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1. An anti-collision process by a host computer of elements matching a given relationship with said host computer enabling the identification of said elements by the latter, each of said elements having an identification number between 0 and a maximum value (MAX); said process being characterized by the following steps: a) transmission by said host computer of a query instruction capable of being received and recognized by any element matching said given relationship with said host computer, b) when at least one of said elements matches said given relationship with said host computer, transmission by the latter of an anti-collision signal including an identification attempt digital value, c) response by any element matching said given relationship with said host computer and having an identification number less than or equal (or greater than or equal) to said digital identification attempt value, and d) detection of a collision between several elements when said host computer receives several responses and in this case, transmission of an anti-collision instruction made up of an identification attempt digital value defined according to a given algorithm, or selection of the element by its identification number when there is only one response. 2. The anti-collision process by a host computer of elements matching a given relationship with said host computer enabling the identification of said elements by the latter, each of said elements having an identification number between 0 and a maximum value (MAX); said process being characterized by the following steps: a) transmission by said host computer of a query instruction capable of being received and recognized by any element matching said given relationship with host computer, b) when at least one of said elements matches said given relationship with said host computer, transmission by the latter of an anti-collision instruction including an identification attempt digital value, c) transmission by said host computer of a new anti-collision instruction including an identification attempt digital value less than the identification attempt digital value transmitted earlier and resulting from an initial algorithm if there is a collision between the responses coming from several of said elements or recording of the identification number of the element by said host computer when only one element exists whose identification number is less than said identification attempt digital value transmitted earlier, d) repetition of step c) until the transmission of an anti-collision instructions made up of an identification attempt digital value leading to the identification of only one of said elements, and in this case, the recording of the identification number of said element, e) transmission by said host computer of a new anti-collision instruction including an identification attempt digital value greater than the identification attempt digital value transmitted earlier and resulting from a second algorithm if there is a collision between the responses coming from several of said elements or recording of the identification number of the element by said host computer when only one element exists whose identification number is less than said identification attempt digital value transmitted earlier, f) repetition of step e) until the transmission of an anti-collision instruction including said maximum value as the identification attempt digital value, and g) repetition of steps c) through f) until the transmission of an anti-collision instruction including said maximum value as the identification attempt digital value results in no response from said elements. 3. The process according to claim 2, including the following steps if there is no response to the anti-collision instruction of steps c) and e) h) verification that said anti-collision instruction does not include said maximum value as the identification attempt digital value, i) transmission by said host computer of a new anti-collision instruction including an identification attempt digital value greater than the identification attempt digital value transmitted earlier and resulting in a third algorithm, and j) repetition of steps c) through g). 4. The process according to claim 3, in which said first algorithm consists in replacing the identification attempt digital value VALID contained in the anti-collision instruction by the new value: VALID=MIN+(VALID−MIN)/N in which MIN designates the lower value of an interval, the upper value of which is VALID and in which are located the identification numbers of the elements to be identified and N designates a down speed parameter whose value is greater is greater than 1. 5. The process according to claim 4, in which said second algorithm consists in replacing MIN by the identification attempt digital value (VALID) contained in the anti-collision instruction which was just transmitted and in replacing said identification attempt digital value by the identification attempt digital value contained in the anti-collision instruction preceding said anti-collision instruction which was just transmitted. 6. The process according to claim 5, in which said third algorithm consist in replacing the digital identification attempt value VALID contained in the anti-collision instruction by the new value: VALID=VALID+(DERCOLL−VALID)/M in which DERCOLL is a variable whose value is equal to MAX or to the identification attempt digital value of the anti-collision instruction preceding the anti-collision instruction which was just transmitted and M designates an up speed parameter having a value greater than 1. 7. The process according to claim 2, in which each of the variable M and N is equal to 2. 8. The process according to claim 1, in which said elements are contactless smart cards and said host computer is a reader of said contactless smart cards. 9. A computer program including instructions implementing the process according to claim 1. 10. A computer program including instructions implementing the process according to claim 2. |
<SOH> TECHNICAL FIELD <EOH>This invention concerns systems in which several elements may be identified simultaneously by a host computer or an equivalent device designed to identify the elements thus resulting in a collision between several elements and specifically concerns an anti-collision process for elements to be identified by a host computer. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The purposes, objects and characteristics of the invention will become more apparent from the following description when taken in conjunction with the accompanying drawings in which: FIG. 1 represents a block diagram of the process according to the invention implemented in each element and namely the chip of a contactless smart card when it is presented in front of a reader, and FIG. 2 represents a block diagram of the process according to the invention implemented in the host computer and namely the identification of contactless smart cards. detailed-description description="Detailed Description" end="lead"? |
Method for the frequency and time synchronization of an odm receiver |
The invention relates to a frequency and time synchronization of a receiver (E) for receiving OFDM signals on a fixed carrier frequency. The inventive method is characterized by determining in a first step the approximate nominal value of the frequency and of the time origin of the OFDM signal via a two-dimensional frequency-time search mode and the determination of the area point with the optimum quality criterion of the OFDM signal or via the evaluation of a synchronization sequence transmitted by the transmitter. In a subsequent second step the phase of at least one of the pilot signals transmitted together with the OFDM signal is determined in the receiver (E) and is averaged across several OFDM signal blocks; and a more exact nominal value of the frequency and of the time origin of the OFDM signal is determined therefrom. The receiver (E) is then synchronized to the frequency so determined and the OFDM signal is demodulated with the time origin value so determined. |
1. A method for frequency and time synchronization of a receiver for receiving an OFDM signal on a fixed carrier frequency, said method comprising: a first step, wherein approximate nominal values for a frequency and a time origin of an OFDM block are determined via: (a) a two-dimensional frequency-time search mode and by determining an area point with an optimum quality criterion of the OFDM signal, or (b) evaluating a synchronization sequence transmitted by a transmitter; and in a second, step subsequent to the first step, wherein more exact nominal values for the frequency and time origin of the OFDM block are determined, wherein the receiver is then synchronized to the frequency determined thereby, and the OFDM signal is demodulated starting with the time-origin value determined thereby, and wherein in the second step in the receiver, a phase of at least one pilot carriers transmitted together with the OFDM signal is determined and averaged across a plurality of OFDM signal blocks and the more exact nominal value for the frequency and time origin of the OFDM block is determined with reference thereto 2. The method according to claim 1, wherein during a transmission time following an initial frequency and time synchronization, only the second step is repeated either continuously periodically or aperiodically. 3. The method according to claim 1, wherein an adaptive digital filter, which is controlled via filter constants calculated in the receiver, is disposed at an input of the OFDM receiver. 4. The method according to claim 3, wherein the adaptive filter is additionally adapted to changing propagation conditions of a transmission channel. 5. The method according to claim 4, wherein: (i) in the first step, a quality criterion of the OFDM signal is determined for every point of a two-dimensional frequency-time search range, which is determined in one dimension by a frequency search range including the nominal frequency of the OFDM signal, and in a second dimension by a time-search range including the nominal origin of the OFDM signal; (ii) the area point with the optimum quality criterion of the OFDM signal is then determined-with reference thereto (iii) finally, the receiver is synchronized to the nominal frequency, taking into consideration the difference between the nominal frequency and the frequency value corresponding to the optimum quality criterion; and (iv) the OFDM signal is demodulated starting with a time value corresponding to the optimum quality criterion. 6. (canceled). 7. The method according to claim 5, wherein a deviation (distance) between the input and an output of an equalizer is used as the quality criterion. 8. (canceled). 9. The method according to claim 7, wherein, either at the start of a transmission or periodically and/or aperiodically during the transmission, a synchronization sequence in a form of a special bit pattern is transmitted by the transmitter, and the optimum quality criterion is determined with reference thereto. 10. The method according to claim 9, wherein equalization is carried out by multiplication of the individual OFDM carriers with a complex value corresponding to an amplitude and phase response of the transmission channel. 11. The method according to claim 10, wherein the averaging of the phase values of the pilot carriers calculated in the second step is carried out by filtering and smoothing across a plurality of OFDM signal blocks. 12. The method according to claim 11, wherein a linear regression is used for filtering. 13. The method according to claim 11, wherein an order statistic filter is used for filtering. 14. The method according to claim 11, wherein a phase-control loop is used for filtering. 15. The method according to claim 14, wherein the calculated phase values are weighted in dependence upon a quality criterion of the OFDM signals and taken into account in the averaging in an appropriately weighted manner. 16. The method according to claim 15, wherein, the quality of the decoding result in the receiver is used as the weighting criterion. 17. The method according to claim 16, wherein an additional adaptive filter, by means of which slow changes can be compensated, is provided in the receiver demodulator. 18. The method according to claim 17, wherein after determining the more exact values for frequency and origin of the OFDM signals, the OFDM signals are demodulated, decoded, and then used to perform a further channel estimation and equalization of the OFDM signal. 19. The method according to claim 18, wherein the sampling clock in the receiver is synchronized with the transmitter sampling clock either by controlling the main oscillator or the sampling clock of the A/D-converter, or by phase displacement in the receiver filter. 20. The method of claim 1, wherein during the first step, the quality criterion is also determined for pilot carriers transmitted together with the OFDM signals. 21. The method of claim 1, wherein in the first step, before the determination of the optimum quality criterion, the transmission function of the transmission channel is estimated for every carrier of the OFDM signal, using pilot carriers transmitted in the OFDM signal, and the OFDM signal is equalized in dependence thereon. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The invention relates to a method for frequency and time synchronization of a receiver used for receiving OFDM signals, which are sent on a fixed carrier frequency. In modern digital technology, Orthogonal Frequency Division and Multiplexing (OFDM) systems are used for data transmission. According to this principle, before transmission, the digital data stream is converted by mapping into complex-value symbols and split into a large number of partial signals, each of which is transmitted on a separate carrier. The DVB-T (Digital Video Broadcasting) system, for example, uses 1,705 and/or 6,817 of these individual carriers. In the receiver, this partial information is combined to form the complete information from the transmitted digital-data stream. This OFDM system is already well known and has been described in greater detail, for example, by HERMANN ROHLING, THOMAS MAY, KARSTEN BRÜNINGHAUS and RAINER GRÜNHEID, Broad-Band OFDM Radio Transmission for Multimedia Applications, Proceedings of the IEEE, Volume 87, No 10, October 1999, page 1778 ff. With systems of this kind, it is important that the receiver is accurately synchronized, with reference to frequency and time, to the OFDM signal blocks transmitted. Doppler and frequency shifts of the individual carriers can occur as a result of movement of the transmitter and/or receiver and/or as a result of differences in frequency. Moreover, it is important that the receiver is also accurately synchronized with reference to time to the origin of the orthogonality interval of the OFDM signal blocks. As a result of differences in propagation delay, depending, for example, on the distance between the transmitter and the receiver, the OFDM signal blocks do not always reach the receiver at the same nominal time. The object of the present invention is to provide a method with which an OFDM receiver of this kind can be synchronized to the received OFDM signal with reference to frequency and time as rapidly and accurately as possible. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention, two successive procedural steps allow rapid frequency and time synchronization of a OFDM receiver. The computational effort required in this context is limited as a consequence of receiving on a fixed carrier frequency, because the fixed frequency mode allows the use of special averaging and smoothing methods. |
Lighting device |
The invention concerns an energy saving electrical system with good energy economy for the ignition, operation and extinguishing of gas-discharge lamps, such as up to four low-pressure fluorescent lamps or the equivalent, high-pressure mercury lamps and both high-pressure and low-pressure lamps of sodium type or metal halogen lamps in alternating current networks. The system comprises a rectifier (1), a capacitor (2), a power transistor (50) and a first transformer and a second transformer (T1, T2), each with several windings. The system furthermore comprises means (46) for stabilising the emission of light during changes of voltage in the supply network, and means (59, 39, 3, 46, 19, 35, 52) for limiting the current through and the voltage across the power transistor (50). Lamps that are to be used are connected to outputs of the windings (98 107), which windings are designed and connected such that they cooperate in order to operate the relevant lamp or lamps with negative and positive currents that are equal in magnitude. |
1. A energy saving system for the ignition, operation and extinguishing of connected gas-discharge lamps which system is connected to the alternating current supply network via a rectifier (1), a capacitor (2), a power transistor (50) and a first transformer (T1) with at least four windings (59-63), which said units are not only part of an ignition circuit for the rapid ignition of the lamps with a high direct voltage, but also part of an oscillator circuit for operation of the lamps at a lower voltage and part of a direct voltage circuit with a lower voltage for the operation of the components that are included in the system, characterised in that the system furthermore comprises means (64, 113, 6, T2, 71, 72, 97), comprising a second transformer (T2) with at least six windings, for the connection and simultaneous ignition of 1-4 luminescent lamps (73-79) or the equivalent, and with a pulse generator (71) and a field effect transistor (72) for the operation of the second transformer (T2), means (61, 43, 7) for the connection of a high-pressure mercury lamp (80) or the equivalent that is supplied with direct current and that has a low ignition voltage and high power; and means (61, 62, 63, 44, 45, 8, 9) for the connection of a high-pressure sodium vapour lamp or metal halogen lamp (81) or the equivalent with an ignition voltage of approximately 4 kV and low operational voltage, means (46) connected to the base of the power transistor (50), in order to stabilise the emission of light from the lamp or lamps when the supply networks voltage changes, means (59, 39, 3, 46, 19, 35, 52) to limit the current and the voltage through the power transistor (50), whereby the electrodes of the lamp or lamps (73-81) are connected to outputs (98-101) of the windings (61-63) of the first transformer (T1) or outputs (102-107) of windings (65-70) of the second transformer (T2) which windings are mutually connected and designed such that they cooperate in order to operate the relevant connected lamp with a negative current amplitude that has the same magnitude as the positive current amplitude and to supply the relevant lamp or lamps with the ignition and operational voltages required. 2. The system according to claim 1, characterised in that it comprises a phototransistor (56) or equivalent element in order to influence the current to the base of the power transistor (50) depending on the incident light and in this way automatically control the ignition, operation and extinguishing of the relevant lamp or lamps. 3. The system according to any one of claim 1, whereby the inputs of the rectifier (1) in the system are connected to the alternating current supply network, and the outputs of the rectifier (1) are connected to electrodes of the capacitor (2), whereby the positive output of the rectifier is connected to a contact (98) of a first winding (61) of the first transformer (T1), and is connected via a first resistor (15) to electrodes of second (16) and third (17) resistors and to the electrode of a second capacitor (4), which is together with the second electrode connected to the anode of a first diode (40) and to the contact of the second winding (60) of the transformer (T1), whereby the cathode of the first diode (40) is connected to the second electrode of the second resistor (16), and whereby a second contact of the second winding (60) of the transformer (T1) is connected to the negative output of the rectifier, to contacts on third (59) and fourth (64) windings of the transformer (T1), to an electrode of a potentiometer (35), to an electrode of a third capacitor (6), to an electrode of a fourth resistor (19) and via a fourth capacitor (3) to the anode of a zener diode (46), characterised in that the system comprises fifth (62) and sixth (63) windings of the transformer (T1), a phototransistor (56), a pulse generator (71), a field effect transistor (72), together with a second transformer (T2) with six windings (65-70), whereby the second resistor (16) is connected to the base of the power transistor (50), to the cathode of the zener diode (46), to the collectors of first and second transistors (51, 52); and that the second electrode of the third resistor (17) is connected to the anode of a second diode (41) whereby its cathode is connected to the anode of the first diode (40), to the second contact of the second winding (60) of the first transformer (T1), to the anode of a third diode (42), the cathode of which is connected to the electrode of a fifth capacitor (5), to the feed output of the generator (71), to the collector of the phototransistor (56), the emitter of which is connected to the base of the first transistor (51) and via a fifth resistor (18) to the emitters of the first and second transistors (51, 52), to the second electrode of the fifth capacitor (5), to a common output of the generator (71), to the source of the field effect transistor (72), to the anode of a fourth diode (97) and to the negative output of the rectifier (1), and that the second contact of the third winding (59) of the first transformer (T1) is connected to the cathode of a fifth diode (39) whereby its anode is connected to the anode of the zener diode (46); and that the emitter of the power transistor (50) is connected to the second electrodes of the fourth resistor (19) and the potentiometer (35), the regulator of which is connected to the base of the second transistor (52), and that the output of the generator (71) is connected to the gate of the field effect transistor (72), the drain of which is connected via the first winding (65) of the second transformer (T2), to the second electrode of the third capacitor (6), to the cathode of a sixth diode (113), the anode of which is connected to the second contact of the fourth winding (64) of the first transformer (T1), the first winding (61) of which is connected with its second contact via a fifth winding (62) to the contact of a sixth winding (63) and to the collector of the power transistor (50); and that the second transformer (T2) is connected with the contact of the second winding (66) to the cathode of the sixth diode (113), and the second contact of the second winding (66) is connected to the cathode of the fourth diode (97) and to third (67) and fourth (68) windings connected in series, and that the output of the field effect transistor (72) is connected via the fifth winding (69) to the contact of the sixth winding (70). 4. The system according to claim 3, characterised in that two lamps (74, 75) connected in series are connected between a common contact (105) to third (67) and fourth (68) windings of the second transformer (T2) on the one side, and between a common contact (104) to fifth (69) and sixth (70) windings of the second transformer (T2) on the other side. 5. The system according to claim 3, characterised in that the second contact (107) of the fourth winding (68) of the second transformer (T2) is connected via four lamps (76-79) connected in series to the second contact (106) of the sixth winding (70) of the second transformer. 6. The system according to claim 3, characterised in that the common contact (99) of first (61) and fifth (62) windings of the first transformer (T1) is connected to the anode of a diode (43) and that its cathode is connected via capacitor (7) and lamp (80) connected in parallel to the positive output (98) of the rectifier. 7. The system according to claim 3, characterised in that the collector (100) of the power transistor (50) is connected to the anode of a diode (44), the cathode of which is connected via a capacitor (8) to the positive output (98) of the rectifier and via a lamp (81) to the cathode of a second diode (45) and via a capacitor (9) to the second contact (101) of the sixth winding (63) of the first transformer (T1) and that the anode of the last-mentioned diode (45) is connected to the cathode of the first-mentioned diode (44). 8. The system according to claim 3, characterised in that the emitter (109) of a phototransistor (57) is connected to the anode of a second zener diode (47), to the electrode and the regulator of a potentiometer (36), to the common output of an amplifier (82), and to the negative output (109) of the rectifier, and that the collector of the phototransistor (57) is connected to the inverse input of the amplifier (82) and via a resistor (20) to the electrode of a further resistor (21), to the supply contact of the amplifier (82) and to the cathode (108) of the third diode, and that the direct input of the amplifier (82) is connected to the second electrode of the potentiometer (36) and to the electrode of a resistor (22), the second electrode of which is connected to the cathode of the second zener diode (47) and to the second electrode of the further resistor (21), and that the output (110) of the amplifier (82) is connected to the base of the first transistor (51). 9. The system according to claim 3, characterised in that the base (110) of the first transistor (51) is connected via a thermoresistor (38) to the cathode (108) of the third diode (42). 10. The system according to claim 3, characterised in that the negative output of the rectifier (109) is connected to common outputs of a microphone (87), an amplifier (83), an amplitude detector (88), to the electrode of a capacitor (10) and with the emitter of a third transistor (53), whereby the output of the microphone (87) is connected to the input of the amplifier (83), the output of which is connected to the input of the amplitude detector (88), the output of which is connected to the second electrode of the capacitor (10) and with the base of the third transistor (53), the collector (110) of which is connected to the base of the first transistor (51) and via a resistor (24) to the supply contacts of the amplitude detector (88) and the amplifier (83) and to the cathode (108) of the third diode (42). 11. The system according to claim 3, characterised in that the negative output of the rectifier (109) is connected to common outputs of a Schmitt trigger (92), a frequency detector (93), an amplifier (84), an amplitude detector (89), to the electrode of a capacitor (11), to the electrode of a further capacitor (12), to the emitter of a third transistor (54), whereby a capacitance electrode (91) is connected to the input of the Schmitt trigger (92) and via a resistor (25) to the output of the Schmitt trigger (92) and to the input of the frequency detector (89), the output of which is connected to the input of the amplifier (84), the output of which is connected to the amplitude detector (89), the output of which is, in turn, connected to the second electrode of the additional capacitor (12) and to the base of the third transistor (54), the collector of which is connected to the base (110) of the first transistor (51) and via a resistor (26) to supply outputs (109) of the amplitude detector, the amplifier, the frequency detector, the Schmitt trigger and the cathode of the third diode (42). 12. The system according to claim 3, characterised in that the negative output of the rectifier (109) is connected to common outputs of an amplifier (85) and an amplitude detector (90), to the cathode of a photodiode (49), to the electrode of a capacitor (13), to the emitter of a transistor (55) and to the emitter of a phototransistor (58), the collector of which is connected to the electrode of a further resistor (28) and to the input of the amplifier (85), the output of which is connected to the input of the amplitude detector (90), the output of which is connected to the second electrode of the capacitor (13) and to the base of the transistor (55), the collector of which is connected to the base (110) of the first transistor (51) and via a resistor (29) to supply outputs (108) of the amplitude detector (90) and the amplifier (85), to the second electrode of the additional resistor (28), to the cathode of the third diode (42) and via a resistor (27) to the anode of the light diode (49). 13. The system according to claim 3, characterised in that the negative output of the rectifier (109) is connected to a common output of a timer (95) and to the negative electrode of an accumulator (94), whereby the cathode (108) of the third diode (42) is connected to the positive electrode of the accumulator (94) and to the supply output of the timer (95), the output of which is connected to the base (110) of the first transistor. 14. The system according to claim 3, characterised in that the regulator of a potentiometer (37) is connected to the anode of a second zener diode (48), to negative supply outputs of an amplifier (86) and a multiplier (96), to the negative output (109) of the rectifier and to one electrode of a capacitor (14), the second electrode of which is connected to the input of the multiplier (96) and via a resistor (34) to the emitter (112) of the power transistor (50), whereby the second input of the multiplier (96) is connected via a resistor (32) with positive supply outputs of the multiplier (96) and the amplifier (86), with the output (108) of the cathode of the third diode (42), and via a resistor (31) both to the cathode of the second zener diode (48) and via a resistor (30) to the inverse input of the amplifier (86), the second input of which is connected to the output of the multiplier (96), and whereby the output (111) of the amplifier is connected to the base of the second transistor (52). 15. The system according to any one of claim 2, whereby the inputs of the rectifier (1) in the system are connected to the alternating current supply network, and the outputs of the rectifier (1) are connected to electrodes of the capacitor (2), whereby the positive output of the rectifier is connected to a contact (98) of a first winding (61) of the first transformer (T1), and is connected via a first resistor (15) to electrodes of second (16) and third (17) resistors and to the electrode of a second capacitor (4), which is together with the second electrode connected to the anode of a first diode (40) and to the contact of the second winding (60) of the transformer (T1), whereby the cathode of the first diode (40) is connected to the second electrode of the second resistor (16), and whereby a second contact of the second winding (60) of the transformer (T1) is connected to the negative output of the rectifier, to contacts on third (59) and fourth (64) windings of the transformer (T1), to an electrode of a potentiometer (35), to an electrode of a third capacitor (6), to an electrode of a fourth resistor (19) and via a fourth capacitor (3) to the anode of a zener diode (46), characterised in that the system comprises fifth (62) and sixth (63) windings of the transformer (T1), a phototransistor (56), a pulse generator (71), a field effect transistor (72), together with a second transformer (12) with six windings (65-70), whereby the second resistor (16) is connected to the base of the power transistor (50), to the cathode of the zener diode (46), to the collectors of first and second transistors (51, 52); and that the second electrode of the third resistor (17) is connected to the anode of a second diode (41) whereby its cathode is connected to the anode of the first diode (40), to the second contact of the second winding (60) of the first transformer (T1), to the anode of a third diode (42), the cathode of which is connected to the electrode of a fifth capacitor (5), to the feed output of the generator (71), to the collector of the phototransistor (56), the emitter of which is connected to the base of the first transistor (51) and via a fifth resistor (18) to the emitters of the first and second transistors (51, 52), to the second electrode of the fifth capacitor (5), to a common output of the generator (71), to the source of the field effect transistor (72), to the anode of a fourth diode (97) and to the negative output of the rectifier (1), and that the second contact of the third winding (59) of the first transformer (T1) is connected to the cathode of a fifth diode (39) whereby its anode is connected to the anode of the zener diode (46); and that the emitter of the power transistor (50) is connected to the second electrodes of the fourth resistor (19) and the potentiometer (35), the regulator of which is connected to the base of the second transistor (52), and that the output of the generator (71) is connected to the gate of the field effect transistor (72), the drain of which is connected via the first winding (65) of the second transformer (T2), to the second electrode of the third capacitor (6), to the cathode of a sixth diode (113), the anode of which is connected to the second contact of the fourth winding (64) of the first transformer (T1), the first winding (61) of which is connected with its second contact via a fifth winding (62) to the contact of a sixth winding (63) and to the collector of the power transistor (50); and that the second transformer (T2) is connected with the contact of the second winding (66) to the cathode of the sixth diode (113), and the second contact of the second winding (66) is connected to the cathode of the fourth diode (97) and to third (67) and fourth (68) windings connected in series, and that the output of the field effect transistor (72) is connected via the fifth winding (69) to the contact of the sixth winding (70). |
<SOH> TECHNICAL FIELD <EOH>The invention concerns electrical technology, namely an energy saving electrical system for the ignition, operation and extinguishing of gas-discharge lamps such as low-pressure fluorescent lamps, high-pressure mercury lamps and both high-pressure and low-pressure lamps of sodium type or metal halogen lamps in alternating current networks. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The system according to the invention is illustrated in the drawings, of which FIG. 1 shows a circuit diagram for the illumination system according to the invention and FIG. 2 shows timing diagrams. detailed-description description="Detailed Description" end="lead"? |
Communal vehicle system |
In a motor vehicle sharing system for managing motor vehicles are parked in a parking area and renting the motor vehicles to users, the motor vehicle is provided with a detector for detecting a start of motor vehicle rental and end of the motor vehicle rental, and an usage data measuring section for starting a measurement for a motor vehicle usage data when the detector detects a start of the motor vehicle rental and completing the measurement for the motor vehicle usage data when the detector detects an end of the motor vehicle rental. The detector contains a position detector for detecting the parking area. The motor vehicle is further provided with a membership list in which a user information is recorded, a charge list, a rentability judging section which refers the information which is inputted by the ser when the user rents the motor vehicle to the record in the membership list so as to judge the rentability of the motor vehicle to the user, a charging data generating section which refers a motor vehicle usage data which is measured from the rented time through the returned time by the usage data measuring section to the record in the charge list so as to produce a charging data tot the user. By doing this, it is possible to perform the rental and return operation of the motor vehicle without relying on the control center 1. |
1. A motor vehicle sharing system for managing motor vehicles are parked in a parking area and renting the motor vehicles to users wherein the motor vehicle is provided with: a detector for detecting a start of motor vehicle rental when a motor vehicle rental is permitted to a user and end of the motor vehicle rental; and an usage data measuring section for starting a measurement for a motor vehicle usage data when the detector detects a start of the motor vehicle rental and completing the measurement for the motor vehicle usage data when the detector detects an end of the motor vehicle rental. 2. A motor vehicle sharing system according to claim 1 wherein: the detector includes a position detector for detecting a parking area; the usage data measuring section starts measuring the motor vehicle usage data when the usage data measuring section detects a departure of the position detector from the parking area; the usage data measuring section completes measuring the motor vehicle usage data when the usage data measuring section detects an arrival of the position detector at the parking area. 3. A motor vehicle sharing system according to claim 1 further comprising a control center wherein the motor vehicle is further provided with: a communication confirming section for confirming whether or not it is possible to communicate to the control center when the usage data measuring section completes measuring the motor vehicle usage data; a temporary data storing and transmitting section for transmitting the motor vehicle usage data to the control center when the communication confirming section judges that it is possible to communicate with the control center, storing temporarily the motor vehicle usage data in an data storing section when the communication confirming section judges that it is not possible to communicate with the control center, and transmitting the motor vehicle usage data to the control center after it is possible to communicate with the control center. 4. A motor vehicle sharing system according to claim 2 wherein: the position detector contains a receiver which receives a signal which is made in a signal generator which is disposed in the parking area; and the position detector judges whether a motor vehicle departs the parking area or arrives at the parking area according to whether or not there is a signal arrived in the receiver. 5. A motor vehicle sharing system according to claim 2 wherein the position detector judges whether a motor vehicle departs the parking area or arrives at the parking area according to a GPS (Global Positioning System). 6. A motor vehicle sharing system according to claims 1 wherein the control center performs calculation process for a used charge according to the motor vehicle usage data. 7. A motor vehicle sharing system according to claims 1 wherein the motor vehicle usage data contains at least a usage time of the motor vehicle, a used fuel amount in the motor vehicle, and a driving distance of the motor vehicle. 8. A motor vehicle sharing system according to claim 1 wherein the motor vehicle is further provided with: a membership list in which information of users who can use motor vehicle motors; a charge list on which a relationship of the motor vehicle usage data which relates to a motor vehicle rental and return and the used charge for the motor vehicle is recorded; a rentability judging section for judging whether or not the motor vehicle can be rented to the user by referring the information which is inputted by the user when the motor vehicle is rented to the records in the membership list; a charging data generating section for making a charging data of the user by referring the motor vehicle usage data which is measured during the rental of the motor vehicle and the return of the motor vehicle by the usage data measuring section to the records in the charge list. 9. A motor vehicle sharing system according to claim 8 further comprising a control center which transmits and receives a charging data with a vehicle wherein: the motor vehicle is provided with a transmitter which transmits a charging data to the control center; and the control center is provided with a charge billing section which calculates a used charge according to the charging data for a predetermined period and bills the used charge to the user. 10. A motor vehicle sharing system according to claim 8 wherein: the control center has a master membership list which contains a latest data of users who can use motor vehicles; and the motor vehicle obtains the master membership list from the control center every time the user uses the motor vehicle and updates the membership list. 11. A motor vehicle sharing system according to claim 8 wherein: the control center has the master membership list which contains a latest data of users who can use motor vehicles; and the motor vehicle obtains the master membership list from the control center periodically and updates the membership list. 12. A motor vehicle sharing system according to claim 8 wherein: the control center has the master membership list which contains a latest data of users who can use motor vehicles; and the motor vehicle obtains the master membership list from the control center and updates the membership list when an information which is inputted by the user is not recorded in the membership list. 13. A motor vehicle sharing system according to claims 8 further comprising a position detector for detecting the parking area wherein the usage data measuring section starts measuring the motor vehicle usage data when a departure of the position detector from the parking area is detected; and the usage data measuring section completes measuring the motor vehicle usage data when an arrival of the position detector at the parking area is detected. 14. A motor vehicle sharing system according to claims 8 wherein the motor vehicle usage data contains at least a usage time of the motor vehicle, a used fuel amount of the motor vehicle, or a driving distance of the motor vehicle. |
<SOH> BACKGROUND ART <EOH>Conventionally, in a motor vehicle sharing system, various ideas are proposed for purposes of efficient use of the motor vehicles by users so as to obtain transportation measures smoothly. Among such proposals, a Patent Publication No. 3,064,615 discloses a technology for a motor vehicle rental system in which motor vehicles are used which are provided with communication measures for transmitting and receiving information which relate to a rental and return of the motor vehicle such as an identification information for identifying the user, a usage permission information for permitting for using the motor vehicle, and a usage information which indicate a usage condition of the motor vehicle. According the Patent Publication, a control center manages the motor vehicles by transmitting and receiving information which relates to the motor vehicle, a rental of the motor vehicle, and a return of the motor vehicles in a plurality of parking areas which are located in distant places from the control center. In the above conventional motor vehicle control system, when a user pushes a return button which is disposed in the motor vehicle in a predetermined parking area, a usage information such as a used charge data is transmitted to the control center. However, the control center receives the usage information and judges in which parking area the motor vehicle is returned according to a position information which is contained in the usage information. The used charge is processed only when the parking area is identified as a designated parking area. Therefore, when a communication between the control center and the motor vehicle is disrupted, there are problems that it is not possible to process the used charge in the control center and the user cannot return the motor vehicle because a card is not returned. The present invention is made in consideration of the above problems. An object of the present invention is to provide a motor vehicle sharing system in which a motor vehicle can perform a motor vehicle rental and return process independently without depending on the control center. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a block diagram for a first embodiment of the present invention. FIG. 2 is a view for a structure in a shared motor vehicle which is used in the first embodiment according to the present invention. FIG. 3 show a port for parking a shared motor vehicle which is used in embodiments according to the present invention. FIG. 4 show an entire operation in a motor vehicle sharing system according to the first embodiment of the present invention. FIG. 5 shows an entire operation in a motor vehicle sharing system according to the first embodiment. FIG. 6 shows an entire operation in a motor vehicle sharing system according to the first embodiment. FIG. 7 shows an entire operation in a motor vehicle sharing system according to the first embodiment. FIG. 8 shows an entire operation in a motor vehicle sharing system according to the first embodiment. FIG. 9 shows an entire operation in a motor vehicle sharing system according to the first embodiment. FIG. 10 shows operations in a motor vehicle sharing system in other example of the embodiment. FIG. 11 is a block diagram for a second embodiment of the present invention. FIG. 12 is a view for a structure in a shared motor vehicle which is used in the first embodiment according to the present invention. FIG. 13 show an entire operation in a motor vehicle sharing system according to the first embodiment of the present invention. FIG. 14 show an entire operation in a motor vehicle sharing system according to the first embodiment of the present invention. FIG. 15 show an entire operation in a motor vehicle sharing system according to the first embodiment of the present invention. FIG. 16 show an entire operation in a motor vehicle sharing system according to the first embodiment of the present invention. FIG. 17 show an entire operation in a motor vehicle sharing system according to the first embodiment of the present invention. FIG. 18 show an entire operation in a motor vehicle sharing system according to the first embodiment of the present invention. detailed-description description="Detailed Description" end="lead"? |
Reconfigurable optical device for wavelength division multiplexing networks |
A reconfigurable optical device for wavelength-division multiplexing networks, comprising two waveguides (A, B) parallel to each other, with two-dimensional confinement, coupled by a bi-directional coupler (C), suitable to selectively drop one and only one of the channels composing the Wavelength-Division multiplexing signal (WDM); the device is reconfigurable as, by appropriately varying the wavelength of the combined pumping beam inside a first waveguide (A), any channel forming the WDM signal can be dropped. |
1. Reconfigurable optical device for wavelength-division multiplexing networks, comprising at least one waveguide (A, B, 14) with two-dimensional confinement, reached by at least one wavelength-division multiplexing, or WDM, input signal (10) and at least one first optical pumping beam (11), said optical device uses non-linear optical interactions between at least one of the channels that form said WDM input signal (10) and said first optical pumping beam (11), characterised in that two optical routes are provided by said at least one waveguide, a first optical route in which a first non-linear optical interaction happens between at least one of the channels that form said WDM input signal (10) and said first optical pumping beam (11), and a second optical route in which a second non-linear optical interaction happens between at least one of the channels that form said WDM input signal (10) and said first optical pumping beam (11). 2. Reconfigurable optical device as claimed in claim 1, characterized in that it has at least two waveguides (A, B), connected by means of at least one directional optical coupler (S), said waveguides (A, B) being produced with a material presenting non-linearity of the second order, said waveguides (A, B) being produced on at least one substrate (S1), using at least one “phase-matching” technique, respectively in a first portion (L1) of a first (A) of said waveguides (A, B) and in a third portion (L3) of a second (B) of said waveguides (A, B), said directional optical coupler (C) having a cut-off frequency between the frequency of said WDM input signal and a sum frequency (WSF). 3. Reconfigurable optical device as claimed in claim 1, characterized in that said WDM input signal comprises a series of channels spaced in frequency and that said first optical pumping beam has a variable and predetermined wavelength (WP) on the basis of the wavelengths (WS) of said channel from which the WDM signal is to be extracted. 4. Reconfigurable optical device as claimed in claim 2, characterized in that, at one of the terminals of said first portion (L1) of said first waveguide (A), at least one selectively dropped channel (DC) from those forming said WDM signal is completely emptied. 5. Reconfigurable optical device as claimed in claim 2, characterized in that a sum frequency signal (WSF), located inside said second waveguide (B), interacts with at least one second optical pumping beam, coupled at at least one input (E) of said second waveguide (B), in order to reconvert said sum frequency signal (WSF) into at least one wavelength of said WDM signal by means of a process to generate a difference frequency, re-obtaining said channel selectively dropped at the start (DC). 6. Reconfigurable optical device as claimed in claim 5, characterized in that by varying the wavelength of said second optical pumping beam, it is possible to translate said selectively dropped channel (DC) to a predefined wavelength value. 7. Reconfigurable optical device as claimed in claim 1, characterized in that said waveguide (14) has at least one mirror (15) at at least one of its ends, said mirror (15) being suitable to totally reflect at least one radiation at a sum frequency (WSF) and to transmit said WDM input signal (10) and said first optical pumping beam (11). 8. Reconfigurable optical device as claimed in claim 7, characterized in that said mirror (15), reflecting only said sum frequency (WSF), separates this from said WDM input signal (10) without at least one dropped channel, and re-couples it inside said waveguide (14), said WDM input signal (10) and said first pumping beam (11) being sent inside at least a first optical circulator (13A) which routes them inside said waveguide (14). 9. Reconfigurable optical device as claimed in claim 8, characterized in that said WDM input signal (10), without said dropped channel, and said first pumping beam (11), by means of at least a second optical circulator (13B), reach an output (17) of said device, said sum frequency (WSF) being totally reflected by said mirror (15) and travelling along said guide (14) in the opposite direction to the direction of said WDM input signal (10). 10. Reconfigurable optical device as claimed in claim 9, characterized in that a second pumping beam (12) is introduced into said second optical circulator (13B) and is coupled inside said waveguide (14), so as to superimpose said reflected sum frequency (WSF), so that a process to generate a difference frequency, between said second pumping beam (12) and said reflected sum frequency (WSF), determines a reconversion of said sum frequency signal (WSF) to an original wavelength value, said first optical circulator (13A) being capable of sending said dropped channel to a different output (19) in relation to the one (17) from which said WDM input signal (10) without said dropped channel is delivered. |
Chemoenzymatic methods for the synthesis of statins and stain intermediates |
The invention provides novel aldolases, nucleic acids encoding them and methods for making and using them, including chemoenzymatic processes for making β,δ-dihydroxyheptanoic acid side chains and compositions comprising these side chains, e.g., [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (atorvastatin, LIPITOR™), rosuvastatin (CRESTOR™), fluvastatin (LESCOL™), related compounds and their intermediates. |
1. An isolated or recombinant nucleic acid comprising a nucleic acid sequence having at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65% 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86% 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more, or 100% sequence identity to SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, or SEQ ID NO:29 over a region of at least about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150 or more residues or the full length of a gene or a transcript, wherein the nucleic acid encodes at leg one polypeptide having an aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. 2-5. (canceled) 6. The isolated or recombinant nucleic acid of claim 1, wherein the nucleic acid sequence encodes a polypeptide having a sequence as set forth in SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, or SEQ ID NO:30. 7. (canceled) 8. The isolated or recombinant nucleic acid of claim 1, wherein the aldolase activity comprises catalysis of the formation of a carbon-carbon bond: an aldol condensation, a 2-deoxyribose-5-phosphate aldolase (DERA) activity; catalysis of the condensation of acetaldehyde as donor and a 2(R)-hydroxy-3-(hydroxy or mercapto)-propionaldehyde derivative to form a 2-deoxysugar, catalysis of the condensation of acetaldehyde as donor and a 2-substituted acetaldehyde acceptor to form a 2,4,6-trideoxyhexose via a 4-substituted-3-hydroxybutanal intermediate; catalysis of the generation of chiral aldehydes using two acetaldehydes as substrates; enantioselective assembling of chiral β,δ-dihydroxyheptanoic acid side chains; enantioselective assembling of the core of [R-(R*,R)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (atorvastatin, or LIPITOR™); rosuvastatin (CRESTOR™) or fluvastatin (LESCOL™); with an oxidation step synthesis of a 3R,5S-6-chloro-2,4,6-trideoxy-erytho-hexonolactone; a thermotolerant aldolase activity; or, a thermostable aldolase activity. 9-23. (canceled) 24. An isolated or recombinant nucleic acid, wherein the nucleic acid comprises a sequence that hybridizes under stringent conditions to a nucleic acid comprising SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, or SEQ ID NO:29, wherein the nucleic acid encodes a polypeptide having an aldolase activity, wherein the stringent conditions comprise a wash step comprising a wash in 0.2×SSC at a temperature of about 65° C. for about 15 minutes. 25-26. (canceled) 27. A nucleic acid probe for identifying a nucleic acid encoding a polypeptide with an aldolase activity, wherein the probe comprises at least 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive bases of a sequence comprising SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ I]D NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, or SEQ ID NO:29, wherein the probe identifies the nucleic acid by binding or hybridization, wherein the stringent conditions comprise a wash step comprising a wash in 0.2×SSC at a temperature of about 65° C. for about 15 minutes. 28-30. (canceled) 31. An amplification primer sequence pair for amplifying a nucleic acid encoding a polypeptide having an aldolase activity, wherein the primer pair capable of amplifying a nucleic acid comprising a sequence as set forth in claim 1 or claim 24, or a subsequence thereof. 32. (canceled) 33. An amplification primer pair, wherein the primer pair comprises a first member having a sequence as set forth by about the first (the 5′) 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more residues of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, and a second member having a sequence as set forth by about the first (the 5′) 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 or more residues of the complementary strand of the firs member. 34. An aldolase-encoding nucleic acid generated by amplification of a polynucleotide using an amplification primer pair as set forth in claim 33. 35-37. (canceled) 38. An isolated or recombinant aldolase encoded by an aldolase-encoding nucleic acid as set forth in claim 34. 39. A method of amplifying a nucleic acid encoding a polypeptide having an aldolase activity comprising amplification of a template nucleic acid with Nan amplification primer sequence pair capable of amplifying a nucleic acid sequence as set forth in claim 1, or a subsequence thereof. 40. A method for making an aldolase comprising amplification of a nucleic acid with an amplification primer pair as set forth in claim 33 and expression of the amplified nucleic acid. 41. An expression cassette comprising a nucleic acid comprising a sequence as set forth in claim 1 or claim 21. 42. A vector comprising a nucleic acid comprising a sequence as set forth in claim 1. 43. A cloning vehicle comprising a nucleic acid comprising a sequence as set forth in claim 1 or claim 24, wherein the cloning vehicle comprises a viral vector, a plasmid, a phage, a phagemid, a cosmid, a fosmid, a bacteriophage or an artificial chromosome. 44-45. (canceled) 46. A transformed cell comprising a nucleic acid comprising a sequence as set forth in claim 1 or an expression cassette as set forth in claim 41. 47-48. (canceled) 49. A transgenic non-human animal comprising a sequence as set forth in claim 1. 50. (canceled) 51. A transgenic plant comprising a sequence as set forth in claim 1 or claim 24. 52. (canceled) 53. A transgenic seed comprising a sequence as set forth in claim 1. 54. (canceled) 55. An antisense oligonucleotide comprising a nucleic acid sequence complementary to or capable of hybridizing under stringent conditions to a sequence as set forth in claim 1, or a subsequence thereof. 56. (canceled) 57. A method of inhibiting the translation of an aldolase message n a cell comprising administering to the cell or expressing in the cell an antisense oligonucleotide comprising a nucleic acid sequence complementary to or capable of hybridizing under stringent conditions to a sequence as set forth in claim 1. 58. A double-stranded inhibitory RNA (RNAi) molecule comprising a subsequence of a sequence as set forth in claim 1. 59. (canceled) 60. A method of inhibiting the expression of an aldolase in a cell comprising administering to the cell or expressing in the cell a double-stranded inhibitory RNA (iRNA), wherein the RNA comprises a subsequence of a sequence as set forth in claim 1. 61. An isolated or recombinant polypeptide (i) having at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63% 64%, 65%, 66%, 67%, 68%, 69% 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or is 100% sequence identity to SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, over a region of at least about 100, 150, 200, 250, 300, 350, 400, 450, 500 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection, or, (ii) encoded by a nucleic acid having at least 50%, 51% 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74% 75% 76%, 77%, 78% 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% 95%, 96% 597% 98%, 99%, or more, or is 100% sequence identity to a sequence as set forth in SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ M NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, or SEQ ID NO:29 over a region of at least about 100, 150, 200, 250, 300, 350, 400, 450, 500 or more residues, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection, or encoded by a nucleic acid capable of hybridizing under stringent conditions to a sequence as set forth in SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, or SEQ ID NO:29. 62-64. (canceled) 65. The isolated or recombinant polypeptide of claim 61, wherein the polypeptide has an aldolase activity. 66. The isolated or recombinant polypeptide of claim 65, wherein the aldolase activity comprises catalysis of the formation of a carbon-carbon bond; an aldol condensation; a 2-deoxyribose-5-phosphate aldolase (DERA) activity; catalysis of the condensation of acetaldehyde as donor and a 2(R-hydroxy-3-(hydroxy or mercapto)-propionaldehyde derivative to form a 2-deoxysugar; catalysis of the condensation of acetaldehyde as donor and a 2-substituted acetaldehyde acceptor to form a 2,4,6-trideoxyhexose via a 4-substituted-3-hydroxybutanal intermediate; catalysis of the generation of chiral aldehydes using two acetaldehydes as substrates; enantioselective assembling of chiral β,δ-dihydroxyheptanoic acid side chains; enantioselective assembling of the core of [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]1H-pyrrole-1-heptanoic acid (atorvastatin, or LIPITOR™); rosuvastatin (CRESTOR™) or fluvastatin (LESCOL™); with an oxidation step synthesis of a 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone; a thermotolerant aldolase activity; or, a thermostable aldolase activity. 67-82. (canceled) 83. An isolated or recombinant polypeptide comprising a polypeptide as set forth in claim 61 and lacking a signal sequence, or having a heterologous signal sequence. 84-92. (canceled) 93. A protein preparation comprising a polypeptide as set forth in claim 61, wherein the protein preparation comprises a liquid, a solid or a gel. 94. A heterodimer comprising a polypeptide as set forth in claim 61 and a second domain. 95-96. (canceled) 97. A homodimer comprising a polypeptide as set forth in claim 61. 98. An immobilized polypeptide, wherein the polypeptide comprises a sequence as set forth in claim 61, or a subsequence thereof. 99. (canceled) 100. An array comprising an immobilized polypeptide as set forth in claim 61 or an immobilized nucleic acid as set forth in claim 1. 101. (canceled) 102. An isolated or recombinant antibody that specifically binds to a polypeptide as set forth in claim 61. 103. (canceled) 104. A hybridoma comprising an antibody that specifically binds to a polypeptide as set forth in claim 61. 105. A method of isolating or identifying a polypeptide with an aldolase activity comprising the steps of: (a) providing an antibody as set forth in claim 102; (b) providing a sample comprising polypeptides; and (c) contacting the sample of step (b) with the antibody of step (a) under conditions wherein the antibody can specifically bind to the polypeptide, thereby isolating or identifying a polypeptide having an aldolase activity. 106. A method of making an anti-aldolase antibody comprising administering to a non-human animal a nucleic acid as set forth in claim 1 or a subsequence thereof in an amount sufficient to generate a humoral immune response, thereby making an anti-aldolase antibody. 107. A method of making an anti-aldolase antibody comprising administering to a non-human animal a polypeptide as set forth in claim 61 or a subsequence thereof in an amount sufficient to generate a humoral immune response, thereby making an anti-aldolase antibody. 108. A method of producing a recombinant polypeptide comprising the steps of: (a) providing a nucleic acid operably linked to a promoter, wherein the nucleic acid comprises a sequence as set forth in claim 1; and (b) expressing the nucleic acid of step (a) under conditions that allow expression of the polypeptide, thereby producing a recombinant polypeptide. 109. (canceled) 110. A method for identifying a polypeptide having an aldolase activity comprising the following steps: (a) providing a polypeptide as set forth in claim 65; (b) providing an aldolase substrate; and (c) contacting the polypeptide with the substrate of step (b) and detecting a decrease in the amount of substrate or an increase in the amount of a reaction product, wherein a decrease in the amount of the substrate or an increase in the amount of the reaction product detects a polypeptide having an aldolase activity. 111. A method for identifying an aldolase substrate comprising the following steps: (a) providing a polypeptide as set forth in claim 65; (b) providing a test substrate; and (c) contacting the polypeptide of step (a) with the test substrate of step (b) and detecting a decrease in the amount of substrate or an increase in the amount of reaction product, wherein a decrease in the amount of the substrate or an increase in the amount of a reaction product identifies the test substrate as an aldolase substrate. 112. A method of determining whether a test compound specifically binds to a polypeptide comprising the following steps: (a) expressing a nucleic acid or a vector comprising the nucleic acid under conditions permissive for translation of the nucleic acid to a polypeptide, wherein the nucleic acid has a sequence as set forth in claim 1; (b) providing a test compound; (c) contacting the polypeptide with the test compound; and (d) determining whether the test compound of step (b) specifically binds to the polypeptide. 113. A method of determining whether a test compound specifically binds to a polypeptide comprising the following steps: (a) providing a polypeptide as set forth in claim 61; (b) providing a test compound; (c) contacting the polypeptide with the test compound; and (d) determining whether the test compound of step (b) specifically binds to the polypeptide. 114. A method for identifying a modulator of an aldolase activity comprising the following steps: (a) providing a polypeptide as set forth in claim 65; (b) providing a test compound; (c) contacting the polypeptide of step (a) with the test compound of step (b) and measuring an activity of the aldolase, wherein a change in the aldolase activity measured in the presence of the test compound compared to the activity in the absence of the test compound provides a determination that the test compound modulates the aldolase activity. 115-117. (canceled) 118. A computer system comprising a processor and a data storage device or a computer readable medium wherein said data storage device or computer readable medium has stored thereon a polypeptide sequence or a nucleic acid sequence, wherein the polypeptide sequence comprises sequence as set forth in claim 61, or a polypeptide encoded by a nucleic acid as set forth in claim 1. 119-122. (canceled) 123. A method for identifying a feature in a sequence comprising the steps of: (a) reading the sequence using a computer program which identifies one or more features in a sequence, wherein the sequence comprises a polypeptide sequence or a nucleic acid sequence, wherein the polypeptide sequence comprises a polypeptide as set forth in claim 61; a polypeptide encoded by a nucleic acid as set forth in claim 1; and (b) identifying one or more features in the sequence with the computer program. 124. A method for comparing a first sequence to a second sequence comprising the steps of: (a) reading the first sequence and the second sequence through use of a computer program which compares sequences, wherein the first sequence comprises a polypeptide sequence or a nucleic acid sequence, wherein the polypeptide sequence comprises a polypeptide as set forth in claim 61 or a polypeptide encoded by a nucleic acid as set forth in claim 1; and (b) determining differences between the first sequence and the second sequence with the computer program. 125-127. (canceled) 128. A method for isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from an environmental sample comprising the steps of: (a) providing an amplification primer sequence pair as set forth in claim 33; (b) isolating a nucleic acid from the environmental sample or treating the environmental sample such that nucleic acid in the sample is accessible for hybridization to the amplification primer pair; and, (c) combining the nucleic acid of step (b) with the amplification primer pair of step (a) and amplifying nucleic acid from the environmental sample, thereby isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from an environmental sample. 129. (canceled) 130. A method for isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from an environmental sample comprising the steps of: (a) providing a polynucleotide probe comprising a sequence as set forth in claim 1, or a subsequence thereof; (b) isolating a nucleic acid torn the environmental sample or treating the environmental sample such that nucleic acid in the sample is accessible for hybridization to a polynucleotide probe of step (a); (c) combining the isolated nucleic acid or the treated environmental sample of step (b) with the polynucleotide probe of step (a); and (d) isolating a nucleic acid that specifically hybridizes with the polynucleotide probe of step (a), thereby isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from an environmental sample. 131-133. (canceled) 133. A method of generating a variant of a nucleic acid encoding a polypeptide with an aldolase activity comprising the steps of: (a) providing a template nucleic acid comprising a sequence as set forth in claim 1; and (b) modifying, deleting or adding one or more nucleotides in the template sequence, or a combination thereof, to generate a variant of the template nucleic acid. 134-142. (canceled) 143. A method for modifying codons in a nucleic acid encoding a polypeptide with an aldolase activity to increase its expression in a host cell, the method comprising the following steps: (a) providing a nucleic acid encoding a polypeptide with an aldolase activity comprising a sequence as set fort in claim 1; and, (b) identifying a non-preferred or a less preferred codon in the nucleic acid of step (a) and replacing it with a preferred or neutrally used codon encoding the same amino acid as the replaced codon, wherein a preferred codon is a codon over-represented in coding sequences in genes in the host cell and a non-preferred or less preferred codon is a codon under-represented in coding sequences in genes in the host cell, thereby modifying the nucleic acid to increase its expression in a host cell. 144-147. (canceled) 148. A method for producing a library of nucleic acids encoding a plurality of modified aldolase active sites or substrate binding sites, wherein the modified active sites or substrate binding sites are derived from a first nucleic acid comprising a sequence encoding a first active site or a first substrate binding site the method comprising the following steps: (a) providing a first nucleic acid encoding a first active site or first substrate binding site, wherein the first nucleic acid sequence comprises a sequence that hybridizes under stringent conditions to a sequence as set forth in SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:1, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, or SEQ ID NO:29, or a subsequence thereof, and the nucleic acid encodes an aldolase active site or an aldolase substrate binding site; (b) providing a set of mutagenic oligonucleotides that encode naturally-occurring amino acid variants at a plurality of targeted codons in the first nucleic acid; and, (c) using the set of mutagenic oligonucleotides to generate a set of active site-encoding or substrate binding site-encoding variant nucleic acids encoding a range of amino acid variations at each amino acid codon that was mutagenized, thereby producing a library of nucleic acids encoding a plurality of modified aldolase active sites or substrate binding sites. 149-151. (canceled) 152. A method for making a small molecule comprising the following steps: (a) providing a plurality of biosynthetic enzymes capable of synthesizing or modifying a small molecule, wherein one of the enzymes comprises an aldolase enzyme encoded by a nucleic acid comprising a sequence as set forth in claim 1; (b) providing a substrate for at least one of the enzymes of step (a); and (c) reacting the substrate of step (b) with the enzymes under conditions that facilitate a plurality of biocatalytic reactions to generate a small molecule by a series of biocatalytic reactions. 153. A method for modifying a small molecule comprising the following steps: (a) providing an aldolase enzyme, wherein the enzyme comprises a polypeptide as set forth in claim 65, or a polypeptide encoded by a nucleic acid comprising a nucleic acid sequence as set forth in claim 1; (b) providing a small molecule; and (c) reacting the enzyme of step (a) with the small molecule of step (b) under conditions that facilitate an enzymatic reaction catalyzed by the aldolase enzyme, thereby modifying a small molecule by an aldolase enzymatic reaction. 154-157. (canceled) 158. A method for determining a functional fragment of an aldolase enzyme comprising the steps of: (a) providing an aldolase enzyme, wherein the enzyme comprises a polypeptide as set forth in claim 65, or a polypeptide encoded by a nucleic acid as set forth in claim 1; and (b) deleting a plurality of amino acid residues from the sequence of step (a) and testing the remaining subsequence for an aldolase activity, thereby determining a functional fragment of an aldolase enzyme. 159. (canceled) 160. A method for whole cell engineering of new or modified phenotypes by using real-time metabolic flux analysis, the method comprising the following steps: (a) making a modified cell by modifying the genetic composition of a cell, wherein the genetic composition is modified by addition to the cell of a nucleic acid comprising a sequence as set forth in claim 1; (b) culturing the modified cell to generate a plurality of modified cells; (c) measuring at least one metabolic parameter of the cell by monitoring the cell culture of step (b) in real time; and, (d) analyzing the data of step (c) to determine if the measured parameter differs from a comparable measurement in an unmodified cell under similar conditions, thereby identifying an engineered phenotype in the cell using real-time metabolic flux analysis. 161-163. (canceled) 164. An isolated or recombinant signal sequence consisting of a sequence as set forth in residues 1 to 16,1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 21, 1 to 22, 1 to 23, 1 to 24, 1 to 25, 1 to 26, 1 to 27, 1 to 28, 1 to 28, 1 to 30 or 1 to 31, 1 to 32 or 1 to 33 of SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, or SEQ ID NO:30, or, residues 1 to 22 of SEQ ID NO:18. 165. A chimeric polypeptide comprising at least a first domain comprising signal peptide (SP) having a sequence as set forth in claim 164, and at least a second domain comprising a heterologous polypeptide or peptide, wherein the heterologous polypeptide or peptide is not naturally associated with the signal peptide (SP). 166-167. (canceled) 168. An isolated or recombinant nucleic acid encoding a chimeric polypeptide, wherein the chimeric polypeptide comprises at least a first domain comprising signal peptide (SP having a sequence as set forth in claim 164 and at least a second domain comprising a heterologous polypeptide or peptide, wherein the heterologous polypeptide or peptide is not naturally associated with the signal peptide (SP). 169. A method of increasing thermotolerance or thermostability of an aldolase polypeptide, the method comprising glycosylating an aldolase, wherein the polypeptide comprises at least thirty contiguous amino acids of a polypeptide as set forth in claim 61, or a polypeptide encoded by a nucleic acid as set forth in claim 1, thereby increasing the thermotolerance or thermostability of the aldolase. 170. A method for overexpressing a recombinant aldolase in a cell comprising expressing a vector comprising a nucleic acid sequence as set forth in claim 1, wherein overexpression is effected by use of a high activity promoter, a dicistronic vector or by gene amplification of the vector. 171. A method of making a transgenic plant comprising the following steps: (a) introducing a heterologous nucleic acid sequence into the cell, wherein the heterologous nucleic sequence comprises a sequence as set forth in claim 1, thereby producing a transformed plant cell; (b) producing a transgenic plant from the transformed cell. 172-173. (canceled) 174. A method of expressing a heterologous nucleic acid sequence in a plant cell comprising the following steps: (a) transforming the plant cell with a heterologous nucleic acid sequence operably linked to a promoter, wherein the heterologous nucleic sequence comprises a sequence as set forth in claim 1; (b) growing the plant under conditions wherein the heterologous nucleic acids sequence is expressed in the plant cell. 175. A method for preparation of a compound having a formula as set forth as intermediate II in FIG. 7, comprising the following steps: (a) providing an aldol donor substrate; (b) providing an aldol acceptor substrate; (c) providing an aldolase; (d) admixing the aldol donor substrate of step (a), the aldol acceptor substrate of step (b), and the aldolase of step (c) under conditions wherein the aldolase can catalyze the aldol condensation reaction between the substrates of steps (a) and (b) thereby producing a compound comprising a structure as set forth as intermediate II in FIG. 7. 176-224. (canceled) 225. A process for making atorvastatin (LIPITOR™) comprising a process as set forth in FIG. 14. 226. A process for making rosuvastatin (CRESTOR™) or fluvastatin (LESCOL™) comprising a process as set forth in FIG. 14 or FIG. 17. 227. A method for preparation of a compound having a formula as set forth as intermediate II in FIG. 7, using a fed-batch process, comprising the following steps: (a) providing an aldol donor substrate; (b) providing an aldol acceptor substrate; (c) providing an aldolase; (d) admixing the aldol donor substrate of step (a), the aldol acceptor substrate of step (b), and the aldolase of step (c) under conditions wherein the aldolase can catalyze the aldol condensation reaction between the substrates of steps (a) and (b), wherein the substrates are fed into the reaction over about at least about 30 minutes to 12 hours at a rate such that they are consumed as fast as they are added. 228-237. (canceled) 238. A method for making 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone (compound 1 of FIG. 14) comprising oxidation of a chlorolactol to a chlorolactone with sodium hypochlorite. 239-242. (canceled) 243. A method for making 3R,5S-6chloro-2,4,6-trideoxy-erythro-hexonolactone (compound I of FIG. 14) comprising a process as set forth in FIG. 15. 244. A method for making an epoxide (-(3R,5S-3-hydroxy-4-oxiranylbutyric acid) (structure 2 in FIG. 16) comprising use of NaCN, DMF and 5% H2O. 245. A method for making (3R,5S)-3,5,6-trihydroxyhexanoic acid comprising a process as set forth in FIG. 16. 246. A method for making (3R,5S)-3,5,6-trihydroxyhexanoic acid comprising a process as set forth in FIG. 16. |
<SOH> BACKGROUND <EOH>The importance of chiral drugs in the pharmaceutical market increases with each year. Single stereoisomers on the market have proven to be safer, exhibit fewer side effects, and are more potent than what achiral drugs have been previously able to afford. The fact that pharmaceutical companies can now consider the practicality of marketing chiral drugs is partially due to the ability of synthetic chemists to be able to obtain high enantiomeric excess in asymmetric bond construction. [R-(R*,R)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (atorvastatin, LIPITOR™), whose structure is set forth in FIG. 5 , belongs to a class of drugs called statins. Statins reduce the level of total cholesterol and LDL by inhibiting HMG-CoA reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate. Atorvastatin is the most potent of the statins. Atorvastatin contains a chiral β,δ-dihydroxyheptanoic acid side chain that requires a significant effort to produce on a large scale. Fluvastatin (LESCOL™) is water soluble and acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. The aldol addition reaction, or aldol condensation, is a fundamental organic chemistry method for the formation and dissociation of carbon-carbon bonds. The aldol condensation can create two contiguous stereogenic centers and, consequently, four stereoisomers. Some control over the stereoselectivity can be obtained by the use of preformed enolates with metals. However, these reagents are stoichiometric and require extensive protecting group chemistry. See, for example, C. H. Heathcock, Aldrichim. Acta (1990): vol. 23, p 99; C. H. Heathcock, Science (1981): vol. 214, p 395; D. A. Evans, Science (1988): vol. 240, p 420; S. Masamune, et al., Angew. Chem. Int. Ed. Engl. (1985): vol. 24, p 1; D. A. Evans, et al., Top. Stereochem. (1982): vol. 13, p 1; C. H. Heathcocket et al., in Comprehensive Organic Synthesis, B. M. Trost, Ed. (Pergamon, Oxford, 1991), vol. 2, pp. 133-319 (1991); and I. Paterson, Pure & Appl. Chem. (1992): vol. 64, 1821. Enantioselectivity can be obtained by using either chiral enol derivatives, chiral aldehydes or ketones, or both. However, recent studies of catalytic antibodies opened ways to obtain enantiomerically pure aldols via resolution. Thus, for some reactions, the problem of complex intermediates may be solved by using relatively reactive compounds rather than the more usual inert antigens to immunize animals or select antibodies from libraries such that the process of antibody induction involves an actual chemical reaction in the binding site. See, for example, C. F. Barbas III, et al., Proc. Natl. Acad. Sci. USA (1991): vol. 88, p 7978 (1991); K D. Janda et al., Proc. Natl. Acad. Sci. USA (1994): vol. 191, p 2532. This same reaction then becomes part of the catalytic mechanism when the antibody interacts with a substrate that shares chemical reactivity with the antigen used to induce it. The mechanisms of aldol condensation by aldolases have been well characterized. C. Y. Lai, et al., Science (1974): vol. 183, p 1204; and A. J. Morris e al., Biochemistry (1994) vol. 33, p 12291. The enzyme 2-deoxyribose-5-phosphate aldolase (DERA) in vivo catalyzes reversible aldol reaction of acetaldehyde and D-glyceraldehyde 3-phosphate to form D-2-deoxyribose-5-phosphate, the sugar moiety of DNA. Consequently this type I aldolase is widespread in nature. It is the only aldolase that accepts two aldehydes as substrates. Recent studies show that, in certain DERA-catalyzed reactions, product of the first aldol condensation can become an acceptor substrate for a second aldol condensation catalyzed by DERA or another aldolase. Thus, DERA and other aldolases can be used in combination for sequential aldol reactions leading to products with multiple chiral centers, starting from simple, non-chiral substrates. Gijsen, H., Wong, C.-H., JACS, vol. 117, 7585-7591. This enzyme can provide a route to a wide range of potentially biologically active compounds, e.g., the synthesis of deoxysugars such as deoxyriboses, 2-deoxyfucose analogs, and 13C-substituted D-2-deoxyribose-5-phosphate. See, for example, U.S. Pat. No. 5,795,749. It also affords a route to a variety of chiral aldehydes as illustrated in FIG. 6 . |
<SOH> SUMMARY <EOH>The invention provides chemoenzymatic processes for making β,δ-dihydroxyheptanoic acid side chains and compositions comprising these side chains, e.g., statins. The invention provides methods for the enantioselective assembling of chiral β,δ-dihydroxyheptanoic acid side chains, including compositions comprising β,δ-dihydroxyheptanoic acid side chain cores, e.g., statins, such as [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (atorvastatin, LIPITOR™), rosuvastatin (CRESTOR™), fluvastatin (LESCOL™), related compounds and their intermediates. In one aspect, the methods provide an enantioselective synthesis of both stereogenic centers of atorvastatin and/or rosuvastatin, and β,δ-dihydroxyheptanoic acid side chain-containing intermediates, in a single transformation from low-cost starting materials. The invention provides methods for preparation of a compound having a formula as set forth as intermediate II in FIG. 7 , comprising the following steps: (a) providing an aldol donor substrate; (b) providing an aldol acceptor substrate; (c) providing an aldolase; (d) admixing the aldol donor substrate of step (a), the aldol acceptor substrate of step (b), and the aldolase of step (c) under conditions wherein the aldolase can catalyze the aldol condensation reaction between the substrates of steps (a) and (b) thereby producing a compound comprising a structure as set forth as intermediate I in FIG. 7 . In one aspect, the aldol acceptor substrate comprises an aldehyde. In one aspect, the aldehyde aldol acceptor substrate comprises a structure as set forth as aldehyde III in FIG. 7 . In one aspect, R in the aldehyde III of FIG. 7 is selected from the group consisting of a hydrogen group, an alkyl group, a C1-C4 alkoxy group, a halogen, a cyan group and an azido group. In one aspect, R in the aldehyde III of FIG. 7 is chlorine and aldehyde III is chloroacetaldehyde. In one aspect the method further comprises converting the intermediate II in FIG. 7 to a compound comprising a β,δ-dihydroxyheptanoic acid side chain. In one aspect, the compound comprising a β,δ-diydroxyheptanoic acid side chain comprises a structure as set forth in formula I of FIG. 7 . In one aspect, the aldolase is a 2-deoxyribose-5-phosphate aldolase (DERA), e.g., a recombinant 2-deoxyribose-5-phosphate aldolase (DERA). In one aspect, the aldolase comprises a polypeptide as set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30. In one aspect, the aldolase comprises a polypeptide of the invention, or, a polypeptide encoded by a nucleic acid of the invention. In one aspect, the aldol donor substrate comprises an acetaldehyde. In one aspect, the aldol donor substrate comprises an acetaldehyde and the aldol acceptor substrate comprises an aldehyde. In one aspect, the acetaldehyde is present in stoichiometric excess over the aldehyde. In one aspect, the reaction of step (d) is carried out in the absence of light. In one aspect, the reaction of step (d) is carried out at a temperature comprising a range from about 5° C. to about 45° C. and a pH value of about 6.5 to 8.5. In one aspect, the method further comprises converting the intermediate II in FIG. 7 to a lactone compound. In one aspect, the lactone is a chloro-lactone, e.g., a 6-chloro-2,4,6-trideoxyerythro-hexonolactone. In one aspect, the lactone is crystalline. In one aspect, the crystalline lactone is purified by recrystallization. In one aspect, the formation of 6-chloro-2,4,6-trideoxyerythro-hexonolactone (chloro-lactone VI in FIG. 9 ) is carried out under oxidation conditions, e.g., comprising bromine (Br 2 ), BrCO 3 and water, a bromine/barium carbonate oxidation, as illustrated in FIG. 9 . In one aspect, the method comprises a bromine/barium carbonate oxidation with sodium hypochlorite (NaOCl) in acetic acid (HOAc) and water. In one aspect, the method further comprises converting the lactone compound to a compound as set forth as intermediate VIII in FIG. 10 . In one aspect, the method further comprises converting the chloro-lactone to a compound set forth as lactone IX of FIG. 10 . In one aspect, the chloro-lactone is converted to a compound set forth as lactone IX of FIG. 10 by subjecting the chloro-lactone to a cyanide displacement under conditions wherein the chloro group of the lactone is replaced by a cyan group CN. In one aspect, the method further comprises converting the lactone 1× to an intermediate VII of FIG. 10 . In one aspect, the lactone IX is converted to an intermediate VII of FIG. 10 under conditions comprising treatment with MeOH and Dowex or MeOH and K 2 CO 3 , wherein the lactone ring opens and the intermediate VII is formed. In one aspect, the method further comprises further comprising converting the intermediate VII to an intermediate VIII of FIG. 10 . In one aspect, the method further comprises processing the lactone to a compound comprising formula I of FIG. 7 . In one aspect, all reactions occur in a single reaction vessel. In one aspect, the intermediate II in FIG. 7 is a chloro-substituted intermediate having a structure as set forth as intermediate II in Route I, FIG. 8 . In one aspect, the intermediate II in Route I, FIG. 8 is converted to a lactone by a process comprising CN-displacement, lactal oxidation and nitrile reduction. In one aspect, the intermediate II in Route I, FIG. 8 is converted to a lactone by a process comprising bromine/barium carbonate oxidation to a chlorolactone. The method using bromine/barium carbonate oxidation can comprise oxidation with sodium hypochlorite (NaOCl) in acetic acid (HOAc) and water, as illustrated in FIG. 9 . In one aspect, the intermediate II in FIG. 7 is a cyan-substituted intermediate having a structure as set forth as intermediate II in Route II, FIG. 8 . In one aspect, the intermediate II in Route II, FIG. 8 is converted to a lactone by a process comprising lactal oxidation and nitrile reduction. In one aspect, the intermediate II is an N 3 -substituted intermediate having a structure as set forth as intermediate II in Route III, FIG. 8 . In one aspect, the intermediate II in Route III, FIG. 8 is converted to a lactone by a process comprising lactal oxidation and azide reduction. In one aspect, the method further comprises oxidation of the compound comprising intermediate II in FIG. 7 , wherein R is a halogen, to make a compound comprising 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone (formula 1 in FIG. 14 ). In one aspect, the oxidation conditions comprise CN— displacement, lactal oxidation and nitrile oxidation. In one aspect, R is a chlorine. In one aspect, the method further comprises processing the 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone to make (3R,5R)-6-cyano-3,5,-dihydroxyhexanoic acid (compound I of FIG. 14 ). In one aspect, the process comprises ring-opening. In one aspect, the process comprises ring-opening with cyanide. In one aspect, the method further comprises processing (3R,5R)-6-cyano-3,5,-dihydroxyhexanoic acid (compound I of FIG. 14 ) to make [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (atorvastatin, LIPITOR™). In one aspect, the method further comprises processing the 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone to make (3R,5S)-3,5,6-trihydroxyhexanoic acid (compound H of FIG. 14 ). In one aspect, the process comprises nucleophilic displacement. In one aspect, the nucleophilic displacement process comprises use of a hydroxide, e.g., sodium hydroxide. In one aspect, the method further comprises processing (3R,5S)-3,5,6-trihydroxyhexanoic acid (compound II of FIG. 14 ) to make a rosuvastatin (CRESTOR™). In one aspect, the method further comprises processing (3R,5S)-3,5,6-trihydroxyhexanoic acid (compound II of FIG. 14 ) to make fluvastatin (LESCOL™). The invention provides processes for making [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (atorvastatin, LIPITOR™) comprising a process as set forth in FIG. 14 , FIG. 17 and FIG. 18 . FIG. 18 illustrates a process of the invention comprising a chemoenzymatic route to make an atorvastatin (LIPITOR™) intermediate. The invention provides a process for making compound I of FIG. 18 using a DERA, e.g., using a DERA of the invention, using a process as set forth in FIG. 18 . The invention provides a process for making compound II of FIG. 18 using a DERA, e.g., using a DERA of the invention, using a process as set forth in FIG. 18 . The invention provides a process for making compound III of FIG. 18 using a DERA, e.g., using a DERA of the invention, using a process as set forth in FIG. 18 . The invention provides a process for making compound II of FIG. 18 from compound I of FIG. 18 using dimethyloxypropane, MeOH and H 2 SO 4 , as set forth in FIG. 18 . The invention provides a process for making compound III of FIG. 18 from compound II of FIG. 18 using H 2 , Raney Nickel, 7N NH 3 at 46° C., as set forth in FIG. 18 . These are a concise and simple syntheses from inexpensive materials. The invention provides processes for making rosuvastatin (CRESTOR™) comprising a process as set forth in FIG. 14 and FIG. 17 . The invention provides processes for making rosuvastatin (CRESTOR™) and fluvastatin (LESCOL™) comprising a process as set forth in FIG. 17 . The invention provides methods for preparation of a compound having a formula as set forth as intermediate II in FIG. 7 , using a fed-batch process, comprising the following steps: (a) providing an aldol donor substrate; (b) providing an aldol acceptor substrate; (c) providing an aldolase; (d) admixing the aldol donor substrate of step (a), the aldol acceptor substrate of step (b), and the aldolase of step (c) under conditions wherein the aldolase can catalyze the aldol condensation reaction between the substrates of steps (a) and (b), wherein the substrates are fed into the reaction over about at least about 30 minutes to about 12, 15, 18, 21, 24 or more hours at a rate such that they are consumed as fast as they are added. In one aspect, one of the substrates is chloroacetaldehyde, and the substrates are fed into the reaction at a rate such that they are consumed as fast as they are added and the chloroacetaldehyde does not reach inhibitory concentration. In one aspect, the substrates are fed into the reaction over a time range of about 1 to 10 hours, or, about 2 to 8 hours, or, about 2 to 4 hours, or, about 2 to 3 hours. In one aspect, the method further comprises processing intermediate II as in FIG. 7 to make an atorvastatin (LIPITOR™). In one aspect, the method further comprises processing intermediate II as in FIG. 7 to make a rosuvastatin (CRESTOR™) and/or fluvastatin (LESCOL™). In one aspect, the aldolase is a 2-deoxyribose-5-phosphate aldolase (DERA), e.g., a recombinant 2-deoxyribose-5-phosphate aldolase (DERA). In one aspect, the aldolase comprises a polypeptide as set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30. In one aspect, the aldolase comprises a polypeptide of the invention, or, a polypeptide encoded by a nucleic acid of the invention. The invention provides methods for making 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone (compound 1 of FIG. 14 ) comprising oxidation of a chlorolactol to a chlorolactone with sodium hypochlorite. In one aspect, the chlorolactone comprises a crystalline chlorolactone. In one aspect, the chlorolactol comprises a crude chlorolactol. In one aspect, the chlorolactol is dissolved in glacial acetic acid, and about 1 equivalent of aqueous sodium hypochlorite is fed into the solution. In one aspect, about 1 equivalent of aqueous sodium hypochlorite is fed into the solution over about 3 hours. The invention provides methods for making 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone (compound 1 of FIG. 14 ) comprising a process as set forth in FIG. 14 and/or FIG. 15 . The invention provides methods for making an epoxide (-(3R,5S-3-hydroxy-4-oxiranylbutyric acid) (structure 2 in FIG. 16 ) using a process as set forth in FIG. 16 . In one aspect, the method comprises use of NaCN (e.g., 3 equivalents of NaCN), dimethylformamide (DMF) and water (e.g., 5% H 2 O, DMF with 5% water by volume). In another aspect, the method comprises use of 2.2 equivalents of NaCN, water (e.g., 5% H 2 O) at about 40° C., for about 20 hours. These processes can generate the intermediate (3R,5R)-6-cyano-3,5,-dihydroexyhexanoic acid (a protected side chain intermediate). In one aspect, this is a one-pot process. In one aspect of the reaction in FIG. 16 and FIG. 18 , the lactone ring is opened and chloride is displaced by hydroxide, again through the epoxide intermediate, to access the trihydroxy acid. The reaction conditions can comprise 2 equivalents of sodium hydroxide in water. The invention provides methods for making (3R,5S)-3,5,6-trihydroxyhexanoic acid comprising a process as set forth in FIG. 16 and FIG. 18 , e.g., through the epoxide intermediate-(3R,5S-3-hydroxy-4-oxiranylbutyric acid. In one aspect, the process comprises use of water and NaOH. In one aspect, this is a one-pot process. In one aspect, the invention provides a one pot process to make statin intermediates comprising a lactone opening and a cyanide displacement through epoxide intermediates (e.g.,-(3R,5S-3-hydroxy-4-oxiranylbutyric acid, structure 2 in FIG. 16 ), as set forth in FIG. 16 and FIG. 18 . In one aspect, the invention provides a one pot process for making (3R,5S)-3,5,6-trihydroxyhexanoic acid comprising a process as set forth in FIG. 16 and FIG. 18 . The methods can further comprise synthesis of atorvastatin (LIPITOR™), rosuvastatin (CRESTOR™), fluvastatin (LESCOL™) and related compounds. A complete exemplary process for the synthesis of statin intermediates (for, e.g., synthesis of atorvastatin (LIPITOR™), rosuvastatin (CRESTOR™), fluvastatin (LESCOL™) and related compounds) is illustrated in FIG. 21 . In alternative aspects various steps of the process, or the entire process, is a one-pot process. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:5 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:7 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:9 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:11 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:13 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:15 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%,70%, 71%, 72%, 73%,74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:17 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%,74%,75%,76%,77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:19 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant nucleic acids comprising a nucleic acid sequence having at least about 99%, 99.5%, 99.8%, or more, or complete (100%) sequence identity to SEQ ID NO:21 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. In alternative aspects, the isolated or recombinant nucleic acid encodes a polypeptide comprising a sequence as set forth in SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, or SEQ ID NO:22. In one aspect these polypeptides have an aldolase activity. In one aspect, the sequence comparison algorithm is a BLAST algorithm, such as a BLAST version 2.2.2 algorithm. In one aspect, the filtering setting is set to blastall −p blastp −d “nr pataa”−F F and all other options are set to default. In one aspect, the aldolase activity comprises catalysis of the formation of a carbon-carbon bond. In one aspect, the aldolase activity comprises an aldol condensation. The aldol condensation can have an aldol donor substrate comprising an acetaldehyde and an aldol acceptor substrate comprising an aldehyde. The aldol condensation can yield a product of a single chirality. In one aspect, the aldolase activity is enantioselective. The aldolase activity can comprise a 2-deoxyribose-5-phosphate aldolase (DERA) activity. The aldolase activity can comprise catalysis of the condensation of acetaldehyde as donor and a 2(R)-hydroxy-3-hydroxy or mercapto)-propionaldehyde derivative to form a 2-deoxysugar. The aldolase activity can comprise catalysis of the condensation of acetaldehyde as donor and a 2-substituted acetaldehyde acceptor to form a 2,4,6-trideoxyhexose via a 4-substituted-3-hydroxybutanal intermediate. The aldolase activity can comprise catalysis of the generation of chiral aldehydes using two acetaldehydes as substrates. The aldolase activity can comprises enantioselective assembling of chiral β,δ-dihydroxyheptanoic acid side chains. The aldolase activity can comprise enantioselective assembling of the core of [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (Atorvastatin, or LIPITOR™), rosuvastatin (CRESTOR™) and/or fluvastatin (LESCOL™). The aldolase activity can comprise, with an oxidation step, synthesis of a 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone. In one aspect, the isolated or recombinant nucleic acid encodes a polypeptide having an aldolase activity which is thermostable. The polypeptide can retain an aldolase activity under conditions comprising a temperature anywhere in a range of between about 1° C. to about 5° C., about 5° C. to about 15° C., about 15° C. to about 25° C., about 25° C. to about 37° C., 37° C. to about 95° C.; between about 55° C. to about 85° C., between about 70° C. to about 95° C., or, between about 90° C. to about 95° C., 96° C., 97° C. or more. In another aspect, the isolated or recombinant nucleic acid encodes a polypeptide having an aldolase activity which is thermotolerant. The polypeptide can retain an aldolase activity after exposure to a temperature anywhere in a range of between about 1° C. to about 5° C., about 5° C. to about 15° C., about 15° C. to about 25° C., about 25° C. to about 37° C., 37° C. to about 95° C.; between about 55° C. to about 85° C., between about 70° C. to about 95° C., or, between about 90° C. to about 95° C., 96° C., 97° C. or more. In one aspect, the polypeptide can retain an aldolase activity under conditions comprising about pH 6.5, pH 6, pH 5.5, pH 5, pH 4.5 or pH 4. In another aspect, the polypeptide can retain an aldolase activity under conditions comprising about pH 7, pH 7.5 pH 8.0, pH 8.5, pH 9, pH 9.5, pH 10, pH 10.5 or pH 11. In one aspect, the polypeptide can retain an aldolase activity after exposure to conditions comprising about pH 6.5, pH 6, pH 5.5, pH 5, pH 4.5 or pH 4. In another aspect, the polypeptide can retain an aldolase activity after exposure to conditions comprising about pH 7, pH 7.5 pH 8.0, pH 8.5, pH 9, pH 9.5, pH 10, pH 10.5 or pH 11. In one aspect, the isolated or recombinant nucleic acid comprises a sequence that hybridizes under stringent conditions to a sequence as set forth in SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ED NO:17, SEQ ID NO:19 or SEQ ID NO:21, wherein the nucleic acid encodes a polypeptide having an aldolase activity. The nucleic acid can at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850 or residues in length or the full length of the gene or transcript, with or without a signal sequence, as described herein. The stringent conditions can be highly stringent, moderately stringent or of low stringency, as described herein. The stringent conditions can include a wash step, e.g., a wash step comprising a wash in 0.2×SSC at a temperature of about 65° C. for about 15 minutes. The invention provides a nucleic acid probe for identifying a nucleic acid encoding a polypeptide with an aldolase activity, wherein the probe comprises at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, or more, consecutive bases of a sequence of the invention, e.g., as exemplary sequence SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19 or SEQ ID NO:21, and the probe identifies the nucleic acid by binding or hybridization. The probe can comprise an oligonucleotide comprising at least about 10 to 50, about 20 to 60, about 30 to 70, about 40 to 80, or about 60 to 100 consecutive bases of a sequence as set forth in SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19 or SEQ ID NO:21. The invention provides a nucleic acid probe for identifying a nucleic acid encoding a polypeptide with an aldolase activity, wherein the probe comprises a nucleic acid of the invention, e.g., a nucleic acid having at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19 and/or SEQ ID NO:21, or a subsequence thereof, over a region of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850 or more consecutive residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by visual inspection. The invention provides an amplification primer sequence pair for amplifying a nucleic acid encoding a polypeptide having an aldolase activity, wherein the primer pair is capable of amplifying a nucleic acid comprising a sequence of the invention, or fragments or subsequences thereof. In one aspect, one or each member of the amplification primer sequence pair comprises an oligonucleotide comprising at least about 10 to 50 consecutive bases of the sequence, or about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 consecutive bases of the sequence. The invention provides amplification primer pairs, wherein the primer pair comprises a first member having a sequence as set forth by about the first (the 5′) 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more residues of a nucleic acid of the invention, and a second member having a sequence as set forth by about the first (the 5′) 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more residues of the complementary strand of the first member. The invention provides aldolases generated by amplification, e.g., polymerase chain reaction (PCR), using an amplification primer pair of the invention. The invention provides methods of making an aldolase by amplification, e.g., polymerase chain reaction (PCR), using an amplification primer pair of the invention. In one aspect, the amplification primer pair amplifies a nucleic acid from a library, e.g., a gene library, such as an environmental library. The invention provides methods of amplifying a nucleic acid encoding a polypeptide having an aldolase activity comprising amplification of a template nucleic acid with an amplification primer sequence pair capable of amplifying a nucleic acid sequence of the invention, or fragments or subsequences thereof. The amplification primer pair can be an amplification primer pair of the invention. The invention provides expression cassettes comprising a nucleic acid of the invention or a subsequence thereof. In one aspect, the expression cassette can comprise the nucleic acid that is operably linked to a promoter. The promoter can be a viral, bacterial, mammalian or plant promoter. In one aspect, the plant promoter can be a potato, rice, corn, wheat, tobacco or barley promoter. The promoter can be a constitutive promoter. The constitutive promoter can comprise CaMV35S. In another aspect, the promoter can be an inducible promoter. In one aspect, the promoter can be a tissue-specific promoter or an environmentally regulated or a developmentally regulated promoter. Thus, the promoter can be, e.g., a seed-specific, a leaf-specific, a root-specific, a stem-specific or an abscission-induced promoter. In one aspect, the expression cassette can further comprise a plant or plant virus expression vector. The invention provides cloning vehicles comprising an expression cassette (e.g., a vector) of the invention or a nucleic acid of the invention. The cloning vehicle can be a viral vector, a plasmid, a phage, a phagemid, a cosmid, a fosmid, a bacteriophage or an artificial chromosome. The viral vector can comprise an adenovirus vector, a retroviral vector or an adeno-associated viral vector. The cloning vehicle can comprise a bacterial artificial chromosome (BAC), a plasmid, a bacteriophage P1-derived vector (PAC), a yeast artificial chromosome (YAC), or a mammalian artificial chromosome (MAC). The invention provides transformed cell comprising a nucleic acid of the invention or an expression cassette (e.g., a vector) of the invention, or a cloning vehicle of the invention. In one aspect, the transformed cell can be a bacterial cell, a mammalian cell, a fungal cell, a yeast cell, an insect cell or a plant cell. In one aspect, the plant cell can be a potato, wheat, rice, corn, tobacco or barley cell. The invention provides transgenic non-human animals comprising a nucleic acid of the invention or an expression cassette (e.g., a vector) of the invention. In one aspect, the animal is a mouse. The invention provides transgenic plants comprising a nucleic acid of the invention or an expression cassette (e.g., a vector) of the invention. The transgenic plant can be a corn plant, a potato plant, a tomato plant, a wheat plant, an oilseed plant, a rapeseed plant, a soybean plant, a rice plant, a barley plant or a tobacco plant. The invention provides transgenic seeds comprising a nucleic acid of the invention or an expression cassette (e.g., a vector) of the invention. The transgenic seed can be a corn seed, a wheat kernel, an oilseed, a rapeseed (a canola plant), a soybean seed, a palm kernel, a sunflower seed, a sesame seed, a peanut or a tobacco plant seed. The invention provides an antisense oligonucleotide comprising a nucleic acid sequence complementary to or capable of hybridizing under stringent conditions to a nucleic acid of the invention. The invention provides methods of inhibiting the translation of an aldolase message in a cell comprising administering to the cell or expressing in the cell an antisense oligonucleotide comprising a nucleic acid sequence complementary to or capable of hybridizing under stringent conditions to a nucleic acid of the invention. The invention provides an antisense oligonucleotide comprising a nucleic acid sequence complementary to or capable of hybridizing under stringent conditions to a nucleic acid of the invention. The invention provides methods of inhibiting the translation of an aldolase message in a cell comprising administering to the cell or expressing in the cell an antisense oligonucleotide comprising a nucleic acid sequence complementary to or capable of hybridizing under stringent conditions to a nucleic acid of the invention. The antisense oligonucleotide can be between about 10 to 50, about 20 to 60, about 30 to 70, about 40 to 80, about 60 to 100, about 70 to 110, or about 80 to 120 bases in length. The invention provides methods of inhibiting the translation of an aldolase, e.g., an aldolase, message in a cell comprising administering to the cell or expressing in the cell an antisense oligonucleotide comprising a nucleic acid sequence complementary to or capable of hybridizing under stringent conditions to a nucleic acid of the invention. The invention provides double-stranded inhibitory RNA (RNAi) molecules comprising a subsequence of a sequence of the invention. In one aspect, the RNAi is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more duplex nucleotides in length. The invention provides methods of inhibiting the expression of an aldolase, e.g., an aldolase, in a cell comprising administering to the cell or expressing in the cell a double-stranded inhibitory RNA (iRNA), wherein the RNA comprises a subsequence of a sequence of the invention. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 9&0%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:6 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:8 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:10 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:12 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%,90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:14 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:16 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%,78%,79%,80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ ID NO:18 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300 or more residues, encodes at least one polypeptide having aldolase activity, and the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, or complete (100%) sequence identity to SEQ DD NO:20 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides comprising a nucleic acid sequence having at least about 99%, 99.5%, 99.8%, or more, or complete (100%) sequence identity to SEQ ID NO:22 over a region of at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350 or more residues, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by a visual inspection. The invention provides isolated or recombinant polypeptides encoded by nucleic acid comprising a sequence as set forth in SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19 or SEQ ID NO:21. In alternative aspects, the isolated or recombinant polypeptides comprise a sequence as set forth in SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, or SEQ ID NO:22. In one aspect these polypeptides have an aldolase activity. Another aspect of the invention provides an isolated or recombinant polypeptide or peptide including at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 or more consecutive bases of a polypeptide or peptide sequence of the invention (e.g., the exemplary SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, or SEQ ID NO:22), sequences substantially identical thereto, and the sequences complementary thereto. The peptide can be, e.g., an immunogenic fragment, a motif (e.g., a binding site), a signal sequence, a prepro sequence or an active site. In one aspect, the isolated or recombinant polypeptide of the invention (with or without a signal sequence) has an aldolase activity. In one aspect, the aldolase activity comprises catalysis of the formation of a carbon-carbon bond. In one aspect, the aldolase activity comprises an aldol condensation. The aldol condensation can have an aldol donor substrate comprising an acetaldehyde and an aldol acceptor substrate comprising an aldehyde. The aldol condensation can yield a product of a single chirality. In one aspect, the aldolase activity is enantioselective. The aldolase activity can comprise a 2-deoxyribose-5-phosphate aldolase (DERA) activity. The aldolase activity can comprise catalysis of the condensation of acetaldehyde as donor and a 2(R)-hydroxy-3-(hydroxy or mercapto)-propionaldehyde derivative to form a 2-deoxysugar. The aldolase activity can comprise catalysis of the condensation of acetaldehyde as donor and a 2-substituted acetaldehyde acceptor to form a 2,4,6-trideoxyhexose via a 4-substituted-3-hydroxybutanal intermediate. The aldolase activity can comprise catalysis of the generation of chiral aldehydes using two acetaldehydes as substrates. The aldolase activity can comprises enantioselective assembling of chiral β,δ-dihydroxyheptanoic acid side chains. The aldolase activity can comprise enantioselective assembling of the core of [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid (atorvastatin, or LIPITOR™), rosuvastatin (CRESTOR™) and/or fluvastatin (LESCOL™). The aldolase activity can comprise, with an oxidation step, synthesis of a 3R,5S-6-chloro-2,4,6-trideoxy-erythro-hexonolactone. In one aspect, the aldolase activity is thermostable. A polypeptide of the invention can retain an aldolase activity under conditions comprising a temperature anywhere in a range of between about 1° C. to about 5° C., about 5° C. to about 15° C., about 15° C. to about 25° C., about 25° C. to about 37° C., 37° C. to about 95° C.; between about 55° C. to about 85° C., between about 70° C. to about 95° C., or, between about 90° C. to about 95° C., 96° C., 97° C. or more. In another aspect, the aldolase activity is thermotolerant. A polypeptide of the invention can retain an aldolase activity after exposure to a temperature anywhere in a range of between about 1° C. to about 5° C., about 5° C. to about 15° C., about 15° C. to about 25° C., about 25° C. to about 37° C., 37° C. to about 95° C.; between about 55° C. to about 85° C., between about 70° C. to about 95° C., or, between about 90° C. to about 95° C., 96° C., 97° C. or more. In one aspect, the polypeptide can retain an aldolase activity under conditions comprising about pH 6.5, pH 6, pH 5.5, pH 5, pH 4.5 or pH 4. In another aspect, the polypeptide can retain an aldolase activity under conditions comprising about pH 7, pH 7.5 pH 8.0, pH 8.5, pH 9, pH 9.5, pH 10, pH 10.5 or pH 11. In one aspect, the polypeptide can retain an aldolase activity after exposure to conditions comprising about pH 6.5, pH 6, pH 5.5, pH 5, pH 4.5 or pH 4. In another aspect, the polypeptide can retain an aldolase activity after exposure to conditions comprising about pH 7, pH 7.5 pH 8.0, pH 8.5, pH 9, pH 9.5, pH 10, pH 10.5 or pH 11. In one aspect, the isolated or recombinant polypeptide can comprise the polypeptide of the invention that lacks a signal sequence and/or a prepro domain. In one aspect, the isolated or recombinant polypeptide can comprise the polypeptide of the invention comprising a heterologous signal sequence and/or prepro domain, such as a heterologous aldolase or a non-aldolase signal sequence. In one aspect, the invention provides a signal sequence comprising a peptide comprising/consisting of a sequence as set forth in residues 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 21, 1 to 22, 1 to 23, 1 to 24, 1 to 25, 1 to 26, 1 to 27, 1 to 28, 1 to 28, 1 to 30, 1 to 31, 1 to 32, 1 to 33, 1 to 34, 1 to 35, 1 to 36, 1 to 37, 1 to 38, 1 to 39, 1 to 40, 1 to 41, 1 to 42, 1 to 43, 1 to 44 of a polypeptide of the invention, e.g., the exemplary SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22. The invention provides isolated or recombinant peptides comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or more, or complete sequence identity to residues 1 to 22 of SEQ ID NO:18, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by visual inspection. These peptides can act as signal sequences on its endogenous aldolase, on another aldolase, or a heterologous protein (a non-aldolase enzyme or other protein). In one aspect, the invention provides chimeric proteins comprising a first domain comprising a signal sequence of the invention and at least a second domain. The protein can be a fusion protein. The second domain can comprise an enzyme. The enzyme can be an aldolase. The invention provides chimeric polypeptides comprising at least a first domain comprising signal peptide (SP), a prepro domain, a catalytic domain (CD), or an active site of an aldolase of the invention and at least a second domain comprising a heterologous polypeptide or peptide, wherein the heterologous polypeptide or peptide is not naturally associated with the signal peptide (SP), prepro domain or catalytic domain (CD). In one aspect, the heterologous polypeptide or peptide is not an aldolase. The heterologous polypeptide or peptide can be amino terminal to, carboxy terminal to or on both ends of the signal peptide (SP), prepro domain or catalytic domain (CD). In one aspect, the aldolase activity comprises a specific activity at about 37° C. in the range from about 1 to about 1200 units per milligram (U/mg) of protein, or, about 100 to about 1000 units per milligram of protein, or, about 200 to about 800 units per milligram of protein. In another aspect, the aldolase activity comprises a specific activity from about 100 to about 1000 units per milligram of protein, or, from about 500 to about 750 units per milligram of protein. Alternatively, the aldolase activity comprises a specific activity at 37° C. in the range from about 1 to about 750 units per milligram of protein, or, from about 500 to about 1200 units per milligram of protein. In one aspect, the aldolase activity comprises a specific activity at 37° C. in the range from about 1 to about 500 units per milligram of protein, or, from about 750 to about 1000 units per milligram of protein. In another aspect, the aldolase activity comprises a specific activity at 37° C. in the range from about 1 to about 250 units per milligram of protein. Alternatively, the aldolase activity comprises a specific activity at 37° C. in the range from about 1 to about 100 units per milligram of protein. In another aspect, the thermotolerance comprises retention of at least half of the specific activity of the aldolase at 37° C. after being heated to the elevated temperature. Alternatively, the thermotolerance can comprise retention of specific activity at 37° C. in the range from about 1 to about 1200 units per milligram of protein, or, from about 500 to about 1000 units per milligram of protein, after being heated to the elevated temperature. In another aspect, the thermotolerance can comprise retention of specific activity at 37° C. in the range from about 1 to about 500 units per milligram of protein after being heated to the elevated temperature. The invention provides the isolated or recombinant polypeptide of the invention, wherein the polypeptide comprises at least one glycosylation site. In one aspect, glycosylation can be an N-linked glycosylation. In one aspect, the polypeptide can be glycosylated after being expressed in a P. pastoris or a S. pombe. The invention provides protein preparations comprising a polypeptide of the invention, wherein the protein preparation comprises a liquid, a solid or a gel. The invention provides heterodimers comprising a polypeptide of the invention and a second protein or domain. The second member of the heterodimer can be a different aldolase, a different enzyme or another protein. In one aspect, the second domain can be a polypeptide and the heterodimer can be a fusion protein. In one aspect, the second domain can be an epitope or a tag. In one aspect, the invention provides homodimers comprising a polypeptide of the invention. The invention provides immobilized polypeptides having an aldolase activity, wherein the polypeptide comprises a polypeptide of the invention, a polypeptide encoded by a nucleic acid of the invention, or a polypeptide comprising a polypeptide of the invention and a second domain. In one aspect, the polypeptide can be immobilized on a cell, a metal, a resin, a polymer, a ceramic, a glass, a microelectrode, a graphitic particle, a bead, a gel, a plate, an array or a capillary tube. The invention provides arrays comprising an immobilized polypeptide, wherein the polypeptide is an aldolase of the invention or is a polypeptide encoded by a nucleic acid of the invention. The invention provides arrays comprising an immobilized nucleic acid of the invention. The invention provides an array comprising an immobilized antibody of the invention. The invention provides isolated or recombinant antibodies that specifically bind to a polypeptide of the invention or to a polypeptide encoded by a nucleic acid of the invention. The antibody can be a monoclonal or a polyclonal antibody. The invention provides hybridomas comprising an antibody of the invention. The invention provides methods of isolating or identifying a polypeptide with an aldolase activity comprising the steps of: (a) providing an antibody of the invention; (b) providing a sample comprising polypeptides; and, (c) contacting the sample of step (b) with the antibody of step (a) under conditions wherein the antibody can specifically bind to the polypeptide, thereby isolating or identifying an aldolase. The invention provides methods of making an anti-aldolase antibody comprising administering to a non-human animal a nucleic acid of the invention, or a polypeptide of the invention, in an amount sufficient to generate a humoral immune response, thereby making an anti-aldolase antibody. The invention provides methods of producing a recombinant polypeptide comprising the steps of: (a) providing a nucleic acid of the invention operably linked to a promoter; and, (b) expressing the nucleic acid of step (a) under conditions that allow expression of the polypeptide, thereby producing a recombinant polypeptide. The method can further comprise transforming a host cell with the nucleic acid of step (a) followed by expressing the nucleic acid of step (a), thereby producing a recombinant polypeptide in a transformed cell. The method can further comprise inserting into a host non-human animal the nucleic acid of step (a) followed by expressing the nucleic acid of step (a), thereby producing a recombinant polypeptide in the host non-human animal. The invention provides methods for identifying a polypeptide having an aldolase activity comprising the following steps: (a) providing a polypeptide of the invention or a polypeptide encoded by a nucleic acid of the invention, or a fragment or variant thereof, (b) providing an aldolase substrate; and, (c) contacting the polypeptide or a fragment or variant thereof of step (a) with the substrate of step (b) and detecting an increase in the amount of substrate or a decrease in the amount of reaction product, wherein a decrease in the amount of the substrate or an increase in the amount of the reaction product detects a polypeptide having an aldolase activity. The invention provides methods for identifying an aldolase substrate comprising the following steps: (a) providing a polypeptide of the invention or a polypeptide encoded by a nucleic acid of the invention; (b) providing a test substrate; and, (c) contacting the polypeptide of step (a) with the test substrate of step (b) and detecting an increase in the amount of substrate or a decrease in the amount of reaction product, wherein a decrease in the amount of the substrate or an increase in the amount of the reaction product identifies the test substrate as an aldolase substrate. The invention provides methods of determining whether a compound specifically binds to an aldolase comprising the following steps: (a) expressing a nucleic acid or a vector comprising the nucleic acid under conditions permissive for translation of the nucleic acid to a polypeptide, wherein the nucleic acid and vector comprise a nucleic acid or vector of the invention; or, providing a polypeptide of the invention (b) contacting the polypeptide with the test compound; and, (c) determining whether the test compound specifically binds to the polypeptide, thereby determining that the compound specifically binds to the aldolase. The invention provides methods for identifying a modulator of an aldolase activity comprising the following steps: (a) providing a polypeptide of the invention or a polypeptide encoded by a nucleic acid of the invention; (b) providing a test compound; (c) contacting the polypeptide of step (a) with the test compound of step (b); and, measuring an activity of the aldolase, wherein a change in the aldolase activity measured in the presence of the test compound compared to the activity in the absence of the test compound provides a determination that the test compound modulates the aldolase activity. In one aspect, the aldolase activity is measured by providing an aldolase substrate and detecting an increase in the amount of the substrate or a decrease in the amount of a reaction product. The decrease in the amount of the substrate or the increase in the amount of the reaction product with the test compound as compared to the amount of substrate or reaction product without the test compound identifies the test compound as an activator of aldolase activity. The increase in the amount of the substrate or the decrease in the amount of the reaction product with the test compound as compared to the amount of substrate or reaction product without the test compound identifies the test compound as an inhibitor of aldolase activity. The invention provides computer systems comprising a processor and a data storage device wherein said data storage device has stored thereon a polypeptide sequence of the invention or a nucleic acid sequence of the invention. In one aspect, the computer system can further comprise a sequence comparison algorithm and a data storage device having at least one reference sequence stored thereon. The sequence comparison algorithm can comprise a computer program that indicates polymorphisms. The computer system can further comprising an identifier that identifies one or more features in said sequence. The invention provides computer readable mediums having stored thereon a sequence comprising a polypeptide sequence of the invention or a nucleic acid sequence of the invention. The invention provides methods for identifying a feature in a sequence comprising the steps of: (a) reading the sequence using a computer program which identifies one or more features in a sequence, wherein the sequence comprises a polypeptide sequence of the invention or a nucleic acid sequence of the invention; and, (b) identifying one or more features in the sequence with the computer program. The invention provides methods for comparing a first sequence to a second sequence comprising the steps of: (a) reading the first sequence and the second sequence through use of a computer program which compares sequences, wherein the first sequence comprises a polypeptide sequence of the invention or a nucleic acid sequence of the invention; and, (b) determining differences between the first sequence and the second sequence with the computer program. In one aspect, the step of determining differences between the first sequence and the second sequence further comprises the step of identifying polymorphisms. In one aspect, the method further comprises an identifier (and use of the identifier) that identifies one or more features in a sequence. In one aspect, the method comprises reading the first sequence using a computer program and identifying one or more features in the sequence. The invention provides methods for isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from an environmental sample comprising the steps of: (a) providing an amplification primer sequence pair for amplifying a nucleic acid encoding a polypeptide with an aldolase activity, wherein the primer pair is capable of amplifying a nucleic acid of the invention; (b) isolating a nucleic acid from the environmental sample or treating the environmental sample such that nucleic acid in the sample is accessible for hybridization to the amplification primer pair; and, (c) combining the nucleic acid of step (b) with the amplification primer pair of step (a) and amplifying nucleic acid from the environmental sample, thereby isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from an environmental sample. In one aspect, each member of the amplification primer sequence pair comprises an oligonucleotide comprising at least about 10 to 50 consecutive bases of a nucleic acid sequence of the invention. In one aspect, the amplification primer sequence pair is an amplification pair of the invention. The invention provides methods for isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from an environmental sample comprising the steps of: (a) providing a polynucleotide probe comprising a nucleic acid sequence of the invention, or a subsequence thereof; (b) isolating a nucleic acid from the environmental sample or treating the environmental sample such that nucleic acid in the sample is accessible for hybridization to a polynucleotide probe of step (a); (c) combining the isolated nucleic acid or the treated environmental sample of step (b) with the polynucleotide probe of step (a); and, (d) isolating a nucleic acid that specifically hybridizes with the polynucleotide probe of step (a), thereby isolating or recovering a nucleic acid encoding a polypeptide with an aldolase activity from the environmental sample. In alternative aspects, the environmental sample comprises a water sample, a liquid sample, a soil sample, an air sample or a biological sample. In alternative aspects, the biological sample is derived from a bacterial cell, a protozoan cell, an insect cell, a yeast cell, a plant cell, a fungal cell or a mammalian cell. The invention provides methods of generating a variant of a nucleic acid encoding an aldolase comprising the steps of: (a) providing a template nucleic acid comprising a nucleic acid of the invention; (b) modifying, deleting or adding one or more nucleotides in the template sequence, or a combination thereof, to generate a variant of the template nucleic acid. In one aspect, the method further comprises expressing the variant nucleic acid to generate a variant aldolase polypeptide. In alternative aspects, the modifications, additions or deletions are introduced by error-prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, sexual PCR mutagenesis, in vivo mutagenesis, cassette mutagenesis, recursive ensemble mutagenesis, exponential ensemble mutagenesis, site-specific mutagenesis, gene reassembly, gene site saturated mutagenesis (GSSM), synthetic ligation reassembly (SLR) and/or a combination thereof. In alternative aspects, the modifications, additions or deletions are introduced by a method selected from the group consisting of recombination, recursive sequence recombination, phosphothioate-modified DNA mutagenesis, uracil-containing template mutagenesis, gapped duplex mutagenesis, point mismatch repair mutagenesis, repair-deficient host strain mutagenesis, chemical mutagenesis, radiogenic mutagenesis, deletion mutagenesis, restriction-selection mutagenesis, restriction-purification mutagenesis, artificial gene synthesis, ensemble mutagenesis, chimeric nucleic acid multimer creation and/or a combination thereof. In one aspect, the method is iteratively repeated until an aldolase having an altered or different activity or an altered or different stability from that of an aldolase encoded by the template nucleic acid is produced. In one aspect, the altered or different activity is an aldolase activity under an acidic condition, wherein the aldolase encoded by the template nucleic acid is not active under the acidic condition. In one aspect, the altered or different activity is an aldolase activity under a high temperature, wherein the aldolase encoded by the template nucleic acid is not active under the high temperature. In one aspect, the method is iteratively repeated until an aldolase coding sequence having an altered codon usage from that of the template nucleic acid is produced. The method can be iteratively repeated until an aldolase gene having higher or lower level of message expression or stability from that of the template nucleic acid is produced. The invention provides methods for modifying codons in a nucleic acid encoding an aldolase to increase its expression in a host cell, the method comprising (a) providing a nucleic acid of the invention encoding an aldolase; and, (b) identifying a non-preferred or a less preferred codon in the nucleic acid of step (a) and replacing it with a preferred or neutrally used codon encoding the same amino acid as the replaced codon, wherein a preferred codon is a codon over-represented in coding sequences in genes in the host cell and a non-preferred or less preferred codon is a codon under-represented in coding sequences in genes in the host cell, thereby modifying the nucleic acid to increase its expression in a host cell. The invention provides methods for modifying codons in a nucleic acid encoding an aldolase, the method comprising (a) providing a nucleic acid of the invention encoding an aldolase; and, (b) identifying a codon in the nucleic acid of step (a) and replacing it with a different codon encoding the same amino acid as the replaced codon, thereby modifying codons in a nucleic acid encoding an aldolase. The invention provides methods for modifying codons in a nucleic acid encoding an aldolase to increase its expression in a host cell, the method comprising (a) providing a nucleic acid of the invention encoding an aldolase; and, (b) identifying a non-preferred or a less preferred codon in the nucleic acid of step (a) and replacing it with a preferred or neutrally used codon encoding the same amino acid as the replaced codon, wherein a preferred codon is a codon over-represented in coding sequences in genes in the host cell and a non-preferred or less preferred codon is a codon under-represented in coding sequences in genes in the host cell, thereby modifying the nucleic acid to increase its expression in a host cell. The invention provides methods for modifying a codon in a nucleic acid encoding an aldolase to decrease its expression in a host cell, the method comprising (a) providing a nucleic acid of the invention encoding an aldolase; and, (b) identifying at least one preferred codon in the nucleic acid of step (a) and replacing it with a non-preferred or less preferred codon encoding the same amino acid as the replaced codon, wherein a preferred codon is a codon over-represented in coding sequences in genes in a host cell and a non-preferred or less preferred codon is a codon under-represented in coding sequences in genes in the host cell, thereby modifying the nucleic acid to decrease its expression in a host cell. In alternative aspects, the host cell is a bacterial cell, a fungal cell, an insect cell, a yeast cell, a plant cell or a mammalian cell. The invention provides methods for producing a library of nucleic acids encoding a plurality of modified aldolase active sites or substrate binding sites, wherein the modified active sites or substrate binding sites are derived from a first nucleic acid comprising a sequence encoding a first active site or a first substrate binding site the method comprising: (a) providing a first nucleic acid encoding a first active site or first substrate binding site, wherein the first nucleic acid sequence comprises a nucleic acid of the invention; (b) providing a set of mutagenic oligonucleotides that encode naturally-occurring amino acid variants at a plurality of targeted codons in the first nucleic acid; and, (c) using the set of mutagenic oligonucleotides to generate a set of active site-encoding or substrate binding site-encoding variant nucleic acids encoding a range of amino acid variations at each amino acid codon that was mutagenized, thereby producing a library of nucleic acids encoding a plurality of modified aldolase active sites or substrate binding sites. In alternative aspects, the method comprises mutagenizing the first nucleic acid of step (a) by a method comprising an optimized directed evolution system, gene site-saturation mutagenesis (GSSM), and synthetic ligation reassembly (SLR). The method can further comprise mutagenizing the first nucleic acid of step (a) or variants by a method comprising error-prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, sexual PCR mutagenesis, in vivo mutagenesis, cassette mutagenesis, recursive ensemble mutagenesis, exponential ensemble mutagenesis, site-specific mutagenesis, gene reassembly, gene site saturated mutagenesis (GSSM), synthetic ligation reassembly (SLR) and a combination thereof. The method can further comprise mutagenizing the first nucleic acid of step (a) or variants by a method comprising recombination, recursive sequence recombination, phosphothioate-modified DNA mutagenesis, uracil-containing template mutagenesis, gapped duplex mutagenesis, point mismatch repair mutagenesis, repair-deficient host strain mutagenesis, chemical mutagenesis, radiogenic mutagenesis, deletion mutagenesis, restriction-selection mutagenesis, restriction-purification mutagenesis, artificial gene synthesis, ensemble mutagenesis, chimeric nucleic acid multimer creation and a combination thereof. The invention provides methods for making a small molecule comprising the steps of: (a) providing a plurality of biosynthetic enzymes capable of synthesizing or modifying a small molecule, wherein one of the enzymes comprises an aldolase enzyme encoded by a nucleic acid of the invention; (b) providing a substrate for at least one of the enzymes of step (a); and, (c) reacting the substrate of step (b) with the enzymes under conditions that facilitate a plurality of biocatalytic reactions to generate a small molecule by a series of biocatalytic reactions. The invention provides methods for modifying a small molecule comprising the steps: (a) providing an aldolase enzyme encoded by a nucleic acid of the invention; (b) providing a small molecule; and, (c) reacting the enzyme of step (a) with the small molecule of step (b) under conditions that facilitate an enzymatic reaction catalyzed by the aldolase enzyme, thereby modifying a small molecule by an aldolase enzymatic reaction. In one aspect, the method comprises providing a plurality of small molecule substrates for the enzyme of step (a), thereby generating a library of modified small molecules produced by at least one enzymatic reaction catalyzed by the aldolase enzyme. In one aspect, the method further comprises a plurality of additional enzymes under conditions that facilitate a plurality of biocatalytic reactions by the enzymes to form a library of modified small molecules produced by the plurality of enzymatic reactions. In one aspect, the method further comprises the step of testing the library to determine if a particular modified small molecule that exhibits a desired activity is present within the library. The step of testing the library can further comprises the steps of systematically eliminating all but one of the biocatalytic reactions used to produce a portion of the plurality of the modified small molecules within the library by testing the portion of the modified small molecule for the presence or absence of the particular modified small molecule with a desired activity, and identifying at least one specific biocatalytic reaction that produces the particular modified small molecule of desired activity. The invention provides methods for determining a functional fragment of an aldolase enzyme comprising the steps of: (a) providing an aldolase enzyme comprising an amino acid sequence of the invention; and, (b) deleting a plurality of amino acid residues from the sequence of step (a) and testing the remaining subsequence for an aldolase activity, thereby determining a functional fragment of an aldolase enzyme. In one aspect, the aldolase activity is measured by providing an aldolase substrate and detecting an increase in the amount of the substrate or a decrease in the amount of a reaction product. In one aspect, a decrease in the amount of an enzyme substrate or an increase in the amount of the reaction product with the test compound as compared to the amount of substrate or reaction product without the test compound identifies the test compound as an activator of aldolase activity. The invention provides methods for whole cell engineering of new or modified phenotypes by using real-time metabolic flux analysis, the method comprising the following steps: (a) making a modified cell by modifying the genetic composition of a cell, wherein the genetic composition is modified by addition to the cell of a nucleic acid of the invention; (b) culturing the modified cell to generate a plurality of modified cells; (c) measuring at least one metabolic parameter of the cell by monitoring the cell culture of step (b) in real time; and, (d) analyzing the data of step (c) to determine if the measured parameter differs from a comparable measurement in an unmodified cell under similar conditions, thereby identifying an engineered phenotype in the cell using real-time metabolic flux analysis. In one aspect, the genetic composition of the cell can be modified by a method comprising deletion of a sequence or modification of a sequence in the cell, or, knocking out the expression of a gene. In one aspect, the method can further comprise selecting a cell comprising a newly engineered phenotype. In another aspect, the method can comprise culturing the selected cell, thereby generating a new cell strain comprising a newly engineered phenotype. The invention provides methods of increasing thermotolerance or thermostability of an aldolase polypeptide, the method comprising glycosylating an aldolase polypeptide, wherein the polypeptide comprises at least thirty contiguous amino acids of a polypeptide of the invention; or a polypeptide encoded by a nucleic acid sequence of the invention, thereby increasing the thermotolerance or thermostability of the aldolase polypeptide. In one aspect, the aldolase specific activity can be thermostable or thermotolerant at a temperature in the range from greater than about 37° C. to about 95° C. The invention provides methods for overexpressing a recombinant aldolase polypeptide in a cell comprising expressing a vector comprising a nucleic acid comprising a nucleic acid of the invention or a nucleic acid sequence of the invention, wherein the sequence identities are determined by analysis with a sequence comparison algorithm or by visual inspection, wherein overexpression is effected by use of a high activity promoter, a dicistronic vector or by gene amplification of the vector. The invention provides methods of making a transgenic plant comprising the following steps: (a) introducing a heterologous nucleic acid sequence into the cell, wherein the heterologous nucleic sequence comprises a nucleic acid sequence of the invention, thereby producing a transformed plant cell; and (b) producing a transgenic plant from the transformed cell. In one aspect, the step (a) can further comprise introducing the heterologous nucleic acid sequence by electroporation or microinjection of plant cell protoplasts. In another aspect, the step (a) can further comprise introducing the heterologous nucleic acid sequence directly to plant tissue by DNA particle bombardment. Alternatively, the step (a) can further comprise introducing the heterologous nucleic acid sequence into the plant cell DNA using an Agrobacterium tumefaciens host. In one aspect, the plant cell can be a potato, corn, rice, wheat, tobacco, or barley cell. The invention provides methods of expressing a heterologous nucleic acid sequence in a plant cell comprising the following steps: (a) transforming the plant cell with a heterologous nucleic acid sequence operably linked to a promoter, wherein the heterologous nucleic sequence comprises a nucleic acid of the invention; (b) growing the plant under conditions wherein the heterologous nucleic acids sequence is expressed in the plant cell. The invention provides methods of expressing a heterologous nucleic acid sequence in a plant cell comprising the following steps: (a) transforming the plant cell with a heterologous nucleic acid sequence operably linked to a promoter, wherein the heterologous nucleic sequence comprises a sequence of the invention; (b) growing the plant under conditions wherein the heterologous nucleic acids sequence is expressed in the plant cell. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. All publications, patents, patent applications, GenBank sequences and ATCC deposits, cited herein are hereby expressly incorporated by reference for all purposes. |
Therapeutic compositions that alter the immune response |
The invention is therapeutic methods and compositions that alter the immunogenicity of the host. |
1. A method for prolonging survival in a cancer patient, the method comprising identifying a patient having CA125 levels at or below about 35 units/mL and administering to the patient a xenogeneic antibody specific for CA125 antigen. 2. The method according to claim 1, wherein the patient is an ovarian cancer patient. 3. The method according to claim 1, wherein the level of CA125 antigen is from about 5 units/mL to about 35 units/mL. 4. The method according to claim 3, wherein the level of CA125 antigen is from about 9.5 units/mL to about 35 units/mL. 5. The method according to claim 1, wherein the antibody is a murine antibody. 6. The method according to claim 1, wherein the antibody is murine monoclonal antibody B43.13. 7. The method according to claim 1, wherein the antibody is administered at a low dose. 8. The method according to claim 7, wherein the dose is from about 0.1 μg to about 2 mg per kg of body weight of the patient. 9. A method for prolonging time to disease relapse in a cancer patient following initial treatment with chemotherapy and/or surgery, the method comprising identifying a patient who has undergone initial treatment and has CA125 levels at or below about 35 units/mL and administering to the patient a xenogeneic antibody specific for CA125 antigen. 10. The method according to claim 9, wherein the antibody is a monoclonal antibody. 11. The method according to claim 9, wherein the patient is an ovarian cancer patient. 12. The method according to claim 9, wherein the level of CA125 antigen is from about 5 units/mL to about 35 units/mL. 13. The method according to claim 12, wherein the level of CA125 antigen is from about 9.5 units/mL to about 35 units/mL. 14. The method according to claim 9, wherein the antibody is a murine antibody. 15. The method according to claim 9, wherein the antibody is a monoclonal antibody. 16. The method according to claim 9, wherein the antibody is murine monoclonal antibody B43.13. 17. The method according to claim 9, wherein the antibody is administered at a low dose. 18. The method according to claim 17, wherein the dose is from about 0.1 μg to about 2 mg per kg of body weight of the patient. 19. A method for prolonging survival in a cancer patient following initial treatment with chemotherapy and/or surgery, the method comprising identifying a patient who has undergone initial treatment and has CA125 levels at or below about 35 units/mL and administering to the patient a xenogeneic antibody specific for CA125 antigen. 20. The method according to claim 19, wherein the patient is an ovarian cancer patient. 20. The method according to claim 19, wherein the level of CA125 antigen is from about 5 units/mL to about 35 units/mL. 21. The method according to claim 19, wherein the level of CA125 antigen is from about 9.5 units/mL to about 35 units/mL. 22. The method according to claim 19, wherein the antibody is a murine antibody. 23. The method according to claim 19, wherein the antibody is a monoclonal antibody. 24. The method according to claim 19, wherein the antibody is murine monoclonal antibody B43.13. 25. The method according to claim 19, wherein the antibody is administered at a low dose. 26. The method according to claim 24, wherein the dose is from about 0.1 μg to about 2 mg per kg of body weight of the patient. 27. A method for inducing a host immune response against a multi-epitopic in vivo CA 125 antigen present at a level of from about 5 units/mL to about 30 units/mL that does not elicit an effective host immune response, the method comprising contacting the antigen with a composition comprising a binding agent that specifically binds to a first epitope on the antigen, and allowing the binding agent to form a binding agent/antigen pair, whereby a host immune response is elicited against a second epitope on the antigen. 28. A method for altering a host immune response against a CA125 antigen present at a level of from about 5 units/mL to about 30 units/mL, comprising administering to the host a composition comprising a binding agent that specifically binds to the antigen and alters the immune response against the antigen, the binding agent present in the composition being non-radiolabeled, and being present in an amount of from about 0.1 μg to about 2 mg per kg of body weight of the host. 29. A method for inducing a host immune response against a multi-epitopic in vivo CA125 antigen present at a level of from about 5 units/mL to about 30 units/mL, the method comprising contacting the multi-epitopic antigen with a composition comprising a binding agent exclusive of B43.13 that specifically binds to a first epitope on the antigen, and allowing the binding agent to form a binding agent/antigen pair, whereby a host immune response is elicited against a second epitope on the antigen. 30. A method for altering the host immune response against a CA125 antigen present at a level of from about 5 units/mL to about 30 units/mL, comprising administering to the host a composition comprising a binding agent exclusive of B43.13 that specifically binds to the antigen and alters the immune response against the antigen, the binding agent being present in an amount of from about 0.1 μg to about 2 mg per kg of body weight of the host. 31. A method for inducing a host immune response against a CA125 multi-epitopic antigen present in a host's serum at a level from about 5 units/mL to about 35 units/mL, which antigen does not elicit an effective host immune response, the method comprising contacting the antigen with a composition comprising a binding agent that specifically binds to the antigen and allowing the binding agent to form a binding agent/antigen pair wherein a beneficial host immune response is elicited against the antigen. 32. A method for inducing a host immune response against a multi-epitopic in vivo CA125 antigen present at a level of from about 5 units/mL to about 9.5 units/mL that does not elicit an effective host immune response, the method comprising contacting the antigen with a composition comprising a binding agent that specifically binds to a first epitope on the antigen; and allowing the binding agent to form a binding agent/antigen pair, whereby a host immune response is elicited against a second epitope on the antigen. |
<SOH> BACKGROUND ART <EOH>In vertebrates, the mechanisms of natural and specific immunity cooperate within a system of host defenses, the immune system, to eliminate foreign invaders. The hypothesis that the immune system ought to be able to recognize tumors and thus could be recruited in the fight against cancer has been a driving force behind outstanding efforts of many immunologists. This approach is attractive because of the unique ability of the immune system to specifically destroy affected cells while mostly sparing normal tissue. Moreover, the initial immune response is known to leave behind a long-term memory that serves to protect from the same disease in the future. No drug treatment for cancer can claim such specificity or memory. An immunotherapeutic strategy for the treatment of cancer and other diseases or conditions involve one or more components of the immune system to trigger a complex cascade of biological reactions focused on eliminating a foreign molecule from the host. Vertebrates have two broad classes of immune responses: antibody responses, or humoral immunity, and cell-mediated immune responses, or cellular immunity. Humoral immunity is provided by B lymphocytes, which, after proliferation and differentiation, produce antibodies (proteins also known as immunoglobulins) that circulate in the blood and lymphatic fluid. These antibodies specifically bind to the antigen that induced them. Binding by antibody inactivates the foreign substance, e.g., a virus, by blocking the substance's ability to bind to receptors on a target cell or by attracting complement or the killer cells that attack the virus. The humoral response primarily defends against the extracellular phases of bacterial and viral infections. In humoral immunity, serum alone can transfer the response, and the effectors of the response are protein molecules, typically soluble, called antibodies. Lymphocytes produce these antibodies and thereby determine the specificity of immunity; it is this response that orchestrates the effector limbs of the immune system. Cells and proteins, such as antibodies, that interact with lymphocytes play critical roles in both the presentation of antigen and in the mediation of immunologic functions. Individual lymphocytes respond to a limited set of structurally related antigens. As noted in more detail below, this function is defined structurally by the presence of receptors on the lymphocyte's surface membrane that are specific for binding sites (determinants or epitopes) on the antigen. Lymphocytes differ from each other not only in the specificity of their receptors, but also in their functions. One class of lymphocytes, B cells, are precursors of antibody-secreting cells, and function as mediators of the humoral immune response. Another class of lymphocytes, T cells, express important regulatory functions, and are mediators of the cellular immune response. The second class of immune responses, cellular immunity, involve the production of specialized cells, e.g., T lymphocytes, that react with foreign antigens on the surface of other host cells. The cellular immune response is particularly effective against fungi, parasites, intracellular viral infections, cancer cells and other foreign matter. In fact, the majority of T lymphocytes play a regulatory role in immunity, acting either to enhance or suppress the responses of other white blood cells. These cells, called helper T cells and suppressor T cells, respectively, are collectively referred to as regulatory cells. Other T lymphocytes, called cytotoxic T cells, kill, for example, virus-infected cells or tumor cells. Both cytotoxic T cells and B lymphocytes are involved directly in defense against infection and are collectively referred to as effector cells. There are a number of intercellular signals important to T cell activation. Under normal circumstances an antigen degrades or is cleaved to form antigen fragments or peptides. Presentation of antigen fragments to T-cells is the principal function of MHC molecules, and the cells that carry out this function are called antigen-presenting cells (APC: including but not limited to dendritic cells, macrophages, and B cells). The time course of an immune response is subdivided into the cognitive or recognition phase, during which specific lymphocytes recognize the foreign antigen; the activation phase, during which specific lymphocytes respond to the foreign antigen; and the effector phase, during which antigen-activated lymphocytes mediate the processes required to eliminate the antigen-carrying target cells. Lymphocytes are immune cells that are specialized in mediating and directing specific immune responses. T cells and B cells become morphologically distinct only after they have been stimulated by an antigen. The capture and processing of an antigen by APCs is essential for the induction of a specific immune response. APCs capture antigens via specific receptors, such as Fc receptors or mannose receptors, or the APCs non-specifically phagocytose antigen. The capture through specific receptors is more efficient; antigens can be presented better when in complex with, for example, an antibody. Such a complex can be formed by injecting an antibody to a circulating antigen (e.g., PSA or CA 125), and the immune complexes can be targeted to dendritic cells and macrophages through the Fc-receptors present on these cells. However the high number of Fc receptors on neutrophils may considerably limit this process. Imunotherapy is based on the principle of inducing or activating the immune system to recognize and eliminate undesirable cells, such as neoplastic cells. The key elements in any immunotherapy is to induce or trigger the host immune system to first recognize a molecule as an unwanted target, and then to induce the system to initiate a response against that molecule. In healthy hosts, the immune system recognizes surface features of a molecule that is not a normal constituent of the host (i.e., is “foreign” to the host). Once the recognition function occurs, the host must then direct a response against that particular foreign molecule. Both the recognition and the response elements of the immune system involve a highly complex cascade of biological reactions. In most immunologically based disorders, at least one of the steps in the recognition phase, or at least one of the steps in the response phase, are disrupted. Virtually any disruption in either of these complex pathways leads to a reduced response or to the lack of any response. The inability of the immune system to destroy a growing tumor has been attributed, among other factors, to the presence of tumor-associated antigens (TAA) that induce immunological tolerance and/or immunosuppression. For example, in some kinds of cancer, the cancer itself tricks the host into accepting the foreign cancer cell as a normal constituent, thus disrupting the recognition phase of the immune system. The immunological approach to cancer therapy involves modification of the host-tumor relationship so that the immune system is induced or amplifies its response to the TAAs. If successful, inducing or amplifying the immune system can lead to tumor regression, tumor rejection, and occasionally, to tumor cure. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is a method and composition for generating both a humoral and/or a cellular immune response by administering a binding agent that specifically binds to a pre-selected soluble antigen. In accordance with the invention, the binding agent-soluble antigen complex alters the immunogenic condition of the host by generating new immunogens that are recognizable by the immune system. This leads to a humoral and/or a cellular response. In one embodiment of the invention, the immune response comprises an anti-tumor response and/or cell killing. The present invention is a comprehensive method for the treatment of certain diseases and conditions that includes, but is not limited to, targeting a pre-determined antigen, preferably a multi-epitopic antigen and/or preferably soluble; administering a binding agent, preferably a monoclonal antibody, and inducing a comprehensive immune response against the disease or condition that generated the target antigen. In a preferred embodiment of the invention, the binding agent or the binding agent/antigen complex induces the production of a humoral response, as evidenced in part by the production of anti-antigen (e.g., anti-tumor or anti-inflammation) antibodies, Ab3 and/or Ab1c; and/or induces the production of a cellular response, as evidenced in part by the production of T-cells that are specific for the binding agent, the binding agent/antigen complex, and/or the antigen. The present invention also includes methods and compositions for altering the immunogenic state of the host organism. In altering the immunogenic state, the compositions and methods of the present invention increase, decrease, or maintain the host's immunogenic state. An example of deriving a therapeutic benefit by increasing the immunogenicity includes but is not limited to treatments for cancer or some infectious diseases. An example of decreasing the immunogenicity includes but is not limited to treatments for rheumatoid arthritis. An example of maintaining immunogenicity includes but is not limited to supplemental treatments for patients that have become tolerant to antigens after an initial response. In a most preferred embodiment of the invention, the methods and compositions do not decrease the antigenicity of the active component in the therapeutic composition. The present invention also includes methods and compositions for increasing the over-all host response to a disease or condition. These methods and compositions produce a therapeutic benefit for the recipient. The present invention also is a therapeutic composition comprising an active agent, or binding agent, that specifically binds to a pre-determined soluble antigen, wherein the binding agent, upon binding to the antigen, forms a complex that is both antigenic and immunogenic. The compositions and methods of the present invention may also include one or more steps or substances that increase the over-all immunogenicity. The therapeutic compositions and methods of the present invention are suitable for the treatment of any disease or cancer that produces a soluble antigen, preferably a multi-epitopic antigen. The present invention also includes a method for designing new therapeutic agents comprising selecting a soluble antigen, preferably an antigen that has been determined to be multi-epitopic; and selecting a binding agent that specifically binds to said antigen to form a complex. In accordance with the invention, the binding agent, the binding agent/antigen complex, and/or the antigen lead to the production of a humoral and/or cellular response in vivo. In a preferred embodiment of the invention, the method for designing a new therapeutic agent results in a binding agent or the binding agent/antigen complex that induces the production of a humoral response, as evidenced in part by the production of anti-tumor or anti-inflammation antibodies, Ab3 and/or Ab1c; and/or induces the production of a cellular response, as evidenced in part by the production of T-cells that are specific for the binding agent, the binding agent/antigen complex, and/or the antigen. Although several investigators have shown that antigen-specific antibodies can enhance the immune response to those antigens presented in a complex form, the present invention is the first to demonstrate that the injection of an antibody against a single epitope can induce a multi-epitopic immune response in cancer patients, provided that the patients' sera contained the respective antigen. The present invention also demonstrates that this antibody injection can change the patient's immune response in such a way that the self-protein CA125 can now be recognized by the immune system. Stimulation of T cells reactive with subdominant or cryptic epitopes of self-proteins has been suggested as an important factor in inducing immunity to a pre-determined antigen, e.g., an antigen involved in a disease or condition such as cancer or auto-immunity. Antibody-enhanced or -altered presentation of an antigen, such as CA125, in an antibody complex, e.g., bound to MAb-B43.13, by B cells (antibody-specific), or macrophages or dendritic cells (both F c receptor mediated), may result in presentation of different peptides to the immune system than those obtained by presentation of the antigen alone. This can lead to sufficient presence of antigen-specific peptides from subdominant or cryptic epitopes which may in turn stimulate low-affinity T cells that escaped clonal deletion in the thymus or re-stimulate T cells which were suppressed. The immune response induced by exogenous administration of an antibody to a circulating self-antigen can therefore be compared to that observed in auto-immune diseases. This may also explain why presence of immune complexes of antigen with autologous human antibodies is often not correlated with improved survival. Human B cells recognize preferably immune-dominant epitopes of the antigen, leading to presentation of epitopes against which T cells were formed during fetal development. Murine antibodies on the other hand, recognize immune-dominant epitopes in mice which are not necessarily equivalent to the human immune-dominant epitopes. The capture and processing of an antigen, e.g., PSA, by B-cells may also occur through the interaction of the membrane bound Ab2 with the anti-antigen/antigen (e.g., anti-PSA/PSA) complexes and in a similar manner through the interaction of membrane bound Ab3 with the antigen (complexed or not with the anti-PSA antibody). Although applicants do not wish to be bound by any particular theory of operability, it is believed that the observed immunological response achieved by the present invention is attributable to an interaction between a newly formed antigen and the human patient's immune system. As noted above, a portion of the immune response includes inducing the production of anti-(anti-idiotype) antibodies by the patient. Within this set of anti-(anti-idiotype) antibodies are those that are directly complimentary to the paratope of an anti-idiotype antibody. It is further believed that the paratope of the anti-idiotype antibody presents an “internal” image of the tumor cell epitope identified (i.e., selectively bound) by the idiotype antibody and, therefore, the anti-(anti-idiotype) antibodies will also bind the tumor antigen. In effect, the present method induces a immunological response to the first antigen, e.g., a tumor antigen, by presenting a second antigen (the paratope of the anti-idiotype antibody, which shares homologies with the tumor antigen) to a portion of the patient's resulting antibodies. The present invention concerns altering immunogenicity in a manner that produces a beneficial or therapeutically desirable effect. As used herein and as described in more detail below, a beneficial or desirable immune response is one that produces a therapeutically desirable result. A beneficial therapeutic response will typically include activation of the immune system and/or one or more of its components, induction of the immune system and/or one or more of its components, and/or a T cell immune response, and/or a humoral immune response, and/or reduction in tumor burden, and/or an increase in survival time, and/or the like. For example, for a cancer such as ovarian cancer, a beneficial or desirable immune response includes the production of an antibody that immunoreacts with a previously non-immunoreactive ovarian cancer antigen. In this example, the immune response to an antigen is increased. In another example, for a condition such as inflammation, a beneficial or desirable immune response includes the production of an antibody that immunoreacts with a previously immunoreactive antigen so that it becomes non-immunoreactive. In this example, the immune response is decreased. In transplantation, the immune system attacks MHC-disparate donor tissue leading to graft rejection, in autoimmune disease it attacks normal tissues, and in allergy the immune system is hyper-responsive to otherwise harmless environmental antigens. It is now recognized that immunosuppressive therapy may be appropriate for treating each of these disorders. |
Method of well treatment |
The invention provides a method of well treatment comprising introducing into the matrix surrounding a hydrocarbon well bore hole an emulsion the discontinuous phase of which comprises a non-polymerizable, water or oil miscible liquid carrier, a polymerizable monomer and a thermally activated polymerization initiator, said monomer constituting from 2 to 40% wt. of said discontinuous phase. |
1. A method of well treatment comprising introducing into the matrix surrounding a hydrocarbon well bore hole an emulsion the discontinuous phase of which comprises a non-polymerizable, water or oil miscible liquid carrier, a polymerizable monomer and a thermally activated polymerization initiator, said monomer constituting from 2 to 40% wt. of said discontinuous phase. 2. A method as claimed in claim 1 wherein said discontinuous phase contains both non-crosslinking and crosslinking monomers. 3. A method as claimed in claim 1 wherein said discontinuous phase is oil-miscible and wherein the continuous phase of said emulsion is aqueous. 4. A method as claimed in claim 1 wherein said emulsion further contains a stabilizer. 5. A method as claimed in claim 1 wherein said discontinuous phase contains 2 to 30% wt. of a non-crosslinking oil-soluble monomer, 0.5 to 20% wt. of a crosslinking oil soluble monomer, and 0.04 to 0.15% wt. of a polymerization initiator. 6. A method as claimed in claim 1 wherein said monomer is a styrenic monomer. 7. A method as claimed in claim 1 wherein said monomer is an acrylic or vinyl monomer. 8. A method as claimed in claim 1 wherein the droplets of the discontinuous phase in said emulsion have a particle size D (v, 0.5) of from 1 to 50 μm. 9. A method as claimed in claim 1 wherein said bore hole is a producer hole. 10. A well treatment chemical emulsion the discontinuous phase of which comprises a non-polymerizable, water or oil miscible liquid carrier, a polymerizable monomer and a thermally activated polymerization initiator, said monomer constituting from 2 to 40% wt. of said discontinuous phase. 11. An emulsion as claimed in claim 10 wherein said discontinuous phase contains 85 to 98% wt. of a saturated liquid hydrocarbon. 12. An emulsion as claimed in claim 10 further containing a stabilizer. 13. An emulsion as claimed in claim 10 whereof said discontinuous phase constitutes 2 to 40% by volume. 14. A well treatment chemical emulsion the discontinuous phase whereof comprises a polymerizable monomer, a thermally-activated polymerization initiator, and a non-polymerizable, water or oil miscible liquid carrier as a hydrocarbon well treatment agent. |
Utilization of a process gas mixture and method for laser beam welding |
The invention describes process gas mixtures for laser beam welding that contain at least one noble gas component. Pursuant to the invention the process gas mixture contains between 50 vpm and 15.0% by volume hydrogen. The process gas can preferably contain one or more of the noble gas components helium, argon and neon. Moreover, the process gas can contain nitrogen. The process gas mixtures can be used in a method for laser beam welding, especially for welding high-grade steels, wherein a focused laser beam is directed at the workpiece surface that is to be machined. Special benefits are associated with ternary or quaternary process gas mixtures with helium and/or neon, hydrogen and nitrogen (for austenitic steels) and helium and/or neon, hydrogen and argon (for titanium or titanium-stabilized steels). |
1-11. (canceled) 12. A welding gas mixture for a laser beam welding process, comprising hydrogen in an amount between 0.005% and 1.50% by volume; and one of helium between 5% and 75% and neon between 10% and 80% and a combination of helium and neon between 5 and 80% by volume. 13. The welding gas mixture pursuant to claim 12, wherein the gas mixture contains hydrogen between 0.01 and 5.0% by volume. 14. The welding gas mixture pursuant to claim 12, wherein the gas mixture contains argon. 15. The welding gas mixture pursuant to claim 12, wherein the gas mixture contains helium between 15 to 50% by volume. 16. The welding gas mixture pursuant to claim 12, wherein the gas mixture contains neon between 20 to 60% by volume. 17. The welding gas mixture pursuant to claim 12, wherein the gas mixture contains an overall portion of helium and neon of 15 to 60% by volume. 18. The welding gas mixture pursuant to claim 12, wherein the gas mixture contains nitrogen. 19. The welding gas mixture pursuant to claim 12, wherein the gas mixture is a ternary mixture of one of: Helium, hydrogen and nitrogen; Helium, hydrogen and argon; Neon, hydrogen and nitrogen; and Neon, hydrogen and argon. 20. The welding gas mixture pursuant to claim 12, wherein the gas mixture is a quaternary mixture of one of: Helium, neon, hydrogen and nitrogen; and Helium, neon, hydrogen and argon. 21. The welding gas mixture pursuant to claim 19, wherein the welding mixture gas contains one of: 20 to 50% by volume helium and/or neon, 50 vpm (0.005% by volume) to 15.0% by volume hydrogen and the remainder being argon; and 20 to 50% by volume helium and/or neon, 50 vpm (0.005% by volume) to 15.0% by volume hydrogen and the remainder being nitrogen. 22. A method for laser beam welding, comprising the steps of: directing a focused laser beam at a workpiece to be machined; and flowing a welding gas mixture having a composition according to claim 1, wherein said welding gas mixture is flowed against said workpiece surface by at least one nozzle arranged one of coaxially and at an angle to an axis of said focused laser beam. 23. The welding gas mixture pursuant to claim 15, wherein the gas mixture contains helium between 20 to 35% by volume. 24. The welding gas mixture pursuant to claim 16, wherein the gas mixture contains neon between 25 to 45% by volume. 25. The welding gas mixture pursuant claim 17, wherein the gas mixture contains an overall portion of helium and neon between 20 to 45%. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to the use of a process gas mixture for laser beam welding, wherein the process gas mixture contains at least one noble gas. The invention furthermore relates to a method for laser beam welding, wherein a focused laser beam is directed at the workpiece surface that is to be machined and a process gas flow is conducted against the workpiece surface via at least one nozzle that is arranged coaxially and/or at an angle in relation to the laser beam axis. The characteristics of laser radiation, especially its intensity and good focusability, have led to the fact that today use of lasers in many material machining areas. Known laser machining equipment unless a laser machining head, possibly with a nozzle that is arranged coaxially to the laser beam. Laser machining equipment is frequently used in connection with CNC controls. Process gases are employed with different objectives, in particular also as protective gases, in various machining methods, including in laser beam welding processes. It is intended to optimize gas mixtures with respect to these objectives. Process gases are generally required on or at least in the surroundings of the machined area especially when functioning as protective gases in a pure state, i.e. without interfering components of the ambient atmosphere. German Reference DE 196 16 844 A1 discloses a method for laser welding metallic workpieces while employing a process gas that flushes the weld area and consists of a mixture of at least one inert gas and hydrogen. The process gas then contains at least one noble gas and/or nitrogen as the inert gas. The process gas contains hydrogen at a percentage from 1 to 30% by volume. The metallic workpieces mentioned are workpieces made of austenitic steel, austenitic-ferritic steel or of a nickel base alloy. The effect of adding hydrogen pursuant to DE 196 16 844 A1 is that the formation of plasma flares, i.e. a plasma formation in the process gas already before the laser beam hits the metal surface, is prevented or reduced. German Reference DE 43 15 849 C1 provides a method for the CO 2 laser beam welding of aluminum alloys while employing a shielding gas or gas mixture, which is directed at the welding point on the workpiece surface through shielding and working nozzles for plasma control. The welding shielding gas consists of either pure neon or a gas mixture comprising argon, helium, nitrogen, carbon dioxide, hydrogen and oxygen with pure neon, wherein the volume portion of pure neon in the respective mixture is more than 25%. detailed-description description="Detailed Description" end="lead"? Laser beam welding with the aid of process gases accomplishes above all one objective. At high laser output levels the plasma formation (as a function of laser output, laser type, energy density, evaporated material volume, welding speed and also of the protective gas type) must be presented from becoming too great. Otherwise the laser radiation is absorbed, deflected and/or disturbed by the generated plasma, causing the welding process to become unstable or even to collapse. The basic tasks of the process gas are the control and, especially with high laser output levels, the reduction of plasma. Beneficial for the solution of this problem are gases such as helium with high thermal conductivity and a high ionization temperature. However, there are other possibilities for influencing the welding process through the selection of the process gas. By means of a gas, the weld seam can be covered and thus protected from damaging effects by the ambient atmosphere (protective gas). Favorable factors here are low flow speeds and heavy gases, which can be supplied coaxially and/or at an angle (e.g. about 30°) to the laser beam axis. Other possible objectives such as metallurgical optimization and/or a maximization of the speed and/or quality (spatters, drilling, seam geometry) are today still largely neglected. Moreover the price of the process gas that is employed plays quite a considerable role in its selection. When welding high-grade steels, the most important tasks that have to be fulfilled in the optimization of the welding process through the selection of the process gas include the freedom from oxide, as well as plasma control, weld speed and weld depth. The gases that can be employed as a rule and hereby offer conditions with different benefit levels in every respect. Particularly with the laser beam welding of high-grade steels—especially when laser beam welding austenitic steels—but also with the laser beam welding of titanium or of titanium-stabilized steels it is problematic to find suitable compositions for the process gas mixtures that lead to an optimization of the welding process. It is, therefore, the object of the present invention to present a process gas mixture for use in laser beam welding and a method for laser beam welding of the above-described kind, which improves and optimizes the laser machining process through a suitable gas composition. Hereby economical aspects shall be considered as much as possible as well. This object is achieved pursuant to the invention in that the process gas mixture on one hand comprises between 50 vpm (0.005% by volume) and 15.0% by volume hydrogen and on the other hand 5 to 75% by volume helium or 10 to 80% by volume neon or an overall portion of helium and neon of 5 to 80% by volume. Hydrogen can easily take energy away from the plasma because it has a high thermal capacity and thermal conductivity. However, it forms plasma already at low temperatures (e.g. at 4,000° C.). The process gas mixture pursuant to the invention contains between 50 vpm (0.005% by volume) and 15.0% by volume, preferably between 0.01 and 5.0% by volume, particularly between 0.5 and 4.5% by volume hydrogen. It has been shown that process gas mixture with a hydrogen portion as that pursuant to the invention lead to good welding results. Hydrogen can aid in binding oxygen and thus minimizing oxidation. Moreover, an increased speed in the laser beam welding process can be achieved through the addition of hydrogen in the process gas. A limitation of the hydrogen portion in the process gas mixture is furthermore also recommended for safety reasons because higher hydrogen percentages can facilitate ignition. Preferably a binary mixture of helium or neon and hydrogen or particularly preferred a ternary, quaternary or higher gas mixture comprising preferably hydrogen and helium and/or neon is used. Pursuant to the invention, the process gas contains one or more of the noble gas components helium, argon and neon. Helium dilutes and thus controls the plasma the best because with helium the plasma formation occurs not until temperatures between 15,000° C. and 20,000° C. are reached. The less expensive argon has a lesser effect than helium with respect of the plasma. Argon can be employed especially for highly reactive metals such as titanium or titanium-stabilized steels. Neon is between helium and argon in its physical and chemical properties. The process gas can contain especially 5 to 75% by volume, preferably 15 to 50% by volume, particularly preferred 20 to 35% by volume helium. Benefits during laser beam welding however can also be achieved when the process gas contains especially 10 to 80% by volume, preferably 20 to 60% by volume, particularly preferred 25 to 45% by volume neon. Process gas mixtures containing helium and neon are also suitable. The process gas can here have an overall portion of helium and neon of 5 to 80% by volume, preferably 15 to 60% by volume, particularly preferred 20 to 45% by volume. Beneficially the process gas can contain nitrogen. The likewise inexpensive nitrogen has an effect comparable to argon regarding plasma control. However the use of nitrogen-containing process gas mixtures should be avoided when welding highly reactive metals such as titanium or titanium-stabilized steels because it can lead to nitrite formation. It has been found that an optimization with respect to the various objectives of the process gas can be achieved excellently through the composition of the process gas mixtures. In the designs of the invention ternary or quaternary process gas mixtures are recommended due to their excellent suitability for laser beam welding. The ternary process gas mixture can here be composed of Helium, hydrogen and nitrogen, Helium, hydrogen and argon, Neon, hydrogen and nitrogen or Neon, hydrogen and argon. The quaternary process gas mixture can here be composed in particular of Helium, neon, hydrogen and nitrogen, or Helium, neon, hydrogen and argon. Pursuant to the invention beneficially ternary or quaternary process gas mixtures with 20 to 50% by volume helium and/or neon, 50 vpm (0.005% by volume) to 15.0% by volume hydrogen and the remainder being argon or 20 to 50% by volume helium and/or neon, 50 vpm (0.005% by volume) to 15.0% by volume hydrogen and the remainder being nitrogen can be used. In the above-listed ternary and quaternary mixtures, the hydrogen portion can also be between 0.01 and 5.0% by volume or even between 0.5 and 4.5% by volume. For laser beam welding austenitic steels, pursuant to the invention the use of a process gas mixture is recommended that consists of helium and/or neon and additionally nitrogen. For laser beam welding titanium or titanium-stabilized steels, pursuant to the invention the use of a process gas mixture is recommended that contains helium and/or neon and additionally hydrogen and argon. When laser beam welding austenitic steels, titanium or titanium-stabilized steels the helium portion in ternary mixtures is preferably around 25% by volume. With a partial or complete substitution of helium with neon, the percentage used should be accordingly higher than the helium portion. The process gas mixtures described above can be used beneficially in a method for laser beam welding, especially for welding high-grade steels or titanium or titanium-stabilized steels. A focused laser beam is directed at the workpiece surface that is to be machined and at least one process gas flow is directed against the workpiece surface via at least one nozzle that is arranged coaxially or at an angle to the laser beam axis. A focused laser beam within the framework of the invention should be interpreted as a laser beam that is substantially focused on the workpiece surface. Apart from the primarily employed method with laser radiation that is focused on the workpiece surface, the invention can also be applied to the rarely used variation with radiation that is not exactly focused on the workpiece surface. The invention is in principle not limited to the use of special types of lasers. For the laser beam welding process above all CO 2 lasers or Nd:YAG lasers are suitable. detailed-description description="Detailed Description" end="tail"? |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to the use of a process gas mixture for laser beam welding, wherein the process gas mixture contains at least one noble gas. The invention furthermore relates to a method for laser beam welding, wherein a focused laser beam is directed at the workpiece surface that is to be machined and a process gas flow is conducted against the workpiece surface via at least one nozzle that is arranged coaxially and/or at an angle in relation to the laser beam axis. The characteristics of laser radiation, especially its intensity and good focusability, have led to the fact that today use of lasers in many material machining areas. Known laser machining equipment unless a laser machining head, possibly with a nozzle that is arranged coaxially to the laser beam. Laser machining equipment is frequently used in connection with CNC controls. Process gases are employed with different objectives, in particular also as protective gases, in various machining methods, including in laser beam welding processes. It is intended to optimize gas mixtures with respect to these objectives. Process gases are generally required on or at least in the surroundings of the machined area especially when functioning as protective gases in a pure state, i.e. without interfering components of the ambient atmosphere. German Reference DE 196 16 844 A1 discloses a method for laser welding metallic workpieces while employing a process gas that flushes the weld area and consists of a mixture of at least one inert gas and hydrogen. The process gas then contains at least one noble gas and/or nitrogen as the inert gas. The process gas contains hydrogen at a percentage from 1 to 30% by volume. The metallic workpieces mentioned are workpieces made of austenitic steel, austenitic-ferritic steel or of a nickel base alloy. The effect of adding hydrogen pursuant to DE 196 16 844 A1 is that the formation of plasma flares, i.e. a plasma formation in the process gas already before the laser beam hits the metal surface, is prevented or reduced. German Reference DE 43 15 849 C1 provides a method for the CO 2 laser beam welding of aluminum alloys while employing a shielding gas or gas mixture, which is directed at the welding point on the workpiece surface through shielding and working nozzles for plasma control. The welding shielding gas consists of either pure neon or a gas mixture comprising argon, helium, nitrogen, carbon dioxide, hydrogen and oxygen with pure neon, wherein the volume portion of pure neon in the respective mixture is more than 25%. detailed-description description="Detailed Description" end="lead"? Laser beam welding with the aid of process gases accomplishes above all one objective. At high laser output levels the plasma formation (as a function of laser output, laser type, energy density, evaporated material volume, welding speed and also of the protective gas type) must be presented from becoming too great. Otherwise the laser radiation is absorbed, deflected and/or disturbed by the generated plasma, causing the welding process to become unstable or even to collapse. The basic tasks of the process gas are the control and, especially with high laser output levels, the reduction of plasma. Beneficial for the solution of this problem are gases such as helium with high thermal conductivity and a high ionization temperature. However, there are other possibilities for influencing the welding process through the selection of the process gas. By means of a gas, the weld seam can be covered and thus protected from damaging effects by the ambient atmosphere (protective gas). Favorable factors here are low flow speeds and heavy gases, which can be supplied coaxially and/or at an angle (e.g. about 30°) to the laser beam axis. Other possible objectives such as metallurgical optimization and/or a maximization of the speed and/or quality (spatters, drilling, seam geometry) are today still largely neglected. Moreover the price of the process gas that is employed plays quite a considerable role in its selection. When welding high-grade steels, the most important tasks that have to be fulfilled in the optimization of the welding process through the selection of the process gas include the freedom from oxide, as well as plasma control, weld speed and weld depth. The gases that can be employed as a rule and hereby offer conditions with different benefit levels in every respect. Particularly with the laser beam welding of high-grade steels—especially when laser beam welding austenitic steels—but also with the laser beam welding of titanium or of titanium-stabilized steels it is problematic to find suitable compositions for the process gas mixtures that lead to an optimization of the welding process. It is, therefore, the object of the present invention to present a process gas mixture for use in laser beam welding and a method for laser beam welding of the above-described kind, which improves and optimizes the laser machining process through a suitable gas composition. Hereby economical aspects shall be considered as much as possible as well. This object is achieved pursuant to the invention in that the process gas mixture on one hand comprises between 50 vpm (0.005% by volume) and 15.0% by volume hydrogen and on the other hand 5 to 75% by volume helium or 10 to 80% by volume neon or an overall portion of helium and neon of 5 to 80% by volume. Hydrogen can easily take energy away from the plasma because it has a high thermal capacity and thermal conductivity. However, it forms plasma already at low temperatures (e.g. at 4,000° C.). The process gas mixture pursuant to the invention contains between 50 vpm (0.005% by volume) and 15.0% by volume, preferably between 0.01 and 5.0% by volume, particularly between 0.5 and 4.5% by volume hydrogen. It has been shown that process gas mixture with a hydrogen portion as that pursuant to the invention lead to good welding results. Hydrogen can aid in binding oxygen and thus minimizing oxidation. Moreover, an increased speed in the laser beam welding process can be achieved through the addition of hydrogen in the process gas. A limitation of the hydrogen portion in the process gas mixture is furthermore also recommended for safety reasons because higher hydrogen percentages can facilitate ignition. Preferably a binary mixture of helium or neon and hydrogen or particularly preferred a ternary, quaternary or higher gas mixture comprising preferably hydrogen and helium and/or neon is used. Pursuant to the invention, the process gas contains one or more of the noble gas components helium, argon and neon. Helium dilutes and thus controls the plasma the best because with helium the plasma formation occurs not until temperatures between 15,000° C. and 20,000° C. are reached. The less expensive argon has a lesser effect than helium with respect of the plasma. Argon can be employed especially for highly reactive metals such as titanium or titanium-stabilized steels. Neon is between helium and argon in its physical and chemical properties. The process gas can contain especially 5 to 75% by volume, preferably 15 to 50% by volume, particularly preferred 20 to 35% by volume helium. Benefits during laser beam welding however can also be achieved when the process gas contains especially 10 to 80% by volume, preferably 20 to 60% by volume, particularly preferred 25 to 45% by volume neon. Process gas mixtures containing helium and neon are also suitable. The process gas can here have an overall portion of helium and neon of 5 to 80% by volume, preferably 15 to 60% by volume, particularly preferred 20 to 45% by volume. Beneficially the process gas can contain nitrogen. The likewise inexpensive nitrogen has an effect comparable to argon regarding plasma control. However the use of nitrogen-containing process gas mixtures should be avoided when welding highly reactive metals such as titanium or titanium-stabilized steels because it can lead to nitrite formation. It has been found that an optimization with respect to the various objectives of the process gas can be achieved excellently through the composition of the process gas mixtures. In the designs of the invention ternary or quaternary process gas mixtures are recommended due to their excellent suitability for laser beam welding. The ternary process gas mixture can here be composed of Helium, hydrogen and nitrogen, Helium, hydrogen and argon, Neon, hydrogen and nitrogen or Neon, hydrogen and argon. The quaternary process gas mixture can here be composed in particular of Helium, neon, hydrogen and nitrogen, or Helium, neon, hydrogen and argon. Pursuant to the invention beneficially ternary or quaternary process gas mixtures with 20 to 50% by volume helium and/or neon, 50 vpm (0.005% by volume) to 15.0% by volume hydrogen and the remainder being argon or 20 to 50% by volume helium and/or neon, 50 vpm (0.005% by volume) to 15.0% by volume hydrogen and the remainder being nitrogen can be used. In the above-listed ternary and quaternary mixtures, the hydrogen portion can also be between 0.01 and 5.0% by volume or even between 0.5 and 4.5% by volume. For laser beam welding austenitic steels, pursuant to the invention the use of a process gas mixture is recommended that consists of helium and/or neon and additionally nitrogen. For laser beam welding titanium or titanium-stabilized steels, pursuant to the invention the use of a process gas mixture is recommended that contains helium and/or neon and additionally hydrogen and argon. When laser beam welding austenitic steels, titanium or titanium-stabilized steels the helium portion in ternary mixtures is preferably around 25% by volume. With a partial or complete substitution of helium with neon, the percentage used should be accordingly higher than the helium portion. The process gas mixtures described above can be used beneficially in a method for laser beam welding, especially for welding high-grade steels or titanium or titanium-stabilized steels. A focused laser beam is directed at the workpiece surface that is to be machined and at least one process gas flow is directed against the workpiece surface via at least one nozzle that is arranged coaxially or at an angle to the laser beam axis. A focused laser beam within the framework of the invention should be interpreted as a laser beam that is substantially focused on the workpiece surface. Apart from the primarily employed method with laser radiation that is focused on the workpiece surface, the invention can also be applied to the rarely used variation with radiation that is not exactly focused on the workpiece surface. The invention is in principle not limited to the use of special types of lasers. For the laser beam welding process above all CO 2 lasers or Nd:YAG lasers are suitable. detailed-description description="Detailed Description" end="tail"? |
Gene involved in v(d)j recombination and/or dna repair |
The invention related to a new gene and protein involved in V(D)J recombination and/or DNA repair. The invention also relates to methods of diagnosis and therapy using these gene and protein. The invention also relates to transgenic animals over- or under-expressing said gene. |
1. An isolated nucleic acid molecule selected from the group consisting of: a) SEQ ID No 1, nucleotides 39-2114 of SEQ ID No 1, or nucleotides 60-2114 of SEQ ID No 1 and b) an isolated and purified nucleic acid comprising the nucleic acid of a). 2. A vector comprising the nucleic acid molecule of claim 1. 3. A host cell comprising the vector of claim 2. 4. A process of producing a protein involved in V(D)J recombination and/or DNA repair comprising the steps of: a) expressing the nucleic acid molecule of claim 1 in a suitable host to synthesize a protein involved in V(D)J recombination and/or DNA repair and b) isolating the protein involved in V(D)J recombination and/or DNA repair. 5. An isolated nucleic acid molecule that is the complement of the isolated nucleic acid molecule of claim 1. 6. An isolated protein or peptide coded by the nucleic acid of claim 1. 7. A monoclonal or polyclonal antibody that specifically recognizes the protein or peptide of claim 6. 8. A method for the determination of the type of SCID in a patient comprising the step of analyzing the nucleic acid chosen in the group consisting of SEQ ID No 1, nucleotides 39-2114, 60-2114, 39-1193, and 60-1193 of SEQ ID No 1 in said patient, a mutation in said nucleic acid allowing the classification of said SCID as radiosensible SCID. 9. A method of diagnosis in a patient, including a prenatal diagnosis, of a condition chosen in the group consisting of a SCID, a predisposition to cancer, a immune deficiency, and the carriage of a mutation increasing the risk of progeny to have such a disease, comprising the step of analyzing the nucleic acid chosen in the group consisting of SEQ ID No 1, nucleotides 39-2114, 60-2114, 39-1193, and 60-1193 of SEQ ID No I, and/or the protein coded by said nucleic acid in said patient, a mutation in said nucleic acid and/or protein indicating a increased risk of having a SCID. 10. A method of identification of a compound capable of binding to the nucleic acid of claim 1 or 5, or to the protein of claim 6, comprising the steps of a) contacting said nucleic acid or protein with a candidate compound, and b) determining the binding between said candidate compound and said nucleic acid or protein. 11. A compound identified by the method of claim 10. 12. The compound of claim 11, wherein said compounds binds to the β-lactamase region of the protein of claim 6. 13. One of the nucleic acid of claim 1 or 5, the vector of claim 2, the host cell of claim 3, the protein of claim 6, the antibody of claim 7, and the compound of claim 11, as a medicament. 14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient with at least one of the nucleic acid of claim 1 or 5, the vector of claim 2, the host cell of claim 3, the protein of claim 6, the antibody of claim 7, and the compound of claim 11. 15. A method for the therapy of a severe combined immunodeficiency (SCID), comprising administering to a subject at least one of the nucleic acid of claim 1 or 5, the vector of claim 2, the host cell of claim 3, the protein of claim 6, the antibody of claim 7, the compound of claim 11 and the pharmaceutical composition of claim 14. 16. A method for the therapy of cancer in a patient, comprising administering to said patient at least one of the nucleic acid of claim 1 or 5, the vector of claim 2, the host cell of claim 3, the protein of claim 6, the antibody of claim 7, the compound of claim 11 and the pharmaceutical composition of claim 14, preferably in addition with a genotoxic agent, the use being simultaneous, separate or sequential. 17. A method of biotherapy in a patient comprising administering to said patient at least one of the nucleic acid of claim 1 or 5, the vector of claim 2, the host cell of claim 3, the protein of claim 6, the antibody of claim 7, the compound of claim 11 and the pharmaceutical composition of claim 14. 18. A transgenic non-human mammal having integrated into its genome the nucleic acid sequence of claim 1, operatively linked to regulatory elements, wherein expression of said coding sequence increases the level of the ARTEMIS protein and/or the level of V(D)J recombination and/or DNA repair of said mammal relative to a non-transgenic mammal of the same species. 19. A transgenic non-human mammal whose genome comprises a disruption of the endogenous ARTEMIS gene, wherein said disruption comprises the insertion of a selectable marker sequence, and wherein said disruption results in said non-human mammal exhibiting a defect in V(D)J recombination and/or DNA repair as compared to a wild-type non-human mammal. 20. The transgenic mammal of claim 19, wherein said disruption is a homozygous disruption. 21. The transgenic mammal of claim 20, wherein said homozygous disruption results in a null mutation of the endogenous gene encoding ARTEMIS. 22. The mammal of claim 18 or 19 which is a mouse. 23. An isolated nucleic acid comprising an ARTEMIS knockout construct comprising a selectable marker sequence flanked by DNA sequences homologous to the endogenous ARTEMIS gene, wherein when said construct is introduced into a non-human mammal or an ancestor of said non-human mammal at an embryonic stage, said selectable marker sequence disrupts the endogenous ARTEMIS gene in the genome of said non-human mammal such that said non-human mammal exhibits a defect in V(D)J recombination and/or DNA repair as compared to a wild type non-human mammal. 24. A vector comprising the nucleic acid of claim 23. 25. A mammalian host cell whose genome comprises a disruption of the endogenous ARTEMIS gene, wherein said disruption comprises the insertion of a selectable marker sequence. 26. A method of screening compounds that modulate V(D)J recombination and/or DNA repair comprising contacting a compound with the non-human mammal of claim 19 or the host cell of claim 25, and determining the increase or decrease of V(D)J recombination and/or DNA repair into said non-human mammal or said host cell as compared to the V(D)J recombination and/or DNA repair of said non-human mammal or said host cell prior to the administration of the compound. 27. A method of testing the genotoxicity of compounds comprising contacting a compound with the non-human mammal of claim 19 or the host cell of claim 25, and determining the increase or decrease of V(D)J recombination and/or DNA repair into said non-human mammal or said host cell as compared to the V(D)J recombination and/or DNA repair of said non-human mammal or said host cell prior to the administration of the compound. 28. A method of modulation of the expression and/or activity of the protein ARTEMIS in a cell, comprising contacting said cell with at least a compound selected in the group consisting of the nucleic acid of claim 1 or 5, the vector of claim 2, the host cell of claim 3, the protein of claim 6, the antibody of claim 7, the compound of claim 11 and the pharmaceutical composition of claim 13. 29. A non human transgenic mammal whose genome comprises a first disruption that is of the endogenous ARTEMIS gene, and a second disruption that is of the endogenous p53 gene. 30. The transgenic mammal of claim 29, wherein at least said first disruption or said second disruption is an homozygous disruption. 31. The transgenic mammal of claim 29, wherein said first disruption and said second disruption are homozygous disruptions. 32. The transgenic mammal of claim 29, which is a mouse. 33. A method for providing a model for studying pro-B cell lymphomas, comprising providing the transgenic mammal of claim 31 to a person in need of such model for studying pro-B cell lymphomas. 34. The acid nucleic of claim 1, wherein said acid nucleic comprises nucleotides 39-1193 or nucleotides 60-1193 of SEQ ID No 1. |
<SOH> BACKGROUND OF THE INVENTION <EOH>B and T lymphocytes recognize foreign antigen through specialized receptors: the immunoglobulins and the T cell receptor (TCR) respectively. The highly polymorphic antigen-recognition regions of these receptors are composed of variable (V), diversity (D), and joining (J) gene segments which undergo somatic rearrangement prior to their expression by a mechanism known as V(D)J recombination (Tonegawa, 1983). Each V, D, and J segment is flanked by Recombination Signal Sequences (RSSs) composed of conserved heptamers and nonamers separated by random sequences of either 12 or 23 nucleotides. RSSs serve as recognition sequences for the V(D)J Recombinase. V(D)J recombination can be roughly divided into three steps. The RAG1 and RAG2 proteins initiate the rearrangement process through the recognition of the RSS and the introduction of a DNA double strand break (dsb) at the border of the heptamer (Schatz et al., 1989; Oettinger, 1990). RAG1 and RAG2 are the sole two factors required to catalyze DNA cleavage in cell-free systems (McBlane et al., 1995; Van Gent et al., 1995; Eastman et al., 1996) in a reaction reminiscent of retroviral integration and transposition (van Gent et al., 1996; Roth and Craig, 1998). Three acidic residues, DDE, were shown to compose the active site carried by RAG1 (Kim et al., 1999; Landree et al., 1999; Fugmann et al., 2000). The restricted expression of both RAG1 and RAG2 genes to immature B and T lymphocytes confines V(D)J recombination to the lymphoid lineage. At the end of this phase, which causes a DNA damage, the chromosomal DNA is left with two hairpin-sealed coding ends (CE), while the RSSs and the DNA intervening sequences are excised from the chromosome as blunt, phosphorylated signal ends (SE) (Roth et al., 1992; Schlissel et al., 1993; Zhu and Roth, 1995). The subsequent step consists in recognition and signaling of the DNA damage to the DNA repair machinery. From now on, ubiquitous enzymatic activities are involved. The description of the murine scid situation, characterized by a lack of circulating mature B and T lymphocytes (Bosma et al., 1983), as a general DNA repair defect accompanied by an increased sensitivity to ionizing radiation or other agents causing DNA dsb provided the link between V(D)J recombination and DNA dsb repair (Fulop, 1990; Biedermann, 1991; Hendrickson, 1991). This was further confirmed by the analysis of Chinese ovary cell lines (CHO), initially selected on the basis of their defect in DNA repair, which turned out to have impaired V(D)J recombination in vitro (Taccioli et al., 1993). This led to the description of the Ku70/Ku80/DNA-PKcs complex as a DNA damage sensor (review in (Jackson and Jeggo, 1995)). Briefly, DNA-PKcs is a DNA-dependant protein kinase that belongs to the Phosphoinositol (PI) kinase family, which is recruited at the site of the DNA lesion through the interaction with the regulatory complex Ku70/80 that binds to DNA ends (Gottlieb and Jackson, 1993). Cells from scid mice lack DNA-PK activity owing to a mutation in the DNA-PKcs encoding gene (Blunt et al., 1996; Danska et al., 1996). This severely compromises the V(D)J recombination process, ultimately leading to an arrest in both B and T cell development. More recently, two other proteins, NBS1 and γ-H2AX, have been identified on the site of chromosomal rearrangement in the TCR-α locus in thymocytes (Chen et al., 2000). NBS 1, which is mutated in the Nijmegen breakage syndrome, participates in the formation of the RAD50/MRE11/NBS1 complex involved in DNA repair (Carney et al., 1998; Varon et al., 1998). γ-H2AX represents the phosphorylated form of histone H2A in response to external damage and is considered as an important sensor of DNA damage (Rogakou et al., 1998; Rogakou et al., 1999; Paull et al., 2000). The biological implication of this observation is not yet fully understood, but it indicates that the RAD50/MRE11/NBS1 complex may cooperate with the DNA-PK complex in sensing and signaling the RAG1/2-mediated DNA dsb to the cellular DNA repair machinery. In the final phase of the V(D)J rearrangement, the DNA-repair machinery per se will ensure the re-ligation of the two chromosomal broken ends. This last step resembles the well-known DNA non-homologous end joining (NHEJ) pathway in the yeast Sacchaomyces cerevisiae (review in (Haber, 2000)) and involves the XRCC4 (Li et al., 1995) and the DNA-Ligase IV (Robins and Lindahl, 1996) factors. The crystal structure recently obtained for XRCC4 demonstrates the dumb-bell like conformation of this protein and provides a structural basis for its binding to DNA as well as its association with DNA-Ligase IV (Junop et al., 2000). All the animal models carrying a defective gene of either one of the known V(D)J recombination factors, either natural (murine and equine scid) or engineered through homologous recombination, have a profound defect in the lymphoid developmental program owing to an arrest of the B and T cell maturation at early stages (Mombaerts et al., 1992; Shinkai et al., 1992; Nussenzweig et al., 1996; Zhu et al., 1996; Jhappan et al., 1997; Shin et al., 1997; Barnes et al., 1998; Frank et al., 1998; Gao et al., 1998; Gao et al., 1998; Taccioli et al., 1998). In the cases of DNA-LigaseIV and XRCC4 this phenotype is also accompanied by an early embryonic lethality caused by massive apoptotic death of postmitotic neurons (Barnes et al., 1998; Frank et al., 1998; Gao et al., 1998). In humans, several immune deficiency conditions are characterized by faulty T and/or B cell developmental program (Fischer et al., 1997). In about 20% of the cases, the severe combined immunodeficiency (SCID) phenotype is caused by a complete absence of both circulating B and T lymphocytes, associated with a defect in the V(D)J recombination process, while Natural Killer (NK) cells are present. Mutations in either the RAG1 or RAG2 gene account for a subset of patients with this condition (Schwarz et al., 1996; Comeo et al., 2000; Villa et al., 2001). In some patients (RS-SCID), the T-B-SCID defect is not caused by RAG1 or RAG2 mutations and is accompanied by an increased sensitivity to ionizing radiations of both bone marrow cells (CFU-GMs) and primary skin fibroblasts (Cavazzana-Calvo et al., 1993), as well as a defect in V(D)J recombination in fibroblasts (Nicolas et al., 1998). Although this condition suggests that RS-SCID could have a general DNA-repair defect reminiscent of the murine scid situation, DNA-PK activity was found normal in these patients and the implication of the DNA-PKcs gene has been unequivocally ruled out by genetic means in several consanguineous families (Nicolas et al., 1996). A role for all the other known genes involved in V(D)J recombination/DNA repair was equally excluded as being responsible for RS-SCID condition (Nicolas et al., 1996). The gene defective in RS-SCID therefore encodes a yet undescribed factor. The inventors recently assigned the disease related locus to the short arm of human chromosome 10, in a 6.5 cM region delimited by two polymorphic markers D10S1664 and D10S674 (Moshous et al., 2000), a region shown to be linked to a similar SCID condition described in Athabascan speaking American Indians (A-SCID) (Hu et al., 1988; Li et al., 1998). |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to the identification and cloning of the Artemis gene, localized in this region of Chromosome 10. Artemis codes for a novel V(D)J recombination and/or DNA repair factor that belongs to the metallo β-lactamase superfamily and whose mutations give rise to the human RS-SCID condition. In particular, the present invention relates to an isolated nucleic acid molecule selected from the group consisting of: a) SEQ ID No 1, nucleotides 39-2114 of SEQ ID No 1, or nucleotides 60-2114 of SEQ ID No 1 b) an isolated and purified nucleic acid comprising the nucleic acid of a) c) an isolated nucleic acid that specifically hybridizes under (highly) stringent conditions to the complement of the nucleic acid of a) (under high stringency conditions of 0.2×SSC and 0.1% SDS at 55-65° C.), preferably wherein said nucleic acid encodes a protein that is involved in the V(D)J recombination and/or DNA repair d) an isolated nucleic acid having at least 80% homology with the nucleic acid of a), preferably over the full length of SEQ ID No 1, and preferably wherein said nucleic acid encodes a protein that is involved in the V(D)J recombination and/or DNA repair e) a fragment of the nucleic acid of a) comprising at least 15 nucleotides, with the proviso that said fragment is not entirely comprised between nucleotides 158-609, 607-660, or 29-537 of SEQ ID No 1. The present invention also relates to the polypeptides coded by the nucleic acid of the invention and to different uses that can be made with the objects of the invention. |
Supporting base for a denture model and articulator which works in conjunction with the supporting base |
The invention relates to a base for a denture model and an articulator (15) for preparing dental prosthesis parts, such as cast inlay fillings, crowns, bridges, prosthetic dentures and the like, in which positive reproductions of teeth or rows of teeth can be fixed on a baseplate (1, 1a), guide elements comprising at least one dimensionally stable rail (5) and at least one row of pins (4) parallel thereto being formed on the baseplate (1, 1a) and forming corresponding guide surfaces at the tooth stumps during curing of a moulding material of the denture models. A particular embodiment of the articulator (15) is oriented not with respect to the temporomandibular joint, as to date, but with respect to the cusps of the teeth of the respective tooth models. |
1. Base for a denture model and articulator (15) for preparing dental prosthesis parts, such as cast inlay fillings, crowns, bridges, prosthetic dentures and the like, in which positive reproductions of teeth or rows of teeth can be fixed on a dimensionally stable baseplate (1, 1a), guide elements (3, 4, 5) being provided on the baseplate (1, 1a) and the articulator (15) having a bottom (10) and a flap (11), each for receiving a baseplate (1, 1a), and the flap (11) being movable relative to the bottom (10) and connected via a pivot axle (7), characterized in that, as guide elements, at least one dimensionally stable rail (5) and at least one row of pins (4) parallel thereto are firmly connected to the baseplate (1, 1a) and form corresponding guide surfaces at the tooth stumps during curing of the moulding material of the denture models. 2. Base according to claim 1, characterized in that a displaceable or removable guide jacket (3) is provided as an additional guide element on the sidewalls (2) of the baseplate (1, 1a). 3. Base according to claim 1, characterized in that the guide jacket is produced from a plastic having low surface adhesion or surface roughness, preferably from a plastic such as, for example, Teflon® or the like. 4. Base according to claim 1, characterized in that at least two rows of pins (4), which are preferably arranged in gaps, are provided. 5. Base according to claim 1, characterized in that the baseplate (1) is produced from metal, in particular aluminium, and that the rail (5) is formed integrally with the plate. 6. Base according to claim 5, characterized in that the at least one rail (5) is in the form of a groove or in the form of a rib. 7. Base according to claim 1, characterized in that the baseplate (1, 1a) can be connected to the bottom (10) or to the flap (11) by means of a magnetic holder. 8. Base with articulator (15) according to claim 1, characterized in that the flap (11) is removably connected to the bottom (10) via a pivot axle (7). 9. Base according to claim 8, characterized in that the flap (11) is displaceable relative to the pivot axle (7) and can be locked on the latter. 10. Base according to claim 8, characterized in that at least one lateral path (8), the shape of which is preferably tailored to the tooth cusps of the denture model, is coordinated with the pivot axle (7) in a component fixed to the bottom. 11. Base according to claim 8, characterized in that the ends of the pivot axle (7) which each rest against a lateral path (8) are spherical. 12. Base according to claim 8, characterized in that the pivot axle (7) can be locked in the lateral paths (8) by means of catch member (9). 13. Base according to claim 1, characterized in that the lateral path (8a) is adjustable in height relative to the bottom (10). 14. Base according to claim 1, characterized in that the lateral path (8a) is spherical. 15. Base according to claim 1, characterized in that the lateral path (8a) is replaced by a rubber-mounted bearing (19) or bearing (19) mounted using a material having similar properties. 16. Base according to claim 1, characterized in that the bearing (19) is installed in an interchangeable component (20) which has a fixed bearing (21) at its other end, either the rubber-mounted bearing (19) or the fixed bearing (21) being capable of being made to engage the pivot axle (7a). 17. Base according to claim 1, characterized in that the interchangeable component (20) can be locked by means of a lock (22), preferably having a bayonet socket. 18. Base according to claim 1, characterized in that the bearing (19) has two planar clamping surfaces. 19. Base according to claim 1, characterized in that the columns (6) can be displaceably positioned in the perpendicular and/or the horizontal direction. 20. Base according to claim 1, characterized in that the baseplate (1, 1a) is coloured or black in order to permit good contrast with moulding material residues. 21. Base according to claim 1, characterized in that a support device (13) which is approximately C-shaped or has a bulge is provided, so that the path for operability of the baseplate (1, 1a) is free, in particular on the incisal side. 22. Base according to claim 1, characterized in that a support device (13) which can be adjustably positioned as desired on a central axle of the articulator (15) to the left or right or along an extension of the central axle of the articulator (15) and can be laterally rotated is provided. 23. Base according to claim 1, characterized in that a support device (13) which can be fastened both in the bottom (10) and optionally in the flap (11) is provided. 24. Base according to claim 1, characterized in that a support device (13) which can be fastened both on the underside and on the top of the flap (11) is provided. 25. Base according to claim 1, characterized in that a support device (13) which can be fastened on the top of the flap (11) is provided, so that the swivelled-back flap (11) can be supported in an approximately horizontal or horizontal position. 26. Base according to claim 1, characterized in that the support device (13) can be inserted into a recess (16a) in the bottom (10) or into one of the recesses (16b, c) in the flap (11), and that the support device (13) is preferably secured by means of an O-ring of nonslip material to prevent it from falling out accidentally. 27. Base according to claim 1, characterized in that the support device (13) is provided in the form of an incisal metal pin (17) whose end with which it is supported on the bottom (10) is provided with a plastic tip (18). 28. Base according to claim 1, characterized in that the support device (13) is adjustable in height. |
Data referencing system |
This application describes a method of referencing content in an application. The method comprises, for a content element, creating a reference to the content element and associating that reference with the content element. This enables the content (for example, text or images) to be dissociated from other features related to content; for example, its presentation on the screen. In this way, control over presentation may be achieved separately from control of the content itself. In an example, a Content Provider 402 provides referenced content to an Operator 404. A Programme Provider 400 sends referenced scenarios to the Operator 404. The Operator 404 resolves the reference and sends data for broadcast by the Broadcaster 406. |
1-90. (Canceled) 91. A method of preparing a received content element for presentation, comprising: receiving data including a content element, reviewing the received data to identify a reference associated with the content element, and using the reference to determine the presentation configuration for the content element. 92. A method according to claim 91, comprising using the reference to determine the location of the content element in the received data. 93. A method according to claim 91, further including the step of using the reference to identify a container for the content element. 94. A method according to claim 93, wherein the container contains the presentation configuration criteria for the content element. 95. A method according to claim 93, further comprising determining the number of containers required for presenting the content element. 96. A method according to claim 91, comprising the step of associating the content element with a container. 97. A method according to claim 96, wherein said associating step comprises: reading a logical reference element of the container, recovering the content element in the received data corresponding to the logical reference element, and linking the content element with the container. 98. A method according to claim 91, further comprising converting the content element in the container into a broadcastable form. 99. A method according to claim 97, further comprising reviewing the received data to identify the size of the content element and comparing the content element size with the predetermined maximum size for presentation of the content element. 100. A method according to claim 99, further comprising: identifying that the size of the content element is larger than the predetermined maximum size for presentation of the content element, identifying an excess portion of the content element being in excess of the predetermined maximum size of presentation, and preparing the excess portion for presentation. 101. A method according to claim 100, wherein preparing the excess portion for presentation includes linking the excess portion with a further container. 102. A method according to claim 91, further comprising sending the data for broadcast. 103. A method of determining the presentation of content, the method comprising: receiving the content to be presented, identifying a presentation criterion, analyzing the content with respect to the presentation criterion, and determining the presentation of the content. 104. A method according to claim 103, further comprising: receiving updated content, analyzing the content, and determining a presentation of the updated content. 105. Apparatus for preparing a received content element for presentation, comprising: means for receiving data including a content element, means for reviewing the received data to identify a reference associated with the content element, and means for using the reference to determine the presentation configuration for the content element. 106. Apparatus according to claim 105, comprising means for using the reference to determine the location of the content element in the received data. 107. Apparatus according to claim 105, further including a container for the content element, the container being associated with the reference for the content element. 108. Apparatus according to claim 107, wherein the container contains the presentation configuration criteria for the content element. 109. Apparatus according to claim 105, further comprising means for determining the number of containers required for presenting the content element. 110. Apparatus according to claim 105, comprising means for associating the content element with a container. 111. Apparatus according to claim 110, wherein said associating means comprises: means for reading a logical reference element of the container, means for recovering the content element in the received data corresponding to the logical reference element, and means for linking the content element with the container. 112. Apparatus according to claim 105, further comprising means for converting the content element in the container into a broadcastable form. 113. Apparatus according to claim 111, further comprising means for reviewing the received data to identify the size of the content element and means for preparing the content element size with the predetermined maximum size for presentation of the content element. 114. Apparatus according to claim 113, further comprising: means for identifying that the size of the content element is larger than the predetermined maximum size for presentation of the content element, means for identifying an excess portion of the content element being in excess of the predetermined maximum size of presentation, and means for preparing the excess portion for presentation. 115. Apparatus according to claim 114, wherein the means for preparing the excess portion for presentation includes means for linking the excess portion with a further container. 116. Apparatus according to claim 105, further comprising means for sending the data for broadcast. 117. Apparatus of determining the presentation of content, the apparatus comprising: means for receiving the content to be presented, means for identifying a presentation criterion, means for analyzing the content with respect to the presentation criterion, and means for determining the presentation of the content. 118. A computer program product comprising code for preparing a received content element for presentation, comprising: receiving data including a content element, reviewing the received data to identify a reference associated with the content element, and using the reference to determine the presentation configuration for the content element. 119. A computer program product according to claim 118, further comprising code for using the reference to determine the location of the content element in the received data. 120. A computer program product according to claim 118, further comprising code for using the reference to identify a container for the content element. 121. A computer program product according to claim 120, wherein the container contains the presentation configuration criteria for the content element. 122. A computer program product according to claim 120, further comprising code for determining the number of containers required for presenting the content element. 123. A computer program product according to claim 118, further comprising code for associating the content element with a container. 124. A computer program product according to claim 123, further comprising code for: reading a logical reference element of the container, recovering the content element in the received data corresponding to the logical reference element, and linking the content element with the container. 125. A computer program product according to claim 124, further comprising code for converting the content element in the container into a broadcastable form. 126. A computer program product according to claim 125, further comprising code for reviewing the received data to identify the size of the content element, and comparing the content element size with the predetermined maximum size for presentation of the content element. 127. A computer program product according to claim 126, further comprising code for: identifying that the size of the content element is larger than the predetermined maximum size for presentation of the content element, identifying an excess portion of the content element being in excess of the predetermined maximum size of presentation, and preparing the excess portion for presentation. 128. A computer program product according to claim 127, wherein preparing the excess portion for presentation includes linking the excess portion with a further container. 129. A computer program product according to claim 118, further comprising code for sending the data for broadcast. 130. A computer program product comprising code for determining the presentation of content, the method comprising: receiving the content to be presented, identifying a presentation criterion, analyzing the content with respect to the presentation criterion, and determining the presentation of the content. |
Method and apparatus for endpoint detection using partial least squares |
An apparatus and method for detection of a feature etch completion within an etching reactor. The method includes determining a correlation matrix by recording first measured data regarding a first etch process over successive time intervals to form a first recorded data matrix, assembling a first endpoint signal matrix using target endpoint data for a specific etch process, performing a partial least squares analysis on the recorded data matrix and the first endpoint signal matrix to refine the recorded data matrix, and computing a correlation matrix based upon the refined recorded data matrix and the first endpoint signal matrix. The method further includes performing a second etch process to form a second recorded data matrix. The correlation matrix and the second recorded data matrix are analyzed to determine whether an endpoint of the second etch process has been achieved. |
1. A method for detection of a feature etch completion, the method comprising the steps of: determining a correlation matrix by: recording first measured data regarding a first etch process over successive time intervals to form a first recorded data matrix, assembling a first endpoint signal matrix using target endpoint data for a specific etch process, performing a partial least squares analysis on the first recorded data matrix and the first endpoint signal matrix to refine the first recorded data matrix, and computing a correlation matrix based upon the refined recorded data matrix and the first endpoint signal matrix; and performing a second etch process to form a second recorded data matrix, wherein the correlation matrix and the second recorded data matrix are analyzed to determine whether an endpoint of the second etch process has been achieved. 2. The method according to claim 1, wherein said step of performing a partial least squares analysis includes the steps of: calculating variable importance in projection data defined as an influence on the first endpoint signal matrix of the first measured data; and refining the first recorded data matrix based upon an analysis of the variable importance in projection data. 3. The method according to claim 2, wherein the step of refining the first recorded data matrix comprises analyzing the variable importance in projection data to determine if a variable within the first recorded data matrix can be eliminated as having minimal impact on the first endpoint signal matrix. 4. The method according to claim 3, wherein the variable having a variable importance in projection data value below a predetermined threshold value is discarded. 5. The method according to claim 3, wherein the variable having a variable importance in projection data value within a predetermined range is discarded. 6. The method according to claim 3, wherein at least a first derivative of a variable importance in projection data value with respect to a variable number is used to select a threshold value for the variable importance in projection data below which the variable is discarded. 7. The method according to claim 1, wherein said step of performing a second etch process comprises the steps of: initiating the second etch process within a processing chamber; recording second measured data regarding the second etch process over successive time intervals to form the second recorded data matrix of at least one recorded data vector; calculating at least one endpoint signal by multiplying the at least one recorded data vector and at least one weighting vector of the correlation matrix; determining whether the endpoint has been achieved by inspecting the at least one end point signal; and stopping the etch process when the endpoint has been achieved. 8. The method according to claim 1, wherein the first etch process and the second etch process are performed within a single processing chamber. 9. The method according to claim 1, wherein the correlation matrix is calculated for a selected etch process performed within a selected processing chamber. 10. The method according to claim 1, wherein the target data is determined by experimentation within a selected processing chamber, and wherein the selected processing chamber is utilized for the second etch process. 11. The method according to claim 1, wherein the measured data is optical emission data. 12. The method according to claim 1, wherein the measured data is electrical signal data. 13. The method according to claim 1, wherein the measured data is match network capacitor setting data. 14. The method according to claim 1, wherein the first recorded data matrix, the first endpoint signal matrix, and the correlation matrix are defined by a relationship: {overscore (XB)}={overscore (Y)}, where {overscore (X)} represents the first recorded data matrix having m by n data points, {overscore (B)} represents the correlation matrix having n by p data points, and {overscore (Y)} represents the first endpoint signal matrix having m by p data points. 15. The method according to claim 1, wherein data of a given instant in time within the first recorded data matrix and the second recorded data matrix is mean-centered by computing a mean value of elements in a column of a respective matrix and subtracting the mean value from each element. 16. The method according to claim 1, wherein data of a given instant in time within the first recorded data matrix and the second recorded data matrix is normalized by determining a standard deviation of data in a column of a respective matrix. 17. An apparatus comprising: an etching reactor configured to perform an etch process therein, said etch process being driven by a power source connected to said etching reactor; an end-point detector for detecting an endpoint of said etching process, said end-point detector comprising a detecting section and a calculating section, said detecting section being configured to sequentially detect data relating to the etch process within said etching reactor, said calculating section being configured to determine a correlation matrix using first measured data regarding a first etch process over successive time intervals to form a first recorded data matrix, assemble a first endpoint signal matrix using target endpoint data for a specific etch process, perform a partial least squares analysis on the first recorded data matrix and the first endpoint signal matrix to refine the first recorded data matrix, compute a correlation matrix based upon the refined recorded data matrix and the first endpoint signal matrix, and form a second recorded data matrix for a second etch process, wherein said calculating section is configured to analyze the correlation matrix and the second recorded data matrix and produce an endpoint signal when an endpoint of the second etch-process has been achieved; and a controller configured to receive said endpoint signal from said calculating section, said controller being configured to control said power source based upon said endpoint signal. 18. The apparatus according to claim 17, wherein said detecting section comprises a photodetector configured to sequentially detect an emission spectrum within said etching reactor. 19. The apparatus according to claim 18, wherein said photodetector section comprises a high resolution optical emission spectroscopy sensor. 20. The apparatus according to claim 18, wherein said etching reactor includes a vacuum chamber having a view window made of transparent material throughwhich said detecting section detects the emission spectrum. 21. The apparatus according to claim 17, wherein said etching reactor is a capacitively coupled plasma reactor including a vacuum chamber, a pair of parallel plate electrodes provided within said vacuum chamber, a gas injection line connected to said vacuum chamber, and a gas exhaust line connected to said vacuum chamber, wherein said power source is a high frequency power source connected to one of said pair of parallel plate electrodes. 22. The apparatus according to claim 17, wherein said etching reactor is selected from a group consisting essentially of a multi-frequency capacitively coupled plasma reactor, an inductively coupled plasma reactor, an electron cyclotron resonance reactor, and a helicon plasma reactor. 23. The apparatus according to claim 17, wherein said calculating section is configured to calculate variable importance in projection data defined as an influence on the first endpoint signal matrix of the first measured data, and refine the first recorded data matrix based upon an analysis of the variable importance in projection data. 24. The apparatus according to claim 23, wherein said calculating section is configured to refine the first recorded data matrix by analyzing the variable importance in projection data to determine if a variable within the first recorded data matrix can be eliminated as having minimal impact on the first endpoint signal matrix. 25. The apparatus according to claim 17, wherein said detecting section is configured to sequentially detect electrical signal data relating to the etch process within said etching reactor. 26. The apparatus according to claim 17, wherein said detecting section is configured to sequentially detect match network capacitor setting data relating to the etch process within said etching reactor. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates generally to endpoint detection during semiconductor manufacturing. 2. Discussion of the Background The inventors have identified problems with conventional processing reactors and methods of using those reactors that are solved by the present invention. Typically, during semiconductor processing, a (dry) plasma etch process is utilized to remove or etch material along fine lines or within vias or contacts patterned on a silicon substrate. The plasma etch process generally involves positioning a semiconductor substrate with an overlying patterned, protective layer, for example a photoresist layer, into a processing chamber. Once the substrate is positioned within the chamber, an ionizable, dissociative gas mixture is introduced within the chamber at a pre-specified flow rate, while a vacuum pump is throttled to achieve an ambient process pressure. Thereafter, a plasma is formed when a fraction of the gas species present are ionized by electrons heated via the transfer of radio frequency (RF) power either inductively or capacitively, or microwave power using, for example, electron cyclotron resonance (ECR). Moreover, the heated electrons serve to dissociate some species of the ambient gas species and create reactant specie(s) suitable for the exposed surface etch chemistry. Once the plasma is formed, any exposed surfaces of the substrate are etched by the plasma. The process is adjusted to achieve optimal conditions, including an appropriate concentration of desirable reactant and ion populations to etch various features (e.g., trenches, vias, contacts, etc.) in the exposed regions of substrate. Such substrate materials where etching is required include silicon dioxide (SiO2), poly-silicon and silicon nitride. As the feature size shrinks and the number and complexity of the etch process steps used during integrated circuit (IC) fabrication escalate, the requirements for tight process control become more stringent. Consequently, real time monitoring and control of such processes becomes increasingly important in the manufacture of semiconductor ICs. For example, one such monitoring and control diagnostic necessary for the timely completion of an etch step or process is endpoint detection. Endpoint detection refers to the control of an etch step and, in particular, to the detection of the feature etch completion or the exact instant in time when the etch front reaches the etch stop layer. If the etch process endpoint is improperly detected, then severe under-cutting of the feature may occur due to over-etching or partially complete features may result due to underetching. As a result, poor endpoint detection could lead to devices of poor quality that are subject to increased risk of failure. Therefore, the accurate and precise completion of an etch process is an important area for concern during the manufacturing process. One approach used for endpoint detection is to monitor the emission intensity of light at a pre-specified wavelength in time using optical emission spectroscopy (OES). Such a method might identify a wavelength corresponding to a chemical species present in the etch process that shows a pronounced transition at the etch process endpoint. Subsequently, a resultant signal is analyzed to detect distinct variations in the emission intensity which, and the analysis of the resulting signal is then used to correlate with the completion of an etch process. Typically, the species selected corresponds to a reactive species or a volatile etch product. For example, the selected wavelength may correspond to CO* emission when etching SiO 2 and polymer films, N 2 * or CN* emission when etching nitride films, SiF* emission when etching poly-silicon and AMCl* emission when etching aluminum. In addition to the approach of monitoring the emission intensity at a single wavelength as described above, another approach is to monitor the light intensity at two wavelengths and record the ratio (or some mathematical manipulation thereof) of the two intensities. For instance, one wavelength is chosen for a specie whose concentration decays at an endpoint and a second wavelength is chosen for a specie whose concentration increases at the endpoint. Therefore, the ratio gives improved signal to noise. However, as the IC device sizes have decreased, and the exposed open areas have correspondingly decreased, single and dual wavelength endpoint detection schemes have found limited use due to their reduced robustness for extracting a low signal-to-noise (SIN) endpoint signal from the process. Subsequently, process engineers have been presented with the formidable challenge of selecting the right wavelengths with sufficient robustness in a manufacturing environment and, as a result, more sophisticated endpoint detection schemes have arisen. The sophisticated endpoint detection schemes sample data at thousands of wavelengths (i.e. a broad emission spectrum is recorded at each instant in time during the etch process) and multivariate data analysis techniques such as Principal Component Analysis (PCA) are applied to extract the endpoint signal. In PCA, several techniques, including eigenvalue analysis, singular value decomposition (SVD), and nonlinear partial least-squares (NiPALS) have been employed to identify the principal directions in the multi-dimensional space, where the variance in the data scatter is greatest. The dimension of the multi-dimensional space is equivalent to the number of variables recorded, i.e. the number of discrete wavelengths of the emission intensity are recorded. And therefore, PCA will identify the directions in the multi-dimensional space where the variations in the emission intensity are greatest. In other words, the principal component acts as a series of weighting coefficients for each variable. Typically, the first three or four principal components (corresponding to the three or four largest eigenvalues) are selected and employed for deriving the three or four endpoint signals from the newly recorded data. However, a shortcoming of the use of PCA for multivariate analysis of optical emission data includes the mathematical rigor and complexity such an analysis entails, and, more importantly, the lack of use of physical criteria associated with the etch process to extract a reduced set of data including the endpoint signal(s). Therefore, what is needed is an improved apparatus and method for endpoint detection which overcomes the shortcomings identified above. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, the present invention advantageously provides an apparatus and a method for improved detection of a feature etch completion. An embodiment of the present invention advantageously provides a method including the steps of determining a correlation matrix by recording first measured data regarding a first etch process over successive time intervals to form a first recorded data matrix, assembling a first endpoint signal matrix using target endpoint data for a specific etch process, performing a partial least squares analysis on the first recorded data matrix and the first endpoint signal matrix to refine the first recorded data matrix, and computing a correlation matrix based upon the refined recorded data matrix and the first endpoint signal matrix. The method further includes performing a second etch process to form a second recorded data matrix, where the correlation matrix and the second recorded data matrix are analyzed to determine whether an endpoint of the second etch process has been achieved. The preferred embodiment of the method of the present invention is defined such that the step of performing a partial least squares analysis includes the steps of calculating variable importance in projection data defined as an influence on the first endpoint signal matrix of the first measured data, and refining the first recorded data matrix based upon an analysis of the variable importance in projection data. The step of refining the first recorded data matrix includes analyzing the variable importance in projection data to determine if a variable within the first recorded data matrix can be eliminated as having minimal impact on the first endpoint signal matrix. The variable used discarded during refinement can be defined as having a variable importance in projection data value below a predetermined threshold value, or within a predetermined range. Alternatively, the refinement can be defined such that at least a first derivative of a variable importance in projection data value with respect to a variable number is used to select a threshold value for the variable importance in projection data below which the variable is discarded. The preferred embodiment of the method is defined such that the step of performing a second etch process includes the steps of initiating the second etch process within a processing chamber, recording second measured data regarding the second etch process over successive time intervals to form the second recorded data matrix of at least one recorded data vector, calculating at least one endpoint signal by multiplying the at least one recorded data vector and at least one weighting vector of the correlation matrix, determining whether the endpoint has been achieved by inspecting the at least one end point signal, and stopping the etch process when the endpoint has been achieved. In the preferred embodiment, the first etch process and the second etch process are performed within a single processing chamber. The correlation matrix is preferably calculated for a selected etch process performed within a selected processing chamber. The target data is preferably determined by experimentation within a selected processing chamber, and the selected processing chamber is utilized for the second etch process. In the preferred embodiment, the measured data is optical emission data, however alternatively the measured data can be electrical signal data and/or match network capacitor setting data. In the preferred embodiment, the first recorded data matrix, the first endpoint signal matrix, and the correlation matrix are defined by a relationship: in-line-formulae description="In-line Formulae" end="lead"? {overscore (XB)}={overscore (Y)}, in-line-formulae description="In-line Formulae" end="tail"? where {overscore (X)} represents the first recorded data matrix having m by n data points, {overscore (B)} represents the correlation matrix having n by p data points, and {overscore (Y)} represents the first endpoint signal matrix having m by p data points. The data of a given instant in time within the first recorded data matrix and the second recorded data matrix is preferably mean-centered by computing a mean value of elements in a column of a respective matrix and subtracting the mean value from each element, or normalized by determining a standard deviation of data in a column of a respective matrix. An embodiment of the present invention advantageously provides an apparatus including an etching reactor configured to perform an etch process therein, where the etch process is driven by a power source connected to the etching reactor, and an end-point detector for detecting an endpoint of the etching process. The end-point detector includes a detecting section configured to sequentially detect data relating to the etch process within the etching reactor. The endpoint detector further includes a calculating section configured to determine a correlation matrix using first measured data regarding a first etch process over successive time intervals to form a first recorded data matrix, assemble a first endpoint signal matrix using target endpoint data for a specific etch process, perform a partial least squares analysis on the first recorded data matrix and the first endpoint signal matrix to refine the first recorded data matrix, compute a correlation matrix based upon the refined recorded data matrix and the first endpoint signal matrix, and form a second recorded data matrix for a second etch process. The calculating section is configured to analyze the correlation matrix and the second recorded data matrix and produce an endpoint signal when an endpoint of the second etch process has been achieved. The apparatus further includes a controller configured to receive the endpoint signal from the calculating section, and the controller is configured to control a drive of the power source based upon the endpoint signal. The preferred embodiment of the apparatus of the present invention is configured such that the detecting section includes a photodetector configured to sequentially detect an emission spectrum within the etching reactor. The photodetector section preferably includes a high resolution optical emission spectroscopy sensor. The etching reactor preferably includes a vacuum chamber having a view window made of transparent material throughwhich the detecting section detects the emission spectrum. The preferred etching reactor is a capacitively coupled plasma reactor including a vacuum chamber, a pair of parallel plate electrodes provided within the vacuum chamber, a gas injection line connected to the vacuum chamber, and a gas exhaust line connected to the vacuum chamber, wherein the power source is a high frequency power source connected to one of the pair of parallel plate electrodes. Alternatively, the etching reactor can be a multi-frequency capacitively coupled plasma reactor, an inductively coupled plasma reactor, an electron cyclotron resonance reactor, or a helicon plasma reactor. In the preferred embodiment, the calculating section is configured to calculate variable importance in projection data defined as an influence on the first endpoint signal matrix of the first measured data, and refine the first recorded data matrix based upon an analysis of the variable importance in projection data. The calculating section is preferably configured to refine the first recorded data matrix by analyzing the variable importance in projection data to determine if a variable within the first recorded data matrix can be eliminated as having minimal impact on the first endpoint signal matrix. In alternative embodiments, the detecting section is configured to sequentially detect electrical signal data and/or match network capacitor setting data relating to the etch process within the etching reactor. |
Agent for the prevention and treatment of sexually transmitted diseases-I |
Use of a polylysine, polyamidoamine or polypropylenimine dendrimer having naphthyl disulphonate terminal groups as a topically applied agent in prophylaxis or treatment of sexually transmitted diseases. |
1. A compound of the formula I, II or III: wherein R represents a group of the formula IV: or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein said pharmaceutically acceptable salt is selected from metallic salts such as the aluminium, calcium , lithium, magnesium, potassium, sodium and zinc salts, and organic salts with organic amines such as N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, ethylenediamine, dicyclohexylamine, meglumine (N-methylglucamine) and procaine, or quaternary amines such as choline, and sulphonium and phosphonium salts. 3. The compound SPL-7013 herein or a pharmaceutically acceptable salt thereof. 4. The compound SPL-7304 herein or a pharmaceutically acceptable salt thereof. 5. The compound SPL-7320 herein or a pharmaceutically acceptable salt thereof. 6. A topical pharmaceutical composition for prophylactic or therapeutic treatment of sexually transmitted diseases in a human patient, which comprises a compound according to claim 1, in association with at least one pharmaceutically acceptable, topical carrier or diluent. 7. A method for the prophylactic or therapeutic treatment of sexually transmitted diseases in a human patient, which comprises topical administration to the patient of an effective amount of a compound according to claim 1. 8. A method according to claim 7 wherein said disease is a vaginally or rectally sexually transmitted disease selected from HSV-1, HSV-2, HIV-1, HIV-2 and HPV infection, and Chlamydia trachomatis infection. 9. Use of a compound according to claim 1 in the manufacture of a medicament for topical administration in the prophylactic or therapeutic treatment of sexually transmitted diseases in a human patient. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The global incidence, morbidity, and mortality of sexually transmitted diseases (STDs) caused by HIV, HSV, and other viral and microbial pathogens is estimated at several hundred millions individuals worldwide. One approach for the control the transmission of STDs is the use of topically applied, female/male-controlled vaginal, or rectal microbicides that inactivate the relevant pathogens. Consequently, the development of new, safe, topical microbicides for intravaginal or intrarectal use for the prevention and treatment of STDs is an important target for novel drug development. International Patent Application Nos. PCT/AU95/00350 (WO 95/34595) and PCT/AU99/00763 (WO 00/15240), the contents of which are incorporated herein by reference, disclose a new class of polyvalent agents—the dendrimers, highly branched macromolecules with a definite envelope of polyanionic or cationic surface groups, which have been shown to exhibit a range of antiviral and antimicrobial activity with minimal toxicity. Unlike small molecular structures of most antivirals, these dendrimers are a class of polyvalent, highly branched macromolecular compounds formed by iterative reaction sequences starting from an initial core molecule with successive layers or stages being added in successive “generations” to build up a three-dimensional, highly ordered polymeric compound. Dendrimers are characterised by the following features: i. an initiator core which may have one or more reactive sites and be point-like or of significant size so as to effect the final topology of the dendrimer; ii. layers of branched repeating units attached to the initiator core; iii. functional terminal groups (such as anionic- or cationic-containing moieties) attached to the surface of the dendrimer, optionally through linking groups. These macromolecular compounds are synthesised from monomeric building blocks with multiple branches or tree-like structures, and the outside surface of the molecule carries a number of functional groups that lead to recognition by a biological receptor. The preparation of dendrimers is well known, and is described by way of example in U.S. Pat. Nos. 4,289,872 and 4,410,688 (describing dendrimers based on layers of lysine units), as well as U.S. Pat. Nos. 4,507,466, 4,558,120, 4,568,737 and 4,587,329 (describing dendrimers based on other units including polyamidoamine or PAMAM dendrimers). In antiviral and antimicrobial testing, a subset of these dendrimer structures have unexpectedly shown exceptional activity against a broad spectrum of microorganisms associated with sexually transmitted diseases, that makes them agents of choice for the development of a vaginal or rectal microbicide for the prophylaxis and treatment of sexually transmitted diseases. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the present invention, there is provided a compound of the formula I, II, or III: wherein R represents a group of the formula IV: or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts such as the aluminium, calcium, lithium, magnesium, potassium, sodium and zinc salts, as well as organic salts made from organic amines such as N,N′-dibenzyl-ethylenediamine, chloroprocaine, diethanolamine, ethylenediamine, dicyclohexylamine, meglumine (N-methylglucamine) and procaine, quaternary amines such as choline, and sulphonium and phosphonium salts. Particularly preferred compounds of the present invention are the compounds referred to herein as SPL-7013, SPL-7304 and SPL-7320 the structures of which consist of polylysine dendrimer, polyamidoamine (PAMAM) dendrimer, and polypropylenimine dendrimer scaffolds respectively with the active surface groups consisting of 32 naphthyl disulphonic acid groups as sodium salts. Each of the naphthyl-disulphonate functional surface groups is attached to the branched dendrimer scaffold with an amido-methyleneoxy linkage to the 32 terminal groups. The present invention also provides a topical pharmaceutical composition for prophylactic or therapeutic treatment of sexually transmitted diseases in a human patient, which comprises a compound of the formula I, II, or III above or a pharmaceutically acceptable salt thereof, in association with at least one pharmaceutically acceptable, topical carrier or diluent. In another aspect, the present invention also provides a method for the prophylactic or therapeutic treatment of sexually transmitted diseases in a human patient, which comprises topical administration to the patient of an effective amount of a compound of the formula I, II, or III above or a pharmaceutically acceptable salt thereof. In yet another aspect, the invention provides use of a compound of the formula I, II, or III above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for topical administration in the prophylactic or therapeutic treatment of sexually transmitted diseases in a human patient. detailed-description description="Detailed Description" end="lead"? |
Method of treating a part in order to alter at least one of the properties thereof |
Process for the treatment of a component, at least one zone to be treated of which located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, consisting: in placing the component (1) to be treated at a thermal energy level below said specified level (7); and in subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) generated by a particle emission means (3), this emission means being regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level. |
1. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, characterized in that it consists: in placing the component (1) to be treated at a thermal energy level below said specified level (7); and in subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) generated by a particle emission means (3), this emission means being regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level. 2. The process of claim 1, and choosing a power flux exclusively adapted for producing said thermal energy density. 3. The process of claim 1, in which said specified thermal energy level corresponds to a specified temperature. 4. The process of claim 1, in which said component is made of a single material or of several parts of different materials. 5. The process of claim 1, in which said component has a surface structure and/or a volume structure. 6. The process of claim 1, in which said power flux consists of a flux of particles such as electrons and/or protons and/or ions and/or atoms and/or molecules. 7. The process of claim 1, in which said power flux is formed by a flux of particles consisting or composed of elements of atomic number Z less than or equal to six, which are not dopants for the constituent material or materials of said component, in any one of their isotopic species, in any one of their molecular forms and in any ionization state, including the neutral state. 8. The process of claim 1, in which said particles are essentially monokinetic. 9. The process claim 1, and choosing a component whose zone to be treated includes impurities. 10. The process of claim 9, of which said impurities have a segregation coefficient, relative to the constituent material of at least said part to be treated, of less than one. 11. The process of claim 9, and performing a prior step of introducing said impurities into the material. 12. The process of claim 9, in which said step of introducing said impurities includes at least one epitaxial growth. 13. The process of claim 9, in which said impurities are introduced at least partly during application of said power flux. 14. The process of claim 1, in which the constituent material of at least said zone to be treated comprises silicon and in that at least said zone to be treated contains impurities chosen from aluminium and/or bismuth and/or gallium and/or indium and/or antimony and/or tin. 15. The process of claim 1, in which the constituent material of at least said zone to be treated comprises silicon-germanium. 16. The process of claim 1, and subjecting said component to a flux whose power is constant over time and the position of which varies with respect to the material so that a given region of the material sees the flux only for one or more time intervals corresponding to the duration of the desired pulses. 17. The process of claim 1, and in which the power flux is spatially constant with respect to the material to be treated and the intensity thereof is in the form of one or more pulses so as to vary the as a function of time. 18. The process of claim 1, and varying the position of the concentrated part of said power flux relative to said zone to be treated. 19. The process of claim 1, in which said power flux is chosen so as to produce a thermal energy density above the said specified thermal energy level corresponding to the liquefaction of the constituent material of said zone to be treated. 20. The process of claim 1, in which said power flux is chosen so as to produce a thermal energy density above the said specified thermal energy level having the effect of generating inclusions in the constituent material of said zone to be treated. 21. The process of claim 20, in which said inclusions are precipitates and/or bubbles and/or microbubbles and/or defects and/or changes of phase and/or of chemical composition and/or fractures and/or cavities. 22. The process of claim 1, in which said power flux is chosen so as to product a thermal energy density above the said specified thermal level having the effect of weakening said zone to be treated. 23. The process of claim 1, in which said power flux is chosen so as to produce a thermal energy density above the said specified thermal level having the effect of welding or brazing together two parts of said component that are in contact in said zone to be treated. 24. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level corresponding to a specified temperature level, consisting of: placing the component (1) to be treated at a temperature level below said specified temperature level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) generated by a particle emission means (3), and in which said emission means are regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified temperature level. 25. The process of claim 24, in which said power flux consists of a flux of particles such as electrons and/or protons and/or ions and/or atoms and/or molecules. 26. The process of claim 24, in which said power flux is formed by a flux of particles consisting or composed of elements of atomic number Z less than or equal to six, which are not dopants for the constituent material or materials of said component, in any one of their isotopic species, in any one of their molecular forms and in any ionization state, including the neutral state. 27. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, consisting of: placing the component (1) to be treated at a thermal energy level below said specified level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) chosen so as to produce a thermal energy density above the said specified thermal energy level corresponding to the liquefaction of the constituent material of said zone to be treated and generated by a particle emission means (3) consisting of a flux of particles such as electrons and/or protons and/or ions and/or atoms and/or molecules, and in which said emission means are regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level corresponding to the said liquefaction. 28. The process of claim 27, in which said particles are essentially monokinetic. 29. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, consisting of placing the component (1) to be treated at a thermal energy level below said specified level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) chosen so as to produce a thermal energy density above the said specified thermal energy level corresponding to the liquefaction of permitting to liquefy the constituent material of said zone to be treated and generated by a particle emission means (3), this emission means being regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level corresponding to the said liquefaction; and in which said power flux is formed by a flux of particles consisting or composed of elements of atomic number Z less than or equal to six, which are not dopants for the constituent material or materials of said component, in any one of their isotopic species, in any one of their molecular forms and in any ionization state, including the neutral state. 30. The process of claim 29, in which said particles are essentially monokinetic. 31. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, in which said component is chosen so as to includes at least in said zone impurities having a segregation coefficient, relative to the constituent material of at least said part to be treated, of less than one and consisting of placing the component (1) to be treated at a thermal energy level below said specified level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) chosen so as to produce a thermal energy density above the said specified thermal energy level corresponding to the liquefaction of the constituent material of said zone to be treated and generated by a particle emission means (3), this emission means being regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level corresponding to the said liquefaction. 32. The process of claim 31, in which the constituent material of at least said zone to be treated comprises silicon and in that at least said zone to be treated contains impurities chosen from aluminium and/or bismuth and/or gallium and/or indium and/or antimony and/or tin. 33. The process of claim 31, in which the constituent material of at least said zone to be treated comprises silicon-germanium. 34. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, consisting of placing the component (1) to be treated at a thermal energy level below said specified level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4)) chosen so as to produce a thermal energy density above the said specified thermal energy level corresponding to the liquefaction of the constituent material of said zone to be treated and generated by a particle emission means (3), in which this emission means are regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level corresponding to the said liquefaction; and in which the power flux is constant over time and the position of which varies with respect to the material so that a given region of the material sees the flux only for one or more time intervals corresponding to the duration of the desired pulses. 35. The process of claim 34, in which said power flux consists of a flux of particles such as electrons and/or protons and/or ions and/or atoms and/or molecules. 36. The process of claim 34, in which said power flux is formed by a flux of particles consisting or composed of elements of atomic number Z less than or equal to six, which are not dopants for the constituent material or materials of said component, in any one of their isotopic species, in any one of their molecular forms and in any ionization state, including the neutral state. 37. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, consisting of: placing the component (1) to be treated at a thermal energy level below said specified level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4)) chosen so as to produce a thermal energy density above the said specified thermal energy level corresponding to the liquefaction of the constituent material of said zone to be treated and generated by a particle emission means (3), in which this emission means being regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level corresponding to the said liquefaction; and in which the power flux is spatially constant with respect to the material to be treated and the intensity thereof is in the form of one or more pulses so as to vary the as a function of time. 38. The process of claim 37, in which said power flux consists of a flux of particles such as electrons and/or protons and/or ions and/or atoms and/or molecules. 39. The process of claim 37, in which said power flux is formed by a flux of particles consisting or composed of elements of atomic number Z less than or equal to six, which are not dopants for the constituent material or materials of said component, in any one of their isotopic species, in any one of their molecular forms and in any ionization state, including the neutral state. 40. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, consisting of: placing the component (1) to be treated at a thermal energy level below said specified level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) chosen so as to produce a thermal energy density above the said specified thermal energy level having the effect of generating inclusions in the constituent material of said zone to be treated and generated by a particle emission means (3), in which this emission means are regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level having the effect of generating the said inclusions. 41. The process of claim 40, in which said specified thermal energy level corresponds to a specified temperature. 42. The process of claim 40, in which the constituent material of at least said zone to be treated comprises silicon and in that at least said zone to be treated contains impurities chosen from aluminium and/or bismuth and/or gallium and/or indium and/or antimony and/or tin. 43. The process of claim 40, in which the constituent material of at least said zone to be treated comprises silicon-germanium. 44. A process for the treatment of a component, at least one zone to be treated of which, located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level, consisting of: placing the component (1) to be treated at a thermal energy level below said specified level (7); and subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux (4) chosen so as to produce a thermal energy density to produce a thermal energy density above the said specified thermal level having the effect of weakening said zone to be treated and generated by a particle emission means (3), and in which said emission means are regulated so as to produce a thermal energy density (5) that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level having the effect of the said weakening. 45. The process of claim 44, in which said specified thermal energy level corresponds to a specified temperature. 46. The process of claim 44, in which the constituent material of at least said zone to be treated comprises silicon and in that at least said zone to be treated contains impurities chosen from aluminium and/or bismuth and/or gallium and/or indium and/or antimony and/or tin. 47. The process of claim 44, in which the constituent material of at least said zone to be treated comprises silicon-germanium. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a process for the treatment of a component with a view to modifying at least one of its properties, this process being such that the invention is completely different from the prior art described above, both as regards the technical problems that it poses and as regards the means that it employs and the results that it allows to be obtained. One objective of the present invention is to provide a treatment process for modifying at least one property of the component in at least one zone to be treated located in the depth, that is to say at a distance from a surface of this component, without impairing or affecting the properties of the component in the space separating this surface from the zone to be treated and further in the depth, beyond this zone to be treated. Another objective of the present invention is to provide a treatment process that in particular imposes no constraints either on the nature or on the structure of the constituent material or materials of the component to be treated. Another objective of the present invention is to provide a treatment process whose operating cost is in particular relatively low. Another objective of the present invention is to provide a treatment process allowing, in particular, savings to be made as regards to the constituent material or materials of the component to be treated. Another objective of the present invention is to provide a treatment process that can be applied especially in the field of membranes and thin films, especially semiconductor thin films, in the field of the production of wafers or plates of material, in the field of the production of semiconductor wafers or slices, especially those made of silicon, of semiconductors of the IV type, IV-IV type, III-V type and II-VI type, in order to obtain electronic or optoelectronic components, such as photovoltaic cells or elements, and in the field of the welding or brazing of parts of a workpiece. The subject of the present invention is a process for the treatment of a component, at least one zone to be treated of which located in the depth of this component at a certain distance from the surface thereof, has at least one property that can be modified when this zone is subjected to a thermal energy density above a specified treatment level. According to the invention, this process consists in placing the component to be treated at a thermal energy level below said specified level; and in subjecting, through its aforementioned surface, for a specified time and in the form of at least one pulse, said component to a power flux generated by a particle emission means, this emission means being regulated so as to produce a thermal energy density that is concentrated on or has a localized maximum in said zone to be treated and reaching, in at least part of this zone, a level above said specified treatment level. The process according to the invention preferably consists in choosing a power flux exclusively adapted for producing said thermal energy density. According to the invention, said specified thermal energy level may advantageously correspond to a specified temperature. According to the invention, said component may advantageously be made of a single material or of several parts of different materials. According to the invention, said component may advantageously have a surface structure and/or a volume structure. According to the invention, said power flux preferably consists of a flux of particles such as electrons and/or protons and/or ions and/or atoms and/or molecules. According to the invention, said power flux may advantageously be formed by a flux of particles consisting or composed of elements of atomic number Z less than or equal to six, which are not dopants for the constituent material or materials of said component, in any one of their isotopic species, in any one of their molecular forms and in any ionization state, including the neutral state. According to the invention, said particles may advantageously be essentially monokinetic. According to the invention, the process may advantageously consist in choosing a component whose zone to be treated includes impurities. According to the invention, said impurities preferably have a segregation coefficient, relative to the constituent material of at least said part to be treated, of less-than one. According to the invention, the process may advantageously include a prior step of introducing said impurities into the material. According to the invention, said step of introducing said impurities preferably includes at least one epitaxial growth. According to the invention, said impurities may advantageously be introduced at least partly during application of said power flux. According to the invention, the constituent material of at least said zone to be treated may advantageously comprise silicon and at least-said zone to be treated contains impurities chosen from aluminium and/or bismuth and/or gallium and/or indium and/or antimony and/or tin. According to the invention, the constituent material of at least said zone to be treated may advantageously comprise silicon-germanium. According to the invention, the process may advantageously consist in subjecting said component to a flux whose power is constant over time. According to the invention, the process may advantageously consist in varying the intensity of the power flux. According to the invention, the process may advantageously consist in varying the position of the concentrated part of said power flux relative to said zone to be treated. According to a variant of the invention, said power flux is preferably chosen so as to liquefy the constituent material of said zone to be treated. According to another variant of the invention, said power flux is preferably chosen so as to produce inclusions in the constituent material of said zone to be treated. According to the invention, said inclusions may advantageously be precipitates and/or bubbles and/or microbubbles and/or defects and/or changes of phase and/or of chemical composition and/or fractures and/or cavities. According to another variant of the invention, said power flux is preferably chosen so as to weaken said zone to be treated. According to another variant of the invention, said power flux is preferably chosen so as to weld or braze together two parts of said component that are in contact in said zone to be treated. detailed-description description="Detailed Description" end="lead"? The present invention will be better understood thanks to the following non-limiting explanations as regards the component to be treated. The component to be treated may be of a bulk form or be in the form of one or more thin layers, and be either homogeneous or heterogeneous in form and/or have a surface structure and/or a volume structure. One particular example is a block of single-crystal silicon cut longitudinally from a cylindrical ingot. Another example is a silicon wafer on which a silicon-germanium or silicon-germanium-carbon layer 500 angstroms in thickness is grown, on which a five micron silicon layer is grown. The component may consist of at least two parts, made of one material or of different materials, in simple contact at a common surface that consequently constitutes an interface within this material. The power flux used in the invention may be applied through one of the surfaces of the material-so as to create a zone of high thermal energy at this interface, for example to produce welding or brazing. The material may also include impurities, defined as atoms or molecules or particles, that are in a stable or metastable state, i.e. unable to change discernibly, under, standard temperature conditions. In one particular, method implementation, the purpose of the treatment of the material having these impurities is to generate inclusions. The inclusions may be particle agglomerates, bubbles, both of substantially spherical shape and of flattened shape, resulting for example from the vaporization of the material or from the impurities passing into a gas phase, precipitates of atoms or molecules, precipitates of defects, cavities structural defects, fractures, new chemical compounds, new phases, or any combination of these elements. The impurities may be everywhere in the material, but must be at least partly in or near the treatment zone. One step of introducing said impurities into the material may be provided prior to and/or during the treatment. For example, if the desired impurity contains hydrogen, it may possibly be partly introduced during application of the power flux if the latter consists of a flux of hydrogen based particles. This introduction step may be carried out during fabrication of the material or subsequently. In particular, in situ doping, diffusion, ion implantation, film deposition and epitaxial growth techniques may be used. The present invention will also be better understood thanks to the following non-limiting explanations as regards the power flux employed. When a flux of power P is directed for a time Δt onto a material capable of absorbing this power, the material absorbs an amount of energy E a equal to PΔt. If the intensity of the power flux is not constant over the time Δt, the energy E a absorbed may be calculated by dividing the time Δt into time intervals δt in which the power flux may be considered as being constant and adding the contributions corresponding to each time interval δt. The absorbed energy E a density profile, i.e. the curve representing the amount of energy absorbed per unit volume as a function of the depth d, depends on the power flux parameters, i.e. the experimental conditions and, in particular, the nature of the power flux and of its characteristics, and also of the material itself. If the power flux parameters vary over the course of time, the shape of the absorbed energy density profile varies over time. At a given instant, the absorbed energy density profile is obtained by taking into account the contributions relating to each of the intervals δt. In the case of a flux of particles, the kinetic energy of each particle or particle energy e is determined by its mass and its velocity, and this kinetic energy e is generally measured in electron volts or a multiple of this unit. In the case of monokinetic particles that are completely absorbed in the material, the energy E a is equal to Ne and the power P is equal to Ne/Δt=E a /Δt, where N is the number of particles that have been directed into the material during the time interval Δt. It is therefore obvious that the power is very strongly dependent on the time Δt, for the same value of absorbed energy E a During penetration of the particles into the material, the kinetic energy of these particles is extremely rapidly transformed in the material, through various physical mechanisms, such as electron excitation (transfer of energy to electrons), phonon creation, or ionization or displacement of atoms, or the breaking of chemical bonds, into essentially thermal energy, i.e. into heat. The increase in the thermal energy density is generally manifested by an increase in the temperature and/or a supply of energy for activating physical and/or chemical reactions such as, for example, phase changes or chemical-reactions. The effect of the power flux is therefore to create one or more thermal energy sources. The heat or thermal energy in a material changes according to the known laws in physics, called the heat equations, that take into account the thermal parameters of the material, the thermal conditions at the interfaces and at then surfaces, the initial conditions and the thermal energy sources that represent, at each point in the material, the amplitude of the thermal energy density supplied to the material as a function of time. For example, the basic equations governing the physics of heat in solids will be found in the reference document “ Conduction Of Heat In Solids ”, second edition, by H. S. Carslaw and J. C. Jaeger, Oxford University Press, Walton Street, Oxford OX2 6DP. By solving these equations, it is possible to determine the thermal energy density profile in the material as a function of time, that is to say the temperature and the state of the various phases. To solve these equations in the general case must be carried out on a computer using numerical methods known per se, for example using the finite-difference methods or the finite-element method. Generally speaking, the thermal energy density profile resulting from a pulsed power flux directed onto the material is not in the steady state, i.e. it changes with time, during and after the time Δt, and its natural tendency is to broaden. For a given amount of thermal energy, the broadening that takes place is to the detriment of the thermal energy density level. Now, to treat a material in a specified zone it is necessary for the thermal energy in the treatment zone to reach a sufficient level capable of activating the desired process. It is therefore absolutely essential for the thermal energy resulting from the power flux to be concentrated in the treatment zone. To achieve this, the solutions is, on the one hand, for the energy to be absorbed in a depthwise concentrated manner in and/or near the treatment zone and, on the other hand, for the duration of the power flux to be sufficiently short and the intensity of the power flux to be high enough for the thermal energy profile to remain sufficiently concentrated and for its level to be sufficient for the treatment of the material in question. More precisely, according to the invention, it is preferred to use a flux of light particles chosen, possibly in combination, from electrons or ions or atoms or molecules consisting or composed of elements of low atomic number Z, in any one of their isotopic species, in any one of their molecular forms and in any ionization state, including the neutral state. The expression “elements of low atomic number Z” is understood to mean those in which Z, i.e. the number of protons in the nucleus, is less than or equal to 6. In particular, Z will be chosen to be less than 3 and preferably equal to 1, corresponding to hydrogen. This is because, for said light particles, it is possible to find conditions such that, during their penetration into a material, these particles transfer energy to the material in the form of a profile concentrated at a certain depth. These conditions correspond to particles with a particle energy that is higher the higher their Z. For example, it is possible to obtain a deposited energy profile having a peak at a depth of approximately 20 microns with 1.2 MeV protons or 5 MeV helium ions or 10 MeV lithium ions or 25 MeV carbon ions. For a given maximum depth, these profiles are generally narrower the lower the atomic number Z of the particle. To avoid any problem of undesirable doping when the material is a semiconductor, these particles are chosen from those that are not dopants for said material. For example, in the case in which the material is silicon, if it is desired not to create p-doping, then boron is excluded. In the case of electrons, it is possible to calculate, using suitable software, the distribution of the energy density as a function of the depth in a material subjected to a flux of monoenergetic electrons. This distribution may also be found directly in databases such as EMID (Electron Material Interaction Database) published by IDEA (Institute for Data Evaluation) and the Radiation Dynamics Group (RDG) of Kharkov National University of Ukraine. A profile having a bell-shaped curve is obtained, having a maximum at a depth that depends on the energy of the electrons. FIG. 2 a gives the energy deposition profile for 40 keV electrons in silicon. This calculation is carried out under the assumption that the dimensions of the electron flux over the surface are substantially larger than the lateral dispersion of the electron path in the material. In the above example, this assumption is justified whenever the dimensions of the electron flux over the surface of the material are appreciably greater than 10 microns. Otherwise, the shape of the curve depends on the dimensions of the flux; however, the same type of calculation may be carried out and does give a curve of similar shape. The table below gives the calculated approximate values of the depth of the maximum in the energy deposition profile in the case of silicon. Energy (in keV) 5 10 20 40 60 100 Depth (in microns) 0.11 0.33 1.2 4 8 20 The process may be carried out using protons, that is to say hydrogen ions. Other types of light particles may be used, although implementation of the method is more favorable when a narrow energy deposition profile with particles of the lowest possible Z is desired. The penetration of ions into a material is accompanied essentially by two braking mechanisms, namely “electronic braking” and “nuclear braking”. To simplify matters, nuclear braking contributes essentially to transferring energy to the atoms of the material and electron braking contributes essentially to transferring energy to the electrons of the material. Using simulation software, such as TRIM or SRIM, it is possible to calculate the distribution of the absorbed energy density as a function of the depth in a material subjected to a flux of monoenergetic particles. A bell-shape profile having a maximum of a depth that depends on the energy of the particles is obtained. It is important to note that this absorbed energy deposition profile is in general different from that of the concentration profile of the species, which represents the density of the implanted species as a function of the depth, and is also different from the density profile of the defects created. It may be observed that the more monokinetic the particle flux, the narrower the energy deposition peak and the more concentrated the energy. If it is desired for the energy deposition to have a broader peak, or even several peaks, it is possible to use particles of different energies, or even different particles. To obtain a zone of high thermal energy density in the treatment zone, it is therefore necessary: to choose particle flux parameters such that most of this power is deposited in/or near the treatment zone; to choose a time Δt, during which the power flux is directed onto the material, that is short enough for the thermal energy resulting from the primary energy to be able to build up in and near the treatment zone before it diffuses away from this zone; and to choose the intensity of the particle flux so that, during the time Δt, the energy supplied by the particles is sufficient for said thermal energy density level to be reached in the treatment zone. The time Δt may be calculated by simulation using known suitable software, generally using finite-difference methods or finite-element methods. Another way of determining this time is a method that is simpler to implement. It consists firstly in roughly determining the value of the maximum time and then in adjusting it by means of several experiments. For a rough determination, we consider the root mean square deviation σ p of the energy deposition profile resulting from the interaction of the particle flux with the material and the root mean square deviation σ t of the desired thermal energy profile (σ t is necessarily at least equal to σ p ). Next, the time Δt is estimated from the following inequality: in-line-formulae description="In-line Formulae" end="lead"? 2 L t 2 =2 DΔt<σ t 2 −σ p 2 in-line-formulae description="In-line Formulae" end="tail"? in which L t is the thermal diffusion length and D is the thermal diffusivity at the temperature in question. This calculation gives a better approximation the more σ t exceeds σ p . For example, in silicon in which the thermal diffusivity at high temperature is of the order of 0.1 cm 2 /s for a desired thermal energy profile with a root square deviation σ t of 3 microns and an absorbed energy profile with a root square deviation σ p of the order of 1 micron, this corresponds to a maximum time Δt of around 0.4 microseconds. When Δt is known, it is then possible for the shape of the thermal energy density profile in the material to be determined precisely and, since the level to be reached in the treatment zone is known, it is possible by numerical integration to deduce therefrom the total amount of thermal energy and therefore to determine the necessary power intensity level over the time Δt. The flux must therefore be in the form of a pulse of a high power and short duration so that the required thermal energy level is reached in the layer to be treated. If the treatment of the material requires a longer time than that permitted by a single pulse, it is possible to apply several pulses so that the cumulative time is suited to the treatment. Additionally, but not necessarily, it may be advantageous for certain types of process not only to control the duration of the high thermal energy level but also to control the rise and/or fall of the thermal energy level. To do this, it is possible to modulate the amplitude of the pulse as a function of time. To produce a power flux in the form of a pulse, several methods of implementation are possible: use of a power flux that is spatially constant with respect to the material to be treated, the intensity of which as a function of time is in the form of one or more pulses; use of a power flux whose intensity as a function of time is constant, but the position of which varies with respect to the material so that a given region of the material sees the flux only for one or more time intervals corresponding to the duration of the desired pulse (or of the desired pulses); and a combination of the two above methods of implementation. To produce a power flux whose position varies with respect to the material, that is to say with respect to the treatment zone and approximately perpendicular to the latter, it is possible, for example, to produce the particle flux in the form of concentrated beams (using, for example, a quadrople lens focussing system) and by means of a system using time-dependent electromagnetic forces (for example by means of coils) and to move the beam relative to the material (scanning), i.e. relative to the treatment zone and perpendicular to the latter. In the reference article “ Focused MeV Ion Beams for Materials Analysis and Microfabrication ”, MRS BULLETIN, February 2000, Volume 25, No. 2 (a publication of the Materials Research Society), page 33 to 37, an example of equipment for producing focused scanned proton beams is given on page 34 in figure 2. Although the application described in that example does not relate to the present invention, the principles used to generate the proton beam and to move it relative to the material may be used for our invention. However, it should be noted that, that to produce beams for obtaining the desired current density, it is necessary for the energy of the protons to exhibit little dispersion. Otherwise, chromatic aberrations (owing to the dispersions in the energy of the protons and therefore dispersion in their velocity) would broaden the focal spot. It is therefore recommended to make use of an ion accelerator capable of low energy dispersion. Conventional electrostatic accelerators of the Van De Graaff type, with electrical charge transport by belts or chains, are very limited in this field. An electrostatic accelerator of the singletron type sold by HVEE (High Voltage Engineering Europa BV) better meets the requirements as it allows energy dispersions within the 10 − 5 range. Further details will be found in the following reference article: “ The novel ultrastable HVEE 3.5 MeV singletron accelerator for nanoprobe applications” , D. J. W. Mous, R. G. Haitsma, T. Butz, R.-H. Flagmeyer, D. Lehmann and J. Vogt in Nuclear Instruments and Methods in Physics Research B 130, 31-36, (1997). It is also possible to leave the beam fixed in space and to move the component relative to the beam, for example by fastening-this component to a wheel that rotates at high speed. In one non-limiting embodiment, a 1 MeV proton beam is formed with a diameter of about 100 microns and a current of about 2.6 mA. This beam is directed onto silicon wafers fastened to the peripheral part of the surface of a disk about 2 m in diameter rotating at a speed of about 3 200 rpm ( FIG. 4 ). Under these conditions, upon passing beneath the beam any point on the wafer receives a power flux pulse of about 0.3 microseconds duration. This pulse is suitable for the thermal energy density reached between a depth of 12 microns and a depth of 17 microns to be around 7000 J/cm 3 . The rotation movement of the disk may be combined with a displacement movement of the spindle of the disk parallel to itself so that the treatment with the proton flux can be applied, for example, at each point on the wafers. To produce a power flux whose intensity as a function of time is in the form of one or more pulses, it is possible to use, for example in the case of protons, a machine operating according to the principles of certain machines used for heating plasmas by the injection of an intense pulsed beam of particles. In general, these machines comprise means for producing a very dense plasma, means for extracting and accelerating the ions in a very high electric field and, optionally, means for preventing any breakdown (arc formation) in the extracting and accelerating gaps, for example by the use of judicially positioned magnetic fields (magnetic isolation of the accelerating gaps). An example of such equipment is described in the John B. Greenly patent US-RE-37,100. In the case of electrons, it is possible to use a machine of the type described in the reference article “ Principles of high current electron beam acceleration ”, Stanley Humphries Jr., Nuclear Instruments and Methods in Physics Research A258(1987) 548-565. Alternatively, the electron beam may be generated by means of an electron gun having a cold emission cathode of the microtip type with the associated electrode or electrodes, similar to those used in flat screens (field emission displays) based on microtips. The following non-limiting example shows how to realize the principles of the invention. The material is a single-crystal silicon wafer 200 mm in diameter and about 750 microns in thickness. The surface may or may not be covered with thin films. This material contains antimony atoms with a concentration, for example, of around 10 16 cm −3 to 2×10 19 cm −3 . With a power flux transported by a 1 MeV proton beam, the surface is irradiated with a current density of 50 A.cm −2 for a time of 0.2 microseconds. An energy of around 10 J.cm −2 is thus deposited. A zone between a depth of about 12 microns and a depth of about 17 microns is thus created in which the thermal energy density level reached is greater than or equal to about 7000 J.cm −3 . These values are given as a starting point. A fine adjustment may be made in order to take into account the change with time of the power flux pulse and the thermal conditions of the material, in particular at its surface. This thermal energy density level is sufficient to activate the desired material treatment described below. The thermal energy density level reached makes it possible to liquefy the material in a treatment zone lying between a depth of about 12 microns and a depth of about 17 microns, the extension of which-zone, in a plane parallel to the surface through which the power flux is introduced, is defined by the lateral dimensions of this flux, thus defining a liquid zone bounded by a solid/liquid interface above the approximately 12 micron depth and a solid/liquid interface below the 17 micron depth. Most of the antimony atoms pre-existing in the solid phase in this zone, or near it, are in the liquid phase. Upon resolidification that occurs during cooling, the two solid/liquid interfaces each advance at their own rate toward each other ( FIG. 6 ), thus reducing the width of the liquid zone. Because of the low value of the segregation coefficient (sometimes called the distribution coefficient) of antimony in silicon, that is to say because of the tendency of antimony atoms to remain in the liquid phase rather than passing into the solid phase, the advance of the two solid/liquid interfaces has the effect of pushing the antimony atoms in front of them into the liquid phase, thus resulting in an ever greater concentration of antimony atoms in the liquid phase. When the liquid phase has disappeared, all the antimony atoms are necessarily in the material in the solid state. This results locally in a very high concentration of impurities in a narrow zone near the depth referred to as the meeting depth, at which the two solid/liquid interfaces meet and therefore at which the liquid phase completely disappears. Under judicially chosen experimental conditions, it is possible then to be in a situation in which the antimony atoms are at a concentration such that these atoms can no longer be normally incorporated into the solid phase, thus giving rise to precipitates., structural defects, formation of heterogeneous mixtures, etc. It is thus possible to weaken the material through this mechanism and achieve a separation between that part of the material lying between the surface and the weakened zone and the rest of the material. It should be noted that, after the treatment, the sub-surface part of the material, lying between the surface and the high thermal energy zone, remains in the solid and crystalline state in accordance with the basic principles of the invention and that the part of the material lying between the subsurface zone and the vicinity of the meeting front may retain its crystalline properties, since the material may undergo epitaxial regrowth during the resolidification phase from the solid crystalline material of the subsurface zone. The resolidification phenomenon may be more complex than that described above since the advance of the two —upper and lower —interfaces may be combined with an advance of the lateral interfaces, and even with the formation of discontinuous liquid zones separated by resolidified zones. However, whatever the complexity of the mechanisms involved, this always results in the impurities being concentrated in a very small volume of material. In this example, the antimony atoms may have been introduced during growth of the ingot from which the wafer was obtained, giving an approximately homogeneous concentration throughout the volume. The antimony atoms may, in another method of implementation, be, for example, in a subsurface layer some 20 microns in thickness. In the latter case, this high antimony concentration may be obtained: by growing an antimony-doped layer 20 microns in thickness by epitaxy on a scarcely doped or undoped silicon substrate. It is also possible in a different manner to use a highly antimony-doped silicon wafer on which a single-crystal layer of scarcely or lightly doped silicon is grown by epitaxy, if it is desired to preserve a lightly doped layer on the surface in order to fabricate devices. The thickness of this scarcely doped layer in the particular case indicated above (1 MeV protons) may have a thickness of up to around twelve microns. While keeping a lightly doped surface layer, it is also possible to have localized antimony doping within a deep layer. This is obtained for example by producing, on the surface of a wafer, an antimony-doped layer (for example, by 10 15 cm −2 ion implantation at 150 keV followed by a diffusion heat treatment of 6 hours at 1150° C.), followed by epitaxial growth of scarcely doped or undoped silicon with a thickness of around twelve microns. In the above example, antimony atoms were used. The principle also operates with other atoms having a low segregation coefficient relative to silicon, such as for example, but implying no limitation, aluminum, bismuth, gallium, indium and tin. The choice of other impurities or atoms is possible. This choice depends on the constraints of the intended application. For example, an atom such as antimony will be chosen if it is desired for the residual doping of the treated zone to be of the n type, while an atom such as aluminum will be chosen if it is desired for the residual doping of the treated zone to be of the p type. In all these examples, in which epitaxial growth is used, the epitaxial process may either be a process of the CVD type or a process of the liquid phase epitaxy type; in particular, a liquid phase epitaxy of silicon from a bath of molten tin or aluminum or indium in which silicon has been dissolved, may be one of the preferred ways of producing photovoltaic cells. To illustrate, generally and schematically, the present invention and in particular the above examples and explanations, reference may be made to the appended FIG. 1 which shows, in cross section, a component 1 of parallelepipedal shape, that has a front flat surface 2 at a certain distance away from which an apparatus 3 for emitting a particle flux 4 is installed. This power flux 4 is introduced into the component 1 perpendicular to its surface 2 and produces, in the component 1 , a thermal energy density whose profile or curve 5 at the end of the power flux pulse has been shown. The profile 5 is, parallel to the surface 2 , approximately in the form of a bell or a peak, and the maximum of this profile 5 lies in a treatment zone 6 localized in the depth at a certain distance from the surface 2 of the component 1 . Of course, the power flux 4 could be introduced into the component 1 at another angle of incidence than that corresponding to normal incidence. With a component 1 placed at a thermal energy level below the specified treatment level 7 , in particular at a temperature below a specified treatment value, the thermal energy density 5 produced by the power flux 4 exhibits a peak 5 a that reaches the specified treatment level 7 and exceeds-this level over a thickness d such that at least one property of the constituent material of the zone 6 to be treated is modified in this thickness d and over the surface corresponding approximately to the cross section of the power flux 4 . It follows that the properties of the rest of the component 1 , and in particular its part 8 lying between the surface 2 and the zone 6 and its part 9 lying beyond this zone 6 are not impaired or modified. FIG. 2 a shows a curve 10 that represents the approximately bell-shaped profile of the energy density deposited as a function of the depth, produced in a silicon wafer by an electron flux and FIG. 2 b shows a curve 11 that represents approximately the depth of the maximum energy density deposited by an electron flux or electron beam in a silicon wafer. FIG. 3 shows a curve 12 that represents the profile, with a pronounced peak, of the deposited energy density as a function of the depth, produced in a silicon wafer by a proton flux. FIG. 4 shows, in side view and from above, a treatment apparatus 13 that comprises a rotating plate 14 on which a component 1 to be treated is placed between its center and its edge. The component 1 passes in front of a power flux 4 in such a way that this component 1 is subjected, at each revolution of the plate 14 , to a pulse of the power flux 4 . The number of revolutions that the plate 14 must perform depends on the treatments to be obtained that were described above. FIG. 5 shows, in cross section, a component 1 to be treated, formed by a wafer from which it is desired to extract slices 15 . To do this, a particle flux 4 is applied that weakens the material in a zone 6 to be treated at a depth away-<from its surface 2 , corresponding to the thickness of the desired slice, in such a way that this slice 15 is thus separable. In an example, this arrangement is particularly advantageous from a technical standpoint and from a cost standpoint for producing thin silicon photovoltaic cells, in particular with a thickness of the order of 10 to 100 microns. FIG. 6 shows the component 1 to be treated, formed by two parts- 16 and 17 that are in contact via an interface 18 and that it is desired to weld or braze. To do this, a particle flux 4 is applied that causes a temperature rise and/or melting in a zone 6 to be treated that includes the interface 18 , suitable for welding or brazing the two parts 16 and 17 to each other. FIG. 7 shows, in cross section, a component 19 , for example made of silicon containing impurities having a segregation coefficient of less than 1 relative to silicon, such as antimony, aluminum, bismuth, gallium, indium or tin. As described with reference to FIG. 1 , a pulsed proton flux 4 is applied, the flux being introduced into the component 19 through its surface 20 , the deposited energy density-having a profile corresponding to that shown in FIG. 3 . By tailoring the conditions of application of the proton flux 4 for this purpose, liquefaction of the silicon occurs in a zone 21 to be treated lying in the depth and located within the region of the peak of the deposited energy profile. The liquid silicon phase 21 a contained approximately between two solid/liquid interfaces 22 and 23 approximately parallel to the surface 20 progressively increases in thickness during the application of the proton flux 4 , as shown by the arrows 24 and 25 attached to the interfaces, before reaching the maximum. Because of the thermal diffusion in the rest of the component 19 , the liquefaction phase is followed by a silicon resolidification phase that results in a progressive reduction in the distance between the interfaces 22 and 23 , as shown by the arrows 26 and 27 attached to these interfaces. This resolidification phase generally, and essentially, occurs after the pulse of the proton flux 4 has been applied. During the aforementioned silicon liquefaction phase, the impurities pass into solution in the liquid phase 21 a. During the aforementioned silicon resolidification phase, the impurities have a tendency to remain in the liquid phase 21 a in such a way that, at the end of the silicon resolidification phase, these impurities are concentrated in the part 21 b of the zone 21 to be treated that resolidifies last, i.e. in a silicon volume whose thickness is much less than the afore-mentioned maximum thickness of the liquid phase 21 a. These impurities may therefore be in the part 21 b with concentration levels much higher than that of the solubility limit in the solid phase, thus forming precipitates and/or crystal defects that weaken the silicon in the concentration zone. The weakened part 21 b may then constitute a zone for separating or breaking the component 19 into two parts. The present invention is not limited to the examples described above Many alternative versions are possible without departing from the scope of the appended claims. detailed-description description="Detailed Description" end="tail"? |
Non-stop active car headrest |
The object of the invention is a non-stop-active car headrest, used as additional head support in seats, particularly in cars. A non-stop-active car headrest in the form of a closed container (2) consists of at least one layer (8), and preferably several elastic layers (8) and (9) filled with an elastic filling (10), and is provided with a negative pressure system nozzle (7) with a shut-off valve, while the container (2) is supported from the back with at least one elastic element (4), bent out in the direction of passenger's head. |
1. Non-stop-active car headrest in the form of a closed container characterised in that the container (2) consists of at least one layer (8), and preferably several elastic layers (8) and (9) filled with an elastic filling (10), preferably elastic air-filled balls and/or elastic foam balls, and is provided with a negative pressure system nozzle (7) with a shut-off valve, while the container (2) is supported from the back with at least one elastic element (4), bent out in the direction of passenger's head. 2. The headrest according to claim 1, characterised in that the elastic element (4) is preferably in a form of a leaf spring. 3. The headrest according to claim 1, characterised in that the elastic element (4) is preferably in a form of a rotating shock absorber. 4. The headrest according to claim 1, characterised in that the container (2) is preferably filled with granulated plastic in the form of EPS foam balls. 5. The headrest according to claim 1 or 2, characterised in that the container (2) is preferably ellipsoidal in shape. |
Apparatus |
Various items of apparatus are disclosed including: 1) a gun (2) having a body (3), a trigger mechanism (4-21), a barrel (34), a magazine for holding a plurality of projectiles, and a traversing mechanism (44) for advancing the magazine stepwise and unidirectionally through a transverse aperture (30) through the body (3), 2) a device for dosing an exact amount of propellant material into the magazine, 3) a device for inserting a primer into the magazine, 4) a device for removing a used primer from the magazine and/or seating a projectile in the magazine, and (5) bullets of which one is particularly designed for the user with the gun (2). |
1-46. (canceled) 47. A small arms bullet comprised of a bullet body of a non-ductile metallic substance and of circular cylindrical form having tow ends and a ductile drive band closely encircling said bullet body at a location between said two ends. 48. A bullet according to claim 47, wherein the maximum external diameter of said band is greater than the maximum external diameter of said body. 49. A bullet according to claim 47, wherein said drive band comprises a ridge and a groove about its circumference, and said ridge is located ahead of said groove and projects radially outwardly beyond an external peripheral surface of said body. 50. A bullet according to claim 49, wherein the maximum external diameter of said band is greater than the maximum external diameter of said body and is a maximum external diameter of said ridge. 51. A bullet according to claim 47, wherein said drive band comprises ridges and grooves about its circumference, and each ridge is located immediately ahead of an associated groove and projects radially outwardly beyond an external peripheral surface of said body. 52. A bullet comprised of a bullet body and a ductile drive band closely encircling said bullet body, wherein said drive band comprises a ridge and a groove about its circumference, and said ridge is located ahead of said groove and projects radially outwardly beyond an external peripheral surface of said body. 53. A bullet according to claim 52, wherein the maximum external diameter of said band is greater than the maximum external diameter of said body and is a maximum external diameter of said ridge. 54. A gun comprising a magazine for holding a plurality of projectiles, a body, a trigger mechanism for triggering the firing of a projectile from said magazine, a barrel for receiving and ejecting the fired projectile, a traversing mechanism for advancing said magazine stepwise and unidirectionally through a transverse aperture through said body, said magazine being arranged to be loaded with said projectiles from the front of said magazine into a plurality of chambers each having an opening at said front of said magazine, a propellant-material-receiving, rearward portion and a projectile-receiving, forward portion, the arrangement being such that, if a double charge of propellant material is loaded in said chamber, a projectile then loaded in said chamber would extend beyond said front of said magazine so that said magazine would be prevented from advancing through said transverse aperture. 55. A gun according to claim 54, wherein a bullet-seating shoulder defines the boundary between said rearward portion and said forward portion. 56. A gun according to claim 54, wherein each chamber includes a rearwardly open sub-chamber for loading with a primer, and a short bore interconnecting said sub-chamber and said rearward portion. 57. A gun according to claim 54, wherein said magazine is a linearly displaceable, load block. 58. A gun according to claim 54, wherein said magazine is a rotary cylinder. 59. In combination: a gun comprising a magazine for holding a plurality of projectiles, a body, a trigger mechanism for triggering the firing of a projectile from said magazine, a barrel for receiving and ejecting the fired projectile, a traversing mechanism for advancing said magazine stepwise and unidirectionally through a transverse aperture through said body, said magazine being arranged to be loaded with said projectiles from the front of said magazine into a plurality of chambers each having an opening at said front of said magazine, a propellant-material-receiving, rearward portion and a projectile-receiving, forward portion, propellant material in said rearward portion, and a cylindrical bullet in said forward portion. 60. A gun according to claim 59, wherein a bullet-seating shoulder defines the boundary between said rearward portion and said forward portion. 61. A gun according to claim 59, wherein each chamber includes a rearwardly open sub-chamber for loading with a primer, and a short bore interconnecting said sub-chamber and said rearward portion. 62. A gun according to claim 59, wherein said magazine is a linearly displaceable, load block. 63. A gun according to claim 59, wherein said magazine is a rotary cylinder. 64. A gun comprising a magazine for holding a plurality of projectiles, a body, guiding surface portions of said body and serving to guide linearly advance of said magazine through a transverse aperture through said body, a trigger mechanism for triggering the firing of a projectile from said magazine, a barrel for receiving and ejecting the fired projectile, a traversing mechanism for advancing said magazine stepwise and unidirectionally through said transverse aperture, said magazine being arranged to be loaded with said projectiles from the front of said magazine. |
<SOH> BACKGROUND OF THE INVENTION <EOH>According to a first aspect of the present invention, there is provided a gun comprising a magazine for holding a plurality of projectiles, a body, a trigger mechanism for triggering the firing of a projectile from said magazine, a barrel for receiving and ejecting the fired projectile from said magazine, a barrel for receiving and ejecting the fired projectile, a traversing mechanism for advancing said magazine stepwise and unindirectionally through a transverse aperture through said body, said magazine being arranged to be loaded with said projectiles from the front of said magazine into a plurality of chambers each having an opening at said front of said magazine, a propellant-material-receiving, rearward portion and a projectile-receiving, forward portion, the arrangement being such that, if a double charge of propellant material is loaded in said chamber, a projectile then loaded in said chamber would extend beyond said front of said magazine so that said magazine would be prevented from advancing through said transverse aperture. Owing to this aspect of the present invention, it is possible for shooters interested in a muzzle-loading style of shooting with cylindrical bullets to do so in a multi-shot manner. In addition, the firing of a cylindrical bullet when a chamber has been “double-charged” with excess propellant material, which can lead to dangerous consequences when using highly volatile smokeless propellants, cannot occur. The magazine can take the form a linearly displaceable, load block or a rotary cylinder. According to a second aspect of the present invention, there is approved in combination: a gun comprising a magazine for holding a plurality of projectiles, a body, a trigger mechanism for triggering the firing of a projectiles from said magazine, a barrel for receiving and ejecting the fired projectile, a traversing mechanism for advancing said magazine stepwise and unidirectionally through a transverse aperture through said body, said magazine being arranged to be loaded with said projectiles from the front of said magazine into a plurality of chambers each having an opening at said front of said magazine, a propellant-material-receiving, rearward portion and a projectile-receiving, forward portion, propellant material in said rearward portion, and a cylindrical bullet in said forward portion Owing to this aspect of the present invention, it is possible for shooters interested in a muzzle-loading style of shooting with cylindrical bullets to do so in a multi-shot manner. According to a third aspect of the present invention, there is provided a gun comprising a magazine for holding a plurality of projectiles, a body, guiding surface portions of said body and serving to guide linearly advance of said magazine through a transverse aperture through said body, a trigger mechanism for triggering the firing of a projectile from said magazine, a barrel for receiving and ejecting the fired projectile, a traversing mechanism for advancing said magazine stepwise and unidirectionally through said transverse aperture, said magazine being arranged to be loaded with said projectiles from the front of said magazine. Owing to this aspect of the present invention, it is possible for shooters interested in a muzzle-loading style of shooting with a magazine in the form of a rectangular chamber block to do so in a multi-shot manner. According to a fourth aspect of the present invention, there is provided dosing apparatus for a firearm, comprising a container for receiving flowable material, a receiving device having therein a hole of a predetermined volume and for filling with material from said container, and an outlet through which the predetermined volume of said material in said hole leaves said apparatus, said receiving device being displaceable to move said hole between said container, where said hole is filled with said material, and said outlet, where the material in said hole is fully discharged. According to a fifth aspect of the present invention, there is provided a method of loading a firearm with flowable material, comprising delivering said material from a container into a hole of a predetermined volume to fill said hole with said material, displacing said hole from said container to an outlet leading towards said firearm and fully discharging said material from said hole into said outlet. Owing to these aspects of the invention, it is possible for a shooter to load an accurate amount of the material into the firearm, not only reliably, but also rapidly. According to a sixth aspect of the present invention, there is provided dosing apparatus comprising a container for receiving flowable material, a receiving device having therein a hole of a predetermined volume and for filling with material from said container, and an outlet through which the predetermined volume of said material in said hole leaves said apparatus, said receiving device being displaceable to-and-fro to move said hole between said container, where said hole is filled with said material, and said outlet, where the material in said hole is fully discharged. Owing to this aspect of the invention, it is possible to provide a relatively simple dosing apparatus. According to a seventh aspect of the present invention, there is provided apparatus for inserting a primer into a projectile housing for a gun, comprising a primer supporting device, a primer inserting device and a projectile housing supporting device at respective opposite sides of said primer supporting device, and an operating device to operate said primer inserting device to force a primer in said primer supporting device into a projectile housing supported by said projectile housing supporting device. According to an eighth aspect of the present invention, there is provided a method of inserting a primer into a projectile housing for a gun, comprising supporting said primer in a primer supporting device, supporting said projectile housing in a projectile housing supporting device, and causing a primer inserting device to force said primer into said projectile housing. Owing to these aspects of the invention, it is possible for a shooter to insert quickly a new primer. The projectile housing can be, for example, a cartridge, a rectangular load block or a cylinder. According to a ninth aspect of the present invention, there is provided apparatus for removing a used primer from a magazine for a gun, comprising a magazine supporting device, and a primer removing device operable to remove said primer from said magazine. According to a tenth aspect of the present invention, there is provided a method of removing a used primer from a magazine for a gun, comprising supporting said magazine in a magazine supporting device and operating a primer removing device to remove said primer from said magazine. Owing to these aspects of the invention, it is possible for a shooter to remove quickly a used primer. Advantageously, the apparatus for removing a used primer may also have a projectile-loading device for loading a projectile into the magazine and, preferably, the primer removing device and the projectile-loading device may be operated by an operating device common to both. According to an eleventh aspect of the present invention, there is provided apparatus comprising: a gun having a body, a trigger mechanism, a barrel, a magazine for holding a plurality of projectiles, and a traversing mechanism for advancing said magazine stepwise and unidirectionally through a transverse aperture through said body, a device for dosing an exact amount of propellant material into said magazine, a device for inserting a primer into said magazine, and a device for removing a used primer from said magazine and/or seating a projectile in said magazine. Owing to this aspect of the invention, it is possible to provide a shooter interested in a muzzle-loading style of shooting with a complete shooting package. Owing to the various aspects of the invention, it is possible for shooters to remove quickly used primer, insert quickly new primers, and place exact amounts of propellant material and load projectiles into the magazine, so enabling a faster turnaround in shooting, therefore allowing a shooter to shoot more shots in a given time period. The propellant material may be nitro-cellulose, a smokeless propellant powder. The primers may be of the standard type, as used in metallic centre-fire cartridges. The primers contain a percussive material, such as fulminate of mercury, to ignite the nitro-cellulose powder since nitro-cellulose requires a hotter flame to be produced when the firing pin strikes than do traditional black powder propellants. According to a twelfth aspect of the present invention, there is provided a wad-cutting, flat-based bullet of soft metallic material and of cylindrical form having a front end and a rear end, said rear end having a gas-check cap attached thereto. Owing to this aspect of the present invention, it is possible to provide a shooter with a soft-metallic wad-cutting bullet with a gas-check cap on its base to prevent damage to the base region of the bullet on firing. According to a thirteenth aspect of the present invention, there is provided a bullet of cylindrical form and including at the front thereof a dome serving to cooperate with a centering portion of a loading pin for loading said bullet in a chamber. Owing to this aspect of the invention, it is possible to ensure that the chamber is correctly aligned with the loading pin. According to a fourteenth aspect of the present invention, there is provided a combination comprising a firearm chamber, a propellant charge at a rearward portion of said chamber, sand a bullet at a forward portion of said chamber, there being substantially no expansion volume remaining in said chamber for gas produced during firing of said bullet. Owing to this aspect of the invention, it is possible to avoid the firing of the bullet with an excessive propellant charge in the chamber. According to the fifteenth aspect of the present invention, there is provided a small arms bullet comprised of a bullet body of a non-ductile metallic substance and of circular cylindrical form having two ends and a ductile drive band closely encircling said bullet body at a location between said two ends. Owing to this aspect of the invention, it is possible to provide shooters interested in small arms shooting with a bullet with an increased range for a given small arms size. By small arms, what is meant is any arms size up to but not including heavy artillery weapons. According to the sixteenth aspect of the present invention, there is provided a bullet comprised of a bullet body and a ductile drive band closely encircling said bullet body, wherein said drive band comprises a ridge and a groove about is circumference, and said ridge is located ahead of said groove and projects radially outwardly beyond an external peripheral surface of said body. Owing to this aspect of the invention, it is possible to provide a bullet which has a drive band and the body of which, upon firing, does not deform. In order that the invention may be clearly and completely disclosed, reference will now be made, by way of example, to the accompanying drawings, in which: FIG. 1 shows a fragmentary vertical axial section through a firearm in the form of a pistol, FIG. 2 shows a view similar to FIG. 1 of a second version of the pistol, FIG. 3 shows a perspective view of a magazine for the pistol of FIG. 1 or 2 with a vertical axial section through a chamber of the magazine, FIG. 4 shows a perspective view of a magazine for a firearm in the form of a revolver, shown partially in section, FIG. 5 is a front elevation o the magazine of FIG. 3 for use in the pistol of FIG. 1 or 2 , FIG. 6 is an underneath plan view of the magazine of FIG. 3 , FIG. 7 shows a section taken on the line VII-VII of FIG. 5 , FIG. 8 shows a perspective view of a powder dosing device, FIG. 9 shows a perspective, partially sectional view of a primer inserting tool for inserting primers into the magazine of FIG. 3 , FIG. 10 shows a perspective view of a tool for removing used primers from and seating projectiles into the magazine of FIG. 3 , FIG. 11 shows half in elevation and half in axial section a soft-metallic, wad-cutting bullet, FIG. 12 is an elevational view of a rifle bullet body, and FIG. 13 is a fragmentary elevational view of the bullet with a drive band installed. detailed-description description="Detailed Description" end="lead"? Referring to FIGS. 1 and 2 , the firearm 2 includes a body 3 which mounts a trigger mechanism that includes a trigger 4 . When the trigger 4 in FIG. 1 is pulled backwards by a shooter's finger, a trigger bar 6 , urged against a set screw 5 in the body 3 by compression springs 7 and 13 , moves anti-clockwise about a transverse axis 8 , so that firstly one and then the other of two set screws 10 in the bar 6 and providing a so-called “two-stage trigger” press against a bent 12 which is thereby turned, against the action of the compression spring 13 , anti-clockwise about a transverse axis 14 . In FIG. 2 , the trigger 4 is, in this version, disposed more forwardly to lie almost directly beneath the transverse axis 8 . When the trigger 4 is pulled backwards by a shooter's finger, the trigger bar 6 , urged against the set screw 5 in the body 3 by the spring 7 , moves anti-clockwise about the transverse axis 8 to an extent limited by a set screw 9 . Instead of the “two-stage trigger” arrangement provided by the set screws 10 of FIG. 1 , there is, in FIG. 2 , a stepped portion 10 ′ in the trigger bar 6 , which, on the anti-clockwise motion of the trigger bar 6 around the axis 8 , presses against the bent 12 which is, again, turned, against the action of the compression spring 13 , anti-clockwise about the transverse axis 14 . In FIGS. 1 and 2 , an abutment 16 on the bent 12 holds a sear 18 substantially stationary until the bent 12 turns to a point where the abutment 16 slides past the sear 18 . At this point, the sear 18 is turned downwardly sharply, rotating anti-clockwise about a transverse axis 20 under the force acting on a detent 21 thereof from a firing pin 22 (shown in FIG. 1 in its position after firing and in FIG. 2 in its position before firing). When the firearm 2 is in a cocked condition, the firing pin 22 is in a position such that a groove 24 therein is engaged by the detent 21 and a compression spring 26 is exerting a force on the pine 22 to the left in FIG. 2 . When the firing pin 22 is released by the sear 18 the compression spring 26 forces the pin 22 towards the front of the firearm 2 and a point 28 of the pin 22 penetrates into a transverse aperture 30 through the body 3 . Forward of the aperture 30 is a bore 32 of a barrel 34 of the firearm, a cocking mechanism of which includes a slide 36 reciprocable longitudinally of the firearm and urged forwardly by a compression spring 38 beneath the barrel 34 . The spring 38 encircles a headed rod 40 which is fixed at is rearward end to the slide 36 and which at its headed forward end serves as an abutment for the forward end of the spring 38 , the rearward end of which abuts against a shoulder 42 in the body 3 . The slide 36 has fixed thereto two upwardly projecting pins 44 and 46 . The pin 46 is arranged to come to bear on an annular shoulder 48 of the firing pin 22 when the slide 36 is displaced rearwardly against the action of the spring 38 and so pushes the firing pin 22 back into its cocked position. That rearward stroke of the pin 46 is accompanies by a rearward stroke of the pin 44 from its full-line, foremost end position shown in FIG. 1 to its rearmost end position 44 ′ shown in dot-dash lines ( FIG. 2 shows the pin in its rearward position 44 ′ only). A magazine 50 , as shown in FIGS. 3, 5 , 6 and 7 , is mountable in the aperture 30 so as to extend transversely of the firearm 2 and is formed at its underneath surface with a groove system 52 of a zig-zag form in which the pin 44 engages, so that reciprocation of the pin 44 between its foremost and rearmost end positions produces reliably unidirectional linear stepwise advance of the magazine 50 through the aperture 30 , each full reciprocation of the pin 44 ending with each of five chambers 54 of the magazine 50 in turn aligned with the point 28 and the barrel 32 . Each chamber 54 consists of a rearwardly open sub-chamber 56 for loading with a percussion cap type primer 63 , a forwardly open sub-chamber 58 for loading, from the front, firstly with a propellant charge 63 into a propellant-receiving rearward portion 58 ′ and secondly with a cylindrical bullet 64 into a projectile-receiving forward portion 58 ″, and a short bore 60 interconnecting and co-axial with the sub-chambers 56 and 58 . The boundary between the two portions 58 ′ and 58 ″ is defined by a bullet seating shoulder 58 ′″. In use, with the firing pin 22 already cocked, as shown in FIG. 2 , the slide 36 is displaced rearwards part-way and then a fully loaded magazine 50 is inserted into the aperture 30 with its end 50 ′ leading, so that the pin 44 can enter an open-sided end 52 ′ of the groove system 52 . Then the slide 36 is returned to its foremost position, so that the pin 44 rides into a first, forward, aligning portion 52 a of the system 52 . The firearm can then be fired. A later full reciprocation of the slide 36 not only cocks the firing pin 22 but also then brings the pin 44 into a second, forward, aligning portion 52 b of the system 52 . The firing and cocking cycle is repeated until the pin 44 leaves the opposite end 52 ″ of the system 52 . In FIG. 4 , the magazine 50 is in the form of a cylinder to be used with muzzle loading revolvers. The chambers 54 are distributed around a central bore 66 which runs longitudinally through the cylinder 50 for receiving a mounting pin of a revolver. A ratchet 68 of a ratchet mechanism produces reliable unidirectional stepwise advancement of the cylinder 50 through an aperture in the muzzle loading revolver, with each firing ending with each of six chambers 54 of the cylinder 50 in turn aligned with the point of the firing pin and the barrel of the revolver. Referring to FIG. 8 , a powder dosing device 70 has a powder holding container 72 which is mounted on top of a body 74 and into which propellant powder is placed. The powder falls into an fills a hole 76 which is of a predetermined volume so that the exact amount of powder is measured to give optimum results on firing. The hole 76 is formed in a reciprocable bar 78 contained within the body 74 . The bar 78 has an arm 80 coaxially attached to it which extends externally of the body 74 and terminates in a flat button 82 . Once powder has filled the hole 76 a shooter pushes the button 82 towards the body 74 with his finger or thumb to move the bar 78 against the action of a compression sprint 84 . This moves the hole 76 inwards until it becomes aligned over an opening 86 through which the powder contained within the hole 76 empties into a conduit 88 . The conduit 88 is of an external diameter to fit into the sub-chambers 58 of the magazine 50 . In this way, the exact amount of propellant material can be delivered into any one of the propellant-receiving portions 58 ′ of the sub-chambers 58 . If too much propellant material is placed into the portion 58 ′, by the shooter's inadvertently loading the sub-chamber 58 twice or more with a dosage of propellant before firing, such overcharging being potentially dangerous for the shooter, the bullet 64 will protrude from the sub-chamber 58 in question. This prevents the magazine 50 from passing through the aperture 30 in either the pistol of FIG. 1 or 2 or the revolver at least to an extent to allow that particular sub-chamber 58 to reach a firing position and therefore prevents any consequential accidents whilst shooting. FIG. 9 shows a primer inserting tool 90 . The magazine 50 of FIGS. 3, 5 , 6 and 7 fits into a supporting seat 92 with the sub-chamber 56 for receiving a primer facing inwardly towards a primer inserting plunger 94 . Located between an end 100 of the plunger 94 and the seat 92 is a conduit 95 in which primers, from a primer storage device 98 , align themselves in a single column. The primer located at the base of that column lies immediately in front of the end 100 of the plunger 94 and immediately behind an aligned sub-chamber 56 of a magazine 50 in the seat 92 . An operating press 102 is connected to the plunger 94 , and by the shooter's pressing down on a pad 104 of the press 102 the plunger 94 is pushed forward against the action of a spring 106 . The forward movement of the plunger 94 causes its end 100 to force the primer, located at the base of the column in the conduit 96 , into the aligned sub-chamber 56 of the magazine 50 located in the seat 92 . The seat 92 has on its base a pin 108 for engaging in the groove system 52 on the base of the magazine 50 for aligning each sub-chamber 56 . The shooter manually places the magazine in the seat 92 to align a particular sub-chamber 56 in the magazine to be loaded with a primer, with the pin 108 holding steady the magazine in the seat 92 . The shooter repeats this procedure for each sub-chamber 56 , with the magazine 50 being advanced through the seat 92 by the shooter. Referring to FIG. 10 , a magazine de-primer and projectile loading tool 112 comprises a base 114 , a magazine supporting section 116 which includes a de-priming seat 116 ′ and a projectile loading seat 116 ″, a de-priming pin 118 , a projectile loading pin 120 having a concave pressing surface 121 , and a handle 122 . The pins 118 and 120 are each mounted at one end on the handle 122 by way of pin-and-slot connections 123 and are vertically guided in respective cylindrical bores in a horizontal arm 125 fixed relative to the base 114 . The other end of the de-priming pin 118 is suspended by the handle 122 over the de-priming seat 116 ′. Likewise, the other end of the projectile loading pin 120 is suspended by the handle 122 over the projectile loading seat 116 ″. Once propellant material has been dosed in the portion 58 ′ the bullet 64 Is inserted into the portion 58 ″. The magazine 50 , with each of its sub-chambers 58 loaded with the propellant material and a bullet loosely seated, is then placed in the seat 116 ″ of the tool 112 with the sub-chamber 58 and the bullet 64 facing vertically upwards towards the pin 120 . By the shooter's operating the handle 122 , the pin 120 pushes the bullet further into the sub-chamber 58 to seat it finally against the shoulder 58 ′″. This operation is repeated for each sub-chamber 58 , with the magazine 50 being advanced through the seat 116 ″ by the shooter. Once a magazine has been used by the shooter, the used percussion cap primers need to be removed before the magazine can be used again. The magazine is placed in the de-priming seat 116 ′ with the sub-chamber 58 facing upwards towards the pin 118 . The de-priming part 124 of the pin 118 is shaped to fit into the sub-chamber 58 with its point 126 designed to project through the short bore 60 and push any used primer out of the sub-chamber 56 . The used primers fall through the seat 116 ′ and a bore 128 in the body 114 into a primer collecting cavity 130 . A plug 131 for closing the opening to the cavity 130 can be removed from the body 114 to permit disposal of used primers collected therein. Each of the firearms shown in FIGS. 1 and 2 and the revolver can be made to order to provide a safe smokeless powder gun for those interested in such shooting and can be provided, in package form, with one or more of the powder dosing device, the primer inserting tool and the de-priming and projectile-loading tool described with reference to FIGS. 8 to 10 . Referring to FIG. 11 , the bullet 64 is a wad-cutting, flat-based bullet and has a cylindrical body 140 of a caliber to be loaded into the sub-chamber 58 of the magazine 50 . The bullet 64 is also of a sufficient overall length that, when the bullet 64 is loaded into the sub-chamber 58 of the magazine 50 subsequent to a single measured dose propellant material using the powder dosing device 70 , the tip of a domed portion 142 of the bullet 64 is substantially co-planar with the rim of the front opening of the sub-chamber 58 . Therefore, as already mentioned with reference to FIG. 8 , if more than a single dose of propellant material were to be placed in the portion 58 ′, the bullet will protrude from the sub-chamber 58 and therefore indicate a potentially dangerous overcharging. The pressing surface 121 matches the surface of the dome 142 and cooperates therewith to align the sub-chamber 58 , and thus the magazine 50 , with the pin 120 . The bullet 64 also has at its rear end a gas-check cap 144 of any suitable material, preferably copper. The body 140 of the bullet 64 is composed of a soft metallic material, softer than copper, preferably a mixture of predominantly lead and a small amount of tin, for example a mixture of 99.5% lead and 0.5% tin, the tin being present to prevent the oxidization of the lead. This relatively soft metallic material enables the rear end of the body 140 of the bullet 64 to be squeezed into the cap 144 during forming of the bullet. The cap 144 prevents damage to the base of the bullet 64 . Owing to the anti-overcharging feature, the bullet 64 is pressed down on the propellant material in the sub-chamber 58 when loaded into the magazine 50 , leaving in the sub-chamber 58 no expansion volume for gas when the propellant material is ignited on firing. In the absence of such a cap 144 , the large and sudden pressure increase at the base of the bullet 64 , caused by the ignition of the propellant material, would deform the relatively soft metallic body 140 , possibly leading to the soft metallic material of the bullet 64 becoming spattered around inside the sub-chamber 58 . The cap 144 prevents such deforming of the bullet 64 on firing and therefore provides for consistent shooting. Consistent shooting of the bullet 64 can be aided by a lubricating fluid applied, particularly, to that surface of the bullet 64 which contacts the wall of the sub-chamber 58 . The application of the lubricating fluid removes the need for the bullet to include grease grooves around its circumference. At its front end, the bullet 64 has an annular wad-cutting ridge 146 to cut through and thus clearly mark a position on a target where the bullet hits that target. Referring to FIGS. 12 and 13 , a bullet 200 has a body 202 which has a similar profile to existing rifle bullets with a boat-tailed rear portion 204 . However, the body 202 also has a co-axial, annular recess 206 in a mid-portion of the body 202 . The body 202 is of an optimal weight achieved by using heavier and harder material than that of conventional rifle bullets. The body 202 is made from a non-ductile hard metal or hard metal matrix, and preferably of alcanite (sintered tungsten and copper). This results in the body 202 being harder than the rifle barrel out of which the bullet 200 will be shot. Thus, the bullet 200 cannot be made to swage into the rifling of the barrel. The portion of the body 202 a of the body 202 where the diameter of the body 202 is greatest is, therefore, designed to fit the bore of the rifle barrel with a close tolerance to keep it precisely aligned with the barrel axis. Additionally, the hard non-deforming body 202 will preserve the dynamic balance of the bullet 200 . Furthermore, the increased weight of the bullet 200 allows its length to be kept at an optimal minimum. In this way, the amounts of energy wasted as heat when the bullet 200 travels through the barrel is minimized. The Greenhill formula: T = 150 × D R where: T is the twist required (number of inches for one revolution), D is the bullet diameter (in inches) and R is the bullet length to diameter ratio (length divided by diameter), establishes the barrel twist necessarily so that a bullet of a given length will be adequately stabilized. It should be noted that the use of heavier material and the effect of shortening the overall length for a given weight, means that to comply with Greenhill's formula the bullet 200 does not have to spin so fast to maintain stability. Therefore, less energy is expended to impart spin which means more energy to impart forward motion which further means that a higher thermal efficient is achieved. In order to impart the desired spin to the bullet 200 that the rifling generates and referring to FIG. 2 , the bullet body 202 carries a closely encircling drive band 208 of a ductile material and fitted into the annular recess 206 . Once fitted on the bullet body 202 , the band 208 has a slightly larger diameter than the part 202 a where the diameter of the body 202 is greatest and the band 208 is designed to seal the bullet 200 against the barrel wall. The material for the band 208 needs to be both ductile enough to swage readily into the rifling and strong enough in shear to spin the bullet without distortion. The band 208 thus takes the rifling of the barrel with the minimum force. It is desirable that in sealing the bullet 200 within the rifle barrel the seal should be adequate, but should not generate excessive friction in the barrel. Therefore, the contact area between the bullet 200 and the barrel is kept as small as possible. To enable the band 208 to engage the rifling without exerting excessive force on the barrel or attempting to distort the bullet, the band 208 may have a series of alternate ridges 210 , the diameter of which is equal to the rifled diameter, and grooves 212 which have a diameter smaller than the rifle barrel bore diameter. When the bullet 200 is fired the ductile material of each ridge 210 is displaced by the forward motion of the bullet 200 engaging into the rifling and is easily swaged into the immediately following groove 212 without increasing pressure between the bullet an the barrel. The band 208 can be made of any suitable ductile metallic or non-metallic material and is attached to the body 202 securely in the recess 206 . This can be done by mechanical means if the band 208 is made of ductile metal such as copper, or by molding-on if it is made from a suitable ductile polymer. The profile of the bullet 200 , which is similar to that of current types, gives the desired performance owing to its aerodynamic efficiency. However, the bullet 200 , once fired, remains supersonic for a longer period of time. The result of having the heavy bullet body 202 at a minimum length together with a drive band 208 is that less pressure is generated in the breech and the time that the bullet 200 spends in the barrel is reduced with reduced friction being imparted on the bullet 200 . This gives a higher muzzle velocity, extended range and more uniform performance with any bullet/cartridge/powder-charge combination. The bullet 200 thus allows a shooter to shoot, with accuracy, over a longer range for a given size of the fire arm. Thus, for a given range desired, the size of arm to be carried is kept to a minimum. This removes the harmonic effect (the way a barrel “wags”) which is a result of increasing barrel length when achieving longer ranges with the larger of the small arms. detailed-description description="Detailed Description" end="tail"? |
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