The present invention describes a method for producing a useful metabolite using a bacterium of the family Enterobacteriaceae, particularly a bacterium belonging to the genus Escherichia, which has been modified to contain a gene(s) expression system including elements of the LysR-type protein-regulated transcriptional machinery modified in such a way that auto-inducible positive feedback regulation of the system is mediated by a coinducer. The method is suitable for producing branched-chain L-amino acids, particularly L-valine, L-isoleucine and L-leucine; and D-pantothenic acid.

Field of the Invention
The present invention relates to the microbiological industry, and specifically to a method for producing useful metabolites by fermentation of a bacterium of the family Enterobacteriaceae, wherein the LysR-type protein-regulated expression system of the bacterium has been modified in such a way that functionality of said expression system is mediated by a coinducer, and as a result, the expression levels of the genes regulated by said expression system are enhanced. More specifically, the expression system and the method can be useful for improving the production of metabolites from synthetic pathways of L-amino acids, such as the branched-chain L-amino acid.
Brief Description of the Related Art
Conventionally, L-amino acids are industrially produced by fermentation methods utilizing strains of microorganisms obtained from natural sources, or mutants thereof. Typically, the microorganisms are modified to enhance production yields of L-amino acids.
Many techniques to enhance L-amino acid production yields have been reported, including transformation of microorganisms with recombinant DNA (see, for example, U.S. Pat. No. 4,278,765) and alteration of regulatory regions such as promoter, leader sequence, and/or attenuator or others known to the person skilled in the art (see, for example, US20060216796 A1 and WO9615246 A1). Other techniques for enhancing production yields include increasing the activities of enzymes involved in amino acid biosynthesis and/or desensitizing the target enzymes to the feedback inhibition by the resulting L-amino acid (see, for example, WO9516042 A1, EP0685555 A1 or U.S. Pat. Nos. 4,346,170, 5,661,012, and 6,040,160). For example, the mutant bacterial acetohydroxy-acid synthetase I (also referred to as acetolactate synthase I, hereinafter AHAS I) which is resistant to feedback inhibition by L-valine has been utilized for improving branched-chain L-amino acid production in corresponding L-amino acid producing strains (Russian Patent No. 2355763).
The biosynthesis of branched-chain L-amino acids (BCAAs), such as L-valine, L-leucine, and L-isoleucine, occurs through a branched biosynthetic pathway. Acetolactate synthase (the enzyme classification (EC) number 18.104.22.168) catalyzes the reaction in the first step in the pathway, which is common to all three amino acid's biosynthetic pathways. The reaction includes condensation of activated acetaldehyde (2-(α-hydroxyethyl)thiamine diphosphate) derived from pyruvate with either pyruvate or 2-oxobutanoate to yield 2-acetolactate (AL) or 2-aceto-2-hydroxybutanoate (AHB), respectively. AL is a precursor of L-valine and L-leucine, and AHB is a precursor of L-isoleucine. In Escherichia coli (E. coli), for example, reactions between pyruvate molecules, as well as reactions between pyruvate and 2-oxobutanoate, are catalyzed by the three AHAS isozymes, AHAS I, AHAS II, and AHAS III, which are encoded by the ilvBN, ilvGM, and ilvIH genes, respectively. AHAS I and AHAS III are the targets for the end-product inhibition (also referred to as feedback inhibition) by L-valine. The feedback inhibition by the end-product plays a major role in the physiological control of these pathways in bacteria.
The products of the AHAS catalyzed reaction, AL or AHB, are the substrates for 2-acetohydroxy acid isomeroreductase IlvC (EC 188.8.131.52) which is encoded by the ilvC gene, a member of the ilvYC operon. The ilvYC operon of E. coli is a prototypical LysR protein-regulated system which is the most common type of positive regulatory system in bacteria, and can be found in prokaryotic bacterial families ranging from Enterobacteriaceae to Rhizobiaceae (Rhee K. Y. et al., Proc. Nat. Acad. Sci. USA, 1999, 96:14294-14299). The ilvY gene encodes the LysR-type regulatory protein IlvY, a transcriptional regulator, which binds in a highly cooperative fashion to two tandem operator regions in the divergent-overlapping ilvYC promoter region (FIG. 1). Upon binding to the first operator region, the IlvY regulator negatively auto-regulates transcription from the ilvY promoter thus attenuating its own synthesis. Apart from this function, IlvY plays a pivotal role in activation of transcription of the ilvC gene. Activation of ilvC transcription requires binding of the IlvY regulator to the second operator region and additional binding of a coinducer such as 2-acetolactate (AL) or 2-aceto-2-hydroxybutanoate (AHB) to a preformed IlvY/DNA complex. Upon binding a coinducer, a conformational change in the protein/DNA complex occurs that remodels the −35 region of the ilvC promoter and drastically increases RNA polymerase binding capacity (Rhee K. Y. et al., J. Biol. Chem., 1998, 273:11257-11266).
In the L-valine and L-leucine biosynthesis, 2-acetolactate (AL) is converted by the IlvC protein into 2,3-dihydroxy-3-methylbutanoate (also referred to as 2,3-dihydroxy-isovalerate, DHIV) (FIG. 2). In L-isoleucine biosynthesis, 2-aceto-2-hydroxybutanoate (AHB) is converted by IlvC into 2,3-dihydroxy-3-methylpentanoate (also referred to as 2,3-dihydroxy-3-methylvalerate, DHMV).
Recently, auto-inducible gene expression systems were recognized as being very attractive for enhancing expression of a desired gene over routine genetic approaches. For example, the literature provides an artificially designed positive feedback-based gene expression system that can function as a genetic signal amplifier heightening the sensitivity to protein inducer signals as well as increasing maximum expression levels without the need for the external cofactor acyl homoserine lactone (AHL, also abbreviated as HSL) (Nistala G. J. et al., J. Biol. Eng., 2010, 4:4). The designed system utilizes a constitutively active variant of the quorum-sensing (QS) regulator LuxR (lux operon) from Vibrio fischeri, which is auto-inducer (AHL)-independent due to the Ala221Val point mutation (Sayut D. J. et al., Biochem. Biophys. Res. Commun., 2007, 363:667-673; Poellinger K. A. et al., FEMS Microbiol Lett., 1995, 129:97-101). A similar gene expression system with slight variations has been applied to manipulate the expression kinetics of a model membrane protein, cytochrome bd quinol oxidase in E. coli (Bansal K. et al., J. Biol. Eng., 2010, 4:6).
The auto-inducible positively feedback regulated activation system based on quorum-sensing machinery from V. fischery (lux bioluminescence genes) and an endogenous source of an auto-inducer (HSL) have been utilized for expressing recombinant proteins such as as antigens to prepare pharmaceutical compositions (WO2010136897 A2).
However, no data has been reported to date describing a LysR-type protein-regulated gene(s) expression system modified in such a way that the functionality of said expression system is mediated by a coinducer, and the use thereof for production of useful metabolites from the biosynthetic pathway of L-amino acid such as branched-chain L-amino acids and/or a branched off pathway thereof.

Auto-indicible expression system, and the use thereof for producing useful metabolites using a bacterium of the family


Systems, devices, and methods for performing a microphone test routine are disclosed during an initial setup of a speech recognition program and at a predetermined time intervals during use of the speech recognition program to detect recognition errors associated with the microphone.

This invention relates to voice recognition software, and more particularly to microphone setup for voice recognition tutoring software to assist in reading development.
A microphone receive varying pressure waves in the air and converts the pressure waves into varying electrical signals. In order to produce a good quality signal, the microphone should be set up correctly. In reading fluency software, setup of the microphone can influence signal quality, which can influence the comparison of received audio to stored patterns for pronunciation and fluency determinations. Microphone setups often include placement of the microphone relative to the user and adjustment of the gain based on the strength of the received signals.

Microphone setup and testing in voice recognition software


A method of treating a disorder of the alimentary system in an animal by administration to the animal an effective amount of an extract of a plant of the genus Hoodia or Trichocaulon; or a compound of the formula

This application is filed claiming priority from co-pending Application No. GB9925457.5 filed Oct. 27, 1999.
This invention relates to the reduction of gastric acid secretion in animals including humans; to methods of treating conditions or disorders associated with or exacerbated by gastric acid secretion; to pharmaceutical compositions useful in carrying out such methods; and to the use of certain extracts and compounds in the treatment of human and non-human animals, generally mammals.
Excessive secretion of gastric acid can lead to or aggravate a number of disorders, for example oesophageal reflux disease, e.g. reflux oesaphagitis, haemorrhage in and benign ulceration of the stomach and duodenum (including those complicating NSAID therapy). These conditions tend to be more problematical in obese patients and patients with hiatus hernia. The present invention is directed, in part, to the treatment of these conditions and of ancillary indications, e.g. to provide relief of reflux-like symptoms (e.g. heartburn) and/or ulcer-like symptoms (e.g. epigastric pain) associated with acid-related dyspepsia; for general dyspeptic symptoms; and for prophylaxis of acid aspiration.
Non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin (acetylsalicylic acid), are well-known and widely used for their anti-inflammatory and antipyretic properties. A major side effect is their tendency to damage the wall of the stomach; this adverse property is acid-dependent and is generic to the NSAIDs. The present invention is also concerned with means for mitigating these adverse effects.
It is known from International Patent Publication No. WO 98/46243 that extracts of certain plants of the genus Trichocaulon or Hoodia possess appetite suppressant properties. This document also discloses certain specific compounds which possess appetite suppressant activity. Among these is the compound 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one; the structural formula of this compound is given as formula (1) in WO 98/46243. We have found that this compound is effective in reducing the secretion of gastric acid; accordingly, the compound finds application in the present invention. Derivatives of this compound are also effective in the present invention; such derivatives have the general formula
which
R=alkyl;
R1=H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2=H, or one or more 6-deoxy carbohydrate, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof;
in which the acyl group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94;
and in which the dashed lines indicate the optional presence of a double bond in the C4-C5 or C5-C6 positions.
Thus, according to a first aspect of the present invention, there is provided a method of reducing gastric acid secretion in an animal, which comprises administering to said animal:
(a) an extract of a plant of the genus Hoodia or Trichocaulon; or
(b) a compound of the formula
xe2x80x83wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
Advantageously, when R1 is an organic ester group it is tigloyl,benzoyl or anthraniloyl. In a preferred embodiment, R is an alkyl group having from one to four carbon atoms, R1 is tigloyl or anthraniloyl; and a double bond is present in the C5-C6 position.
Advantageously, R2 is trisaccharide group. The component sugars of said trisaccharide group are preferably 6-deoxy and/or 2,6-dideoxy hexoses. In some embodiments, the terminal hexose moiety is thevetosyl.
The compound may be 3-O-[-xcex2-D-thevetopyranosyl-(1-4)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one.
According to a second aspect of the present invention, there is provided a method of treating a disorder of the alimentary system in an animal, which comprises administering to the animal
(a) an extract of a plant of the genus Hoodia or Trichocaulon; or
(b) a compound of the formula
xe2x80x83wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
This method can conveniently be used in the treatment of reflux oesophagitis. It is also expected to find application in the treatment of epigastric pain; dyspepsia; gastric ulceration; and acid aspiration.
According to a third aspect of the present invention, there is provided a method of protecting a mammalian gastro-intestinal tract from damage caused by a non-steroidal anti-inflammatory drug, which comprises administering an effective amount of:
(a) an extract of a plant of the genus Hoodia or Trichocaulon; or
(b) a compound of the formula
xe2x80x83wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
According to a fourth aspect, the present invention provides a method of protecting a mammalian gastro-intestinal tract from damage caused by a non-steroidal anti-inflammatory drug, which comprises administering an effective amount of [3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof.
When a plant extract is used in the invention, it is presently preferred to use an extract from the plant Hoodia gordonii or Hoodia currori. Advantageously, the said extract comprises spray-dried sap of the plant Hoodia gordonii.
The methods in accordance with this invention are applicable to the treatment of humans.
According to a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising a non-steroidal anti-inflammatory drug and a compound of the formula
wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
in which the acyl-group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94;
and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position.
A preferred pharmaceutical composition of this type utilises the compound 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof. The pharmaceutical compositions of this invention are conveniently prepared in unit dosage form; they may also include a pharmaceutically acceptable diluent, excipient or carrier.
According to a sixth aspect of the present invention, there is provided method of treating a condition or disorder caused by or exacerbated by gastric acid secretion in an animal, which comprises administering to the animal a pharmaceutical composition as just defined. The animal may be a human.
According to a seventh aspect, the present invention provides the use of a compound of the formula
wherein:
R=an alkyl group containing from one to four carbon atoms;
R1=H, an alkyl group containing from one to four carbon atoms, or an organic ester group;
R2=H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose, or a combination thereof;
in which the acyl group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94; and in which the dashed bonds indicate the optional presence of a double bond at the C4-C5 position or the C5-C6 position,
in the manufacture of a medicament for the treatment of a disorder caused by or exacerbated by gastric acid secretion. For such use, the compound may be 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof.
According to an eighth aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for the treatment of conditions and disorders caused by or exacerbated by gastric acid secretion. The condition or disorder for which the medicament is intended may be reflux oesophagitis; or gastric or duodenal ulceration; gastro-duodenal erosion; or epigastric pain.
According to a ninth aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for the treatment of conditions and disorders caused by or exacerbated by gastric acid secretion.
According to a tenth aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for the treatment of reflux oesophagitis.
According to an eleventh aspect, the present invention provides the use of an extract of a plant of the genus Hoodia or Trichocaulon in the manufacture of a medicament for preventing or reducing gastric damage associated with use of a non-steroidal anti-inflammatory drug.
According to a twelfth aspect, the present invention provides the use of 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one or a derivative thereof in the manufacture of a medicament for preventing or reducing gastric damage associated with use of a non-steroidal anti-inflammatory drug.
The extracts of a plant of the genus Hoodia or Trichocaulon useful in the present invention may generally be prepared by extracting sap from the plant and then spray-drying the sap. Alternatively, solvent extraction procedures may be employed. In either case, fractionation of the initial extract, e.g. by column chromatography, may follow in order to generate am extract with enhanced activity.
The extract may be prepared from plant material such as the stems and roots of plants of the genus Hoodia or the genus Trichocaulon; these genera include succulent plants which grow in the arid regions of southern Africa. Advantageously, the plant extract is obtained from one of the following species: Trichocaulon piliferum; Trichocaulon officinale; Hoodia currorii; Hoodia gordonii; and Hoodia lugardii.
The plant material may be homogenised in the presence of a suitable solvent, e.g. a methanol/methylene chloride solvent, by means of a device such as a Waring blender. The extraction solution may then be separated from residual plant material by an appropriate separation procedure such as, for example, filtration or centrifugation. The solvent may, for example, be removed by means of a rotary evaporator, preferably in a water bath at a temperature of 60xc2x0 C. The separated crude extract may then be further extracted with methylene chloride and water before being separated into a methylene chloride extract and a water extract. The methylene chloride extract may have the solvent removed by, for example, a rotary evaporator and the resultant extract may be further purified by way of a methanol/hexane extraction. The methanol/hexane extraction product may then be separated to yield a methanol extract and a hexane extract. The methanol extract may be evaporated to remove the solvent in order to yield a partially purified active extract.
The partially purified active extract may be dissolved in methanol, and may be further fractionated by column chromatography, employing silica gel as an adsorption medium and a chloroform/30% methanol mixture as eluent. A plurality of different fractions may be obtained, and each may be evaluated, by suitable bioassaying procedures, to determine their activity. High activity fractions may be further fractionated, e.g. by column chromatography using silica gel as an adsorption medium and a 9:1 chloroform:methanol eluent. This process may be repeated using silica gel as an adsorption medium and a 9:1 ethylacetate:hexane eluent.
Alternatively, the plant product may be compressed or macerated to extract sap therefrom, then filtered to remove unwanted solids and freeze-dried. The freeze-dried sap product may then be further purified, if desired, for example using chromatographic fractionation such as described above.
The derivatives of 3-O-[-xcex2-D-thevetopyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl-(1xe2x86x924)-xcex2-D-cymaropyranosyl]-12xcex2-O-tigloyloxy-14-hydroxy-14xcex2-pregn-5-en-20-one which find use in this invention are advantageously of the formula:
in which
R=alkyl;
R1=H, alkyl, tigloyl, benzoyl, or any other organic ester group;
R2=H or alkyl;
R3=H or OH;
in which the acyl group Rxe2x80x94(Cxe2x95x90O)xe2x80x94 group can be in the reduced form Rxe2x80x94(Cxe2x80x94OH)xe2x80x94;
and in which the dashed lines indicate the optional presence of a further bond in the C4-C5 or C5-C6 positions;
The invention will be illustrated by the following Examples:

Abstract: is described.


The circular animal toilet enclosure of this invention has a bottom section removably coupled to a rotatable flywheel floorboard, a cover cylinder removably coupled to the bottom section, a top section removably coupled to the cover cylinder, and a controller for the enclosure. The rotatable flywheel floorboard has pivoting serrated portions for grinding excreta while the floorboard is rotating. The cover cylinder has fixed serrated portions aligned with the pivoting serrated portions for grinding excreta while said floorboard is rotating. The cover cylinder also has at least one door, and at least one shower head in fluid communication with a water supply, an upper ring, waste collection tube, and a second drive motor. The upper ring is in fluid communication with both the rotatable flywheel floorboard and the waste collection tube. The waste collection tube is in fluid communication with a sewer. The second drive motor is removably coupled to the rotatable flywheel floorboard. The enclosure is controlled by electric and electronic devices for periodically energizing an enclosure control system.

As the density of human population continues to grow in the more affluent countries, the total number of domestic pets has created an increasing problem of how to simply and safely dispose of pet excreta. Any system or product that can solve this problem must be reliable, compatible with the natural instincts of pets, not expensive to buy and operate, easy to manufacture with few moving parts to allow a reasonable manufacturer's guarantee period as well as being readily acceptable by health and police officials.
In review of the previous art in the field, the following patents were consulted:
U.S. Pat. No.InventorDate3,817,213ChalmarsJun. 18, 19743,949,429HallApr. 13, 19763,964,437BrownJun. 22, 19764,010,970CampbellMay 8, 19774,050,415Knochel et alSep. 27, 19774,117,555DennisOct. 3, 19784,185,861BernerMay 29, 19804,196,693UversawApr. 8, 19804,228,554TumminaroOct. 21, 19804,660,506NalvenApr. 28, 19876,014,946RymerJan. 18, 20006,039,370Dooley, Jr. et alMar. 31, 20006,457,435BridgesOct. 1, 20026,554,335Kelly, et alApr. 29, 20036,561,131SchwartzMay 13, 20036,568,348BedardMay 27, 2003
The listed patents can be grouped under a few headings relative to their design and the difficulties and problems that might arise if they were in wide usage by the public.
The first grouping could be: use of the same device by both animals and humans. This is exemplified by the patents of Hall, 1976 and Rymer, 2000. These patents use a modified toilet seat that expands and contracts enough to manually arrange it as a seat for use by both humans and animals. Many humans would shy away from such use and it is very difficult to train an animal to void excreta while sitting or standing on a toilet stool seat.
The second grouping could be: use of a funnel shaped floor or platform. This is presented in patents by Brown, 1976 and by Tumminaro, 1980. The sloping floor, while stable, creates a training problem for use by any animal and in the case of Brown required that a human push a button to initiate cleaning action.
The third grouping could be: unstable floor or platform in order to initiate some mechanical action by downward movement of the floor. This is presented in patents by Knochel et al, 1977, Dennis, 1978, Unversaw, 1980, and Nalvern, weight down on a surface and it begins to move downward which would make training animals for this type of animal toilet very difficult.
The fourth grouping could be: the use of drain holes for removal of excreta in a flat stable board. This is exemplified by the patent of Bridges, 2002. Although it has the use of electronics to assist in the activation of cleaning of the flat stable board, there is no good mechanism for the cleaning of the underside of the board. It is removable to assist in this. The board also contains permanent open holes to allow the excreta to pass through. These holes are open while the animal is in the unit and constitute a hazard for harm to the legs of the animal.
The fifth group is probably not strictly an animal toilet so that it could be called: catch pouch on a pole or a pooper bag. Both Dooley, 2000, and Kelly, 2003, present this concept very well in their patents. However, this system is not automatic and requires a great deal of human intervention.
The sixth group could be entitled: the complex litter box. This concept is presented well in the patents of Schwartz, 2003, and Bedard, 2003. However, the use is limited to cats and involves special clumpable litter wherein the urine is removed as clumps of congealed litter along with fecal material by mechanical means such as rakes.
Although several patents have been issued for animal toilet inventions over many years, none have successfully solved the problem by presenting an acceptable method to the general public for rapid, simple economical disposal of dog and cat excreta. There has been no change in the handling of dog and cat excreta as compared to that of human excreta which has progressed from outdoor toilets to modern indoor toilets in bathrooms of first world people. A parallel development has been the invention of modern day washers and dryers for clothes and for dishes.


A method, performed by one or more computer devices, may include generating a sequence script for a venue event, wherein the sequence script is configured to synchronize a plurality of user devices located at the venue during the venue event to form one or more images discernable when the devices are viewed collectively. The method may further include obtaining user registration information associated with the venue event, wherein the user registration information identifies user devices registered to participate in the generation of the one or more images; detecting a trigger event associated with the sequence script; and orchestrating the plurality of user devices to form the one or more images, in response to detecting the trigger event.

Spectators at large scale events, such as sport stadiums, often participate in group activities while attending an event. For example, the spectators may perform a group chant to cheer on a sports team, may hold up lighters in the air, or may stand up or raise their arms to participate in a wave that travels through a section of the stadium. The spectators may find it difficult to coordinate such participatory events.

Orchestrating user devices to form images at venue events


The present invention is directed to a method for preparing 3,4-trans-4-ethyl-1,3-disubstituted (substituted phenyl)pyrrolidine-2-one represented by the formula (1) ##STR1## which comprises the steps of dissolving 4-ethyl-1,3-disubstituted (substituted phenyl)-3-pyrroline-2-one in an inert solvent, and then reducing the same with sodium boron hydride in the presence of methanol.

(a) Field of the Invention
The present invention relates to a method for preparing a pyrrolidine derivative represented by the formula (1) ##STR2## (wherein R.sup.1 is a hydrogen atom, halogen atom or methyl group; R.sup.2 is a hydrogen atom, alkyl group having 1 to 3 carbon atoms, trifluoromethyl group, haloalkoxy group having 1 to 3 carbon atoms, alkoxy group having 1 to 4 carbon atoms, nitro group, cyano group, phenoxy group, hydroxyl group or halogen atom; X is a hydrogen atom, halogen atom, trifluoromethyl group, alkyl group having 1 to 3 carbon atoms, cyano group or nitro group; and n is 1 or 2 and denotes the number of substituents represented by X, and in the case of n=2, the substituents of X may be identical or different, but R.sup.1, R.sup.2 and Xn are not simultaneously hydrogen).
3,4-trans-4-ethyl-1,3-disubstituted (substituted phenyl)pyrrolidine-2-one represented by this formula has a herbicidal activity.
(b) Description of the Prior Art
It has already been disclosed that certain kinds of pyrrolidine-2-one derivatives have a herbicidal activity (U.S. Pat. No. 4,110,105, EP-A-134,564, U.S. Pat. No. 4,874,422 and U.S. Pat. No. 4,960,457). Thus, 3-chloro-4-chloromethyl-1-(3-trifluoromethylphenyl)pyrrolidine-2-one (general name "flurochloridone") is on the market as a herbicide. In EP 387,869, there are described parts of compounds which can be prepared by the method of the present invention.
These compounds can all be manufactured by a radical cyclizing reaction using tributyltin hydride, and in this case, the pyrrolidine-2-one derivative is obtained as a mixture of a 3,4-trans isomer and a cis isomer. Since the 3,4-trans isomer only has the herbicidal activity, this known method is not preferable as a manufacturing process of the herbicidal compound.
A compound represented by the formula (1) can be obtained by subjecting a compound represented by the formula (2) ##STR3## (wherein R.sup.1, R.sup.2, X and n are as defined above) to a catalytic hydrogenation reaction using palladium, platinum or the like as a catalyst. However, this reaction is not preferable, because when a chlorine atom or bromine atom is present in a substituent on the benzene ring, the elimination reaction of this halogen atom occurs together with the reduction of a double bond a the 3 and 4 positions of 3-pyrroline-2-one and it is very difficult to separate the desired compound.
Among the compounds represented by the formula (1), only compounds in which a steric configuration at the 3 and 4 positions of the pyrrolidine-2-one is in the trans state have the herbicidal activity. In the catalytic hydrogenation reaction using the metallic catalyst, the cis isomer is only obtained. In order to obtain the trans isomer, it is necessary to further carry out isomerization by the use of a base, which involves one more process step. Since this isomerization is an equilibrium reaction, the cis isomer partially remains in the obtained reaction product, and therefore this known technique is unsatisfactory as the preparation method of the compound for the herbicide.

Method for preparing pyrrolidine derivatives


A stabilizer can include an attachment surface and a non-stick surface. Multiple stabilizers can be arranged in a stack, e.g., such that the attachment surface of one stabilizer is engaged with the non-stick surface of another stabilizer. A stabilizer can be removed from the stack and attached to an item having a curved surface along the length of the item. The item, with the stabilizer attached, can be positioned on a conveyance surface, e.g., such that the stabilizer is between the conveyance surface and the item.

Inventory systems, such as those in warehouses, supply chain distribution centers, airport luggage systems, and custom-order manufacturing facilities, face significant challenges in storing and transporting inventory items. The inventory items can be moved around. As the amount of inventory stored at a single location continues to grow, inefficient utilization of system resources, including space and equipment can result in lower throughput, unacceptably long response times, an ever-increasing backlog of unfinished tasks, and, in general, poor system performance. The inventory items can have various sizes and shapes that may use stabilization devices while moving around the inventory system.


Antisense compounds, compositions and methods are provided for modulating the expression of G-alpha-12. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding G-alpha-12. Methods of using these compounds for modulation of G-alpha-12 expression and for treatment of diseases associated with expression of G-alpha-12 are provided.

A vast majority of biologically active molecules including growth factors, cytokines, neurotransmitters and hormones transduce signals via specific cell-surface receptors. Some of these receptors are then coupled to heterotrimeric GTP-binding proteins (G proteins) which, upon activation, relay signals to a variety of cellular effectors including at least four phospholipase C (PLC) variants and adenylyl cyclases.
G proteins mediate external signals by forming heterotrimers consisting of an alpha, beta and gamma subunit. Several isoforms of each subunit have been identified and therefore, through subunit heterogeneity, G proteins effectively integrate multiple signaling cascades. The alpha subunits of G proteins contain the GTP binding site and intrinsic catalytic GTPase activity. Based on sequence similarity and function, these subunits have been classified into four major groups; Gs, which stimulate adenylyl cyclases; Gi, which inhibit adenylyl cyclases; Gq, which activate PLC isoforms and G12/13, which mediate pathways associated with cell growth and differentiation (Hamm, J. Biol. Chem., 1998, 273, 669-672).
G-alpha-12 is a member of the G12/13 subfamily of G proteins and is activated by a variety of stimuli. It has been shown to participate in several kinase cascades including MAPK, ERK and JNK (Jho et al., J. Biol. Chem., 1997, 272, 24468-24474; Voyno-Yasenetskaya et al., J. Biol. Chem., 1996, 271, 21081-21087) as well as being phosphorylated by protein kinase C (Kozasa and Gilman, J. Biol. Chem., 1996, 271, 12562-12567). Consequently, G-alpha-12 has been shown to participate in cellular processes as diverse as mitogenesis (Mitsui et al., J. Biol. Chem., 1997, 272, 4904-4910), regulation of pH (Lin et al., J. Biol. Chem., 1996, 271, 22604-22610) and platelet activation (Collins et al., Oncogene, 1997, 15, 595-600).
The primary function of G-alpha-12, however, is believed to be the mediation of cell differentiation and growth. Therefore the manifestations of altered G-alpha-12 expression, specifically as it relates to the development of cancer, have been the most broadly investigated.
Cellular transformation and acquisition of the metastatic phenotype are the two main changes normal cells undergo during the progression to cancer and these processes are believed to be linked to the expression of G-alpha-12.
G-alpha-12 was first isolated from a soft tissue sarcoma cDNA library and overexpression of the protein was shown to be sufficient to induce cellular transformation (Chan et al., Mol. Cell. Biol., 1993, 13, 762-768).
In studies of NIH3T3 and Rat-1 fibroblasts, constitutively active mutant forms of G-alpha-12 were shown to induce transformation as indicated by increased proliferation, loss of contact inhibition, focus formation and increased DNA synthesis (Voyno-Yasenetskaya et al., Oncogene, 1994, 9, 2559-2565).
Results from studies in human embryonic kidney cells demonstrated that constitutive activation of G-alpha-12 stimulated RhoA-dependant phosphorylation of p125 focal adhesion kinase, paxillin and p130 Crk-associated substrate, all of which have been implicated in the regulation of proliferation and transformation (Needham and Rozengurt, J. Biol. Chem., 1998, 273, 14626-14632).
Finally, studies using both antisense vectors expressing a 43 base fragment of mouse G-alpha-12 in antisense orientation and constitutively active forms of G-alpha-12 to investigate retinoic acid-stimulated differentiation of P19 mouse embryonal carcinoma cells found that G-alpha-12 activity was essential to the differentiation process (Jho et al., J. Biol. Chem., 1997, 272, 24468-24474; Jho and Malbon, J. Biol. Chem., 1997, 272, 24461-24467).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of G-alpha-12 and strategies aimed at inhibiting or investigating G-alpha-12 function have involved the use of antibodies, mutant forms of the protein which are constitutively active and antisense expression vectors.
These strategies are untested as therapeutic protocols and consequently there remains a long felt need for additional agents capable of effectively inhibiting G-alpha-12 function. Therefore, antisense oligonucleotides may provide a promising new pharmaceutical tool for the effective and specific modulation of G-alpha-12 expression.

Antisense inhibiton of human G-alpha-12 expression


A high performance, efficiency compact optical light beam and modifier system with reduced artifacts is presented. The design may incorporate a spiral entrance aperture with corresponding spiral masks where modification is accomplished by rotating the masks about the central axis relative to the entrance aperture. Light recapture or complex, continuous optics may be employed to increase the optical efficiency, reduce the physical dimensions, integrate condensing, or image projection functions in a reduced number of optical components.

Light beam optical and control systems applied illumination fixtures are well known and the subject of extensive invention for millennia including historic navigational lighthouses and beacons. With the advent of the carbide and electric light sources, applications included railroad search lights, automobile headlights and interior lighting. Architectural and theatrical lighting borrowed from extensively from these technologies.
Construction of an inexpensive, compact, high efficiency, color and intensity control system with acceptable image optics has been a long-sought goal and the subject of extensive invention. These systems are almost exclusively concentric, radial, aligned and axially symmetric.
Representative examples include patents by Naujoks, U.S. Pat. No. 1,045,063; Centeno, U.S. Pat. No. 2,186,203; Colao, U.S. Pat. No. 3,881,810 Gulliksen, U.S. Pat. No. 4,316,241; Solomon, U.S. Pat. No. 4,811,182; Bornhorst, U.S. Pat. No. 5,882,107; Callahan, U.S. Pat. No. 4,697,227; Richardson, U.S. Pat. Nos. 6,048,081, 6,142,652, 6,502,961; Wood, U.S. Pat. No. 6,796,683 and others. Construction of a compact, high resolution light beam modifier as disclosed by the prior art is expensive, inefficient or replete with visual artifacts.


A peripheral device with accessory identification capability includes a device body and at least one accessory. The device body includes a processing unit disposed therein. The at least one accessory is releasably attached to the device body and selectively coupled to the processing unit. When the at least one accessory is attached to the device body and coupled to the processing unit, the processing unit identifies the at least one accessory and instructs at least one function of the device body to be performed, based on at least one identification code of the identified at least one accessory.

The conventional peripheral devices, computer mice for example, are already equipped with removable function modules, such as an optical sensor module, laser sensor module and so on, so that the computer mouse can have different functions according to the different removable function modules. However, the conventional peripheral devices neither identify the removable decorative accessories thereof, such as different decorative cases, nor do they perform the corresponding functions of identified accessories.

Peripheral device with accessory identification capability


A program pulse is applied to a set of non-volatile storage elements. The magnitude of the program pulse is chosen to be low enough such that no non-volatile storage elements will be over programmed. The non-volatile storage elements are tested to determine whether at least one non-volatile storage element (or some other minimum number) has been programmed past a test threshold. If so, the set of non-volatile memory elements is considered to have one or more fast programming non-volatile storage elements and future programming is performed using a smaller increment value for subsequent program pulses. If the set of non-volatile memory elements is not determined to have one or more fast programming non-volatile storage elements, then a larger increment value is used for subsequent program pulses until one non-volatile storage element (or some other minimum number) has been programmed past the test threshold, at which point the smaller increment value is used for subsequent program pulses.

1. Field of the Invention
The present invention relates to programming non-volatile memory.
2. Description of the Related Art
Semiconductor memory devices have become more popular for use in various electronic devices. For example, non-volatile semiconductor memory is used in cellular telephones, digital cameras, personal digital assistants, mobile computing devices, non-mobile computing devices and other devices. Electrical Erasable Programmable Read Only Memory (EEPROM) and flash memory are among the most popular non-volatile semiconductor memories.
Both EEPROM and flash memory utilize a floating gate that is positioned above and insulated from a channel region in a semiconductor substrate. The floating gate is positioned between source and drain regions. A control gate is provided over and insulated from the floating gate. The threshold voltage of the transistor is controlled by the amount of charge that is retained on the floating gate. That is, the minimum amount of voltage that must be applied to the control gate before the transistor is turned on to permit conduction between its source and drain is controlled by the level of charge on the floating gate.
When programming an EEPROM or flash memory device, typically a program voltage is applied to the control gate and the bit line is grounded. Electrons from the channel are injected into the floating gate. When electrons accumulate in the floating gate, the floating gate becomes negatively charged and the threshold voltage of the memory cell is raised so that the memory cell is in the programmed state. More information about programming can be found in U.S. patent application Ser. No. 10/379,608, titled "Self Boosting Technique," filed on Mar. 5, 2003; and in U.S. patent application Ser. No. 10/629,068, titled "Detecting Over Programmed Memory," filed on Jul. 29, 2003, both applications are incorporated herein by reference in their entirety.
Some EEPROM and flash memory devices have a floating gate that is used to store two ranges of charges and, therefore, the memory cell can be programmed/erased between two states (an erased state and a programmed state). For example, FIG. 1 shows a graph depicting two threshold voltage distributions. The x axis plots threshold voltage and the y axis plots the number of memory cells. Threshold voltage distribution 2 is less than zero volts. In one embodiment, threshold voltage distribution 2 corresponds to erased memory cells that store data "1." Threshold voltage distribution 4 is greater than zero volts. In one embodiment, threshold voltage distribution 4 corresponds to programmed memory cells that store data "0."
A multi-state flash memory cell is implemented by identifying multiple, distinct allowed threshold voltage ranges separated by forbidden voltage ranges. Each distinct threshold voltage range corresponds to a predetermined value for the set of data bits. FIG. 2 illustrates threshold voltage distributions for memory cells storing two bits of data (e.g., four data states). In one embodiment, threshold voltage distribution 2 represents memory cells that are in the erased state (e.g., storing "11"), having negative threshold voltage levels. Threshold voltage distribution 10 represents memory cells that store data "10," having positive threshold voltage levels. Threshold voltage distribution 12 represents memory cells storing data "00." Threshold voltage distribution 14 represents memory cells that are storing "01." In other embodiments, each of the distributions can correspond to different data states than described above. In some implementations (as exemplified above), these data values (e.g. logical states) are assigned to the threshold ranges using a gray code assignment so that if the threshold voltage of a floating gate erroneously shifts to its neighboring physical state, only one logical bit will be affected. The specific relationship between the data programmed into the memory cell and the threshold voltage ranges of the cell depends upon the data encoding scheme adopted for the memory cells. For example, U.S. Pat. No. 6,222,762 and U.S. patent application Ser. No. 10/461,244, "Tracking Cells For A Memory System," filed on Jun. 13, 2003, both of which are incorporated herein by reference in their entirety, describe various data encoding schemes for multi-state flash memory cells. Additionally, the present is applicable to memory cells that store more than two bits of data.
Threshold voltage distributions 2 and 4 show the erased and programmed voltage-distributions when no verify operations are used. These distributions can be obtained by programming or erasing the memory cells with one single programming or erase pulse. Depending on the memory array size and the variations in the production process, the threshold voltage distribution 4 has a certain width, known as the natural Vt width.
As can be seen from FIG. 2, distributions 10, 12, and 14 (corresponding to programming a multi-state device) need to be much narrower than the natural Vt width of distribution 4. To achieve such narrower threshold voltage distributions a process that uses multiple programming pulses and verify operations, such as that described by FIGS. 3A, 3B, and 3C, can be used.
FIG. 3A depicts a programming voltage signal Vpgm that is applied to the control gate as a series of pulses. The magnitude of the pulses is increased with each successive pulse by a pre-determined step size (e.g., 0.2 v–0.4 v), depicted in FIG. 3A as ΔVpgm. In the periods between the pulses, verify operations are carried out. As the number of programmable states increase, the number of verify operations increases and more time is needed. One means for reducing the time-burden is a more efficient verified process, such as the process that is disclosed in U.S. patent application Ser. No. 10/314,055 "Smart Verify For Multi-State Memories," filed Dec. 5, 2002, incorporated herein by reference in its entirety. In reality, the pulses of FIG. 3A are separated from each other by a time period for verification. However, to make FIG. 3 more readable, the time period for verification is omitted from the drawing.
FIG. 3B depicts the voltage signal applied to a bit line for the associated memory cell being programmed. FIG. 3C depicts the threshold voltage of the memory cell being programmed. Note that the graph in FIG. 3C is smoothed out to make it easier to read. After each programming pulse, a verify operation is carried out (not shown.) During the verify operation, the threshold voltage of the memory cell to be programmed is checked. If the memory cell of the threshold voltage is larger than the target value (e.g., Vverify), then programming for that memory cell is inhibited in the next cycle by raising the bit line voltage from 0 v to Vinhibit (e.g., at time t4).
As with other electronic devices, there is a consumer demand for memory devices to program as fast as possible. For example, the user of a digital camera that stores images on a flash memory card does not want to wait between pictures for an unnecessary long period of time. In addition to programming with reasonable speed, to achieve proper data storage for a multi-state memory cell, the multiple ranges of threshold voltages of the multi-state memory cells should be separated from each other by sufficient margin so that the level of the memory cell can be programmed and read in an unambiguous manner. Additionally, a tight threshold voltage distribution is recommended. To achieve a tight threshold voltage distribution, small program steps have typically been used, thereby, programming the threshold voltage of the cells more slowly. The tighter the desired threshold voltage distribution the smaller the steps and the slower the programming process.
One solution for achieving tight threshold voltage distributions, without unreasonably slowing down the programming process, includes using a two-phase programming process. The first phase, a coarse programming phase, includes an attempt to raise a threshold voltage in a faster manner and paying less attention to achieving a tight threshold voltage distribution. The second phase, a fine programming phase, attempts to raise the threshold voltage in a slower manner in order to reach the target threshold voltage, while also achieving a tighter threshold voltage distribution. One example of a coarse/fine programming methodology can be found in U.S. Pat. No. 6,643,188, incorporated herein by reference in its entirety.
FIGS. 4 and 5 provide more detail of one example of a coarse/fine programming methodology. FIGS. 4A and 5A depict the programming pulses Vpgm applied to the control gate. FIGS. 4B and 5B depict the bit line voltages for the memory cells being programmed. FIGS. 4C and 5C depict the threshold voltage of the memory cells being programmed. This example of FIGS. 4 and 5 uses two verify levels, indicated in the Figures as Vver1 and Vver2. The final target level is Vver1. When a threshold voltage of the memory cell has reached Vver1, the memory cell will be inhibited from further programming by applying an inhibit voltage to the bit line corresponding to that memory cell. For example, the bit line voltage can be raised to Vinhibit (See FIG. 4B and FIG. 5B). However, when a memory cell has reached a threshold voltage close to (but lower than) the target value Vver1, the threshold voltage shift to the memory cell during subsequent programming pulses is slowed down by applying a certain bias voltage to the bit line, typically in the order of 0.3 v to 0.8 v. Because the rate of threshold voltage shift is reduced during the next few programming pulses, the final threshold voltage distribution can be narrower than with the methods depicted in FIG. 3. To implement this method, a second verify level that is lower than that of Vver1 is used. This second verify level is depicted in FIGS. 4 and 5 as Vver2. When the threshold voltage of the memory cell is larger than Vver2, but still lower than Vver1, the threshold voltage shift to the memory cell will be reduced for subsequent programming pulses by applying a bit line bias Vs (FIG. 5B). Note that in this case, two verify operations are required for each state. One verify operation at the corresponding Vver1 for each state, and one verify operation at the corresponding Vver2 for each state. This may increase the total time needed to program the memory cells. However, a large ΔVpgm step size can be used to speed up the process.
FIGS. 4A, 4B, and 4C show the behavior of a memory cell whose threshold voltage moves past Vver2 and Vver1 in one programming pulse. For example, the threshold voltage is depicted in FIG. 4C to pass Vver2 and Vver1 in between t2 and t3. Thus, prior to t3, the memory cell is in the coarse phase. After t3, the memory cell is in the inhibit mode.
FIGS. 5A, 5B, and 5C depict a memory cell that enters both the coarse and fine programming phases. The threshold voltage of the memory cell crosses Vver2 in between time t2 and time t3. Prior to t3, the memory cell is in the coarse phase. After t3, the bit line voltage is raised to Vs; therefore, the memory cell is in the fine phase. In between t3 and t4, the threshold voltage of the memory cell crosses Vver1; therefore, the memory cell is inhibited from further programming by raising the bit line voltage to Vinhibit.
One problem experienced by non-volatile memory, particularly multi-state memory, is that over-programming can occur. During the programming process, the memory cells are programmed to a certain target state defined by the threshold voltage range for that particular set of data. When a memory cell is programmed to a certain threshold voltage range, the threshold voltage of that cell should not exceed the maximum allowed threshold voltage for that range. For example, looking at FIG. 2, if the memory cell is to be programmed to target state 10, the memory cell's threshold voltage should be raised to be higher than Vv1, however should stay below Vmax 1, the maximum allowable threshold voltage for distribution 10. When the threshold voltage of the memory cell exceeds the allowable range, there may be a failure when reading the data later on. This phenomenon is called over-programming. In some cases, error correction can be used to correct errors caused by over-programming. However, some over-programming cannot be rectified by error correction. Additionally, error correction can be very time consuming.
FIG. 6 depicts erased threshold voltage distribution 2 and programmed threshold voltage distribution 80. Threshold voltage distribution 80 includes a set of one or more memory cells that program faster than normal. These fast memory cells are candidates for being over-programmed. For example, after one program pulse, instead of obtaining threshold voltage distribution 4 of FIG. 1, the population of memory cells that includes one or more fast cells will result in threshold voltage distribution 80 of FIG. 6. Threshold voltage distribution 80 includes fast memory cells 82.
FIGS. 7A, 7B, and 7C further illustrate a problem with fast memory cells that can be over-programmed. FIG. 7A, depicts the threshold voltage distributions 2, 10, 12 and 14 for a two-bit multi-state memory cell. FIG. 7B shows natural erased threshold voltage distribution 2 and programmed threshold voltage distribution 84. In one embodiment, distribution 84 is associated with the population of memory cells intended to be programmed to distribution 10, after one programming pulse. As can be seen, the distribution is moved over towards what should be distribution 10. Distribution 84 includes a set of fast memory cells, some of which exceed the read verify point Vr1. As can be seen from FIG. 7A, the read verify point is the voltage level used to distinguish between threshold voltage distribution 10 and threshold voltage distribution 12. Therefore, after one programming pulse, some of the memory cells in threshold voltage distribution 84 already have an error because they have a threshold voltage distribution greater than Vr1. At the end of the programming process, those memory cells intended to be in threshold voltage distribution 10 will likely be in distribution 86, as depicted in FIG. 7C. The difference between threshold voltage distribution 86 and threshold voltage distribution 10 of FIG. 7A, is that threshold voltage distribution 86 includes a set of fast memory cels (the front-end tail of distribution 86) that have threshold voltage that exceeds Vr1. These fast bits with a threshold voltage greater than Vr1 can return an error when read.

High speed programming system with reduced over programming


A redundant disk storage system having data stored on one disk and identical data on second disk, wherein the data stored on the second disk is in a different radial location determined by an offset. The offset could be such that the data on the first disk is stored near the inner circumference and the identical data is stored on the second disk near the outer circumference. Moreover, a RAM associated with each disk drive which stores the address and offset eliminates a RAM in the main disk controller.

A hard disk drive for recording data on a magnetic disk which is a magnetic recording medium for recording and reading data is an essential device for storing large amounts of data and programs in computer systems. Since a hard disk drive contains moving mechanical parts, a failure is relatively liable to occur. Such a failure may prevent the hard disk drive from reading or storing data and programs which, in turn, may stop the entire computer system using the drive.
To prevent the consequences of such a loss, a multiplexed disk recording controller (redundant disk array) for multiplexing the hard disk drive and recording data, etc., in the multiplexed hard disk drive based on a command from a host computer and reading data, etc., from the multiplexed hard disk drive has already been proposed. The multiplexed disk controller is provided with a redundant array of independent disks (RAID), e.g., RAID 0, RAID 1, RAID 3, and RAID 5. RAID 0, RAID 3, and RAID 5 each divide data among a plurality of hard disk drives. RAID 1 records data on two hard disk drives redundantly.
In the multiplexed disk recorder to which RAID 1 is applied (hereafter redundant disk storage system), identical data and programs are stored on two hard disk drives at all times. Redundancy is given so that, if a failure occurs in one hard disk drive, data reading, etc., can be done using the remaining drive.
The redundant disk storage system processes data when it receives a data recording command or a write command from a host computer; that is, a write command or parameter received from a host computer is sent to the first hard disk drive, then also sent to the second hard disk drive. When both drives can transfer and record data (data-transfer-enabled), data from the host computer is simultaneously sent to the pair of drives, thereby recording sent data on both magnetic disks of the pair of drives.
Moreover, the redundant disk storage system processes data by either a first or second method described as follows; when it receives a data read command (read command) from a host computer.
In the first method, a read command is sent to only one of a pair of hard disk drives, and processing waits until the hard disk drive to which this read command is sent is able to read data (read-enabled possible). When this drive is read-enabled, to read data, information indicating read-enabled is sent to the host computer and the required data is transferred from the hard disk drive to the host computer.
In this method, the control program is simple, but a long time is required for authorizing a failure in the hard disk drive in which a read command is received, and, moreover, a read command must be sent to the remaining hard disk drive after failure authorization. Therefore, if a failure occurs in either drive, a long time is required from read command receiving to the completion of magnetic disk data reading.
In the second method, both of a pair of hard disk drives are issued a read command and required data is transferred from whichever one of the pair of drives becomes data-transfer-enabled first.
Use of this method shortens the read time upon a failure in a hard disk drive compared to the first method because, even for a failure in either hard disk drive, only one of the pair of drives must be able to transfer data. However, in this method, if necessary data is recorded near the internal circumference on the hard disk, the read voltage of data read by the magnetic head is low and data may not be recognized in some cases. Therefore, the drive itself must repeat a retry to read data or the redundant disk storage system must retry sending a parameter or command to the drive again, if necessary. Retry by the drive itself or the redundant disk storage system eventually enables data to be read. Therefore, if required data is recorded near the internal circumference on the hard disk, the probability of not reading data rises or a long read time is needed.
Moreover, using the first or second method in a redundant disk storage system, read heads of the two hard disk drives are both positioned where said data is recorded or at the first position at the end of the first data reading. Therefore, the first and the second methods do not differ greatly in the time for movement from the location of data previously recorded to that of required data.
Moreover, in the conventional redundant disk storage system, it was difficult to incorporate a hard disk drive in a computer, e.g., a personal computer, because of increased scale accompanied by increased recording capacity. Therefore, at least one hard disk drive was connected externally. Where a hard disk drive was installed outside the computer, the interface of the hard disk drive had to be connected with a cable. In this case, to avoid malfunctioning due to noise, a small computer system interface (SCSI) suitable for an external hard disk drive was generally used to connect the redundant disk controller and a pair of hard disk drives, thereby making the data capacities of tens of G bytes possible.
In contrast, the AT interface was generally used in personal computers having a small built-in hard disk drive. However, an AT interface was not used in the redundant disk drive because the maximum capacity of a hard disk drive which can be used by a host with which an AT interface is connected was limited to 528 M bytes because of basic input and output system (BIOS) restrictions.
However, large-capacity hard disk drives have been downsized rapidly by the development of an magneto-respective head and other technology. It has become possible to manufacture even a 3.5-inch hard disk drive having a capacity exceeding G bytes which can be built into personal computers. Moreover, with the addition of ATA specifications by ANSI, it has become possible for BIOS to access a large capacity (the same level as for a small computer system interface (SCSI) hard disk drive with an AT interface. Accordingly, the necessity of mirroring is increasing rapidly even in small hard disk drives used for personal computers.
In this connection, in the redundant disk controller connected to a host computer having an AT interface, internal data RAM was needed. This is because synchronization timing between the host and hard disk drive is difficult and a consecutive transfer of 256 words of data was needed for processing an Identify Drive command. That is, the Identify Drive command is executed once for initialization immediately after power is turned on. The Identify Drive command enables the host computer to receive parameter information from the hard disk drive. A parameter block consists of 256 words of data. The command requests the consecutive transfer of 256 words of data from the drive to the host computer in units of 16 bits. This parameter must to be partially modified for the controller to operate a pair of hard disk drives. Therefore, data RAM for storing 256 words of data had to be incorporated into the controller. Thus, the controller circuit structure was complicated and of increased cost.

Method and apparatus for redundant disk storage system with offset

International Business Machines Corporation


An exercise machine having a user interface engaged by a user to perform exercises using the exercise machine is disclosed in which an electric, direct current (DC), servo control motor is used as the force producing element to which the user interface is mechanically connected and in which a digital data processor, operatively connected to the electric motor, is used for monitoring the position and direction of movement of the linkage relative to the electric DC servo motor and for controlling the electric DC servo motor to operate as one of a generator or a motor depending upon the determined position and direction of movement of the linkage is disclosed. The force exerted by the electric motor, whether it is operating as a motor or a generator, is dependant upon the position and direction of movement of the mechanical linkage as well as upon the force exerted by the user on the mechanical linkage, and other parameters, depending upon which one of three modes of operation is selected.

The present invention relates generally to various types of physical fitness training equipment which usually employ a weight stack as the force producing element. More particularly, the present invention relates to a method of and apparatus for the force generation and control of such an exercise machine in which the weight stack is replaced by the disclosed force generation and control system which provides better control and a better workout for the user of the physical fitness training equipment.
Typical physical fitness training equipment utilizes a weight stack sliding on vertical rods under the influence of gravity as the force producing element. Movement of the weight stack by the user is caused by tension created in a cable that attaches to the top of the weight stack. In the past, there have been numerous applications of computer technology to the production of physical fitness training equipment. These attempts were typically aimed at overcoming known limitations imposed by the interactions of the weight stack-based, cable-actuated exercise system and the human muscular and skeletal structure. Examples of such prior art devices are the electrically controlled exercise system disclosed in U.S. Pat. No. 4,828,257 to Dyer et al., the exercise apparatus disclosed in U.S. Pat. No. 4,620,703 to Greenhut et al. and the muscle exercise and/or rehabilitation apparatus using linear motion disclosed in U.S. Pat. No. 4,907,797. In addition, two prior art patents which deal with the use of a motor to simulate a weight stack are U.S. Pat. No. 5,020,794, to Englehardt et al., for a motor control for an exercise machine simulating a weight stack and U.S. Pat. No. 5,117,170, to Keane et al., for a motor control circuit for a simulated weight stack.
While each approach of the prior art to exercise system force generation imposes its own special set of undesirable traits, a number of the known advances have improved attainable results by successfully addressing one or more of the known problem characteristics of the interactions of the exercise system and the human muscular and skeletal structure. However, although limited success has been attained, high-technology and exercise equipment have not achieved their ultimate convergence in the marketplace. This is attested by the thousands of exercise machines of various types that continue to rely on rubber and iron as the force producing elements. A user-friendly, high-technology solution, tailored to the exercise system user, and in which the known limitations imposed by the interactions of the exercise system and human muscular/skeletal structure are overcome has not previously been described. Prior art systems have typically failed to fuse the required technical and physiological techniques into a cohesive approach to producing an efficient, easy-to-use exercise system that is also well-suited to the human muscular and skeletal structure.

Force generation and control system for an exercise machine


A device (2) for pulling a cartridge case (4) in a pulling direction (10) out of an axial bore of a die (6) which, as seen from the axial bore, comprises a male thread (20) on the outside to hold the die (6) in a reloading press is provided. The device (2) comprises:                a support plate (12) for holding the die (6) aligned with its axial bore in the pulling direction 10) and secured against a movement in the pulling direction (10) in a die bore (18)        a lifting plate (14) arranged at a distance (16) before the support plate (12) as seen in the pulling direction (10), comprising a pulling element (24) with retaining members aligned against the pulling direction (10), wherein the retaining members are arranged in such a way to hold the cartridge case (4) at an end of the pulling element (24) opposite the lifting plate (14), and        drive members (32, 34) for driving the support plate (12) and the lifting plate (14) apart in and/or against the pulling direction (10).

Sports shooters and hunters often load empty cartridge cases, which brings not only financial benefits but also better results than factory-loaded ammunition. For reconditioning empty cartridge cases, a trimmer calibration device is already known from DE 10 2013 020 748 B3 which is used to process the interior and exterior dimensions of cartridge cases in a die body by means of a milling machine, which is also known as trimming. Firing a cartridge case usually leads to an increase in its diameter along its entire length, as well to a linear expansion of the cartridge case.
A reloading press for cartridge cases is known from DE 400 83 82 C2. DE 10 2004 04 64 62 A1 describes a combined setting and trimming die for reloading devices for cartridge cases. Reloading empty cartridge cases is also known from U.S. Pat. Nos. 3,204,518 A and 2,571,272 A.
The problem, however, that arises over and over again in all these devices, is that the cases are stuck in the calibrated die and can only be removed forcibly or not at all, wherein the die may be damaged and/or become unusable. This can cause great effort and trouble as well as added costs.
In general, cartridge cases to be filled should be calibrated by a die before reloading. As already mentioned, stuck cartridge cases are a major problem if they have to be removed from the calibrating tool, i.e. the die.
In particular, there is a risk of the cartridge case being deformed to a different dimension, wherein it is very difficult to remove the stuck cartridge case, in particular when the upper edge of the cartridge case is damaged. This may be caused by material fatigue after repeated reloading of the cartridges, or by an inferior quality of the material, a too-soft brass alloy or improper use. Even if the edge of the cartridge is not damaged, it is often impossible to remove the cartridge from the die.
Removing a cartridge stuck in a die by the known devices often fails in practice. The reasons for this are as follows:                material fatigue        insufficient quality of the brass alloy        incorrect or off-vertical bore hole and thus an inclination of the thread.
The force to remove a stuck cartridge from the die exceeds the load capacity of the devices used, which usually ends up with the fixing screw being torn out of the thread of the bottom of the cartridge. The effort to remove said stuck cartridge is considerable and often causes the polished inner surface of the die to be damaged so that the die can no longer be used or only to a limited extent.
The salvage of dies according to the current state of technology is uncertain, and often fails due to the said reasons. After an unsuccessful attempt, it is very work-intensive to remove the cartridge from the tool, and the expensive die may end up being damaged, wherein it is often no longer suitable for further use, because the inside tolerances have changed. The calibration tolerances of a cartridge are extraordinarily small which has two fundamental reasons:
1. Safety of the rifle/pistol/revolver used and thus the safety of the persons operating this equipment.
2. The accuracy of the bullets which in many ways is also an absolutely necessary safety factor.


An electrical assembly for use in various operating environments such as a casing of a combustion turbine 10 is provided. The assembly may include an electrical energy-harvesting device 51 disposed in a component within the casing of the turbine to convert a form of energy present within the casing to electrical energy. The harvesting device is configured to generate sufficient electrical power for powering one or more electrical devices therein without assistance from an external power source. One example of electrical devices wholly powered by the energy harvesting device may be a sensor 50 connected for sensing a condition of the component within the casing during operation of the combustion turbine. Another example of electrical devices wholly powered by the energy harvesting device may be a transmitter in communication with the sensor for wirelessly transmitting the data signal outside the casing.

Combustion turbines are used for a variety of applications such as driving an electric generator in a power generating plant or propelling a ship or an aircraft. Firing temperatures in modern gas turbine engines continue to increase in response to the demand for higher efficiency engines. Superalloy materials have been developed to withstand the corrosive high temperature environment that exists within a gas turbine engine. However, even superalloy materials are not able to withstand extended exposure to the hot combustion gas of a present generation gas turbine engine without some form of cooling and/or thermal insulation.
Thermal barrier coatings are widely used for protecting various hot gas path components of a gas turbine engine. The reliability of such coatings is critical to the overall reliability of the machine. The design limits of such coatings are primarily determined by laboratory data. However, validation of thermal barrier coating behavior when subjected to the stresses and temperatures of the actual gas turbine environment is essential for a better understanding of the coating limitations. Such real world operating environment data is very difficult to obtain, particularly for components that move during the operation of the engine, such as the rotating blades of the turbine.
Despite the substantial sophistication of modern turbine engines, such as gas turbines for generating electrical power or aircraft engines for commercial and military use, designers and operators have had relatively limited information regarding the internal status of the turbine engine components during operation. This is due to the harsh operating conditions, which have prevented the use of traditional sensors for collecting reliable information of critical engine components.
Many present turbines are equipped with sensors capable of somewhat limited functions such as exhaust gas-path temperature measurements, flame detection and basic turbine operating conditions. Based on this information, turbine operators such as utility companies operate engines in a passive mode, in which maintenance is scheduled based on prior histories of similar engines. Engine rebuilds and routine maintenance are performed in the absence of a prior knowledge of the remaining or already utilized life of individual components. The lack of specific component information makes early failure detection very difficult, often with the consequence of catastrophic engine failure due to abrupt part failure. This results in inefficient utilization, unnecessary downtime and an enormous increase in operating cost.
Presently, the gas turbine industry approach is to depend on the measurement of gas path temperature, which is related back to specific component problems based on experience and history regarding a class of engines. This approach is highly subjective and only allows for determining already severe situations with an engine. It does not provide indications of impending damage or insight into the progression of events leading up to and causing engine damage due to component degradation or failure.
The instrumentation of a component such as a blade or vane within a steam turbine typically includes placing wire leads on the balance wheel, which continue on to the blade airfoil. The wire leads are typically held together by an epoxy. These wires are routed from within the component to the turbine casing. The pressure boundary of a component may be breached to introduce a sensor such as a thermocouple and a braze is back filled to hold the thermocouple in place. Each thermocouple sensor has wire leads coming out of the component that are connected back to a diagnostic unit. Instrumenting a plurality of components of a turbine in this manner results in an extensive network of wires just for monitoring the single operating condition of temperature. Instrumenting components using this technique is expensive, which is a barrier to instrumenting a large number of components within a single turbine. Further, the wire leads and data transfer is frequently poor, which can result in costly repairs and flawed data analysis.
Embedded and/or surface-mounted sensor technology together with wireless telemetry are increasingly being used for real-time structural health monitoring and prognostics of critical components in present turbine engines to meet the demanding requirements of the future. However, these wireless sensors and their associated electronics (e.g., transmitters, receivers, transceivers, etc.,) need electric power sources that last as long as the sensing application itself. Since the operating environments and physical constraints in a gas turbine render it difficult for conventional powering approaches to be fully effective, e.g., battery-powered approach and galvanic power coupling, it is desirable to provide active power generation modalities for powering these wireless sensors/telemetry systems through scavenging or harvesting electrical power from one or more forms of energy available in the operating environment of the combustion turbine.

Electrical assembly for monitoring conditions in a combustion turbine operating environment


A switching arrangement for a high voltage load provides high voltage pulses to the load. The switching arrangement includes switching modules, where n is typically (75). A load capacitance is Cd is required to avoid voltage overshoot at the load and is provided by a capacitance of nCd arranged in parallel with each switch.

1) Field of the Invention
This invention relates to high voltage switching apparatus, and in particular, but not exclusively to a switching apparatus for providing pulses to a pulse switched load.
2) Description of Related Art
Our UK patent applications GB9929074.5 and GB9928049.7 describe a pulsed switching apparatus for an eht load such as a magnetron. A stack of FET switch modules are arranged in an oil filled chamber surrounded by four capacitors which are mounted within a plastics housing. The switch stack receives an eht supply, typically at about −55 kv and delivers a series of eht pulses to the magnetron. The switch also includes various control circuitry which operates at lt voltages. This circuitry controls functions such as triggering of the FET switches.
In these devices, when the load is switched, it is desirable for the voltage to rise smoothly to the operating voltage as shown in FIG. 1. In practice, however, there is a tendency to a voltage overshoot as shown in FIG. 2. This is because the load is not a purely resistive load but is of a non-linear nature and includes a capacitive component.
A known way of correcting for this voltage overshoot is to include a further capacitance in parallel with the load as shown in FIG. 3. In that figure, the load is shown as RL, the switch as S and the added capacitance as Cd. The problem with this approach is that the added capacitance is large, typically in the order of 200 pF, expensive and very large in size. It is therefore desirable to find an alternative way of compensating for voltage overshoot.


In a reproduction apparatus, such as a copier, having a fusing station which includes a heated coated fuser roller and a pressure roller forming a nip for fusing a receiver passing through said nip, the fusing station is mounted for lateral movement in relation to the movement of the receiver through the nip.

Generally, a fusing unit for fixing toner images in a reproduction apparatus has a heated fuser roller. The fuser roller is of cylindrical shape with a metallic core over which is formed an elastomeric layer. The elastomeric layer of the fuser roller makes contact with a pressure roller to form a fusing nip through which a receiver, carrying the toner images is passed to fuse the toner images to the receiver. This type fusing unit is known to have high thermal efficiency with minimal danger of causing a fire if receiver jamming occurs. A problem, however, with this type of fusing unit is the elastomeric layer has a tendance to swell, step or groove over a period of use, typically in the range of 100,000 or more copies, resulting in wrinkling or other unacceptable fusing performance. This swelling and grooving occurs at the portion of the fuser roller near the ends of the receiver and outward therefrom where the fuser roller is not protected, during fusing, from the pressure roller by the presence of the receiver between the fuser roller and the pressure roller. Accordingly, in such end portions of the fuser roller, high stresses are created between the directly contacting surfaces of the fuser roller with the pressure roller. As a net result, the thin outer layer or coating, of the fuser roller, in the unprotected area tends to fail. This failure is hastened by continued use of the same width receiver or large volume runs of the same width receiver constantly moving across the same area of the fuser roller.


The present invention provides a cartridge that retains clips in their slots and also facilitates removal of the clips by a clip applier. The slots are provided with at least one and preferably two retaining members that protrude from and preferably run substantially parallel to the slot-defining walls. The retaining members interfere with the clip to an extent sufficient to retain the clip in the slot while permitting relative movement between the clip and the saddle. In a preferred embodiment, the legs of the clip are flared to further facilitate engagement between the clip legs and the grooves of the applier jaws.

Hemostatic clips provide a rapid and efficient means for closing off blood vessels during surgery. Hemostatic clips generally are V-shaped and formed from a soft, biocompatible metal. Typically, hemostatic clips are supplied in a molded cartridge with multiple clip-containing slots. The clips are removed from their slots individually, when needed, by a clip applier. A typical clip applier has a pair of relatively movable jaws with grooves to receive the legs of the clip.
When pressed into a slot in the cartridge, the clip applier automatically grips the clip securely so that the clip can be removed from the slot and held by the applier. The applier then is used to position the V-shaped clip over a blood vessel and to compress the legs of the clip together so that the blood vessel is closed off. Afterward, the applier is disengaged from the clip and may be used to remove another clip from the cartridge.
In the past, cartridges have been designed to hold the clips relatively securely in their slots to guard against accidental release of the clips. The structures that have been used to secure clips in their slots typically have not permitted much movement of the clip within the slot. Typically, the legs of the clip are straddled and tightly fit over a "saddle." The clip often is retained on the saddle by a retaining member designed to abut the upper edge of the clip, holding the clip tightly in place on the saddle.
Unfortunately, the features used in the past to retain the clips in their slots also have made it difficult to remove the clips from their slots with an applier. A structure that would hold clips securely in their slots, but would also permit easy removal of the clips by an applier, would be highly desirable.

Easy loading hemostatic clip and cartridge


Face milling cutter with a shaft section and a tool section, whereby the front end of the tool section has at least one flat, arched, lower cutting edge, a rounded corner cutting edge, and a peripheral cutting edge, whereby the lower cutting edge has a radius r1 from 1 to 2 times d1 and begins at a distance of 0.1 to 0.2 d1 to the axis of the shaft section, whereby d1 is the diameter of the flight circle of the axially parallel tangent to the rounded corner cutting edge.

A face milling cutter of the initially named type is also known from DE 100 52 963 A1. It has a shaft that accommodates cutting plates in the front area in the circumferential direction of spaced pockets. Each cutting plate has three cutting-edge sections that are engaged with the component. An arched lower cutting edge that merges into a corner-cutting edge towards the perimeter is provided on the forehead end On its part. It merges into a peripheral cutting edge that lies back in an angle for the creation of a flank. With the face milling cutter, a high feed rate is to be achieved for the smoothest possible tool surfaces.


An optical material for lithographic applications is selected from crystal materials by a testing method. The crystal materials are preferably quartz and/or alkali or alkaline earth halides, especially fluorides, or mixed crystals. The testing method includes three tests to measure irreversible radiation damage: 1) the optical material is irradiated with ultraviolet radiation at 193 nm and the non-intrinsic fluorescence intensity at 740 nm is measured; 2) the optical material is irradiated with high energy density laser light and a change in respective absorptions before and after irradiation at 385 nm is measured; and 3) the optical material is irradiated with an X-ray or radioactive source to form all possible color centers and a difference of respective surface integrals of corresponding absorption spectra in ultraviolet spectral and/or visible spectral regions is measured before and after irradiation.

1. The Field of the Invention
The present invention relates to a method of testing optical materials by irradiating with high energy density radiation to determine long-term stability of their transmission properties, to the optical materials obtained with this testing method, and to uses of the optical materials obtained by this testing method.
2. The Related Art
Electronic computer components such as computer chips and other integrated circuits are manufactured by optical lithography. During their manufacture these circuit structures are imaged by a photomask on a support provided with a photo-lacquer, a so-called wafer, and the circuits and/or entire electronic devices including them are produced by irradiation. Since the requirements for computer performance are always increasing, increasingly smaller circuits are required. Because of that the respective circuit structures must be imaged ever more sharply, i.e. with greater resolution, which leads to the use of ever smaller wavelengths for irradiation of the photo-lacquer. However radiation with a shorter wavelength has a correspondingly higher energy.
It is also known that materials for optical elements absorb radiation passing through them so that the intensity of the radiation is generally less after passing through those materials than its initial value immediately prior to entering the materials. Moreover additional absorption and scattering effects occur at the surfaces though which the radiation passes, which similarly leads to a reduction of the transmission of the radiation. It is also known that the amount of absorption depends not only on the wavelength of the radiation, but also on the energy density or the fluence. When the path length of a light beam through the entire optical material of a lens system can be longer than a meter without more during irradiation of these smaller chip structures or circuits, absorption of the radiation passing through the lens system is a great problem. For these optical systems it is thus desired that the absorption is kept as small as possible, i.e. these systems and their elements should have a high permeability or transmission at least for the respective working wavelengths that are used in the system. It is also known that the absorption comprises material-specific (intrinsic) parts and so-called non-intrinsic parts, which result from inclusions, impurities and/or crystal defects. Intrinsic absorption is constant and depends on the nature of the material. It is independent of the quality of the material and thus does not decrease. The additional non-intrinsic absorption depends on the quality of the material, i.e. depends on the extent of the above-mentioned impurities, crystal defects, etc and thus can be avoided, at least theoretically. It leads to quality losses in the optical material and thus in the lens system.
Energy, which leads to heating of the material, is deposited in the optical material by intrinsic and non-intrinsic absorption. This sort of heating of the material has the disadvantage that optical properties, such as the index of refraction change, since the index of refraction depends not only on the wavelength of the light but also on the temperature of the optical material, which leads to changes in the imaging behavior in an optical component used for beam formation. Furthermore heating of an optical component leads to thermal expansion and thus to a change of the lens geometry. These phenomenon produce a change of the lens focal point and to some extent blur the projected image formed by a heated lens. In photolithography, as it is used for making computer chips and electronic circuits, this causes a decrease in quality and an increase in waste and thus is not desired.
Furthermore in many materials a portion of the absorbed radiation not only is converted into heat but also into fluorescence, which similarly is produced by impurities and crystal defects.
Attempts have thus already been made to determine the optical quality of these materials prior to their processing into optical elements. Thus WO 2004/027 395 describes a method for determining the properties of an optical material used for making optical elements, in which a radiation-induced absorption is measured in an optical material by irradiating it with an exciting radiation and measuring the total fluorescence comprising the intrinsic portion induced by this exciting radiation and the non-intrinsic portion. The non-intrinsic portion of the fluorescence is determined during and/or immediately after the irradiation.
In German Patent Document DE 103 35 457.3 A1 a method is described for quantitative determination of properties of the crystals used for optical elements at high energy densities, in which the radiation-dependent transmission at wavelengths in the ultraviolet (UV) is determined by radiation-induced fluorescence. In this method at least one induced fluorescence intensity maximum is determined by measuring nonlinear absorption processes at various fluences (H), determining the slope of the transmission curve from that determination, |dT/dH|, and the transmission from this slope. The so-called rapid damage process RDP may be established with this method.
In German Patent Document DE 100 50 349 A1 a method for determining the radiation stability of crystals is described. In this method the change of the absorption coefficient is measured before and after irradiation. In a first measurement the absorption spectrum A of a crystal, or of a piece of the crystal split off or cleaved from it, is measured over a predetermined wavelength range from λ1 to λ2 by means of a spectrophotometer. Then the crystal or cleaved piece of it is irradiated with an energetic radiation source for forming all theoretically possible color centers. After the irradiation the absorption spectrum B of the crystal or cleaved piece of it is measured in a second absorption measurement over the same wavelength range from λ1 to λ2. Subsequently the surface integral of the difference spectrum formed from the absorption spectra A and B over the range of wavelengths from λ1 to λ2 is formed and divided by the thickness D of the crystal. The absorption coefficient Δk induced by the working wavelength used in later applications is determined from this result.
European Patent Document EP 0 875 778 A1 states that the absorption of a CaF2 crystal is essentially caused by sodium impurities, which are typically in a range of about 0.1 ppm, in an image focusing optical system for a UV laser. According to that the other possible impurities, such as strontium, etc, contribute to the production of non-intrinsic absorption to an essentially small extent.
In European Patent Document EP 0 875 778 A1 a material to be tested is irradiated with an energetic ArF laser with a frequency of several hundred Hz for several seconds or minutes and the absorption spectrum prior to or after irradiation is determined. The irradiated energy per pulse amounts to 1 μJ to several Joule per pulse with a pulse duration of 10 to 20 ns. It was established that the absorption produced on irradiation of quartz glass and CaF2 with a laser does not correspond with that, which is measured by the weak light beam of a spectrophotometer. Thus it was found that the permeability or transmission of the material at the start of irradiation drops comparatively rapidly until after about 104 pulses and after that remains constant. Moreover it was expressly established that subsequently the transmission does not change further, so that the absorption is determined after about 104 to 105 pulses.
However all these methods only determine short-time, reversible radiation damage. This short-time reversible radiation damage is reversible by further irradiation or heat treatment, which means that the radiation damaged structures again relax. Up to now it was thought that the irreversible radiation damage that is known to occur in quartz glass, which causes a slow and irreversible increase in absorption during long-term use of this optical material over several years, did not occur in crystals. In the meantime however long-duration tests established that irreversible permanent damage also occurs in crystals after 108 to 109 laser pulses at energy densities of from 5 to 25 mJ/cm2 over a period of several weeks.
The current procedure for determining this permanent damage comprises determining the transmission T and/or the absorption A per input energy density or fluence H for the optical material measured and from that determining the slope of this curve |dT/dH| and/or |dA/dH|. The amount of absolute transmission or the initial absorption at an input energy density H=0 may then be ascertained from this curve by extrapolation to 0. This value normalized to the sample thickness is characterized as the initial absorption k0. Subsequently the optical material is irradiated with a higher energy density of about 1 Giga pulse with 10-12 mJ/cm2 and after this irradiation as described previously the initial absorption and/or absolute transmission is determined. The difference of the respective determined initial absorptions k0 (or absolute transmissions) before and after irradiation is a reliable measure for the long-term stability of the optical material. Optical materials with Δk0 values of >4×10−4 cm−1 have proven to be unusable.
Since the service life of this sort of lens system in steppers often amounts to ten years and more, a statement regarding the irreversible radiation damage that would occur over time is already required and unsuitable materials must be sorted out. Thus not only considerably costs for expensive manufacture of optical lens systems, but also illumination errors are avoided, whereby the yields during chip manufacture are increased. A simple determination of these long-term stabilities, which as much as possible is performable in a few hours, has currently not been possible and currently only occurs by the above-described pulsed laser shot method that takes several weeks.
The determination of long-term absorption increase in an endurance or stability test performed in a comparative short time has not been possible for practical reasons. Up to now no possible procedure has been found, with which a statement regarding the change of optical material properties over the entire service life can be obtained from experimental results obtained over a short time interval.

Method of testing optical materials by irradiating with high energy density radiation, optical materials selected by said method and uses thereof