The present invention relates to in vitro and ex vivo methods of screening for modulators, homologues, and mimetics of lethal factor mitogen activated protein kinase kinase (MAPKK) protease activity, as well as methods of treating cancer by administering LF to transformed cells.

The present invention relates to in vitro and ex vivo methods of screening for modulators, homologues, and mimetics of lethal factor mitogen activated protein kinase kinase (MAPKK) protease activity, as well as methods of treating cancer by administering LF to tranformed cells.
Anthrax toxin, produced by Bacillus anthracis, is composed of three proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF) (Leppla, Handbook of Natural Toxins 8:543-572 (Moss et al., eds., 1995)). PA alone has no toxic effect upon cells, but instead binds to specific cell surface receptors. Upon proteolytic activation to a 63-kDa fragment (PA63), PA forms a heptameric membrane-inserted channel, which mediates the entry of EF and LF into the cytosol via the endosomal pathway (Gordon et al., Infect. Immun. 56:1066-1069 (1988); Milne et al., J. Biol Chem. 269:20607-20612 (1994)). Thus, EF or LF are toxic to cells when combined with PA.
EF is an adenylate cyclase, and together with PA forms a toxin referred to as edema toxin (Leppla, Proc. Natl. Acad. Sci. USA 79:3162-3166 (1982)). LF and PA together form a toxin referred to as lethal toxin (xe2x80x9cLTxe2x80x9d). Until the present discovery, however, the specific activity of LF in the cell was unknown. Lethal toxin is the dominant virulence factor produced by B. anthracis and is the major cause of death of infected animals (Pezard et al., Infect. Immun. 59:3472-3477 (1991)). Intravenous injection of lethal toxin causes death of Fisher 344 rats in as little as 38 minutes (Ezzell et al., Infect Immun. 45:761-767 (1984)), and incubation in vitro with mouse macrophages causes lysis in 90-120 minutes (Friediander, J. Biol Chem. 261:7123-7126 (1986)).
LF contains a limited sequence homology to a putative zinc-binding site at residues 686-690, HEFGH, characteristic of metalloproteases (Klimpel et al., Mol. Microbiol. 13:1093-1100 (1994)). Substitution of the H or E residues inactivates LF (e.g., as in the recombinant LF mutant E687C) (Klimpel et al., 1994, supra) and decreases its binding of zinc (Klimpel et al., 1994, supra; Kocki et al., FEMS Microbiol. Lett. 124:343-348 (1994)). Certain metalloprotease inhibitors also protect macrophages against lethal toxin (Klimpel et al., 1994, supra; Menard et al., Biochem J. 320:687-691 (1996)). However, no physiological substrate has been identified for LF, and LF protease activity has not been demonstrated.
The present invention thus identifies anthrax lethal factor (LF) as a protease, which acts as an inhibitor of the mitogen activated protein kinase (MAPK) signal transduction pathway. The present invention also identifies specific substrates for LF protease activity. For example, LF cleaves MAPK kinases 1, 2, and 3 (MEK) at specific sites in their N-termini, thereby preventing activation of MAPK (ERK2). LF is thus useful for inhibition of cancer cells that have an activated MAPK signal transduction pathway. Furthermore, the present invention provides means for assaying in vivo and in vitro for modulators and mimetics of LF, for use in treating cancer.
In one aspect, the present invention provides an in vitro method for screening modulators of lethal factor (LF) mitogen activated protein kinase kinase (MAPKK) protease activity, the method comprising the steps of: (i) providing LF in an aqueous solution, wherein the LF has MAPKK protease activity in the solution; (ii) contacting LF with substances suspected of having the ability to modulate MAPKK protease activity; and (iii) assaying for the level of LF MAPKK protease activity.
In another aspect, the present invention provides a kit for screening in vitro for modulators of lethal factor (LF) mitogen activated protein kinase kinase (MAPKK) protease activity, the kit comprising; (i) a container holding LF, wherein the LF has MAPKK protease activity; and (ii) instructions for assaying for LF MAPKK protease activity.
In another aspect, the present invention provides an in vivo method for screening modulators of lethal factor (LF) mitogen activated protein kinase kinase (MAPKK) protease activity, the method comprising the steps of: (i) contacting a living cell with LF, wherein the LF has MAPKK protease activity; (ii) contacting the cell with substances suspected of having the ability to modulate MAPKK protease activity; and (iii) assaying for the level of LF MAPKK protease activity.
In another aspect, the present invention provides an in vitro method for screening mimetics of lethal factor (LF) having mitogen activated protein kinase kinase (MAPKK) protease activity the method comprising the steps of: (i) providing a compound suspected of being an LF mimetic in an aqueous solution; and (ii) assaying for the level of MAPKK protease activity.
In another aspect, the present invention provides an in vivo method for screening for mimetics of lethal factor (LF) having mitogen activated protein kinase kinase (MAPKK) protease activity, the method comprising the steps of: (i) contacting a living cell with a compound suspected of being an LF mimetic; and (ii) assaying for the level of MAPKK protease activity.
In another aspect, the present invention provides a method for inhibiting proliferation of a cancer cell, the method comprising the step of contacting the cell with LF, wherein the LF has MAPKK protease activity.
In one embodiment, the LF is recombinant. In another embodiment, the MAPKK1 or MAPKK2 is recombinant. In another embodiment, the recombinant MAPKK1 or recombinant MAPKK2 is linked to a detectable moiety.
In one embodiment, the assay is a Mos-induced activation of MAPK assay in a Xenopus oocyte. In another embodiment, the assay is an MAPKK1 or MAPKK2 mobility assay. In another embodiment, the assay is an MBP phosphorylation assay.
In one embodiment, the step of contacting the cell comprising transducing the cell with an expression vector encoding LF. In another embodiment, the step of contacting further comprises contacting a cell with LF in the presence of protective antigen (PA). In another embodiment, the PA is a fusion protein targeted to the cancer cell.
In another embodiment, the mitogen activated protein kinase (MAPK) signal transduction pathway is activated in the cell.
In one embodiment, the cell is a human cell. In another embodiment, the cell is a Xenopus oocyte. In another embodiment, the cell is a cancer cell. In another embodiment, the cancer cell is from a sarcoma. In another embodiment, the cell is from a transformed cell line. In another embodiment, the cell line is transformed with Ras.
In another aspect, the invention provides methods for reversing a transformed phenotype in a cell by treating the cell with LT. In one embodiment, morphological changes associated with transformation are reversed. In another embodiment, the diffuse pattern of actin distribution that is characteristic of transformed cells is reversed. In another embodiment, the rate and extent of proliferation of a transformed cell is inhibited. In another embodiment, the ability of a transformed cell to grow independently of anchorage to a substrate is reversed.
In another aspect, the invention provides a method for identifying a three-dimensional structure of MAPKK or LF proteins, the method comprising the steps of: (i) receiving input of at least 10 contiguous amino acids of the amino acid sequence of MAPKK or LF, or at least 30 contiguous nucleotides of the nucleotide sequence of a gene encoding MAPKK or LF, and conservatively modified variants thereof; and (ii) generating a three-dimensional structure of the protein encoded by the amino acid sequence.
In one embodiment, the amino acid sequence is a primary structure and the generating step includes the steps of: (i) forming a secondary structure from said primary structure using energy terms encoded by the primary structure; and (ii) forming a tertiary structure from said secondary structure using energy terms encoded by said secondary structure. In another embodiment, the generating step includes the step of forming a quaternary structure from said tertiary structure using anisotropic terms encoded by the tertiary structure. Another embodiment further comprises the step of identifying regions of the three-dimensional structure of the protein that bind to ligands and using the regions to identify ligands that bind to the protein.

Anthrax lethal factor is a MAPK kinase protease

The United States of America as represented by the Department of Health and Human Services


An electronic asset utilization system is constituted of a stationary terminal 11, such as a set-top box (STB), a mobile terminal 13, such as a portable cellular phone, and a server 15. The server 15 receives an order for an electronic asset from the stationary terminal 11 or the mobile terminal 13; downloads to the stationary terminal 11 or the mobile terminal 13 an electronic asset and an exchange or receipt certificate to be described later; retains the thus-issued electronic asset, exchange certificate, or receipt certificate; and settles a charge billed to the thus-ordered electronic asset.

The present invention relates to an electronic asset utilization system and an electronic asset utilization method, which are intended to effect utilization of an electronic prepaid card or an electronic ticket (which will hereinafter be collectively referred to as "electronic asset"), such as purchase of electronic asset. Further, the present invention relates to a server for use with the electronic asset utilization system and method, as well as to a recording medium on which there is recorded a program for carrying out the electronic asset utilization method.
References to the figures referred to in this section may provide a parenthetical second reference number to refer to the diagrammatic representation of a transaction taking place (a "verb") utilizing an element, while the non-parenthetical reference numbers refer to the element (a "noun") itself that is, if appropriate, involved in the transaction.
Next will be described the existing prepayment-type settlement system using a prepaid card, by reference to FIG. 13.
In the drawing, a prepaid card terminal 2601 disposed in a retail outlet 2606 is to settle transactions by use of a prepaid card. The prepaid card terminal 2601 is connected to a central system 2602 of a prepaid card issuer 2607 by way of a communications line 2604. In some retail outlets, the prepaid card terminal 2601 is connected to the central system 2602 of the prepaid card issuer 2607 by way of a POS (point-of-sale) system disposed in the retail outlet and the communications line 2604.
Before purchasing a commodity product at the retail outlet 2606 through use of a prepaid card, a consumer 2605 first purchases a prepaid card 2600 (2609) from a prepaid card sales shop 2603 by paying cash (2608). The proceeds of the sale of the prepaid card are sent to the prepaid card issuer 2607 from the prepaid card sales shop 2603 (2610).
The consumer 2605 hands the prepaid card 2600 over to a clerk in the retail outlet 2606 (2611) and asks him to settle the transaction by use of the prepaid card. When the clerk inserts the prepaid card 2600 into a card reader of the prepaid card terminal 2601 and performs a prepaid-card settlement operation, the prepaid card terminal 2601 reads, from the prepaid card, data pertaining to the available balance of the card (hereinafter referred to simply as "balance data") and writes, into the prepaid card 2600, new balance data calculated by deduction of the cost of the commodity product from the balance data. The prepaid card terminal 2601 prints, through use of a printer, an accounting statement on which appear a bill citing the commodity price and the new balance data pertaining to the prepaid card 2600. The clerk hands over to the consumer 2605 (2612 and 2613) the purchased commodity, the prepaid card 2600, and the accounting statement, thus terminating the settlement of the transaction using the prepaid card.
Subsequently, the prepaid card terminal 2601 bills a charge to the central system 2602 of the prepaid card issuer 2607 on the basis of the amount deduced from the prepaid card 2600, byway of the communications line 2604(2614). Upon being charged, the prepaid card issuer 2607 pays the charge to the retail outlet 2606 (2615).
There may be a case where a prepaid card is purchased from a prepaid card vending machine or a case where the prepaid card terminal 2601 is embodied as a vending machine or a public phone having the capability of settling a transaction by use of a prepaid card. Any of these embodiments is in principle based on the same mechanism. As described in Japanese Patent Publication No. 103426/1994, a system for performing mutual authentication between a prepaid card and a card reader/writer through use of an electronic signature has been put forward as a security measure. An IC card equipped with an IC chip capable of reserving an electronic prepaid card or balance data has recently come into use in place of a prepaid card.
By reference to FIG. 14, next will be described an existing sales system for selling tickets for various events, public performances, or movies and allowing entry of audience into a hall. Like the previously-described settlement, this sales system also employs a prepayment method.
In the drawing, a ticketing terminal 2617 is disposed in a ticket shop 2620 and is to issue a ticket. The ticketing terminal 2617 is connected to a ticket issuer 2621 by way of a communications line 2619.
In a case where the consumer 2605 purchases a ticket for an event, a public performance, or a movie, he calls the central system 2618 of the ticket issuer 2621 and reserves a desired ticket (2624). The central system 2618 carries out booking of the requested ticket and issues a reservation number to the consumer 2605 (2625). The consumer 2605 who has received the reservation number goes to the ticket shop 2620 and asks a clerk to issue the ticket by telling her the reservation number.
The clerk performs a ticketing operation by entry of the reservation number into the ticketing terminal 2617. The ticketing terminal 2617 transmits the reservation number to the central system 2618 of the ticket issuer 2621 by way of the communications line 2619 (2627). In response to the transmission of the reservation number, the central system 2618 transmits to the ticketing terminal 2617 (2628) data pertaining to the booked ticket. The ticketing terminal 2617 prints the thus-received ticket data on a paperboard specified by the ticket issuer 2621 and outputs the thus-printed paperboard as a ticket 2616. The clerk delivers (2630) the thus-issued ticket 2616 to the consumer 2605 in exchange for cash (2629), thus terminating the sale of the ticket.
The proceeds of the sale of the ticket are transmitted to the ticket issuer 2621 after a commission for the ticket shop 2620 has been deducted from the proceeds. After a commission for the ticket issuer 2621 has been deduced from the proceeds, the remainder is paid to the promoter of the event (2634).
The consumer 2605 goes to an event hall 2623 designated for the ticket 2616 and hands the ticket 2616 over to a responsible official 2622 (2632). After having visually checked whether or not the details of the ticket 2616 are correct, the official 2622 allows the consumer 2605 to enter the hall (2633).
Next will be described a broadcast view system which allows viewing of a digital television broadcast by use of a communications satellite (CS) or a like satellite. In an existing broadcast view system, after having established contract with a broadcaster, the user receives a broadcast program and key data to be used for decoding the program through use of a dedicated receiving terminal (set-top box: STB). The thus-decoded broadcast program is displayed on a TV screen. When the user views a pay-per-view program, a charging operation is performed, whereby billing information and historic data are written into the IC card inserted in the receiving terminal. The billing information is periodically transmitted to the broadcaster by way of a communications line, and the charge is settled.
As prepaid cards have become widespread, the existing settlement system has encountered a drawback of an increase in the number of problems, such as sale or use of counterfeit cards and unauthorized billing performed by the retail outlets 2606. Instances of unauthorized billing performed by the retail outlets 2606 are divided into distinct categories; for example, charging an amount higher than the real price of a commodity product or than an amount appearing on the display of the prepaid card terminal 2601 without the user's knowledge, and charging, to the central system 2602, an amount higher than the amount deducted from the prepaid card 2600. At the time of settlement, the prepaid card terminal 2601 in principle rewrites only the balance data recorded on the prepaid card 2600. Therefore, unauthorized billing can be readily performed by modification of the prepaid card terminal 2601.
Further, in the existing settlement system, the prepaid card 2600 per se is inserted directly into the prepaid card terminal 2601. There is a chance of tampering with the information recorded on the prepaid card 2600 by modification of the prepaid card terminal 2601 or unauthorized reading of the personal information recorded on the prepaid card 2600, which would usually not be read at the time of settlement.
For these reasons, demand exists for the prepaid card terminal 2601 and a settlement system, which have a higher degree of reliability and security. For example, a physical measure must be taken against unauthorized modification of the prepaid card terminal 2601, such as sealing a housing of the prepaid card terminal 2601 in order to prevent disassembly thereof. However, such a countermeasure hinders reduction in the size or cost of the prepaid card terminal 2601.
In the existing settlement system, the consumer 2605 cannot directly ascertain the amount deducted from the prepaid card 2601. For this reason, the retail outlet 2606 must hand over, to the consumer 2605, an accounting statement having printed thereon a bill specifying the commodity price and the available balance of the prepaid card 2600. However, submission of such an accounting statement hinders an increase in sales efficiency and saving of resources.
Further, the storage capacity of the prepaid card 2601 is limited and comparatively small, and hence a large amount of information cannot stored in the prepaid card. For this reason, a prepaid card encounters difficulty in storing information of various types into a single card.
In the existing sales system, even when the ticket has already been booked online, the user has to go to the ticket shop 2630 in order to purchase and request issuance of a ticket. The sales system encounters a problem of the user being subjected to inconvenience of having to go to the ticket shop 2620 in the end. Further, in the existing sales system, the officer 2622 has to visually examine the tickets 2616 at the entrance of the event hall 2623, thus deteriorating the efficiency of examination work and involving a potential of causing an examination failure. Further, there is a fear of a consumer gaining unauthorized entry through use of a counterfeit ticket or a like ticket.
In the existing broadcast view system, payment of a charge for pay service, such as a pay-per-view broadcast program, is limited to a withdrawal from a bank account or settlement with a credit card. Further, in the existing broadcast system, billing information and history information are accumulated in a receiving terminal, and these information items are collected periodically. Therefore, there has been a necessity for ensuring a communications line for establishing communication with a server of the broadcaster.

Electronic asset utilization system, electronic asset utilization method, server for use with electronic asset utilization system, and recording medium having recorded thereon electronic asset utilization method

Abstract: The stationary terminal 11, the mobile terminal 13, and the server 15 are connected to a communications network.

Matsushita Electric Industrial Co., Ltd.


A burner debris collection apparatus for projectors aims to assist collecting burner debris includes debris collection ducts located on a bracing bracket which holds a socket and tracks located on the bracing bracket for mounting the socket by sliding. The debris collection ducts communicate with the tracks. After a burner has been blasted, the burner debris scattered in the tracks are pushed by a replacing socket (including a good burner) into the debris collection ducts. A debris collection tray may be provided on the debris discharge outlets of the debris collection ducts to collect the discharged burner debris.

Ellipsoidal ultra-high pressure discharge lamps (UHPs) can generate great brightness and high luminance, thus are widely used as the main lighting source on projectors or optical instruments. In general, the burner of a UHP discharge lamp includes a bulb filled with a hign pressure inertial gas (about 180 atm.–250 atm.). The bulb is made from amorphous quartz glass durable to temperature about 1300° C. . The optimal operation temperature is 900° C.–1100° C. The bulb could blast if the temperature were not properly controlled. Moreover, quality defects also will cause the bulb to blast.
The burner of the UHP discharge lamp or halogen lamp generally is mounted in a sealed chamber surrounding by an ellipsoidal reflection cup and a transparent front lamp shade. The reflection cup is mounted on a socket which is movably installed on an optical module of the projector. Such a modular design allows the damaged burner and the socket to be removed together for replacement when the burner has been damaged or blasted. As the UHP discharge lamp operates at a high temperature, the reflection cup. or the socket generally has ventilation apertures to facilitate heat dissipation so that cooling air can flow into the lamp shape to disperse heat of the burner.
While such a design resolves the heat dissipation problem, it also creates channels to scatter the debris when the burner blasts. To prevent the burner debris from scattering around while maintaining the heat dissipation function, some projectors have a filter installed in the channels leading to the exterior (sucn as R.O.C. patent publication No. 562913, entitled "Light source and projectors). But such a design makes handling of the burner debris very difficult.
In general, the socket is removed from the bottom of the projector for replacement. When the burner has blasted or replacement is needed, the projector has to be turned upside down to expose the socket. Then the socket and the blasted burner may be removed together. The common practice is to send the projector to the vendor's repair center for replacement and debris clearing by the professionals. The heat dissipation design of the reflection hood mentioned above makes clearing of burner debris difficult. This is especially true for the burner debris scattered in the mounting tracks of the socket.

Burner debris collection apparatus for projectors


In an embodiment, a method of creating a skimming preview of a video includes electronically receiving a plurality of video shots, analyzing each frame in a video shot from the plurality of video shots, where analyzing includes determining a saliency of each frame of the video shot. The method also includes determining a key frame of the video shot based on the saliency of each frame the video shot, extracting visual features from the key frame, performing shot clustering of the plurality of video shots to determine concept patterns based on the visual features, and generating a reconstruction reference tree based on the shot clustering. The reconstruction reference tree includes video shots categorized according to each concept pattern.

The fast evolution of digital video has brought many new applications and consequently, research and development of new technologies, which will lower the costs of video archiving, cataloging and indexing, as well as improve the efficiency, usability and accessibility of stored videos are greatly needed. Among all possible research areas, one important topic is how to enable a quick browse of a large collection of video data and how to achieve efficient content access and representation.
To address these issues, video abstraction techniques have emerged and have been attracting more research interest in recent years. There are two types of video abstraction: video summary and video skimming. Video summary, also called a still abstract, is a set of salient images selected or reconstructed from an original video sequence.
Video skimming, also called a moving abstract, is a collection of image sequences along with the corresponding audios from an original video sequence. Video skimming is also called a preview of an original video, and can be classified into two sub-types: highlight and summary sequence. A highlight contains the most interesting and attractive parts of a video, while a summary sequence renders the impression of the content of an entire video. Among all types of video abstractions, summary sequence conveys the highest semantic meaning of the content of an original video.
One prior art method is uniform sampling the frames to shrink the video size while losing the audio part, which is similar to the fast forward function seen in many in digital video players. Time compression methods can compress audio and video at the same time to synchronize them, using frame dropping and audio sampling. However, the compression ratio can be limited by speech distortion in some cases. Frame-level skimming mainly relies on the user attention model to compute a saliency curve, but this method is weak in keeping the video structure, especially for a long video. Shot clustering is a middle-level method in video abstraction, but its readability is mostly ignored. Semantic level skimming is a method trying to understand the video content, but can be difficult to realize its goal due to the "semantic gap" puzzle.


The present disclosure relates generally to immunoglobulin-related compositions (e.g., antibodies or antigen binding fragments thereof) that can bind to and neutralize the activity of L1-CAM protein. The antibodies of the present technology are useful in methods for detecting and treating a L1-CAM-positive cancer in a subject in need thereof.

The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or constitute prior art to the present technology.
The advent of chimeric antigen receptor (CAR) technology (Sadelain M et al., Cancer Discov 3:388-98 (2013)) is rapidly expanding the therapeutic investigations of anti-L1-CAM redirected gene-modified T cells, with several clinical trials using L1-CAM-CAR modified T cells: NCT00889954 (all L1-CAM(+) cancers), NCT01935843 (L1-CAM(+) solid tumors). See Hong H et al., J Immunother 37:93-104 (2014). While T cells can effectively target tumors having low levels of L1-CAM, there are concerns regarding potential bystander toxicity in normal tissues that have low levels of L1-CAM expression.
Apart from toxicity, cell harvesting, processing, storage, transport and product release regulations for lymphocyte therapy can be challenging, especially when the cells have to be genetically modified. T cell exhaustion, survival and homing are suboptimal despite the infusion of billions of these cells. Further, CAR-modified T cells are no exception to the immunosuppressive tumor microenvironment, where Tregs, tumor associated macrophages and myeloid suppressor cells work in concert to circumvent the anti-tumor properties of CAR modified T-cells. Furthermore, CAR modified T-cells are subject to the same immunosuppressive constraints confronted by classic T-cells, including anergy following engagement of CTLA4 by B7 or PD-1 by PD-L1 (B7-H1) on tumor cells. Clinically effective alternatives to CAR modified T-cell therapy for the treatment of cancer are thus warranted.


This disclosure describes systems and methods for priority flow control in a network switching device having two or more egress queue managers for managing egress queues of ports of the network switching device. A first egress queue manager determines respective fill levels of packet data that is buffered in egress queues. The first egress queue manager generates a data structure that relates a port of the egress queue manager at which selected packets are ingressed and a port or an egress queue of the egress queue manager from which the selected packets are to be egressed. The first egress queue manager signals to one or more other egress managers the respective fill levels of egress queues along with other information to enable at least one of the other egress queue managers to make a priority flow control decision for one of the ports managed by the other egress queue manager.

The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the inventors hereof, to the extent that the work is described in this background section, as well as aspects of the description that do not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted to be prior art against the present disclosure.
The volume of traffic that is electronically communicated across the Internet and other packet switching communication networks is enormous and continues to grow rapidly due to mounting demand. Increased capacity and throughput necessitates an ability to handle increasingly large numbers of traffic flows, which necessitates the ability to concurrently manage queue buffers for storing concurrent traffic flows. There are limits, however, to the sizes of integrated circuitry that are commercially available to implement such network switching devices.
One approach to increasing the throughput of a network switching device is to implement the device in a distributed architecture, such as an upscaled modular architecture that includes multiple instances of interconnected network switching circuitry, for instance, utilizing parallel processing cores, parallel queue managers, and the like, that serve a large number of network ports. This approach, however, gives rise to technical challenges.
A conventional network switching device (e.g., a single-chip device, single-processing-core device, or any other type of device having a centralized or non-distributed architecture), for instance, typically implements a priority flow control procedure to pause or resume the incoming data flow at its ingress port based on whether that ingress port is causing congestion in the network switching device. The network switching device typically determines whether to pause or resume the traffic for a particular ingress port based on an amount of data from an ingress port the device has buffered. For example, if the device has received more than a threshold amount of data from a particular ingress port, indicated for example by a fill level of a device buffer, the device pauses the incoming data for that ingress port until the buffered data can be transmitted from the device via one or more egress ports. In a distributing network switching architecture, challenges arise in implementing priority flow control since egress queue managers may need to implement priority flow control procedures based in part on ingress data from ingress ports to which they are not directly coupled.

Priority flow control in a distributed network switch architecture


A system to collect heterogeneous scalar measurement data over a network from a plurality of devices connected to the network, and normalize the collected heterogeneous scalar measurement data based on a mathematical transform of collected scalar measurement data into a common mathematical space. The transformed scalar measurement data is displayed in graphical representations such that transformed scalar measurement data from a particular network device can be displayed alongside a graphical representation of a transformed scalar measurement data from a different particular network device. Thus, transformed scalar measurement data from different heterogeneous network devices can be aggregated and displayed in the same graphical representation.

With the growing reliance on networks, and accordingly network stability, network administrators need to be able to monitor and troubleshoot networks, which can be accomplished through use of monitoring devices on the networks. Examples of devices from which measurements may need to be taken include, for example, routers) switches, servers, clients, PCs, telecommunications equipment, voice gateways, etc. An example of a monitoring and/or troubleshooting of a network may include a network administrator viewing usage of a network on a display or having the capability to access additional measurement data of that network usage by drilling down to more detailed measurement data. Typically, the displaying of measurement data will include displaying graphs or plots illustrating graphically the measurement data versus a predetermined unit, e.g., an average usage of a network per hour. Drilling down to more detailed measurement data may include the capability to access measurement data used in formulating such graphically illustrated measurement data, i.e., the ability to view or print out the raw data used in generating the graphic or reformulating the graphic based on more fine criteria.
Typically, the monitoring of such network devices is accomplished seamlessly since all the network devices may be controlled by one protocol, for example, SNMP. However, multiple other protocols exist, such as XML and CMIP, which are also used by the network devices when transferring measurement data or by a control unit collecting measurement data from multiple network devices. Similarly, measurement data, which is collected by a network device, transferred from the network device, and collected by a control unit, will have a particular format, e.g., floating point, integer, negative value capability, positive value capability, binary, hexadecimal, logarithmic, etc.
Scalar measurement data from a plurality of network devices that are not all monitored using the same protocol is typically defined as being heterogeneous as to its source. In contrast, scalar measurement data from a plurality of network device that are monitored using the same protocol is typically defined as homogeneous as to its source. In networks containing network devices that are controlled by heterogeneous protocols, network administrators are required to individually monitor or display the network devices controlled by that protocol, separate from other network devices controlled by another protocol, or to monitor or display in a single graphic illustration measurement data from multiple network devices when all the network devices are not controlled by the same protocol. In some instances, network administrators create individualized simplified homogeneous solutions. For example, in a network containing CMIP and SNMP protocols, a CMIP management system can be set up with a gateway to receive SNMP data. The gateway then emulates the SNMP data to correspond to CMIP data based on a simplification of the differences between SNMP and CMIP data, so the measurement data can all be collected and displayed based on the CMIP protocol. However, such solutions must be individually designed, tested, and implemented. Further, individual design, testing, and implementation occupies valuable time and resources. A need exists for a universal data model that is able to commonly display the heterogeneous scalar measurement data.

This patent is subject to a terminal disclaimer.

Method and apparatus for displaying measurement data from heterogeneous measurement sources


A sensing circuit for detecting data stored in a memory cell of an EEPROM by current detecting method is disclosed. The sensing circuit includes a constant current source supplying circuit for supplying a constant current. A loading circuit generates a current the same as the constant current generated by the current source supplying circuit when the memory cell sends out a logic low state signal, so that the data accessing speed during reading the data stored in the memory cell is increased.

1. Field of the Invention
The present invention relates to a sensing circuit for a memory device, and more particularly to a current sensing type sensing circuit for reading data stored in an electrical erasable programmable memory (EEPROM).
2. Description of the Prior Art
It is known that an electrical erasable programmable memory (abbreviated EEPROM) includes a number of memory cells therein and is capable of storing data in the memory cells. The data stored in the EEPROM is either in the form of conductive or non-conductive state, and the data state may be sensed by a sensing circuit.
FIG. 1 is a schematic circuit diagram showing a conventional memory cell of an EEPROM. The memory cell 1 of the EEPROM is mainly composed of a MOS transistor 11 and an EEMOS transistor 12. The EEMOS transistor 12 serves as a storage element for the memory cell. The logic level at point VD is low voltage level when the memory cell circuit is in conductive status, which means that the data stored in the memory cell is logic low level "0". On the contrary, the point VD is at floating level when the memory cell circuit is in non-conductive status, which means that the data stored in the memory is logic high level "1".
A threshold voltage Vt of the EEMOS transistor determines whether the EEMOS transistor 12 is conductive or non-conductive. In case the threshold voltage Vt is larger than the gate voltage VG of the transistor, the EEMOS transistor will be non-conductive. On the contrary, in case the threshold voltage Vt is lower than the gate voltage VG of the transistor, the EEMOS transistor will be conductive. So, the data stored in the memory cell may be detected by a sensing circuit by detecting the voltage level at point VD.
During reading the data stored in the memory cell of the EEPROM, the relative points of the EEPROM memory cell are listed below:
______________________________________ read mode VG VS VD VCG ______________________________________ 1 0 V 0 V 2 V 5 V 0 0 V 0 V 0 V 5 V ______________________________________
As mentioned above, the data stored in the memory cell may be read by a sensing circuit by sensing the voltage level of the memory cell of the EEPROM. Once the sensing circuit detects the data, the data will be sent to an amplifying circuit which is used to amplify the accessed data. Typically, the amplifying circuit is an inverted amplifying circuit.
FIG. 2 is a schematic circuit diagram of a prior art sense amplifying circuit, which mainly includes a PMOS transistor 21, a NMOS transistor 22, two inverters 23 and 24. The PMOS transistor 21 serves as a pull-up transistor. The gate of the NMOS 22 is controlled by a bias control signal CO. The source of the NMOS 22 is coupled to the memory cell of the EEPROM for receiving the data sent from the EEPROM.
In operation, the voltage level at intersection point between the PMOS 21 and the NMOS 22 may be charged or discharged by means of the operation of the PMOS 21 and the NMOS 22. The voltage level may be detected by the inverters 23 and 24. However, it is found that the sensing speed of this prior art sensing circuit is slow because that the voltage charging operation is limited. Especially, the discharging speed of the memory cell is rather slow during detecting logic level "0" because that the discharging speed of the circuit is low.


An active optical beam shaping system includes a first deformable mirror arranged to at least partially intercept an entrance beam of light and to provide a first reflected beam of light, a second deformable mirror arranged to at least partially intercept the first reflected beam of light from the first deformable mirror and to provide a second reflected beam of light, and a signal processing and control system configured to communicate with the first and second deformable mirrors. The first deformable mirror, the second deformable mirror and the signal processing and control system together provide a large amplitude light modulation range to provide an actively shaped optical beam.

1. Field of Invention
The field of the currently claimed embodiments of this invention relates to active optical beam shaping systems and methods, and more particularly to active optical beam shaping systems and methods using sequential deformable mirrors.
2. Discussion of Related Art
Exo-planetary systems that are directly imaged using existing facilities (Marois et al. 2008; Kalas et al. 2008; Lagrange et al. 2010) give a unique laboratory to constrain planetary formation at wide separations (Rafikov 2005; Dodson-Robinson et al. 2009; Kratter et al. 2010; Johnson et al. 2010), to study the planetary luminosity distribution at critical young ages (Spiegel & Burrows 2012; Fortney et al. 2008) and the atmospheric properties of low surface gravity objects (Barman et al. 2011b,a; Marley et al. 2010; Madhusudhan et al. 2011). Upcoming surveys, conducted with instruments specifically designed for high-contrast (Dohlen et al. 2006; Graham et al. 2007; Hinkley et al. 2011), will unravel the bulk of this population of self-luminous Jovian planets and provide an unprecedented understanding of their formation history. Such instruments will reach the contrast required to achieve their scientific goals by combining Extreme Adaptive Optics systems (Ex-AO, Poyneer & V'eran (2005)), optimized coronagraphs (Soummer et al. 2011; Guyon 2003; Rouan et al. 2000) and nanometer class wavefront calibration (Sauvage et al. 2007; Wallace et al. 2009; Pueyo et al. 2010). In the future, high-contrast instruments on Extremely Large Telescopes will focus on probing planetary formation in distant star forming regions (Macintosh et al. 2006), characterizing both the spectra of cooler gas giants (V'erinaud et al. 2010) and the reflected light of planets in the habitable zone of low mass stars. The formidable contrast necessary to investigate the presence of biomarkers at the surface of earth analogs (>1010) cannot be achieved from the ground beneath atmospheric turbulence and will require dedicated space-based instruments (Guyon 2005).
The coronagraphs that will equip upcoming Ex-AO instruments on 8 meter class telescopes have been designed for contrasts of at most ˜10−7. Secondary support structure (or spiders: 4 struts each 1 cm wide, ˜0.3% of the total pupil diameter in the case of Gemini South) have a small impact on starlight extinction at such levels of contrasts. In this case, coronagraphs have thus been optimized on circularly symmetric apertures, which only take into account the central obscuration (Soummer et al. 2011). However, high-contrast instrumentation on future observatories will not benefit from such gentle circumstances. ELTs will have to support a substantially heavier secondary than 8 meter class observatories do, and over larger lengths: as a consequence, the relative area covered by the secondary support will increase by a factor of 10 (30 cm wide spiders, occupying ˜3% of the pupil diameter in the case of TMT). This will degrade the contrast of coronagraphs only designed for circularly obscured geometries by a factor ˜100, when the actual envisioned contrast for an ELT exo-planet imager can be as low as ˜10−8 (Macintosh et al. 2006). While the trade-offs associated with minimization of spider width in the space-based case have yet to be explored, secondary support structures will certainly hamper the contrast depth of coronagraphic instruments of such observatories at levels that are well above the 1010 contrast requirement. As a consequence, telescope architectures currently envisioned for direct characterization of exo-earths consist of monolithic, off-axis, and thus un-obscured, telescopes (Guyon et al. 2008; Trauger et al. 2010). Coronagraphs for such architectures take advantage of the pupil symmetry to reach a theoretical contrast of ten orders of magnitude (Guyon et al. 2005; Vanderbei et al. 2003a,b; Kasdin et al. 2005; Mawet et al, 2010; Kuchner & Traub 2002; Soummer et al. 2003). However, using obscured on-axis and/or segmented apertures take full advantage of the limited real estate associated with a given launch vehicle and can allow larger apertures that increase the scientific return of space-based direct imaging survey. Recent solutions can mitigate the presence of secondary support structures in on-axis apertures. However these concepts present practical limitations: APLCs on arbitrary apertures (Soummer et al. 2009) and Shaped Pupils (Carlotti et al. 2011) suffer from throughput loss for very high contrast designs, and PIAAMCM (Guyon et al. 2010a) rely on a phase mask technology whose chromatic properties have not yet been fully characterized. Moreover, segmentation will further complicate the structure of the telescope's pupil: both the amplitude discontinuities created by the segments gaps and the phase discontinuities resulting from imperfect phasing will thus further degrade coronagraphic contrast. Devising a practical solution for broadband coronagraphy on asymmetric, unfriendly apertures is an outstanding problem in high contrast instrumentation. Therefore, there remains a need for improved beam shaping systems and methods.

Active beam shaping system and method using sequential deformable mirrors


Techniques for the suggestion and completion of deep learning models are disclosed including receiving a set of data and determining at least one property of the data. A plurality of characteristics of a computing device and a plurality of deep learning models are received and a score for each of the plurality of deep learning models is determined based on the received computing device characteristics and the determined at least one property of the data. The plurality of deep learning models are ranked for presentation to a user based on the determined scores. One or more of the deep learning models are presented on a display based on the ranking. A selection of one of the deep learning models is received and the selected deep learning model is trained using the set of data.

The construction of a deep learning model for a set of target data is often a complex task. For example, each deep learning model may be constructed according to a variety of parameters such as a number of nodes, number of layers, number of nodes per layer, types of layers, or other similar parameters. These parameters are typically selected based on a manual analysis of the task at hand and the data set to be used for training the model.

Suggestion and completion of deep learning models from a catalog

International Business Machines Corporation


A flash memory device has a precharging section for precharging adequately in advance internal data lines included in an Y-decoder section whenever a process of inputting data into page buffer is performed, error in a second process of inputting data may be reduced by preventing the maintenance of data loaded to data lines in a first process of inputting data prior to the second process.

The present invention relates to a semiconductor memory device, and more particularly relates to a flash memory device and a method of inputting data.
A common flash memory device can be erased and reprogrammed many times and has the ability to retain data even when power is turned off, and so it has been employed in various semiconductor memory devices.
The flash memory device employs page buffers for speeding up the programming or reading of large data. Accordingly, program and read operations in the flash memory device are performed on a page basis by the page buffers.
FIG. 1 is a view illustrating circuitry of a Y-decoder section in a common flash memory device.
Referring to FIG. 1, the Y-decoder section 10 is employed to input data into one of the page buffers PB0 to PBn. FIG. 1 shows schematically latch LAT0 and a data input circuit DIC0 of page buffer PB0, in the left top corner. The Y-decoder section 10 includes a plurality of selecting sections 10A to 10S connected between the page buffers PB0 to PBn and data lines DL0 to DLk.
The selecting sections 10A to 10S have the same structure, e.g. 10A includes N-MOS transistors NC0 to NCc, NB0 to NBb, NA0 to NAx.
The Y-decoder section 10 connects a page buffer selected from the page buffers PB0 to PBn to a data line, e.g. DL0 selected from the data lines DL0 to DLk in response to Y-decoder driving signals YC_DRV<0:C>, YB_DRV<0:B> and YA_DRV<0:A>, thereby forming a data input path.
An operating controller 11 is connected respectively to the data lines DL0 to DLk, thereby supplying the data lines DL0 to DLk with a ground voltage or a supply voltage in accordance with discharging signals DL0_DIS to DLk_DIS. Accordingly, the data input path is discharged to a low level by the discharging signals DL0_DIS to DLk_DIS in a process of inputting data.
FIG. 2 is a timing diagram illustrating signals related to operation of inputting data using the Y-decoder section in FIG. 1.
Hereinafter, a process of inputting data in the flash memory device will be described in detail with reference to FIG. 1 and FIG. 2. It is assumed that first data "0" is inputted into page buffers PB0 to PB3, and second data "1" is inputted into page buffers PBk to PBk+3.
The operating controller 11 connects data line, e.g. DL0 to the supply voltage in response to a discharge signal having low level. Additionally, the Y-decoder section 10 connects internal data lines YA, YB and YC to the data line DL0 in accordance with first, second and third driving signals YC_DRV<0:C>, YB_DRV<0:B> and YA_DRV<0:A> having high level. As a result, the internal data lines YA, YB and YC are precharged to high level.
Then, the first, second and third driving signals YC_DRV<0:C>, YB_DRV<0:B> and YA_DRV<0:A> are disabled so that the data line DL0 is disconnected from the internal data lines YA, YB and YC
Subsequently, the operating controller 11 connects the data line, e.g. DL0 to the ground voltage in response to discharge signal DL0_DIS having high level, thereby discharging the data line DL0. The N-MOS transistor NC0 and the N-MOS transistor NB0 are turned on in response to the third driving signal YC_DRV<0> and the second driving signal YB_DRV<0>, respectively, and so the first internal data line YC is connected to the data line DL0, and the second internal data line YB is connected to the first internal data line YC. As a result, the data line DL0 is connected to the second internal data line YB through the first internal data line YC.
Then, the N-MOS transistor NA0 is turned on in response to the first driving signal YA_DRV<0>, and so the input/output data line YA is connected to the second internal data line YB. In this case, an N-MOS transistor NDI1 in the data input circuit DIC0 is turned on in response to a data input signal nDI, and so the input/output data line YA is connected to the latch LAT0. Accordingly, the data line DL0 coupled to the ground voltage is connected to the first internal data line YC, the second internal data line YB, the input/output data line YA and the latch LAT0 in the page buffer PB0, and so "0" data is inputted into the page buffer PB0.
Subsequently, first driving signals YA_DRV<1> to YA_DRV<3> are enabled in sequence, and so first data "0" is inputted in sequence into the page buffer PB1 to PB3. The operating controller 11 connects the data line DL0 to the supply voltage in response to the discharge signal DL0_DIS having low level. In addition, the Y-decoder section 10 connects the internal data lines YB and YC and the input/output data line YA to the data line DL0 in accordance with the first, second and third driving signals YC_DRV<0:C>, YB_DRV<0:B> and YA_DRV<0:A> having high level. Consequently, the input/output data line YA and the internal data lines YB and YC are precharged to a high level. Here, since many internal data lines must be precharged through one data line, e.g. DL0 during a predetermined period of time, the internal data lines may be precharged incompletely.
Then, the second data "1" is inputted into the page buffers PBk to PBk+3. Particularly, the third driving signal YC_DRV<0> is disabled, and the third driving signal YC_DRV<C> is enabled. Accordingly, new data path {circle around (2)} different from the data path {circle around (1)} formed when the first data was inputted is formed, and so the second data is inputted into the selected page buffers PBk to PBk+3. In this case, the first data "0" may be with loading condition by the data lines precharged incompletely in the precharging process, e.g. input/output data line YA connected to the page buffers PB0 to PB3.
This phenomenon occurs because the data lines are increased as the data capacity of a memory device is increased, and the memory device uses lower voltages, and so data lines are precharged incompletely.
In this case, the second data "1" is inputted into the page buffers PBk to PBk+3 accordingly as the data input signal DI is provided. In case that the input/output data line YA connected to the page buffers PB0 to PB3 is precharged incompletely, i.e. keeps low level, the second data "1" is inputted again into the page buffers PB0 to PB3 which were latching the first data "0" as shown in 'A' of FIG. 2, and so errors may occur in the process of inputting the data.

Flash memory device having a function for reducing data input error and method of inputting the data in the same


A battery pack cooling and body pressure relief system for a vehicle having a passenger cabin is disclosed. The system may include an intake air flow duct connected between the passenger cabin and the battery pack, and an air flow duct connected between the exhaust air outlet and the body pressure relief valve. The system may include a one-way cabin pressure relief vent connected to the air flow duct and configured to selectively allow for air flow into the air flow duct, and may include a duct pressure relief vent connected to the air flow duct and configured to selectively allow for air flow out of the air flow duct into the vehicle.

The present invention relates generally to body pressure relief systems for automotive vehicles, and more particularly for automotive vehicles having a battery pack.
Some modern automotive vehicles are propelled by electric motors, whether a fuel cell, hybrid electric vehicle or a pure electric vehicle. These vehicles include battery packs for storing electric charge used to drive the motor. A significant amount of energy flow into and out of the battery pack can occur, which may raise the temperature of the battery pack above levels that are desirable. Consequently, some of these vehicles use various techniques for cooling the battery pack. Given the additional cost and complexity of cooling a battery pack, it is thus desirable to cool it in the most efficient and least costly way possible.
Also, since some vehicles are sold in a conventional drivetrain arrangement (without a battery pack) in addition to hybrid electric vehicle models, it is desirable to minimize changes to the bodies of the vehicles between the two types while still providing for the proper functioning of both vehicle types.


A vehicle side rear-view mirror assembly having a means for exposing a blind spot includes a mirror housing, a support frame, a backing plate, a mirror glass; a connecting means which connects the mirror glass to the backing plate such that the mirror glass is pivoted on the connecting means about a rotating axis. A motion actuator rotates the mirror glass about the rotating axis. The assembly further includes adjustment means to adjust the predetermined position of the mirror glass, which includes a motion height adjustment means to adjust the height of the motion actuator, and a rotating axis defining member which can be rotated by a rotating means independently of the backing plate and the mirror glass. A switch is installed on a steering wheel to activate the motion actuator, the switch having two conductive wires which can be connected by a conductive metal piece.

While driving a vehicle, a driver must constantly review his surroundings to avoid a collision. Side rear-view mirrors assist a driver in reviewing the surroundings generally disposed behind the driver without the driver having to turn his head more than necessary.
Blind spots exist on either side of the vehicle. Blind spots are spaces that are not visible to the driver through the rear-view mirrors and the driver must turn his head to view the blind spots.
Customarily, the side rear-view mirrors are provided with means for adjusting the orientation of the mirrors. For an electrically powered adjustment, two electric motors are generally provided, one for adjusting the orientation about a vertical axis and the other for adjusting the orientation about a horizontal axis.
However, these adjusting devices are not suitable for a driver to use for exposing blind spots while driving because the devices rotate the mirrors slowly and using such devices while driving can be very dangerous.
Various means for exposing blind spots by rotating the side rear-view mirrors from a normal position to a predetermined position have been introduced, but they operate rather slowly and lack mechanism to avoid interference between such means and the existing adjusting devices. To be effective, the blind spot exposing means should work very fast. A means for exposing blind spots requires at least one motor or motion actuator and the adjusting devices usually include two motors.
Besides, the conventional means for exposing blind spots do not have a means to adjust or change the predetermined position. The predetermined position should vary depending on a driver's height, preferential driving posture, etc.
Accordingly, to solve the above problems, a need for a vehicle side rear-view mirror assembly having a means for exposing a blind spot and for adjusting the predetermined position has been present for a long time considering the expansive demands in the everyday life. This invention is directed to solve these problems and satisfy the long-felt need.

Vehicle side rear-view mirror assembly having means for exposing blind spot


An information processing device, a data processing method thereof, an input device, and an input controlling method are described. The information processing device is capable of responding to an input operation of an input device, and the input device includes an input component located at end portion thereof. The information processing device includes a sensing module capable of sensing a position of the input component with respect to the sensing module when the distance between the input component and the sensing module satisfies a first predetermined condition, a first controlling module judging whether the information processing device satisfies a second predetermined condition when the distance satisfies the first predetermined condition, responds to an input operation corresponding to the position of the input component with respect to the sensing module when the information processing device satisfies the second predetermined condition, or otherwise, does not respond thereto.

This application claims priority to Chinese patent application No. 201310455341.3 filed on Sep. 29, 2013, the entire contents of which are incorporated herein by reference.
The present invention relates to an information processing device, a data processing method applied to the information processing device, an input device and an input controlling method applied to the input device.
Nowadays, an input device such as stylus is widely used with information processing devices such as a tablet computer, and suspension operation function to the input device can be supported by most information processing devices. The suspension operation function enables a user to achieve a specific operation with the input device such as stylus without touching the screen of the information processing device. However, with the suspension operation function, a problem is that the stylus may easily be triggered by mistake. For example, an undesired suspension operation may easily to be generated when instead of using the stylus, the user instead directly places the stylus horizontally on the surface of the screen. At this moment, the distance from the stylus to the screen is within the range of suspension operation distance, and a suspension operation not desired by the user is generated. And, a mistaken operation such as cursor drifting may even be generated.
To solve the above problem, conventionally, a valid suspension operation distance is reduced; however, as the stylus is made to be smaller and smaller, this solution has a limitation, and may affect the user's operation experience.

Information processing device supporting suspension operation function, data processing method thereof, input device and input controlling method thereof


Object of the present invention is to provide a method for manufacturing a printed wiring board which enables fine wiring formation at low costs and with high yields without introducing any special equipment, and a printed wiring board manufactured by the method. To achieve the object, a method for forming the wiring pattern adopted includes steps; for forming a laminate having a structure in which a copper foil layer formed using copper foil without roughening treatment having surface roughness (Rzjis) at a bonding surface of 2 μm or less and thickness of 5 μm or less is laminated to a conductive layer via an insulating layer; for providing a blind-hole composed of a hole perforating the copper foil layer and the insulating layer; and a bottom composed of the conductive layer in the laminate; for filling-up the blind-hole by a electro-plated copper in the time for depositing an electro-plated copper layer on a surface of the electroless-plated copper layer to make the total thickness of a copper layer provided on the insulating layer 15 μm or less, for providing of an etching resist layer having thickness of 15 μm or less and for etching of the copper layer.

Specifications of semiconductor integrated circuit devices (hereinafter referred to as "semiconductor devices") including microprocessor for computers have been made faster in operation speed and more multifunctional in recent years. Depending on such an increase in the operating speed and functions of semiconductor devices, the terminal pitch of a semiconductor device tends to be narrower and narrower. Accordingly, a finer wiring pattern is required for a packaging board or the like which is a printed wiring board for mounting a semiconductor device (hereinafter referred to as "packaging board or the like") due to a decrease in the terminal pitch of the semiconductor devices.
In the packaging board or the like, interlayer connection between an outer-layer circuit (surface-layer circuit) where a semiconductor device is mounted and an inner-layer circuit is achieved by filled via-holes (non-perforated holes) and/or plated through-holes (perforated holes). For example, Patent Document 1 discloses a method for manufacturing the packaging board or the like in which interlayer connection between an outer layer and an inner layer is achieved by non-perforated holes and perforated-holes; a copper foil to be an outer layer is laminated on an inner-layer board on which the inner-layer circuit is formed via insulating layer, the non-perforated holes and the perforated-holes for interlayer connection are provided, and an electroless-plated copper layer and an electro-plated copper layer are formed inside of the non-perforated holes and the perforated-holes and on the outer-layer copper foil. In the method, inside of the non-perforated holes are filled-up by electroless-plated copper and electro-plated copper to finish filled via-holes. Next, a plated copper layer composed of an electroless-plated copper and an electro-plated copper having a specific thickness is formed on the inner walls of each through-hole. Then, an outer-layer circuit is formed by a subtractive method. By the way, a packaging board or the like in the current marketplace requires a fine wiring pattern with the pitch of 40 μm or less and line/space (hereinafter referred to as L/S) of 20 μm/20 μm or less for the outer-layer circuit, for example, as a measure to a decreasing terminal pitch of a semiconductor device.

Manufacturing method of printed wiring board and printed wiring board


In a vehicle seat, a bracket contact member is fixed to a seat back frame and contacts support brackets in an initial use position, to suppress rearward tilting of a head rest with respect to the seat back frame. While suppressing rearward tilting, forward tilting of the head rest with respect to the seat back frame from the initial use position, by inertia force in the event of a rear-end collision of a vehicle, is not suppressed by the contact member.

1. Field of the Invention
The invention relates to a vehicle seat that has a head rest.
2. Description of Related Art
A vehicle seat described in Japanese Patent Application Publication No. 2004-017826 (JP 2004-017826 A) includes support brackets, head rest supports and a back receiving member. The support brackets are fixed to a seat back frame. The head rest supports are respectively connected to the support brackets, and a head rest is connected to the upper end portions of the head rest supports. The back receiving member is coupled to the lower end portions of the head rest supports. In the vehicle seat, when the back receiving member is pressed by the back of a seated occupant in the event of a rear-end collision of a vehicle, the head rest supports tilt forward with respect to the support brackets while deforming elastic members provided between the head rest supports and the support brackets. By so doing, the head rest connected to the head rest supports is moved forward, and the head of the seated occupant is received by the head rest so as not to be further moved rearward.
In the thus configured vehicle seat, the head rest moves forward in the event of a rear-end collision of the vehicle. By so doing, it is possible to reduce a period of time (so-called contact time) from occurrence of the rear-end collision to when the head of the passenger contacts the head rest. By so doing, it is possible to improve the whiplash reducing effect of the head rest. However, the large back receiving member and the elastic members are required, so there is still room for improvement in terms of simplification of the configuration.


A system, method and device are provided which determine the position of a mobile station in connection with consulting signal delay transmission data from an almanac for the purpose of identifying the nearest set of base stations. Thereafter, the position of the mobile station is determined using multilateration.

Previous methods of achieving assisted global positioning system (A-GPS) fixes have been subject to degraded performance in networks which make use of repeaters to provide better phone service coverage in a network. Typically, in a method which uses the time difference of arrival (TDOA) to calculate the position of a mobile station (MS), the distance between a mobile station and a base transceiver station/tower (BTS) can be determined given the speed of light and the transmit/receive times of a signal transmission between the BTS and the MS. A BTS holds the radio transceivers that define a cell and coordinate the radio-link protocols with the mobile MS. A cell defines a geographic area and is usually divided into sectors. A sector references a cell which divides its coverage area into several divisions. The number of sectors supported is variable, but it's common for there to be three. However, there exist 1 and 6 sector cells and possibly even 2, 4 and 5 sector cells defined by the radio transceivers held by a BTS. Typically, at least three towers are required to determine the MS position. Multilateration is the name applied to the technique of determining position from a MS-transmitting signal to more than one receiving tower. Forward link multilateration is the name applied to the A-GPS method wherein the MS receives signals from transmitting towers to determine position. Timing is critical to either technique of multilateration as an error of a mere μs in clock synchronization (e.g., among receiving/transmitting towers) can result in an error in MS position determination of about 984 feet. Until now, other network-aided MS position determining methods roughly determined the sources of the signals received by the mobile station. Since these signal source determinations generally don't analyze a great many possible signal sources, error in source determination is likely. This error is propagated through to the determination of the location of the mobile station in that error in the identification of the sources of the signals likely leads to an error in determining the location of the mobile station.
Reference numerals have been carried forward.

Method for finding the location of a mobile terminal in a cellular radio system


A memory system includes one or more memory chips, and a repair information storage chip including a nonvolatile memory configured to store a repair information of the one or more memory chips, wherein during an initial operation of the memory system, the repair information stored in the repair information storage chip is transmitted to the one or more memory chips.

1. Field
Exemplary embodiments of the present invention relate to a memory system, and more particularly, to a technology for storing and transmitting repair information in a memory system.
2. Description of the Related Art
FIG. 1 is a diagram for illustrating a repair operation of a conventional memory device.
Referring to FIG. 1, the conventional memory device includes a cell array 110, a row circuit 120, and a column circuit 130. The cell array 110 includes a plurality of memory cells. The row circuit 120 is configured to enable a word line selected by a row address R_ADD. The column circuit 130 is configured to access (read or write) data of a bit line selected by a column address C_ADD.
A row fuse circuit 140 is configured to store a row address, corresponding to a memory cell having a defect in the cell array 110, and generate a repair row address REPAIR_R_ADD. A row comparison unit 150 is configured to compare the repair row address REPAIR_R_ADD stored in the row fuse circuit 140 to the row address R_ADD inputted from an external source. When the repair row address REPAIR_R_ADD coincides with the row address R_ADD, the row comparison unit 150 controls the row circuit 120 to enable a redundant word line instead of the word line designated by the row address R_ADD.
A column fuse circuit 160 is configured to store a column address, corresponding to a memory cell having a defect in the cell array 110, and generate a repair column address REPAIR_C_ADD. A column comparison unit 170 is configured to compare the repair column address REPAIR_C_ADD from the column fuse circuit 160 to the column address C_ADD inputted from an external source. When the repair column address REPAIR_C_ADD coincides with the column address C_ADD, the column comparison unit 170 controls the column circuit 130 to access a redundant bit line, instead of the bit line designated by the column address C_ADD.
The row fuse circuit 140 and the column fuse circuit 160 (hereinafter referred to as the fuse circuits) of FIG. 1 use laser fuses. The laser fuse stores high or low data depending on whether the fuse is cut or not. The laser fuse may be programmed in a wafer state, but may not be programmed after the wafer is mounted in a package. To overcome such a concern, an E-fuse may be used. The E-fuse may include a transistor. When the E-fuse includes a transistor, the E-fuse stores data by changing resistance between a gate and a drain/source.
FIG. 2 is a diagram illustrating that the E-fuse including a transistor operates as a resistor or capacitor.
Referring to FIG. 2, the E-fuse includes a transistor T. When a normal power supply voltage which the transistor T may tolerate is supplied to a gate G, the E-fuse operates as a capacitor C. Therefore, there is no current flowing between the gate G and a drain D or source S (hereinafter referred to as a drain-source D-S). However, when a high voltage, which the transistor T may not stand, is applied to the gate G, gate oxide of the transistor T may become inoperable and short the gate G and the drain-source D-S. In this case, the E-fuse operates as a resistor R. Therefore, a current flows between the gate G and the drain-source D-S.
Such a characteristic may be used to recognize the data of the E-fuse through a resistance value between the gate G and the drain-source D-S of the E-fuse. To recognize the data of the E-fuse, (1) the size of the transistor T may be increased to directly recognize the data without a separate sensing operation, or (2) an amplifier may be used to sense a current flowing in the transistor T without increasing the size of the transistor T. In the above-described two methods, however, the transistor T forming the E-fuse must be enlarged, or the amplifier for amplifying data must be provided for each E-fuse. Therefore, both methods have limitations and concerns over the size and space.
Because of the above-described concerns related to the size and space, it may not be easy to apply the E-fuse to the fuse circuits 140 and 160 of FIG. 1. Therefore, as disclosed in U.S. Pat. Nos. 6,904,751, 6,777,757, 6,667,902, 7,173,851, and 7,269,047, researches have been conducted on a method for performing a repair operation using data stored in an E-fuse array including a plurality of E-fuses (in this case, the entire area may be reduced because an amplifier is shared).

Memory system and operating method thereof


A method adjusts fuel injection to account for fuel puddling in the engine intake. The fuel is adjusted based on the ethanol content of the fuel in the puddle, and the make-up of the various fuel components in the puddle. In this way, it is possible to better account for the effects of these parameters on puddle evaporation.

In modern engines, the air-fuel ratio (AFR) in the cylinder may be controlled close to stoichiometry to maintain high emission conversion efficiency of the exhaust catalyst system. One of the issues that affects the accuracy of AFR regulation is that a fraction of injected fuel sticks to the port walls, in so-called "puddles." Fuel from the puddles evaporates at a rate that depends on many factors including wall temperature, manifold pressure, and fuel volatility. Engine control strategies may include compensation for the fuel-puddling (also called wall-wetting) effect, but the complexity of the underlying physics makes the strategy complicated and the calibration process time consuming. Part of the complexity is due to the varying volatility of fuels available at the pump (e.g., depending on the season and location) and the requirement that some vehicles run on flex fuels which can be a variable mixture of gasoline and ethanol (C2H5OH), with up to 85% percent of ethanol. The blending leads to different behavior of the fuel in terms of vaporization and puddle formation.
Current approaches address the physics of fuel vaporization by modeling, for example, multiple puddles, and multiple fuel components. The fuel components might include the standard gasoline components (e.g., pentane, iso-octane, etc.) as well as ethanol for flex fuel applications. Another set of approaches are based on simpler "black box" models, for which the parameters are determined by matching the model output to the observed (e.g., measured) air-fuel ratio.
The inventors of the present application have recognized a problem in such previous solutions. The multi-component, multi-puddle models are complex and typically require a significant amount of computational resources to run in real time. They are also nonlinear, and hence, not conducive for transient fuel puddle compensation. The black box models rely on numerous calibrations to attempt to compensate for the fuel-puddling. The calibrations are typically time intensive and may not effectively compensate for the port puddling effect because the physics of the process is not captured well by the simplified model. In particular, these models are not capable of tracking the fraction of ethanol in the port puddle as opposed to the fraction of ethanol in the tank. Consequently, an effective transient fuel compensation may not be achieved, thereby degrading engine emissions.
Accordingly, in one example, some of the above issues may be addressed by a method of adjusting an amount of fuel injection to an engine based on an ethanol content of fuel in a port puddle. Further, in some embodiments, the adjustment may be further based on the percent ethanol of the injected fuel. Further, in some embodiments, such an approach may include determining the amount of fuel evaporated from the puddle based on selected components of the fuel and their respective vapor pressures via a multi-component fuel model. The vapor pressures may be identified via text-book values and, hence, may be accessed via a look-up table, for example, as opposed to via calibration. By reducing the amount of calibratable tables referenced in determining a fuel injection compensation, an amount of a fuel injection may be more efficiently and rapidly determined, as described in more detail herein.
It should be understood that the summary above is provided to introduce in simplified form a selection of concepts that are further described in the detailed description. It is not meant to identify key or essential features of the claimed subject matter, the scope of which is defined uniquely by the claims that follow the detailed description. Furthermore, the claimed subject matter is not limited to implementations that solve any disadvantages noted above or in any part of this disclosure.

Multi-component transient fuel compensation


A macroglobulin is used to improve the signal-to-background ratio in an affinity binding assay employing a proteinase (or precursor) as a label. The macroglobulin entraps unbound labeled reagent, thereby reducing its signal generating activity, relative to that of the affinity complex.

1. Field of the Invention
This invention relates to affinity binding assays, such as immunoassays and nucleic acid hybridization assays, in which enzymes are used as labels and the presence or level of a substance is inferred from the enzymatic activity observed.
2. Description of the Background Art
Affinity Binding Assays. Measurement or detection of minute amounts of analytes, especially but not exclusively substances of biological origin, typically relies on processes of molecular recognition to achieve specificity. By molecular recognition is meant a highly specific interaction between two molecules, by virtue of which they bind to each other with high affinity The complex so formed is typically denoted as an "affinity complex"; and one of its members is often designated as a "ligand" of the other. This phenomenon forms the basis of the well known technique of affinity chromatography. Prominent illustrative examples of molecular recognition are antibody-antigen complex formation and hydridization of complementary nucleic acids (cf. Journal of Molecular Recognition for further examples).
Analytical protocols are typically classified as "homogeneous" or "heterogeneous". Heterogeneous assays are those in which at least one component of the affinity complex is necessarily immobilized on a surface during all or part of the analysis, i.e. such immobilization is methodologically functional. Conversely, homogeneous assays do not require immobilization of either member of the affinity complex, i.e. the analysis occurs substantially in solution.
For a homogeneous assay to be successful, there must be a difference between the signal produced by the labeled reagent in the free and in the bound state. Amos, U.S. Pat. No. 4,442,218 (1984) permits a binding reaction to take place within the pores of an insoluble porous monolith. The signal produced by the labeled species, once bound within the pore, is attenuated relative to the signal emitted by the free label species. Zuk, U.S. Pat. No. 4,256,834 employs three reagents: an insolubilized ligand, a labeled (e.g. fluorescein) anti-ligand, and an insolubilized anti-label (e.g., anti-fluorescein antibody bound to charcoal). When the first two reagents form an affinity complex, the third, the signal repressor, is obstructed from interacting with the label. Free labeled anti-ligand, however, is complexed by the anti-label and its signal production is inhibited. Zuk, U.S. Pat. No. 4,281,061, discloses an assay which features a labeled ligand, an antiligand, an anti(antiligand), and a polyvalent macromolecule which can modulate the signal produced by the labeled ligand. Ligand, antiligand, and anti(antiligand) bind to form a matrix which either encloses the macromolecule (resulting in enhanced interaction) or excludes it (resulting in diminished interaction). The macromolecule is typically an antibody. Carrico, U.S. Pat. No. 4,743,535 (1988) teaches use of an antibody which binds to double-stranded but not single stranded DNA in a nucleic acid hybridization assay. The antibody sterically interferes with signal generation by the affinity complex. Halfman, U.S. Pat. No. 4,640,898 forms micelles which can distinguish unbound labeled conjugate and the conjugate as part of an affinity complex. See also Rubenstein U.S. Pat. No. 3,817,837; Ullman, U.S. Pat. No. 3,996,345; Rubenstein, U.S. Pat. No. 3,935,074.
Homogeneous assays offer several advantages relative to heterogeneous assays, including the following:
i) no immobilization step is required; PA1 ii) time-consuming and labour-intensive washing steps are unnecessary; PA1 iii) capable of performance in a simple, reusable container such as a test tube, by addition of reagents without liquid withdrawal; PA1 iv) more rapid analysis due to improved mass-transfer kinetics.
In spite of these advantages very few operational homogeneous assay systems have been developed to-date. An important advantage of the present invention is that it functions in either homogeneous or heterogeneous assay formats. Moreover homogeneous assays employing the invention complement existing technology which can only measure analytes that are small molecules (Chan, 1987).
Another functional distinction is between competitive and non-competitve assays. A competitive assay relies on at least one process of competition between labelled and unlabelled species (e.g. analyte, antibody, DNA probe, etc.) for binding to a complementary molecule through a process of molecular recognition. Conversely a non-competitive assay requires only binding of a labelled probe to the analyte by a molecular recognition process. Because of thermodynamic constraints competitive assays are typically about one thousand-fold less sensitive than non-competitive assays: "Thus, the detection limit of antigens by competitive immunoassay is at femtomole [10.sup.-15 mol] or higher levels in most cases...The detection limit of antigens by non-competitive two-site enzyme immunoassay with appropriate techniques is at attomole [10.sup.-18 mol] levels." (Ishikawa et al , 1991).
In spite of these recognized advantages of non-competitive, homogeneous assays, it appears that no such systems have been developed to the point of practical utility. Thus, "Although competitive assays were used in early EIA [enzyme immunoassay] there has subsequently been a progressive increase in the use of non-competitive or immunoenzymometric assays...These assays all use solid-phase reagent, either an antibody or antigen." (Gould and Marks, 1988). Similarly all of the homogeneous immunoassay methods described by Ngo (1985) are of the competitive type. A significant advantage of the present invention is its general applicability in a non-competitive, homogeneous assay format, thereby deriving most or all of the benefits described above.
Assay Sensitivity. Heretofore detection methods relying on molecular recognition processes have suffered from compromises between detection limit and analysis time. Thus, "...although the theoretical detectability of catalyst [sic] could be as low as a single molecule, practical considerations of time and the inevitability of backgrounds have limited the sensitivity of enzyme-based assays." (Bates, 1987). The detection limit of heterogeneous assays has always been constrained by a non-specific, "background" (zero analyte) signal. Although to some extent reducible, such background has not heretofore been susceptible to substantial elimination: "In two-site enzyme immunoassay for antigen, enzyme-labelled antibody non-specifically (non-immunologically and physically) adsorbs to antibody-coated solid phase to various extents. This is one of the major obstacles to improvement in sensitivity and various attempts have been made to reduce the non-specific binding." (Ishikawa et al., 1991). None of these previous attempts have met with unqualified success.
The various sources of background signal were described as follows by Pruslin et al. (1991): "The OD (absorbance) measurements obtained in an assay include, in addition to the values for the specific antibody/antigen reaction, summary values designated `background`. That designation includes all contributions to the OD that are not attributable to the specific antibody/antigen reaction under test. Those non-specific contributions are demonstrable by including a set of test wells with serum (antibody) but with antigen omitted, and a set of wells with the series of antigen concentrations, but with serum omitted.
In the first instance, the revealed `background` may be due to reactivity of antibodies, other than the test antibody, with antigenic moieties in the reagents or to non-reactive serum components that are detected by the enzyme-labeled probe, second antibody. For the second set of `control` wells, those with serum omitted, the revealed `background` may be due to impurities in the antigen solution with which the probe antibody is reactive or to adventitious deposits of the enzyme-labeled probe on the well surface."
Considerable efforts have been expended to minimize the background signal in immunoassays. Present methods employed to this end include rigorous washing with surfactants (Mohammad and Esen, 1989), application of protein solutions to block non-specific adsorption sites (Pruslin et al., 1991), and careful selection of solid-phase and solution-phase antibodies (Aoyagi et al., 1991). In spite of such measures background interference remains, and complex and not entirely unambiguous calculations to compensate for same are necessary (Pruslin et al., 1991).
In order to reduce the fundamental limitation of non-specific background signal interference several reversible capture or transfer methods have been developed. These methods are all characterized by at least one transfer of analytical markers, especially the analyte itself, between two surfaces, generally for the purpose of background reduction. Lejeune et al. (1990) detected about 1.times.10.sup.-19 mol of human growth hormone in four hours using two immunoaffinity resins. Ishikawa et al. (1991) describe methods developed to "transfer the complex of analytes and labelled reactants from solid phase to solid phase without dissociation." These repetitive and labour intensive procedures permit the measurement of about 1.times.10.sup.-21 mol (about 600 molecules) of antigen in 15 to 40 hours. Nevertheless, "One of the greatest obstacles limiting the sensitivity of non-competitive solid phase enzyme immunoassays is the non-specific binding of enzyme-labelled reactants to solid phase." (ibid.) Similar reversible capture methods using the avidin-biotin interaction were recently advocated for background reduction prior to polymerase chain reaction (PCR) amplification of DNA (Yolken et al., 1991).
Direct unamplified measurement of small amounts of specific nucleic acids or oligonucleotides suffers from the same compromise between detection limit and analysis time as found with present immunochemical methods. Molecular recognition of complementary DNA strands (hybridization) was used by Syvanen et al. (1986) to detect as few as 4.times.10.sup.5 molecules of nucleic acid in 3 hours. Similarly, 6.times.10.sup.4 molecules of viral DNA were detected in 4 hours by use of an oligonucleotide (i.e. nucleotide polymer) probe coupled to enzyme (Urdea et al., 1987). Such methods suffer from interference due to high background signal when applied to crude samples (Hames and Higgins, 1985). Thus Syvanen et al. (1986) could detect no fewer than 5.times.10.sup.5 cells; and a detection limit of 2.times.10.sup.7 bacterial cells in 4.5 to 5 hours was reported by Kennedy et al. (1989). The recognized limitations of direct methods of nucleic acid detection led to the development of various DNA amplification schemes.
Enzymatic Amplification of Signal. Another method used to increase sensitivity is enzymatic amplification of the initial signal. Direct (unamplified) immunochemical analysis faces fundamental limitations due to equilibrium, kinetic and mass transport constraints. Thus, "while improvement in sensitivity and detection limit might always be made in principle by choosing an antibody-antigen pair with higher affinity, this improvement is made at the expense of an increased response time." (Eddowes, 1987/88). Although about 3.times.10.sup.-15 mol of substance per ml are detectable in less than one hour (Liabakk et al., 1990), detection of 7.times.10.sup.-17 mol of substance requires 18 hours (Aoyagi et al., 1991). The practical limit for detection of Salmonella by direct immunochemical assay was recently reported as 10.sup.3 to 10.sup.4 cells/ml in 2 to 3 hours (Luk and Lindberg, 1991).
Enzymatically amplified immunoassays employing alkaline phosphatase combined with cofactor cycling have been reported to be capable of detecting 10.sup.5 molecules during long incubation times (Bates, 1989). More recently less than 10.sup.-19 mol (about 6.times.10.sup.4 molecules) of substance have been detected in 2 hours, but ten thousand times this amount had to be present for detection within an hour (Durkee et al., 1990).
Several immunochemical detection or measurement methods employing enzymatic amplification are disclosed in the patent literature. Eur. Pat. No. 123,265 (Hall and Hargreaves, 1983) teaches that signal amplification can be achieved by covalent coupling of an analyte molecule to a zymogen such as trypsinogen. In U.S. Pat. No. 4,463,090 (Harris, 1984) signal amplification is obtained by a 3- or 4-stage enzyme cascade initiated by an enzyme or zymogen coupled to an immuno-reactive substance. This patent stipulates that it is necessary to use a different enzyme/zymogen pair at each amplification stage, thus limiting the amplification effect to a 3 or 4-stage geometric increase. In U.S. Pat. No. 4,598,042 (Self, 1981) it is disclosed that signal amplification can be achieved when the product of a primary enzyme, especially alkaline phosphatase, participates in a secondary enzyme cycle. U.S. Pat. No. 4,745,054 (Rabin et al., 1988) teaches that two inactive fragments can be combined to form an active enzyme which then activates a second enzyme leading to a detectable result. None of these enzyme cascade methods exploit the most effective type of amplification, namely an exponential increase with time.
Although heretofore not applied to amplification of enzymatic activity coupled to a substance capable of molecular recognition of an analyte, exponential amplification is well known in the biochemical literature. For example, trypsinogen (zymogen) formed in the pancreas of mammals is converted to trypsin by traces of trypsin or enteropeptidase in the intestine (Moss et al., 1987). This so-called "autocatalytic" process produces an exponential increase in the amount of enzyme (Pechere and Neurath, 1957). This principle has been used to measure low concentrations of trypsin after amplification by activation of trypsinogen (Mayer et al., 1974; Aisina et al., 1975; Kazanskaya et al., 1983).
Several strategies for ultra-sensitive detection of nucleic acids based on their exponential amplification have recently been reviewed (Kwoh and Kwoh, 1990). The polymerase chain reaction (PCR) amplification method has rapidly achieved wide acceptance in research applications in spite of its numerous limitations and disadvantages (Lizardi and Kramer, 1991). While PCR methodology has in principle a detection limit of a single oligonucleotide, it suffers from the heretofore universal problem of background interference, as well as from contamination by amplifiable DNA (Kwok and Higuchi, 1989). Furthermore the procedure requires several hours to achieve significant amplification using dedicated and sophisticated equipment. Although detection of 1 to 2 cells has been accomplished in a 5 to 7 hour period, complex manipulations are required for analysis of actual crude samples (Bej et al., 1990). Finally, since the amplification yield in each cycle varies unpredictably, PCR is not well suited for quantitative measurement of nucleic acid concentration (Lizardi and Kramer, 1991). Since PCR analyses for ribonucleic acid (RNA) simply add an initial RNA to DNA transcription step they suffer from all of the above disadvantages (Rose, 1990).
Q-beta amplification, another nucleic acid analysis method under development, has a detection limit of about 2,000 molecules of DNA, but also suffers from several disadvantages (Lizardi and Kramer, 1991). Specifically this technique requires repetitive, multi-step, mass-transfer limited operations to reduce the background signal level prior to amplification. Although amplification with Q-beta replicase is rapid, these multiple hybridization steps appear to impose a minimum analysis time of several hours. Furthermore, contamination and background interference are once again limitations: "A problem that remains to be solved in order to reach the theoretical detection limit of one molecule is the removal of the few hundred probe molecules that are carried along non-specifically with the probe-target complexes during washing, despite reversible target capture. These non-specifically bound probe molecules are also amplified, giving rise to a background signal". (ibid). Finally, as for the PCR technique, dedicated and sophisticated equipment is required.
Signal modulation or amplification is further described in Mize, U.S. Pat. No. 4,835,099, Mapes, U.S. Pat. No. 4,904,583, Schulte, U.S. Pat. No. 4,962,024, Boguslaski, U.S. Pat. No. 4,791,055, Faring, U.S. Pat. No. 4,785,080, and Perlman, U.S. Pat. No. 4,810,631.
Use of Enzyme Inhibitors in Affinity Binding Assays. Enzyme inhibitors have been used as binding reagents (see March, U.S. Pat. No. 4,430,264; Gattaz, U.S. Pat. No. 5,006,462; Newman, U.S. Pat. No. 5,057,430) and as labels (Kasahara, U.S. Pat. No. 4,582,792 and U.S. Pat. No. 4,649,105; Taguchi, U.S. Pat. No. 5,035,995; Bloch, U.S. Pat. No. 4,789,630; Hakomori, U.S. Pat. No. 4,904,596; Matsuura, U.S. Pat. No. 4,894,326; Skov, U.S. Pat. No. 4,869,875; Navinski, U.S. Pat. No. 4,843,010; Maggio, U.S. Pat. No. 4,828,981; Stavrianopoulos, U.S. Pat. No. 4,772,548). See also Bauma, U.S. Pat. No. 5,006,473. Several patents teach use of an enzyme inhibitor to selectively inhibit the activity of an enzyme label. See Ito, U.S. Pat. No. 4,966,856 and 4,868,106; Leeder, U.S. Pat. No. 4,837,395; Gedden, U.S. Pat. No. 4,810,635; Ullman, U.S. Pat. No. 4,913,983; Yoshida, U.S. Pat. No. 4,341,866.
Yoshida, U.S. Pat. No. 4,208,479 teaches an immunoassay which involves bringing together an analyte and a labeled receptor so as to form a complex which sterically inhibits the approach of a macromolecular modifier, which otherwise would physically or chemically interact with the label to reduce its signal production. Where the label was an enzyme the disclosed modifiers were principally anti-(enzyme) antibodies and certain small, organic, irreversible inhibitors. For example, for serine proteases, the preferred inhibitor was physostigmine. Similar inhibitor systems were set forth for use with fluorescent labels. The teachings of Yoshida, U.S. Pat. No. 4,233,401 and Yoshida, U.S. Pat. No. 4,341,866 are similar.
Louderback, U.S. Pat. No. 4,668,0630, teaches use of a reversible inhibitor to protect an enzyme (lactate hydrogenase).
Alpha2-Macroglobulin. Assays for alpha2-macroglobulin have been described, see Siddiqui, U.S. Pat. No. 4,607,010, but A2M has not previously seen service as a signal modulator in a binding assay. A2M is also mentioned in Silvestrini, U.S. Pat. No. 5,047,509; Lorier, U.S. Pat. No. 5,013,568; Harpel, U.S. Pat. No. 4,629,694; Teodorescu, U.S. Pat. No. 4,499,186; and Schrenk, U.S. Pat. No. 4,414,332 and U.S. Pat. No. 4,393,139.

Use of macroglobulins to improve the signal-to-background ratio in affinity binding assays