RAM2 VK; CDR1 of RAM3 VH; CDR2 of RAM3 VH; CDR3 of RAM3 VH; CDR1 of RAM3 VK; CDR2 of RAM3 VK; or CDR3 of RAM3 VK having the amino acid sequences shown underlined in FIG. 6. 5. A recombinant human antibody according to claim 4 comprising a CDR selected from: CDR3 of RAM1 VH; CDR3 of RAM2 VH; or CDR3 of RAM3 VH having the sequence as shown in FIG. 6. 6. A recombinant human antibody according to claim 4 or claim 5 comprising two or more CDRs selected from: CDR1 of RAM1 VH; CDR2 of RAM1 VH; CDR3 of RAM1 VH; CDR1 of RAM1 VK; CDR2 of RAM1 VK; CDR3 of RAM1 VK; CDR1 of RAM2 VH; CDR2 of RAM2 VH; CDR3 of RAM2 VH; CDR1 of RAM2 VK; CDR2 of RAM2 VK; CDR3 of RAM2 VK; CDR1 of RAM3 VH; CDR2 of RAM3 VH; CDR3 of RAM3 VH; CDR1 of RAM3 VK; CDR2 of RAM3 VK; or CDR3 of RAM3 VK having the sequence shown in FIG. 6. 7. A recombinant human antibody according to claim 6 wherein the two or more CDRs are from the same RAM clone. 8. A recombinant human antibody according to claim 7 wherein CDR1, CDR2, CDR3 of the light chain and CDR1, CDR2 and CDR3 of the heavy chain are all from the same RAM clone. 9. A recombinant human antibody according to claim 8 wherein the CDRs are all from RAM1. 10. A recombinant human antibody according to claim 8 wherein the CDRs are all from RAM2. 11. A recombinant human antibody according to claim 8 wherein the CDRs are all from RAM3. 12. A recombinant human antibody according to claim 6 comprising the VH domain of RAM1 having the amino acid sequence shown as RAM1 VH in FIG. 6 (the entire top line of the first box in FIG. 6). 13. A recombinant human antibody according to claim 6 comprising the VH domain of RAM2 having the amino acid sequence shown as RAM2 VH in FIG. 6 (the entire top line of the second box in FIG. 6). 14. A recombinant human antibody according to claim 6 comprising the VH domain of RAM3 having the amino acid sequence shown as RAM3 VH in FIG. 6 (the entire top line of the third box in FIG. 6). 15. A recombinant human antibody according to claim 6 comprising the VL domain of RAM1 having the amino acid sequence shown as RAM1 VK in FIG. 6 (the entire bottom line of the first box in FIG. 6). 16. A recombinant human antibody according to claim 6 comprising the VL domain of RAM2 having the amino acid sequence shown as RAM2 VK in FIG. 6 (the entire bottom line of the second box in FIG. 6). 17. A recombinant human antibody according to claim 6 comprising the VL domain of RAM3 having the amino acid sequence shown as RAM3 VK in FIG. 6 (the entire bottom line of the third box in FIG. 6). 18. A recombinant human antibody according to claim 12 further comprising the VL domain of RAM1 having the amino acid sequence shown as RAM1 VK in FIG. 6 (the entire bottom line of the first box in FIG. 6). 19. A recombinant human antibody according to claim 13 further comprising the VL domain of RAM2 having the amino acid sequence shown as RAM2 VK in FIG. 6 (the entire bottom line of the second box in FIG. 6). 20. A recombinant human antibody according to claim 14 further comprising the VL domain of RAM3 having the amino acid sequence shown as RAM3 VK in FIG. 6 (the entire bottom line of the third box in FIG. 6). 21. A recombinant human antibody according to any one of the preceding claims which comprises a constant region selected from: gamma 1; gamma 2; gamma 3; gamma 4; my; alfa 1; alfa 2; delta; or epsilon isotypes. 22. A recombinant human antibody according to claim 21 wherein the constant region is selected from: the gamma 1; gamma 2; gamma 3; or gamma 4 isotypes, to form an IgG molecule. 23. A recombinant human antibody according to claim 22 wherein the constant region is selected from: the gamma 1 or the gamma 3 isotypes, to form an IgG1 or IgG3 isotype. 24. A recombinant human antibody according to claim 23 having the allotype G1m(a,z), G1m(f), G3m(b), G3m(c3c5), G3m(c3) or G3m(s). 25. A recombinant human antibody according to claim 24 having the allotype G1m(a,z) or G3m(b). 26. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a recombinant human antibody according to any one of the preceding claims. 27. A nucleic acid molecule according to claim 26 in the form of a recombinant vector. 28. A host cell comprising a nucleic acid according to claim 27. 29. A method of expressing in a host cell an antibody according to any one of the preceding claims from a nucleic acid molecule according to claim 27. 30. A method of producing an antibody comprising culturing a host cell according to claim 28 under appropriate conditions. 31. A method according to claim 30, wherein the host cell is a plant cell. 32. A method according to claim 30 or claim 31 further comprising isolating said antibody from the cell culture. 33. A method according to claim 32 further comprising admixing the isolated antibody with a suitable further component, such as another antibody or an excipient or carrier. 34. A recombinant human antibody according to any one of claims 1 to 25 for use in the treatment of a malarial disease. 35. The use of a recombinant human antibody according to any one of claims 1 to 25 in the manufacture of a medicament for the treatment of malaria. 36. A recombinant human antibody according to claim 34 or use according to claim 33 wherein the dose is 10 μg to 10 mg antibody per kg body weight. 37. A recombinant human antibody or use according to claim 36 wherein the dose is 1.5 mg to 3.5 mg antibody per kg body weight. 38. A recombinant human antibody or use according to claim 37 wherein the dose is 2 mg antibody per kg body weight. 39. A recombinant human antibody according to any one of claims 1 to 25 for use in the prophylaxis of a malarial disease. 40. The use of a recombinant human antibody according to any one of claims 1 to 25 in the manufacture of a medicament for the prophylaxis of a malarial disease. 41. A recombinant human antibody according to claim 39 or use according to claim 40 wherein the dose is 0.1 mg to to 3 mg antibody per kg body weight. 42. A recombinant human antibody or use according to claim 41 wherein the dose is 0.2 mg to 2 mg antibody per kg body weight. 43. A recombinant human antibody or use according to claim 42 wherein the dose is 0.5 mg to 1.5 mg antibody per kg body weight. 44. A recombinant human antibody according to claim 43 wherein the dose is 0.75 mg to 1 mg antibody per kg body weight. 45. A recombinant human antibody or use according to claim 44 wherein the dose is most preferably 1 mg antibody per kg body weight. 46. A nucleic acid molecule according to claim 26 or 27 for use in the treatment or prophylaxis of a malarial disease. 47. Use of a nucleic acid molecule according to claim 26 or 27 in the treatment or prophylaxis of a malarial disease. 48. A method comprising causing or allowing binding of an antibody according to any one of claims 1 to 25 to a target antigen. 49. A method of diagnosis of malaria comprising taking a sample of bodily fluid from an individual, contacting the sample with an antibody according to any one of claims 1 to 25 and determining the binding of that antibody to the sample, thereby determining the presence or absence of a target antigen in the sample. 50. A purified recombinant human antibody reacting specifically with the C-terminus region of the Merozoite Surface Protein-3 anti-gen of P. falciparum able to mediate the monocyte-mediated, anti-body-dependent ADCI effect resulting in P. falciparum killing under in vitro conditions. 51. A recombinant human antibody according to claim 50 reacting specifically with the C-terminus region of the Merozoite Surface Protein-3 antigen of P. falciparum able to induce a fast and anti-gen specific decrease, for example a five fold decrease, in P. falciparum parasitemia into human RBCs grafted into immunocompromised BXN mice. 52. A recombinant human antibody reacting specifically with the C-terminus region of the Merozoite Surface Protein-3 antigen of P. falciparum able to fully clear the P. falciparum parasitemia in the P. falciparum/immunocompromised BXN mice. 53. A recombinant human antibody reacting specifically with the C-terminus region of the Merozoite Surface Protein-3 antigen of P. falciparum able to exert a profound biological effect upon Plasmodium falciparum under both in vitro and in vivo conditions. 54. A recombinant human antibody reacting specifically with the C-terminus region of the Merozoite Surface Protein-3 antigen of P. falciparum able to exert the same degree of P. falciparum parasite killing as that obtained with polyclonal antibodies of human origin, affinity-purified on either an MSP-3.b synthetic peptide or a C-terminus recombinant MSP-3 protein. 55. A composition containing at least the human recombinant antibody or a fragment thereof according to claim 50 to 54. 56. A process of treatment of a malaria infection characterizd by the step of administration to an infected patient of a purified antibody accordint to claim 50 to 54 or a composition according to claim 55. 57. A method for screening a phage display library comprising the following steps: (i) attaching a target molecule, such as an antigen, to a bead using a suitable linker; (ii) admixing a first amount of such beads with attached target molecule with a first population of phage from a phage display library, which library expresses sequences, such as antibody sequences, which may bind to the target molecule; (iii) selecting from the first population of phage a second population of phage, wherein the second population of phage is enriched in phage which bind to the target molecule; (iv) admixing said second population of phage with a second amount of beads, wherein said second amount of beads is smaller than said first amount; (v) selecting from said second population of phage a third population of phage, wherein said third population of phage enriched in phage which bind to the target molecule. 58. A method according to claim 57 wherein steps (iv) and (v) are repeated to produce a fourth population of phage. 59. A method according to claim 57 or claim 58 wherein the target molecule is an antigen and the phage display library contains antibody sequences. 60. A method according to any one of claims 57 to 59 further comprising the step of producing a complete antibody. 61. An antibody produced or producible by the method of claim 60. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS AND TABLE I <EOH>FIG. 1 shows ELISA reactivity with various truncated versions of MSP-3. Fab-ΔpIII fragments produced from the three distinct clones were analysed in ELISA. Truncated recombinantly produced, MSP-3 22-257 (black bars) , MSP-3 194-257 (grey bars) were used as coating antigens in separate analyses. An ELISA for detection of Fab fragments (Anti-Fab) was included to ensure use of comparable amounts of the various Fab fragments (white bars). Background was measured as reactivity with the control Fab against HibCP and as reactivity with buffer. Reactivities are indicated as OD 405 -OD 490 . Bars indicated median values and error-bars indicated 2 times standard deviation of triplicates. FIG. 2 shows results of the antigen competition experiments. Fab-ΔpIII from the three distinct clones were competed with soluble panning antigen in ELISA. All three clones were susceptible to competition with soluble MSP-3 194-257 . A constant amount of Fab-ΔpIII produced from each of the three distinct clones was mixed with varying amounts of competition antigen, MSP-3 194-257 , and applied to ELISA wells coated with the same antigen. Percent reactivity in the ELISA was calculated taking the reactivity with no antigen added as 100%. FIG. 3 shows a schematic representation of the entire MSP-3 antigen (top, MSP-3 1-380 ) and the relationship of the truncated antigens (MSP-3 22-257 , MSP-3 194-257 , MSP-3 190-217 and MSP-3 211-237 used). The numbering above has been assigned according to the P. falciparum clone D10, sequenced by McColl et al. 1994 (Genbank accession number L07944). As this numbering may be different when aligned with other clones, the MSP-3 194-257 (Oeuvray et al. 1994, accession number AF024624) amino acid sequence has been written in the figure. The intact antigen comprises 12 heptad repeats, equally distributed into the three heptad repeat regions (HELIX 1, HELIX 2, HELIX 3). Analyses of the sequence of the regions suggest that they have an amphipatic α-helical secondary structure and in the presence of all three regions can obtain the structure of a coiled-coil three-stranded helical bundle (McColl et al. 1994; Mulhern et al. 1995). The helix regions and signal peptide (SIGNAL) are indicated as boxes at the top of the drawing. The dimorphic areas described by Huber et al. (1997) are indicated with gray shading. The MSP-3 190-217 peptide represents the Helix 3 sequence of the K1 clone (McColl et al. 1997, accession number U08851). The motif represented by amino acid residues 220-230, ILGWEFGGGVP, is indicated by oval figures. This motif is present in MSP-3 as well as in the other Plasmodium falciparum antigen MSP-6 (Trucco et al. 2001). FIG. 4 shows the results of the flow cytometry analyses of the reactivity of recombinant antibodies with schizonts. Panel A1 illustrates forward scatter and side scatter for ethanol-fixed and permeabilized infected red blood cells, and panel A2 illustrates the same parameters for similarly treated non-infected red blood cells. The gating was placed to include the majority of the infected cells. The gating was used for the histograms described below. Panel B1 to 4 illustrates histograms of various recombinant anti-malaria antibodies compared with the control antibody directed against HibCP antigen (grey shaded curve). The control histogram has 2% of the events under the bar designated M1 in panel B1. B1 shows RAM1 in the Fab-ΔpIII format. The bar covers 76% of the events registered. B2 shows RAM2 in the Fab-ΔpIII format. The bar covers 28% of the events registered. B3 shows RAM3 in the Fab-ΔpIII format. The bar covers 4% of the events registered. B4 shows RAMl in the IgG1 format. The bar covers 47% of the events registered. The control in the IgG1 format has 4% of the events under the bar. Schizonts were purified from asynchronous P. falciparum culture. Fixation and permeabilization was carried out with ethanol. Primary reaction with recombinant antibody was carried out over night and the FITC-labeled secondary antibody was incubated with the cells for 30 minutes. FIG. 5 shows a schematic representation of the panning procedure. Three parallel series (A to C) of panning were carried out for 4 rounds designated 1 to 4. The number of antigen-coated beads used in each round was reduced by a constant reduction factor through the study. The number of beads used for each stage is indicated in the figure. FIG. 6 shows the deduced amino acid sequences of the three clones. The entire VH and VK sequences of each clone, RAM1, RAM2 and RAM3 are shown and boxed. Amino acid residues in the CDR regions are underlined. We have chosen to show the Kabat CDR definitions (Kabat et al. 1991). FIG. 7 shows the immunoblotting of P. falciparum clone 3D7 schizont and merozoite proteins reacted with RAM1, RAM2 and RAM3 produced as IgG1. All three lanes show a blotting of proteins from purified schizonts separated under reducing conditions on a 4-12% gradient gel. RAM1 IgG1 was reacted with the blotting in lane 1, RAM2 IgG1 was reacted with the blotting in lane 2 and RAM3 IgG1 was reacted with the blotting in lane 3. RAM1 reacts with two proteins of molecular weights 51 and 53 kD, respectively. RAM2 reacts with two proteins of approximately relative molecular weights of 64 kD and 14 kD, respectively. RAM3 reacts with a protein of approximately relative molecular weight of 64 kD identical to the protein recognized by RAM2. FIG. 8 shows Immunofluorescence microscopy. Panels represent immunofluorescence microscopy of fixed culture of P. falciparum clone 3D7 incubated with FITC-conjugated RAM1IgG1, or RAM2 IgG1 or RAM3 IgG1 followed by a FITC conjugated secondary anti-human Fab. Dots in the A (left) panels indicate red cells carrying antigen reactive with RAM1, RAM2 or RAM3. The B (right) panels represents the same slides stained for DNA with propidium iodide. Large dots in B panels indicate red cells infected with late stage schizonts. By comparing the location of the dots in the A and B panels it is observed that the larger dots in B panels are duplicated in the left panels. Small dots in the B panels are not duplicated in A panels. This demonstrates that late-stage schizonts harbouring merozoites do display the antigen reactive with RAM1, RAM2 or RAM3 whereas early stages do not. Asynchronous in vitro P. falciparum culture was air-dryed on a slide, fixed with acetone and reacted with FITC-conjugated RAM1 IgG1, or reacted with RAM2 IgG1 or RAM3 IgG1 followed by FITC-conjugated anti-human Fab. No reactivity was detectable with glutaraldehyde fixation. FIG. 9 shows the ELISA reactivity of RAM1 IgG1, RAM2 IgG1 and RAM3 IgG1 with the synthetic peptides MSP-3 190-217 and MSP-3 211-237 . Also the larger recombinant MSP-3 194-257 has been included. Error bars represent 2 times standard deviation of duplicates. FIG. 10 shows the results from the PEPSCAN screening. The entire sequence MSP-3 194-257 was covered by synthesis of 34 sets of 14-mer and 15-mer peptides comprising contiguous amino acid sequences. The two peptides were linked by a proprietary linker substituting two amino acid residues on the location of the linker (PEPSCAN). Thus one single set of peptides covers a stretch of 31 amino acid residues with two amino acid residues replaced in positions 15 and 16 by the proprietary linker residues. The linked peptides were furthermore chemically coupled to the matrix to allow washing and repeated use. The overlap between two adjacent sets of peptides was two amino acid residues. This collection of peptides was examined for reactivity with RAM1 and RAM2 produced as IgG1. RAM2 reacts with the amino-terminal, the middle and the carboxy-terminal part of the antigen but yields the highest reactivity with the middle part. RAM1 reacts only weakly with the peptides produced by this method. RAM3 was tested as Fab-ΔpIII in PEPSCAN without response. FIG. 11 shows the inhibitory effect of immune serum on the binding of RAM1 IgG1 to MSP-3 194-257 . The FITC-conjugated RAM1 IgG1 antibody was applied to ELISA wells coated with MSP-3 194-257 were pre-incubated for two hours with dilutions of immune or negative control serum and then a constant amount of FITC-conjugated RAM1 IgG1antibody was applied to each well. Immune serum blocked the binding of RAM1. FIG. 12 Construction of expression vectors. The V-regions of the plasmids can be exchanged by cutting with BsmI in the 5′ end and by cutting with HpaI or BsiWI or HindIII in the 3′ end. Before ligation of vector and V region, the V regions of RAM1, RAM2 or RAM3 need to be cut with the same restriction enzymes as the vectors. VH regions are then ligated to pLNOH2 and VK regions are ligated to PLNOK. The constant region of pLNOH2 can be exchanged by cutting with BamHI and HindIII, isolating the vector part and introducing (by ligation) another constant region cut with the same enzymes. In order to produce a complete antibody the plasmids (both pLNOH2 and pLNOK) are co-transfected into CHO cells. The V and C-regions are assembled by mRNA splicing. Alternatively the genes can be assembled into one vector thus harbouring the VH plus CH and VL plus CL. This insures that the two genes are present in equimolar numbers. Abbreviations: CMV=CMV promoter, L=leader, VH=variable heavy, VK=variable kappa, CH=constant heavy chain gene, CK=constant kappa chain gene, BGHpA =Bovine Growth Hormone polyadenylation site, f1=f1 origin, SV40ori=SV40 origin/promoter Neo=gene for neomycin resistance, Amp =gene for ampicillin resistance FIG. 13 Antibody competition. Fab fragments from clone RAM3 were produced in two versions. One version was fusion protein tagged with a truncated phage protein, ΔpIII, designated Fab-ΔpIII, and another version was normal Fab fragments without the ΔpIII tag. The ΔpIII-tag is readily detected using an antibody directed to the phage pIII protein. Thus Fab without ΔpIII can be present as competitor but only Fab-ΔpIII will be detected. Amounts of RAM1, RAM2 and RAM3 Fab-ΔpIII yielding OD 405 of approximately 1 in ELISA on a coating of MSP-3 194-257 were used. The binding of the Fab-ΔpIII was then competed by the addition of increasing amounts of competitor, RAM3 without ΔpIII. This figure shows that Fab RAM3 is able to compete Fab-ΔpIII RAM1 to the same extent as it competes Fab-ΔpIII RAM2. This demonstrates that binding of the clones RAM1 and RAM2 is dependent on the epitope used by clone RAM3. The lower competitive effect of RAM3 on the binding of Fab-ΔpIII RAM3 could be explained by a higher affinity of RAM3 as compared to RAM1 and RAM2. The effect of this would be that the competitive effect of RAM3 towards RAM1 and RAM2 would be larger than towards RAM3 itself. FIG. 14 shows the organization of heavy and light chain genes in pLNOH2 and pLNOK, respectively, and the resulting antibody structure. The part of an antibody responsible for binding to antigen is the variable region, the V-region. This region consists of two separate polypeptides. One polypeptiUe comes from the light chain and the other from the heavy chain. In the intact antibody the variable region polypeptide from the light chain extends into the constant domain of the light chain, thus giving rise to an approximately 200 amino acid residues long polypeptide with a total of two domains. In the intact antibody the variable region from the heavy chain extends into the constant domains 1 to 3 giving rise to a 400 amino acid residues long polypeptide with a total of four domains. In the intact antibody two heavy chains combine with two light chains. Thus an intact antibody contains two V-regions and is able to bind to two antigens at the same time. The constant regions of the heavy chain interacts with the effector functions of the immune system. FIG. 15 shows the effects of inoculations of normal human monocytes, polyclonal anti-RESA antibodies and polyclonal anti-MSP3 antibodies from immune human donors on parasitemia in the P.f.-HuRBC-BXN mouse model. FIG. 16 compares the effects of chloroquine and polyclonal anti-MSP3 antibodies from immune human donors on parasitemia in P.f.- HuRBC-BXN mice. FIG. 17 shows the effects of inoculations of normal human monocytes, polyclonal anti-RESA antibodies and polyclonal anti-MSP3 antibodies from immune human donors on parasitemia in the P.f.-HuRBC-BXN mouse model. FIG. 18 compares the effects of total IgG from immune donors and antibodies affinity purified on the MSP3b peptide on parasitemia in P.f.-HuRBC-BXN mice, Each curve represents the mean of results from six mice. FIG. 19 shows the effects on parasitemia in one P.f.-HuRBC-BXN mouse of inoculations of human monocytes alone, in combination with an IgG1 control antibody, and in combination with RAM1 IgG1. detailed-description description="Detailed Description" end="lead"? Table I shows the results of screening of single clones from the three series after the fourth panning. |
Gene expression profile biomarkers and therapeutic targets for brain aging and age-related cognitive impairment |
A statistical and functional correlation strategy to identify changes in cellular pathways specifically linked to impaired cognitive function with aging. Analyses using the strategy identified multiple groups of genes expressed in the hippocampi of mammals, where the genes were expressed at different levels for several ages. The aging changes in expression began before mid-life. Many of the genes were involved in specific neuronal and glial pathways with previously unrecognized relationships to aging and/or cognitive decline. The processes identified by the strategy suggest a new hypothesis of brain aging in which initially decreased neuronal activity and/or oxidative metabolism trigger separate but parallel genomic cascades in neurons and glia. In neurons, the cascade results in elevations in calcium signaling and reductions of immediate early gene signaling, biosynthesis, synaptogenesis and neurite remodeling. In contrast, glia undergo increased lipid metabolism and mediate a cycle of demyelination and remyelination that induces antigen presentation, inflammation, oxidative stress and extracellular restructuring. These identified genes and the proteins they encode can be used as novel biomarkers of brain aging and as targets for developing treatment methods against age-related cognitive decline, Alzheimer's Disease and Parkinson's Disease. |
1. A method for identifying a biomarker for brain aging, wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, comprising the steps of: (a) obtaining a set of polynucleotides obtained from a set of brain samples, wherein the members of the set of brain samples were obtained from members of a set of mammals, wherein the set of mammals contains more than two members and wherein the set of mammals comprises young, mid-aged and aged members; (b) identifying the identity and amount of the members of the set of polynucleotides present in the brain samples; (c) deleting from the set of polynucleotides; (1) quality control oligonucleotides; (2) polynucleotides in which the difference between the young and the aged members did not comprise at least 75% of the maximum normalized difference among the members; and (d) testing by a conventional statistical test for a significant effect of aging across the young, mid-aged and aged members; wherein the polynucleotides, and polypeptide encoded by said polynucleotides, that are both significantly altered in an age-dependent fashion across age are identified as biomarkers for brain aging. 2. The identification method of claim 1, further comprising the step of: (e) correlating the identity and amount of the members of the set of polynucleotides present in the brain samples with cognitive performance in a behavioral test, using a conventional statistical correlation test; wherein the polynucleotides, and polypeptide encoded by said polynucleotides, that are both significantly altered in an age-dependent fashion as well as significantly correlated with cognitive performance across age are identified as biomarkers for brain aging. 3. The identification method of claim 1, wherein the biomarker for brain aging is a biomarker for an age-related neurodegenerative condition. 4. The identification method of claim 3, wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 5. The identification method of claim 1, wherein the brain sample is a hippocampal sample. 6. The identification method of claim 1, wherein the mammal is selected from the group consisting of rat, mouse and human. 7. The identification method of claim 1, wherein the biomarker for brain aging is an expressed sequence tag (EST). 8. The identification method of claim 1, further comprising, in the deletion step (c), the step of: (3) deleting, from the set of polynucleotides, polynucleotides for expressed sequence tags (ESTs) which have not been associated with known genes. 9. The identification method of claim 1, further comprising, in the deletion step (c), the step of: (3) deleting, from the set of polynucleotides, polynucleotides that are not expressed sequence tags (ESTs). 10. The identification method of claim 1, wherein the conventional statistical test in step (d) is ANOVA or student's t test. 11. The identification method of claim 1, wherein the testing in step (d) is testing by 1-way ANOVA for a significant effect of aging p<0.05. 12. The identification method of claim 1, wherein the behavioral tests of step (e) specifically test for cognitive deficits related to the region of the brain from which the brain sample has been obtained in step (a). 13. The identification method of claim 1, wherein the identification of the identity and amount of the members of the set of polynucleotides present in the brain samples in step (b) is by microarray analysis. 14. The identification method of claim 1, wherein the significant effect in step (d) is p<0.025. 15. The identification method of claim 1, wherein the significant effect in step (d) is p<0.01. 16. The identification method of claim 1, wherein the significant effect in step (d) is p<0.001. 17. The identification method of claim 1, wherein the behavioral test in step (e) is selected from the group consisting of the Morris spatial water maze (SWM) and the object memory task (OMT). 18. The identification method of claim 1, wherein the behavioral tests in step (e) are selected from the group consisting of tests for Alzheimer's disease and tests for Parkinson's disease. 19. The identification method of claim 1, wherein the correlation of the identity and amount of the members of the set of polynucleotides present in the brain samples with cognitive performance in behavioral tests is a Pearson or Spearman correlation of expression with behavior. 20. The identification method of claim 19, wherein the correlation is p<0.025. 21. The identification method of claim 19, wherein the correlation is p<0.01. 22. The identification method of claim 19, wherein the correlation is p<0.001. 23. A set of biomarkers for brain aging, comprising mammalian polynucleotides and polypeptides encoded by said polynucleotides: (a) wherein the set of biomarkers comprises at least two members; (b) wherein the brain expression patterns of the members of the set are significantly altered with aging as determined by a conventional statistical test, with p<0.05; (c) wherein the brain expression patterns of the members of the set are correlated across age groups with cognitive performance in behavioral tests, using a conventional statistical correlation test with a correlation of p<0.05 between brain expression and cognitive performance; and (d) wherein the cognitive performance in behavioral tests significantly altered with aging as determined by a conventional statistical test. 24. The set of biomarkers of claim 23, wherein the biomarkers further correlate with a behavioral measure of functional impairment. 25. The set of biomarkers of claim 23, wherein the behavioral measure of functional impairment is a test for an age-related neurodegenerative condition. 26. The set of biomarkers of claim 25, wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 27. The set of biomarkers of claim 23, wherein the mammal is selected from the group consisting of rat, mouse and human. 28. The set of biomarkers of claim 23, wherein the conventional statistical method in step (b) is ANOVA or student's t-test. 29. The set of biomarkers of claim 23, wherein the correlation in step (c) is tested by a correlation test selected from the group consisting of Pearson's correlation test and Spearman's correlation test. 30. The set of biomarkers of claim 23, wherein the age groups in step (c) comprises young, mid-aged and aged. 31. The set of biomarkers of claim 23, wherein the conventional statistical test in step (d) is ANOVA or student's t-test. 32. The set of biomarkers of claim 23, wherein at least one member of the set of biomarkers is a polynucleotide, or a polypeptide encoded by said polynucleotide, selected from the group consisting of L03294 (Lpl, lipoprotein lipase) (SEQ ID NO:37); M18416 (Egr1, Early growth response 1 (Krox-24)) (SEQ ID NO:8); S68245 (Ca4, carbonic anhydrase 4) (SEQ ID NO:38); M64780 (Agm, Agrin) (SEQ ID NO:1); M27207 (Col1a1, Procollagen-type I (alpha 1)) (SEQ ID NO:32); X16554 (Prps1, Phosphoribosyl pyrophosphate synthetase 1) (SEQ ID NO:51); M92433 (NGFI-C, Zinc-finger transcription factor (early response gene)) (SEQ ID NO:9); AA859975 (LOC64201, 2-oxoglutarate carrier) (SEQ ID NO:39); L08595 (Nuclear receptor subfamily 4, group A, member 2) (SEQ ID NO:10); M24542 (RISP, Rieske iron-sulfur protein) (SEQ ID NO:40); AI030089 (Nopp130, nucleolar phosphoprotein p130) (SEQ ID NO:11); AF104362 (Omd, Osteomodulin (osteoadherin)) (SEQ ID NO:33); L46873 (Slc15a1, Oligopeptide transporter) (SEQ ID NO:47; AI176689 (MAPKK 6, mitogen-activated protein kinase kinase 6) (SEQ ID NO:19); U66470 (rCGR11, Cell growth regulator) (SEQ ID NO:52); AF016387 (RXRG, retinoid X-receptor gamma) (SEQ ID NO:12); M18467 (Got2, glutamate oxaloacetate transaminase 2) (SEQ ID NO:41); X54793 (Hsp60, heat shock protein 60) (SEQ ID NO:62); X64401 (Cyp3a3, Cytochrome P450-subfamily IIIA (polypeptide 3)) (SEQ ID NO:42); M37584 (H2afz, H2A histone family (member Z)) (SEQ ID NO:53); L21192 (GAP-43, membrane attached signal protein 2 (brain)) (SEQ ID NO:2); AA875047 (TCPZ, T-complex protein 1 (zeta subunit)) (SEQ ID NO:63); U90610 (Cxcr4, CXC chemokine receptor) (SEQ ID NO:54); AF003904 (CRH-binding protein) (SEQ ID NO:27); U83880 (GPDH-M, glycerol-3-phosphate dehydrogenase, mitochondrial) (SEQ ID NO:43); X89703 (TPCR19, Testis Polymerase Chain Reaction product 19) (SEQ ID NO:20); D63886 (MMP16, matrix metalloproteinase 16) (SEQ ID NO:34); J05499 (GLS, glutaminase (mitochondrial)) (SEQ ID NO:44); D21799 (Psmb2, Proteasome subunit (beta type 2)) (SEQ ID NO:64); AA800794 (HT2A, zinc-finger protein) (SEQ ID NO:13); U90887 (Arg2, arginase type II) (SEQ ID NO:45); S82649 (Narp, neuronal activity-regulated pentraxin) (SEQ ID NO:3); M74223 (VGF, neurosecretory protein) (SEQ ID NO:4); AA874794 (Bex3, brain expressed X-linked 3) (SEQ ID NO:55); M15191 (Tac1, Tachykinin) (SEQ ID NO:28); AA892506 (coronin, actin binding protein 1A) (SEQ ID NO:56); L04485 (MAPPK1, mitogen-activated protein kinase kinase 1) (SEQ ID NO:21); AA799641 (S 164, Contains a PWI domain associated with RNA splicing) (SEQ ID NO:14); AA817892 (Gnb2, Guanine nucleotide binding protein (beta 2 subunit)) (SEQ ID NO:22); AA893939 (DSS1, deleted in split hand/split foot protein 1) (SEQ ID NO:57); AF000901 (P58/P45, Nucleoporin p58) (SEQ ID NO:23); AF087037 (Btg3, B-cell translocation gene 3) (SEQ ID NO:58); AB000280 (PHT1, peptide/histidine transporter) (SEQ ID NO:48); M87854 (Beta-ARK-1, beta adrenergic receptor kinase 1) (SEQ ID NO:24); U06099 (Prdx2, Peroxiredoxin 2) (SEQ ID NO:59); AF058795 (Gb2, GABA-B receptor) (SEQ ID NO:25; AA800517 (VAP1, vesicle associated protein) (SEQ ID NO:26); U63740 (Fez1, Protein kinase C-binding protein Zeta1) (SEQ ID NO:5); U53922 (Hsj2, DnaJ-like protein (RDJ1)) (SEQ ID NO:65); U78102 (Egr2, Early growth response 2) (SEQ ID NO 5); U44948 (SmLIM, smooth muscle cell LIM protein) (SEQ ID NO:16); U87627 (MCT3, putative monocarboxylate transporter) (SEQ ID NO:49); AB020504 (PMF31, highly homologus to mouse F-box-WD40 repeat protein 6) (SEQ ID NO:67); M21354 (Col3a1, collagen type III alpha-1) (SEQ ID NO:35); AA893664 (Temo, sertoli cell marker (KIAA0077 protein fragment)) (SEQ ID NO:68); AB010437 (CDH8, Cadherin-8) (SEQ ID NO:36); M22756 (Ndufv2, mitochondrial NADH dehydrogenase (24 kDa)) (SEQ ID NO:46); AA799389 (Rab3B, ras-related protein) (SEQ ID NO:50); AI172476 (Tieg-1, TGF-beta-inducible early growth response protein 1) (SEQ ID NO:60); AF091563 (Olfactory receptor) (SEQ ID NO:29); M64376 (Olfactory protein) (SEQ ID NO:30); J04488 (Ptgds, Prostaglandin D synthase) (SEQ ID NO:69); X71127 (c1qb, complement component 1-q (beta polypeptide)) (SEQ ID NO:70); J03752 (Microsomal GST-1, glutathione S-transferase) (SEQ ID NO:71); J03481 (Qdpr, Dihydropteridine reductase) (SEQ ID NO:115); L40362 (MHC class I RT1.C-type protein) (SEQ ID NO:72); M94918 (Hbb, beta hemoglobin) (SEQ ID NO:125); M55534 (Cryab, alpha crystallin polypeptide 2) (SEQ ID NO:105); U17919 (Aif1, allograft inflammatory factor 1) (SEQ ID NO:73); M15562 (MHC class II RT1.u-D-alpha chain) (SEQ ID NO:74); AA799645 (Phospholemman, FXYD domain-containing ion transport regulator 1) (SEQ ID NO:130); X13044 (Cd74, CD74 antigen) (SEQ ID NO:75); M24324 (RTS, MHC class I RT1 (RTS) (u haplotype)) (SEQ ID NO:76); U31866 (Nclone10) (SEQ ID NO:126); M32062 (Fcgr3, Fc IgG receptor III (low affinity)) (SEQ ID NO:77); AF095741 (Mg87) (SEQ ID NO:151); L03201 (Ctss, cathepsin S) (SEQ ID NO:131); M27905 (Rpl21, Ribosomal proteinL21) (SEQ ID NO:132); D38380 (Tf, Transferrin) (SEQ ID NO:127); AA893493 (RPL26, Ribosomal protein L26) (SEQ ID NO:133); AJ222813 (118, interleukin 18) (SEQ ID NO:78); E13541 (Cspg5, chondroitin sulfate proteoglycan 5) (SEQ ID NO:102); X54096 (Lcat, Lecithin-cholesterol acyltransferase) (SEQ ID NO:110); L40364 (RT1Aw2, RT1 class Ib) (SEQ ID NO:79); D28111 (MOBP, myelin-associated oligodendrocytic basic protein) (SEQ ID NO:106); M32016 (Lamp2, lysosomal-associated membrane protein 2) (SEQ ID NO:142); X13167 (NF1-A, nuclear factor 1 A) (SEQ ID NO:89); U26356 (S100A1, S100 protein (alpha chain)) (SEQ ID NO:95); AI231213 (Kangai 1, suppression of tumorigenicity 6) (SEQ ID NO:80); AI170268 (Ptgfr, Prostaglandin F receptor) (SEQ ID NO:81); X62952 (Vim, vimentin) (SEQ ID NO:119); AI014169 (Vdup1, vitamin D-upregulated) (SEQ ID NO:152); AA850219 (Anx3, Annexin A3) (SEQ ID NO:96); D84477 (Rhoa, ras-related homolog A2) (SEQ ID NO:97); X52477 (C3, Complement component 3) (SEQ ID NO:82); X52619 (Rpl28, Ribosomal protein L28) (SEQ ID NO:134); X06554 (S-MAG, myelin-associated glycoprotein C-term) (SEQ ID NO:107); Z50144 (Kat2, kynurenine aminotransferase II) (SEQ ID NO:116); X14181 (RPL18A, Ribosomal protein L18a) (SEQ ID NO:135); AA892333 (Tuba1, alpha-tubulin) (SEQ ID NO:120); U67082 (KZF-1, Kruppel associated box (KRAB) zinc finger 1) (SEQ ID NO:90); U11760 (Vcp, valosin-containing protein) (SEQ ID NO:121); AF048828 (VDAC1, voltage-dependent anion channel 1) (SEQ ID NO:98); M31076 (TNF-alpha, Transforming growth factor (alpha)) (SEQ ID NO:136); S83279 (HSDIV, 17-beta-hydroxysteroid dehydrogenase type IV) (SEQ ID NO:111); AI102103 (Pik4cb, Phosphatidylinositol 4-kinase) (SEQ ID NO:99); X56325 (Hba1, alpha 1 hemoglobin) (SEQ ID NO:128); X73371 (FCGR2, Low affinity immunoglobulin gamma Fc receptor II) (SEQ ID NO:83); X78848 (Gsta1, Glutathione-S-transferase (alpha type)) (SEQ ID NO:84); U92564 (Roaz, Olf-1/EBF associated Zn finger protein) (SEQ ID NO:91); AI171462 (Cd24, CD24 antigen) (SEQ ID NO:137); X83231 (PAIHC3, Pre-alpha-inhibitor, heavy chain 3) (SEQ ID NO:103); AF097593 (Ca4, cadherin 2-type 1 (neuronal)) (SEQ ID NO:104); X68283 (Rpl29, Ribosomal protein L29) (SEQ ID NO:138); S55427 (Pmp, peripheral myelin protein) (SEQ ID NO:108); AA818025 (Cd59, CD59 antigen) (SEQ ID NO:85); E01534 (Rps15, Ribosomal protein S15) (SEQ ID NO:143); U37138 (Sts, Steroid sulfatase) (SEQ ID NO:112); X55572 (Apod, Apolipoprotein D) (SEQ ID NO:113); AI028975 (AP-1, adaptor protein complex (beta 1)) (SEQ ID NO:144); L16995 (ADD1, adipocyte determination/differentiation-dependent factor 1) (SEQ ID NO:92); U07971 (Transamidinase, Glycine amidinotransferase, mitochondrial) (SEQ ID NO:117); L07736 (Cpt1a, Carnitine palmitoyltransferase 1 alpha (liver)) (SEQ ID NO:114); AI237535 (LitaF, LPS-induced TNF-alpha factor) (SEQ ID NO:93); AI175486 (Rps7, Ribosomal protein S7) (SEQ ID NO:145); U32498 (RSEC8, rat homolog of yeast sec8) (SEQ ID NO:122); X53504 (RPL12, Ribosomal protein L12) (SEQ ID NO:139); AF023621 (Sort1, sortilin) (SEQ ID NO:146); AF083269 (P41-Arc, actin-related protein complex 1b) (SEQ ID NO:123); AA891810 (GST, Glutathione S-transferase) (SEQ ID NO:86); M77694 (Fah, fumarylacetoacetate hydrolase) (SEQ ID NO:118); M22357 (MAG, myelin-associated glycoprotein) (SEQ ID NO:109); AI230712 (Pace4, Subtilisin-like endoprotease) (SEQ ID NO:147); AF008439 (NRAMP2, Natural resistance-associated macrophage protein 2) (SEQ ID NO:129); U77829 (Gas-5, growth arrest homolog) (SEQ ID NO:140); U92081 (Gp38, Glycoprotein 38) (SEQ ID NO:87); AA891445 (Skd3, suppressor of K+ transport defect 3) (SEQ ID NO:148); AI177161 (Nfe212, NF-E2-related factor 2) (SEQ ID NO:94); AF031430 (Stx7, Syntaxin 7) (SEQ ID NO:149); L35921 (Ggamma, GTP-binding protein (gamma subunit)) (SEQ ID NO:100); X62322 (Gm, Granulin) (SEQ ID NO:88); AF028784 (GFAP, glial fibrillary acidic protein) (SEQ ID NO:124); AI234146 (Csrp1, Cysteine rich protein 1) (SEQ ID NO:141) and mammalian homologues thereof. 33. The set of biomarkers of claim 23, wherein at least one member of the set of biomarkers is an expressed sequence tag (EST). 34. The set of biomarkers of claim 23, for use in the measurement of age-dependent cognitive decline. 35. The set of biomarkers of claim 34, wherein the age-dependent cognitive decline is an age-related neurodegenerative condition. 36. The set of biomarkers of claim 35, wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 37. The set of biomarkers of claim 23, for use in the measurement of degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline. 38. A set of biomarkers for brain aging, comprising mammalian polynucleotides and polypeptides encoded by said polypeptides: (a) wherein the set of biomarkers comprises at least two members; (b) wherein the brain expression patterns of the members of the set are significantly altered with aging as measured by a conventional statistical method at a significance level of p<0.01. 39. The set of biomarkers of claim 38, wherein the mammal is selected from the group consisting of rat, mouse and human. 40. The set of biomarkers of claim 38, wherein the conventional statistical method is ANOVA or student's t-test. 41. The set of biomarkers of claim 38, wherein at least one member of the set of biomarkers is a polynucleotide, or a polypeptide encoded by said polynucleotide, selected from the group consisting of AA891651 (rc_AA891651 EST195454 cDNA) (SEQ ID NO:173); AI070108 (rc_AI070108 UI-R-Y0-lu-a-09-0-UI.s1 cDNA) (SEQ ID NO:170); AI176689 (mitogen-activated protein kinase kinase 6) (SEQ ID NO:19); AI012051 (rc_AI012051 EST206502 cDNA) (SEQ ID NO:191); AI233365 (rc_AI233365 EST230053 cDNA) (SEQ ID NO:157); AA892532 (rc_AA892532 EST196335 cDNA) (SEQ ID NO:154); AA893185 (rc_AA893185 EST196988 cDNA) (SEQ ID NO:399); AA964320 (rc_AA964320 UI-R-C0-gu-e-09-0-UI.s1 cDNA) (SEQ ID NO:177); AA963449 (rc_AA963449 UI-R-E1-gj-e-08-0-UI.s1 cDNA) (SEQ ID NO:153); AA859632 (rc_AA859632 UI-R-E0-bs-h-08-0-UI.s1 cDNA) (SEQ ID NO:172); AI169265 (Atp6s1) (SEQ ID NO:219); AA850781 (rc_AA850781 EST193549 cDNA) (SEQ ID NO:181); AJ222813 (interleukin 18) (SEQ ID NO:78); D38380 (Transferrin) (SEQ ID NO:127); J03481 (dihydropteridine reductase) (SEQ ID NO:115); M24542 (Rieske iron-sulfur protein) (SEQ ID NO:40); L03294 (Lipoprotein lipase) (SEQ ID NO:37); L19998 (sulfotransferase family 1A, phenol-preferring, member 1) (SEQ ID NO:321); U53922 (DnaJ-like protein (RDJ1)) (SEQ ID NO:65); X54793 (liver heat shock protein (hsp60)) (SEQ ID NO:62); X62952 (vimentin) (SEQ ID NO:119); M55534 (Crystallin, alpha polypeptide 2) (SEQ ID NO:105); J03752 (microsomal glutathione S-transferase 1) (SEQ ID NO:71); X64401 (Cytochrome P450, subfamily 111A, polypeptide 3) (SEQ ID NO:42); X78848 (Gsta1) (SEQ ID NO:84); AF016387 (retinoid X receptor gamma) (SEQ ID NO:12); AF031430 (syntaxin 7) (SEQ ID NO:149); AF051561 (solute carrier family 12, member 2) (SEQ ID NO:322); AF076183 (cytosolic sorting protein PACS-1a (PACS-1)) (SEQ ID NO:231); AF095576 (adaptor protein with pleckstrin homology and src homology 2 domains) (SEQ ID NO:18); AF095741 (MG87) (SEQ ID NO:151); AF097593 (cadherin 2, type 1, N-cadherin (neuronal)) (SEQ ID NO:104); AF104362 (osteoadherin) (SEQ ID NO:33); D10699 (ubiquitin carboxy-terminal hydrolase L1) (SEQ ID NO:234); D28111 (myelin-associated oligodendrocytic basic protein) (SEQ ID NO:106); D37951 (MIBP1 (c-myc intron binding protein 1)) (SEQ ID NO:230); D84477 (RhoA) (SEQ ID NO:97); L13202 (RATHFH2 HNF-3/fork-head homolog-2 (HFH-2)) (SEQ ID NO:220); L26292 (Kruppel-like factor 4 (gut)) (SEQ ID NO:218); L46873 (solute carrier family 15 (oligopeptide transporter), member 1) (SEQ ID NO:47); M13100 (RATLIN3A long interspersed repetitive DNA sequence LINE3 (L1Rn)) (SEQ ID NO:435); M27207 (procollagen, type I, alpha 1) (SEQ ID NO:32); M92433 (Zinc-finger transcription factor NGFI-C (early response gene)) (SEQ ID NO:9); M94918 (Hemoglobin, beta) (SEQ ID NO:125); M94919 (Hemoglobin, beta) (SEQ ID NO:452); S55427 (Peripheral myelin protein) (SEQ ID NO:108); S68245 (carbonic anhydrase 4) (SEQ ID NO:38); S82649 (Narp=neuronal activity-regulated pentraxin); U10894 (allograft inflammatory factor 1) (SEQ ID NO:453); U26356 (RNSHUNA1 S100A1 gene) (SEQ ID NO:95); U75397 (RNKROX2 Krox-24) (SEQ ID NO:454); U75405 (procollagen, type I, alpha 1) (SEQ ID NO:217); U77829 (RNU77829 gas-5 growth arrest homolog non-translated sequence) (SEQ ID NO:140); U92081 (glycoprotein 38) (SEQ ID NO:87); X06554 (RNMAGSR myelin-associated glycoprotein (S-MAG) C-term) (SEQ ID NO:107); X13167 (Nuclear Factor IA) (SEQ ID NO:89); X14181 (RRRPL18A ribosomal protein L18a) (SEQ ID NO:135); X56325 (Hemoglobin, alpha 1) (SEQ ID NO:128); X60351 (Crystallin, alpha polypeptide 2) (SEQ ID NO:455); E13541 (chondroitin sulfate proteoglycan 5) (SEQ ID NO:102); M22357 (1B236/myelin-associated glycoprotein (MAG)) (SEQ ID NO:109); M24026 (RT1 class Ib gene) (SEQ ID NO:456); M24324 (MHC class I RT1 (RTS) (u haplotype)) (SEQ ID NO:76); J04488 (Prostaglandin D synthase) (SEQ ID NO:69); M15191 (Tachykinin (substance P, neurokinin A, neuropeptide K, neuropeptide gamma)) (SEQ ID NO:28); M74223 (VGF) (SEQ ID NO:4); U17254 (immediate early gene transcription factor NGFI-B) (SEQ ID NOS:225 & 257); U08259 (Glutamate receptor, ionotropic, N-methyl D-aspartate 2C) (SEQ ID NO:323); U19866 (activity regulated cytoskeletal-associated protein) (SEQ ID NO:7); L40364 (RT1 class Ib gene) (SEQ ID NO:79); U17919 (allograft inflammatory factor 1) (SEQ ID NO:73); U78102 (early growth response 2) (SEQ ID NO:15); U67082 (KRAB-zinc finger protein KZF-1) (SEQ ID NO:90); U77777 (interleukin 18) (SEQ ID NO:319); D78018 (Nuclear Factor IA) (SEQ ID NO:457); U92564 (Olf-1/EBF associated Zn finger protein Roaz) (SEQ ID NO:91); AF008439 (Solute carrier family 11 member 2 (natural resistance-associated macrophage protein 2)) (SEQ ID NO:129); AB003726 (RuvB-like protein 1) (SEQ ID NO:6); M83561 (Glutamate receptor, ionotropic, kainate 1) (SEQ ID NO:101); AI639151 (mixed-tissue library cDNA clone rx02802 3) (SEQ ID NO:438); AI639247 (mixed-tissue library cDNA clone rx03939 3) (SEQ ID NO:160); AI639381 (mixed-tissue library cDNA clone rx01495 3) (SEQ ID NO:196); AI639532 (mixed-tissue library cDNA clone rx01030 3) (SEQ ID NO:189); AA799645 (FXYD domain-containing ion transport regulator 1) (SEQ ID NO:130); AA900516 (Pdi2) (SEQ ID NO:150); AI014169 (Vdup1) (SEQ ID NO:152); AI030089 (Nopp140) (SEQ ID NO:1); AI102299 (Bid3) (SEQ ID NO:320); AA818025 (CD59 antigen) (SEQ ID NO:85); AI170268 (Prostaglandin F receptor) (SEQ ID NO:81); AI171462 (CD24 antigen) (SEQ ID NO:137); AI171966 (ESTs, Highly similar to SPS2 MOUSE SELENIDE, WATER DIKINASE 2 [M. musculus]) (SEQ ID NO:437); AI176456 (ESTs, Weakly similar to ABP2_HUMAN ENDOTHELIAL ACTIN-BINDING PROTEIN [H. sapiens]) (SEQ ID NO:182); AI177161 (NF-E2-related factor 2) (SEQ ID NO:94); AI179576 (Hemoglobin, beta) (SEQ ID NO:458); AI230712 (Subtilisin-like endoprotease) (SEQ ID NO:147); AI230914 (farnesyltransferase beta subunit) (SEQ ID NO:229); AI231213 (kangai 1 (suppression of tumorigenicity 6), prostate) (SEQ ID NO:80); AI237731 (Lipoprotein lipase) (SEQ ID NO:459); M83745 (Protein convertase subtilisin/kexin, type I) (SEQ ID NO:226); M27905 (ribosomal protein L21) (SEQ ID NO:132); M32016 (Lysosomal-associated membrane protein 2) (SEQ ID NO:142); M11071 (RT1 class Ib gene) (SEQ ID NO:460); M15562 (MHC class II RT1.u-D-alpha chain) (SEQ ID NO:74); M15880 (Neuropeptide Y) (SEQ ID NO:31); L08595 (nuclear receptor subfamily 4, group A, member 2) (SEQ ID NO:10); M18416 (Early growth response 1) (SEQ ID NO:8); L40362 (MHC class I RT1.C-type protein) (SEQ ID NO:72); Z50144 (kynurenine/alpha-aminoadipate aminotransferase) (SEQ ID NO:116); X71127 (complement component 1, q subcomponent, beta polypeptide) (SEQ ID NO:70); U44948 (smooth muscle cell LIM protein (SmLIM)) (SEQ ID NO:16); AA850219 (Annexin A3) (SEQ ID NO:96); X73371 (FCGR2) (SEQ ID NO:83); X57281 (Glycine receptor alpha 2 subunit (glycine receptor, neonatal)) (SEQ ID NO:235); X83231 (pre-alpha-inhibitor) (SEQ ID NO:103); X52477 (Complement component 3) (SEQ ID NO:82); X16554 (phosphoribosyl pyrophosphate synthetase 1) (SEQ ID NO:51); X78605 ((Sprague Dawley) rab4b ras-homologous GTPase) (SEQ ID NO:66); X82445 (nuclear distribution gene C homolog (Aspergillus)) (SEQ ID NO:232); X52619 (ribosomal protein L28) (SEQ ID NO:134); X68283 (ribosomal protein L29) (SEQ ID NO:138); X13044 (CD74 antigen (invariant polpypeptide of major histocompatibility class II antigen-associated)) (SEQ ID NO:75); X54096 (Lecithin-cholesterol acyltransferase) (SEQ ID NO:110); U31866 (Nclone10) (SEQ ID NO:126); U72620 (Lot1) (SEQ ID NO:224); U66470 (rCGR11) (SEQ ID NO:52); M31018 (RT1 class Ib gene) (SEQ ID NO:461); U90887 (arginase type II) (SEQ ID NO:45); M18467 (Glutamate oxaloacetate transaminase 2, mitochondrial (aspartate aminotransferase 2)) (SEQ ID NO:41); M64780 (Agrin) (SEQ ID NO:1); U87627 (putative monocarboxylate transporter (MCT3)) (SEQ ID NO:49); AF019974 (Chromogranin B, parathyroid secretory protein) (SEQ ID NO:223); L03201 (cathepsin S) (SEQ ID NO:131); AB008538 (HB2) (SEQ ID NO:324); D89340 (dipeptidylpeptidase III) (SEQ ID NO:222); M77694 (fumarylacetoacetate hydrolase) (SEQ ID NO:118); M32062 (Fc-gamma receptor) (SEQ ID NO:77); L21192 (brain abundant, membrane attached signal protein 2) (SEQ ID NO:2); M37584 (H2afz) (SEQ ID NO:53); AA858588 (ESTs, Weakly similar to ODP2 RAT DIHYDROLIPOAMIDE ACETYLTRANSFERASE COMPONENT OF PYRUVATE DEHYDROGENASE COMPLEX [R. norvegicus]) (SEQ ID NO:184); AA858617 (rc_AA858617 UI-R-E0-bq-b-06-0-UI.s1 cDNA) (SEQ ID NO:161); AA859562 (rc_AA859562 UI-R-E0-by-b-03-0-UI.s1 cDNA) (SEQ ID NO:403); AA859626 (rc_AA859626 UI-R-E0-bs-h-02-0-UI.s1 cDNA) (SEQ ID NO:155); AA859690 (rc_AA859690 UI-R-E0-bx-e-11-0-UI.s1 cDNA) (SEQ ID NO:396); AA859777 (rc_AA859777 UI-R-E0-bu-e-10-0-UI.s1 cDNA) (SEQ ID NO:188); AA859975 (LOC64201) (SEQ ID NO:39); AA860030 (UI-R-E0-bz-e-07-0-UI.s2 cDNA) (SEQ ID NO:404); AA866291 (rc_AA866291 UI-R-A0-ac-e-12-0-UI.s3 cDNA) (SEQ ID NO:164); AA866409 (rc_AA866409 UI-R-E0-ch-a-03-0-UI.s1 cDNA) (SEQ ID NO:171); AA866411 (NDN) (SEQ ID NO:61); AA874794 (Bex3) (SEQ ID NO:55); AA874887 (rc_AA874887 UI-R-E0-ci-g-10-0-UI.s1 cDNA) (SEQ ID NO:180); AA875004 (rc_AA875004 UI-R-E0-cb-b-07-0-UI.s1 cDNA) (SEQ ID NO:397); AA875037 (rc_AA875037 UI-R-E0-cb-a-03-0-UI.s1 cDNA) (SEQ ID NO:439); AA875047 (TCPZ) (SEQ ID NO:63); AA875059 (rc_AA875059 UI-R-E0-cb-f-04-0-UI.s1 cDNA) (SEQ ID NO:190); AA875129 (rc_AA875129 UI-R-E0-bu-e-01-0-UI.s2 cDNA) (SEQ ID NO:401); H31418 (rc_H31418 EST105434 cDNA) (SEQ ID NO:183); H31665 (rc_H31665 EST105952 cDNA) (SEQ ID NO:158); H32977 (rc_H32977 EST108553 cDNA) (SEQ ID NO:179); H33725 (associated molecule with the SH3 domain of STAM) (SEQ ID NO:228); AA891037 (rc_AA891037 EST194840 cDNA) (SEQ ID NO:398); AA891445 (Skd3) (SEQ ID NO:148); AA891690 (ESTs, Weakly similar to SERC_HUMAN PHOSPHOSERINE AMINOTRANSFERASE [H. sapiens]) (SEQ ID NO:440); AA891717 (USF1) (SEQ ID NO:17); AA891734 (rc_AA891734 EST195537 cDNA) (SEQ ID NO:436); AA891785 (rc_AA891785 EST195588 cDNA) (SEQ ID NO:185); AA891810 (ESTs, Highly similar to GTK1 RAT GLUTATHIONE S-TRANSFERASE, MITOCHONDRIAL [R. norvegicus]) (SEQ ID NO:86); AA891965 (rc_AA891965 EST195768 cDNA) (SEQ ID NO:175); AA892333 (Tuba1) (SEQ ID NO:120); AA892353 (ESTs, Moderately similar to JC5823 NADH dehydrogenase [H. sapiens]) (SEQ ID NO:159); AA892511 (rc_AA892511 EST196314 cDNA) (SEQ ID NO:400); AA892986 (rc_AA892986 EST196789 cDNA) (SEQ ID NO:434); AA893032 (ESTs, Moderately similar to CALX RAT CALNEXIN PRECURSOR [R. norvegicus]) (SEQ ID NO:174); AA893082 (rc_AA893082 EST196885 cDNA) (SEQ ID NO:433); AA893493 (RPL26) (SEQ ID NO:133); AA893607 (rc_AA893607 EST197410 cDNA) (SEQ ID NO:195); AA893708 (KIAA0560) (SEQ ID NO:227); AA893743 (rc_AA893743 EST197546 cDNA) (SEQ ID NO:156); AA894104 (rc_AA894104 EST197907 cDNA) (SEQ ID NO:165); AA799449 (EST, Weakly similar to UBP4 MOUSE UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 4 [M. musculus]) (SEQ ID NO:187); AA799779 (acyl-CoA:dihydroxyacetonephosphate acyltransferase) (SEQ ID NO:221); AA799803 (ESTs, Weakly similar to K1CU RAT KERATIN, TYPE I CYTOSKELETAL 21 [R. norvegicus]) (SEQ ID NO:186); AA799854 (rc_AA799854 EST189351 cDNA) (SEQ ID NO:193); AA799996 (rc_AA799996 EST189493 cDNA) (SEQ ID NO:166); AA800693 (rc_AA800693 EST190190 cDNA) (SEQ ID NO:402); AA800708 (ESTs, Weakly similar to S28312 hypothetical protein F02A9.4-Caenorhabditis elegans [C. elegans]) (SEQ ID NO-176); AA800794 (HT2A) (SEQ ID NO:13); AA800948 (Tuba4) (SEQ ID NO:233); and mammalian homologues thereof. 42. The set of biomarkers of claim 38, wherein at least one member of the set of biomarkers is an expressed sequence tag (EST). 43. The set of biomarkers of claim 38, for use in the measurement of age-dependent cognitive decline. 44. The set of biomarkers of claim 43, wherein the age-dependent cognitive decline is an age-dependent neurodegenerative condition. 45. The set of biomarkers of claim 44, wherein the age-dependent neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 46. The set of biomarkers of claim 38, for use in the measurement of the degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline. 47. The use of an expressed sequence tag (EST) in an assay for aging in a mammal, wherein the EST is selected from the group consisting of AA963449 (UI-R-E1-gj-e-08-0-UI.s1 cDNA) (SEQ ID NO:153); AA892532 (EST196335 cDNA) (SEQ ID NO:154); AA859626 (UI-R-E0-bs-h-02-0-UI.s1 cDNA) (SEQ ID NO:155); AA893743 (EST197546 cDNA) (SEQ ID NO:156); AI233365 (EST230053 cDNA) (SEQ ID NO:157); H31665 (EST105952 cDNA) (SEQ ID NO:158); AA892353 (ESTs, Moderately similar to JC5823 NADH dehydrogenase) (SEQ ID NO:159); AI639247 (mixed-tissue library cDNA clone rx03939 3) (SEQ ID NO:160); AA858617 (UI-R-E0-bq-b-06-0-UI.s1 cDNA) (SEQ ID NO:161); AI639429 (mixed-tissue library cDNA clone rx00973 3) (SEQ ID NO:162); AA858620 (UI-R-E0-bq-b-09-0-UI.s1 cDNA) (SEQ ID NO:163); AA866291 (UI-R-A0-ac-e-12-0-UI.s3 cDNA) (SEQ ID NO:164); AA894104 (EST197907 cDNA) (SEQ ID NO:165); AA799996 (EST189493 cDNA) (SEQ ID NO:166); AA892805 (EST196608 cDNA) (SEQ ID NO:167); AI639019 (mixed-tissue library cDNA clone rx01107 3) (SEQ ID NO:168); AA799538 (EST189035 cDNA) (SEQ ID NO:169); AI070108 (UI-R-Y0-lu-a-09-0-UI.s1 cDNA) (SEQ ID NO:170); AA866409 (UI-R-E0-ch-a-03-0-UI.s1 cDNA) (SEQ ID NO:171); AA859632 (UI-R-E0-bs-h-08-0-UI.s1 cDNA) (SEQ ID NO:172); AA891651 (EST195454 cDNA) (SEQ ID NO:173); AA893032 (ESTs, Moderately similar to CALX calnexin precursor) (SEQ ID NO:174); AA891965 (EST195768 cDNA) (SEQ ID NO:175); AA800708 (ESTs, Weakly similar to S28312 hypothetical protein F02A9.4); AA964320 (UI-R-C0-gu-e-09-0-UI.s1 cDNA) (SEQ ID NO:177); AA893173 (EST196976 cDNA) (SEQ ID NO:178); H32977 (EST108553 cDNA) (SEQ ID NO:179); AA874887 (UI-R-E0-ci-g-10-0-UI.s1 cDNA) (SEQ ID NO:180); AA850781 (EST193549 cDNA) (SEQ ID NO:181); AI176456 (ESTs, Weakly similar to endothelial actin-binding protein); H31418 (EST105434 cDNA) (SEQ ID NO:183); AA858588 (ESTs, Weakly similar to ODP2 dihydrolipoamide acetyl transferase) (SEQ ID NO:184); AA891785 (EST195588 cDNA) (SEQ ID NO:185); AA799803 (ESTs, Weakly similar to K1CU cytoskeletal keratin (type 1)) (SEQ ID NO:186); AA799449 (EST, Weakly similar to UBP4 ubiquitin carboxyl-terminal hydrolase 4) (SEQ ID NO:187); AA859777 (UI-R-E0-bu-e-10-0-UI.s1 cDNA) (SEQ ID NO:188); AI639532 (mixed-tissue library cDNA clone rx01030 3) (SEQ ID NO:189); AA875059 (UI-R-E0-cb-f-04-0-UI.s1 cDNA) (SEQ ID NO:190); AI012051 (EST206502 cDNA) (SEQ ID NO:191); AA800549 (EST190046 cDNA) (SEQ ID NO:192); AA799854 (EST189351 cDNA) (SEQ ID NO:193); AA892520 (EST196323 cDNA) (SEQ ID NO:194) and mammalian homologues thereof. 48. The use of claim 47, wherein the assay for aging is a measurement of age-dependent cognitive decline. 49. The use of claim 48, wherein the age-dependent cognitive decline is an age-dependent neurodegenerative condition. 50. The use of claim 49, wherein the age-dependent neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 51. The use of claim 47, wherein the assay for aging is a measurement of the degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline. 52. A set of biomarkers for brain aging, comprising mammalian polynucleotides and polypeptides encoded by said polynucleotides: (a) wherein the set of biomarkers comprises at least two members; and (b) wherein the brain expression patterns of the members of the set are significantly altered with aging as determined by a conventional statistical method, with p<0.05. 53. The set of biomarkers of claim 52, wherein the set contains at least one member selected from the group consisting of AA685974 (EST108806 cDNA) (SEQ ID NO:414); AA799396 (EST188893 cDNA); AA799479 (ESTs, Highly similar to NADH-ubiquinone oxidoreduct.) (SEQ ID NO:295); AA799481 (EST188978 cDNA) (SEQ ID NO:411); AA799529 (EST189026 cDNA) (SEQ ID NO:382); AA799599 (EST189096 cDNA) (SEQ ID NO:380); AA799636 (EST189133 cDNA) (SEQ ID NO:392); AA799680 (EST189177 cDNA) (SEQ ID NO:390); AA799724 (ESTs, Highly similar to DNA-directed RNA polymerase I) (SEQ ID NO:199); AA799773 (EST189270 cDNA) (SEQ ID NO:450); AA799779 (acyl-CoA:dihydroxyacetonephosphate acyltransferase) (SEQ ID NO:221); AA799858 (EST189355 cDNA) (SEQ ID NO:422); AA800026 (EST189523 cDNA) (SEQ ID NO:423); AA800318 (EST189815 cDNA) (SEQ ID NO:432); AA800622 (EST190119 cDNA) (SEQ ID NO:385); AA800693 (EST190190 cDNA) (SEQ ID NO:402); AA800948 (Tuba4) (SEQ ID NO:233); AA801286 (Inositol (myo)-1(or 4)-monophosphatase 1) (SEQ ID NO:265); AA817887 (profilin) (SEQ ID NO:291); AA818025 (CD59 antigen) (SEQ ID NO:85); AA818240 (Nuclear pore complex protein) (SEQ ID NO:312); AA818487 (cyclophilin B) (SEQ ID NO:294); AA819500 (ESTs, Highly similar to AC12_HUMAN 37 kD subunit) (SEQ ID NO:283); AA819708 (Cox7a3) (SEQ ID NO:247); AA848831 (lysophosphatidic acid G-protein-coupled receptor, 2) (SEQ ID NO:328); AA852046 (EST194815 cDNA) (SEQ ID NO:444); AA859545 (ESTs, Weakly similar to hypothetical protein C09H6.3) (SEQ ID NO:425); AA859562 (UI-R-E0-by-b-03-0-UI.s1 cDNA) (SEQ ID NO:403); AA859643 (UI-R-E0-bs-a-08-0-UI.s1 cDNA) (SEQ ID NO:412); AA859645 (attractin) (SEQ ID NO:346); AA859690 (UI-R-E0-bx-e-11-0-UI.s1 cDNA) (SEQ ID NO:396); AA859848 (UI-R-E0-cc-h-10-0-UI.s1 cDNA) (SEQ ID NO:426); AA859954 (Vacuole Membrane Protein 1) (SEQ ID NO:271); AA859980 (T-complex 1) (SEQ ID NO:278); AA860030 (UI-R-E0-bz-e-07-0-UI.s2 cDNA) (SEQ ID NO:404); AA866257 (ESTs) (SEQ ID NO:248); AA866299 (UI-R-A0-ac-f-12-0-UI.s3 cDNA) (SEQ ID NO:449); AA866432 (UI-R-E0-ch-e-06-0-UI.s1 cDNA) (SEQ ID NO:441); AA866477 (UI-R-E0-br-h-03-0-UI.s1 cDNA) (SEQ ID NO:418); AA874830 (UI-R-E0-cg-f-04-0-UI.s1 cDNA) (SEQ ID NO:378); AA874874 (ESTs, Highly similar to alcohol dehydrogenase class III) (SEQ ID NO:258); AA874969 (ESTs, Highly similar to c-Jun leucine zipper interactive) (SEQ ID NO:263); AA874995 (UI-R-E0-cf-d-08-0-UI.s1 cDNA) (SEQ ID NO:393); AA875004 (UI-R-E0-cb-b-07-0-UI.s1 cDNA) (SEQ ID NO:397); AA875019 (UI-R-E0-cb-f-08-0-UI.s1 cDNA) (SEQ ID NO:417); AA875032 (UI-R-E0-cb-h-09-0-UI.s1 cDNA) (SEQ ID NO:379); AA875037 (UI-R-E0-cb-a-03-0-UI.s1 cDNA) (SEQ ID NO:439); AA875129 (UI-R-E0-bu-e-01-0-UI.s2 cDNA) (SEQ ID NO:401); AA875257 (UI-R-E0-cq-d-12-0-UI.s1 cDNA) (SEQ ID NO:413); AA891037 (EST194840 cDNA) (SEQ ID NO:398); AA891041 (un B proto-oncogene) (SEQ ID NO:290); AA891221 (EST195024 cDNA) (SEQ ID NO:387); AA891476 (EST195279 cDNA) (SEQ ID NO:415); AA891537 (EST195340 cDNA) (SEQ ID NO:389); AA891690 (ESTs, Weakly similar to p-serine aminotransferase) (SEQ ID NO:440); AA891727 (EST195530 cDNA) (SEQ ID NO:405); AA891734 (EST195537 cDNA) (SEQ ID NO:436); AA891774 (EST195577 cDNA) (SEQ ID NO:447); AA891810 (EST195613 cDNA) (SEQ ID NO:86); AA891880 (Loc65042) (SEQ ID NO:243); AA891916 (membrane interacting protein of RGS16) (SEQ ID NO:209); AA891944 (EST195747 cDNA) (SEQ ID NO:451); AA891950 (EST195753 cDNA) (SEQ ID NO:416); AA892146 (EST195949 cDNA) (SEQ ID NO:443); AA892298 (EST196101 cDNA) (SEQ ID NO:394); AA892414 (EST196217 cDNA) (SEQ ID NO:409); AA892511 (EST196314 cDNA) (SEQ ID NO:400); AA892520 (EST196323 cDNA) (SEQ ID NO:194); AA892538 (EST196341 cDNA) (SEQ ID NO:395); AA892637 (EST196440 cDNA) (SEQ ID NO:424); AA892775 (Lysozyme) (SEQ ID NO:354); AA892796 (EST196599 cDNA) (SEQ ID NO:406); AA892813 (EST196616 cDNA) (SEQ ID NO:381); AA892986 (EST196789 cDNA) (SEQ ID NO:434); AA893082 (EST196885 cDNA) (SEQ ID NO:433); AA893185 (EST196988 cDNA) (SEQ ID NO:399); AA893199 (EST197002 cDNA) (SEQ ID NO:391); AA893224 (EST197027 cDNA) (SEQ ID NO:428); AA893320 (EST197123 cDNA) (SEQ ID NO:388); AA893584 (EST197387 cDNA) (SEQ ID NO:383); AA893690 (EST197493 cDNA) (SEQ ID NO:386); AA893708 (KIAA0560) (SEQ ID NO:227); AA893717 (EST197520 cDNA) (SEQ ID NO:408); AA893743 (EST197546 cDNA) (SEQ ID NO:156); AA893788 (ESTs, Highly similar to chromobox protein homolog 5) (SEQ ID NO:299); AA893946 (EST197749 cDNA) (SEQ ID NO:429); AA894305 (EST198108 cDNA) (SEQ ID NO:384); AA924925 (ER transmembrane protein Dri 42) (SEQ ID NO:372); AA942685 (cytosolic cysteine dioxygenase 1) (SEQ ID NO:249); AA955306 (ras-related protein rab10) (SEQ ID NO:365); AA955388 (Na+K+ transporting ATPase 2, beta polypeptide 2) (SEQ ID NO:307); AA957132 (N-acetylglucosaminyltransferase I) (SEQ ID NO:375); AB000778 (Phoshpolipase D gene 1) (SEQ ID NO:357); AB006451 (Tim23) (SEQ ID NO:253); AB008538 (HB2) (SEQ ID NO:324); AB016532 (period homolog 2 (Drosophila)) (SEQ ID NO:259); AF000899 (p58/p45, nucleolin) (SEQ ID NO:286); AF007554 (Mucin1) (SEQ ID NO:266); AF007758 (synuclein, alpha) (SEQ ID NO:260); AF007890 (resection-induced TPI (rs11)) (SEQ ID NO:262); AF008554 (implantation-associated protein (IAG2)) (SEQ ID NO:331); AF013144 (MAP-kinase phosphatase (cpg21)) (SEQ ID NO:281); AF016269 (kallikrein 6 (neurosin, zyme)) (SEQ ID NO:301); AF016296 (neuropilin) (SEQ ID NO:325); AF019974 (Chromogranin B, parathyroid secretory protein) (SEQ ID NO:223); AF020046 (integrin alpha E1, epithelial-associated) (SEQ ID NO:284); AF021935 (Ser-Thr protein kinase) (SEQ ID NO:302); AF023087 (Early growth response 1) (SEQ ID NO:269); AF030050 (replication factor C) (SEQ ID NO:327); AF030088 (RuvB-like protein 1) (SEQ ID NO:280); AF040954 (putative protein phosphatase 1 nuclear targeting subunit) (SEQ ID NO:213); AF051561 (solute carrier family 12, member 2) (SEQ ID NO:322); AF055477 (L-type voltage-dependent Ca2+ channel (?1D subunit)) (SEQ ID NO:207); AF074608 (MHC class I antigen (RT1.EC2) gene) (SEQ ID NO:340); AF076183 (cytosolic sorting protein PACS-1a (PACS-1)) (SEQ ID NO:231); AF095927 (protein phosphatase 2C) (SEQ ID NO:246); AI010110 (SH3-domain GRB2-like 1) (SEQ ID NO:273); AI012589 (glutathione S-transferase, pi 2) (SEQ ID NO:356); AI013627 (defender against cell death 1) (SEQ ID NO:208); AI013861 (3-hydroxyisobutyrate dehydrogenase) (SEQ ID NO:342); AI045249 (heat shock 70 kD protein 8) (SEQ ID NO:245); AI102031 (myc box dependent interacting protein 1) (SEQ ID NO:370); AI102299 (Bid3) (SEQ ID NO:320); AI102839 (cerebellar Ca-binding protein, spot 35 protein) (SEQ ID NO:203); AI102868 (EST212157 cDNA) (SEQ ID NO:420); AI104388 (heat shock 27 kD protein 1) (SEQ ID NO:296); AI136891 (zinc finger protein 36, C3H type-like 1) (SEQ ID NO:275); AI168942 (branched chain keto acid dehydrogenase E1) (SEQ ID NO:268); AI169265 (Atp6s1) (SEQ ID NO:219); AI171966 (ESTs, Highly similar to selenide, water dikinase 2) (SEQ ID NO:437); AI175973 (ESTs, Highly similar to NADH dehydrogenase) (SEQ ID NO:198); AI176491 (EST220076 cDNA) (SEQ ID NO:410); AI176595 (Cathepsin L) (SEQ ID NO:351); AI176621 (iron-responsive element-binding protein) (SEQ ID NO:272); AI 77404 (EST221024 cDNA) (SEQ ID NO:431); AI178204 (EST221869 cDNA) (SEQ ID NO:421); AI178921 (Insulin degrading enzyme) (SEQ ID NO:215); AI228548 (ESTs, Highly similar to DKFZp586G0322.1) (SEQ ID NO:316); AI230247 (selenoprotein P, plasma, 1) (SEQ ID NO:300); AI230778 (ESTs, Highly similar to protein-tyrosine sulfotrans. 2) (SEQ ID NO:277); AI230914 (farnesyltransferase beta subunit) (SEQ ID NO:229); AI231807 (ferritin light chain 1) (SEQ ID NO:332); AI232268 (LDL receptor-related protein associated protein 1) (SEQ ID NO:244); AI235344 (geranylgeranyltransferase type I (GGTase-I)) (SEQ ID NO:304); AI237007 (ESTs, Highly similar to flavoprot.-ubiquin. Oxidoreduct.) (SEQ ID NO:376); AI638971 (mixed-tissue library cDNA clone rx04989 3) (SEQ ID NO:446); AI638997 (mixed-tissue library cDNA clone rx05048 3) (SEQ ID NO:430); AI639151 (mixed-tissue library cDNA clone rx02802 3) (SEQ ID NO:438); AI639209 (mixed-tissue library cDNA clone rx00680 3) (SEQ ID NO:419); AI639257 (mixed-tissue library cDNA clone rx01119 3) (SEQ ID NO:448); AI639477 (mixed-tissue library cDNA clone rx02351 3) (SEQ ID NO:407); D00569 (2,4-dienoyl CoA reductase 1, mitochondrial) (SEQ ID NO:311); D10262 (choline kinase) (SEQ ID NO:214); D10699 (ubiquitin carboxy-terminal hydrolase L1) (SEQ ID NO:234); D10854 (aldehyde reductase) (SEQ ID NO:285); D10874 (lysosomal vacuolar proton pump (16 kDa)) (SEQ ID NO:211); D16478 (mitochondrial long-chain enoyl-CoA hydratase) (SEQ ID NO:250); D17309 (delta 4-3-ketosteroid-5-beta-reductase) (SEQ ID NO:364); D28110 (myelin-associated oligodendrocytic basic protein) (SEQ ID NO:309); D28557 (cold shock domain protein A) (SEQ ID NO:313); D29766 (v-crk-associated tyrosine kinase substrate) (SEQ ID NO:202); D37951 (MIBP1 (c-myc intron binding protein 1)) (SEQ ID NO:230); D45247 (proteasome subunit RCX) (SEQ ID NO:212); D45249 (protease (prosome, macropain) 28 subunit, alpha) (SEQ ID NO:338); D78308 (calreticulin) (SEQ ID NO:293); D83948 (adult liver S1-1 protein) (SEQ ID NO:298); D88586 (eosinophil cationic protein) (SEQ ID NO:251); D89340 (dipeptidylpeptidase III) (SEQ ID NO:222); D89730 (Fibulin 3, fibulin-like extracellular matrix protein 1) (SEQ ID NO:344); D90211 (Lysosomal-associated membrane protein 2) (SEQ ID NO:345); E03229 (cytosolic cysteine dioxygenase 1) (SEQ ID NO:252); H33086 (EST108750 cDNA) (SEQ ID NO:427); H33725 (associated molecule with the SH3 domain of STAM) (SEQ ID NO:228); J02752 (acyl-coA oxidase) (SEQ ID NO:368); J02773 (heart fatty acid binding protein) (SEQ ID NO:289); J05022 (peptidylarginine deiminase) (SEQ ID NO:362); J05031 (Isovaleryl Coenzyme A dehydrogenase) (SEQ ID NO:288); J05132 (UDP-glucuronosyltransferase) (SEQ ID NO:330); K02248 (Somatostatin) (SEQ ID NO:270); L00191 (Fibronectin 1) (SEQ ID NO:350); L13202 (RATHFH2 HNF-3/fork-head homolog-2 (HFH-2)) (SEQ ID NO:220); L19998 (sulfotransferase family 1A, phenol-preferring, member 1) (SEQ ID NO:321); L24896 (glutathione peroxidase 4) (SEQ ID NO:318); L25605 (Dynamin 2) (SEQ ID NO:349); L26292 (Kruppel-like factor 4 (gut)) (SEQ ID NO:218); L29573 (neurotransmitter transporter, noradrenalin) (SEQ ID NO:216); L42855 (transcription elongation factor B (SIII) polypeptide 2) (SEQ ID NO:274); M10068 (NADPH-cytochrome P-450 oxidoreductase) (SEQ ID NO:254); M13100 (long interspersed repetitive DNA sequence LINE3) (SEQ ID NO:435); M19936 (Prosaposin-sphingolipid hydrolase activator) (SEQ ID NO:366); M23601 (Monoamine oxidase B) (SEQ ID NO:361); M24104 (synaptobrevin 2) (SEQ ID NO:303); M24104 (Vesicle-associated membrane protein (synaptobrevin 2)) (SEQ ID NO:303); M24852 (Neuron specific protein PEP-19 (Purkinje cell protein 4)) (SEQ ID NO:239); M31174 (thyroid hormone receptor alpha) (SEQ ID NO:264); M36453 (Inhibin, alpha) (SEQ ID NO:206); M55015 (nucleolin) (SEQ ID NO:348); M57276 (Leukocyte antigen (Ox-44)) (SEQ ID NO:367); M58404 (thymosin, beta 10) (SEQ ID NO:282); M80550 (adenylyl cyclase) (SEQ ID NO:204); M83745 (Protein convertase subtilisin/kexin, type I) (SEQ ID NO:226); M89646 (ribosomal protein S24) (SEQ ID NO:371); M91234 (VL30 element) (SEQ ID NO:329); M93273 (somatostatin receptor subtype 2) (SEQ ID NO:197); M93669 (Secretogranin II) (SEQ ID NO:256); M99485 (Myelin oligodendrocyte glycoprotein) (SEQ ID NO:360); S53527 (S100 calcium-binding protein, beta (neural)) (SEQ ID NO:343); S61868 (Ryudocan/syndecan 4) (SEQ ID NO:334); S72594 (tissue inhibitor of metalloproteinase 2) (SEQ ID NO:333); S77492 (Bone morphogenetic protein 3) (SEQ ID NO:276); S77858 (non-muscle myosin alkali light chain) (SEQ ID NO:287); U04738 (Somatostatin receptor subtype 4) (SEQ ID NO:261); U07619 (Coagulation factor III (thromboplastin, tissue factor)) (SEQ ID NO:377); U08259 (Glutamate receptor, N-methyl D-aspartate 2C) (SEQ ID NO:323); U10357 (pyruvate dehydrogenase kinase 2 subunit p45 (PDK2)) (SEQ ID NO:310); U14950 (tumor suppressor homolog (synapse associ. protein)) (SEQ ID NO:306); (immediate early gene transcription factor NGFI-B) (SEQ ID NO:225); U18771 (Ras-related protein Rab-26) (SEQ ID NO:205); U27518 (UDP-glucuronosyltransferase) (SEQ ID NO:279); U28938 (receptor-type protein tyrosine phosphatase D30) (SEQ ID NO:242); U38379 (Gamma-glutamyl hydrolase) (SEQ ID NO:292); U38801 (DNA polymerase beta) (SEQ ID NO:257); U67080 (r-MyT13) (SEQ ID NO:341); U67136 (A kinase (PRKA) anchor protein 5) (SEQ ID NO:336); U67137 (guanylate kinase associated protein) (SEQ ID NO:339); U72620 (Lot1) (SEQ ID NO:224); U75405 (procollagen, type I, alpha 1) (SEQ ID NO:217); U75917 (clathrin-associated protein 17) (SEQ ID NO:240); U77777 (interleukin 18) (SEQ ID NO:319); U78517 (cAMP-regulated guanine nucleotide exchange factor II) (SEQ ID NO:369); U89905 (alpha-methylacyl-CoA racemase) (SEQ ID NO:238); V01244 (Prolactin) (SEQ ID NO:317); X02904 (glutathione S-transferase P subunit) (SEQ ID NO:355); X05472 (2.4 kb repeat DNA right terminal region) (SEQ ID NO:442); X06769 (FBJ v-fos oncogene homolog) (SEQ ID NO:200); X06916 (S100 calcium-binding protein A4) (SEQ ID NO:335); X13905 (ras-related rab1B protein) (SEQ ID NO:315); X14323 (Fc receptor, IgG, alpha chain transporter) (SEQ ID NO:352); X16933 (RNA binding protein p45AUF1) (SEQ ID NO:373); X53427 (glycogen synthase kinase 3 alpha (EC 2.7.1.37)) (SEQ ID NO:241); X53504 (ribosomal protein L12) (SEQ ID NO:139); X54467 (cathepsin D) (SEQ ID NO:314); X55153 (ribosomal protein P2) (SEQ ID NO:347); X57281 (Glycine receptor alpha 2 subunit) (SEQ ID NO:235); X58294 (carbonic anhydrase 2) (SEQ ID NO:359); X59737 (ubiquitous mitochondrial creatine kinase) (SEQ ID NO:297); X60212 (ASI homolog of bacterial ribosomal subunit protein L22) (SEQ ID NO:305); X62950 (pBUS30 with repetitive elements) (SEQ ID NO:326); X67805 (Synaptonemal complex protein 1) (SEQ ID NO:210); X72757 (cox VIa gene (liver)) (SEQ ID NO:374); X74226 (LL5 protein) (SEQ ID NO:353); X76489 (CD9 cell surface glycoprotein) (SEQ ID NO:308); X76985 (latexin) (SEQ ID NO:236); X82445 (nuclear distribution gene C homolog (Aspergillus)) (SEQ ID NO:232); X84039 (lumican) (SEQ ID NO:237); X89696 (TPCR06 protein) (SEQ ID NO:201); X97443 (integral membrane protein Tmp21-I (p23)) (SEQ ID NO:358); X98399 (solute carrier family 14, member 1) (SEQ ID NO:267); Y17295 (thiol-specific antioxidant protein (1-Cys peroxiredoxin)) (SEQ ID NO:337); Z48225 (protein synthesis initiation factor eIF-2B delta subunit) (SEQ ID NO:255); Z49858 (plasmolipin) (SEQ ID NO:363) and mammalian homologues. 54. The set of biomarkers of claim 52, wherein at least one member of the set of biomarkers is an expressed sequence tag (EST). 55. The set of biomarkers of claim 52, for use in the measurement of age-dependent cognitive decline. 56. The set of biomarkers of claim 55, wherein the age-dependent cognitive decline is an age-dependent neurodegenerative condition. 57. The set of biomarkers of claim 56, wherein the age-dependent neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 58. The set of biomarkers of claim 52, for use in the measurement of the degree of the safety or effectiveness of compounds or procedures directed against age-related cognitive decline. 59. The use of a biomarker for brain aging in the treatment of cognitive decline in aging in a mammal, (a) wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, selected from the group consisting of: (1) a biomarker selected from the set of biomarkers of claim 23; (2) a biomarker selected from the set of biomarkers of claim 38; (3) a biomarker selected from the set of expressed sequence tags (EST) of claim 47; and (4) a biomarker identified by the method of claim 1; and (b) wherein the treatment is targeted to a polynucleotide corresponding to the biomarker or to a polypeptide encoded by said polynucleotide. 60. The use of claim 59, wherein at least one member of the set of biomarkers is an expressed sequence tag (EST). 61. The use of claim 59, wherein the cognitive decline in aging is an age-related neurodegenerative condition. 62. The use of claim 61, wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 63. The use of a biomarker for brain aging, in identification of a medicament for the treatment of cognitive decline in aging in a mammal, (a) wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, selected from the group consisting of: (1) a biomarker selected from the set of biomarkers of claim 23; (2) a biomarker selected from the set of biomarkers of claim 38; (3) a biomarker selected from the set of expressed sequence tags (EST) of claim 47; and (4) a biomarker identified by the method of claim 1; and (b) wherein the treatment is targeted to a polynucleotide corresponding to the biomarker or to a polypeptide encoded by said polynucleotide. 64. The use of claim 63 wherein at least one member of the set of biomarkers is an expressed sequence tag (EST). 65. The use of claim 63, wherein the cognitive decline in aging is an age-related neurodegenerative condition. 66. The use of claim 65, wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease. 67. A medicament, device or procedure for the treatment of cognitive decline in aging in a mammal, (a) wherein the medicament is identified by the use of a biomarker, (b) wherein the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide, selected from the group consisting of: (1) a biomarker selected from the set of biomarkers of claim 23; (2) a biomarker selected from the set of biomarkers of claim 38; (3) a biomarker selected from the set of expressed sequence tags (EST) of claim 47; and (4) a biomarker identified by the method of claim 1; and (c) wherein the treatment is targeted to a polynucleotide corresponding to the biomarker or to a polypeptide encoded by said polynucleotide. 68. The medicament, device or procedure of claim 67, wherein the cognitive decline in aging an age-related neurodegenerative condition. 69. The medicament, device or procedure of claim 67, wherein the age-related neurodegenerative condition is Alzheimer's disease or Parkinson's disease. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Brain aging processes are enormously complex phenomena that affect multiple systems, cell types and pathways, and result in cognitive decline and increased risk of Alzheimer's disease (AD). Landfield P W et al., J Neurobiol 23: 1247-1260 (1992). Although several biological mechanisms have been putatively linked to brain aging or Alzheimer's disease, including inflammation, oxidative stress, Ca 2+ dyshomeostasis (Landfield, P W & Pitler T A, Science 226: 1089-1092 (1984); Landfield P W et al., J Neurobiol 23: 1247-1260 (1992)), mitochondrial dysfunction and chronic exposure to adrenal stress hormones (Landfield P W et al., Science 214: 581-584 (1981); Porter N M & Landfield P W, Nature Neurosci 1: 3-4 (1998)), the specific mechanisms and pathways, if any, through which they are linked to impaired brain function are not understood. It is widely thought that gene expression changes contribute to many aspects of declining function with aging. Finch C E, Longevity, Senescence and the Genome, 37-42 (Univ. Chicago Press, Chicago, 1990). It is also thought that gene expression changes are important for processing and storage of memory. However, not all genes that change expression in the brain with aging are thought to be important for cognition. Gene-expression changes that specifically contribute to age-related memory decline should selectively change with brain aging and should be correlated specifically with measures of age-associated cognitive decline; that is, a subset of the full set of aging-dependent genes should also correlate with age-related cognitive decline. See, Lockhart D J & Barlow C, Nat Rev Neurosci 2: 63-68 (2001) and Mimics K, Nat Rev Neurosci 2: 444-447 (2001). If a subset of age-dependent genes also shows expression patterns directly correlated with age-related memory decline, then such a subset of “aging and cognition-related genes” (ACGs) would be extremely helpful as biological indexes (“biomarkers”) for assessing or diagnosing the degree of age-related cognitive impairment in individual subjects. In turn, the ability to measure aging-related cognitive impairment quantitatively is essential for discovering new therapeutic targets, and developing new strategies and pharmaceutical compounds for counteracting normal age-related cognitive decline and/or age-related neurodegenerative diseases, including Alzheimer's disease (AD) or Parkinson's disease (PD). Identifying ACGs in any mammalian species therefore, might have great therapeutic usefulness. Moreover, because of the well-established homologies of most genes across mammalian species and because of the clear similarities in patterns of brain aging and cognitive decline across species, identification in any mammal would have human health implications. Furthermore, because the primary risk factor for Alzheimer's disease and Parkinson's disease is aging itself, therapeutic approaches developed for aging-related cognitive impairment should also help ameliorate cognitive decline from age-related neurodegenerative disease. Thus, there is a clear need for identifying ACGs but, to date, such genes have not been discovered for any mammal. Gene microarray technology provides a powerful approach for unraveling the complex processes of aging. To date, however, its impact has been limited by statistical problems, small sample sizes, and difficulty in assessing functional relevance. Moreover, studies that have examined gene expression during brain aging using microarrays have not used sample sizes large enough to provide adequate statistical power for formal statistical testing. Lee C K et al., Nature Genetics 25: 294-297 (2000); Jiang C H et al., Proc Natl Acad Sci USA 98: 1930-1934 (2001) Therefore, even the genes they have reported to change with aging have not been validated by accepted statistical criteria. The extremely large data sets generated by microarrays pose formidable bioinformatics and resource problems that have to date limited the impact of this powerful technology. Because of these difficulties, most microarray studies have relied on simple fold change comparisons in small samples. However, neither fold change analyses nor the small sample protocols widely used allow the direct estimates of variance necessary for defining type I error (false positives). In addition, fold change criteria, by definition, select for large changes. Therefore, they exhibit low detection sensitivity (high false negatives, or type II error), and are unable to identify the modest changes that often characterize functionally important (and, therefore, tightly regulated) genes. The inability to assign type I error is a particularly critical problem for microarray studies because the thousands of comparisons of gene expression in such analyses greatly increase the expected false positives. For example, even if group sizes were sufficient for formal statistical analyses, and 5000 gene transcripts were each tested by t-test for differences between two conditions at p≦0.05, the false positive rate is equal to the p-value and, consequently, 5% of the 5000 tested transcripts (250) would be expected to be found significant by chance alone. Although microarray studies have some important offsetting advantages that improve statistical confidence (e.g., co-regulation of genes within a functional group), there is increasing recognition that microarray experiments should generally meet the same statistical standards as other biological experiments or, at least, should systematically estimate the degree of statistical uncertainty. Several strategies to improve statistical confidence have been developed for small-sample microarray studies, but these generally rely on indirect estimates of variance and/or greatly sacrifice sensitivity (i.e., stringent p-values). Another highly important problem of microarray studies is that of determining which of the hundreds of expression changes that may be observed are likely to be functionally relevant. Correlation analysis is one quantitative approach to linking gene expression with function, although it also requires relatively large sets of independent samples. Expression-function correlations fulfill a key prediction of a causal relationship (i.e., that causally related variables should co-vary) and therefore, can serve as a valuable tool for the identification of candidate functionally relevant genes. Nonetheless, there have been few correlation studies attempting to link cognitive dysfunction with univariate gene expression patterns across individual subjects, much less using the massive amounts of data generated in microarray analyses. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides a statistical and functional correlation strategy to identify changes in cellular pathways specifically linked to impaired cognitive function with aging. The bioinformatics and functional correlation strategy improves the power of microarray analyses and provides the ability to test whether alterations in specific hippocampal pathways are correlated with aging-related cognitive impairment. The invention is useful for application in large, well-powered groups and for controlling type I error (false positives), enhancing detection sensitivity (reducing type II false negatives) and determining which aging changes in expression are most closely correlated with declining brain function. Accordingly, the invention provides a method for identifying a biomarker for brain aging, where the biomarker is a polynucleotide or a polypeptide encoded by said polynucleotide. The method involves first obtaining a set of polynucleotides obtained from a set of brain samples (such as hippocampal samples), where the members of the set of brain samples were obtained from members of a set of mammals, wherein the set of mammals contains more than two members, with at least young, mid-aged and aged members, and then identifying the identity and amount of the members of the set of polynucleotides present in the brain samples. The method then involves the steps of deleting certain non-biomarker polynucleotides from the set of polynucleotides, testing by a conventional statistical method (such as) for a significant effect of aging across the young, mid-aged and aged members; and correlating the identity and amount of the members of the set of polynucleotides present in the brain samples with cognitive performance in behavioral tests. By use of the methods of the invention, one skilled in the genomics art can identify multiple groups of related genes, many representing processes with previously unrecognized relationships to aging and/or cognitive dysfunction. Thus, the invention also provides compositions of matter comprising sets of genes, expressed sequence tags (ESTs), polynucleotides and polypeptides encoded by said polynucleotides identified as being involved in the aging processes. These sets usefully result in a statistically validated, comprehensive overview of mammalian, including human, functional brain aging. In particular, the set of genes can be used for the diagnosis of human age-related disease, such as an age-related neurodegenerative condition, including Alzheimer's disease or Parkinson disease. The invention provides a set of biomarkers for brain aging, where (a) the set of biomarkers comprises at least two members; (b) the brain expression patterns of the members of the set are significantly altered with aging as determined by a conventional statistical method (such as ANOVA or student's t test), with p<0.05; (c) the brain expression patterns of the members of the set are correlated (using a conventional statistical correlation test, e.g., tested by Pearson's or Spearman's correlation test) across age groups with cognitive performance in behavioral tests, with a correlation of p<0.05 (or with a more stringent correlation of p<0.01 or p<0.001) between brain expression and cognitive performance; and (d) the cognitive performance in behavioral tests significantly altered with aging as determined by a conventional statistical method. The biomarkers may also correlate with a behavioral measure of functional impairment, such as an age-related neurodegenerative condition, including Alzheimer's disease or Parkinson's disease. The invention also provides a set of at least two biomarkers for brain aging, where where the brain expression patterns of the members of the set are significantly altered with aging as measured by a conventional statistical correlation test at a significance level of p<0.01. The invention further provides a set of at least two biomarkers for brain aging, where the brain expression patterns of the members of the set are significantly altered with aging as determined by a conventional statistical method, with p<0.05 (or a more stringent correlation, such as p<0.025, p<0.01 or p<0.001). In one example of the invention, rats in three age groups (Young, Mid-Aged, Aged) were characterized on two memory tasks and each mammal's hippocampal CA1 region was analyzed by a microarray analysis for gene expression. These analyses identified multiple groups of genes, many representing pathways with previously unrecognized relationships to aging and/or cognitive decline. The analysis showed that for all groups, the aging changes in expression began by mid-life. In one aspect of the invention, the known interactions of the identified processes suggest an integrative model of specific cellular cascades that begin in mid-life and eventually impair cognitive function and increase neuronal vulnerability. Initially decreased neuronal activity and/or oxidative metabolism trigger separate but parallel genomic cascades in neurons and glia. In neurons, the cascade results in reductions of immediate early gene signaling, biosynthesis, synaptogenesis and neurite remodeling. In contrast, glia undergo increased lipid metabolism and mediate a cycle of demyelination and remyelination that induces antigen presentation, inflammation, oxidative stress and extracellular restructuring. Intervention studies based on these findings can identify the cause and effect interactions among the complex processes of brain aging. |
On-line virtual catalogue or flyer |
The present application relates to a NEW, “REVOLUTIONARY”, patent pending, “Internet” Technology—VIRTUAL “Catalogue” Shopping. The New, VIRTUAL “Catalogue” Shopping software will “Revolutionize” the way products are “Marketed” and “Presented” for sale on the Internet and the way Consumers and Businesses Shop Online. |
1. A method for providing a virtual on-line catalogue or flyer, comprising: displaying information relating to a product or service; providing a symbol within the displayed information for selection by a user; and recording an identification of the product or service for purchase upon detecting the user's selection of the symbol. 2. The method of claim 1 wherein: the displaying step includes displaying an image of the product; and the providing step includes displaying an icon overlaid on the image. 3. The method of 1 wherein: the displaying step includes displaying textual information relating to the product or service; and the providing step includes displaying an icon overlaid on the textual information. 4. The method of claim 1 wherein the recording step includes recording the identification in an electronic shopping basket. 5. The method of claim 1, further including transferring a network connection of the user to another web site upon detecting the selection of the symbol. 6. The method of claim 1, further including transferring a network connection of the user to a web site providing electronic order processing for on-line purchases of products or services based upon the selection of the symbol. 7. The method of claim 5 wherein the transferring step includes transferring the network connection to a web site corresponding with an entity providing the products or services. 8. The method of claim 5 wherein the transferring step includes transmitting an identification of the user along with the transfer of the network connection. 9. The method of claim 1, further including displaying instructions relating to selection of the symbol for purchase of the product or service. 10. The method of claim 1 wherein the providing step includes displaying at least one of the following: an icon; one or more words; one or more letters; alphanumeric information; or a graphic. 11. The method of claim 1, further including permitting selection of the symbol by one or more of the following: a touch screen; a cursor control device; or keyed input. 12. The method of claim 1 wherein the displaying step includes selectively displaying textual information in multiple languages. 13. The method of claim 1 wherein: the displaying step includes displaying information relating to a plurality of products or services; and the providing step includes providing a plurality of symbols within the displayed information for selection by a user; and further including associating the plurality of symbols with a plurality of individual web sites. 14. The method of claim 13, further including transferring, upon detecting the user's selection of one of the symbols, a network connection of the user to one of the plurality of web sites associated with the selected symbol. 15. The method of claim 1 wherein the providing step includes displaying an icon for selection by the user to add an identification of the corresponding product to an electronic shopping basket without any additional user input. 16. The method of claim 1, further including displaying, upon detecting the user's selection of the symbol, a warning window permitting the user to confirm the selection of the product or service for purchase or to cancel the selection. 17. The method of claim 1, further including providing a confirmation of the selection of the symbol. 18. The method of claim 17 wherein the providing step includes providing one or more of the following as the confirmation: a text message; an audible sound; highlighting the symbol; flashing the symbol; altering a visual appearance of the symbol; or in any other way. 19. The method of claim 1 wherein the providing step includes associating the symbol with a plurality of products or services. 20. A method for providing a virtual on-line catalogue or flyer, comprising: specifying a plurality of electronic pages for displaying information relating to products or services in a plurality of categories; displaying a symbol relating to an index identifying the plurality of categories; displaying at least a portion of the index upon detecting a user's selection of the symbol; and electronically linking the identification of the categories in the index with the pages for the corresponding products or services. 21. The method of claim 20, further including: detecting a user's selection of one of the identified categories in the index; and displaying one of the pages corresponding with the selected category. 22. The method of claim 21 wherein the displaying the one or more pages step includes displaying a first page within an organized set of pages for the selected category. 23. The method of claim 20, further including: displaying a symbol relating to an index page; and displaying the index within a margin of each displayed page upon detecting a user's selection of the symbol relating to the index page. 24. The method of claim 20, further including specifying one or more of the following as the categories within the index: types of product; gender-specific products; products as gifts; products for particular occasions; products within a particular price range; or many other “categories”. 25. The method of claim 20 wherein the displaying the index step includes displaying the identifications of the categories in one or more of the following orders: alphabetical order; reverse alphabetical order; non-alphabetical order; an order based upon particular criteria; or a random order. 26. The method of claim 20 wherein the displaying the symbol step includes displaying the symbol at a particular location within each displayed page. 27. The method of claim 20, further including: receiving an identification of a particular product type; searching for information relating to the particular product type; and displaying an identification of pages resulting from the search. 28. The method of claim 20 wherein the displaying the index step includes displaying a separate page or pages containing the index, the separate page or pages being displayed at the beginning, end, or in between a plurality of pages for a particular web site. 29. A method for providing a virtual on-line catalogue or flyer, comprising: specifying a plurality of electronic pages for displaying information relating to products or services in a plurality of categories; organizing the plurality of pages in a particular order; displaying a current one of the plurality of pages; and selectively displaying at least a portion of the particular order along with an identification of the current displayed page within the order. 30. The method of claim 29 wherein the selectively displaying step includes: displaying a list identifying at least a portion of the pages in numerical order; and identifying in the list a category for each identified page. 31. The method of claim 29, further including: permitting the user to select an identification of a particular page within the displayed order of pages; and displaying the particular page upon detecting the user's selection of the identification of the particular page. 32. The method of claim 29, further including electronically linking identifications of the pages in the displayed order within the corresponding pages. 33. The method of claim 29 wherein the selectively displaying step includes displaying the portion of the particular order in a pull-down menu; a pop-up window; or in any other visual way. 34. A method for providing a virtual on-line catalogue or flyer, comprising: specifying a plurality of electronic pages for displaying information relating to products or services in a plurality of categories; organizing the plurality of pages in a particular order; recording, based upon user input, an identification of a set of the pages; and displaying only pages within the set of pages upon selection by the user. 35. The method of claim 34, further including permitting the user to add an identification of one of the pages to the set. 36. The method of claim 34, further including permitting the user to delete an identification of one of the pages from the set. 37. The method of claim 34, further including permitting the user to specify a particular order in which to display the pages within the set. 38. The method of claim 34 wherein the displaying step includes invoking the display of only the pages in the set upon detection of the user's selection of a favorites symbol. 39. The method of claim 34 wherein the displaying step includes: organizing the pages of the set in a particular order; and displaying the pages in the order upon detecting the user's repeated selection of a next page symbol. 40. The method of claim 39, further including providing an indication of a last displayed page in the order. 41. The method of claim 34, further including saving the identification of the set of pages associated with an identification of the user. 42. The method of claim 34, further including deleting the identification of the set of pages based upon a time parameter. 43. The method of claim 34, further including saving the identification of the set of pages based upon session-related information. 44. The method of claim 34, further including associating the set of pages with a wish list for specifying products desired by the user. 45. A method for providing a virtual on-line catalogue or flyer, comprising: displaying, within a page, an image relating to a plurality of products or services; detecting a selection of the image by a user; and displaying on a separate page a larger image of the plurality products based upon the selection by the user. 46. The method of claim 45 wherein the displaying the separate page step including displaying additional information relating to the plurality of products or services. 47. The method of claim 45, further including displaying instructions for purchasing one of the products or services. 48. The method of claim 45, further including transferring a network connection of the user to another web site for display of the separate page. 49. The method of claim 48 wherein the transferring step includes transferring the network connection to a web site corresponding with an entity providing the products or services. 50. The method of claim 48 wherein the transferring step includes transmitting an identification of the user along with the transfer of the network connection. 51. A method for providing a virtual on-line catalogue or flyer, comprising: displaying, within a page, an image relating to a plurality of products or services; detecting a selection of a section of the image by a user; and displaying on a separate page a larger image of the section of the image based upon the selection by the user. 52. The method of claim 51 wherein the displaying the separate page step includes displaying additional information relating to products or services identified within the section of the image. 53. The method of claim 51, further including displaying instructions for purchasing one of the products or services. 54. The method of claim 51, further including transferring a network connection of the user to another web site for display of the separate page. 55. The method of claim 54 wherein the transferring step includes transferring the network connection to a web site corresponding with an entity providing the products or services. 56. The method of claim 54 wherein the transferring step includes transmitting an identification of the user along with the transfer of the network connection. 57. A method for providing a virtual on-line catalogue or flyer, comprising: specifying a plurality of electronic pages for displaying information relating to products or services in a plurality of categories; organizing the plurality of pages in a particular order having a first page and a last page; displaying the pages according to the order based upon a user's selection of a next page; and displaying a particular one of the pages upon detecting the user's selection of the next page while viewing the last page. 58. The method of claim 57 wherein the displaying the particular page step includes displaying the first page upon detecting the user's selection of the next page while viewing the last page. 59. The method of claim 57 wherein the displaying the particular page step includes transferring a network connection of the user to a particular page of another web site upon detecting the user's selection of the next page while viewing the last page. 60. The method of claim 57, further including: displaying a home button; and displaying a particular preprogrammed page upon detecting the user's selection of the home button. 61. The method of claim 60 wherein the displaying the particular preprogrammed page step includes displaying the home page of an entity providing the products or services. 62. A method for providing a virtual on-line catalogue or flyer, comprising: specifying a plurality of templates for electronic pages, the templates having varying configurations and layouts of sections for containing content; receiving a selection of one of the plurality of templates; receiving content for the selected template; entering the content into the sections based upon user input; and formatting the selected template with the received content into an electronic page for displaying information relating to products or services identified by the received content. 63. The method of claim 62 wherein the specifying step includes specifying at least one of the templates having overlapping sections. 64. The method of claim 62 wherein the receiving content step includes receiving at least one of the following: images; digitized photographs; icons; symbols; description information; pricing information; textual information; graphics; or other data. 65. The method of claim 62 wherein the entering step includes generating a displayed border around at least one of the sections. 66. The method of claim 62, further including deleting one or more of the sections from the selected template based upon user input. 67. The method of claim 62, further including adding one or more new sections to the selected template based upon user input. 68. The method of claim 62 wherein the formatting step includes formatting the selected template into a web page for network transmission. 69. A method for providing a virtual on-line catalogue or flyer, comprising: specifying a template for electronic pages, the templates having a plurality of connected sections forming a grid; receiving multiple selections of the sections; joining the selected sections to form a plurality content sections based upon the multiple selections; receiving content for the content sections; entering the content into the content sections based upon user input; and formatting the selected template with the received content into an electronic page for displaying information relating to products or services identified by the received content. 70. The method of claim 69 wherein the joining step includes forming polygonal shapes or curvilinear shapes for the content sections. 71. The method of claim 69 wherein the receiving content step includes receiving at least one of the following: images; digitized photographs; icons; symbols; description information; pricing information; textual information; graphics; or other data. 72. The method of claim 69 wherein the formatting step includes formatting the selected template into a web page for network transmission. 73. A method for providing a virtual on-line catalogue or flyer, comprising: specifying a template for electronic pages, the templates having a plurality of dots forming a grid; receiving multiple selections of the dots; joining the selected sections to form a plurality content sections based upon the multiple selections; receiving content for the content sections; entering the content into the content sections based upon user input; and formatting the selected template with the received content into an electronic page for displaying information relating to products or services identified by the received content. 74. The method of claim 73 wherein the joining step includes forming polygonal shapes or curvilinear shapes for the content sections. 75. The method of claim 73 wherein the receiving content step includes receiving at least one of the following: images; digitized photographs; icons; symbols; description information; pricing information; textual information; graphics; or other data. 76. The method of claim 73 wherein the formatting step includes formatting the selected template into a web page for network transmission. 77. A method for providing a virtual on-line catalogue or flyer, comprising: displaying within a page information relating to a product or service; providing a way for a user to select the product or service for purchase; assembling the page for display from information in one or more stored locations; and configuring the page in a static format wherein the page maintains a same presentation. 78. The method of claim 77 wherein the configuring step includes configuring the page in one of a plurality of weights relating to varying sizes of the corresponding page for electronic transmission and display. 79. The method of claim 78 wherein the configuring step includes selecting a particular one of the weights for the page based upon a download speed requirement of a particular user or market. 80. The method of claim 77, further including: allowing a user to select a download option; and transmitting the page in a particular weight based upon the selected download option. 81. The method of claim 77 wherein the configuring step includes providing templates or grids for use in configuring the page in a plurality of weights. 82. The method of claim 78 wherein the configuring step includes selecting a percentage adjustment for the weights based upon a viewable area of a display device for presentation of the page. 83. The method of claim 77 wherein the assembling step includes assembling the page to contain static features, dynamic features, or a combination of static and dynamic features. 84. The method of claim 77, further including transmitting the page as a single unit or as multiple components. 85. A method for providing a virtual on-line catalogue or flyer having an adjustable weight page, comprising: displaying within a page information relating to a product or service; providing a way for a user to select the product or service for purchase; and configuring the page in a plurality of weights relating to varying sizes of the corresponding page for electronic transmission and display. 86. The method of claim 85 wherein the configuring step includes selecting a particular one of the weights for the page based upon a connection speed requirement of a particular user or market. 87. The method of claim 85, further including: allowing a user to select a download option; and transmitting the page in a particular one of the weights based upon the selected download option. 88. The method of claim 85 wherein the configuring step includes providing templates or grids for use in configuring the page in the plurality of weights. 89. The method of claim 85 wherein the configuring step includes selecting a percentage adjustment for the weights based upon a viewable area of a display device for presentation of the page. 90. The method of claim 85, further including assembling the page to contain static features, dynamic features, or a combination of static and dynamic features. 91. The method of claim 85, further including transmitting the page as a single unit or as multiple components. 92. The method of claim 85 wherein the configuring step includes performing the configuring automatically based upon programmatic control or performing the configuring manually based upon user input. 93. An apparatus for executing the method recited in claim 1. 94. A computer program product, comprising: a computer-readable medium containing instructions for controlling a computer system to perform the method recited in claim 1. |
<SOH> I. INTRODUCTION <EOH>The present application relates to a NEW, “REVOLUTIONARY”, patent pending, “Internet” Technology—VIRTUAL “Catalogue” Shopping. The New, VIRTUAL “Catalogue” Shopping software will “Revolutionize” the way products are “Marketed” and “Presented” for sale on the Internet and the way Consumers and Businesses Shop Online. Basically, the NEW, “Revolutionary” VIRTUAL “Catalogue” Shopping system may TRULY Replicate or Duplicate the ease and convenience of consumers (or businesses) shopping for products from a beautiful, “PRINTED”, full color Catalogue or Flyer—BUT, when shopping on the Internet. Contrarily, TODAY almost ALL, if not all, Online Retailers use the time-consuming, frustrating, Standard “Category/Sub-Category” system, which requires consumers to “pin-down” the EXACT type of product (s) which he/she may want to view (by selecting a product category and, subsequently, several additional sub-categories of products) BEFORE they see any photos, descriptions or pricing information of the many products for sale (except for a few “featured” products). This STRICT, regimented procedure severely restricts the amount of “Impulse” buying done by consumers on the Internet today, and also wastes a tremendous amount of consumers' time by their “clicking” back-and-forth to the various categories and sub-categories within any of the Online Retailers' web sites—particularly when the consumers DO NOT know EXACTLY what specific products they would like to buy (which is very, very common). The Standard “Category/Sub-Category” system simply does NOT allow consumers the opportunity or convenience of BROWSING on the Internet, like they can through a Retail Store or printed Catalogue or Flyer—to see if there are any products which they may wish to purchase—many on “Impulse”. Alternatively, the “Revolutionary” VIRTUAL “Catalogue” Shopping system provides a great, NEW, fast and efficient shopping experience for consumers—its like “opening up” and “BROWSING” through a beautiful, “PRINTED”, full color “Catalogue” or “Flyer”. Consequently, Online customers will see “good-size” photos with descriptions and pricing information for ALL products, STARTING right at the beginning of the VIRTUAL “Catalogue”—WITHOUT the consumers having to FIRST pick a specific category and, subsequently, many, many additional sub-category listings (to select or pin down the EXACT TYPE of product which they are interested in buying) BEFORE being able to review “Specific” product photographs &/or listings, as required when shopping today at the vast majority, if not all, of Online Retailers. In essence, VIRTUAL “Catalogue” Shopping will provide consumers with a UNIQUE, Online “Catalogue” or “Flyer” format, which has been successfully used by major Retailers and Mail Order/Catalogue Houses in Canada, U.S.A. and other countries throughout the world for decades & decades (by sending beautiful, “PRINTED”, full color Catalogues and Flyers to consumers' homes). The VIRTUAL “Catalogue” Shopping system provides ONE of the very best, NEW, great, “consumer-friendly” shopping experiences for ALL consumers on the Internet and, in particular, for those consumers who do NOT know EXACTLY what they want to buy—they simply want to BROWSE quickly through pictures of a WIDE variety of products (like Retail/Mail Order Catalogues & Flyers) to get some ideas and, in many cases, purchase on “Impulse” from the great photos and descriptive information provided. It has been proven over decades & decades that consumers thoroughly enjoy quickly “glancing” or “BROWSING” through full color, “PRINTED” Catalogues and Flyers (with great photos of each product, descriptions and pricing/savings information). Not only do consumers look for “specific” items in same, but they also see items (Photos) which they “Impulse” Buy because of the great, eye-catching, attractive “pictorial” presentations (with accompanying product descriptions and pricing information) of these items. In addition, glancing through Catalogues and Flyers is also extremely helpful in assisting consumers in deciding on “specific” items to buy as “gifts” or for their home, office, cottage, car, themselves, etc. The NEW, Revolutionary VIRTUAL “Catalogue” Shopping system captures ALL of these market-proven advantages of the beautiful, “printed”, full color Catalogues and Flyers. Basically, there is a tremendous NEED for the “Revolutionary” VIRTUAL “Catalogue” Shopping system on the Internet today. Consumers, businesses and Online Retailers will be saying—“AT LAST !!—A system on the Internet which may TRULY replicate Catalogue and Retail Store shopping”. Following are just a few of the MAIN reasons why the VIRTUAL “Catalogue” Shopping system will be a welcomed addition to the Internet, not only by Consumers, but also by E-tailers, Search Engine Companies, Internet Service Providers and Computer Software & Systems Companies: Since the present VIRTUAL “Catalogue” Shopping Technology very specifically FILLS the above mentioned “VOID”, among other things, (it REALLY does DUPLICATE “Catalogue” Shopping), our VIRTUAL “Catalogue” Shopping Technology may also become a very major component in the next generation of e-commerce sites (both Business-to-Consumer & Business-to-Business). The potential number of customers for VIRTUAL “Catalogue” Shopping is absolutely enormous—Tens (if not hundreds) of thousands of E-tailers (both B-to-C and B-to-B), as well as thousands of Search Engine Companies, Internet Service Providers, Computer Software & Systems Companies, etc. worldwide. In addition, the present “Revolutionary” VIRTUAL “Catalogue” Shopping Technology is totally adaptable to providing the very best possible “pictorial” presentation of products, in a very consumer-friendly manner, on the smaller (compared to PC's) “hand-held” devices (& PDA's) connected to the Internet. This market is expected to grow at astronomical rates in the next 2-5 years. Furthermore, the exceptional “pictorial” presentation of products (with product descriptions and pricing information) in the VIRTUAL “Catalogue” Shopping system will also create a fantastic, eye-catching, easy-to-use, consumer-friendly shopping system for consumers using their own TELEVISIONS, for example, for Internet shopping. Just imagine how appealing any of the VIRTUAL “Catalogue” Shopping web pages would appear on small or large television screens—as consumers just easily & casually “flip” through the Catalogue pages on their TELEVISION screens, WITHOUT having to endure the cumbersome, time-consuming frustrating steps required in the Standard “Category/Sub-Category” systems used Online TODAY. Considering the enormous anticipated growth rates in the near future of consumers using their televisions for the Internet, the potential growth for VIRTUAL “Catalogue” Shopping in this area ALONE is very, very substantial. Since these consumers, in general, would be less “computer literate” than those using PC's &/or “hand-held” devices, the simplified method of shopping with the VIRTUAL “Catalogue” Shopping system would be a tremendous advantage for them. II. VIRTUAL “Catalogue” Shopping—SUPPLEMENT, NOT A REPLACEMENT The new, VIRTUAL “Catalogue” Shopping System is designed to be a SUPPLEMENT, for example, to the many small, medium and large Online E-tailers currently marketing their products on the Internet—it will provide consumers with a NEW, “Revolutionary”, FAST, CONVENIENT, FUN, Easy-To-Use” system to Shop Online. VIRTUAL “Catalogue” Shopping is NOT necessarily intended to REPLACE the Standard “Category/Sub-Category” systems currently used by thousands & thousands of E-tailers (Business-to-Consumer & Business-to-Business) for selling their products Online, although it may alternatively operate alone. Our UNIQUE, VIRTUAL “Catalogue” Shopping system ties-in with any of these E-tailers' “Back-End” systems—such as customer ordering, credit card processing, checking customer credit, inventory control, sales statistics, information gathering, etc. Consequently, the “Revolutionary” VIRTUAL “Catalogue” Shopping system simply provides E-tailers with an ADDITIONAL, NEW, EXCITING, system (which is exceptionally consumer-friendly) to sell some (or all—for smaller e-tailers) of their products on THEIR OWN web sites. Ties-In—No Interruption to E-tailers' Current Online Business The VIRTUAL “Catalogue” Shopping system allows E-tailers to, for example, simply, quickly and economically EXPAND their web site to include the new VIRTUAL “Catalogue” Shopping system on their web site, along with their current Online system. There is NO NEED, in some implementations, for E-tailers to change or alter their current Category/Sub-Category systems—therefore, the VIRTUAL “Catalogue” Shopping system may be introduced on any E-tailer's web site without causing any interruptions to their current Online business. Selection and Number of Products E-tailers which sell 750-1,000 or more products on their web site would probably use the VIRTUAL “Catalogue” Shopping &/or VIRTUAL “Flyer” Shopping systems to feature only some, NOT ALL, of their products, although all products may be featured. In some implementations, periodically, these E-tailers would select specific products to be featured in their VIRTUAL “Catalogue” or VIRTUAL “Flyer”. They would select these products from a WIDE range of different types of products which they currently sell—similar to the marketing procedure used for many decades by “brick-&-mortar” retailers for their various Catalogues and Flyers to promote a very limited number of their very best &/or great value &/or specialty buy, etc. products sold in each of their various departments. As a result, consumers would be able to quickly (by “flipping” on-line through the VIRTUAL “Catalogue” pages) view a WIDE range & variety of different types of products from a specific e-tailer, WITHOUT enduring the time-consuming, frustrating procedure of “Clicking back-&-forth” in the various Category & Sub-Category selections of the e-tailer's web site. The number of products to be featured on a typical VIRTUAL “Catalogue” Shopping or VIRTUAL “Flyer” Shopping web page could range from 5 to 15, for example, depending on the types of products, i.e. clothing, jewelry, toys, etc. Therefore, a typical 50 to 100 page Catalogue or Flyer would include 250 to 1,500 products—more likely averaging 500 to 1,000 products. Any number of pages and products may be used. Example of Positioning in Web Site Depending on the number and types of products which a particular e-tailer sells on its web site, it may decide to POSITION the VIRTUAL “Catalogue” Shopping or VIRTUAL “Flyer” Shopping system either at the beginning of its web site to feature a very WIDE range of products (which will quickly & clearly show the consumers the great range of products offered through out the entire web site), &/or at the beginning of all, or some, of its main Category Selections such as Women's Clothing, Jewelry, Giftware, etc. (to feature the WIDE variety of products and price ranges available within each of its main Categories). Use of VIRTUAL “Catalogue” Shopping & VIRTUAL “Flyer” Shopping Logos Our VIRTUAL “Catalogue” Shopping logo can be used in conjunction with the trademarks of many E-tailers, Mail Order/Catalogue Houses and “Brick-&-Mortar” Retailers. Alternatively, some major E-tailers may desire to use our VIRTUAL “Flyer” Shopping logo (in lieu of VIRTUAL “Catalogue” Shopping) in order to convey to their customers that same represents their Online “FLYER”—similar to their Printed “FLYERS” which they send to consumers' homes frequently to promote specific products carried in their “brick-&-mortar” stores. III. CURRENT ONLINE CATALOGUES Some current “Brick-&-Mortar” retail stores, which also produce printed Catalogues, place their Catalogues Online for customers to view—i.e. they simply “SCAN in” their PRINTED Catalogues in the normal, PRINTED “Portrait” format—Not the “Landscape” format which is used for computer monitors TODAY. Since the above mentioned current Online Catalogues are typically not designed specifically to display on the Internet (as is VIRTUAL “Catalogue” Shopping), most of their pictures appear too small (compared to VIRTUAL “Catalogue” Shopping) when displayed via the Internet on computer monitors. In addition, the printed “Words” or “Copy” describing their various products, including pricing, is typically NOT READABLE—it is too small when displayed on a computer screen. Even if consumers “blew up” the copy, it is NOT READABLE due to the resolution of the “printed” copy. Some, not many, e-tailers provide Online Flyers (instead of Online Catalogues), BUT the same problems with the current Online Catalogues also apply to the Online Flyers. Under the current systems, if consumers want to READ some COPY for a particular product (as featured in a photograph in the Catalogue), they must “Click on” that photograph which then results in a “Second Page” or “Window” being downloaded and displayed, with the relevant copy. If the consumer then quickly reviews the Copy &/or Price and determines that he/she is simply NOT interested in same, he/she then has to “leave” that Page or Window and return to the Catalogue—a colossal waste of time for the consumers, as well as being frustrating and annoying. Therefore, with the prior method of displaying Catalogues on the Internet (by “SCANNING in” same), ONE of the most IMPORTANT features of PRINTED Catalogues & Flyers is LOST—i.e. allowing customers to view the product descriptions and pricing information of the products in the Catalogues or Flyers at the SAME TIME as they are looking at the beautiful, “good size” pictures of the products (on the SAME PAGES in the Catalogues or Flyers). This IMPORTANT FEATURE is a PRIME ADVANTAGE of the NEW, UNIQUE, “Revolutionary” VIRTUAL “Catalogue” Shopping & VIRTUAL “Flyer” Shopping systems—which are specifically designed for the Internet, providing the required amount of space on EACH Internet Web Page for “Copy” (using a very legible size of type), which will be displayed close or adjacent, for example, to the “Photographs” of the corresponding products. IV. ONLINE SHOPPING SYSTEMS In this section, we have basically outlined the major features of the current Online Shopping Systems used on the Internet TODAY, as well as the unique, “Revolutionary” features offered by the new VIRTUAL “Catalogue” Shopping and VIRTUAL “Flyer” Shopping systems. We have also provided comparisons between the aforesaid systems. A. Standard “Category/Sub-Category” Systems—Used by Online Retailers Today Basically, almost ALL Online Retailers today utilize a Standard “Category/Sub-Category” system to direct a consumer on their web site to a “Specific” product category, BEFORE providing “photographs” &/or “product listings” of the “Specific” products within the last sub-category selected by a consumer. Therefore, in almost ALL (if not ALL) cases, a consumer must FIRST select a product category and several sub-categories BEFORE reviewing actual photographs &/or listings of “Specific” products offered for sale by the e-tailer, and the vast majority of “other” Online Retailers today. In these cases, AFTER a consumer “finds” a particular product (usually with a very small photo) in which he/she may be interested, the consumer may “click to” a new web page with a “reasonable” size photograph (if available) of that particular product. After reviewing the larger photo and additional description, or just reading the additional description (if NO photo is available), the consumer may quickly determine that it is not what he/she “thought it would be” or is just “not interested” in it or it is “just too expensive”—meanwhile a significant amount of the consumer's time was “wasted”, and he/she returns back to the “product photographs &/or listings” to find other products—and the “time-consuming” procedure continues on and on. Nevertheless, this system has proven to be enormously successful for some major e-tailers—there is basically no other way to present same due to their large numbers of different products. The VIRTUAL “Catalogue” Shopping system provides a much different approach than the above, allowing customers to review great photographs and product descriptions (including prices) STARTING right at the beginning of an e-tailer's web site, for example, (&/or major category section)—WITHOUT the customer's need to FIRST select or pin down the EXACT TYPE of product which he/she may be interested in purchasing. The VIRTUAL “Catalogue” Shopping system is outlined in more detail in the following sections herein. It is important to demonstrate the UNIQUENESS of how the VIRTUAL “Catalogue” Shopping system will function (particularly how consumers are able to review &/or find the photographs &/or descriptions of the various products for sale in a web site) compared to the vast majority of Online Retailers. Because of the enormous numbers of different products sold by many major Online Retailers, it is virtually impossible for them to provide photos of each product, or a substantial portion of their products, STARTING right at the beginning of their web site in order for customers to “quickly” BROWSE through them (like the VIRTUAL “Catalogue” Shopping system). INSTEAD, with many e-tailers, a customer must FIRST select a product category and, immediately thereafter, several other product sub-categories in order to reach actual product listings (with or without very small pictures) of a number of products offered for sale within ONLY the last sub-category selected. In the following Section, we have outlined the various steps which a customer must take while shopping at an exemplary in order to see ACTUAL product listings &/or photographs of the various products offered for sale on its web sites. detailed-description description="Detailed Description" end="lead"? |
Hydrogen evolution inhibiting additives for zinc electrowinning |
A cetylpyridinium salt, cetylpyridinium chloride (CPC) is used as a hydrogen evolution inhibitor (a current efficiency improver) in a commercial zinc electrowinning process. Zinc electrowinning compositions containing a) antimony and b) antimony and glue were tested. Adding CPC at a 0.05 mM concentration to the electrowinning liquor resulted in increased current efficiency for both electrolytes. |
1. A method of improved zinc electrowinning, comprising: adding a cetylpyridinium salt additive to a zinc electrowinning electrolyte. 2. A method according to claim 1, wherein said cetylpyridinium salt is a cetylpyridinium halide. 3. A method according to claim 2, wherein said cetylpyridinium halide is cetylpyridinium chloride. 4. A method according to claim 3, wherein said cetylpyridinium chloride is at 0.05 millimolar (mM) concentration in said zinc electrowinning liquor. 5. A method according to claim 1, wherein said zinc electrowinning electrolyte contains zinc sulfate. 6. A method according to claim 1, wherein said zinc electrowinning electrolyte contains antimony. 7. A method according to claim 1, wherein said zinc electrowinning electrolyte contains glue. 8. A method according to claim 7, wherein said glue is animal glue. 9. A method according to claim 8, wherein said animal glue is gelatin. |
<SOH> BACKGROUND <EOH>Improving the energy efficiency of the zinc electrowinning process by inhibition of the parasitic hydrogen evolution reaction, which occurs in parallel with zinc deposition, is of major technological and commercial interest. One way of minimizing the cathodic hydrogen evolution is by the use of additives, generally organic compounds, which selectively increase the hydrogen evolution overpotential. Mackinnon et al. (Journal of Applied Electrochemistry, Volume 20, pages 728-736, 1990) and Scott et al. (Journal of Applied Electrochemistry, Volume 18, pages 120-127, 1988) describe the use of animal glue in combination with antimony to improve the current efficiency for zinc electrowinning when compared to additive-free electrolytes. There is a need for improved additives that minimize hydrogen evolution during zinc electrowinning while providing the same or improved performance over traditional additives. Therefore, it is an object of this invention to provide improved additives for zinc electrowinning that minimize hydrogen evolution while providing similar or improved performance over traditional additives. |
<SOH> SUMMARY <EOH>Cetylpyridinium chloride (CPC), a cetylpyridinium salt, was tested as an additive in a zinc electrowinning process in two separate zinc electrowinning electrolyte compositions: 1) with antimony and 2) with both antimony and glue. The CPC additive had the most significant influence in the presence of antimony or antimony+glue combination, where it increased the current efficiency by 23.2% and 7.6%, respectively. Moreover, the presence of 0.05 mM CPC did not increase the overall cell voltage. detailed-description description="Detailed Description" end="lead"? |
Diazacycloalkanes as oxytocin agonists |
Compounds according to general formula (1), wherein G1 is NR5R6 or a fused polycyclic group are novel. They are selective and potent oxytocin agonists. Pharmaceutical compositions of such compounds are useful in the treatment of, inter alia, erectile dysfunction. |
1. A compound according to general formula 1, or a pharmaceutically acceptable salt thereof wherein: G1 is selected from a group according to general formula 2, a group according to general formula 3, a group according to general formula 4, a group according to general formula 5, a group according to general formula 6 and a group according to general formula 7; A1 is selected from CH2)CH(OH), NH, N-alkyl, O and S; A2 is selected from CH2, CH(OH), C(O) and NH; A3 is selected from S, NH, N-alkyl, —CH═CH— and —CH═N—; A4 and A5 are each selected from CH and N; A6 is selected from CH2, NH, N-alkyl and 0; A7 and A11 are selected from C and N; A8 and A9 are selected from CH, N, NH, N(CH2)dR7 and S; A10 is selected from —CH═CH—, CH, N, NH, N(CH2)dR7 and S; A12 and A13 are selected from N and C; A14, A15 and A16 are selected from NH, N—CH3, S, N and CH; X1 is selected from O and NH; R1, R2 and R3 are each selected from H, alkyl, O-alkyl, F, Cl and Br; R4 is selected from H, alkyl, alkenyl, alkynyl, optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyridyl, (CO)—O— (CH2)eR8, —(CH2)eR8, —CH2—CH═CH—CH2R8, —CH2—C≡C—CH2R8, —(CH2)9—CH(OH)—(CH2)h—R8, —(CH2)i—O—(CH2)i—R8 and R5 and R6 are independently selected from alkyl, Ar and —(CH2)f—Ar; R7 is selected from H, alkyl, optionally substituted phenyl, F, OH, O-alkyl, O-acyl, S-alkyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, CN, CF3, optionally substituted pyridyl, optionally substituted thienyl and optionally substituted furyl; R8 is selected from H, alkyl, alkenyl, alkynyl, acyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrollyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, F, OH, hydroxyalkyl, O-alkyl, O-acyl, S-alkyl, NH2, NH-alkyl, N(alkyl)2, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, NH-acyl, N(alkyl)-acyl, N3, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON(alkyl)2, CN and CF3; Ar is selected from optionally substituted thienyl and optionally substituted phenyl; a is 1 or 2, bis 1, 2 or 3; c is 1 or 2, d is 1, 2 or 3; e is 1, 2, 3 or 4; f is 1, 2 or 3 and g, h, i and are all independently 1 or 2; provided that: not more than one of A8, A9 and A10 is NH, N(CH2)dR7 or S; A7 and A11 are not both simultaneously N; Neither A7 nor A11 is N if one of A8, A9 and A10 is NH, N(CH2)dR7 or S; if A10 is —CH═CH— then A8 is N, A9 is CH and both A7 and A11 are C; if A10 is not —CH═CH— then one of A8, A9 and A10 is NH, N(CH2)dR7 or S or one of A7 and A11 is N; not more than one of A14, A15 and A16 is NH, N—CH3 or S; A12 and A13 are not both simultaneously N; if one of A14, A15 and A16 is NH, N—CH3 or S then A12 and A13 are both C; and one of A14, A15 and A16 is NH, N—CH3 or S or one of A12 and A13 is N. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of R1, R2 and R3 is H and at least one is not H. 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one of R1, R2 and R3 is selected from an alkyl group, F. Cl and Br and the others are H. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from a methyl group and Cl, and R2 and R3 are H. 5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X1 is NH. 6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein a is 1 and b is 2. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G1 is a group according to general formula 3. 8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein c is 2. 9. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein A1 is CH2 and A2 is NH. 10. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein A1 is NH or N-alkyl and A2 is C(═O). 11. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein A3 is S and A4 and A5 are both CH. 12. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein A3 is —CH═CH— and A4 and A5 are both CH. 13. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein A3 is —CH═N— and A4 and A5 are both CH. 14. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein A3 is —CH═CH—, A4 is CH and A5 is N. 15. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G1 is a group according to general formula 6 or 7. 16. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein A3 is S and A4 and A5 are both CH. 17. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein A3 is —CH═CH— and A4 and A5 are both CH. 18. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein A3 is —CH═N— and A4 and A5 are both CH. 19. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein A3 is —CH═CH—, A4 is CH and A5 is N. 20. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G1 is a group according to general formula 4 or 6 21. A compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein A6 is NH. 22. A compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein A8 is NH or N—(CH2)d—R7. 23. A compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein A9 is N and A10 is CH. 24. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or Cl, R2 and R3 are both H and X1 is NH. 25. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or Cl, R2 and R3 are both H, X1 is NH, a is 1 and b is 2. 26. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G1 is a group according to general formula 6, A4, A5 and A10 are all CH, A6 is NH, A7 and A11 are both C, A8 is N—(CH2)d—R7 and A9 is N. 27. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or C1, R2 and R3 are both H, X1 is NH, a is 1, b is 2, G1 is a group according to general formula 6, A4, A5 and A10 are all CH, A6 is NH, A7 and A11 are both C, AB is N—(CH2)d—R7 and A9 is N. 28. A compound according to claim 1 selected from 5-(4-(4-cyclopropylmethylpiperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 5-(4-(4-benzylpiperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 5-(4-(4-(3-hydroxybenzyl)piperazine-1-carbonylaminomethyl)-3-methylbenzoyl) 1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 5-(4-(4-(3-hydroxymethylbenzyl)piperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 1-methyl-5-(3-methyl-4-(4-(4-picolyl)piperazine-1-carbonylaminomethyl)benzoyl)-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 5-(4-(4-(2-hydroxyethyl)piperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 1-methyl-5-(3-methyl-4-(4-(3-(methylthio)propyl)piperazine-1-carbonylaminomethyl)benzoyl)-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 5-(4-(4-(2-aminoethyl)piperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine, 5-(4-(4-(2-hydroxyethyl)piperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[4,5-c]pyrido[2,3-b][1,4]diazepine, and pharmaceutically acceptable salts thereof. 29. At least one optical isomer of a compound or salt according to claim 1. 30. A pharmaceutical composition which comprises a compound, salt or isomer according to claim 1 as an active agent. 31. A pharmaceutical composition according to claim 30 which is a tablet or capsule for oral administration. 32. A pharmaceutical composition according to claim 30 which is for the treatment of male erectile dysfunction. 33. A use for a compound, salt or isomer according to claim 1, which is as a component in the manufacture of a pharmaceutical composition. 34. A use according to claim 33 wherein the pharmaceutical composition is to be used in the treatment of male erectile dysfunction. 35. A method of treating male or female sexual disorders which comprises the administration to a person in need of such treatment of an effective amount of a compound, salt or isomer according to claim 1. |
<SOH> BACKGROUND <EOH>Neurophyseal Hormones The neurophyseal hormones oxytocin (OT) and vasopressin (VP) are cyclic nonapeptides secreted by the posterior pituitary gland. The structure of oxytocin is shown below. Vasopressin differs from oxytocin in that it has phenylalanine at position 3 in place of isoleucine and arginine at position 8 in place of leucine. Both hormones are synthesised in vivo as larger precursors, neurophysins, which are subject to post-translational processing to release the mature peptides. OT and VP act through a family of heptahelical receptors. The first target organs to be identified for OT were the uterus, where it is implicated in the onset and progress of labour, and mammary glands, where it is involved in the regulation of milk expression. Other organs also express OT receptors, and it is clear that OT has a range of physiological roles that have not been fully elaborated yet. In particular, it has been suggested that OT acting in the CNS is involved in the erectile response in males, and in the regulation of female sexual arousal. For example, OT is erectogenic when administered i.c.v. to male rats. It also has erectogenic activity when given iv., but the doses required are up to two orders of magnitude greater, which is consistent with a central mode of action. Oxytocin Agonists and Antagonists A number of peptide analogues of OT are known in the literature. These include both agonists and antagonists. OT and its agonists are used, for example, to accelerate labour and to increase uterine muscle tone to control post-partum bleeding, and one antagonist, atosiban, has recently been registered as a treatment for pre-term labour. However, the peptidic nature of these compounds means that they are not likely to be bioavailable after oral dosing or to cross efficiently into the CNS. In order to get drugs that can be given orally and to be able to exploit the central effects of OT, attention has increasingly turned to non-peptides. As a result, there are many publications describing non-peptide OT antagonists in early-stage development. So far, however, there have been no reports of non-peptide OT agonists. This is not unexpected, as it is generally held that it is easier to find a receptor antagonist than an agonist. So there remains a need for non-peptide OT receptor agonists. Such compounds should preferably be selective for the OT receptor over the VP receptors. They could be expected to show therapeutic utility in male and female sexual dysfunction, particularly male erectile dysfunction, in promoting labour, in controlling post-partum bleeding, in increasing milk let-down as well as a number of other indications. |
<SOH> SUMMARY OF THE INVENTION <EOH>We describe herein a series of potent and specific OT receptor agonists. In a first aspect, the present invention comprises novel compounds according to general formula 1, and pharmaceutically acceptable salts thereof. G 1 is a group according to general formula 2, 3, 4, 5, 6 or 7. A 1 is CH 2 , CH(OH), NH, N-alkyl, O or S; A 2 is CH 2 , CH(OH), C(═O) or NH; A 3 is S, NH, N-alkyl, —CH═CH— or —CH═N—; A 4 and A 5 are each CH or N; A 6 is CH 2 , NH, N-alkyl or O; A 7 and A 11 are C or N; A 8 and A 9 are CH, N, NH, N(CH 2 ) d R 7 or S; A 10 is —OH═COH—, CH, N, NH, N—(CH 2 ) d —R 7 or S; A 12 and A 13 are N or C and A 14 , A 15 and A 16 are NH, N—CH 3 , S, N or CH, provided that not more than one of A 8 , A 9 and A 10 is NH, N—(CH 2 ) d —R 7 or S; that A 7 and A 11 are not both simultaneously N; that neither A 7 nor A 11 is N if one of A 8 , A 9 and A 10 is NH, N—(CH 2 ) d —R 7 or S; that if A 10 is —CH═CH— then A 8 is N, A 9 is CH and both A 7 and A 11 are C; that if A 10 is not —CH═CH— then one of A 8 , A 9 and A 10 is NH, N—(CH 2 ) d —R 7 or S or one of A 7 and A 11 is N; that not more than one of A 14 , A 15 and A 16 is NH, N—CH 3 or S; that A 12 and A 13 are not both simultaneously N; that if one of A 14 , A 15 and A 16 is NH, N—CH 3 or S then A 12 and A 13 are both C; and that one of A 14 , A 15 and A 16 is NH, N—CH 3 or S or one of A 12 and A 13 is N. X 1 is O or NH. R 1 , R 2 and R 3 are each H, alkyl, O-alkyl, F, Cl or Br. R 4 is H, alkyl, optionally substituted phenyl, pyridyl, thienyl or furyl, or is (CH 2 ) e —R 8 . R 5 and R 6 are each independently alkyl, Ar or CH 2 ) f —Ar, where Ar is optionally substituted phenyl or thienyl. R 7 and R 8 are each independently H, alkyl, optionally substituted phenyl, pyridyl, thienyl or furyl, F, OH, O-alkyl, S-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN or CF 3 . a is 1 or 2, b is 1, 2 or 3, c is 1 or 2, d is 1, 2 or 3; e is 1, 2 or 3 and f is 1, 2 or 3. In a second aspect, the present invention comprises pharmaceutical compositions of these novel compounds, which compositions are useful for the treatment of, inter alia, male erectile dysfunction. In further aspects, the present invention comprises the use of such compositions in therapy and therapeutic methods using the compositions. detailed-description description="Detailed Description" end="lead"? |
Keeping persistency while switching between modalities |
Disclosed is a method and device for keeping persistency while switching between modalities, which include: (1) searching out the last operation state of the application service accessed by the user from the user history, in response to a request for accessing an application service from a user; (2) connecting to the application service and continuing to execute the application service from the last operation state; (3) updating the last operation state in the user history based on the execution result of the application service. A user could flexibly selects different favorable terminal to continue with unfinished application service by adopting the invention. |
1. A method for accessing an application service in a pervasive network comprising: in response to a user request to access the application service, recalling the last operation state of the application service from a user history; connecting to the application service and continuing to execute the application service from the last operation state; and updating the last operation state in the user history based on the execution result of the application service. 2. The method according to claim 1 further comprising: returning the execution result to the user using a contact method appropriate to the user. 3. The method according to claim 2, wherein the contact method is that which is used by the user when requesting access to the application service. 4. The method according to claim 2, wherein the contact method is selected from a plurality of contact methods pre-registered by the user. 5. Apparatus for providing access to an application service in a pervasive network comprising: means for recalling the last operation state of the application service accessed by the user from the user history responsive to a request for accessing an application service from a user; means for connecting to said application service and continuing to execute said application service from said last operation state; and means for updating the last operation state in the user history based on said execution result of said application service. 6. The apparatus according to claim 5, further comprising: means for presenting said execution result to said user using a contact method appropriate to the user. 7. The apparatus according to claim 6, wherein the contact method is that which is used by said user when requesting access to said application service. 8. The apparatus according to claim 6, wherein the contact method is selected from a plurality of methods pre-registered by said user. 9. Apparatus for keeping persistency in a computer network comprising: a user history module for recording the historical call information of at least one user for at least one application service based on the user ID; logon control module for identifying or verifying the user requesting access to an application service, retrieving the historical call information of the user for the application service from the user history module, and extracting the call ID of the last operation of the user for the application service from the historical call information; a session management module for connecting to the application service and executing the application service based on the historical call information, and for updating the historical call information recorded in the user history module based on the execution result; and a connection management module, for setting up the connection to the session management module based on the extracted call ID. 10. The apparatus according to claim 9, further comprising: a user registrar module for registering information on at least one device used by a user for connection, the connection management module being operable to select one device from the user register module for the user to receive the execution result of the application service. 11. The apparatus according to claim 10, further comprising: means for presenting the execution result to the selected device. 12. The apparatus according to claim 11, wherein said terminal is the one used by the user when requesting access to the application service. 13. The apparatus according to claim 11, wherein the device is selected from a plurality of terminals pre-registered by the user. |
<SOH> BACKGROUND OF THE INVENTION <EOH>With the Internet becoming pervasive in every field of society, there appear more and more intelligent devices capable of processing information. These devices, for example, include PCs, mobile phones, palmtop computers, etc., most of which can be connected with a network to process information. Such a network is often referred to as a pervasive network. When a user accesses an application service, he/she prefers using one of those devices in one specific environment, for example using a PC to access the application service in the office, while using another different device in another specific environment, for example using a mobile phone to continue executing the application service in the car. That is to say, “keeping persistency” is required for the same application service even after switching from one device to another different device. However, for the current technology in accessing the same application service via multiple devices, a user can only be allowed to use one device to access the same application service from the beginning to the end. And if the user switches to another device to access the application service, he has to access the application service from scratch. The current technology does not solve the problem on how to keep persistency in this situation. Nowadays, applications tend to become more and more modularized, but not a big packed module any more. An application may consist of a plurality of highly modularized independent components (hereinafter named application logic components). So the whole procedure to execute an application becomes to execute all the independent application logic components one by one. The present invention makes use of this modularization to solve the “persistency maintenance” issue. |
<SOH> SUMMARY OF THE INVENTION <EOH>An aim of the invention is to provide a method and device for keeping persistency while switching between modalities, so that a user using multiple terminal devices to access an application service can continue to execute the application service using device B from the last operation state point when using device A, instead of from scratch. Users can use different terminal devices flexibly to continue to execute an unfinished application service by implementing the invention. In a first aspect, the invention provides a method offering continuous service, which includes the following steps: (1) searching out the last operation state of the application service accessed by the user from the user history, in response to a request for accessing an application service from a user; (2) connecting to the application service and continuing to execute the application service from the last operation state; (3) updating the last operation state in the user history based on the execution result of the application service. A second aspect of the invention also provides an apparatus for offering continuous service, which includes: means for searching out the last operation state of the application service accessed by the user from the user history in response to a request for accessing an application service from a user; means for connecting to the application service and continuing to execute the application service from the last operation state; means for updating the last operation state in the user history based on the execution result of the application service. In a third aspect, the invention also provides a device offering continuous service, which includes a user history module for recording the historical call information of at least one user for at least one application service based on the user ID; a logon control module for identifying or verifying the user requesting for accessing an application service, retrieving the historical call information of the user for the application service from the user history module, and extracting the call ID of the last operation of the user for the application service from the historical call information; a session management module for connecting to the application service and executing the application service based on the historical call information, and for updating the historical call information recorded in the user history module based on the execution result; and a connection management module for setting up the connection to the session management module based on the extracted call ID. In one embodiment, the start point for the next time to execute the same application will be determined based on the last operation state information recorded for all the application logic components of the application, when a modularized application is executed. Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings: |
Method for obtaining electric energy from the environment |
Up to now, conventional wind power rotors, which have a horizontal shaft and are mounted on high self-supporting poles, serve to utilize wind energy. These installations are confined to designated installation sites and, due to economical reasons, have a certain minimum size that often causes them to considerably detract from the natural scenery. The inventive method provides that the movement which is induced by changes in mechanical load, in at least one direction of displaceably mounted or elastically moving structures or parts of structures is converted into electric energy by means of mechanical/electrical energy converters situated between moving and stationary parts of structures or at selected points of elastic motion of the structures or parts of structures. This results in wind ene eing utilized over a large area. |
1. Method for the production of electric energy from the environment wherein the movement caused by the mechanical load change, in at least one direction of movably supported or intrinsically elastically movable edifices or edifice parts by means of mechanical/electrical energy transducers arranged between movable and solid edifice parts or on selected points of elastic movement of the edifices or edifice parts, is transformed into electric energy. 2. Method according to claim 1, wherein the mechanical/electrical energy transducers are arranged locally and parallel to securing systems of edifice parts. 3. Method according to claim 1, wherein the mechanical/electrical energy transducers are arranged locally and in series to securing systems of edifice parts. 4. Method according to one of the previous claims, wherein facade parts are moveably joined with the edifice by way of mechanical/electrical energy transducers. 5. Method according to the claims 1 to 3, wherein facade parts are provided with frames which are moveably joined to the edifice by way of mechanical/electrical energy transducers. 6. Method according to claim 1, wherein the edifice parts are retracted into their initial position by means of spring elements following a movement caused by the wind. 7. Method according to claim 1, wherein the edifice parts are arranged in such a way that, after a movement caused by the wind, they retract into their initial position as a result of their own weight. 8. Method according to claim 1, wherein the mechanical/electrical energy transducers are integrated into point-fastenings. 9. Method according to claim 1 wherein the mechanical/electrical energy transducers are arranged in parallel to bridge pedestal supports. 10. Method according to claim 1, wherein the mechanical/electrical energy transducers are integrated into bridge pedestal supports. 11. Method according to claim 1, wherein the mechanical/electrical energy transducers are compiled electrically in series/parallel connections. 12. Method according to claim 1, wherein electromagnetic transducers are used as mechanical/electrical energy transducers. 13. Method according to claim 1, wherein piezoelectric transducers are used as mechanical/electrical energy transducers. 14. Building, wherein it has facade parts which are moveably supported in at least one direction and has mechanical/electrical energy transducers arranged between the building body and the facade parts, where the electric energy of these transducers produced by the movement of the facade parts resulting from the mechanical load change is collectable in batteries or is to be fed into the network (grid). |
Polishig fluid for metallic films and method for producing semiconductor substrate using the same |
A polishing fluid for metallic films, wherein the etching rate is 10 nm/min. or less, the polishing rate under a load of 10 KPa is 200 nm/min. or more, and the contrast, a ratio of the above-mentioned polishing rate to the etching rate, is 20 or more; and a method for producing a semiconductor substrate using the same. |
1. A polishing fluid for metallic films, the polishing fluid having an etching rate of 10 nm/min. or less, a polishing rate under a load of 10 KPa of 200 nm/min. or more, and a contrast ratio of the polishing rate to the etching rate of 20 or more. 2. A polishing fluid for metallic films, comprising a polyoxo acid and/or a salt thereof, a water-soluble polymer and/or a non-ionic surfactant, and water. 3. A polishing fluid for metallic films according to claim 2, comprising a particulate composite material consisting of a polyoxo acid and/or a salt thereof and a non-ionic surfactant. 4. A polishing fluid for metallic films according to anyone of claims 2 to 3, wherein abrasive grains are substantially not contained. 5. A polishing fluid for metallic films according to claim 2 or 3, wherein said polyoxo acid and/or a salt thereof is a heteropoly acid and/or a salt thereof. 6. A polishing fluid for metallic films according to claim 2 or 3, wherein the HLB of the non-ionic surfactant is 5 to 12. 7. A polishing fluid for metallic films according to claim 2 or 3, wherein the non ionic surfactant is a polyoxyethylene ether of a saturated type higher alcohol having 8 to 24 carbon atoms. 8. A polishing fluid for metallic films according to claim 2 or 3, wherein the non ionic surfactant is a combination of two or more kinds of non-ionic surfactants with different HLBs. 9. A method for producing a semiconductor substrate comprising a step of polishing a metallic film formed on the semiconductor substrate, wherein the polishing is carried out with a polishing fluid for metallic films according to any one of claims 1 to 3 under a load of 15 KPa or less. 10. A method for producing a semiconductor substrate comprising a step of polishing a metallic film formed on the semiconductor substrate with a polishing stool, wherein the polishing is carried out with a polishing fluid for metallic films according to any one of claims 1 to 3 at a relative velocity between the semiconductor substrate and the polishing stool of 40 m/min. or more. 11. A method according to claim 9, wherein, in the step of polishing, the polishing is carried out with a polishing pad not subjected to a dressing treatment. 12. A method according to claim 9, wherein, in the step of polishing, the polishing is carried out with a polishing pad having an average surface roughness (Ra) of 1,000 nm or less on its surface. 13. A method according to claim 9, wherein, in the step of polishing, the polishing is carried out with a polishing fluid for metallic films according to any one of claims 1 to 3 and by a polishing pad containing an inorganic filler. 14. A method according to claim 9, wherein the relative dielectric constant (K) of the insulating film constituting the semiconductor substrate is 2.5 or less. 15. A polishing fluid for metallic films according to claim 1, wherein abrasive grains are substantially not contained. 16. A method according to claim 10, wherein, in the step of polishing, the polishing is carried out with a polishing pad not subjected to a dressing treatment. 17. A method according to claim 10, wherein, in the step of polishing, the polishing is carried out with a polishing pad having an average surface roughness (Ra) of 1,000 nm or less on its surface. 18. A method according to claim 10, wherein, in the step of polishing, the polishing is carried out with a polishing fluid for metallic films according to any one of claims 1 to 3 and by a polishing pad containing an inorganic filler. 19. A method according to claim 10, wherein the relative dielectric constant (K) of the insulating film constituting the semiconductor substrate is 2.5 or less. |
<SOH> BACKGROUND ART <EOH>Due to the rapid progress of the LSI technique, integrated circuits tend to be scaled down and employ more the structure of multilevel interconnection, from day to day. The introduction of multilevel interconnection integrated circuits is an important factor aggravating the unevenness of the semiconductor surface which, together with the scale down of integrated circuits, promotes disconnection, reduction of electric capacity and occurrence of electromigration and results in the reduction of yield and reliability of the product. Thus, a variety of processing techniques have hitherto been developed for making flat the metallic wirings and interlayer dielectric in the multilevel interconnection substrates. One of such techniques is the CMP (chemical mechanical polishing) technique. The CMP technique is necessary for the flattening of interlayer dielectrics, formation of buried distribution wires, formation of plugs, etc. in the production of semiconductors. CMP is carried out by rotating a carrier and a polishing pad respectively while pushing a flat wafer usually made of a semiconductor material, set on the carrier against the wet polishing pad under a constant pressure. At this time, a polishing fluid introduced between the wafer and the polishing pad progresses the polishing of wirings and convexities of dielectrics mainly by way of the mechanical polishing action, accompanied by some chemical action to achieve the desired flattening. There have hitherto been made a number of proposals using various polishing fluids and polishing methods for polishing metallic film in semiconductor substrates. As in Toshiro Doi, et al.: “CMP Technique in the Flattening of Semiconductors” Page 235, July 1998, published by Kogyo Chosakai, in the CMP of a metallic film, an oxidant present in a polishing fluid chemically oxidizes the surface of the metallic film and converts it into a passive state and lowers the pH value to be in the acidic region to cause slight corrosion of the metal (etching). Under such a condition, mechanical polishing is carried out by a polishing pad and abrasive grains. For instance, as polishing fluids for metallic films composed of aluminum or the like formed on a semiconductor substrate, polishing fluid obtained by dispersing aluminum oxide as abrasive grains in an aqueous solution of nitric acid having a pH value of 3 or less (U.S. Pat. No. 4,702,792), polishing fluid obtained by mixing abrasive grains composed of aluminum oxide or silicon dioxide with an acidic aqueous solution of sulfuric acid, nitric acid, acetic acid or the like (U.S. Pat. No. 4,944,836), etc. can be referred to. Among such polishing fluids, polishing fluids prepared by using aluminum oxide or silicon dioxide as abrasive grains and dispersing the abrasive grains in a solution of oxidant such as hydrogen peroxide and the like, such as the one obtained by dispersing aluminum oxide in an aqueous solution of hydrogen peroxide and phosphoric acid (U.S. Pat. No. 5,209,816) are usually and widely used. When aluminum oxide is used as an abrasive grain for flattening a metallic film on a semiconductor substrate, however, the α-form of aluminum oxide is disadvantageous in that defects such as microscratches, orange peel and the like may appear on the surface of a metallic film or dielectric, even though it shows a high polishing rate. On the other hand, when the γ-form of aluminum oxide, amorphous alumina or silicon dioxide is used as the abrasive grains, a sufficient polishing rate cannot be achieved upon polishing a metallic film even though the appearance of defects such as microscratches and orange peel on the surface of a metallic film or dielectric can be suppressed. As above, polishing fluids prepared by dispersing abrasive grains composed of a metallic oxide such as aluminum oxide, silicon dioxide or the like in an aqueous solution have a problem of surface scratches caused by the low dispersibility of the abrasive grain itself. In addition to the above, there are various practical problems, such as dishing (a phenomenon that the central part of a metallic film is excessively polished as compared with the peripheral part as seen in 4 of FIG. 1D ) and the generation of defects such as pits, voids or the like, etc., due to an excessive progress of wet etching, in the cases where a liquid oxidant, such as hydrogen peroxide, or a metallic etchant, such as ammonium persulfate or the like is used (JP-A-6-313164). With the aim of overcoming these disadvantages, methods in which a chemical reagent capable of forming a protective film on the surface of metallic film, such as an anticorrosive agent, chelating agent or the like, is added to the polishing fluid have been proposed (JP-A-8-83780, JP-A-11-195628). However, although such chelating agent can suppress the etching and prevent the occurrence of dishing, etc., it causes a problem that a protective film is formed even in the area to be polished to thereby extremely lower the polishing rate. Although it has been attempted to optimize the amount of etching agent or chelating agent in order to overcome the above-mentioned problem, it is difficult to find out the conditions under which both of the requirements, high polishing rate and less etching and dishing, are met. In addition to this problem, there was also a problem that the results of processes are not reproducible as the results are apt to be influenced by other process conditions. Further, there has been an attempt to obtain a polishing rate of 200 nm/min. or more by mechanically removing the above-mentioned protecting film under a high polishing pressure of 20 KPa or more (JP-A-2000-252242). However, in the case of porous type low-dielectric constant type insulating films, which will be widely used hereafter, due to their low film strength and low adhesiveness to a substrate, an excessive stress to a substrate causes the peeling and breakage of insulating film. Further, when mechanical polishing with a pad is carried out under an enhanced polishing pressure, the influence of the pad surface becomes greater upon polishing, so that the control of the state of the pad surface by conventional dressing becomes difficult, and thus the process control becomes more difficult. Further, such a technique accelerates the consumption of costly pads to increase the process cost. Now, polyoxo acids, particularly heteropoly acid, have high acidity and oxidizing activity, as mentioned in “Chemistry of Poly Acids” (edited by Japanese Chemical Society, published by Gakkai Shuppan Center, August 1993), and the use of these substances in the treatment for making a metal into a passive state or an etching treatment of a metal is described in JP-A-9-505111, etc. An example of actual use of a heteropoly acid as an etching agent for a semiconductor surface (Applied Surface Science, Vol. 135, No. 1/4, pp. 65-70 (1998, 10.8) and an attempt to use a polyoxo acid or its salt as an etching agent for polishing (JP-A-2000-119639) have been disclosed. Especially in the latter paper, there are described two embodiments, namely an embodiment of using only polyoxo acid or its salt as an etching agent for polishing (i.e. the first polishing fluid composition) and an embodiment of adding thereto known abrasive grains (i.e. the second polishing fluid composition). In the case of the first polishing fluid composition, if a heteropoly acid is used alone as an etching agent for polishing metallic films, it acts as a liquid oxidant as it is soluble in water. Therefore, both of the above-mentioned two requirements, i.e. polishing rate and dishing-suppressing performance, cannot be satisfied simultaneously. In other words, if the concentration of heteropoly acid is increased in order to improve the polishing rate, etching is simultaneously promoted to cause dishing. On the other hand, if a basic substance such as ammonia is added to the heteropoly acid and the resulting heteropoly acid salt is used, even though the etching may be suppressed, the polishing rate simultaneously decreases and the polishing does not progress efficiently. Thus, it has been proposed to mix abrasive particles into the first polishing fluid composition to prepare a second polishing fluid composition for the purpose of enhancing the polishing rate. However, this provides nothing more than mechanical polishing by the use of abrasive particles, wherein a high polishing load is necessary to achieve a high polishing rate. Accordingly, such a technique does not meet the object of the present invention which is to achieve a high polishing rate under a low load. Beside the above, a technique of dispersing abrasive grains in a fluid containing heteropoly acid to prepare an aqueous dispersion for chemical-mechanical polishing has also been proposed (EP-A-1123956). However, also in this case, actually, a high polishing load of about 30 KPa has to be applied, for achieving a high polishing rate of 300 nm/min., while suppressing the etching property causing the dishing. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIGS. 1A to 1 D are outlined cross-sectional views illustrating examples of the formation of metallic wirings using the CMP technique. detailed-description description="Detailed Description" end="lead"? Hereinbelow, the present invention will be explained more concretely. As used in the present invention, the term “etching rate” means the thickness of a metallic film which disappears over a certain period of time, when a substrate with a metallic film formed thereon is immersed in a vigorously stirred polishing fluid. Specifically, a container having an inner diameter of 5 cm is filled with 80 ml of a polishing fluid, and the polishing fluid is stirred at 25,000 rpm by means of Homogenizer ULTRA-TURRAX T8 manufactured by IKA-WERKE Co. (with shaft S8N-8G). A substrate of Si wafer (15 mm square) having a metallic film formed thereon is immersed in the polishing fluid under stirring for 3 minutes. From the difference in the thicknesses of the metallic film before and after the immersion, the thickness of the metallic film having disappeared per unit period of time is calculated. As used in the present invention, the term “polishing rate” means the thickness of metallic film which disappears over a certain period of time, when a semiconductor substrate is polished by a general-purpose polishing apparatus for a semiconductor substrate under predetermined conditions. Specifically, polishing of a substrate (4″ silicon wafer having a Cu film with a thickness of 1 μm) is carried out by using Polishing Apparatus MA-300D manufactured by Musashino Denshi Co. (stool diameter 300 nm), and using IC-1400 Rodel Nitta Co. (made of foamed polyurethane) as a polishing pad, under a predetermined load, while feeding the polishing fluid at a rate of 50 ml/min., under a condition that the relative velocity between the substrate and the polishing stool is 50 m/min. From the thicknesses of Cu film before and after the polishing, the thickness of the metallic film having disappeared per unit period of time is calculated. The present inventors have found that, when a polishing fluid having the above-standardized properties in specific ranges is used, it is possible to polish the metallic film on a semiconductor with excellent properties, such as: that polishing can be carried out under a low load at a high rate; that the occurrence of defects on the polished surface such as scratches, dishing, erosion, etc. can be suppressed; that the process control, such as control of the surface state of the polishing pad, can be simplified; and that the cost of the process can be lowered by reducing the consumption of pads, etc. First of all, if a polishing fluid having an etching rate of 10 nm/min. or less is used, corrosion of a metal surface can be controlled, so that the metal surface is not much roughened at the time of polishing, and no great dishing occurs when a substrate having a pattern is polished. Next, if a polishing rate under a load of 10 KPa is 200 nm/min. or more and a contrast, i.e. the ratio of the polishing rate/etching rate, is 20 or more in a polishing fluid for metallic films, it is possible to fulfil both the improvement of polishing performance, such as prevention of dishing, and the shortening of polishing time simultaneously, both of which are problems to be solved in a CMP process under a condition of low load. As polishing fluids having the performance standardized in the present invention, polishing fluids comprising polyoxo acid and/or a salt thereof, a water-soluble polymer and/or a nonionic surfactant, and water can be referred to. The polishing fluids of the present invention may contain other ingredients, such as usually employed abrasive grains, oxidants and the like, so far as their presence does not disturb the effect of the present invention or the desired purpose, as will be mentioned later. However, the object of the present invention can be fundamentally achieved by the above-mentioned ingredients only. Especially, the polishing fluid of the present invention is characterized in that it substantially does not contain abrasive grains which have been used in the conventional polishing fluids. The polyoxo acids used in the present invention are the products of the condensation of an oxygen acid containing Mo, V, W, Ti, Nb, Ta or the like as a constitutional element. Isopoly acid and heteropoly acid belong to said polyoxo acid. “Isopoly acid” means a condensed oxygen acid containing at least one of the above-mentioned constitutional elements of polyoxo acids and includes polymolybdic acid, polyvanadic acid, polytungstic acid, polytitanic acid, polyniobic acid, polytantalic acid, etc. Among these acids, preferably usable in the present invention for the purpose of polishing a metal are polymolybdic acid, polyvanadic acid and polytungstic acid from the viewpoint of the ability of etching (oxidizing or dissolving) the metal. “Heteropoly acids” are acids obtained by incorporating a hetero element into the above-mentioned isopoly acids as a central element, and are constituted from a condensed co-ordinated element, a central element and oxygen. Herein, the “condensed co-ordinated element” means the constitutional element of the above-mentioned polyoxo acids. As preferable examples thereof, at least one member selected from the group consisting of Mo, W and V can be referred to. In addition to them, Nb, Ta and the like may also be included in the preferable elements. The central element of the heteropoly acid is at least one element selected from the group consisting of P, Si, As, Ge, Ti, Ce, Mn, Ni, Te, I, Co, Cr, Fe, Ga, B, V, Pt, Be and Zn. The atomic ratio between the condensed co-ordinated element and the central element (condensed co-ordinated element/central element) is 2.5 to 12. As concrete examples of the above-mentioned heteropoly acid, phosphomolybdic acid, silicomolybdic acid, phosphovanadomolybdic acid, silicovanadomolybdic acid, phosphotungstomolybdic acid, silicotungstomolybic acid, phosphovanadotungstomolybdic acid, silicovanadotungstomolybdic acid, phosphovanadotungstic acid, silicovanadotungstic acid, phosphomolyboniobic acid, boromolybdic acid, borotungstomolybdic acid, borovanadomolybdic acid, borovanadotungstic acid, cobaltomolybdic acid, cobaltovanadotungstic acid, phosphotungstic acid, silicotungstic acid, phosphovanadic acid, silicovanadic acid, and the like can be referred to, although these acids are not limitative. Among the above-mentioned polyoxo acids, preferable are heteropoly acids from the viewpoint of acid strength and oxidizing power sufficient to etch a metal as used for the purpose of polishing; and further preferable are phosphomolybdic acid, silicomolybdic acid, and vanadium-introduced products thereof such as phosphovanadomolybdic acid, silicovanadomolybdic acid, and the like. The polyoxo acids may be used alone or in the form of a mixture thereof. It is also possible to use these polyoxo acids in the form of polyoxo acid salts prepared by adding a basic substance to the polyoxo acids, for the purpose of adjusting the acidity of the resulting polishing fluid composition to control the polishing performance thereof. As the polyoxo acid salt, salts formed between the polyoxo acid and a metal, ammonium or an organic amine can be referred to. Although the content of polyoxo acid and/or salt thereof in the polishing fluid of the present invention is not particularly limited, it is preferably 0.1-30% by weight and further preferably 0.5-15% by weight. If the content of polyoxo acid or salt thereof is lower than the above-mentioned range, it may be difficult to exhibit a sufficient polishing rate. When said content exceeds the above-mentioned range, there can be observed no conspicuous improvement in polishing performance brought about by the increment. The water-soluble polymer used in the present invention includes, but is not limited to, ethers such as polyethylene glycol, polypropylene glycol, polyethylene glycol alkyl ether and the like; vinyl polymers such as polyvinyl alcohols, polyvinyl pyrrolidone, polyacrolein and the like; polycarboxylic acids and salts thereof such as polyacrylic acid, polymethacrylic acid, polyacrylamide, polyamic acid, ammonium salts of polyacrylic acid, and the like; polysaccharides such as methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate, cellulose nitrate, cellulose sulfate, pectin and the like; and gelatin, starch, albumin etc. It has been reported that these water-soluble polymers are incorporated into a polishing fluid composition as a thickener (JP-A-8-302338) or as a surfactant (JP-A-2000-252242). However, the object of using the water-soluble polymer in the present invention is different from those of this prior art. Thus, in the present invention, a water-soluble polymer is used in combination with the polyoxo acid, by which the progress of etching can be suppressed and the occurrence of dishing can be controlled while maintaining a high polishing rate even under a low load. Among the water-soluble polymers mentioned above, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol and cellulose derivatives are preferable from the viewpoint of polishing performances, such as the suppression of etching and the improvement of polishing rate under a low load, or from the viewpoint of the dispersibility of the formed particles. As to the water-soluble polymer to be added, not only the species thereof but also the molecular weight thereof markedly affect the performance of the polishing fluid. Although there is a general tendency that a higher molecular weight of the water-soluble polymer to be added gives a higher effect of suppressing the etching, the actual results are quite diverse because the dispersibility of particles and polishing rate are also related, depending on the kind of water-soluble polymer. The content of the water-soluble polymer in the polishing fluid of the present invention is not particularly limited, but varies depending on the kind of the polymer and the kind and quantity of polyoxo acid or salt thereof. Preferably, however, it is in the range of 0.01-50% by weight and more preferably 0.05-30% by weight. If its amount is smaller than the above-mentioned range, sufficient etching-suppressing effect cannot be achieved, and it may be difficult to control the occurrence of dishing. If its amount exceeds the above-mentioned range, the polishing fluid becomes difficult to handle, because of a rise in viscosity, for example. When used in combination with the above-mentioned polyoxo acid, the non-ionic surfactant of the present invention makes it possible to suppress the progress of etching while maintaining a high polishing rate under a low load and thereby suppressing the occurrence of dishing. Surprisingly, this effect is not found when an ionic surfactant such as an anionic or cationic surfactant is used, but is found especially remarkably when a non-ionic surfactant, especially a non-ionic surfactant having an HLB of 5-12 is used. As referred to herein, the term “HLB” (Hydrophile-Lipophile Balance) is a parameter indicating the hydrophilic character of a surfactant. In the case of the non-ionic surfactants used in the present invention, this value is in the range of from 0 to 20. A higher value of HLB means a higher hydrophilic character. As said non-ionic surfactant, the polyethylene glycol type and polyhydric alcohol type non-ionic surfactants described in “Shin Kaimenkasseizai Nyuumon (Introduction to the New Surfactants)” Takehiko Fujimoto, Nov. 1, 1960, published by Sanyo Kasei Kogyo K. K., page 92, Tables 2.5.1, can be used. The polyethylene glycol type non-ionic surfactants are those prepared by adding ethylene oxide to various hydrophobic groups to introduce a hydrophilic group into the molecule, and examples thereof include higher alcohol ethylene oxide adducts, alkylphenol ethylene oxide adducts, fatty acid ethylene oxide adducts, polyhydric alcohol fatty acid ester ethylene oxide adducts, higher alkylamine ethylene oxide adducts, fatty acid amide ethylene oxide adducts, fatty oil ethylene oxide adducts, polypropylene glycol ethylene oxide adducts, and the like. On the other hand, the polyhydric alcohol type non-ionic surfactants are those prepared by bonding a hydrophilic polyhydric alcohol to a hydrophobic fatty acid via an ester group or an amide group. Examples thereof include glycerol fatty acid esters, pentaerythritol fatty acid esters, sorbitol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, alkanolamine fatty acid amides, and the like. Among the above-mentioned non-ionic surfactants, those having an HLB value of 5 to 12 are preferably used in the present invention. If the HLB is smaller than 5, the polishing particles formed have too strong hydrophobicity, which may result in the precipitation of the particles or a phase separation due to low dispersibility. On the other hand, if the HLB is greater than 12, the polishing particles have too high hydrophilicity, which may make it difficult to form the particles and to exhibit the etching-suppressing effect. The non-ionic surfactants of the present invention are preferably those classified as said polyethylene glycol type surfactants. As examples thereof, polyoxyethylene ethers of higher alcohols having 8-24 carbon atoms, polyoxyethylene ethers of alkylphenols, and polyoxyethylene ethers of polypropylene glycol (PLURONIC type) can be referred to, among which polyoxyethylene ethers of higher alcohols having 8-24 carbon atoms are especially preferable. The polyoxyethylene ethers of higher alcohols having 8-24 carbon atoms can be divided into an unsaturated type having a carbon-carbon double bond such as an oleyl group in the molecule thereof and a saturated type having no carbon-carbon double bond at all. Because a saturated group does not undergo oxidative deterioration and shows no change in performance over time, polyoxyethylene ethers of saturated type higher alcohols are preferable. Examples thereof include polyoxyethylene decyl ether, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene 2-ethylhexyl ether, polyoxyethylene tridecyl ether, polyoxyethylene isostearyl ether, polyoxyethylene synthetic alcohol ether (said synthetic alcohol has 12-15 carbon atoms), and the like. These non-ionic surfactants may be used alone. However, if two or more kinds of the surfactants different from one another in HLB are used in combination, the excellent properties of the polishing fluid of the present invention, namely high dispersibility and low etching property of the formed polishing particles, high polishing rate property under a low load, etc. can be exhibited easily. Furthermore, when two or more kinds of non-ionic surfactants different from one another in HLB are used in combination, it is possible to mix together the surfactants previously and thereafter mix them with polyoxo acid (or salt thereof) or mix the surfactants simultaneously with polyoxo acid (or salt thereof). Preferably, however, a surfactant having a higher HLB is firstly mixed with polyoxo acid (or salt thereof) and thereafter the surfactant having a lower HLB is mixed thereinto. Such a procedure is advantageous in that a low etching property and high polishing rate property under a low load can be exhibited while maintaining a high dispersibility of the formed polishing particles. In the polishing fluid of the present invention, the content of the non-ionic surfactant is not particularly limited. Although it may vary depending on the kind of the surfactant used and the kind and amount of the polyoxo acid (or salt thereof), the content of the surfactant is usually 0.1-50% by weight and preferably 0.5-25% by weight. If its content is smaller than the above-mentioned range, sufficient etching-suppressing effect cannot be exhibited and occurrence of dishing cannot be controlled. If its content is higher than the above-mentioned range, deterioration in the handling property of the product, such as a rise in viscosity, can occur. The polishing fluid of the present invention is characterized by comprising a water-soluble polymer and/or a non-ionic surfactant. In order to achieve a high polishing rate, however, the use of a non-ionic surfactant is preferable. In the polishing fluid of the present invention, water is usually used as a medium. The dissolution or dispersion of the polyoxo acid (or salt thereof) and the water-soluble polymer and/or the nonionic surfactant is usually carried out by stirring. A process wherein a sufficient dispersion is carried out by the use of a homogenizer, ultrasonic waves, a wet type medium mill, or the like is preferably employed. Preferably, the thus-prepared polishing fluid is in a highly dispersed state in water, of a composite material (micelle particles) in which polyoxo acid (or a salt thereof) is incorporated into micelles formed from a water-soluble polymer and/or a non-ionic surfactant due to an interaction between the polyoxo acid (or a salt thereof) and the water-soluble polymer and/or non-ionic surfactant. The case where a non-ionic surfactant is used is especially preferable because the existence of the non-ionic surfactant facilitates the formation of the composite material. The “composite material” referred to herein fundamentally can be subjected to a particle size measurement by the wet type particle size analyzer and observation of the above structure by means of a transmission type electron microscope. It preferably has a number average particle size in the range of about 10 nm to 1 μm as determined by means of a wet type particle size analyzer. Although composite materials having a number average particle size of smaller than about 10 nm or composite materials which are so fine that their particle size cannot be measured and exist in a highly dispersed state are also included in the scope of the present invention, such composite materials are disadvantageous because they generally give a highly viscous composition. Thus, if workability at the time of polishing is taken into consideration, composite material particles, the particle size of which is measurable and the structure of which is observable as mentioned above are preferable. Although the details of the mechanism of polishing with the polishing fluid of the present invention are not clearly known, it is considered that the micelle particles formed through the interaction between polyoxo acid (or salt thereof) and water-soluble polymer and/or non-ionic surfactant act as polishing particles exhibiting a chemical polishing action, and can exhibit a high polishing rate even under a low load while maintaining a low etching rate and suppressing the occurrence of dishing. As noted above, the polishing particle of the present invention is a micelle-form particle, which is essentially different in nature from the abrasive grain used for the purpose of mechanical polishing. Accordingly, in the present invention, the problems in the conventional mechanical polishing, such as scratches due to coagulated abrasive grains, the damage to the underlying substrate due to the load at the time of polishing, etc. can be eliminated. In the polishing fluid of the present invention, it is also possible to use abrasive grains for the purpose of additionally enhancing the polishing rate and giving some factors of mechanical polishing, so far as the above-mentioned problems such as scratching, etc. do not occur. However, it is a characteristic feature of the present invention that the polishing fluid substantially does not contain abrasive grains. When an abrasive grain is used, its content is preferably less than 1% by weight. Examples of the abrasive grain used herein include inorganic particles such as silicon dioxide, titanium oxide, cerium oxide, aluminum oxide, zirconium oxide, magnesium oxide and the like; organic fine particles such as styrene copolymers, acrylic copolymers, polyvinyl chloride, polyacetal, saturated polyester, polyamide, polyimide, polycarbonate, phenoxy resin, polyolefin, olefin copolymers and the like; and organic particles such as amorphous carbon, carbon black and the like. Abrasive grains usually used for the purpose of mechanical polishing are inorganic particles having high hardness. Since the polishing fluid of the present invention is very low in the property of etching a metallic film, namely the property which causes dishing, it is usually unnecessary to use a protecting film-forming agent with the polishing fluid. However, it is also possible to add a compound that forms a chelate or a complex with a metallic film to further suppress the etching, if necessary, as long as the addition of such a compound does not lower the polishing rate substantially. Especially when the metal is copper or a copper alloy consisting mainly of copper, the addition of benzotriazole or quinaldic acid as a chelating agent is effective. As an anti-corrosive agent, in addition to the above, benzotriazole derivatives such as tolyltriazole, benzotriazolecarboxylic acid and the like, cystine, haloacetic acid, glucose, dodecylmercaptan and the like can be referred to. As to the amount of the anti-corrosive agents used in the present invention, an amount of 100 ppm or less and preferably 50 ppm or less is sufficient for the purpose, which is much smaller than the amount of anti-corrosive agent added to the conventional abrasive grains. Inversely, addition of the anti-corrosive agent in too large of an amount is undesirable, because it causes a decrease in the polishing rate and makes it impossible to achieve the desired polishing performance. Into the polishing fluid of the present invention, a known oxidant may be incorporated for the purpose of improving the polishing rate of metallic film, as long as its addition does not cause excessive etching. As the oxidants which can be incorporated, known oxidants can be referred to, the examples of which include peroxides such as hydrogen peroxide and the like, perchloric acid, perchloric acid salts, periodic acid, periodic acid salts, persulfuric acid, persulfuric acid salts, nitric acid salts, etc. According to the need, an acid may be incorporated into the polishing fluid of the present invention. The polishing performance of metallic film can be controlled by varying the kind of acid to be added and the pH value of the resulting slurry. As the acid to be incorporated, known inorganic acids such as sulfuric acid, phosphoric acid, nitric acid and the like and known organic acids such as oxalic acid, citric acid, malic acid, acetic acid and the like can be referred to. According to the need, a water-soluble alcohol such as methanol, ethanol, n-propanol, isopropanol, ethylene glycol, glycerin and the like may be added to the polishing fluid of the present invention. The polishing fluid prepared in the above-mentioned manner is applied for the polishing and flattening of a metallic film formed on a semiconductor substrate. The metallic films on semiconductor substrate to be polished include metallic films for known wirings, plugs, contact metal layers and barrier metal layers, and the metallic film is composed of a metal selected from the group consisting of aluminum, copper, tungsten, titanium, tantalum, aluminum alloys, copper alloys, titanium nitride, tantalum nitride and the like. Among the above-mentioned metals, the present invention is suitably applied to metallic films composed of copper or copper alloys which have low surface hardness and thus are apt to form defects such as scratches, dishing, etc. It is also possible, however, to apply the present invention to the polishing of barrier metals composed of tantalum or the like. Upon carrying out the polishing by the use of the polishing fluid of the present invention, a polishing method having a special characteristic feature is employed for fully exhibiting the performance of the polishing fluid. The present invention also relates to a method for producing a semiconductor substrate comprising such a polishing step. The load in the polishing is extremely low, i.e. 15 KPa or less, preferably 10 KPa or less, and more preferably 5 KPa or less. This is for the reason that, since the polishing fluid of the present invention can give a high polishing rate under such a low load, it is unnecessary to carry out the polishing under a high load as in the conventional polishing. As a result, polishing can be carried out without applying an excessive stress to the substrate, which makes it possible to avoid the problem of peeling of metallic film due to the breakage of insulating film even in the manufacture of semiconductors with a porous type low dielectric constant insulating film, which is expected to be introduced and become the main innovation in the near future. Further, when the load during polishing is low, the influence of the pad surface on polishing is less, which facilitates the troublesome procedure of controlling the pad surface. Further, since the consumption of pads can be lessened, the process cost can be lowered. Therefore, as noted above, a variety of effects can be expected. During polishing, the relative velocity between the semiconductor substrate and the polishing stool is preferably a high value of 40 m/min. or more. That is, even in the case where the factor of mechanical polishing is low as in the present invention, a higher polishing rate can be achieved and thereby the polishing time can be shortened by the contact between the polishing fluid and substrate at a high velocity. The polishing fluid for metallic film according to the present invention has another characteristic feature in that it makes the dressing treatment of a polishing pad, which has been essential in the prior art, unnecessary. As referred to herein, the term “dressing treatment” means a step initially carried out on a polishing pad in the unused state and/or a step of refreshing the surface of used polishing pads. As to the dressing in the former meaning, slight dressing is often necessary because the existence of foreign material or burrs on the surface of the pad may cause scratch-formation at the time of polishing. However, when the polishing fluid of the present invention is used, the dressing in the latter meaning is unnecessary. That is, in the case of using a conventional polishing fluid containing the usual abrasive grains, the pad surface is finely fluffed by using a disc or a ring-form conditioner into the surface of which minute diamonds or the like are embedded, so that the abrasive grains in the slurry are held among the fluffs and a desired polishing rate is exhibited. Accordingly, a periodic control of the fluffing state of the pad surface is necessary for avoiding the deterioration of polishing performance. Further, the conventional polishing pad has a foamed structure for the sake of enhancing the holding property of abrasive grains in the slurry. With the progress of polishing, abrasive grains are taken into the pores to prevent the substitution with fresh abrasive grains to cause a gradual decrease in polishing rate. For the purpose of preventing this phenomenon, dressing is carried out with the aim of refreshing the surface of the pad. In the case of the present invention, contrariwise, substantially no abrasive grains are contained in the polishing fluid, so that no periodic dressing for the purpose of refreshing is necessary. This makes it unnecessary to carry out the troublesome step of dressing, and thereby the production process can be simplified and at the same time the consumption of costly pads can be suppressed and the process cost can be reduced. In the method of the present invention, it is recommended to carry out the polishing with a flat pad having an average surface roughness (Ra) of 1,000 nm or less. According to the prior art, as has been mentioned above, the surface of the polishing pad is intentionally roughened by the procedure of dressing in order to achieve a desired polishing rate. However, if polishing is carried out with a pad low in surface flatness and smoothness, the unevenness on the surface promotes the occurrence of dishing and makes it impossible to carry out precise polishing. In the case of the present invention, contrariwise, the desired polishing rate can be obtained even when polishing is carried out with a pad of very high flatness (Ra is 1,000 nm or less). Accordingly, a precise polishing can be carried out without reducing the polishing rate. According to the present invention, it is also possible to carry out polishing by the use of a pad containing an inorganic filler. Usually, a product prepared by foaming an organic polymer, such as polyurethane and the like, is used as a polishing pad. When a metallic film containing tantalum or a tantalum-containing compound, which are difficult to polish, is to be polished, by the use of the inorganic filler-containing pad, a mechanical factor of polishing is added and the polishing can be carried out with high efficiency. An inorganic filler-containing pad can be obtained by adding and dispersing a variety of inorganic fillers into a resin, such as polyurethane or the like, and thereafter forming the mixture into the form of a polishing pad. Specifically, the constituents of a urethane resin, namely an alcohol component such as a diol, polyol or the like and an isocyanate group-containing compound having a functionality of 2 or more are mixed together and reacted to form a urethane resin. Subsequently, an inorganic filler is added to the thus-obtained resin and kneaded to disperse the inorganic filler uniformly. After forming the uniform mixture thus-obtained into a polishing pad, a crosslinking reaction is carried out by a method of heat treatment or the like to obtain an inorganic filler-containing pad. As the inorganic fillers which can be used in the present invention, those conventionally used as abrasive grains, as have been mentioned above, can be referred to. Examples thereof include at least one member selected from silicon dioxide, titanium oxide, cerium oxide, aluminum oxide, zirconium oxide, chromium oxide, iron oxide, tin oxide, zinc oxide, composite metal oxides, metal hydroxides, silicon nitride and titanium nitride. When these inorganic fillers are added to a pad resin, the surface of the inorganic fillers may be coated with an organic silicon compound, such as a silane coupling agent or the like, in order to improve the dispersed state and the affinity at the resin/inorganic filler interface. As the inorganic filler, those having a particle diameter of 1 nm to 10 μm can be used, and those having a particle diameter of 10 nm to 5 μm are particularly preferable. When the particle diameter is smaller than 1 nm, it is difficult to achieve a sufficient polishing rate. If the particle diameter is larger than 10 μm, defects, such as scratching and the like, are apt to appear at the time of polishing to give an undesirable result. The amount of the inorganic filler in the constitutional resin is 0.1% by volume to 10% by volume, and preferably 1% by volume to 5% by volume. If the amount of the inorganic filler is too small, the addition of the inorganic filler does not exhibit sufficient effect. If the amount thereof is too large, problems arise in the formation of the pad, or the hardness becomes too high to cause defects, such as scratching and the like, at the time of polishing. As such inorganic filler-containing polishing pad, those that are prepared by adding cerium oxide to an urethane resin, such as MHC series manufactured by RODEL NITTA Co., can be used in the present invention. The present invention is particularly effectively applicable to the cases where low dielectric constant insulating film in which the insulating film constituting a semiconductor substrate has a dielectric constant (K) of 2.5 or less is used, and particularly the case where porous type low dielectric constant insulating films which are mechanically fragile are used. That is, in the field of insulating films, it is being studied to make the K value thereof closer to unity as much as possible by giving the films a porous structure by introducing an air layer into the film. In the case of such a structure, however, the film is generally fragile. In the course of CMP processing of the film, therefore, the insulating film can be broken and peeling of the metallic film can take place due to insufficient adhesiveness. Thus, it is necessary to carry out the polishing while minimizing the stress applied to the substrate. The present invention makes it possible to carry out the polishing under a low load and thus can satisfy this requirement of the process. Hereinbelow, a method for producing a semiconductor substrate will be explained concretely. At first, as shown in FIG. 1A , an insulating film 2 is formed on a semiconductor substrate 1 , such as a silicon substrate or the like, and thereafter, trenches for metallic wiring or openings for contact wirings are formed on the insulating film 2 by photolithography or etching. Subsequently, as shown in FIG. 1B , a barrier metal layer 3 constituted of titanium nitride (TiN), tantalum nitride (TaN) or the like is formed on the trenches or opening part on the insulating film 2 by sputtering, CVD or the like. Subsequently, as shown in FIG. 1C , metallic film 4 for wiring is embedded so that the thickness thereof becomes higher than the height of the trenches or openings formed on the insulating film 2 . Subsequently, as shown in FIG. 1D , the superfluous metallic film present in the areas other than the trenches or opening parts are removed by a polishing treatment with the polishing fluid of the present invention. Further, the series of steps mentioned above are repeated as necessary, whereby a semiconductor substrate having a multilevel interconnection structure as an electronic part can be obtained. In the production of the above-mentioned semiconductor substrate, the polishing of the metallic film on the semiconductor substrate can be carried out by applying the above-mentioned polishing fluid for metallic films and carring out the method for producing a semiconductor substrate. Hereinbelow, the present invention will be explained by reference to examples. The present invention is by no means limited by these examples. Characteristic properties and polishing performance of a polishing fluid were evaluated according to the methods mentioned below. <Measurement of Particle Diameter> (1) Fine particles (smaller than 5 μm): Measured by a wet type particle size analyzer (MICROTRAC UPA-9230, manufactured by Nikkisou-sha). (2) Coarse particles (5 μm or larger): Measured by a wet type particle size analyzer (LA-700, manufactured by Horiba Seisakusho). In the descriptions given hereafter, the term “average particle diameter” means a number-average particle diameter. <Evaluation of Surface Scratch> A silicon wafer which has been polished in the aforementioned measurement of polishing rate is washed and dried, and then the surface of the semiconductor wafer was spotlighted in a dark room, and the presence or absence of one of more scratches is judged by visual observation. <Evaluation of Dishing> By the same method as in the above-mentioned measurement of polishing rate, a 4″ pattern wafer cut out from a 8″ wafer (SKW6-2 specification: oxide film 0.8 μm, TaN 24 nm, Cu 1.5 μm) was polished under a prescribed load, and a line and space part having intervals of 50 μm is measured with a desk-top type small-sized probe microscope: Nanopics (manufactured by Seiko Insturuments Co.), to determine the quantity of dishing on the Cu surface embedded in the space parts. In this evaluation of dishing, the period of time required for completely polishing a prescribed film thickness is calculated from the measured polishing rate, and a ten percent longer period of time based on this value is used as the polishing time (10% overpolishing). <Measurement of Pad Surface Roughness (Ra)> Roughness of pad surface is measured by the use of the desk-top type small-sized probe microscope (Nanopics) used in the above-mentioned dishing measurement. <Polishing Conditions> The conditions described below are adopted as standard conditions of polishing, unless otherwise stated. Polishing apparatus: Polishing Apparatus MA-300D, manufactured by Musashino Denshi Co. Load: 5 KPa Relative velocity between substrate and polishing stool: 50 m/min. Amount of polishing fluid supplied: 50 ml/min. Polishing pad: After fixing IC-1400 (made of foamed polyurethane) on a polishing stool and dipping it in water, a treatment is carried out under a load of 20 KPa for one hour by the use of a 4″ bare silicon wafer, to remove the defects present on the initial surface of the pad, such as burrs and the like, after which the substrate is subjected to polishing. The polishing rate (PR 10 ) used for specifying the polishing fluid indicates the value under a load of 10 KPa. The examples shown below are examples of the cases of combining polyoxo acid with a nonionic surfactant. |
Process for recovering caprolactam from aqueous caprolactam product using situ prepared alkali amino caproate |
The invention relates to a continuous process for recovering caprolactam from aqueous caprolactam product, said aqueous caprolactam product comprising (i) caprolactam, (ii) impurities, and (iii) water, said process comprising: adding alkali hydroxide to the aqueous caprolactam product, in an amount of not more than 100 mmol alkali hydroxide per kg of caprolactam; reacting at least part of the added alkali hydroxide to form alkali amino caproate, to obtain a caproate-enriched caprolactam product; and distilling the caproate-enriched caprolactam product at reduced pressure. |
1. Continuous process for recovering caprolactam from aqueous caprolactam product, said aqueous caprolactam product comprising (i) caprolactam, (ii) impurities, and (iii) water, said process comprising: adding alkali hydroxide to the aqueous caprolactam product, in an amount of not more than 100 mmol alkali hydroxide per kg of caprolactam; reacting at least 50 mol. % of the added alkali hydroxide to form alkali amino caproate, to obtain a caproate-enriched caprolactam product; and distilling the caproate-enriched caprolactam product at reduced pressure. 2. Process according to claim 1, wherein the process comprises reacting at least 75 mol. % of the added alkali hydroxide to form alkali amino caproate prior to said distilling. 3. Process according to claim 1, wherein the residence time of the added alkali hydroxide is sufficiently long such as to effect said reaction prior to said distilling. 4. Process according to claim 3, wherein said residence time is at least 30 minutes. 5. Process according claim 1, wherein the aqueous caprolactam product to which the alkali hydroxide is added comprises at least 15 wt. % of caprolactam and at least 3 wt. % of water. 6. Process according to claim 1, wherein the caproate-enriched caprolactam product comprises at least 95 wt. % of caprolactam. 7. Process according to claim 1, wherein caproate-enriched caprolactam product comprises less than 2 wt. % of water. 8. Process according to claim 1, wherein the process comprises purifying the aqueous caprolactam product in one or more steps after said adding and prior to said distilling. 9. Process according to claim 8, wherein said one or more steps include separating water from the aqueous caprolactam product by evaporation. 10. Process according to claim 1, wherein said distilling is effected at a temperature between 100 and 200° C. 11. Process according to claim 1, wherein said distilling is effected at a pressure of less than 10 kPa. 12. Process according to claim 1, wherein said distilling includes separating out low-boiling impurities from the caproate-enriched caprolactam product and/or separating out high-boiling impurities from the caproate-enriched caprolactam product. 13. Process according to claim 12, wherein said distilling includes, in a first step, separating out as a top product low-boiling impurities from the caproate-enriched caprolactam while leaving caprolactam product containing high-boiling impurities as a bottom product, and, in a second step, separating out high-boiling impurities from the bottom product, and recovering caprolactam as a top product. 14. Process according to claim 1, wherein the process comprises: adding the alkali hydroxide to a stream of the aqueous caprolactam product; feeding a stream of the caproate-enriched product to a distilliation zone in which the distillation at reduced pressure is effected; wherein the alkali hydroxide is added to the stream at a point which is chosen such that the residence time of the added alkali hydroxide in the stream is sufficiently long such as to effect said reaction of said at least part of the added alkali hydroxide prior to said feeding. 15. Process according to claim 1, wherein the alkali hydroxide is continuously added to the aqueous caprolactam product. |
Forming an embossed coated substrate |
The invention relates to a process of forming an embossed coated substrate. The process comprises the steps of: (I) forming on a substrate at least one coating whose composition comprises a radiation-curable polyurethane dispersion, (II) embossing the coated substrate on a relief surface, (III) irradiating the embossed coated substrate to cure the polyurethane-containing coating. An application of the process is the manufacturing of caul paper. |
1. Process of forming an embossed coated substrate comprising the steps of: (I) forming on a substrate at least one coating whose composition comprises a radiation-curable polyurethane dispersion, (II) embossing the coated substrate on a relief surface, (III) irradiating the embossed coated substrate to cure the polyurethane-containing coating. 2. Process according to claim 1, comprising drying the coating between step (I) and (II). 3. Process according to claim 2, comprising drying the coating at a temperature comprised between 60 and 120° C. 4. Process according to claim 2, comprising drying the coating during 30 seconds to 5 minutes. 5. Process according to claim 1, comprising embossing the coated substrate by contact with a relief surface of a roller. 6. Process according to claim 1, comprising embossing the coated substrate at a temperature comprised between 60 and 220° C. 7. Process according to claim 1, comprising embossing the coated substrate during 1 to 20 seconds. 8. Process according to claim 1, comprising embossing the coated substrate with a pressure comprised between 5 and 30 kg/cm2. 9. Process according to claim 1, comprising forming on the substrate at least two coatings of different composition. 10. Process according to claim 9, wherein the upper coating of the least two coatings has a composition containing a silicone additive, preferably an acrylated silicone additive. 11. Process according to claim 9, wherein the upper coating of the least two coatings has a greater hardness than the lower coating. 12. Process according to claim 1, wherein irradiation is made with ultraviolet radiation. 13. Process according to claim 1, comprising an ulterior step of releasing the embossed coating from the substrate. 14. Process according to claim 1, wherein the embossed coating is released from the substrate and transfered to another substrate. 15. Embossed coated substrate comprising a substrate bearing an embossed coating whose composition comprises a radiation-curable polyurethane dispersion. |
Commodity rental apparatus, commodity rental system, and commodity rental method |
A commodity rental apparatus includes an input unit, a containing unit, and a return unit. The input unit selects a predetermined commodity and inputs commodity rental information. The containing unit has a commodity containing column having a data carrier, reads an identification number of a commodity selected by a commodity number input by a user via an antenna arranged at the column, and specifies a commodity. Furthermore, the specified commodity is carried from the containing column to the commodity pick-up unit, so that the user can picks it up. The return unit reads rental information recorded on the data carrier of the commodity returned through a return hole via an antenna arranged in the vicinity of the return hole, accepts the commodity, and contains it in a stocker to which it is conveyed by a predetermined convey mechanism. |
1. A commodity rental apparatus comprising: an input unit that selects a commodity to input rental information for renting the selected commodity; a containing unit that contains a commodity with a record tag on which identification information for identifying the commodity is recorded in advance to deliver the commodity selected by the input unit after executing reading/writing of predetermined information onto the record tag; a return unit that accepts a commodity to be returned, and reads rental information recorded on the record tag of the commodity to generate return information; and a control unit that is connected to the input unit to control the containing unit and the return unit, wherein the control unit reads identification information recorded on the record tag based on rental information sent from the input unit, identifies the commodity to be delivered from the containing unit, records rental information on the record tag of the commodity, and records return information sent from the return unit on the record tag of the commodity when the commodity is accepted by the return unit. 2. The commodity rental apparatus according to claim 1, further comprising a card processing unit that executes reading/writing of predetermined information onto a membership card, wherein the control unit is connected to the card processing unit, records rental information on the membership card at the time of delivering the commodity from the containing unit, and updates rental information of the membership card based on return information sent from the return unit when the commodity is accepted by the return unit. 3. A commodity rental apparatus comprising: input means for selecting a predetermined commodity to input rental information for renting the selected commodity; containing means, which includes a column containing a commodity with a record tag on which identification information for identifying the commodity is recorded in advance and a first reader/writer section that is wirelessly communicable with the record tag, for identifying the commodity selected by the input section based on identification information recorded on the record tag to deliver the commodity from the column after writing rental information of the commodity sent from the input means; return means, which includes a return hole through which a commodity to be returned is accepted, a stocker that contains the commodity, and a second reader/writer section that is wirelessly communicable with the record tag of the commodity, for reading rental information recorded on the record tag of the commodity to generate return information; and information management means, which is connected to the input means and the return means, for recording rental information sent from the input means to update the recorded rental information based on return information sent from the return means. 4. The commodity rental apparatus according to claim 3, wherein the first reader/writer section and the second reader/writer section read information recorded on the record tag via antennas respectively arranged in the vicinity of the column and the return hole, and produce a radio wave for recording predetermined information on the record tag. 5. The commodity rental apparatus according to claim 4, further comprising: storage means for storing stock information for each commodity; and stock management means for detecting a response radio wave from each record tag of the commodities contained in the column using the first recorder/writer section to read identification information of the commodities to obtain the number of stocks according to the kind of commodity to generate stock information, and store the stock information by the storage means. 6. A commodity rental system comprising: a commodity rental apparatus that rents a commodity; and a management server that is connected to the commodity rental apparatus via a network, wherein the commodity rental apparatus comprises return means, which includes a return hole through which a commodity to be returned is accepted, a stocker that contains the commodity, and a second reader/writer section that is wirelessly communicable with the record tag of the commodity, for reading rental information recorded on the record tag of the commodity to generate return information, and containing means, which includes a column containing a commodity with a record tag on which identification information for identifying the commodity is recorded in advance and a first reader/writer section that is wirelessly communicable with the record tag, for identifying the commodity selected by the input section based on identification information recorded on the record tag to deliver the commodity from the column after writing rental information of the commodity sent from the input means, the commodity rental apparatus transmits identification information and rental information of the commodity to the management server when the commodity is delivered by the containing means, the management server stores rental information sent from the commodity rental apparatus to be associated with identification information, the commodity rental apparatus sends the management server sends the management server a request for rental information corresponding to the identification information of a commodity when the return means accepts the commodity, generates return information by the return means based on rental information sent from the management server in response to the request, and transmits the return information to the management server, and the management server updates rental information based on return information sent from the commodity rental apparatus. 7. The commodity rental system according to claim 6, wherein the management server is communicable with a terminal via the network, when receiving a commodity name indicating a predetermined commodity and rental information of the commodity, the management server generates a reservation number, stores rental information to be associated with the reservation number, and transmits the reservation number to the terminal, and when the reservation number is input by the input means, the commodity rental apparatus sends the management server a request for rental information corresponding to the reservation number, and selects the commodity to deliver by the containing means based on rental information sent from the management server in response to the request. 8. The commodity rental system according to claim 6, wherein the management server further comprises an advertisement database that stores advertisement information of the commodity, the commodity rental apparatus further comprises display means for outputting advertisement information, and requests advertisement information of the commodity of the management server with a predetermined timing, the management server extracts the advertisement information of a predetermined commodity from the advertisement database in response to the request and transmits it to the commodity rental apparatus, and the commodity rental apparatus receives advertisement information sent from the management server and output it by the display means. 9. A commodity rental method comprising: the input step of selecting a kind of a predetermined commodity with a record tag on which identification information for identifying the commodity is recorded in advance to input rental information for renting the commodity corresponding to the selected kind; the rental step of reading identification information recorded on the record tag to select a commodity corresponding to the kind of the commodity selected in the input step and record rental information of the commodity input in the input step on the record tag of the selected commodity to deliver; the rental information storage step of storing identification information and rental information of the commodity; the return step of accepting a commodity to be returned to read identification information of the commodity; the return information generation step of reading rental information corresponding to identification information of the commodity read and returned in the return step to generate return information based on the rental information; and the update step of updating rental information stored in the rental information storage step based on the return information. 10. A computer program product that records a computer program on a computer-readable storage medium, the computer program functioning as: means for detecting the kind of commodity and the number of commodities with a record tag on which identification information for identifying the commodity is recorded based on the identification information; means for reading identification information recorded on the tag record based on rental information input by a user to select one commodity of a kind corresponding to rent information and record rental information on the record tag of the commodity; means for recording rental information on a membership card; means for accepting a commodity to be returned to read rental information recorded on the record tag of the commodity and generate return information based on the rental information; and means for updating the rental information of the membership card based on the return information to record the return information on the record tag of the accepted commodity. |
<SOH> BACKGROUND ART <EOH>In recent years, there have become widespread automatic rental apparatuses or automatic vending machines for storage media such as VCT (Video Cassette Tape), CD (Compact Disk), DVD (Digital Versatile Disk) and like that record images or music information thereon. At the store where such automatic rental apparatus is installed (for example, unmanned video rental store), there is no need to station salespersons who provide service for selling or renting commodities. Accordingly, this makes it possible to save personnel costs and fix business hours arbitrarily (around-the-clock service is possible), thereby increasing merits in maintenance and management. However, from viewpoint of users, this provides a restriction in use, resulting in a poor usability as compared with the general store such as a video rental store. For example, at the time of using the automatic rental apparatus, since a membership card, which is issued for each automatic rental apparatus, is used even at the same chain store, the membership card corresponding to each automatic rental apparatus must be used to perform rental and return at the time of using multiple automatic rental apparatuses, so that the procedure is complicated. For this reason, Unexamined Japanese Patent Publication 10-49734 discloses an automatic rental apparatus in which an IC card is used as a user (membership) card. According to this automatic rental apparatus, since all information on the rental and return of the commodity is recorded on one IC card, even a different automatic rental apparatus is available using one IC card. However, even in this case, since the rental commodity is managed by only the automatic rental apparatus that stores the commodity, the user must return the rent commodity to the automatic rental apparatus that provided rental service. For example, regarding the commodity, which the user rent by an automatic rental apparatus at a location where he/she went out, he/she cannot return it to an automatic rental apparatus located close to his/her house. Moreover, stock information and rental information on the commodities in the automatic rental apparatus are stored in only the relevant automatic rental apparatus. Accordingly, for instance, in order to replenish commodities, the salesperson must go to the place where each automatic rental apparatus is installed and check individual stock information and the like, so that efficiency is poor. Moreover, when there is no stock of a desired commodity in the specific automatic rental apparatus, the user cannot grasp the stock of the desired commodity in the other automatic rental apparatus, so that he/she cannot rent the desired commodity even if he/she goes to a place where another automatic rental apparatus is installed, resulting in poor usability. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a block diagram illustrating a configuration of a commodity rental system according to an embodiment of the present invention; FIG. 2 is a front view of a commodity rental system according to an embodiment of the present invention; FIG. 3 is a schematic view illustrating an outline structure of a containing unit of a commodity rental system according to an embodiment of the present invention; FIG. 4 is a schematic view illustrating an example of rental information stored by a management server according to an embodiment of the present invention; FIG. 5 is a flowchart illustrating a commodity rental procedure using a commodity rental system according to an embodiment of the present invention; FIG. 6 shows an example of an initial screen of a commodity rental apparatus of a commodity rental system according to an embodiment of the present invention; FIG. 7 shows an example of a rental information input screen of a commodity rental apparatus of a commodity rental system according to an embodiment of the present invention; FIG. 8 is a flowchart illustrating a commodity return procedure using a commodity rental system according to an embodiment of the present invention; FIG. 9 shows an example of a return confirmation screen of a commodity rental system according to an embodiment of the present invention; FIG. 10 shows an example of a rental application screen of a commodity rental system according to a modification of the present invention; FIG. 11 shows an example of a rental confirmation screen of a commodity rental system according to a modification of the present invention; FIG. 12 is a front view of a commodity rental apparatus according to a modification of the present invention; FIG. 13 is a schematic view illustrating an internal structure of a commodity containing unit of a commodity rental apparatus according to a modification of the present invention; FIG. 14 is a schematic view illustrating the outline and internal structures of a return unit of a commodity rental apparatus according to a modification of the present invention; and FIG. 15 shows another structural example of a containing unit of a commodity rental apparatus according to an embodiment of the present invention. detailed-description description="Detailed Description" end="lead"? |
Method and device for the transfer of snmp messages over udp with compression of periodically repeating sequences |
The invention concerns the transfer of messages using an UDP transport. A typical example is offered by the SNMP messages, used to perform the communication (C1, C2) between manager units (M, M′) and agent units (A, A′) within a system for the management of data communication networks, such as internet. The payload of messages and preferably the messages as a whole shall undergo a compression operation based on the recognition of sequences that periodically appear in the message. |
1. Method for the transfer over UDP (User Datagram Protocol) of messages incorporating a payload (O1D), characterised in that it comprises the step of submitting at least said payload to a compression step (302, 104, 204) based on the recognition of sequences that periodically appear in the messages. 2. Method according to claim 1, characterised in that said compression step is performed according to a technique of gzip type, such as zLib. 3. Method according to claim 1, characterised in that it comprises the step of indicating the executed compression step into the message transferred over UPD. 4. Method according to claim 3, characterised in that it uses a bit field of the UDP header to indicate the executed compression step (302). 5. Method according to claim 4, characterised in that the bits from bit 62 to bit 69 of the UDP header are used to indicate the executed compression step {302). 6. Method according to claim 5, characterised in that it comprises the step of setting to 1 at least one among the bits 62 to 69 of the header of the UDP message. 7. Method according to claim 1, applied to the transfer of SNMP messages, characterised in that the compression step comprises the following operations: reading (100) an entire SNMP message, encoding {102) the read message in hexadecimal format, and submitting the message encoded in the hexadecimal form to a compression (104). 8. Method according to claim 1, applied to the transfer of SNMP messages, characterised by a reception step comprising the operations of. submitting a received message to a de-compression step (204) complementary to said compression step, so that the message submitted to the de-compression step can be obtained in hexadecimal format, decoding (202) the message submitted to the de-compression step (204) starting from the hexadecimal format, and reconstructing (200) the entire SNMP message starting from the decoded message. 9. Method according to claim 7, characterised in that it comprises an encapsulating operation into a standard SNMP message of the message submitted to said compression step (104). 10. Method according to claim 9, characterised in that it comprises the operations of: reading by bytes (108) the message submitted to said compression step {104) and converting (110) it into a corresponding message in ASCII characters, generating {112) a set of Variable Bindings, including a first OID indicative of the size of the original file and subsequent OID/value pairs carrying parts of said message submitted to said compression step (104), converted into ASCII characters, reconstructing a header information of the SNMP message, encoding (114) the SNMP message so obtained into a hexadecimal format so as to generate the UDP payload, and transferring (116) over UDP the payload so generated. 11. Method according to claim 8, characterised in that the reception step comprises the operations of: receiving the message submitted to said compression step as a UDP payload (216), submitting the payload so received to a hexadecimal decoding operation (214), recognising and assembling (212) the Variable Binding of the message submitted to hexadecimal decoding, and submitting the message recognised and assembled in the recognising and assembling operation (212) to a decoding operation from ASCII to binary (210), submitting the message decoded in binary form to said de-compression step {204). 12. Method according to claim 7, characterised in that it comprises the step of integrating the message submitted to said compression step {104) through encapsulation over UDP. 13. Method according to claim 12, characterised in that it comprises the steps of: configuring said message submitted to said compression step (104) as PDU payload of an UDP message (payload of PDU-UDP), and transferring the payload of PDU-UDP created this way from a given transmission port of a transmitter to a given reception port of a receiver. 14. Method according to claim 13, characterised in that it includes the steps of: receiving said message as a payload of a PDU-UDP received at the reception port, and extracting said payload from said UDP message. 15. Method according to claim 13, characterised in that it comprises the step of transmitting between a transmission terminal (M, M′; A, A′) and a receiving terminal (A, A′; M, M′) a synchronisation message of SNNP type, identifying said transmission port and/or said reception port. 16. System for managing data communication networks, including at least one manager unit (M, M′) and at least one agent unit (A, A′), communicating with one another over at least one channel (C1, C2) through the transmission of messages, characterised in that said messages are transferred over UDP following the method based on claim 1. 17. Data processing product, directly loadable into the internal memory of a digital processor and including parts of software code to perform the method according to claim 1, when the product is run on a digital processor. |
<SOH> BACKGROUND ART <EOH>The application called “agent” (hereinafter: agent) with its respective network manager over the SNMP messages has associated a database currently called “Management Information Base” or , short, MIB. Within such a database, the information is collected relating to the management and monitoring of the corresponding node or network element. In particular such information includes the following: MIB variables, that may be read by the Network Manager to derive information about the network element; MIB variables that may be written by the Network Manager to cause actions on the network element; and events (traps) that the same agent may cause towards the Network Manager (manager) with respect to specific situations. The communication at SNMP level essentially includes therefore: messages required to read/write the above variables (GetRequest, GetNextRequest, SetRequest, GetBulk), sent out by the Network Manager, and response messages (GetResponse) and trap messages, transmitted by the agent. The set of all the variables/traps managed by an agent are bound to the network element and specifically represent the relating MIB, i.e. they show the operation mode and the intrinsic characteristics of the network element to the Network Manager. Each variable or trap is individually identified by a string in the ASN.1 notation (Abstract Syntax Notation One), called Object IDentifier or OID. La framework of the string is, for instance, of “1.3.6.1.2.1.4.21” type, indicative of the fact that ASN.1 notation allows the representation of objects according to a hierarchical tree structure A part of the MIB has been defined as a standard and is supported by any agent, whereas other variables and some traps are specific for each manufacturer and in some cases also characteristic of a particular apparatus typology. The SNMP protocol, born in 1988, has undergone some evolutions during the years. In particular new messages typologies have been defined which the agents must be able to understand. The MIB standard, that each agent must be able to support, has been extended. On the filing date of this application, the versions being used are the 1st and the 2nd versions, whereas the standardisation of version 3 is currently under way. The size of a MIB varies according to the apparatus type and can even be of the order of some hundred kBytes, corresponding to some hundred OIDs. The diagram in FIG. 1 of the attached drawings shows the typical components of an SNMP message. The content of each component is written in ASCII characters and its maximum permissible size is equal to the maximum size of an UDP message, the data entity that carries it, equal to 65,507 bytes or octets (of which about 64 kbytes are designed for the information to be carried). In particular, in the same diagram of FIG. 1 the presence may be noticed of a message header and of a PDU (Protocol Data Unit) part, of which the part denoted by 1 collects messages such as GetRequest, GetNextRequest, SetRequest and GetResponse, the part denoted by 2 collects GetBulk messages, whereas the part denoted by 3 generally concerns trap type messages. More specifically, in the header of SNMP messages the following information is present: Version Number: number of the SNMP version used for message composition (V 1 , V 2 , V 3 , . . . ), and Community Name: a kind of password that allows access through reading and writing to the objects contained in the MIB module. The following information is available within the PDU PDU type: message typology that in the version 1 contains instructions such as GetRequest, GetNextRequest, SetRequest and Request, whereas version 2 may also contain instructions such as GetBulkRequest e InformRequest; Request id: individual identifier of the message assigned by the manager and utilised by the agent when answering, in order that the manager might associate the requested response with the appropriate reference; Error status: set to 0 in all message typologies, except for the response messages, wherein, if set to 1, it means that an error is present; Error Index: it indicates which one among the requested variables (OID) has caused the error, and Variable Bindings: these are OID/value pairs; the values are “null” in the case of requests, and compiled in the case of response messages. In particular, the part just on the left side of FIG. 1 shows a typical structure of the part collecting the above Variable Bindings. In the present invention and in the captions appearing in some figures of the appended drawings, the choice has been made of mentioning—for the different elements being considered—the corresponding acronyms/names/initials in the English language. This has been done for the sake of a clear and straightforward description. The above acronyms, names and initials are currently used at international level by those skilled in the art, since no translations into the different national languages have been developed during the years. The transmission of the SNMP message, made possible over UDP, allows the data packet exchange between two computers linked to the network. The UDP message format namely consists of a header whose main data are the IP address of the computer transmitting the message, the IP address of the destination computer and the size of the PDU being transported. In turn, the PDU format is formed by a header part and by a data part currently called “Payload” or “Octet Data”. The header therefore contains the following data: source port, destination port, size of the transported unit, integrity check (CHECKSUM) of the data unit. The methodology currently adopted for transferring a SNMP messages over UDP (from the manager to the agent, and vice-versa) is based in essence on the fact that the complete SNMP message is coded by means of the BER (Basic Encoding Rules) methodology. This way of operating allows one to convert the bytes forming the SNMP message into a hexadecimal structure suitable to be used as a payload of the UDP message. The UDP transfer service of the data thus obtained essentially envisages: at the transmission stage: reading of the SNMP message and subsequent hexadecimal coding (BER encode) of the message, for its transmission over UDP, and at the reception stage: after the reception over UDP, the hexadecimal decoding (BER decode) of the DDU and the subsequent reconstruction of the message. The current application practice proves that in the data communication networks such as internet, the need arises of transferring a bulk of information in terms of requests/responses conveyed in the form of SNMP messages. Owing to the total size of the information, the time required for the relating transfer and network traffic thus generated, the solutions conventionally adopted for transferring SNMP messages in a standard format generally exhibit a rather poor efficiency. For this reason three IEFT specifications have already been proposed—at a draft level—to tackle the issue. The first proposal (known as SNMP Object Identifier Compression, rev. April 2001—draft-ietf-eos-oidcompression-00. txt) is based on the concept that the majority of the information contained in the MIB is referred to by OID, formed by a constant and rather large part and by a variable and very small part. Starting from this principle, the proposal aim is the encoding, according to an algorithm, of the constant part of the OID through a shorter numbering. This solution optimises only in part the quantity of information being transferred, without considerably reducing its size. The second proposal (known as “Efficient Transfer of Bulk SNMP Data, rev. April 2001—draft-ietf-eos-snmpbulk-00. txt”) faces the issue of the management of the GetBulk instruction that allows the simultaneous collection of a given set of information. The instruction introduced in the SNMP version 2 does not allow the optimisation of the collection, since the manager has to declare the number of elements to be collected, without knowing how many elements form the set of information requested. Amendments to the UDP protocols have been suggested with a modification of the encode algorithm of the message (from BER to PER, which stands for Packet Encoding Rules) or with resort to a transfer mode of FTP (acronym of File Transfer Protocol) type. The solution described in the above cited document, is the introduction of a new instruction at the agent side, called GetColsRequest, and of relating message at manager side, capable of recognising the number of elements to be transferred, identifying the end of the requested set and optimising therefore requests and network traffic. However, also this solution does not allow one to optmise the management of sizes and number of messages being sent. The third solution taken into account (known as “SNMP Payload Compression—rev. April 2001—draft-irtf-nmrg-snmp-compression-01.txt”) is in principle similar to the first proposal, since it suggests a differential encoding algorithm called “OID Delta Compression” or ODC. Starting from an OID root, such a solution envisages to memorise the subsequent OID assigning to the OID a code associated to the OID root, followed by the varying part of OID. Substantially, the variations are stored in terms of differential increments, as compared to the root element. This solution has the drawback of being incompatible with previous versions of the protocol. Further, it allows an estimated saving by about 30% for particularly recursive OID values, i.e. data arrays, and it is substantially inefficient in the event of a low number of recursive items. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>The invention will now be described by way of a non-limiting example, with reference to the attached drawings, wherein: FIG. 1 , relating to the background technique, has already been previously described; FIG. 2 shows in the form of a general block diagram a typical application architecture of the solution according to the invention; FIGS. 3 to 5 , each subdivided into two parts relating to transmission (part a) and to reception (part b) respectively, illustrate different types of embodiments of the solution according to the invention in the form of a flow chart; FIG. 6 is an additional flow chart illustrating the general characteristics of the solution according to the invention; and FIGS. 7 and 8 depict, according to modalities substantially similar to those adopted in FIG. 1 , the embodiment criteria of the solution according to the invention, illustrated in two possible variations. detailed-description description="Detailed Description" end="lead"? |
Method of manufacturing structural units |
A method of producing an improved structural unit with anisotropic load characteristics includes producing a multiplicity of first building elements that are constructed from fiber-reinforced plastics material; producing at least on second building element that is of a different material to the first building elements; and adhering the first and second building elements together to form the improved structural unit. |
1. A method of producing an improved structural unit with anisotropic load characteristics, said method comprising: producing a multiplicity of first building elements that are constructed from pultruded fiber-reinforced plastics material; producing at least one second building element that is of a different material to said first building elements; and adhering said first and second building elements together to form a structural unit having anisotropic load characteristics. 2. The method of claim 1 wherein the first building elements are produced using polyester, vinylester or epoxy resin plastics and produced using a glass, carbon or kevlar fiber. 3. The method of claim 1 wherein the second building elements are produced using fiber-reinforced plastic but with a different plastic and/or fiber to that of the first building elements. 4. The method of claim 1 wherein the second building element is produced from concrete, timber, plastics, metal or the like. 5. The method of claim 4 wherein the concrete maybe prefabricated or cast in situ. 6. The method of claim 1 wherein the second building element is used to improve the load carrying characteristics of the structural unit. 7. The method of claim 1 wherein the second building element provides additional tensile, sheer or compressive strength to the structural member. 8. The method of claim 1 wherein the first and/or second building elements have at least two sides of its outer periphery that are substantially flat. 9. The method of claim 1 wherein the second building element is placed between two first building elements. 10. The method of claim 1 wherein the second building element is located adjacent said first building elements. 11. The method of claim 1 wherein the first building elements are tubular. 12. The method of claim 1 wherein the first building elements are produced using standard shapes and/or lengths. 13. The method of claim 1 wherein the first building element is shaped differently to the second building element. 14. The method of claim 1 wherein the building elements are adhered together using adhesive. 15. The method of claim 14 wherein the adhesive absorbs stresses and/or potential cracking between the two building elements. 16. The method of claim 15 wherein the adhesive is an epoxy based. 17. The method of claim 1 wherein the building elements are adhered to each other so that the structural unit is curved. 18. The method of claim 1 wherein bulkheads, diaphragms, strong points and/or internal ties are used to produce the structural units. 19. A structural unit produced in accordance with claim 1. 20. A structural unit comprising: a multiplicity of first building elements that are constructed from pultruded fiber-reinforced plastics material; at least one second building element that is of a different material to said first building elements; and the first and second building elements being adhered together to form a structural unit having anisotropic load characteristics. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The superior physical properties of fibre-reinforced plastic are well recognised. However, to date, there have been difficulties with producing viable structural elements of fibre-reinforced plastic due to cost constraints. One approach used to produce fibre-reinforced plastic structural elements has been to use large moulds to produce the structural element. However, the mould that is required is specific to that application. Therefore, if another structural element needs to be produced, another mould is required reducing cost effectiveness. Further, this type of manufacture of fibre-reinforced plastics to produce structural elements is difficult due to shrinkage and high temperatures, making the moulds difficult to produce. Another approach to producing fibre-reinforced plastic structural elements has been through the use of pultrusion. This method suffers significantly less from the problems of shrinkage or temperature control. However, the dies and machines needed are expensive to produce. Further, the dies are specific to a single application and pultrusion can only be used for structures of continuous cross-section. That is, many complex shapes cannot be produced using pultrusion. One problem associated with both methods is that any structure that is produced is limited to the inherent physical characteristics of the type of fibre-reinforced plastics. In many instances, this limits the use of fibre-reinforced plastic for a particular application. For a representative example of the prior art approach to composite structures, reference may be made to U.S. Pat. No. 5,794,402, in the name of Dumlao et al. This patent describes a modular structural section including a beam and a load bearing deck formed of a polymer matrix composite material. The deck is described as a sandwich panel having a lower surface, an upper surface and a core of hollow, elongate core members. The Dumlao method bonds together fibre composite modules made of specific resin and fibres to make a larger structure, The larger structure is made only from the materials of the individual modules and, therefore, has essentially the properties of the specific resin and fibres. The larger structure does not have any particular structural advantages compared to the modules. |
<SOH> SUMMARY OF THE INVENTION <EOH>In one form, though not the only or broadest form, the invention resides in a method of producing an improved structural unit with anisotropic load characteristics, said method including the steps of: producing a multiplicity of first building elements that are constructed from fibre-reinforced plastics material; producing at least one second building element that is of a different material to said first building elements; and adhering said first and second elements together to form the improved structural unit. The inventor has found that a surprising advantage is obtained by bringing together disparate materials with quite different characteristics to form structural units that can be built into structures. The properties of the structures, such as stiffness, strength and mass, are tailorable by selection of the materials of the first and second building elements. The properties are tailorable as both the first and second building members are able to withstand loading in their own right. That is, the individual building element would be able to be loaded if they were not adhered together. The first building elements may be produced using polyester, vinylester or epoxy resin plastics and produced using a glass, carbon or keviar fibre. Preferably, the first building elements are pultruded. The second building elements may also be produced using fibre-reinforced plastic but with a different plastic and/or fibre to that of the first building elements. The second building element may also be produced from any suitable material such as concrete, timber, plastics, metal or the like, The concrete may be prefabricated or cast in situ. The second building element may be used to improve the load carrying characteristics of the structural unit. The second building element may provide additional tensile, sheer or compressive strength to the structural member. Preferably, the first and/or second building elements have at least two sides of its outer periphery that are substantially flat. The second building element may be placed between two first building elements. Alternately, the second building element may be located adjacent said first building elements. The first building elements may be of uniform cross-section throughout their length. The first building elements may be tubular. The first building elements are produced using standard shapes and/or lengths. The first and second building elements may be of a variety of different shapes and/or different sizes. Preferably, the building elements are adhered together using adhesive. The adhesive may be used not only to bond building elements together, but to absorb stresses and/or potential cracking that may occur when two different materials are combined together. The adhesive may be epoxy resin. The building elements may be adhered to each other to enable the structural unit to be curved. Bulkheads, diaphragms, strong points and/or internal ties can be used to produce the structural units. The structural units produced using this method may be used in conjunction with each other to produce an improved structure. |
Time delay evaluation |
The invention concerns a method to evaluate whether a statistical time delay (TD) between a first event and a second event of a device under test is better than a test limit (TL). The method comprises the steps of: performing a minimum number N of tests and evaluating the time delay (TD) from each test; modelling a first probability distribution (P1) as a function of the elapsed time from the first occurrence of the first event to the first occurrence of the second event; obtaining a second probability distribution (P2) as a function of the elapsed time from the first occurrence of the first event to the N-th occurrence of the second event; performing a statistical transformation in order to obtain a third probability distribution (P3) as a function of the N-th occurence of the second event; deciding to pass the device under test according to the comparison of P3 with the test limite. |
1. A method to evaluate whether a statistical time delay (TD) between a first event (CS) and a second event (RM) of a device under test (DUT) is better than a test limit (TL) comprising the steps Performing a minimum number N of tests and evaluating the individual time delay (TD) from each test, Modeling a first probability distribution (P1) of the evaluated time delays (TD) as a function of the elapsed time from the first occurrence of the first event (CS) to the first occurrence of the second event (RM), Obtaining a second probability distribution (P2) of the evaluated time delays (TD) as a function of the elapsed time from the first occurrence of the first event (CS) to the N-th occurrence of the second event (RM) by performing the N-1-th self convolution of the first probability distribution (P1), Performing a statistical transformation (ST) in order to obtain a third probability distribution (P3) of the evaluated time delays (TD) as a function of the N-th occurrence of the second event (RM), Deciding to pass the device under test (DUT), if a certain percentage of the area of the third probability distribution (P3) is on a good side (GS) of the test limit (TL2), or Deciding to fail the device under test (DUT), if a certain percentage of the area of the third probability distribution (P3) is on a bad side (BS) of the test limit (TL2), otherwise Repeating the steps of the method with an incremented number N of tests: 2. Method according to claim 1, characterized by grouping the evaluated time delays (TD) from the individual tests into classes (CL) before modeling the first probability distribution (P1). 3. Method according to claim 1 or 2, characterized in that the device under test (DUT) is a user equipment (UE), especially a mobile station, in a cellular mobile communication system and the first event is a cell quality swap (CS) of the cellular mobile communication system. 4. Method according to claim 3, characterized in that the second event is a registration message (RM) issued by the user equipment (UE) in order to register to another cell (Cell 1,; Cell 2) of the cellular mobile communication system as a response to the cell quality swap (CS). 5. Method according to claim 4, characterized by fitting free parameters of an error model (EM) for modeling the first probability distribution (P1). 6. Method according to claim 5, characterized in that a free parameter of the error model (EM) is a random equally distributed delay (S) due to the fact that the cell swap (CS) and the first physical measurement of the user equipment (UE) are uncorrelated. 7. Method according to claim 6, characterized in that a free parameter of the error model (EM) is a constant processing delay (PD) of the user equipment (UE). 8. Method according to claim 7, characterized in that a free parameter of the error model (EM) is the standard deviation (σ) of a gaussian distribution of additive white gaussian noise. 9. Method according to claim 8, characterized in that a free parameter of the error model (EM) is a parameter (k) of a filter function due to linear distortion in the user equipment (UE). 10. Method according to claim 9, characterized in that the filter function has the form of formula Fn=(1−a)·Fn-1+a·Mn whereby Fn is the updated filtered measurement result, Fn-1 is the old filtered measurement result, Mn is the latest received measurement result and a=1/2(k/2), where k is the free parameter. 11. Method according to claim 9, characterized in that, a free parameter of the error model (EM) is a deviation parameter (L) due to a linearity error. |
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