A III-nitride power device for controlling high currents as an interdigitated electrode pattern for increasing device rating while decreasing device dimensions. Fingers of the interdigitated electrode pattern have tips with smaller dimensions than the remainder of the fingers. The tapered finger design balances current flow in the electrode fingers to reduce device resistance while permitting a more compact construction.

1. Field of the Invention
The present invention relates generally to a class of field effect transistors based on III-nitride materials, and relates more particularly to a field effect transistor layout geometry for carrying high current.
2. Description of Related Art
Column III-nitride alloy used in semiconductors, including AlN, GaN and InN may be used to produced devices that exhibit large dielectric breakdown fields, and are capable of high power, high frequency switching. A typical application for III-nitride semiconductors is in the construction of emitters for cell phone base stations. III-nitride semiconductors have a large dielectric breakdown field of greater than 2.2 MV/cm, while providing high mobility for carriers, making them excellent for power applications.
The device is fabricated for the high power applications where III-nitride materials are advantageous, have a high electron mobility and are referred to variously as heterojunction field effect transistors (HFETs), high electron mobility transistors (HEMTs) or modulation doped field effect transistors (MODFETs). These types of devices are typically able to withstand high voltages such as in the range of 100 Volts, while operating at high frequencies, typically in the range of 2-100 GHz. These types of devices may be modified for a number of types of applications, but typically operate through the use of piezoelectric polarization fields to generate a two dimensional electron gas (2DEG) that allows transport of very high current densities with very low resistive losses. The 2DEG is formed, for example, at an interface of AlGaN and GaN materials in these conventional III-nitride HEMT devices.
The formation of a high electron mobility channel in III-nitride semiconductor materials permits devices to be constructed that are capable of operating well in high current applications. This feature of III-nitride semiconductor devices results in an improvement by a factor of ten in the resistance area product (RA) when compared to state of the art silicon based devices. The switching speed of these devices is also many times higher than that of conventional silicon devices, while switching losses are much lower. These attributes all contribute to permitting the construction of high frequency, low loss devices for high current applications.
Previously, III-nitride semiconductor devices fabricated for high voltage, high frequency applications have often been formed as planar devices with ohmic contacts located on either side of a gate contact that controls the conduction channel between the two ohmic contacts. This type of planar structure is illustrated in FIG. 1 in device 10. Device 10 is a simple MISFET constructed using III-nitride materials. Device 10 includes a body layer 15, overlaid by a barrier layer 17, both of which are composed of III-nitride materials. Layer 17 has an in-plane lattice constant that is lower than that of layer 15, which contributes to producing interface strain and high electron mobility 2DEG 13. A source 12 and a drain 14 are coupled to barrier layer 17 through low resistance ohmic contacts 18, to form current carrying electrodes for device 10. A gate 16 is positioned between source 12 and drain 14, and is separated from layer 17 by a dielectric layer 11. The application of an electric potential to gate 16 interrupts the conduction channel formed by 2DEG 13, to prevent current conduction between source 12 and drain 14. Device 10 is accordingly a depletion mode, or nominally on device. Exemplary constructs of device 10 provide for body layer 15 to be composed of GaN, while area layer 17 is composed of AlGaN. Source 12 and drain 14 offer the same functionality, and may be interchangeable, or simply referred to as ohmic contacts. Gate 16 is formed as an electrode and is composed of a conductor, such as metal or conductive semiconductor material.
Device 10 illustrates a III-nitride semiconductor structure that is capable of switching high voltages dependent upon the thickness of dielectric layer 11, and the separation of gate 16 from either of source 12 or drain 14. A MISFET constructed according to the structure of device 10 may carry up to approximately 1 A/MM per unit of gate length on the device. These types of devices have been used successfully in low current, high power, high frequency applications. For high current applications, such as applications that may control ten or more amps of current, the structure of device 10 is impractical due to the dimensional requirements of a device in such an application. For example, if device 10 were constructed for use with an application in which ten or more amps of current were switched and controlled, device 10 would have dimensions of approximately 10 microns by 10 mm, which would not be practically suitable for use in real world applications. Accordingly, it would be desirable to produce an HFET device such as a MISFET that is capable of controlling ten or more amps of current, while meeting the dimensional needs of real world applications.
Designs to overcome the above drawbacks have been previously presented in silicon devices, where the resultant device is much more compact and is manufactured and handled with greater ease for real world applications. A plan view of a high current MISFET device 20 is illustrated in FIG. 2. Device 20 has interdigitated portions of a drain electrode 22 and a source electrode 24 extending between an alternating with each other. A gate electrode 26 is formed in a serpentine shape between interdigitated drain portions 23 and interdigitated source portions 25. Gate electrode 26 is separated from drain and source electrodes 22, 24 with a dielectric 21. Device 20 may be a smaller segment of a larger device, where power connections are made to device 20 along runners 22A and 24A to contact drain and source electrodes 22, 24, respectively. A number of devices 20 may be ganged together to obtain a desired current rating, while individual devices 20 are constructed to have desired maximum voltage ratings.
Device 20 provides a more symmetrical design widely used in presently fabricated current control devices. However, when a III-nitride semiconductor device is constructed according to the configuration of device 20, the higher current applications for which such a device is used introduce additional problems in the operation of such a device. Due to the large amounts of current passed between drain and source electrodes 22, 24, under gate electrode 26, the resistance of the material used to construct electrodes 22, 24 increases in significance with respect to overall operation of device 20. Accordingly, current flowing through runners 22A, 24A tends to diminish towards the tips of finger portions 23, 25, due to the resistance of the material used to make finger portions 23, 25. More current flows in finger portions 23, 25 closer to runners 22A, 24A, respectively than at the tips of finger portions 23, 25. This variation in current flow due to the resistance of finger portions 23, 25 results in a power loss related to the length of finger portions 23, 25. Accordingly, it would be desirable to produce a design for a MISFET structure using III-nitride semiconductor material that has a lower on resistance, with improved resistance-area product (RA).
A drawback of III-nitride HEMT devices that permit high current densities with low resistive losses is the limited thickness that can be achieved in the strained AlGaN/GaN system. The difference in the lattice structures of these types of materials produces a strain that can result in dislocation of films grown to produce the different layers. This results in high levels of leakage through a barrier layer, for example. Some previous designs have focused on reducing the in-plane lattice constant of the AlGaN layer to near where the point of relaxation occurs to reduce the dislocation generation and leakage. However, the problem of limited thickness is not addressed by these designs.
Another solution is to add insulation layers to prevent leakage problems. The addition of an insulator layer can reduce the leakage through the barrier, and typical layers used for this purpose are silicon oxide, silicon nitride, sapphire, or other insulators, disposed between the AlGaN and metal gate layers. This type of device is often referred to as a MISHFET and has some advantages over the traditional devices that do not have an insulator layer.
While additional insulator layers can permit thicker strained AlGaN/GaN systems to be constructed, the confinement layer produced by the additional insulator results in lower current carrying capacity due to the scattering effect produced on electrons at the GaN/insulator interface. Also, the additional interface between the AlGaN layer and the insulator results in the production of interface trap states that slow the response of the device. The additional thickness of the oxide, plus the additional interfaces between the two layers, also results in the use of larger gate drive voltages to switch the device.
Conventional device designs using nitride material to obtain nominally off devices rely on this additional insulator to act as a confinement layer, and may reduce or eliminate the top AlGaN layer. These devices, however, typically have lower current carrying capacity due to scattering at the GaN/insulator interface.
Accordingly, it would be desirable to produce a nominally off HEMT switching device or FET that has a low leakage characteristic with fewer interfaces and layers that can still withstand high voltage and produce high current densities with low resistive losses. Presently, planar devices have been fabricated with GaN and AlGaN alloys through a number of techniques, including MOCVD (metal organic chemical vapor deposition) as well as molecular beam epitaxy (MBE) and hydride vapor phase epitaxy (HVPE).
Materials in the gallium nitride material system may include gallium nitride (GaN) and its alloys such as aluminum gallium nitride (AlGaN), indium gallium nitride (InGaN) and indium aluminum gallium nitride (InAlGaN). These materials are semiconductor compounds that have a relatively wide direct bandgap that permits highly energetic electronic transitions to occur. Gallium nitride materials have been formed on a number of different substrates including silicon carbide (SiC), sapphire and silicon. Silicon substrates are readily available and relatively inexpensive, and silicon processing technology has been well developed.

III-nitride device with improved layout geometry


A fiber optic splice enclosure for housing an interconnection contained in a splice tray between at least one optical fiber of a feeder cable and at least one optical fiber of a drop cable is provided. The optical fiber of the feeder cable is at least partially contained in a feeder cable buffer or transportation tube. The fiber optic splice enclosure includes a support frame arranged in the enclosure. The support frame includes a central office side and a drop side. A basket is arranged on the support frame for storing slack of a spliced buffer tube transitioning to the splice tray. The spliced storage arrangement is sized so as to be able to store slack of the spliced feeder cable buffer tube while maintaining a predetermined tube bend radius. A splice tray mounting arrangement is arranged on the drop side of the support frame for supporting the splice tray.

There is an ever-increasing demand for high-speed or high-bandwidth communication channels for delivering high-speed data and video services. To meet this demand, telecommunications service providers are developing networks (sometimes referred to as outside plant networks) that extend the higher bandwidth of fiber optic components all the way to the end-user businesses and homes (referred to as premises). In such networks, there are distribution points where a distribution, feeder or branch cable is interconnected with one or more drop cables that are routed to the premises. At such distribution points, the side coming from the service provider is generally referred to as the central office or CO side while the side leading to the premises is generally referred to as the drop side. A distribution, branch or feeder cable typically includes a sheath surrounding a plurality of buffer tubes with each buffer tube housing a plurality of optical fibers.
Enclosures are used to house fiber optic cable interconnections and splices and certain fiber optic components (e.g., splitters and couplers) at various locations in a fiber optic network. Existing fiber optic enclosures, however, are not well suited for use at distribution points close to the end-user premises. Technicians will have to access the interior of the enclosures at such distribution points on a fairly regular basis to add new splices for the premises of additional subscribers or to disconnect service to subscribers canceling service. Vault-type enclosures that are buried in the ground are one type of enclosure commonly used in fiber optic networks. Such vaults are thought to be necessary to protect the integrity of the optical fibers and splices. However, to gain access to the splices in the vault, a bulky lid with multiple bolts must be removed and a sealed splice case, also with multiple fasteners and cable sealing provisions, removed from the interior of the vault. As a result, accessing and servicing such vaults is time-consuming, and thus expensive, making them unsuitable for use at distribution points close to premises that will have to be accessed by technicians on a regular basis.
In addition, performing splicing operations in the field can also be very awkward when working with buried vault enclosures. In particular, when the sealed splice case is removed, lengthy slack fiber loops must also be removed from the vault so that the splice case can reach a clean area where the splicing can be performed. Once the splice case is situated in the clean splicing area, actually gaining access to the splices can sometimes involve the removal of over a dozen threaded fasteners. Once the splicing operation is completed, these steps must be performed in reverse order to replace the splice case back in the vault. Failure to properly reseal the cable openings and tighten the fasteners often results in water leakage into the splice case that may cause undesirable optical signal degradation.
The routing and management of the fiber optic cables in such vaults can also lead to problems. For example, with such vaults, there is a significant risk that a technician will disrupt the unopened buffer tubes (known as "express buffer tubes") that extend in an uninterrupted manner through the vault in the course of performing the splicing operation. Obviously, this issue is of particular significance when the vault is being used at a distribution point to premises that will have to be accessed frequently for field splicing operations. The cable routing and management in such vaults can also be quite complicated further increasing the potential for errors by technicians performing work on the equipment in the vault.
Other types of enclosures used in fiber optic networks have similar issues and drawbacks. For instance, despite being installed above-ground, accessing the interior of many pedestal-type enclosures can be quite awkward. Removal and replacement of the cover on the pedestal is a particular problem. Moreover, many pedestal enclosures have complicated cable management systems. These enclosures are also relatively inflexible in their set-up making them difficult or impossible to optimize for the needs of a specific application.


The present invention provides a nucleic acid analyzing apparatus which achieves highly accurate analytical ability even in single molecule DNA analysis. The nucleic acid analyzing apparatus detects locations of fluorescent bright spots in image information about light emission, deletes defective bright spots, and thereby creates intensity trace data about proper bright spots.

1. Field of the Invention
The present invention relates to a nucleic acid analyzing apparatus and, more particularly, to a nucleic acid analyzing apparatus such as a genetic tester/analyzer which observes fluorescence produced, for example, on a reaction device for single molecule DNA analysis and conducts analysis based on luminance of fluorescent bright spots.
2. Background Art
Regarding a typical nucleic acid analyzing method, Non-Patent Document 1 proposes a method which traps, molecule by molecule, a DNA test piece to be analyzed, on a DNA probe formed on a substrate surface, elongates bases one at a time, detects the bases using fluorometry, and thereby determines a base sequence.
Available analytical methods for reaction devices include a microarray analysis method which uses a semiconductor chip. The method has been used in the field of gene expression analysis. To detect a targeted gene polymorphism known as an SNP, the method hybridizes a target with a reaction spot to which a probe has been adsorbed in advance. Expression of the gene polymorphism can be optically detected if DNA to be linked is marked with fluorescent molecules.
The conventional microarray analysis method and the like shoot images of fluorescent bright spots produced in a specimen and perform gene analysis using resulting image information. Image shooting and image processing are indispensable to the present field and are important processes which govern reliability of specimen analysis results.
In particular, in the field or the like of multiple molecule fluorescent DNA detection by a microarray analysis method which uses a semiconductor chip, using a CCD or the like which is a two-dimensional imaging element as an optical detection element, reaction spots on a DNA chip can be associated easily with pixels in an output image by bringing the reaction spots on a DNA chip into one-to-one correspondence with CCD pixels or by using a reduction/binning function of a CCD camera. Consequently, in the field of conventional gene analysis apparatus, images and other data acquired by an imaging element can be used without preprocessing.
For example, Patent Document 4 proposes a method for performing fluorescent detection using a small number of pixels by placing image magnification of a focusing/image-forming optical system and a pixel pitch of a two-dimensional sensor in a predetermined relationship when reaction devices are arranged at equal intervals.    [Patent Document 1] JP Patent Publication (Kokai) No. 2006-337245 A    [Patent Document 2] JP Patent Publication (Kokai) No. 2007-10325 A    [Patent Document 3] JP Patent Publication (Kokai) No. 2004-101376 A    [Patent Document 4] JP Patent Publication (Kokai) No. 2007-322185 A    [Non-Patent Document 1] P.N.A.S. 2003, Vol. 100, pp. 3960-3964    [Non-Patent Document 2] Physical Review Letters 2006, 96, pp. 113002-113005    [Non-Patent Document 3] Anal. Chem. vol. 78, 6238-6245    [Non-Patent Document 4] Nanotechnology, 2007, vol. 18, pp. 044017-044021    [Non-Patent Document 5] J. Comput. Theor. Nanosci. 2007, vol. 4, pp. 686-691    [Non-Patent Document 6] Nanotechnology, 2006 vol. 17, pp. 475-482    [Non-Patent Document 7] P.N.A.S. 2006, Vol. 103, pp. 19635-19640


A trajectory for a vehicle can be generated using a lateral offset bias. The vehicle, such as an autonomous vehicle (AV), may be directed to follow reference trajectory for through an environment. The AV may determine a segment associated with the reference trajectory based on curvatures of the reference trajectory, determine a lateral offset bias associated with the segment based at least in part on, for example, one or more of a speed or acceleration of the vehicle, and determine a candidate trajectory for the autonomous vehicle based at least in part on the lateral offset bias. The candidate trajectory may then be used to control the autonomous vehicle.

Various methods, apparatuses, and systems are utilized by autonomous vehicles to guide such autonomous vehicles through environments including various static and dynamic objects. For instance, autonomous vehicles may utilize route planning methods, apparatuses, and systems to guide autonomous vehicles through congested areas with other moving vehicles (autonomous or otherwise), moving people, stationary buildings, etc. In some examples, a vehicle may not follow an intended route which may lead to inaccurate or imprecise vehicle handling.

Trajectory generation using lateral offset biasing


A variable rate transmission method that can vary the transmission rate of data. A transmitting side supplies a transmitted data sequence to an error detecting encoder 105 and a frame memory 103. The frame memory 103 stores data of a variable length to be transmitted in one frame. The error detecting encoder 105 calculates an error detecting code (such as CRC code) for each frame of the transmitted data. A multiplexer 104 adds the calculated error detecting code ahead of the transmitted data to place it at the initial position of the frame, and sequentially outputs the data sequence frame by frame. A receiving side calculates an error detecting code of the data in each transmitted frame in the same manner as the transmitting side, and compares the calculated error detecting code with the error detecting code at the initial position of the frame. The end bit of the frame data is decided as a position at which the two error detecting codes coincide. This makes it possible to transmit variable length data without informing the receiving side of the data length in each frame. This is equivalent that the transmission rate can be varied freely.

In CDMA mobile communications, the output data (transmitted data) from a voice codec undergoes primary modulation, followed by secondary modulation using a pseudorandom sequence (spreading code sequence), to be spectrum-spread to a wideband signal and transmitted. The bit rate of the spreading code sequence is called a chip rate, and is tens to hundreds of times faster than the transmission rate. Generally, the primary modulation uses binary or quadrature phase shift keying, and the secondary modulation uses binary phase shift keying.
Considering voice communications, the information amount of a transmitted voice signal is not constant, but varies from time to time. Accordingly, the transmission rate can be changed by dividing the transmitted data into frames of a fixed duration, and by transmitting data of a variable bit length in each frame, thereby achieving effective transmission of information in each frame period. This can obviate useless transmission, thereby saving power consumption of the transmitter.
The following method is taken to transmit data of a different transmission rate in the CDMA system. First, data whose transmission rate is lower than the frame transmission rate is transmitted using a part of transmission frames (see, for example, R. Padovani, "Reverse link performance of IS-95 based cellular systems", IEEE Personal Communications, vol.1, pp.28-34, 3rd Quarter 1994). On the other hand, data whose transmission rate is higher than the frame transmission rate is divided into a plurality of transmission channels, and the divided data are spread using different spreading codes to be transmitted.
It is necessary in this method, however, to provide a receiving side with the transmission rate information. Alternatively, when the transmission rate information is not provided, it is necessary to predetermine the values the transmission rate can take, to carry out the error detection of the received data for all the transmission rates, and to output the received data with the transmission rate at which the error is not detected as the right data.
In this case, if an error occurs during the transmission of the transmission rate information, the effective length in the received frames cannot be decided, which makes it difficult to correctly recover the transmitted data at the receiving side even if no error has occurred during the data transmission.
Thus, it is difficult for the conventional data transmission method to vary the transmission rate during the communications to achieve a variable rate transmission. In addition, when the data is transmitted at a rate considerably lower than a maximum transmission rate, burst transmission occurs because of blanks in the frames, during which data transmission is not carried out. Such burst-like transmission presents a problem in that it causes an EMI (Electromagnetic Interference).
FEC (Forward Error Correction) of the transmitted data is generally used to improve the transmission quality in the case where many errors can occur during transmission as in a mobile communications environment. In this case, the transmitting side transmits transmitted data (including the transmission rate information) which has undergone error correcting encoding, and the receiving side carries out the error correcting decoding followed by extraction of the transmission rate information to decide the effective data length in each received frame. Accordingly, the transmission rate information cannot be obtained until the end of the error correcting decoding. Thus, the decoding is performed before deciding the data length to be decoded, and hence the error correction cannot fully achieve its effect.
On the other hand, there are some data in the transmitted data that can greatly degrade the received data quality when they are corrupted. For example, control data requires transmission quality higher than voice data. Also, the voice data includes some which can greatly degrade the quality and others which cannot, depending on the voice encoding method. In other words, the transmitted data includes data of various degrees of importance.
In view of this, a transmission method is adopted in TDMA (Time Division Multiple Access), which uses error correcting codes of different correcting power in accordance with the degree of importance of the transmitted data (see, for example, "Personal digital cellular telecommunication system RCR standard, RCR STD-27", Research & Development Center for Radio System). This method, however, lacks flexibility to transmit various data of different transmission rates.
As described above, high speed data is divided and spread to a plurality of signals using different spreading codes, and the spread signals are combined to be transmitted. To demodulate such signals at a receiving side using coherent detection, the transmitting side must periodically inserts pilot symbols into transmitted data (see, for example, S. Sampei, "Fading Compensation for 16QAM in Land Mobile Communications", The Transactions of the Institute of Electronics, Information and Communication Engineers of Japan B-II, Vol. J72-B-II pp. 7-15, January 1989, or its revised version, S. Sampei, et al. "Rayleigh Fading Compensation for QAM in Land Mobile Radio Communications", IEEE Transactions on Vehicular Technology, VOL. 42. No. 2, MAY 1993). This method will make it necessary for the plurality of transmission channels to send the same pilot symbols when the method is applied to the signals spread with the plurality of the spreading codes. The respective channels, however, experience the same fading, and hence it is unnecessary to send the pilot symbols through the plurality of channels. Since multiple users share the same frequency band in CDMA, transmission of superfluous signals will reduce the number of users that can be accommodated in a limited frequency band because it will increase interference to other users by an amount corresponding to the transmission power necessary to send the superfluous signals.
Furthermore, the high speed signal must be divided into a plurality of signals followed by spreading using different spreading codes and by combining of the spread signals, and the combined signal is converted into a radio frequency band followed by power amplification to be transmitted. If the plurality of spread signals are combined in the same phase, the amplitude of the combined signal will increase in proportion to the number of divided signals. This will require a high peak power liner transmission power amplifier. Such a power amplifier demanding large power consumption is unsuitable to portable telephones which require low power consumption.

Variable rate transmission method, transmitter and receiver using the same


Systems and methods for providing product samples to users in autonomous vehicles, thereby allowing businesses to advertise their products via the rideshare platform. A physical advertising platform is provided leveraging existing rideshare and delivery infrastructure to allow businesses to advertise their products by providing samples in rideshare vehicles and/or with rideshare vehicle deliveries. Consumers have the opportunity to try new products from local businesses that they may otherwise not be exposed to. In some implementations, a rideshare application interface can allow users to see what new local product samples are available. In some examples, a user can select one or more product samples to try.

Autonomous vehicles, also known as self-driving cars, driverless vehicles, and robotic vehicles, are vehicles that use multiple sensors to sense the environment and move without human input. Automation technology in the autonomous vehicles enables the vehicles to drive on roadways and to accurately and quickly perceive the vehicle's environment, including obstacles, signs, and traffic lights. The vehicles can be used to pick up passengers and drive the passengers to selected destinations. The vehicles can also be used to pick up packages and/or other goods and deliver the packages and/or goods to selected destinations.
While passengers are riding in autonomous vehicles, targeted ads can be played and/or displayed. However, for most products, digital screen-based and audio platforms offer a limited glimpse into the actual product. It can be difficult for businesses to convey their product experience on these platforms.


An emergency aid is provided along with a recovery method incorporating same for use by a person who has fallen through the surface of a frozen body of water. The aid includes a pair of support elements that each have a hand grip. Each support element includes at least one tooth for limiting lateral movement of the element relative to the ice surface. The support elements are releasably connected together along a common axis. In first and second embodiments of the invention, a bore is defined in at least one of the hand grips for receiving a corresponding portion of the other hand grip. In a third embodiment of the invention a collar surrounds both hand grips. The recovery method comprises the steps of accessing the emergency aid, disconnecting the support elements, thrusting the teeth of the support elements into the ice surface, and pulling upon the hand grips to move oneself onto the ice surface.

Every year a number of people are killed by falling through the surface of a frozen body of water and drowning in the freezing waters below. These tragedies most frequently occur to snowmobilers, skaters, skiers, ice fisherman, and pedestrians crossing the ice surface. Often the victims are unable to pull themselves from the water onto the ice surface because the ice surface lacks any rigid protrusions that may be gripped.
There is a need for an aid that may be carried by persons who are travelling along an ice surface. The aid would provide means for gripping the ice surface to assist a person in pulling themselves onto the ice surface. The aid would be convenient and safe to carry and would be simple to access when a person has fallen through the ice.

Ice emergency aid and recovery method incorporating same


An antifouling article including a base material, a diamond-like carbon layer and an antifouling coating layer formed of a surface-treating agent on the diamond-like carbon layer. The surface-treating agent includes a group having a carbon-carbon unsaturated bond, a group having a carbon-nitrogen unsaturated bond, or a leaving group.

A certain fluorine-containing compound is known to be able to provide excellent water-repellency, oil-repellency and antifouling property, when it is used in a surface treatment of a base material. A layer obtained from a surface-treating agent containing a fluorine-containing compound (also referred to as a "surface-treating layer" hereinafter) is applied to various base materials such as glasses, plastics, fibers and building materials, as a so-called functional thin coating.
Known as such a fluorine-containing compound is a perfluoropolyether group-containing silane compound having a perfluoropolyether group in a molecular backbone and having a hydrolyzable group bonded to a Si atom at the molecular terminal or the terminal portion (see Patent Literatures 1 and 2). When a surface-treating agent containing this perfluoropolyether group-containing silane compound is applied to a base material, the hydrolyzable group bonded to a Si atom reacts with a Si—OH group of the base material and the hydrolyzable groups react with each other between the molecules of the compound to form a —Si—O—Si— bond, thereby obtaining a surface-treating layer.
Known as another fluorine-containing compound is a compound having a perfluoropolyether group or a perfluoroalkylene group in a molecular backbone and further containing —OH, —SH, —NR112 (R11 is a hydrogen atom or a lower alkyl group) or the like at the molecular terminal (Patent Literature 3). Patent Literature 3 discloses that such a fluorine-containing compound as above is used to form a surface-treating layer on a surface of a base material following diamond-like carbon.


A core destroying machine utilizes a single processing rotor cooperable with an arcuate screen member to disintegrate aeration cores therebetween. The arcuate screen member is configured to discharge thatch from the single processing rotor in a generally vertical direction into engagement with a rotating fluff roll. The fluff roll is configured with a pair of opposing rigid bats affixed to a central shaft for rotation around an axis of rotation. A plurality of extruded flexible plastic cords extend from the rigid bats into the direction of rotation of the fluff roll to engage the thatch portions discharged from the processing rotor and urge the thatch portions rearwardly into a collection hopper. The flexible plastic cords yield to any earthen pieces of aeration cores that might be discharged from the processing rotor to permit the discharged earthen pieces to be recycled back toward the processing rotor. The processing rotor can be driven in opposing directions to enable the core destroying machine to be operated in a core collection mode. The fluff roll is operable to direct the intact aeration cores passing over the top of the processing rotor rearwardly into the collection hopper.

This invention relates generally to a machine for receiving green or dry cores from a turf aeration machine that removes plugs or cores of earth from the ground, such as is done on golf courses to enhance the growth of the grasses, and removing the earth from the vegetation thatch. This invention relates more specifically to an apparatus that utilizes a rotating scrubbing action to reduce the cores to the vegetation thatch and return the earth to the ground, while collecting the remaining vegetation thatch.
Aeration machines are well known in the art. These machine drive a hollow tine into the ground to create a plug of earth that is lifted above the surface of the ground and deposited on the surface. Generally, green cores, i.e. cores of earth freshly elevated from the moist ground, have to be dried for 2 to 4 hours, depending on the weather conditions, before the earthen portion can be removed from the vegetation thatch on top of the plug and the associated root system. It is preferable to return the earthen portion of the cores to the ground; however, the organic matter needs to be removed from the aerated site. Alternatively, the cores can be removed from the aerated site and taken to a remote location for subsequent handling.
While the task of aerating is a highly labor intensive job, the cost of clean-up after aeration is as great as aeration itself. Known core processing machines, such as found in U.S. Pat. No. 1,368,113 and in U.S. Pat. No. 3,410,350, suffer from a substantial problem of plugging, particularly if the cores are not adequately dried before collecting and processing. If the cores are not dried adequately, the moist earthen portion from the cores plug the core processing machines. Under some conditions, the cores can be dried too much and the earth cannot be broken-up properly for satisfactory disposal thereof.
Using golf courses as an exemplary environment typically utilizing aeration to improve the quality of the turf on which the players play, it is undesirable to hinder play for the aeration process. Golf courses and their members do not want their pastime interrupted by maintenance crews and, as a result, the aeration is intentionally done in as short a time as possible. The cores can be picked-up and removed from the ground and taken to a remote location, but this process is very labor intensive and requires the transportation of the green cores from the course. Even cores temporarily left on the ground immediately following the aeration process can be run over by the aeration machine on its next pass, creating problems with a clean pick-up of the cores. Preferably, the cores are not left on the ground for an indeterminate period, even in areas not highly frequented, as mowing becomes complicated due to the cores plugging the mowers and prematurely dulling mower blades.
Current core destroying technology involves the utilization of a machine commonly referred to as a xe2x80x9cverti-cutterxe2x80x9d. This machine is provided with a series of vertically oriented blades that are passed over the surface of the ground to slice cores into finer particles. If the cores are still wet, also know as being xe2x80x9cgreenxe2x80x9d, the verti-cutter can become plugged or wrapped with the vegetation thatch, associated root system and moist earth that is separated from the rest of the core and carried around the vertical blades.
Other known core destroying machines use a cylindrical rotating screen to separate the earth from the organic matter. Such machines require extensive screening area and become quite cumbersome in both handling and operation. Furthermore, the longitudinally extending rotary screen requires a consolidation of the swath of cores into a transversely smaller area, resulting in a dense collection of cores to be destroyed and a concentrated distribution of earth discharged back to the ground. Also, machines using a rotary screen are difficult to couple to an aeration machine so as to receive green cores directly therefrom.
A rotary aeration core processing machine, such as depicted and described in U.S. Pat. No. 6,142,239, entitled xe2x80x9cCore Guide Apparatus for Aeration Core Harvesting Machinexe2x80x9d and granted to Kenneth R. Underhill on Nov. 7, 2000, can be configured with a single processing rotor or paddle assembly, which will provide an adequate destruction of the aeration cores, or alternatively pass the aeration cores over the top of the paddle assembly to be collected in a hopper positioned rearwardly of the processing rotor. To provide sufficient screen contact with the single processing rotor, the thatch portion of the aeration cores remaining after the earthen portion has been disintegrated and passed through the holes in the screen, was found to be too light to move rearwardly into the collection hopper. Accordingly, it would be desirable to provide an apparatus to cause the thatch portion to move rearwardly after being discharged from the single processing rotor, without interfering with the collection of the intact aeration cores when passing over top of the single processing rotor when placed into a core collection mode of operation.
It is an object of this invention to provide a core destroying machine operable to disintegrate wet or dry aeration cores with a single processing rotor while effecting a rearward transfer of the thatch portion after being discharged from the single processing rotor.
It is another object of this invention to provide a rotatable fluff roll positioned above the single processing rotor to engage thatch discharged from the single processing rotor and cause the thatch to move rearwardly into a collection hopper.
It is an advantage of this invention that the organic thatch material of the aeration cores is swept rearwardly by the fluff roll into a collection vessel.
It is still another object of this invention to provide a fluff roll construction that will not interfere with the passage of aeration cores into the collection hopper when the machine is being operated in a core collection mode.
It is a feature of this invention that the fluff roll is formed with extruded flexible plastic cords that are operable to engage pieces of thatch to propel them rearwardly into the collection hopper.
It is another advantage of this invention that the extruded flexible plastic cords will yield to any earthen pieces of aeration cores discharged from the single processing roll to allow the earthen pieces to be re-cycled back to the processing rotor.
It is yet another object of this invention to provide a core destroying machine that is operable to destroy green aeration cores while utilizing a single rotary processing rotor.
It is still another feature of this invention that the paddle members of the processing rotor are formed as a rigid panel attached to a central rotor shaft for rotation therewith.
It is a yet another advantage of this invention that the paddle members are mounted to cooperate with screen mounted fins to help disintegrate aeration cores received from the core collection mechanism.
It is a further advantage of this invention that the operation of the core destroying machine is simple and efficient to enhance the effectiveness of the core destroying machine.
It is still a further feature of this machine that the comb member is also cooperable with the brush core pick-up mechanism to prevent the cores from being recirculated with the brush mechanism, thereby moving the aeration cores into engagement with the paddle members of the processing rotor.
It is still another feature of this invention that the core destroying machine reduces labor, minimizes compaction on the ground, enhances thatch decomposition, destroys both wet or dry cores, and provides flexibility for use at night as well as during the daylight hours.
It is still a further advantage of this invention that labor costs are reduced because of the reduced need for handling the wet aeration cores discharged from the aerator and because the aeration cores are handled faster.
It is yet a further advantage of this invention that the combined operation of an aerator and an attached core destroyer results in less traffic over the ground and, therefore, less compaction of the aerated ground surface.
It is still another object of this invention to provide a drive mechanism for a core destroying machine that is operable to convert the machine into a core collecting machine that merely collects the cores in a receptacle instead of destroying them.
It is yet a further feature of this invention that the single core destroying machine can be used selectively as a core destroying and a core collecting machine.
It is yet a further advantage of this machine that the drive mechanism can be changed to convert the machine between core destroying and core collecting modes by simply re-orienting a drive belt entrained around drive members for the rotary beaters.
It is still another feature of this invention that the fluff roll is driven in the same rotation direction whether the machine is in a core destroying mode of operation or a core collecting mode of operation.
It is yet another object of this invention to provide a core destroying machine that is operable to disintegrate wet or dry aeration cores and which is durable in construction, inexpensive of manufacture, carefree of maintenance, facile in assemblage, and simple and effective in use.
These and other objects, features and advantages are accomplished according to the instant invention by providing a core destroying machine utilizing a single processing rotor cooperable with an arcuate screen member to disintegrate aeration cores therebetween. The arcuate screen member is configured to discharge thatch from the single processing rotor in a generally vertical direction into engagement with a rotating fluff roll. The fluff roll is configured with a pair of opposing rigid bats affixed to a central shaft for rotation around an axis of rotation. A plurality of extruded flexible plastic cords extend from the rigid bats into the direction of rotation of the fluff roll to engage the thatch portions discharged from the processing rotor and urge the thatch portions rearwardly into a collection hopper. The flexible plastic cords yield to any earthen pieces of aeration cores that might be discharged from the processing rotor to permit the discharged earthen pieces to be re-cycled back toward the processing rotor. The processing rotor can be driven in opposing directions to enable the core destroying machine to be operated in a core collection mode. The fluff roll is operable to direct the intact aeration cores passing over the top of the processing rotor rearwardly into the collection hopper.

Fluff roll for aeration core processing machine


A wired circuit board is provided having enhanced reliability of electrical connection between a metal substrate and a shield layer to achieve significant noise reduction reliably. An insulating base layer is formed on the metal substrate, while resin layers are formed on the metal substrate with a predetermined space provided from the both widthwise sides of the insulating base layer. A conductor layer is formed having a predetermined wired circuit pattern on the insulating base layer. Thereafter, an insulating cover layer is formed on the insulating base layer in such a manner as to cover the conductor layer. Then, a shield layer is laminated on the metal substrate to cover the insulating cover layer and also is put in close contact with the resin layers at end portions thereof by a vacuum film-forming method or by plating.

1. Field of the Invention
The present invention relates to a wired circuit board and, more particularly, to a flexible wired circuit board with a metal substrate having a shield layer formed thereon.
2. Description of the Prior Art
Along with an increasing demand for size reduction and high integration of an electric device or an electronic device in recent years, required qualities for a flexible wired circuit board with a metal substrate, such as, for example, finer pattern of the wired circuit and higher thickness precision constituent material, are increasingly becoming severe.
The finer the wired circuit pattern becomes, the higher and weaker the signal frequency becomes particularly in a suspension board with circuit to be mounted on a hard disk drive, so that influence of noise on the signal is increasingly becoming noticeable.
For reduction of noise, proposals have been made such as, for example, arranging a ground wire in the vicinity of the wiring pattern, or widening space between wires of the wiring pattern. However, these proposals are not sufficient for the noise reduction required in these days.
Accordingly, a further proposal has been made for covering an insulating cover layer that covers the wiring with a conductive shield layer in order to achieve the currently required significant noise reduction.
For example, Japanese Laid-open (Unexamined) Patent Publication No. 2003-69170 proposes improvement of a printed board comprising (i) a signal conductor and (ii) a ground conductor extending along the signal conductor, which are formed on a substrate in the form of wiring pattern, and (iii) an insulating layer to cover the wiring patterns, wherein a non-insulating section is formed in the insulating layer to expose a part of the ground conductor therefrom, and also a conductor layer is formed to cover the insulating layer over the signal conductor and is brought into conduction with the ground conductor via the non-insulating section, so that unwanted radiation is reduced.
Also, in the suspension board with circuit, when a conductive shield layer is formed to cover the insulating cover layer by plating or the like so as to be electrically connected to the metal substrate, the effect of significant noise reduction can be provided.
However, JP Unexamined Patent Publication No. 2003-69170 cited above has the disadvantage that since the conductor layer is formed by a conductive tape or film, the conductor layer strips off too easily.
On the other hand, in the suspension board with circuit mentioned above, when the shield layer is formed by plating or the like, the shield layer is well contacted with the insulating cover layer, but is poorly contacted with the metal substrate, so that the shield layer strips from the metal substrate gradually from an end thereof.


A method of receiving downlink channel, a method of sending downlink channel, a terminal and a base station are provided. The method includes: determining a TCI state of a downlink control channel, where in the case that the terminal switches back to an original BWP, the TCI state is a TCI state of a CORESET last used on the original BWP by the terminal, and the downlink control channel is sent on the CORESET of the original BWP; and receiving the downlink control channel according to the TCI state.

In the fifth generation (5G) communication system, the operating frequency band supported by the system is increased to above 6 GHz, up to about 100 GHz, thereby adopting a multi-beam transmission in the 5G communication system. For the multiple beam transmission, the 5G communication system can indicate the beam information to the terminal through a transmission configuration indication (Transmission Configuration Indication, TCI) state. In addition, in the 5G communication system, a maximum channel bandwidth of each carrier is 400 MHz, while the maximum bandwidth supported by the terminal may be less than 400 MHz, so a bandwidth part (Bandwidth Part, BWP) concept is newly introduced in the 5G communication system, the UE may work on multiple BWPs. In this way, in actual applications, a BWP switching or movement of the terminal will occur. However, in the 5G communication system in the related art, it is not clear how to configure the TCI state in these situations, resulting in a low reliability and accuracy of data transmission.

Method of receiving downlink channel, method of sending downlink channel, terminal and base station


An image processing apparatus comprises a first estimation unit configured to estimate a deformation between a first image and a second image under a first condition and obtain first deformation information; a second estimation unit configured to estimate a deformation between the first image and the second image under a second condition different from the first condition and obtain second deformation information; and an obtaining unit configured to obtain one of an estimation error and reliability of the deformation at a point on an image based on a difference between the first deformation information and the second deformation information.

Field of the Invention
The present invention relates to an image processing apparatus and an image processing method.
Description of the Related Art
In imaging diagnosis using a medical image (three-dimensional tomographic image representing information about the inside of an object), a doctor performs diagnosis while comparing images captured by a plurality of imaging apparatuses (modalities) in different body postures at different times with imaging parameters, and the like. Since postures and shapes of an object differ between images, identification of a lesion area and comparison are difficult. Thus, alignment between a plurality of images is attempted. Conversion and deformation of the posture can be performed on one image to generate an image coincident with the other image.
However, the result of general alignment contains an error and is not always accurate. The doctor therefore cannot determine how reliable the alignment result is.
As a method of estimating an alignment error, Japanese Patent Laid-Open No. 2013-198722 discloses a method based on the instability (ambiguity of the solution) of a deformation parameter estimated as the result of deformation alignment. Based on the variation range of the estimated position of a point corresponding to a point of interest upon intentionally varying an unstable parameter, the method in Japanese Patent Laid-Open No. 2013-198722 estimates the error of the estimated position.
However, the error estimation method described in Japanese Patent Laid-Open No. 2013-198722 cannot consider a factor other than the instability of the estimated parameter.
The present invention provides a technique for providing a method of obtaining an estimation error or reliability in alignment (especially alignment arising from interpolation) between a plurality of images.

Image processing apparatus and image processing method


A stylet wire assembly is disclosed which sealingly engages the proximal end of a medical catheter, and allows the unobstructed injection or evacuation of fluids into or from a patient's body through the catheter while the stylet wire is in place therein. The disclosed assembly includes a stylet wire and a housing. The housing has a catheter fluid communication port at its distal end and anchors the stylet wire into its closed proximal end with the stylet wire extending through the catheter fluid communication port at the distal end of the housing. This anchoring is accomplished by means of a plug which has been injection molded about the crimped proximal end of the stylet wire and bonded to the distal end of the remainder of the housing. An external fluid communication port allows for fluid communication into and out of said housing in transverse orientation relative to the axis of said stylet wire within said housing and distally of the anchoring of the stylet wire into the proximal end of the housing. The distal end of the housing sealingly engages the proximal end of a medical catheter in fluid communication between the catheter fluid communication port of the housing and the fluid conduit of the catheter by means of the combined effect of a female threaded portion which advances over the end of the catheter and an inner sealing tubular portion which advances within the fluid conduit of the catheter. A fluid conduit provides fluid communication within the housing between the catheter fluid communication port and the external fluid communication port. Upon removal of the stylet wire assembly, the proximal end of the medical catheter can be connected directly to an infusion/evacuation tube without the need for sealing the second port of the standardly used T-fitting.

The present invention relates generally to devices which provide stiffening reinforcement for catheters and other medical probes for placement into the body of a patient. In particular, this invention relates to stylet wire assemblies which are to be maintained in place within a catheter while the catheter is being used for fluid infusion or evacuation.
Many medical procedures require the insertion of a catheter into the body. Catheters are usually made of flexible or pliable material to facilitate insertion into and advancement within the body. These devices, however, sometimes lack sufficient rigidity when used in certain situations and require reinforcement in order to maintain their desired structures. Stylet wires used to stiffen catheters for this purpose are well known in the prior art.
In some situations, it is necessary to maintain the stylet wire in place while the catheter is being used for fluid infusion or evacuation. When this is done, access into and through the fluid conduit of the catheter must be kept open while the stylet is in place within the catheter. This is commonly accomplished by using a T-fitting which connects to the proximal end of the catheter. With the stylet wire inserted into the catheter through an axial opening in the T-fitting, fluids can be inserted and/or evacuated through the T-fitting's transverse port. The fitting of catheters with T-fittings for this purpose adds to the cost of manufacturing these devices, and sometimes unnecessarily so, since they do not always need to be used in conjunction with a stylet wire in place. Also, when such a catheter fitted with a T-fitting is used for infusion or evacuation without a stylet wire in place, the user of the device must first be sure to cap the second port on the T-fitting. If the cap is not properly placed, or is forgotten, fluids may leak or even spurt out through this unsealed port causing, at the least, inconvenience, and possibly even, failure of the procedure.
Prior art devices have also been designed which have incorporated into the stylet wire assembly itself the capability to provide fluid communication through the catheter while the stylet wire is in place within the catheter. U.S. Pat. No. 5,026,351 to Dizon discloses an IV stylet catheter having a housing attached to a stylet which is received into the catheter. The Dizon device allows fluid to be injected through the housing and into the catheter with the device placed therein. U.S. Pat. No. 4,659,328 to Potter et al. and U.S. Pat. No. 4,798,593 to Iwatschenko also disclose structures which incorporate a fluid communication fitting into a stylet wire assembly to allow for fluid communication through a catheter while the stylet wire is in place. In each of these prior art devices, fluid communication is necessarily constricted by the anchoring of the wire within the housing of the assembly, as any fluids must pass the anchoring structure in order to enter or exit the assembly. The anchorage of the wire in these devices thus presents an obstruction to the flow of fluid through the catheter, thereby preventing the catheter from functioning as optimally as possible.


A very low frequency (VLF) antenna includes a metal monopole and a dielectric metamaterial cladding surrounding a periphery of the monopole.

Very low frequency (VLF) radio transmissions are generally defined as radio transmissions having a frequency in a range of about 3 to about 30 kilohertz (kHz), which is referred to as the "VLF band." The VLF band frequencies, that is, frequencies in a range of about 3 to about 30 kHz, correspond to wavelengths of about 100 to about 10 kilometers, respectively. Due to its low frequency and correspondingly limited bandwidth, the VLF band is primarily used to transmit low-data-rate coded signals because audio and/or video communication via the VLF band is impracticable.
Although the VLF band has relatively limited bandwidth, it is well-suited for very-long-range communication. First, because VLF radio signals have large wavelengths (e.g., about 10 to about 100 kilometers), they can diffract around large obstacles, including man-made structures and mountain ranges. Further, VLF radio signals are readily propagated over long distances due to the Earth-ionosphere waveguide mechanism. The ionosphere is a conductive layer of electrons and ions at about 60 to about 90 kilometers altitude above the Earth, and the ionosphere reflects VLF radio signals back toward Earth. Because both the ionosphere and the Earth are conductive, VLF radio signals are reflected between the ionosphere and the Earth, creating a waveguide a few wavelengths high, allowing VLF radio signals propagate very long distances, up to about 20,000 kilometers from the emission source.
Due to its various limitations (e.g., limited bandwidth) and advantages (e.g., very-long-distance propagation), the VLF band is used for radio navigation services, government time radio stations, and secure communications. Because VLF radio signals can penetrate at least 40 meters of saltwater, the VLF band is one method of secure communications between land-based stations and deployed submarines. By communicating via VLF radio signals, land-based stations and deployed submarines can communicate with each other without requiring the submarine to surface, thereby ensuring the submarine's position remains hidden from reconnaissance assets, including radar, ships, aircraft, and reconnaissance satellites.
However, due to the relatively large wavelengths of VLF radio signals (i.e., about 10 to about 100 kilometers) and because VLF radio signals propagate vertically (e.g., are vertically polarized) with respect to the Earth, ideal VLF antennas would be the same height as the wavelength of the emitted VLF radio signals. Due to materials limitations and air traffic concerns, a 10-100 kilometer tall antenna is not feasible, and even a quarter-wave antenna designed to emit VLF radio signals at 30 kHz would be about 2.5 kilometers high. As such, existing VLF antennas are electrically short, that is, they are a small fraction of a wavelength tall. Thus, existing VLF antennas are relatively inefficient, radiating only about 10% to 50% of the transmitted power. Accordingly, high power transmitters are paired with the existing VLF antennas to compensate for the low efficiency of existing VLF antennas and to enable long distance communication.

Dielectrically boosted very low frequency antenna


An electronic device includes a substrate, a plurality of transistors and a plurality of drain contact holes. The transistors are disposed on the substrate. Each transistor has a semiconductor, a source and a drain. The drains are electrically connected to the semiconductors through the drain contact holes. A number of the drain contact holes is less than a number of the drains. The electronic device of the embodiment of the disclosure has better reliability or better display quality.

Display panels have been widely used in electronic devices such as mobile phones, televisions, monitors, tablet computers, car displays, wearable devices, and desktop computers. With the vigorous development of electronic products, the requirements for display quality on electronic products are getting higher, making electronic devices used for display increasingly light, thin, short, small, frameless, and larger or higher resolution display effects Improve.


The present invention is directed to antibodies and fragments thereof having binding specificity for PCSK9. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the VH, VL and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-PCSK9 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-PCSK9 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-PCSK9 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with PCSK9.

1. Field of the Invention
This invention pertains to novel antibodies and antibody fragments that specifically bind to human Proprotein Convertase Subtilisin-like/Kexin type 9 (hereinafter "PCSK9") and compositions containing. In addition the invention relates to nucleic acids encoding said antibodies and antibody fragments and the use thereof to express said antibodies and antibody fragments in desired host cells. Also, the invention relates to therapeutic and diagnostic use of these antibodies and antibody fragments.
More particularly, the invention provides rabbit antibodies and humanized and chimeric antibodies derived therefrom specific to PCSK9 as well as antibody fragments specific to PCSK9 which include e.g., Fab′, F(ab′)2, Fv, scFv fragments, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, monovalent antibodies such as MetMab like antibodies, and IgNAR.
Further, the invention provides nucleic acids and host cells containing that encode for and result in the expression of the subject anti-PCSK9 antibodies, i.e., rabbit antibodies and antibody fragments and modified forms thereof including by way of example humanized and chimeric antibodies derived therefrom as well as antibody fragments which include e.g., Fab′, F(ab′)2, Fv, scFv fragments, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, monovalent antibodies such as MetMab like antibodies, and IgNAR.
Also the invention relates to expression systems for the manufacture of the inventive anti-PCSK9 antibodies, including yeast, fungi, mammalian, and other cells useful for the manufacture of antibodies and antibody fragments.
Also, the invention relates to novel antibodies and antibody fragments that specifically bind to human PCSK9 which compete with and/or specifically bind to the same or overlapping epitope(s) on PCSK9 as any of the anti-PCSK9 antibodies and antibody fragments exemplified herein.
The invention further pertains to the in vivo use of the subject anti-PCSK9 antibodies and antibody fragments alone or in association with other active agents or drugs. for blocking, inhibiting or neutralizing PCSK9.
The invention further pertains to the in vivo use of the subject anti-PCSK9 antibodies and antibody fragments alone or in association with other active agents or drugs. for blocking or inhibiting the interaction of PCSK9 with LDLR.
The invention also specifically relates to methods for treating or preventing disorders of cholesterol or lipid homeostasis and disorders associated therewith including by way of example hypercholesterolemia, hyperlipidemia, hypertriglyceridaemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, metabolic syndrome, acute coronary syndrome, xanthoma, hypertension, angina, obesity, diabetes and vascular inflammation, by the administration of the subject anti-PCSK9 antibodies and antibody fragments, wherein the subject antibodies and antibody fragments may be used alone or in association with other active agents.
The invention further specifically relates to methods of preventing or treating diseases and disorders associated with PCSK9, e.g., diseases associated with increased or decreased levels of PCSK9 and/or mutations in the PCSK9 gene that affect PCSK9 protein expression, primary sequence and/or function by administering said antibodies or fragments thereof alone or in combination with other active agents.
The present invention further provides methods for improving blood cholesterol markers associated with increased risk of heart disease using the subject antibodies and antibody fragments alone or in association with other active agents. These markers include, but are not limited to, high total cholesterol, high LDL, high total cholesterol to HDL ratio and high LDL-C to HDL ratio.
The present invention further provides methods for treating or preventing any of the following conditions or complications associated therewith such as hypercholesterolemia, heart disease, metabolic syndrome, diabetes, coronary heart disease, stroke, cardiovascular diseases, Alzheimer's disease and generally dyslipidemias, which can be manifested, for example, by an elevated total serum cholesterol, elevated LDL, elevated triglycerides, elevated VLDL, and/or low HDL. Some non-limiting examples of primary and secondary dyslipidemias that can be treated using an antibody or antibody fragment according to the invention, either alone, or in combination with one or more other agents include the metabolic syndrome, diabetes mellitus, familial combined hyperlipidemia, familial hypertriglyceridemia, familial hypercholesterolemias, including heterozygous hypercholesterolemia, homozygous hypercholesterolemia, familial defective apoplipoprotein B-100; polygenic hypercholesterolemia; remnant removal disease, hepatic lipase deficiency; dyslipidemia secondary to any of the following: dietary indiscretion, hypothyroidism, drugs including estrogen and progestin therapy, beta-blockers, and thiazide diuretics; nephrotic syndrome, chronic renal failure, Cushing's syndrome, primary biliary cirrhosis, glycogen storage diseases, hepatoma, cholestasis, acromegaly, insulinoma, isolated growth hormone deficiency, and alcohol-induced hypertriglyceridemia.
In addition, antibody or antibody fragment according to the invention can also be useful in preventing or treating atherosclerotic diseases, such as, for example, coronary heart disease, coronary artery disease, peripheral arterial disease, stroke (ischaemic and hemorrhagic), angina pectoris, or cerebrovascular disease and acute coronary syndrome, myocardial infarction. In some embodiments, the antibody or antibody fragment according to the invention is useful in reducing the risk of: nonfatal heart attacks, fatal and non-fatal strokes, certain types of heart surgery, hospitalization for heart failure, chest pain in patients with heart disease, and/or cardiovascular events because of established heart disease such as prior heart attack, prior heart surgery, and/or chest pain with evidence of clogged arteries. In some embodiments, the antibody or antibody fragment according to the invention and methods can be used to reduce the risk of recurrent cardiovascular events.
The invention also particularly relates to the use of the subject anti-PCSK9 antibodies and antibody fragments in any of the aforementioned therapeutic indications or conditions in combination with other drugs that are typically used to treat such disorders, wherein the antibody and other drug or agent may be co-administered or separately administered. Non limiting examples of drugs that may be co-administered with the subject antibodies or antibody fragments or used in the same therapeutic regimen include by way of example statins, ACE inhibitors, Angiotensin II receptor blockers (ARBs), Antiarrhythmics, Antiplatelet Drugs, aspirin, beta blockers, amiodarone, digoxin, aspirin, anti-clotting agents, digoxin, diuretics, heart failure drugs, vasodilators, blood thinners, other anti-cholesterol drugs such as holestyramine (Questran), gemfibrozil (Lopid, Gemcor), Omacor, and pantethine, other anti-hypertensives, antidiabetigenic drugs such as Alpha-glucosidase inhibitors, Biguanides, Dipeptidyl peptidase-4 inhibitors, Insulin therapies, Meglitinides, Sulfonylurea, and Thiazolidinediones, and other drugs used to treat conditions wherein the treated individual may have high cholesterol.
The invention further relates to compositions containing the subject anti-PCSK9 antibodies or antibody fragments, especially compositions are suitable for in vivo administration, e.g., subcutaneous, intravenous, intradermal, intranasal, rectal, vaginal, intrathecal, oral, and other administrable dosage forms.
The invention further relates to compositions containing the subject anti-PCSK9 antibodies or antibody fragments, especially compositions suitable for in vivo administration, e.g., subcutaneous, intravenous, intradermal, intranasal, rectal, vaginal, intrathecal, oral, and other administrable dosage forms which contain another active agent such as statins, ACE inhibitors, Angiotensin II receptor blockers (ARBs), Antiarrhythmics, Antiplatelet Drugs, aspirin, beta blockers, amiodarone, digoxin, aspirin, anti-clotting agents, digoxin, diuretics, heart failure drugs, vasodilators, blood thinners, other anti-cholesterol drugs such as holestyramine (Questran), gemfibrozil (Lopid, Gemcor), Omacor, and pantethine, other anti-hypertensives, antidiabetigenic drugs such as Alpha-glucosidase inhibitors, Biguanides, Dipeptidyl peptidase-4 inhibitors, Insulin therapies, Meglitinides, Sulfonylurea, and Thiazolidinediones, and other drugs used to treat conditions wherein the treated individual may have high or aberrant lipid or cholesterol levels.
The invention further relates to storage stable forms containing the subject anti-PCSK9 antibodies or antibody fragments, e.g., lyophilisates, suspensions, and buffered or temperature stable compositions.
The invention also pertains to methods of using the subject antibodies and antibody fragments that specifically bind to PCSK9 in screening assays to detect and monitor the levels of PCSK9 in serum samples, potentially for the diagnosis of diseases and disorders associated with PCSK9 or identifying individuals wherein the administration of the subject antibodies and antibody fragments that specifically bind to PCSK9 may have a therapeutic or prophylactic effect or for monitoring the effects of a treatment designed to modulate or neutralize PCSK9 or block cholesterol synthesis, e.g., a treatment involving administration of one of the subject anti-PCSK9 antibodies or antibody fragments.
2. Description of Related Art
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein (Horton et al., 32(2) Trends Biochem. Sci. 71-77 (2007); Seidah and Prat, 85(7) J. Mol. Med. 685-96 2007). In vitro experiments have shown that adding PCSK9 to HepG2 cells lowers the levels of cell surface LDLR (Benjannet et al., 279 J. Bio. Chem. 48865-75 (2004); Lagace et al., 116(11) J. Clin. Invest. 2995-3005 (2006); Maxwell et al., 102(6) Proc. Nat. Acad. Sci. 2069-74 (2005); Park et al., 279 J. Biol. Chem. 50630-38 (2004)). (While this protein is generally referred to as PCSK9, it is noted that this protein and corresponding gene has also been referred to in the patent and non-patent literature by other names including PSEC0052, FH3, HCHOLA3, LDLCQ1, NARC-1, NARC1, PC9).
Experiments with mice have shown that increasing PCSK9 protein levels decreases levels of LDLR protein in the liver (Benjannet et al., 279 J. Bio. Chem. 48865-75 (2004); Lagace et al., 116(11) J. Clin. Invest. 2995-3005 (2006); Maxwell et al., 102(6) Proc. Nat'l Acad. Sci. 2069-74 (2005); Park et al., 279 J. Biol. Chem. 50630-38 (2004)), while PCSK9 knockout mice have increased levels of LDLR in the liver (Rashid et al., 102(15) Proc. Nat'l Acad. Sci. 5374-79 (2005)). Additionally, various human PCSK9 mutations that result in either increased or decreased levels of plasma LDL-C have been identified (Kotowski et al., 78(3) Am. J. Hum. Genet. 410-22 (2006); Zhao et al., 79(3) Am. J. Hum. Genet. 514-23 (2006)). PCSK9 has been shown to directly interact with the LDLR protein, be endocytosed along with the LDLR, and co-immunofluoresce with the LDLR throughout the endosomal pathway (Lagace et al., 116(11) J. Clin. Invest. 2995-3005 (2006)). Several mutations in human PCSK9 cause gain-of-function effects in humans, including hypercholesterolemia, increased LDL-C cholesterol levels, and increased risk of coronary heart disease. (Garnier, 11(3) Am. J. Cardiovasc. Drugs 145-52 (2011)). Even rarer human PCSK9 mutations induce loss-of-function, resulting in lowered LDL-C levels and a 88% reduction in coronary heart disease risk. (Id.) PCSK9 interacts with the LDLR via the EGF domain and the complex is internalized. In the endosome, the lower pH results in an increased affinity between PCSK9 and LDLR and the complex is targeted for degradation in the lysosome (Horton et al., April Supp., J. Lipid Res. S172-177 (2009), Sci. 928-33 (2003)).
Several lines of evidence demonstrate that PCSK9, in particular, lowers the amount of hepatic LDLR protein and thus compromises the liver's ability to remove LDL cholesterol from the circulation. Adenovirus-mediated overexpression of PCSK9 in the livers of mice results in the accumulation of circulating LDL-C due to a dramatic loss of hepatic LDLR protein, with no effect on LDLR mRNA levels; Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875; Maxwell & Breslow, 2004 PNAS 101:7100-7105; Park et al., 2004 J. Biol. Chem. 279:50630-50638; and Lalanne et al., 2005 J. Lipid Res. 46:1312-1319. The effect of PCSK9 overexpression on raising circulating LDL-C levels in mice is completely dependent on the expression of LDLR, again, indicating that the regulation of LDL-C by PCSK9 is mediated through downregulation of LDLR protein. In agreement with these findings, mice lacking PCSK9 or in which PCSK9 mRNA has been lowered by antisense oligonucleotide inhibitors have higher levels of hepatic LDLR protein and a greater ability to clear circulating LDL-C; Rashid et al., 2005 PNAS 102:5374-5379; and Graham et al., 2007 J. Lipid Res. 48(4):763-767. In addition, lowering PCSK9 levels in cultured human hepatocytes by siRNA also results in higher LDLR protein levels and an increased ability to take up LDL-C; Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875; and Lalanne et al., 2005 J Lipid Res. 46:1312-1319. Together, these data indicate that PCSK9 action leads to increased LDL-C by lowering LDLR protein levels.
A number of mutations in the gene PCSK9 have also been conclusively associated with autosomal dominant hypercholesterolemia ("ADH"), an inherited metabolism disorder characterized by marked elevations of low density lipoprotein ("LDL") particles in the plasma which can lead to premature cardiovascular failure; see Abifadel et al., 2003 Nature Genetics 34:154-156; Timms et al., 2004 Hum. Genet. 114:349-353; Leren, 2004 Clin. Genet. 65:419-422. A later-published study on the S127R mutation of Abifadel et al., supra, reported that patients carrying such a mutation exhibited higher total cholesterol and apoB100 in the plasma attributed to (1) an overproduction of apoB100-containing lipoproteins, such as low density lipoprotein ("LDL"), very low density lipoprotein ("VLDL") and intermediate density lipoprotein ("IDL"), and (2) an associated reduction in clearance or conversion of said lipoproteins; Ouguerram et al., 2004 Arterioscler. Thromb. Vasc. Biol. 24:1448-1453.
PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 100(3) Proc. Nat'l Acad. Sci. 928-33 (2003)). Humans have nine prohormone-proprotein convertases that can be divided between the S8A and S8B subfamilies (Rawlings et al., 34 Nucleic Acids Research D270-72 (2006)). Furin, PC1/PC3, PC2, PACE4, PC4, PC5/PC6 and PC7/PC8/LPC/SPC7 are classified in subfamily S8B. Crystal and NMR structures of different domains from mouse furin and PC1 reveal subtilisin-like pro- and catalytic domains, and a P domain directly C-terminal to the catalytic domain (Henrich et al., 10(7) Nature Structural Bio. 520-26 (2005); Tangrea et al., 320(4) J. Mol. Bio. 801-12 (2002)). Based on the amino acid sequence similarity within this subfamily, all seven members are predicted to have similar structures (Henrich et al., 345(2) J. Mol. Bio. 211-27 (2005)). SKI-1/S1P and PCSK9 are classified in subfamily S8A. Sequence comparisons with these proteins also suggest the presence of subtilisin-like pro- and catalytic domains (Sakai et al., 2(4) Mol. Cell. 505-15 (1998); Seidah et al., 100(3) Proc. Nat'l Acad. Sci. 928-33 (2003); Seidah et al., 96(4) Proc. Nat'l Acad. Sci. 1321-26 (1999)). In these proteins, the amino acid sequence C-terminal to the catalytic domain is more variable and does not suggest the presence of a P domain.
Prohormone-proprotein convertases are expressed as zymogens, and they mature through a multi step process. The function of the pro-domain in this process is two-fold. The pro-domain first acts as a chaperone and is required for proper folding of the catalytic domain (Ikemura et al., 262 J. Biol. Chem. 7859-64 (1987)). Once the catalytic domain is folded, autocatalysis occurs between the pro-domain and catalytic domain. Following this initial cleavage reaction, the pro-domain remains bound to the catalytic domain where it then acts as an inhibitor of catalytic activity (Fu et al., 275 J. Biol. Chem. 16871-78 (2000)). When conditions are correct, maturation proceeds with a second autocatalytic event at a site within the pro-domain (Anderson et al., 16 Nature 1508-18 (1997)). After this second cleavage event occurs the pro-domain and catalytic domain dissociate, giving rise to an active protease.
Autocatalysis of the PCSK9 zymogen occurs between Gln152 and Ser153 (VFAQ|SIP) (Naureckiene et al., 420(1) Archives of Biochem. & Biophysics 55-67 (2003)), and has been shown to be required for its secretion from cells (Seidah et al., 100(3) Proc. Nat'l Acad. Sci. 928-33 (2003)). A second autocatalytic event at a site within PCSK9's pro-domain has not been observed. Purified PCSK9 is made up of two species that can be separated by non-reducing SDS-PAGE; the pro-domain at 17 Kd, and the catalytic plus C-terminal domains at 65 Kd. PCSK9 has not been isolated without its inhibitory pro-domain, and measurements of PCSK9's catalytic activity have been variable (Naureckiene et al., 420(1) Archives of Biochem. & Biophysics 55-67 (2003); Seidah et al., 100(3) Proc. Nat'l Acad. Sci. 928-33 (2003)).
Accordingly, there is substantial evidence indicating that PCSK9 plays a role in the regulation of LDL; that the expression or upregulation of PCSK9 is associated with increased plasma levels of LDL cholesterol, that the corresponding inhibition or lack of expression of PCSK9 is associated with reduced LDL cholesterol plasma levels; and that decreased levels of LDL cholesterol are associated with sequence variations in PCSK9 have been found to confer protection against coronary heart disease; Cohen, 2006 N. Engl. J. Med. 354:1264-1272.
In clinical trials, reductions in LDL cholesterol levels have been directly related to the rate of coronary events; Law et al., 2003 BMJ 326:1423-1427. Also, moderate lifelong reduction in plasma LDL cholesterol levels was found to correlate with a substantial reduction in the incidence of coronary events; Cohen et al., supra. This was the case even in populations with a high prevalence of non-lipid-related cardiovascular risk factors; supra. Accordingly, there is great benefit to be reaped from the managed control of LDL cholesterol levels.
Based thereon, the identification of other molecules which may be used to modulate cholesterol levels and block or inhibit or neutralize the activity of PCSK9 would be of great interest. The present invention advances these interests by providing novel antagonists of PCSK9 for use for in blocking, inhibiting or neutralizing one or more of the activities of PCSK9 and/or in blocking the interaction of PCSK9 with LDLR and/or for the treatment of therapeutic conditions identified herein especially those involving or associated with high or aberrant lipid or cholesterol levels.


Monomeric metal complexes having desirable luminescence properties are provided. In one embodiment, a monomeric metal compound is represented by the formula (ArN)M(L)x, where ArN is an arylamido ligand, and M may be any metal capable of exhibiting luminescent properties, for example, a d10 metal. L may be a tertiary phosphine.

Luminescent transition metal compounds have been widely studied for their use in biological imaging, photochemical catalysis, light-driven fuel production, and electroluminescent devices. Conventionally, noble metal emitters have been used, but the high cost of such emitters has led to the investigation of copper as a low cost, biologically relevant alternative. The most thoroughly studied copper emitters are monomers supported by modified polypyridine and phenanthroline ligands. However, these compounds suffer from low quantum efficiencies and short luminescence lifetimes.
Recently, copper (I) amidophosphine compounds have been identified as a new class of highly luminescent compounds. Mononuclear and binuclear copper (I) compounds featuring bidentate and tridentate arylamidophosphine ligands have been found to exhibit quantum efficiencies of as high as 70%. However, the syntheses of these compounds which includes catalytic aryl amination and the use of lithium reagents and/or strong phosphide nucleophiles, has limited the synthetic versatility of these compounds.


A method for interference reduction in a stationary radar unit of a frequency-modulated continuous-wave (FMCW) type is provided. A sequence of beat signals is received, and a reference beat signal is calculated as an average or a median of one or more of the beat signals in the sequence. By comparing a difference between a beat signal and the reference beat signal, or a derivative of the difference, to one or more thresholds, a segment which is subject to interference is identified. The segment of the beat signal is replaced by one or more of a corresponding segment of an adjacent beat signal in the sequence, and a corresponding segment of the reference beat signal.

Using radar for surveillance monitoring and in vehicles becomes more and more popular as this allows the distance, velocity, and angle of objects to be measured. For example, a radar unit may be used as a complement to a surveillance camera to provide information about objects in the scene. As the use of radars becomes more common, there is an increasing risk that different radars start to interfere with each other. To exemplify, a radar used to monitor traffic may be subject to interference from radars mounted in vehicles passing by. As a consequence of the interference, the function of the radar may worsen or completely fail in worst case.
An approach of reducing interference is to set all disturbed data samples in the base band radar data to zero. However, that approach introduces artifacts as the radar data is transformed and processed in the frequency domain to calculate distances, velocities, and angles of objects. These artifacts may in the end lead to false detection of objects. There is thus room for improvements.

Method, device, and system for interference reduction in a frequency-modulated continuous-wave radar unit


A quantum computer includes a unit including thin films A, B and C each containing a physical-system group A, B and C formed of physical systems A, B and C, the films A, B and C being alternately stacked in an order of A, B, C, A, . . . , each of the systems A, B and C having three-different-energy states |0>x, |1>x , |e>x, a quantum bit being expressed by a quantum-mechanical-superposition state of |0>x and |1>x , a light source generating light beams having angular frequencies ωA(E), ye, g, ωA(E), ye, e, ωx, ye, gg, ωx, ye, ge, ωx, ye, eg and ωx, ye, ee, ωA(E), ye, g, a unit controlling frequencies and intensities of the beams, and a unit measuring intensity of light emitted from or transmitted through physical-system group A(E) contained in a lowest one of the thin films A to detect a quantum state of the group A(E).

1. Field of the Invention
The present invention relates to a quantum computer and method using physical systems in a thin film.
2. Description of the Related Art
The state of the nuclear spin of each rare earth metal ion in crystal has a coherence time (the time of holding a quantum mechanical superposition state) specifically long as a solid. This property is a most important one required for physical systems that realize, in a solid state, a quantum information processing device, such as a quantum computer, which expresses information using superposition of states of each physical system and executes information processing. Further, the state of the nuclear spin of each rare earth metal ion in crystal can be controlled and read, using light of low noise that has excellent controllability. Because of these properties, the state of the nuclear spin of each rare earth metal ion in crystal is extremely suitable for realization of a quantum information processing device in a solid state.
There is a method in which when using nuclear spins in crystal as quantum bits, the states of the nuclear spins of individual ions are used as quantum bits, and differences between the ions in transition angular frequencies unique to solids, which are distributed in inhomogeneous broadening and do not change with time (in the case of gases, the inhomogeneous broadening is based on the motion of individual atoms and molecules, and hence their transition angular frequencies vary momentarily because of changes in the quantities of their motion due to their collision), are utilized to adjust the frequency of light applied to the ions so as to individually operate the quantum bits. This method employs an optical resonator, and the individual quantum bits contained therein are made to resonate with a common resonator mode, therefore can be processed substantially completely in a frequency domain. Namely, when accessing individual quantum bits or coupling quantum bits, the positional relationship between the quantum bits in a real space is not so important, with the result that a quantum computer, which does not require strict microfabrication of, for example, electrodes, can be realized (see, for example, Opt. Commun. 196, 119 (2001)).
Another method has been proposed, in which differences in transition angular frequency between ions contained in crystal are utilized for accessing individual quantum bits, as in the above-described method, whereby strict processing of crystal and electrodes is not needed (see, for example, Phys. Rev. A, 71, 062328 (2005)). In this method, a group of ions having transition angular frequencies that fall within a certain range set in units of quantum bits is used as a single quantum bit. This structure aims to obtain a read signal of a higher level than in the case of using a single ion as a quantum bit. In this structure, the dipole-dipole interaction of ions is utilized for coupling quantum bits. Namely, the ion-ion interaction (dipole-dipole interaction) of ions providing a certain quantum bit, and ions providing another quantum bit and located adjacent to the first-mentioned ions, is utilized.
However, it is considered that in this method, if the number of quantum bits is increased, the number of ions providing one quantum bit is reduced and accordingly the level of the read signal is reduced. It is also considered that if the number of quantum bits is increased, the average distance between physical systems expressing two quantum bits is increased to thereby weaken the interaction for coupling. If only ions of higher interaction levels are selected, the number of ions providing one quantum bit is further reduced.
There is yet another method in which quantum bits are discriminated using differences in transition angular frequency between physical systems that provide the quantum bits.
In this method, three types of physical systems adjacent to each other which are interactive are arranged cyclically (see, for example, Science 261, 1569 (1993)). Physical systems of different types have different transition angular frequencies, and physical systems of the same type have the same transition angular frequency. When a light beam that resonates with the physical systems of one of the three types is applied to the entire physical systems, the physical systems of the one type are operated in parallel. This parallel operation is repeated while the frequency of the applied light beam is changed to change the type of physical systems to be operated. During executing the parallel operation, the physical system located at an end is operated independently of the other physical systems, and the fact that the transition angular frequency of a certain physical system changes in accordance with the quantum state of the physical system adjacent thereto is utilized, thereby executing reading and writing data.
Further, in this method, an atomic group (monomeric substance) forming a macromolecular chain is regarded as a physical system, and only two states, i.e., the excited state and ground state of the monomeric substance, are used as a quantum bit. Thus, there is no concrete description concerning a physical system that has a sufficiently long coherence time, and concerning a method necessary to use a system (such as a state of a nuclear spin) as a quantum bit.
As a method of realizing a practical quantum computer using a large number of quantum bits, it is desirable to use a method that satisfies the following conditions:
(1) Quantum bits have a sufficiently long coherence time;
(2) The method is advantageous in that, for example, it is not necessary to process crystal and/or form electrodes by strict microfabrication;
(3) A physical system group formed of a large number of physical systems can be used as a single quantum bit to obtain a read signal of high level; and
(4) A sufficient scalability in the number of quantum bits is realized.
However, such a method as satisfies the above conditions is not known at present.

Quantum computer and quantum computing method


Polyisocyanate mixtures are isolated in pure or more concentrated form from isomeric mixtures by liquid-liquid extraction using a two-phase system. The two phases are 1) a non-polar solvent phase and 2) a polar solution in which a hydrogen halide is present. In a preferred embodiment, the extraction is carried out in a countercurrent extractor.

The present invention relates to a new process for isolating polyisocyanate mixtures in pure or concentrated form from polyisocyanate mixtures containing at least two polyisocyanate isomers.
It is known that polyisocyanate mixtures can be purified by fractional distillation. For example, in DE-OS 3,145,010, the isolation of high-purity 4,4'-diisocyanato-diphenylmethane (hereinafter referred to as "4,4'-MDI") from a polyisocyanate mixture such as is obtained by phosgenation of aniline/formaldehyde condensation products is disclosed. Disadvantages of this five-stage distillation process are the expense of the apparatus for the multiple distillation of the polyisocyanate mixture and, associated therewith, the high thermal stress of the process product, 4,4'-MDI.
The separation of 2,4'-diisocyanato-diphenylmethane (hereinafter "2,4'-MDI") and 4,4'-MDI from polyisocyanate mixtures of the type described in DE-OS 3,145,010 by distillation and subsequent crystallization is disclosed in DE-OS 2,425,658. In this disclosed process, a distillate containing 2,4'-MDI and 4,4'-MDI is first obtained from the crude polyisocyanate mixture. Cooling of this distillate to a temperature of from 40.degree. C. to 18.degree. C. for 5-6 hours results in the crystallization of high purity 4,4'-MDI. This process is disadvantageous because of the long cooling-down time required for the crystallization and, associated therewith, the strict temperature control requirements.
The continuous separation of polyisocyanate isomer mixtures of tolylene 2,4-diisocyanate (hereinafter "2,4-TDI") and tolylene 2,6-diisocyanate (hereinafter "2,6-TDI") by partial crystallization in a tubular crystallizer is described in DE-OS 3,220,439. In this disclosed process, the isomer mixture is cooled from 30.degree. C. to 6.degree. C. in 5 hours by passing it through a cooled tube. A 2,4-TDI-rich product is obtained after the crystallizate is melted at 20.degree. C. and the mother liquor is drained off. The mother liquor can be further purified. A disadvantage of this process is the long time necessary for the crystallization.
U.S. Pat. No. 4,246,187 discloses a process which is based on the same principle as that disclosed in DE-OS 3,220,439. In the process disclosed in U.S. Pat. No. 4,246,187, the isomer mixture of 2,4-TDI and 2,6-TDI is cooled to a temperature near 6.degree. C. in a heat exchanger in the form of a skimmer centrifuge. The mother liquor obtained is centrifuged off and the crystallizate is continuously discharged. A disadvantage of this process is the technically demanding continuous discharge of solids from the reaction mixture.
In the process described in published Application JP 49 003 981, the stereoisomers of 4,4'-diisocyanato-dicyclohexylmethane (hereinafter "H.sub.12 -MDI"), that is cis,cis-, cis,trans- and trans,trans-isomers, are separated from aliphatic hydrocarbons by fractional crystallization. To this end, the stereoisomer mixture is dissolved completely at temperatures near 40.degree. C. in the solvent used, and the trans,trans-rich H.sub.12 -MDI isomer mixture crystallizing out on cooling to 10.degree. C. is isolated.
A better separating effect is achieved by the process disclosed in published Application JP 53 046 944. In this disclosed process, the pure trans,trans stereoisomers of the H.sub.12 -MDI are isolated by treating the starting isomer mixture in organic solvents, for example o-chlorobenzene, with gaseous hydrogen chloride. The carbamic acid chlorides which are formed are less soluble than the free isocyanates and precipitate out from the reaction mixture. This process is disadvantageous because of the technical resources required for continuous separation from the reaction mixture of the carbamic acid chloride solids.
The separation of isomer mixtures of 2,4-TDI and 2,6-TDI by introduction of gaseous hydrogen halide into a benzene solution is described by A. S. Shevlyakov et al. in Sin. Fiz.-Khim. Polim., 5, 66 (1968); CA 70, 3390 h.
The known processes either yield the purified polyisocyanate isomers as solids which can not be continuously worked up without the expenditure of large technical resources, or recover the purified polyisocyanate isomers by distillation, which due to the thermal stress associated therewith may result in contamination with by-products.

Process for isolating polyisocyanate isomers from polyisocyanate mixtures