A system and method enables de-duplication in a storage system architecture comprising one or more volumes distributed across a plurality of nodes interconnected as a cluster. De-duplication is enabled through the use of file offset indexing in combination with data content redirection. File offset indexing is illustratively embodied as a Locate by offset function, while data content redirection is embodied as a novel Locate by content function. In response to input of, inter alia, a data container (file) offset, the Locate by offset function returns a data container (file) index that is used to determine a storage server that is responsible for a particular region of the file. The Locate by content function is then invoked to determine the storage server that actually stores the requested data on disk. Notably, the content function ensures that data is stored on a volume of a storage server based on the content of that data rather than based on its offset within a file. This aspect of the invention ensures that all blocks having identical data content are served by the same storage server so that it may implement de-duplication to conserve storage space on disk and increase cache efficiency of memory.

A storage system typically comprises one or more storage devices into which information may be entered, and from which information may be obtained, as desired. The storage system includes a storage operating system that functionally organizes the system by, inter alia, invoking storage operations in support of a storage service implemented by the system. The storage system may be implemented in accordance with a variety of storage architectures including, but not limited to, a network-attached storage environment, a storage area network and a disk assembly directly attached to a client or host computer. The storage devices are typically disk drives organized as a disk array, wherein the term "disk" commonly describes a self-contained rotating magnetic media storage device. The term disk in this context is synonymous with hard disk drive (HDD) or direct access storage device (DASD).
The storage operating system of the storage system may implement a high-level module, such as a file system, to logically organize the information stored on volumes as a hierarchical structure of data containers, such as files and logical units. For example, each "on-disk" file may be implemented as set of data structures, i.e., disk blocks, configured to store information, such as the actual data for the file. These data blocks are organized within a volume block number (vbn) space that is maintained by the file system. The file system may also assign each data block in the file a corresponding "file offset" or file block number (fbn). The file system typically assigns sequences of fbns on a per-file basis, whereas vbns are assigned over a larger volume address space. The file system organizes the data blocks within the vbn space as a "logical volume"; each logical volume may be, although is not necessarily, associated with its own file system.
A known type of file system is a write-anywhere file system that does not over-write data on disks. If a data block is retrieved (read) from disk into a memory of the storage system and "dirtied" (i.e., updated or modified) with new data, the data block is thereafter stored (written) to a new location on disk to optimize write performance. A write-anywhere file system may initially assume an optimal layout such that the data is substantially contiguously arranged on disks. An example of a write-anywhere file system that is configured to operate on a storage system is the Write Anywhere File Layout to (WAFL®) file system available from Network Appliance, Inc., Sunnyvale, Calif.
A plurality of storage systems may be interconnected to provide a storage system environment configured to service many clients. Each storage system may be configured to service one or more volumes, wherein each volume stores one or more data containers. Yet often a large number of data access requests issued by the clients may be directed to a small number of data containers serviced by a particular storage system of the environment. A solution to such a problem is to distribute the volumes serviced by the particular storage system among all of the storage systems of the environment. This, in turn, distributes the data access requests, along with the processing resources needed to service such requests, among all of the storage systems, thereby reducing the individual processing load on each storage system. However, a noted disadvantage arises when only a single data container, such as a file, is heavily accessed by clients of the storage system environment. As a result, the storage system attempting to service the requests directed to that file may exceed its processing resources and become overburdened, with a concomitant degradation of speed and performance.
One technique for overcoming the disadvantages of having a single file that is heavily utilized is to stripe the file across a plurality of volumes configured as a striped volume set (SVS), where each volume is serviced by a different storage system, thereby distributing the load for the single file among a plurality of storage systems interconnected as a cluster. A technique for data container (file) striping is described in U.S. patent application Ser. No. 11/119,278 of Kazar et al., entitled STORAGE SYSTEM ARCHITECTURE FOR STRIPING DATA CONTAINER CONTENT ACROSS VOLUMES OF A CLUSTER. File striping improves raw performance and reliability across the cluster of storage systems by distributing data among different storage systems generally based on an offset within the file at which the data is located. Each storage system is configured to serve an underlying physical volume embodied as an aggregate comprising one or more groups of disks.
It is generally desirable to eliminate duplicate data on storage resources, such as disks, and to ensure the storage of only a single instance of data to thereby achieve storm age compression. Such elimination of data duplication (de-duplication) also results in a more efficient use of cache memory. De-duplication in the exemplary file system ensures that if two blocks contain the same data, and thus have the same content, only one copy of the block is maintained on disk and two references (pointers) are directed to (i.e., share) that block. Low-level indirect blocks typically include vbn pointers to data blocks, which vbns are mapped to disk block numbers (dbns) on disk. In the case of de-duplication, different vbns refer to the same dbn. For example, if data stored at vbn 15 and vbn 32 were identical, that data would be retrieved from disk from the same location and, therefore, cached at the same location in memory. This enables not only a reduction of storage space consumption, but also a performance improvement since a data block that is shared by many files is more likely to be resident in cache when needed again.
An example of a technique for eliminating duplicate data is described in U.S. patent application Ser. No. 11/105,895, filed on Apr. 13, 2005, entitled METHOD AND APPARATUS FOR IDENTIFYING AND ELIMINATING DUPLICATE DATA BLOCKS AND SHARING DATA BLOCKS IN A STORAGE SYSTEM, by Ling Zheng, et al, the contents of which are hereby incorporated by reference. Here, data de-duplication operations are performed on fixed size blocks. When a new block is to be stored, a hash value is computed as a fingerprint of the block. The fingerprint is then compared with a hash table containing fingerprints of previously stored blocks. If the new block's fingerprint is identical to that of a previously stored block, there is a high degree of probability that the new block is identical to the previously stored block. In such a case, the two blocks are compared to test whether they are indeed identical. If so, the new block is replaced with a pointer to the previously stored block, thereby reducing storage resource consumption.
However, de-duplication generally takes place at the aggregate level; that is, for sharing to occur, all references to that data must occur within the same aggregate. As noted, file striping across a storage system cluster typically distributes data among the different storage systems based on an offset within a file, not based on the content of the data. As a result, a data access request directed to a first block of a first file may be forwarded to a first storage system, whereas an access request to a second block of that file may be forwarded to a second storage system. Thus, despite the content of the data, the access requests are directed to different systems. Accordingly, the efficiency of de-duplication is compromised because only a portion of the data is available to search for a duplicate; there is no attempt to route identical blocks of data onto a single storage system. The present invention is directed to ensuring that a block of data is stored on a stores age system based on the content of that data block rather than based on its offset within a file.

System and method for enabling de-duplication in a storage system architecture


In this invention we disclose methods of automatically configuring a wireless node when it initially powers on and seeks to integrate into an existing wireless network. The wireless node could be part of an ad hoc, software defined network. One such network could be LTE network. The auto-configuration methods disclosed herein can be executed on wireless nodes throughout their operation. In alternate embodiments, the methods disclosed could be used to create a new configuration based on changed environmental conditions, location or node capability change. These embodiments allow wireless nodes to migrate to better quality connections if they become available.

When a new network node is installed in a wireless communication network, it must be configured to fit within the network. In most instances, network nodes have some pre-configured information stored within their memories. When they are powered on during installation, they typically go through a start-up sequence. The start-up sequence is designed to take a new node from its initial powering up to being a fully functioning node within a network. The start-up sequence typically requires the new node to discover itself, its peers, its neighbors, its master, its location, its network, its attachment, and hundreds of other properties about itself and its environment well known to those of skill in the art.
After this discovery process, the new node ideally joins an existing network, which requires authentication. Authentication itself involves the new node providing information about itself including its state, its capabilities, its identifying data, knowledge exchange capabilities, its configuration, identifying information about its software, and so forth. Although many in the art follow these general principles, the incantations used to reach the desired result are widely varied in terms of node discovery, the protocols used, the roles of the various nodes and network entities and so forth. It is still the case that node configuration and start-up sequences are not optimized.
In the prior art, most of the configuration data for a node was entered at the manufacturing site according to information provided by the network operator controlling the network into which the node would ultimately be installed. When the operator installed the node, he or she added additional, site-specific configuration information. In this way, network nodes were largely preconfigured by node manufacturers. This method of configuring a new node is costly and requires precise tracking because, if a node preconfigured for a certain location ends up being installed at another location, the technician installing the node has to manually perform reconfiguration from scratch.
More recently, auto-configuration methods have reduced the amount of time required to configure new nodes. When an auto-configuration module is executed, it makes certain assumptions about the node to be configured and the network into which it is assimilating. First, it is assumed that the new node has a secure and dedicated connection to a next-hop neighbor. Second, nodes are either statically pre-configured for a particular location, or they have the ability to connect to a server that can facilitate configuration. When a node is pre-configured, it has most of the information that it needs to integrate into a network, but not all. Accordingly, the operational expenditure for installing the node can be high because experienced technicians have to install the node and complete the configuration process. In addition, pre-configured nodes are designed to be deployed at a particular location. If that location changes, the nodes must be reconfigured.
When a node obtains its configuration information by contacting a server, it uses, for example and without limitation, a dynamic host configuration protocol ("DHCP") or a domain name server ("DNS") or both to establishes a secure connection with an initial server, which could called "InitMaster." If the node uses DNS, it performs a DNS query using a preconfigured IP domain for the server to obtain the IP address for the server. The secure connection could be made using IPSec or other well-known connection techniques.
After the node has established a secure connection, it provides its location and capability information, which may include information related to its hardware configuration, to the server. Having received this information, the server would determine whether it would serve the node or whether it should provide information sufficient for the node to establish a connection with another server, which could be called "ServMaster."
From there, the node could again provide location and capability information to the ServMaster. The ServMaster could, in turn, provide the remaining configuration information needed for the node to integrate into the network. This remaining configuration information could be preset or dynamically generated. At this point, the node is configured and ready to operate within the network.
As previously stated, these auto-configuration processes are for wired nodes. Auto-configuration for wireless nodes is more complicated because the new node has to choose a next-hop node, which often means choosing from more than one potential next-hop node. Once it has chosen a next-hop node, it must establish a trusted connection between itself and that node before it tries to establish a connection with the InitServer. Ideally, wireless nodes would not be pre-configured in terms of the role they play within a network because that would allow them to be flexible and to adapt to network conditions in a real-time way. There is, therefore, a need to allow wireless nodes to utilize an auto-discovery mechanism that allows other network nodes to discover new nodes as they are powered on. When the new node is powered on, it can automatically be configured to join an existing network.

Start-up sequence and configuration for a radio node


Method and apparatus for making a decorative pattern on a finger or toe nail using fixture that may be a two part hinged fixture that receives a screen and holds it in juxtaposition to a nail. Articulated arms or a base plate position the fixture relative to the finger or toe, with the nail exposed through the fixture. A screen is inserted into the fixture. A coloring liquid is put onto the screen and is expressed through the screen by a squeegee that coacts with the fixture and resiliently deflects the screen. The part of the fixture holding the screen can be pivoted up and away from the nail to avoid smearing and facilitate changing of the screen. Multi-color patterns can be made by using a plurality of screens with different coloring liquids, such as nail polishes or lacquers.

Although coloring or otherwise decorating finger and toe nails with patterns is a common practice, usually this is done manually in a painstaking and tedious manner. Prior art apparatus and methods exist for effecting such decoration plastic or have employed a simple stencil that usually consists of a metal plate with holes through which nail lacquer can be applied to a nail. Unfortunately, the fit between the plate and nail is poor and lacquer either is smeared when the plate is removed from the nail or leaks under the plate.

Method and apparatus for applying decoration to nails


A composite integrally includes a resin and a coagulation inhibitor, and is used to be mixed with fibers. The composite is a powder whose volume average particle diameter is 1 μm or more to 100 μm or less, and at least a portion of the coagulation inhibitor is arranged in a surface of the composite.

Depositing a fiber-like material and causing a bonding force between the deposited fibers to obtain a sheet-like or film-like formed body has been performed for a long time. Typical examples thereof include manufacturing paper by pulp molding (paper-forming) using water. Even in present times, pulp molding is widely used as an example of a method of manufacturing paper. The paper manufactured by pulp molding generally includes a structure by cellulose fibers derived from wood or the like being entangled with one another, and being partially bonded to one another by a binder (paper strengthening agent (such as a starch paste and a water-soluble resin)).
According to the pulp molding, it is possible for the fibers to be deposited in a state where uniformity is favorable, and, in a case where a paper strengthening agent is used in the bonding between fibers, it is possible for the paper strengthening agent to be dispersed (distributed) in a state where the uniformity in the paper surface is good. However, because the pulp molding is a wet method, it is necessary to use large volumes of water, and the necessity of dewatering and drying or the like arises after forming the paper, and therefore the energy or time consumed is extremely large. It is necessary to suitably process the water used as waste water. Accordingly, it is difficult to respond to modern demands for energy savings, environmental protection, and the like. The apparatuses used in pulp molding frequently need large scale utilities and infrastructure such as water, power, and drainage facilities, and size reductions are difficult. From this viewpoint, there is an expectation of methods, referred to as dry methods, that use no or almost no water as paper manufacturing methods in place of pulp molding.
PTL 1 discloses a waste paper board formed by mixing and defibrating waste paper pulp and a thermal fusion bondable powder with a dry method, and subjecting these to hot pressing or the like.

Sheet manufacturing apparatus, composite manufacturing method, sheet, and composite


A blowing system for controlling the aerodynamics of a ground vehicle comprises a source of compressed air, a valve for regulating the flow of the compressed air, and a plenum for discharging the air at a rear portion of the vehicle. The air discharged through the plenum prevents flow separation and consequently reduces the drag on the vehicle. It may also increase lift, reducing effective weight and thus rolling resistance of the tires, or decrease lift to improve tire traction and handling. The blowing system may have separate plenums for the left and right sides of the vehicle whereby vortex roll-up and flow separation which occur on only one side of the vehicle may be eliminated. Asymmetrical blowing of only one plenum will produce rolling and yawing moments to restore the vehicle's lateral/directional stability when exposed to a side wind. Further, the blowing system may have a lower plenum for reattaching flow, generating a negative lift or download to increase traction, braking, and handling and for generating pitch trim. The blowing system may have a number of sensors for detecting various conditions, such as the direction and pressure of a relative wind, turbulence at the rear of the vehicle, braking, or angle of steering. The blowing system may be responsive to one or more of these conditions to selectively adjust the aerodynamics of the vehicle.

The aerodynamics of ground vehicles are adversely influenced by a number of factors, such as separated air flow-fields and vortex formation and shedding. When a ground vehicle encounters a relative wind, such as when the vehicle is in motion, the air travels along the surface of the vehicle and typically separates from the vehicle at the rear portion of the vehicle. The separated flow-fields cause an increased drag on the vehicle, increased fuel consumption, and an increased level of noise perceived within the interior of the vehicle, plus a loss in cruise efficiency and in economic operation. Resulting lift can positively or adversely effect the vehicle's performance and control.
In general, the vortex formation and shedding is the result of a flow around curved surfaces between differential upper and lower surface pressure distributions. With ground vehicles, a vortex formation is caused by unlike pressure distributions between the upper and lower surfaces of the ground vehicle which induces a drag on the vehicle. The drag increase caused by the vortex thus formed varies in proportion to the square of the lift coefficient experienced by the vehicle and in proportion to the square of the vehicle's velocity.
Because of the above-noted problems, ground vehicles have been designed to be more streamlined so as to reduce the amount of flow separation and vortex formation. While recent ground vehicles are much more streamlined than past models, the recent designs still have a value of practical vehicle drag which is much higher than that of an ideal streamlined body. Thus, today's ground vehicles still experience a significant amount of flow separation and vortex formation.
Some additional aerodynamic problems are related to the sensitivity of a ground vehicle to side winds or to the vehicle being yawed relative to the flow direction, such as when the vehicle is cornering or when it receives gusts from passing vehicles. These situations, such as when the car is cornering or receiving side gusts, can yield both directional instabilities about a vertical yaw axis and lateral instabilities about a horizontal roll axis. As a result of these directional instabilities about the yaw and roll axes, a driver of the vehicle may have difficultly in maintaining control at any time that the relative wind is not from straight ahead of the vehicle. There is therefore a need to provide greater stability to a ground vehicle when it receives relative wind from a direction other than from straight ahead of the vehicle.
The variation in yaw-sensitivity for a standard car and for a streamlined car is plotted in FIG. 1(A). As evident from FIG. 1(A), the standard sharp-cornered car is stable even up to 35.degree. of yaw angle because the flow of air around the front corners of the car separates and prevents increasing side loads and yawing moment. The streamlined car, in contrast, begins to show rapid aerodynamic force changes at yaw angles as low as 20.degree. and therefore experiences lateral or directional instabilities. Since recent designs of cars are more streamlined, the cars tend to become unstable at lower angles of yaw.
A further problem experienced by ground vehicles is ground effect which is caused by the proximity of the lower surface of the car to the roadway over which it is moving. The problem of ground effect can dramatically change the flow-field around the lower surface of the car compared to its "free-stream" flow pattern. As evident from FIG. 1(B), depending upon the particular design of the ground vehicle, both the lift and drag can increase or decrease significantly as the clearance between the ground and the lower surface of the vehicle is reduced. The ground effect, however, is rather unpredictable and is difficult to control.
Lift generated by a streamlined car can also cause control problems; it can effectively reduce vehicle weight and thus reduce tire traction and cornering ability. Some high speed vehicles employ spoilers or inverted airfoils to reduce this lift. Both will cause increased download to increase tire traction and handling. However, the increased lift and reducing rolling resistance can improve cruise efficiency.
The various aerodynamic forces acting upon a ground vehicle, such as flow separation, vortex formation, side winds, and ground effect, can dramatically influence the performance, economy of operation and control of the ground vehicle. Some conventional approaches to the problem have included designing the vehicles with more streamlined shapes, equipping them with larger wheels to remove the lower surface of the car from the road to decrease ground effect, and the use of numerous mechanical devices, such as air dams and spoilers.
While these conventional approaches may reduce to some effect the above-noted problems, each of the approaches is limited in its effectiveness or desirability. For instance, streamlined shapes may be too limiting in the internal dimensions of the vehicle, the passenger and payload room, as well as resulting in a more expensive vehicle to manufacture. While larger wheels may reduce the ground effect in some vehicles, the larger wheels may cause lateral instability due to the high center of gravity thus created and may increase the risk of roll-over for the vehicle. As for mechanical aerodynamic controls, these devices add weight and undue complexity to the vehicle. Further, since the mechanical controls usually cause drag at off-design conditions, e.g., lower or higher speeds, the mechanical controls desirably must be mechanically adjustable, which further adds to the weight and complexity.
Another approach in improving the aerodynamics of a ground vehicle involves redirecting air through portions of the vehicle. U.S. Pat. No. 3,437,371 to Gallie et al. provides an example of such a system in which air is drawn in through slots at the rear portion of the vehicle and is routed through pipes to the front of the vehicle. The front area of the vehicle is at a low pressure and provides the suction force to draw the air in through the slots in the rear of the vehicle thereby to reduce the amount of flow separation. This system has minimal benefit on the aerodynamics of the vehicle inasmuch as the amount of suction force generated at the front of the vehicle will likely at most speeds be insufficient to alter the flow at the rear of the vehicle, especially in view of the amount of friction generated within the air pipes or ducts. This system further suffers from a disadvantage that the suction forces cannot be controlled independently of the vehicle's speed.
Another type of system reduces the flow separation by blowing air out of a region of the vehicle thus eliminating reliance on suction or low pressure areas. For instance, U.S. Pat. No. 5,407,245 to Geropp discloses a system in which air is drawn in through openings in a rear region of the vehicle and is blown out along lines of separation of the vehicle. The system uses a pair of blowers to draw air in through openings formed in the rear surface of the vehicle and to force the air out of bores or slots at or near the separation region. This type of system still depends upon recirculating air through the car but is better able to reduce flow separation and the amount of drag on the vehicle.
The system disclosed in the Geropp patent, while reducing the flow separation, has several apparent disadvantages. The system employs blowers which add a further drain on the vehicle's power system and present another mechanical component requiring maintenance or repair. Also, the system is not easily incorporated into existing cars as it is located at the very rear of the vehicle and necessarily reduces the amount of available trunk space. Furthermore, a rear bumper and its associated structure, which are apparently not taken into consideration by Geropp, can significantly impair the amount of air drawn in through the openings and the ability of the system to reduce flow separation. Thus, while the Geropp system would be able to reduce flow separation, the system is apparently not optimally designed for existing automobiles.
The conventional systems designed to improve the aerodynamics of a vehicle have been primarily limited to reducing drag by reducing the amount of flow separation. Some of the other aerodynamic problems in a vehicle, such as yaw sensitivity, vortex formation, and ground effect, have been mainly ignored.

Pneumatic aerodynamic control and drag-reduction system for ground vehicles


The invention provides a method and apparatus for reconstituting beverages wherein superheated reconstituting liquid and beverage concentrate are delivered into a mixing chamber having an adjustable volume. The mixing chamber is the volume between two coaxially arranged tapered elements which are disposed one inside of the other. Final beverage product emanates from an aperture in the tip of the outer tapered element. At least one tapered element can be displaced in the longitudinal direction so that the volume of the mixing chamber decreases and approaches zero as the tapered elements are moved closer together. Thus, when the system is shutdown the volume of the mixing chamber is allowed to approach zero so that very little product is susceptible to degradation in the mixing chamber due to prolonged exposure to high temperatures during a shutdown. The reduced volume mixing chamber may be flushed with reconstituting liquid. In addition, the temperature of the mixing chamber can be controlled during a shutdown by adjusting the temperature of water contained within the walls of the tapered elements.

1. Field of the Invention
The invention relates to a system for reconstituting beverages using superheated constituting liquid to simultaneously effect a sterilization or pasteurization of the beverages. More particularly, the invention relates to a system of the aforementioned type wherein the reconstituting process can be intermittently interrupted and restarted again without any risk of product degradation or loss of aseptic conditions.
2. Description of Related Art
Various processes for reconstituting and pasteurizing beverages have been described. Reconstitution and pasteurization have been carried out separately. In such processes the heat treatment is carried out indirectly by heating the reconstituted beverage in a tank or directly by injecting high-temperature steam into the beverage. Alternatively, the reconstituted beverage can also be passed as droplets into a jet of high-temperature steam. Indirect heat treatment has the disadvantage of creating undesirable deposits on the tank walls or a caramelization phenomenon. Direct heat treatment has the disadvantage of producing a product having a quantity of excess water which must subsequently be removed.
In an attempt to overcome the disadvantages associated with separate reconstituting and pasteurizing steps, processes have been developed wherein both steps are carried out simultaneously. For example, processes have been developed wherein water is heated to a temperature such that it produces a reconstituted product whose temperature is similar to that at which pasteurization is to be carried out. In accordance with this process superheated water and concentrate continuously flow into a mixing chamber where the reconstituted beverage is aseptically produced.
In processes of this type it is important that all piping and equipment downstream of the mixing chamber remain sterile. Maintaining such aseptic conditions can be problematical where the system is shutdown. During a shutdown sterilization of concentrate in the mixing chamber may be incomplete. The temperature of the mixing chamber will drop during the shutdown. When the system is restarted, unsterile product can emanate from the mixing chamber and pass downstream to contaminate the system. This problem is particularly apparent in the case of a mixing chamber having a large volume.
Attempts have been made to solve the problem of contamination after a shutdown by introducing concentrate into the mixing area from a pipe which runs upward. In this way, during a shutdown, the force of gravity tends to urge concentrate away from the sterile mixing zone. However, this effort has not been entirely successful. For example, in the case of a pulp-containing concentrate like orange juice pulp may float on the concentrate in the area of the mixing zone to the contaminate the zone.
Another problem which can occur during a shutdown is degradation of product in the mixing chamber caused by prolonged exposure of the concentrate to high temperatures. There is therefore a need for a system wherein the temperature of the mixing chamber can be lowered during a shutdown and then raised again before restarting the system so as to avoid both product degradation during the shutdown and loss of aseptic conditions when the system is restarted.
Accordingly, it is an object of the present invention to provide a process for reconstituting beverages which can be interrupted and restarted without adversely affecting the sterility of the system.
It is a further object of the invention to provide an apparatus for reconstituting beverages having a mixing chamber whose temperature can be controlled during a shutdown of the apparatus so as to avoid product degradation caused by prolonged exposure of the beverage to high temperatures.
It is yet a further object of the invention to provide an apparatus for reconstituting beverages having a mixing chamber which can be adjusted so as to minimize its volume during a shutdown of the apparatus thereby allowing the chamber to be flushed with a small amount of water and permitting cooling and reheating of the chamber without the risk of altering the flavor or other qualities (e.g., Brix) of the product.
It is a further object of the invention to provide an apparatus of the type described above wherein a constant holding time may be provided for a product in the mixing chamber notwithstanding variations in the flow rate.

Method for aseptically reconstituting beverages


The present invention relates to novel and excellent small-molecule-compounds that specifically antagonize BMP signal pathways, and these compounds can be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus can be used to treat diseases or pathological symptoms related to BMP signal pathway including inflammation, cardiovascular diseases, hematopoietic diseases, cancer, osteodystrophia, or the like, particularly, fibrodysplasia ossificans progressiva, and the present invention relates to provision of a pharmaceutical and pharmacological agent used for specifically antagonizing the BMP signal pathways and acting on the BMP signal pathways in the prevention and treatment or experimental application since the compounds can be beneficial for regulating cell differentiation and/or cell proliferation.

BMP and TGF-β signal pathways are essential for normal organ development and pattern formation, and also essential for normal remodeling and pathological remodeling of mature tissues. Defects in the BMP signal pathway have been suggested as causes of many congenital and acquired disease processes including hereditary hemorrhagic telangiectasia, primary pulmonary hypertension, familial juvenile polyposis, and sporadic renal cell carcinoma and prostate cancer.
It has been suggested that attenuation in BMP signal can cause certain disease conditions related to defects in signaling components. However, it has been suggested that, excessive BMP signal can cause expression of pathological symptoms in some situations (Non Patent Literature 1).
An ability to regulate BMP signal is used to provide a method of preventing or treating such symptoms, a method of studying the same, and a method of determining underlying causes of such symptoms.
(Treatment of Anemia Including Anemia Due to Iron Deficiency and Chronic Diseases)
For an overview, see (Non Patent Literature 2).
Inflammatory anemia (also called anemia of chronic diseases) is observed in patients with chronic infections, autoimmune diseases (systemic lupus erythematosus and rheumatoid arthritis, and Castleman's disease, etc.), inflammatory bowel disease, cancer (including multiple myeloma), and renal failure.
Inflammatory anemia is often caused by inappropriate expression of the peptide hormone hepcidin. Hepcidin causes decomposition of ferroportin of important proteins enabling iron transportation from intracellular stores of macrophages and iron transportation from intestinal epithelial cells. Many patients with renal failure have erythropoietin deficiency and excessive hepcidin expression in combination. BMP signal induces hepcidin expression, and inhibition of hepcidin expression with a BMP signal inhibitor increases an iron level. The BMP signal inhibitor described in this specification can be used to treat anemia due to chronic diseases or inflammation and anemia related to a high hepcidin state.
Increased IL-6 in inflammatory anemia due to various causes, the effect of chronic IL-6 administration in vivo, protection of IL-6-deficient rodents from anemia (Non Patent Literature 2), and pro-inflammatory cytokine IL-6 are thought to be intrinsic causes of increased hepcidin expression in inflammatory conditions. Stimulation of hepatocellular carcinoma cell lines due to IL-6 induces hepcidin expression, and on the other hand, it has been described that a treatment with a BMP signal inhibitor inhibits IL-6-induced hepcidin expression (Non Patent Literature 3). In addition, it has been described that systemic iron administration in mice and zebra fish quickly activates BMP responsive SMAD and hepcidin expression in the liver, and BMP antagonistic action effectively blocks such response (Non Patent Literature 3). Such data suggest that iron-mediated and inflammation-mediated regulation of hepcidin and circulating iron levels require BMP signal transduction. The BMP signal inhibitor described in this specification can be used to change availability of iron in various situations for therapeutic benefits.
The BMP signal inhibitor described in this specification, (i) enhances efficacy of dietary iron and oral iron supplementation (these are safer than intravenous iron administration) and increases a serum iron concentration; (ii) increases accumulation of hemoglobin in the blood before surgery or allows oneself to donate blood before surgery; and (iii) enhances efficacy of erythropoietin and its related substances, and thus can be used in anemic conditions, and accordingly can reduce a dosage of erythropoietin to be administered for anemia, and can minimize known erythropoietin toxicity and side effects (hypertension, cardiovascular events, and tumor proliferation).
(Treatment of Fibrodysplasia Ossificans Progressiva (FOP))
Fibrodysplasia ossificans progressiva (FOP) is a hereditary disease in which cartilage tissues and bone tissues are ectopically formed in soft tissues such as skeletal muscle, tendons, and ligaments in which bone tissues are not generally formed (Non Patent Literatures 5 and 6). In this disease, ectopic ossification occurs throughout the body including the face, ectopic bone tissues and existing bone tissues are combined together, a movable range of joints is significantly reduced, and deformation of the body is caused (Non Patent Literatures 5 and 6).
In ectopic ossification in FOP, in addition to chronically progressing according to this growth, acute ectopic ossification that proceeds with symptoms called flare-up caused by muscle damage, viral infections or the like is known (Non Patent Literature 7). Flare-up is swelling in which an inflammation reaction and long term pain are main symptoms, and is induced by bruises, falls, intramuscular injections, and the like which cause muscle damage, and also sudden cases in which causes are not clear are known. In FOP, since ectopic bone tissues are formed after flare-up, invasive medical procedures such as biopsy and surgery are contraindicated, and ectopic bone tissues cannot be surgically removed. In addition, since ectopic bone tissues formed due to FOP are formed by normal chondrocytes and osteoblasts, and metabolized in the same manner as in normal bone tissues, it is not possible to remove only ectopic bone tissues through internal medicine using drugs and the like.
Currently, no fundamental treatment methods for preventing ectopic ossification in FOP have been found, and only symptomatic therapies for inflammation, pain, and the like are being performed. Therefore, it is very difficult to remove ectopic bone tissues formed due to FOP, and the development of drugs that can be expected to have a preventive effect before ectopic ossification begins is awaited.
Regarding genes responsible for FOP, the activin-like kinase 2 (ALK2) gene that encodes one type of receptor for bone morphogenetic proteins (BMPs) that induce ectopic osteogenesis in soft tissues including skeletal muscle tissue has been identified (Non Patent Literature 4). ALK2 is the same as a gene called activin A type receptor 1 (ACVR1). ALK2 with amino acid substitution has been found in familial and sporadic FOP cases (Non Patent Literature 4).
Human and mouse ALK2 is a single-pass type transmembrane protein having a signal peptide composed of 509 amino acids, and functions as a transmembrane serine/threonine kinase receptor that binds to BMP (Non Patent Literatures 5 and 6), and this binds to BMP in the extracellular domain at the N terminal side, and activates a downstream intracellular information transmission system at intracellular serine/threonine kinase sites.
BMP receptors are classified into two types: a type I receptor containing ALK2 and a type II receptor according to their structures and functions (Non Patent Literatures 5 and 6). The type II receptor is a constitutively active enzyme that exhibits kinase activity without binding to BMP. On the other hand, the type I receptor containing ALK2 is an inactive enzyme when it does not bind to BMP and exhibits kinase activity depending on binding to BMP. This is thought to be caused by the fact that, due to binding to BMP, a kinase for the type II receptor phosphorylates the intracellular domain of the type I receptor as a substrate, changes a three-dimensional structure, and activates the type I receptor (Non Patent Literatures 5 and 6).
It is known that, when a specific amino acid in the intracellular domain of the type I receptor is substituted, a constitutively active receptor is activated independently from the type II receptor (Non Patent Literatures 5 and 6). When this constitutively active mutant of the type I receptor is over-expressed, an intracellular information transmission system is activated even if a BMP stimulation is not applied. Therefore, the type I receptor is thought to be a molecule responsible for transmitting BMP signal from the outside of cells to the inside of cells.
ALK2 mutations identified from familial and typical sporadic FOP cases were R206H mutants in which Arg206 was substituted with His (Non Patent Literature 4). It has been found that all gene mutations identified from FOP cases so far cause amino acid mutations in the ALK2 intracellular domain. Many of such FOP case mutations are concentrated near an ATP binding region in the ALK2 intracellular domain (Non Patent Literature 8).
When ALK2 mutants identified in FOP are over-expressed in cultured cells, a BMP intracellular information transmission system is activated even if a BMP stimulation is not applied (Non Patent Literature 9). Thus, regarding FOP therapeutic agents, small-molecule inhibitors for ALK2 kinase, RNAi and exon skipping methods for specifically inhibiting expression of genetically mutated ALK2, downstream transcription factor inhibitors for ALK2 receptors, activin neutralizing antibodies, ALK2 antibodies, and osteoblast differentiation inhibitors using BMP signal inhibition, and the like have been developed (Patent Literatures 1 to 4, and Non Patent Literatures 5, 6, 10, and 11).
In recent years, several small-molecule compounds having a BMP signal inhibitory effect have been reported. For example, pyrazolo[1,5-a]pyrimidine derivatives are disclosed in WO2009/114180 (Patent Literature 1), and WO2014/138088 (Patent Literature 2), and 3,5-diarylpyridine derivatives are disclosed in WO2015/148654 (Patent Literature 3). For FOP therapeutic agents, it is necessary to exhibit pharmaceutical efficacy according to oral administration rather than injection having a risk of muscle damage that contributes to flare-up, but BMP signal inhibitors that allow oral absorption have not been reported yet. In addition, FOP therapeutic agents based on nucleic acids such as RNAi that specifically inhibit expression of genetically mutated ALK2 do not have established effective drug delivery methods. An antibody medicine (Patent Literature 4) in which act on the ALK2 extracellular domain to inhibit signals and activin neutralizing antibodies (Non Patent Literature 7) are expected to express ALK2-signal specific pharmacological effects. However, there are concerns that intravenous administration having a high risk of the occurrence of flare-up in FOP patients is required, and drugs are poorly distributed in muscle tissues.
As described above, in the development of BMP signal inhibitors so far, pharmacokinetics has been major problem. However, a small-molecule BMP signal inhibitor in the present invention has an excellent pharmacokinetic profile that is expected to express pharmaceutical efficacy via oral administration. In the present invention, in pharmacokinetic studies using rodents, clinical development candidates showed a high bioavailability (>90%).
In order to prevent excessive osteogenesis in response to trauma, musculoskeletal stress or inflammation, the small-molecule BMP signal inhibitor of the present invention can be administered systemically or locally to concentrate or limit the effect in a trauma or inflammation site.
The small-molecule BMP signal inhibitor in the present invention can be used as a chronic treatment to reduce spontaneous osteogenesis in highly susceptible individuals. In individuals with FOP in whom osteoma or affected bone occurs most frequently in connection with trauma, in order to prevent abnormal osteogenesis, a temporary treatment can be performed before, during, or after such a traumatic event.
A temporary treatment using the small-molecule BMP signal inhibitor in the present invention can be performed before, during or immediately after necessary or urgent medical procedures or surgical procedures (and also important immune treatments and tooth extraction) in individuals with FOP in order to prevent pathological calcification. A combination treatment with other bone inhibitors, immunomodulative drugs or anti-inflammatory drugs (such as NSAIDs, steroids, cyclosporin, cyclophosphamide, azathioprine, methotrexate, rituximab, etanercept, or similar drugs) can inhibit ectopic osteogenesis in the above disorders and increase efficacy of the BMP signal inhibitor.
(Treatment of Ligament Ossification)
Involvement of ossification of the posterior longitudinal ligament (OPLL), ossification of the yellow ligament (OYL), and ossification of the anterior longitudinal ligament (OALL) with systemic factors and local factors has been reported (Non Patent Literature 12), and it has been reported that BMP is involved in such ossification procedures (Non Patent Literature 13). In addition, it has been reported that BMP receptors and activin receptors are highly expressed in OPLL patient tissues (Non Patent Literature 14, and Non Patent Literature 15).
Specific inhibitors of BMP signal such as compounds described in this specification can be used to prevent osteogenesis in ligaments in response to trauma, musculoskeletal stress or inflammation. The compounds can also be used to ease regression of affected bone. The BMP signal inhibitor can be administered systemically or locally to concentrate or limit the effect in a trauma or inflammation site.
(Treatment of Cancer)
Excessive BMP signal transduction (this can be caused due to BMP overexpression, or paradoxically, as a result of deficiency in BMP type II receptor expression (Non Patent Literature 1, and Non Patent Literature 16)) can contribute to tumorigenesis, some solid tumors (including breast cancer and prostate cancer), and bone cancer, lung cancer and renal cell carcinoma proliferation (Non Patent Literature 17) or metastasis (Non Patent Literature 18). In addition, the presence of constitutively active mutation forms of ALK2 in children with high-grade glioma and medium to high-grade astrocytoma has been reported (Non Patent Literature 19).
When BMP overexpression, increased BMP signal activity related to BMP type II receptor deficiency, or BMP signal enhancement due to the presence of constitutively active mutation forms of ALK2 contributing to pathogenesis, inhibiting BMP signal activity at the level of the BMP type I receptor (downstream of both ligands and type II receptors) using the BMP inhibitor described in this specification can be an effective method of normalizing BMP signal activity and then potentially inhibiting tumor proliferation or metastasis.
As either an auxiliary chemical treatment or a primary chemical treatment, the BMP signal inhibitor described in this specification can be used to slow down or stop proliferation or metastasis of the above tumor cells (as well as other tumor constituting cell types) for clinical advantages. Similarly, the BMP signal inhibitor described in this specification can also be used to reduce bone metastatic properties of certain types of cancer (for example, adenocarcinoma such as prostate cancer and breast cancer). In addition, the compounds described in this specification can be used to inhibit osteoblast activity in either bone-forming tumors or bone-derived tumors (such as osteosarcoma) (as an auxiliary chemical treatment or a primary chemical treatment). In addition, the compounds described in this specification can be used to inhibit osteoclastic activity (also regulated by BMP through the action of RANKL in BMP target genes), and osteoclastic activity which is abnormally increased in medical conditions such as multiple myeloma and other bone targeting tumors. When the BMP inhibitor is applied in such medical conditions, the presence of osteolytic lesions and bone fractures due to involvement of a tumor can be reduced.
(Immune Regulation)
It has been reported that BMP attenuates inflammatory responses or immune responses (Non Patent Literature 20), and BMP can impair an individual's ability to fight infectious diseases (specifically, viral infections, bacterial infections, fungal infections, parasitic infections, or human type Mycobacterium tuberculosis infections). Thus, the BMP signal inhibitor described in this specification can enhance inflammatory responses or immune responses, which can allow an individual to more quickly eliminate infectious diseases.
There is increasing evidence that BMP receptors are expressed on cell surfaces of lymphocytes and other immune cells, and thus BMP regulates differentiation and maturation of various humoral and cellular immunological compartments, and BMP also regulates humoral and cellular immune responses in mature organisms. Like the effects of many immunologically important cytokines that are generally known, effects of BMP signals on immune cells can be situation-specific and thus effects of BMP signals increasing or decreasing differentiation or functions of a specific lymphocyte population are empirically determined. The BMP antagonistic action using the compounds described in this specification can be an effective strategy for intentionally biasing differentiation of cellular immune compartments, congenital immune compartments, or humoral immune compartments for treatments, or a strategy for therapeutically biasing immune responses in the mature immune system. Such strategies can target innate disorders in cellular immunity, innate immunity or humoral immunity, or can target disorders in which immune responses are inappropriately weak (for example, if immune treatments using other methods are difficult or ineffective, the compound can be used as an adjuvant for promoting favorable antigen sensitization or can target disorders in which immune responses are excessive or inappropriate (for example, autoimmunity and autosensitization)).
The BMP signal inhibitor described in this specification can also be effective in intentional induction of immune tolerance in some situations (that is, in allogenic transplantation or autoimmunity).
(Treatment of Pathological Osteogenesis)
The BMP signal inhibitor described in this specification can be used to improve pathological osteogenesis/bone fusion in inflammatory disorders such as ankylosing spondylitis or other seronegative spondylarthroses (autoimmunity and inflammation in the above disorders stimulate osteogenesis) (Non Patent Literature 21). As one application of the above compounds, the compounds are used to prevent excessive osteogenesis in patients with specifically spondylitis or chronic rheumatoid arthritis after joint surgery. The BMP signal inhibitor described in this specification can also be used to prevent calcinosis (dystrophic soft tissue calcification) in diseases such a systemic lupus erythematosus, scleroderma, and dermatomyositis.
Due to blunt traumatic damage to muscles, in certain individuals, abnormal osteogenesis in muscles is caused, and thereby a disorder called traumatic myositis ossificans can occur (Non Patent Literature 22). Head trauma and burns can induce ectopic osteogenesis (Non Patent Literature 23), which can significantly impair patient rehabilitation and recovery. A treatment using the BMP signal inhibitor described in this specification, or a treatment with an anti-inflammatory drug (for example, non-steroidal anti-inflammatory drugs such as indomethacin and ibuprofen) that is generally prescribed to treat the above symptoms as necessary, is useful to prevent pathological osteogenesis in individuals susceptible to pathological osteogenesis or is useful to reduce or regress lesions in individuals with pathological osteogenesis that has developed recently or previously. Although reports of ossification developing in other muscles (including myocardium) in the presence of damage or trauma are very rare, similar treatments with the BMP signal inhibitor described in this specification are useful in such situations.
(Treatment of Ectopic Osteogenesis and Maladaptive Osteogenesis)
BMP signals and their transcriptional target are suggested as the cause of initial vascular remodeling and medium-term vascular remodeling and calcification in Monckeberg vascular calcification diseases and atherosclerotic vascular diseases (Non Patent Literature 24). BMP and BMP-induced bone differentiation are also suggested as the cause of heart valve calcification. Innate heart valves can be calcified specifically if they are abnormal for a long time. A typical example is the aortic bicuspid valves, and such valves generally cause calcification, which results in stenosis. Cardiac surgery is often required for patients with calcific aortic stenosis for valve replacement. Abnormal calcification can adversely affect the functions of the prosthetic vascular grafts or heart valve. For example, prosthetic heart valves cause stenosis and calcification which often lead to leakage.
The BMP signal inhibitor described in this specification can be used to inhibit only vascular or valve calcific diseases, and can be used to inhibit vascular or valve calcific diseases combined with atherosclerotic diseases, renal diseases, renal osteodystrophy or parathyroid diseases.
The BMP signal inhibitor described in this specification is administered systemically or administered locally, or directly incorporated into a prosthetic material or other grafts (for example, into a mixture having polymers covering or constituting all or a part of a graft or a prosthetic component), and thus can be used to inhibit calcification of a prosthetic vascular material or a valve material.
In some cases, it is desirable to intentionally inhibit bone fracture healing at specific sites to delay bone fracture healing after bone fracture or to prevent functional damage due to misadaptive osteogenesis. For example, when bone fracture has occurred but it is not possible to perform surgery immediately due to medical or practical reasons, until final surgery or treatment can be performed, bone fracture healing can be delayed or stopped temporarily by use of the BMP signal inhibitor described in this specification. This is so that, for example, the need for later intentional bone refracturing to secure an appropriate positional relationship between fractured bone surfaces of bone fragments can be reduced. When a treatment period is relatively short, it is anticipated that a normal bone fracture healing process will occur upon discontinuation of a BMP signal inhibitor. In other cases, for example, when bone fracture directly affects joints, new bone growth can impair functions with even a small amount. In this case, systemic or local inhibition of BMP activity (by systemic delivery of the BMP signal inhibitor described in this specification or by the local delivery of the BMP signal inhibitor described in this specification through the diffusion from a local graft or a matrix) can be used in a target region to inhibit bone fracture healing or prevent fracture calluses.
(Treatment of Skin Diseases)
In proliferation of keratinocytes cultured in vitro, BMP inhibits keratinocyte proliferation and promotes differentiation (Non Patent Literature 25). For patients who need skin grafts (for example, after burns), skin grafts are prepared from cultured keratinocytes. Keratinocytes can be derived from other animals (xenograft), but they are only temporary because they are rejected by the immune system. Keratinocytes can be derived from patients themselves and can be grown on a cell sheet in a laboratory (cultured epithelial autograft). Patients do not reject keratinocytes derived from their own body. The BMP signal inhibitor described in this specification can be added to a keratinocyte culture to promote keratinocyte proliferation, and thereby patients can receive grafts faster.
Improvement in Epithelialization:
BMP6 is highly expressed in skin injury lesions, and BMP6 at a high level is detected in chronic human wounds with various causes (Non Patent Literature 26). In mice in which BMP5 is overexpressed in the skin, improvement in epithelialization with significantly delayed re-epithelialization and skin wound recovery (Non Patent Literature 26) can reduce scar formation. Superficial administration or systemic administration of the BMP signal inhibitor described in this specification can be used to improve skin wound epithelialization, for example, in treatments of decubital ulcers (bed sores) or skin scars that have not healed or have not sufficiently healed (for example, in patients with peripheral vascular diseases, diabetes mellitus, and venous insufficiency). The compounds are also expected to reduce scar formation.
Promotion of Body Hair Growth:
hair follicle growth of the scalp has a cycle with three phases: a growth phase (proliferation phase), a regression phase (retrogression phase), and a resting phase (telogen phase). Recent evidence suggests that BMP signals delay transition from the resting phase to the growth phase (Non Patent Literature 27). Inhibition of BMP signal transduction using the BMP signal inhibitor described in this specification can shorten the resting phase and increase the number of hair follicles in the growth phase. The BMP signal inhibitor described in this specification can be used in treatment situations in which there are insufficient hair follicles are or when body hairs are lost at a higher frequency than they grow. Such situations include androgenic alopecia (male pattern alopecia), alopecia areata, and telogen effluvium.
Treatment of Psoriasis:
Psoriasis is an inflammatory skin disorder that occurs often in skin trauma and subsequent repair and after inflammation (Koebner phenomenon). Since overexpression of BMP6 in the skin of mice leads to skin lesions similar to those observed in patients with psoriasis (Non Patent Literature 28), BMP may be involved in an inflammatory mechanism causing psoriasis and its repair. The BMP signal inhibitor described in this specification can be superficially or systemically administered to treat established psoriasis or prevent the onset of psoriasis after skin damage.
Treatment of Corneal Scarring:
BMP6 expression is related to conjunctiva scarring (Non Patent Literature 29). The BMP signal inhibitor described in this specification can be used to prevent or treat corneal scarring and consequent blindness.
(Prevention or Treatment of Osteoporosis)
It has been reported that, in BMPR1A conditional KO mice, bone elasticity and toughness have been enhanced and become more effective in combination with exercise (Non Patent Literature 30). In addition, it can be clearly understood that, in this mechanism, attenuation of BMP signals promotes cross-link formation of collagen in osteogenesis and promotes accumulation of minerals in the femur (Non Patent Literature 31). The BMP signal inhibitor described in this specification that inhibits BMP signal transduction can be used to increase bone mass and bone density.
In addition, the BMP signal inhibitor described in this specification can be used to provide a bone mass loss ameliorating agent that allows a long-term stay in space. That is, this provides a guideline that administration of the BMP signal inhibitor is effective for a reduction in the bone mass in a microgravity environment which is one of space medical problems. In addition, in Japan with the declining birthrate and aging population, it is predicted that the number of bedridden elderly people will be 2.3 million in 2025 and that there will be 2.60 million middle-aged people (Annual Report on Health, Labor and Welfare 2011). The BMP signal inhibitor described in this specification can be used to develop a bone mass reduction preventive drug or an osteoporosis therapeutic agent for elderly people.
(Treatment of Systemic Hypertension)
Injection of BMP4 induces systemic hypertension in mice (Non Patent Literature 32). Vascular smooth muscle cells express various BMP ligands. BMP increases expression of voltage-gated potassium channels, and accordingly, increases contraction of vascular smooth muscles (Non Patent Literature 33), and the BMP signal inhibitor described in this specification that inhibits BMP signal transduction can be used to lower a blood pressure. A sustained reduction in blood pressure in patients with hypertension is expected to prevent myocardial infarction, congestive heart failures, cerebrovascular diseases, and renal failure. The BMP inhibitor described in this specification can be used to target hypertension in specific vascular beds such as pulmonary hypertension via local delivery (for example, via an aerosol).
(Treatment of Pulmonary Hypertension)
BMP signal transduction contributes to the cause of pulmonary hypertension. For example, mice with a reduced BMP4 level are protected from pulmonary hypertension and pulmonary vascular remodeling induced due to breathing over the long term at a low oxygen concentration (Non Patent Literature 34). In addition, mutations in genes that encode type II BMP receptors (BMPRII) are frequently observed in patients with sporadic and familial pulmonary arterial hypertension. It is expected that reduction in BMP signal transduction will cause pulmonary hypertension. However, Yu et al have reported that BMPRII deficiency paradoxically increases BMP signal transduction according to some BMP ligands (Non Patent Literature 16), and thereby a modulation in BMP signal transduction using the BMP signal inhibitor described in this specification can actually contribute to the improvement of pulmonary hypertension.
The BMP signal inhibitor described in this specification can be used to prevent the development of the disease in patients at risk of pulmonary arterial hypertension (for example, patients with BMPRII mutations) or treat patients with idiopathic or acquired pulmonary arterial hypertension. Reduction in pulmonary hypertension in individuals treated with the BMP signal inhibitor described in this specification is expected to reduce short breath, right ventricular hypertrophy, and right ventricular failures.
(Treatment of Ventricular Hypertrophy)
A BMP10 level increases in hypertrophied ventricles of rats with hypertension, and the BMP ligands induce hypertrophy in cultured neonatal rat ventricular myocytes (Non Patent Literature 35). According to inhibition of BMP10 signal transduction using the BMP signal inhibitor described in this specification, ventricular hypertrophy can be prevented and treated. Ventricular hypertrophy can lead to congestive heart failures due to diastolic dysfunction. The BMP signal inhibitor described in this specification is expected to prevent and treat congestive heart failures.
(Treatment of Angiogenesis)
There are two types of age-related macular degeneration: atrophy type and exudative type. In the exudative type, there is accompanying neovascularity from the vascular choroid, and bleeding and exudation under the retina occur, rapidly progress, and cause deterioration in eyesight. The cause is thought to be secretion of cytokines such as a vascular endothelial growth factor (VEGF) and induction of choroidal neovascularization, and an anti-VEGF drug therapy in which neovascularity is prevented by neutralizing increased VEGF in the eye due to age-related macular degeneration is performed. Anti-VEGF drugs that can be used clinically in Japan include RNA aptamer preparations, humanized anti-VEGF neutralizing antibodies, and soluble decoy receptor fusion proteins. Such anti-VEGF drugs significantly reduce intraocular VEGF when repeatedly administered through intravitreal injection every 4 to 8 weeks, and regress choroidal neovascularization, and as a result, the eyesight can be improved and maintained. However, there are cases in which it is not possible to completely eliminate exudative changes even if intravitreal injection is performed monthly, and there are cases in which there is repeated recurrence during the course of long term treatment and the eyesight deteriorates. It is suggested that there are many factors other than VEGF that affect the development and progression of age-related macular degeneration and BMP is involved as one of them.
Involvement of signals in angiogenesis through ALK1 receptors has been reported and the relationship of signal transduction activation by its ligand BMP9 with blood vessel extension in tumor proliferation has been revealed (Non Patent Literature 36). Such findings suggest that the BMP signal inhibitor can be used as an anti-cancer agent that has an effect of preventing angiogenesis, and inhibition of BMP signal using the BMP signal inhibitor described in this specification could be an effective method of potentially inhibiting tumor proliferation or metastasis. In addition, there is a limit to treatment in which only VEGF is inhibited in order to prevent angiogenesis in exudative type age-related macular degeneration, and a treatment in which other factors are inhibited is desirable. Therefore, it is expected that the BMP signal inhibitor described in this specification would be locally (such as eye drops) or systemically administered as a small-molecule drug, and prevent bleeding and exudation under the retina, and as a result, prevent and treat blindness.
(Treatment of Neurological Disorders)
Treatment of Spinal Cord Injury and Neurological Disorders:
BMP is a potent inhibitory factor for axonal regeneration in the adult spinal cord after spinal cord injury (Non Patent Literature 37). It has been reported that BMP expression increases in oligodendrocytes and astrocytes around an injury site after spinal cord contusion. Intrathecal administration of noggin as a BMP signal inhibitor leads to enhancement in motor activity and significant regrowth of the corticospinal tract after spinal cord contusion.
Repulsive guidance molecule a (RGMa) inhibits axon proliferation and recovery, and synapse re-formation after spinal cord injury, and the effects of RGMa are blocked by antibodies for RGMa (Non Patent Literature 38). RGMa enhances BMP signal transduction (Non Patent Literature 39), and this suggests that BMP signal transduction can be the cause of axon proliferation and recovery interruption.
Based on this consideration, the BMP signal inhibitor described in this specification is expected to enhance axon proliferation and recovery after spinal cord injury. The BMP signal inhibitor described in this specification is expected to prevent and treat neurological disorders related to a wide range of disorders including diabetes mellitus. The BMP signal inhibitor described in this specification is expected to treat any of pains and motor dysfunctions related to neurological disorders.
Treatment of Neurological Disorders Related to Central Nervous System Inflammation:
BMP4 and BMP5 are detected in multiple sclerosis and Creutzfeldt-Jakob disease lesions (Non Patent Literature 40). BMP is also detected in mice with experimental autoimmune encephalomyelitis (animal models with multiple sclerosis) (Non Patent Literature 41). The BMP signal inhibitor described in this specification can be used to prevent and treat multiple sclerosis and other neurological disorders that are related to central nervous system inflammation or related to misadaptive damage repair processes mediated by BMP signals.
Treatment of Dementia:
A BMP signal transduction inhibitor can promote neurogenesis in neural progenitor cells of mice (Non Patent Literature 42). The BMP signal inhibitor described in this specification can be used to enhance neurogenesis in various neurological disorders involving an accelerated loss of neurons (including cerebrovascular diseases and Alzheimer's disease, and other dementias).
Change in Memory and Learning:
BMP signal transduction has an important role in the development and maintenance of neurons involved in memory and cognitive activity. For example, mice deficient in chordin as a BMP signal inhibitor had improved spatial learning but had degraded exploratory behavior in a novel environment (Non Patent Literature 43). The BMP signal inhibitor described in this specification can be used to change or prevent memories or learning (including, for example, amnesia in anesthesia or other situations in which pain is caused), and can be used to prevent post-traumatic stress disorders.
(Treatment of Arteriosclerosis)
Much evidence suggests that BMP ligands are pro-inflammatory and proatherogenic in blood vessel walls (Non Patent Literature 44). Knockdown of BMP4 expression reduces inflammatory signals and on the other hand, knockdown of BMP inhibitors (for example, follistatin or noggin) increases inflammatory signals. The BMP signal inhibitor described in this specification can be used to reduce vascular inflammation related to atherosclerotic arteriosclerosis, autoimmune diseases, and other vasculitis. The BMP signal inhibitor described in this specification is expected to reduce acute coronary syndromes (angina pectoris and heart attack), transient ischemic attack, strokes, peripheral vascular diseases, and other vascular ischemia events due to the reduced atherosclerotic arteriosclerosis. In addition, in so far as atherosclerotic arteriosclerosis contributes to the cause of aneurysm formation, the BMP signal inhibitor described in this specification can be used to slow the progress of aneurysm formation, which can reduce frequent occurrence of aneurysm structures and the need for vascular surgery.
Since BMP and many BMP-inducible gene products that affect matrix remodeling are overexpressed in initial atherosclerotic lesions, BMP signals can promote plaque formation and progress (Non Patent Literature 45). BMP signal transduction activity in atherosclerotic plaque can therefore represent a form of maladaptive damage repair or can contribute to inflammation. BMP signals can gradually induce differentiation of resident vascular cell populations or neovascular cell populations into osteoblast-like cells, which can lead to short-term or medium-term calcification of blood vessels (Non Patent Literature 46). Calcific vascular diseases or arteriosclerosis is related to a reduced vascular index and an increased risk of cardiovascular events and an increased mortality rate, and is particularly problematic when associated with potential atherosclerotic diseases (Non Patent Literature 47). However, when signals contributing to the progress of atherosclerotic lesions and calcific lesions are blocked, all such lesions can regress (Non Patent Literature 48). Yu et al. found that the inhibitor against the BMP type I receptor activity is effective in treatments for atherosclerotic plaque and vascular calcification (Non Patent Literature 49), and the inhibitors against the BMP type I receptor activity described in this specification can be used to inhibit the progress of atherosclerotic plaque and vascular calcification in vivo.
(Proliferation, Engraftment and Differentiation of Progenitor Cells Including Embryonic Cells and Adult Stem Cells In Vitro and In Vivo)
BMP signals are important to regulate differentiation and regeneration of progenitor cell populations and stem cell populations (in addition, tissues in some situations), and this regulation prevents differentiation into differentiation lines (and on the other hand, directs differentiation in other situations). The BMP signal inhibitor described in this specification can be used (i) to maintain a pluripotent state of stem cell populations or pluripotent cell populations in vivo or in vitro; (ii) to proliferate stem cell populations or pluripotent cell populations in vivo or in vitro; (iii) to direct differentiation of stem cell populations or pluripotent cell populations in vivo or in vitro; (iv) to manipulate or direct differentiation of stem cell populations or pluripotent cell populations in vivo or in vitro (either alone, in a combination with other treatments, or in series with other treatments); and (v) to regulate dedifferentiation from differentiation cell populations to pluripotent populations or precursor populations.
BMP signals are required for many stem cell lines and precursor series to determine whether they proliferate, differentiate into specific tissue lines, reach and integrate specific tissue types, or cause programmed cell death. Often, BMP signals interact with signals provided by growth factors (bFGF, PDGF, VEGF, HBEGF, PIGF, and others), sonic hedgehog, notch, and the Wnt signal pathway and affect the above changes (Non Patent Literature 50). The BMP signal inhibitor described in this specification can be used to direct differentiation of stem cells (for example, embryonic stem cells) or tissue precursor cells into specific lines for therapeutic applications (Non Patent Literature 51). In addition, in certain cell populations, the BMP signal inhibitor described in this specification can be effective in preventing differentiation and promoting proliferation in order to produce a sufficient number of cells effective for clinical applications. Exact combinations of BMP signal inhibitors, growth factors or signaling molecules can be very specific to cells and tissue types.
For example, some embryonic stem cell lines need to be co-cultured with a leukemia inhibitory factor (LIF) in order to inhibit differentiation of some cultured embryonic stem cell lines and maintain pluripotency (Non Patent Literature 50). The use of the BMP signal inhibitor described in this specification can be used to maintain pluripotency in the absence of LIF. Other ES cell lines need to be co-cultured with specific feeder cell layers in order to maintain pluripotency. The use of the BMP signal inhibitor described in this specification, alone or an in combination with other drugs, can be effective in maintaining pluripotency when contamination with feeder cell layers is a concern or a DNA or protein component makes it difficult or prevents the use of cells for human treatment.
In another example, in some situations, inhibition of BMP signals with proteins such as noggin just before LIF inhibition in the culture can induce differentiation into myocardium cell differentiation lines (Non Patent Literature 52). The use of the pharmacological BMP signal inhibitor described in this specification can have similar (if not, potent) effects. The differentiation cells can be therapeutically introduced into pathological myocardium. In addition, such a treatment can actually be more effective for engrafted progenitor cells that have already reached pathological myocardium. A systemic treatment using a BMP signal proteinaceous inhibitor (such as noggin) is very expensive and requires a complex dosing method. Systemic or local delivery of the BMP signal inhibitor described in this specification can bias differentiation of the progenitor cells in situ to functional myocardium cells.
(Application of Compounds Having Varying Degrees of Selectivity: A Compound that Inhibits BMP Signal Transduction Via a Specific BMP Type I Receptor or a Compound that Affects Signal Transduction Via TGF-β and an Activin Receptor)
The BMP signal inhibitor described in this specification inhibits activity of BMP receptors: ALK2, ALK3, and ALK6. Some of them inhibit ALK2 and ALK3 to a higher degree than ALK6, and have a relatively higher selectivity with respect to a specific BMP receptor. It is thought that certain diseases can be caused due to signal transduction dysfunction of certain specific receptors.
For example, fibrodysplasia ossificans progressiva (FOP) is a disease caused by abnormal (constitutively active) ALK2 functions (Non Patent Literature 4). In addition, the presence of constitutively active mutation forms of ALK2 in pediatric high-grade glioma and medium to high grade astrocyte species has been reported (Non Patent Literature 19). In such examples, the BMP signal inhibitor described in this specification that specifically antagonizes a function of some BMP receptors can have advantages of reduced toxicity or side effects or higher efficacy, or can have all of these advantages.
Some of the BMP signal inhibitors described in this specification can have a high degree of selectivity for BMP compared with TGF-β, and activin receptor signal transduction. Other compounds can have a lower specificity and target other pathways in addition to BMP signal. For example, in a tumor treatment, when specific tumor molecular phenotyping of a certain patient exhibits dysregulation of a plurality of pathways, a drug that inhibits BMP signal and one or more of the above pathways can have a beneficial effect (for example, reduction in size of tumor).
(Application of Compound in Species Other than Human)
The BMP signal inhibitor described in this specification can be used to treat subjects (for example, humans, household pets, livestock, and other animals) according to the use of a dosage and a dosage regimen that are appropriately determined by those skilled in the art, and parameters of the dosage and the dosage regimen can be changed depending on, for example, the type and degree of a disorder to be treated, overall health conditions of a subject, a therapeutic index of the compound and an administration pathway. A standard clinical test can be used to optimize the dosage and frequency of administration for a certain specific pharmaceutical composition of the present invention. Examples of administration pathways that can be used include oral administration, parenteral administration, intravenous administration, intraarterial administration, subcutaneous administration, intramuscular administration, surface administration, intracranial administration, intraorbital administration, ocular administration, intraventricular administration, intracapsular administration, intravertebral administration, intracisternal administration, intraperitoneal administration, intranasal administration, aerosol administration, and suppository administration.
(Inhibition of BMP Signal Transduction in Insects)
Some of the BMP signal inhibitors described in this specification can have activity for arthropod BMP receptors, and presumably, have selectivity for arthropod BMP receptors relative to chordate BMP receptors. Inhibition of BMP signal transduction in arthropod larvae or eggs can cause serious developmental abnormalities and probably can cause impairment in their reproductive ability (for example, dorsalization similar to that observed when the pathway is inhibited in zebra fish and Drosophila). When the BMP signal inhibitor described in this specification has a much stronger selectivity for arthropod BMP receptors than human BMP receptors, the BMP signal inhibitor described in this specification can be used as an insecticide or a pest control agent that is apparently less toxic and safer than current strategies from a viewpoint of protection of the environment.
In addition to administration to patients in a treatment method, the BMP signal inhibitor described in this specification can be used to treat cells and tissues transplanted into patients and structural materials ex vivo. For example, the compounds can be used to treat explanted tissues that can be used, for example, in transplantation.
While the present invention is generally described here, the present invention will be more easily understood with reference to the following examples. The following examples are included to simply exemplify specific aspects and embodiments of the present invention, and do not limit the present invention.


Techniques for processing cocoa mass are provided. In general, the techniques involve solvent extraction of cocoa fat from cocoa mass, to achieve a desirable cocoa butter and low-fat cocoa powder. In one preferred process, the cocoa mass is the result of grinding cocoa nibs, with absence of a mechanical pressing and heating step, to advantage. Preferred products and uses are characterized.

Cocoa beans may be processed into cocoa butter and cocoa powder. Cocoa butter represents a portion of the fat content isolated from the cocoa beans. The cocoa powder represents remaining solids, after processing to recover cocoa butter.
Cocoa butters are widely utilized food additives. For example, cocoa butter is used in the production of chocolate. Cocoa powder is also used as a food additive for flavor and color, for example, to produce chocolate flavored milk, cake mixes and brownie mixes.
In general, cocoa beans are harvested in tropical countries. Beans from different regions do provide somewhat different tastes or characteristics. For example, for chocolate, many European manufacturers prefer beans from Ghana and Nigeria (Ivory Coast) because of their flavor. For top quality chocolate, South American, West Indian and other so-called flavor beans are often used. The pressing industry may select beans containing fat with higher melting points, such as those obtained from Malaysia. Regardless of the source, the same general processing techniques have been used.
In typical processing, the cocoa beans are harvested within a husk. Typically, the beans are dried in the fields, and dehusked. The beans are then subjected to various forms of heating, for example to intense infrared treatment, to pop the shells and in some instances for microbiological control. The shelled beans are generally referred to as cocoa nibs. The nibs are separated from the shells, for processing.
In typical processing operations, the nibs are roasted and in some instances subjected to dutching (alkali treatment or alkalization). The nibs are then ground, often with significant generation of heat.
The grinding is generally done to provide a fineness in the mass such that there will be no grittiness felt in the mouth, when eating resulting products containing the cocoa powder. The grinding is normally carried out in a series of mills; for example, pre-grinding to a size of less than 300 microns using a hammer mill, blade mill, disc mill or ball mill, followed by fine grinding using a triple disc mill or staged agitator ball mills. In general, sufficient grinding is conducted so that the resulting cocoa powder, after separation of the cocoa butter, will have a particle size of less than 1 wt. % retained on a 200 micron sieve and less than 30% retained on a 30 micron sieve. A typical average particle size would be between 2 microns and 20 microns.
Some manufacturers do not grind the nibs sufficiently to achieve this fineness, but rather engage in further refinement with later processing steps.
In general, the mass which results from grinding of the nibs is referred to as "cocoa mass" or "cocoa liquor". At room temperature, it is a thick solid mass; however, when heated above the melting point of the fat it forms a viscous, flowable slurry. Typical cocoa liquors contain about 50-58% fat and 42-50% powder (or remaining solids), by weight. The moisture content of cocoa liquor is generally at a maximum of about 2.5%. The pH is typically within a range of 5.2-6.0. The shell content, by weight, is generally no more than about 1.75%. The fat content of cocoa liquor is that portion generally referred to as "cocoa butter", after it has been separated from a remainder of the mass.
In general, about 30% of the world cocoa bean crop is converted into cocoa mass in a country where it is grown. This material is sometimes referred to as "original" liquor or mass. In later processing, such mass is not necessarily used alone, but sometimes is blended with mass or liquor from other sources.
In conventional "press" processing, cocoa liquor is mechanically pressed, to physically "squeeze" a portion of the fat out. In some instances the mass may be washed, to modify flavor or color. Generally up to about 80-85% of the fat content (of the 50-58%) can be removed from the cocoa mass, by mechanical pressing. This typically leaves a cake comprising about 10-20% butter (often 11-12%), by weight, the remaining comprising cocoa powder. Cocoa powder with a fat content of about 10% or below is often referred to as low-fat cocoa powder. The fat which is isolated by mechanical pressing is typically called "press butter".
The time and pressure it takes to remove the fat by pressing, to generate isolated press butter, increases substantially when the process is practiced to reduce the residue cake from about 20% fat content to about 11% fat content or lower. To reduce the fat content from 20% to about 10% may require twice as long of a processing (pressing) operation, as to reduce to 20%. Indeed, it may not be practical or even possible to get to less than about 5-9% fat, by weight, in the resulting cocoa cake, by conventional pressing techniques.
According to one report, whole cocoa beans have been processed without previous deshelling by continuous expeller techniques. The expeller cake and various resulting cocoa waste materials would then apparently be defatted by means of solvent extraction. The defatted residues from such a process, however, would be unlikely to be useful as food products, since they would contain large particles, such as shells and miscellaneous ditrious associated with the shells, which provide an unpleasant feel to the product. The isolated fat from such sources (which may include fats from portions of the cocoa bean other than just nibs) would also likely be of inferior quality.
Herein the term "cocoa butter" will be used to refer to the fat which is isolated from cocoa mass, during a separation process. Cocoa butter, which primarily comprises triglycerides of acids such as oleic acid, palmitic acid, and stearic acid, is a relatively valuable vegetable oil commodity. It is somewhat unique among vegetable oils, because of the combination of its taste, mouth feel and melt characteristics. These, in part, result from crystalline forms of some of its constituents, which provide for a sharp melting point just below body temperature. Also, the heat required to melt the crystals in cocoa butter results in a characteristic "cooling" sensation in the mouth, a highly desired quality of cocoa butters when used as food additives.
The remaining mass resulting from pressing of the cocoa mass, is referred to herein as "cocoa cake". As indicated above, with conventional press processing, the cocoa cake comprises about 10-20% cocoa butter, by weight. Again, this represents the (practical) maximum extent to which typical, conventional, mechanical pressing operations can remove cocoa fat from the cocoa liquor.
Typically, the resulting cocoa cake (after butter recovery) also comprises a useful commodity. It is generally ground into a powder and packaged for a variety of used. For example, cocoa powder made in this manner is used as a flavorant (and for color) in such materials as cake mixes, frostings, cookies, chocolate and drink mixes.
Conversion of the cocoa cake to the cocoa powder is no trivial matter. Due to the fat content, typically 10% or greater, the cocoa cake after pressing will be a clumped-together mass. To convert it to a powder, it must be cooled sufficiently and maintained sufficiently cool, while it is broken up; and, in some instances it must be further ground and sieved, again without generation of sufficient heat to reclump, due to the fat content. In general it must be maintained below about 27-300C., or the fat content will tend to melt and generate clumping.
Cocoa beans have been processed by pressing generally in the manner described above for many decades. As indicated, the two principal commodities obtained are: the cocoa butter isolated from the pressing steps; and, the cocoa powder, typically containing about 10-20% cocoa fat by weight.
In some applications, the fat content (10-20%) of the cocoa powder has been found undesirable. These are applications in which it is desired that the ultimate food product which is manufactured contain relatively low amounts of various added fats or oils. In recent years, then, processes of reducing the fat content of cocoa powder have been examined. In general, fat-free cocoa powders, i.e., cocoa powders containing no more than about 0.5% by weight cocoa butter, have been generated by extracting the cocoa powder obtained after pressing, via a supercritical carbon dioxide extraction. The supercritical extraction reduces the residual fat content of the cocoa powder, leaving the powder defatted.


A Sheet Set Manager for a computer-implemented graphics program allows drawings to be organized logically as a Sheet Set comprising a collection of Sheets and Subsets of Sheets, wherein each Sheet comprises a drawing, layout or view. The Sheet Set Manager is a graphical user interface for displaying, accessing and managing the Sheet Sets, Subsets and Sheets, as well as editing components of the Sheet Sets, Subsets and Sheets.

1. Field of the Invention
The present invention relates generally to graphics programs, and in particular, to a sheet set manager for a graphics program.
2. Description of the Related Art
For drafting and design professionals, drawing sets are used to communicate design intent. In most cases, drafting and design professionals will present or deliver their design presentations and deliverables to their clients many times during a project. These design presentations and deliverables are typically an organized set of drawing sheets that systematically specify a design. Each sheet in the set comprises a composition of model data and annotative data that is used to express a specific area, part, or view of the design.
In most graphics programs, the highest level of organization provided is a file. Historically, in the absence of automated tools, many users have adopted standards for manually organizing their files, through file contents and file naming conventions. One such standard is the National CAD Standards (NCS), which dictates a consistent method that firms can use to structure their files to work like physical sets of drawing sheets. However, while it is currently possible to manually organize a set of drawing sheets using files, the result does not fit well into users' actual workflow.
Accordingly, what is needed are automated tools for organizing sets of drawing sheets. Specifically, there is a need in the art for a set of tools for use with computer-implemented graphics programs that assists users to create, deploy, manage, and publish sets of drawing sheets.

This patent is subject to a terminal disclaimer.

Automatic view creation in a sheet set manager for a graphics program


Disclosed herein is a vehicle transport apparatus for parking systems. The vehicle transport apparatus of the present invention includes a first platform, onto which a vehicle is placed, a second platform, which is provided in a parking space, and a pair of carriers and which move between the first platform and the second platform. Each carrier includes a main frame, a drive wheel which is provided in the main frame, a drive motor which rotates the drive wheel; a pair of arms which are rotatably mounted to each of opposite sides of the main frame, and a hydraulic device which rotates the arms. The arms lift the wheels when extracted from the main frame, and the carriers transports the vehicle lifted by the arms from one platform to another platform.

Recently, automatic parking systems have been widely used for efficiently parking a large number of vehicles in limited spaces. Such a parking system includes a structure, such as a parking building or a parking tower, having therein a plurality of parking spaces, and a transport mechanism, which is provided in the structure and puts vehicles into or extracts them from the inner space of the structure.
Furthermore, in the parking system, a vehicle support plate which is called a pallet is used for parking vehicles. In detail, when a vehicle is placed at a predetermined position near an entrance of the structure for parking, the entrance opens. Thereafter, a driver parks the vehicle at a desired position on a pallet, which is provided at the bottom of the structure. Subsequently, the driver comes out through the entrance and operates a control panel, which is provided around the entrance, such that a parking process is conducted. Then, the transport mechanism, such as an elevator, carries the pallet, on which the vehicle is loaded. Subsequently, the transport mechanism places the vehicle along with the pallet into a vacant parking space, thus completing the parking process. Therefore, a pallet must be provided to every parking space in the structure. However, the conventional parking system using the pallet has the following disadvantages.
First, a lot of time is required to put a vehicle into or to extract it from the parking system. For example, when the vehicle is put into the parking system, the transport mechanism moves to a vacant parking space, takes a vacant pallet, and moves along with the vacant pallet to the entrance. Furthermore, when it is desired to consecutively park a plurality of vehicles into parking spaces of the parking system, because the above-mentioned parking processes are repeatedly conducted, time consumption increases. Moreover, when it is desired to extract the vehicles from the parking spaces of the parking system, the transport mechanism must put a vacant pallet for a first vehicle into a related parking space prior to extracting a subsequent vehicle after the first vehicle has been extracted. As such, because it is required to put the pallets into and to extract them from the parking spaces, the time required to put the vehicle into the parking system and extract it therefrom increases. Therefore, the waiting time at the entrance increases, so that the entrance of the parking system is congested, thus inconveniencing drivers.
Second, because a pallet must be provided in each parking space, and incidental equipment for the pallet is required, the parking system is very complex and has an increased volume. Accordingly, the incidence of malfunction is increased, and installation cost and maintenance cost are increased.
Third, every time the pallet is moved, noise and vibration occur. That is, typically, each pallet is larger than a vehicle so as to support the vehicle. As such, when a large pallet is put into or extracted from a parking space, vibration and noise occur. Disclosure of Invention Technical Problem
Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a vehicle transport apparatus for a parking system which rapidly parks and extracts vehicles in and from the parking system, and a method for automatically transporting a vehicle using the same.
Another object of the present invention is to provide a vehicle transport apparatus for a parking system which has a simple structure.
A further object of the present invention is to provide a vehicle transport apparatus for a parking system which reduces vibration and noise.

Apparatus for transporting a motor vehicle in a parking system