Compounds comprising two human GlxI inhibitors covalently linked via a chemical linker are provided, wherein each of said two human GlxI inhibitors, which may be the same or different, is an S-substituted glutathione or an S-substituted glutathione prodrug, wherein said GlxI inhibitors each have a γ-glutamyl amino group, wherein said chemical linker is covalently bound to each GlxI inhibitor via said γ-glutamyl amino group, and wherein said chemical linker has a length of at least 50 Angstroms. Monovalent irreversible inactivators of human GlxI are also provided. An antineoplastic composition is provided, which comprises a compound described above and a pharmaceutically acceptable carrier. In vitro and in vivo methods of preventing or inhibiting the growth and proliferation of neoplastic cells and/or tumors are also provided.

Recent advances in understanding the metabolism of methylglyoxal in mammalian cells suggest that the glutathione (GSH)-dependent glyoxalase enzyme system is a useful target for antitumor drug development (Creighton et al, Drugs of the Future, 25:385-392 (2000)). The physiological function of this detoxification pathway is to remove cytotoxic methylglyoxal from cells as D-lactate via the sequential action of the isomerase glyoxalase I (GlxI) and the thioester hydrolase glyoxalase II (GlxII), as shown in Scheme 1 below (Creighton et al, "Glutathione-Dependent Aldehyde Oxidation Reactions", In Molecular Structure and Energetics: Principles of Enzyme Activity, Liebman et al, Eds.; VCH Publishers, 9: 353-386 (1988)).

Methylglyoxal is a highly reactive alpha-ketoaldehyde that arises as a normal by-product of carbohydrate metabolism (Richard et al, Biochemistry, 30:4581-4585 (1991)) and is capable of covalently modifying proteins and nucleic acids critical to cell viability (Reiffen et al, J. Cancer Res. Clin. Oncol., 107:206-219 (1984); Ayoub et al, Leuk. Res., 17:397-401 (1993); Baskaran et al, Biochem. Int., 212:166-174 (1990); Ray et al, Int. J. Cancer, 47:603-609 (1991); White et al, Chem-Biol. Interact., 38:339-347 (1982); and Papoulis et al, Biochemistry, 34:648-655 (1995)).
Inhibitors of GlxI have long been sought as possible anticancer agents, because of their potential ability to induce elevated concentrations of methylglyoxal in tumor cells (Creighton et al (2000), supra), and because of the observation that rapidly dividing tumor cells are exceptionally sensitive to the cytotoxic effects of exogenous methylglyoxal (Ray et al, supra; White et al, supra; and Papoulis et al, supra). The basis of this sensitivity is not well understood, but appears to arise, in part, from methylglyoxal induced activation of the stress-activated protein kinases c-Jun NH2-terminal kinase 1 (JNK1) and p38 mitogen-activated protein kinase (MAPK), which leads to caspase activation and apoptosis (programmed cell death) in tumor cells (Sakamoto et al, Clinical Cancer Research, 7:2513-2518 (2001); and Sakamoto et al, J. Biol. Chem., 277:45770-45775 (2002)). Moreover, methylglyoxal is probably genotoxic, on the basis of its ability to covalently modify nucleotide bases in DNA (Papoulis et al, supra).
Further, inhibitors of hGlxI that are hydrolytically destroyed by the thioester hydrolase GlxII offer a selective strategy for specifically inhibiting tumor cells, as normal cells contain much higher concentrations of GlxII than tumor cells. Table 1 below shows a comparison of the activities of GlxI and GlxII in normal versus cancer cells (Creighton et al (2000), supra).
TABLE 1Reported Glyoxalase Activitiesin Normal Cells versus Cancer CellsGlyoxalase Activity(mU/mg protein)TissueGlxIGlxIIGlxI/GlxIINormalbrain (human)1113 ± 19817 ± 1561.4liver (human) 209 ± 56360 ± 130.6heart (hamster) 339 ± 24280 ± 471.2kidney (human) 323 ± 48330 ± 861.0lymphocytes (mouse) 360 ± 30200 ± 301.8Tumormelanoma B16 (mouse) 370 ± 160 66 ± 185.6leukemia L1210 (mouse) 310 ± 30 20 ± 315.5glioblastoma (human) 290 ± 56 53 ± 105.5fibroadenoma mammae 419 ± 73 27 ± 715.5(human)bladder HT-1107 542 ± 38 8 ± 167.8(human)prostate PC-3 (human)4206 ± 294 45 ± 393.4testis T1 (human)4767 ± 275 94 ± 1251.0colon HT29 (human) 542 ± 59 11 ± 149.3
Thus, normal cells should be able to detoxify thioester inhibitors of hGlxI much more rapidly than the corresponding tumor cells, resulting in much higher steady concentrations of the inhibitors in tumor cells. Consistent with this hypothesis, the diethylester prodrug form of S—(N-p-chlorophenyl-N-hydroxycarbamoyl) glutathione (CHG), which is both an inhibitor of hGlxI and a substrate for hGlxII (Murthy et al, J. Med. Chem., 37:2161 (1994)), is significantly more toxic to murine leukemia L1210 cells than to normal splenic lymphocytes in culture, reflecting the 10-fold lower activity of hGlxII in L1210 cells versus splenic lymphocytes (Kavarana et al, J. Med. Chem., 42:221-228 (1999)).
Since an ideal chemotherapeutic agent should be highly specific for cancer cells and therefore have minimal side effects, GlxI inhibitors are attractive anticancer agents because of their selective accumulation in tumor cells rather than normal cells.
Further, an antitumor strategy targeting hGlxI provides benefits over more established chemotherapies that attack rapidly dividing tumor cells at various stages of mitosis, or that arrest tumor cells at some stage in the cell cycle. For example, many of the small molecule antitumor drugs currently in use target rapidly dividing tumor cells by either directly or indirectly inhibiting DNA and/or protein synthesis. Thus, these drugs will also adversely affect rapidly dividing normal cells, like those of the intestinal epithelium and bone marrow. As a result, side-effects of antitumor agents currently in use often include myelosuppression, intestinal disorders, dose-dependent cardiotoxicity, pulmonary fibrosis, anaphylactic reactions, alopetia, and anorexia.
A class of transition state analogue inhibitors of hGlxI are known which are S—(N-aryl/alkyl-N-hydroxycarbamoyl)glutathiones. Specifically, these thioester derivatives of GSH mimic the stereoelectronic features of the tightly bound transition state species that flank the ene-diolate intermediate that forms along the reaction coordinates of the enzyme. As such, these compounds are the strongest known competitive inhibitors of hGlxI, with inhibition constants (Kis) in the mid-nanomolar range: S—(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione (CHG), Ki=46 nM; S—(N-p-bromophenyl-N-hydroxy-carbamoyl)glutathione (BHG), Ki=14 nM; S—(N-p-iodophenyl-N-hydroxy-carbamoyl)glutathione (IHG), Ki=10 nM; and S—(N-hexyl-N-hydroxycarbamoyl)glutathione, Ki=16 nM (Kalsi et al, J. Med. Chem., 43:3981-3986 (2000)). These transition state analogue inhibitors are hereinafter called "reversible competitive inhibitors."
Moreover, the reversible competitive inhibitors are also slow substrates for bovine liver GlxII, which suggests that these compounds can selectively inhibit tumor cells over normal cells (Murthy et al, supra).
The effectiveness of the reversible competitive inhibitors can be measured by their specificity for the GlxI active site and by the time they occupy the active site, thereby blocking access of the enzyme's natural substrate (GSH-methylglyoxal thiohemiacetal). An inhibitor with a low competitive inhibition constant (Ki) associates with the active site of an enzyme with higher affinity and greater specificity, and therefore, occupies the active site for a longer period of time than inhibitors with higher Ki values.
The competitive inhibitors have been shown to be lethal to different human and murine tumor cell lines in culture when administered as diethyl ester prodrugs (U.S. Pat. No. 5,616,563) (Kavarana et al, supra). Di- or mono-ester prodrugs are employed since the charged glutathionyl precludes rapid diffusion into cells. After diffusion, these prodrugs undergo de-esterification inside the cell. The diethyl ester prodrugs of S—(N-phenyl-N-hydroxycarbamoyl)glutathione, PHG(Et)2; S—(N-p-bromophenyl-N-hydroxycarbamoyl)glutathione, BHG(Et)2; and S—(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione, CHG(Et)2, inhibit the growth of murine leukemia L1210 cells in culture with IC50 values of 63, 16, and 5 μM, respectively, after 72 hours of incubation.
In vivo efficacy studies with CHG(Et)2 by Sharkey et al, Cancer Chemother. and Pharmacol., 46:156-166 (2000), which is herein incorporated by reference, also support the hypothesis that competitive inhibitors of GlxI are potentially important antitumor agents. For example, bolus i.v. administration of CHG(Et)2 inhibited the growth of human prostate PC3 tumors in athymic nude mice. The potency of CGH (Et)2 was as good as the positive control cisplatin without the cisplatin-associated haemopoetic toxicity. However, no effect was observed by continuous infusion of CHG(Et)2 over 12 days, suggesting that, when administered by continuous infusion, not enough drug is available to be absorbed by such a rapidly growing tumor. Further, the efficacy of CHG(Et)2 against murine melanotic melanoma implanted subcutaneously in (Es-1e) mice was also evaluated. After, a preliminary pharmacokinetic study that showed significant accumulation of drug in melanoma following i.v. bolus administration of CHG(Et)2, the efficacies of CHG(Et)2 and the dicyclopentyl diester prodrug CHG(cyclopentyl)2 were evaluated. All of the drugs gave results that were statistically significant from the vehicle control. CHG(Et)2 and CHG(cyclopentyl)2 were as effective as the positive control adriamycin, but at much higher dosages. There were no detectable side-effects observed in any of the trials. Similar results were obtained with athymic nude mice bearing human colon HT29 tumors. Potency was as good as the positive control vincristin when the drug was administered by continuous i.v. infusion, without any detectable side-effects. However, efficacy was not observed by bolus administration, indicating that this slowly growing tumor was not sufficiently exposed to drug. Thus, the method of drug delivery (bolus infusion versus continuous infusion) is an important aspect of efficacy.
All three in vivo efficacy studies required high doses of prodrug to inhibit tumor growth (80 mg/kg body mass). A subsequent series of studies by Sakamoto et al (2001) showed that the dicyclopentyl diester of a weaker competitive inhibitor of GlxI, (S-p-bromobenzyl)glutathione (BBG), effectively inhibited lung tumor cell lines NCI-H460, NCI-H226, A549, NCI-H23, DMS273, DMS114, NCI-H522 in vitro, and DMS144 and human prostate DU145 in nude mice bearing human cancer xenografts. Further, it was discovered that BBG is effective against human lung tumors (DMS114) in mice at dosages of 100 mg/kg (Sakamoto et al (2001), supra), with no evidence of adverse side effects during the 21 days of administration. Taken together, these studies show that inhibition of GlxI is an important chemotherapeutic strategy in cancer control.
In order to improve this antitumor strategy, more effective GlxI inhibitors must be developed that will be effective at much lower dosages. The large dosages currently required for antitumor activity increase the probability that toxic side effects or adverse reactions will develop when these compounds are used over long periods of time. Thus, there is a need in the art for more potent inhibitors that have a greater binding affinity or specificity for the active site of GlxI such that they may be administered at lower dosages than known GlxI inhibitors to effectively inhibit tumor growth.

Inactivators and bivalent inhibitors of glyoxalase I and methods of inhibiting tumor growth

University of Maryland, Baltimore County


The present invention provides compositions and methods for preparing protein drug conjugate and its application to stem cell therapy and treating cancer cells. The composition is an antibody-binding-therapeutic drug conjugate that binds antibodies targeted to cancer or stem cells. The method of using the composition includes the steps of combining an antibody that targets the cancer cells or stem cells with a sample for a time sufficient to allow said antibody to bind the targeted cells present in said sample and adding the antibody-binding-drug conjugate for a time sufficient to allow binding to the antibody bound to the targeted cells. The presence of the drug reduces the number of or eliminates the targeted cancer cells or stem cells. A similar method is disclosed for selecting antibodies that may be effective antibody drug conjugates.

Monoclonal antibody (mAb) for the treatment of cancer, like AVASTIN™ (anti-VEGF) for colon cancer, RITUXAN™ (Rituximab; anti-CD20) for Non-Hodgkin's Lymphoma and HERCEPTIN™ (anti-Her2) for breast cancer have demonstrated that unconjugated antibodies can improve patient survival without the toxicity experienced with conventional chemotherapy treatments.
Monoclonal antibodies bind to target cells and activate the immune system to eliminate the cell. Increased efficiency can be achieved by conjugating a therapeutic agent to mAbs to form an antibody drug conjugate (ADC). ADCs deliver the therapeutic agent directly to the cell without the need for activating the immune response system. The linkage of the antibody to the drug can be direct, or indirect via a linker. One of components believed to be important for developing effective and well-tolerated ADCs is the composition and stability of the linker. For some types of ADCs, the linker desirably provides serum stability, yet selectively releases the drug at or within the target cell.
Attachment of a linker to a mAb can be accomplished in a variety of ways, such as through surface lysines, reductive-coupling to oxidized carbohydrates, and through cysteine residues liberated by reducing interchain disulfide linkages. A variety of ADC linkage systems have been described in the literature, including hydrazone-, disulfide- and peptide-based linkages. Some hydrazone and disulfide-based linkers can be labile in circulation, resulting in release of drug outside the targeted tissue. It is believed that this premature release of drug might lead to systemic toxicity or organ-specific toxicity and/or less than optimal therapeutic efficacy. Peptide-based linker strategies may provide linkers of higher stability; however, the increased associated hydrophobicity of some linkers may lead to aggregation, particularly with strongly hydrophobic drugs. Such aggregation may lead to non-specific uptake of the ADCs into non-targeted tissues, potentially affecting non-target toxicity.
Consequently, there remains a need for targeted delivery of drugs, resulting in reduction or elimination of targeted cells while reducing toxicity to non-target cells.
These and other limitations and problems of the past are solved by the present invention. The recitation of any reference in this application is not an admission that the reference is prior art to this application.

Antibody-binding protein-drug conjugate and methods of use


A method for purification of glycerol, especially crude glycerol from biodiesel production. The method uses gel-type acidic ion exchange resin beads to separate fatty acid salts and inorganic salts from the crude glycerol.

This patent application claims the benefit of the earlier filed European Patent application serial number 07290412.1 filed on Apr. 4, 2007 under 37 CFR 1.55(a).
This invention relates generally to a method for purification of glycerol, especially crude glycerol derived from biodiesel production.
High fuel prices and environmental concerns are driving development of alternative fuels, especially those derived from renewable resources. One such fuel, commonly known as "biodiesel" fuel, commonly contains methyl esters of fatty acids, and is burned in diesel engines. One source of biodiesel fuel is transesterification of triglycerides, such as vegetable oils with alcohols, typically with methanol. Glycerol is produced as a byproduct of this process, and typically is contaminated with salts of fatty acids and inorganic salts. The prior art discloses methods purification of glycerol, e.g., by ion exclusion chromatography in D. R. Asher & D. W. Simpson, J. Phys. Chem., vol. 60, pp. 518-21 (1956).
However, poor separation is achieved by prior art methods.
The problem addressed by this invention is to find an improved method for purification of glycerol.


A code disc is spline-connected to an operation unit supported such that it can rotate and move vertically and sandwiched between a center cylinder and a return spring. Rotation of the operation unit is detected by photointerruptors through the code disc and vertical movement of the operation unit is detected by a photointerruptor through a cylinder.

1. Field of the Invention
The present invention relates to a composite operation type input device which is capable of carrying out an input operation with two different pressing and rotation operations.
2. Description of the Related Art
Heretofore, as an example of this type of composite operation type input device, there has been known a device which comprises a rotary operation unit having an annular rotary knob, a slider which is rotated by this rotary knob, a printed board having a contact point pattern in sliding contact with this slider, a pressing operating unit having an operation shaft which can move vertically on the inner side in the radial direction of the rotary knob, and a push switch which is pressed by an end of this operation shaft and mounted on the printed board.
In the composite operation type input device which is constituted as described above, when an operator rotates the rotary knob, the slider rotates together with the rotary knob and moves the contact point pattern on the printed board, whereby a rotation operation detection signal corresponding to the contact position between the slider and the contact point pattern is output. When the operator presses down the operation shaft by a predetermined stroke, the actuator of the push switch is pressed down by the end of the operation shaft, whereby a movable contact point incorporated in the push switch contact a fixed contact point to output a pressing operation detection signal.
In the above conventional composite operation type input device, the rotation operation mechanism including the rotary knob and the pressing operation mechanism including the operating shaft are separated from each other so that they can act independently without interfering with each other. However, when these two independent operation units are installed adjacent to each other in a limited space, the resulting structure becomes complicated, thereby making it difficult to cut the cost. Further, since a part to be rotated is mounted around a part to be pressed, it is difficult to prevent an increase in the diameter of the rotation operation mechanism with the result that the whole device becomes large in size. Further, when the rotation operation is repeated, the contact sites of the slider and the contact point pattern gradually wear away, thereby making it difficult to maintain desired detection accuracy for a long time.

Composite operation type input device for carrying out pressing and rotation operations with common operation unit


An antenna which includes a rigid boom and a plurality flexible antenna elements attached to the boom. The antenna elements have curved cross-sections and are made from a material which allows them to resiliently bend upon contacting an object. The antenna is particularly suitable for mobile field use such as tracking objects tagged with radio frequency transmitters. In such use, the flexible antenna elements easily bend when contacting objects such as branches, brush and other vegetation so as not to become entangled and prevent movement of the antenna.

There are a number of situations in which antennas are used in field environments. For example, animals are often tagged with radio transmitters which enable the monitoring of migratory and/or territorial habits. The location of such tagged animals is often monitored by a radio receiver attached to a hand-held antenna. Other examples of situations in which antennas are used in field environments include the tracking of hunting dogs that are equipped with radio transmitters, military field tracking operations, weather balloon tracking, etc.
In field environments associated with such procedures, the use of an antenna having fixed or rigid elements can be bothersome, particularly when it is necessary to move through forests, woods, and other areas of brush or vegetation.
Antennas typically used for tracking or locating radio transmitter-tagged objects comprise planar structures which include a plurality of rigid dipole elements that extend from a central boom. As is known, the length of the dipole elements can vary, depending on the frequency of the signal which is to be received.
The use of flexible antenna elements has been suggested in remotely deployable antennas. U.S. Pat. Nos. 5,214,439 and 5,196,858 to Reed disclose deployable antennas which include S-shaped antenna elements that are wound around spools located in an elongated housing or drum. The antenna elements are deployed or extended from the drum by rotating the spools relative to the drum. U.S. Pat. No. 4,977,408 to Harper et al. discloses a deployable antenna which is similar to the deployable antennas of Reed. The deployable antenna of Harper et al. utilizes C-shaped antenna elements which are wound around spools.
U.S. Pat. No. 4,355,315 to Zoulek discloses a log periodic directional antenna which includes a plurality of stainless steel spring-type antenna elements that are provided as half elements which are mounted to opposite sides of the boom. Zoulek's antenna is designed to provide either horizontal or vertical polarization when mounted to a mast.
The present invention provides an antenna having flexible elements which allows the antenna to be used in rough field environments where the antenna is likely to encounter various obstacles during use.


A machine readable assaying system including an assay card having a machine readable assaying indicia located upon a surface of the card. At least one analysis element is provided with the assaying indicia, and is capable of monitoring a parameter to detect and optically signal the presence or absence of a desired state. The analysis elements composing, at least in part, an assaying mechanism in the form a pattern of elements, generally additionally including at least one fixed element, and or at least one blank region.

1. Field of the Invention
The invention relates to changeable encoded information carrying characters, including bar-code like indicia. More particularly, the present invention relates to embodiments of machine readable, changeable or alterable indicia, wherein the change is related to one or more monitored parameters or variable quantities.
2. Background and Objects of the Invention
The advent of machine readable indicia has been long noted in the art. Such indicia, including for example bar code symbols and other specialized characters, enable encoded data to be read by suitable known apparatus to accurately determine the encoded data. It is this characteristic that has lead to the rapid acceptance of such coding arrangements as defacto standards, especially in inventory intensive establishments that must manage and track a large plurality of items with a significant accuracy. Presently there are a number of industry symbologies and accepted standards available in the art, and a full range of devices to accurately and rapidly read (scan) these indicia.
There is also an on-going need to provide assaying methods, manufactures, and apparatus that provide "assay result indications" which are not subject to errors due to human interpretation, transcription, and or translation. The assay may be required to monitor or determine the levels of parameters and variable quantities. For example, the monitoring of temperature, humidity, saline concentrations (of a fluid), gas concentrations (e.g., the level of exhaust fume gases), chemical residues and associated concentrations, light intensities, magnetic field strengths, radiation exposures, etc. It should also be noted that it is often advantageous to provide an assaying means with a `memory` capability. For example, it may be desired to monitor if the maximum temperature a package reached in transit, has exceeded a critical level.
Objects of the present invention are, therefore, to provide new and improved assaying arrangements to monitor one or more parameters (or variables) having one or more of the following capabilities, features, advantages and/or characteristics:
an assaying system that produces machine readable result indications; PA1 machine readable indicia having changeable or alterable encoded data content; PA1 assay provided by `elements` composing a machine readable indicia; PA1 a reliable and expeditious assaying arrangement; PA1 provides assay means wherein changes and results detected and indicated may be provided as not "human readable", and thus are not subject to interpretation and possibly unauthorized dissemination; PA1 may be employed on-site using a number of relatively low cost "off-the-shelf" components; PA1 assaying means includes analysis elements that are arranged to provide an optically detectable machine readable change in the assaying indicia; and PA1 inherently configurable to restrict an assay administrator, or other persons, access to the assay results.
The above indicated advantages, characteristics, objects, and or associated novel features of the present invention, as well as others, will become better understood with a careful review of the description and figures provided herein. Attention is called to the fact, however, that the drawings are illustrative only. Variations are contemplated as being part of the invention, limited only by the scope of the appended claims.

Changeable machine readable assaying indicia


A method and a device for transmitting electronic mail messages using a mobile wireless telephone network short message service are provided. An electronic mail message is transmitted by using the at least one short message which includes a short message header portion and a short message data portion. The short message data portion includes a user data header portion having: a) an identifying data field to identify that the short message data portion includes addressing information in accordance with RFC 822, and b) a length data field identifying a length of the addressing information in accordance with RFC 822. The addressing information in accordance with RFC 822 includes data fields differentiated from one another by keywords.

The publication "SMS-E-Mail Parameter," T2(99)-1068 Change Request to 23.040 discusses a method of transmitting Internet e-mail using the SMS short message service, an Internet e-mail plus address and identification data are transmitted with an SMS short message in a telecommunications network in various headers of the SMS short message for transmission of Internet e-mail over the Internet.

This patent is subject to a terminal disclaimer.

Method of transmitting electronic mail messages


An access circuit for efficiently accessing a buffer memory in accordance with an instruction from an external circuit. An access data unit for accessing a SDRAM in one operation clock cycle of the access circuit may be switched between one byte, one word, and two words. The switching of the access data unit is performed in accordance with a data unit designation signal generated by decoding address data, which is provided to a control unit, with an address decoder. The memory interface receives a request signal that is in accordance with the data unit designation signal from a request generator and accesses the buffer memory in the access data unit that is in accordance with the request signal.

The present invention relates to an access circuit for accessing a buffer memory in accordance with a command from an external circuit.
FIG. 1 is a block diagram showing an access circuit 220 and its peripheral circuits, which are used in a prior art digital versatile disc (DVD) recording-reproducing device. A control unit 200 controls each circuit of the recoding-reproducing device. A buffer RAM 210 temporarily stores data, which is recorded to a DVD or which is reproduced from the DVD. The control unit 200 retrieves the data recorded in the buffer RAM 210 via the access circuit 220. The control unit 200 also directly rewrites the data stored in the buffer RAM 210.
When accessing the buffer RAM 210, the control unit 200 designates the head address of the data storage section in the RAM 210 that the control unit 200 is trying to access. From the head address, the access circuit 220 accesses one word of data in the data storage section. In such a manner, to access the buffer RAM 210, the control unit 200 designates the head address of a data storage section and whether it will write data or read data.
The unit of data quantity (data length) transferred between the prior art access circuit 220 and the buffer RAM 210 is fixed at one word. This may lengthen the time for accessing the control unit 200 and the buffer RAM 210.
For example, the following procedures are taken when re-writing one byte of data in the buffer RAM 210. The access circuit 220 first reads one word of data from the buffer RAM 210. The control unit 200 then rewrites just one byte of the read data. The access circuit 220 then writes the rewritten one byte of data and the remaining byte of the read data to the buffer RAM 210. In this manner, to change one byte of data, the access circuit 220 reads one word of data and after the control unit 200 rewrites one byte of the data, writes one word of data to the buffer RAM 210. This increases the time for accessing the buffer RAM 210 and is thus inefficient.
Further, when the control unit 200 successively accesses two words, for each word, the control unit 200 designates the head address of the data that is to be accessed via the access circuit 220. In other words, even if the two words of data are recorded in continuous recording sections of the buffer RAM 210, the control unit 200 must designate addresses twice. This increases the time for accessing the buffer RAM and is thus inefficient.
In addition to a DVD recording-reproducing device, the same problem occurs in an access circuit that accesses a buffer memory in accordance with a command from an external circuit.

Access circuit with various access data units


Techniques are disclosed to facilitate cooperative mapping for safe and efficient trajectory planning and collision avoidance by allowing nearby agents to share contextual information. The described techniques also function to extend the mapping range of a single agent by leveraging observations made by multiple agents. Furthermore, the techniques as described herein function to reduce uncertainty in trajectory planning by allowing agents to “see” behind occlusions, thus taking advantage of observations made by neighboring agents from different points of view. An efficient hardware implementation of the system is also presented that leverages the methodologies as discussed herein.

Maps are essential tools that enable the deployment of so-called "agents," which are mobile computing systems associated with self-driving/driverless cars or robots in public spaces. The more complete a map is, the more information is available for each agent to plan a safe and efficient trajectory from its current position to its desired goal. Most environments of interest, however, are not static but change over time due to factors such as the activity and/or movement of people and objects within the environment. Therefore, maps used for navigation by such agents need to be updated continuously based on information collected online by the agents using sensors, which are typically carried onboard or embedded in the infrastructure and communicated to the agents. Current techniques to update these maps generally require excessive processing and/or memory storage, and thus have been inadequate.
The exemplary aspects of the present disclosure will be described with reference to the accompanying drawings. The drawing in which an element first appears is typically indicated by the leftmost digit(s) in the corresponding reference number.

Cooperative mapping for autonomous vehicles, robots or multi-agent systems


A reception frequency band is selected at 11.7 GHz–12.2 GHz, the local oscillating frequencies of local oscillators are determined at 10.75 GHz and 13.85 GHz, respectively, and each intermediate frequency band is selected at 950 MHz–1450 MHz and 1650 MHz–2150 MHz, respectively, so that the harmonic component of the frequency difference between local oscillation signals output from each local oscillator is not present in the frequency band of each intermediate frequency signal output from each mixer and in the reception band of polarization signals applied to input terminals.

1. Field of the Invention
The present invention relates to low noise converters, particularly a low noise converter employed as an LNB (Low Noise Block down-converter) incorporated in a receiver of an antenna for satellite signal transmission/reception, converting two input signals differing in polarization into signals of different intermediate frequencies (IF) for transmission to an indoor unit (indoor receiver), and a receiver apparatus including such a low noise converter.
2. Description of the Background Art
FIG. 14 is a block diagram showing a first conventional LNB. The LNB of FIG. 14 is directed to satellite broadcasting/communication reception that allows reception of a plurality of polarized waves, employed for receiving the Ku band satellite signals of the United States.
According to FIG. 14, a reception signal of input frequency 11.7 GHz–12.2 GHz is divided into a horizontal polarization signal and a vertical polarization signal by a cross polarization separator (not shown), which are applied to input terminals 1 and 2, respectively. The signals applied through these two input terminals are respectively picked up by an antenna probe. Each input signal is amplified with low noise by low noise amplifiers LNA 3–6, and then passes through BPFs (Band Pass Filter) 7 and 8 functioning to pass through signals of a desired frequency band and removing signals of an image frequency band.
Then, one signal is applied to a mixer circuit (mixer) 11 together with an oscillation signal of 10.75 GHz output from a local oscillator 209. At mixer 11, the signal is frequency-converted into a signal of an intermediate frequency band-of 950 MHz–1450 MHz. The other signal is applied to a mixer 12 together with an oscillation signal of 10.15 GHz output from a local oscillator 210. At mixer 12, the signal is frequency-converted into a signal of the intermediate frequency band of 1550 MHz–2050 MHz. The signals of these two bands are combined at a combine circuit 215 and transmitted to an IF amplifier 16 to be amplified so as to have appropriate noise and gain characteristics for output from one IF output terminal 17.
IF output terminal 17 receives via a coaxial cable a direct current voltage superimposed on an output signal from an indoor receiver (not shown). A power supply circuit 18 converts that direct current voltage into a predetermined potential, which is applied to respective circuits.
FIG. 15 is a block diagram of a second conventional LNB. The LNB of FIG. 15 receives at input terminals 1 and 2 two signals differing in polarization as signals from a satellite having the frequency of 12.2–12.7 GHz. When the signals from a satellite correspond to a right-hand polarized wave and a left-hand polarized wave, the signals pass through a transducer connected at a preceding stage to the converter to convert the two circularly-polarized waves into two linearly-polarized waves, which are applied to the two input terminals of the converter.
The subsequent operation is similar to that of the first conventional LNB. The signals pass through low noise amplifiers 3–6 and BPFs 7 and 8 which are the band filters for image suppression. Then, one is applied to mixer 11 to which a local oscillation signal having the oscillating frequency of 11.25 GHz is applied from a local oscillator 209A. The other is transmitted to mixer 12 to which a local oscillation signal having an oscillating frequency of 14.35 GHz is applied from a local oscillator 210A. The signals are further transmitted to a LPF (Low Pass Filter) 13 having a transmitting frequency of 950–1450 MHz and to an HPF (High Pass Filter) 14 having a transmitting frequency of 1650–2150 MHz, respectively. The signals of these bands are combined at combine circuit 215, and then applied to IF amplifier 16 to be amplified and output from IF output terminal 17, likewise the first conventional LNB.
In the LNB of FIG. 14, harmonic components of 1200 MHz and 1800 MHz that are two times and three times, respectively, the frequency difference of the local oscillation signals output from the two local oscillators 209 and 210 (10.75 GHz–10.15 GHz=0.6 GHz) are included as spurious harmonic components in the IF bands of 950 MHz–1450 MHz and 1550 MHz −2050 MHz, respectively. Some measures must be taken to suppress this level.
Possible measures include enhancing the shields of the two local oscillators 209 and 210 as well as the two mixers 11 and 12. However, this approach will render the structure complex and increase the cost. It is to be noted that the two IF bands converted at the two different local oscillators 209 and 210 are in the ranges of 950 MHz–1450 MHz and 1550 MHz–2050 MHz, respectively, and the guard band frequency band therebetween is 1450 MHz–1550 MHz. In other words, this guard band is 100 MHz, which is narrow. In order to take advantage of this guard band frequency band at LPF 13 and HPF 14 prior to obtaining signals of respective IF bands to suppress the noise level of one IF band from affecting the other frequency band, an LPF and an HPF superior in cut-off characteristics will be required. Such requirements will increase the cost.
In the second conventional LNB of FIG. 15, the frequency difference of the local oscillation signals output from local oscillators 209A and 210A is 3.1 GHz, and a fourfold harmonic component thereof is 12.4 GHz, This becomes a spurious harmonic component for a signal of 12.2–12.7 GHz received from a satellite, acting as an interference wave with respect to a reception signal of 12.4 GHz. To suppress such a wave, the two local oscillators 209A and 210A or mixers 11 and 12 must be subjected to some measures such as shield enhancement, likewise the first conventional LNB. Thus, the cost will be increased.

Low noise converter employed in satellite broadcast reception system and receiver apparatus


A water heater restraint for securing a vertical cylindrical water heater adjacent a wall. The restraint has an elongated strap surrounding the water heater and is secured to a wall by a pair of clamps which each have at least one hole. Each clamp guides one end of the elongated strap on its rear surface before fastening the end of the elongated strap to the wall by at least one fastener which extends through the hole(s), through the wall, and into wall studs behind the wall.

The field of the invention pertains to support brackets and fastener assemblies. The invention relates more particularly to support brackets and fastener assemblies used to brace-support vertically-oriented water heaters to the walls and wall studs of homes, commercial buildings, or the like. Such bracing-supporting protects a water heater against movement during an earthquake which may cause damage to the water heater as well as potentially cause fire or water damage from breakage in gas or water lines.
Water heaters have been brace-supported to walls and wall studs in a variety of ways to prevent lateral movement during an earthquake. One bracket is shown in U.S. Pat. No. 4,955,573 where a joint tie-strap having a plurality of holes is lag-bolted to wall studs behind a wallboard. A strap or outer collar surrounding a water heater and a second support are each independently tap-screwed to the joint tie-strap through the plurality of holes. In U.S. Pat. No. 5,020,760 a bracket assembly for holding a water heater in a corner is shown. U-shaped bracket mounting flanges are bolted to the corner walls, a bracket is bolted to the U-shaped bracket mounting flanges, and a belt surrounding the water heater is affixed to the bracket by independent means. In U.S. Pat. No. 5,190,260 a wooden beam is fastened to wall studs behind a wallboard. A pair of brackets is fastened to the wooden beam, and a strap is independently affixed to the pair of brackets. And finally U.S. Pat. No. 5,487,518 shows a water heater restraint for holding a water heater to wall studs behind a wallboard. A bi-channel strut is fastened to the wall studs behind the wallboard and a pair of slidably positionable gussets are fastened to the bi-channel strut. A strap surrounding the water heater is independently fastened to the slidably positionable gussets.
In all of the above prior disclosures, a first component is separately and independently fastened to a wall to serve as a mounting platform upon which all other components of the water heater bracing device are affixed. Most notably, a strap component which surrounds the water heater is fastened to the first component or a second component secured to the first component, but is not fastened directly to the wall itself. This use of a separately and independently fastened first component as a mounting platform for a strap component unnecessarily lengthens the installation time of existing bracing devices. It does so without significantly improving reliability, durability, and/or safety of the bracing devices. It also increases the production cost of existing bracing devices due to the greater number of parts involved. Currently, however, there is no effective, reliable, and economical device for securing a water heater directly to a wall and its supporting wall studs.
In addition, as indicated above, the means for fastening the first component directly to the wall has typically been with bolts or screw pieces. The use of bolts and screws, however, can be a time consuming and arduous process, especially for the non-professional installer. Instead, the use of a nail fastener which is pre-mounted in a piece to be fastened has been known to provide substantial benefits to the installation process.
As seen in U.S. Pat. No. 2,961,210 one embodiment of a pre-mounted fastener assembly shows a fastener which is preset at a ninety-degree angle in a conduit clip made of a deformable material. A second embodiment shows a fastener which is preset at a ninety-degree angle in an electrical box also made of a deformable material. However, the pre-mounted fastener assembly in this prior disclosure is designed primarily to prevent damaging thin sheets when fastened by an explosively driven nail. It does not particularly serve to shorten or facilitate the fastening process. More importantly, it does not contemplate or provide a means to optimally resist a known lateral force in a given direction in the piece to be fastened. Where such a force is known, a fastener would be able to provide greater resistance when fastened in a direction which forms an acute angle with the known force vector. This prior disclosure also does not provide for using a pre-mounted fastener in combination with a slidable strap for brace-supporting water heaters to walls.
In summary, there is a need for a simpler, less expensive, reliable, and easy-to-install water heater brace-supporting device which is positionable anywhere along a wall. Such a device is also needed to facilitate installation for many individuals having little or no mechanical or construction experience, while leaving little room for error and without sacrificing the quality of the installation. Additionally, the time saving benefits of including a pre-mounted fastener to facilitate the installation of water heater restraint devices have largely gone unrealized.


The invention relates to rimless eyeglasses comprising a bridge (13) interconnecting two lenses (V), and two side branches (11) connected to respective side zones of the corresponding lenses (V). In accordance with the invention, each side branch (11) essentially presents a wire structure comprising two main portions (11.1, 11.2) extending towards the rear or said branch, said main portions extending forwards, passing through two through holes (21, 22) in the lens (V), and being connected together in the vicinity of the front face of said lens by a front portion (11.3), a flexible bushing (15) being interposed in each through hole (21; 22) in order to clamp the associated main portion (11.1; 11.2) so as to hold the side branch (11) in place on the corresponding lens (V).

Rimless eyeglasses, also known as drilled-lens glasses due to the holes formed through the thickness of the lenses for fastening the frame, are becoming more and more widespread.
Reference can be made in particular to the following documents: WO 2004/003632 A, WO 02/21193 A, EP 1 107 042 A, WO 96/05535 A, U.S. Pat. No. 6,447,517 A, U.S. Pat. No. 5,042,933, US 2003/0058401, WO 00/26716 A, EP 1 382 988 A, WO 03/014804 A, WO 02/095482 A, WO 02/095481 A, and WO 81/01749 A.
In the above-mentioned arrangements, two holes or else one hole and an open notch in the side, are provided for each element constituting the frame, i.e. the bridge and each of the side branches.
In most circumstances, the fastening ends of the side branches are of a configuration that is complex, with multiple bends, thus implying a fabrication cost that is high. Furthermore, it is sometimes necessary to perform such bending in situ, after threading an end of the branch through a hole in the lens while said end was still rectilinear and had yet to be bent, as shown in document US A 2004/0051843, which is particularly inconvenient for the operator.
Reference can also be made to document FR 2 723 649 A which describes a wire frame having tenons comprising two superposed branches passing through the lenses from front to back, by passing through associated holes. The ends of those branches that project rearwards from the lenses receive protective caps that are secured by adhesive.
More recently, the Applicant has proposed a frame arrangement in which the wire structure is very simple, thereby making it convenient and fast to assemble with the lenses, not requiring any special tooling, and likewise without the fastening of the frame on the lenses leading to any risk of the corresponding zone of the lenses being weakened, in particular as a result of excessive clamping, as described in document WO 2006/027428 A. The wire structure in question has single-wire side branches that are terminated by J-shaped distal ends, with a long portion passing through a through hole in the lens having a flexible clamping bushing interposed therein, and with a short anti-rotation portion turned rearwards and passing through an open notch in the side or through another hole in the lens, but without clamping the lens between said long portion and said short portion.

Rimless eyeglasses having side branches essentially of wire structure


An integral door knob assembly for mounting on a face of a door has a spring return so that the door knob rotates to one position when released. A shank formed integral with or attached to the door knob is formed of plastic material eliminating the requirement of a separate plastic bushing in the rose member, and has flexible fingers to provide a snap lock between a spring assembly member and the end of the shank to hold the knob assembly to the rose member. The spring assembly member is also formed of plastic material and has sufficient flexibility to allow a torsion spring to be inserted and removed.

In the past a single door knob assembly has been made of several different components which are held together by snap rings or by staking. Apart from the necessity of making the individual components, there are several stages of manufacture required to complete the assembly. The door knob assembly which comprises a door knob rotatable in a rose member has in the past generally been made of metal components and requires a special non-friction bushing to permit rotation between a door knob shank and the rose member. The bushing forms a bearing for easy rotation of the knob to disengage and re-engage a latch member to open and close the door.
By utilizing plastic materials for the integral door knob assembly of the present invention, the number of required components for the assembly is significantly reduced and the requirement of a separate non-friction bushing for rotation purposes is obviated by the present invention wherein the shank itself may be made of plastic material suitable as a bearing material. Furthermore, because the present invention utilizes a plastic resin material having flexibility and a snap lock arrangement for ease of assembling the door knob and rose member the need to assemble separate components together using snap rings or a staking operation is eliminated. The present invention results in fewer stages of manufacture and an overall reduction in total manufacture time.

Integral door knob assembly with spring return


A system for forecasting the outbound workload in a switchyard. The system has a processing entity for which receives information on railcar traffic for handling by the switchyard, wherein the railcar traffic includes railcars that are yet to be switched into classification tracks of the switchyard. For every departure train of two or more departure trains, the processing entity applies logic rules to the information to compute a forecast of railcar traffic that will be available to the departure train for transport out of the switchyard. An output releases data derived from the forecast of railcar traffic, describing the traffic available for each train of the two or more departure trains.

A railroad network normally contains one or more switchyards in which railcars are routed from tracks leading from a departure point to tracks going to a destination point. A typical switchyard has four main components, namely receiving tracks, a railcar switching mechanism, a set of classification tracks and a set of departure tracks. Incoming trains deliver railcars in the receiving tracks. The railcars are processed by the switching mechanism that routes individual railcars to respective classification tracks.
Two types of switching mechanisms are in use today. The first one is a hump switch. Switchyards that use a hump switch are referred to as hump yards. A hump switchyard uses a hump over which a railcar is pushed by a locomotive. At the top of the hump the railcar is allowed to roll on the other side of the hump under the effect of gravity. Retarders keep the railcar from reaching excessive speeds. The hump tracks on which the railcar rolls down the hump connect with the classification tracks. A track switch establishes a temporary connection between the hump tracks and a selected one of the classification tracks such that the railcar can roll in the classification tracks. A departure train is constituted when the requisite number of railcars has been placed in a set of classification tracks. When the departure train leaves the switchyard, the set of classification tracks become available for building a new departure train.
The second type of switch mechanism is a flat switch. The principle is generally the same as a hump yard except that instead of using gravity to direct railcars to selected classification tracks, a locomotive is used to push the railcar from the receiving tracks to the selected set of classification tracks.
In order to increase the efficiency of switching operations railway companies have developed the concept of railcar blocking. Under this concept, a block of railcars, hence the name "blocking", may be logically switched as a unit in a switchyard. A block is established on a basis of certain properties shared by the railcars belonging to the block. For instance railcars that have a common destination point on their route can be blocked together. A "block" is therefore a logical entity that helps making switching decisions. For reference it should be noted that generally, two types of blocks exist. There is the so called "yard block" and a "train block". For clarity, the term "block" alone in the present specification encompasses either a yard block or a train block.
The principle of blocking, either yard blocking or train blocking increases the efficiency with which railcars are processed at switchyards. However, it also brings constraints. Very often a train block must be assembled from railcars that arrive on different incoming trains. The train block will be complete and available for departure only when all the railcars that make up the train block have arrived at the switchyard. If one or more of the railcars are delayed the train block cannot be completed and the entire departure train that pulls this train block may leave without the delayed railcars. Such occurrence may create a cascading effect throughout entire segments of the railroad network and have significant financial repercussions for the railroad operator. Specifically, it is not uncommon for an operator to guarantee railcar arrival times to customers and delays incur financial penalties that may be significant.
In general switchyard operations planning is done either manually or via simple management tools. In order to increase the efficiency of those operations there is a need to provide an automated system that can forecast the outbound workload and thus provide the yard master with a projection of the traffic that can be available to departure trains.

System and method for forecasting the composition of an outbound train in a switchyard


An anti-theft device for use with a locomotive horn is disclosed. An angled L-shaped bracket of the anti-theft device has a horizontal portion that is connected to an anti-theft or tamper proof fastener used to attach a base of the horn to the locomotive. A vertical portion of the bracket receives a shackle portion of a padlock for connection with and locking on the bracket. A bushing is placed on the shackle portion of the padlock over the anti-theft fastener to limit slack of the padlock relative to the bracket. When assembled with the locomotive horn, the anti-theft device at least partially covers the anti-theft fastener such that access to and/or removal of at least the anti-theft fastener is substantially prevented. Thus, theft of the horn is reduced and/or prevented.

1. Field
The present invention is generally related to an anti-theft device for preventing removal of a horn on a locomotive.
2. Description of Related Art
Theft of locomotive horns has been a problem in the railroad industry, and can be costly to replace. To reduce horns from being stolen, some users have tried installing high security or anti-theft bolts to secure or mount a base of the horn to the locomotive. However, thieves are able to buy a matching drive or removal device to remove such bolts. Others have tried welding bolts, tabs, and/or collars at mounting portion of the horn and/or over bolts and/or fasteners, but such welds can be ground off to remove the horn. Even if multiple types of bolts and fasteners are used to mount the base of the horn to the locomotive, thieves have found methods for removing horns from the locomotive.


A nitrile group-containing copolymer rubber comprising 10 to 40 wt % of α,β-ethylenically unsaturated nitrile unit (a), 10 to 60 wt % of α,β-ethylenically unsaturated carboxylic acid ester unit (b), and 20 to 70 wt % in total of conjugated diene unit (c) and saturated conjugated diene unit (d), wherein a content ratio “x” of a conjugated diene unit (c) based on the total content of said conjugated diene unit (c) and said saturated conjugated diene unit (d) is 0.08 or smaller, and “x·A” defined as a product of said ratio “x” and a content ratio “A” (%) of said α,β-ethylenically unsaturated nitrile unit (a) is 1.5 or smaller. According to the present invention, a nitrile group-containing copolymer rubber capable to provide a rubber vulcanizate highly balanced in mechanical strength, heat aging resistance, oil resistance, cold resistance and ozone resistance, and a vulcanizable rubber composition using the rubber can be provided.

A highly saturated nitrile group-containing copolymer rubber, as represented by hydrogenated acrylonitrile-butadiene copolymer rubber, draws attention. The highly saturated nitrile group-containing copolymer rubber is superior in heat resistance, oil resistance, ozone resistance, etc., compared to common nitrile group-containing copolymer rubber having a lot of carbon-carbon unsaturated bonds in a main chain structure such as acrylonitrile-butadiene copolymer rubber. However, depending on an amount of nitrile group and content of unsaturated bonds in carbon-carbon bonds, it is liable to be inferior in cold resistance compared to a nitrile group-containing copolymer rubber having a lot of carbon-carbon unsaturated bonds. Generally, cold resistance of the nitrile group-containing copolymer rubber can be enhanced by reducing an amount of nitrile group, but when increasing a degree of saturation in a nitrile group-containing copolymer rubber, cold resistance is not always improved by reducing an amount of nitrile group.
It is continuously required to further advance overall performance such as mechanical strength, heat aging resistance, oil resistance, cold resistance and ozone resistance in many fields including car parts. Therefore, it is required to improve cold resistance of highly-saturated nitrile group-containing copolymer rubber.
To solve this problem, Patent Document 1 proposes a highly-saturated nitrile group-containing copolymer rubber, wherein each of α,β-ethylenically unsaturated nitrile unit (a), α,β-ethylenically unsaturated carboxylic acid ester unit (b), conjugated diene unit (c) and saturated conjugated diene unit (d) is included in a specific ratio, and a total ratio of the (c) and (d) and the ratio of the (d) based on the total ratio are set within a specific range, and the difference between the extrapolated glass transition initiating temperature (Tig) and extrapolated glass transition-ending temperature (Teg) is 10° C. or lower. However, while vulcanizate obtained by vulcanizing this rubber can be improved in cold resistance, oil resistance, dynamic characteristics, etc., heat resistance and ozone resistance may be insufficient.    [Patent Article 1] The Japanese Unexamined Patent Publication (A) No. 2001-114940

Nitrile group-containing copolymer rubber and a vulcanizable nitrile group-containing copolymer rubber composition


Provided herein are methods for reducing levels of blood cholesterol, low-density lipoprotein (LDL), and/or the treatment of diseases associated with high cholesterol, hyperlipidemia, dyslipidemia, or high levels of low-density lipoprotein (LDL), wherein the methods comprise administering a DRP1 inhibitor to a subject in need thereof. In certain embodiments, the subject is selected for treatment as described herein when the subject exhibits intolerance to conventional statin therapy. Also contemplated herein are the use of DRP1 inhibitors in the treatment of cancer and inflammatory disease.

Atherosclerotic coronary heart disease (CHD) is a major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include, but are not limited to, hypertension, diabetes mellitus, family history, male gender, cigarette smoke, high serum cholesterol, high low density lipoprotein (LDL) cholesterol levels and low high density lipoprotein (HDL) cholesterol levels. Clinical studies have shown that elevated levels of total cholesterol or LDL cholesterol can play a role in the pathogenesis of human atherosclerosis, thus lipid lowering agents are an important therapy for the treatment and/or prevention of atherosclerosis.
LDL cholesterol levels can be lowered by administration of HMG-CoA reductase inhibitors. This class of drugs inhibits the enzyme HMG-CoA reductase, which is rate-limiting in cholesterol synthesis by the liver. In addition, these agents increase the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. One potential drawback of HMG-CoA reductase inhibitors is the side-effect profile, including, e.g., liver toxicity.
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease family member that binds to and regulates LDL receptor expression on the surface of cells. Inhibition of the LDL receptor-PCSK9 interaction is an attractive alternative approach to the treatment of cholesterol disorders. While substantial effort has been made to find agents that target PCSK9, small molecule PCSK9 inhibitor development has, so far, been unsuccessful.

Modulation of PCSK9 and LDLR through DRP1 inhibition


A game apparatus obtains a captured image captured by a camera. First, the game apparatus detects an object area of the captured image that includes a predetermined image object based on pixel values obtained at a first pitch across the captured image. Then, the game apparatus detects a predetermined image object from an image of the object area based on pixel values obtained at a second pitch smaller than the first pitch across the object area of the captured image.

1. Field of the Invention
The present invention relates to a storage medium having stored therein an image recognition program for recognizing a predetermined image object from an image captured by an image-capturing section, an image recognition apparatus, an image recognition system, and an image recognition method.
2. Description of the Background Art
There are conventional techniques for detecting a predetermined image object from an image (captured image) captured by an image-capturing section such as a camera. For example, Non-Patent Document 1 (Hirokazu Kato, Mark Billinghurst, Koichi Asano, Keihachiro Tachibana, "An Augmented Reality System and its Calibration based on Marker Tracking", Journal of Virtual Reality Society of Japan, Vol. 4, No. 4, 1999) describes performing an image recognition process on a marker included in an image captured by a camera in an augmented reality technique. In Non-Patent Document 1, connected regions are extracted by binarizing the captured image using a fixed threshold value, and those of the connected regions with an appropriate size and shape are selected as marker candidates, which are subjected to pattern matching so as to detect a marker.
With the recognition method described in Non-Patent Document 1, the image recognition process is performed by pixels of the captured image as input. Therefore, when the input image has a high resolution (high definition), the amount of time required for the image recognition process is increased. On the other hand, if the image recognition process is simply performed with a lower precision (at coarser pixel pitches) than the pixel pitch of the input captured image, the marker detection precision is lowered.

Storage medium having image recognition program stored therein, image recognition apparatus, image recognition system, and image recognition method


A display system includes a light writable display associated with an identification code and arranged to receive an image wise pattern of light to form an image on the display; a display writer for producing the image wise pattern of light for writing the image on the display; a scanner connected to the display writer for sensing the identification code; and a processor linked to the scanner and the display writer and responsive to the identification code for programming the display writer to write an image associated with the identification code.

Retail stores offer goods for sale and need to provide customers with information on item pricing. Price labels typically provide information describing an item, the price for that item, and a machine readable code for the item, typically in UPC bar code format. The price of items often changes rapidly, requiring that printed retail labels be manually changed. Items that are on sale often have a larger secondary label, called a shelf-talker, that highlights items on sale for customers. The process of writing and changing retail pricing is costly, primarily in the labor required to replace tags. Systems have been proposed to address the problem of using digital data transmission to electrically changeable retail labels known as Electronic Shelf Labels (ESL).
U.S. Pat. No. 5,448,226, issued Sep. 5, 1995 to Failing, Jr. et al. describes an ESL system having a plurality of electronic price labels fitted into rails. The rails provide power and communication to each label. Connection to the rail can be provided through direct electrical connection to a conductor in the rail or a radio frequency (RF) interface. The label can be powered though direct electrical connection to power conductors in the rail, a battery or solar cell. Such a system requires expensive complex electronic and communication structures.
U.S. Pat. No. 6,186,555, issued Feb. 13, 2001 to Rawlings describes paper shelf-talkers that can be attached to conventional paper shelf labels to identify items on sale. Adhesive strips are applied to a perforated substrate that is printed to align text with the adhesive label. Attaching such a shelf-talker to a label requires the assembly to be discarded when pricing is changed. U.S. Pat. No. 5,771,005, issued Jun. 23, 1998 to Goodwin III describes an auxiliary electronic display that can be attached to an electronic price label (sic). The auxiliary display acts as an electronic shelf talker to identify special prices on goods.
U.S. Pat. No. 6,130,603, issued Oct. 10, 2000 to Briechle provides a good reference for current Electronic Shelf Labels. Independent modules contain a power supply, antenna and controller. The controller is attached to a conventional liquid crystal display that requires periodic refreshing to maintain an image. Displays in ESLs currently display data on simple seven segment numeric data. An internal power supply expends about half its power maintaining the display image and the other half of the power maintaining the RF link. Such displays have limited display resolution, and must incorporate expensive and bulky controller and transmission electronics. Such displays further must incorporate a power supply which further increases cost and size.
U.S. Pat. No. 5,751,257 issued May 12, 1998 to Sutherland shows an electronic shelf label having first and second substrates. Sutherland omits the expensive controller and power portions of the ESL, using a programming device translated across a series of pins and to write segments of an electronic display formed between the two glass substrates. The Sutherland apparatus requires the device to be positioned at a specific initial position, and translate specific sequence and rate to update the shelf tag. The information displayed in the Sutherland apparatus is limited to low resolution images.
There is a need therefore for an improved display system having a low cost rewritable shelf label with high resolution.

Apparatus and means for updating a memory display


In a telecommunication system (10) for providing multimedia broadcast services to many user equipments (40–45), a physical random access channel (39) is provided for uplink transmission of power control information from the user equipments to a radio site (30, 35). Based upon a comparison of signal-to-noise ratios (53) each particular user equipment sends (55) or inhibits from sending a power control signal to the radio site to which it is coupled. When the radio site of the telecommunication system detects a power control signal (73), the radio site adjusts the transmission power of a broadcast channel intended for reception by multiple user equipments (75) to be incrementally greater than the previous power (81). For lack of detection of a power control signal, adjusts the transmission power of a broadcast channel to be incrementally lower than the previous power.

The present invention pertains to power control in mobile telecommunications systems and more particularly to mobile channel power control for multimedia broadcast and multicast ("MBMS") services.
Mobile telecommunications systems transmit information wirelessly over the air. Power of the transmitted signals is a driving consideration in today's mobile telecommunication services since the power varies with the distance between the mobile telecommunication station and the user's equipment.
Today multimedia services, which are broadcast wirelessly, require large amounts of power. The power required to serve multiple users for multimedia functions can be as high as 50% of the power of the mobile telecommunication cell site.
Typical mobile telecommunications channels are switched between a dedicated channel and broadcast channels to support multimedia services. The switching is based upon the number of users of a particular multi-media service. The switching requires complex signaling. Switching furthermore is slow and uses over-the-air resources inefficiently, such as soft handoffs. Multimedia cells must be turned off when there are no users served by the cell in order to conserve power for the remainder of channels in the mobile telecommunication system, which requires that users be tracked and counted.
Accordingly, it would be highly advantageous to have methodology for controlling power for cell sites which serve point-to-point and point-to-multipoint multimedia services.

Physical random access channel power control method for multimedia broadcast/multicast service


A method and apparatus for collecting medical data from a test subject while optionally preserving anonymity for the test subject. The method includes steps of collecting a sample from the test subject and taking biometric data from the test subject. The biometric data permit a high order of probability of correlation of the test subject with the sample and with test results derived from the sample. The method optionally further includes a step of providing the test subject with a unique correlating code also for permitting unique correlation of the test subject with the sample and with test results derived from the sample, and further desirably includes a step of labeling the sample with information including the biometric data.

1. Field of the Invention
This invention relates to a method, apparatus and system for anonymously providing medical data for humans including infectious status.
More particularly, the present invention relates to anonymously providing medical data for humans via unforgeable correlation characteristics.
In a further and more specific aspect, the instant invention concerns a method and apparatus for voluntarily and anonymously providing medical data for humans and allowing the subject to share that information with a chosen associate or associates.
2. Prior Art
Medical data collection, storage and display systems of great variety in construction and purpose are often employed for medical and non-medical purposes. Examples include the systems described in U.S. Pat. No. 4,737,912 entitled "Medical Image Filing Apparatus", issued to Ichikawa, hereby incorporated herein by reference, directed to a medical image filing and display system and the like.
Another example is described in U.S. Pat. No. 5,193,541 entitled "Health Examination Method And System Using Plural Self-Test Stations And A Magnetic Card", issued to Hatsuwi, hereby incorporated herein by reference. This patent is directed to a system for storing medical data on magnetic media contained on a card, wherein the patient provides samples and the like to a variety of testing stations that also record the self-test data on the card.
A further example is taught in U.S. Pat. No. 5,325,294 entitled "Medical Privacy System", issued to Keene, hereby incorporated herein by reference. This patent describes a system and method for retrieving medical data from a database and sharing these medical data voluntarily with another party while protecting against unauthorized access by unauthorized parties.
A feature common to such systems is a means for identifying a particular patient or client and the associated, relevant medical records. Two particular and possibly overlapping areas where such concerns arise are: (I) sample collection and (II) testing to determine human health characteristics including infectious status of humans, and especially HIV status.
.sctn. I. Sample collection.
Various types of samples may be collected for various purposes, including blood typing, drug testing and testing for infectious or genetic diseases. Depending on the purpose of the testing, various specific biological specimens may be collected. Often, but not always, these are bodily fluids. In some cases, tissues, hair or nail clippings may be preferred.
A. Urine testing.
Several commercially available urine test specimen collection devices and systems are known for collecting and identifying human urine donated as test material. Typically, these collection systems have a plastic receptacle or reservoir into which the test subject urinates and a plastic top or cover which attaches by threaded attachment.
As with most specimens for laboratory testing, it is desirable to have a way of linking the specimen as originating from the test subject from which the specimen is collected. This linked identification is needed in order to allow the testing laboratory to report results correctly linked to the individual from whom the test material was obtained. Typically, the name of the test subject and other identifying indicia are written by hand on a label (or, alternatively, a computer-generated label is prepared including the linking data) and the label is affixed by adhesive sticker to the urine container or urine collection device side wall.
This label, attached either after or preferably prior to urine donation, is affixed to the receptacle side wall rather than the top because the currently available urine containers have tops which are often interchangeable from container to container. Thus, a label attached only to the top can be inadvertently transferred with another top and transferred to another container, incorrectly placing thereby the name of one patient onto the urine container holding the urine of a different patient. This may result in erroneously reported lab results leading to improper diagnosis and treatment of the patient or improper identification of one individual as having used some drug or substance.
Further, in testing of human urine in the laboratory, there is a need from time to time for anonymity in certain circumstances such as in double blind studies or where the test subject wishes to have anonymity as in HIV testing and in certain circumstances for urine drug testing associated with employment. In such circumstances, one known method for accomplishing the task of secure and specific identification of the specimen to the test subject while maintaining anonymity has been to attach a unique alphanumeric identifying number or code via a label that is attached to the sample collection container or device.
A first limitation of such a numerical system is that one subject may give the corresponding chit to a second individual and then the second individual may portray the test material and test results as originating from and linked to him- or her-self rather than from the true test subject. A further limitation is that the alphanumeric code, if provided to the test subject or researcher in the form of a disposable paper chit, may be lost. Correlation of the test specimen and container or device may then be hindered or completely corrupted. Additionally, computerized linkage of an alphanumeric code to other data may be subject to input error by a keyboard operator in some circumstances.
Where these types of records are drug testing results, they are usually collected by and for a single employer; a subsequent employer may well be denied access to these records for any of many reasons. A prior employer may wish to limit liability against suit by a dismissed employee, and the employee may well dispute the accuracy of the testing process. Because samples are typically labeled before or, alternatively, after testing, possibility of confusion between test subjects is a very real concern.
What is needed is a system, apparatus or method wherein a secure and verifiable yet anonymous identification and linkage is established between the urine sample collection device or container and the urine donation. Ideally, this linkage occurs or is established simultaneously with collection of the urine sample. Furthermore, there is a need for urine specimen collection devices that are anatomically easy to hold and use and that, at the same time, allow for ease of affixing of identifying data to the collection device.
B. Phlebotomy blood sample collection.
Samples of blood are typically collected by puncturing the skin and removing by vacuum a sample of whole blood. A tourniquet is typically applied to the arm or in some cases the leg of the test subject and the skin surface is swabbed with alcohol to disinfect. Subsequently the test subject is asked often to grip a rubber grip so that the natural muscle compression leading to blood flow in the venous system is utilized to cause the vein to engorge and swell indicating that blood volume has increased in the vein. Then a needle attached to a syringe is inserted into the vein and a quantity of blood is removed. Other common means of phlebotomy or blood sample procurement are via indwelling lines such as catheters or by blood lancet puncture of skin such as infant heel and subsequent daubing of blood from skin surface into capillary tubes or absorbent paper card.
C. Oral mucosal transudate sample collection.
Oral mucosal transudate (OMT) samples may be collected and these may be tested to determine either infectious disease status or to identify foreign substances, such as therapeutic or recreational drugs, present in the body. Breathalyzer tests are frequently administered, especially in the context of testing drivers for alcohol intoxication. In both instances, chain of custody issues may render the sample inoperative or inappropriate in medical evaluation and/or as legally operative evidence.
D. Breathalyzer sampling.
Commercially available breath test collection devices are employed, for example, to assess human alcohol level by measurement of breath alcohol levels. Typically these devices utilize roadside measurement and the test is administered by law enforcement officials. Use of the resulting alcohol measurement number is envisaged for subsequent legal proceedings. In order to do so, a positive means for identifying the test subject is needed. All of the currently available breathalyzer systems incorporate means of identification of the specimen as originating from the test subject from whom the specimen is collected such as photo or driver's license number or the like. In order to maintain specimen integrity and to link the results to the individual from whom the breath test material was taken, the name or other numerical identifier of the test subject is typically written or affixed by coded sticker or the like attached to the printout of the test results. The limitation of such a numerical identification system is that one attorney may allege that the corresponding test subject is not the attorney's client but rather some other individual and then the test results may not be admissible in court. Alternatively, the test subject is taken to a hospital where a blood sample is taken and a legal chain of custody is maintained for results to be acceptable to a court of law. This procedure involves time and expense for the law enforcement official and laboratory.
E. Hair and fingernail sample collection.
Hair and fingernails both include metabolites of substances ingested by the subject and either may be used to determine drug use in particular. Both types of samples are subject to contamination from external sources, e.g., walking through a room laden with marijuana smoke or working with the hands immersed in chemical baths. For these and other reasons, testing of this type of specimen has not met with widespread acceptance. Additionally, chain of custody is an issue relevant to testing these types of specimens.
.sctn. II. Sample evaluation.
Once collected, biological samples are evaluated to determine a variety of characteristics. These include (A) drug testing, (B) testing for diseases such as infectious diseases and (C) testing to identify genetic predisposition for developing disease.
A. Drug testing.
Drug testing may be carried out on any of many types of samples collected from a test subject. Urine testing is particularly common and is widely believed to be less intrusive than testing that measures for metabolites over a longer interval of the test subject's recent life. Hair samples, for example, may be tested to determine drug usage over a relatively long period of time, however, relatively little is known about the actual accuracy of such tests. Breath samples and oral mucosal transudate samples may provide useful or legally significant information regarding recent drug use or about disease status of the individual.
B. Infectious disease monitoring.
Human disease status is highly confidential information subject to misuse by any of a variety of agencies or individuals. For example, some doctors will advise patients not to seek human immunodeficiency virus (HIV) testing via the doctor because the records generated in the process of testing for HIV may be used by insurance companies to deny insurance coverage to the individual requesting the test results.
The reasoning seems to be that if the individual sought to ascertain HIV status information, the individual must have reason to suspect a positive HIV status. The individual therefore is adjudged likely (i) to have engaged in high-risk behavior, (ii) to continue to engage in high-risk behavior and (iii) to have an enhanced probability (compared to other population segments) of developing (a) HIV-positive status and (b) later, acquired immune deficiency syndrome (AIDS), presently a frequently fatal condition. People may well be denied employment if it is suspected that they are at risk of developing an HIV-positive status or of contracting AIDS subsequent to infection by HIV.
Accordingly, it is desirable, particularly with respect to HIV testing, to be tested in a way that completely protects the individual identity of the test subject. One such system is provided in some states through Planned Parenthood, which (i) collects a blood sample from the test subject and (ii) collects whatever identifying indicia the test subject cares to provide, such as a pseudonym. The agency typically then (iii) links the identifying indicia, the test sample and a unique identifying code or serial number in a computer database or other log and (iv) informs the test subject that test results are to be expected to be available following a set interval of one to two weeks, which interval is for shipping the test sample to a suitable laboratory or other testing facility and receiving the results of the analysis therefrom.
The test sample and code or serial number are then (v) sent to a remote site for testing and analysis. Results are then (vi) sent back to the test site (or any other designated place). The test subject (vii) returns to the test site or goes to a designated office and (viii) is advised of the test results. If warranted, (ix) appropriate counseling is provided along with follow-up services. Additionally, (x) a paper record is often provided with an indication of the test results.
Unfortunately, because the test subject often provides a pseudonym, a third party has no way of knowing that a particular record is actually the product of a test conducted on samples provided by the individual presenting such a record. Moreover, the paper record is easily forged or mutilated to alter the information contained thereon, in part because there is no standard or unforgeable format for such records. In short, this system affords an individual test subject great confidence in both the anonymity and the trustworthiness of the test result, but this system does not provide the test subject with any verifiable way of providing the test results to a third party. Additionally, recent multiple-drug therapies can reduce presence of HIV and indicia of HIV to immeasurably low levels but these therapies introduce detectable levels of drugs into the bloodstream of the test subject.
Further, the situations in which people might meet and desire to know or communicate to each other the infectious disease status of one another do not lend themselves to accessing of data during the course of normal business hours. Social settings in which persons might meet and form a mutual desire for sexual activity tend to be focused on hours other than normal business hours, for example, in the evening at a nightclub. If there were a method for reliably and anonymously exchanging information such as indicia of HIV-negative status and the date on which the sample providing this result was collected, it would need to be useful in such settings or in conjunction therewith in order to be effective in controlling the spread of this deadly disease.
Accordingly, it is desirable to provide reliable data on health and/or infectious status in an anonymous fashion whereby the person viewing the data has some assurance that the data correspond to the individual with whom they are considering carrying out such activities. However, this alone is not necessarily sufficient because it is desirable to be able to have access to the data on a twenty-four-hour-a-day basis, and also because identification cards and the like may not correspond to the bearer thereof. Therefore, it is appropriate and useful to base the correlation process on parameters unique to the individual whilst continuing to ensure anonymity of the test subject, the test results and the fact that the test subject had the testing performed.
C. Genetic testing.
Laboratory testing for genetic markers of disease and hereditary susceptibility to diseases or specific conditions is a rapidly developing area of medicine. Current methods include DNA and RNA analysis based on hybridization techniques such as fluorescence in situ hybridization, restriction length polymorphism and polymerase chain reaction for amplification of nucleic acid.
The diseases and hereditary predispositions to disease for which genetic testing is currently available include sickle cell anemia, muscular dystrophy of various types, fragile X disease, chronic myelogenous leukemia, predisposition to development of cancer such as breast cancer gene BRCA-1 or colon cancer gene. These issues have had considerable public attention focused on them because they may be used to discriminate against some people in specific settings, e.g., in the making of hiring and downsizing decisions, in permitting the individual to obtain health insurance and the like.
A woman with BRCA1 has a lifetime risk of developing breast cancer of 85% versus 11% lifetime risk for a woman who does not have the BRCA1 gene. Surveillance by mammogram or other means to detect the earliest sign of tumor in the high risk women is prudent. Newer techniques, such as DNA chip technology, portend cost reductions and more widely available testing in the near future.
In order to combat these varied problems, some form of correlation that is unique to the individual, that is not based on a photograph or the like of the individual and that does not employ a transferable or forgeable identity device (such as an identity card) is required. The form of correlation needs to be highly reliable and also must operate rapidly in real time to provide "go/no-go" identification in a short period of time (e.g., a minute or less).
While the various mentioned prior art devices function as apparatus for collecting, storing and retrieving human medical data, certain inherent deficiencies preclude adequate, satisfactory performance of the purpose of reducing risk of exposure of the individual identities of persons using the system.
It would be highly advantageous, therefore, to remedy the foregoing and other deficiencies inherent in the prior art.
Accordingly, it is an object of the present invention to provide improvements in anonymous human health and/or medical data collection and retrieval.
Another object of the present invention is the provision of an improved method and apparatus for anonymously providing human health and/or medical data in a secure and tamper-free fashion that allows a person to share those data with another party.
An additional object of the instant invention is the provision of an improved method and apparatus for providing human health and/or medical data in a way that allows another party to have great confidence that the data provided are reliable and that they correspond to the party rendering the data available to them.
Still a further additional object of the present invention is to provide an improved method, apparatus and system for anonymously collecting human health and/or medical data and allowing retrieval of the data in a secure fashion that permits twenty-four hour access thereto.
And another object of the present invention is to provide an improved method, apparatus and system for collecting, storing and retrieving human health and/or medical data in an anonymous fashion that does not rely on forgeable identification devices.
Still another object of the present invention is the provision of a method, system and apparatus for displaying and sharing human health and/or medical data with a chosen person or people.
Yet another object of the instant invention is to provide a method, system and apparatus for retrieving human health and/or medical data in a secure fashion that also provides a high degree of confidence in the test subject of the anonymity of the test subject.
Yet still another object of the instant invention is the provision of a method, system and apparatus for identifying individuals free of HIV indicia in a reliable and anonymous fashion in order to stem the spread of a presently a frequently fatal disease.
And a further object of the invention is to provide a voluntary method, system and apparatus for identifying individuals who are free of HIV indicia and/or indicia of recreational drug usage without risk of compromising the individual's identity.
Still a further object of the immediate invention is the provision of a method, apparatus and system for collecting, storing and retrieving human health and/or medical data in a secure and tamper-free fashion that also guarantees that (i) the individual retrieving the data is also the individual to whom the human health and/or medical data are pertinent and (ii) that the individual retrieving the data has access only to medical records relevant to that specific individual and no other medical data.
Yet a further object of the invention is to provide a new system and method for anonymously testing for human HIV status and/or antigens or antibodies for human diseases and/or drug levels of therapeutic drugs known to be used in treatment of infectious diseases and/or drug levels of "recreational" drugs.
And still a further object of the invention is the provision of method and apparatus, according to the foregoing, which is intended to allow rapid, real-time access to human health and/or medical data and the date of collection of the sample from which the data are derived, by only the donor of the sample from which the information is derived, while preserving the anonymity of the test subject and also providing any other party with whom the test subject chooses to share the data great confidence that the data apply to the test subject.

Method, apparatus and system for verification of human medical data


A first connector, a second connector and an electrical connector assembly having the first connector and the second connector are provided. The first connector includes an insulating housing and a locking plate embedded in the insulating housing, and a plurality of first power terminals, a plurality of first signal terminals and a plurality of first braking terminals mounted in the insulating housing; the locking plate is provided with a locking mechanism protruding upwardly. The second connector includes a terminal block, a cover body covering the terminal block, a locking slidable cover slidably mounted on the cover body and a plurality of second power terminals, a plurality of second signal terminals and a plurality of second braking terminals mounted in the terminal block. The locking slidable cover is capable of sliding forwardly and rearwardly relative to the cover body, and is capable of being locked together with the locking mechanism. It is adapted to a servo motor, saves space and is easy to assemble.

At present, the traditional servo motor on the market is generally provided with two connectors on a surface of the servo motor, one of the two connectors is used to realize the transmission function of power supply and braking, and the other of the two connectors provides the function of signal transmission. On this kind of servo motor, two connecting wires are needed to connect the servo motor and a driving equipment, which is complicated in assembling and the manufacturing cost is relatively high. Especially on a servo motor with a small size, it is difficult to assemble, and at the same time, it is also a great challenge to the structure design of the connector.
Chinese utility model patent application issuance publication No. CN207834743U discloses a fast-locking type connector, which includes a plug device, a receptacle device and a lock lever, wherein: the receptacle device is locked on the motor; the plug device is inserted on the receptacle device; the lock lever is mounted to an outer side of the plug device, and a barbed hook is provided on the lock lever, the lock lever can lock the receptacle device and the plug device through the barbed hook. The technical solution of the utility model patent application adopts the lock lever to realize the connection of the plug device and the receptacle device, saves the assembling time of the plug device and the receptacle device, and improves the assembling efficiency of a single connector. However, in this solution, only the power terminal and the braking terminal are integrated into one connector. For a servo motor, another connector is needed to provide signal transmission function, that is, two connectors need to be provided on the servo motor, which is cumbersome to assemble. At the same time, the plug device of the fast-locking type connector is locked together with the receptacle device by rotating of the lock lever, but in some applications with a compact space (such as when a space above the plug device is extremely narrow and cannot be used for the rotation of the lock lever), it is not suitable to use the above fast-locking type connector, so it needs to be further improved.

First connector, second connector and electricalconnector assembly


Disclosed herein are a carbonyl reductase variant and its use in the preparation of (R)-4-chloro-3-hydroxybutyrate. The carbonyl reductase variant is obtained by mutating phenylalanine-85 in an amino acid sequence as shown in SEQ ID NO:4 to methionine. An amino acid or amino acids at one or more positions other than position 85 in the amino acid sequence of the carbonyl reductase may be further replaced. The application also provides a recombinant expression vector carrying the gene encoding the carbonyl reductase variant, a genetically-engineered bacterium carrying the carbonyl reductase variant gene and glucose dehydrogenase gene, and an application of this bacterium in the asymmetric reduction of 4-chloroacetoacetate to prepare (R)-4-chloro-3-hydroxybutyrate.

(R)-4-chloro-3-hydroxybutyrate is an important class of chiral compounds, which is widely used in the synthesis of many valuable drugs and active molecules, such as a diet supplement L-carnitine (Chinese Patent No. 104726507; Journal of Shenyang University of Chemical Technology, 2017, 31, p 311-314). The biological asymmetric reduction of chloroacetoacetate is simple, efficient, highly selective, environmentally friendly and economical for the preparation of (R)-4-chloro-3-hydroxybutyrate. Kim and Sakai, et al. (J. Microbiol. Biotechnol., 2010, 20, 1300-1306; Tetrahedron, 2006, 62, 6143-6149) disclosed the catalytic reduction of ethyl 4-chloroacetoacetate using the carbonyl reductase YOL151W from Saccharomyces cerevisiae to prepare ethyl (R)-4-chloro-3-hydroxybutyrate, with an excellent enantioselectivity (97% ee). However, such process has an extremely low substrate concentration (≤10 g/L, mass percent concentration ≤1%), which limits its industrial application.
Until now, no report on the modification of YOL151W through site-directed mutagenesis based on protein structure information has been found to prepare an enzyme variant with enhanced reducing ability for 4-chloroacetoacetate and use such enzyme variant for the high substrate concentration synthesis of (R)-4-chloro-3-hydroxybutyrate.

Carbonyl reductase variant and its use in preparation of (R)-4-chloro-3-hydroxybutyrate