The invention provides low surface tension surfactants based on amino alcohol and also provides for their use in aqueous coating formulations, said surfactants being preparable by reacting at least one secondary amine of formula (I):

Water-based paints and coatings are used on a large scale industrially. Critical to effective wetting of the substrate is the lowering of the surface tension of the aqueous system by means of a surfactant. It is not only the lowering of the static surface tension to a small value that is decisive here, but also the corresponding lowering of the dynamic surface tension. A low dynamic surface tension is needed in particular for high-speed applications: for example, when applying coatings by spraying, or in printing operations. Furthermore, the surfactants used must not create any surface defects, must not cause any turbidity, and should be low-foaming. That means, they should not promote the build-up of significant amounts of foam.
Although nonionic surfactants such as alkylaryl ethoxylates or alcohol ethoxylates or ethylene oxide (EO)-propylene oxide (PO) copolymers are for sure capable of reducing the static surface tension, the high molecular weight and resultant low molecular mobility of these classes of compounds mean that it is not possible to lower the dynamic surface tension to a value which is acceptable to the user.
Conversely, some anionic surfactants, such as the sodium salts of monoalkyl or dialkyl sulfosuccinates, are able effectively to reduce the dynamic surface tension, but using them leads to severe build-up of foam in application, and the finished coating reacts sensitively to water.
More recently a new class of surfactants has been developed based on acetylenic glycols and their alkoxylates. The properties of these surfactants are situated between those of the surfactants outlined above. With these new surfactants it is possible to reduce both the static and the dynamic surface tension, with the values which can be achieved not entirely matching those of the nonionic and anionic surfactants. But, on the plus side, these surfactants provide comparatively low-foam formulations (EP-B-0 897 744, U.S. Pat. No. 2,997,447).
In view of these properties, surfactants of this kind have been able to establish themselves convincingly in numerous applications. Their properties are primarily attributed to the rigid acetylenic alkyl spacer, which, as a result of the restricted degrees of freedom, dictates a kind of preorientation of polar and nonpolar groups. Responsibility for these properties is additionally ascribed to the small distance between the polar groups and to the low molecular weight (<300 g/mol), which allows the surfactant molecules to be highly mobile.
A problem with compounds of this type is that, in applications, foam build-up reoccurs after a very short time. For the user, on the other hand, it is very important to prevent this new foam build-up for as long as possible. The alternative would be to add defoamers, whose possible consequences include unwanted defects of the coating film and problems with interlayer adhesion.
There was therefore a need to provide compounds which not only allow effective reduction in static and dynamic surface tension but also prevent foam build-up/new foam build-up effectively for a long period of time; i.e., e.g., a time period greater than 60 seconds.
In an effort to overcome the disadvantages of the prior art and to provide compounds which significantly reduce dynamic surface tension and at the same time effectively inhibit the (re)formation of foam for a long time it has now surprisingly been found that this objective can be achieved by means of amino alcohols preparable by reacting amines, preferably secondary amines, containing at least one amine hydrogen with glycidyl compounds.

Low surface tension surfactants based on amino alcohol and their use

Abstract: with at least one diepoxide of formula (IV):

Abstract: and/or with at least one triepoxide of formula (IV):

Abstract: in essentially equivalent amounts of amine hydrogen atoms and epoxide groups.


As a novel vinylidene fluoride polymer and its use, provided are a binder composition, an electrode mixture, an electrode, and a non-aqueous electrolyte secondary battery including the vinylidene fluoride containing the vinylidene fluoride polymer. The vinylidene fluoride polymer includes a first structural unit derived from vinylidene fluoride and a second structural unit derived from a monomer other than vinylidene fluoride. The monomer to be the second structural unit is a primary amine, a secondary amine, or a tertiary amine having at least one of a hydroxyl group and a carboxyl group, and the content of the second structural unit is from 0.05 to 20 mol % when the total of structural units derived from all the monomers constituting the vinylidene fluoride polymer is 100 mol %.

Vinylidene fluoride copolymers mainly containing repeating units derived from vinylidene fluoride are widely used as binder resins for batteries such as lithium ion secondary batteries. The binder resin is used to adhere an electrode active material to a current collector.
For example, Patent Document 1 discloses a vinylidene fluoride copolymer containing hydroxyethyl acrylate (HEA) having a hydroxy group.
Patent Document 2 discloses a binder resin containing a vinylidene fluoride copolymer containing a structural unit derived from vinylidene fluoride, a structural unit derived from a monomer containing a carboxyl group, and a structural unit derived from a monomer containing a functional group having a nitrogen atom.

Vinylidene fluoride polymer, binder composition, electrode mixture, electrode, and non-aqueous electrolyte secondary battery, and method for producing electrode mixture


A circuit board inspection apparatus aims to inspect a circuit board panel which contains a plurality of sub-panels. The panel is bonded with a panel barcode and each sub-panel is bonded with a different sub-panel barcode. The circuit board inspection apparatus includes an automatic optic inspection (AOI) system to inspect the circuit board panel and read the panel barcode and the sub-panel barcode, a data link module to link data contained in the panel barcode and the sub-panel barcode and generate linkage data, and a database to store the linkage data. The relationship of the panel and the sub-panel may still be maintained through the linkage data provided by the data link module even after the panel and the sub-panel have been separated.

(1) Field of the Invention
The present invention relates to a circuit board inspection apparatus and particularly to an automatic inspection apparatus for handset circuit boards.
(2) Description of the Prior Art
Automatic optic inspection (AOI) has been successfully applied on the production lines of printed circuit board (PCB) after nearly ten years of research and development. With the circuit elements increasingly miniaturized and condensed, surface mount technology (SMT) factories in the PCB manufacturing industry have to adopt AOI apparatus on the production lines. This is because the small and condensed electronic elements on the circuit board can no longer be identified by operator's eyes on the production lines. AOI system provides a reliable and consistent inspection, and keeps accurate inspection records. In addition, the AOI system can execute the inspection repeatedly and accurately. The inspection scope includes whether the elements have void soldering, short circuit, deformation or shortage, and whether the elements are soldered properly without deviation or uneven solder paste distribution. Finally computers are used to store, analyze and process the inspection results.
The handset main board fabrication process also needs the help of AOI system. As the size of the handset shrinks continuously, the main board also shrinks. To rely on human eye to inspect whether the elements are precisely and properly soldered on the main board is very difficult and inefficient. Hence the AOI system becomes the only and most efficient equipment. However, there are still problems when using the AOI system to inspect the handset main boards as indicated below.
Refer to FIG. 1 for a handset main board (abbreviated panel 10 hereinafter) which generally contains four identical sub-panels 12 (ranging from 4 to 12 sub-panels). Each sub-panel 12 has many surface mount devices(SMD) (not shown in the drawing) soldered on the upper and lower surfaces thereof. The panel 10 has to go through an inspection process to check whether the devices are accurately soldered on each sub-panel 12.
Refer to FIG. 2 for a conventional panel inspection process. First, inspection of the upper surface of a panel is executed. The process includes: bonding a barcode 14 on the upper surface of the panel 10(step 101); next, performing inspection through an AOI system (step 102); the AOI system determining whether defects are found on the soldered elements of the sub-panel 12(step 103) and at the same time reading the barcode 14 of the panel 10; performing manual inspection if the AOI system determines any soldered element on any sub-panel 12 is defective (step 104); confirming again abnormal conditions of the soldered elements on the sub-panel 12(step 105); proceeding panel repair process if the inspection result proves the defect existed and generating repair records (step 106); continuing inspection of the lower surface of the panel 10 if no defect is found in the upper surface inspection.
At step 103, if it is determined that there is no defect on the soldered elements of the sub-panel 12, directly proceed the inspection of the lower surface of the panel 10 (step 107 to step 113). The processes are same as those previously discussed, details are omitted. The barcode 14 of the panel 10 mainly aims to identify the panel 10 and link to the inspection and repair records of the panel 10 for the follow on process and analysis. However, in the later stage processes, after the panel 10 and the sub-panel 12 are separated, the individual sub-panel cannot be identified with its original panel. As a result, the corresponding inspection records are useless. In view of this problem, the present invention aims to provide a circuit board inspection apparatus that can link the inspection records of the panel to the corresponding sub-panel after they are separated.


A fluorescent lamp includes a ballast, a holder, a power regulating switch, and a fluorescent tube. The power regulating switch includes a housing, a base, plurality of inductors, a plurality of first contacts, a plurality of second contacts, a plurality of conducting bridges, a plurality of push rods, and a plurality of elastic members. The circuit of the power regulating switch has different values of inductance and output power by provision of the inductors, and the output power of the power regulating switch is regulated by the electrical connection between each of the first contacts and the respective different second contact so as to fit the fluorescent tube of different power specifications.

1. Field of the Invention
The present invention relates to a lamp and, more particularly, to a fluorescent lamp.
2. Description of the Related Art
A conventional fluorescent lamp comprises a ballast, a holder mounted on the ballast, and a fluorescent tube detachably mounted on the holder and electrically connected with the ballast. The ballast provides a determined starting voltage and a stabilized current to the fluorescent tube so that the fluorescent tube is lighted successively and stably. The ballast has a determined output power. However, the fluorescent tube has different power specifications (such as 13, 18 and 26 watt), so that the ballast cannot fit the fluorescent tubes having different power specifications, thereby limiting the versatility of the ballast and the fluorescent lamp.

Flourescent lamp whose ballast has an output power that is regulated for flourescent tubes of different power specifications


A conversion tool enables XPS documents to be automatically converted into the Open XPS format and for Open XPS-formatted documents to be automatically converted into the XPS format. The conversion tool may convert content types, package-level relationships, part-level attributes, and image parts into a format supported by either document format.

XML Paper Specification (XPS) is a paginated document format developed by Microsoft that specifies the content and appearance of an electronic document. Open XML Paper Specification (OpenXPS) is a paginated document format that is based on XPS but which differs in some respects from the format used in XPS. OpenXPS is a standard adopted by the European Computer Manufacturers Association (ECMA) as ECMA-388. The OpenXPS standard requires conformance to the schema defining the OpenXPS format and the XPS specification requires conformance to the schema defining the XPS format. Due to the differences between the two formats, it may not be possible for XPS and OpenXPS documents to be used interchangeably.

Conversion tool for XPS and OpenXPS documents


An image display apparatus which enables observation of a clear image at a wide field angle with substantially no reduction in the brightness of the image, and which is extremely small in size and light in weight and hence unlikely to cause the observer to be fatigued. The apparatus includes an image display device (6) and an optical system (5) for projecting an image displayed by the image display device (6) and for leading the projected image to an observer's eyeball (7). The optical system (5) includes a first optical element (3) filled with a medium having a refractive index larger than 1. The first optical element (3) has, in the sequence of backward ray tracing, a first surface (11) serving as both a refracting surface and an internally reflecting surface; a second surface (12) which is a reflecting surface decentered or tilted with respect to an observer's visual axis (2); and a third surface (13) which is a refracting surface closest to the image display device (6). The optical system (5) further includes a second optical element (4) provided between the observer's eyeball (7) and the first optical element (3) and having two refracting surfaces. Assuming that the focal length of the second optical element (4) is f.sub.2, and the focal length of the optical system (5) is f.sub.A, the condition of 0.01<f.sub.A /f.sub.2 <0.3 is satisfied.

The present invention relates to an image display apparatus and, more particularly, to a head- or face-mounted image display apparatus that can be retained on the observer's head or face.
As an example of conventional head- or face-mounted image display apparatus, an image display apparatus disclosed in Japanese Patent Application Unexamined Publication (KOKAI) No. 3-101709 (1991) is known. In this image display apparatus, as shown in FIG. 19, an image that is displayed by an image display device is transmitted as an aerial image by a relay optical system including a positive lens, and the aerial image is projected into an observer's eyeball as an enlarged image by an optical system formed from a concave reflecting mirror.
Japanese Patent Application Unexamined Publication (KOKAI) No. 62-214782 (1987) discloses another type of conventional image display apparatus. As shown in FIGS. 20(a) and 20(b), the conventional image display apparatus is designed to enable an image of an image display device to be directly observed as an enlarged image through an ocular lens.
U.S. Pat. No. 4,026,641 discloses another type of conventional image display apparatus. In the conventional image display apparatus, as shown in FIG. 21, an image of an image display device is transferred to a curved object surface by an image transfer device, and the image transferred to the object surface is projected in the air by a toric reflector.
U.S. Pat. No. Reissued 27,356 discloses another type of conventional image display apparatus. As shown in FIG. 22, the apparatus is an optical system designed to project an object surface on an exit pupil by a semitransparent concave mirror and a semitransparent plane mirror.
However, an image display apparatus of the type in which an image of an image display device is relayed, as in the image display apparatus shown in FIG. 19, must use several lenses as a relay optical system in addition to an optical system, regardless of the type of optical system. Consequently, the optical path length increases, and the optical system increases in both size and weight.
In a layout such as that shown in FIGS. 20(a) and 20(b), the amount to which the apparatus projects from the observer's face undesirably increases. Further, because an image display device and an illumination optical system are attached to the projecting portion of the apparatus, the apparatus becomes increasingly large in size and heavy in weight.
Because a head-mounted image display apparatus is fitted to the human body, particularly the head, if the amount to which the apparatus projects from the user's face is large, the distance from the supporting point on the head to the center of gravity of the apparatus is long. Consequently, the weight of the apparatus is imbalanced when the apparatus is fitted to the observer's head, causing the observer to be readily fatigued. Further, when the observer moves or turns with the apparatus fitted to his/her head, the apparatus may collide with something. That is, it is important for a head-mounted image display apparatus to be small in size and light in weight. An essential factor in determining the size and weight of the apparatus is the arrangement of the optical system.
However, if an ordinary magnifier alone is used as an optical system, exceedingly large aberrations are produced, and there is no device for correcting them. Even if spherical aberration can be corrected to a certain extent by forming the configuration of the concave surface of the magnifier into an aspherical surface, other aberrations such as coma and field curvature remain. Therefore, if the field angle for observation is increased, the image display apparatus becomes impractical. Alternatively, if a concave mirror alone is used as an optical system, it is necessary to use not only ordinary optical elements (lens and mirror) but also a device for correcting field curvature by an image transfer device (fiber plate) having a surface which is curved in conformity to the field curvature produced, as shown in FIG. 21.
In a coaxial optical system in which an object surface is projected on an observer's pupil by using a semitransparent concave mirror and a semitransparent plane mirror as shown in FIG. 22, because two semitransparent surfaces are used, the brightness of the image is reduced to as low a level as 1/16, even in the case of a theoretical value.
Further, because field curvature that is produced by the semitransparent concave mirror is corrected by curving the object surface itself, it is difficult to use a flat display, e.g. an LCD (Liquid Crystal Display), as an image display device.


Materials and methods for preparing (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid and structurally related compounds via enzymatic kinetic resolution are disclosed.

1. Field of Invention
This invention relates to methods and materials for preparing enantiomerically-enriched γ-amino acids via enzymatic kinetic resolution, and is particularly useful for preparing γ-amino acids that exhibit binding affinity to the human α2δ calcium channel subunit, including pregabalin and related compounds.
2. Discussion
Pregabalin, (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid, is related to the endogenous inhibitory neurotransmitter γ-aminobutyric acid (GABA), which is involved in the regulation of brain neuronal activity. Pregabalin exhibits anti-seizure activity, as discussed in U.S. Pat. No. 5,563,175 to R. B. Silverman et al., and is thought to be useful for treating, among other conditions, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, and various psychiatric disorders, including mania and bipolar disorder. See, respectively, U.S. Pat. No. 6,242,488 to L. Bueno et al., U.S. Pat. No. 6,326,374 to L. Magnus & C. A. Segal, and U.S. Pat. No. 6,001,876 to L. Singh; U.S. Pat. No. 6,194,459 to H. C. Akunne et al.; U.S. Pat. No. 6,329,429 to D. Schrier et al.; U.S. Pat. No. 6,127,418 to L. Bueno et al.; U.S. Pat. No. 6,426,368 to L. Bueno et al.; U.S. Pat. No. 6,306,910 to L. Magnus & C. A. Segal; and U.S. Pat. No. 6,359,005 to A. C. Pande, which are herein incorporated by reference in their entirety and for all purposes.
Pregabalin has been prepared in various ways. Typically, a racemic mixture of 3-aminomethyl-5-methyl-hexanoic acid is synthesized and subsequently resolved into its R- and S-enantiomers. Such methods may employ an azide intermediate, a malonate intermediate, or Hofman synthesis. See, respectively, U.S. Pat. No. 5,563,175 to R. B. Silverman et al.; U.S. Pat. Nos. 6,046,353, 5,840,956, and 5,637,767 to T. M. Grote et al.; and U.S. Pat. Nos. 5,629,447 and 5,616,793 to B. K. Huckabee & D. M. Sobieray, which are herein incorporated by reference in their entirety and for all purposes. In each of these methods, the racemate is reacted with a chiral acid (a resolving agent) to form a pair of diastereoisomeric salts, which are separated by known techniques, such as fractional crystallization and chromatography. These methods thus involve significant processing beyond the preparation of the racemate, which along with the resolving agent, adds to production costs. Moreover, the undesired R-enantiomer is frequently discarded since it cannot be efficiently recycled, thereby reducing the effective throughput of the process by 50%.
Pregabalin has also been synthesized directly using a chiral auxiliary, (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone. See, e.g., U.S. Pat. Nos. 6,359,169, 6,028,214, 5,847,151, 5,710,304, 5,684,189, 5,608,090, and 5,599,973, all to R. B. Silverman et al, which are herein incorporated by reference in their entirety and for all purposes. Although these methods provide pregabalin in high enantiomeric purity, they are less desirable for large-scale synthesis because they employ comparatively costly reagents (e.g., the chiral auxiliary) that are difficult to handle, as well as special cryogenic equipment to reach required operating temperatures, which can be as low as −78° C.
A recently published U.S. patent application discusses a method of making pregabalin via asymmetric hydrogenation of a cyano-substituted olefin to produce a chiral cyano precursor of (S)-3-aminomethyl-5-methylhexanoic acid. See commonly assigned U.S. Patent Application No. 2003/0212290 A1 to Burk et al., published Nov. 13, 2003, which is herein incorporated by reference in its entirety for all purposes. The cyano precursor is subsequently reduced to give pregabalin. The asymmetric hydrogenation employs a chiral catalyst that is comprised of a transition metal bound to a bisphosphine ligand, such as (R,R)-Me-DUPHOS. The method results in substantial enrichment of pregabalin over (R)-3-(aminomethyl)-5-methylhexanoic acid.
The method discussed in U.S. Patent Application No. 2003/0212290 A1 represents a commercially viable method for preparing pregabalin, but further improvements would be desirable for various reasons. For example, bisphosphine ligands, including the proprietary ligand (R,R)-Me-DUPHOS, are often difficult to prepare because they possess two chiral centers, which adds to their cost. Furthermore, asymmetric hydrogenation requires the use of special equipment capable of handling H2, which adds to capital costs.

Preparation of pregabalin and related compounds


A process cartridge according to one aspect of the invention comprises: an image carrier configured to carry a developer image and having a transfer position capable of transferring the developer image to a recording sheet; and an elastically-deformable cantilever-shaped guide plate including a distal end portion being unsupported, and having a first surface and a second surface that is opposite to the first surface. A leading end of the recording sheet is guided on the first surface in a conveying direction, such that the leading end is guided toward the transfer position after the leading end is brought into contact with the image carrier. The distal end portion of the guide plate is bent toward the second surface side to form a bent portion.

In general, in an electrophotographic image forming apparatus such as a laser printer, a photosensitive drum configured to carry a developer image contacts with a transfer roller applied with a transfer bias for attracting the developer image. When a sheet passes through a space between the photosensitive drum and the transfer roller, the developer image moves toward the transfer roller, whereupon the developer image is transferred to the sheet, to thus form an image. Incidentally, in such an image forming apparatus, when the photosensitive drum is separated from the sheet at a position upstream of a transfer position (which is located between the photosensitive drum and the transfer roller) with respect to the direction of a conveyance of a sheet, a developer will disperse if electric discharge arises in the space, thereby staining the sheet with the dispersed developer (a so-called preliminary transfer).
In relation to such circumstances, JP-A-2005-128482 discloses bringing a leading end of a sheet into contact with a photosensitive drum by means of a guide plate formed from a flexible film and subsequently guiding the sheet toward a transfer position, thereby preventing occurrence of a preliminary transfer.
However, when a guide plate is formed from a flexible film as in the previously-described technique, the guide plate that has remained deflected thus far returns to its original position when a trailing end (an upstream end) of the sheet passes by the guide plate, thereby causing vibrations. This may generate a noise.

Process cartridge and image forming apparatus with guide plate


An ethylene-propylene rubber composition vulcanizable with sulfur in which the rubber component totally or mainly composed of EPDM is incorporated with a zinc oxide, a carbon black, and other ingredients. The EPDM has an iodine value of 20 to 35 and an active zinc oxide is incorporated therein as the zinc oxide in an amount of 1 to 10 PHR. Even with a sulfur vulcanization system, this ethylene-propylene rubber composition is permitted to have compression set resistance equivalent to that of conventional SBR and is improved in heat resistance as well.

The present invention relates to an ethylene-propylene rubber composition obtained by vulcanization with sulfur, in which the rubber component totally or mainly composed of an ethylene-.alpha.-olefin-diene copolymer (hereinafter "EPDM" for short) is incorporated with a zinc oxide, a carbon black and other ingredients. In particular, this invention is concerned with an ethylene-propylene rubber composition best suited for high-pressure reinforcing hoses (ex. a brake hose as shown in FIG. 1), gaskets, and so forth. The vulcanized rubber layers of the hoses are required to have improved compression set resistance because the hoses have squeezed hose-joints. The gaskets are required to maintain good sealing properties over a prolonged period.
This invention will be explained specifically, but not exclusively, with reference to a brake hose.
In the present disclosure, unless otherwise stated, the unit "parts" is given by weight, and the unit "PHR" is a quantity with respect to 100 parts of rubber polymer.
The inner rubber layers of brake hoses have been generally made of styrene-butadiene rubber (hereinafter "SBR" for short). But today the replacement of SBR by EPDM is being under investigation so as to satisfy demands of improving heat-resistance and other properties of the hoses.
However, applying general EPDM compositions to the inner layer of a brake hose causes a problem that maintaining good sealing properties between an inner rubber layer 1 of a brake hose and a nipple 11a of a hose joint 11 under such severe conditions as stated above is difficult, especially preventing compression set of the rubber layer is difficult.
We have already reached an invention involving a inner layer made of a specific type of EPDM rubber vulcanized with peroxides in order to solve the above problem and filed the invention as a Japanese patent application (see Japanese published unexamined patent application sho 63(1988)-241051).
However, the peroxides used for vulcanization (of which safety care should be taken) are not only intractable but must be handled in an inert gas atmosphere as well, resulting in considerable productivity drops.
This problem may be solved by using sulfur vulcanization, but those skilled in the art are asserting that even with this it is impossible to impart sufficient compression-set resistance to EPDM rubber.


A dithering system yielding two-dimensional dither functioning is implemented without line memories. For each primary input color, a feedback loop outputs an color input signal plus error that can be preset to different values. The desired result is that vertical artifacts on a display formed from the output signals are relocated to different locations on consecutive display lines. If signal magnitude from the feedback loop output exceeds the magnitude of the video system creating the display, signal magnitude is preset to a value representing error at the start of the display line.

Many graphic and video displays in use receive an input digital data stream (which may be a digitized analog data stream) that is used to modulate output light intensity, for example in LCD laptop computer displays, and desktop flat panel displays. Typically three channels of data are used to create the display: red, green, and blue primaries, from which a wide spectrum of visible light can be created. More specifically, the display is represented by pixels (picture elements), where each pixel is represented by three colors (red, blue, green), and each color has eight bits of information.
Thus, it is known that to represent images with photo-realistic quality requires at least eight bits of information per color per display pixel. But for reasons that include cost, many LCD displays are manufactured that can accept only fewer than eight bits per color, perhaps only six bits or even fewer bits.
Using fewer than eight bits per color creates an image artifact known as quantizing. This undesired effect is especially noticeable in display areas of gradual change in the image. Although a smooth transition in display output intensity should be presented, the quantized image instead exhibits large jumps in output intensity. The term "quantization error" will be used herein to refer to the difference between a display image represented with eight bits per color and a display image represented with fewer than eight bits per color.
It is known in the art to reduce visibility of the quantization error by storing the difference between eight bit per color pixel values and the quantized image pixel values, and by modifying the quantized image pixel values based on such pixel error. The goal, not always attained, is to create an error pattern that is less visibly noticeable to the human eye. This process of modifying the pixel values is commonly referred to as "dithering" the image.
Representing an image with fewer bits per pixel than the original source data began with development of algorithms intended to enable black and white line printers to make a reasonable representation of photographic and computer generated images. Understandably such printers could only display one bit per pixel, e.g., black or white. Prior art methods beginning with that published in 1976 by Floyd and Steinberg sought to disperse the error between the displayed (or printed) pixel value and the original pixel value to neighboring pixels. This was done by adding the accumulated error from previous pixels to the value of the current pixel before quantizing the current pixel. After quantization, a new error signal (the difference between what was displayed for that pixel and the original pixel value plus incoming error) was applied to the following pixels in a manner intended to make the viewable error less noticeable. How to propagate the accumulated error signal differentiate various dither algorithms from each other.
Typically the error was propagated in two dimensions, using a two-dimensional mask or filter function. In video systems images are displayed on a screen sequentially from left to right, and top to bottom. Thus, propagating the error occurs in the horizontal direction to the right (as the user views the screen) and in the vertical direction downward. Understandably this requires some memory to store a portion of the error signal for use on display lines following the current display line. The need to propagate a portion of the error signal in the vertical direction arises mainly from artifacts generated by the dither process.
Generally, if dither is applied in the horizontal direction only, and an image is displayed in which successive lines are similar, the dither artifact will repeat in the same location on every line. This type of artifact is easily noticeable to the human eye, and appears as an error in the displayed image.
What is needed then is a system and method for dithering image data that preferably requires less memory than existing dithering.
The present invention provides such a method and system for dithering.

System and method for dithering with reduced memory


There is provided a sump mounting structure of a dishwasher having a tub and a sump assembly mounted on a bottom of the tub. The sump mounting structure includes at least one mounting hook unit extending from an outer circumference of the sump assembly and a mounting ring unit associated with the mounting hook unit to prevent the mounting hook unit from shaking.

1. Field of the Invention
The present invention relates to a dishwasher, and more particularly, to a sump mounting structure that allows a sump assembly to be easily dismounted from a bottom of tube in a state where a dishwasher is fixed, thereby improving maintenance service efficiency.
2. Description of the Related Art
Generally, a dishwasher is a machine that washes and dries dishes loaded on upper and lower racks by spraying washing water pumped by the washing pump toward the upper and lower racks through spraying nozzles. The dishwasher includes a tub defining an outer appearance of the dishwasher, at least one rack disposed in the tub to load dishes, at least one spraying nozzle for spraying washing water to surfaces of the dishes, and a sump assembly mounted on a floor of the tub to reserve the washing water. Foreign objects such as food wastes adhered to the dishes are removed from the dishes by pressure applied by washing water sprayed from a spraying nozzle. The food wastes removed from the dishes are collected on a floor of the tub.
The sump assembly supplying the washing water into the tube of the dishwasher is generally mounted on a bottom of the tub.
In the dishwasher of the related art, a special holder is used to assemble the sump assembly to the tub. In this case, the sump assembly is fixed to the tub by screws.
Therefore, when it is intended to separate the sump assembly from the tub to repair or change a damaged or broken component disposed in the sump assembly, the dishwasher must be turned upside down to release the screws. This is time-consuming and there is a lot of labor required.

Dish washer and sump mounting structure thereof


A method of adjusting an elevator speed comprising the steps of determining a desired creep period, determining an actual creep period, determining a difference between the desired creep period and the actual creep period, determining a deceleration time for minimizing the difference between the desired creep period and the actual creep period, and adjusting the elevator speed in response to the deceleration time.

Modern elevator systems utilize sophisticated software and controllers which control most aspects of an elevator's operation. The controllers gather information from various sources in the elevator system and use such information to efficiently operate the elevator. Thus, elevator speed, elevator creep period, starting, stopping, floor positioning or leveling, and the like are all governed by the controller. Each of these functions are affected by variations in floor distances, friction, and stiction. Many older buildings, for example, have large variations in the distance between each landing. Additionally, friction and stiction varies from one elevator system to another, and also within each elevator system.
In a closed loop elevator system, the elevator functions mentioned above are generally monitored by using an encoder which measures motor shaft revolutions and translates the results into machine readable feedback signals delivered to the controller microprocessor. The controller uses these feedback signals to determine the present status of the elevator functions. If a deviation from a desired result is detected, then the controller attempts to provide appropriate compensation. For example, conventional elevator systems determine the time to begin deceleration during an elevator run by using the feedback signals supplied by the encoder. The encoder, however, introduces added expense and complexity into the elevator system. Accordingly, it is desirable to perform the above mentioned functions without the use of an encoder.


A feedforward current from a feedforward current setting module, a target location trajectory from a position control module, and a correction value from a correction value setting module are produced for an elapsed time from each seek start time, namely at each sampling timing of a predetermined sample count. In the position control module, the position feedback control in response to an error between a target location and real position is performed in combination with the feedforward current. On a seek distance of one track, a coarse time is set to be 3 samples, for example. By intentionally slipping the target location trajectory from its ideal value, an overshoot and undershoot are restricted.

The present invention relates to a disk storage device that performs seek control of positioning a head to a target location at a fast speed, and, more specifically, to a disk storage apparatus which performs seek control over a short seek distance of 1 to 10 tracks to handle a sector servo having a relatively long sampling period for sampling a head location signal.
In the prior art disk storage apparatuses such as magnetic disk storage apparatuses, a head is mounted on each data surface of a plurality of disk media. In such a disk storage apparatus, the head switching time is substantially shorter than the time required for traversing one track, namely the one track seek time. To access data that continues beyond one track, a target track address is first sought, and then head switching is performed to access data on a different data surface but in the same track. As track pitch is narrowed with the increase of memory capacity, the offset between heads relatively increases, and thus offset correction is required when head switching is performed. For this reason, the head switching time is going to be equal to or exceed the one track seek time. Furthermore, the relative position of one head to another is likely to change with time, and the seek time is not constant. To write or read continuous data in the prior art, data over different data surfaces but in the same track is written or read, while head switching is performed. In the future, however, it is likely that a faster seek control is achieved by sequentially writing or reading data to or from the same disk surface on a one track seek basis, followed by head switching to shift to the next track.
FIG. 1 shows the change of the head location versus elapsed time in a typical seek control. Seek time, coarse time, settling condition and settling time frequently used in the following discussion are defined as follows. Seek time is the time from the reception of a seek command to positioning the head to its target location with its settling condition met. After the seek, the position error to the target location is measured. The settling condition is the condition that assures position error to within the permissible range of position error. The coarse time that is included in the seek time is the time the head takes to reach the target location from its seek start position, and excludes the settling time. The settling time is the time the head takes to satisfy the settling condition from its arrival to the target location.
I. Position gain
To perform a seek, the current location should be accurately acquired. In the magnetic storage disk apparatus, a location signal, for example, two-phase servo signal, is recorded on a disk medium so that the offset between tracks is determined. This position offset signal is typically an analog signal, and is thus fed to an MPU through an AD converter. To convert the output of the AD converter into a value in the unit of actual track, it should be multiplied by the gain that is beforehand measured on a track by track basis in order to achieve an appropriate position gain.
II. Loop gain
Since the force constant BL of a VCM (Voice Coil Motor) for driving a head actuator usually varies with track position, loop gain should be corrected to make the servo bandwidth of a control system constant. The force constant BL of the VCM and gain of an electric circuit system vary depending on temperature and the like, and correction gain stored beforehand in a firmware becomes unable to match the real value. Since the control system is designed and adjusted such that with no error taking place and its gain corrected, overshoot and undershoot are minimized and the settling time is shortest, variations of gain leads to a prolonged settling time. For this reason, the loop gain should be corrected so that the servo bandwidth of the control system is constant over all tracks.
III. Bias force
External force exerted to the actuator varies from place to place. Correction is required to make an external bias force constant regardless of place.
IV. Head-to-head offset
Head switching is required when the track numbers (cylinder numbers) are the same but with different head numbers. In this case, a head-to-head offset takes place. A one track seek needing head switching is associated with the offset involved in head switching, and thus results in 1.2 track seek in practice, affecting the seek time.
V. Mechanical resonance
Current characteristic with respect to the location of VCM is expressed by an equation that is proportional to a double integral. In practice, however, the current characteristic is influenced by the mechanical resonance between the actuator and the head. Depending on seek current, a mechanical resonance takes place, and a vibration remains after the seek. This post-seek vibration is called residual vibration. If a large residual vibration is generated, a long settling time is required before the vibration ceases.
VI. Runout
A target track on the disk is not concentric but slightly deformed in practice. Among deviation components from an ideal track, a component in synchronism with rotation is called a repeatable runout, and a component not in synchronism with rotation is called non-repeatable runout. The effect of the repeatable and non-repeatable runouts is problematic because of the following two reasons. First, a problem arises from the same track. In the course of the settling determination immediately after a seek, the settling condition remains difficult to satisfy due to the effect of the repeatable and non-repeatable runouts, and thus the settling time is prolonged.
FIGS. 2A and 2B plot the maximum values of each amplitude of the repeatable runout RRO and non-repeatable runout NRRO on each track when a position control system is track following to a target location in a 3.5-inch magnetic disk storage apparatus. As seen from these figures, the repeatable and non-repeatable runout values vary greatly from track to track. A second problem lies in adjacent tracks. To traverse from a current track to an adjacent track, traveling a distance of one track is sufficient enough theoretically. In practice, however, seek distance varies with time and place because of the effect of the repeatable and non-repeatable runouts. FIG. 2C plots the ranges of variations in track pitch measured on each track when one track seek to the adjacent track is performed. In this test, the track pitch varies within a range of .+-.20%.
The disk storage apparatus should perform seek control in optimum fashion to shorten the seek time. To this end, it is necessary to reduce variables such as the position gain, loop gain, bias force, head-to-head offset, mechanical resonance, and repeatable and non-repeatable runouts in disk rotation, as much as possible. The position gain, loop gain, bias force, and head-to-head offset can be measured beforehand, and their effect is canceled by making correction with respect to the current location. Resonance presents no problem in a dedicated servo control apparatus. Specifically, in the dedicated servo control, a head location signal is always obtained from a servo head arranged on a dedicated servo embedding servo information, and a head location is detected in a short sampling period. The effect of strong vibration is avoided by inserting a filter that filters out components on or in the vicinity of a resonance frequency from output currents. In a sector servo control or embedded servo control in which servo information is discretely recorded on tracks of the data surfaces, the sampling period of the head location signal is long. Constructing a filter is physically impossible. There is a possibility that the effect of resonance cannot be excluded. The repeatable runout and non-repeatable runout cannot be fully eliminated, because the tracks are different in shape from track to track. In a short-distance seek control, such as one track seek, precluding the effect of the resonance and repeatable and non-repeatable runouts is vitally important. In the prior art disk storage apparatus using sector servo control having a long sampling period, even a relatively short-distance seek control as short as 1 through 4 tracks needs a long coarse time of 10 samples or longer under the effect of the repeatable and non-repeatable runouts. Hence, a need exists for a faster seek control.

Disk storage apparatus having head overshoot and undershoot control


The present disclosure provides systems and methods for non-destructively estimating the thickness of buried concrete without excavation. An example method may include placing one or more first accelerometers at a plurality of vertical positions below the surface of the ground at an approximate first distance from a vertical edge of the buried concrete each time. The method may further include, for each position in the plurality of vertical positions, generating a dispersive wave in the buried concrete and determining a time of arrival of the dispersive wave at the one or more first accelerometers. The method may further include estimating the thickness of the buried concrete based on at least the times of arrival of the dispersive waves at the one or more first accelerometers.

Concrete structures often include both above- and below-grade portions. The above-grade portion is exposed above the surface of the ground (i.e., exposed concrete), while the below-grade portion is buried beneath the surface of the ground (i.e., buried concrete). The exposed concrete is often referred to as a pier or a pedestal, or less commonly, as a column. The buried concrete is often referred to as a pad, a footing, a foundation, or an anchor block. Concrete structures having both above- and below-grade portions are used in many industries for diverse purposes, including to support infrastructures such as cellular telephone towers, transmission line towers, and wind turbines.
In many circumstances, it is desirable to determine or estimate the thickness of the below-grade portion of such concrete structures. This will help to evaluate, for example, whether the concrete structure is suitable for new, updated, or adapted uses as well as any increased load capacity for such uses. Knowing the thickness of below-grade concrete is particularly useful in the telecommunications field because the recently-adopted 5G cellular standard may require different or additional equipment than that required for predecessor technologies. Thus, existing cellular telephone towers may be retrofitted with the different or additional equipment, which could pose different load conditions on the towers.
In some circumstances, the thickness of the below-grade portion of such concrete structures may be unknown. For example, the engineering plans for such structures may be lost, destroyed, or unable to be located. Other times, the structure may not have been built according to design specifications. Uncertainty about the thickness of below-grade concrete is also common in countries that lack rigorous inspection guidelines or regulations.
Current methods for determining or estimating the thickness of below-grade concrete are inefficient. Known methods require excavating around the concrete structure to expose the buried concrete portion, which can lie several feet or more below the surface of the ground. Excavation requires manual labor and/or the use of heavy machinery, both of which are expensive, labor-intensive, time-consuming, and potentially dangerous. Further, excavation is not always practical or possible. When a concrete structure to be investigated is located on a mountain or a hill, it may be difficult or impossible to transport the excavating machinery to the structure. When a concrete structure is located in a rocky area, it may be challenging and expensive to excavate in such areas to expose the concrete.
Another inefficiency in current methods is the risk that while excavating, underground utilities may be inadvertently damaged, causing disruption to nearby residents and business owners. Also, the infrastructure supported by the concrete structures to be excavated, such as cellular telephone towers, often have to be shut down during the excavation, resulting in service disruptions.
A more efficient way of estimating the thickness of below-grade concrete is therefore needed.

Systems and methods for estimating concrete thickness


Planarizing machines and methods for accurately planarizing microelectronic workpieces. Several embodiments of the planarizing machines produce a planar surface at a desired endpoint in the microelectronic workpieces by (a) quickly reducing variances on the surface of the workpiece using a planarizing medium that removes topographical features but has a low polishing rate on planar surfaces; and (b) subsequently planarizing the wafer on a planarizing medium that has a higher polishing rate on planar surfaces than the first polishing medium.

Mechanical and chemical-mechanical planarizing processes (collectively "CMP") remove material from the surface of semiconductor wafers, field emission displays or other microelectronic substrates in the production of microelectronic devices and other products. FIG. 1 schematically illustrates a CMP machine 10 with a platen 20, a carrier assembly 30, and a planarizing pad 40. The CMP machine 10 may also have an under-pad 25 attached to an upper surface 22 of the platen 20 and the lower surface of the planarizing pad 40. A drive assembly 26 rotates the platen 20 (indicated by arrow F), or it reciprocates the platen 20 back and forth (indicated by arrow G). Since the planarizing pad 40 is attached to the under-pad 25, the planarizing pad 40 moves with the platen 20 during planarization.
The carrier assembly 30 has a head 32 to which a substrate 12 may be attached, or the substrate 12 may be attached to a resilient pad 34 in the head 32. The head 32 may be a free-floating wafer carrier, or an actuator assembly 36 may be coupled to the head 32 to impart axial and/or rotational motion to the substrate 12 (indicated by arrows H and I, respectively).
The planarizing pad 40 and a planarizing solution 44 on the pad 40 collectively define a planarizing medium that mechanically and/or chemically removes material from the surface of the substrate 12. The planarizing pad 40 can be a soft pad or a hard pad. The planarizing pad 40 can also be a fixed-abrasive planarizing pad in which abrasive particles are fixedly bonded to a suspension material. In fixed-abrasive applications, the planarizing solution 44 is typically a non-abrasive "clean solution" without abrasive particles. In other applications, the planarizing pad 40 can be a non-abrasive pad composed of a polymeric material (e.g., polyurethane), resin, felt or other suitable materials. The planarizing solutions 44 used with the non-abrasive planarizing pads are typically abrasive slurries with abrasive particles suspended in a liquid.
To planarize the substrate 12 with the CMP machine 10, the carrier assembly 30 presses the substrate 12 face-downward against the polishing medium. More specifically, the carrier assembly 30 generally presses the substrate 12 against the planarizing liquid 44 on a planarizing surface 42 of the planarizing pad 40, and the platen 20 and/or the carrier assembly 30 move to rub the substrate 12 against the planarizing surface 42. As the substrate 12 rubs against the planarizing surface 42, material is removed from the face of the substrate 12.
CMP processes should consistently and accurately produce a uniformly planar surface on the substrate to enable precise fabrication of circuits and photo-patterns. During the construction of transistors, contacts, interconnects and other features, many substrates develop large "step heights" that create highly topographic surfaces. Such highly topographical surfaces can impair the accuracy of subsequent photolithographic procedures and other processes that are necessary for forming sub-micron features. For example, it is difficult to accurately focus photo patterns to within tolerances approaching 0.1 micron on topographic surfaces because sub-micron photolithographic equipment generally has a very limited depth of field. Thus, CMP processes are often used to transform a topographical surface into a highly uniform, planar surface at various stages of manufacturing microelectronic devices on a substrate.
In the highly competitive semiconductor industry, it is also desirable to maximize the throughput of CMP processing by producing a planar surface on a substrate as quickly as possible. The throughput of CMP processing is a function, at least in part, of the polishing rate of the substrate assembly and the ability to accurately stop CMP processing at a desired endpoint. Therefore, it is generally desirable for CMP processes to provide a controlled polishing rate (a) across the face of a substrate to enhance the planarity of the finished substrate surface, and (b) during a planarizing cycle to enhance the accuracy of determining the endpoint of a planarizing cycle.
One concern of CMP processing is that it is difficult to control the polishing rate. The polishing rate typically varies across the surface of the workpiece or during a planarizing cycle because (a) topographical areas with high densities of small features may polish faster than flat peripheral areas, (b) the distribution of abrasive particles in the slurry varies across the face of the workpiece, (c) velocity and thermal gradients vary across the surface of the workpiece, (d) the condition of the surface of the planarizing pad varies, (e) the topography of the workpiece changes, and (f) several other factors. The variance in the polishing rate may not be uniform across the workpiece, and thus it may cause different areas on the workpiece to reach the endpoint at different times. This produces over-polishing in areas with high polishing rates, and under-polishing in other areas with lower polishing rates.
The variance in the polishing rate can be particularly difficult to control when slurries with very small abrasive particles are used on wafers with a high density of small features. It is becoming increasingly important to use very small abrasive particles in CMP slurries because the feature sizes of the microelectronic components are decreasing to produce high performance/capacity products, and the small particle sizes enable mechanical removal of material from workpieces without damaging or otherwise impairing the small components. The slurries with small particle sizes, however, may produce different results as the surface of the planarizing pad changes throughout a run of workpieces, or even during a single planarizing cycle of one workpiece. This can produce inconsistent results that reduce the reliability of CMP processing. Therefore, there is a strong need to provide a planarizing process that can accurately endpoint a planarizing cycle without significantly increasing the time to planarize each workpiece.

Method for planarizing microelectronic workpieces


Logically imaging a memory area or a portion thereof while the memory area is offline. For each partition of a selected volume of the memory area, the logical files are captured along with volume and partition information and stored in an image file to enable logical restoration of the captured image.

Disk imaging is widely used to backup and restore data on computer storage media. Disk imaging, as known in the art, captures a snapshot of the data on a computer hard disk. The captured image may be used subsequently to re-create the disk. Existing disk imaging solutions are sector based. That is, these solutions copy the disk physical data as it is laid out on the hard disk sector by sector, in raw binary format, regardless of whether the data is useful or not (e.g., even empty space is captured). Further, files that should not be captured, such as page files, are also captured resulting in large image files that inefficiently use storage resources. Existing systems that store the large image files on storage resources accessible over a network also inefficiently use network resources.
Existing file backup solutions save the logical content of the file system in online mode (e.g., while executing an operating system stored at least in part on the file system). However, files such as some subset of operating system files cannot be captured while the file system is online. Further, the existing file backup solutions do not preserve information relating to the disk partition, boot sector, and the like. As such, the existing file backup solutions cannot restore an entire disk to a prior state.
Defragmentation tools, as known in the art, move file segments around on a disk to minimize the physical separation of logically continuous file segments. Existing defragmentation tools operating on a file system execute in online mode (e.g., while an operating system stored at least in part on the file system is being executed). As such, the existing defragmentation tools are limited at least in that critical file system data and files locked by the executing operating system cannot be defragmented. Further, if the disk is mostly full, the defragmentation process requires a significant amount of time to complete.

File system based offline disk management


The present invention provides a method of inhibiting a member of a family of Protein Tyrosine Phosphatases (PTPases, PTPs) such as PTP1B, TC-PTP, CD45, SHP-1, SHP-2, PTPα, PTPε, PTPμ, PTPδ, PTPσ, PTPζ, PTPβ, PTPD1, PTPD2, PTPH1, PTP-MEG1, PTP-LAR, and HePTP by exposing said Ptpase member by administration to a host or otherwise to at least one compound with certain structural, physical and spatial characteristics that allow for the interaction of said compound with specific residues of the active site of PTP1B and/or TC-PTP. These compounds are indicated in the management or treatment of a broad range of diseases such as autoimmune diseases, acute and chronic inflammation, osteoporosis, various forms of cancer and malignant diseases, and type I diabetes and type II diabetes, as well as in the isolation of PTPases and in elucidation or further elucidation of their biological function.

Protein phosphorylation is now well recognized as an important mechanism utilized by cells to transduce and regulate signals during different stages of cellular function (Hunter, Phil. Trans. R. Soc. Lond. B 353: 583–605 (1998); Chan et al., Annu. Rev. Immunol. 12: 555–592 (1994); Zhang, Curr. Top. Cell. Reg. 35: 21–68 (1997); Matozaki and Kasuga, Cell. Signal. 8: 113–19 (1996); Fischer et al, Science 253:401–6 (1991); Flint et al., EMBO J. 12:1937–46 (1993)). The level of tyrosine phosphorylation is balanced by the opposing action of protein tyrosine kinases and protein tyrosine phosphatases. There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins (or peptides) that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs).
The PTPases are a family of enzymes that can be classified into two groups: a) intracellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases. In addition, dual-specificity phosphatases and low molecular weight phosphatases are able to dephosphorylate phospho tyrosyl proteins. See, e.g., WO 97/39746; WO 97/40017; WO 99/15529; WO 97/08934; WO 98/27065; WO 99/46236; WO 99/46244; WO 99/46267; WO 99/46268 and WO 99/46237.
Intracellular PTPases: Most known intracellular type PTPases contain a single conserved catalytic phosphatase domain consisting of 220–240 amino acid residues. The regions outside the PTPase domains are believed to play important roles in localizing the intracellular PTPases subcellularly (Mauro, L. J. and Dixon, J. E. TIBS 19: 151–155 (1994)). The first intracellular PTPase to be purified and characterized was PTP1B, which was isolated from human placenta (Tonks et al., J. Biol. Chem. 263: 6722–6730 (1988)). Shortly after, PTP1B was expressed recombinantly (Charbonneau et al., Proc. Natl. Acad. Sci. USA 86: 5252–5256 (1989); Chernoff et al., Proc. Natl. Acad. Sci. USA 87: 2735–2789 (1989)). Other examples of intracellular PTPases include (1) T-cell PTPase/TC-PTP (Cool et al. Proc. Natl. Acad. Sci. USA 86: 5257–5261 (1989)), (2) rat brain PTPase (Guan et al., Proc. Natl. Acad. Sci. USA 87:1501–1502 (1990)), (3) neuronal phosphatase STEP (Lombroso et al., Proc. Natl. Acad. Sci. USA 88: 7242–7246 (1991)), (4) ezrin-domain containing PTPases: PTPMEG1 (Guet al., Proc. Natl. Acad. Sci. USA 88: 5867–57871 (1991)). PTPH1 (Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949–5953 (1991)), PTPD1 and PTPD2 (Møller et al., Proc. Natl. Acad. Sci. USA 91: 7477–7481 (1994)); FAP-1/BAS (Sato et al., Science 268: 411–415 (1995); Banville et al., J. Biol. Chem. 269, 22320–22327 (1994); Maekawa et al., FEBS Letters 337: 200–206 (1994)), and SH2 domain containing PTPases: PTP1C/SH-PTP1/SHP-1 (Plutzky et al., Proc. Natl. Acad. Sci. USA 89: 1123–1127 (1992); Shen et al., Nature Lond. 352: 736–739 (1991)) and PTP1D/Syp/SH-PTP2/SHP-2 (Vogel et al., Science 259: 1611–1614 (1993); Feng et al., Science 259: 1607–1611 (1993); Bastein et al., Biochem. Biophys. Res. Comm. 196: 124–133 (1993)).
Receptor-type PTPases consist of a) a putative ligand-binding extracellular domain, b) a transmembrane segment, and c) an intracellular catalytic region. The structures and sizes of the putative ligand-binding extracellular domains of receptor-type PTPases are quite divergent. In contrast, the intracellular catalytic regions of receptor-type PTPases are very homologous to each other and to the intracellular PTPases. Most receptor-type PTPases have two tandemly duplicated catalytic PTPase domains.
The first receptor-type PTPases to be identified were (1) CD45/LCA (Ralph, S. J., EMBO J. 6: 1251–1257 (1987)) and (2) LAR (Streuli et al., J. Exp. Med. 168: 1523–1530 (1988)) that were recognized to belong to this class of enzymes based on homology to PTP1B (Charbonneau et al., Proc. Natl. Aced. Sci. USA 86: 5252–256 (1989)). CD45 is a family of high molecular weight glycoproteins and is one of the most abundant leukocyte cell surface glycoproteins and appears to be exclusively expressed upon cells of the hematopoietic system (Trowbridge and Thomas, Ann. Rev. Immunol. 12: 85–116 (1994)).
The identification of CD45 and LAR as members of the PTPase family was quickly followed by identification and cloning of several different members of the receptor-type PTPase group. Thus, 5 different PTPases, (3) PTPα, (4) PTPβ, (5) PTPδ, (6) PTPε, and (7) PTPζ, were identified in one early study (Krueger et al., EMBO J. 9: 3241–3252 (1990)). Other examples of receptor-type PTPases include (8) PTPγ(Barnea et al., Mol. Cell. Biol. 13: 1497–1506 (1995)) which, like PTPζ (Krueger and Saito, Proc. Natl. Acad. Sci. USA 89: 7417–7421 (1992)) contains a carbonic anhydrase-like domain in the extracellular region, (9) PTPμ (Gebbink et al., FEBS Letters 290: 123–130 (1991)), (10) PTPκ (Jiang et al., Mol. Cell. Biol. 13: 2942–2951 (1993)). Based on structural differences the receptor-type PTPases may be classified into subtypes (Fischer et al., Science 253: 401–406 (19991)): (I) CD45; (II) LAR, PTPd, (11) PTPσ; (III) PTPβ, (12) SAP-1 (Matozaki et al., J. Biol. Chem. 269: 2075–2081 (1994)), (13) PTP-U2/GLEPP1 (Seimiya et al., Oncogene 10: 1731–1738 (1995); Thomas et al., J. Biol. Chem. 269: 19953–19962 (1994)), and (14) DEP-1; (IV) PTPα,_PTPε. All receptor-type PTPases except Type III contain two PTPase domains. Novel PTPases are frequently identified, and it is anticipated that between 100 and more than 500 different species will be found in the human genome.
PTPases are the biological counterparts to protein tyrosine kinases (PTKs). Therefore, one important function of PTPases is to control, and especially down-regulate, the activity of PTKs. However, a more complex picture of the function of PTPases has emerged. Thus, several studies indicate that some PTPases act as positive mediators of cellular signaling. As an example, the SH2 domain-containing SHP-2 acts as a positive mediator in insulin-stimulated Ras activation (Noguchi et al., Mol. Cell. Biol. 14: 6674–6682 (1994)) and of growth factor-induced mitogenic signal transduction (Xiao et al., J. Biol. Chem. 269: 21244–21248 (1994)), whereas the homologous SHP-1 acts as a negative regulator of growth factor-stimulated proliferation (Bignon and Siminovitch, Clin. Immunol. Immunopathol. 73: 168–179 (1994)). Another example of PTPases as positive regulators has been provided by studies designed to define the activation of the Src-family of tyrosine kinases. In particular, several lines of evidence indicate that CD45 is positively regulating the activation of hematopoietic cells, and that the mechanism of such positive regulation may involve dephosphorylation of the C-terminal tyrosine of Fyn and Lck (Chan et al., Annu. Rev. Immunol. 12: 555–592 (1994)).
The association of many PTPases with cell proliferation, tranformation and differentiation has now been established. PTP1B, a phosphatase whose structure was the first PTPase to be elucidated (Barford et al., Science 263:1397–1404 (1994)) has been shown to be involved in insulin-induced oocyte maturation (Flint et al., The EMBO J. 12:1937–46 (1993)) and the overexpression of this enzyme has been implicated in p185c-erb B2-associated breast and ovarian cancers (Weiner, et al., J. Natl. cancer Inst. 86:372–8 (1994); Weiner et al., Am. J. Obstet. Gynecol. 170:1177–883 (1994)). The association with cancer is on the basis of evidence that overexpression of PTP1B is statistically correlated with increased levels of p185 c-erb B2 in ovarian and breast cancer. The role of PTP1B in the etiology and progression of the disease has not yet been elucidated. Inhibitors of PTP1B therefore would help clarify the role of PTP1B in cancer and in some cases provide therapeutic treatment for certain forms of cancer.
PTPases: the Insulin Receptor Signaling Pathway/Diabetes
Insulin is an important regulator of different metabolic processes and plays a key role in the control of blood glucose. Defects related to its synthesis or signaling lead to diabetes mellitus. Binding of insulin to the insulin receptor (IR) causes rapid (auto)phosphorylation of several tyrosine residues in the intracellular part of the β-subunit. Three closely positioned tyrosine residues (the tyrosine-1150 domain) must all be phosphorylated to obtain full activity of the insulin receptor tyrosine kinase (IRTK) which transmits the signal further downstream by tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-1) (Wilden et al., J. Biol. Chem. 267: 16660–16668 (1992); Myers and White, Diabetes 42: 643–650 (1993); Lee and Pilch, Am. J. Physiol. 266: C319–C334 (1994); White et al., J. Biol. Chem. 263: 2969–2980 (1988)). The structural basis for the function of the tyrosine-triplet has been provided by X-ray crystallographic studies of IRTK that showed the tyrosine-1150 domain to be autoinhibitory in its unphosphorylated state (Hubbard et al, Nature 372: 746–754 (1994)) and of the activated IRTK (Hubbard, EMBO J. 16: 5572–5581 (1997)).
Several studies clearly indicate that the activity of the auto-phosphorylated IRTK can be reversed by dephosphorylation in vitro (reviewed in Goldstein, Receptor 3: 1–15 (1993); Mooney and Anderson, J. Biol. Chem. 264: 6850–6857 (1989)), with the tri-phosphorylated tyrosine-1150 domain being the most sensitive target for protein-tyrosine phosphatases (PTPases) as compared to the di- and mono-phosphorylated forms (King et al., Biochem. J. 275: 413–418 (1991)). This tyrosine-triplet functions as a control switch of IRTK activity and IRTK appears to be tightly regulated by PTP-mediated dephosphorylation in vivo (Khan et al., J. Biol. Chem. 264: 12931–12940 (1989); Faure et al., J. Biol. Chem. 267: 11215–11221 (1992); Rothenberg et al., J. Biol. Chem. 266: 8302–8311 (1991)). The intimate coupling of PTPases to the insulin signaling pathway is further evidenced by the finding that insulin differentially regulates PTPase activity in rat hepatoma cells (Meyerovitch et al., Biochemistry 31: 10338–10344 (1992)) and in livers from alloxan diabetic rats (Boylan et al., J. Clin. Invest 90:174–179 (1992)).
Until recently, relatively little was known about the identity of the PTPases involved in IRTK regulation. However, the existence of PTPases with activity towards the insulin receptor can be demonstrated as indicated above. Further, when the strong PTPase-inhibitor pervanadate is added to whole cells an almost full insulin response can be obtained in adipocytes (Fantus et al., Biochemistry 28: 8864–8871 (1989); Eriksson et al., Diabetologia 39: 235–242 (1995)) and skeletal muscle (Leighton et al., Biochem: J. 276: 289–292 (1991)). In addition, other studies show that a new class of peroxovanadium compounds act as potent hypoglycemic compounds in vivo (Posner et al., supra). Two of these compounds were demonstrated to be more potent inhibitors of dephosphorylation of the insulin receptor than of the EGF-receptor, thus indicating that even such relatively unselective inhibitors may show some specificity in regulating different signal transduction pathways.
It was recently found that mice lacking the protein tyrosine phosphatase-1B gene (PTP1B) (Elchebly et al., Science 283: 1544–1548 (1999)) yielded healthy mice that showed increased insulin sensitivity and were resistant to diet-induced obesity. These results were confirmed by Kaman at al Mol. Cell Biol. 20:5479–5489 (2000). The enhanced insulin sensitivity of the PTP−/− mice was also evident in glucose and insulin tolerance tests.
The PTP-1B knock-out mouse showed many characteristics which would be highly desirable results for an anti-diabetes treatment. Most importantly, the knock-out mice grew normally and were fertile and have exhibited no increased incidence of cancer. Blood glucose and insulin levels were lowered, and insulin sensitivity increased. Moreover, the insulin-stimulated tyrosine phosphorylation levels of IR and IRS-1 were found to be increased/prolonged in muscle and liver—but not in fat tissue. Thus, the main target tissues for this type of approach would appear to be insulin action in liver and muscle.
Several other "diabetic" parameters were also improved, including plasma triglycerides which were decreased in the knock-out mice. The knock-animals also exhibited a resistance to weight gain when placed on a high-fat diet. This is in contrast to the action of the PPARγ agonist class of insulin sensitizers, which rather induce weight gain (Murphy & Nolan, Exp. Opin. Invest. Drugs 9:1347–1361, 2000), and would suggest that inhibition of PTP-1B could be a particularly attractive option for treatment of obese Type II diabetics.
This is also supported by the fact that the heterozygous mice from this study showed many of these desirable features. The reduction in weight gain of the knock-out animals on the high fat diet was found to be due to a decreased fat cell mass, although differences were observed with respect to fat cell number. Leptin levels were also lower in the knock-out mice, presumably as a reflection of the decreased fat mass. Significantly, the Klaman et al group also found that the knock-out animals had an increased energy expenditure of around 20% and an increased respiratory quotient compared to the wild-type; again, heterozygote animals displayed an intermediate level of energy expenditure. Therefore, inhibition of this enzyme may be an effective anti-diabetic and perhaps also anti-obesity therapy.
It should also be rioted that in the PTP-1B knock-out mice the basal tyrosine phosphorylation level of the insulin receptor tyrosine kinase does not appear to be increased, which is in contrast to the situation after insulin treatment where there is an increased or prolonged phosphorylation. This might indicate that other PTPs are controlling the basic phosphorylation state of the insulin receptor in the knock-out mice—and is expected to do so in man.
Also other PTPases have been implicated as regulators of the insulin signaling pathway. Thus, it was found that the ubiquitously expressed SH2 domain containing PTPase, PTP1 D/SHP-2 (Vogel et al., 1993, supra), associates with and dephosphorylates IRS-1, but apparently not the IR it self (Kuhné et al., J. Biol. Chem. 268: 11479–11481 (1993); (Kuhné et al., J. Biol. Chem. 269: 15833–15837 (1994)).
Other studies suggest that receptor-type or membrane-associated PTPases are involved in IRTK regulation (Faure et al., J. Biol. Chem. 267: 11215–11221 (1992), (Haring et al., Biochemistry 23: 3298–3306 (1984); Sale, Adv. Prot. Phosphatases 6: 159–186 (1991)).
While previous reports indicate a role of PTPα in signal transduction through src activation (Zheng et al., Nature 359: 336–339 (1992); den Hertog et al., EMBO J. 12: 3789–3798 (1993)) and interaction with GRB-2 (den Hertog et al., EMBO J. 13: 3020–3032 (1994); Su et al., J. Biol. Chem. 269: 18731–18734 (19.94)), Møller, Lammers and coworkers provided results that suggest a function for this phosphatase and its close relative PTPε as negative regulators of the insulin receptor signal (Møller et al., 1995 supra; Lammers, et al., FEBS Lett. 404:37–40 (1997). These studies also indicated that receptor-like PTPases may play a significant role in regulating the IRTK, including through direct influence on the insulin receptor itself.
Other studies have shown that PTP1B and TC-PTP are likely to be involved in the regulation of several other cellular processes in addition to the described regulatory roles in insulin signaling. Therefore, PTP1B and/or TC-PTP as well as other PTPases showing key structural features with PTP1B and TC-PTP are likely to be important therapeutic targets in a variety of human and animal diseases. The compounds of the present invention are useful for modulating or inhibiting PTP1B and/or TC-PTP and/or other PTPases showing key structural features with said PTPases and thus elucidating their function and for treating disease states in which said modulation or inhibition is indicated.
Further, PTPases influence the following hormones or diseases or disease states: somatostatin, the immune system/autoimmunity, cell—cell interactions/cancer, platelet aggregation, osteoporosis, and microorganisms, as disclosed in PCT Publication WO 99/15529.
PTPases: the Immune System/Autoimmunity
Several studies suggest that the receptor-type PTPase CD45 plays a critical role not only for initiation of T cell activation, but also for maintaining the T cell receptor-mediated signaling cascade. These studies are reviewed in: (Weiss A., Ann. Rev. Genet. 25: 487–510 (1991); Chan et al., Annu. Rev. Immunol. 12: 555–592 (1994); Trowbridge and Thomas, Annu. Rev. Immunol. 12: 85–116 (1994)).
CD45 is one of the most abundant of the cell surface glycoproteins and is expressed exclusively on hemopoetic cells. In T cells, it has been shown that CD45 is one of the critical components of the signal transduction machinery of lymphocytes. In particular, there is evidence that CD45 phosphatase plays a pivotal role in antigen-stimulated proliferation of T lymphocytes after an antigen has bound to the T cell receptor (Trowbridge, Ann. Rev. Immunol, 12: 85–116 (1994)). Several studies indicate that the PTPase activity of CD45 plays a role in the activation of Lck, a lymphocyte-specific member of the Src family protein-tyrosine kinase (Mustelin et al., Proc. Natl. Acad. Sci. USA 86: 6302–6306 (1989); Ostergaard et al., Proc. Natl. Acad. Sci. USA 86: 8959–8963 (1989)). Studies using transgenic mice with a mutation for the CD45-exon6 exhibited a lack of mature T cells. These mice did not respond to an antigenic challenge with the typical T cell mediated response (Kishihara et al., Cell 74:143–56 (1993)). Inhibitors of CD45 phosphatase would therefore be very effective therapeutic agents in conditions that are associated with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. Another important function of CD45 phosphatase inhibitors is in effecting immunosuppression, where such a result is indicated, e.g., in transplantation and other conditions in need of immunosuppressive treatment.
CD45 has also been shown to be essential for the antibody mediated degranulation of mast cells (Berger et al., J. Exp. Med. 180:471–6 (1994)). These studies were also done with mice that were CD45-deficient. In this case, an IgE-mediated degranulation was demonstrated in wild type but not CD45-deficient T cells from mice. These data suggest that CD45 inhibitors could also play a role in the symptomatic or therapeutic treatment of allergic disorders, such as asthma, allergic rhinitis, food allergies, eczema, urticaria and anaphylaxis. Another PTPase, an inducible lymphoid-specific protein tyrosine phosphatase (HePTP) has also been implicated in the immune response. This phosphatase is expressed in both resting T and B lymphocytes, but not non-hemopoetic cells. Upon stimulation of these cells, mRNA levels from the HePTP gene increase 10–15 fold (Zanke et al., Eur. J. Immunol. 22: 235–239 (1992)).
Likewise, the hematopoietic cell specific SHP-1 acts as a negative regulator and thus appears to play an essential role in immune cell development in accordance with the above-mentioned important function of CD45, HePTP and SHP-1, selective PTPase inhibitors are early development candidates or prototype drugs both as immunosuppressors and as immunostimulants. Recent studies illustrate the potential of PTPase inhibitors as immunmodulators by demonstrating the capacity of the vanadium-based relatively nonselective PTPase inhibitor, BMLOV, to induce apparent B cell selective apoptosis compared to T cells (Schieven et al., J. Biol. Chem. 270: 20824–20831 (1995)).
PTPases: Cell—Cell Interactions/Cancer
Focal adhesion plaques, an in vitro phenomenon in which specific contact points are formed when fibroblasts grow on appropriate substrates, mimic, in certain respects, cells and their natural surroundings. Several focal adhesion proteins are phosphorylated on tyrosine residues when fibroblasts adhere to and spread on extracellular matrix (Gumbiner, Neuron 11: 551–564 (1993)). However, aberrant tyrosine phosphorylation of these proteins can lead to cellular transformation. The intimate association between PTPases and focal adhesions is supported by the finding of several intracellular PTPases with ezrin-like N-terminal domains, e.g. PTPMEG1 (Gu et al., Proc. Natl. Acad. Sci. USA 88: 5867–5871 (1991), PTPH1 (Yang and Tonks, Proc. Natl. Acad. Sci. USA 88: 5949–5953 (1991)) and PTPD1 (Møller et al., Proc. Natl. Acad. Sci. USA 91: 7477–7481 (1994)). The ezrin-like domains show similarity to several proteins that are believed to act as links between the cell membrane and the cytoskeleton. PTPD1 was found to be phosphorylated by and associated with c-src in vitro and is hypothesized to be involved in the regulation of phosphorylation of focal adhesions (Møller et al., supra).
PTPases may oppose the action of tyrosine kinases, including those responsible for phosphorylation of focal adhesion proteins, and may therefore function as natural inhibitors of transformation. TC-PTP, and especially the truncated form of this enzyme (Cool et al., Proc. Natl. Acad. Sci. USA 87: 7280–7284 (1990)), can inhibit the transforming activity of v-erb and v-fms (Lammers et al., J. Biol. Chem. 268: 22456–22462 (1993), Zander et al., Oncogene 8: 1175–1182 (1993)). Moreover, it was found that transformation by the oncogenic form of the HER2/neu gene was suppressed in NIH 3T3 fribroblasts overexpressing PTP1B (Brown-Shimer et al., Cancer Res. 52: 478482 (1992)).
The expression level of PTP1B was found to be increased in a mammary cell line transformed with neu (Zhay et al., Cancer Res. 53: 2272–2278 (1993)). The intimate relationship between tyrosine kinases and PTPases in the development of cancer is further evidenced by the recent finding that PTPe is highly expressed in murine mammary tumors in transgenic mice over-expressing c-neu and v-Ha-ras, but not c-myc or int-2 (Elson and Leder, J. Biol. Chem. 270: 26116–26122 (1995)). Further, the human gene encoding PTPγ was mapped to 3p21, a chromosomal region which is frequently deleted in renal and lung carcinomas (LaForgia et al., Proc. Natl. Acad. Sci. USA 88: 5036–5040 (1991)).
PTPases appear to be involved in controlling the growth of fibroblasts. In a recent study it was found that Swiss 3T3 cells harvested at high density contain a membrane-associated PTPase whose activity on an average is 8-fold higher than that of cells harvested at low or medium density (Pallen and Tong, Proc. Natl. Acad. Sci. USA 88: 6996–7000 (1991)).
Two closely related receptor-type PTPases, PTPκ and PTPμ, can mediate homophilic cell—cell interaction when expressed in non-adherent insect cells, suggesting that a normal physiological function for these PTPases in cell-to-cell signalling (Gebbink et al., J. Biol. Chem. 268: 16101–16104 (1993), Brady-Kalnay et al., J. Cell Biol. 122: 961–972 (1993); Sap et al., Mol. Cell. Biol. 14: 1–9 (1994)). Interestingly, PTPκ and PTPμ do not bind to each other (PTPκ does self-associate), despite their structural similarity (Zondag et al., J. Biol. Chem. 270: 14247–14250 (1995)).
From the studies described above it is apparent that PTPases play an important role in regulating normal cell growth. Additionally, as pointed out above, PTPases may also function as positive mediators of intracellular signaling and thereby induce or enhance mitogenic responses. Increased activity of certain PTPases might therefore result in cellular transformation and tumor formation. See, Zheng, supra; Uchida et al., J. Biol. Chem. 269: 12220–12228 (1994 Hunter, Cell 80: 225–236 (1995). Inhibitors of specific PTPases are therefore likely to be of significant therapeutic value in the treatment of certain forms of cancer.
PTPases: Platelet Aggregation
PTPases are centrally involved in platelet aggregation. Thus, agonist-induced platelet activation results in calpain-catalyzed cleavage of PTP1B with a concomitant 2-fold stimulation of PTPase activity (Frangioni et al., EMBO J. 12: 4843–4856 (1993)). The cleavage of PTP1B leads to subcellular relocation of the enzyme and correlates with the transition from reversible to irreversible platelet aggregation in platelet-rich plasma. In addition, the SH2 domain containing PTPase, SHP-1, was found to translocate to the cytoskeleton in platelets after thrombin stimulation in an aggregation-dependent manner (Li et al., FEBS Lett. 343: 89–93 (1994)).
Although some details in the above two studies have been questioned, there is overall agreement that PTP1B and SHP-1 play significant functional roles in platelet aggregation (Ezumi et al., J. Biol. Chem. 270: 11927–11934 (1995)). In accordance with these observations, treatment of platelets with the PTPase inhibitor pervanadate leads to significant increase in tyrosine phosphorylation, secretion and aggregation (Pumiglia et al., Biochem. J. 286: 441–449 (1992)).
PTPases: Osteoporosis
The rate of bone formation is determined by the number and the activity of osteoblasts. In turn, these are determined by the rate of proliferation and differentiation of osteoblast progenitor cells, respectively. Histomorphometric studies indicate that the osteoblast number is the primary determinant of the rate of bone formation in humans (Gruber et al., Mineral Electrolyte Metab. 12: 246–254 (1987), reviewed in Lau et al., Biochem. J. 257: 23–36 (1989)). Acid phosphatases/PTPases are implicated in negative regulation of osteoblast proliferation. Thus, fluoride, which has phosphatase inhibitory activity, has been found to increase spinal bone density in osteoporotics by increasing osteoblast proliferation (Lau et al.; supra). Consistent with this observation, an osteoblastic acid phosphatase with PTPase activity was found to be highly sensitive to mitogenic concentrations of fluoride (Lau et al., J. Biol. Chem. 260: 4653–4660 (1985), Lau et al., J. Biol. Chem. 262: 1389–1397 (1987), Lau et al., Adv. Protein Phosphatases 4: 165–198 (1987)). The mitogenic action of fluoride and other phosphatase inhibitors (molybdate and vanadate) may thus be explained by their inhibition of acid phosphatases/PTPases that negatively regulate the cell proliferation of osteoblasts. The complex nature of the involvement of PTPases in bone formation is further suggested by the recent identification of a novel parathyroid regulated, receptor-like PTPase, OST-PTP, expressed in bone and testis (Mauro et al., J. Biol. Chem. 269: 30659–30667 (1994)). OST-PTP is up-regulated following differentiation and matrix formation of primary osteoblasts and subsequently down-regulated in the osteoblasts which are actively mineralizing bone in culture. In addition, it was recently observed that vanadate, vanadyl and pervanadate all increased the growth of the osteoblast-like cell line UMR106. Vanadyl and pervanadate were stronger stimulators of cell growth than vanadate. Only vanadate was able to regulate the cell differentiation as measured by cell alkaline phosphatase activity (Cortizo et al., Mol. Cell. Biochem. 145: 97–102 (1995)). More important, several studies have shown that biphosphonates, such as alendronate and tiludronate, inhibit PTPase activity in osteoclasts and that the inhibition of PTPase activity correlated with the inhibition of in vitro osteoclast formation and bone resorption. (Scmidt, et al., Proc. Natl. Acad. Sci. U.S.A. 93: 3068–3073, 1996; Murakami et al., Bone 20:399–404, 1997; Opas et al., Biochem. Pharmacol. 54: 721–727, 1997; Skorey et al., J. Biol. Chem. 272: 22472–22480, 1997. Thus other PTPase inhibitors are potentially effective in countering osteoclast activity, and thus treating osteoporosis.
PTPases: Microorganisms
Dixon and coworkers have called attention to the fact that PTPases may be a key element in the pathogenic properties of Yersinia (reviewed in Clemens et al. Molecular Microbiology 5: 2617–2620 (1991)). This finding was rather surprising since tyrosine phosphate is thought to be absent in bacteria. The genus Yersinia comprises 3 species: Y. pestis (responsible for the bubonic plague), Y. pseudoturberculosis and Y. enterocolitica (causing enteritis and mesenteric lymphadenitis). A dual-specificity phosphatase, VH1, has been identified in Vaccinia virus (Guan et al., Nature 350: 359–263 (1991)). These observations indicate that PTPases may play critical roles in microbial and parasitic infections, and they further point to PTPase inhibitors as a novel, putative treatment principle of infectious diseases. Availibility of PTPase inhibitors would help shed light in all the foregoing specualations about PTPase function because they would enable assaying techniques which would answer some of these questions as will be illustrated below.

Method of inhibiting protein tyrosine phosphatase 1B and/or T-cell protein tyrosine phosphatase 4 and/or other PTPases with an Asp residue at position 48


A cassette type radiographic image solid-sate detector that is an FPD compatible with a CR cassette, thin-shaped with s sufficient strength, capable of preventing a housing from being deformed by external stress to deal with an external shock, and capable of portable radiography. The cassette type radiographic image solid-state detector comprises a detector unit including a scintillator layer for converting incident radiation into light and a signal detecting section for receiving the light obtained by the conversion by the scintillator layer and converting the light to an electrical signal, a housing including a housing body formed of carbon fibers and a first cover member and a second cover member covering openings of the housing body and containing the detector unit. The thickness of the housing in the direction of incidence of the radiation conforms to JIS Z 4905. At least one of the cover members is structured to be insertable into the detector unit.

A radiographic image represented by an X-ray image and captured by radiation has found widespread application for the purpose of disease diagnosis and others.
The radiographic image for medical treatment was captured using a screen film in the conventional method. However, the successful digitization of a radiographic image in recent years has allowed a CR (Computed Radiography) apparatus to come into widespread use, for example, wherein the radiation having passed through a subject is accumulated on a stimulable phosphor sheet wherein a stimulable phosphor layer is formed. The stimulable phosphor sheet is then scanned by a beam of laser, so that the stimulable light emitted from the stimulable phosphor sheet is subjected to photoelectric conversion, whereby image data is obtained (for example, Patent Literatures 1 and 2).
A cassette (for example, Patent Literatures 1 and 2) incorporating a recording medium such as a screen film or a stimulable phosphor sheet is used to capture a radiographic image. It should be noted that the CR cassette used for radiographing with a CR apparatus is designed and manufactured according to the JIS-based dimensions of the screen/film cassette in order to ensure continued use of the existing device such as the cassette holder or Bucky's table having been introduced to conform to the conventional cassette for screen/film use. To put it another way, the compatibility of the cassette dimensions is maintained, and the effective use of the devices and digitization of the image data have been achieved.
In recent years, as a device for acquiring a radiographic image for medical use, a FPD (Flat Panel Detector) has come to be known as a detector capable of detecting the radiation having been applied, and acquiring the digital image data (for example, Patent Literature 3).
Further, a portable radiographic apparatus (portable FPD) wherein this FPD is incorporated in a housing has come to be put into commercial use (for example, Patent Literatures 4 and 5). Such a portable detector is characterized by easy transportation, and can be brought to the medical ward of a patient for radiographing. Further, the position and angle can be freely adjusted in conformity to the position and angle of the position to be radiographed, and this apparatus is expected to be utilized over a wide range.
As described in the Patent Literatures 4 and 5, in the portable detector, a grip is provided on one end of the enclosure for incorporating the FPD for easy transportation. This is intended to improve the maneuverability of the detector by a radiographer and others because the weight of this detector is increased as compared to the CR cassette as the entire detector by the use of a rigid housing for protecting the internal detection panel.    Patent Literature 1: Japanese Unexamined Patent Application Publication No. 2005-121783    Patent Literature 2: Japanese Unexamined Patent Application Publication No. 2005-114944    Patent Literature 3: Japanese Unexamined Patent Application Publication No. Hei 9-73144    Patent Literature 4: Japanese Unexamined Patent Application Publication No. 2002-311527    Patent Literature 5: U.S. Pat. No. 7,189,972

Cassette type radiographic image solid-state detector


A rotor tip bleed air tailoring system in which a rotor blade is located upstream from an outer stator vane and an inner stator vane. The inner stator vane and outer stator vane are separated by a splitter which extends to the tip region of the rotor blade and separates air exiting the rotor blade into regions of distinctly different pressures.

The present invention pertains to gas turbine engines, and more particularly, to a system and method for better utilizing rotor tip bleed air.
In the past, gas turbine engine pressurized bleed air has been used for a variety of functions which have included turbine cooling, nozzle cooling, purge, pressurization and customer bleed. The source of this pressurized bleed air is most often from the compression system. Rotor blades, in a given stage of a compressor, by performing work upon the air in the air flow path of the compressor, increase the pressure of the airflow. Thus, the downstream pressure in a compressor is greater than the upstream pressure. Stator vanes reduce the tangential momentum in the air received from the adjacent upstream rotor blades so that additional tangential momentum can be imparted by the next downstream rotor at more desirable inlet conditions.
Typically, bleed air is extracted upon exit from a stator vane as the flow path MACH number is lower at this location and the swirl is better controlled. The bleed air can then be piped through proper conduits to a desired user location. The pressure of the bleed air at its source (i.e., the exit point from the stator) must exceed the pressure required at its point of desired use since pressure is lost as air traverses through bends and corners in a conduit.
In a gas turbine engine, the compression process is generally divided into a number of stages. The location of each stator vane in a compressor can be viewed as a possible source of bleed air. Thus, in a given system, it is known what source pressure must exist to achieve a desired pressure at a user location. However, if the source pressure is too high, a system penalty will be introduced as a result of wasted and non-utilized work which of course contributes to engine inefficiency. It is desirable to reduce the number of compression stages to save weight, reduce parts count and lower cost. For the same overall component pressure ratio, the number of possible bleed sources is reduced thus making it more difficult to match the desired level of pressure.
For a hypothetical example, consider the following table:
______________________________________ STAGE N STAGE N + 1 STAGE N + 1 EXIT PRESSURE EXIT PRESSURE RATIO PRESSURE ______________________________________ CASE A 100 1.30 130 CASE B 95 1.40 133 CASE C 110 1.40 154 ______________________________________
Stage N in the above table has an exit pressure of 100 for Case A, an exit pressure of 95 for Case B and an exit pressure of 110 for Case C. The pressure can be viewed as total pressure psi. However, if bleed air, having a source pressure of 120 is required, an exit pressure at stage N is insufficient for Case A, Case B and Case C. In stage N+1, an excess exit pressure exists in Case A (130-120=10), an excess exists in Case B (133-120-13), and an excess exits in Case C (154-120=34). The selection of a stage for supplying bleed air depends on the pressure drop between the stage and zone of use.
In summary, if the pressure is insufficient, it cannot be utilized at all, but if it is too great, penalties result from the excess pressure. This excess pressure is a result of excess work being performed. The pressure in excess of the desired pressure results in wasted work which is a penalty to the system. If additional work is performed on the bleed air, the bleed air is given a higher temperature which necessitates a greater quantity of bleed air for cooling purposes.
Thus, a need exists for a system and method for obtaining a desired bleed air exit pressure to enhance engine efficiency.

System and method for tailoring rotor tip bleed air