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A. Field of the Invention
This invention relates generally to data processing systems and, more particularly, to electronic delivery systems.
B. Description of the Related Art
The world is quickly becoming wired. Nearly all households and businesses both have telephone and cable access. Now, more that ever, consumers may choose from a plurality of transmission mediums to access the Internet, such as cable, telephone, satellite, or some other high speed connection. As more consumers gain access to the Internet though a multitude of available transmission mediums, things previously done in the real world are now available through the Internet using at least one of the transmission mediums.
Probably the most commercialized use of the Internet is the World Wide Web. Every day, more people gain access to the Web, and every day, people are using the Web to shop online. Online shopping provides a level of convenience consumers want, need and will soon demand. Electronic commerce or “e-commerce” is the term often used to refer, at least in part, to online shopping on the Web.
With the explosive growth of online shopping on the Internet, the need for online delivery of digital items has also considerably grown. Online delivery refers to delivery of electronic items using an electronic format in any transmission medium. For example, a book, movie, or even a single track from a CD may be delivered to a consumer as a digital item. Consumers desire these digital items delivered immediately in a format suitable for viewing or playback using a consumer device, such as a computer. With the number of online stores that provide digital delivery growing exponentially every year, consumer devices capable of ordering, receiving, and viewing have also become more prevalent.
For example, WebTV, a popular Internet consumer device, is capable of ordering, and receiving digital items using more than one transmission medium. That is, the WebTV device provides access to the Internet as well as access to a conventional TV. Although the WebTV device enables consumers to use multiple transmission mediums using the same device, it does so at the expense of limited upgradeability. A consumer cannot specify a new transmission medium for delivery, unless the WebTV device supports the transmission medium. Even more so, any cross coupling of transmission mediums is provided at the WebTV device. And, in most instances, when shopping online using the WebTV device, the consumer initiates the shopping session by visiting a site. Only at that time, may the consumer then select an item to purchase, and then have the item delivered to the WebTV device.
Therefore, there is a need for a system capable of centralizing the cross coupling of transmission mediums with limited configuration requirements at a consumer's location. Such a system not only permits a consumer to shop online using one transmission medium and receive a purchased item using a different transmission medium, but also it permits easy upgrades, or the addition of new transmission mediums without having to modify any consumer device.
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A bridge plug can be set downhole to isolate portions of a wellbore. Some bridge plugs are retrievable from the wellbore, while others are intended to be permanently set. Retrievable bridge plugs can be set downhole using wireline, slickline, or coiled tubing and can temporarily isolate portions of the wellbore for a treatment operation or the like. Once the operation is completed, the bridge plugs can be retrieved.
As shown in FIG. 1A, a typical retrievable bridge plug 20 according to the prior art has a mandrel 22 with a wireline coupling 24, slips 26, and packing element 28. This bridge plug 20 is a Wireline Retrievable Bridge Plug (WRP bridge plug) available from Weatherford—the assignee of the present disclosure. For deployment, operators use wireline, slickline or coiled tubing (not shown) connected by a wireline or hydraulic setting tool (not shown) to the coupling 24 and deploy the bridge plug 20 to a desired point in the borehole casing (not shown). At the desired point, the plug 20 is set using the wireline or hydraulic setting tool (not shown). As the plug 20 is set, its slips 26 engage the casing, and its packing element 28 engages the casing to isolate the annulus above and below the plug 20. In general, a central portion 24a of the coupling 24 is manipulated relative to an external portion 24b so that the inner mandrel 22 moves relative to an outer sleeve 23 to compress the packing elements 28 between gage rings 29a-b and to push the slips 26 outward between wedge members (not labeled).
For retrieval, a pulling tool (not shown) is run on a tubing string downhole to the setting depth. Fluid is circulated to clear the plug 20 of debris. Once clear, the pulling tool is set down to the coupling 24 with a predetermined amount of load to shift an equalizing sleeve 25 on the plug 20. With the sleeve 25 shifted, differential pressure above and below the plug 20 equalizes so downhole pressure below the plug 20 will not force it uphole until the slips 26 and packing elements 28 are released. After equalizing the pressure differential, a predetermined amount of tension is applied by the pulling tool on the plug 20 to release the slips 26 and packing elements 28.
When used during operations, several of these retrievable bridge plugs 20 can be run in the wellbore and stacked one above another to temporarily isolate and treat multiple zones of the wellbore. When this is done, it is difficult to retrieve more than one of the bridge plugs 20 on a single run with tubing. Unfortunately, fluid cannot be circulated past the topmost bridge plug 20 to wash sand and other debris off the bridge plugs 20 disposed downhole from it in the wellbore. Without the ability to circulate fluid, it is not possible to clean debris from the lower bridge plugs 20, latch onto them, and release them in a single run. In addition, this conventional wireline-set retrievable bridge plug 20 has a tendency of resetting after being released. This resetting prevents subsequent downwards movement of the bridge plug 20, making it difficult to retrieve an uppermost plug 20 and then move it downhole without resetting before releasing a lower plug 20.
Because of the tendency of the retrievable plugs 20 to reset and the inability to circulate fluid to clear debris, operators must perform multiple trips or runs with a tubing string to retrieve all the bridge plugs 20 in the wellbore. For example, operators must circulate fluid at the topmost plug 20 to wash away debris so tubing can be coupled to the plug 20. Then, this plug 20 must be removed from the wellbore entirely so that a new run can be made to clear debris from the next lower bridge plug 20 to run it out of the wellbore. As expected, such operations can be time consuming and expensive and can expose the formation to excessive fluid losses.
To overcome the limitations of the typical retrievable bridge plug 20, Weatherford has developed another bridge plug according to the prior art for tandem retrieval. As shown in FIG. 1B, this retrievable bridge plug 30 is a modified version of the WRP bridge plug described above and has similar components. In particular, the plug 30 includes a mandrel 32, slips 36, and packing element 38 as before. Likewise, the plug 30 is set in much the same manner as before. For example, the plug 30 is run downhole, and a setting tool (not shown) coupled to the coupling 34 manipulates the central portion 34a relative to the outer portion 34b so that an inner mandrel 32 shifts relative to an outer sleeve 33 and causes the slips 36 to set and the packing element 38 to be compressed between gage rings 39a-b.
In contrast to the previous arrangement, however, this bridge plug 30 incorporates a releasing mechanism intended to keep the plug 30 in a locked position after release. As shown, the plug 30 includes a lower extension 45 coupled to the inner mandrel 32 and extending down from the plug 30. When the mandrel 32 is shifted (uphole) during retrieval procedures of the plug 30, the extension 45 is moved up further into the plug 30, and a wedge and ring arrangement 37 on the plug 30 engages a widened and serrated portion of the extension 45 to help lock the plug 30 once released.
As also shown in FIG. 1B, a retrieval head 40 attached to a tubing string or other plug (not shown) couples to the coupling 34 at the top of the plug 30 for retrieval. The retrieval head 40 is used to equalize, release, and retrieve the plug 30 during operation. Moreover, the extension 45 has a retrieval head 40 coupled to its distal end allowing the depicted plug 30 to retrieve a lower plug in tandem. The retrieval head 40 has a collet 42 that can catch the outer portion 34b of the coupling 34 and has an outer sleeve 44 that can open the equalizing sleeve 35 at the top of the plug 30.
As noted above, the plug 30's releasing mechanism helps keep the plug 30 in a locked position after release. Combined with the extension 45 and retrieval head 40, the plug 30 has been used in operations where several such plugs 30 have been retrieved in tandem. However, the plug 30 still fails to adequately address circulating fluid down to the next plug to clear it of debris for tandem retrieval. Although fluid may find its way past the plug 30 during retrieval operations so that fluid can clear some debris away from the lower plug 30, a great deal of fluid may be lost in the process. Therefore, more fluid is lost to the formation during retrieval. Moreover, additional amounts of fluid are required to clear debris from even lower plugs and can result in undesirable loss of fluid to the formation.
The subject matter of the present disclosure is directed to overcoming, or at least reducing the effects of, one or more of the problems set forth above.
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The present invention relates in general to data processing systems, and in particular, to an electronic circuit having latch scan chains, as well as to a method and a system for initializing or reinitializing the electronic circuit.
The most common method for delivering test data from electronic large vector sets with corresponding long tester time and memory circuit or chip inputs to internal circuits under test and observing their outputs, is the so-called scan-design or test data register (TDR) scan chain-design. In scan-design, registers (so called flip-flops or latches) in the design are connected in one or more scan chains which are used to gain access to internal nodes of the chip. Test patterns are shifted in via these scan chain(s), functional clock signals are pulsed to test the circuit during the capture cycle, and the results are then shifted out to chip output pins and compared against the expected results or accumulated internally through some compression/signature logic.
Straightforward application of scan techniques can result in requirements. Test compression techniques address this problem, by decompressing the scan input on chip and compressing the test output. Large gains are possible since any particular test vector usually only needs to set and/or examine a small fraction of the scan chain bits.
Integrated circuits having memory arrays that are designed and manufactured with memory built-in self test (MBIST) circuitry are well-known in the art. Integrated circuits employing MBIST generally include multiple different size arrays of memory elements that require testing. Typically, during MBIST testing, a test vector is written into an array and then a read operation is performed with the results analyzed to confirm proper operation of the array under the test vector. Within a given component or section of an integrated circuit, each array of that component is conventionally tested in series in order to analyze any result of the application of the respective test vector with the respective array.
U.S. Pat. No. 8,423,846 B2 discloses an integrated circuit having an MBIST circuitry configured to serially test multiple arrays of memory elements within a component of the integrated circuit and to also conduct parallel default initialization of the serially tested arrays. The parallel array clean up serves, inter alia, to reduce the time required to set the memory elements within the arrays to an initial state. Accordingly, this feature assists the integrated circuit to expeditiously exit a power off state with respect to the components in which it is implemented.
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Taconite ore is a lean iron ore material extensively found in the Lake Superior region of the United States. The ore is generally composed of up to about 1 percent iron silicate, about 1 to 10 percent magnetite, about 1 to 30 percent hematite, and the remainder consisting primarily of quartz. Taconite rock is usually mined by open pit methods. It is then pulverized and the granulated material is subjected to magnetic extraction. The resultant tailings have been considered to be of little or no value, particularly since further extraction of the residual iron materials still contained therein is economically unfeasible. As a result, the taconite tailings have been discarded by depositing them into natural waterbodies, artificial ponds, etc. and have heretofore been a major source of pollution.
On the other hand, various organic resins have been used extensively in molding operations. These resins include those materials which are capable of undergoing further polymerization or polyaddition reactions during the molding process. The resins are normally mixed with fillers, dilutents, plasticizers, and/or other auxillary agents. These agents include various organic compounds or polymers as well as various inorganic compounds, such as glass, carbon, metals, metal oxides or metal salts. The particular additives used are generally dependent upon the ability of the resin to incorporate the additive and the end product desired. Such compositions have been known in which the filler is the dominant component and these compositions have normally resulted in products which have a relatively low density or are easily friable. These compositions are so highly filled that it has been found that products formed from these materials would not be capable of withstanding large forces or stresses. In many instances they would not be of sufficient strength to support bending forces due to their own weight.
I have found that taconite iron ore material, particularly tailings which contain at least one percent (1%) magnetite therein, can be converted into a useful composition, the physical properties of which so nearly resemble natural slate that end use products previously made of natural slate can now be molded of my inventive composition.
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The invention relates generally to wood-burning furnaces and the like, and more particularly to freestanding jacketed wood stoves adapted for maximum heating efficiency and safety.
Wood-burning heating stoves have been well known for a long time. As petroleum fuel became more available in the past, usage of wood stoves declined significantly. As a result, very few homes built in the last 75 years rely on wood stoves for heating. However, recent rapid increases in petroleum fuel costs have stimulated a resurgence in interest in the use of wood as heating fuel. Fireplaces are notoriously inefficient in heating a home. Therefore, many households, even those having fireplaces, are adopting wood stoves as a principal or back-up heat source.
Because many modern homes were not originally designed to accommodate wood stoves, use of conventional wood stoves in such homes presents a serious safety hazard. Most wood stoves rely principally upon radiation for transferring heat into an associated room. Hence, they tend to have extremely hot outer surfaces, typically 300.degree.-350.degree. F. This presents a safety hazard to occupants of the home who might inadvertently touch the stove. As a result, the number of wood stove-related burns has increased substantially in recent years.
Conventional wood stoves also create a fire hazard if the walls and floor adjacent the stove are not adequately protected from heat radiating from the stove. Adequate protection requires that a floor beneath the stove, and any wall adjacent the stove, be made of a material that is unaffected by intense radiate heat, such as brick or stone. Use of such materials adds significantly to the cost of retrofitting a home to receive a wood stove. A less expensive alternative, asbestos sheeting, is inadequate to protect the underlying floor from heat radiated by conventional wood stoves. Such stoves often produce floor temperatures more than 200.degree. F. above ambient temperatures. Moreover, asbestos is no longer readily available due to the recognition of health hazards in the manufacture and use of asbestos. Consequently, not realizing the dangers involved, or being unwilling to bear the additional expense, many homeowners have retrofitted their homes with wood stoves without taking adequate precautions. This has resulted in a substantial increase in home fire losses in recent years.
These safety problems are prompting more stringent regulation of wood stoves and how they are installed. Building code regulations affecting wood stoves are becoming more restrictive and are being policed more thoroughly in many parts of the country. Underwriting Laboratories (UL) standards for wood stoves were recently made more stringent as well. Compliance with the new UL standards is expected to be required in the future by both home insurers and local building regulatory agencies. Most conventional wood stoves fail to meet these standards. Hence, a wood stove capable of meeting these standards in needed.
Another problem is that existing wood stoves are generally less efficient than gas- or oil-fired heat furnaces. This is due in part to the fact that wood stoves typically heat radiatively. Consequently, a wood stove must generate more heat in order to adequately warm remote parts of the room or house in which it is situated. Also, existing wood stoves generally do not burn their fuel as completely as petroleum-fueled furnaces. A significant portion of the heat value of the wood escapes up the chimney in the form of unburnt gases. Finally, existing wood stoves are generally less efficient at extracting the heat produced by a fire. As a result, the cost advantages of burning wood over gas or oil are diminished.
An additional problem with existing wood stoves is that some of the unburnt gases condense in the chimney flue to form deposits of creosote. If creosote deposits are allowed to accumulate, a flue fire or explosion can occur. Such a fire or explosion can result in loss of the home in which the stove is situated. This danger can be avoided by cleaning the chimney flue periodically, but many existing stoves are extremely difficult to clean. It would be preferable if such deposits did not form at all. However, if such deposits do form, which is unavoidable with certain types of wood, it would be preferable if the stoves were arranged so that it would be very easy to clean the chimney flue without disconnecting and moving the stove.
A further problem is that unburnt gases emitted from the chimney pollute the air. Air pollution and smog due to burning of wood to heat homes has already become a significant problem in some areas. This problem is expected to worsen, if unchecked, as use of wood stoves increases. Consequently, several governmental air quality control agencies are investigating the possibility of regulating the use of wood stoves and the maximum level of pollutant emissions per stove. Hence, there is a need to reduce wood stove emissions of unburnt gases.
A wide variety of solutions to the above-described problems have been proposed. Many of these proposals have focused on modifying existing fireplaces to obtain some of the advantages of wood stoves without incurring excessive costs. One approach has been to install glass doors, either alone or in combination with some form of heat extractor and blower for circulating ambient air through enclosed tubes into contact with the fire or hot coals, and then expelling the air back into the room. Another approach has been to provide a jacketed fireplace insert such as those disclosed in U.S. Pat. Nos. 4,015,581 and 4,166,444 to Martenson. In such fireplace inserts, air is circulated into a jacketed airspace along the side, rear and top walls of the firebox to be warmed before returning to the room. However, such proposals fail to attain the efficiency of existing wood stoves.
Another proposed approach calls for a free-standing jacketed fireplace such as is disclosed in U.S. Pat. No. 2,703,567 to Manchester et al. This fireplace has a partially jacketed firebox and employs an upwardly inclined baffle or smoke shelf inside the firebox to deflect the flames toward the front of the firebox to radiate most of the heat forwardly into the room, rather than against the firebox walls. Consequently, little benefit is obtained from the jacketed airspace.
Another free-standing fireplace, proposed in U.S. Pat. No. 3,190,279 to Davis, has a surrounding enclosure and is mounted on a ventilated pedestal. However, the enclosure is not contoured to maximize heat extraction. It is spaced a substantial distance apart from the firebox walls so as to remain cool. A heat deflection plate inside the firebox helps to keep the firebox walls cool by deflecting the flames forwardly toward the front of the fireplace. The pedestal merely provides passive ventilation beneath the fireplace. It does nothing to contribute to the operation of the fireplace or to aid in circulating air into contact with the firebox walls.
U.S. Pat. No. 3,981,292 to Lilly et al. proposes a free-standing fireplace having heat tubes passing through an upper portion of the firebox from a plenum on one side, to outlet openings on the opposite side. A blower protruding from the rear of the fireplace blows ambient air through the plenum into the heat tubes to be heated before returning to the room. U.S. Pat. No. 4,150,658 to Woods discloses a wood stove of similar design. However, neither of these designs employs a jacket extending completely around the firebox. Moreover, the protruding blowers are unsightly and obstruct passage behind the apparatus.
Another form of wood stove is disclosed in U.S. Pat. No. 4,121,560 to Knight. The Knight patent discloses a firebox having a shield along the outer side of its rear wall and a rearwardly protruding blower mounted in an opening in the center of the shield to direct air into contact with the firebox and to circulate heated air around an associated room. However, the firebox is not completely jacketed. Its surfaces remain exposed. Also, no effort is made to maximize the efficiency of heat extraction from the firebox walls.
U.S. Pat. Nos. 4,092,976 and 4,147,153 to Buckner, disclose a partially jacketed wood stove having a blower for blowing air through an air space to hot air outlets. However, this design has several drawbacks. One drawback is the disadvantageous position of the rearwardly protruding blower. Another is that the hot radiant surfaces of the top and front walls are exposed, presenting a safety hazard. Moreover, the side and bottom walls of the jacket are likely to be too hot to safely touch or to permit positioning the stove near an unprotected wall or floor. A third drawback is that the stove requires a complex system of baffles to distribute airflow in the airspace. A fourth drawback is that the hot air outlets, positioned at the front of the stove on opposite sides of the doors, expell a concentrated blast of hot air forwardly into the room. As a result, regions along the lateral sides of the stove and at a distance therefrom are likely to be inadequately heated. Also, the air outlets are blocked whenever the doors are opened. A further drawback is that the door handles in such stoves can become too hot to touch. Simply substituting wooden handles does not solve this problem because the handles soon become scorched or charred.
U.S. Pat. No. 3,952,721 to Patterson also discloses a jacketed wood stove. This stove avoids some of the drawbacks of the Buckner design. However, the side, rear and bottom walls of the jacket are likely to become too hot to safely touch or to allow positioning of the stove near an unprotected floor or wall, but not hot enough to radiatively heat distant regions along the lateral sides of the stove. Warm air is expelled only from the front of the stove. Another drawback is that--although this design provides, to some extent, for progressive heating of air circulating through the airspace--it has no blower to take full advantage of progressive heating. Nor could such a blower be added to Patterson's design without radical changes. Finally, the hot frontal surfaces of the firebox are exposed, presenting a safety hazard. The door handle is also likely to become too hot to touch with bare hands.
Accordingly, there remains a need for a wood burning heating stove which can be safely installed and used in modern homes without incurring great expense, and which will efficiently extract heat from a wood fire and distribute the heat uniformly around the room in which the stove is situated.
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Conventionally, sealing of an aluminum-like metal container used in a lithium battery for a mobile device has been performed by pulse seam welding in which a YAG pulsed laser light is irradiated along a junction line between an opening of the container and a sealing member fitted into the opening. More specifically, when sealing an aluminum-like metal container, a YAG pulsed laser light is irradiated to each processing point in a three-level waveform. That is, first, cutting is performed with a high-speed, high-peak pulsed laser, and when the aluminum-like metal material starts to melt, laser power is immediately suppressed to around half to perform final welding. Subsequently, laser power is further reduced to around half to perform annealing in order to relieve residual stress. Welding is performed in this manner using the three-level waveform YAG pulsed laser light because the aluminum-like metal material has a high reflectance and a high thermal conductivity yet a low melting point, and is further characterized by a rapid increase in laser absorptance once melted.
However, while usable for sealing a lithium battery for a mobile device, the three-level waveform YAG pulsed laser light cannot be used for sealing a lithium battery for a hybrid vehicle. This is because while sufficient joint strength can be achieved with a penetration amount of around 0.2 mm in the case of a lithium battery for a mobile device, a penetration amount of around 0.5 mm is required in the case of a large-size lithium battery for a hybrid vehicle, and increasing laser power so as to satisfy such a deep penetration creates spatters.
Meanwhile, conventionally, the use of a superimposed laser light in which a pulsed laser light is superimposed with a CW laser light in pulse seam welding has been proposed (for example, refer to Japanese Patent Laid-Open No. 2004-337881) According to the pulse seam welding using a superimposed laser light, since a pulsed laser light can be irradiated to a processing point that is in a state in which laser light is easily penetratable due to preheating by a CW component, spatterless welding can be performed. A conventional laser apparatus that generates the aforementioned superimposed laser light will now be described.
FIG. 6 is a schematic diagram showing a general configuration of a conventional laser apparatus that generates a superimposed laser light in which a pulsed laser light is superimposed with a CW laser light. The laser apparatus includes a YAG pulsed laser oscillator 101 that oscillates a pulsed laser light having an oscillation wavelength of 1064 nm. A pulsed laser light oscillated by the oscillator 101 passes through an SI optical fiber 102 and is incident to a collimator lens 103. The pulsed laser light collimated by the collimator lens 103 is incident to a dichroic mirror 104.
In addition, the laser apparatus includes a high-output semiconductor laser 105 that oscillates a CW laser light. The CW laser light oscillated by the high-output semiconductor laser 105 is incident to the dichroic mirror 104.
The dichroic mirror 104 superimposes the pulsed laser light from the collimator lens 103 with the CW laser light from the high-output semiconductor laser 105 to generate a superimposed laser light, and causes the superimposed laser light to be incident to a focusing lens 106. The focusing lens 106 focuses the pulsed laser light and the CW laser light superimposed by the dichroic mirror 104 at a processing point.
As shown in FIG. 6, a focus spot 107 of the pulsed laser light having passed through the optical fiber 102 takes a circular shape similar to a core shape of the optical fiber 102. On the other hand, a focus spot 108 of the CW laser light oscillated by the high-output semiconductor laser 105 generally does not take a circular shape, and takes a linear shape as shown in FIG. 6.
When performing pulse seam welding using a superimposed laser light in which the circular-shaped pulsed laser light is superimposed with the linear-shaped pulsed laser light, the major axis direction of the focus spot 108 of the CW laser light is set in a direction aligned with a junction line and the superimposed laser light is relatively moved along a longitudinal direction of the junction line. Accordingly, since the pulsed laser light can be irradiated on a processing point that is in a state in which laser light is easily penetratable due to preheating by a CW component, spatterless welding can be performed.
However, while the superimposed laser light in which the circular-shaped pulsed laser light is superimposed with the linear-shaped CW laser light achieves spatterless welding that satisfies a desired penetration amount when sealing an NiH battery for a hybrid vehicle which uses a steel-like metal container, the superimposed laser light is unable to satisfy a desired penetration amount when sealing a lithium battery for a hybrid car which uses an aluminum-like metal container because heat escapes to the surroundings from a tip of a linear-shaped CW component. In addition, increasing the CW component in order to attain a preheating effect causes deformation of the container and subsequently widens a gap between a wall surface of an opening of the container and the sealing member, which in turn creates a disadvantage that laser light leaks to an inner electrode and damages the inner electrode.
As seen, the conventional laser welding technique is not capable of performing pulse seam welding of thick aluminum-like metal material such as the sealing of an aluminum-like metal container used in a lithium battery for a hybrid vehicle.
Furthermore, the sealing of an aluminum-like metal container used in a lithium battery for a hybrid vehicle has the following disadvantages. Firstly, with aluminum-like metal material, since laser absorption factor varies significantly due to minute differences in surface conditions such as scratches, coarseness and staining, the penetration amount also varies significantly due to surface conditions. On the other hand, during the sealing of an aluminum-like metal container, when laser light penetrates the sealing member, a spatter occurs from the penetrated portion and, in turn, causes a short circuit. Since a short circuit in a lithium battery has a risk of causing a fire, the penetration amount must be controlled so as to prevent the laser light from penetrating the sealing member. Therefore, it is necessary to stabilize the penetration amount even when surface conditions vary.
Moreover, since aluminum-like metal material has a high reflectance and, in particular, has only a laser absorption factor of 7% with respect to YAG pulsed laser light, pulse seam welding of an aluminum-like metal container requires a YAG pulsed laser light in the kW range. Therefore, in order to supply power in excess of 30 kW to an excitation light source to obtain a kW-range YAG pulsed laser light, output current in the order of several hundred amperes must be controlled at the power source for the excitation light source. Meanwhile, since a lithium battery for a hybrid vehicle is about ten times as large as a lithium battery for a mobile device, an increased welding speed is required from a productivity perspective. Increasing welding speed requires reducing a pulse width (welding time) of a pulsed laser light, which in turn requires that a pulse be raised at high speed. Therefore, at the power source for the excitation light source, it is necessary to control the output current in the order of several hundred amperes to be supplied to the excitation light source to a current signal having a high-speed rise and a short pulse width.
However, with a dropper power source, raising a current signal in the order of several hundred amperes at high speed significantly increases equipment size. Therefore, the dropper power source is unsuitable for a laser apparatus to be used to weld aluminum-like metal material. On the other hand, with a chopper/inverter power source that controls output current by switching an internal switch element, clock synchronization is essential. Therefore, a jitter in the order of several ten μs occurs in a chopping clock period signal (drive signal) that drives the switch element and, consequently, a jitter in the order of several ten μs also occurs in the output current. As a result, since reducing the pulse width of a current signal to be supplied to the excitation light source increases the proportion of a jitter component (fluctuation component) and causes a significant power fluctuation in the pulsed laser light, a stable penetration amount cannot be achieved. For example, when the pulse width of the current signal to be supplied to the excitation light source is set to 0.3 ms, a jitter component of 30 μs causes a 10% power fluctuation and penetration amounts also vary by about 10%.
Therefore, with a general dropper power source or a chopper/inverter power source, pulse reduction of a current signal to be supplied to an excitation light source could not be achieved. Consequently, a YAG pulsed laser light whose pulse width is 2 ms or more has been generally used to seal a lithium battery for a mobile device.
In addition, since the pulse width is set to 2 ms or higher, the energy of the YAG pulsed laser light increases. Thus, conventionally, a GI optical fiber could not be used and an SI optical fiber has been used. This is because, with a GI optical fiber, a spatter occurs from an edge surface of a laser exit aperture when the energy of the laser light is increased. However, an SI optical fiber is prone to damages due to on-site adherence of dust and the like during fiber exchange.
Moreover, an SI optical fiber has a small aperture of 0.6 mm to 0.4 mm. Meanwhile, since a lithium battery for a hybrid car has a large size, as far as the fitting relationship between the opening of the container and the sealing member is concerned, the gap between a wall surface of the opening and the sealing member is larger in comparison to a lithium battery for a mobile device. Therefore, when using an SI optical fiber with a small aperture, a wide spot diameter must be set for the pulsed laser light. As a result, power transmissibility to a processing point is reduced in comparison to a wide-aperture GI optical fiber.
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Today more and more steel or concrete post and beam buildings are being built. Construction techniques for building walls have been changing significantly including metal channel framing and stay-in-place insulated forms where concrete is installed within these forms.
Rigid insulation boards have been installed on metal channels for years Insulating walls have embedded channels within insulation blocks embedding the metal channels within the rigid insulation. Some insulated concrete forms (ICF's) have embedded plastic connectors within their rigid insulation blocks also separating the rigid foam from the plastic connectors.
There have been various attempts on creating a form mold to pour a concrete column or beam within a wall. Some patents uses metal channels to help reduce the pressure produced by using a rigid foam material to form concrete beam or columns. Another type of patents uses foam blocks with vertical and horizontal chambers to form concrete columns and beams. Another type of panel is a composite panel that uses fiber concrete boards the panel surfaces as well as interior bracing within the panel with rigid foam at the interior. Another type of panel is when the foam molds create a continuous chamber to pour a solid concrete wall.
The creation of a spacer blocks and spacer insulation walls allow various types of horizontal bracing channels and electrical chases or troughs to pass through the wall and concrete columns for additional flexibility and the various connectors to form the walls. In addition the structural insulating wall can be formed with a variety of closed cell rigid insulating materials like polystyrene, cellular light weight concrete or aerated autoclaved concrete all requiring various types of connectors.
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1. Field of the Invention
The present invention relates to vacuum cleaners, and more particularly, to a vacuum cleaner having an improved dust collector assembly.
2. Description of the Related Art
In general, the vacuum cleaner draws dust-laden air from a floor of a room, removes the dust from the air, and discharges only the air again.
FIG. 1 illustrates a perspective view of a related art vacuum cleaner. As shown, the vacuum cleaner is provided with a body 1, and a suction nozzle 2.
The body 1 has a suction means mounted therein for drawing room air. Air is drawn from the floor to the body 1 through the suction nozzle 1 by a suction force generated at the body 1.
The body 1 has a lower body 5 and an upper body 6. The lower body 5 has the suction means mounted therein, and the upper body 6 has electric components mounted therein for controlling the vacuum cleaner. The body 1 has wheels 8 secured to opposite sides of a lower portion thereof, and the wheel 8 has an outlet 8a for discharging air having foreign matters removed from the air drawn through the suction nozzle 2.
Between the body 1 and the suction nozzle 2, there are a suction hose 3b, an operation part 4, and an extension tube 3a. The suction hose 3b is formed of a flexible material, and the operation part 4 is at an end of the suction hose 3b. The extension tube 3a makes the suction hose 3b and the suction nozzle 2 in communication.
Upon application of power through a power line, the vacuum cleaner is at a standby condition. If a user operates the operation part 4, an appropriate suction force is generated at the suction means in the body. The suction force is transmitted to the suction nozzle 2 through the suction hose 3b, the operation part 4, and the extension tube 3a in succession.
According to this, dust-laden air is drawn through the suction nozzle 2. The dust is separated from the air at a dust collecting box 10, to discharge only the air through the outlet 8a. By repeating this process, cleaning of the floor is performed.
However, the related art vacuum cleaner has the following problems.
First, the related art vacuum cleaner has a structure of the dust collecting box difficult to clean, to require much time, or to have inconvenience in cleaning the dust collecting box after finish of the operation.
Second, dismounting of the filter from an inside of the vacuum cleaner is not easy, to cause difficulty in replacement and cleaning of the filter.
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Epoxides such as ethylene oxide, propylene oxide, 1,2-butene oxide and the like are useful intermediates for the preparation of a wide variety of products. The oxirane functionality in such compounds is highly reactive and may be ring-opened with any number of nucleophilic reactants. For example, epoxides may be hydrolyzed to yield glycols useful as anti-freeze components, food additives, or reactive monomers for the preparation of condensation polymers such as polyesters.
Polyether polyols generated by the ring-opening polymerization of epoxides are widely utilized as intermediates in the preparation of polyurethane foams, elastomers, sealants, coatings, and the like. The reaction of epoxides with alcohols provides glycol ethers, which may be used as polar solvents in a number of applications.
Many different methods for the preparation of epoxides have been developed. One such method involves the epoxidation of an olefin in a liquid phase reaction using an organic hydroperoxide as the oxidizing agent and certain solubilized transition metal compounds as catalyst. The early work in this field concluded that optimum epoxidation rates and selectivity to epoxide generally are obtained using metallic catalysts which are soluble in an organic reaction medium. For example, U.S. Pat. No. 3,350,422 teaches in Example 6 that while vanadium naphthenate (a soluble catalyst) provided 72% hydroperoxide conversion and 38% selectivity to propylene oxide, vanadium pentoxide (an insoluble species) gave only 34% hydroperoxide conversion and 6% propylene oxide selectivity. Similarly, U.S. Pat. No. 3,351,635 teaches that metals such as molybdenum, tungsten and titanium are most effective as epoxidation catalysts when dissolved in the epoxidation reaction mixture. Poorly soluble species such as molybdenum trioxide thus are initially inactive and only become suitable for use in such application when converted to a soluble active form by reaction with alcohol, glycol, hydroperoxide or the like (see, for example, the discussion in Sheldon, J. Mol. Cat. 7, pp. 107-126 (1980)).
A distinct disadvantage of an epoxidation process which utilizes a soluble metallic compound as catalyst is the difficulty associated with recovering the catalyst for reuse in subsequent runs. When the other components of an epoxidation reaction mixture (typically, epoxide, unreacted olefin, solvent, unreacted hydroperoxide, and the alcohol derived from the reacted hydroperoxide) are relatively volatile, these components may be separated from the soluble non-volatile catalyst by distillation and the catalyst recovered in the form of a bottoms stream. A problem associated with such a method, however, is that the bottoms stream may tend to accumulate certain heavy substances such as acids and polymers which may have a deleterious effect on epoxide selectivity or olefin conversion when the stream is reused. The catalyst may also have a tendency to precipitate from solution if the bottoms stream is overly concentrated; recycle of a relatively large bottoms stream may thus be required, which will detrimentally affect the productivity of the epoxidation process. It would therefore be highly desirable to develop an insoluble (heterogeneous) epoxidation catalyst which has high activity and selectivity and which may be readily recovered in active form from an epoxidation reaction mixture by filtration or similar separation techniques or which may be utilized in the form of a fixed bed or the like.
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1. Field of the Invention
The present invention relates to a digital data processing system and, more particularly, to a multiprocess digital data processing system suitable for use in a data processing network and having a simplified, flexible user interface and flexible, multileveled, internal mechanisms.
2. Description of Prior Art
A general trend in the development of data processing systems has been towards systems suitable for use in interconnected data processing networks. Another trend has been towards data processing systems wherein the internal structure of the system is flexible, protected from users, and effectively invisible to the user and wherein the user is presented with a flexible and simplified interface to the system.
Certain problems and shortcomings affecting the realization of such a data processing system have appered repeatedly in the prior art and must be overcome to create a data processing system having the above attributes. These prior art problems and limitations include the following topics.
First, the data processing systems of the prior art have not provided a system wide addressing system suitable for use in common by a large number of data processing systems interconnected into a network. Addressing systems of the prior art have not provided sufficiently large address spaces and have not allowed information to be permanently and uniquely identified. Prior addressing systems have not made provisions for information to be located and identified as to type or format, and have not provided sufficient granularity. In addition, prior addressing systems have reflected the physical structure of particular data processing systems. That is, the addressing systems have been dependent upon whether a particular computer was, for example, an 8, 16, 32, 64 or 128 bit machine. Since prior data processing systems have incorporated addressing mechanisms wherein the actual physical structure of the processing system is apparent to the user, the operations a user could perform have been limited by the addressing mechanisms. In addition, prior processor systems have operated as fixed word length machines, further limiting user operations.
Prior data processing systems have not provided effective protection mechanisms preventing one user from effecting another user's data and programs without permission. Such protection mechanisms have not allowed unique, positive identification of users requesting access to information, or of information, nor have such mechanisms been sufficiently flexible in operation. In addition, access rights have pertained to the users rather than to the information, so that control of access rights has been difficult. Finally, prior art protection mechanisms have allowed the use of "Trojan Horse arguments". That is, users not having access rights to certain information have been able to gain access to that information through another user or procedure having such access rights.
Yet another problem of the prior art is that of providing a simple and flexible interface user interface to a data processing system. The character of user's interface to a data processing system is determined, in part, by the means by which a user refers to and identifies operands and procedures of the user's programs and by the instruction structure of the system. Operands and procedures are customarily referred to and identified by some form of logical address having points of reference, and validity, only within a user's program. These addresses must be translated into logical and physical addresses within a data processing system each time a program is executed, and must then be frequently retranslated or generated during execution of a program. In addition, a user must provide specific instructions as to data format and handling. As such reference to operands or procedures typically comprise a major portion of the instruction stream of the user's program and requires numerous machine translations and operations to implement. A user's interface to a conventional system is thereby complicated, and the speed of execution of programs reduced, because of the complexity of the program references to operands and procedures.
A data processing system's instruction structure includes both the instructions for controlling system operations and the means by which these instructions are executed. Conventional data processing systems are designed to efficiently execute instructions in one or two user languages, for example, FORTRAN or COBOL. Programs written in any other language are not efficiently executable. In addition, a user is often faced with difficult programming problems when using any high level language other than the particular one or two languages that a particular conventional system is designed to utilize.
Yet another problem in conventional data processing systems is that of protecting the system's internal mechanisms, for example, stack mechanisms and internal control mechanisms, from accidental or malicious interference by a user.
Finally, the internal structure and operation of prior art data processing systems have not been flexible, or adaptive, in structure and operation. That is, the internal structure and operation of prior systems have not allowed the systems to be easily modified or adapted to meet particular data processing requirements. Such modifications may include changes in internal memory capacity, such as the addition or deletion of special purpose subsystems, for example, floating point or array processors. In addition, such modifications have significantly effected the users interface with the system. Ideally, the actual physical structure and operation of the data processing system should not be apparent at the user interface.
The present invention provides data processing system improvements and features which solve the above-described problems and limitations.
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The present invention relates to a safety vacuum syringe for blood sampling conformed to ergonomics, and more particularly to provide a safety vacuum syringe for blood sampling conformed to health care workers and scavengers conveniently and safely.
Many diseases can be examined by a blood test, such as diabetes, hepatitis, syphilis, and AIDS. However, hepatitis, syphilis, and AIDS can be transmitted by a blood test. Hepatitis and syphilis can be cured by medicine now, but AIDS is still studying right now. Health care workers are susceptible to accidental and potentially infectious needle strikes because of the careless handing of the syringe after use. The resulting mini-accidents caused by an accidental needle strike typically require a blood test for such disease as AIDS and hepatitis. Therefore, avoiding accidental needle strike is very important for health care workers.
After finished of blood sampling, health care workers have to cover the needle cover on the needle and then withdraw in order to avoid health care workers and scavengers or further more other workers impaling themselves.
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{
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A tag may be thought of as a keyword or term associated with or assigned to a content item, such as a webpage, a digital image, a video clip, an internet bookmark, etc., which serves to describe the content item and enable classification of the content item. Tags are typically chosen informally and personally by end users who use a content item and assign one or more tags to the content item, which may be accomplished through the bookmarking process. As the digital environment continues to expand, the number of users of content items is increasing dramatically. Inherent in the increase of the number of users who view and interact with content items is an increase in the number of tags associated with a given content item that are personal to a user and may not accurately reflect the content of the of the content item. In essence, as more users tag a content item, the larger the spectrum of the subject of the tags, and thus, the greater the likelihood that the tags associated with the content item do not accurately reflect the content contained therein.
Thus, there is a need in the art for systems, methods and computer program products that allow for the determination of the quality of tags associated with a web document in reflecting the content of the web document.
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{
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This invention is concerned with dentifrice abrasives. In particular, it involves an improved silica abrasive.
Modern dentifrice compositions contain numerous components that have various therapeutic and cosmetic functions. Most of these compositions contain an abrasive cleansing agent which aids in the removal of adherent deposits on the teeth. Particulate matter of specific hardness and certain particle size, shape and structure are utilized as such abrasives. These particles must also be compatible with other toothpaste ingredients and safe for repeated human use. Abrasives that are described in the patent literature and have found commercial application include silica xerogels, hydrated silicas, hydrated aluminas, calcium carbonate, dicalcium phosphate (anhydrous and dihydrate), calcium pyrophosphate, and insoluble sodium metaphosphate. These agents are usually 2 to 30 micrometers (.mu.m) in size. Products of about 10 .mu.m appear to find the most commercial acceptance. Insoluble crystalline materials such as quartz have been found too abrasive for safe use on human teeth.
The use of silica xerogels is described in U.S. Pat. No. 3,538,230 to Pader & Weisner. This patent teaches that hydrogels prepared by acidifying a sodium silicate solution and then dried to a water content of 0.6 to 6% provide a xerogel that can be used as an abrasive especially for translucent and transparent toothpastes. U.S. Pat. No. 4,153,680 to Seybert teaches the use of a hydrogel as an abrasive for a dentifrice. This patent discloses that hydrogels prepared by neutralizing a sodium silicate solution and dried to between 17 and 32% water are effective abrasives. An important teaching of this patent is that the gel cannot be dried significantly below the level desired and then rehydrated to produce an effective product.
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{
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Field of the Invention
The present invention relates to an amorphous oxide. The present invention also relates to a field effect transistor using an amorphous oxide.
Related Background Art
In recent years, flat panel display (FPD) is commercialized as the results of progress of liquid crystal techniques, electroluminescence (EL), and the related techniques. The FPD is driven by an active matrix circuit comprising a field-effect thin film transistor (TFT) employing an amorphous silicon thin film or polycrystalline silicon thin film as the active layer formed on a glass substrate.
For smaller thickness, lighter weight, and higher impact strength of the FPD, use of a lightweight and a flexible resin substrate is investigated in place of the glass substrate. However, the transistor employing the silicon thin film cannot by directly formed on a less heat-resistant resin substrate, since the production of the silicon thin film transistor requires a relatively high-temperature in the process,
Therefore, for the TFT, use of an oxide semiconductor thin film such as a ZnO thin film is actively investigated which enables film formation at a lower temperature (Japanese Patent Application Laid-Open No. 2003-298062).
However, TFTs using conventional oxide semiconductor thin films have not provided performances on the same level as of TFTs using silicon.
The present invention relates to an amorphous oxide, and also, to a field effect transistor using the amorphous oxide.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are useful as antibiotics, and to pharmaceutical compositions comprising such compounds. The compounds are useful medications for the prophylaxis and treatment of various bacterial infections.
The following publications are cited in this application:
Storm et al., xe2x80x9cPolymyxin and related peptide antibiotics,xe2x80x9d Ann. Rev. Biochem., 46: 723-763 (1977).
Weinstein et al., xe2x80x9cSelective chemical modifications of Polymyxin B,xe2x80x9d Bioorganic and Medicinal Chemistry Letters, 8: 3391-3396 (1998).
Kimura and Matsunaga, xe2x80x9cPolymyxin B octapeptin and polymyxin B heptapeptide are potent outer membrane permeability-increasing agents,xe2x80x9d Journal of Antibiotics, 45(5): 742-749 (1992).
Srinivasa and Ramachandran, xe2x80x9cChemical modification of peptide antibiotics: Part VI-Biological activity of derivatives of polymyxin B,xe2x80x9d Indian J. Biochemistry and Biophysics, 14: 54-58 (1978).
PCT WO 88/00950 to Fauchere et al.
DE Patent No. 1,906,699 to Pfizer.
DE Patent No. 2,204,887 to Rhone-Poulenc.
J. E. Kapusnik-Uner, M. A. Sande, H. F. Chambers in Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeutics,xe2x80x9d 9h Ed. (J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, A. G. Gilman, Eds.); McGraw-1-Ell, New York: p 1123-1153 (1996).
M. R. W. Brown, S. M Wood, J. Pharm. Pharmacol. 24: 215-218 (1972).
S. Srimal, N. Surolia, S. Balasubramanian, A. Surolia, Biochem. J., 315: 679-686 (1996).
J. L. Shenep, R. P. Barton, et al., J. Infect. Dis. 151: 1012-1018 (1984).
M. G. Tauber, A. M. Shibl, C. J. Hackbarth, J. W. Larrick, M. A. Sande, Antimicrob. Agents Chemother. 156: 456-462 (1987).
G. S. Doig, C. M. Martin, et al., Crit. Care Med. 25:1956-1961 (1997).
C. Verwaest, J. Verhaegen, P. Ferdinande, M. Schetz, G. Van Den Berghe, L. Verbist, P. Lauwers, Crit. Care Med. 25: 63-71 (1997).
G. S. Bauldoff, D. R. Nunley, J. D. Manzetti, J. H. Dauber, R. J. Keenan, Transplantation 64: 748-752 (1997).
P. Diot, F. Gangadoux, C. Martin, H. Ellataoui, Y. Furet, M. Breteau, E. Boissinot, E. Lemarie, Eur. Resp. J. 10: 1995-1998 (1997).
S. E. Bucklin, P. Lake, L. Logdberg, D. C. Morrison, Antimicrobial Agents Chemother. 39: 1462-1466 (1995).
B. L. Jaber, B. J. Pereira, Am. J. Kidney Dis. 30(Suppl. 4): S44-56 (1997).
J. R. Berg, C. M. Spilker, S. A. Lewis, J. Membrane Biol. 154: 119-130 (1996).
L. Weinstein in xe2x80x9cThe Pharmacological Basis of Therapeutics,xe2x80x9d 5 1h Ed. (L. S. Goodman, A. Gilman, Eds.); MacMillan, N.Y.:, p1230-1233 (1975).
Physician""s Desk Reference, Medical Economics Co., Oradell, N.J.: (1993).
M. Helander, Y. Kato, I. Kilpelainen, R. Kostiainen, B. Lindner, K. Nummila, T. Sugiyama, T. Yokochi, Eur. J. Biochem. 237: 272-278 (1996).
Entries 2542 and 7734, The Merck Index, 12 th Edition, Merck and Co., Whitehouse Station, N.J.: (1996).
K. Vogler, R. O. Studer, W. Lergier, P. Lanz, Helv. Chim. Acta 43: 1751-1760 (1960).
K. Vogler, R. O. Studer, P. Lanz, W. Lergier, E. Boehni, Experientia 20: 365-366 (1964).
T. Kurihara, H. Takeda, H. Ito, Yakugaku Zasshi 92: 129-134 (1972).
K. Nakajima, Chem. Pharm. Bull. 15: 1219-1224 (1967).
M. Teuber, Z. Naturforsch. Teil B 25: 117 (1970).
Y. Kimura, H. Matsunaga, M. Vaara, J. Antibiot. 45: 742-749 (1992).
S. Chihara, A. Ito, M Yahata, T. Tobita, Y. Koyama, Agric. Biol. Chem. 38: 521-529 (1974).
S. Chihara, A. Ito, M Yahata, T. Tobita, Y. Koyama, Agric. Biol. Chem. 38: 1767-1777 (1974).
S. Chihara, T. Tobita, et al., Agric. Biol. Chem. 37: 2455-2462 (1973).
D. A. Stoma, K. S. Rosenthal, P. E. Swanson, Ann. Rev. Biochem. 46: 723-763 (1977).
M. Vaara, Drugs Exp. Clin. Res. 17: 437-444 (1991).
PCT WO 90/15628.
G. Radhakrishna, L. K. Ramachandran, Indian J. Biochem. Biophys. 20: 213-217 (1983).
C. P. Coyne, J. T. Moritz, J. Endotoxin Res. 1: 207-215 (1994).
J. L. Fauchere, K. Mosbach CH Appl. 86/315106 August 1986.
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
2. State of the Art
Bacteria are ubiquitous microbes capable of causing significant morbidity and mortality in infected individuals. Healthy individuals, having intact immune systems, rapidly eliminate pathogenic bacteria. However, many conditions render patients vulnerable to bacterial infection. Thus, individuals suffering from primary immunodeficiency disorders, such as AIDS, commonly develop infections. Alternatively, individuals may become susceptible to bacterial infection as the result of secondary immunodeficiencies due to other underlying disorders. For example, patients with diseases such as diabetes, connective tissue disorders, or trauma frequently develop complications due to severe bacterial infections. In such patients, overwhelming bacterial infections may result in a cascade of physiological changes leading to septic (or endotoxic) shock, which often culminates in the patient mortality.
Although most bacteria are capable of producing sepsis, a sub-class of bacteria, known as Gram-negative bacteria, which includes Eschericia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are the usual etiologic agents. The profound pathogenic effects of these microbes are due to a structural component, unique to Gram-negative bacteria, known as an outer membrane.
The outer membrane, which surrounds the bacterial cell, and protects it from environmental assaults, includes a molecule known as lipopolysaccharide (LPS). LPS is a complex structure with three components: 1) an outer region consisting of polymerized di- to penta-saccharide repeating units whose composition varies with bacterial species; 2) an inner region including of oligosaccharides linked by a sugar 2-keto-3-deoxy-C-mannose-octonate to a disaccharide backbone; and lipid A. This latter molecule, a glucosamine disaccharide with attached phosphate and acyl (fatty acid) groups, is responsible for most of the biological activity of the molecule.
The pathological effects of LPS are due to both intact LPS present in the outer membrane of the cell (bound LPS) and LPS that is released from the membrane and shed into blood (soluble LPS). Regardless of form, LPS elicits its biological effects by binding to a receptor found on a mononuclear phagocyte known as a monocyte. The interaction stimulates cellular processes resulting in the release of pro-inflammatory mediators such as TNF-xcex1, IL-1xcex2, IL-6 and PGE2, which, then leads to arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea and organ dysfunction that characterize septic shock.
Bacterial infections are usually treated with a molecularly diverse group of agents known as antibiotics, which act by a wide variety of mechanisms well known to those skilled in the art. While these drugs are sometimes capable of resolving the effects of bacteremia, infections with Gram-negative bacteremia presents special challenges. For example, treatment with conventional antibiotics while leading to the death of the pathogen, results in the release of toxic bacterial components, such as LPS. Thus, treatment with antibiotics may increase the amount of LPS or products of LPS such as endotoxin into the circulation.
Certain antibiotics, however, are able to neutralize the action of LPS, and mitigate its effects by binding to the molecule. Examples of such antibiotics include the polymyxin, circulin and octapeptin antibiotics, most notably polymyxin B and polymyxin E (also known as colistin), which are cyclic polypeptide compounds produced by strains of Bacillus polymyxa.
The lipid-bearing, polycationic polymyxin forms a complex with anionic phospholipids of the LPS and inserts into the membrane. This event disrupts the LPS, leading to loss of essential intracellular components and rapid bacterial cell death. In addition to its killing effects on intact bacteria, polymyxin also has high affinity for xe2x80x9cfreexe2x80x9d LPS components, most importantly, the lipid A portion of the lipopolysaccharide of the LPS (endotoxin). Complexation of lipid A by polymyxin prevents most of the pathophysiologic consequences of endotoxin in experimental systems.
Combinations of polymyxin B sulfate and/or colistin sulfate with various other compounds are widely used in opthalmic, otic, and topical applications against Gram-negative organisms. Strains of Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, and Shigella are typically sensitive to polymyxins at concentrations of 0.05-2.0 micrograms/mL in vitro, while most strains of Pseudomonas aeruginosa are inhibited by less than 8 micrograms/mL. Intrinsically resistant strains include Proteus mirabilis, Serratia marcesens, Providencia, and Edwardsiella tarda. More recently introduced uses of the polymyxins include the use of oral colistin for prophylactic gut clearance and of nebulized colistin for treatment of Pseudomonas infections in cystic fibrosis patients. In current development are the systemic use of macromolecular polymyxin-dextran conjugates and the extracorporeal use of polymyxin adsorbents for intervention in Gram-negative sepsis.
Polymyxin was at an earlier time administered parenterally and colistin sulfate is formulated for parenteral use; however, parenteral use of polymyxins is rare due to their nephrotoxicity and neurotoxicity. These effects are believed to have as their source the interaction of the polymyxins with phospholipids of mammalian cells. Neurological side effects of colistin administration include circumoral parasthesia pain at the site of intramuscular injection, numbness, tingling, or formication in the extremities, generalized pruritis, vertigo, dizziness, slurring of speech, and respiratory paralysis via neuromuscular blockade. Nephrological side effects include acute tubular necrosis, interstitial nephritis, proteinuria, hematuria, cylindruria, azotemia, and reduced glomerular filtration rate. The magnitude of these effects increases with continued therapy; however, the effects are generally reversible upon cessation of treatment.
For these reasons, polymyxin B, in intravenous form, is only given to hospitalized patients under constant supervision. Polymyxins and related antibiotics are not used routinely for systemic infections. Application of polymyxins to intact skin, denuded skin, or mucous membranes results in no systemic reactions because the drugs are poorly absorbed. Side effects following large (600 mg) oral doses of the antibiotic include nausea, vomiting, and diarrhea. Neurotoxic reactions have additionally been observed, the most severe being respiratory paralysis when given soon after anesthesia and/or muscle relaxants.
Given polymyxin""s significant systemic toxicities, the advent of anti-pseudomonal xcex2-lactams, the fluoroquinolone family of antibacterial agents, and aminoglycosides effective against Gram-negative organisms superseded parenteral use of polymyxin.
Antibacterial agents are important weapons in the fight against pathogenic bacteria. However, an increasing problem with respect to the effectiveness of antibacterial agents relates to the emergence of strains of bacteria that are highly resistant to such agents. Microbial resistance to the polymyxins is slow to develop and typically involves alterations in the composition of LPS components.
It would therefore be desirable to find antibacterial agents that are active against Gram-negative bacteria, in particular, drug resistant strains. It would also be advantageous to have antibacterial agents that demonstrate high activity and selectivity toward their targets and have high bioavailability, low toxicity, for example, nephrotoxicity, and other side effects. The present invention provides such agents.
This invention is directed to novel multibinding polymyxin, circulin and octapeptin antibiotics. The multibinding compounds of this invention are useful in the treatment and prevention of bacterial infections.
In particular, the compounds can be used to treat bacterial infections caused by Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, Enterobacter sp., Salmonella sp., Pasteurella sp., Bordetella sp., Shigella sp., Proteus mirabilis, and Serratia marcesens.
In one of its composition aspects, this invention provides a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises a polymyxin, circulin or octapeptin antibiotic or other suitable compound which binds to the LPS present in bacteria, in particular, Gram-negative bacteria.
In another of its composition aspects, this invention provides a multibinding compound of formula I:
(L)p(X)qxe2x80x83xe2x80x83I
wherein each L is independently a ligand comprising a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS and/or which demonstrates antibacterial properties; each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from 1 to 20; and pharmaceutically-acceptable salts thereof.
Preferably, q is less than p in the multibinding compounds of this invention.
Examples of suitable ligands include polymyxin A, polymyxin B1, polymyxin B2, polymyxin D1, polymyxin E1, polymyxin E2, circulin A, octapeptin A1, octapeptin A2, octapeptin A3, octapeptin B1, octapeptin B2, octapeptin B3, octapeptin C1. The xcex3-amino group on the DAB subunits on the ligands is a preferred site for attachment to the linker(s).
In still another of its composition aspects, this invention provides a multibinding compound of formula II:
Lxe2x80x2xe2x80x94Xxe2x80x2xe2x80x94Lxe2x80x2xe2x80x83xe2x80x83II
wherein each Lxe2x80x2 is independently a ligand comprising a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS and/or which demonstrates antibacterial properties; and Xxe2x80x2 is a linker; and pharmaceutically-acceptable salts thereof.
Preferably, in the above embodiments, each linker (i.e., X, Xxe2x80x2 or Xxe2x80x3) independently has the formula:
xe2x80x94Xaxe2x80x94Zxe2x80x94(Yaxe2x80x94Z)mxe2x80x94Ybxe2x80x94Zxe2x80x94Xaxe2x80x94
wherein
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NRxe2x80x94, xe2x80x94C(S), xe2x80x94C(S)Oxe2x80x94, xe2x80x94C(S)NRxe2x80x94 or a covalent bond where R is as defined below;
Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(O)xe2x80x94, xe2x80x94NRxe2x80x2C(O)NRxe2x80x2xe2x80x94, xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x95x90C(Xa)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94P(O)(ORxe2x80x2)xe2x80x94Oxe2x80x94, xe2x80x94S(O)nCRxe2x80x2Rxe2x80x3xe2x80x94, xe2x80x94S(O)nxe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94 and a covalent bond; where n is 0, 1 or 2; and R, Rxe2x80x2 and Rxe2x80x3 at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.
In yet another of its composition aspects, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrates antibacterial properties; and pharmaceutically-acceptable salts thereof.
This invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formula I or II.
The multibinding compounds of this invention are effective antibiotics, which are useful for treating a variety of bacterial infections. Accordingly, in one of its method aspects, this invention provides a method for treating various bacterial infections. Examples of such infections include infections caused by Enterobacter sp., E. coli, Klebsiella sp., Salmonella sp., Pasteurella sp., Bordetella sp., Shigella sp., Pseudomonas aeruginosa, Proteus mirabilis, and Serratia marcesens.
When used to treat bacterial infections, for example, the method involves administering to a patient having a bacterial infection a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrates antibacterial properties; and pharmaceutically-acceptable salts thereof.
This invention is also directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to various sites on bacteria. The diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage. The library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarizability and/or polarization. The library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like.
This invention is also directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to sites on various bacteria. The diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage. The library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarizability and/or polarization. The library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like.
This invention is also directed to libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to various sites on bacteria. These libraries are prepared via the methods described above and permit the rapid and efficient evaluation of what molecular constraints impart multibinding properties to a ligand or a class of ligands which bind to the LPS present in bacteria, especially gram negative bacteria, and/or which demonstrate antibacterial properties.
Accordingly, in one of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties, which method comprises:
(a) identifying a ligand or a mixture of ligands which includes a polymyxin, circulin or octapeptin compound or other suitable compound which binds to the LPS present in bacteria and/or which demonstrates antibacterial properties, wherein each ligand contains at least one reactive functionality;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and
(d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties.
In another of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties, which method comprises:
(a) identifying a library of ligands which includes polymyxin, circulin or octapeptin and other suitable compounds which bind to the LPS present in bacteria and/or which demonstrate antibacterial properties wherein each ligand contains at least one reactive functionality;
(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and
(d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties.
The preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b). Sequential addition is preferred when a mixture of different ligands is employed to ensure heteromeric or multimeric compounds are prepared. Concurrent addition of the ligands occurs when at least a portion of the multimer compounds prepared are homomultimeric compounds.
The assay protocols recited in (d) can be conducted on the multimeric ligand compound library produced in (c) above, or preferably, each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).
In one of its composition aspects, this invention is directed to a library of multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties which library is prepared by the method comprising:
(a) identifying a ligand or a mixture of ligands which include polymyxin, circulin or octapeptin compounds or other suitable compounds which bind to the LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrate antibacterial properties; wherein each ligand contains at least one reactive functionality;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
In another of its composition aspects, this invention is directed to a library of multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties and which may possess multivalent properties which library is prepared by the method comprising:
(a) identifying a library of ligands which includes a polymyxin, circulin or octapeptin compound or other suitable compounds which bind to the LPS present in bacteria and/or which demonstrate antibacterial properties wherein each ligand contains at least one reactive functionality;
(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
In a preferred embodiment, the library of linkers employed in either the methods or the library aspects of this invention is selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarizability and/or polarization and amphiphilic linkers. For example, in one embodiment, each of the linkers in the linker library may comprise linkers of different chain length and/or having different complementary reactive groups. Such linker lengths can preferably range from about 2 to 100 xc3x85.
In another preferred embodiment, the ligand or mixture of ligands is selected to have reactive functionality at different sites on the ligands in order to provide for a range of orientations of said ligand on said multimeric ligand compounds. Such reactive functionality includes, by way of example, carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates and precursors thereof. It is understood, of course, that the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.
In other embodiments, the multimeric ligand compound is homomeric (i.e., each of the ligands is the same, although it may be attached at different points) or heteromeric (i.e., at least one of the ligands is different from the other ligands).
In addition to the combinatorial methods described herein, this invention provides for an iterative process for rationally evaluating what molecular constraints impart multibinding properties to a class of antibacterial multimeric compounds or ligands. Specifically, this method aspect is directed to a method for identifying multimeric ligand compounds possessing multibinding properties with respect to the LPS present in certain bacteria, especially Gram-negative bacteria, or which possess antibacterial properties, which method comprises:
(a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which bind to the LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrate antibacterial properties; with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands;
(b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties;
(c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties;
(d) evaluating what molecular constraints imparted multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)-(c) above;
(e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration;
(f) evaluating what molecular constraints imparted enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above;
(g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints.
Preferably, steps (e) and (f) are repeated at least two times, more preferably at from 2-50 times, even more preferably from 3 to 50 times, and still more preferably at least 5-50 times.
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A prior-art washing/drying machine having a drying function is configured such that air in a washing tub in which garment is contained is heated by circulating the air from the washing tub through a drying air duct and, for dehumidification of hot and wet air flowing out of the washing tub, water is supplied into the drying air duct and heat-exchanged with the air in a drying process (see, for example, Patent Documents 1, 2 and 3).
Patent Document 1 proposes an arrangement which includes a water-cooled dehumidifier typically requiring about 6-liter water for dehumidification, and is configured such that bathwater is supplied as dehumidification water and, when the bathwater is exhausted, the drying process is continued by using tap water (see paragraphs [0003] to [0005] in Patent Document 1).
Patent Document 2 proposes a technique of controlling the supply amount of dehumidification water to be supplied for heat exchange based on a difference between the temperature of hot air flowing out of a washing tub before the heat exchange and the temperature of the dehumidification water after the heat exchange with the hot air without excess and deficiency of the dehumidification water, while ensuring effective dehumidification (see [SUMMARY] and paragraphs [0003] to [0008] and [0020] in Patent Document 2).
Patent Document 3 proposes a technique of performing an intermittent cooling water supply control by detecting the temperature of air taken out of a washing tub and heat-exchanged with cooling water and the temperature of the cooling water after the heat exchange with the air, calculating the average of the temperatures, and supplying the cooling water for the heat exchange based on the average in order to ensure higher drying capability and reduction of the consumption of the cooling water for water saving (see [SUMMARY] and [Claim 1] in Patent Document 3). Patent Document 1: JP-A-2002-35492 Patent Document 2: JP-A-2003-236290 Patent Document 3: JP-A-2006-247185
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A lithographic apparatus is a machine that applies a desired pattern onto a substrate, usually onto a target portion of the substrate. A lithographic apparatus can be used, for example, in the manufacture of integrated circuits (ICs). In that instance, a patterning device, which is alternatively referred to as a mask or a reticle, may be used to generate a circuit pattern to be formed on an individual layer of the IC. This pattern can be transferred onto a target portion (e.g., including part of, one, or several dies) on a substrate (e.g., a silicon wafer). Transfer of the pattern is typically via imaging onto a layer of radiation-sensitive material (resist) provided on the substrate. In general, a single substrate will contain a network of adjacent target portions that are successively patterned. Known lithographic apparatus include so-called steppers, in which each target portion is irradiated by exposing an entire pattern onto the target portion at one time, and so-called scanners, in which each target portion is irradiated by scanning the pattern through a radiation beam in a given direction (the “scanning”-direction) while synchronously scanning the substrate parallel or anti parallel to this direction. It is also possible to transfer the pattern from the patterning device to the substrate by imprinting the pattern onto the substrate.
In lithographic processes, it is desirable to frequently make measurements of the structures created, e.g., for process control and verification. One or more parameters of the structures are typically measured or determined, for example the overlay error between successive layers formed in or on the substrate. There are various techniques for making measurements of the microscopic structures formed in a lithographic process. Various tools for making such measurements are known, including scanning electron microscopes, which are often used to measure critical dimension (CD), and specialized tools to measure overlay, the accuracy of alignment of two layers in a device. An example of such a tool is a scatterometer developed for use in the lithographic field. This device directs a beam of radiation onto a target on the surface of the substrate and measures one or more properties of the redirected radiation—e.g., intensity at a single angle of reflection as a function of wavelength; intensity at one or more wavelengths as a function of reflected angle; or polarization as a function of reflected angle—to obtain a “spectrum” from which a property of interest of the target can be determined. Determination of the property of interest may be performed by various techniques: e.g., reconstruction of the target structure by iterative approaches such as rigorous coupled wave analysis or finite element methods, library searches, and principal component analysis.
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1. Field of the Invention
The present invention relates generally to control circuits and, more particularly, to a circuit for detecting the discharge state, or voltage level, of a battery, so that a lamp can be appropriately turned ON or OFF.
2. Description of the Background
FIG. 1 shows a circuit useful in energizing a metal halide lamp such as used in a camera. In FIG. 1, a DC voltage Vcc is supplied across voltage source terminals 6 and 6' and such DC voltage source might comprise a secondary battery of the camera and consist of a nickel-cadmium battery or the like. The DC voltage Vcc supplied by the secondary battery is consumed by the load, so that the fluctuation in voltage at terminal 6 is relatively large.
The voltage across terminals 6 and 6' is connected through a power switch 21 to a fixed contact 22a of a switch 22 and to a closed or "make" contact 27a of a relay 27. A movable contact 22b of switch 22 is electrically connected to a movable contact 27b of relay 27, to one end of a relay drive coil 24, to a cathode of a reverse current blocking diode 23, and to an input terminal 25a of an integrated circuit (IC) that operates as a voltage detecting circuit 25. Voltage detecting circuit 25 supplies a high-level signal at an output terminal 25b thereof when the DC voltage applied to input terminal 25a is higher than a predetermined voltage level, and supplies a low level signal at output terminal 25b when the DC voltage Vcc is lower than the predetermined voltage level.
Output terminal 25b of voltage detecting circuit 25 is connected to the base of a switching transistor 26, whose collector is connected to an anode of diode 23 and to the other end of relay drive coil 24. The emitter of transistor 26 is connected to ground, and the movable contact 27b of relay 27 is connected to one side of a metal halide lamp 19 that comprises the load in the circuit. The other side of metal halide lamp 19 is connected to ground. The other contact 27c of relay 27 is the open or "break" contact.
In the operation of the above-described control circuit, if the metal halide lamp 19 is to be turned ON the power switch 21 is closed and the switch 22 is manually depressed to the closed state. Switch 22 is ON or closed only so long as it remains manually depressed. At that time, the magnitude of the voltage Vcc supplied from the DC voltage source to input terminal 25a of voltage detecting circuit 25 is detected thereby. If the detected voltage falls within a predetermined voltage range, voltage detecting circuit 25 generates a high-level voltage at output terminal 25b, thereby biasing the base of switching transistor 26 so that switching transistor 26 is turned ON. Thus, relay drive coil 24 is excited by voltage Vcc and movable contact 27b resting on break contact 27c is moved into contact with make contact 27a, whereby the voltage Vcc from voltage source terminal 6 is supplied to metal halide lamp 19. Therefore, metal halide lamp 19 is turned ON, and a current flows through relay drive coil 24 causing relay 27 to keep itself pulled in.
Under this condition, if the voltage Vcc from the DC voltage source decreases to the predetermined, minimum acceptable value, a low-level voltage will be developed at output terminal 25b of voltage detecting circuit 25, whereby switching transistor 26 is turned OFF and the current flowing through the relay drive coil 24 is interrupted. Thus, movable contact 27b of relay 27 will return to break contact 27c and relay 27 will be turned OFF. If relay 27 is released from the pulled in state, the power to lamp 19 is interrupted, which is the same as power switch 21 being turned OFF.
According to the above-described arrangement, metal halide lamp 19 must be turned ON and OFF by use of manual switch 22, and voltage detecting circuit 25 for detecting whether the voltage of the DC voltage source has fallen below a predetermined value must be formed of an integrated circuit, which results in an expensive control circuit. Furthermore, a relay must be controlled, which results in a control circuit that consumes more power than is desirable.
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Botanical classification/cultivar designation: Chrysanthemum ajania pacificum cultivar Laika.
The present invention relates to a new and distinct cultivar of Chrysanthemum plant, botanically known as Chrysanthemum ajania pacificum and referred to by the name xe2x80x98Laikaxe2x80x99.
The new Chrysanthemum is the product of a planned breeding program conducted by the Inventor in Staden-Oostnieuwkerke, Belgium. The objective of the breeding program is to develop new cultivars of Chrysanthemum ajania pacificum with unique inflorescence forms, attractive ray and disc coloration and little to no pollen.
The new Chrysanthemum originated from a open-pollination made by the Inventor in October, 2000, in Staden-Oostnieuwkerke, Belgium, of the Chrysanthemum ajania pacificum cultivar Zarros Rose, not patented, as the female, or seed, parent with an unknown Chrysanthemum selection, not patented, as the male, or pollen, parent. The new Chrysanthemum was discovered and selected by the Inventor as a single plant within the progeny of the stated open-pollination in a controlled environment in Staden-Oostnieuwkerke, Belgium.
Asexual reproduction of the new Chrysanthemum by terminal cuttings in Staden-Oostnieuwkerke, Belgium has shown that the unique features of this new Chrysanthemum are stable and reproduced true to type in successive generations.
The cultivar Laika has not been observed under all possible environmental conditions. The phenotype may vary somewhat with variations in environment such as temperature, daylength and light intensity, without, however, any variance in genotype.
The following traits have been repeatedly observed and are determined to be the unique characteristics of xe2x80x98Laikaxe2x80x99. These characteristics in combination distinguish xe2x80x98Laikaxe2x80x99 as a new and distinct cultivar:
1. Numerous small inflorescences without ray florets; typically grown as a spray type.
2. Freely branching growth habit.
3. Early flowering response.
4. Good postproduction longevity.
Plants of the new Chrysanthemum can be compared to plants of the female parent, the cultivar Zarros Rose. In side-by-side comparisons conducted in Staden-Oostnieuwkerke, Belgium, plants of the new Chrysanthemum differed from plants of the cultivar Zarros Rose in the following characteristics:
1. Natural flowering date for plants of the new Chrysanthemum was about four to five weeks later than natural flowering date for plants of the cultivar Zarros Rose.
2. Plants of the new Chrysanthemum had yellow-colored inflorescences whereas plants of the cultivar Zarros Rose had pink-colored inflorescences.
Plants of the new Chrysanthemum can also be compared to plants of the cultivar Silver and Gold, not patented. In side-by-side comparisons conducted in Staden-Oostnieuwkerke, Belgium, plants of the new Chrysanthemum differed from plants of the cultivar Silver and Gold in the following characteristics:
1. Plants of the new Chrysanthemum were more rounded than plants of the cultivar Silver and Gold.
2. Plants of the new Chrysanthemum and plants of the cultivar Silver and Gold differed in leaf coloration.
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Poor early detection coupled with ineffective treatments for advanced disease is responsible for the low 5-year survival rates of certain cancers, including ovarian and lung cancers. Development of new diagnostic/prognostic markers would significantly enhance disease detection and improve survival.
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It is well known to remove layers of calloused tissue using rigid abrading stones or other rigid devices. However, such rigid devices suffer from the disadvantage that they do not desirably conform to complexly curved skin contours, such as at the heel of the human foot.
Also, such rigid devices must be applied directly against the foot surface to be abraded by hand, which requires that the user be able to bend to the extent necessary to touch the sole of his or her foot. This is not always possible, especially for persons suffering from arthritis, back injury or other debilitating condition.
Although flexible abrasive sheets such as that disclosed in U.S. Pat. No. 4,459,987 can be used more effectively to abrade the surface of tissue at complexly curved skin contours, again the use of such hand-held sheets in foot callus removal requires that the user be sufficiently limber to reach the sole of his or her foot. Thus persons with arthritis or some other disability cannot conveniently use such flexible abrasive sheets to remove foot calluses.
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The present invention relates to an apparatus for a tenter frame for drying a web of knitted material, the tenter frame being of the type having a feed roller for feeding the web along a feed path through a pair of opposed finger assemblies for smoothing the edges of the fabric to a pair of endless belts having vertical needles for securing the web during transport through a drying chamber.
In the handling of knitted fabric in a tenter frame, a fabric web is fed along a path to ultimately pass through a drying chamber in which the web is dried. To ensure that the web is of uniform width and generally planar during its travel through the drying chamber, the lengthwise edges of the web are pressed onto a plurality of uniformly spaced, upright pins mounted on a pair of spaced apart endless belt assemblies which extend into and through the drying chamber. The assemblies on which the respective rollers and endless belts forming the nip are mounted are pivotably adjustable to accommodate changes in web width, which pivoting causes relative movement of the assemblies with respect to the feed roller. To ensure that the web maintains its width as it is fed into the nip in which a pair of spaced pin rollers press the web border onto the pins, a series of opposed fingers smooth the respective lengthwise borders of the web. The pair of endless belts then transport the web in generally flat disposition through the drying chamber.
The tenter frame is often provided with a support belt of the endless belt type running parallel to the feed path and positioned just below the web of knitted material for supporting the web during its travel so that sagging, which is detrimental, is avoided. The support belt extends from the feed roller to a position adjacent the nip. The support belt is driven by the feed roller so the belt travels in sychronization with the feed of the web.
Since the support belt is driven by the feed roller, it travels in synchronization with the rate of feed of the web into the drying chamber. However, problems arise in maintaining the synchronization of the support belt with the web since the distance between the feed roller and the nip region varies as the endless belt assemblies are pivoted to accommodate changes in the width of the web and this causes corresponding changes in the tension of the support belt since it is coupled to the feed roller. Additionally, the relative distance between the feed roller and the nip may change as the endless belt assemblies expand due to heat during operation and this change of position, in turn, creates a change in the distance between the feed roller and the nip regions. Accordingly, practical difficulties are encountered in maintaining the support belt at a suitable tension while driving the belt in synchronization with the rate of feed of the web.
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{
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1. Field of the Invention
The present invention relates to a semiconductor device having improved contact characteristics between a semiconductor layer and a metal electrode.
2. Description of the Related Art
A high-density, high-performance MOS integrated circuit formed on an Si substrate is conventionally attained by micropatterning elements. More specifically, it is very important to decrease the gate length of a field effect transistor (FET) in order to not only decrease the element area but also improve the current driving force and the operation speed of the element. In this case, although the junction depth of a diffusion layer must be decreased to prevent a short-channel effect, a decrease in thickness of the diffusion layer is limited.
The ON-resistance of a MOSFET is determined by not only the channel resistance but also a sum of parasitic resistances such as the diffusion layer resistance of a source-drain region and the contact resistance between a metal and the source-drain region. Therefore, even when the junction depth of the diffusion layer is maximally decreased, when the channel resistance becomes equal to the parasitic resistance by micropatterning, a further increase in driving force cannot be expected, and the operation speed is not improved.
In a conventional FET, the thickness of a diffusion layer of a source-drain region is decreased. However, even when the thickness of the diffusion layer is maximally decreased, there is a large contact resistance between the source-drain region and a metal electrode. For this reason, an increase in driving force of the FET cannot be expected, and the operation speed cannot increased.
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The circulating component of the mammalian circulatory system comprises various cell types, including red and white blood cells of the erythroid and myeloid cell lineages. See, e.g., Rapaport (1987) Introduction to Hematology (2d ed.) Lippincott, Philadelphia, Pa.; Jandl (1987) Blood: Textbook of Hematology, Little, Brown and Co., Boston, Mass.; and Paul (ed.) (1993) Fundamental Immunology (3d ed.) Raven Press, N.Y.
For some time, it has been known that the mammalian immune response is based on a series of complex cellular interactions, called the “immune network.” Recent research has provided new insights into the inner workings of this network. While it remains clear that much of the response does, in fact, revolve around the network-like interactions of lymphocytes, macrophages, granulocytes, and other cells, immunologists now generally hold the opinion that soluble proteins, known as lymphokines, cytokines, or monokines, play a critical role in controlling these cellular interactions. Thus, there is considerable interest in the isolation, characterization, and mechanisms of action of cell modulatory factors, an understanding of which should lead to significant advancements in the diagnosis and therapy of numerous medical abnormalities, e.g., immune system and other disorders.
Lymphokines apparently mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth, and differentiation of pluripotential hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages making up a complex immune system. These interactions between cellular components are necessary for a healthy immune response. These different cellular lineages often respond in a different manner when lymphokines are administered in conjunction with other agents.
The chemokines are a large and diverse superfamily of proteins. The superfamily is subdivided into three branches, based upon whether the first two cysteines in the classical chemokine motif are adjacent (termed the “C-C” branch) or spaced by an intervening residue (“C-X-C”), or a new branch which lacks two cysteines in the corresponding motif, represented by the chemokines known as lymphotactins. See, e.g., Schall and Bacon (1994) Current Opinion in Immunology 6:865-873; and Bacon and Schall (1996) Int. Arch. Allergy & Immunol. 109:97-109.
Many factors have been identified which influence the differentiation process of precursor cells, or regulate the physiology or migration properties of specific cell types. These observations indicate that other factors exist whose functions in immune function were heretofore unrecognized. These factors provide for biological activities whose spectra of effects may be distinct from known differentiation or activation factors. The absence of knowledge about the structural, biological, and physiological properties of the regulatory factors which regulate cell physiology in vivo prevents the modification of the effects of such factors. Thus, medical conditions where regulation of the development or physiology of relevant cells is inappropriate remain unmanageable.
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1. Field of the Invention
The present invention relates to an image encoding device, and an image encoding method, and more specifically, it relates to an image encoding device, and an image encoding method, whereby deterioration in image quality can be reduced even when repeating encoding and decoding of an image by employing a long GOP configuration.
2. Description of the Related Art
Hitherto, with an image encoding method such as MPEG2 (Moving Picture Experts Group 2) or the like, it is a great problem to maintain subjective image quality to ideally distribute a code amount.
For example, an ideal code amount distribution of a still image is a state in which distortion is uniformly encoded (with a fixed quantized scale). When reaching a code amount whereby this distortion becomes great, subjective image quality can be enhanced by biasing the distortion toward a high-frequency component or complicated portion.
Now, for example, with International Publication WO96/28937, an image signal encoding method has been disclosed wherein the image quality of a decoded image can be improved by employing code amount control according to a feed forward method to enable control adapted to the local property of an image quality signal. The feed forward method is for determining a suitable quantizing scale in a range where a generated code amount does not exceed a target generated code amount by calculating a code amount to be generated in increments of equal lengthening regarding a plurality of quantizing scales.
On the other hand, with code amount control such as TM5 proposed as a test model with MPEG2, or the like, code amount control is performed by performing feedback control using relationship between the remaining amount of a virtual buffer, a quantization index at the time of previous encoding, and a generated code amount.
Also, in order to suppress deterioration in image quality at the time of repeating encoding and decoding of an image, for example, with International Publication WO2009/035144, the quantizing parameter and quantizing matrix used at the last encoding are detected.
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{
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The present invention relates to an electronic balance having a built-in calibration weight.
In general, a conventional electronic balance includes a load detecting unit having a combination of an electromagnetic force balance mechanism and a load sensor in a housing. The load detecting unit detects a load applied to a sensitive member in proportion to a load of a sample placed on a sample plate.
In the electronic balance having the load detecting unit as described above, there may be deviation (error) in a measured result (displayed value) according to a change in an environmental condition, such as a temperature and an air pressure, and lapse of time. Therefore, in order to accurately measure a weight of a sample all the time, it is required to carry out an automatic measurement sensitivity calibration (hereinafter, simply referred to as “sensitivity calibration”). Normally, a weight for the sensitivity calibration is disposed in the electronic balance, and the electronic balance includes a sensitivity calibration mechanism for calibrating the sensitivity by applying the weight.
FIG. 6 is a view showing a sensitivity calibration mechanism in a conventional electronic balance disclosed in Japanese Patent Publication (Kokai) No. 2000-74730. As shown in FIG. 6, in the sensitivity calibration mechanism, a sensitive member 3 is an upright member extending vertically, and an upper end portion thereof protrudes outside through a hole provided in a housing 1. A sample plate 2 is supported on a leading end of the sensitive member 3. A cap-shape weight receptacle 8 is disposed at the vicinity of an upper end portion of the sensitive member 3, for example, right under a supporting portion of the sample plate 2.
The sample plate 2 is an integrated part having a disc shape as a whole, and has a peripheral portion bent downwardly and a hole for inserting the leading end of the sensitive member 3 at a central portion of a lower surface thereof. A calibration weight 4 having a disc shape with a center thereof arranged coaxially with an axis of the sensitive member 3 is disposed in a space between the lower surface of the sample plate 2 and an upper surface of the housing 1.
When a sliding cam mechanism 6 drives a vertically moving bar 5 to push the calibration weight 4 upwardly, the vertically moving bar 5 and a weight holding member 7 hold the calibration weight 4, and the load of the calibration weight 4 is removed from the load detecting unit. When the vertically moving bar 5 is lowered, the load of the calibration weight 4 is applied to the sensitive member 3, so that the calibration is carried out with the calibration weight 4.
In the electronic balance having the calibration weight 4 of the pushing-up type mechanism described above, it is necessary to adjust a height of the vertically moving bar 5 abutting against a lower surface 4a of the calibration weight 4 and an engagement between the weight holding member 7 and the calibration weight 4. It is difficult to simplify a process of the adjustment, thereby causing an obstacle for mass production.
Therefore, in a recent electronic balance, as shown in FIG. 7, an elastic member 9 such as rubber is inserted between the weight holding member 7 for pressing the calibration weight 4 and a column 10 for adjusting a relative height between the weight holding member 7 and the vertically moving bar 5. Alternatively, the vertically moving bar 5 is formed to be extendable for adjusting the relative height between the weight holding member 7 and the vertically moving bar 5.
The conventional electronic balances have the structures as described above. In the electronic balance wherein the elastic material 9 such as rubber is inserted between the weight holding member 7 and the column 10 for adjusting the space between the weight holding member 7 and the leading end of the vertically moving bar 5 as shown in FIG. 7, it is necessary to adjust the space between the weight holding member 7 and the leading end of the vertically moving bar 5 for each electronic balance. However, it is difficult to adjust the height of the weight holding member 7, thereby causing variation in the height. Also, torque applied to a motor in the sliding cam mechanism 6 may vary for each product, thereby causing variation in sound of the motor.
In the electronic balance wherein the vertically moving bar 5 is extended to hold the calibration weight 4, the structure becomes complicated, thereby increasing manufacturing cost. When the electronic balance is transported, the vertically moving bar 5 tends to be displaced downwardly due to vibration or dropping, so that the load sensor may be damaged.
In view of the problems described above, it is an object of the invention to provide an electronic balance wherein the problems described above are solved.
Further objects and advantages of the invention will be apparent from the following description of the invention.
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The present invention relates to valves and, in particular, to a valve with a special handle that tracks the usage of the valve to enable logging and billing. The valve handle may thus be used not only to dispense a gas but, in combination with the disclosed procedure, to provide a method for conveniently providing tracking of the use of the gas and subsequent billing for medical treatments using the gas.
Some medical treatments involve the use of gases that are inhaled by the patient. In the past, medical gas suppliers have charged for the gas in the cylinder at the time of delivering the filled cylinder to the user. This method has been used both for industrial and medical uses. Pharmaceutical gases, dispensed by prescription, have great variability of use from patient to patient due to treatment regimen and dispensing methods. A method of charging for treatment time would be a desirable way for allocating the true value of the product. However, in the past, there has not been a way to automatically track the duration of treatments by cylinder or to tie the treatments to the patients who receive the treatments in order to make it easy to bill for use of the gas. Such a method is provided in accordance with the present invention.
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Speed, accuracy, and portability have been recurrent and difficult to achieve goals for devices that scan, measure or otherwise collect data about 3D objects for purposes such as reproduction. With the advent of computers, such devices have useful application in many fields, such as digital imaging, computer animation, topography, reconstructive and plastic surgery, dentistry, architecture, industrial design, anthropology, biology, internal medicine, milling and object production, and other fields. These computer-aided systems obtain information about an object and then transform the shape, contour, color, and other information to a useful, digitized form.
The technology currently available for shape digitizing falls into two distinct but related groups: mechanical systems and optical systems. All systems within those two general categories struggle with the basic criteria of speed, accuracy, and portability in measuring and generating information about an object.
A mechanical system acquires data about an object through the use of a probe that has a sensitive tip. The mechanical system scans an object by manually moving its probe tip across the object's surface and taking readings. Generally, the probe connects to a mechanical arm, and the system tracks the probe's position in space using angle measuring devices as the arm moves. The system calculates the position of the probe with coordinates known from the angle measuring devices.
Although mechanical systems scan with generally high accuracy, the rate at which a mechanical system acquires data is relatively slow and can take several hours for scanning and digitizing. A typical mechanical system measures only one point at a time and can digitize only small, solid objects.
As an alternative to mechanical systems, there are several types of optical object shape digitizers which fall into two basic categories: systems based on triangulation and alternative systems. A triangulation system projects beams of light on an object and then determines three-dimensional spatial locations for points where the light reflects from the object. Ordinarily, the reflected light bounces off the object at an angle relative to the light source. The system collects the reflection information from a location relative to the light source and then determines the coordinates of the point or points of reflection by triangulation. A single dot system projects a single beam of light which, when reflected, produces a single dot of reflection. A scan line system sends a plane of light against the object which projects on the object on a line and reflects as a curvilinear-shaped set of points describing one contour line of the object. The location of each point in that curvilinear set of points can be determined by triangulation.
Some single dot optical scanning systems use a linear reflected light position detector to read information about the object. In such systems a laser projects a dot of light upon the object. The linear reflected light position detector occupies a position relative to the laser which allows the determination of a three dimensional location for the point of reflection. A single dot optical scanner with a linear reflected light position detector can digitize only a single point at a time. Thus, a single dot optical scanning system, like the mechanical system described above, is relatively slow in collecting a full set of points to describe an object. Single dot optical scanners are typically used for applications such as industrial engineering. The digitizing speed is usually slow and is limited by the mechanics of the scanning system, i.e., the moving and positioning of the light beam. However, accuracy of these systems can be high. A scanning head can be mounted on a high-precision, but costly, positioning system to take a digitized image of the object's shape with generally good accuracy. However, because of the high cost, slow speed, and lack of flexibility, single dot optical scanners find generally only limited application.
Scan line systems offer one solution to the speed time bottleneck of single point triangulation system. Those systems typically employ a 2D imager, such as a charged coupled device (CCD) camera, for signal detection. The systems project a light plane (i.e., a laser stripe) instead of just one dot and then read the reflection of multiple points depicting the contour of an object at a location that is a distance from the CCD camera and from which the position can be triangulated. Some embodiments of the scan line-type system attach the CCD camera to a rotating arm or a moving platform. During scanning, either the object moves on a known path relative to the camera and laser, or the camera and laser, together, move around the object. In any case, such systems usually depend on this type of fixed rotational movement and typically use a bulky, high-precision mechanical system for positioning. Because of the use of mechanical positioning devices, resealing flexibility can be very limited, e.g., a scanner designed for objects the size of a basketball may not be useful for scanning apple-sized objects.
Some laser stripe triangulation systems currently available are further limited because the laser stripe stays at a fixed angle relative to the camera and the system makes its calculations based on the cylindrical coordinates of its rotating platform. The mathematical simplicity in such a projection system complicates the hardware portion of these devices as they typically depend on the rotational platform mentioned. Also, the simplified geometry does not generally allow for extremely refined reproduction of topologically nontrivial objects, such as objects with holes in them (e.g., a tea pot with a handle). Full realization of triangulation scanning with a non-restrictive geometry has not been achieved in the available devices.
The laser stripe triangulation systems currently available are also burdened by factors that place upper limits on scanning speed. The laser stripe triangulation systems which use a rotational platform are constrained by the speed at which the platform or arm can rotate the object without moving or shaking it. Some systems take 15 or so seconds to complete a 360.degree. scan. A target object, such as a person or an animal, may have difficulty staying still for such a scan time.
Another speed limitation is that the laser stripe triangulation systems typically can only generate one light stripe per camera image. As laser stripe triangulation systems generate a single laser stripe and project that stripe upon the object, the CCD camera captures an image of the stripe in a frame image--one laser stripe per CCD camera frame. Thus, the collection of laser information in some systems is subject to the speed limitations of the camera.
Additionally, for those optical triangulation systems employing a computer, there is the further problem of processing the incoming data. The CCD camera typically outputs frames of picture information at a rate of 30 or more frames per second. Each frame is composed of a two dimensional frame matrix of pixels and contains, for example, 640.times.480 pixel values of light intensity information. Thus, laser stripe triangulation systems must sort through many megabytes of information. These systems typically require very powerful computers and have sizeable memory requirements. In addition, they take a relatively long time to process the incoming CCD information into a viable set of points concerning the object. The points created can depict the object, but the system that create them are also limited in that they typically do not achieve a sophisticated model of the object.
Apart from optical triangulation systems (single dot or scan line systems), there are alternative optical scanning systems which present a scanning solution different from those employing triangulation techniques. Range meters and multi-camera systems are among those categorized as "alternative" systems. Range meter systems typically use an infrared pulsed laser and mechanical scanning techniques to project a dot laser across an object and then measure the phase delay of the reflected signal. As range meter systems typically incorporate a single dot method of data collection, they generally have the speed limitations that are intrinsic to single-point scanners. Additional accuracy problems occur because depth coordinates are not sufficiently accurate, such that in some systems, when an object is large, ghosts can appear on the scan.
Another type of alternative scanning system is a stereoscopic system which uses several CCD cameras located at known distances from each other. The captured images are processed with a pattern recognition system which maps the various points of an object captured by the cameras, thereby obtaining the shape/contour information. One advanced stereoscopic system uses 16 CCD cameras. Although each camera in such a system has a small exposure time, it takes several minutes to analyze the data for each scan. This can cause the system to delay, sometimes up to six minutes per scan. In this type of system, the device must also project a special grid on an object to obtain reference points for gluing a complete 3D picture. In addition, accuracy is sometimes a problem because stereoscopic scanning relies on light reflecting properties. The systems make assumptions based on Lambertian reflecting properties to determine resolution surface features of the scanned objects. Different surfaces can dictate different results for the same object.
Thus, for devices that scan, measure or otherwise collect data about an object, it would be a substantial advance if a scanner could be created that could rapidly gather highly accurate data concerning a 3D object. It would also be an advance if the device could rapidly process the data in a fashion that did not require a large computing system (and allow for portable embodiments), and after computing, create a descriptive model from the data points collected about the object.
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Smart cards, whether they are contactless and/or have contacts, are used inter alia in cashless payment transaction or as access authorization. The smart cards usually include a smart card module (FIG. 1A illustrates by way of example an at least inter alia contactless smart card module 100), having a chip 110 for storing and/or processing the confidential data or data having a monetary value, which chip for forming the smart card 101 can be arranged in a smart card body 220 (see FIG. 1B: the smart card body 220 is also equipped with a booster antenna 222 by way of example for an at least inter alia contactless utilization, said booster antenna comprising a chip coupling region 224, within which the smart card module 100 can be arranged). The chip can be mounted on a chip carrier 116, e.g. a substrate or a leadframe, and can customarily be encapsulated (not visible in the schematic plan view) in order to protect the contacting and the chip 110 against mechanical loads.
The encapsulation is usually formed by a covering compound or an encapsulation material being applied to the already mounted and contacted chip 110. The encapsulation can be formed for example as so-called glob top applied by dispensing, or a so-called mold cap formed by applying a molding compound under high pressure.
In some smart card modules or smart cards, however, an external access to the chip may be possible. External access means that the chip can be exposed chemically, mechanically, by a laser and/or plasma and can be contacted externally in the functioning state. Such methods are used for manipulating chips or e.g. to read out the data stored in the chip 110. One aim of such attacks may also be to ascertain the chip design for reproductions. Another conceivable aim of the attack is to use the chip 110 improperly in some other way.
An attack includes stripping away the chip encapsulation in such a way that the chip 110 is exposed as far as possible without being destroyed and such that it still functions electrically. The unprotected chip 110 can then be examined with regard to its mode of functioning and the stored data during its operation by physical attacks. The physical attacks may include for example so-called “probing”, in which the signals of the chip are tapped off and evaluated. In so-called “forcing” the conductor tracks of the chip are rewired at a microscopic level in order to manipulate the functional sequence of the chip.
On the part of the electrical industry, particularly in the field of pay television, also referred to as pay TV, and cashless payment transactions, there is great interest in preventing attacks on the corresponding chips. Companies incur great financial losses owing to manipulation of the semiconductor chips used for decrypting the pay TV programs broadcast in an encrypted fashion.
A further field that is particularly affected by smart card manipulations is the field of credit and cash cards. Owing to the improper manipulation of credit cards or cash cards, the affected companies and/or card holders incur financial damage.
Another field of application in which the smart cards should be protected against manipulation is the storage of security-relevant or sensitive data, for example in smart cards used as access authorization, electronic passports or patient cards having data concerning medical history.
Without additional protection of the chip surface, the chip 110 can be attacked as soon as the encapsulation (e.g. the molding compound) has been removed.
Such attacks may generally concern any type of packaged, e.g. encapsulated, semiconductor components (e.g. chips), also referred to as semiconductor packages: in addition to the smart card modules described, for example, including semiconductor packages which can be used on printed circuit boards in a wide variety of applications.
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1. Field of the Invention
The invention relates to apparatus for protecting a weight lifter who, during performance of weight lifting exercises using a bench press apparatus, finds that he is unable to complete an exercise and return the barbell to its upper, receiving position.
2. Description of the Prior Art
The recent interest in physical fitness is leading more and more persons to engage in a regular program of exercising in order to improve and maintain their personal fitness. Exercises such as jogging, aerobics, tennis, racquetball and weight lifting have enjoyed a great increase in interest in recent years.
The increasing pressures and time constraints of modern life have dictated that many persons perform their exercise routines alone, rather than in the company of others. In the case of weight lifting, and in particular, use of a brench press, this solo exercising can be quite dangerous. If, in the middle of a bench pressing exercise one finds that one cannot complete a lift of the barbell, injury can occur when collapse of the weight lifter's arms allows the barbell to contact his chest, neck or head.
There have been numerous attempts in the prior art to preclude such injury by the provision of safety stands for use during bench press exercises. To date, these safety stands have been cumbersome to use, and somewhat ineffectual. Simple safety stands, such as those provided by McIntosh in U.S. Pat. No. 4,205,838, present a rather small target for an exhausted weight lifter to engage with the barbell weights, and are also provided with a rather narrow base portion, which might allow the stands to tip over if the barbell is misaligned at the time contact, is made with the stand. Milnar, U.S. Pat. No. 4,411,425, provides safety stands which are rigidly attached to the weight lifting bench but they again represent a rather small target for an exhausted weight lifter with a heavy barbell, the target being placed in an awkward position also.
Other prior art devices of note include U.S. Pat. No. 4,262,901 to Faust and U.S. Pat. No. 4,368,884 to Colvin. While the Faust device provides sufficient stability for the safety apparatus, as well as an adequate target for the weight lifter, its design can easily interfere with exercises which the weight lifter may wish to perform. Also, with the use of larger weight disks, the barbell must be assembled within the safety device in order for proper use to occur. A deficiency of the Colvin apparatus is that, once the barbell has been laid to rest upon the safety apparatus, weights cannot be removed from the barbell until it is relocated to the bench press barbell holder. This may not be possible in the case of a weight lifter exercising alone, and thus, he will be unable to perform any additional exercises until help arrives so that he may relocate and unload the bar.
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Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.
Secreted proteins have various industrial applications, including as pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].
Membrane-bound proteins and receptors can play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.
Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interactions. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.
Efforts are being undertaken by both industry and academia to identify new, native receptor or membrane-bound proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor or membrane-bound proteins.
1. PRO1560
The tetraspan family of proteins has grown to include approximately 20 known genes from various species, including drosophila. The tetraspans are also known as the transmembrane 4 (TM4) superfamily and are proposed to have an organizing function in the cell membrane. Their ability to interact with other molecules and function in such diverse activities as cell adhesion, activation and differentiation, point to a role of aggregating large molecular complexes. Skubitz, et al., J. Immunology, 157:3617-3626 (1996). The tetraspan group has also emerged as a set of proteins with prominent functions in Schwann cell biology. Mirsky and Jessen, Curr. Opin. Neurobiol., 6(1):89-96 (1996). Tetraspans (also sometimes called tetraspanins) are further described in Maecker, et al., FASEB, 11:428-442 (1997). Thus, members of the tetraspan family are of interest.
2. PRO444
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO444.
3. PRO1018
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1018.
4. PRO1773
The primary and rate-limiting step in retinoic acid biosynthesis requires the conversion of retinol to retinal. Retinol dehydrogenase proteins are enzymes which function to recognize holo-cellular retinol-binding protein as a substrate, thereby catalyzing the first step of retinoic acid biogenesis from its substrate. Various retinol dehydrogenase genes have been cloned and characterized, wherein the products of these genes are suggested as potentially being useful for the treatment of retinitis pigmentosa, psoriasis, acne and various cancers (Chai et al., J. Biol. Chem. 270:28408-28412 (1995) and Chai et al., Gene 169:219-222 (1996)). Given the obvious importance of the retinol dehydrogenase enzymes, there is significant interest in the identification and characterization of novel polypeptides having homology to a retinol dehydrogenase. We herein describe the identification and characterization of novel polypeptides having homology to a retinol dehydrogenase protein, designated herein as PRO1773 polypeptides.
5. PRO1477
Glycosylation is an important mechanism for modulating the physiochemical and biological properties of proteins in a stage- and tissue-specific manner. One of the important enzymes involved in glycosylation in Saccharomyces cerevisiae is alpha 1,2-mannosidase, an enzyme that catalyzes the conversion of Man9GlcNAc2 to Man8GlcNAc2 during the formation of N-linked oligosaccharides. The Saccharomyces cerevisiae alpha 1,2-mannosidase enzyme of is a member of the Class I alpha 1,2-mannosidases that are conserved from yeast to mammals. Given the important roles played by the alpha 1,2-mannosidases and the mannosidases in general in glycosylation and the physiochemical activity regulated by glycosylation, there is significant interest in identifying novel polypeptides having homology to one or more mannosidases. We herein describe the identification and characterization of novel polypeptides having homology to a mannosidase protein, designated herein as PRO1477 polypeptides.
6. PRO1478
Recently, a new subfamily of galactosyltransferase genes that encode type II transmembrane proteins was identified from a mouse genomic library (Hennet et al., (1998) J. Biol. Chem. 273(1):58-65). Galactosyltransferases, in general, are all of interest. Beta 1,4-galactosyltransferase is been found in two subcellular compartments where it is believed to perform two distinct function. Evans, et al., Ioessays, 17(3):261-268 (1995). Beta 1,4-galactosyltransferase is described as a possible transducing receptor in Dubois and Shur, Adv. Exp. Med. Biol., 376:105-114 (1995), and further reported on in Shur, Glycobiology, 1(6):563-575 (1991). Expression and function of cell surface galactosyltransferase is reported on in Shur, Biochim. Biophys. Acta., 988(3):389-409 (1989). Moreover, the receptor function of galactosyltransferase during mammalian fertilization is described in Shur, Adv. Exp. Biol., 207:79-93 (1986), and the receptor function during cellular interactions is described in Shur, Mol. Cell Biochem., 61(2):143-158 (1984). Thus, it is understood that galactosyltransferases and their related proteins are of interest.
7. PRO831
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO831.
8. PRO1113
Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.
All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglubular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415-421 (October 1994).
A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome, Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats and Ruoslahti, E. I., et al., WO9110727-A by La Jolla Cancer Research Foundation reporting that decorin binding to transforming growth factorβ has involvement in a treatment for cancer, wound healing and scarring. Related by function to this group of proteins is the insulin like growth factor (IGF), in that it is useful in wound-healing and associated therapies concerned with re-growth of tissue, such as connective tissue, skin and bone; in promoting body growth in humans and animals; and in stimulating other growth-related processes. The acid labile subunit of IGF (ALS) is also of interest in that it increases the half-life of IGF and is part of the IGF complex in vivo.
Another protein which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Of particular interest is LIG-1, a membrane glycoprotein that is expressed specifically in glial cells in the mouse brain, and has leucine rich repeats and immunoglobulin-like domains. Suzuki, et al., J. Biol. Chem. (U.S.), 271(37):22522 (1996). Other studies reporting on the biological functions of proteins having leucine rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7): 1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidney disease involvement).
9. PRO1194
The nuclear genes PET117 and PET 119 are required for the assembly of active cytochrome c oxidase in S. Cerevisiae, and therefore, are of interest. Also of interest are nucleic acids which have sequence identity with these genes. PET genes are further described in McEwen, et al., Curr. Genet., 23(1):9-14 (1993).
10. PRO1110
The bone marrow plays many important roles in the mammal. One of those roles is to provide a source of various progenitor cells that differentiate into important cells and other components of the blood and immune systems. As such, the function of the myeloid system is of extreme interest.
We herein describe the identification and characterization of novel polypeptides having homology to myeloid upregulated protein, designated herein as PRO1110 polypeptides.
11. PRO1378
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1378.
12. PRO1481
Efforts are being undertaken by both industry and academia to identify new, native proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel proteins. We herein describe the identification and characterization of a novel protein designated herein as PRO1481.
13. PRO1189
There has been much interest in the identification of receptor proteins on stem cells and progenitor cells which may be involved in triggering proliferation or differentiation. A type II transmembrane protein was identified in proliferating progenitor cells in the outer perichondrial rim of the postnatal mandibular condyle proliferation. The investigators concluded that E25 could be a useful marker for chondro-osteogenic differentiation (Deleersnijder, et al. J. Biol. Chem. 271(32):19475-19482 (1996)).
14. PRO1415
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1415.
15. PRO1411
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1411.
16. PRO1295
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1295.
17. PRO1359
Enzymes such as hyaluronidase, sialyltransferase, urokinase-type plasminogen activator, plasmin, matrix metalloproteinases, and others, play central roles in the catabolism of extracellular matrix molecules. As such, these enzymes and inhibitors thereof, may play roles in metastatic cancer and the treatment thereof. Van Aswegen and du Plessis, Med. Hypotheses, 48(5):443-447 (1997). For the foregoing reason, as well as their diversity in substrate specificity example, sialyltransferases are of particular interest. For example, a peptide of interest is the GalNAc alpha 2,6-sailytransferase as described in Kurosawa, et al., J. Biol. Chem., 269(2):1402-1409 (1994). This peptide was constructed to be secreted, and retained its catalytic activity. The expressed enzyme exhibited activity toward asialomucin and asialofetuin, but not other glycoproteins tested. As sialylation is an important function, sialyltransferases such as this one, and peptides related by sequence identity, are of interest. Sialyltransferases are further described in the literature, see for example, Sjoberg, et al, J. Biol. Chem., 271(13):7450-7459 (1996), Tsuji, J. Biochem., 120(1):1-13 (1996) and Harduin-Lepers, et al., Glycobiology, 5(8):741-758 (1995).
18. PRO1190
Kang et al. reported the identification a novel cell surface glycoprotein of the Ig superfamily (J. Cell biol. (1997) 138(1):203-213). Cell adhesion molecules of the Ig superfamily are implicated in a wide variety of biological processes, including cell migration, growth control, and tumorigenesis. The Kang et al. studies suggest that loss of CDO function may play a role in oncogenesis. Accordingly, the identification of additional CDO-like molecules, and more generally, cell adhesion molecules of the Ig superfamily, is of interest.
19. PRO1772
Peptidases are enzymatic proteins that function to cleave peptide substrates either in a specific or non-specific manner. Peptidases are generally involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different peptidase enzymes from a variety of different mammalian and non-mammalian organisms have been both identified and characterized. The mammalian peptidase enzymes play important roles in many different biological processes including, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
In light of the important physiological roles played by peptidase enzymes, efforts are currently being undertaken by both industry and academia to identify new, native peptidase homologs. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. We herein describe the identification of novel polypeptides having homology to various peptidase enzymes, designated herein as PRO1772 polypeptides.
20. PRO1248
Putative protein-2 (PUT-2) is a homolog of the human disease genes L1CAM, G6PD and P55 (Riboldi Tunnicliffe et al., Genome Analysis, submitted). As such, there is interest in identifying novel polypeptides and encoding DNA having homology to the PUT-2 protein. We herein describe the identification and characterization of novel polypeptides having homology to PUT-2 protein, designated herein as PRO1248 polypeptides.
21. PRO1316
Dickkopf (Dkk) is a family of secreted proteins having a high degree of homology in the cysteine-rich domains (i.e., 80-90%). Dkk-1, the first discovered member, of this family has potent head-inducgin activity on the Spemann organizer. Glinka et al., Nature 391 (6665): 357-362 (1988). The Spemann organizer of the amphibian embryo can be subdivided into two discrete activities, namely trunk organizer and head organizer. Dkk-1 has been found to be both sufficient and necessary to cause head induction in Xenopus embryos and is further a potent antagonist of Wnt signaling, suggesting that the Dkk genes encode an entire family of Wnt inhibitors.
Members of the Wnt gene family function in both normal development and differentiation as well as in tumorigenesis. Wnts are encoded by a large gene family whose members have been found in round worms, insects, cartilaginous fish, and vertebrates. Holland et al., Dev. Suppl., 125-133 (1994). Wnt genes encode a family of secreted glycoproteins that modulate cell fate and behavior in embryos through activation of receptor-mediated signaling pathways.
Studies of mutations in Wnt genes have indicated a role for Wnts in growth control and tissue patterning. In Drosophila, wingless (wg) encodes a Wnt-related gene (Rijsewik et al., Cell, 50: 649-657 (1987)) and wg mutations alter the pattern of embryonic ectoderm, neurogenesis, and imaginal disc outgrowth. Morata and Lawerence, Dev. Biol., 56: 227-240 (1977); Baker, Dev. Biol., 125: 96-108 (1988); Klingensmith and Nusse, Dev. Biol., 166: 396-414 (1994). In Caenorhabditis elegans, lin-44 encodes a Wnt homolog which is required for asymmetric cell divisions. Herman and Horvitz, Development, 120: 1035-1047 (1994). Knock-out mutations in mice have shown Wnts to be essential for brain development (McMahon and Bradley, Cell, 62: 1073-1085 (1990); Thomas and Cappechi, Nature, 346: 847-850 (1990)), and the outgrowth of embryonic primordia for kidney (Stark et al., Nature, 372: 679-683 (1994)), tail bud (Takada et al., Genes Dev., 8: 174-189 (1994)), and limb bud. Parr and McMahon, Nature, 374: 350-353 (1995). Overexpression of Wnts in the mammary gland can result in mammary hyperplasia and tumors, ((McMahon, supra (1992); Nusse and Varmus, H. E., Cell 69: 1073-1087 (1992)), and precocious alveolar development. Bradbury et al., Dev. Biol., 170: 553-563 (1995). Moreover, constitutive expression of Wnt4 in virgin hosts of transplanted mammary epithelium resulted in highly branched tissue, similar to a pregnancy-like growth pattern. Bradbury et al., Dev. Biol. 170: 553-563 (1995).
The Wnt/Wg signal transduction pathway plays an important role in the biological development of the organism and has been implicated in several human cancers. This pathway also includes the tumor suppressor gene, APC. Mutations in the APC gene are associated with the development of sporadic and inherited forms of human colorectal cancer. For example, elevated levels of Wnt-2 have been observed in colorectal cancers. Vider, B-Z. et al., Oncogene 12: 153-158 (1996).
22. PRO1197
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1197.
23. PRO1293
Immunoglobulins are antibody molecules, the proteins that function both as receptors for antigen on the B-cell membrane and as the secreted products of the plasma cell. Like all antibody molecules, immunoglobulins perform two major functions: they bind specifically to an antigen and they participate in a limited number of biological effector functions. Therefore, new members of the Ig superfamily and fragments thereof are always of interest. Molecules which act as receptors by various viruses and those which act to regulate immune function are of particular interest. Also of particular interest are those molecules which have homology to known Ig family members which act as virus receptors or regulate immune function. Thus, molecules having homology to Ig superfamily members and fragments thereof (i.e., heavy and light chain fragments) are of particular interest.
We herein describe the identification and characterization of novel polypeptides having homology to an immunoglobulin heavy chain variable region protein, designated herein as PRO1293 polypeptides.
24. PRO1380
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1380.
25. PRO1265
The identification of novel secreted proteins involved in physiological and metabolic pathways is of interest because of their potential use as pharmaceutical agents. Of particular interest is the identification of novel polypeptides that are potentially involved in immune response and inflammation mechanisms. A novel polypeptide has recently been identified that is expressed in mouse B cells in response to IL4. The gene encoding this polypeptide is referred to as interleukin-four induced gene 1, or “FIG. 1” (Chu et al. Proc. Natl. Acad. Sci (1997) 94(6):2507-2512).
26. PRO1250
Long chain fatty acid CoA ligase is an enzymatic protein that functions to ligate together long chain fatty acids, a function that plays important roles in a variety of different physiological processes. Given the importance of this enzymatic protein, efforts are currently being undertaken to identify novel long chain fatty acid CoA ligase homologs. We herein describe the identification and characterization of novel polypeptides having homology to long chain fatty acid CoA ligase, designated herein as PRO1250 polypeptides.
27. PRO1475
N-acetylglucosaminyltransferase proteins comprise a family of enzymes that provide for a variety of important biological functions in the mammalian organism. As an example, UDP-N-acetylglucosamine: alpha-3-D-mannoside beat-1,2-N-acetylglucosaminyltransferase I is an enzymatic protein that catalyzes an essential first step in the conversion of high-mannose N-glycans to hybrid and complex N-glycans (Sarkar et al., Proc. Natl. Acad. Sci. USA. 88:234-238 (1991). Given the obvious importance of the N-acetylglucosaminyltransferase enzymes, there is significant interest in the identification and characterization of novel polypeptides having homology to an N-acetylglucosaminyltransferase protein. We herein describe the identification and characterization of novel polypeptides having homology to an N-acetylglucosaminyltransferase protein, designated herein as PRO1475 polypeptides.
28. PRO1377
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1377.
29. PRO1326
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1326.
30. PRO1249
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1249.
31. PRO1315
Many important cytokine proteins have been identified and characterized and shown to signal through specific cell surface receptor complexes. For example, the class II cytokine receptor family (CRF2) includes the interferon receptors, the interleukin-10 receptor and the tissue factor CRFB4 (Spencer et al., J. Exp. Med. 187:571-578 (1998) and Kotenko et al., EMBO J. 16:5894-5903 (1997)). Thus, the multitude of biological activities exhibited by the various cytokine proteins is absolutely dependent upon the presence of cytokine receptor proteins on the surface of target cells. There is, therefore, a significant interest in identifying and characterizing novel polypeptides having homology to one or more of the cytokine receptor family. We herein describe the identification and characterization of a novel polypeptide having homology to cytokine receptor family-4 proteins, designated herein as PRO1315 polypeptides.
32. PRO1599
Granzyme M is a natural killer cell serine protease. The human gene is 7.5 kilobases, has an exon-intron structure identical to other serine proteases, and is closely linked to the serine protease gene cluster on chromosome 19p13.3. (Pilat et al., Genomics, 24:445-450 (1994)). Granzyme M has been found in two human natural killer leukemia cell lines, unstimulated human peripheral blood monocytes and untreated purified CD3-CD56+ large granular lymphocytes. (Smyth et al., J. Immunol., 151:6195-6205 (1993)).
33. PRO1430
Reductases form a large class of enzymatic proteins found in a variety of mammalian tissues and play many important roles for the proper functioning of these tissues. They are antioxidant enzymes that catalyze the conversion of reactive oxygen species to water. Abnormal levels or functioning of reductases have been implicated in several diseases and disorders including strokes, heart attacks, oxidative stress, hypertension and the development of both benign and malignant tumors. For example, malignant prostate epithelium may have lowered expression of such antioxidant enzymes [Baker et al., Prostate 32(4):229-233 (1997)]. International patent application no. WO9622360-A1 describes a prostate specific reductase that is useful for diagnosing and treating prostate cancer and screening new antagonists. Inhibitors of alpha-reductase have been used in the treatment of benign prostatic hyperplasia (Anderson, Drugs Aging (1996) 65):388-396). For these reasons, the identification of new members of the reductase family has been of interest for the treatment and diagnosis of cancers and other diseases and disorders.
34. PRO1374
Prolyl 4-hyroxylase (P4HA) catalyzes the formation of 4-hydroxyproline in collagens. Annunen, et al., J. Biol. Chem., 272(28):17342-17348 (1997); Helaakoski, et al., PNAS USA, 92(10):4427-4431 (1995); and Hopkinson, et al., Gene, 149(2):391-392 (1994). This enzyme and molecules related thereto are of interest.
35. PRO1311
The tetraspan family of proteins, also referred to as the “transmembrane 4 (TM4) superfamily”, are proposed to have an organizing function in the cell membrane. It is believed that they interact with large molecular complexes and function in such diverse activities as cell adhesion, activation and differentiation (see Maecker et al. FASEB (1997) 11:428-442). Accordingly, the identification of new members of the tetraspan family of proteins is of interest. Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
36. PRO1357
Ebnerin is a cell surface protein associated with von Ebner glands in mammals. Efforts are being undertaken by both industry and academia to identify new, native proteins and specifically those which possess sequence homology to cell surface proteins such as ebnerin or other salivary gland-associated proteins. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. We herein describe the identification of novel polypeptides having significant homology to the von Ebner minor salivary gland-associated protein, designated herein as PRO1357 polypeptides.
37. PRO1244
One type of transmembrane protein that has received attention is implantation-associated uterine protein. Deficiencies or abnormalities of this protein may be a cause of miscarriage. Therefore, the identification and characterization of implantation-associated proteins is of interest.
38. PRO1246
Bone-related sulphatase is an enzymatic protein that has been shown to degrade sulphate groups of proteoglycan sugar chains in bone tissue (Australian Patent Publication No. AU 93/44921-A, Mar. 3, 1994). Because of its specific sulphatase activity, it has been suggested that bone-related sulphatase may find use in the treatment of bone metabolic diseases. As such, there is significant interest in identifying and characterizing novel polypeptides having sequence similarity to bone-related sulphatase. We herein describe the identification and characterization of novel polypeptides having homology to bone-related sulphatase, designated herein as PRO1246 polypeptides.
39. PRO1356
Clostridium perfringens enterotoxin (CPE) is considered to be the virulence factor responsible for causing the symptoms of C. perfringens type A food poisoning and may also be involved in other human and veterinary illnesses (McClane, Toxicon. 34:1335-1343 (1996)). CPE carries out its adverse cellular functions by binding to an approximately 50 kD cell surface receptor protein designated the Clostridium perfringens enterotoxin receptor (CPE-R) to form an approximately 90,000 kD complex on the surface of the cell. cDNAs encoding the CPE-R protein have been identified characterized in both human and mouse (Katahira et al., J. Cell Biol. 136:1239-1247 (1997) and Katahira et al., J. Biol. Chem. 272:26652-26658 (1997)). Since the CPE toxin has been reported to cause a variety of illnesses in mammalian hosts and those illnesses are initiated by binding of the CPE toxin to the CPE-R, there is significant interest in identifying novel CPE-R homologs. We herein describe the identification and characterization of novel polypeptides having homology to the CPE-R, designated herein as PRO1356 polypeptides.
40. PRO1275
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1275.
41. PRO1274
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1274.
42. PRO1412
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1412.
43. PRO1557
The identification of secretory proteins that play roles in neural development are of interest. Such proteins may find use in the understanding of and possible treatment of neurological diseases and disorders. Chordin protein, which has been isolated from Xenopus, is a potent dorsalizing factor that regulates cell-cell interactions in the organizing centers of Xenopus head, trunk and tail development (Sasai et al., (1994) Cell 79(5):779-790; see also Mullins, (1998) Trends Genet. 14(4):127-129; and Kessel et al. (1998) ) Trends Genet. 14(5):169-171). It may be used as a component of culture medium for culturing nerve and muscle cells, and may have use in the treatment of neurodegenerative diseases and neural injury (U.S. Pat. No. 5,679,783).
44. PRO1286
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1286.
45. PRO1294
The extracellular mucous matrix of olfactory neuroepithelium is a highly organized structure in intimate contact with chemosensory cilia that house the olfactory transduction machinery. The major protein component of this extracellular matrix is olfactomedin, a glycoprotein that is expressed in olfactory neuroepithelium and which form intermolecular disulfide bonds so as to produce a polymer (Yokoe et al., Proc. Natl. Acad. Sci. USA 90:4655-4659 (1993), Bal et al., Biochemistry 32:1047-1053 (1993) and Snyder et al., Biochemistry 30:9143-9153 (1991)). It has been suggested that olfactomedin may influence the maintenance, growth or differentiation of chemosensory cilia on the apical dendrites of olfactory neurons. Given this important role, there is significant interest in identifying and characterizing novel polypeptides having homology to olfactomedin. We herein describe the identification and characterization of a novel polypeptide having homology to olfactomedin protein.
We herein describe the identification and characterization of novel polypeptides having homology to olfactomedin protein, designated herein as PRO1294 polypeptides.
46. PRO1347
Butyrophilin is a milk glycoprotein that constitutes more than 40% of the total protein associated with the fat globule membrane in mammalian milk. Expression of butyrophilin mRNA has been shown to correlate with the onset of milk fat production toward the end pregnancy and is maintained throughout lactation. Butyrophilin has been identified in bovine, murine and human (see Taylor et al., Biochim. Biophys. Acta 1306:1-4 (1996), Ishii et al., Biochim. Biophys. Acta 1245:285-292 (1995), Mather et al., J. Dairy Sci. 76:3832-3850 (1993), Ogg, et al., Mamm. Genome, 7(12):900-905 (1996), Sato, et al., J. Biochem., 117(1):147-157 (1995) and Banghart et al., J. Biol. Chem. 273:4171-4179 (1998)) and is a type I transmembrane protein that is incorporated into the fat globulin membrane. It has been suggested that butyrophilin may play a role as the principle scaffold for the assembly of a complex with xanthine dehydrogenase/oxidase and other proteins that function in the budding and release of milk-fat globules from the apical surface during lactation (Banghart et al., sura). Given that butyrophilin plays a role in mammalian milk production, there is substantial interest in identifying novel butyrophilin homologs.
47. PRO1305
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1305.
48. PRO1273
The lipocalin protein family is a large group of small extracellular proteins. The family demonstrates great diversity at the sequence level; however, most lipocalins share characteristic conserved sequence motifs. Lipocalins are known to be involved in retinol transport, invertebrate cryptic coloration, olfaction and pheromone transport, and prostaglandin synthesis. The lipocalins have also been implicated in the regulation of cell homoeostasis and the modulation of the immune response, and as carrier proteins, to act in the general clearance of endogenous and exogenous compounds. Flower, Biochem. J., 318(Pt 1):1-14 (1996); Flower, FEBS Lett., 354(1):7-11 (1994). Thus, novel members of the lipocalin protein family are of interest.
49. PRO1302
CD33 is a cell-surface protein that is a member of the sialoadhesin family of proteins that are capable of mediating sialic-acid dependent binding with distinct specificities for both the type of sialic acid and its linkage to subterminal sugars. CD33 is specifically expressed in early myeloid and some monocyte cell lineages and has been shown to be strongly associated with various myeloid tumors including, for example, acute non-lymphocytic leukemia (ANLL). As such, CD33 has been suggested as a potential target for the treatment of cancers associated with high level expression of the protein. One CD33 homolog (designated CD33L) is described in Takei et al., Cytogenet. Cell Genet. 78:295-300 (1997). Another study describes the use of CD33 monoclonal antibodies in bone marrow transplantation for acute myeloid leukemia. Robertson, et al., Prog. Clin. Biol. Res., 389:47-63 (1994).
Moreover, studies have reported that members of the sialoadhesion family contribute to a range of macrophage functions, both under normal conditions as well as during inflammatory reactions. Crocker, et al., Glycoconj. J., 14(5):601-609 (1997). Moreover, these proteins are associated with diverse biological processes, i.e., hemopoiesis, neuronal development and immunity. Kelm, et al., Glycoconj. J., 13(6):913-926 (1996). Thus, novel polypeptides related to CD33 by sequence identity are of interest.
50. PRO1283
Olfactory reception occurs via the interaction of odorants with the chemosensory cilia of the olfactory receptor cells located in the nasal epithelium. Based upon the diversity of nasal epithelial-associated odorant binding proteins, the mammalian olfactory system is capable of recognizing and discriminating a large number of different odorant molecules. In this regard, numerous different odorant binding proteins and their encoding DNA have recently been identified and characterized (Dear et al., Biochemistry 30: 10376-10382 (1991), Peysner et al., Science 241:336-339 (1988), Bucket al., Cell 65:175-187 (1991) and Breer et al., J. Recent. Res. 13:527-540 (1993)). Because study of the mechanisms of odorant detection by the mammalian olfactory system are of interest, there is significant interest in identifying novel odorant binding protein. We herein describe the identification and characterization of novel polypeptides having homology to odorant binding proteins, designated herein as PRO1283 polypeptides.
51. PRO1279
Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enzymes from a variety of different mammalian and non-mammalian organisms have been both identified and characterized, including the serine proteases which exhibit specific activity toward various serine-containing proteins. The mammalian protease enzymes play important roles in biological processes such as, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
Neuropsin is a novel serine protease whose mRNA is expressed in the central nervous system. Mouse neuropsin has been cloned, and studies have shown that it is involved in the hippocampal plasticity. Neuropsin has also been indicated as associated with extracellular matrix modifications and cell migrations. See, generally, Chen, et al., Neurosci., 7(2):5088-5097 (1995) and Chen, et al., J. Histochem. Cytochem., 46:313-320 (1998).
We herein describe the identification and characterization of novel polypeptides having homology to neuropsin protein, designated herein as PRO1279 polypeptides.
52. PRO1304
The immunophilins are a family of proteins that function as receptors for immunosuppressant drugs, such as cyclosporin A, FK506, and rapamycin. The immunophilins occur in two separate classes, (1) the FK506-binding proteins (FKBPs), which bind to FK506 and rapamycin, and (2) the cyclophilins, which bind to cyclosporin A. With regard to the FK506-binding proteins, it has been reported that the FK506/FKBP complex functions to inhibit the activity of the serine/threonine protein phosphatase 2B (calcineurin), thereby providing immunosuppressant activity (Gold, Mol. Neurobiol. 15:285-306 (1997)). It has also been reported that the FKBP immunophilins are found in the mammalian nervous system and may be involved in axonal regeneration in the central nervous system through a mechanism that is independent of the process by which immunosuppression is achieved (Gold, supra). Thus, there is substantial interest in identifying novel polypeptides having homology to the FKBP immunophilins.
We herein describe the identification and characterization of novel polypeptides having homology to FK506 binding protein, designated herein as PRO1304 polypeptides.
53. PRO1317
There is considerable interest in the identification of molecules whose expression is increased upon stimulation of leukocyte populations because insights into the structure and function of these molecules may lead to further understanding of the intracellular and intercellular events that accompany activation. One such molecule, CD97, a cell surface antigen that is rapidly upregulated upon activation on lymphocytes, has recently been the subject of several publications (see Eichler et al. in Tissue Antigens (1997) 50(5):429-438; Aust et al., Cancer Res. (1997) 57(9):1798-1806). Leukocytes strongly positive for CD97 are concentrated at sites of inflammation relative to CD97 expression in normal lymphoid tissue. A soluble subunit of CD97, CD97alpha, has been found in the body fluids from inflamed tissues (Gray et al. J. Immunol. (1996) 157(12):5438-5447).
54. PRO1303
Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enzymes from a variety of different mammalian and non-mammalian organisms have been both identified and characterized, including the serine proteases which exhibit specific activity toward various serine-containing proteins. The mammalian protease enzymes play important roles in biological processes such as, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.
Neuropsin is a novel serine protease whose mRNA is expressed in the central nervous system. Mouse neuropsin has been cloned, and studies have shown that it is involved in the hippocampal plasticity. Neuropsin has also been indicated as associated with extracellular matrix modifications and cell migrations. See, generally, Chen, et al., J. Neurosci., 7(2):5088-5097 (1995) and Chen, et al., J. Histochem. Cytochem., 46:313-320 (1998). Other studies have reported that kindling induces neuropsin mRNA in the mouse brain. Okabe, et al., Brain Res., 728(1):116-120 (1996). Additionally, a study has reported that generation of reactive oxygen species has an important role in neuropsin transcript in the limbic areas which might be related to the disturbance in avoidance learning. Akita, et al., Brain Res., 769(1):86-96 (1997). Thus, neuropsins, and related proteins and agents, including agonists and antagonists are of interest.
55. PRO1306
There is much interest in the identification of proteins that play roles in mammalian disease and disorders which could lead to new methods of treatment. A macrophage polypeptide, daintain/allograft inflammatory factor 1 (daintain/AIF1), has been identified in the pancreas of prediabetic rats, and has been determined to have a direct effect on insulin secretion. When injected intravenously in mice in low doses, daintain/AIF1 doses inhibited glucose-stimulated insulin secretion with a concomitant impairment of glucose elimination. At higher doses, daintain/AIF1 potentiated glucose-stimulated insulin secretion and enhanced glucose elimination. Thus, it was suggested that daintain/AIF1 may have a role in connection with the pathogenesis of insulin-dependent diabetes mellitus (Chen et al. Proc. Natl Acad. Sci. (1997) 94(25):13879-13884). AIF-1 has also been implicated in both rat and human allogenic heart transplant rejection (Utans et al. Transplantation (1996) 61(9):1387-1392), and may play a role in macrophage activation and function (Utans et al. J. Clin. Invest. (1995) 95(6):2954-2962).
56. PRO1336
Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.
Leucine-rich proteins are known to be involved in protein-protein interactions. A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats.
Another protein of particular interest which has been reported to have leucine-rich repeats is the slit protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. The slit protein has been characterized and reported to be secreted by glial cells and involved in the formation of axonal pathways in Drosophila as well as the mediation of extracellular protein interactions. Wharton and Crews, Mech. Dev., 40(3):141-154 91993); Rothberg and Artavanis-Tsakonas, J. Mol. Biol., 227(2):367-370 (1992); Rothberg, et al., Genes Dev., 4(12A):2169-2187 (1990); and Rothberg, et al., Cell, 55(6):1047-1059 (1988).
57. PRO1278
Lysozymes are secreted enzymes that preferentially hydrolyze the [beta]-1,4 glucosidic linkages between N-acetylmuramic acid and N-acetylgucosamine which occur in the mucopeptide cell wall structure of certain microoganisms. Lysozyme is of widespread distribution in animals and plants. It has been found in mammalian secretions and tissues including saliva, tears, milk, cervical mucus, leucocytes, kidneys, etc. The identification of new members of the lysozyme family of proteins is of interest because of the variety of roles lysozymes play in metabolic function and dysfunction. Abnormal levels of lysozymes have been implicated in various disease states. Lysozymes have been reported to have anti-microbial, analgesic, and antinociceptive properties. Additional characteristics and possible uses of lysozymes are described in U.S. Pat. No. 5,618,712.
58. PRO1298
Glycosylation can determine the fate of a protein, for example, whether it is secreted or not. Also, glycoproteins play many structural and functional roles, particularly as part of the cell membrane. Therefore, glycosylation is of interest. Studies have reported on the growth-related coordinate regulation of the early N-glycosylation genes in yeast. Kukuruzinska and Lennon, Glycobiology, 4(4):437-443 (1994). Moreover, the relationship between protein glycosylation and fatty acylation of glycoproteins was studied in the wild-type and asparagine-linked glycosylation-deficient mutants in yeast. Appukuttan, FEBS Lett., 255(1):139-142 (1989). The biosynthesis of asparagine-linked oligosaccharides in yeast was also studied using a mutant. Jackson, et al., Glycobiology, 3(4):357-364 (1993). Yeast mutants deficient in protein glycosylation have also been reported in Huffacker and Robbins, PNAS, 80(24):7466-7470 (1983).
59. PRO1301
Cytochrome P450 proteins form a large class of monooxygenase enzymes involved in hydroxylation. Hydroxylation reactions are important in the synthesis of cholesterol and steroid hormones. Enzymes of the cytochrome P450 family play an important role in the metabolism endogenous compounds such as arachidonic acid. These enzymes are also important in the metabolism of foreign substances such as the elimination of drugs from the body [see, for example, Peterson, Aliment. Pharmacol. Ther., 9:1-9 (1995).]. In addition, metabolites generated through the cytochrome P450 pathway may play a role in carcinogenesis, blood pressure regulation and renal function [see, for example, Rahman et al., Am. J. Hypertens., 10:356-365 (1997)].
60. PRO1268
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1268.
61. PRO1269
Granulocytes, the most common type of white blood cell, have the ability to mediate immunologic cytotoxicity against tumor cells and microorganisms. Accordingly, there has been interest in identifying various factors that are produced by these cells because of their potential use as pharmaceutical agents. Patent publication no. WO9729765-A1, to Selsted, describes the identification of granulocyte peptide A which was isolated from bovine and murine granulocytes. Several uses for this peptide were identified including, a therapeutic use, use as an agricultural agent, use as a preservative for food, and use as a water treatment agent.
62. PRO1327
Neurexophilin is a protein that was discovered as a neuronal glycoprotein that was copurified with neurexin I alpha during affinity chromatography on immobilized alpha-latrotoxin (Missler et al., J. Neurosci. 18:3630-3638 (1998)). Recent data has shown that the mammalian brain contains four genes for neurexophilins the products of which share a common structure composed of five domains: (1) an N-terminal signal peptide, (2) a variable N-terminal domain, (3) a highly conserved central domain that is N-glycosylated, (4) a short linker region and (5) a conserved C-terminal domain that is cysteine-rich (Missler et al., supra). These data further demonstrate that the neurexophilins are proteolytically processed after synthesis and bind to alpha-neurexins. The structure and characteristics of neurexophilins indicate that they may function as neuropeptides that may signal via alpha-neurexins. Therefore, there is significant interest in identifying and characterizing novel polypeptides having homology to the neurexophilins.
We herein describe the identification and characterization of novel polypeptides having homology to neurexophilin protein, designated herein as PRO1327 polypeptides.
63. PRO1382
Cerebellin is a secreted, postsynaptic neuroprotein found throughout the brain. The highest concentrations of this protein have been found in the cerebellum. It has also been detected in the pituitary, spinal cord, and adrenal glands (Satoh et al. J. Endocrinol. (1997) 15491):27-34). The feasibility of using cerebellum as a quantifiable marker for the investigation of the maturation of Purkinje cells of the cerebellum and to chart neurodevelopment has been reported (see Slemmon et al. Proc. Natl. Acad. Sci (1985) 82(20):7145-7148). Significantly decreased levels of cerebellin have been found in human brains obtained in post-mortem studies from patients with spinocerebellar degeneration, olivopontocerebellar atrophy (OPCAQ) and Shy-Drager syndrome, suggesting that cerebellin plays important pathophysiological roles in these cerebellar diseases (Mizuno et al. Brain Res. (1995) 686(1): 115-118; Mizuno et al. No To Shinkei (1995) 47(11): 1069-1074). In view of the importance of cerebellin in neurodevelopment and in neurological diseases and disorders, the identification and characterization of members of this protein family is of interest (see also Yiangou et al. J. Neurochem (1989) 53(3):886-889 and Mugnaini et al. Synapse (1988) 2(2):125-138).
64. PRO1328
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1328.
65. PRO1325
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1325.
66. PRO1340
Cadherins are known as the principal mediators of homotypic cellular recognition and play a demonstrated role in the morphogenic direction of tissue development. Cadherins are a diverse family of proteins that have been identified in various tissues including nervous tissue (Suzuki et al., Cell Regul., 2:261-270 (1991)). Ksp-cadherin is a kidney-specific member of the cadherin multigene family (Thomson et al., Biol. Chem, 270:17594-17601 (1995)). Cadherins are thought to play an important role in human cancer (Yap, Cancer Invest., 16:252-261 (1998)).
67. PRO1339
Carboxypeptidases are of interest. Carboxypeptidase E appears to be involved in the biosynthesis of a wide range of peptide hormones. Fricker, Annu. Rev. Physiol., 50:309-321 (1988). This carboxypeptidase has been associated with obesity. Leiter, J. Endocrinol., 155(2):211-214 (1997). Carboxypeptidase M has been reported as being a marker of macrophage maturation. Krause, et al., Immunol. Rev., 161:119-127 (1998). Human mast cell carboxypeptidase has been reported to be associated with allergies. Goldstein, et al., Monogr. Allergy, 27:132-145 (1990). Carboxypeptidase A2 has also been reported on. Faming, et al., J. Biol. Chem., 266(36):24606-24612 (1991). Other carboxypeptidases of particular interest which are known in the art include human pancreatic carboxypeptidase 2, carboxypeptidase al and carboxypeptidase B. Therefore, novel members of the carboxypeptidase family are of interest.
68. PRO1337
Of particular interest is the identification of blood-related proteins which may have potential therapeutic use or may be useful in the diagnosis of blood-related disorders. Thyroxine-binding globulin (TBG) is synthesized by the liver and secreted into the bloodstream. It is the principal thyroid hormone transport protein in human serum (Refetoff et al. Horm. Res. (1996) 45(3-5):128-138). High serum levels of TBG have been found to cause hyperthyroxinaemia (Leahy et al., Postgrad Med. J. (1984) 60(703):324-327). Accordingly, the identification and characterization of TBG proteins is of interest (see Flink et al. Proc. Natl Acad Sci. USA (1986) 83(20):7708-7712; Bartalena et al. Acta Med. Austriaca, (1988) 15 Suppl 1:12-15), including the identification of abnormal TBG proteins (see Refetoff, Endocr Rev. (1989) 10(3):275-293). Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].
69. PRO1342
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1342.
70. PRO1343
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1343.
71. PRO1480
Semaphorins are a large family of transmembrane and secreted proteins, many of which are expressed in the nervous system. Members of the semaphorin family include both ligands and receptors. (Eckhardt et al., Mol. Cell. Neurosci. 9: 409-419 (1997)). Studies have revealed a role for semaphorins in embryonic motor and central nervous system axon guidance and synapse formation. (Catalano et al., Mol. Cell. Neurosci., 11: 173-182 (1998); Kitsukawa et al., Neuron, 19: 995-1005 (1997); Yu et al., Neuron, 20: 207-220 (1998)). Semaphorins have been shown to induce neuronal growth cone collapse and alter their pathway in vivo. (Shoji et al., Development, 125: 1275-1283 (1998)). Members of the semaphorin family have been shown to be immunologically active, inducing cytokine production in human monocytes. (Comeau et al., Immunity, 8: 473-482 (1998)). Semaphorins may also play a role in cancer. Expression of a mouse semaphorin gene is known to correlate with metastatic ability in mouse tumor cell lines. (Christensen et al., Cancer Res., 58: 1238-1244 (1998)).
72. PRO1487
Fringe is a protein which specifically blocks serrate-mediated activation of notch in the dorsal compartment of the Drosophila wing imaginal disc (see Fleming et al., Development, 124(15):2973-81 (1997); Wu et al. Science (1996) 273(5273):355-358). Fringe protein is also involved in vertebrate development where a thickening of the apical ectodermal ridge essential for limb bud outgrowth involves an interaction between dorsal cells that express radical fringe and those that do not (see Wolpert, L. Philos Trans R Soc Lond B Biol Sci 1998) 353(1370):871-875; Kengaku et al. Science (1998) 280(5367): 1274-1277; Cohen et al. Nat. Genet. (1997) 16(3):283-288; Johnston et al. Development (1997) 124(11):2245-2254; Laufer et al. Nature (1997) 1386(6623):366-373; Rodriguez-Esteban et al. Nature (1997) 386(6623):360-366;). ). Therefore, fringe protein is of interest for both its role in development as well as its ability to regulate serrate, particularly serrate's signaling abilities. Also of interest are novel polypeptides which may have a role in development and/or the regulation of serrate-like molecules. Of particular interest are novel polypeptides having homology to fringe protein.
73. PRO1418
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1418.
74. PRO1472
Butyrophilin is a milk glycoprotein that constitutes more than 40% of the total protein associated with the fat globule membrane in mammalian milk. Expression of butyrophilin mRNA has been shown to correlate with the onset of milk fat production toward the end pregnancy and is maintained throughout lactation. Butyrophilin has been identified in bovine, murine and human (see Taylor et al., Biochim. Biophys. Acta 1306:14 (1996), Ishii et al., Biochim. Biophys. Acta 1245:285-292 (1995), Mather et al., J. Dairy Sci. 76:3832-3850 (1993), Ogg, et al., Mamm. Genome, 7(12):900-905 (1996), Sato, et al., J. Biochem., 117(1): 147-157 (1995) and Banghart et al., J. Biol. Chem. 273:4171-4179 (1998)) and is a type I transmembrane protein that is incorporated into the fat globulin membrane. It has been suggested that butyrophilin may play a role as the principle scaffold for the assembly of a complex with xanthine dehydrogenase/oxidase and other proteins that function in the budding and release of milk-fat globules from the apical surface during lactation (Banghart et al., supra). Given that butyrophilin plays a role in mammalian milk production, there is substantial interest in identifying novel butyrophilin homologs. Members of the butyrophilin family are further described in Tazi-Ahnini, et al., Immunogenetics, 47(1):55-63 (1997); Davey, et al., Gene, 199(1-2):57-62 (1997); and Mather and Jack, J. Dairy Sci., 76(12):3832-3850 (1993).
75. PRO1461
Proteases are enzymatic proteins which are involved in many biological processes in mammalian and non-mammalian organisms including digestion, protein activation and inactivation, modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes. Serine proteases comprise a large class of enzymes that exhibit specific activity toward various serine-containing proteins. Trypsin, which is synthesized by the pancreas and secreted to the small intestine, is a well-characterized serine protease that hydrolyzes peptide bonds of ingested proteins. Trypsin-like proteases have been characterized that are cell-surface proteins (see Farley et al. Biochim Biophys Acta (1993) 173(3):350-352; and Leytus et al. Biochemistry (1988) 27(3) 1067-1074). It is believed that some of these trypsin-like proteins may be synthesized as a membrane-bound precursor which matures to a soluble and active protease (Yamaoka et al. J. Biol. Chem (1998) 273(19):11895-11901).
Because of there importance in metabolism and other enzymatic processes, efforts are being undertaken by both industry and academia to identify new, native serine-like proteases. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
76. PRO1410
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1410.
77. PRO1568
The tetraspanin (or tetraspan) family of proteins has grown to include approximately twenty known genes from various species. The tetraspanins are four transmembrane domain membrane-bound molecules which include for example, CD81, CD82, CD9, CD63, CD37 and CD53. Many of these proteins have a flair for promiscuous associations with other molecules, including lineage-specific proteins, integrins, and other transpanins. In terms of function, they are involved in diverse processes such as cell activation and proliferation, adhesion and motility, differentiation and cancer. One study has proposed that these functions may all relate to their ability to act as “molecular facilitators”, grouping specific cell-surface proteins and thus increasing the formation and stability of functional signaling complexes. Maecker, et al., FASEB, 11(6):428-42 (1997). Another study concludes that they are responsible for changes in cell morphology, cell-ECM adhesion and cell-signaling. Skubitz, et al., J. Immunology, 157:3617-3626 (1996). Thus, new members of this family are of interest.
78. PRO1570
Proteases are enzymatic proteins which are involved in many biological processes in mammalian and non-mammalian organisms including digestion, protein activation and inactivation, modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes. Serine proteases comprise a large class of enzymes that exhibit specific activity toward various serine-containing proteins. Trypsin, which is synthesized by the pancreas and secreted to the small intestine, is a well-characterized serine protease that hydrolyzes peptide bonds of ingested proteins. Trypsin-like proteases have been characterized that are cell-surface proteins (see Farley et al. Biochim Biophys Acta (1993) 1173(3):350-352; and Leytus et al. Biochemistry (1988) 27(3):1067-1074). It is believed that some of these trypsin-like proteins may be synthesized as a membrane-bound precursor which matures to a soluble and active protease (Yamaoka et al. J. Biol. Chem (1998) 273(19): 11895-11901).
Of particular interest are human colon carcinoma derived serine proteases SP59, SP60 and SP67 which may be useful to screen for specific inhibitors or modulators to use in treatment of associated disease states and disorders related to these proteins. In Japanese patent J09149790-A, SP60 is reported to be identified, having accession number P_W22986 and 233 amino acids.
79. PRO1317
Members of the semaphorin family of glycoproteins play important roles in the developing nervous system, and more particularly in axonal guidance. Semaphorins have been identified in the human immune system, where they are believed to play functional roles including B-cell signaling (Hall et al. Proc. Natl. Acad. Sci (1996) 93(21):11780-50). A human semaphorin gene, useful in the diagnosis of nervous system an immune disorders, is disclosed in Japanese Pat. No. J10155490-A, published Jun. 16, 1998. The identification of additional members of the semaphorin family if of interest.
80. PRO1780
Enzymatic proteins that may be implicated in metabolic diseases or disorders are of particular interest. The enzymatic addition of sugars to fat-soluble chemicals is an important process that increases their solubility in water and aids in their excretion. In mammals, glucuronic acid is the main sugar that is used to prevent the waste products of metabolism and fat-soluble chemicals from reaching toxic levels in the body. The UDP glucuronosyltransferases that carry out this reaction are part of a super family of UDP glycosyltransferases found in animals, plants and bacteria. In the liver, UDP-glucuronosyltransferase conjugates bilirubin. There are a number of conditions which affect UDP-glucuronosyltransferase activity resulting in unconjugated hyperbilirubinemia. These conditions include genetic disorders such as Crigler-Najjar Syndrome (see Jurgen et al., Biochem. J. (1996) 314:477-483) and Gilbert syndrome, as well as acquired conditions such as Lucey-Driscoll Syndrome. Accordingly, the identification of novel members of the glucuronosyltransferase family is of interest (see Tukey et al., J. Biol. Chem. (1993) 268(20): 15260-6; and WO9212987-A).
81. PRO1486
The cerebellum contains a hexadecapeptide, termed cerebellin, that is conserved in sequence from human to chicken. Three independent, overlapping cDNA clones have been isolated from a human cerebellum cDNA library that encode the cerebellin sequence. The longest clone codes for a protein of 193 amino acids generally termed precerebellin, or a cerebellin precursor. This protein has a significant similarity to the globular region of the B chain of human complement component C1q. The region of relatedness extends approximately over 145 amino acids located in the carboxyl terminus of both proteins. Unlike C1q B chain, no collagen-like motifs are present in the amino-terminal regions of precerebellin. It is believed that cerebellin is not liberated from precerebellin by the classical dibasic amino acid protealytic cleavage mechanism seen in many neuropeptide precursors. The cerebellin precursor has been associated with synaptic physiology. Urade, et al., PNAS, USA, 88(3):1069-1073 (1991). Cerebellin, its precursor, and related molecules, particularly those having sequence identity with cerebellin, are therefore of interest.
82. PRO1433
Efforts are being undertaken by both industry and academia to identify new, native transmembrane and receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane polypeptide designated herein as PRO1433.
83. PRO1490
Enzymatic proteins play important roles in the chemical reactions involved in the digestion of foods, the biosynthesis of macromolecules, the controlled release and utilization of chemical energy, and other processes necessary to sustain life. Acyltransferases are enzymes which acylate moieties. For example, acyl-glycerol-phosphate acyltransferases can act on lysophosphatidic acid as a substrate. The lysophosphatidic acid is converted to phophatidic acid and thus plays a role in forming phosphatidylethanolamine found in membranes. See, Brown, et al., Plant Mol. Biol., 26(1):211-223 (1994). Moreover, 1-acyl-sn-glycerol-3-phosphate acyltransferase (LPAAT) is an enzymatic protein that shows a preference for medium-chain-length fatty acyl-coenzyme A substrates. See, Knutson et al., Plant Physiol. 109:999-1006 (1995)). Thus, acyltransferases play an important role in the biosynthesis of molecules requiring acylation.
We herein describe the identification and characterization of novel polypeptides having homology to a 1-acyl-sn-glycerol-3-phosphate acyltransferase protein, designated herein as PRO1490 polypeptides.
84. PRO1482
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1482.
85. PRO1446
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1446.
86. PRO1558
Methyltransferase enzymes catalyze the transfer of methyl groups from a donor molecule to an acceptor molecule. Methyltransferase enzymes play extremely important roles in a number of different biological processes including, for example, in the electron transport chain in the plasma membrane in prokaryotes and in the inner mitochondrial membrane in eukaryotic cells (see, e.g., Barkovich et al., J. Biol. Chem. 272:9182-9188 (1997), Dibrov et al., J. Biol. Chem. 272:9175-9181 (1997), Lee et al., J. Bacteriol. 179:1748-1754 (1997) and Marbois et al., Arch. Biochem. Biophys. 313:83-88 (1994)). Methyltransferase enzymes have been shown to be essential for the biosynthesis of ubiquinone (coenzyme Q) and menaquinone (vitamin K2), both of which are essential isoprenoid quinone components of the respiratory electron transport chain. Given the obvious importance of the methyltransferase enzymes, there is substantial interest in identifying novel polypeptide homologs of the methyltransferases. We herein describe the identification and characterization of a novel polypeptide having homology to methyltransferase enzymes, designated herein as PRO1558 polypeptides.
87. PRO1604
The identification of novel growth factors is of particular interest because of the roles they play in inducing cellular growth, proliferation and differentiation in both normal states and abnormal states. The identification of growth factors that are over- or under-expressed in abnormal tissues (e.g. tumors) may lead to the development of diagnostic tools and therapeutic agents. Growth factors have been isolated from hepatoma-derived cell lines. Hepatoma-derived growth factors have been isolated from mouse (Japanese Pat. No. J09313185-A, published Dec. 9, 1997) and human (Japanese Pat. No. J06343470-A, published Dec. 20, 1994) tissues. A hepatoma-derived growth factor, isolated from a human hepatoma-derived cell line, has been found to be ubiquitously expressed in several tumor-derived cell lines, as well as in normal tissues (Nakamura et al., J. Biol. Chem (1994) 269(40):25143-9). The growth factor was determined to be a novel heparin-binding protein that is mitogenic for fibroblasts.
88. PRO1491
The neuronal cell body is usually round like any other cell. However, these cells have structures, also referred to as “processes”, which grow from them to form synaptic connections. Some of these processes carry information away from the cell body; sometimes over very long distances. These long and thin processes are axons. The axon is a thin, static tube. Other processes carry information either towards the cell body, or both towards and away from the cell body. These shorter and usually thicker processes are called dendrites. Both axons and dendrites are called neurites.
During development and the growth stage of neurons, neurites are formed by means of growth cones. A growth cone is the growing tip of a neurite. The growth cone is flattened and highly motile. It is where new material is added and further extension of the axon originates. Controlling where the growth cone crawls controls were the axon will be laid down and thus where it will be present.
The growth cone has several defmable parts. The thin, flattened, veil-like processes that stick out and retract from the leading edge are called lamellipodia. The needle-like processes that stick out and retract from the leading edge are called microspikes or filopodia. These are the structures involved in pushing the leading edge of the growth cone forward.
The accurate navigation of growth cones to their appropriate targets requires that they recognize and respond to navigational cues in their immediate environment. Some of these cues encourage extension into certain areas whereas others discourage extension into others. Well characterized molecules that encourage neurite outgrowth in vitro include the extracellular matrix molecule laminin and the neuronal cell surface molecule L1/G4/8D9. These molecules which promote neurite extension are generally widely distributed throughout the body. Laminin immunoreactivity is reasonably widespread in the developing central and peripheral nervous systems. Similarly, L1/G4/8D9 is present on a wide variety of neuronal processes in the developing central nervous system, particularly long projecting axons. It is, therefore, unclear whether the known outgrowth promoting molecules play an important role in self-specific choices growth cones make as they decide between possible routes. Instead, their function is believed to provide a generally permissive environment in which growth cones extend and respond to more specific navigational cues.
Among these more specific cues are molecules that inhibit the motility of particular growth cones. Growth cones have been observed to lose their motile morphology and cease advancing (collapse) on contact with other neurites of different types. Territory formation in vitro may mean the manifestation of a process that leads to selective fasciculation in vivo. Some growth cones have been observed to crawl along specific axonal pathways, or stereotype sequences of axonal pathways in developing embryos. Specific motility inhibiting effects could determine which of several alternative pathways a growth cone will extend on. Growth cones would be expected to prefer growing on axons that do not induce them to collapse while shunning those that do.
It has been observed that, for example, sympathetic growth cones will be inhibited or collapse when coming in contact with retinal neurites. Likewise, growth cones of retinal neurites will collapse when coming in contact with sympathetic neurites. It is believed that such cell activity is achieved through the presence of receptors which specifically respond to specific growth inhibition cues by the molecules which transmit specific cues pertaining to growth. Cues are believed to be present on cell surfaces, particularly on axon surfaces.
When nerve damage occurs, repair is impeded or incapable of occurring due to the failure of neurites to replace damaged axons or dendrites. If an existing neurite is damaged, severed or destroyed, a new neurite is incapable of growing out from the cell body to replace it. The presence of molecules which inhibit neurite growth are believed to be responsible for the difficulty in neurite regeneration. Collapsins are proteins that function to modulate the activity of molecules which modulate growth cone extension.
We herein describe the identification and characterization of novel polypeptides having homology to a collapsin protein, designated herein as PRO1491 polypeptides.
89. PRO1431
The transduction of intracellular signaling is crucial to cell processing such as differentiation, motility and division. Such signal transduction is believed to occur throughout the cell in the form of complex interactions between proteins. Such protein-protein interactions are often mediated by modular domains within signaling proteins. As a result, signal transduction is now modeled as a system in which molecules act in a combination, and the composition of that combination, determines the signal.
Src homology domains (e.g., SH2 and SH3) are two domains found in regions of sequence similarity of proteins involved in signal transduction. Early work on the oncogenic tyrosine kinase Src identified the SH2 domain. Since then, SH2 and SH3 domains have been found in many diverse proteins, making them among the most common type of structural motif. SH2 and SH3 domains are modular in that they fold independently of the protein that contains them, their secondary structure places N- and C-termini close to one another in space, and they appear at variable locations (anywhere from N- to C-terminal) from one protein ot the next (Cohen et al., Cell 80: 237-348, 1995).
Early studies that mutated the SH2 or SH3 domain showed that these two domains were important for function, but it was not until the cloning of unrelated families of signaling proteins such as RAS-GAP, and the Crk oncogene that the modular nature of these domains was revealed. These latter experiments demonstrated that RAS-GAP and Crk bound tightly to receptor tyrosine kinases upon ligand stimulation. Follow-up studies demonstrated that the mechanism of this binding was through the SH2 domain and that receptor autophosphorylation was required. Such a finding implied that activation of the receptor tyrosine kinase could be viewed as a means of changing the binding aspect of the intracellular domain, and the receptor-SH2 containing protein interaction would initiate the signal transduction cascade.
SH3 domains have a more general function than that which is purported for SH2. SH3 binding proteins have been isolated by screening bacteriophage expression libraries with labeled SH3 domains. The results of these experiments showed that SH3 domains would bind to short proline-rich peptides, in particular the motif PxxP. Based on the level of knowledge present at the time of the preparation of the present patent application, all of the SH3 binding sites identified have the property of being proline rich. Binding of an SH3 domain is independent of covalent modification of the binding site, such as phosphorylation as occurs with the SH2 domain. As a result, SH3-ligand interactions are usually constitutive and not inducible, although exceptions do exist. In general, SH3 domains are less likely to act as signal “switches” than as a means of assembling protein complexes via moderate-affinity interactions. Such moderate affinity interactions also imply that the SH3-mediated interactions will be relatively short in duration and remodeled in response to changes in concentration of binding partners.
The resolution of binding characteristics of SH2 and SH3 domains has led to proposed compounds which would block signal transduction. Peptidomimetic ligands based on the sequence of target proteins for SH2 and SH3 domains may represent new lead compounds for the therapy of proliferative diseases that are dependent upon constitutively activated tyrosine kinases (e.g., BCR/ABL in chronic myelogenous and acute lymphocytic leukemias or HER-2/Neu in breast and ovarian cancer).
90. PRO1563
Cellular disintegrin and metalloproteinase (ADAMs) are a family of genes with a sequence similar to those of snake venom metalloproteinases and disintegrins. The ADAMTS-1 gene encodes a new type of ADAM protein with respect to possessing the thrombospondin (TSP) type I motifs, the expression of which is associated with the inflammatory process (Kuno et al., J. Biol. Chem. 273:13912-13917 (1998), Kuno et al., Genomics 46:466-471 (1997) and Kuno et al., J. Biol. Chem. 272:556-562 (1997)). Expression of the ADAMTS-1 gene is induced in kidney and heart by in vivo administration of lipopolysaccharide, suggesting a possible role in the inflammation reaction. In this regard, the ADAMTS-1 protein has been suggested as playing a possible role in various inflammatory processes as well as in the development of cancer cachexia (Kuno et al., 1998, supra). We herein describe the identification and characterization of novel polypeptides having homology to ADAMTS-1 protein, designated herein as PRO1563 polypeptides.
91. PRO1565
Chondromodulin proteins are cartilage-generated matrix components that synergistically stimulate the growth and differentiation of chondrocytes (Suzuki, Connect. Tissue Res. 35:303-307 (1996)). More specifically, chondromodulin-I functions to inhibit the proliferation of vascular endothelial cells and tube formation, thereby functioning to stimulate cartilage growth and inhibiting replacing cartilage by bone in an early stage. Chondromodulin-II, while not capable of inhibiting vascularization like chondromodulin-I, also functions to stimulate osteoclast differentiation and cartilage growth. As such, these two polypeptides are essential for the regulation of the formation of cartilage and endochondral bone structures. Given the extremely important physiological roles played by the chondromodulin proteins, there is significant interest in identifying and characterizing novel polypeptides having homology to these proteins. We herein describe the identification and characterization of novel polypeptides having homology to chondromodulin-I protein, designated herein as PRO1565 polypeptides.
92. PRO1571
Clostridium perfringens enterotoxin (CPE) is considered to be the virulence factor responsible for causing the symptoms of C. perfringens type A food poisoning and may also be involved in other human and veterinary illnesses (McClane, Toxicon. 34:1335-1343 (1996)). CPE carries out its adverse cellular functions by binding to an approximately 50 kD cell surface receptor protein designated the Clostridium perfringens enterotoxin receptor (CPE-R) to form an approximately 90,000 kD complex on the surface of the cell. cDNAs encoding the CPE-R protein have been identified characterized in both human and mouse (Katahira et al., J. Cell Biol. 136:1239-1247 (1997) and Katahira et al., J. Biol. Chem. 272:26652-26658 (1997)). Since the CPE toxin has been reported to cause a variety of illnesses in mammalian hosts and those illnesses are initiated by binding of the CPE toxin to the CPE-R, there is significant interest in identifying novel CPE-R homologs. We herein describe the identification and characterization of novel polypeptides having homology to the CPE-R, designated herein as PRO1679 polypeptides.
93. PRO1572
Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. Human and mouse cDNAs showing homology to the Clostridium enterotoxin receptor (CPE-R) gene have previously been cloned as described in Katahira, et al., J. Biol. Chem., 272(42):26652-8 (1997). They have been classified into two groups, the Vero cell CPE receptor homologues and rat androgen withdrawal apoptosis protein (RVP1). These receptors are thus of interest as are related molecules. Of particular interest is the use of these receptors and related molecules in the identification of modulators of these receptors.
Also of interest are members of the claudin family and molecules related thereto. Claudins are integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. Furuse, et al., J. Cell Biol., 141(7):1539-50 (1998).
94. PRO1573
Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. Human and mouse cDNAs showing homology to the Clostridium enterotoxin receptor (CPE-R) gene have previously been cloned as described in Katahira, et al., J. Biol. Chem., 272(42):26652-8 (1997). They have been classified into two groups, the Vero cell CPE receptor homologues and rat androgen withdrawal apoptosis protein (RVP1). These receptors are thus of interest as are related molecules. Of particular interest is the use of these receptors and related molecules in the identification of modulators of these receptors.
Also of interest is the ventral prostate. 1 protein (RVP.1) which is transcriptionally induced in the regressing rat prostate after castration. This protein is further described in Peacock, et al., Genomics, 46(3):443-9 (1997).
95. PRO1488
Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. Human and mouse cDNAs showing homology to the Clostridium enterotoxin receptor (CPE-R) gene have previously been cloned as described in Katahira, et al., J. Biol. Chem., 272(42):26652-8 (1997), and Katahira, et al., J. Cell Biol., 136(6):1239-1247(1997). They have been classified into two groups, the Vero cell CPE receptor homologues and rat androgen withdrawal apoptosis protein (RVP1). These receptors are thus of interest as are related molecules. Of particular interest is the use of these receptors and related molecules in the identification of modulators of these receptors.
Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
96. PRO1489
Clostridium perfringens enterotoxin (CPE) is considered to be the virulence factor responsible for causing the symptoms of C. perfringens type A food poisoning and may also be involved in other human and veterinary illnesses (McClane, Toxicon. 34:1335-1343 (1996)). CPE carries out its adverse cellular functions by binding to an approximately 50 kD cell surface receptor protein designated the Clostridium perfringens enterotoxin receptor (CPE-R) to form an approximately 90,000 kD complex on the surface of the cell. cDNAs encoding the CPE-R protein have been identified characterized in both human and mouse (Katahira et al., J. Cell Biol. 136:1239-1247 (1997) and Katahira et al., J. Biol. Chem. 272:26652-26658 (1997)). Since the CPE toxin has been reported to cause a variety of illnesses in mammalian hosts and those illnesses are initiated by binding of the CPE toxin to the CPE-R, there is significant interest in identifying novel CPE-R homologs. We herein describe the identification and characterization of novel polypeptides having homology to the CPE-R, designated herein as PRO1489 polypeptides.
97. PRO1474
Avian egg whites are a rich source of protein inhibitors of proteinases belonging to all four mechanistic classes. Ovomucoid and ovoinhibitor are multidomain Kazal-type inhibitors with each domain containing an actual or putative reactive site for a serine proteinase. Cystatin is a cysteine proteinase inhibitor, while ovostatin inhibits proteinases of all four mechanistic classes. For a review of these inhibitors, see Saxena and Tayyab, Cell Mol. Life Sci., 53(1):13-23 (1997). New members of protein inhibitors of proteinases are of interest, particularly those having sequence identity with known inhibitors such as ovomucoid.
Serine protease inhibitors in general are of interest. Serine proteases such as neuropsin have been indicated as associated with extracellular matrix modifications and cell migrations. See, generally, Chen, et al., Neurosci., 7(2):5088-5097 (1995) and Chen, et al., J. Histochem. Cytochem., 46:313-320 (1998). Another serine protease, the enamel matrix serine proteinase, is associated with the degradation of organic matrix in teeth. Simmer, et al., J. Dent. Res., 77(2):377-386 (1998), Overall and Limeback, Biochem J., 256(3):965-972 (1988), and Moradian-Oldak, Connect. Tissue Res., 35(1-4):231-238 (1996). Thus, inhibitors of these proteases are of interest in the case that these mechanisms require control.
98. PRO1508
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1508.
99. PRO1555
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO1555.
100. PRO1485
Lysozymes are secreted enzymes that preferentially hydrolyze the [beta]-1,4 glucosidic linkages between N-acetylmuramic acid and N-acetylgucosamine which occur in the mucopeptide cell wall structure of certain microoganisms. Lysozyme is of widespread distribution in animals and plants. It has been found in mammalian secretions and tissues including saliva, tears, milk, cervical mucus, leucocytes, kidneys, etc. The identification of new members of the lysozyme family of proteins is of interest because of the variety of roles lysozymes play in metabolic function and dysfunction. Abnormal levels of lysozymes have been implicated in various disease states. Lysozymes have been reported to have anti-microbial, analgesic, and antinociceptive properties. Additional characteristics and possible uses of lysozymes are described in U.S. Pat. No. 5,618,712.
Of particular interest is lysozyme C which has been recruited as a digestive enzyme in the stomachs of creatures needing to retrieve nutrients from microorganisms in fermented food. The history of lysozyme C and related proteins are further described in Qasba and Kumar, Crit. Rev. Biochem. Mol. Biol., 32(4):255-306 (1997); Irwin, EXS, 75:347-361 (1996).
101. PRO1564
Glycosylation is a common and complex form of post-translational protein modification. Although a large and increasing number of unique structures is known to exist, most arise from a series of common synthetic intermediates and differ at their periphery glycosyltransferases, which recognize both the oligosaccharide acceptor and features of the underlying protein. UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase is an enzymatic protein that initiates O-glycosylation of specific serine and threonine amino acids in proteins by adding N-acetylgalactosamine to the hydroxy group of these amino acids. Since numerous important biological and physiological events are regulated by protein glycosylation, there is significant interest in identifying and characterizing novel polypeptides having homology to the known glycosylation proteins. We herein describe the identification and characterization of novel polypeptides having homology to an N-acetylgalactosaminyltransferase protein, designated herein as PRO1564 polypeptides.
102. PRO1755
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO1755.
103. PRO1757
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO1757.
104. PRO1758
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1758.
105. PRO1575
Protein Disulfide Isomerase (PDI) enhances formation of disulfide bonds in human serum albumin (HSA). Consequently, PDI assists in the formation of the overall structure of human serum albumin. Co-expression of PDI with human serum albumin increases secretion of HSA by reducing the chance of HSA structural instability and destruction by cellular proteases. Co-expression of PDI and HSA improved localization in the endoplasmic reticulum of eukaryotic cells. (Hayano et al., EP-50941-A (1992)). PDI and the beta-subunit of human prolyl 4-hydroxylase have been shown to be products of the same gene. (Pihlajaniemi et al., EMBO J., 6:64349 (1987)). In addition, copies of the CGHC-containing active site sequences of PDI have been found in an abundant luminal endoplasmic reticulum protein, Erp72. (Mazzarella et al., J. Biol. Chem., 2: 1094-1101 (1990)).
Efforts are being undertaken by both industry and academia to identify new, native receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins.
106. PRO1787
Multiple de novo MPZ (P0) point mutations have been identified in a sporadic Dejerine-Sottas (DDS) case. Warner, et al., Hum. Mutat., 10(1):21-4 (1997). DDS is a severe demyelinating peripheral neuropathy with onset in infancy, and has been associated with mutations in either PMP22 or MPZ. Moreover, mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies have been reported on. Bort, et al., Hum. Genet., 99(6):746-54 (1997). Myelin glycoprotein P0 has been reported on in a number of other studies as well (Blanquet-Grossard, et al., Clin. Genet., 48(6):281-3 (1995), Hayasaka, et al., Nat. Genet., 5(1):31-4 (1993) and Saavedra, et al., J. Mol. Evol., 29(2): 149-56 (1989). Thus, proteins which may belong to the myelin p0 family are of interest.
107. PRO1781
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO1781.
108. PRO1556
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO1556.
109. PRO1759
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO1759.
110. PRO1760
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1760.
111. PRO1561
Phospholipase A2 (PLA2) is a protein which hydrolyzes a 2-acyl ester bond of phospholipids, and examples thereof include cytosolic PLA2 and secretory PLA2 which can be clearly distinguished from each other. It has been known that the cytosolic PLA2 (cPLA2) selectively hydrolyzes phospholipids containing arachidonic acid of which 2-position is esterified. Given these important biological activities, there is significant interest in identifying and characterizing novel polypeptides having homology to phospholipase A2 proteins. We herein describe the identification and characterization of novel polypeptides having homology to human phospholipase A2 protein, designated herein as PRO1561 polypeptides.
112. PRO1567
Colon specific genes (CSGs)and their expression products are described in published international application WO9639419. They are useful diagnostic markers for colon cancer and for colon cancer metastasis and can also be used to screen for potential pharmaceutical and diagnostic agents. The identification of new members of the CSG family is of interest.
113. PRO1693
Insulin-like growth factors have both growth-promoting and insulin-like activities. There are two well characterized plasma IGF-binding proteins in human. The larger protein is an acid-labile protein of 53K which circulates mostly as a 125 to 150 kD complex thought to be composed of IGF-I or IGF-II, the binding protein itself and an acid-labile non-IGF-binding protein with an approximate molecular mass of 100K kD. The smaller protein has an apparent molecular mass of 28K in the non-reduced form and 34K when reduced. These IGF-binding proteins have been shown to play important roles in the physiological activities played by the insulin-like growth factor proteins. As such, there is substantial interest in identifying and characterizing novel polypeptides having homology to the insulin-like growth factor binding proteins. We herein describe the identification and characterization of novel polypeptides having homology to an insulin-like growth factor binding protein, designated herein as PRO1693 polypeptides.
114. PRO1784
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO1784.
115. PRO1605
N-acetylglucosaminyltransferase proteins comprise a family of enzymes that provide for a variety of important biological functions in the mammalian organism. As an example, UDP-N-acetylglucosamine: alpha-3-D-mannoside beat-1,2-N-acetylglucosaminyltransferase I is an enzymatic protein that catalyzes an essential first step in the conversion of high-mannose N-glycans to hybrid and complex N-glycans (Sarkar et al., Proc. Natl. Acad. Sci. USA. 88:234-238 (1991). Given the obvious importance of the N-acetylglucosaminyltransferase enzymes, there is significant interest in the identification and characterization of novel polypeptides having homology to an N-acetylglucosaminyltransferase protein. We herein describe the identification and characterization of novel polypeptides having homology to an N-acetylglucosaminyltransferase protein, designated herein as PRO1605 polypeptides.
116. PRO1788
Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.
Proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglobular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415-421 (Oct. 1994).
A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair have been reported including De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome; Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats and Ruoslahti, E. I., et al.; and WO9110727-A by La Jolla Cancer Research Foundation, reporting that decorin binding to transforming growth factor-α has involvement in a treatment for cancer, wound healing and scarring. Related by function to this group of proteins is the insulin like growth factor (IGF), in that it is useful in wound-healing and associated therapies concerned with re-growth of tissue, such as connective tissue, skin and bone; in promoting body growth in humans and animals; and in stimulating other growth-related processes. The acid labile subunit of IGF (ALS) is also of interest in that it increases the half-life of IGF and is part of the IGF complex in vivo. Ollendorff, V., et al., Cell Growth Differ, 5(2):213-219 (February 1994) identified the GARP gene which encodes a leucine-rich repeat-containing protein that has structural similarities with human GP Ib alpha and GP V platelet proteins, and with the Chaoptin, Toll, and Connectin adhesion molecules of Drosophila.
Another protein which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neurodegenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Of particular interest is LIG-1, a membrane glycoprotein that is expressed specifically in glial cells in the mouse brain, and has leucine rich repeats and immunoglobulin-like domains. Suzuki, et al., J. Biol. Chem. (U.S.), 271(37):22522 (1996). Other studies reporting on the biological functions of proteins having leucine rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4): 1125-1133 (October 1995) (kidney disease involvement); and Almeida, A., et al., Oncogene 16(23):2997-3002 (June 1998) (malignant glioma involvement).
117. PRO1801
Interleukin-10 (IL-10) is a pleiotropic immunosuppressive cytokine that has been implicated as an important regulator of the functions of myeloid and lymphoid cells. It has been demonstrated that IL-10 functions as a potent inhibitor of the activation of the synthesis of various inflammatory cytokines including, for example, IL-1, IL-6, IFN-γ and TNF-α (Gesser et al., Proc. Natl. Acad. Sci. USA 94:14620-14625 (1997)). Moreover, IL-10 has been demonstrated to strongly inhibit several of the accessory activities of macrophages, thereby functioning as a potent suppressor of the effector functions of macrophages, T-cells and NK cells (Kuhn et al., Cell 75:263-274 (1993)). Furthermore, IL-10 has been strongly implicated in the regulation of B-cell, mast cell and thymocyte differentiation.
IL-10 was independently identified in two separate lines of experiments. First, cDNA clones encoding murine IL-10 were identified based upon the expression of cytokine synthesis inhibitory factor (Moore et al., Science 248:1230-1234 (1990)), wherein the human IL-10 counterpart cDNAs were subsequently identified by cross-hybridization with the murine IL-10 cDNA (Viera et al., Proc. Natl. Acad. Sci. USA 88:1172-1176 (1991)). Additionally, IL-10 was independently identified as a B-cell-derived mediator which functioned to co-stimulate active thymocytes (Suda et al., Cell Immunol. 129:228 (1990)).
Recently, a novel cytokine polypeptide which is member of the IL-10-related cytokine family has been identified and characterized. This novel secreted cytokine, designated IL-19, is a 177 amino acid polypeptide having a molecular weight of approximately 20.4 kD (see WO 98/08870, published Mar. 5, 1998). It has been reported that IL-19 is specifically expressed by activated monocytes, wherein increased and/or decreased levels of IL-19 may be associated with one or more physiological disorders that are associated with increased or decreased levels of cytokine production (see WO 98/08870). Specifically, IL-19 is suggested as being capable of inhibiting the synthesis of inflammatory cytokines by cells of the immune system.
Given the obvious importance of the various cytokine polypeptides and, more specifically, immunosuppressive cytokines such as IL-10 and potentially IL-19, there is significant interest in the identification and characterization of novel cytokine polypeptides having homology to IL-10 and/or IL-19. We herein describe the identification and characterization of novel polypeptides having homology to IL-19, designated herein as PRO1801 polypeptides.
118. UCP4
Uncoupling proteins or “UCPs”, believed to play a role in the metabolic process, have been reported in the literature. UCPs were first found and described in the brown fat cells of hibernating animals, such as bears. UCPs were believed to help such hibernators and other cold-weather adapted animals maintain core body temperatures in cold weather by raising their body's resting metabolic rate. Because humans possess relatively small quantities of brown adipose tissue, UCPs were originally thought to play a minor role in human metabolism.
Several different human uncoupling proteins have now been described. [See, generally, Gura, Science, 280:1369-1370 (1998)]. The human uncoupling protein referred to as UCP1 was identified by Nicholls et al. Nicholls et al. showed that the inner membrane of brown fat cell mitochondria was very permeable to proteins, and the investigators traced the observed permeability to a protein, called UCP1, in the mitochondrial membrane. Nicholls et al. reported that the UCP1, by creating such permeability, reduced the number of ATPs that can be made from a food source, thus raising body metabolic rate and generating heat. [Nicholls et al., Physiol. Rev., 64, 1-64 (1984)].
It was later found that UCP1 is indeed expressed only in brown adipose tissue [Bouillaud et al., Proc. Natl. Acad. Sci., 82:445-448 (1985); Jacobsson et al., J. Biol. Chem., 260:16250-16254 (1985)]. Genetic mapping studies have shown that the human UCP1 gene is located on chromosome 4. [Cassard et al., J. Cell. Biochem., 43:255-264 (1990)].
Another human UCP, referred to as UCPH or UCP2, has also been described. [Gimeno et al., Diabetes, 46:900-906 (1997); Fleury et al., Nat. Genet., 15:269-272 (1997); Boss et al., FEBS Letters, 408:3942 (1997); see also, Wolf, Nutr. Rev., 55:178-179 (1997)]. Fleury et al. teach that the UCP2 protein has 59% amino acid identity to UCP1, and that UCP2 maps to regions of human chromosome 11 which have been linked to hyperinsulinaemia and obesity. [Fleury et al., supra]. It has also been reported that UCP2 is expressed in a variety of adult tissues, such as brain and muscle and fat cells. [Gimeno et al., supra, and Fleury et al., supra].
A third human UCP, UCP3, was recently described in Boss et al., supra; Vidal-Puig et al., Biochem. Biophys. Res. Comm., 235:79-82 (1997); Solanes et al., J. Biol. Chem., 272:25433-25436 (1997); and Gong et al., J. Biol. Chem., 272:24129-24132 (1997). [See also Great Britain Patent No. 9716886]. Solanes et al. report that unlike UCP1 and UCP2, UCP3 is expressed preferentially in human skeletal muscle, and that the UCP3 gene maps to human chromosome 11, adjacent to the UCP2 gene. [Solanes et al., supra]. Gong et al. describe that the UCP3 expression can be regulated by known thermogenic stimuli, such as thyroid hormone, beta3-andrenergic agonists and leptin. [Gong et al., supra].
119. PRO193
Efforts are being undertaken by both industry and academia to identify new, native transmembrane proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel transmembrane proteins. We herein describe the identification and characterization of a novel transmembrane protein designated herein as PRO193.
120. PRO1130
Polypeptides such as the human 2-19 protein may function as cytokines. Cytokines are low molecular weight proteins which function to stimulate or inhibit the differentiation, proliferation or function of immune cells. Cytokine proteins often act as intercellular messengers and have multiple physiological effects. Given the physiological importance of immune mechanisms in vivo, efforts are currently being undertaken to identify new, native proteins which are involved in effecting the immune system. We describe herein the identification of a novel polypeptide which has sequence similarity to the human 2-19 protein.
121. PRO1335
Carbonic anhydrase is an enzymatic protein that which aids carbon dioxide transport and release in the mammalian blood system by catalyzing the synthesis (and the dehydration) of carbonic acid from (and to) carbon dioxide and water. Thus, the actions of carbonic anhydrase are essential for a variety of important physiological reactions in the mammal. As such, there is significant interest in the identification and characterization of novel polypeptides having homology to carbonic anhydrase. We herein describe the identification and characterization of novel polypeptides having homology to carbonic anhydrase, designated herein as PRO1335 polypeptides.
122. PRO1329
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1329.
123. PRO1550
Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. We herein describe the identification and characterization of a novel secreted protein designated herein as PRO1550.
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There are a number of situations where hydrocarbon wells are treated by igniting a gas generator in the well and allowing the high pressure combustion products to flow into a subterranean formation intersecting the well. One such treatment is a fracturing treatment, roughly analogous to hydraulic fracturing, where the purpose is to increase the permeability of the formation adjacent the perforations. Rather than fracturing the formation and then propping it open with sand, as in hydraulic fracturing, the mechanism is that the high pressure combustion gases initiate and then erode micro and radial fractures originating from each perforation channel.
Oil and gas wells are subject to many ailments, some of which are treatable by injecting a treatment liquid into the formation. As used herein, a liquid is a material which is at a temperature above its melting point and below its boiling point and includes slurries. Examples are the injection of resins to reduce sand movement into the production string and the injection of solvents to remove asphaltenes accumulating in the zone near the well bore.
Most treatment liquids are injected into hydrocarbon bearing formations with a pump truck by a process known as bullheading, i.e. a truck drives up to the well and pumps the treatment liquid down the production string into the formation. The treatment liquid automatically follows the path of least resistance and enters the zones with the highest permeability. The treatment liquid is usually followed with a chaser liquid that displaces the treatment liquid from the production string so all of the treatment liquid is delivered into the formation. This is a time honored practice that has the advantages of simplicity, low costs, and predictable results provided the zones are very thin and homogenous.
There are some situations where more sophisticated and more expensive means of injecting treatment liquids have been proposed and used. One type of approach is to place the treatment liquid in the well and ignite a gas generating propellant in the production string, as shown in U.S. Pat. Nos. 2,740,478; 4,936,385; 5,101,900; 5,145,013 and 5,443,123. Of more general interest is the disclosure in U.S. Pat. No. 3,029,732.
It is known in the prior art to ignite a gas generating charge and create relatively low pressure gaseous combustion products for the purpose of stimulating a well by cleaning out the perforations in production casing or cleaning out the slots in a slotted liner. Examples are found in U.S. Pat. Nos. 4,064,935 and 4,081,031.
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This specification relates to virtualization systems, and particularly to managing resources in such systems.
Traditional computer system architectures typically include one or more dedicated computer servers for each application being run, and are often designed to include an excessive allocation of resources in order to be able to handle peak demands. Such partitioning of computer systems through dedicated servers and excessive allocation of resources can be costly, inefficient and difficult to scale and manage.
Virtualization, which refers to the abstraction of computer resources from their hardware or software-based physical constructs, is one manner of dealing with the aforementioned problems. A virtualization system includes one or more virtual machines (VMs), each of which is a software implementation of a computer that executes programs or applications as if it was a physical computer. A virtual machine operates like a physical computer and contains, for example, its own virtual (e.g., software-based) central processing unit (CPU), random access memory (RAM), hard disk storage and network interface card (NIC). Each virtual machine in a virtualization system generally runs its own guest operating system (OS), and the virtual machines generally share the underlying physical machine resources of the system.
There are many potential benefits to operating in a virtualization system versus traditional architectures. For example, by permitting the sharing of hardware among applications workloads, virtualization can be used for improving resource utilization and reducing the need for excess resources to absorb peak traffic. Virtualization can also be used to improve the availability and robustness of applications, by shifting workloads among servers to handle fail-over situations. Notwithstanding the potential benefits, operating in a virtualization system presents several challenges and potential pitfalls, including significant operations management challenges.
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1. Field of the Invention
The present invention relates to a flow control valve employed in a refrigerating cycle, and more particularly, to a flow control valve using a direct current(DC) motor for improving the control of flow, and its durability.
2. Description of the Related Arts
Generally, a refrigerating cycle comprises an evaporator, a compressor, a condenser, an expansion valve, etc., and decreases the temperature of its surrounding environment by the mechanism of evaporation, compression, condensation, and expansion of coolant.
Describing the mechanism in more detail, the liquefied coolant inside the evaporator of the refrigerating cycle is evaporated by taking latent heat needed for its evaporation from the air around a cooling line. Then, the air is cooled down, its temperature decreased after its latent heat being taken, thereby maintaining the interior of, for example, a refrigerator operated by the refrigerating cycle at low temperature by its natural circulation or by the operation of a certain fan. The coolant supplied from an expansion valve and the evaporated coolant vapor exist together inside the evaporator, and during the phase transition from the liquid state to the vapor state, there is a certain relation between the pressure and the temperature of the evaporation.
The coolant vapor evaporated from the evaporator is supplied to the compressor to facilitate continuous evaporation of the liquefied coolant even under a low temperature by maintaining a low pressure inside the evaporator. Then, the coolant vapor supplied to the compressor is compressed by a piston of a cylinder so that it becomes easily liquefied because of its increased pressure even by cooling it by a cooling water or a cooling air at room temperature.
Then, the compressed coolant from the compressor is cooled, condensed, and liquefied at the condenser. The condensation at the condenser also occurs in the state that the liquefied coolant and the evaporated coolant exist together like in the above evaporation. During the phase transition from vapor to liquid, there is a certain relation between the pressure and the temperature of the condensation.
Expansion is performed to reduce the pressure of the liquefied coolant by the condenser enough to be easily evaporated in advance before supplying the liquefied coolant to the evaporator. An expansion valve functions to reduce the pressure, which is the expansion, and also to control the flow of the liquefied coolant. That is, the amount of the liquefied coolant to be evaporated inside the evaporator is determined according to the heat amount to be taken away from the interior of a refrigerator, the evaporation temperature and the evaporation pressure. It is very important to supply the proper amount of the liquefied coolant to the evaporator, exactly controlling it so as not to be over/short-supplied.
That is, the expansion valve adiabatically expands the liquefied coolant at a high temperature and a high pressure to the state of a low temperature and a low pressure by the throttling operation and functions as a flow control valve to maintain a supply amount of the liquefied coolant at a certain level according to the load of the evaporator.
Many types of the expansion valves that are commercially known vary the controlling method and structure. Recently, throttling of the flow control valve is widely known because of its high operation capability, fine control, and reduced manufacturing expenses, etc.
One typical embodiment thereof is described herein after with reference of the drawings.
As shown in FIG. 1, the flow control valve comprises a cap 1 having a certain shape, a heating bottom plate 3, which is made of ceramic material, and has an expansion agent opening 2 on both sides, an Al-electrode 5, which is fixably attached on the upper side of the heating bottom plate 3, and has a Ta--Al heating electrode 4 on its middle, a diaphragm 7 having a spacer 6 and fixably attached on the top circumference of the Al-electrode 5, the diaphragm 7 being made of, for example, copper (Cu), attaching layers 8, 9(referred to as "filler"), placed between the top of the Al-electrode 5 and the bottom of the spacer 6, and between the top of the spacer 6 and the bottom of the diaphragm 7 respectively so as to improve the adhesiveness between them, an expansion agent 10, which fills the space between the Al-electrode 5 and the diaphragm 7, a sealing bottom plate 11 fixed on the bottom of the heating bottom plate 3 for shutting down the expansion agent opening 2.
In FIG. 1, reference numeral 12 identifies a power line.
The cap 1 comprises a space 1a occupying a certain space there inside for passing liquefied coolant, and an inlet 1b and an outlet 1c on its top, the liquefied coolant being in communication with the space 1a through the inlet 1b and the outlet 1c.
The flow control valve of the throttling type is constructed in a manner that the Al-electrode 5 having a Ta--Al heating electrode 4 is fixably attached on the top of the heating bottom plate 3, and a lower attaching layer 8, the spacer 6, a upper attaching layer 9, and the diaphragm 7 are sequentially attached on the top of the Al-electrode 5 thereby forming a certain space inside the Al-electrode 5, the spacer 6, and the diaphragm 7.
Then, an expansion agent 10 is induced through the expansion agent opening 2 on the bottom of the heating bottom plate 3, the expansion agent opening 2 is sealed by fixably attaching a sealing bottom plate 11 on the bottom of the heating bottom plate 3, the sealing bottom plate 11 is fixably attached on the bottom of the cap 1, and the power line 12 of the Al-electrode 5 is taken out of the cap 1.
The center of the diaphragm 7 is placed directly under the outlet 1c formed on the cap 1.
In the conventional flow control valve as described above, liquefied coolant is induced through the inlet 1b of the cap 1, passes through the space 1a there inside, and discharged through the outlet 1c to the evaporator. When controlling the flow of the liquefied coolant, power is applied on the Al-electrode 5 through the Ta--Al heating electrode 4 of the Al-electrode 5, the Ta--Al heating electrode 4 of the Al-electrode 5 emits heat, and the expansion agent 10 filling the Al-electrode 5, the spacer 6, and the diaphragm 7 is expanded so that by the heat expansion of the expansion agent 10, as shown in FIG. 2, the center of the diaphragm 7 is expanded toward the outlet 1c of the cap 1, and the whole flow amount of the liquefied coolant is controlled by controlling the amount of the liquefied coolant discharged through the outlet 1c.
However, the conventional throttling type of the flow control valve controls the flow amount of the coolant by heating the Ta--Al heating electrode 4 and expanding the expansion agent 10. However, it has disadvantages, such as the inability to proportionally control the flow. Also, there is a demand for addressing the many difficulties involved with the use of the expansion agent 10.
The above-noted difficulties of use of the expansion agent 10 include imperfection of sealing to completely prevent the leakage of the expansion agent 10 and, the decreased endurance of the diaphragm 7 according to the repeated expansion and the shrinkage of the expansion agent 10. These serve as reasons to decrease the reliability for the flow control valve and shorten the life time of the all components.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to management systems for drilling projects and more particularly, but not by way of limitation, to systems for managing information associated with an underground directional-drilling project including, for example, drilling plans, drilling data, material consumption, equipment wear, equipment maintenance, and project cost.
2. History of the Related Art
The practice of drilling non-vertical wells via directional drilling (sometimes referred to as “slant drilling”) has become very common in energy and mining industries. Directional drilling exposes a larger section of a subterranean reservoir than vertical drilling, and allows multiple subterranean locations to be reached from a single drilling location thereby reducing costs associated with operating multiple drilling rigs. In addition, directional drilling often allows access to subterranean formations where vertical access is difficult or impossible such as, for example, formations located under a populated area or formations located under a body of water or other natural impediment.
Despite the many advantages of directional drilling, high cost associated with completing a well is often cited as the largest shortcoming of directional drilling. This is due to the fact that directional drilling is often much slower than vertical drilling due to requisite data-acquisition steps. Thus, controlling and managing costs becomes a chief concern during directional-drilling.
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{
"pile_set_name": "USPTO Backgrounds"
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It is common for a power a power tool to be provided with battery packages. During the operating of a power tool, unavoidable vibrations require an especially tight connection between the battery package and the power tool to prevent the connection from being loosened. However, the tight connection between the battery package and the power tool makes it difficult for the battery package to be detached from the power tool.
A cordless electric drill with a resilient mechanism for detaching the battery package from a power tool is disclosed in U.S. Patent Application Publication No. 2003/0039880. The resilient pushing mechanism comprises a pair of springs so that the battery package being unlocked can be disengaged and pushed away from the power tool via the resilient force of the pair of pressed springs. One disadvantage of such a mechanism is its complicated mechanical structure. Furthermore, over time, the resiliency of the springs may be reduced with the result of the reduced function of the resilient pushing mechanism due to degradation of material properties over time and as a result of continued use.
The present invention is provided to solve the problems discussed above and other problems, and to provide advantages and aspects not provided by prior battery packages for power tools. A full discussion of the features and advantages of the present invention is deferred to the following detailed description, which proceeds with reference to the accompanying drawings.
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{
"pile_set_name": "USPTO Backgrounds"
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When DSL service is added to the service for a telephone customer, a DSLAM (Digital Subscriber Line Access Multiplexer) must be added to the equipment and connected to the customer's telephone lines through a cross-box or other connection frame. The cross-box or connection frame may have many connections to many customers. A difficulty arises in that the technician making the connections in the cross-box may not properly connect the DSLAM to the customer's telephone lines. For example, the connection from the DSLAM may be made to another customer's lines rather than the telephone lines of the intended customer. When this occurs, the DSL modem at the customer's location will not synchronize with a DSLAM and the customer's DSL service will not activate.
From the perspective of the telephone company technician, the failure of the DSL service to activate could be an improper connection at the customer's location, or it could be an improper connection at the cross-box or connection frame connecting the DSLAM to the telephone lines for the customer. Accordingly, the telephone company does not know whether to dispatch a service person or technician to the customer's location or to dispatch a different service person to the telephone company equipment location containing the cross-box or connection frame connecting the DSLAM to the customer's telephone lines.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Technical Field
The present invention relates to a toner cartridge storing toner.
2. Related Art
As a toner cartridge used in an image forming apparatus such as a copying machine, a printer and the like adopting an electrophotographic system, there has been used a toner cartridge configured so that a feeding developer in a container is supplied to a developing device at a predetermined timing and simultaneously a waste developer including a carrier and the like which are used and deteriorated in the developing process is recovered.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of Invention
The present invention relates to educational software and in some embodiments to a computer-implemented system and method for assisting a user in learning a musical sequence.
2. Description of Related Art
In order to learn a particular musical sequence (e.g. a riff), from a media file (audio file) or a multimedia file (video with synchronized sound), a musician usually slows down the tempo to learn the sequence. However, when the tempo of any media or multimedia file is altered, the pitch of the audio can also be adversely affected, which can confuse the musician. Therefore, there is a need in the art for a solution that compensates for the audio pitch as the tempo of the media or multimedia file is altered.
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{
"pile_set_name": "USPTO Backgrounds"
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Mezzanines are frequently constructed in commercial or industrial establishments to increase the storage or production floor space. The typical mezzanine is supported above the foundation of the building by a series of vertical columns and includes a deck or supporting surface which is bordered by a railing. According to Federal requirements, the railing must be at least forty-two inches high and the openings between horizontal rails cannot exceed twelve inches. In the past the typical railing for a mezzanine has consisted of a series of vertical pipes which extend upwardly from the edge of the deck and cross-shaped or T-shaped fittings are located within each vertical pipe. Cylindrical rails are inserted through the horizontal openings of the cross-shaped and T-shaped fitting. With railings of this type, individual horizontal rails cannot be removed. For example, if it is desired to install or remove a relatively large piece of machinery or equipment from the mezzanine which would require the removal of a section of railing, it would be necessary to remove the entire railing, for individual sections cannot be disassembled. Thus, there has been a need for a railing construction in which individual rails can be removed from the railing.
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{
"pile_set_name": "USPTO Backgrounds"
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Electrical devices that include a number of electrical components (e.g., a power supply, a memory/storage device, a processor, etc.) continue to increase in complexity. Electrical components dissipate unused electrical energy as thermal energy that may reduce the reliability of the electrical components. The reliability of the electrical components and the electrical device may improve by managing the thermal energy created by the electrical components.
Thermal cooling devices such as fans may be used to cool an electrical device and the electrical components thereof. However, thermal management of the electrical device and the electrical components may be limited without an efficient thermal management controller.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to a capacitive-load driving circuit for driving a capacitive load such as the driving circuit of an ink-jet printer head using a piezoelectric element. More particularly, the present invention relates to technology for reducing power consumption as seen from the power supply side in the driving circuit.
The present application is based on Japanese Patent Applications Nos. Hei. 9-277272 and Hei. 10-052197, the contents of which are incorporated herein by reference.
2. Description of the Related Art
In a conventional driving circuit of an ink-jet printer head using a piezoelectric element, ink is sucked and discharged by applying a trapezoidal-wavelike pulse voltage to a piezoelectric element in an ink-jet nozzle to vary the volume of an ink chamber. A push-pull current amplifier circuit using two transistors that are connected together is used in the driving circuit. In the current amplifier circuit, a capacitive load (a piezoelectric element) is charged by a power supply via one transistor, based on the trapezoidal-wavelike pulse voltage (an input signal) that is output from a trapezoidal-wave voltage generating circuit, which is formed at the preceding stage, and the charge is discharged from the capacitive load to ground via the other transistor.
However, the conventional driving circuit has several problems. One problem is high power consumption because the quantity of electricity required to charge the capacitive load is supplied totally from the power supply. Another problem is that a great deal of heat is generated by the transistors because the supply voltage is applied directly across the emitter.sub.-- collector of the transistors when charging of the capacitive load is started. Still another problem is that a great deal of heat is also generated by the transistors because the peak value of the charging voltage is applied directly across the emitter.sub.-- collector of the transistors even when discharging of the capacitive load is started.
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{
"pile_set_name": "USPTO Backgrounds"
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The present invention relates in general to computer system signal processing and more particularly to a method and apparatus for processing errors in a computer system.
No matter how thoroughly a computer system is designed, unintended events may occur in computer systems during actual operation. Errors can happen due to a flaw in the design of the computer system or because of some operational malfunction. A well designed system should be able to anticipate various types of errors that may occur. Several problems arise when refining these general principles to specific implementations. It is difficult to classify all the errors that may possibly occur. There is no standard capability to detect an error and capture information that may assist in evaluating the error, especially when a multitude of errors are detected. There are also no efficient ways for hardware to inform software of an error and the details surrounding the circumstances of the error.
Further, the design of a computer system includes mechanisms for detecting and responding to any errors that may occur during operation. After a computer system""s hardware detects the presence of an error, the computer system""s software is often notified of the occurrence of the error and instructed to take appropriate action. Software development on prototype chips while in laboratory testing is hampered if some errors cannot be induced to happen and the code developed to handle these errors cannot be tested. For example, there may be no capability to generate incoming packets that have an invalid command encoding. Therefore, it is desirable to provide an efficient technique to identify and capture errors that occur during computer system operation. It is also desirable to provide a capability to induce errors into a computer system in order to test error handling software.
From the foregoing, it may be appreciated that a need has arisen for a technique to identify errors and capture information about them and provide a capability to induce the occurrence of errors in a computer system. In accordance with the present invention, a method and apparatus for processing errors in a computer system is provided that substantially eliminates or reduces disadvantages and problems associated with conventional error processing techniques.
According to an embodiment of the present invention, there is provided an apparatus for processing errors in a computer system that includes a request module that can receive incoming packets. A processor module can identify a write operation specified by an incoming request packet. The processor module determines a register specified by the incoming request packet upon which to perform the operation. A registers module maintains registers within which the write operation is performed. The incoming request packet specifies instructions for how to inject an error into the computer system. The processor module performs a write operation by writing information from the incoming request packet into one of the header and data registers of the registers module. The processor module sets an error bit to trigger processing of the injected error.
In detecting errors, the request module receives a request packet and determines whether the request packet has an error. The request module transfers the request packet to the processor module for processing in response to a determination that there is no error in the request packet. Otherwise, the request module stores header and data information associated with the request packet in the header and data registers of the registers module in response to the request module identifying an error in the request packet. The request module sets an error bit in an error register of the registers module to indicate that an error has been identified in the request packet.
The present invention provides various technical advantages over conventional error processing techniques. For example, one technical advantage is to inject errors into a computer system to test the functionality of error handling software. Another technical advantage is to efficiently identify errors and capture information concerning identified errors. Yet another technical advantages is to effectively provide error identification, capture, and injection in a common environment. Other technical advantages may be readily apparent to those of skill in the art in view of the following figures, description, and claims.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to decorative sheet material, a process for producing decorative sheet material, and to products, such as ribbon, pressure-sensitive adhesive tape, laminated products, embossed products and molded products, produced therefrom.
2. Description of the Background Art
The three primary types of decorative ribbon in widespread use today are woven yarn-based ribbon, nonwoven yarn-based ribbon, and foamed, oriented, polypropylene-based ribbon.
The woven yarn-based ribbons are generally the finest ribbons in terms of yarn-like luster, texture, feel, and quality of color. Although the quality of such ribbon is high, manufacturing costs are also relatively high.
The foamed, oriented, polypropylene-based ribbons generally do not offer the aesthetics obtainable with the woven yarn-based ribbons, since these ribbons are generally stiff and have a plastic-appearing surface rather than the yarn-like luster of the woven yarn-based ribbons. An advantage found in these polypropylene-based ribbons is that they can be thermally welded, e.g., by sonic sealing, to form ribbon assemblies, such as those described in U.S. Pat. Nos. 3,637,455 and 4,329,382.
Nonwoven yarn-based ribbons, such as described in U.S. Pat. No. 2,626,883, possess the excellent aesthetics of yarn-like luster, texture, feel, and quality of color found in woven yarn-based ribbons, and can be manufactured much less expensively than the woven yarn-based ribbons. The ribbon described in U.S. Pat. No. 2,626,883 has a tissue-like web of staple viscose rayon fibers and plasticized staple acetate rayon fibers autogenously interbonded at their crossing points to form a network. A monolayer of aligned yarns of non-plasticized continuous acetate rayon filaments is autogenously bonded onto one face of the web of the plasticized acetate rayon fibers.
This composite is impregnated by sizing that superficially coats the yarns. Although the aesthetics of this nonwoven yarn-based ribbon are excellent and manufacturing expenses are less than for producing the woven yarn-based ribbon, deficiencies in the nonwoven yarn-based ribbon are present. The volatile plasticizer used on the staple acetate rayon fibers is costly and requires the use of expensive processing equipment such as oven filter scrubbers. Additionally, such ribbon cannot be sufficiently sonically bonded to form durable ribbon assemblies, but must be bonded by applying adhesive to the areas to be bonded, a method generally more difficult to control than thermal bonding.
U.S. Pat. No. 4,490,427 (Grant et al.) discloses thermally adhesive webs. The webs have substantially parallel fusible polymeric filaments thermally bonded to and interconnected by randomly arranged polymeric fibers. The parallel filaments generally have a diameter substantially greater than the diameter of the interconnecting filaments and adjacent parallel filaments are generally spaced apart 0.5 to 5 mm. Although such a web is thermally adhesive, the web does not possess the aesthetics desired for decorative ribbon and sheet material.
The present invention provides a decorative sheet material which has the excellent aesthetics of the nonwoven yarn-based ribbon material and thermal sealability of the polypropylene film-based ribbons.
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{
"pile_set_name": "USPTO Backgrounds"
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The first adeno-associated viral (AAV) vectors evaluated for gene therapy were based on serotype 2 (AAV2) and were shown to transduce a variety of somatic cells following in vivo delivery [Z. Wu, et al (2006) Mol Ther, 14:316-327]. One of the first clinical successes of gene therapy used an AAV2 vector to restore some aspects of vision following subretinal injection in patients with an inherited form of blindness [A. Kern, et al, (2003) J Virol, 77: 11072-11081; A M Maguire, et al, (2008) N Engl J Med, 358: 2240-2248]. Application of AAV2 vectors for the treatment of other diseases however has not been as successful due to poor transduction efficiencies and various immunologic problems such as pre-existing neutralizing antibodies and T cell activation to the capsid [Wu, et al, cited above]. AAV2 is known to utilize heparan sulfate (HS) proteoglycans as a primary receptor for cellular recognition [Kern et al, cited above]. Additional vectors were developed based on AAV capsids from other existing serotypes such as AAV1 and its close relative AAV6, both of which showed enhanced transduction of muscle and cellular binding mediated by sialyated glycoproteins [Z. Wu et al, (2006) J Virol, 80:9093-9103; W. Xiao, et al, (1999) J Virol, 73: 3994-4003]. Vectors based on AAV5 also require binding to N-linked sialic acid (SA) while showing enhanced transduction in CNS following direct injection in brain [R W Walters et al, (2001) J Biol Chem, 276: 20610-20616; B L Davidson, et al, (2000) Proc Natl Acad Sci USA, 97:3428-3432]. The potential of AAV vectors for human gene therapy was expanded through the discovery of a large and diverse family of novel capsids from latent genomes in human and non-human primate tissues. This expanded family of AAVs number over 120 genomes spanning 6 antigenic clades [G. Gao et al, (2003) Proc Natl Acad Sci USA, 100:6081-6086; G. Gao, et al, (2004) J Virol, 78: 6381-6388; G Gao et al, (2002) Proc Natl. Acad Sci USA, 99: 11854-11859]. High resolution X-ray crystal structures and lower resolution cryo-electron microscopy reconstructed images have been determined for many of the AAV capsids demonstrating a highly conserved core region with a total of 9 surface exposed hypervariable regions [H J Nam et al, (2007) J Virol, 81:12260-12271]. Evaluation of vectors based on these novel endogenous capsids has been quite promising in terms of achieving substantially higher transduction efficiencies with diminished immunological sequelae [G. Gao et al, (2002) Proc Natl Acad. Sci, cited above].
Vectors based on adeno-associated virus (AAV) serotype 9 have emerged as leading candidates for in vivo gene delivery to many organs. AAV9 has shown significant promise in targeting the heart for treatment of cardiomyopathies [L T Bish, et al, (2008) Hum Gene Ther 19: 1359-1368] and neurons for treating diseases such as spinal muscular atrophy [S. Duque, et al, (2009) Mol Ther, 17: 1187-1196; K D Foust et al, (2009) Nat Biotechnol, 27: 59-65]. AAV9 also very efficiently transduces alveolar epithelial cells of the lung without eliciting a humoral response allowing for efficient re-administration of vector [M P Limberis and J M Wilson, (2006) Proc Natl. Acad Sci. USA, 103: 12993-12998]. However, receptor(s) mediating these tropisms have yet to be defined.
What are needed are safe, efficient methods for targeted AAV-mediated delivery of transgenes within a host.
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{
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This invention relates to a bird feeder having an ornamental flower container located within the roof portion of an upright enclosure that is used to contain bird seed. Small openings are formed in a lower portion of the enclosure for delivering measured quantities of bird seed from the enclosure to an annular tray means that encircles the enclosure. The ornamental flower container is removably mounted on the upright enclosure, whereby the container can be lifted from the enclosure when it is desired to pour new bird seed into the enclosure.
Living plants or artificial flowers may be contained within the flower container. The plants will preferably fully occupy the container so that the leaves and blossoms extend above and along outer side areas of the container. The blossoms and plant foliage add an ornamental feature to the bird feeder.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to compressed gas insulated transmission lines for high voltage electric power applications and particularly to longitudinal seams between arcuate sheath sections for forming a sealed cable.
2. Description of the Prior Art
In a typical compressed gas insulated transmission line (CGIT) system, a protective tubular sheath encloses and supports electrical conductors for power transmission. The sheath is filled with a gas, typically sulfur hexafluoride (SF.sub.6) pressurized at about 50 psig.
The major cost of a CGIT line system lies in the fabrication of the sheath. A large diameter conduit is typically constructed of extruded aluminum and consists of a plurality of modular elongated arcuate sections which readily fit together. This construction technique has the advantage that large diameter sheaths, i.e., greater than 20 inches in diameter, can be constructed at a lower cost than comparable spiral welded or rolled and welded pipe, as has generally been required in prior art high voltage isolated phase or three conductor CGIT line systems.
Segmented tongue-in-groove weld joints are known to the art. For example, U.S. Pat. No. 3,864,507, to Fox et al., describes a single conductor cable having longitudinal tongue-in-groove weld joints, wherein the interior of the cable is protected from the weld area. A construction, such as the Fox et al. design, has a number of disadvantages. First of all, the tongue-in-groove configuration requires very accurate extrusions of the tongue and mating groove. Extrusions of suitable accuracy are difficult and relatively expensive, particularly in long sheath segments. Furthermore, it is also very difficult to align the tongue-in-groove joint of large diameter, long length, multiple segment sheaths. Still further, an exterior weld along the joint may not be reliably uniform and may therefore have weaknesses which could develop into undesirable cracks if the seam is strained.
Therefore, an improved joint is needed wherein alignment is simplified, the joint is sufficiently strong, and construction time and costs are minimized.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to an apparatus for driving a light emitting element that can be applied to a light source or a backlight unit, and more particularly, to an apparatus for driving a light emitting element that can limit heat generation of a constant-current circuit including a metal oxide semiconductor (MOS) transistor by limiting a voltage applied to the constant-current circuit required for supplying a constant current to the light emitting element.
2. Description of the Related Art
In general, a light emitting element is an element emitting light. Examples of the light emitting element include a light emitting diode (LED), a laser diode (LD), and an organic light emitting diode (OLED).
The LED, which is one of the light emitting elements, is applied to various fields such as a lighting unit and a backlight unit, and will be applied to various fields in the future.
Two methods are used in driving the LED. One is using DC/DC of a switching mode, and the other is using a current source. Since the method of using the current source has not only a small switching noise but also a simple circuit, it is widely used. However, a heat generation from a MOS transistor included in the current source should be solved.
Hereinafter, a related art apparatus for driving an LED using a current source is described.
FIG. 1 is a view illustrating the construction of a related art apparatus for driving an LED. The apparatus for driving the LED includes a power unit 10 supplying driving power V required for driving a plurality of LEDs, which are light emitting elements, an LED unit 20 including the plurality of LEDs connected to the power unit 10, lit by the driving power from the power unit 10, and connected to each other in series, and a constant-current circuit unit 30 connected between the LED unit 20 and a ground to maintain a constant current flowing through the LED unit 20.
The constant-current circuit unit 30 includes a MOS transistor MOS including a drain connected to the cathode of the plurality of serially connected LEDs of the LED unit 20, a gate and a source, a sensing resistor RS connected between the source of the MOS transistor MOS and the ground, and a comparator 31 comparing a detection voltage VD detected by the sensing resistor RS with a predetermined reference voltage Vref to supply a tuning voltage VT determined by a difference between the two voltages to the gate of the MOS transistor MOS.
In the related art apparatus for driving the LED of FIG. 1 having the above construction, a current flowing through the LED unit 20 can be maintained constant using the constant-current circuit unit 30 supplying a constant current to the LED unit 20.
At this point, a current ILED flowing through the LED unit 20 is determined by the reference voltage Vref of the comparator 31 and the sensing resistor RS between the MOS transistor MOS and the ground as expressed by Equation 1.
ILED = Vref RS . Equation 1
However, in the related art apparatus for driving the LED of FIG. 1, as the driving voltage Vcc increases, a drain-source voltage Vds of the MOS transistor MOS increases. When the drain-source voltage Vds increases, heat is generated from the MOS transistor MOS.
Also, in the case where the LED included in the LED unit 20 is a high power LED, a current flowing through the LED unit 20 increases even more and thus heat generation becomes serious.
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{
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This invention relates to data entry apparatus, more particularly, to an apparatus adapted to be carried by a user for field data entry.
It is known that computer systems are available in a variety of configurations. Portable computers are one category of computer systems that may be used in a number of locations. For example, one common type of portable computing system is the common notebook personal computer with a keyboard and display screen that folds on top of the keyboard for transportation. The notebook personal computer is quite portable when compared to desktop equivalents, and may be transported and used in a variety of selected locations. However, these notebook computers, and many other smaller computer equivalents must often be used with the aid of a table or desk, preferably with the user in a seated position. For example, the architecture of virtually all notebook computers and similarly sized computers require the user to be seated with the computer, preferably on an elevated working surface. Indeed, one would find it almost impossible to work in a standing position with such a computer without a working surface.
Direct entry of digital inspection data on a shop floor or in a manufacturing plant environment has been impractical using notebook/laptop computers (PCs). Further, even screen entry PCs prove to be impractical as they require a place to be set down, and most commonly, a keyboard is needed for data entry.
Another class of computers adapted to be worn by a user designed so that the main components of the computer are generally supported by, or upon, a user""s body. In one approach, a hip mounted PC system having a head supported display is used, the display being in focus with the user""s eye. Data entry is performed by using voice recognition, and the entered information appears on a screen strapped to the user""s forearm. In this approach, the user must talk or look at the display on the eye piece, and the key-board is strapped to the user""s hand. This arrangement is suitable only for a single user since no one else can see the display image. Further, this approach is cumbersome, requiring that the user affix the components to his/her person in a series of carefully planned steps. Similarly, the affixed parts cannot be removed and transferred to another user very quickly.
Other approaches in the area of portable data entry use a holster-mounted single-hand computer entry systems, such as, for example, systems used by grocery store inventory personnel, and also the use of personnel-mounted computer systems, with various parts of the computer system including it""s input/output systems dispersed in several places around a user""s body. In the first case, the computers are small, specialized devices with very small screens for digital displays and a predefined array of keys for specified data entry. In the second case, the computers are indeed general purpose, but the displays are provided as eyebrow screen reflections visible only to the computer wearer. While both types of computer systems have certain advantages in particular environments, there is a need for more general purpose, less expensive, more robust, and safer to use portable data entry apparatus.
Accordingly, the present invention relates to a portable data entry apparatus that overcomes the above identified problems. The data entry apparatus of the present invention includes a support panel holding a data entry computing device secured to a upper surface of the support panel such that a gap is left between the data entry computing device and the upper surface of the support panel. The data entry computing device is a screen-entry personal computer with a display device. This gap enables heat generated by the data entry device to dissipate more readily. A hand grip member is attached so that it is disposed normal to a bottom surface of the support panel. A formed plastic cast attached to the bottom surface of the support panel enables a user to support and raise the data entry apparatus to a working position for facilitating data entry using his/her forearm (near the elbow). A VELCRO(trademark), or other press-on, pull-off retained strap attached to the cast member, may be wrapped around the user""s forearm for added protection to prevent accidental dropping of the data entry apparatus. The data entry apparatus further includes a shoulder strap to enable a user to easily carry the data entry apparatus without the use of the hands, until such time as the data entry process is to begin.
In a parked position on the shoulder strap, the handgrip member faces away from user. In order to position the apparatus for data entry, user""s forearm is passed through the strap attached to the cast member to hold the hand-grip member. The user then raises the apparatus until the data entry device directly faces the user. At this point the user may adjust the shoulder strap to transfer the weight of the apparatus the user""s shoulders. The user may thus be able to relax the forearm supporting the apparatus. This invention also addresses the ergonomics of using a hand-held data entry apparatus by transferring some of the weight of the apparatus from the forearm to shoulders of the user.
After entering data, the apparatus may be quickly released and allowed to hang at the user""s hip, to enable quick parking of the apparatus on a user when not in use. In the parked position, the data entry computing device is protected by the support apparatus from external impacts that might cause damage to the data entry device. Thus, this invention provides an ergonomically friendly, robust, safe, and inexpensive general purpose data entry apparatus for use in factory environments where the apparatus must be carried by personnel to a site, and be held on the person while entering field data.
In one aspect, the present invention provides a data entry apparatus adapted to be carried by a user including a planar member having top and bottom surfaces; a data entry device secured to the top surface leaving a gap therebetween; a first member detachably secured to the bottom surface and towards a first edge of the planar member; and a second member secured to the bottom surface and away from the first edge, the second member enabling a user""s forearm to support to the data entry apparatus. The apparatus further includes a protective member attached to the planar member, the protective member being disposed to operate in open and fold down positions to protect a display unit of the data entry device.
The protective member provides abrasion protection to the display device of the data entry device. The dimensions of the planar member are greater than the dimensions of the data entry device. Further the first member is attached such that it is normal to the planar member. The data entry apparatus further includes a strap assembly attached to the planar member by a rope harness, the strap assembly enabling a user to carry the data entry apparatus over the user""s shoulder without using hands. The second member comprises a strap unit for securing the user""s forearm to the second member to prevent accidental dropping of the data entry apparatus; and a guard member attached to the second member for protecting the user""s forearm.
The first member preferably protects the data entry device from accidental impacts. The first member is a flexible loop strap secured to the planar member by a wingnut fastener. The first member may also be a rigid handgrip member.
The data entry device is attached to the planar member so as to enable natural convection cooling and to minimize heat transmission to a user. The data entry apparatus also has a stylus for enabling data entry; a clip member secured to the top surface; and a lock mechanism for securing the data entry apparatus. The strap assembly enables a user to hold the data entry device in a presentation position. The strap assembly further provides vertical support for the apparatus during data entry.
In another aspect, an apparatus adapted to be carried by a user for data entry including a planar member having a top surface and a bottom surface; a data entry device secured to the top surface; a first means detachably secured to the bottom surface and towards a first edge of the planar member, the first means enabling a user""s forearm to support the apparatus; and a second means secured to the bottom surface of the planar member and away from the first edge.
A gap is provided between said data entry device and the top surface of the planar member. The apparatus further includes a third means secured to the top surface of the planar member for protecting the data entry device, the third means disposed to operate in open and fold down positions.
In yet another aspect, a data entry apparatus adapted to be carried by a user including a planar member having a top surface and a bottom surface; a data entry computing device secured to the top surface leaving a gap therebetween; a first member detachably secured to the bottom surface and towards a first edge of the planar member, the first member being used as a handgrip member while the apparatus is mounted on the user""s forearm; and a second member secured to the bottom surface and away from the first edge, the second member enabling a user""s forearm to support to the data entry apparatus. The apparatus further includes a protective member attached to the planar member, the protective member being disposed to operate in open (data entry) and fold down (carry) positions to provide a visor to minimize reflections during data entry, the protective member further enabling to protect a display unit of the data entry device when the apparatus is hanging by a shoulder strap at the user""s side.
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1. Reservation of Copyright
This patent document contains material subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document, as it appears in the U.S. Patent and Trademark Office patent files or records, but otherwise reserves all copyright rights whatsoever.
2. Field of the Invention
The present invention is related to processes for moving data through a disk media access channel and systems and methods for managing such processes.
3. Description of Background Information
Hard disk drives, tape drives, and other movable storage media devices transfer data between an I/O controller and movable storage media through a media access channel (also known as a read channel). The media access channel is the route over which information is transferred for read, write, and compare operations, and couples an I/O controller to the media. The media access channel may comprise, among various elements, a plural pin serial or parallel interface coupling the I/O controller to an actuator driver, a read/write head, and, for media read operations, a signal converter for converting an analog signal to a sequence of bits representative of data on the media. In the case of a Partial Response Maximum Likelihood (PRML) disk drive read channel, the disk drive comprises digital signal processing components and components for performing maximum likelihood detection, to facilitate the fast and accurate transfer of data between the disk I/O controller and the disk media.
Media access channels, such as the PRML read channel, are provided with sophisticated filtering and other digital signal processing mechanisms for improving disk performance, by improving such disk characteristics as areal density (disk capacity), data transfer speed, yield, and disk noise. Such improvements are being achieved by PRML read channels without inter-symbol interference (ISI), which results from the overlapping of analog signal peaks being transferred through the read/write head at very large speeds. Rather than merely detecting signal peaks from the media, PRML read channels detect the analog signal from the read/write head, convert the signal to a digital signal, and use the digital signal to detect data bits.
Because disk drives are moving to the use of PRML read channels, aimed at increasing the capacity of the disk drive without sacrificing performance, the latency of data transferred between the media and the I/O controller has increased substantially. As media access channels increase in their latency, it becomes more difficult for the I/O controller to manage transfers over the media access channel. The controller may need to fetch from the disk certain data required to perform various processes associated with a particular operation. Due to the latency of the media access channel, before the fetch process receives the requested information, a large quantity of other data, for example, 20 bytes or more, will be moved through the access channel. Accordingly, the information to be fetched is requested early, and information required for a next process that needs information for the fetch process will be requested immediately thereafter. In this way, when the fetched data is obtained, the data associated with the next process will be provided to the controller shortly thereafter. These media access operations must be requested ahead of time keeping in mind their position within the pipeline and the time at which they will be carried out. If the media access operations are not properly carried out taking these factors into account, problems can be encountered such as destroying adjacent blocks of information, misreading information from the media, or failing to read requested information from the media. In addition, a dependent process, if not provided with timely information from a process upon which it depends, could experience an error.
Accordingly, there is a need for mechanisms for structuring data transfer processes involving the disk media access channel so the controller can accurately handle timing issues and efficiently perform read, write, and compare operations in a pipeline fashion while minimizing access delays, data transfer delays, and errors associated with such operations. There is a need for a scheme which allows for the accumulation of status information regarding the processes used to carry out such operations.
4. Definitions of Terms
The following term definitions are provided to assist in conveying to the reader an understanding of the descriptions provided in this patent document.
Pipe: A portion of memory which is coupled to the output of one process as well as to the input of another process, and allows the process to pass information along to the other process.
Pipeline: A structure comprising multiple sequential stages through which a computation flows as time progresses, wherein at any given time a new operation may be initiated at a starting stage (the start of the pipeline) while one or more other (earlier initiated) operations are in progress and thus at later stages (in the middlexe2x80x94moving toward the end) of the pipeline).
Pour: To send a file or output from a program to another file or to a device using a pipe.
The present invention is provided to improve upon storage subsystems. More specifically, the present invention may be provided to improve upon interfacing subsystems for interfacing a storage media controller to a media access channel which couples the storage media controller to a read/write assembly for writing information to and reading information from the storage media. More specifically, the present invention may improve upon read channel interfacing subsystems which interface a disk controller to the read channel which couples the disk controller to a head disk assembly. In order to achieve these objects, one or more aspects of the present invention may be followed in order to bring about one or more specific objects and advantages, such as those noted below.
The present invention, therefore, is directed to a system or method, or one or more components thereof, involving a non-volatile storage subsystem comprising a media I/O controller, a media access channel, and movable storage media. More specifically, the present invention is directed to a non-volatile disk storage subsystem having a read channel coupling a disk controller to a disk head assembly. A read channel interfacing subsystem is provided as part of the storage subsystem, and the read channel interfacing subsystem interfaces a disk controller to the read channel. The read channel interfacing subsystem comprises a set of process units and a pipeline manager. The set of process units includes first, second and third subsets. The first subset is utilized when a disk read operation is carried out via the read channel. The second subset is utilized when a disk write operation is carried out via the read channel. The third subset is utilized when a disk compare operation is carried out via the read channel. Each process unit comprises mechanisms for entering an idle state and for carrying out an operational state flow. The pipeline manager, for each one of the disk read, disk write and disk compare operations, enables and disables each utilized process unit, so each of the utilized process units is done and ready to carry out its operational state flow for a subsequent operation and has poured into a holding register resulting data needed by a dependent process unit within the present operation, all before the occurrence of a predetermined upcoming periodically recurring advance signal.
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Facilities that generate power by nuclear fission often use water for containment of the reaction rate and provide a certain amount of radiation shielding of the fuel in the reactor core (in pressured water and boiling water-type reactors), and to store spent fuel cells. A typical pressure water reactor (PWR) can have on the order of 280 fuel cells in its reactor core. A boiling water reactor (BWR) can have 500 fuel cells in use and in storage. A spent fuel pool can have as many as 5,000 units at any given time. Strict governmental regulation requires that the specific location of each fuel cell in a facility be known at all times. Failure to comply, even in the case of a minor variation, can result in substantial fines.
The operation and maintenance of nuclear facilities requires that the fuel cells contained in the reactor be periodically inspected and replaced. In both PWR and BWR facilities, the reactors are typically refueled every twelve to eighteen months. The refueling process removes spent fuel to the spent fuel pool, relocates existing fuel cells within the reactor core, and inserts new fuel cells. This process involves much more than simply replacing spent cells with new cells, since a significant "shuffling" of the fuel cells already within the reactor must occur in order to balance the radiation level across the reactor core to maintain uniformity. In order to comply with the strict governmental regulations, as well as to enable identification of fuel cells to determine their appropriate position within the core, means must be provided for in situ identification of each individual fuel cell with minimum exposure of personnel to dangerous radiation levels. This requires that the fuel cells be identified while still submerged within the water in the reactor containment or spent fuel pools. This presents a significant problem, however, since the depth of the water, at least in the containment pool, is on the order of 60 feet.
The industry standard is for the fuel cells to be identified with an alphanumeric serial number which is stamped, milled or engraved on the top surface of the fuel cell, or on a bail extending partially across the top of the unit. Typical depths for new characters can be 0.5 to 1.0 mm. Thus, in order to identify a particular fuel cell, it is essential that the serial number be both visible and intelligible. On new fuel cells, the contrast between the background surface and the characters in the serial number is good, and the serial number can easily be read using a common video camera, such as a camcorder. However, this contrast degrades over time due to the enhanced corrosion and/or oxidation of the surface that is caused by the radiation, and sediment buildup on the surfaces of the fuel cell, with the characters becoming as shallow as 0.07 mm.
A number of identification systems have been developed which are intended to allow the identification of fuel cells. For example, U.S. Pat. No. 4,960,984 ('984 patent) which issued to Goldenfield for an invention entitled "Method and Apparatus for Reading Lased Bar Codes on Shiny-Finished Fuel Rod Cladding Tubes," teaches the identification of nuclear fuel rod tubes that are encoded with a bar code by scanning the bar code with a bar code reader. This method requires marking a bar code on the fuel cells in addition to the industry standard alphanumeric code, which may be possible for newly manufactured cells, but could prove very difficult for used fuel cells (spent or in use). Further, the system and method of the '984 patent does not allow identification of a fuel rod tube while the tube is submerged within the reactor pool. Instead, a sophisticated machine is described which receives the fuel rod tube, and directs a laser beam towards the bar code etched in the tube. This laser beam is reflected back to the beam source for decoding to yield the identification information for the fuel cell. While this system may be capable of accurately identifying the fuel cell tube using a pre-existing engraved bar code, it is incapable of obtaining such identification while the fuel cell is submerged within the reactor pool.
Another fuel cell identification system is briefly disclosed in U.S. Pat. No. 5,490,185 ('185 patent), issued to Dent, et al., for an invention entitled "System for Automatic Refueling of a Nuclear Reactor," which includes the use of an optical scanner to identify the bar code or alphanumeric code. While this system includes video capability for identification of the fuel cell while still submerged within the reactor pool, the video feature is described simply as a remotely operated video camera which is attached to the fuel handling equipment. Without special considerations for contrast enhancement, corrosion on the outside surface of the nuclear fuel cells and the buildup of corrosive materials on the surface of the nuclear fuel cell will inhibit the video determination of any identifying markings.
Yet another identification system is disclosed in U.S. Pat. No. 5,089,213 ('213 patent), issued to Omote, et al., entitled "Nuclear Fuel Assembly Identification Code Reader." The '213 patent discloses the use of a combination of a camera and an ultrasonic wave sensor for what is described as a more reliable process for identification of the fuel cell. The device disclosed in the '213 patent combines the data from the camera and the acoustic device to provide the identification, requiring a relatively complex processing program. The two different reading techniques complement each other in an effort to overcome the inadequacies of each system individually. Thus, a significant loss in contrast in the characters would require the system to rely almost exclusively on the acoustic component of the system. The combination of the processing requirements and the multiple independent detection components would make this system relatively complex and expensive
In light of the above-stated inadequacies of the prior art, it would be desirable to provide a system and method for in situ underwater inspection of the nuclear fuel cells in reactor pools and spent fuel pools that is capable of reading existing industry-standard identification characters in which the system is capable of reading the characters in spite of the inevitable degradation of the characters caused by corrosion. It is to such a system that the system and method disclosed herein is directed.
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Exemplary embodiments herein generally relate to a vehicle seat assembly, and more particularly to a center bolster having a hinged portion for a center ISO-FIX attachment of an associated child restraint.
A known vehicle seat assembly includes a pair of outboard seats, each outboard seat having a seatback connected to a seat base or cushion. The seatback of each outboard seat can be moved between an upright, seated position and a folded, stowed position. A stationary center bolster or cushion can be provided between the outboard seats. Typically, a mid-row seating assembly for a vehicle with an aggressive center bolster styling has complex close-out designs for the center ISO-FIX (i.e., the international standard for attachment points for child safety restraints, such as child safety seats or booster seats, in vehicles) attachment of a child restraint to the center bolster. Particularly, as shown in FIG. 9, a center bolster 100 for a mid-row seating assembly includes a seat base or cushion 102 and a seatback 104. Center anchorages or anchor bars 110 are provided for mounting a child safety restraint 112 to the center bolster 100. The child restraint includes side tethers 120 for releasably engaging the anchor bars 110 and a top tether 122 for releasably engaging a top tether anchorage (not shown) provided on the seatback 104 or elsewhere on the vehicle. In the known mid-row seating assembly, it is necessary to mount the center anchor bars 110 on the seat back 104 instead of a support component where the lower anchorages for the outboard seats are mounted. In the secured position, a forward portion of the child restraint 112 is located above the center bolster 110 which can cause the child restraint to at least partially rock or move on the center bolster. Further, the center anchor bars 110 must remain above the seat cushion 102 which may require the anchor bars to be mounted to the seatback 104. This will require reinforcement adding cost and weight to the seatback. Thus, the center ISO-FIX attachment demonstrates many challenges both to seat design and to trim cover/close-out design. For this reason, many vehicle manufacturers remove the center ISO-FIX attachment entirely. If the center ISO-FIX attachment is included in the seat assembly, expensive plastic garnishes, trim cover slits, or flaps are commonly used as close-out designs to conceal the center anchor bars.
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1. Field of the Invention
The present invention concerns methods and systems for predicting the function of proteins. In particular, the invention relates to materials, software, automated systems, and methods for implementing the same in order to predict the function(s) of a protein. Protein function prediction includes the use of functional site descriptors for a particular protein function.
2. Background of the Invention
The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to that invention.
A central tenet of modern biology is that heritable genetic information resides in a nucleic acid genome, and that the information embodied in such nucleic acids directs cell function. This occurs through the expression of various genes in the genome of an organism and regulation of the expression of such genes. The pattern of which subset of genes in an organism is expressed at a particular time in a particular cell defines the phenotype, and ultimately cell and tissue types. While the least genetically complex organisms, i.e., viruses, contain on the order of 10-50 genes and require components supplied by a cell of another organism in order to reproduce, the genomes of independent, living organisms (i.e., those having a genome that encodes for all the information required for the organism to survive and reproduce) that are the least genetically complex have more than 400 genes (for example, Mycoplasma genitalium). More complex, multicellular organisms (e.g., mice or humans) contain genomes believed to be comprised of tens of thousands or more genes, each of which codes for one or more different expression products.
Most organismal genomes are comprised of double-stranded DNA. Each strand of the genomic DNA is comprised of a long polymer of the four deoxyribonucleotide bases A (adenine), T (thymine), G (guanine), and C (cytosine). Double-stranded DNA is formed by the anti-parallel, non-covalent association between two DNA strands. This association is mediated by hydrogen bonding between nucleotide bases, with specific, complementary pairing of A with T and G with C. Each gene in the genomic DNA is expressed by transcription, wherein a single-stranded RNA copy of the gene is transcribed from the double-stranded DNA. The transcribed strand of RNA is complementary to the coding strand of the DNA. RNA is composed of ribonucleotide (rather than deoxyribonucleotide) bases, three of which are similar to those found in DNA: A, G, and C. The fourth RNA ribonucleotide base, uracil (U), substitutes for T found in DNA and is complementary to the A base. Following transcription, the RNAs transcribed from many genes are translated into polypeptides. The particular sequence of the nucleotide bases normally determines what protein, and hence what function(s), a particular gene encodes.
Some genes are transcribed, but not translated; thus, the final gene products of these genes are RNA molecules (for example, ribosomal RNAs, small nuclear PNAs, transfer RNAs, and ribozymes (i.e., RNA molecules having endoribonuclease catalytic activity). However, most RNAs serve as messengers (mRNAs), and these are translated into polypeptides. The particular sequence of the ribonucleotides incorporated into an RNA as it is synthesized is dictated by the gene found in the genomic DNA from which it was transcribed. In the translation of an mRNA, the particular nucleotide sequence determines the particular amino acid sequence of the polypeptide translated therefrom. Briefly, in a coding region of an mRNA (and in its corresponding gene), each nucleotide triplet, or xe2x80x9ccodonxe2x80x9d (of which there are 43, or 64, possibilities) codes for one amino acid, except that three codons code for no amino acids (each being a xe2x80x9cstopxe2x80x9d translation codon). Thus, the sequence of codons (dictated by the nucleotide sequence of the corresponding gene) specifies the amino acid sequence of a particular protein, and it is the amino acid sequence that ultimately determines the three-dimensional structure of the protein. Significantly, three-dimensional structure dictates the particular biological function(s) of any biomolecule, including proteins.
The elegant simplicity of the foregoing schema is obscured by the complexity and size of the genomes found in living systems. For example, the haploid human genome comprises about 3xc3x97109 (three billion) nucleotides spread across 23 chromosomes. However, it is currently estimated that less than 5% of this encodes the approximately 80,000-100,000 different protein-coding genes believed to be encoded by the human genome. Because of its tremendous size, to date only a portion of the human genome has been sequenced and deposited in genome sequence databases, and the positions of many genes and their exact nucleotide sequences remain unknown. Moreover, the biological function(s) of the gene products encoded by many of the genes sequenced so far remain unknown. Similar situations exist with respect to the genomes of many other organisms.
Notwithstanding such complexities, numerous genome sequence efforts designed to determine the exact sequence of the nucleotides found in genomic DNA of various organisms are underway and significant progress has been made. For example, the Human Genome Project began with the specific goal of obtaining the complete sequence of the human genome and determining the biochemical function(s) of each gene. To date, the project has resulted in sequencing a substantial portion of the human genome, and is on track for its scheduled completion in the near future. At least twenty-one other genomes have already been sequenced, including, for example, M. genitalium, M. jannaschii, H. influenzae, E. coli, and yeast (S. cerevisiae). Significant progress has also been made in sequencing the genomes of model organisms, such as mouse, C. elegans, and D. melanogaster. Several databases containing genomic information annotated with some functional information are maintained by different organizations, and are accessible via the internet.
Such sequencing projects result in vast amounts of nucleotide sequence information, which is typically deposited in genome sequence databases. However, these raw data (much of it being known only at the cDNA level), being devoid of corresponding information about genes and protein structure or function, are in and of themselves of extremely limited use (Koonin, et al. (1998), Curr. Opin. Struct. Biol., vol. 8:355-363). Thus, the practical exploitation of the vast numbers of sequences in such genome sequence databases is crucially dependent on the ability to identify genes and, for example, the function(s) of gene-encoded proteins.
To maximize the utility of such nucleotide sequence information, it must be interpreted. For example, it is important to understand where each sequence is located in the genome, and what biological function(s), if any, the sequence encodes, i.e., what is the purpose of the sequence or, if transcribed (or transcribed and translated), the resulting product, in a biological system? For example, is the sequence a regulatory region or, if it is transcribed (or transcribed and translated), does the gene product bind to another molecule, regulate a cellular process, or catalyze a chemical reaction?
To answer these questions, significant effort has been directed towards understanding or describing the biological function(s) coded for in each nucleotide sequence. Predicting the function(s) of biomolecules encoded by genes, particularly proteins, is most often done by sequence comparison to known structures. The basis of this approach is the commonly accepted notion that similar sequences must have a common ancestor, and would therefore have similar structures and related functions. Accordingly, algorithms have been developed to analyze what a particular nucleotide sequence encodes, e.g., a regulatory region, an open reading frame (ORF), particularly for protein sequences, or a non-translated RNA. See, e.g., xe2x80x9cFramesxe2x80x9d (Genetics Computer Group, Madison, Wis.), which is used for identifying ORFs. For sequences predicted or determined to be ORFs, it is possible to determine the amino acid sequence of the protein encoded thereby using simple analytical tools well known in the art. For example, see xe2x80x9cTranslatexe2x80x9d (Genetics Computer Group, Madison, Wis.). However, to date determination of the primary structure of a protein in and of itself provides little, if any, functional information about the protein or its corresponding gene.
A number of methods have been developed in an attempt to glean functional information about a deduced amino acid sequence. The most common computational methods include sequence alignment and analysis of local sequence motifs, although these methods are limited by the extent of sequence similarity between sequences of unknown and known function. Additionally, these methods increasingly fail as sequence identity decreases. Other recently developed computational methods include whole genome comparison (Himmelreich et al., 1997), and analysis of gene clustering (Himmelreich et al., 1997; Tamames et al., 1997). Others have developed experimental methods to analyze protein function on a gemone-wide basis. These methods include, for example, xe2x80x9ctwo hybrid screensxe2x80x9d (Fromont-Racine et al., 1997) and genome-wide scanning of gene expression patterns (Ito and Sakaki, 1996).
Sequence alignment is the method most commonly used in attempts to identify protein function from amino acid sequence. In this method, the extent of amino acid sequence identity between an experimental sequence and one or more sequences whose function(s) is(are) known is computed. Alignment methods such as BLAST (Altschul et al., 1990), BLITZ (MPsrch) (Sturrock and Collins, 1993), and FASTA (Pearson and Lipman, 1988) are typically employed for this purpose. Assignment of function is based on the theory that significant sequence identity strongly predicts functional similarity (Fitch, 1970?).
However, because of the frequent lack of substantial sequence similarity among proteins, these methods often fail (Delseny et al., 1997; Dujon, 1996). Additionally, newly discovered amino acid or nucleotide sequences frequently do not match any known or available sequence. Indeed, many protein amino acid sequences (from 30-60% or more) that have been deduced from genome project-derived nucleotide sequence information represent novel protein families with unknown function, and for which no homologous sequence can be identified (Delseny et al., 1997; Dujon, 1996). Furthermore, such conventional sequence alignment methods cannot consistently detect functional and structural similarities, particularly when sequence identity is less than about 25-30%. Hobohm and Sander, 1995. In practice, roughly half of a given genome falls into one of these two categories or no homology, or less than about 25-30% homology, with a known sequence. Bork and Koonin (1998), Nature Genet., vol. 18: 313-318; E. V. Koonin (1997), Curr. Biol., vol. 7:R656-R659. It is also important to understand that matches with 50% or more identity over a 40-amino acid or smaller stretch of sequences often occur by chance, and if other information is lacking, relationships between such proteins are viewed with caution (Pearson, 1996).
In an attempt to overcome some of the problems associated with employing sequence alignments to help predict protein function, several groups have developed databases of short, local sequence patterns (or xe2x80x9cmotifsxe2x80x9d) designed to help identify a given function or activity of a protein. These databases, notably xe2x80x9cPROSITExe2x80x9d (Bairoch et at., 1997, Nuci. Acid Res., vol. 25:31-36), xe2x80x9cBlocksxe2x80x9d (Henikoff and Henikoff, 1994, Genomics, vol. 19:97-107), and xe2x80x9cPRINTSxe2x80x9d (Attwood and Beck, 1994, Nuci. Acids Res., vol. 22:3590-3596), use local sequence information (i.e., the sequence of several contiguous amino acid residues), as opposed to entire amino acid sequences, in order to try to identify sequence patterns that are specific for a given function.
Function prediction based on local sequence signatures, however, is plagued by the deficiencies that also limit the use of sequence alignment algorithms to predict protein function. Specifically, as sequence diversity within protein families increases, conventional databases of local sequence signatures may no longer recognize experimental protein sequences as belonging to a functional family (Fetrow and Skolnick, 1998, J. Mol. Biol., vol. 281:949-968). In proteins that are distantly related in terms of evolution, it is expected that only those residues required for the specific biological function of a protein will be conserved. That conservation will include not only sequence conservation, but also three-dimensional structural conservation (Holm and Sander, 1994, Proteins, vol. 19:165-173). However, local sequence motifs cannot recognize conserved three-dimensional structurexe2x80x94motifs can only recognize local sequence. Consequently, local sequence motifs may fail to be accurate predictors of protein function because function derives from three-dimensional structure. In other words, local sequence motif analysis is limited where function is dependent upon non-local residues, i.e., amino acids disposed in different regions of a protein""s primary structure.
Many functional sites in proteins are known to comprise non-local residues. However, these residues are brought into functional association as a result of the protein assuming its folded three-dimensional structure, where different regions of the protein (in terms of linear amino acid sequence) may come together. For example, the three-dimensional structure of urease (a protein involved in nucleotide metabolism) was recently compared to those of adenosine deaminase and phosphotriesterase (Holm and Sander, 1997b), proteins that are also involved in nucleotide metabolism. Previous one-dimensional sequence comparisons failed to detect any relationship between these proteins; however, comparison of their three-dimensional structures showed conservation of active site structure. This same active site geometry was later observed in other nucleotide metabolism enzymes which exhibited an even greater diversity of overall sequence and tertiary structure (Holm and Sander, 1997b). In another example, it was determined that critical cysteine residues in the catalytic domain of ribonucleotide reductases were conserved across kingdom boundaries (Tauer and Benner, 1997). However, sequence alignment analysis did not reveal this relatedness because of the non-local nature of the conserved catalytic cysteine residues.
Various efforts have been made to overcome these limitations by, for example, extending local sequence patterns to include structural information. The goal of including such added information is to improve the ability of local sequence patterns to both detect distantly related proteins and differentiate between true and false positives. See, e.g., Kasuya, A. and Thornton, J. M., J. Mol. Biol., vol. 286: 1673-1691 (1999). Others have postulated that the development of databases of 3D-templates, such as those that currently exist for local protein sequence motifs, may help to identify the functions of new protein structures as they are determined and pinpoint their functionally important regions. For example, Wallace, et al. (Protein Science, vol. 5:1001-1013 (1996)) reported the development of a 3D coordinate template for Ser-His-Asp the catalytic triad in serine proteases and triacylglycerol lipases. Initially, those authors selected a single xe2x80x9cseedxe2x80x9d catalytic triad from xcex1-lyitc proteinase 1lpr (see Bone, et al., Biochemistry, vol. 30:10388-10398 (1991)), and coordinate positions were determined for all of the Ser and Asp side chain atoms, as well as for the positions of the atoms in the reference His residue. Root mean square distances (RMSDs) were then determined for all Ser and Asp side chain atoms in a set of serine proteases whose structures were also then known at atomic resolution. This analysis revealed that the positioning of a single oxygen atom in each of the Asp and Ser side chains was highly conserved. Using these data, a 3D template was developed for serine protease activity using the identity of three amino acids, namely Ser, His, and Asp, and the 3D coordinate positions (to an RMSD cut-off of 2 xc3x85) for the functional oxygen atoms in the Ser and Asp side chains and the non-hydrogen atoms of the His side chain. The 3D template was then applied to a test set of high resolution protein structures drawn from the PDB database.
A major shortcoming of the foregoing 3D-template approach (see also Barth, et al. (1993) Drug Design and Discovery, vol. 10:297-317; Gregory, et al. (1993), Protein Eng., vol. 6, no. 1:29-35; Artymiuk, et al. (1994), J. Mol. Biol., vol. 243:327-344; and Fischer, et al. (1994), Protein Sci., vol. 3:769-778), however, is that they require detailed knowledge of atomic positions (particularly for side chain atoms) in both the template structures and the test protein structure. This makes these 3D templates applicable only to high-resolution protein structures determined by x-ray crystallography or NMR spectroscopy. Less than atomic resolution structures and inexact models produced by current protein structure prediction algorithms cannot be analyzed by these methods.
In sum, conventional sequence-based function prediction methods fall short in the prediction of protein function from nucleotide or amino acid sequence information, in part because the technology frequently relies only on sequence information. Current structure-based methods said to have some utility for function prediction also fail in the analysis of sequences of unknown function, including genome sequences, because high-resolution structures, and their accompanying high level of atomic detail, are required. As such, there remains a need for better methods for predicting protein structure and function.
The inventions described and claimed herein solve these needs by providing novel methods and systems for predicting protein function from sequence. Various methods described and claimed herein use sequence and structure information and apply this information to protein structures, particularly inexact models of protein structure, that can be computationally derived from protein or nucleic acid sequences. Using their methods, the inventors have discovered that it is not necessary to accurately predict the overall three-dimensional structure of a particular protein of interest in order to predict its function. Instead, prediction of biological function using the methods described and claimed herein requires only an approximation of the three-dimensional orientation of two or more amino acid residues in a region responsible for the particular function of the protein under investigation. As such, this invention overcomes the problems and limitations of the methods previously utilized in an attempt to identify protein function from either sequence or structure. As those in the art will appreciate, such methods can routinely be adapted with respect to various protein functional sites in order to predict protein function. A more detailed description of the invention is provided below.
3. Definitions
The following terms have the following meanings when used herein and in the appended claims. Terms not specifically defined herein have their art recognized meaning.
As used herein, an xe2x80x9camino acidxe2x80x9d is a molecule (see FIG. 1) having the structure wherein a central carbon atom (the alpha (xcex1)-carbon atom) is linked to a hydrogen atom, a carboxylic acid group (the carbon atom of which is referred to herein as a xe2x80x9ccarboxyl carbon atomxe2x80x9d), an amino group (the nitrogen atom of which is referred to herein as an xe2x80x9camino nitrogen atomxe2x80x9d), and a side chain group, R. When incorporated into a peptide, polypeptide, or protein, an amino acid loses one or more atoms of its amino and carboxylic groups in the dehydration reaction that links one amino acid to another. As a result, when incorporated into a protein, an amino acid is referred to as an xe2x80x9camino acid residue.xe2x80x9d In the case of naturally occurring proteins, an amino acid residue""s R group differentiates the 20 amino acids from which proteins are synthesized, although one or more amino acid residues in a protein may be derivatized or modified following incorporation into protein in biological systems (e.g., by glycosylation and/or by the formation of cystine through the oxidation of the thiol side chains of two non-adjacent cysteine amino acid residues, resulting in a disulfide covalent bond that frequently plays an important role in stabilizing the folded conformation of a protein, etc.). As those in the art will appreciate, non-naturally occurring amino acids can also be incorporated into proteins, particularly those produced by synthetic methods, including solid state and other automated synthesis methods. Examples of such amino acids include, without limitation, xcex1-amino isobutyric acid, 4-amino butyric acid, L-amino butyric acid, 6-amino hexanoic acid, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norlensine, norvaline, hydroxproline, sarcosine, citralline, cysteic acid, t-butylglyine, t-butylalanine, phenylylycine, cyclohexylalanine, xcex2-alanine, fluoro-amino acids, designer amino acids (e.g., xcex2-methyl amino acids, xcex1-methyl amino acids, Nxcex1-methyl amino acids) and amino acid analogs in general. In addition, when an xcex1-carbon atom has four different groups (as is the case with the 20 amino acids used by biological systems to synthesize proteins, except for glycine, which has two hydrogen atoms bonded to the xcex1 carbon atom), two different enantiomeric forms of each amino acid exist, designated D and L. In mammals, only L-amino acids are incorporated into naturally occurring polypeptides. Of course, the instant invention envisions proteins incorporating one or more D- and L- amino acids, as well as proteins comprised of just D- or L-amino acid residues.
Herein, the following abbreviations may be used for the following amino acids (and residues thereof): alanine (Ala, A); arginine (Arg, R); asparagine (Asn, N); aspartic acid (Asp, D); cyteine (Cys, C); glycine (Gly, G); glutamic acid (Glu, E); glutamine (Gln, Q); histidine (His, H); isoleucine (Ile, I); leucine (Leu, L); lysine (Lys, K); methionine (Met, M); phenylalanine (Phe, F); proline (Pro, P); serine (Ser, S); threonine (Thr, T); tryptophan (Trp, W); tyrosine (Tyr, Y); and valine (Val, V). Non-polar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionines. Neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, esparagine, and glutamine. Positively charged (basic amino acids include arginine, lysine and histidine. Negatively charged (acidic) amino acids include aspartic acid and glutamic acid.
As used herein, a xe2x80x9cxcex2-carbon atomxe2x80x9d refers to the carbon atom (if present) in the R group of the side chain of an amino acid (or amino acid residue) that is covalently bonded to the xcex1-carbon atom of that amino acid (or residue). See FIG. 1. For purposes of this invention, glycine is the only naturally occurring amino acid found in mammalian proteins that does not contain a xcex2-carbon atom.
A xe2x80x9cbiomoleculexe2x80x9d refers to any molecule (including synthetic molecules) produced by a cell, found within a cell or organism, or which can be introduced into a cell or organism, or any derivative of such a molecule, and any other molecule capable of performing or having a biological function. Representative examples of biomolecules include nucleic acids and proteins. A xe2x80x9csyntheticxe2x80x9d biomolecule is one that has been prepared, in whole or part, through the use of one or more synthetic chemical reactions.
xe2x80x9cProteinxe2x80x9d refers to any polymer of two or more individual amino acids (whether or not naturally occurring) linked via a peptide bond, and occurs when the carboxyl carbon atom of the carboxylic acid group bonded to the xcex1-carbon of one amino acid (or amino acid residue) becomes covalently bound to the amino nitrogen atom of amino group bonded to the xcex1-carbon of an adjacent amino acid. See FIG. 1. These peptide bond linkages, and the atoms comprising them (i.e., xcex1-carbon atoms, carboxyl carbon atoms (and their substituent oxygen atoms), and amino nitrogen atoms (and their substituent hydrogen atoms)) form the xe2x80x9cpolypeptide backbonexe2x80x9d of the protein. In simplest terms, the polypeptide backbone shall be understood to refer the amino nitrogen atoms, xcex1-carbon atoms, and carboxyl carbon atoms of the protein, although two or more of these atoms (with or without their substituent atoms) may also be represented as a pseudoatom. Indeed, any representation representing a polypeptide backbone that can be used in a functional site descriptor as described herein will be understood to be included within the meaning of the term xe2x80x9cpolypeptide backbone.xe2x80x9d
The term xe2x80x9cproteinxe2x80x9d is understood to include the terms xe2x80x9cpolypeptidexe2x80x9d and xe2x80x9cpeptidexe2x80x9d (which, at times, may be used interchangeably herein) within its meaning. In addition, proteins comprising multiple polypeptide subunits (e.g., DNA polymerase III, RNA polymerase II) or other components (for example, an RNA molecule, as occurs in telomerase) will also be understood to be included within the meaning of xe2x80x9cproteinxe2x80x9d as used herein. Similarly, fragments of proteins and polypeptides are also within the scope of the invention and may be referred to herein as xe2x80x9cproteins.xe2x80x9d
In biological systems (be they in vivo or in vitro, including cell-free, systems), the particular amino acid sequence of a given protein (i.e., the polypeptide""s xe2x80x9cprimary structure,xe2x80x9d when written from the amino-terminus to carboxy-terminus) is determined by the nucleotide sequence of the coding portion of a mRNA, which is in turn specified by genetic information, typically genomic DNA (which, for purposes of this invention, is understood to include organelle DNA, for example, mitochondrial DNA and chloroplast DNA). Of course, any type of nucleic acid which constitutes the genome of a particular organism (e.g., double-stranded DNA in the case of most animals and plants, single or double-stranded RNA in the case of some viruses, etc.) is understood to code for the gene product(s) of the particular organism. Messenger RNA is translated on a ribosome, which catalyzes the polymerization of a free amino acid, the particular identity of which is specified by the particular codon (with respect to mRNA, three adjacent A, G, C, or U ribonucleotides in the mRNA""s coding region) of the mRNA then being translated, to a nascent polypeptide. Recombinant DNA techniques have enabled the large-scale synthesis of polypeptides (e.g., human insulin, human growth hormone, erythropoietin, granulocyte colony stimulating factor, etc.) having the same primary sequence as when produced naturally in living organisms. In addition, such technology has allowed the synthesis of analogs of these and other proteins, which analogs may contain one or more amino acid deletions, insertions, and/or substitutions as compared to the native proteins. Recombinant DNA technology also enables the synthesis of entirely novel proteins.
In non-biological systems (e.g., those employing solid state synthesis), the primary structure of a protein (which also includes disulfide (cystine) bond locations) can be determined by the user. As a result, polypeptides having a primary structure that duplicates that of a biologically produced protein can be achieved, as can analogs of such proteins. In addition, completely novel polypeptides can also be synthesized, as can protein incorporating non-naturally occurring amino acids.
In a protein, the peptide bonds between adjacent amino acid residues are resonance hybrids of two different electron isomeric structures, wherein a bond between a carbonyl carbon (the carbon atom of the carboxylic acid group of one amino acid after its incorporation into a protein) and a nitrogen atom of the amino group of the xcex1-carbon of the next amino acid places the carbonyl carbon approximately 1.33 xc3x85 away from the nitrogen atom of the next amino acid, a distance about midway between the distances that would be expected for a double bond (about 1.25 xc3x85) and a single bond (about 1.45 xc3x85). This partial double bond character prevents free rotation of the carbonyl carbon and amino nitrogen about the bond therebetween under physiological conditions. As a result, the atoms bonded to the carbonyl carbon and amino nitrogen reside in the same plane, and provide discrete regions of structural rigidity, and hence conformational predictability, in proteins.
Beyond the peptide bond, each amino acid residue contributes two additional single covalent bonds to the polypeptide chain. While the peptide bond limits rotational freedom of the carbonyl carbon and the amino nitrogen of adjacent amino acids, the single bonds of each residue (between the xcex1-carbon and carbonyl carbon (the phi (xcfx86) bond) and between the xcex1-carbon and amino nitrogen (the psi ("psgr") bond) of each amino acid), have greater rotational freedom. For example, the rotational angles for xcfx86 and "psgr" bonds for certain common regular secondary structures are listed in the following table:
Similarly, the single bond between a xcex1-carbon and its attached R-group provides limited rotational freedom. Collectively, such structural flexibility enables a number of possible conformations to be assumed at a given region within a polypeptide. As discussed in greater detail below, the particular conformation actually assumed depends on thermodynamic considerations, with the lowest energy conformation being preferred.
In addition to primary structure, proteins also have secondary, tertiary, and, in multisubunit proteins, quaternary structure. Secondary structure refers to local conformation of the polypeptide chain, with reference to the covalently linked atoms of the peptide bonds and xcex1-carbon linkages that string the amino acids of the protein together. Side chain groups are not typically included in such descriptions. Representative examples of secondary structures include xcex1 helices, parallel and anti-parallel xcex2 structures, and structural motifs such as helix-turn-helix, xcex2-xcex1-xcex2, the leucine zipper, the zinc finger, the xcex2-barrel, and the immunoglobulin fold. Movement of such domains relative to each other often relates to biological function and, in proteins having more than one function, different binding or effector sites can be located in different domains. Tertiary structure concerns the total three-dimensional structure of a protein, including the spatial relationships of amino acid side chains and the geometric relationship of different regions of the protein. Quaternary structure relates to the structure and non-covalent association of different polypeptide subunits in a multisubunit protein.
A xe2x80x9cfunctional sitexe2x80x9d refers to any site in a protein that has a function. Representative examples include active sites (i.e., those sites in catalytic proteins where catalysis occurs), protein-protein interaction sites, sites for chemical modification (e.g., glycosylation and phosphorylation sites), and ligand binding sites. Ligand binding sites include, but are not limited to, metal binding sites, co-factor binding sites, antigen binding sites, substrate channels and tunnels, and substrate binding sites. In an enzyme, a ligand binding site that is a substrate binding site may also be an active site.
A xe2x80x9cpseudoatomxe2x80x9d refers to a position in three dimensional space (represented typically by an x, y, and z coordinate set) that represents the average (or weighted average) position of two or more atoms in a protein or amino acid. Representative examples of a pseudoatom include an amino acid side chain center of mass and the center of mass (or, alternatively, the average position) of an xcex1-carbon atom and the carboxyl atom bonded thereto.
A xe2x80x9creduced modelxe2x80x9d refers to a three-dimensional structural model of a protein wherein fewer than all heavy atoms (e.g., carbon, oxygen, nitrogen, and sulfur atoms) of the protein are represented. For example, a reduced model might consist of just the xcex1-carbon atoms of the protein, with each amino acid connected to the subsequent amino acid by a virtual bond. Other examples of reduced protein models include those in which only the xcex1-carbon atoms and side chain centers of mass of each amino acid are represented, or where only the polypeptide backbone is represented.
A xe2x80x9cgeometric constraintxe2x80x9d refers to a spatial representation of an atom or group of atoms (e.g., an amino acid, the R-group of an amino acid, the center of mass of an R-group of an amino acid, a pseudoatom, etc.). Accordingly, such a constraint can be represented by coordinates in three dimensions, for example, as having a certain position, or range of positions, along x, y, and z coordinates (i.e., a xe2x80x9ccoordinate setxe2x80x9d). Alternatively, a geometric constraint can be represented as a distance, or range of distances, between a particular atom (or group of atoms, etc.) and one or more other atoms (or groups of atoms, etc.). Geometric constraints can also be represented by various types of angles, including the angle of bonds (particularly covalent bonds, e.g., xcfx86 bonds and "psgr" bonds) between atoms in an amino acid residue, between atoms in different amino acid residues, and between atoms in an amino acid residue of a protein and another molecule, e.g., a ligand, with ranges for each angle being preferred.
A xe2x80x9cconformational constraintxe2x80x9d refers to the presence of a particular protein conformation, for example, an xcex1-helix, parallel and antiparallel xcex2 strands, leucine zipper, zinc finger, etc. In addition, conformational constraints can include amino acid sequence information without additional structural information. As an example, xe2x80x9cxe2x80x94Cxe2x80x94Xxe2x80x94Xxe2x80x94Cxe2x80x94xe2x80x9d is a conformational constraint indicating that two cysteine residues must be separated by two other amino acid residues, the identities of each of which are irrelevant in the context of this particular constraint.
An xe2x80x9cidentity constraintxe2x80x9d refers to a constraint of a functional site descriptor that indicates the identity of an amino acid residue at a particular location in a protein. (determined by counting the number of amino acid residues in the protein from its amino terminus up to and including the residue in question). As those in the art will appreciate, comparison between related proteins may reveal that the identity of a particular amino acid residue at a given amino acid position in a protein is not entirely conserved, i.e., different amino acid residues may be present at a particular amino acid position in related proteins. In such instances or, alternatively, when an artisan desires to relax the constraint, two or more alternative amino acid residue identities can be provided for a particular identity constraint of a functional site descriptor. Of course, in such cases the invention also envisions different functional site descriptors for the particular biological function that differ by employing different amino acid residue identities (or sets of identities) for the corresponding position. For example, where it is determined by sequence alignment that related proteins have one of two amino acid residues at a particular position in the functional site, a single functional site descriptor therefor may specify the two alternatives. Alternatively, two different functional site descriptors may be generated that differ only with respect to the identity constraint at that position. Similar strategies can be employed with regard to other constraints used in a functional site descriptor according to the invention.
To xe2x80x9crelaxxe2x80x9d a constraint refers to the inclusion of a user-defined variance therein. The degree of relaxation will depend on the particular constraint and its application. As those in the art will appreciate, functional site descriptors for the same biological function can be developed wherein different degrees of relaxation for one or more constraints are what differentiate one such descriptor from another.
Protein structures useful in the practice of the invention can be of different quality. The highest quality determination methods are experimental structure prediction methods based on x-ray crystallography and NMR spectroscopy. In x-ray crystallography, xe2x80x9chigh resolutionxe2x80x9d structures are those wherein atomic positions are determined at a resolution of about 2 xc3x85 or less, and enable the determination of the three-dimensional positioning of each atom (or each non-hydrogen atom) of a protein. xe2x80x9cMedium resolutionxe2x80x9d structures are those wherein atomic positioning is determined at about the 2-4 xc3x85 level, while xe2x80x9clow resolutionxe2x80x9d structures are those wherein the atomic positioning is determined in about the 4-8 xc3x85 range. Herein, protein structures that have been determined by x-ray crystallography or NMR may be referred to as xe2x80x9cexperimental structures,xe2x80x9d as compared to those determined by computational methods, i.e., derived from the application of one or more computer algorithms to a primary amino acid sequence to predict protein structure.
As alluded to above, protein structures can also be determined entirely by computational methods, including, but not limited to, homology modeling, threading, and ab initio methods. Often, models produced by such computational methods are xe2x80x9creducedxe2x80x9d models, i.e., the predicted structures (or xe2x80x9cmodelsxe2x80x9d) do not include all non-hydrogen atoms in the protein. Indeed, many reduced models only predict structures that show the polypeptide backbone of the protein, and such models are preferred in the practice of the invention. Of course, it is understood that once a protein structure based on a reduced model has been generated, all or a portion of it may be further refined to include additional predicted detail, up to including all atom positions.
Computational methods usually produce lower quality structures than experimental methods, and the models produced by computational methods are often called xe2x80x9cinexact models.xe2x80x9d While not necessary in order to practice the instant methods the precision of these predicted models can be determined using a benchmark set of proteins whose structures are already known. The predicted model for each biomolecule may then be compared to a corresponding experimentally determined structure. The difference between the predicted model and the experimentally determined structure is quantified via a measure called xe2x80x9croot mean square deviationxe2x80x9d (RMSD). A model having an RMSD of about 2.0 xc3x85 or less as compared to a corresponding experimentally determined structure is considered xe2x80x9chigh qualityxe2x80x9d. Frequently, predicted models have an RMSD of about 2.0 xc3x85 to about 6.0 xc3x85 when compared to one or more experimentally determined structures, and are called xe2x80x9cinexact modelsxe2x80x9d. As those in the art will appreciate, RMSDs can also be determined for one or more atomic positions when two or experimental structures have been generated for the same protein.
The object of this invention is to enable one or more functions of a protein to be predicted from structural information, for example, from computationally derived models of protein structure (including inexact models) produced from deduced primary amino acid sequences, for example, as may be derived from nucleotide sequence of a novel gene obtained in the course of genome sequencing projects.
The present invention comprises a number of objects, aspects, and embodiments.
One aspect of the invention concerns functional site descriptors (FSDS) that define spatial configurations for protein functional sites that correspond with particular biological functions. It is known that function derives from structure. A functional site descriptor according to the invention provides three-dimensional representation of protein functional site. In some embodiments, the functional site represented by an FSD is a ligand binding domain (e.g., a domain that binds a ligand, for example, a substrate, a co-factor, or an antigen), while in other embodiments, the functional site is a protein-protein interaction site or domain. In certain preferred embodiments, the functional site is an enzymatic active site. Particularly preferred embodiments concern functional sites other than a divalent metal ion binding site.
A functional site descriptor typically comprises a set of geometric constraints for one or more atoms in each of two or more amino acid residues comprising a functional site of a protein. Preferably, at least one of said two or more amino acid residues is also identified as a particular amino acid residue or set of amino acid residues. In preferred embodiments, the said one or more atoms is selected from the group consisting of amide nitrogens, xcex1-carbons, carbonyl carbons, and carbonyl oxygens within a polypeptide backbone, xcex2-carbons of amino acid residues, and pseudoatoms. In particularly preferred embodiments, at least one of said one or more atoms is an amide nitrogen, an xcex1-carbon, a xcex2-carbon, or a carbonyl oxygen within a polypeptide backbone.
In certain embodiments, a functional site descriptor represents 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues (or sets of residues) that comprise the corresponding the functional site. While an FSD may include one or more identity constraints with respect to any amino acid, such constraints preferably make reference to naturally occurring amino acids, particularly naturally occurring L amino acids, including those selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.
The geometric constraints of an FSD preferably are selected from the group consisting of an atomic position specified by a set of three dimensional coordinates, an interatomic distance (or range of interatomic distances), and an interatomic bond angle (or range of interatomic bond angles). When a geometric constraint refers to atomic position, reference is typically made to a set of three dimensional coordinates. Such constraints preferably relate to RMSDs, particularly those that allow the atomic position to vary within a preselected RMSD, for example, by an amount of less than about 3 xc3x85, less than about 2.5 xc3x85, less than about 2.0 xc3x85, less than about 1.5 xc3x85, and less than about 1.0 xc3x85.
Other geometric constraints concern interatomic distances, preferably interatomic distance ranges, or interatomic bond angles range preferably interatomic bond angle ranges.
In some embodiments, an FSD can also include one or more conformational constraints that refer to the presence of a particular secondary structure, for example, a helix, or location, for example, near the amino or carboxy terminus of a protein.
In preferred embodiments, an FSD refers to at least one atom from each of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues that comprise the corresponding functional site. In many embodiments, all of the atoms for which geometric constraints are provided comprise a part of the polypeptide backbone and are selected from the group consisting of xcex1-carbons, amide nitrogens, carbonyl carbons, and carbonyl oxygens. Of course, one or more of such atoms can be a pseudoatom. Representative examples of pseudoatoms are centers of mass, such as may be derived from at least two atoms, such as two or more atoms from one amino acid residue or two or more atoms from at least two amino acid residues of the protein.
Particularly preferred FSDs are those comprising multiple geometric constraints. Representative examples of such FSDs are a three atom functional site descriptor, a four atom functional site descriptor, a five atom functional site descriptor, a six atom functional site descriptor, a seven atom functional site descriptor, an eight atom functional site descriptor, a nine atom functional site descriptor, a ten atom functional site descriptor, an eleven atom functional site descriptor, a twelve atom functional site descriptor, a thirteen atom functional site descriptor, a fourteen atom functional site descriptor, and a fifteen atom functional site descriptor.
Preferably, FSDs according to the invention are implemented in electronic form.
Certain embodiments of the invention also concern libraries of FSDs, in electronic or other form. Preferably, such a library comprises at least two functional site descriptors for at least one of the biological functions represented by the library.
Another aspect of the invention concerns methods of identifying a protein as having a particular biological function. Such methods may also be referred to as function screening methods. Typically, such methods comprise applying a functional site descriptor according to the invention to a structure of a protein and determining whether the protein has the biological function. This determination is made if application of the functional site descriptor reveals that a portion of the structure of the protein matches, or satisfies, the constraints of the functional site descriptor.
In some embodiments of such methods, the structure(s) to which one or more FSDs is(are) applied is(are) of high resolution. High resolution structures can be obtained by a variety of methods, including x-ray crystallography and nuclear magnetic resonance.
Preferred embodiments involve application of one or more FSDs to predicted protein structures, especially inexact, three dimensional structural protein models. Such models can be generated by a variety of techniques, including by application of an ab initio folding program, a threading program, or a homology modeling program.
FSDs can be applied to a protein structures derived from any organism, be they prokaryotic or eukaryotic. Prokaryotic organisms the proteins of which may be screened according to the instant methods include bacteria. Eukaryotic organisms include plants and animals, particularly those of medical or agricultural import. A representative class is mammals, including bovine, canine, equine, feline, ovine, porcine, and primate animals, as well as humans. The methods may also be applied to study viral protein function.
In certain embodiments, the methods of the invention are practiced using plurality of functional site descriptors and/or
a plurality of proteins structures, of the same or different proteins, preferably to a plurality of structures for a plurality of proteins.
Another aspect of the invention concerns methods of making FSDs for functional sites of proteins (other than divalent metal ion binding sites), which FSDs can then be applied to inexact, three dimensional structural proteins models.
Yet another aspect concerns computer program products comprising a computer useable medium having computer program logic recorded thereon for creating a functional site descriptor for use in predicting a biological function of a protein. Such computer program logic preferably comprises computer program code logic configured to perform a series of operations, including determining a set of geometric constraints for a functional site associated with a biological function of a protein; modifying one or more geometric constraints of said set of geometric constraints to produce a modified set of geometric constraints; comparing said modified set of geometric constraints to a data set of functional sites correlated with said biological function to determine whether said modified set of geometric constraint compares favorably with said data set of functional sites correlated with said biological function and, if so; comparing said modified set of geometric constraint(s) to a data set of functional sites not correlated with said biological function to determine whether said modified set of geometric constraints compares favorably with said data set of functional sites not correlated with said biological function and, if so; repeating said modifying and comparing operations to modify one or more of said geometric constraints of said set of geometric constraints to an extent that said modified set of geometric constraints compares favorably with said data set of functional sites correlated with said biological function without encompassing a predetermined amount of data sets not correlated with said biological function.
In preferred embodiments, the operation of determining a set of geometric constraints of a functional site correlated with a biological function of a protein comprises receiving said set of geometric constraints from at least one of the group of a data set of predetermined geometric constraints or from user input. When modifying one or more geometric constraints of said set of geometric constraints to produce a modified set of geometric constraints, a predetermined variance can be associated with one or more of the geometric constraints to adjust the same.
In preferred embodiments, the operation of modifying one or more geometric constraints of said set of geometric constraints to produce a modified set of geometric constraints comprises computing an average value for a geometric constraint within the set of geometric constraints by determining values for said geometric constraint from two different proteins having functional sites that correlate with said biological function, and calculating said average value; computing a standard deviation with respect to such geometric constraint; and applying a multiplier to said computed standard deviation to generate said modified geometry.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
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{
"pile_set_name": "USPTO Backgrounds"
}
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1. Field of the Invention
The present invention relates to a motion picture encoding device and associated motion picture encoding processing program which compresses motion images in view of human visual characteristics.
2. Description of the Related Art
In applications, such as digital television broadcasting, Internet video streaming, DVD, etc., a coding technique with a high compression ratio is required because transmission bandwidth and storage capacity are limited. For instance, an H.264 standard is known as a high compression coding technique which meets such a requirement. Hereinafter, an example of a motion picture encoding device based on the H.264 standard will be described with reference to FIG. 9˜FIG. 15.
FIG. 9 is a block diagram showing an outline configuration of a motion picture encoding device. A subtracter 10 generates a prediction error signal indicating luminance difference by subtracting the prediction block pixel value from the current block pixel value. A quantization/transform section 11 applies integer DCT (Discrete Cosine Transform) to the prediction error signal outputted from the subtracter 10 and a transform coefficient is obtained. Furthermore, this transform coefficient is quantized with a predetermined quantization width and coefficient data is generated. An entropy encoder section 12 performs entropy encoding of the coefficient data generated by the quantization/transform section 11 with Exponential-Golomb codes based on Variable Length Codes (VLC) and applies CABAC (Context-based Adaptive Binary Arithmetic Coding).
An inverse quantization/inverse transform section 13, an adder 14, a loop filter 15 and a frame memory 16 form a local decoding portion. The local decoding portion applies inverse quantization and inverse integer DCT to the coefficient data generated in the quantization/transform section 11, adds the previous prediction block pixel value and generates a decoded image. Further, after the local decoding portion reduces block noise by performing loop filtering to the generated decoded image, it is temporarily stored in the frame memory 16. An intra-frame prediction section 17 calculates the intra-frame prediction block value using the decoded image read out from the frame memory 16.
A motion detection section 18 detects the motion vector of the current block. A motion compensation section 19 calculates the inter-frame prediction block value by performing motion compensation to the reference frame (decoded image read out from the frame memory 16) corresponding to the motion vector detected by the motion detection section 18. A selector 20 selects either the intra-frame prediction block value calculated by the intra-frame prediction section 17 or the inter-frame prediction block value calculated by the motion compensation section 19 corresponding to instructions of a determination section 21 and provides the respective value to the subtracter 10. The determination section 21 estimates the amount of coded data at the time of intra-frame predictive coding as well as the amount of coded data of inter-frame predictive coding and directs the selector 20 to select the coding mode with the smaller amount of coded data.
Next, the operations of the encoding determination processing of the motion picture encoding device according to the above-mentioned configuration will be explained with reference to FIGS. 10 through 15. In the following, after first explaining the operations of the “encoding determination processing”, the separate operations of the “inter-prediction processing”, the “intra-prediction processing” and the “inter D&Q processing” which encompass the encoding determination processing will be outlined.
(1) Operations of the Encoding Determination Processing
FIG. 10 is a flow chart showing operations of the encoding determination processing executed for each input macroblock. This processing is initiated by inputting a 16×16 macroblock image (hereinafter, denoted as “input macroblock”). In Step SF1, each section of the device is initialized. Secondly, in Step SF2, the amount of coded data at the time of inter-frame predictive coding is estimated by the execution of inter-prediction processing. Next, in Step SF3, the amount of coded data for intra-frame predictive coding is estimated and further intra-frame coding (integer DCT, quantization, inverse quantization and inverse integer DCT) is performed by the execution of intra-prediction processing. Then, in Step SF4, the minimum Sum of Absolute Differences SADinter (this is equivalent to the amount of coded data at inter-prediction) obtained in the above-mentioned Step SF2 is judged as to whether or not greater than the minimum Sum of Absolute Differences SADintra (this is equivalent to the amount of coded data at intra-prediction) obtained in the above-mentioned Step SF3.
When the amount of coded data at inter-prediction is greater than the amount of coded data at intra-prediction, the judgment result becomes “YES” and completes this processing. Accordingly, in this case the motion picture encoding device performs video compression with the intra-frame coding executed in the above-mentioned Step SF3.
Conversely, when the amount of coded data at the time of inter-prediction is less than the amount of coded data at the time of intra-prediction, the judgment result of the above-mentioned Step SF4 becomes “NO” and the flow advances to Step SF5, which executes inter D&Q processing to perform inter-frame coding (integer DCT, quantization, inverse quantization and inverse integer DCT). Accordingly, in this case the motion picture encoding device performs video compression with inter-frame coding.
(2) Operations of the Inter-Prediction Processing
Next, the operations of the inter-prediction processing will be explained with reference to FIGS. 11 through 13. When processing has been executed via the above-mentioned Step SF2 (refer to FIG. 10), the flow advances to Step SG1 shown in FIG. 11 and judges whether or not processing has been completed for all of the 4×4 pixel blocks of a 16×16 pixel macroblock partitioned into 16 sub-macroblocks. When processing for all the blocks has been completed, the judgment result becomes “YES” and this processing is completed. Otherwise, the judgment result becomes “NO” and the flow advances to Step SG2.
Additionally, with regard to the association between a 16×16 pixel macroblock and the 4×4 pixel blocks, as illustrated in FIG. 13, the 4×4 pixel blocks within the macroblock are denoted by the block number n.
Next, in Step SG2, a 4×4 pixel block processing object (hereinafter, denoted as the “current block”) pixel value Org is calculated. Subsequently, in Step SG3, MV search processing is executed which searches for a motion vector (MV). In the MV search processing, as shown in Steps SH1˜SH3 of FIG. 12, correlation of the current block is calculated while shifting pixels in the center of the reference block within a search region of the reference frame. Amongst those pixels, the pixel position with the highest correlation (similarity) is extracted as the best motion vector.
MV search processing estimates the correlation of the reference block and the current block with the Sum of Absolute Differences SAD between both blocks. Accordingly, when the pixel position of the highest correlation is extracted as the motion vector, the Sum of Absolute Differences SAD represents the minimum. The minimum Sum of Absolute Differences SADinter is used for Step SF4 (refer to FIG. 10) for judging whether or not to execute inter D&Q processing.
(3) Operations of the Intra-Prediction Processing
Next, the operations of the intra-prediction processing will be explained with reference to FIG. 14. When inter-prediction processing has been executed via Step SF3 mentioned above (refer to FIG. 10), the flow advances to Step SJ1 shown in FIG. 14. In Step SJ1, whether or not processing has been completed for all 4×4 pixel blocks of a 16×16 pixel macroblock partitioned into 16 sub-macroblocks is judged. When processing for all the blocks has been completed, the judgment result becomes “YES” and this processing is completed. Otherwise, the judgment result becomes “NO” and the flow advances to Step SJ2. In Step SJ2, for example in intra 4×4 mode, a prediction block value for each mode amongst a total of nine optional prediction modes is calculated, which are referred to as mode0˜mode8.
Subsequently, in Steps SJ3˜SJ5, the current block Sum of Absolute Differences SAD and the prediction block value for each of the above-mentioned modes is calculated, respectively, and the minimum Sum of Absolute Differences SADintra is obtained from within these results. The minimum Sum of Absolute Differences SADintra is used for Step SF4 (refer to FIG. 10) for judging whether or not to execute inter D&Q processing.
When the minimum Sum of Absolute Differences SAD has been determined, the judgment result in Step SJ3 becomes “YES” and the flow advances to Step SJ6. In Step SJ6, intra-frame coding of the current block is performed using the mode which produces the minimum Sum of Absolute Differences SADintra. Hereinafter, the above-mentioned Steps SJ1˜SJ6 are repeated until processing for all blocks is completed.
(4) Operations of the Inter D&Q Processing
Next, the operations of the inter D&Q processing will be explained with reference to FIG. 15. When processing has been executed via Step SF5 mentioned above (refer to FIG. 10), the flow advances to Step SK1 shown in FIG. 15 and whether or not processing has been completed for all of the 4×4 pixel blocks of a 16×16 pixel macroblock partitioned into 16 sub-macroblocks is judged. If processing has not been completed for all the blocks, the judgment result becomes “NO” and the flow advances to Step SK2.
In Steps SK2˜SK6, the inter-frame prediction block value ref (i, j) is subtracted from the current block pixel value Org (i, j) and proceeds to execute transform processing (integer DCT), quantization processing Q, inverse quantization processing Q-1 and inverse transform processing (inverse integer DCT-1) to the produced prediction error signal. Then, the flow advances to Step SK7. Because of the stepping performed in the inter-frame prediction block value ref (i, j), processing will revert to the above-mentioned Step SK1. Hereafter, the above-mentioned Steps SK1˜SK7 are repeated until processing for all the blocks is completed.
As described above, the motion picture encoding device performs video compression by selectively using either intra-frame coding by correlation in a spatial domain or inter-frame coding by correlation in a temporal domain. A magnitude comparison is executed for each input macroblock between the minimum Sum of Absolute Differences SADinter that is equivalent to the amount of coded data at the time of inter-prediction and the minimum Sum of Absolute Differences SADintra that is equivalent to the amount of coded data at the time of intra-prediction. The coding mode with the smaller Sum of Absolute Differences SAD is selected and compression encoding is performed.
Apart from that, in order to obtain the minimum Sum of Absolute Differences SADintra equivalent to the amount of coded data at the time of intra-prediction, for example, when intra 4×4 mode is selected, it is necessary to calculate the prediction block value for each mode amongst a total of nine optional prediction modes, which are referred to as mode0˜mode8. This situation causes an exponential increase in the calculation amount. Furthermore, the coding technique by the H.264 standard has been described in the conventional prior art, for example, as disclosed by Iain E. G. Richardson “H.264 and MPEG-4 Video Compression: Video Coding for Next-generation Multimedia”, Publisher: John Wiley & Sons, Ltd. (December 2003, First Edition) “6.H.264/MPEG-4 Part 10” (p 159˜p 223) (ISBN: 0470869607).
There are the following issues concerning motion picture encoding devices which perform video compression by selectively using intra-frame coding and inter-frame coding mentioned above.
(a) In many cases intra-frame coding is not selected, except in a case where there is a noticeable difference between an inputted image as compared with a reference image, for example, when a scene changes, when a motion vector has not been detected properly or when there is a substantial luminance variation due to a camera flash, etc. For this reason, there is a problem in that the complexity and number of calculations required for intra-prediction processing (refer to FIG. 14) is simply excessive.
(b) Because a coding determination is performed which uniquely selects either intra-frame coding/inter-frame coding only by a magnitude comparison of the amount of coded data, human visual characteristics are not taken into consideration. This is commonly referred to as the Human Visual System (HVS), the system by which a human eye and brain perceive and interpret visual images. Therefore, there is the possibility of inviting significantly reduced image quality that can easily develop into an image with noticeable noise (luma and chroma noise), such as in the case of quantization error propagation being generated at the time of a motion vector search whereby a fast search algorithm may become ‘trapped’ in a local minimum giving a suboptimal result or during coding at a low bit rate whereby distortion increases the respective quantization value. A local minimum is the concept of a minimum value in a defined section (area) of a block. For instance, this may not be the true global minimum value and is commonly referred to as a false minimum value (false minima).
Consequently, the present invention has been made in view of the above-described circumstances with the purpose of providing a motion picture encoding device and associated motion picture encoding processing program, wherein wasteful calculations will not be performed and coding modes can be determined at a faster speed in view of human visual characteristics.
Furthermore, the present invention aims at providing a motion picture encoding device and motion picture encoding processing program which can rapidly stop quantization error propagation when ‘trapped’ in a local minimum as well as avoid reduced image quality.
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A foot valve is a one-way check valve located at the intake end of a pipe leading to a suction pump. The function of a foot valve is to prevent the loss of priming water when the pump is not in operation. Typical foot valves have a surrounding screen to prevent the intake of large articles that would damage a pump. Such valves are also usually of the same diameter as the pipe to which they are to be connected, rendering them suitable for use at the bottom, or "foot" of a well hole.
Water intake stands for introducing water into a pipe are intended to minimize the intake of sediment and debris from river and lake bottoms. A concern respecting water intake stands is that they should locate the intake near, but not at the bottom of the water body, and they should not protrude substantially above the bottom to an extent that makes them vulnerable to being upset by currents, or by fisherman's lines or anchors.
A basic known way of supporting and stabilizing a water intake is to fasten the intake end of a pump pipe to a box with a perforated lid filled with gravel that is sunk to the bottom of a river or lake bed. This fastening is effected along the upper edge of the box thereby causing the pump pipe to trail downwardly to the bottom as it proceed towards the shore where a suction pump is located. Such an elevated pipe section is vulnerable to being snagged by fishermen's lines or anchors, risking detachment from, or up-ending of, the box.
A simple known commercial stand is that produced by Wally Weights Inc. of Kenora, Ontario, Canada. In one version, the Wally Weight (.TM.) stand consists of a plastic "wheel" with the water intake occurring at the axle location. With a rigid length of intake pipe extending as an axle, the wheel lies on the lake bottom with the intake orifice elevated above the bottom. Provision is made at the intake opening in this stand for a foot valve to be attached. In use, the foot valve would be oriented at an angle between the horizontal and vertical positions.
A second version of a water intake stand from the same source provides for a cone that rises to the pipe intake at its center point. The cone and intake pipe are perforated to allow water to pass therethrough and enter a submersible pump located in the vertically extending central pipe portion of the stand. Such pumps do not always need a foot valve, although one may optionally be present.
Another company selling water intakes is the Big Foot. Manufacturing Co. of Cadillac Mich. U.S.A. The Big Foot(.TM.) intake is in the form of two concentric perforated cylinders having an annulus therebetween. This annulus is filled with pea-sized gravel to strain water passing through to the core where the intake orifice is located.
While these prior art water intakes are able to function as intended, neither fully address the desirable objectives of providing an assembly for supporting a foot valve in conjunction with a water intake stand which is readily portable prior to installation, is relatively stable and anchored once installed along a lake or river bottom and provides a positioning means for locating the intake orifice above the actual bottom of the water source. It is with the objective of providing such a combination of benefits that the invention described hereafter has been conceived.
The invention in its general form will first be described, and then its implementation in terms of specific embodiments will be detailed with reference to the drawings following hereafter. These embodiments are intended to demonstrate the principle of the invention, and the manner of its implementation. The invention in its broadest and more specific forms will then be further described, and defined, in each of the individual claims which conclude this Specification.
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In an impact tool which performs a hammering operation or a hammer drill operation by a tool bit on a workpiece such as concrete, dust is generated during operation. Therefore, some conventional impact tools are provided with a dust collecting device for collecting dust generated during operation. For example, Japanese non-examined laid-open Patent Publication No. 2007-303271 discloses a dust collecting device having a cylindrical hood which is arranged to surround a tool bit. In this dust collecting device, dust generated by operation is sucked up through a front end opening of the hood and collected via a pipe and a dust transfer passage formed within the impact tool body.
The above-described known dust collecting device is configured such that the front end of the hood is fixed in position with respect to the tool body. Therefore, for example, when a longer tool bit than usual is used, the distance between the hood front end and a dust generation area is increased, so that the dust collecting efficiency is reduced.
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Conventionally, various techniques for discriminating whether an object struck by a vehicle is a pedestrian or not have been proposed. For example, disclosed in Japanese Patent Unexamined Publication No. H10-194158 is an object struck discrimination system for discriminating an object struck based on the speed of a vehicle and the acceleration in the forward and rearward directions acting on the vehicle. In such object struck discrimination systems, it is highly demanded to develop a technology for increasing the discrimination accuracy for discriminating an object struck to ensure the protection of a vehicle occupant and/or a pedestrian during a vehicle collision.
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1. Field of the Invention
The present invention relates to a signal line switching circuit, and more specifically to a signal line switching circuit in a semiconductor integrated circuit with a test circuit.
2. Description of Related Art
With a large scaling of semiconductor integrated circuits, a test for checking whether or not various circuits included in the integrated circuit can operate properly has become important. As one means for making the test easy in a large scaled integrated circuit such as a static random access memory (SRAM), many integrated circuits have incorporated therein a signal switching circuit for selecting either a data signal in a normal operation (called a "normal-data signal" hereinafter) or a test signal, in order to investigate existence/non-existence of failure before the integrated circuit is put in a normal operation condition.
In the prior art, this type of signal switching circuit has been used in sense amplifiers of the SRAM, and has been constituted of transfer gates or clocked inverters.
Referring to FIG. 1, there is shown a block diagram of a first example of the conventional signal switching circuit using a set of transfer gates. The shown first signal switching circuit includes a first stage amplifier A1 receiving a pair of complementary normal-data signals "a" and "Ia" having a small amplitude, and outputting a pair of amplified signals "b" and "Ib" on a pair of signal lines "B 1" and "B2". The first signal switching circuit also includes a switching circuit 1 responding to a pair of complementary normal-dam/test selection signals "m" and "Im" so as to select either the signals "b" and "Ib" or a pair of complementary test discrimination result signals "t" and "It" from a test circuit (not shown), and to output a pair of selected signals "c" and "Ic". Furthermore, the first signal switching circuit includes a second stage amplifier A2 receiving and amplifying the pair of selected signals "c" and "Ic" to output a pair of amplified signals "d" and "Id", and an output circuit 6 converting the pair of amplified signals "d" and "Id" into an output signal "e" of a predetermined signal type.
The switching circuit 1 includes a pair of NMOS (N-channel metal- oxide-semiconductor field effect) transistors N11 and N12 having their source connected to receive the signals "b" and "Ib", respectively, and their gate connected in common to receive the normal-data selection signal "m", and also their dram connected to supply the received signals "b" and "Ib" as the selected signals "c" and "Ic", respectively. The switching circuit 1 also includes another pair of NMOS transistors N13 and N14 having their source connected to receive the pair of test discrimination result signals "t" and "It", respectively, and their gate connected in common to receive the test selection signal "Im", and also their drain connected to supply the received signals "t" and "It" as the selected signals "c" and "Ic", respectively.
Now, operation of the first conventional signal switching circuit will be described with reference to FIG. 1. When the normal-data signal is to be outputted, the normal-data/test selection signals "m" and "Im" are set to a high level and to a low level, respectively. The pair of complementary normal-data signals "a" and "Ia" are amplified by the amplifier A1 so as to be outputted as the signals "b" and "Ib", respectively. In response to the normal-data selection signal "m" of the high level, the transistors N11 and N12 are put in a conductive condition, so that the signals "b" and "Ib" pass through the transistors N11 and N12 as they are, and are supplied to the amplifier A2 as the selected signals "c" and "Ic". On the other hand, in response to the test selection signal "Im" of the low level, the transistors N13 and N14 are put in a non-conductive condition, and therefore, the test discrimination result signals "t" and "It" are blocked, so that the signals "c" and "Ic" are not influenced by the test discrimination result signals "t" and "It" at all. The signals "c" and "Ic" are amplified by the amplifier A2, which outputs the amplified signals "d" and "Id" to the output circuit 6, which then supplies the output signal "e".
When the test discrimination result signal is to be outputted, the normal-data/test selection signals "m" and "Im" are set to a low level and to a high level, respectively, in the contrary to the case of outputting the normal-data signal. In response to the test selection signal "Im" of the high level, the transistors N13 and N14 are put in a conductive condition, so that the test discrimination result signals "t" and "It" pass through the transistors N13 and N14 as they are, and are supplied to the amplifier A2 as the selected signals "c" and "Ic". On the other hand, in response to the normal-data selection signal "m" of the low level, the transistors N11 and N12 are put in a non-conductive condition, and therefore, the amplified complementary normal-data signals "b" and "Ib" are blocked. As a result, the signals "c" and "Ic" corresponding to the test discrimination result signals "t" and "It" are amplified by the amplifier A2, which outputs the amplified signals "d" and "Id" to the output circuit 6, which then supplies the output signal "e". In this case, the output signal "e" is indicative of the test discrimination result signals "t" and "It".
Thus, the transistors N11 to N14 of the switching circuit 1 functions as the transfer gate controlled by the normal-data/test selection signals "m" and "Im".
Referring to FIG. 2, there is shown a block diagram of a second example of the conventional signal switching circuit using a set of clocked inverters. In FIG. 2, elements similar or corresponding to those shown in FIG. 1 are given the same Reference Numerals, and explanation thereof will be omitted for simplification of the description.
As seen from comparison between FIGS. 1 and 2, the second example of the conventional signal switching circuit is different from the first conventional signal switching circuit, in which a switching circuit 2 is provided which is constituted of a set of clocked inverters in place of the transfer gates of the switching circuit 1.
The switching circuit 2 includes a pair of clocked inverters I21 and I22 having their selection gate connected in common to receive the normal-data selection signal "m", and their input connected to receive the signals "b" and "Ib", respectively, and also their output for outputting the selected signals "c" and "Ic", respectively, and another pair of clocked inverters I23 and I24 having their selection gate connected in common to receive the test selection signal "Im", and their input connected to receive the test discrimination result signals "t" and "It", respectively, and also their output for outputting the selected signals "c" and "It", respectively,
Operation of the second conventional signal switching circuit is the same as that of the first conventional signal switching circuit, excepting that the selected signals "c" and "Ic" are either the inverted signals of the signals "b" and "Ib", respectively, or the inverted signals of the test discrimination result signals "t" and "It", respectively.
In the first conventional signal switching circuit as mentioned above, it is necessary to enlarge the size of the MOS transistors in order to reduce a conduction resistance and a junction capacitance which are causes for lowering the transmission speed of the signals passing through the MOS transistors put in a transmission path of the normal-data as the transfer gate. In addition, each of the test discrimination result signal and the normal-data/test selection signal is a pair of complementary signals, which correspondingly require a pair of signal lines. Therefore, the chip size has become large.
In the second conventional signal switching circuit as mentioned above, a signal delay corresponding to an inverter of at least one stage occurs because of the clocked inverters inserted in the transmission path of the normal-data. In addition, the number of transistors required for constituting the four clocked inverters is 16, and each of the test discrimination result signal and the normal-data/test selection signal requires a pair of complementary signal lines, similarly to the first conventional signal switching circuit. Accordingly, the chip size has become large, similarly to the first conventional signal switching circuit.
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Among recordable optical discs, there is known an optical disc exploiting e.g. a phase change film. In these recordable optical discs, a spirally extending land(s) and a spirally extending groove(s) are formed. Of these, the grooves are used as recording tracks in which to record data.
Moreover, in these recordable optical discs, on the recording tracks or grooves of which data can be recorded, wobble signals or LPP (land pre pit) signals are prerecorded in edge parts of the recording tracks, that is, in boundary portions of the recording tracks with respect to the grooves.
The wobble signals are those signals recorded by meandering of boundary portions of the land(s) and the groove(s) at a preset period. The meandering shape is such that, when the disc is reproduced at CLV (constant linear velocity) or at CAV (constant angular velocity), the meandering has a preset constant period. For this reason, the wobble signals are used as clocks. The meandering frequency is sometimes modulated by e.g. addresses, in which case a reproduced signal is also used as address information.
The LPP signal is such a signal recorded by forming a pit in a portion of the land. With the LPP signals, the string of pits formed represents an address, such that reproduced signals are used as the address information.
The wobble signals and the LPP signals are detected from return light of laser light illuminated on the recording track (recording groove). In the return light of laser light illuminated on the recording track (recording groove), the wobble signal components and the LPP signal components are contained in the push-pull component (differential component) along the radial direction of the return light.
Specifically, the main laser light beam, illuminated on the recording track (groove), is detected by a four-segment photodetector 101 shown in FIG. 2. The four-segment photodetector 101 is split into two portions along a direction corresponding to the radial direction of the optical disc, while being split into two portions along a direction corresponding to its tangential direction. That is, the four-segment photodetector is split into four portions in a cross-shape. The wobble signal and the LPP signal are included in a differential component of the total light volume (A+D) of the photodetector segments A and D on one side, here on the outer rim side, of the photodetector segments divided along the direction corresponding to the radial direction, and the total light volume (B+C) of the photodetector segments B and C on the other side, here on the inner rim side, of the photodetector segments, that is, ((A+D)−(B+C)). This signal ((A+D)−(B+C)), representing the differential component, is referred to below as the radial push-pull signal.
Of course, these wobble and LPP signals need to be read out not only during readout of data from the recording track but also during recording the data.
For detecting the wobble and LPP signals during data recording, the reflected light of the laser light radiated for recording is detected to generate the radial push-pull signal.
With the phase change disc, for example, pits are recorded by radiating laser light as pulses. Hence, during recording, there is a timing during which pits are being formed on the recording track (write time) and a timing during which pits are not being formed on the recording track (bias time). Thus, in the return light during recording, the signal level during writing (pit level) and the signal level during bias time (read level) become higher and lower, respectively, as shown in FIG. 3.
For this reason, in detecting the wobble and LPP signals during recording, signal processing must be made in such a manner that changes in the light volume of return light during writing and those during bias timing will be sufficiently taken into consideration.
Meanwhile, there are occasions where, even though the light spot illuminated on the optical disc is illuminated on the center of a recording track, the center of the light spot of the return light is not coincident with the center position of the four-segment photodetector 101, as shown in FIG. 4.
There are also occasions where light volume distribution is not symmetrical but distorted relative to the center of the light spot illuminated to the four-segment photodetector 101.
Hence, a time averaged value of the total light volume of the outer rim side photodetector segments (A+D) when the four-segment photodetector 101 is divided into two portions along a line corresponding to the radial direction differs from a time averaged value of the total light volume of the inner rim side photodetector segments (B+C), such that the radial push-pull signal (A+D−(B+C)) is added by an offset.
Moreover, there is a marked difference in the power during the write timing and that during the bias timing. The result is that there is produced a large level difference between an offset E1 of the radial push-pull signal during writing, that is, the difference in the pit level during writing, and an offset E2 of the radial push-pull signal during bias timing, that is, the difference in the read level during bias timing, as shown in FIG. 5. That is, there is produced time change in the offset of the radial push-pull signal, as shown in FIG. 6.
These variations in the offset are conductive to deterioration of the slew rate or generation of ringing, when the detection signals A to D of the four-segment photodetector are transmitted to the downstream side circuitry, as a result of which reproduction characteristics of the wobbles or LPP signals, generated from the radial push-pull signal, are deteriorated.
These problems are felt more keenly when the data are recorded by multiple-speed recording on the optical disc.
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The Internet is a worldwide system of interconnected computer networks that transmits data in packets. Various information and services are carried over the Internet, such as electronic mail (e-mail), online chat rooms, and the World Wide Web (the Web). In particular, the Web is an information space in which online documents called web pages are stored and published for the entire computing world to access. Anyone connected to the Internet can view the myriad of web pages available online by accessing global identifiers called Uniform Resource Identifiers (URIs).
A web page is a simple file containing, for example, text and a set of Hypertext Markup Language (HTML) tags that describe how the text should be formatted on a screen. HTML tags are simple instructions that tell web browsers how a web page should look when it is displayed. For example, HTML tags may describe a web page's fonts, colors, title, etc. Furthermore, web pages may be accessed via the Hypertext Transfer Protocol (HTTP) and may be displayed according to HTML tags by a software package called a web browser. Web browsers identify web pages on web servers by their URIs. Examples of web browsers include Microsoft® Internet Explorer, Opera Netscape Navigator, Firefox, and Thunderbird. Once a web page is retrieved, the web browser interprets the page's HTML tags and displays it accordingly on a screen.
A web site is a collection of individual related web pages. Examples of different types of web sites include archive, business, database, and news sites. One specific type of web site gaining popularity today is the “weblog,” also known as “blog.” A blog is a web site containing periodic articles and posts, usually presented in reverse chronological order. Generally, blogs are much simpler than other web sites. Rather than being composed of many individual pages connected by hyperlinks, blogs are composed of a few templates (usually Main Page, Archive Page, and Individual Article/Item Page), into which content is fed from a database. This allows for easy creation of new pages, since new data is entered into a simple template and then submitted, which effectively adds the article to the blog.
All language is biased by its basic nature and is a consequence of individual history, opinions, context, ethics, experiences, belief structures, or other bias. Consequently, web pages and blog posts are typically slanted to the author's point of view. There are many instances where users may wish to substitute their own preferred biases for those of a web page or blog author.
Since its inception, the Web has rapidly expanded to include a vast and diverse amount of online information and provide a global forum for unregulated public speech. With the advent of new web-building software, such as Microsoft® FrontPage®, Macromedia Dreamweaver, Mozilla Composer, Blogger, Xanga, Typepad, etc., it has become much easier to create and publish information online. As a result, a plethora of web pages, blogs, and other online sources that describe and discuss nearly every aspect of life are readily available on the Web. Internet search engines like Google and Yahoo! search online documents using keyword-driven search technology. However, these services merely direct a user to web pages. They do not synopsize information, alleviate author bias, or allow the user to interpret the information with their own particular bias. Also, as the number of online documents keeps increasing, keyword-driven searches will provide larger results for a user to navigate through for information. Therefore, a need exists to assimilate blogs and web pages by specific topic, analyze them, and summarize their underlying objective content.
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Some chair support structures have been constructed solely of pure tension members and pure compression members. For example, rocking chairs have been provided by support structures having two rigid (i.e., compression) members that each have upper end portions that are spaced from each other and lower end portions that are spaced from each other. The rigid members are oppositely inclined with respect to the horizontal, intersecting each other in side view, and one of the rigid members is positioned intermediate the other. The rigid members are connected to each other near their bottoms by one pair of flexible tension members that prevent the bottoms from sliding apart, and they are also connected above where they intersect by another pair of flexible tension members that prevent the rigid members from falling owing to gravity. The rigid members can pivot about their points of contact with the ground, providing the rocking movement.
Meeker U.S. Pat. No. 1,969,313, Robeson U.S. Pat. No. 4,118,064 and Gilbert U.S. Pat. No. 4,251,106 disclose examples of such support structures for rocking type chairs having seating surfaces provided by sling-type flexible sheets suspended between the upper ends of the rigid members. Meeker and Robeson disclose structures in which each rigid member is a pair of parallel struts connected to each other by horizontal bars and teach that the structures can be modified to prevent rocking by adding pin connections between the rigid members where they intersect. Gilbert discloses a structure in which the rigid member that is longer than the other has a central portion that branches at the lower end to provide two feet and at the upper end to support a sling-type seating surface flexible sheet that also acts as an upper tension member preventing the rigid members from falling owing to gravity; backward pivoting is prevented beyond a certain point by interference of the branched lower ends of the longer rigid member with the diverging lower ends of the other rigid member, and forward pivoting is prevented beyond a certain point by a pair of cords between the rigid members at positions to the rear of where they intersect each other in side view.
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The desmogleins are a family of transmembrane proteins which play an important role in cell adhesion, ensuring that cells within tissue are bound together. In skin, they are major components in desmosomes. Desmosomes are cell-cell adhesion complex between epithelial and certain other cell types. They provide mechanical integrity to keratinocytes by linking to keratin intermediate filaments. Desmogleins form the glue that attaches adjacent skin cells, keeping the skin intact. Desmoglein 1 and 3 are both expressed in stratified squamous epithelia. Desmoglein 1 is dominantly expressed in the differentiated upper layer of epidermis, and Desmoglein 3 is mostly found in basal and suprabasal layers. The differential expression pattern of Desmogleins is important for regulating epidermal functions. Changes of Desmoglein 1 and 3 expression pattern in animal models disrupts keratinocyte proliferation and barrier function of skin. An anticipated benefit for the stimulation of Desmogleins would be an increase in anchoring and adhesion between keratinocytes leading to firmer skin and fewer wrinkles.
Collagen is the body's major structural protein and is composed of three protein chains wound together in a tight triple helix. This unique structure gives collagen a greater tensile strength than steel. Approximately 33 percent of the protein in the body is collagen. This protein supports tissues and organs and connects these structures to bones. In fact, bones are also composed of collagen combined with certain minerals such as calcium and phosphorus. Collagen plays a key role in providing the structural scaffolding surrounding cells that helps to support cell shape and differentiation, similar to how steel rods reinforce a concrete block. The mesh-like collagen network binds cells together and provides the supportive framework or environment in which cells develop and function, and tissues and bones heal.
Collagen is created by fibroblasts, which are specialized skin cells located in the dermis. Fibroblasts also produce other skin structural proteins such as elastin (a protein which gives the skin its ability to snap back) and glucosaminoglycans (GAGs). GAGs make up the ground substance that keeps the dermis hydrated. In order to signal or turn on the production of skin structural proteins, fibroblast cells have specially shaped receptors on their outside membranes that act as binding sites to which signal molecules with a matching shape can fit. When the receptors are bound by the correct combination of signal molecules (called fibroblast growth factors, or FGFs), the fibroblast begins the production of collagen. The stimulation of collagen gives the skin its strength, durability, and smooth, plump appearance.
Dermatopontin is a protein component of the extracellular matrix which is located primarily on the surface of the collagen fibers in the skin. Dermatopontin is believed to play important roles in cell-matrix interactions and matrix assembly (collagen fibrillogenesis). Investigation of dermatopontin knockout mice confirm the involvement of dermatopontin in skin elasticity and collagen accumulation, as the elastic modulus of skin was reported to be 57% lower and collagen content was 40% lower in dermatopontin-null mice than in wild-type mice. Takeda et al., “Targeted disruption of dermatopontin causes abnormal collagen fibrillogenesis,” J. Invest. Dermatol., 2002 September; 119(3):678-83.
It is therefore an object of the invention to provide new compositions and methods for stimulating collagen I, desmogleins, and/or dermatopontin production. It is a further object of the invention to improve the overall appearance of skin, including treating, reversing, and/or preventing signs of aging, such as skin wrinkles, by stimulating collagen I, desmogleins, and/or dermatopontin production with cosmetic compositions comprising effective amounts of 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides.
The foregoing discussion is presented solely to provide a better understanding of nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.
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1. Field of the Invention
The present invention relates to a rearview mirror for indoor or outdoor use which is applied to a vehicle such as a car, and more particularly, to an electrochromic mirror in which the reflectivity can be changed by applying voltage.
2. Description of the Related Art
Conventionally, an “electrochromic mirror” is known (for instance, see Japanese Utility Model Application Publication (JP-Y) No. 62-2587). An electrochromic mirror may be used as a rearview mirror for a vehicle such as a car and can electrically change the reflectivity so as to reduce the glare of the headlight of a following car at night.
As shown in FIG. 2, in an electrochromic mirror 100 disclosed in JP-Y No. 62-2587, a transparent electrode 104, a thin film made of iridium hydroxide (Ir(OH)3) 106, a thin film made of tantalum pentoxide (Ta2O5) 108, a thin film made of tungsten trioxide (WO3) 110, and an aluminum (Al) electrode 112 are sequentially laminated on the back surface of a glass substrate 102 by vacuum deposition or the like. A glass plate 114 for protecting the thin films is adhered to the aluminum (Al) electrode 112 or the like by a sealant (adhesive) 116. When a voltage is applied between the transparent electrode 104 and the aluminum (Al) electrode 112 by a power supply 118, the thin film made of iridium hydroxide (Ir(OH)3) 106 and the thin film made of tungsten trioxide (WO3) 110 react to be colored, and the reflectivity of the electrochromic mirror 100 is changed (see arrow B shown in FIG. 2).
However, if the balance of the film thickness and film quality of each thin film described above is not kept in the electrochromic mirror 100, the thin film which becomes colored once may not return to its original state. In addition, problems exist in that stringent production conditions are required and the formation of a multi-layer film using vacuum deposition is expensive since any variation in the film thickness largely influences the performance.
On the other hand, an electrochromic mirror in which the reflectivity is changed by the coloring reaction of a so-called “electrochromic solution” which is a solution that is electrically colored is known (for instance, see Japanese Patent No. 2672083).
As shown in FIG. 3, in an electrochromic mirror 200 disclosed in Japanese Patent No. 2672083, two glass substrates 202 and 204 are arranged in parallel at a proper interval, and transparent electrode films 206 are respectively formed on the inner surfaces of the glass substrates 202 and 204. An electrochromic solution 210 is enclosed in a cell sealed by a sealant 208 between the transparent electrode films 206. A reflecting film 212 and a protective film 214 are formed on the back surface of the glass substrate 204 (the surface at the lower side in FIG. 3). When a voltage is applied between the transparent electrode films 206 by a power supply 216, the electrochromic solution 210 is colored, and the reflectivity of the electrochromic mirror 200 is changed.
However, when the two glass substrates 202,204 are not adhered together in parallel with a high precision via a sealant 208 in the electrochromic mirror 200, the image of the reflected light (see arrow C shown in FIG. 3) due to the reflecting film 212 does not coincide with that of the reflected light due to the surface of the glass substrate 202 (the surface at the upper side in FIG. 3). Therefore, so-called double images occur, and it is extremely difficult to see by using the mirror. In particular, since a mirror for a car is generally curved, a problem exists in that it is extremely difficult to manufacture the mirror, and thus the cost is high.
Therefore, there is a need in the art for an electrochromic mirror which can be easily manufactured at a low cost, causes no double images, and has a simple structure and high performance.
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Angiotensin II, a main vasoconstrictor hormone of renin-angiotension-aldosterone system (RAAS), plays an important role in pathological physiology of many chronic diseases. The production approach of Angiotensin II which is present in various tissues is mainly as follows: angiotensinogen acted on by renin can be converted to angiotensin I (Ang I) of decapeptide which only has little activity in contraction of blood vessel; and can be further converted by angiotensin converting enzyme to angiotensin II (Ang II) of octapeptide which is the final physiological active substance of renin-angiotension-aldosterone system (RAS) and can induce physiological functions such as contraction of blood vessel and elevation of blood pressure by binding to specific angiotensin II (ATII) receptor.
EP0253310 discloses a series of imidazole derivatives. Research of E. I. Du Pont de Nemours and Company (US) found that a compound of DUP753 has a good effect on lowering blood pressure. It was approved in 1994 and became the first non-peptide type Ang II receptor antagonist, i.e. losartan potassium, which inhibits contraction of blood vessel by selectively blocking the actions of angiotensin II of smooth muscle in blood vessel on its Ang I receptor to achieve the functions of dilating blood vessel and reducing blood pressure.
With the development and marketing of losartan potassium, various medical R&D organizations and companies began studies on structure of Ang II receptor antagonists in succession. U.S. Pat. No. 5,196,444 discloses a series of benzimidazole derivatives and processes for preparation thereof. Such derivatives have angiotensin II antagonistic activity and antihypertensive activity and thereby can be used to treat hypertensive diseases. Among them, candesartan was developed and marketed in 1997 by Takeda Chemical Industries, Ltd. (JP), which releases ester group in vivo and is hydrolyzed to its active metabolite to exert the action of lowering blood pressure.
U.S. Pat. No. 5,616,599 discloses a series of 1-biphenylmethylimidazole derivatives whose structures are similar to that of losartan. The significant difference in structure between them is that the chlorine atom at the 4-position of the imidazole ring of losartan is converted to 1-hydroxy-1-methylethyl and the 5-position of that is converted to a carboxyl group, hydroxyl group or pro-drug structures such as ester or amide. It is demonstrated to have good activity in reducing blood pressure. Therefore, Sankyo Company, Ltd. (JP) developed and marketed a drug of olmesartan.
Compared with other Ang II receptor antagonists marketed subsequently, losartan has more tolerance, fewer side effects and fewer possibilities to cause cough or edema. Studies have suggested that it is effective for reducing serum uric acid, TC and TG, and has no adverse effect on insulin sensitivity, insulin secretion and glucose tolerance of hyperinsulinism patients and is a safe antihypertensive drug. However, only 14 percent of losartan potassium can be metabolized in vivo to its active substance of EXP3174. Although losartan potassium itself has a strong activity in reducing blood pressure, its activity is only 3 percent of that of EXP3174. Molecular polarity of EXP3174 is too strong to get through the cell membrane by passive absorption forms such as diffusion. It is necessary to change its structure to improve its passive absorption.
U.S. Pat. No. 5,298,519 discloses a 5-position carboxyl esterified product of EXP3174, emphasizes on the research of a compound HN-65021, and discloses a test result of lowering blood pressure by oral administration of HN-65021 to show the compound has an activity of lowering blood pressure similar to that of losartan (British Journal of Clinical Pharmacology, 40, 1995, 591-593). It is indicated that converting 5-position carboxyl of the imidazole ring of EXP3174 molecule to a group with a smaller polarity is a tendency of the modification of losartan. It is required to convert the structure of EXP3174 molecule for getting an active compound with a better pharmacological effect of lowering blood pressure.
In summary, there is an urgent need to develop an active compound with an excellent effect of lowering blood pressure, a high efficiency of absorption and conversion and/or a high safety in this field.
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It is general practice in the paper industry to produce a continuous sheet or web of paper which is wound onto large spools. In order to have a continuous operation it is, of course, necessary to have a system for instantaneously switching from winding the web of paper onto a full roll to an empty roll, particularly at modern speeds of paper production. In U.S. Pat. No. 2,461,246 there is shown a method of feeding a tape onto the rotating empty roll core and causing it to be spirally wrapped on that core as it stretches tight across the traveling web of paper and cuts the paper, with the cut edge being led onto the empty roll supported by the cutting tape. Subsequent improvements such as shown in my three U.S. Pat. Nos. 4,659,029; 4,757,950; and 4,783,018 illustrate how a cutting tape can be passed through a guideway underneath a traveling web of paper, perhaps 10 to 20 feet or more wide and be attached to the far side of an empty spool while the operator remains on the near side of the spool. These patents teach the use of mechanical arms to receive a cut end of the tape with adhesive on the tape, and to push the cut end into contact with the empty spool which winds the tape helically around the spool, cutting the paper web as it does, and wrapping the on-coming web around the empty spool. Processing difficulties have arisen to indicate the need for handling errors, such as the failure to apply a suitable amount of adhesive to the tape, which, in turn, means that the tape does not attach itself properly to the empty spool and, therefore, does not cut the traveling web of paper and transfer it to the empty spool. In the modern high speed plants it is very important that any such errors be handled quickly and efficiently. One improvement has been to use double-sided pressure-sensitive adhesive tape as the adhesive strip on the cutting tape. This is disclosed generally in my U.S. Pat. No. 4,783,018 and in my copending patent application Ser. No. 07/494,418 filed Mar. 16, 1990. The present invention provides an improved apparatus for performing this task with double-sided pressure-sensitive adhesive tape. A second application of the present invention is to provide a hand held device to apply a strip of double-sided pressure sensitive adhesive tape to a cutting tape where, for any reason the feeding machinery failed to apply the necessary strip of adhesive to the leading portion of the tape.
It is an object of this invention to provide an improved apparatus for applying a short strip of double-sided pressure-sensitive adhesive tape to the forward portion of a length of cutting tape for use in transferring a traveling web of paper from one windup roll to another. It is another object of this invention to provide a hand held device for applying a strip of double-sided pressure sensitive adhesive tape to a cutting tape, or to any other surface. Still other objects will become apparent from the more detailed description which follows.
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The spine is formed of a column of vertebra that extends between the cranium and pelvis. The three major sections of the spine are known as the cervical, thoracic and lumbar regions. There are 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae, with each of the 24 vertebrae being separated from each other by an intervertebral disc. A series of about 9 fused vertebrae extend from the lumbar region of the spine and make up the sacral and coccygeal regions of the vertebral column.
The main functions of the spine are to provide skeletal support and protect the spinal cord. Even slight disruptions to either the intervertebral discs or vertebrae can result in serious discomfort due to compression of nerve fibers either within the spinal cord or extending from the spinal cord. Disruptions can be caused by any number factors including normal degeneration that comes with age, trauma, or various medical conditions. If a disruption to the spine becomes severe enough, damage to a nerve or part of the spinal cord may occur and can result in partial to total loss of bodily functions (e.g., walking, talking, breathing, etc.). Therefore, it is of great interest and concern to be able to treat and correct ailments of the spine.
When conservative efforts fail, treating spinal ailments very often includes one of or a combination of spinal fusion and fixation. Generally, spinal fusion procedures involve removing some or all of an intervertebral disc, and inserting one or more intervertebral implants into the resulting disc space. Introducing the intervertebral implant serves to restore the height between adjacent vertebrae (“disc height”) and maintain the height, and/or correct vertebral alignment issues, until bone growth across the disc space connects the adjacent vertebral bodies. Resection of ligaments and/or boney elements from the affected spinal area is also common in order to access the disc space and/or decompress impinged nerve or spinal cord tissue.
Fixation systems are often surgically implanted during a fusion procedure to help stabilize the vertebrae to be fused until the fusion is complete or to address instabilities (either preexisting or created by the fusion or decompression procedure itself). Fixation constructs of various forms are well known in the art. Most commonly, the fixation construct is a plate anchored to the anterior column with multiple bone anchors or a posterior fixation construct including multiple anchors and a connecting rod anchored to the posterior elements of the spine. For a posterior fixation construct the anchors (typically pedicle screws) are anchored into the pedicles of each vertebra of the target motion segment. The pedicle is a dense, strong, stem-like structure that projects from the posterior side of the vertebral body. The anchors are then connected by a fixation rod that is locked to each anchor, thus eliminating motion between the adjacent vertebrae of the motion segment. The fixation anchors utilized in posterior fixation constructs generally include an anchor shank and a rod housing. The rod housing includes a pair of upstanding arms separated by a rod channel in which the fixation rod is captured and locked. When constructing the posterior fixation construct the surgeon must align and seat the rod in the rod channel. This can be a challenge as it requires the rod channels of adjacent rod housings to be generally aligned, or alternatively, the rod must be bent to fit.
In addition to simply stabilizing the spine, components of the fixation system can also be utilized to manipulate the positioning of the vertebrae to achieve the desired alignment before movement is arrested. That is, applying a directional force to the anchor shank through the attached housing, for example, via minimally invasive guides, reduction tools, or other instruments that are commonly engaged to the housing and extend out of the patient, causes the associated vertebra to translate or rotate in the direction of the force, thus allowing the surgeon good control to manipulate the relevant vertebrae into a desired position. However, doing so typically causes the rod housings to move relative to each other. Thus, achieving the desired correction (realignment) of the vertebrae while also aligning the rod channels of the housings to effectively seat a rod is a significant challenge and can create difficulties and delays during the surgery.
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2.1. Signal Transduction
Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. The biochemical pathways through which signals are transmitted within cells comprise a circuitry of directly or functionally connected interactive proteins. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of tyrosine residues on proteins. The phosphorylation state of a protein may affect its conformation and/or enzymic activity as well as its cellular location. The phosphorylation state of a protein is modified through the reciprocal actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) at various specific tyrosine residues.
2.2. Protein Tyrosine Kinases and Phosphatases
A common mechanism by which receptors regulate cell function is through an inducible tyrosine kinase activity which is either endogenous to the receptor or is imparted by other proteins that become associated with the receptor. (Darnell et al., 1994, Science 264:1415-1421; Heldin, 1995, Cell 80:213-223; Pawson, 1995, Nature 373:573-580).
Protein tyrosine kinases comprise a large family of transmembrane receptor and intracellular enzymes with multiple functional domains (Taylor et al., 1992 Ann. Rev. Cell Biol. 8:429-62). The binding of ligand allosterically transduces a signal across the cell membrane where the cytoplasmic portion of the PTKs initiates a cascade of molecular interactions that disseminate the signal throughout the cell and into the nucleus. Many receptor protein tyrosine kinase (RPTKs), such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) undergo oligomerization upon ligand binding, and the receptors self-phosphorylate (via autophosphorylation or transphosphorylation) on specific tyrosine residues in the cytoplasmic portions of the receptor (Schlessinger and Ullrich, 1992, Neuron, 9:383-91, Heldin, 1995, Cell 80:213-223). Cytoplasmic protein tyrosine kinases (CPTKs), such as Janus kinases (e.g., JAK1, JAK2, TYK2), Src kinases (e.g., src, lck, fyn) are associated with receptors for cytokines (e.g., IL-2, IL-3, IL-6, erythropoietin) and interferons, and antigen receptors. These receptors also undergo oligomerization, and have tyrosine residues that become phosphorylated during activation, but the receptor polypeptides themselves do not possess kinase activity.
Like the PTKs, the protein tyrosine phosphatases (PTPS) comprise a family of transmembrane and cytoplasmic enzymes, possessing at least an approximately 230 amino acid catalytic domain containing a highly conserved active site with the consensus motif [I/V]HCXAGXXR[S/T]G. The substrates of PTPs may be PTKs which possess phosphotyrosine residues or the substrates of PTKs. (Hunter, 1989, Cell 58:1013-16; Fischer et al., 1991, Science 253:401-6; Saito & Streuli, 1991, Cell Growth and Differentiation 2:59-65; Pot and Dixon, 1992, Biochem. Biophys. Acta, 1136:35-43).
Transmembrane or receptor-like PTPs (RPTPs) possess an extracellular domain, a single transmembrane domain, and one or two catalytic domains followed by a short cytoplasmic tail. The extracellular domains of these RPTPs are highly divergent, with small glycosylated segments (e.g., RPTP.alpha., RPTP.epsilon.), tandem repeats of immunoglobulin-like and/or fibronectin type III domains (e.g., LAR) or carbonic anhydrase like domains (e.g., RPTP.gamma., RPTP.beta.). These extracellular features might suggest that these RPTPs function as a receptor on the cell surface, and their enzymatic activity might be modulated by ligands. Intracellular or cytoplasmic PTPs (CPTPs), such as PTP1C, PTP1D, typically contain a single catalytic domain flanked by several types of modular conserved domains. For example, PTP1C, a hemopoietic cell CPTP is characterized by two Src-homology 2 (SH2) domains that recognize short peptide motifs bearing phosphotyrosine (pTyr).
In general, these modular conserved domains influence the intracellular localization of the protein. SH2-containing proteins are able to bind pTyr sites in activated receptors and cytoplasmic phosphoproteins. Another conserved domain known as SH3 binds to proteins with proline-rich regions. A third type known as pleckstrin-homology (PH) domain has also been identified. These modular domains have been found in both CPTKs and CPTPs as well as in non-catalytic adapter molecules, such as Grbs (Growth factor Receptor Bound), which mediate protein-protein interactions between components of the signal transduction pathway (Skolnik et al., 1991, Cell 65:83-90; Pawson, 1995, Nature 373:573-580).
Multiprotein signaling complexes comprising receptor subunits, kinases, phosphatases and adapter molecules are assembled in subcellular compartments through the specific and dynamic interactions between these domains with their binding motifs. Such signaling complexes integrate the extracellular signal from the ligand-bound receptor and relay the signal to other downstream signaling proteins or complexes in other locations inside the cell or in the nucleus (Koch et al., 1991, Science 252:668-674; Pawson, 1994, Nature 373:573-580; Mauro et al., 1994, Trends Biochem Sci 19:151-155; Cohen et al., 1995, Cell 80:237-248).
2.3. Abnormal Signal Transduction in Human Diseases
The levels of tyrosine phosphorylation required for normal cell growth and differentiation at any time are achieved through the coordinated action of PTKs and PTPs. Depending on the cellular context, these two types of enzymes may either antagonize or cooperate with each other during signal transduction. An imbalance between these enzymes may impair normal cell functions leading to metabolic disorders and cellular transformation.
For example, insulin binding to the insulin receptor, which is a PTK, triggers a variety of metabolic and growth promoting effects such as glucose transport, biosynthesis of glycogen and fats, DNA synthesis, cell division and differentiation. Diabetes mellitus which is characterized by insufficient or a lack of insulin signal transduction can be caused by any abnormality at any step along the insulin signaling pathway. (Olefsky, 1988, in "Cecil Textbook of Medicine," 18th Ed., 2:1360-81).
It is also well known, for example, that the overexpression of PTKs, such as HER2, can play a decisive role in the development of cancer (Slamon et al., 1987, Science 235:77-82) and that antibodies capable of blocking the activity of this enzyme can abrogate tumor growth (Drebin et al., 1988, Oncogene 2:387-394). Blocking the signal transduction capability of tyrosine kinases such as Flk-1 and the PDGF receptor have been shown to block tumor growth in animal models (Millauer et al., 1994, Nature 367:577; Ueno et al., Science, 252:844-848).
Relatively less is known with respect to the direct role of tyrosine phosphatases in signal transduction; PTPs may play a role in human diseases. For example, ectopic expression of RPTP.alpha. produces a transformed phenotype in embryonic fibroblasts (Zheng et al., Nature 359:336-339), and overexpression of RPTP.alpha. in embryonal carcinoma cells causes the cells to differentiate into a cell type with neuronal phenotype (den Hertog et al., EMBO J 12:3789-3798). The gene for human RPTP.gamma. has been localized to chromosome 3p21 which is a segment frequently altered in renal and small lung carcinoma. Mutations may occur in the extracellular segment of RPTP.gamma. which renders a RPTP that no longer respond to external signals (LaForgia et al., Wary et al., 1993, Cancer Res 52:478-482). Mutations in the gene encoding PTP1C (also known as HCP, SHP) are the cause of the motheaten phenotype in mice which suffer severe immunodeficiency, and systemic autoimmune disease accompanied by hyperproliferation of macrophages (Schultz et al., 1993, Cell 73:1445-1454). PTP1D (also known as Syp or PTP2C) has been shown to bind through SH2 domains to sites of phosphorylation in PDGFR, EGFR and insulin receptor substrate 1 (IRS-1). Reducing the activity of PTP1D by microinjection of anti-PTP1D antibody has been shown to block insulin or EGF-induced mitogenesis (Xiao et al., 1994, J Biol Chem 269:21244-21248).
It has been reported that some of the biological effects of insulin can be mimicked by vanadium salts such as vanadates and pervanadates. Vanadates and pervanadates are known to be non-specific phosphatase inhibitors. However, this class of compounds is toxic because each compound contains a heavy metal (U.S. Pat. No. 5,155,031; Fantus et al., 1989, Biochem., 28:8864-71; Swarup et al., 1982, Biochem. Biophys. Res. Commun. 107:1104-9).
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Conventional storage systems suffer from several drawbacks. In particular, conventional storage systems, such as the PODS storage system, require a user to rent relatively large storage containers. While these containers can be suitable for bulk storage, these containers are typically too large for seasonal or situational storage, wherein small quantities of items need to be stored. Examples of seasonal or situational storage can include winter clothes, snow gear, sports gear, camera gear, and art supplies. This leads to storage inefficiencies for the user, wherein the user is paying for extra (i.e., unutilized) storage space. Furthermore, the relatively large size of the containers precludes the user from dynamically adjusting the amount of storage space that is rented, based on the volume of items that the user desires to store. Additionally, since a user is typically associated with only one storage unit, and rents a larger container when more volume is needed, conventional storage methods only permit users to identify their storage unit according to the storage unit number or the user identifier within the system, and does not allow the user to identify the storage unit according to the storage unit contents.
Conventional storage methods can additionally be inefficient for storage systems. First, the unused space in the storage container is wasted space that can be rented to another user, thereby increasing the storage system user base and potentially increasing profits. Second, the relatively large containers require specialized equipment for movement and transport, such as specialized lifts and trucks.
Thus, there is a need in the physical storage field to create a new and useful method and system of storing and tracking physical items.
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This invention relates generally to methods and apparatus for monitoring a person.
According to the National Center for Health Statistics Monitoring Health Care in America. Quarterly Fact Sheet. September 1996, cerebrovascular disease is the third leading cause of death in America, accounting for over 154,000 deaths in 1994. This fact is true despite death rates from stroke having actually dropped nearly every year since 1950. In 1993, 109 years of potential life were lost due to stroke for every 100,000 persons under age 65. Stroke is the third leading cause of death for all people age 45 and over. In 1993 the national death rate from stroke was 26.5 deaths per 100,000 population. During the period 1990-92, age-adjusted death rates by State ranged from 20.8 for Rhode Island to 40.0 for South Carolina. Regionally, cerebrovascular disease mortality is highest for Indiana and what is referred to as the “stroke belt,” the southeastern states of Louisiana, Mississippi, Alabama, Georgia, North Carolina, South Carolina, Virginia, Tennessee, Kentucky, and Arkansas. The lowest rates are in Colorado, New Mexico, Arizona, Nebraska, Iowa, and Florida, as well as the northeastern states of Maine, Vermont, New York, Massachusetts, Connecticut, and Rhode Island. According to 1994 data, nearly 3 million Americans have suffered strokes at some point, or 1 per 100 population. Five percent of males aged 65 and over and 6 percent of women in the same age group have suffered a stroke.
A stroke occurs when a blood vessel (artery) that supplies blood to the brain bursts or is blocked by a blood clot. Within minutes, the nerve cells in that area of the brain are damaged, and they may die within a few hours. As a result, the part of the body controlled by the damaged section of the brain cannot function properly. An ischemic stroke is caused by a reduction in blood flow to the brain. This can be caused by a blockage or narrowing in an artery that supplies blood to the brain or when the blood flow is reduced because of a heart or other condition. A hemorrhagic stroke develops when an artery in the brain leaks or bursts and causes bleeding inside the brain tissue or near the surface of the brain. Prior to a stroke, a person may have one or more transient ischemic attacks (TIAs), which are a warning signal that a stroke may soon occur. TIAs are often called mini strokes because their symptoms are similar to those of a stroke. However, unlike stroke symptoms, TIA symptoms usually disappear within 10 to 20 minutes, although they may last up to 24 hours. Symptoms of a stroke begin suddenly and may include: numbness, weakness, or paralysis of the face, arm, or leg, especially on one side of the body; vision problems in one or both eyes, such as double vision or loss of vision; confusion, trouble speaking or understanding; trouble walking, dizziness, loss of balance or coordination, or severe headache.
Early detection and treatment of stroke is essential to recovery from a stroke.
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The present disclosure relates to polymer compositions. More specifically, the present disclosure relates to biodegradable nanopolymer compositions, methods for making and using the biodegradable nanopolymer compositions and biodegradable articles made from the polymer compositions.
Packaging material and disposable beakers, cups and cutlery are used widely nowadays and allow food material to be sold and/or consumed under hygienic conditions. Such disposable materials and objects are highly desired by consumers and retailers because they may be simply disposed of after use and do not have to be washed and cleaned like conventional dishes, glasses or cutlery.
Unfortunately, the widespread and growing use of such disposable materials results in a mounting amount of litter produced each day. Currently, the plastic waste is either provided to garbage incinerators or accumulates in refuse dumps. These methods of waste disposal cause many problems for the environment.
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The present disclosure relates generally to supporting packet-based multimedia services in a communications system.
Telecommunications systems, such as Universal Mobile Telecommunications System (UMTS) wireless networks, are evolving into systems that may carry both voice and data traffic via fixed, wireless, and satellite networks. Part of this evolution includes developing and providing packet frameworks for the delivery of IP based, real-time, conversational, multimedia services. For example, an IP multimedia subsystem (IMS) standard has been defined as part of a third generation partnership project (3GPP) to provide such services.
Standards (such as IMS) that address the delivery of multimedia services via a packet based network generally require quality of service (QoS) mechanisms that are intended to ensure a certain level of quality. However, most wireless packet networks require relatively substantial enhancements before such QoS mechanisms can be provided, which slows down the implementation of the associated standards. For example, while IMS provides a framework to support the delivery of multimedia services in a wireless network, most wireless networks need upgrades to their access/radio layers, as well as to their packet core/general packet radio service (GPRS) subsystems before IMS can be properly supported. Implementing these upgrades may involve a considerable amount of time and expense, as the upgrades will need to be developed, deployed and tested.
Accordingly, what is needed is an improved system and method to provide for the delivery of IP based, real-time, conversational, multimedia services. It is desirable to deliver these services to mobile devices via networks that may not support QoS mechanisms specified for the delivery of such services, or networks which are not capable of efficiently carrying IP based traffic.
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Treatment of sleep disordered breathing (SDB), such as obstructive sleep apnea (OSA), by a respiratory treatment apparatus such as a continuous positive airway pressure (CPAP) flow generator system involves a delivery of air (or other breathable gas) at pressures above atmospheric pressure to the airways of a patient via a conduit and/or a mask. Typically, the mask fits over the mouth and/or nose of the patient, or may be an under-nose style mask such as a nasal pillows or nasal cushion style mask. Pressurized air flows to the mask and to the airways of the patient via the nose and/or mouth. A washout vent in the mask or conduit may be implemented to discharge the exhaled gas from the mask to atmosphere.
Respiratory treatment apparatus may include a flow generator, an air filter, an air delivery, conduit connecting the flow generator to the mask, various sensors and a microprocessor-based controller. The flow generator may include a servo-controlled motor and an impeller. The flow generator may also include a valve capable of discharging air to atmosphere as a means for altering the pressure delivered to the patient as an alternative to motor speed control. The sensors may measure, amongst other things, motor speed, gas volumetric flow rate and outlet pressure, such as with a pressure transducer, flow sensor or the like. The controller may also include data storage capacity with or without integrated data retrieval/transfer and display functions. Positive airway pressure may be delivered in many forms.
As previously mentioned, a CPAP treatment may maintain a treatment pressure across the inspiratory and expiratory levels of the patient's breathing cycle at an approximately constant level. Alternatively, pressure levels may be adjusted to change synchronously with the patient's breathing cycle. For example, pressure may be set at one level during inspiration and another lower level during expiration for patient comfort. Such a pressure treatment system may be referred to as bi-level. Alternatively, the pressure levels may be continuously adjusted to smoothly replicate changes in the patient's breathing cycle. A pressure setting during expiration lower than inspiration may generally be referred to as expiratory pressure relief. As described by Sullivan in U.S. Pat. No. 4,944,310, positive airway pressure treatments typically provide gas under pressures to the patient in the range of 4 to 15 cmH2O from the device and may involve flow rates of at about 120 liters/minute. Some of the air may escape via an end restriction or vent and not be delivered to the patient. These pressure settings may also be adjusted based on the detection of conditions of the patient's airway or respiration. For example, treatment pressure may be increased in the detection of partial obstruction, apnea or snoring. In some cases, positive airway pressure may be adapted to provide ventilation support. For example, a patient's ventilatory needs may be supported on a breath-by-breath basis by automatically calculating a target ventilation and adjusting the pressure support generated by an apparatus, such as a bi-level pressure treatment apparatus, so as to achieve the target ventilation.
Respiratory treatment apparatus are sometimes provided with accessory components for comfort conditioning of the flow or pressurized air supplied by the flow generator. For example, the supplied air may be applied to a humidifier to humidify and warm the treatment gas prior to its delivery to a patient. Similarly, various heating elements can be connected with a delivery conduit to help in maintaining a particular temperature of the supplied gas as it is conducted to the patient from a supply unit or humidifier.
There may be a desire to improve efficiency of heating and/or humidification and/or pressurised delivery of a breathable gas for respiratory treatments.
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1. Field of the Invention
This invention generally relates to pneumatic actuators, and more specifically, relates to an apparatus and method for indicating movement of a pneumatic actuator.
2. Background Art
Pneumatic actuators are very cost effective actuators, and are found in many applications, such as manufacturing, aerospace, and commercial vehicles. Generally, in the operation of, for example, a linear pneumatic actuator, a high-pressure fluid is conducted to the actuator to extend or retract a piston. Movement of the piston may then be used to actuate some other mechanism such as a switch or valve.
Currently, at least in many specific applications, there is no available method to indicate the movement of a pneumatic actuator other than a visual observation through a window located on the actuator body. This feature, though, cannot be used if the actuator is in a very inaccessible area. Also, the window cannot be read from a long distance.
For example, pneumatic actuators are used in sheet making processes to control the amount of steam applied to the formed sheets. In this application, the pneumatic actuator may be mounted on a beam in a relatively inaccessible location and operated from a remote distance. As a result, any window on the actuator body is inaccessible and too far away from the operator to be used to see movement of the actuator. Moreover, the actuator may be enclosed in a protective dust cover, which makes it even more difficult to observe movement of the actuator.
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Formulations and blends comprising polycarbonates are known to degrade upon prolonged exposure to sunlight or other forms of light. One of the effects observed is yellowing of the polycarbonate blend/formulation. This problem has been alleviated by the use of light absorbers or light blockers in the polycarbonate blends. Thus ultraviolet light absorbers (UVA) By are known to be used in polycarbonate formulations to protect these formulations from degradation due to exposure to different forms of light.
Use of Hindered Amine Light Stabilizers (HALS) to stabilize polyolefins has been known. Commercially used HALS have been based mainly on 2,2,6,6-tetramethyl piperidine, except for those based on piperazinones. U.S. Pat. Nos. 4,190,571; 4,292,240; 4,480,092; and 5,071,981 disclose some of the piperazinone based HALS. In addition U.S. Pat. Nos. 3,919,234, 3,920,659 and 4,208,522 disclose some piperazine dione based HALS.
The use of HALS in polycarbonates is not very common. The stabilizing effect of HALS on polycarbonate formulations/blends has been described as "minor", see for example Thompson and Klemchuk, in Polymer Durability; R. L. Clough et al., ACS Advances in Chemistry 249, 1995, pp 303-317. The use of UVA in polycarbonate formulations has provided a way to retard the rate of degradation of polycarbonates as a result of exposure to light. This method however does not offer a complete protection of polycarbonate formulations from light induced degradation or discoloration. There is thus a continued need for a method or formulation that will help protect polycarbonate based formulations/blends from degradation or discoloration due to exposure to light.
It has been surprisingly found that use of the piperazinone and piperazine dione based HALS, and a polyether based polymer in polycarbonate compositions, exhibits a synergistic effect in protecting the polycarbonate compositions from light induced degradation. This synergistic effect increases the photostability of polycarbonate compositions thereby slowing the yellowing and degradation of polycarbonate compositions.
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1. Field of the Invention
The present invention relates to a vision tester, and more particularly to a vision tester that is capable of measuring a dynamic visual acuity.
2. Description of the Prior Art
A static vision tester measures the ability to see things that are not moving, which is to say, static visual acuity. However, when a person is driving a car, it is necessary for the driver to be able to judge, quickly and accurately, obstacles, signals, signs, and so forth, and as such, emphasis is being placed on the measurement of a dynamic visual acuity. The dynamic visual acuity is the term used to designate the ability of an observer to discriminate an object when there is relative movement between the observer and the object.
The reduction of the dynamic visual acuity is accelerated and expanded by such factors as speed, fatigue and advancing age, and at high speed the dynamic visual acuity can be halved. Thus, imprecise judgement with respect to the danger involved means that driving at high speed becomes dangerous, so it is important to measure the dynamic visual acuity.
Up until now, however, there has not been any vision tester that can quantitatively measure the dynamic visual acuity, simply and accurately.
An object of the present invention is to provide a vision tester that has a simple arrangement and is able to accurately measure a dynamic visual acuity.
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One or more example embodiments of the inventive concepts relate to a non-contact type communication apparatus, a system and/or a method of operating the system. For example, at least some example embodiments relate to a card reader for communicating with a near-field communication (NFC) card, a system including the card reader, and/or a method of operating the card reader.
An NFC card reader may restore a signal component that overlaps with a magnetic field component of 13.56 MHz induced by an antenna, and may convert the restored signal to a digital signal. When the amplitude of the restored signal is low, the restored signal may not easily be converted into the digital signal, therefore, to amplify the restored signal to a level sufficient to convert the restored signal into a digital signal, the NFC card reader may amplify the restored signal before converting the restored signal.
When a distance between a card and the card reader is large, the card reader may need to use a high gain when performing signal amplification to restore a low-amplitude signal to a level sufficient to establish communication. In contrast, when the distance between the card and the card reader is small, the card reader may need to use a low gain so as to prevent a high-amplitude signal from being saturated.
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1. Field of the Invention
The present invention relates to a probe card measuring electric characteristics of a semiconductor device (measurement objective) such as an LSI chip.
2. Description of the Related Art
As shown in FIG. 11, a typical conventional probe card basically has a main substrate 1 having an electrode, on an upper surface thereof, connected to an electrode of a measuring instrument, a probe unit 2 arranged so as to be opposite to a lower surface of the main substrate 1 and having a plurality of probes, a contact pin 3 interposed between the main substrate 1 and the probe unit 2 and electrically connecting both, and a reinforcing plate 4 attached to the upper surface of the main substrate 1.
When this probe card is used at high temperature or low temperature, the temperature distribution of the main substrate 1, and the reinforcing plate 4 of the probe card is changed to cause thermal expansion or thermal shrinkage. In other words, the probe card is deformed (warped). The plane of the probe card A is distorted. The deformation due to heat is caused by fixing a plurality of planar members having different thermal expansion coefficients in a face-to-face contact state. In the case of this probe card, the deformation due to heat is caused by the fixed relation between the main substrate 1, and the reinforcing plate 4.
When the probe card is deformed in this way, variations in the height of the probes occur. When using the probe card in such a state to measure a measurement objective, while some probes are brought into contact with some electrodes of the measurement objective, the remaining probes are not brought into contact with the remaining electrodes of the measurement objective. Thus, there is a problem that the probe card A cannot stably measure electric characteristics of a measurement objective in an environment at high temperature or low temperature.
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Unless otherwise indicated herein, the materials described in this section are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section.
Vehicles can be configured to operate in an autonomous mode in which the vehicle navigates through an environment with little or no input from a driver. Such autonomous vehicles can include one or more sensors that are configured to detect information about the environment in which the vehicle operates. The vehicle and its associated computer-implemented controller use the detected information to navigate through the environment. For example, if the sensor(s) detect that the vehicle is approaching an obstacle, as determined by the computer-implemented controller, the controller may adjust the directional controls of the vehicle to cause the vehicle to navigate around the obstacle.
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1. Field of the Invention
Embodiments of the present invention generally relate to downhole logging and production operations and particularly to deployment of downhole tools on non-electric cable.
2. Description of the Related Art
Costs associated with downhole drilling and completion operations have been significantly reduced over the years by the development of tools that can be deployed down a well bore to perform operations without pulling production tubing. Downhole tools are typically attached to a support cable and subsequently lowered down the well bore to perform the desired operation. Some support cables, commonly referred to as wirelines, have electrically conductive wires through which voltage may be supplied to power and control the tool.
FIG. 1 illustrates an exemplary electric downhole tool 110 attached to a wireline 120, lowered down a well bore 130. The wireline 120 comprises one or more conductive wires 122 surrounded by an insulative jacket 124. The conductive wires 122 supply a voltage signal to the tool 110 from a voltage source 140 at the surface 150. Typically, an operator at the surface 150 controls the tool 110 by varying the voltage signal supplied to the tool 110. For example, the operator may apply and remove the voltage signal to cycle power on and off, adjust a level of the voltage signal, or reverse a polarity of the voltage. The tool 110 is designed to respond to these voltage changes in a predetermined manner. As an example, an inflatable setting tool may toggle between a high volume-low pressure pump and a low volume high-pressure pump when power is cycled.
A less expensive, non-electric support cable is commonly referred to as slickline. Because slickline has no conductive lines to supply power to the attached tool, the types of the tools deployed on slickline are typically non-electric tools, such as placement and retrieval tools, mandrels, etc. Recently, battery powered tools have recently been developed for slickline operation. Operation of the battery powered tools may be initiated by lowering a slip ring device down the slickline that comes in contact with a switching device on a top surface of the tools. Alternatively, operation of the tools may be initiated by a triggering device that generates a trigger signal, for example, based upon bore hole pressure (BHP), bore hole temperature (BHT), and tool movement. Regardless of the method of initiation, the absence of electrically conductive wires prevents conventional surface intervention used to control wireline tools, which typically limits tools deployed on slickline to simple tools requiring little or no control, such as logging tools.
Accordingly, what is needed is an improved method and apparatus for operating electric downhole tools deployed on slickline.
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This invention relates generally to semiconductor technology, semiconductor processing, and the formation of complementary metal oxide semiconductor integrated circuits.
Complementary metal oxide semiconductor integrated circuits include NMOS transistors and PMOS transistors. Generally, these transistors may be made by forming a gate dielectric and then forming NMOS and PMOS gate structures on top of that dielectric. The gate electrode structures may be made of polysilicon, silicide, or metal.
A dummy gate electrode, such as a polysilicon gate electrode, may also be formed over a gate dielectric. Then the dummy gate electrode may be removed and replaced with a metal gate electrode. In such a process, different metal gate electrodes may be utilized for the NMOS and PMOS transistors, but a common dielectric is utilized.
Thus, there is a need for complementary metal oxide semiconductor fabrication techniques.
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A variety of tools have been developed for use in clearing an obstruction from a toilet, sink, and the like. For example, the most commonly used toilet plungers are relatively simple devices that are designed for non-professional plumbers. These simplistic plungers generally include a dome-like force cup with a rod attached thereto. The force cup is brought into contact with a drain outlet and pushed down by the rod to create pressure against the clog. While simple to use and relatively inexpensive, these types of toilet plungers have several drawbacks. Use of these plungers usually results in water and/or waste splashing out of the toilet to the surrounding area during use. In addition to requiring inconvenient additional clean-up, resulting contact of the toilet's contents with the user is unsanitary and may pose health risks. Furthermore, these common plungers often require a significant amount of physical effort by the user and often (either because of the user or design) are not effective.
Other devices utilize water pressure to dislodge toilet obstructions. For example, U.S. Pat. No. 4,768,237 discloses a toilet plunger having a conventional suction cup and handle. The handle of the device includes a connection for the supply of pressurized water deliverable to the clogged toilet outlet. U.S. Pat. No. 4,238,860 discloses a device that includes a pressurized water receiving-cup and a fitting to be secured within the outlet as water is passed therethrough. These water pressure devices are generally positioned in a sealing engagement with the outlet duct opening so as to rely on a general build up of pressure between the device and the obstruction to dislodge the obstruction. These devices also present a risk that water and other waste in the toilet bowl will splash on the user and surrounding area.
U.S. Pat. No. 2,697,842 discloses a combination hand and air force pressure pump and plunger. This device uses a complex arrangement of valves and conduits for causing a pressure differential at the drain clog. The plunger can be reversed on the base stem of the pump and a flexible hose extends therefrom. However, when used as hand plunger, the device is subject to many of the same disadvantages noted above, e.g., toilet contents such as water/waste contacting the user and using the force pressure mode requires a hook-up to an external pressurized air source. Furthermore, the device includes a piston having a felt or leather piston member making it unsuitable for contacting liquid to which it may be exposed. For example, felt or leather pistons do not easily dry-out, easily degrade upon water contact and may provide an environment for microbial growth.
Toilet plungers, toilet brushes, and similar cleaning devices are commonly known since little substantive change has taken place in this industry since the fist crude plungers and brushes arrived on the market. Furthermore, conventional products do not provide high-end toilet brushes and plungers that bring design, value and most importantly, sanitization to the bathroom. Pathogens (including bacteria and viruses) found in the bathroom (or other areas where plungers/brushes are used) cause serious health problems, and in extreme cases, can even cause death. Conventional methods for keeping these areas sanitized were limited to cleansing chemicals. Such chemicals pose a risk to occupants and also, ultimately, to the environment.
These conventional cleaning devices do not address health concerns, as they have no convenient sterilization capability. Often, storage of these products occurs in a damp, dark environment such as a container or the corner of the room. If contaminated, the brush, plunger, or other cleaning device becomes a breeding ground for viruses and bacteria and many other pathogens. Toddlers, children, pets, as well as adults, who come in contact with these plungers are exposed to the pathogens and risk becoming sick or carriers of the pathogens. The problem is exacerbated in public-use areas such as hospitals, restaurants, dormitories, hotels, and even nursing homes.
The introduction of products with disposable cleaning ends (such as disposable toilet brushes) is one attempt to address this sterilization and cleanliness issue. For example, SC Johnson's Scrubbing Bubbles Fresh Brush, Clorox's Toilet Wand and Scotch Brite's Disposable Scrubbers are products aimed at reducing contamination. However, aside from the increased cost burden, these products still require a non-disposable component (such as a shaft, handle, arm, body, etc.), that may serve as a breeding ground for such pathogens.
UV light sterilization is a safe and proven technology that is widely used in hospitals, air and water purification, food processing and packaging, medical packaging. UV light sterilization is also found in toothbrush holders and surface cleaning sterilizers.
Ultraviolet (UV) light is part of the light spectrum between 100 and 400 nanometers (nm), just below the violet end of the visible spectrum. UV technology is a non-chemical approach to disinfection. In this method of disinfection, no chemicals are added, which makes this process simple, inexpensive and low maintenance.
UV sterilizers use germicidal lamps designed and calculated to produce a certain dosage of ultraviolet light. The principle of design is based on a product of time and intensity. Both parameters require specified levels for successful disinfection.
Accordingly, there remains to be a need for improved plumbing related products.
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The present invention relates to the fields of integrated circuits, networking, systems and processes for packet communications, and especially communication of real time information such as voice, audio, images, video and other real time information over packet.
The Internet has long been usable for Internet file transfers and e-mail by packet switched communication. A different technology called circuit switched communication is used in the PSTN (public switched telephone network) wherein a circuit is dedicated to each phone call regardless of whether the circuit is being communicated over in silent periods. Packet switched networks do not dedicate a channel, thereby sharing a pipe or channel among many communications and their users. Packets may vary in their length, and have a header for source information, destination information, number of bits in the packet, how many items, priority information, and security information.
A packet of data often traverses several nodes as it goes across the network in xe2x80x9chops.xe2x80x9d In a stream of data, the packets representative thereof may, and often do, take different paths through the network to get the destination. The packets arrive out of order sometimes. The packets are not only merely delayed relative to the source, but also have delay jitter. Delay jitter is variability in packet delay, or variation in timing of packets relative to each other due to buffering within nodes in the same routing path, and differing delays and/or numbers of hops in different routing paths. Packets may even be actually lost and never reach their destination. Delay jitter is a packet-to-packet concept for the present purposes, and jitter of bits within a given packet is a less emphasized subject herein.
Voice over Packet (VOP) and Voice over Internet Protocol (VoIP) are sensitive to delay jitter to an extent qualitatively more important than for text data files for example. Delay jitter produces interruptions, clicks, pops, hisses and blurring of the sound and/or images as perceived by the user, unless the delay jitter problem can be ameliorated or obviated. Packets that are not literally lost, but are substantially delayed when received, may have to be discarded at the destination nonetheless because they have lost their usefulness at the receiving end. Thus, packets that are discarded, as well as those that are literally lost, are all called xe2x80x9clost packetsxe2x80x9d herein except where a more specific distinction is made explicit or is plain from the context.
The user can rarely tolerate as much as half a second (500 milliseconds) of delay, and even then may avoid using VOP if its quality is perceptibly inferior to other readily available and albeit more expensive transmission alternatives. Such avoidance may occur with delays of 250 milliseconds or even less, while Internet phone technology hitherto may have suffered from end-to-end delays of as much as 600 milliseconds or more.
Hitherto, one approach has stored the arriving packets in a buffer, but if the buffer is too short, packets are lost. If the buffer is too long, it contributes to delay.
If the network is very congested, and the packet is routed by a large number of hops, the ratio of lost packets to sent packets in a given time window interval can rise not just to 5-10% but even to 25% or more, and the real-time communication becomes degraded. VOP quality requires low lost packet ratio measured in a relatively short time window interval (length of oral utterance for instance, with each packet representing a compressed few centiseconds of speech). By contrast, text file reception can reorder packets during a relatively much longer window interval of reception of text and readying it for printing, viewing, editing, or other use. Voice can be multiplexed along with other data on a packet network inexpensively over long distances and internationally, at low expense compared with circuit-switched PSTN charges.
A Transport Control Protocol (TCP) sometimes used in connection with the IP (Internet Protocol) can provide for packet tags, detection of lost and out-of-order packets by examination of the packet tags and retransmission of the lost packets from the source. TCP is useful for maintaining transmission quality of e-mail and other non-real-time data. However, the delay inherent in the request-for-retransmission process currently may reduce the usefulness of TCP and other ARQ (automatic retransmission request) approaches as a means of enhancing VOP communications.
RTP (Real Time Transport Protocol) and RTCP (RTP Control Protocol) add time stamps and sequence numbers to the packets, augmenting the operations of the network protocol such as IP. However, these do not provide QoS (Quality of Service) control.
For real-time communication some solution to the problem of packet loss is imperative, and the packet loss problem is exacerbated in heavily-loaded packet networks. Also, even a lightly-loaded packet network with a packet loss ratio of 0.1% perhaps, still requires some mechanism to deal with the circumstances of lost packets.
A conventional speech compression algorithm has a portion that samples, digitizes and buffers speech in a frame buffer in frame intervals (e.g. 20 milliseconds), or frames, and another portion that compresses the sampled digitized speech from one of the frames while more speech is being added to the buffer. If the speech is sampled at 8 kiloHertz, then each 20 millisecond example frame has 160 analog speech samples (8xc3x9720). If an 8-bit analog to digital converter (ADC) is used, then 1280 bits (160xc3x978) result as the digitized form of the sampled speech in that 20 millisecond frame. Next the compression algorithm converts the 1280 bits to fewer bits carrying the same or almost the same speech information. Suppose the algorithm provides 8:1 compression. Then 1280/8 bits, or 160 bits of compressed or coded speech result from compression. The compressed speech is then put in the format of a packet, thus called packetized, by a packetizer process.
For every frame of compressed speech in a packet, loss of that packet means loss of each frame in that packet. There then arises the problem how to create 160 bits or more of lost compressed speech. One known approach simply repeats the most recent previous frame that is available at the receiving destination. Another known approach fills the output frame with silence (zeroes). Reduction of packet loss and packet loss handling strategy are very important challenges in advancing VOP technology.
In one form of the invention, a process of sending packets of real-time information at a sender includes steps of initially generating at the sender the packets of real-time information with a source rate greater than zero kilobits per second, and a time or path or combined time/path diversity rate, the amount of diversity initially being at least zero kilobits per second. The process sends the packets, thereby resulting in a quality of service QoS, and optionally obtains at the sender a measure of the QoS. Another step compares the QoS with a threshold of acceptability, and when the QoS is on an unacceptable side of said threshold increases the diversity rate and sends not only additional ones of the packets of real-time information but also sends diversity packets at the diversity rate as increased. Also, rate/diversity adaptation decision may be performed at receiver.
Increasing the diversity rate while either reducing or keeping unchanged the overall transmission rate is an important new improvement in even solely-time-diversity embodiments.
Further forms of the invention involve new criteria for initiating adaptation transitions, and new types of transitions including number of packets-per-second transitions, diversity transitions, source rate transitions and mixtures thereof.
In another form of the invention a single-chip integrated circuit includes a processor circuit, and a source rate/diversity control. Here again, the diversity is contemplated to be time diversity, path diversity and combined time/path diversity in various embodiments.
Other forms of the invention encompass other processes, improved packets and packet ensembles, integrated circuits, chipsets, computer add-in cards, information storage articles, systems, computers, gateways, routers, cellular telephone handsets, wireless base stations, appliances, and packet networks, and other forms as claimed.
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The goal of plant breeding is to combine in a single variety/hybrid various desirable traits. For field crops, these traits may include resistance to diseases and insects, tolerance to heat and drought, reducing the time to crop maturity, greater yield, and better agronomic quality. With mechanical harvesting of many crops, uniformity of plant characteristics such as germination and stand establishment, growth rate, maturity, and fruit size, is important.
Field crops are bred through techniques that take advantage of the plant's method of pollination. A plant is self-pollinated if pollen from one flower is transferred to the same or another flower of the same plant. A plant is cross-pollinated if the pollen comes from a flower on a different plant.
Plants that have been self-pollinated and selected for type for many generations become homozygous at almost all gene loci and produce a uniform population of true breeding progeny. A cross between two homozygous lines produce a uniform population of hybrid plants that may be heterozygous for many gene loci. A cross of two plants each heterozygous at a number of gene loci will produce a population of hybrid plants that differ genetically and will not be uniform.
Corn plants (Zea mays L.) can be bred by both self-pollination and cross-pollination techniques. Corn has separate male and female flowers on the same plant located on the tassel and the ear, respectively. Natural pollination occurs in corn when wind blows pollen from the tassels to the silks that protrude from the tops of the incipient ears.
The development of corn hybrids requires the development of homozygous inbred lines, the crossing of these lines, and the evaluation of the crosses. Pedigree breeding and recurrent selection breeding methods are used to develop inbred lines from breeding populations. Breeding programs combine the genetic backgrounds from two or more inbred lines or various other broad-based sources into breeding pools from which new inbred lines are developed by selfing and selection of desired phenotypes. The new inbreds are crossed with other inbred lines and the hybrids from these crosses are evaluated to determine which of those have commercial potential.
Pedigree breeding for single-gene traits starts with the crossing of two genotypes, each of which may have one or more desirable characteristics that is lacking in the other or which complement the other. If the two original parents do not provide all of the desired characteristics, other sources can be included in the breeding population. In the pedigree method, superior plants are selfed and selected in successive generations. In the succeeding generations the heterozygous condition gives way to homogeneous lines as a result of self-pollination and selection. Typically in the pedigree method of breeding five or more generations of selfing and selection is practiced: F.sub.1 .fwdarw.F.sub.2 ; F.sub.2 .fwdarw.F.sub.3 ; F.sub.3 .fwdarw.F.sub.4 ; F.sub.4 .fwdarw.F.sub.5, etc.
Backcrossing can be used to improve an inbred line. Backcrossing transfers a specific desirable trait from one inbred or source to an inbred that lacks that trait. This can be accomplished for example by first crossing a superior inbred (A) (recurrent parent) to a donor inbred (non-recurrent parent), which carries the appropriate gene(s) for the trait in question. The progeny of this cross is then mated back to the superior recurrent parent (A) followed by selection in the resultant progeny for the desired trait to be transferred from the non-recurrent parent. After five or more backcross generations with selection for the desired trait, the progeny will be heterozygous for loci controlling the characteristic being transferred, but will be like the superior parent for most or almost all other genes. The last backcross generation would be selfed to give pure breeding progeny for the gene(s) being transferred.
A single cross hybrid corn variety is the cross of two inbred lines, each of which has .a genotype which complements the genotype of the other. The hybrid progeny of the first generation is designated F.sub.1. In the development of hybrids only the F.sub.1 hybrid plants are sought. Preferred F.sub.1 hybrids are more vigorous than their inbred parents. This hybrid vigor, or heterosis, can be manifested in many polygenic traits, including increased vegetative growth and increased yield.
The development of a hybrid corn variety involves three steps: (1) the selection of plants from various germplasm pools; (2) the selfing of the selected plants for several generations to produce a series of inbred lines, which, although different from each other, each breed true and are highly uniform; and (3) crossing the selected inbred lines with unrelated inbred lines to produce the hybrid progeny (F.sub.1). During the inbreeding process in corn, the vigor of the lines decreases. Vigor is restored when two unrelated inbred lines are crossed to produce the hybrid progeny (F.sub.1). An important consequence of the homozygosity and homogeneity of the inbred lines is that the hybrid between any two inbreds will always be the same. Once the inbreds that give a superior hybrid have been identified, the hybrid seed can be reproduced indefinitely as long as the homogeneity of the inbred parents is maintained.
A single cross hybrid is produced when two inbred lines are crossed to produce the F.sub.1 progeny. A double cross hybrid is produced from four inbred lines crossed in pairs (A.times.B and C.times.D) and then the two F.sub.1 hybrids are crossed again (A.times.B).times.(C.times.D). Much of the hybrid vigor exhibited by F.sub.1 hybrids is lost in the next generation (F.sub.2). Consequently, seed from hybrid varieties is not used for planting stock.
Corn is an important and valuable field crop. Thus, a continuing goal of plant breeders is to develop high-yielding corn hybrids that are agronomically sound based on stable inbred lines. The reasons for this goal are obvious: to maximize the amount of grain produced with the inputs used and minimize susceptibility to environmental stresses. To accomplish this goal, the corn breeder must select and develop superior inbred parental lines for producing hybrids. This requires identification and selection of genetically unique individuals which in a segregating population occur as the result of a combination of crossover events plus the independent assortment of specific combinations of alleles at many gene loci which results in specific genotypes. Based on the number of segregating genes, the frequency of occurrence of an individual with a specific genotype is less than 1 in 10,000. Thus, even if the entire genotype of the parents has been characterized and the desired genotype is known, only a few if any individuals having the desired genotype may be found in a large F.sub.2 or S.sub.0 population. Typically, however, the genotype of neither the parents nor the desired genotype is known in any detail.
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User interfaces have traditionally relied on input devices such as keyboards, which require physical manipulation by a user. Increasingly, however, it is desired to utilize more natural input mechanisms such as audio and speech.
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The present invention relates generally to puller tools for removing internal bearings, bushings, sleeves and the like, and more particularly to a puller tool useful in removing the aforementioned items from a blind hole.
A widely recognized difficulty in the servicing of precision spindles is the removal of tapered roller, and angular contact bearings from deep within a blind hole. Removal is problematic because, while an inner roller portion of the bearing is often easily extracted, an outer sleeve of the bearing remains lodged within the hole in close circumferential fit and with a distal annular face thereof flush against a bottom seat surface of the hole. A similar problem is encountered in other service industries, for example in the automotive repair industry, where bearings must be removed from wheel/brake housings.
A variety of puller tools have been developed for extracting internally seated bearings and like items having an axial bore or opening extending between opposite annular faces thereof. A first type of puller tool is generally characterized by means insertable within the bore or opening for engaging an inner wall of the item, or for engaging a specially formed recess, hole, or step in the inner wall. Examples of this first type of puller tool may be found in U.S. Pat. Nos. 4,110,886; 2,662,276; and 2,380,068. A second type of puller tool is generally characterized by means insertable through the bore or opening for engaging a distal annular face of the item. Examples of this second type of puller tool are disclosed in U.S. Pat. Nos. 5,251,368; 5,058,255; 3,945,104; and 3,083,449.
Puller tools of the first type mentioned above have the disadvantage that they usually require a specially formed step or hole in the inner wall of the item to be extracted for engagement by the puller tool, because the distal annular face of the item is not engaged. If the puller tool is designed to directly engage the inner wall, damage to the inner wall may occur, a result which is not acceptable in expensive, high-precision bearings. Puller tools of the second type require clearance adjacent the distal annular face of the item to permit engagement of the face by the puller tool. Consequently, where the item is seated within a blind hole with its distal annular face flush against a bottom or seat surface of the hole, puller tools of the second type are ineffective.
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With the development of Electronic Commerce (e-commerce), more and more users purchase items using e-commerce services. In general, an e-commerce website owns tens of millions or even hundreds of millions of items, and thus the users have to search the website to find desired items. A server associated with the website may perform searches based on keywords provided by the users, and return results corresponding to the keywords.
In response to a keyword, the server may produce a larger number of search results. Accordingly, the search results need to be sorted and/or ranked according to a certain order during presentation. The server may take comprehensive consideration into how to rank these search results. For example, search results may be ranked according to a correlation between the search results and a keyword, previous click-through rates, previous deals associated with the search results, and etc. For an e-commerce website, to improve the sales volume of a commodity, the server may also consider deal feasibilities (e.g., deal conversion rates and positive feedback rates of search results).
Currently, a server of an e-commerce website ranks search results based on the correlation and deal feasibility predictions that are generally obtained based on manual analysis on historical data, empirical determination of commodity characteristics and weights of the search results (i.e. a specific commodity), and/or calculations according to a certain formula. Commodity characteristics refer to factors that are capable of affecting the deal feasibility of the commodity (e.g., sale volumes, positive feedback rates, and deal conversion rates). Since determination of characteristics and weights by empirical setting is relatively random and subjective, errors often occur. The returned search results may differ significantly from what the users desired, or ranking of the search results may not satisfy the users. Because the server may only return a certain number of search results, the users may not receive their desired results. To obtain their desired results, the users may modify keywords and re-submit queries. This causes the server to have increased data transmission, which undoubtedly increases the burden on the server and occupies a lot of network resources or even leads to network congestion. Meanwhile, this also indicates that the search results returned by the server have a large amount of irrelevant data, and server resources and network resources are therefore wasted.
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In hybrid vehicles, energy storage components are known, such as special batteries, ultra capacitors, compressed materials, and flywheels for improving the fuel efficiency. This is particularly important for plug-in vehicles, because the battery has a limited energy capacity; any cost effective approach that can store and reuse the wasted energy must be utilized.
Hsu, U.S. Pat. No. 7,134,180 issued Nov. 14, 2006, describes a dual-rotor axial gap motor with a PM rotor (rotor with permanent magnets) and a second rotor for use in a hybrid vehicle. The second rotor is referred to as an uncluttered rotor because it couples only slip energy with the excitation coils due to the peripherally-oriented excitation coils.
There remains a need to provide a drive system for hybrid vehicles that will accomplish acceleration and braking while saving energy.
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The Internet and the World Wide Web have made great strides at bringing the world to the average home. Incredibly rich and detailed information about almost any part of the globe may reside merely a few keystrokes away from the typical computer user. But the typical computer user loses access to this rich pool of information once leaving home. Of course, the computer user could regain access to rich sources of information by reconnecting his computer to an electronic network after leaving home, but such connections are typically cumbersome and their availability is often limited.
Consider, for example, a computer user at a museum who wants information related to an exhibit at the museum. Typically, she would have to locate a public telephone, physically connect her computer to the telephone, establish a network connection via a dialup modem, and then begin her information retrieval search. Not only is this process cumbersome and inconvenient, but as soon as the computer user disconnects from the network, she will typically lose access to the information provided by the network. Of course, the computer user could save some of the information in memory on her computer, but she will nevertheless likely lose all interactive abilities to manipulate the information provided by the network once disconnected, and she will definitely lose the ability to posit new queries after disconnection.
Consider another computer user visiting a baseball park, for example. This computer user could conceivably bring with him a computer having an ability to connect to the Internet wirelessly through the public telephone network. Once connected, the computer user could then locate information about the baseball park and/or the relevant baseball teams and could theoretically continue reviewing the information provided over the electronic network throughout the entire game or even longer. Unfortunately, this computer user will typically have to pay more for this service and its related equipment than for a connection over a typical dialup network. In addition, the wireless connection between the computer user and the network may become broken for various reasons, such as interference, and once the connection is broken, the computer user will lose all access to the information provided by the network. Worse still, the computer user may have to contend for an available wireless connection, especially since this computer user will not be competing with just other visitors to the baseball park but with everyone who wants to connect to the wireless network. In fact, suppose the computer user is attending a popular baseball game and many other spectators also have established wireless connections. The computer user will not only have to contend for bandwidth in establishing a connection to the wireless network, but the computer user may also have to contend for access to particular information resources, e.g., the home team's website. Such website may have limited abilities for correctly processing requests during an access request surge, e.g., thousands of spectators at a major league baseball game all concurrently trying to access a wireless network and then trying to access their team's website.
The problem has thus far been examined from the viewpoint of the individual computer user. The problem assumes an added dimension when considered from the point of view of society as a whole. Imagine a large telecommunications network whose capacity is sapped by thousands of computer users who are not using their connections to in electronic network to learn about distant, remote places but are instead using their electronic network connections to access information about people and places standing-fight in front of them. Even if a telecommunications network could support a vast number of such connections, the situation would still remain inherently wasteful and may be likened to telephoning someone within speaking range.
Thus, individual computer users should benefit from improvements in their ability to access information at remote locations. Likewise, society as a whole should benefit if such improvements are undertaken in a manner that does not inappropriately consume available resources.
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The present invention relates to an apparatus for filling or bleeding fluid out of a container which is closed by a plug.
Certain Navy applications require that oil-filled cables be towed from the stern of a ship. It is important that these cables be free of any air bubbles since any air entrapment in the cable causes degraded performance depending upon the depth at which the cable is towed. In the past, these air bubbles have been removed from these oil-filled cables by many man-hours of labor under hazardous conditions. A group of workmen was required to lay a large section of the cable on the fantail of the ship and stop it off so as to resist the pull of the remainder of the cable payed out from the stern of the ship. The cable is then raised progressively from stern to forward until the air bubbles are at a forward entry port of the cable, and then men stand on the cable to create a pressure to expel the bubbles from the port. Complete removal of all of the air bubbles is almost impossible by this procedure and, depending upon the sea state, this operation can be quite hazardous.
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1. Field of the Invention
The present invention relates to magnetic resonance scanning apparatus for imaging parts of a human head comprising a plurality of RF coils configured to receive an RF signal. In particular, the invention relates to neurological imaging apparatus.
2. Description of the Related Art
In a magnetic resonance imaging system for imaging parts of a human head, it is known to have RF (radio frequency) transmitting coils which transmit RF pulses to the head, and separate RF coils configured to receive the consequently emitted RF signals from the various tissues of the head.
Typically, the receiving RF coils form an array of small sized coils surrounding the head of a human subject. In recent years, a technique referred to as parallel imaging has been developed which allows each coil in an array to provide a different signal, and thereby provide further spatial information and reduce required scanning times. Such coil arrays are configured on a rigid circular former that surrounds the head giving reasonable clearance to allow the head good access, and therefore spaced away from the head, typically on a diameter of 27 cm or more, or they are based on dome shaped rigid structures that cover the top of the head but not below the eyes. One continuing problem with such RF receiving coils is the less than optimal signal to noise ratios of the signals they produce.
A further problem with existing RF receiving coils is the claustrophobic effect they can have on the human subject, due to their appearance over their face.
Yet another problem with such receiving coil arrays is that they generally rely on the human subject to keep their head stationary during the several minutes it takes to perform the scan.
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{
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In the technical field of secret computation that involves processing data while concealing the data by secret sharing, there is a known conventional technique (referred to as “share quotient computation”) that involves determining a quotient q of the division by a value p of a sum aZ of a sequence of distributed numbers x0, . . . , xm-1 that are smaller than an arbitrary modulo p (that is, a value q in an expression aZ=a+qp, where 0≤a<p, and 0≤q<m):
[ Formula 1 ] a Z := ∑ i < m x i
A technique that achieves the share quotient computation is bit decomposition (Non-patent literature 1).
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1. Field of the Invention
The present invention relates to a fuel cell vehicle and a method of controlling a fuel cell and a storage battery provided in the fuel cell vehicle.
2. Description of the Related Art
A typical polymer electrolyte fuel cell includes an electrolyte membrane (electrolyte)-electrode assembly in which an electrolyte membrane formed by a polymer ion exchange membrane (a cation exchange membrane) is held between an anode electrode and a cathode electrode, and separators between which the assembly is held. Fuel cells of this type are in general provided as fuel cell stacks each obtained by stacking a specific number of cells each including an electrolyte membrane-electrode assembly and separators.
In such a fuel cell stack, a fuel gas, for example, a hydrogen-containing gas, supplied to the anode electrode is hydrogen-ionized by an electrode catalyst, passes through the electrolyte membrane moistened to an appropriate level, and moves to the cathode electrode. Electrons produced in this movement are taken by an external circuit and are used as direct-current electric energy. The cathode electrode is supplied with an oxidant gas, for example, an oxygen-containing gas such as air. Therefore, the hydrogen ions, the electrons, and the oxygen react to each other at the cathode electrode, whereby water is produced.
Japanese Unexamined Patent Application Publication No. 2001-325976 ([0064] to [0067] and FIG. 6) proposes a technique relating to a fuel cell vehicle that runs on a fuel cell, such as the one described above, and a storage battery both functioning as drive sources with a motor functioning as a power source.
In the technique proposed by Japanese Unexamined Patent Application Publication No. 2001-325976, the output of the fuel cell is made to follow the degree of accelerator opening (an output required by a load) in such a manner as to become higher as the remaining capacity in the storage battery becomes smaller.
In such a technique, however, in which the output of the fuel cell is controlled to follow the output required by the load, the fuel cell may be overloaded and the durability of the fuel cell may be reduced because of, for example, a high possibility of damage on the electrolyte membrane. Consequently, the durability of the fuel cell vehicle may be reduced.
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This invention relates to partially dehydrated reaction products derived from (A) a hydrocarbyl substituted succinic acid or anhydride, and (B) a polyol, polyamine, hydroxyamine or mixture of two or more thereof. The invention also relates to a process for making these partially dehydrated reaction products. The inventive reaction products are useful as emulsifiers in making emulsions, especially explosive emulsions and emulsion fertilizers.
Explosive emulsions typically comprise a continuous organic phase and a discontinuous oxidizer phase containing water and an oxygen-supplying source such as ammonium nitrate, and an emulsifier. Examples of such explosive emulsions are disclosed, inter alia, in U.S. Pat. Nos. 4,708,753 and 5,920,031. In U.S. Pat. No. 4,708,753 the emulsifier is a salt derived from a hydrocarbyl-substituted carboxylic acid or anhydride, or ester or amide derivative of said acid or anhydride, the hydrocarbyl substituent having an average of from about 20 to about 500 carbon atoms, and an amine. In U.S. Pat. No. 5,920,031 the emulsifier is the product made by the reaction of component (A) with component (B). Component (A) is a substituted succinic acylating agent, said substituted succinic acylating agent consisting of substituent groups and succinic groups wherein the substituent groups are derived from a polyalkene, said acylating agents being characterized by the presence within their structure of an average of at least 1.3 succinic groups for each equivalent weight of substituent groups. Component (B) is ammonia and/or a mono-amine.
U.S. Pat. No. 5,512,079 discloses an emulsion fertilizer comprising a discontinuous aqueous phase comprising at least one fertilizer component such as ammonium nitrate; a continuous oil phase; and an emulsifier. The emulsifier is the reaction product of a hydrocarbyl substituted succinic anhydride acylating agent and a tertiary alkanol amine.
A problem in the explosive emulsion and emulsion fertilizer arts relates to the fact that it is desirable to lower the viscosities of the emulsions in order to improve their pumping and handling characteristics. It is also desirable to make emulsions with relatively high aqueous phase to organic phase weight ratios. This is advantageous with explosive emulsions because it permits the delivery of more of the oxygen-supplying source with the same weight of emulsion. Similarly, this is advantageous with emulsion fertilizers because it permits the delivery of more of the fertilizer component with the same weight of emulsion. Unexpectedly, by use of the inventive reaction products as emulsifiers it is possible to formulate explosive emulsions and emulsion fertilizers having these characteristics. Going beyond explosive emulsions and emulsion fertilizers, the inventive reaction products are useful as emulsifiers in a wide variety of applications.
PCT publication WO96/25384 discloses monomeric, aligomeric and polymeric bisesters of alkyl- or alkenyldicarboxylic acid derivatives and polyalcohols, and their use as solubilizers, emulsifiers and/or detergents. The bisesters are described as being useful in formulating cosmetic compositions, detergents and cleaners, pharmaceutical compositions, foodstuffs and crop protection compositions. A process for preparing these bisesters is disclosed.
This invention relates to a composition comprising a partially dehydrated product made by:
(I) reacting (A) a hydrocarbyl substituted succinic acid or anhydride with (B) a polyol, a polyamine, a hydroxyamine, or a mixture of two or more thereof, to form a first intermediate product comprising: an ester, partial ester or mixture thereof when (B) is a polyol; an amide, imide, salt, amide/salt, partial amide or mixture of two or more thereof when (B) is a polyamine; or an ester, partial ester, amide, partial amide, amide/salt, imide, ester/salt, salt or a mixture of two or more thereof when (B) is a hydroxyamine, a mixture of a polyol and a polyamine, a mixture of a polyol and a hydroxyamine, a mixture of a polyamine and a hydroxyamine, or a mixture of a polyol, a polyamine and a hydroxyamine; the hydrocarbyl substitutent of said acid or anhydride having an average of about 8 to about 200 carbon atoms; and
(II) heating said first intermediate product at an effective temperature to form a second intermediate product with water of reaction being formed, and separating a portion of said water of reaction from said second intermediate product to form said partially dehydrated product, when (A) is said succinic anhydride the amount of water of reaction that is separated is from about 0.2 to about 0.9 moles of said water of reaction per equivalent of said succinic anhydride, when (A) is said succinic acid the amount of water of reaction that is separated is from about 1.2 to about 1.9 moles of said water of reaction per equivalent of said succinic acid, said partially dehydrated product having an acid number in the range of about 20 to about 100 mg of KOH/g.
This invention also relates to a process, comprising:
(I) reacting (A) a hydrocarbyl substituted succinic acid or anhydride with (B) a polyol, a polyamine, a hydroxyamine, or a mixture of two or more thereof, to form a first intermediate product comprising: an ester, partial ester or mixture thereof when (B) is a polyol; an amide, imide, salt, amide/salt, partial amide or mixture of two or more thereof when (B) is a polyamine; or an ester, partial ester, amide, partial amide, amide/salt, imide, ester/salt, salt or a mixture of two or more thereof when (B) is a hydroxyamine; a mixture of a polyol and a polyamine, a mixture of a polyol and a hydroxyamine, a mixture of a polyamine and a hydroxyamine, or a mixture of a polyol, a polyamine and a hydroxyamine; the hydrocarbyl substituent of said acid or anhydride having an average of about 8 to about 200 carbon atoms; and
(II) heating said first intermediate product at an effective temperature to form a second intermediate product with water of reaction being formed, and separating a portion of said water of reaction from said second intermediate product to form said partially dehydrated product, when (A) is said succinic anhydride the amount of water of reaction that is separated is from about 0.2 to about 0.9 equivalents of said water of reaction per equivalent of said succinic anhydride, when (A) is said succinic acid the amount of water of reaction that is separated is from about 1.2 to about 1.9 moles of said water of reaction per equivalent of said succinic acid, said partially dehydrated product having a total acid number in the range of about 20 to about 100 mg of KOH/g.
This invention also relates to emulsions, comprising: an organic phase; an aqueous phase; and an emulsifying amount of the foregoing partially dehydrated product.
As indicated above, the inventive partially dehydrated reaction products are useful as emulsifiers in formulating emulsions for a wide variety of applications. These include one or more of the following: lubricants or functional fluids; fuels; paints; coatings; inks; caulks or adhesives; fertilizers or agricultural chemicals; refinery or oil-field products; mining products; explosives; commodity chemical manufacturing processes; processes involving the use of emulsions containing 2-acrylamido-2-methyl-1-propane sulfonic acid monomer; and the like.
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Machines, for example backhoes, excavators, graders, and loaders, commonly have linkage that is movable to control the motion of a connected tool such as a bucket, a blade, a hammer, or a grapple. When equipped with a single tool, these machines become specialized machines that are primarily used for a single purpose. Although adequate for some situations, the single purpose machines can have limited functionality and versatility. A tool coupler assembly can be used to increase the functionality and versatility of a host machine by allowing different tools to be quickly and interchangeably connected to the linkage of the machine.
Tool coupler assemblies are generally known and include a frame connected to the linkage of a machine, and hooks or latches that protrude from the frame. The hooks of a tool coupler assembly engage corresponding pins of a tool to thereby connect the tool to the linkage. To help prevent undesired disengagement of the hooks from the pins, tool coupler assemblies can be equipped with a hydraulic piston that locks the hooks in place against the pins.
When connecting or disconnecting a tool to a host machine, precautions should be taken to help ensure the procedure is performed properly. For example, the tool should be in a desired resting position before decoupling is performed so that the tool does not move in an unexpected manner after the decoupling. In addition, fluid provided to the hydraulic piston of the tool coupler assembly should be at a pressure that allows proper operation of the tool coupler assembly without causing damage to the assembly.
The tool coupler assembly of the present disclosure addresses one or more of the needs set forth above and/or other problems of the prior art.
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{
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The invention generally relates to internal combustion engines and, more particularly, to single or multi-cylinder two stroke cycle internal combustion engines.
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{
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a printed circuit board, and, more particularly, to electroconductive paste to be enclosed in a through hole connecting circuits disposed on the two sides of a printed circuit board.
2. Description of the Related Art
Hitherto, double-side printed circuit boards have been designed in such a manner that predetermined patterns of electroconductive bodies are formed by two sheets of copper foil laminated on the two sides of an insulating substrate of a copper laminated board, through holes being formed at predetermined positions in the substrate, and electroconductive paste which is normally made of copper paste being enclosed in predetermined through holes so that electrical connection between two circuits on the two sides of the insulating substrate is established.
The other manufacturing processes such as mounting of the electronic parts, soldering, and forming insulating coating are performed in known ways. Thus detailed description of these factors will be omitted here.
There has, however, been a demand for the size of such printed circuit boards to be reduced in accordance with the trend for reducing the size of electronic parts. Furthermore, in order to reduce the number of manufacturing processes, a significant degree of automation has been achieved. This raises the problem that when a copper paste is introduced from one side into the through holes by means of silk screen printing, the copper paste cannot be properly adhered to the conductive body of the circuit disposed on the reverse side, leading to a condition of defective conduction.
If an excessive amount of copper paste is supplied on the silk screen when silk screen printing with copper paste is performed, the copper paste overflows the target regions, causing short circuits or the like between the circuits on the two sides. There is, therefore, a certain limitation to the amount of paste that can be supplied on the silk screen, but this restricted amount of paste is insufficient to overcome the problem of defective conduction.
To this end, an object of the present invention is to provide a printed circuit board capable of overcoming the above-described problems and of displaying a high level of reliability and in which the generation of defective conduction can be prevented without comprising the conventionally achieved level of facility for manufacture and maximized economic advantage.
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{
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This disclosure is directed to flexible sheet-like composites comprising a fabric layer and a film layer, and processes for constructing such composites. More particularly, this disclosure describes various flexible sheet-like substrates that are lightweight, rupture or burst resistant, and suitable for use in constructing a variety of structures used in fluid-containment, especially gas containment, and other applications, and the processes by which such composites can be fabricated. In the most general case, the composites of this disclosure are comprised of a woven textile fabric to which has been laminated a flexible film. Two principal embodiments are disclosed: a first embodiment without a reinforcing layer, and a second embodiment with a structurally robust, bias-oriented reinforcing layer, preferably interposed between the fabric and the film. Various alternative constructions applicable to each of these principle embodiments, such as variations in fabric construction details, yarn composition, fabrication techniques, film composition and configuration, etc., are also set forth as part of the respective discussions of each of these embodiments.
Among other aspects, special attention in each embodiment is paid to the matter of (1) evenly loading the individual yarns comprising the textile fabric as a means for providing rupture resistance and dimensional stability (specifically including resistance to skewing forces) to the composite, (2) configuring the layers of the composite to reduce weight without unacceptable loss in strength, and (3) providing means within the laminate structure to allow for the passage of lamination gasses and the flow of adhesive, to assure sufficient bonding between the outer layers of the laminate and thereby provide resistance to de-lamination, particularly whenever the composite structure is subjected to stress. Structures constructed using the composites described herein, which may include, for example, lighter-than-air airships, provide exceptional resistance to bow, bias, and skew as well as a high tear and tensile strength that is uniform across the width and length of the composite substrate and, consequently, any structures made from such composites.
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Liquid composite moulding for processes such as resin transfer moulding hold great industrial interest for manufactures of complex thick composite structures. At present, one significant drawback to the widespread introduction of such structures into advanced engineering applications is the low toughness of the resin system suited to these processes. This disadvantage is particularly acute in the domain of civil aerospace where the material properties of composites are extremely demanding.
The low viscosity required for liquid composite moulding precludes the use of thermoplastic toughening agents. This results in composite structures with a low toughness, and therefore limited damage tolerant performance.
One solution to this problem is the augmentation of conventional composite structures with carbon nanotubes (CNTs). It has been demonstrated in the literature that secondary carbon nanotubes can be grown on the surfaces of primary carbon fibres.
If the carbon nanotubes can be grown with an appropriate concentration relative to each other, self-alignment can be obtained as a result of the van der Waals interactions between the tubes.
Thus an aligned CNT structure can be formed between the fibres. However, no process currently exists for the practical fabrication of composite components exhibiting such a structure.
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The following acronyms are used in this disclosure:
CoMP Coordinated Multipoint
CP Cyclic Prefix
LTE Long Term Evolution (4G)
MAC Medium Access Control
NR New Radio (5G)
OFDM Orthogonal Frequency Division Multiplexing
PCI Physical Cell Identity
PHY Physical
PSS Primary Synchronization Signal
RRC Radio Resource Control
SB SS Block
SFN Single Frequency Network
SI System Information
SINR Signal to Interference plus Noise Ratio
SNR Signal to Noise Ratio
SS Synchronization Signal
SSS Secondary Synchronization Signal
TRP Transmission Reception Point
UE User Equipment
UMTS Universal Mobile Telecommunication System (3G)
In order to allow for flexible operation of wireless communication systems, such as LTE, UMTS and NR networks, for example, the network broadcasts system information (SI) to user equipment (UE). The SI may include information necessary for the UE to access the network, such as system bandwidth and random access configuration information, for example. The SI may be divided into different parts, for example into system information blocks as in LTE, or into minimal or other types of SI, as in NR. Furthermore, different SI parts may be delivered in different ways, for instance by broadcasting in one cell, single-frequency-network (SFN) transmission in multiple cells, multi-cast transmission to a set of UEs or unicast (dedicated) transmission to a single UE.
In a typical initial access procedure, a UE starts to search for synchronization signals (SS), where different SS typically correspond to different cells. Typically, different cells can be distinguished by different IDs, which are embedded in the SS. As discussed herein, terminology commonly used when describing an LTE system will be used, such as “Physical Cell Identity (PCI).” It should be understood, however, that the discussion of LTE systems is merely exemplary, and the present disclosure is not limited to LTE systems. In some systems, the SS is divided into multiple parts, where different parts carry an identity, and the PCI is a combination of the partial identities. In LTE, for example, the SS is divided into PSS and SSS, which both carry independent identities, and the PCI is a combination of the PSS identity and the SSS identity.
An SI validity area is a set of cells in which some or all SI is valid, as described in 3GPP TSG-RAN WG2 Meeting #95 (Aug. 22-26, 2016) document R2-165202 entitled, “Quantitative Analysis of On-demand SI Delivery,” the contents of which are incorporated herein it its entirety. By default and in state-of-the-art systems, the SI validity area is a single cell. However, by defining an SI validity area larger than one cell, a UE may avoid receiving and decoding the same (some or all) SI repeatedly when it moves between cells in the set. With a single-cell SI validity area, a UE needs to decode the SI each time it moves to a new cell, since it cannot assume that the SI of the new cell is the same as the SI of a previously received and decoded SI of another cell. Note that the SI validity area may be different for different parts of the SI as described in 3GPP TSG-RAN WG2 Meeting #95bis (Oct. 10-14, 2016) document R2-166353 entitled, “NR System Information Areas for Other SI,” the contents of which are incorporated herein it its entirety. For example, one SI part could be valid in a small number of cells, e.g. a single cell, and another SI part could be valid in a large number of cells. A group of cells for which a part of the SI is valid is also called a SI group herein.
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During the 1950's and 1960's many pharmaceutical concerns launched extensive programs to synthesize modified corticosteroids. The objective was to create systemically active compounds having more potent anti-flammatory activity than the naturally occuring corticoids but without correspondingly elevated levels of side effects such as interference with the pituitary-adrenal relationship (leading to adrenal insufficiency) and effects on electrolyte balance and glucose metabolism.
The initial efforts resulted in certain quite potent compounds of the prednisolone series having a 9.alpha.floro constituent in combination with 16-.alpha. or .beta.-methyl or 16.alpha.hydroxy substitution, such as Betamethasone, dexamethasone, and triamcinolone. Certain compounds having 16-.alpha.methyl substitution along with a 6.alpha.floro substituent (paramethasone) or with combined 6.alpha., 9.alpha.floro substitution (flumethasone) also proved interesting. Prednisolone derivitives having a 6.alpha.floro substituent and 16.beta.-methyl substitution were apparently not explored and these are the subjects of this invention. In the above noted prior art compounds, the problem of electrolyte imbalance (primarily sodium retention with potassium depletion) was substantially reduced. Various theories were advanced for this with one or more groups being said to enhance potency (.DELTA.' and 9.alpha.F) either with (9.alpha.F) or without (.DELTA.') some degree of potentiation of mineralcorticoid activity and with other substituents (16-OH,.alpha.CH.sub.3 or .beta.CH.sub.3) being said to attenuate somewhat the mineralcorticoid effect. In any event, when the lower doses made possible by enhanced potency were used, observed electrolyte activity was reduced and it is generally accepted today that at therapeutic doses the compounds which are .DELTA.'.sup.4 dienes with 6.alpha. and/or 9.alpha.halogen substitution combined with 16-methyl or 16.alpha.hydroxy substitution do not cause an unacceptable degree of electrolyte imbalance.
Despite these early successes, significant separation of other side effects, such as glycogen diposition, from therapeutic activity proved difficult. It was later noted that in some cases the 16.alpha.methyl substitution could, by itself, be employed to augment anti-inflammatory activity somewhat more than glycogen deposition and that 16.beta.methyl substitution could be employed to diminish glycogenic properties somewhat without altering the anti-inflammatory activity.
The above noted first prepared modified cortosteroids and their esters and other derivatives are still widely used today in various forms, and betamethasone and its esters still represent today almost one-third of the prescriptions written in the United States for topical steroids. Dexamethasone, fluromethasone and paramethasone are also still used clinically today, although to a much lesser degree.
Despite: (1) the above general and accepted statements about the relationship of structure and biological activity (2) the initial and continued success for almost twenty years of Betamethasone (9.alpha.difloro 16.beta.-methyl prednisolone) and its esters as topical anti-inflammatory agents and (3) the use for over a decade of paramethasone acetate (6.alpha.Floro-16.alpha.methyl-prednisolone-21-acetate) as a systemic anti-inflammatory agent, there remarkably appears to have been no discovery of the 6.alpha.-floro-16.beta.-methyl-prednisolone or its esters.
In the mid-1960's, attention turned to attempts at development of highly effective topical corticoids with little or no systemic effects. The former objective was pursued through a combination of potentiated anti-inflammatory activity per se and/or improved absorption through the stratum corneum. The latter objective was pursued through reduction of systemic activity per se and/or reduction in the ability to migrate from the epidermis into the dermis after penetration of the stratum corneum.
Two important corticoids developed at that time which are still major factors today are the 16-17 acetonides of Triamcinolone and its 6.alpha., 9.alpha.difloro counterpart, fluocinolone. For some reason, still not fully understood, triamcinolone acetonide is about ten times as active as Triamcinolone topically, but only equiactive systemically. Fluocinolone acetonide is essentially ineffective systemically even though it is perhaps even more active topically than its Triamcinolone counterpart. For topical steroids these compounds plus related Fluandrenalone (6.alpha.F, 16.alpha.OH, hydrocortisone 17,21 acetonide) today represent more than one half of all prescriptions in the United States. While due to the acetonide formation they differ significantly in structure from the compounds of this invention, they are mentioned here because of their importance in the overall mileau.
At the end of the 1960's, much attention was given to the esters of the earlier discussed compounds and of other compounds, such as beclomethasone (the resulting dipropionate), which had not found earlier commercial use. In some, but by no means all instances, the esterification at 17 and/or 21 was found to improve the potency of therapeutic effect as evaluated by Vasoconstriction assays. What is most striking from the literature of that time is the unpredictability of the results of esterification when trying to apply knowledge gained with one skeletal series to another skeletal series. Mostly this is due to the subtle alteration of the shapes of molecules caused by even minor structural differences and it is on the basis of shape that hormones are recognized by their receptors.
One of the most completely explored series of esters is those of Betamethasone (9.alpha.F, 16.beta.- CH.sub.3). When esterified in the 17 position, betamethasone is potentiated from activity of 1% of fluocinalone acetonide to up to 350% of fluocinolone acetonide as the ester chain increases from acetate through butyrate and propionate up to valerate, the latter compound being one of the most widely used topical anti-inflammatory agents today. The 17-benzoate, U.S. Pat. No. 3,529,060, has recently been found to be of equal activity to the valerate. Esterification in the 21-position also causes some potentiation of anti-inflammatory activity, but primarily imparts more long acting effects as was expected, from early findings, mentioned previously, on the 21-acetates of betamethasone. As noted earlier, the esters of Betamethasone today represent almost one-third of prescriptions for topical steroids in the United States.
Another series receiving a lot of attention were the 6,9 difloroprednisolones (16 unsubstituted) through the work of Gardi, et al described for example in the Journal of Medicinal Chemistry, 15, 556 (1972) and 15,783 (1972), in Steroids, 16:6, 663 (1970), and in U.S. Pat. Nos. 3,780,177 (6,9 difloroprednisolone 17-butyrale, 21-acylates), 3,784,692 (the corresponding 17 propionates, 21 acylates), 3,691,214 (17-valerates) and 3,857,941 (17-benzoates). Commercial uses of these compounds has not yet begun in the United States.
Finally, the diacetate of 6,9 difloro-16.beta.methyl prednisolone was discovered by Upjohn to be a very interesting compound subsequently commercialized in the United States. However, none of the other esters seem to have received attention.
An excellent summary of the history of structural modifications of corticosteroids appears as Chapter 9, Anti-inflammatory Steroids, in Anti-Inflammatory Agents, Scheerer (Ed), Academic Press (1974).
This relative activity is surprising since in the 9.alpha.Floro compounds the 16.alpha.-methyl series (Dexamethasone) are known to be more active than the 16.beta.methyl series (betamethasone).
As noted earlier, I have now discovered the 6.alpha.Floro, 16.beta.methyl prednisolone diesters and have found that these compounds are important anti-inflammatory agents, certain of which are of superior potency to 6.alpha.floro, 16.alpha.methyl counterparts in the cotton pellet granuloma rat assay and quite active in the modified McKensie vasoconstriction assay in man. In addition, unlike paramethasone per se, certain members of the series exhibit only limited effect on the thymus and adrenal glands.
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