An electromagnetic switch mounted on a starter for cranking an internal combustion engine includes an excitation coil for driving a plunger upon supplying electric current to the excitation coil. A conductor member led out from the excitation coil is connected to an outside cable to supply electric current to the excitation coil. The conductor member is made of a thin plate to be easily led out from a molded contact cover and is connected to a reinforcing member made of a thick plate that is embedded in the contact cover. The outside cable is connected to the reinforcing member so that the thin conductor member is not damages by a high vibration of an engine. The outside cable is easily connected to the reinforcing member with a screw after completion of the electromagnetic switch.

1. Field of the Invention
The present invention relates to an electromagnetic switch to be mounted on a starter for cranking an internal combustion engine, and more particularly to a structure for leading out a conductor member in the electromagnetic switch.
2. Description of Related Art
An electromagnetic switch to be mounted on a starter for cranking an internal combustion engine usually includes a plunger driven by an excitation coil and a movable contact moving in an axial direction of the plunger according to movement of the plunger. Electric current is supplied to the excitation coil from an on-board battery through a conductor member connected to the excitation coil. The conductor member is led out through a molded contact cover and extends outside to be connected to an outside cable connected to the battery through an ignition switch. It is required to connect the conductor member to the outside cable by a screw-fastening or welding without using solder-connection in order to withstand a high vibration transferred from an automotive vehicle. At the same time, the conductor member has to be easily led out from the contact cover in an automated manufacturing process.
To meet these requirements, an electromagnetic switch is proposed in JP-A-2002-313205. In this electromagnetic switch, a lead terminal having a high mechanical strength is used in place of a fragile conductor member for supplying excitation current. Since the lead terminal is led out straight in the axial direction through the contact cover, the electromagnetic switch can be assembled in an automated manufacturing line. In the proposed electromagnetic switch, however, a large connecting portion for electrically connecting the lead terminal to the outside cable cannot be provided at an end of the lead terminal, because the lead terminal has to be led out through a through-hole formed in the contact cover. It is, of course, possible to connect a large connecting portion having a female screw hole to the end of the lead terminal by welding after the process of assembling the switch is completed. However, this requires an additional step in the manufacturing process.
Further, to give a sufficient mechanical strength to the lead terminal against high vibration, it is necessary to use a bulky lead terminal which requires enlargement of the contact cover in size. A portion of the lead terminal led out from the contact cover vibrates in a manner of a cantilever supported at a point leading out the lead terminal. Therefore, the size of the lead terminal cannot be made unreasonably large. Further, if the lead terminal is vibrated due to vibration of the outside cable, there is a possibility that the lead terminal may be disconnected.
Another conductor member structure of the electromagnetic switch is proposed in JP-A-2004-111231. In this structure, an end of the outside cable is connected to a molded cover via an eyelet terminal. If a large stress is imposed on the eyelet terminal, there is a possibility that connection of the eyelet terminal to the molded cover is loosened and a conductor member connected to the excitation coil may be disconnected due to vibration transferred from an engine.


A temporary pipe plug comprised of a lightweight main body encircled by an outer sealing surface. The outer sealing surface has a rounded edge which contacts the gasket on the bell end of a sewer or water pipe. A boss is affixed to the main body which provides attachment of a chain to the plug. The chain is used for easy removal of the plug.

This invention relates generally to pipe plugs and more specifically to temporary pipe plugs as used during the construction of sewer lines and the like.
In the course of construction of sewer or water lines, it is often desirable to plug the open end of a pipe in a temporary or semi-temporary manner. The simplest means for effecting a sort of plugging is to prop a piece of plywood of suitable size against the open end of the pipe and to hold it in place by driving a stake behind it. This method, although widely used, does not afford a good seal and allows gravel and other debris to enter the pipe.
Other more sophisticated devices are available but each has certain drawbacks when compared with the present invention. None of these are known to be available in sizes larger than 12 inches in diameter.
A plug is available in which an expandable mass of rubber is squeezed between two metal plates by means of a threaded member, the latter of which extends beyond the end of the pipe. This plug is awkward to install and with the threaded portion exposed, the plug may be dislodged or broken if the threaded member is struck by a tool during the course of construction.
Air bags have also been used to temporarily seal the ends of pipes, but they are subject to puncture and require an air line to install them.
Other Plugs, such as ductile iron plugs, may be used in a temporary manner to seal a pipe. However, these plugs are very heavy and must be pushed into place with a backhoe. They are very difficult to remove.
The present invention overcomes the problems associated with the above-mentioned plugs. The present invention provides a lightweight, durable and inexpensive temporary pipe plug. The plug of this invention may be installed and removed manually. When in place, the plug is virtually flush with the end of the pipe it seals and, therefore, not subject to damage by tools or machinery being used in its vicinity.
It is one object of the present invention to provide a temporary pipe plug that may be installed and removed manually.
Another object of the present invention is to provide a pipe seal that is not susceptible to damage from the use of tools and machinery in its vicinity.
Yet another object of the invention is to provide a temporary pipe plug that may be conveniently made in virtually any size.
In accordance with the invention, a temporary plug for placement into an open end of a pipe, includes a rigid body portion including an outer peripheral surface in close proximity to an inner peripheral surface of the pipe when the plug member is in place in the pipe. Sealing means is interposed between the outer peripheral surface of the body portion and the inner peripheral surface of the pipe for preventing debris from entering the pipe. Handle means is connected to the body portion for allowing manual removal of the plug from the pipe.
In one embodiment, the body portion comprises a multi-layer body member to which a peripheral sealing ring is mounted. In another embodiment, a peripheral groove is formed in an outer surface of the body portion, and a resilient sealing ring is positioned in the groove.
In yet another embodiment, the outer edge of the body portion is provided with a ramped or angled surface which contacts an angled sealing surface formed on an internal gasket mounted to the pipe. The angled outer surface of the body portion provides contact with the gasket along less than the entire length of the gasket sealing surface, to facilitate manual removal of the body portion. In one form, the angled outer surface extends linearly, when viewed in cross-section, between the front face and the rear face of the body portion. In another form, a pair of flat surfaces or lands are provided on the outer surface of the body portion. A first, smaller diameter land is located forwardly of the angled surface and a second, larger diameter land is located rearwardly of the angled surface. The angled surface extends between the rear of the smaller diameter land and the front of the larger diameter land.
In a further embodiment, the outer edge of the body portion is defined by a sealing ring which extends throughout the width of the body portion, between the front and rear faces of the body portion. The ring is preferably formed of a thermoplastic material. In one form, the ring defines an annular internal space, with a central lip extending inwardly into the annular space. A laminated core is secured to the ring within the annular internal space defined by the ring. The core consists of a front member and a rear member, placed one on either side of the lip and engaging the edges of the lip. One or more intermediate members may be positioned between the front member and the rear member inwardly of the lip. The front member, the rear member, and any intermediate members are secured together by any satisfactory means, such as threaded fasteners, to secure the members making up the laminated core to the sealing ring. In another form, the temporary plug may be an integral one-piece member molded of a thermoplastic material, with the sealing ring making up the outer peripheral portion of the one-piece member.
The handle means preferably comprises a flexible elongated member, such as a chain or cable, connected to the body portion. The chain or cable normally hangs downwardly to prevent interference with work being performed around the end of the pipe, and it can be grasped by the user to remove the plug member from the pipe.
The invention further contemplates a method of temporarily sealing the end of the pipe, substantially in accordance with the foregoing summary.
Other objects, features and advantages of the invention will be apparent when the description is considered in conjunction with the accompanying drawings.

Plug for temporarily sealing the end of a pipe


A mobile communication terminal includes a receiver (2) receiving a radio wave from base stations, a detector (5, 6, 7) detecting spread codes from the signal received by the receiver (2), a demodulator (8) demodulating the received signal with the spread codes detected by the detector (5, 6, 7), a decoder (9) decoding data demodulated by the demodulator (8), and a control unit (4) controlling processing during cell search, and stopping processing of the data in response to reception of invalid data. Since the control unit (4) stops the processing of the data if it receives the invalid data, the cell search can be performed fast.

In recent years, mobile communication terminals such as a portable telephone and a mobile telephone have been widely used, and various kinds of multiple access methods have been developed for use in such mobile communication systems. Among them, a CDMA (Code Division Multiple Access) method has been employed in portable telephones and others because it has high quality reception capability through the exploitation of multipath fading, and can achieve a high utilization efficiency of radio resource (can increase a subscriber capacity).
FIG. 8 is a schema which shows that the mobile station can receive a number of radio waves transmitted from adjacent cells via multiple propagation paths (multipath). In general, a plurality of base stations (BS1–BS5) are arranged regularly, and cells of the base stations form a regular polygon if these base stations are arranged to cover a service area with as high a electric field as possible, as is well known and shown in FIG. 8. When a mobile communication terminal (MS) performs the cell search, it receives a plurality of radio waves from respective base stations, and additionally receives radio waves (multipath), which are transmitted from various base stations, and are shifted in timing from each other due to wave reflection and diffraction. This multipath is not necessary, and therefore is deleted during the cell search operation by an appropriate manner.
A stepwise search method has been known as a fast cell search method. FIG. 9 shows a processing procedure for detecting and deleting multipath components in the stepwise search method. First, slot timing for those including multipath components is detected (short-period detection) (S101). Detection of slots is performed by detecting search codes of the slots. By detecting the frame timing code, the frame timing is detected (long-period detection), and further the code group is detected (S102).
In addition to the code group, the candidate codes which belong to the group is further evaluated (S103), and finally a spread codes is identified. Information such as spread codes, which is required for recognizing the multipath, is stored in a memory 110 (S104). In this manner, the multipath is recognized based on the information of code and timing stored in memory 110, and the multipath is deleted from the obtained information (S105). The information, from which the multipath is deleted as described above, is decoded so that an amount of decode processing is reduced, and fast cell search can be achieved.
However, the multipath is deleted after all the slot timing, frame timing and codes for one slot are detected and stored in memory 110. This results in a problem that the time required for the entire cell search cannot be reduced.
The invention has been developed for overcoming the above problem, and a first object of the invention is to provide a mobile communication terminal allowing fast cell search.
A second object of the invention is to provide a mobile communication terminal allowing accurate identification of spread codes.
A third object of the invention is to provide a communication method allowing fast cell search.
A fourth object of the invention is to provide a communication method allowing precise identification of spread codes.

Mobile communication terminal and method of communication


A method for forming a semiconductor device includes forming a photoresist layer over a substrate and patterning the photoresist layer to form photoresist portions. A second layer is formed over the substrate in areas not covered by the photoresist portions and the photoresist portions are removed. After removing the photoresist portions, the second layer is used to modify the substrate to create at least a portion of the semiconductor device.

The present disclosure relates generally to the manufacturing of semiconductor devices, and more particularly to a photolithography process in semiconductor manufacturing.
During the manufacturing of semiconductor devices, one of the requirements is a suitable depth of focus (DOF) window. Generally, an effective DOF covers all the variations of the photoresist thickness, local substrate topology step height, and wafer center and edge step height differences. It is desired that a semiconductor device be manufactured within the desired critical dimension (CD) specification without scum or top loss defects.
As the sizes of semiconductor devices continue to decrease, semiconductor manufacturers strive to devise photolithography processes that accommodate the needs of customers.

System and method for photolithography in semiconductor manufacturing

Taiwan Semiconductor Manufacturing Company, Ltd.


An operating system and method for an engine is provided in which at least some fuel is preheated prior to delivery to the combustion system of the engine. A control system is also provided to operate the engine at higher than normal excess air ratios. The system can be provided in kit form for retrofitting in existing engines.

1. Field of the Invention
The present invention relates to fuel system and method for providing fuel to a combustion chamber of an engine for combustion therein, in particular in which the fuel is preheated at moderate pressures to maximize vaporization in the combustion chamber, and in which substantially leaner fuel air mixtures are provided than hitherto, wherein substantial advantages in fuel consumption are achieved. The present invention relates to such a system also comprising means for providing combustion stability for improving engine life.
2. Prior Art
In an internal combustion engine, a fuel/air mixture necessary for the combustion process in the combustion chamber of each cylinder is provided typically by a fuel injection system or a carburetor upstream of or within the inlet manifold, the combustible mixture comprising droplets of fuel of differing sizes entrained in a stream of air. As is well known, at relatively lower temperatures, fuel droplets tend to be of larger diameter and less homogeneously distributed in the air stream than at relatively higher temperatures.
The fuel entry point (typically by way of the carburetor or fuel injector) is generally distanced from the intake port of each combustion chamber by a length of ducting. Typically, the fuel droplets, being distanced away from the hot walls, are kept relatively cool inhibiting full fuel vaporization, and further, the effect of the air stream enhances mutual absorption of droplets into larger droplets. The result is that the fuel/air mixture reaching the combustion chamber comprises a substantially fuel-rich centrally flowing portion comprising a high proportion of fuel droplets that cannot combust rapidly enough when ignited because of their relatively large size, and thus relatively large volume: surface area ratio, and poor availability of oxygen due to non-homogeneous mixing of the air and fuel. The higher the engine rpm, the greater the tendency for the fuel to migrate to the centre of the air stream.
Thus, a proportion of the fuel, typically between 10% and 30% or even higher, is not properly utilized by the engine for generating power, and remains unburnt or is burnt late in the power cycle, being at least partially transformed into pollutants that, to avoid being discharged into the atmosphere, require expensive catalytic converters in the exhaust system for their neutralization. Further, the incomplete combustion of the fuel also results in the formation of carbon deposits, reducing the service life of the ignition units, pistons, valves and the engine in general.
One attempt at increasing the combustion efficiency has focused on pre-heating the fuel prior to injection or to carburetion. Many patents on the subject discuss atomization and/or partial vaporization of fuel. Vaporization systems relate to systems in which the fuel is vaporized, i.e., transformed into the gaseous state of the fuel. In atomization systems, on the other hand, the fuel droplets are broken down into fine liquid particles which are carried along by the airstream, though some amount of vaporization may also occur. However, the presence of liquid droplets or particles, no matter how fine, reduces the efficiency of combustion. Even when stoichiometric air-fuel ratios (i.e., wherein the air factor, λ (the ratio of quantity of air used/theoretical air requirement) is unity) are used, there is still an inefficiency in the combustion process. Generally this inefficiency can be explained in terms of the outer layers of each fuel droplet being progressively combusted, and thus the overall combustion process continues as the piston begins to travel in the power stroke. Accordingly, some of the combustion occurs at the lower pressures present during this downstroke, and thus the efficiency of the combustion process is diminished. To obtain optimum performance, all the combustion occurs at about top dead centre (TDC), where pressure is at its highest.
U.S. Pat. No. 4,372,278 describes a fuel system for an engine, in which fuel is said to be vaporized by a combination of high pressure and high temperature of the fuel itself, in contrast to many other types of ostensibly "vaporization systems", which according to this reference are really atomization systems. Such high temperatures and pressures may reach 250° C. and 600 psi, respectively. However, the system described by U.S. Pat. No. 4,372,278 has a number of disadvantages. For example, heating the fuel to elevated temperatures and pressures requires the fuel system to be designed to withstand high temperature fuel circulating around the fuel system. Such a system increases capital costs of the engine, and moreover the high temperature and pressure of the fuel increases risk of damage and injury in case of accidents.
In U.S. Pat. No. 3,762,378 a fuel injection system is described in which fuel is injected directly into the combustion chamber of a cylinder. The fuel is preheated in the injector arrangement prior to injection into the cylinder. The fuel line to the injector includes a heat exchanger arrangement in the exhaust conduit of the cylinder, which also serves to preheat the fuel. The fuel is preheated to a temperature above its ignition temperature, and ignites in the combustion chamber as a result of then being introduced into an environment having a lower pressure than in the injector and oxygen to support combustion. A retractor valve in the fuel conduit to the injector maintains the fuel pressure in the injector above the critical pressure of the fuel but below the opening pressure of the valve head of the injector between pressure pulses.
U.S. Pat. No. 2,881,828 describes a fuel injection system for a diesel engine, in which the fuel temperature is controlled thermostatically by means of heat exchange between the inlet and outlet fuel lines to the injector.
In U.S. Pat. No. 3,738,334, a preheater arrangement heats fuel prior to the carburetor using a heat exchanger arrangement coupled to the exhaust gases.
In addition, prior art fuel heating systems also suffer from the following problem. By heating the fuel droplets to a high temperature, there increases the possibility of premature combustion of the droplets, even before they are fully atomized or vaporized. Pre-ignition problems may develop, and, the fuel is not fully burnt, leading to low running efficiency and an increase in the pollutants emitted to the atmosphere. Such problems are neither discussed nor hinted with respect to such prior art high temperature and pressure fuel heating systems.
In WO 00/25015, a device is provided for improving the atomization and mixing of fuel droplets in the air-fuel mixture upstream of the combustion chamber. Further, a combustion stability means is provided for providing an atomized medium to the combustion chamber during the induction stroke. The medium is described as comprising methanol and acetic acid, which is aerated and siphoned off to the air inlet system of the engine. The methanol improves the vaporization characteristics of the acetic acid. According to this aspect of the invention, an atomizer is provided for ensuring a high degree of atomization of the medium is provided. Such a system may generally help in cleaning parts of the engine and in reducing the possibility of pre-ignition of the fuel-air mixture.
Other devices for enhancing engine performance by providing water in a fine mist state are known, for example as disclosed by U.S. Pat. Nos. 3,767,172 and 4,076,002. However, while improving engine performance, use of water injection in internal combustion engines has certain drawbacks including the formation of calcium and slag deposits on the valves, pistons and spark plugs.

Operating system, kit and method for engine


A slurry filtration system for supplying a slurry to a polisher to perform a chemical mechanical polishing process. The system comprises a first three-way valve, to receive the slurry supplied from an external system; a slurry pump, to control the slurry flowing from the first three-way valve, and to maintain a circulating state of the slurry within the circulating system after the chemical mechanical polishing process comes to a stop; a slurry filter, to filter a plurality of large size particles in the slurry pumped from the slurry pump; a second three-way valve, to supply the slurry flowing from the filter to the polisher; and a transportation pipe, connecting between the first and the second three-way valves to transport the slurry from the second three-way valve back to the first three-way valve when the polishing process has stopped.

1. Field of the Invention
The invention relates in general to a filtration circulation system of a chemical mechanical polisher, and more particularly, to a circulation system which maintains a constant flow of slurry in a polisher to prevent the deposit of particles.
2. Description of the Related Art
Chemical mechanical polishing (CMP) is the only technique that provides a global planarization of devices for very large scaled integration (VLSI), or even ultra-large scaled integration (ULSI). In chemical mechanical polishing, a polishing apparatus similar to a grinder is adapted with an appropriate chemical agent to planarize uneven profiles of chips. A slurry is commonly used as a chemical agent in chemical mechanical polishing. The slurry comprises a colloidal silicon dioxide or a dispersoid of alumina mixed with the solution of potassium hydroxide (KOH) or ammonium hydroxide. The very highly abrasive particles in such a slurry and some added oxidant and organic solvent therein are used to facilitate the polishing process.
Therefore, the factors which determine the resultant planarization from chemical mechanical polishing include the components of slurry distribution and size of slurry particles, slurry supplying speed, and pH value of the slurry. In chemical mechanical polishing systems, a filter is installed for filtering slurry particles in a large size in order to reduce the scratch on the surface during polishing. However, while the polishing process stops or after a duration of operation, these large size particles deposit. In addition, while the polishing is in process, small size particles easily agglomerate into large size particles. The scratch on surfaces of chips during polishing is inevitable. Moreover, the deposit of large size particles blocks the filter and affects the slurry flow. Once the slurry flow is affected, scratches or damage to the chips become even more severe.
FIG. 1 shows a filtration system in a conventional chemical mechanical polisher. As shown in the figure, a slurry is controlled by a switch 10 to flow through a slurry pump 12. The slurry is then pumped by the slurry pump 12 to a slurry filter 14. After the particles of large size have been filtered by the filter 14, the flow of slurry is controlled by another switch 16 to flow to a polisher for performing a chemical mechanical polishing. While the polisher stops working, the switches 10 and 16 are shut, so that the slurry in the slurry filtration system 18 can not maintain a flowing and circulating state. The particles in the slurry therefore agglomerate into large particles. To avoid the deposit or agglomeration of particles, a deionized water (DI water) is used in the filtration system 18 to clean the residue slurry for polishing. Therefore, while performing chemical mechanical polishing, it is difficult to supply slurry into the filtration system 18 in a timely fashion. For example, the concentration of the abrasive particles is insufficient to performing polishing at the beginning of the process. A long duration is required to supply slurry with a sufficient concentration of small size particles. The stability and performance of chemical mechanical polishing processes are thus affected.


A Distributed-Structure-based parallel module structure and parallel processing method. One object is to provide a novel sequence-net computer architecture. A parallel operating structure with N+1 independent flow-sequences is created, and the N+1 flow-sequences control independently the distributed token via the sequence-net instructions to realize the parallel operating of module. Wherein N flow-sequences is regular type, a new consistency flow-sequence Sc running independently is composed by consistency tokens. The distributed token connecting among multi-machines support the co-operation running among N+1 flow-sequences.

1. Field of Invention
This invention relates to a distributed structure and a parallel processing technology in computer technology and, in particular, to a distributed-structure-based parallel module structure and parallel processing method.
2. Discussion of Related Art
Since the last 30 years, the research funds and qualified people have been heavily investing in the fields of distributed structure and parallel processing of computer. However many key problems still haven not been solved.
The expected target of the computer structure research is the industrialization. It is particularly true with respect to the achievements obtained in the single CPU computer field owing to its industrialization. For this target, the generality of parallel computer system is far more important than its speed. Toward the generality, many wide gaps can not get through so far.
Although there are many difficulties, works are continued. Today, the research of distributed system still aims at the distributed operating system, and the parallel processing schemes have been focused on three types of structure: symmetric multiprocessor (MP), massively parallel processing system (MPP), and network of workstations (NOW).
FIG. 1A is a schematic diagram of shared memory structure in previous art.
In previous art, the hardware layer of MP enters to a shared-memory-oriented structure. Therefore, from the point of view of programming, it is the common abstraction capability of MP that a plurality of processors 100 shown in FIG. 1A are connected to a shared memory 102 through an internal connection network 101 having various structures, wherein the shared memory 102 may be distributed or centralized in structure.
The advantage of shared memory allows each processor to access shared memory directly by the instructions of single processor. The recent trend of development is the implementation of unified addressing for distributed memory so that the read/write operation in different time, known as non-uniform memory access (NUMA), will be effected.
In a data-sharing model, it is the advantage of instruction direct access that there is no distributed memory structure parameters appearing in programming. However, the data-sharing model does not provide the principle of modeling in a MP hardware environment for user, and also does not provide a direct solution for program synchronization of N processors in general distributed computing.
FIG. 1B is a schematic diagram of network of workstation (NOW) structure.
A plurality of computers in distributed structure are connected by a communication interface. It is their common capability in configuration that a plurality of program flows 103 are connected in a form defined by communication mode 104 respectively, and connected by the communication program control in program flow 103. They have the advantage of distributed structure, but there is still a difficulty of modeling by user.
Regardless of data sharing or massage passing, the multi-machine system is also in difficulty with its data processing and synchronization between a plurality of program flows 100 (or 103). The structures shown in FIG. 1A and FIG. 1B can not work out a solution to the problems of synchronization and modeling at hardware layer. In fact, a common understanding on the key of difficulty in distributed system and parallel processing is not achieved up to now. Some viewpoint considers that the difficulties of distributed system are the real-time ability and the schedulability, and the difficulties of parallel processing are the parallel programming and parallel compiling. However, the parallel processing and parallel compiling are also problems to the distributed system, and the real-time ability and schedulablity are also needed in the parallel processing. The generality, which is the most important problem, is still a research target for distant future without any courage to face it today.
Similarly to the viewpoint of some experts, the inventor considers that "the previous research on parallel processing does not expose the main contradiction (or enter to the real nucleus of problem)", and the corresponding works should be taken.
Summarizing the previous arts shown in FIG. 1A and FIG. 1B, on the promise of multi-machine architecture, the parallel processing must be characterized by two features as follows:
(1) The control of system running must be a plurality of independent asynchronous-programs; and
(2) The data must be transferred in real-time among a plurality of programs when N distributed programs are performed in parallel (these data are known as data in parallel module or "modular data" for brief).
According to the features described, at least 3 problems must be tackled for implementing a proper model operation and programmability in parallel processing as follows:
(1) the determination of validation has to be made before using a modular data transferred for the program flow;
(2) the configuration parameters should be generated in a hardware transmission path between processors for the data, but they are not the parameters of application model and could not appear in the programming interface; and
(3) In the system operation, not only the synchronization of programs should be implemented, but also the dead lock must be prevented.
Only the three problems described above have a solution, the discussion on parallel processing efficiency (that is, speed) can be tackled.
For decades of years, these three problems (referred briefly to as "3* problem" below) is are obvious, and easy to analysis. However, an optimum scheme for total solution of 3* problem is still not suggested.
The 3* problems is are caused by the fact that the control interface for N programs and a naked-processor comprised of "N independent programs+interconnection structure for multi-machine" are provided by almost all hardware. This interface is substantially intended to tackle the multi-machine problem in the field of Turing machine.
A basic configuration of Turing machine comprising a Turing machine tape (named state tape below) and a read-write head is shown in FIG. 1C.
The Turing machine aims at a state processing, and definitions including "step-by-step", "left shift or right shift", "contents of process state square", etc. Only are provided to the read-write head and the acceptance from reader is required. Based on the concept of process "state tape" of Turing machine in previous art, the "algorithm" discipline is developed with a great contribution to the advance of computer technology. Thus, part of the functions in read-write head such as the moving way shall belong to the algorithm naturally.
The Turing machine is a very important abstraction model in computer science with a clear description of "state element" in computer science and engineering. However, it was only a product in computer budding period without the problems of multi-machine architecture. Its limitation appears when it enters to a multi-machine environment (distributed and parallel processing).
The feature of "N independent programs+interconnection structure between processor" is corresponding to one state tape shared by a plurality of read-write heads, and not departs from the field of Turing machine. The invention recognizes that from the view point of multi-program, the effect eventually corresponds to "one state tape shared by a plurality of read-write heads", no matter it is a shared memory or a massive passing in previous art.
In some previous arts, it is expected that the synchronization of read-write head can be coordinated by the determination of state-tape information so that the 3* problem can be resolved. The invention recognizes that 3* problem is really a problem, but it is neither a total problem, nor a nucleus of problem. The deeper layer problem is unable to describe and summarize by the Turing machine, and a breakthrough is necessary to make for the Turing machine limitation and the interface of "N programs+interconnection structure between processors" resulted from hardware structure. The invention recognizes that it is necessary to reconsider the problems in a wider range and a deeper layer and to introduce another element for computer science and engineering.
To simplify the description of a new computer element related to the invention, some new concepts and discoveries will introduced herein.
Firstly, the concepts of "flow" and "sequence" will be introduced. A flow represents a dynamic and serial independent-driving configuration, and a sequence represents a static order, generally, a flow results from the hardware structure, and a sequence result from the model analysis. Based on this definition, a computer structure can be abstracted into a flow structure and the Petri-network (it implicates a state description) and the likes are recognized as representation in sequence aspect. The match between a flow and a sequence (may be referred to as a flow-sequence) indicates that a sequence is allowed to load on a flow, and the flow-sequence is running in accordance with the sequence loaded under a driving of the flow. The computer program, in fact, is the result of match with 'flow' and 'sequence', that is, it is represented with instruction, and also is a flow-sequence with high controllable capability at hardware layer (not all the flow-sequences can be converted into a program).
A flow, a sequence and a match between them are three concepts. The previous various concepts in computer field are developed on the basis of the matching with 'flow' and 'sequence'.
Because the basic thoughts of the invention is a match from 'sequence layer' (representing model) for structure and from 'flow layer' (representing structure) for model and after the two matching, the invention discover sequence-net, which can match for both flow layer and sequence layer. Therefore, it will be happened that a same structure and relative symbol (for example, Sc and Si) indicates the sequence of a model in the model environment (without the flow concept of computer structure), but indicates a flow in the computer structure environment (without the sequence concept of model), and indicates flow-sequence (in the flow-sequence matching state) in the application environment. In this specification text, it seems that there is confusion in the symbol of Sc, Si and the likes. But it is feature that this invention owns, and it is necessary for describing the thoughts of the invention. So that in the sequence-net computer description, it should be the flow-sequence state which combines flow with sequence.
When a model can be implemented in a single processor, the algorithm will be solvable. However, the same model may be unable to implement in multi-machine, but it can not be recognized that the algorithm is unable to solve for this reason. Therefore, the relation between model and computer structure is not dependent on the algorithm. In this invention, an "adaptability" is introduced to represent the relation between model and computer structure. A well solution of adaptability means the achievement of generality of computer structure. Thus, the adaptability is the key target of research for industrialization.
Two fundamental laws discovered in the research of flow and sequence aimed at adaptability is incorporated directly herein.
(1) An N sequences parallel-processing model comprises N+1 or more sequences in fact, wherein the N+1st sequence is an global sequence.
(2) A flow from the structure is required to match each sequence from the model respectively for forming a flow-sequence, that is, the flow-sequence pairing law.
Furthermore, an inference can be drawn in below:
N+1 sequences can be combined into one sequence (thus, a flow-sequence pairing in single processor is formed).
The laws and inference show the relation steps as follows:
The first step of adaptability research is the permission of modeling. The algorithm research can be entered only after the permission of modeling. According to the concepts of flow and sequence, the match between flow and sequence is the premise of the permission of modeling. Therefore, the quality of a match between flow and sequence is one of the key factors affected the adaptability.
In addition, they show that there are differences between the single-processor and the multi-machine in research environment as follows:
The single-processor has a natural match between flow and sequence, and enters to the algorithm research with the match condition. On the other hand, the distributed and parallel processing enters to the algorithm research without a sufficient match condition.
From the research described above, a fully new viewpoint emerged: there are two elements, "flow-sequence" and "state", in the computer science.
The "state" element is familiarized through the Turing machine. Ever since the beginning of computer, the state element has been a very important factor. The most abstract and succinct summarization is made for the state element by the Turing machine. The research of state element is deepened by the algorithm for the purpose of running a model in a computer. In fact, the computer background for state element research is the single-processor structure due to its natural match property.
For the "flow-sequence", although it is not familiarized in its form, it has been perceived by anyone in the art without an expression of it only. In the definition of read-write head in the Turing machine, pair of matching flow-sequences is implicated to represent the feature of single-processor structure. However, for the separation of flow-sequence, the implementation of sequence description, and the deepening of sequence research, the Turing machine is powerless, and a creative research approach and description method is required.
The invention recognizes that the flow-sequence is an independent layer in a computer architecture, and the "flow-sequence element" is same important as that of state element. The research of flow-sequence element will be described by sequence-net below, and one of the research targets is the adaptability between model and computer structure. The invention, as the first research on flow-sequence element, yields an entirely new result. In the previous art, the flow-sequence element is in a state of necessity realm (an objective law necessary to obey although without consciousness) all the time. Thus in the operational application example of parallel processing, it is inevitable to comprise a matching process for flow-sequence element unconsciously (but can not yield a good result).
The invention recognizes that all the previous theories can not allow the "flow and sequence" element to display it talent, and a reconstruction of a layer and method capable of the problem description is required. The invention will start from a most general flow chart.
An abstraction of a typical parallel processing flow chart is shown in FIG. 1D.
This is a structure representation abstracted from a flowchart often appearing on a desk or a workshop wall. In FIG. 1D, the interconnection relation between flow steps is indicated by token mode, and it is taken as a typical parallel module and description method in the invention. According to the invention, the flowchart shows a plurality of parallel sequences and the relation among then in a model and a flow in the flowchart is referred to as a sequence. The flowchart comprises three sequences S1-S3 and four sets of combined token 108. Sequence Si (i=1, 2, 3) (the specific numbers of index I are omitted in below description) are three independent sequences, and the interconnection functions among them are indicated by the combined tokens T1, T2, T3 and T4. The combined token 108 consists of a plurality of tokens including a source token 105 {circle around (·)} and a destination token 106 {circle around (1)} both inserted into the corresponding positions in each sequence Si respectively. Among the sequences, the token transmission path structures 109 are required by the combined token 108.
The parallel run of three sequences are functioned as follows:
A source token value=1 (Valid) is generated when a sequence Si passes a source token 105. The value (=1) of source token 105 is sent to a destination token 106. A test token value is required when a sequence Si passes a destination token. If the tested token value=0 (invalid), the sequence Si will be waiting; if the test token value=1 (valid), the running of sequence Si will continue.
For a model, the run coordination process of several sequences Si described above is very clear for human understanding without any question. In fact, it is the original form of parallel module in previous art even though it is not defined clearly.
The sequence Ms of a module that exists in the interconnection of sequences Si is shown in FIG. 1E.
Based on the component feature of sequence Si and token, a set of directional line can be found in FIG. 1D. They are running zigzag from left to right through the sequences and the combined tokens 108 by branching and passing to indicate the running order among sequence, and are referred to as the sequence of (parallel) module Ms 110 as shown in FIG. 1E.
It is obviously that there are two different parameters in a Ms. The one is an arrow line overlapping with each sequence Si in horizontal direction to represent the sequence of combined token 108 during running. The another one is an arrow line overlapping with internal transmission path structure in vertical direction, and is generated by the multi-machine structure. The key intention of Ms is the sequence of combined token, and the Ms is independent of each Si, however, in a distributed structure environment, the Ms is superimposed sectionally on these Sis, and implemented by the token transfer so that a large amount of structure parameters are mixed into the Ms.
The sequence of module Ms is an global sequence with distribution property in sequence structure. The global property refers to an autonomous sequence defined by the interconnection relation of N sequences Si. The distribution property refers to the distribution of Ms among each Si and its transfer relation among each Si. Thus, the sequences contained in an Ms can not separated from each Si, and also affects the structure of each Si.
The sequence Ms 110 indicates the character of internal sequences of a parallel module. In FIG. 1D, it shows that there is one (at least) global sequence Ms 110 in addition to N (N=3 in here) local sequences. Therefore, One of the basic character of a parallel module is the possession of N+1 sequences (at least) (may be equivalent to N+2, N+3 . . . sequences).
It is also an understanding result from the flowchart by a viewpoint of computer structure that there are N+1 sequences in a parallel module. Thus, there is a misconception, which is neglected very easily, between such result and the intelligent understanding of human brain limited on FIG. 1D. The model's sequence Ms is neglected in previous art due to the misconception. At the same time, a huge amount of data structures and synchronization parameters are increased in the control due to the interconnection of multi-machine structure, known as the information explosion, and the requirement for eliminating them is very hard to realize in previous art. Although the increment of structure parameter is eliminated, the Ms described above will be removed at the same time for the misconception. However, the elimination of Ms is not allowed since it is a model parameter and not the proliferating parameters from a multi-machine structure. How to input the model parameter Ms? This is not only the actual target for computer architecture research in previous art, but also a main source to cause all the problems. Furthermore, it is a start point the invention departs from the previous art.
After the description of FIGS. 1A-FIG. 1E, the points of previous art will be more apparent by observing and explaining it again from a new viewpoint.
The existence of Ms is neglected in previous art.
In the previous parallel processing technology, the efforts are only made toward the structure without the research of a general character over the span across model and computer structure. The distinction of various architectures is the differences in hardware interconnection structure, but they are consistency in neglecting Ms and attempting parallel running control with N independent programs. Therefore, from a standpoint of the invention, the common problem in previous art belongs to a same type that the multi-machine problems are solved by the concept of Turing machine. There are N+1 sequences in a model in fact, and N independent sequences can only be supported by the structure of N computers. Thus, the problem that who can support the N+1st global sequence Ms occurs. Naturally, one may associate such problem with the basic concept "N+1 unknown numbers can not be solved by N equations" in the high school algebra.
The invention recognizes that this is the problem for previous art in thinking.
In the description of the 3* problem originated from the structure research, the problem of N+1st global sequence is not referred. In the previous art, the synchronization only relates to N programs as a traditional understanding in previous art, and the N+1st sequence factor is not taken into account. Obviously, the concept of 3* problem in previous art is error since the key problem, the match between flow and sequence, is neglected, and the object effect of multi-machine synchronization is the implementation of the sequence of Ms.
The reasons for the limitation appearing in the Turing machine faced with the distributed and parallel processing will be described in below:
In the structure defined by Turing machine, the match between one flow and one sequence is complete, and the flow is combined with sequence. Therefore, the Turing machine can not work as a base for the research of flow-sequence element since it represents the state element abstractly in the condition of the accomplishment of a match between flow and sequence.
The reasons for the possession of a match between flow and sequence in a single-processor will be described:
N+1 sequences (N local sequences and 1 global sequence) in a model can be combine into one sequence to support a match between flow and sequence in a single-processor.
In a single-processor, the parallel module shown in FIG. 1D corresponds to a multi-process. In the environment of single-processor, the sequence Ms 110 of a module existed in fact is converted into "a serial sequence generated and arranged in time order", and each sequence Si is divided into small blocks respectively. Then each small blocks is arranged to meet the requirement of Ms and N number of Si at the same time, and a serial sequence consistent with original N+1 sequences is generated. After the accomplishment of the combination of a plurality of sequences into one sequence, the match with a flow comprised in the single-processor structure in performed. The match is complete at the hardware layer already, thus the single processor is capable of modeling at the hardware layer.
Furthermore, in a single-processor, The environment of 3* problem is changed greatly. The "shared memory" in multi-machine is replaced by the instruction-addressing memory in a single-processor. Each flow-sequence Si is converted into the multi-process in a single-processor without the structure parameters in the access data from the memory, and the data transmission among Sis is converted into a "read after be written" order for a same memory address. Therefore, in the single-processor structure, the token structure shown in FIG. 1D and FIG. 1E disappears, and the sequence element is hidden. For the sequence of module Ms, the works remain a "read after be written" process only, and become an intellectual act corresponding to the algorithm without any relation to the computer structure in the form. This is the reason for the natural possession of a match between flow and sequence, the human effort only directs to the processing form for Ms (for example, converting into a direct valuated statement, or a grammar structure). Moreover, in these processes, Ms enters to the running control of computer as an input information included in the program objectively. As a result, the single processor can further enter to a better adaptability from the match ability, and make a success in the generality.
The model that can be matched on flow-sequence in previous art will be described in below:
In the multi-machine structure, there are N flows naturally, and N independent sequences can be supported. However, there are N+1 sequences in a model in fact, so they can not be matched. In the previous research on distributed and parallel processing, the research of flow-sequence element is not introduced into the computer architecture, and the environment for solution is located in the environment of "N independent programs+interconnection structure for multi-machine", furthermore, the problem of matching flow and sequence is neglected.
However, according to the principle that the sequence is a model parameter, the user model in any architecture can not operate without the input of Ms. Furthermore, according to the principle of the match among N+1 flow-sequences, the N+1st "global flow" structure capable of supporting the global sequence Ms can be found from the system inevitably for any applicable case in previous art.
The "time slice" structure often used in a parallel system forms the N+1st self-driving flow, which is independent of N single-processor programs, by timing interruption. Obviously, during the matching of the N+1st flow-sequence, the global sequence Ms lies in a distributed sequence state shown in FIG. 1E, and the time slice flow is an global flow having a structure capable of matching with the Ms sequence in distributed state. As a result, the algorithm is limited to a mode that "the synchronization is handled (to solve the communication problem) after the internal computing of time slice", The control interface of the mode is "N programmable programs+one time slice flow-sequence".
The Ms structure shown in FIG. 1E can be implemented by the meticulous programming of the programs in each flow-sequence Si. In this case, however, the N+1st flow is a virtual-driving flow superimposed on each flow-sequence Si and connected by tokens, Therefore, for the matching of the N+1st flow-sequence, not only N programs related should be programmed, but also a large amount of multi-machine structure parameters must be handled. Furthermore, this mode relates to the specific model, and an individual matching is required. Although it can be running, it can not provide the general modeling for the user. The invention recognizes that such mode still not reaches stage for a match between flow and sequence in the instruction layer. Therefore, the establishment for a match between flow and sequence with the previous art may be expected only with the high-level language layer.
The reasons for unsuccessful multi-machine adaptability will be described in below:
Firstly, in the multi-machine structure, there are N flows naturally, which can support N independent sequences, though there are N+1 sequences in a model actually. In previous art, however, the working habit was not changed in its research of distributed and parallel processing, and the flow-sequence element is not introduced into the computer architecture (same for the previous single-processor architecture research). Furthermore, the environment of solution is located in the environment of "N independent programs+interconnection structure for multi-machine". The problem of matching flow and sequence is neglected. As a result, in the previous art, a structure capable of matching can emerge without the teaching of a well-found theory and method.
Secondly, it is an important concept that the sequence of module Ms is a parameter of input information, and an essential breakthrough is made hardly for an architecture research without such concept. In the previous art, the algorithm in the signal-processor environment is simulated, and the problem of sequence Ms solution is excluded from the architecture research, leaving it to the algorithm or modeling. Thus, the modeling is very difficult, and various characters of sequence Ms are generated naturally, even though the matching is successful. The unifying multi-machine operating system can not be generated since there is no processing specification for Ms. Therefore, the arrangement of leaving Ms with the algorithm is a direct reason for the failure to generalize so that the industrialization can not be realized forever in previous art.
Thirdly, in the previous example capable of matching, N+1 flows are consistent with N+1 sequences in their numbers, and the match between flow and sequence is obtained so that a multi-machine system can be operated. For the match between flow and sequence, some different modes are developed. However, the layer and control interface in all these matching modes can not meet the need of diversity for adaptability.
In the previous technology capable of modeling, the distributed structure in a model is not improved so that the N+1st flow built unconsciously by a user must be an "global+distributed" flow. Because it is very difficult to build such a flow in the multi-machine structure, an global parameter (for example, time or synchronous instruction, etc.) must be introduced to generate an global flow based on the new parameter, and the Ms should be modified to match with the new parameter. After the implementation of an associated match between the N+1st flow and the new parameter, the match between flow and sequence for original N programs should to changed to connect the N+1st flow-sequence (based an other parameters). At last, the system is operational, and the system modeling is clear. However, the generality of model is limited by the new parameter, moreover, the well adaptability is lost.
All the N+1st flow build can not reside in the hardware layer and enter to the instruction flow format as those in the single-processor. Therefore, the matching quality of all N+1 flows (especially the N+1st flow) is the essential reason for the failure to popularize these applications.

Distributed-structure-based parallel module structure and parallel processing method


The present invention relates to tyrosine kinase inhibitors that contain a zinc-binding moiety and their use in the treatment of tyrosine related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

Protein kinases (PK) are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins. Many aspects of cell life such as cell growth, differentiation, proliferation, cell cycle and survival, depend on protein kinase activities. Furthermore, abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, there is a great deal of effort directed to identifying ways to modulate protein kinase activities.
Growth factor receptors with PTK activity are known as receptor tyrosine kinases ("RTKs"). They comprise a large family of transmembrane receptors with diverse biological activity. At present, at least nineteen distinct subfamilies of RTKs have been identified. Examples of RTKs subfamily include VEGFR-1, VEGFR-2, Flt-3 c-Kit and PDGFR.
In addition to the RTKs, there also exists a family of entirely intracellular PTKs called "non-receptor tyrosine kinases" or "cellular tyrosine kinases". This latter designation, abbreviated "CTK", will be used herein. CTKs do not contain extracellular and transmembrane domains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak and Ack) have been identified. The Src subfamily appear so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. For a more detailed discussion of CTKs, see Bolen, Oncogene, 1993, 8:2025-2031.
Chronic myeloid leukaemia (CML) is a stem cell disease characterized by an increased production and accumulation of clonal BCR-ABL-positive cells in haematopoietic tissues. Treatment of CML has been greatly enhanced by the development of Imatinib mesylate, a specific inhibitor of the BCR-ABL tyrosine kinase. However, relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. Dasatinib, an second generation BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. In addition to inhibiting BCR-ABL, dasatinib has been reported to block activities of the SFKs, Lyn and Src on human prostate cancer cells (Nam, S., et al., Cancer Res 2005, 2005, 65 (20), 9185-9188.

Elucidation of the complex and multifactorial nature of various diseases that involve multiple pathogenic pathways and numerous molecular components suggests that multi-targeted therapies may be advantageous over mono-therapies. Recent combination therapies with two or more agents for many such diseases in the areas of oncology, infectious disease, cardiovascular disease and other complex pathologies demonstrate that this combinatorial approach may provide advantages with respect to overcoming drug resistance, reduced toxicity and, in some circumstances, a synergistic therapeutic effect compared to the individual components.
Certain cancers have been effectively treated with such a combinatorial approach; however, treatment regimes using a cocktail of cytotoxic drugs often are limited by dose limiting toxicities and drug-drug interactions. More recent advances with molecularly targeted drugs have provided new approaches to combination treatment for cancer, allowing multiple targeted agents to be used simultaneously, or combining these new therapies with standard chemotherapeutics or radiation to improve outcome without reaching dose limiting toxicities. However, the ability to use such combinations currently is limited to drugs that show compatible pharmacologic and pharmacodynamic properties. In addition, the regulatory requirements to demonstrate safety and efficacy of combination therapies can be more costly and lengthy than corresponding single agent trials. Once approved, combination strategies may also be associated with increased costs to patients, as well as decreased patient compliance owing to the more intricate dosing paradigms required.
In the field of protein and polypeptide-based therapeutics it has become commonplace to prepare conjugates or fusion proteins that contain most or all of the amino acid sequences of two different proteins/polypeptides and that retain the individual binding activities of the separate proteins/polypeptides. This approach is made possible by independent folding of the component protein domains and the large size of the conjugates that permits the components to bind their cellular targets in an essentially independent manner. Such an approach is not, however, generally feasible in the case of small molecule therapeutics, where even minor structural modifications can lead to major changes in target binding and/or the pharmacokinetic/pharmacodynamic properties of the resulting molecule.
Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). HDAC's are represented by X genes in humans and are divided into four distinct classes (J Mol Biol, 2004, 338:1, 17-31). In mammalians class I HDAC's (HDAC1-3, and HDAC8) are related to yeast RPD3 HDAC, class 2 (HDAC4-7, HDAC9 and HDAC10) related to yeast HDA1, class 4 (HDAC11), and class 3 (a distinct class encompassing the sirtuins which are related to yeast Sir2).
Csordas, Biochem. J., 1990, 286: 23-38 teaches that histones are subject to post-translational acetylation of the, ε-amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HAT1). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, access of transcription factors to chromatin templates is enhanced by histone hyperacetylation, and enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome (Taunton et al., Science, 1996, 272:408-411). In the case of tumor suppressor genes, transcriptional silencing due to histone modification can lead to oncogenic transformation and cancer.
Several classes of HDAC inhibitors currently are being evaluated by clinical investigators. The first FDA approved HDAC inhibitor is Suberoylanilide hydroxamic acid (SAHA, ZOLINZA®) for the treatment of cutaneous T-cell lymphoma (CTCL). Other HDAC inhibitors include hydroxamic acid derivatives, PXD101 and LAQ824, are currently in the clinical development. In the benzamide class of HDAC inhibitors, MS-275, MGCD0103 and CI-994 have reached clinical trials. Mourne et al. (Abstract #4725, AACR 2005), demonstrate that thiophenyl modification of benzamides significantly enhance HDAC inhibitory activity against HDAC 1.
Recent advances suggest that HDAC inhibitors in combination with other targeted agents may provide advantageous results in the treatment of cancer. For example, co-treatment with SAHA significantly increased EGFR2 antibody trastuzumab-induced apoptosis of BT-474 and SKBR-3 cells and induced synergistic cytotoxic effects against the breast cancer cells (Bali, Clin. Cancer Res., 2005, 11, 3392). HDAC inhibitors, such as SAHA, have demonstrated synergistic antiproliferative and apoptotic effects when used in combination with gefitinib in head and neck cancer cell lines, including lines that are resistant to gefitinib monotherapy (Bruzzese et al., Proc. AACR, 2004). Pretreating gefitinib resistant cell lines with the HDAC inhibitor, MS-275, led to a growth-inhibitory and apoptotic effect of gefitinib similar to that seen in gefitinib-sensitive NSCLC cell lines including those harboring EGFR mutations (Witta S. E., et al., Cancer Res, 2006, 66:2, 944-50). The HDAC inhibitor PXD101 has been shown to act synergistically to inhibit proliferation with the EGFR1 inhibitor TARCEVA® (erlotinib) (WO2006082428A2). Synergy between NVP-LAQ824 and imatinib mesylate was demonstrated against BCR/ABL-expressing K562 myeloid leukemia cell lines. (Weisberg et al., Leukemia. 2004, 18, 1951).
Current therapeutic regimens of the types described above attempt to address the problem of drug resistance by the administration of multiple agents. However, the combined toxicity of multiple agents due to off-target side effects as well as drug-drug interactions often limit the effectiveness of this approach. Moreover, it often is difficult to combine compounds having differing pharmacokinetics into a single dosage form, and the consequent requirement of taking multiple medications at different time intervals leads to problems with patient compliance that can undermine the efficacy of the drug combinations. In addition, the health care costs of combination therapies may be greater than for single molecule therapies. Moreover, it may be more difficult to obtain regulatory approval of a combination therapy since the burden for demonstrating activity/safety of a combination of two agents may be greater than for a single agent. (Dancey J & Chen H, Nat. Rev. Drug Dis., 2006, 5:649). The development of novel agents that target multiple therapeutic targets selected not by virtue of cross reactivity, but through rational design will help improve patient outcome while avoiding these limitations. Thus, enormous efforts are still directed to the development of selective anti-cancer drugs as well as to new and more efficacious combinations of known anti-cancer drugs.

This patent is subject to a terminal disclaimer.

Tyrosine kinase inhibitors containing a zinc binding moiety


A vehicle includes a primary air conditioning device and an auxiliary air conditioning device each having a condenser, a receiver drier, an evaporator, and an expansion valve, an electrical air conditioning compressor coupled to the primary and the auxiliary air conditioning devices for operating the primary and the auxiliary air conditioning devices, and an alternator coupled to the electrical air conditioning compressor for energizing the electrical air conditioning compressor to operate the primary and the auxiliary air conditioning devices, and for allowing the auxiliary air conditioning device to be actuated to supply the cooling air to cool the vehicle even when the engine of the vehicle is shut off.

1. Field of the Invention
The present invention relates to an automotive vehicle, and more particularly to an automotive vehicle including an auxiliary air conditioning system or device or apparatus in addition to a primary air conditioning system or device or apparatus for providing or supplying a cooling air to cool the cabinet or the interior of the vehicle when the engine of the vehicle is shut off, without using or consuming the electric power or energy of the main engine starting battery that is required to be provided for starting or re-starting the engine.
2. Description of the Prior Art
Typical automotive vehicles comprise air conditioning system or device or apparatus for providing or supplying a cooling air to cool the cabinet or the interior of the vehicle, and normally comprise a mechanical air conditioning compressor coupled to an engine of the vehicle for being rotated or driven by the engine of the vehicle and for providing or supplying a cooling air to cool the cabinet or the interior of the vehicle and for allowing the drivers and the passengers to stay in the vehicles, particularly during the hot summer days.
For example, U.S. Pat. No. 4,135,368 to Mohr et al., U.S. Pat. No. 4,448,034 to Shimada et al., U.S. Pat. No. 5,102,041 to Fujiki et al., U.S. Pat. No. 6,367,270 to Niimi et al., U.S. Pat. No. 7,028,496 to Komatsu, U.S. Pat. No. 7,743,627 to Eisenhour, and U.S. Pat. No. 8,118,087 to Saida et al. disclose several of the typical automotive vehicles each also comprising air conditioning system or device or apparatus including a mechanical air conditioning compressor coupled to an engine of the vehicle for being rotated or driven by the engine of the vehicle and for providing or supplying a cooling air to cool the cabinet or the interior of the vehicle, and a main engine starting battery disposed in the engine room for supplying the electric energy to energize the electrical parts or elements of the vehicle. Normally, a 12 VDC main engine starting battery is required to be provided for a regular vehicle, and a 24 VDC main engine starting battery is required to be provided for a heavy truck for starting or re-starting the engine of the vehicle.
However, the main engine starting battery may not be consumed or used to energize the other electrical parts or elements of the vehicle, otherwise, the main engine starting battery may not provide and supply enough electric power or energy to re-start the engine of the vehicle, and the mechanical air conditioning compressor may not be powered or actuated or operated by the main engine starting battery, and should be coupled to the engine of the vehicle and should be rotated or driven by the engine of the vehicle in order to provide or supply the cooling air to cool the cabinet or the interior of the vehicle. When the engine of the vehicle is shut off, the mechanical air conditioning compressor may no longer be actuated or operated by the engine of the vehicle and may not provide or supply the cooling air to cool the cabinet or the interior of the vehicle.
In some conditions, such as in a traffic jam, most of the automotive vehicles may not be moved and should be wait in line, or may be parked on the road for a long time, but the temperature in the cabinet or in the interior of the vehicle may be great or may be at a high value that the drivers and the passengers may feel uncomfortable, such that the engines of the vehicles should be kept actuated or operated to rotate or drive the mechanical air conditioning compressor and to provide or supply the cooling air to cool the cabinet or the interior of the vehicle as long as the drivers and the passengers are seated within the vehicles, and such that the engines of the vehicles should continuously consume the gasoline and may waste a lot of precious energy. In addition, the running or the actuation or the operation of the vehicles may normally generate a great amount of carbon dioxide and some toxic gases which may seriously pollute our environment.
The present invention has arisen to mitigate and/or obviate the afore-described disadvantages of the conventional air conditioning systems for the vehicles.

Auxiliary air conditioning device for vehicle


A high frequency connector includes a first module and a second module for signal transmission. The two modules are easily manufactured and assembled. The disclosed high frequency connector can maneuverably connect with the connector thereof according to the required direction of signal transmission so that competent transmissive connection is achieved when the two modules are assembled and thus preventing generation of noise. The volume of each of the two modules is precisely designed so that the high frequency connector facilitates reduction in power loss when being implemented for the purpose of signal transmission.

1. Technical Field
The present invention relates to high frequency connectors and, more particularly, to a high frequency connector comprising two modules that can be easily manufactured and promptly assembled. The two modules of the disclosed high frequency connector can maneuverably connect with each other according to a required direction of signal transmission, so that a competent transmissive connection can be achieved when the two modules are assembled, and thus preventing generation of noise. The volume of each of the modules is precisely designed so that the high frequency connector facilitates reduction in power loss when being implemented for the purpose of signal transmission.
2. Description of Related Art
A presently developed high frequency connector for the purpose of signal transmission is typically constructed by assembling a first module 10 and a second module 20 (referring to FIGS. 1 through 3). The first module 10 (referring to FIG. 1) comprises a connecting element 101 having a through hole 102 at a predetermined position thereon for receiving a hollow connecting tube 103. The connecting tube 103 has a threaded section 104 formed at the outer periphery thereof. The connecting element 101 and the connecting tube 103 are fastened together by making the connecting peripheries welded or wedged. The second module 20 (referring to FIG. 2) comprises a connecting element 201 having a through hole 202 at a predetermined position thereon for receiving a hollow connecting tube 203. Similarly, the connecting element 201 and the connecting tube 203 are fastened together by making the connecting peripheries welded or wedged. To combine the two modules 10 and 20, referring to FIGS. 3 and 3A, a C-shaped retaining ring 205 is coupled with an annular groove 2041 on the combining section 204 extending from the second module 20. Further, a needle 206 jutting out from the second module 20 is received by a recess of a needle 105 inserted at the corresponding end of the first module 10 so that insulators 106 therein can be connected mutually. After the two modules 10, 20 are assembled for the purpose of signal transmission, the needles 105, 206 therein get connected mutually. At this time, the line contact between the two modules is liable to have intermittent interruptions due to external forces, which consequently leads to signal interference resulting in the generation of noise. Further, since the C-shaped retaining ring 205 assembled on the second module 20 is of a flat form, it is liable to have elastic fatigue after a period of use. Consequently, the combination between the two modules 10, 20 may become loosened and fail to bear relatively higher torsion force.


Provided is a display stream codec for a display device including an encoder, wherein the encoder is configured to determine a fallback display mode as a display mode for a current block to be encoded, represent a mode signaling of the fallback display mode that is identical to a mode signaling of a regular display mode corresponding to the fallback display mode, encode the current block in accordance with the fallback display mode using a same signaling syntax as the corresponding regular display mode, and send the encoded current block.

Due to continued increase in pixel bandwidth associated with display technology, especially for mobile displays and virtual reality (VR) displays, VESA (Video Electronics Standard Association) has issued a Call for Technologies (CfT) for a display stream codec that supports higher compression rates while allowing for increased computational complexity with respect to display stream compression (DSC).
VESA has developed a new display interface compression standard for mobile/smartphone displays, called VESA Display Codec for Mobile (VDC-M). As a new display compression standard, VDC-M targets higher compression ratios than Display Stream Compression (DSC), while still maintaining visually lossless quality, at the cost of increased complexity. VDC-M is fixed rate display stream codec, and therefore has a fixed bitrate, and may support compression rates down to 6 bits/pixel for a RGB 4:4:4 source. VDC-M is a block-based codec with a block size of 8×2 pixels.
It should be noted that information disclosed in this Background section is only for enhancement of understanding of the embodiments of the present disclosure and may include technical information acquired in the process of achieving the inventive concept. Therefore, it may contain information that does not form prior art.


This invention provides a method of treating immunoinflammatory bowel disease in a mammal in need thereof which comprises administering an antiimmunoinflammatory amount of rapamycin, alone or in combination with cyclosporin A. As such, rapamycin, alone or in combination with cyclosporin A, is useful in treating bowel diseases such as ulcerative colitis, Crohn's disease, ulcerative proctitis, and the like.

Skin diseases such as contact hypersensitivity, atopic dermatitis, and psoriasis are characterized by hyperproliferative and inflammatory skin disorders. A large population suffers from these disorders, psoriasis; for example, afflicts approximately 2% of the population in Western countries [Ziboh, V.A. Psoriasis: Hyperproliferative/Inflammatory skin disorder, Drug Development Research 13: 137-146, (1988)]. Human skin diseases like psoriasis are characterized by histopathologically distinct patterns of infiltration by T cells, B cells, monocytes and granulocytes. These leukocyte cell infiltrations are the consequence of expression of intercellular adhesion molecules and release of cytokine and chemotactic factors by nonhematopoietically derived cells (e.g. keratinocytes) of the skin which in turn augment hyperplasia.
Current treatment of immunologically mediated skin disorders involves the use of antiinflammatory agents such as glucocorticoids and antiproliferative agents such as methotrexate, 5-fluorouracil, and retinoids. Recently, use of the immunosuppressive agent cyclosporin A has been reported to give clinical improvement of psoriasis [Ellis, J. Am. Med. Assoc. 256: 3110-3116, (1986)]. However, its usefulness in psoriasis is limited due to high incidence of nephrotoxicity [Ellis, New England J. Med. 324: 277-84, (1991)], and the observation of relapse after cessation of the treatment with cyclosporin A [Griffiths, J. Am. Acad. Dermatol. 23: 1242-1247, (1990)].
Rapamycin, a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus [U.S. Pat. No. 3,929,992] has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Martel, R., Can. J. Physiol. Pharm. 55: 48 (1977)], inhibit murine T-cell activation [Staruch, M., FASEB 3: 3411 (1989)], and prolong survival time of organ grafts in histoincompatible rodents [Morris, R., Med. Sci. Res. 17: 877 (1989)].

Method of treating immunoinflammatory bowel disease


A still imaging apparatus includes an imaging device, a storage device, and a positional displacement correcting device. The imaging device continuously executes imaging of a plurality of times with exposure amounts different from each other. The storage device stores a plurality of original images acquired by the imaging of the plurality of times executed by the imaging device. The positional displacement detecting device detects positional displacements of common objects included in the plurality of original images stored in the storage device and stores a plurality of corrected original images whose positional displacements are corrected based on detected positional displacements in the storage device through updating.

1. Field of the Invention
The present invention relates to an electronic still imaging apparatus using a solid state imaging device such as a charge coupled device (CCD), etc., and more particularly to an electronic still imaging apparatus for executing dynamic rage expanded imaging for forming a single image by synthesizing a plurality of original images picked up in a different exposure amount, to an electronic still imaging apparatus and an electronic still imaging method having a function for acquiring a synthesis image having a wide dynamic range by synthesizing image signals of a plurality of images each having a different exposure amount and output from a solid state imaging device.
2. Description of the Related Art
Many trials have been proposed to execute dynamic-range-expanded imaging using an electronic still imaging apparatus, and, for example, an imaging system for synthesizing at least two original images acquired by being picked up in a different exposure amount has been known.
When a camera shake arises in imaging at a time this imaging system is employed, an image becomes blurred between timings at which an original image is picked up twice, thereby each pixel does not correspond to the same point of an object.
Accordingly, the image quality of a synthesis is collapsed, that is, it is extremely deteriorated to an unacceptable level.
Jpn. Pat. Appln. KOKAI Publication No. 2002-165138 discloses a technology for avoiding collapse of image quality by employing an imaging sequence in which two images are picked up particularly at continuous timing as well as by permitting to use dynamic-range-expanded imaging only when a shutter speed shorter than a predetermined camera shake limit shutter speed can be used.
Although this technology is very effective to avoid the collapse of the image quality, application of the dynamic-range-expanded imaging is limited only to an object having high luminance to which a high speed shutter can be used.
In general, in an electronic camera using a CCD imaging device, when an image is picked up using an AE exposure (preliminary imaging) and recorded, a pickup image signal is converted into digital image data by an A/D converter.
When it is assumed that the A/D converter has 10 conversion bits, the output value of the image data is located within the range of 0 to 1023.
Of the image data within this range, image data whose value is 32 or less on a dark side, for example, is less reliable by affecting on a noise.
Further, since it is contemplated that image data is partly saturated on a bright side, image data having a value up to about 960 can be used.
Accordingly, brightness that can be recognized within the usable data range of 32 to 960 is about 30 times (960/32≈30), and this brightness is expressed by about five stages of Bv (luminance) value.
In contrast, since an electronic camera ordinarily has 16 stages of exposure possible ranges Bv(−3) to Bv(13), it can be found that the camera cannot cover the entire extent of brightness when the AE exposure is executed once because the number of conversion bits of the A/D converter is ordinarily 10 bits.
Therefore, when a range covered by an exposure executed once is overlapped to realize the AE exposure in correspondence to the entire extent of brightness in the exposure possible range of the camera, the AE exposure must be executed about four times as shown by exposures A, B, C, D in FIG. 14.
The exposure conditions of the respective exposures A, B, C, D are ordinarily adjusted by an electronic shutter of a CCD imaging device and a gain of a CDS circuit.
FIG. 15 is a table showing examples of an exposure condition to the medians (11, 7, 3, −1) of the respective luminance values Bv of the exposures A, B, C, D of FIG. 14.
Here, Av shows an aperture value, Tv shows a shutter speed, and Sv shows sensitivity, respectively.
Note that the Av, Tv, and Sv values corresponding to the Bv value are calculated from a known program diagram as shown in FIG. 17.
The AE exposure condition of a final imaging is calculated from the image data acquired from the AE exposure executed four times as described above, and a method of calculating the exposure condition will be described below.
First, as shown in FIG. 16, a specific region within an imaging angle of view, from which an edge portion is removed, of a pickup image acquired by preliminary imaging executed four times is divided into 9×9 blocks, the average values of RGB signals in each divided block are calculated, and luminance Y′ is calculated from the average values based on the following expression (1).Y′=0.299R+0.587G+0.114B  (1)
A weighed average value Y is calculated by multiplying the luminance Y′ by weighing coefficients (1 or 2) shown in the respective divided blocks shown in FIG. 16.
Then, the weighed average value Y is calculated as to the respective image signals acquired by the respective exposures A, B, C, D, and an AE exposure (preliminary imaging), which has a weighed average value within the range of 32-960, is selected from the four exposures A, B, C, D.
For example, it is assumed that the exposure C is selected and that Y=500.
At this time, the Bv value of an object is as shown in the following expression (2).Bv=3(aimed Bv value of exposure C)+log2[500/200(AE target value)]=4.3  (2)
The expression (2) means that when an object having brightness of the Bv value (3) is picked up with the exposure C, Y is set to 200 and that a shift amount from Bv value(3) is determined from the ratio of the calculated weighed average value Y of luminance and 200 (AE target value).
The Tv and Av values are determined from the Bv value determined as described above using the program diagram shown in FIG. 17.
For example, when the intersection P of the vertical line of a Bv value 4.3 and the sensitivity line of an Sv value 4 (ISO: 50) is determined and the intersection Q of a slant line passing through the intersection P and the program block is determined, and the aperture value Av and the shutter speed Tv at the intersection Q show the exposure condition in this imaging.
Incidentally, a solid state imaging device such as a CCD imaging device, and the like is ordinarily used in imaging apparatuses such as TV cameras, video cameras, digital cameras, and the like.
However, the solid state imaging device is disadvantageous in that the dynamic range thereof is very narrow as compared with that of a silver salt photographic film.
To solve this drawback, there has been proposed a method of acquiring an image having a dynamic range expanded by reading out image signals of two images having a different exposure amount from a single imaging device and synthesizing them.
For example, Jpn. Pat. Appln. KOKAI Publication No. 2000-92378 proposes an imaging apparatus having a function of creating a synthesis image having a wide dynamic range by creating image signals of a plurality of images of the same object, the images each having a different exposure amount, that is, a long time exposure and a short time exposure and by subjecting the image signals to synthesis processing, wherein imaging can be executed by selecting one imaging mode from at least two imaging modes of an ordinary imaging mode, a forcible wide dynamic range imaging mode, and an automatic wide dynamic range imaging mode.
In an ordinary single exposure imaging, when light measuring processing is executed by executing a preliminary imaging exposure four times in order to determine a proper exposure condition, a predetermined time is taken from a time a shutter is pressed to a time a final exposure is executed, from which a considerably long time lag of the shutter arises.
A similar shutter time lag is also arisen in the imaging apparatus having the function for acquiring the image having the expanded dynamic range by reading out the imaging signals of the plurality of images having the different exposure amount from the single imaging device and by synthesizing the imaging signals, when light measuring processing is executed by executing a preliminary imaging exposure four times as in the imaging executed in the single exposure imaging in order to determine a proper exposure condition when exposures are executed four times under a different exposure condition or to set the number of times of exposures.

Electronic still imaging apparatus and method having function for acquiring synthesis image having wide-dynamic range


A vibrating gyroscope having a vibratable body in the form of a triangular prism, piezoelectric elements formed on side surfaces of the vibrating body and having the same vibration characteristics and a detection circuit having two input terminals connected to two of the piezoelectric elements to detect the difference between the outputs from the two piezoelectric elements, the two detection piezoelectric elements being selected such that the difference between their outputs with respect to a change in ambient atmosphere temperature is the smallest.

1. Field of the Invention
The present invention relates to a vibrating gyroscope which can be used for a navigation system that provides navigational guidance by detecting a rotational angular velocity to detect the position of a moving object, or used for an anti-vibration system, such as a camera-shake prevention apparatus, that prevents the adverse effects of shaking by detecting a rotational angular velocity due to external vibration, such as camera shake.
2. Description of the Related Art
FIG. 1 is a perspective view of an essential portion of an example of a conventional vibrating gyroscope, and FIG. 2 is a front view thereof. As shown in FIGS. 1 and 2, a conventional vibrating gyroscope has a vibrator portion 71. The vibrator portion 71 includes a vibrating body 73 made of a permanently elastic metal generally in the form of a regular triangular prism. Piezoelectric elements 75a, 75b, 75c, each of which is a thin and generally rectangular member, are bonded to central portions of side surfaces of the vibrating body 73 with an adhesive. Of these piezoelectric elements, the piezoelectric elements 75a, 75b are used for driving and detection while the piezoelectric element 75c is used for feedback. A drive circuit (not shown in FIGS. 1 and 2) consisting of an oscillation circuit and a phase circuit is connected across the piezoelectric elements 75a, 75b and the piezoelectric element 75c as a feedback loop for causing self-excited vibration of the vibrating body 73. A detection circuit formed of a differential amplifier, etc. is connected to the piezoelectric elements 75a, 75b.
Two supporting members 77, each of which is a generally square-bottomed U-shaped member formed of a wire rod having a high elastic modulus, are fixed on the ridge line of the vibrating body 73 between the driving and detecting piezoelectric elements 75a and 75b and in the vicinity of nodal points of the vibrating body 73. Ends of the supporting members 77 are fixed to one major surface of a generally rectangular mount base plate 79 made of a glass-epoxy material or the like.
In the vibrating gyroscope, if a drive signal is applied across the feedback piezoelectric element 75c and the driving and detecting piezoelectric elements 75a, 75b, the vibrating body 73 vibrates under a bending mode in a direction perpendicular to the surface on which the feedback piezoelectric element 75c is formed. In the case where the vibrating body 73 is rotated, the direction of vibration of the vibrating body 73 is changed by the Coriolis force so that a difference is caused between the outputs from the piezoelectric elements 75a, 75b in response to the rotational angular velocity. This output difference is processed by signal processing in the detection circuit to detect the rotational angular velocity.
The conventional vibrating gyroscope has the drawback that the vibrating characteristics of the vibrating gyroscope may change or drift in response to the change of the ambient atmosphere. This is because the piezoelectric elements detect a stress other than the Coriolis force due to the differences of the thermal expansion coefficients among the vibrating member, the piezoelectric elements and the adhesive.


A method of creating a protein rich conditioned medium. The method includes culturing mesenchymal stem cells in a container utilizing a first growth medium, allowing a time period for proliferation of the mesenchymal stem cells until a desired level of confluence is achieved in the container, discarding a supernatant from the container, adding a second medium to the container, incubating the mesenchymal stem cells, and collecting the conditioned medium. The method produces significantly higher quantities of byproducts secreted by the mesenchymal stem cells. Byproducts are usable for wound healing, disease treatment, cosmetic, or other beneficial effects when applied or otherwise delivered to a patient.

Mesenchymal stem cells (MSCs) are a specific group of mesoderm origin adult stem cells that are pluripotent. Being pluripotent, they have multi-directional differentiation capabilities. They can become fat, bone, cartilage, tendons, muscle, nerves, ligaments, liver, cardiac muscle, endothelial cells, pancreatic islet cells and many others. In addition, they are cells with low immunogenicity and are naturally immune-modulatory cells. Given their versatility, MSCs have quickly become an ideal cell type used in therapeutics for degenerative and autoimmune conditions, amongst other ailments.
When culturing MSCs in a growth medium, protein byproducts and non-protein byproducts are secreted by the MSCs as they proliferate and continue to be secreted when MSCs have been cultured. The protein byproducts can have significant wound healing, disease treatment, cosmetic, or other beneficial effects when applied or otherwise delivered to a patient. A medium containing such byproducts can be referred to as a conditioned medium.
The protein byproducts have the benefit of being the pure active ingredient desirable for medical treatments or cosmetic applications. Further, the protein byproducts are sterile and safe to use in virtually any circumstance.
While usage of a conditioned medium and creation thereof is known in the art, storage of the conditioned medium and delivery to a patient is problematic due to a liquid consistency of the conditioned medium, short shelf life, temperature instability, and denaturing of proteins within the conditioned medium over time.
A need exists for a stable storage means to stabilize and preserve the conditioned medium. A further need exists for an effective delivery mechanism to the patient.
The present disclosure fulfils the above needs with a formulation for the storage, transportation, and delivery of a conditioned medium.

Formulation for storage, transportation, and delivery of protein rich conditioned medium