A grounding clamp for permitting the grounding of an electrical cable provided with a 2-hole compression connector allowing the grounding of this cable to a metallic pipe. A mechanical clamp provided with a saddle portion and one or more U-bolts is mounted to the pipe. The mechanical clamp is provided with a mounting pad onto which the compression conductor is also mounted. A connection system is provided between the mounting pad and the compression lug allowing the electrical cable to be angled at different directions with respect to the metallic pipe.

It is well known in the art to protect a house, building or other structure from a fire hazard by establishing a connection between the electrical system in the particular edifice and ground. In this manner, the edifice is protected from stray current, short circuits or similar potentially dangerous situations. One particularly effective manner of connecting the electrical system to ground will utilize the employment of a metallic water or similar pipe as the ground connection.
Typical prior art systems and methods for connecting an electrical system to a metallic pipe are shown in U.S. Pat. Nos. 1,864,292; 1,897,186; 1,899,309 all issued to Buchanan; U.S. Pat. No. 1,793,911 issued to Dann and U.S. Pat. No. 2,156,965 issued to Borden. The patent to Borden describes a ground fitting for connecting a ground wire to a waterpipe or other earth electrode. A body member 17 and a ground clamp are provided to connect the ground wire either in parallel to the waterpipe or transverse to the waterpipe. The patent to Dann discusses a ground fitting for an electrical system including a conduit-supporting member provided with a socket adapted to receive one end of a conduit, a clamp adapted to grip a waterpipe or other grounding medium, and a means for pivotally connecting the conduit-supporting member and the clamp together. The patents to Buchanan describe a ground fitting consisting of two members, one of which is anchored to an electrical conduit, and the other of which is clamped to a grounded pipe. Particularly with respect to Buchanan '186, it is noted that these two members can be assembled into a predetermined or limited number of angular positions with respect to one another.
However, it is noted that these prior art references do not utilize a compression connector, housing an electrical cable to be grounded. Additionally, none of these references show a system in which mounting pads are provided directly on the compression connector and an arcuate seat used to connect one or more U-shaped clamping bolts around a metallic pipe in order to allow the electrical cable to be provided at different angles with respect to the metallic pipe.

Grounding pipe/water pipe with compression connectors


A system is provided for regulating a ground speed of a vehicle having an engine and a variable transmission that is driven by the engine. The system includes a mode selector that is movable for selection between a high speed mode of operation and a deceleration mode of operation. The system also includes a controller connected in communication with the mode selector and a manual input. The controller is configured to receive and store a deceleration gear value via the manual input for operation of the system. When the mode selector is selectively positioned for the deceleration mode of operation, the controller is operatively connected to cause the engine to operate at a deceleration engine speed value, and to cause the transmission to automatically shift to the deceleration gear value.

Known cruise control systems have been developed to set a ground speed of vehicle. These known cruise control systems are often employed on work vehicles such as floaters, construction vehicles and the like to maintain an optimum speed during lengthy work trips (e.g., plowing, mowing, hauling, etc.). There are certain circumstances where it is necessary to temporarily drive with a lower speed and then resume driving at the optimum speed. These circumstances include, but are not limited to, the following: turning on the headlands when mowing, where narrow turns have to made and where it is often necessary to drive back and forth; driving faster over bare areas when mowing; and driving downhill when hauling heavy loads.
In particular, a certain known cruise control system has been developed in regulating the ground speed of a floater. Upon activation of this certain known cruise control system, the operator can set an engine speed (i.e. rpm) within a range, and then the transmission would shift through the gears to reach the desired ground speed (engine speed combined with gear equals ground speed). This certain known cruise control system also includes a deceleration mode where the floater automatically slows to a predetermined ground speed to avoid undesired sliding or rutting of the field. This deceleration mode is typically employed when turning the floater around a corner. When the deceleration mode is activated, the system automatically slows the engine speed to a predetermined value, and then the transmission automatically calculates the gear or shifts through the gears to reach the desired ground speed. Upon completion of the turn, the operator deactivates the deceleration mode and the engine resumes to the full preset engine speed.
However, this certain known cruise control system as described above has several drawbacks. For example, even though the transmission can shift down gears on demand, the transmission is known to "hang in gear" and not automatically downshift when the power demand of the engine is low (e.g., light load, firm ground, etc.). When the transmission hangs in gear, the engine is known to propel the floater too fast around turns and causes undesired sliding or rutting of the soil. In response, the operator must manually downshift the transmission, which eases lugging of the engine and slows down the ground speed of the floater. The operator can also deactivate the deceleration mode of the cruise control system, but this defeats the purpose of the deceleration mode feature.
Therefore, there is a need or desire for an enhanced vehicular speed control system that addresses the drawbacks described above. The control system should also be configured to be utilized with a wide variety of production vehicles in addition to those related to agriculture.

Control system for regulating a ground speed of a vehicle


The invention provides a multi-windows color adjustment system and method that divides the picture frame of a display screen into three or more windows so that the user can compare the color tones of the windows and then select the preferred window. The multi-windows color adjustment system includes a memory read/write controller coupled to an image data input for temporarily storing an input image data and executing read/write control, a window control unit coupled to the memory read/write controller for executing size, data flow and color tone controls of the windows, a line buffer coupled to the memory read/write controller and the window control unit for storing a line data, and a color adjustment unit coupled to the window control unit and the line buffer for executing the processing of color adjustment of the image data in the windows subject to the control of the window control unit.

1. Field of the Invention
The present invention relates to a color adjustment system and method and more particularly, to a multi-window color adjustment system and method that divides the picture frame of a display screen into three or more windows so that the user can compare the color tones of the windows and then select the preferred window.
2. Description of the Related Art
A regular TV set provides a color adjustment system for allowing the user to adjust the preferred color tones. In an old design TV set, the user can use the remote controller or adjustment knobs of the TV set to adjust different color parameters such as contrast, brightness, hue, color saturation, and etc. During adjustment, the TV set displays the adjusted color tone and the parameter ratio by means of a bar chart for reference. An advanced TV set provides preset color templates for selection by the user, including the color tone modes of Dynamic, Standard, Movie, and Nature. The user can use the remote controller to select the color parameters conveniently.
However, when using the aforesaid TV color adjustment system, the user can compare the color parameters simply by means of memory. When browsing posterior color tone options, the user may be unable to memorize the former color tone options for comparison. Therefore, this conventional color adjustment method is inconvenient and not practical for real time comparison.
Therefore, it is desirable to provide a multi-windows color adjustment system and method that eliminates the aforesaid problem.

Multi-windows color adjustment system and method


A magnetic recording medium includes a nonmagnetic granular layer that has a granular structure in which a plurality of nonmagnetic grains made of a nonmagnetic material are separated from one another by a Cr oxide. The magnetic recording medium further includes a magnetic granular layer that is formed on the nonmagnetic granular layer and has a granular structure in which a plurality of magnetic grains made of a magnetic material are separated from one another by a nonmagnetic material.

In the computer field, a large amount of information has been handled on a daily basis. A hard disc drive (HDD) is used as an example of an information storage apparatus for recording and reproducing such a large amount of information. The HDD is characterized by having a large storage capacity and accessing information therein at a high speed, and includes a disk-shaped magnetic recording medium and a magnetic head that records information into the magnetic recording medium.
Here, increase in recording density has always been demanded in the magnetic recording medium included in the information storage apparatus. However, in general, there are obstacles to increasing the recording density of a magnetic recording medium. One of the obstacles is so-called medium noise. Medium noise is caused by disturbance in magnetization orientation that carries information in a magnetic recording medium, and appears in a reproduction signal obtained in reproducing information from the magnetic recording medium. In order to be recorded into the magnetic recording medium, information needs to be recorded in an area large enough to provide signal components each having a sufficiently high level not to be buried in this noise (medium noise) attributable to disturbance in magnetization orientation. Accordingly, the information recording density is reduced as the medium noise level is increased.
A method for suppressing disturbance in magnetization orientation, which causes medium noise, is to increase the coercivity of a recording layer for allowing information to be recorded therein in the magnetic recording medium. The coercivity of a recording layer can be increased by reducing the grain size of the magnetic grains forming the recording layer and thus suppressing magnetic interactions among the magnetic grains. For this reason, many attempts have been made to reduce the grain size of the magnetic grains, in order to reduce the medium noise and thus to achieve high recording density of a magnetic recording medium.
For example, the following techniques have been proposed to reduce the grain size of the magnetic grains. In one of the techniques, a recording layer is formed to have a laminated structure of multiple layers. In another technique, multiple magnetic grains in a recording layer are segregated from one another by a nonmagnetic material concentrated at interfaces between the magnetic grains (grain boundaries) to form a granular structure. However, the latter technique of forming a recording layer with a granular structure often causes the following defects in the recording layer. Specifically, in this technique, some of the magnetic grains lying near the surface on which the recording layer is formed might be bonded to one another in the recording layer, which deteriorates the separation of the magnetic grains from one another in the recording layer. With this background, a technique to avoid such defects has been proposed. In this technique, under a recording layer with such a granular structure, formed is a nonmagnetic granular layer having a granular structure in which multiple nonmagnetic grains made of a nonmagnetic material are segregated from one another by another material (see Japanese Laid-open Patent Publication Nos. 2006-309919 and 2006-268972, for example).
In the technique of forming a recording layer with a laminated structure, a first layer is firstly formed as a base for constantly providing fine magnetic grains, and second and subsequent layers are formed on the first layer by growing such fine magnetic grains thereon. Meanwhile, in the technique of forming a recording layer with a granular structure, depending on the amount of a nonmagnetic material at the grain boundaries, grains of a magnetic material are segregated from one another and thus are reduced in grain size.
In this regard, the technique of forming a recording layer with a granular structure has been attracting attention because of its high effectiveness of increasing the coercivity of the recording layer while reducing the medium noise level. This effectiveness is attributed to the fact that, in this technique, not only multiple magnetic grains in the recording layer are reduced in grain size but also segregated from one another by a nonmagnetic material, so that magnetic interactions among the magnetic grains are further suppressed.
Moreover, in the technique of forming a nonmagnetic granular layer, magnetic grains in a recording layer are formed on nonmagnetic grains appearing on the top surface of the nonmagnetic granular layer, on which surface nonmagnetic grains are sufficiently separated from one another. Accordingly, this technique can provide more reliable separation of the magnetic grains from one another in the recording layer.
Recently, the demand for increasing the recording density of a magnetic recording medium has been growing more and more. In response, it has also been demanded that further increase in recording density be achieved in a magnetic recording medium using a nonmagnetic granular layer as described above by a method such as further reducing the grain size of magnetic grains in a recording layer.

Magnetic recording medium and information storage apparatus


Provided are trimmed parallel element protection devices. Some protection devices may include a substrate and first and second terminals at opposite ends of the substrate. The protection devices may further include a first fusible and a second fusible element extending between the first and second terminals, wherein at least one of the first and second fusible elements includes a trimmed portion.

Fuses, which are commonly used as electrical circuit protection devices, provide electrical connections between sources of electrical power and circuit components that are to be protected. Upon the occurrence of a specified fault condition in a circuit, such as an overcurrent condition, a fusible element can melt, or otherwise separate, to interrupt current flow in the circuit path. Protected portions of the circuit are thereby electrically isolated and damage to such portions may be prevented or at least mitigated.
One known issue with existing fuses is imprecise resistance. Thus, a need exists for an improved fuse with a more precise resistance tolerance. It is with respect to these and other considerations that the present improvements have been needed.

Protection device with laser trimmed fusible element


A method and a device for monitoring the handling conditions of at least one object intended to be handled under certain predetermined conditions. The temperature or the temperature as a function of time of at least one object, is monitored to enable it to retain as much as possible of its original quality. To this end, a device is inserted into the object, or between two objects in a stack of objects, including a substantially flat, elongate casing, having a slot-shaped space between two opposed walls of the casing. An elongate slide-shaped body removably inserts into the slot-shaped space of the casting. At one end the slide-shaped body is provided with a technique for indicating, by color change, the exceeding and the falling-short of the predetermined conditions. The color change is thereafter observed visually by withdrawing the slide-shaped body removably inserted in the slot-shaped space of the casing. During the visual observation, the color may be suitably compared with a color scale on the slide-shaped body. Also, the casing of the device may be perforated at one end. Furthermore, at least the portion of the inside of the casing contacting the means when inserted in the casing, may be suitably provided with ridges extending in the longitudinal direction of the casing.

1. Field of the Invention
The present invention relates to a method and a device for time and/or temperature determination, and more specifically to a method for monitoring the handling conditions of at least one object, such as an individual package or a stack of such packages containing refrigerated or frozen products, the object being intended to be handled under certain predetermined conditions, and to a device for carrying out the method.
2. Description of The Related Art
The term "handling" as used in the present context relates to storage, transport and similar treatment of an object, and the expressions "handling conditions" and "conditions" as used in the present context relate to either the temperature prevailing during the handling of the object, or the time and the temperature, i.e. the total or integrated influence of time and temperature on the object during the handling thereof.
There are a great many objects and products, such as foodstuffs, medicines, vaccines, blood products, photographical film etc, that are temperature-sensitive and should be stored or handled at a certain temperature in order to prevent quality degradation. Typical examples of such products are foodstuffs, such as refrigerated foods, e.g. milk, vegetables etc, or frozen foods, e.g. meat, fish, ice-cream etc. For example, in order that a deep-frozen product should have a satisfactory quality when reaching the shop, it should not be subjected to a temperature exceeding e.g. about -15.degree. C. to -18.degree. C., after departure from the producer and until the time of arrival in the shop. For refrigerated foods, the corresponding temperature is about +4.degree.-8.degree. C. On its way from the producer to the consumer, a frozen food passes through a large number of handling steps, such as storage with the producer, transportation from the producer to the wholesaler, storage with the wholesaler, transportation from the wholesaler to the retailer, and storage with the retailer. In all these partial steps, the deep-frozen food must be handled correctly, i.e. at a temperature which does not exceed about -15.degree. C. to -18.degree. C., in order to prevent its quality from degrading. To this end, the temperature of the product is checked at regular intervals in each partial step, i.e. during transport and storage.
One way of performing such checking is to insert a needle-equipped electronic thermometer into a stack of packages containing deep-frozen products, and to read the temperature on the thermometer. However, this involves several disadvantages. First, the electronic thermometer is expensive to manufacture and purchase, and requires for its operation batteries which must be replaced at regular intervals. Moreover, the thermometer must be calibrated for correct indication, and the thermometer needle must on each measuring occasion be held inserted in the stack of packages with frozen products for several minutes to enable the thermometer to adjust itself and display the correct temperature. As deep-frozen products, especially foods, are normally stacked on pallets and at least one check must be made on the products on each pallet, it is understood that the total time for checking e.g. the load on a long-distance truck or in a storeroom is quite considerable and thus involves substantial costs.
There is thus a need to make the observation quicker and less expensive, and preferably also to make possible subsequent observation of the handling of the product to ensure that this handling falls within the limits applying to the product concerned, in respect of its consumability. This is also important in view of the strict products liability currently incumbent upon manufacturers in most countries.
The present invention aims to achieve this and obviate the shortcomings inherent in the prior-art technique, by means of a device which is easy and inexpensive to manufacture and which constantly is at the temperature of the product concerned, to enable a quick temperature observation without any delay for temperature adjustment of the device.
If one wishes to perform a more complete observation of the handling conditions of a product, and thus of its quality, it is further possible according to the invention, instead of only checking the temperature, also to check both temperature and time, more specifically by making an integration of the temperature conditions to which the product is subjected over the time during which the handling of the product takes place.

Method and device for monitoring handling conditions


A mobile station includes a public land mobile network registration unit that registers public land mobile networks including a public land mobile network input by a manual operation, wherein the public land mobile network input by the manual operation is not detected, and a public land mobile network selecting unit that selects a public land mobile network specified by the manual operation, among the public land mobile networks registered in the public land mobile network registration unit, wherein the public land mobile networks registered in the public land mobile network registration unit include the public land mobile network which is not detected.

There are some mobile terminal devices which may be used in a country other than a contracted country. In a case where a mobile terminal device is allowed to be used in a country other than the contracted country, it is possible that a roaming agreement has been concluded between an operator in the contracted country and another operator in the country other than the contracted country. Radio communication systems provided by an operator may include a GSM (Global System for Mobile Communications) (registered trademark) system and a WCDMA (Wideband Code Division Multiple Access) system. Further, an LTE (Long Term Evolution) system may be included.
A mobile station operates on its home public land mobile network (PLMN: public land mobile network) or equivalent home PLMN. The mobile station selects a PLMN. Two types of selection methods, i.e., an automatic mode and a manual mode, are defined as operations for selecting the PLMN. In the automatic mode, a list of PLMNs in priority order is utilized. The highest priority PLMN among available and allowable PLMNs is selected. In the manual mode, the mobile station indicates available PLMNs to a user. Only when the user manually selects, the mobile station attempts to obtain a service in the selected PLMN.
A case is explained where a PLMN is selected in the automatic mode.
FIG. 1 shows an example of processes from the power-on of a mobile station until the location registration is performed.
The power supply of the mobile station is turned on (step S12).
The mobile station performs a cell search (step S14). The mobile station detects available frequency ranges and cells that are to be candidates for a serving cell. The cell search may be referred to as a "band search."
The mobile station performs PLMN selection (step S16). The mobile station selects a PLMN that is available for the mobile station among the cells that are detected at step S14. For example, a USIM (Universal Subscriber Identity Module) card is attached to the mobile station. The USIM card stores a telephone number for which a contract has been established with an operator; and a priority order to be recorded by the operator, which is for establishing a connection with another operator's PLMN. When a PLMN is to be selected in accordance with the priority order, for PLMNs having the same priority order, the mobile station selects the PLMN randomly from the PLMNs whose electric field strengths are greater than or equal to a predefined value. Further, when there are no PLMNs whose electric field strengths are greater than or equal to the predefined value, the mobile station selects the PLMN in accordance with a descending order of signal levels.
The mobile station performs cell selection (step S18). The mobile station detects candidate cells which are available to the mobile station, based on broadcast information from the PLMN which is selected at step S16.
The mobile station performs location registration (step S20). The mobile station selects a cell to which the location registration is to be performed among the cells detected at step S18. Then the mobile station performs the location registration to the selected cell.
A case is explained where a PLMN is selected in the manual mode.
Irrespective of whether the operation mode is the manual mode or the automatic mode, when the power supply of the mobile station is turned on, or when the mobile station returns from an out-of-coverage state, the PLMN is selected to which the location registration has been performed at a previous time. In the automatic mode, for a case where there are no PLMNs to which the location registration has been performed at the previous time, another PLMN is automatically selected. In the manual mode, after that, it is possible for a user to manually select another PLMN.
In the manual mode, for selecting the PLMN, only the detected PLMNs are displayed in a list, and the user selects one PLMN from the list. It is not possible to select PLMNs that are not detected.


Provided is an operation lever adapted to make a blade perform an action other than an up and down action by rotatably a grip around the shaft center of a lever shaft. The operation lever has a lever shaft operable back and forth, corresponding to an up and down action of a blade of a dozer unit, and a grip provided on an upper part of the lever shaft and capable of rotating in a clockwise direction and counterclockwise direction from a neutral position around a shaft center of the lever shaft by a predetermined rotation angle, corresponding to an angle action or a tilting action of the blade. The grip includes a return-to-neutral spring adapted to return the grip from a rotated position to a neutral position, and the rotation angle of the grip in the clockwise direction is set to be different from that in the counterclockwise direction.

There has been a construction machine that includes a dozer unit and is adapted to operate the blade of the dozer unit with an operation lever. The operation lever of the construction machine has a lever shaft and a grip provided on the upper part of the lever shaft. Construction machines having an operation lever are disclosed in Japanese Unexamined Patent Publications, JP-A-2009-52285 and JP-A-2011-53789.
JP-A-2009-52285 discloses that the blade performs an up and down action by performing a swing operation of the operation lever back and forth, whereas the blade performs a tilting action by operating an operation switch provided on the grip. Also, JP-A-2009-52285 discloses that by operating a pedal provided on the front side of an operator seat, the blade performs an angle action.
In the operation lever described in JP-A-2011-53789, the grip has a grip main body attached to the lever shaft and an operation switch provided on the upper part of the grip main body. JP-A-2011-53789 discloses that the blade performs an up and down action by performing a swing operation of the operation lever back and forth, whereas the blade performs an angle action by operating the operation switch provided on the grip. On the upper part of the lever shaft, the grip main body is attached, and is not configured to rotate around the shaft center of the lever shaft.
Further, each of JP-A-2011-53789 and JP-A-2005-120821 discloses a grip including: a grip main body gripped by the palm and finger; and a switch that is arranged at the top of the grip main body and operable with the thumb. The grip main body has: a thenar eminence reception surface brought into contact with the thenar eminence; a palm reception surface brought into contact with the middle part of the palm and the hypothenar eminence; a finger reception surface brought into contact with the fingers; and an open surface that is located between the tips of the fingers and the thenar eminence and can be arranged with the thumb when the grip main body is gripped by the hand.


An information processing apparatus includes a control unit configured to perform control for selecting settings for an imaging operation of an imaging unit based on surrounding sound obtained by a sound obtaining unit and an image generated by the imaging unit.

The present disclosure relates to an information processing apparatus. More specifically, the present disclosure relates to an information processing apparatus, an imaging apparatus, and an information processing method which are designed to control an imaging operation, and a program which causes a computer to execute the method.
In recent years, information processing apparatuses (imaging apparatuses such as a digital still camera) which image a target such as a person, generate an image (image data), and record the generated image (image data) as image content (image file) have been widely used. In order to clearly record the image (image data) to be recorded, it is important to appropriately set parameters relating to an imaging operation when the information processing apparatus performs an imaging operation. For this reason, multiple techniques to appropriately set the parameters relating to the imaging operation have been proposed.
For example, an imaging apparatus which analyzes feature amounts of an audio signal obtained during a target imaging operation and controls image processing parameters based on the feature amounts of the analyzed audio signal has been proposed (see Japanese Unexamined Patent Application Publication No. 2010-147587, for example).

Apparatus and method for controlling settings of an imaging operation


A method is provided for the production of a bovine pancreatic protein with a specific desoxyribonuclease activity of at least 6,000 units per mg of protein. Methylotrophic yeast is used as a heterologous host organism. The bovine pancreatic protein is secreted into the growth medium from which it is purified.

The present invention relates to the production of recombinant bovine pancreatic desoxyribonuclease I in methylotrophic yeast. In particular, the present invention relates to a bovine pancreatic desoxyribonuclease I that is secreted by the methylotrophic yeast into the growth medium from which it is purified. Also provided are use and kits of the recombinant bovine pancreatic desoxyribonuclease I.
Bovine pancreatic desoxyribonuclease I is an industrial product with a wide range of applications. For instance, applications in the field of cell biology make use of bovine pancreatic desoxyribonuclease I in standard laboratory procedures for the purpose of dissociating cell tissue and isolating single cells. Such processes are always accompanied by rupture and lysis of some cells. As a consequence, DNA is released from these cells into the intercellular space and/or the dissociation medium and causes unwanted cell clumping. Adding bovine pancreatic desoxyribonuclease I to the dissociation medium is a preferred means to prevent unwanted cell clumping as the enzyme has been shown not to be cytotoxic in concentrations of up to 1 mg/ml. Thus, cell clumping is prevented by hydrolysing DNA. For purposes of tissue culture, bovine pancreatic desoxyribonuclease I is also used in combination with other enzymes such as collagenase or trypsin (Kaighn, M. E., In: Tissue culture, methods and applications; Kruse, P. F. & Patterson, M. K., eds., Academic Press, New York & London, 1973, 54–58).
Regarding the fields of molecular biology and nucleic acid biochemistry, bovine pancreatic desoxyribonuclease I is used in applications such as nick translation, the production of random DNA fragments, desoxyribonuclease I protection assays such as transcription factor footprinting, removal of DNA template after in vitro transcription, removal of DNA from RNA samples prior to applications such as RT-PCR, and removal of DNA from other preparations generated by biological and/or biochemical procedures, to name but a few (Sambrook, Fritsch & Maniatis, Molecular Cloning, A Laboratory Manual, 3rd edition, CSHL Press, 2001). Thus, removal of DNA is effected by hydrolysing DNA.
DNase I is also used in medical applications aimed at reducing the viscoelasticity of pulmonary secretions (Liao, T. H., J. Formos. Med. Assoc. 96 (1997) 481–487). Whereas for this particular purpose desoxyribonuclease I of human origin is the preferred enzyme, desoxyribonuclease I from bovine pancreas is preferred for the different kinds of research use exemplified above. Thus, bovine pancreatic desoxyribonuclease I is an enzyme that is produced in an industrial scale and sold as a regular industrial product (e.g. desoxyribonuclease I from bovine pancreas EC 220.127.116.11, Item No. 1284932 in the 2002 catalogue of Roche Diagnostics GmbH, Mannheim).
Bovine pancreatic desoxyribonuclease I has a molecular weight of about 30,000 daltons and an enzymatic activity optimum at pH 7.8. Bovine pancreatic desoxyribonuclease I hydrolyses phosphodiester linkages of DNA, preferentially adjacent to a pyrimidine nucleotide yielding DNA molecules with a free hydroxyl group at the 3′ position and a phosphate group at the 5′ position. The average chain length of a limit digest is a tetranucleotide. There are four desoxyribonucleases derived from bovine pancreas which are all glycoproteins. They differ from each other either in a carbohydrate side chain or polypeptide component. Bovine pancreatic desoxyribonuclease I has diverse chemical activity acting upon single stranded DNA, double stranded DNA and chromatin (Liao, T. H., Mol. Cell Biochem. 34 (1981) 15–22). Similarly to other desoxyribonucleases, bovine pancreatic desoxyribonuclease I appears to be modulated in vivo by actin which is taking the effect as a cellular inhibitor (Lazarides, E., and Lindberg, U., Proc. Natl. Acad. Sci. USA 71 (1974) 4742). Moreover, like other desoxyribonucleases, bovine pancreatic desoxyribonuclease I is activated by divalent metal ions. Maximum activation is attained with Mg2+ and Ca2+. A metallosubstrate, such as a magnesium salt of DNA is necessary. Citrate completely inhibits magnesium-activated but not manganese-activated desoxyribonuclease I. Desoxyribonuclease I is inhibited by chelating agents such as EDTA, and by sodium dodecyl sulfate (Sambrook, Fritsch & Maniatis, Molecular Cloning, A Laboratory Manual, 3rd edition, CSHL Press, 2001).
When desoxyribonuclease activity is quantified, the present document refers to "units". Thus, the nucleolytic activity of bovine pancreatic desoxyribonuclease I is quantified using a photometric assay similar to Kunitz, M. (J. Gen. Physiol. 33 (1950) 349–62 and 363). The "specific desoxyribonuclease activity" or "specific activity" of a given preparation is defined as the number of units per mg of potein in the preperation, determined by the method described in detail in Example 12.
A "methylotrophic yeast" is defined as a yeast that is capable of utilising methanol as its carbon source. The term also comprises laboratory strains thereof. In case a methylotrophic yeast strain is auxotrophic and because of this needs to be supplemented with an auxiliary carbon-containing substance such as, e.g. histidine in the case of a methylotrophic yeast strain unable to synthesise this amino acid in sufficient amounts, this auxiliary substance is regarded as a nutrient but not as a carbon source.
A "vector" is defined as DNA which can comprise, i.e. carry and maintain the DNA fragment of the invention, including, for example, phages and plasmids. These terms are understood by those of skill in the art of genetic engineering. The term "expression cassette" denotes a nucleotide sequence encoding a pre-protein, operably linked to a promoter and a terminator. As for vectors containing an expression cassette, the terms "vector" and "expression vector" are synonyms.
The term "oligonucleotide" is used for a nucleic acid molecule, DNA (or RNA), with less than 100 nucleotides in length.
"Transformation" means introducing DNA into an organism so that the DNA is replicable, either as an extrachromosomal element or by chromosomal integration.
The term "expression" and the verb "to express" denote transcription of DNA sequences and/or the translation of the transcribed mRNA in a host organism resulting in a pre-protein, i.e. not including post-translational processes.
A nucleotide sequence "encodes" a peptide or protein when at least a portion of the nucleic acid, or its complement, can be directly translated to provide the amino acid sequence of the peptide or protein, or when the isolated nucleic acid can be used, alone or as part of an expression vector, to express the peptide or protein in vitro, in a prokaryotic host cell, or in a eukaryotic host cell.
A "promoter" is a regulatory nucleotide sequence that stimulates transcription. These terms are understood by those of skill in the art of genetic engineering. Like a promoter, a "promoter element" stimulates transcription but constitutes a sub-fragment of a larger promoter sequence.
The term "operably linked" refers to the association of two or more nucleic acid fragments on a single vector so that the function of one is affected by the other. For example, a promoter is operably linked with a coding sequence, i.e. a nucleotide sequence encoding a protein or a pre-protein, when it is capable of affecting the expression of that coding sequence, i.e., that the coding sequence is under the transcriptional control of the promoter.
The term "polypeptide" or "protein" denotes a polymer composed of more than 90 amino acid monomers joined by peptide bonds. The term "peptide" denotes an oligomer composed of 90 or fewer amino acid monomers joined by peptide bonds. A "peptide bond" is a covalent bond between two amino acids in which the α-amino group of one amino acid is bonded to the α-carboxyl group of the other amino acid.
The term "pre-protein" denotes a primary translation product that is a precursor of a mature protein, i.e. in this case a protein results from post-translational processing of a pre-protein.
The term "post-translational processing" denotes the modification steps a pre-protein is subjected to, in order result in a mature protein in a cellular or extracellular compartment.
A "signal peptide" is a cleavable signal sequence of amino acids present in the pre-protein form of a secretable protein. Proteins transported across the cell membrane, i.e. "secreted", typically have an N-terminal sequence rich in hydrophobic amino acids about 15 to 30 amino acids long. Sometime during the process of passing through the membrane, the signal sequence is cleaved by a signal peptidase (Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P. (eds), Molecular Biology of the Cell, fourth edition, 2002, Garland Science Publishing). Many sources of signal peptides are well known to those skilled in the art and can include, for example, the amino acid sequence of the α-factor signal peptide from Saccharomyces cerevisiae and the like. Another example is the bovine signal peptide of the native bovine pancreatic desoxyribonuclease I pre-protein. In general, the pre-protein N-terminus of essentially any secreted protein is a potential source of a signal peptide suitable for use in the present invention. A signal peptide can also be bipartite comprising two signal peptides directing the pre-protein to a first and a second cellular compartment. Bipartite signal peptides are cleaved off stepwise during the course of the secretory pathway. A specific example therefor is the prepro peptide of the α-factor from Saccharomyces cerevisiae (Waters et al., J. Biol. Chem. 263 (1988) 6209–14).
Pre-proteins with an N-terminal signal peptide are directed to enter the "secretory pathway". The secretory pathway comprises the processes of post-translational processing and finally results in secretion of a protein. Glycosylation and the formation of disulfide bonds are processes that are part of the secretory pathway prior to secretion. In the present document it is understood that proteins secreted by methylotrophic yeast strains have passed through the secretory pathway.
Until presently, a major source of bovine pancreatic desoxyribonuclease I is pancreatic tissue obtained from slaughtered cattle. The enzyme is usually purified from the tissue material using chromatographic separation techniques such as those described by Funakoshi, A., et al., J. Biochem. (Tokyo) 88 (1980) 1113–1138; Paudel, H. K., and Liao, T. H., J. Biol Chem. 261 (1986) 16006–16011; and Nefsky, B., and Bretscher, A., Eur. J. Biochem. 179 (1989) 215–219. The purification process under the conditions of a research laboratory yields a specific activitiy in the range of 1,000 units per mg of protein obtained from 400 g of tissue, as explicitly reported by Paudel, H. K., and Liao, T. H., J. Biol Chem. 261 (1986) 16006–16011. In an upscaled industrial process, the isolation of bovine pancreatic desoxyribonuclease I from bovine pancreatic tissue yields preparations of isolated enzyme which usually exhibit a specific activity of 3,500 units per mg of protein (our own unpublished observation). Commercial preparations of research-grade bovine pancreatic desoxyribonuclease I purified from bovine pancreas usually have a specific activity below this value as exemplified by Roche products (Roche Diagnostics GmbH, Mannheim, Germany; catalogue items as of November 2002) having the catalogue numbers 1284932 (2,000 units/mg), 104132 (3,000 units/mg), 104159 (2,000 units/mg), and Sigma-Aldrich products (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; catalogue items as of November 2002) having the catalogue numbers D5025 (2,000 units/mg) D4263 (2,000 U/mg), D4513 (2,000 units/mg), DN-25 (400–800 units/mg). Generally, pancreas tissue as source for bovine pancreatic desoxyribonuclease I poses a problem as this tissue has a high content of other digestive pro-enzymes and their activated forms. On the one hand, the mixture from which the desired enzyme is purified is therefore very complex and requires elaborate separation techniques. On the other hand, proteases among the digestive enzymes may destroy the desired protein, especially during the first steps of the purification process when pancreatic tissue is homogenised. One could also speculate that pancreatic tissue homogenate contains inhibitory substances that inactivate a substantial portion of the bovine pancreatic desoxyribonuclease I, thereby limiting the specific activity of active enzyme that can be purified from this source.
It is also known to the art that recombinant expression of an enzymatically active bovine pancreatic desoxyribonuclease I protein in a bacterial host is possible. However, overexpression poses a problem owing to the intrinsic toxicity of an endonuclease for a bacterial cell. Apparently, toxicity is caused by intracellular degradation of host cell DNA with high levels of active bovine pancreatic desoxyribonuclease I enzyme being present in the bacterial cytoplasm. In a bacterial cell transcription and translation are tightly connected as opposed to eukaryotic cells where these processes take place in separate compartments, i.e. the nucleus and the cytoplasm. Thus, the selection of bacterial clones overexpressing bovine pancreatic desoxyribonuclease I at the same time promotes instability of these clones (e.g. genetic instability) and/or the recombinant desoxyribonuclease protein to be produced. Attempts to overcome this problem were mainly based on tightly regulated and inducible bacterial expression systems.
Worrall, A. F., and Connolly, B. A. (J. Biol. Chem. 265 (1990) 21889–21895) expressed an active bovine pancreatic desoxyribonuclease I protein in E. coli making use of a synthetic coding sequence adapted to the codon usage of the host organism. Transcriptional expression was under the control of the λpL promoter. The recombinant protein was produced intracellularly and afterwards solubilised by means of sonication. The recombinant active protein was found to be toxic for the bacterial host stain. Thus, expression yield was in the range between 100 μg to 1 mg/l culture. The specific activity of the recombinant active bovine pancreatic desoxyribonuclease I from E. coli was found to be identical to that of the native protein. The value given in the document (5×108 units/g of protein) was not the true value of the preparation but was corrected for purity. The recombinant bovine pancreatic desoxyribonuclease I protein was purified only partially and the document is completely silent about the specific desoxyribonuclease activity of a substantially pure and/or research-grade product.
Chen, C. Y., et al. (Gene 206 (1998) 181–184) expressed in E. coli a cDNA representing the original bovine pancreatic transcript. The construct was expressed in the strain BL21(DE3)pLysE and transcribed by an IPTG-inducible T7 polymerase. However, overexpression of an active bovine pancreatic desoxyribonuclease I was found to be limited in quantity and the product appeared to be toxic for the bacterial host organism. Due to cell lysis upon induction, bovine pancreatic desoxyribonuclease I activity was found in the supernatant but also in the cellular fraction of the culture. desoxyribonuclease enzyme activity was measured using an assay for enzyme activity that differed from the Kunitz assay in that there are changes with respect to divalent cations and their concentration in the reaction buffer, as well as its pH. However, generally the units detected by this assay appear to be comparable to those of the Kunitz assay. According to the assay of this document, the approximate yield from the induced culture was 3,500 units/l. The specific enzyme activity of the recombinant bovine pancreatic desoxyribonuclease I produced in E. coli was 908 units/mg was in the same range as the specific activity of native bovine pancreatic desoxyribonuclease I purified in parallel from pancreatic tissue (938 units/mg).
As it is commonly observed when post-translationally processed proteins of eukaryotic origin are expressed in a prokaryotic host system, the bovine pancreatic desoxyribonuclease I obtained by means of recombinant expression in E. coli markedly differs from the native protein. Particularly N-glycosylation which is a hallmark of the native pancreatic desoxyribonuclease I protein is absent in the recombinant product derived from prokaryotic expression systems. Glycosylation does not take place in E. coli and the publications by Worrall, A. F., and Connolly, B. A., J. Biol. Chem. 265 (1990) 21889–21895 as well as Chen, C. Y., et al., Gene 206 (1998) 181–184, confirm that the recombinantly produced bovine pancreatic desoxyribonuclease I proteins were not glycosylated. Also, folding of the protein and the formation of disulfide bonds are controlled differently in eukaryotic cells (Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P. (eds), Molecular Biology of the Cell, fourth edition, 2002, Garland Science Publishing). Above all, the formation of disulfide bridges in the recombinantly produced protein can be assumed to occur randomly once SH groups of the protein come in contact with aerial oxygen.
Glycosylated bovine pancreatic desoxyribonuclease I also was expressed in cultured mammalian cells. Nishikawa, A., et al. (J. Biol. Chem. 272 (1997) 19408–19412) produced bovine pancreatic desoxyribonuclease I as well as human desoxyribonuclease I in COS-1 cells in order to study mannose phosphorylation of these proteins. The document is however completely silent regarding yield or activity of the recombinant desoxyribonuclease I produced. A further glycosylation study on bovine pancreatic desoxyribonuclease I was published by Nishikawa, A., and Mizuno, S., Biochem. J. 355 (2001) 245–248, dealing with the efficiency of N-linked glycosylation of bovine pancreatic desoxyribonuclease I. Also this document is completely silent regarding yield or activity of the recombinant desoxyribonuclease I produced.
Recombinant expression of human pancreatic desoxyribonuclease I in embryonic kidney 293 cells was described by Shak, S., Proc. Natl. Acad. Sci. USA 87 (1990) 9188–9192 as well as by the same author in WO 90/07572. In the latter document it is stated that the specific activity of recombinant human pancreatic desoxyribonuclease from 293 cells appeared to be comparable to that of bovine desoxyribonuclease (Sigma, product D5025) which was used as a reference. According to the supplier's (Sigma) catalogue the product has a specific activity of 2,000 units/mg which puts the recombinantly expressed human pancreatic desoxyribonuclease I protein in the same range. Moreover, according to the invention described in WO 90/07572, recombinant desoxyribonuclease is preferably expressed in mammalian cells but also in prokaryotes, fungi, yeast, pichia, insects and the like. However, apart from expression in mammalian cells the document does not disclose any other example for eukaryotic expression systems. Moreover, the document is completely silent regarding glycosylation, the formation of disulfide bridges and the specific activity of recombinant desoxyribonuclease when produced in other eukaryotic expression systems. Furthermore, the document is completely silent on the impact of secretion on the yield of the desired protein as well as on its activity.
Using a similar expression system as in WO 90/07572, WO 96/26278 describes the production of human desoxyribonuclease I variants that exhibit a reduced binding affinity to actin. EP 1 122 306 discloses the expression of a human desoxyribonuclease II in HeLa cells.
The methods that are provided by the state of the art to produce a bovine pancreatic protein with desoxyribonuclease activity have certain disadvantages. The present invention provides an improved method.
It is an object of the invention to provide a cost-effective alternative source for bovine pancreatic desoxyribonuclease I. It is a further object of the invention to purify bovine pancreatic desoxyribonuclease I as a recombinant protein synthesised by a non-animal host organism. It is another object of the invention to provide an expression system in which the host organism tolerates the recombinant bovine pancreatic desoxyribonuclease I better than bacteria. Another object of the invention is to provide an expression system which simplifies and accelerates the separation of bovine pancreatic desoxyribonuclease I from cellular or media components, therefore conserving enzyme activity which otherwise may be lost. Yet another object of the invention is to provide a production procedure that leads to an enzyme preparation with a high specific activity. Yet another object of the invention is that the production procedure is amenable to upscaling towards a cost-effective industrial process.

Recombinant bovine pancreatic desoxyribonuclease I with high specific activity


The present invention relates to novel lip/cheek probes for detection of pulse-based differences in light absorbence across the vascularized tissue of a lip or cheek of a patient. These probes are fabricated to provide signals to estimate arterial oxygen saturation, and/or to obtain other photoplethysmographic data. The present invention also relates to a combined probe/cannula. The present invention also relates to other devices that combine a pulse oximeter probe with a device supplying oxygen or other oxygen-containing gas to a person in need thereof, and to sampling means for exhaled carbon dioxide in combination with the novel lip/cheek probes. In certain embodiments, an additional limitation of a control means to adjust the flow rate of such gas is provided, where such control is directed by the blood oxygen saturation data obtained from the pulse oximeter probe.

Diseases, acute injuries, and other conditions can adversely affect blood flow to and in the limbs. In a general sense, agents and factors that may affect and lower circulation to the limbs, also known as peripheral circulation, include certain drugs, especially vasoconstrictors, poor perfusion per se due to shock, such as results from low blood volume, or septic or cardiogenic shock, certain traumas, external pressure (as from bums), hypothermia, and other mechanical abnormalities or injuries. In particular, decreased peripheral circulation may be caused by a number of disorders within the body including, but not limited to, atherosclerosis, Raynaud's disease, Buerger's disease, chronic obstructive pulmonary diseases (COPD), and embolic occlusive disease.
Poor blood flow reduces the amount of oxygen that is carried in the blood stream to cells. Emergency rooms, intensive care units, bum units, operating rooms, and ambulances treat a variety of critically ill patients in need of continuous monitoring of real time hemoglobin saturation and/or blood pressure readings. If oxygen levels in the blood become very low at peripheral sites, a variety of problems may occur which include inadequate resuscitation, cell death or necrosis that can lead to non-healing lesions, gangrene and amputation of limbs. Also, in progressive diabetes and other conditions that may result in atherosclerosis that affect peripheral circulation and perfusion, non-invasive measurement of circulation and/or resistance status is useful to monitor the progression of the disease and the effectiveness of treatments.
Also, many patients, especially among the elderly, are on chronic oxygen therapy; they are in need of supplemental oxygen on a routine basis. Such patients may have impaired and/or diminished cardiopulmonary capacity. When such patients are ambulatory, their supply of oxygen (usually a tank of compressed oxygen or liquid oxygen) must be transported with them wherever they travel. Oxygen from such supply passes through a regulator and thence, typically, via a tube to the nose where it is inhaled (e.g., via a nasal cannula or the like). Alternatively, the oxygen may be delivered by a cannula directly into the trachea (transtracheal supplemental oxygen). Embodiments of the present invention combine the supply of oxygen or oxygen-rich air with a pulse oximeter that adjusts the release of the supply to better match the actual bodily requirement based on the measured blood oxygen saturation. A pulse oximeter that receives the signal from the pulse oximeter probe is located a distance from the probe itself, and provides a blood oxygen saturation measurement to the user (and/or to a remote monitor), and/or, in certain embodiments acts to adjust the inflow rate or quality of the oxygen or oxygen-rich gas being supplied. This, depending on each particular user and his/her baseline settings, can either extend the life of a given supply of compressed oxygen or oxygen-rich gas, or provide oxygen or oxygen-rich gas on a more accurate, as-needed basis, in the latter case improving the health and/or performance of the user.
As to the latter benefit of this aspect of the present invention, provision of an accurate, as-needed supply of oxygen reduces the risk of and/or alleviates problems of hypoxia that are associated with improper adjustment of supplemental oxygen to patients in need thereof. Hypoxia, low oxygen delivery, or hypoxemia, low oxygen tension in the blood, cause a number of maladies including polycythemia (increased hematocrit) which leads to abnormal clotting. Polycythemia is a compensatory mechanism to chronic hypoxemia that typically builds up over weeks to months. It is typical in persons with chronic lung disease (and also persons living at high altitudes).
A more immediate, primary physiologic compensatory response to oxygen deficit is increased cardiac output. This is normal, such as during increased physical exertion. However, in persons who have impaired cardiocirculatory reserve, increased cardiac output in response to low arterial oxygen level can, under certain circumstances, eventually lead to death. The second immediate physiologic compensatory response to oxygen deficit is the extraction of more oxygen from hemoglobin within the capillaries of the body's organs. This normally happens either during an increase in oxygen demand (i.e., exercise, fever, shivering, etc.), or during normal demand but decreased oxygen delivery (i.e., due to inadequate blood flow, anemia, hypoxia). In such instances, metabolically active cells draw additional oxygen from the red blood cells which ultimately resulting in a decrease in the mixed venous blood's oxygen saturation falling from a typical 65% to 80% level to levels as low as 32% (see Hemodynamic Monitoring—Invasive and Noninvasive Clinical Application, by Gloria Oblouk Darovic, 3rd Ed., 2002, Chapter 12). Chronic hypoxemia can lead to a switch by metabolically active cells to anaerobic metabolism, which, especially in patients with limited cardiopulmonary reserve, can lead to lactic acidosis and eventually death.
Hypoxemia also causes cognitive dysfunction either acutely or chronically which can lead to early dementia and death. Generally, based on the compensatory mechanisms and effects on body tissues, chronic hypoxemia may affect all organs in the body leading to failure of any or all organs.
In general, blood oxygen levels are currently measured by pulse oximetry, which can be divided into transmittance and reflectance types. Transmittance, or transillumination oximetry, involves the process whereby a sensor measures light extinction as light passes through a portion of blood-perfused tissue. Light is transmitted from one side of a portion of blood-perfused tissue, and is recorded by a sensor situated across the portion of tissue. Reflectance oximetry, on the other hand, has both the light source and the sensor on one side of the tissue, and measures reflectance back from the tissue. For both types of oximetry, multiple signals from the light sensor, or detector, are used to estimate the oxygen saturation and pulse rate from changes in absorption of the light detected throughout blood pulse cycles. The technology is based on the differential absorbence of different wavelengths of light by different species of hemoglobin.
Conventional pulse oximetry measurement in certain classes of patients, for instance severely burned patients, can be a significant challenge, yet this monitoring data is vital in operating room and intensive care settings. Most current pulse oximetric approaches depend upon available peripheral sites permitting transillumination oximetry which is sufficient for most surgical conditions and procedures. However, in one example, patients with severe burns often have only a few sites suitable for the effective placement of the transmitting pulse oximeter sensor. These patients often have severe circulatory compromise rendering the current peripheral pulse oximeters less effective.
The technology of pulse oximeters is well known (See "Pulse Oximetry: Principles and Limitations," J. E. Sinex, Am. J. Emerg. Med., 1999, 17:59–66). Pulse oximetry includes a sensor, or probe, with light source(s) generating at least two different wavelengths of light, and a detector placed across a section of vascularized tissue such as on a finger, toe, or ear lobe. Pulse oximetry relies on the differential absorbance of the electromagnetic spectrum by different species of hemoglobin. In a typical system, two distinct wavelength bands, for instance 650–670 nm and 880–940 nm, are used to detect the relative concentrations of oxygenated hemoglobin (oxyhemoglobin) and non-oxygenated reduced hemoglobin, respectively. The background absorbance of tissues and venous blood absorbs, scatters and otherwise interferes with the absorbance directly attributable to the arterial blood. However, due to the enlargement of the cross-sectional area of the arterial vessels during the surge of blood from ventricular contraction, a relatively larger signal can be attributed to the absorbance of arterial hemoglobin during the systole.
By averaging multiple readings and determining the ratio peaks of specific wavelengths, a software program can estimate the relative absorbance due to the arterial blood flow. First, by calculating the differences in absorption signals over short periods of time during which the systole and diastole are detected, the peak net absorbance by oxygenated hemoglobin is established. The signals typically are in the hundreds per second. The software subtracts the major "noise" components (from non-arterial sources) from the peak signals to arrive at the relative contribution from the arterial pulse. As appropriate, an algorithm system may average readings, remove outliers, and/or increase or decrease the light intensity to obtain a result. The results from one site provide a measurement of arterial oxygen saturation at that site, and also allows calculation of the shape of the pulse at the placement site of the probe, which can be developed into a plethysymograph. Among the various sources of signal interference and modification, it is noted that the shape of red blood cells changes during passage through arterial and venous vessels. This change in shape affects scattering of the light used in pulse oximetry. Algorithms are designed to correct for such scattering.
More sophisticated pulse oximetry systems detect at more than merely two bands, such as the 650–670 nm and 880–940 nm wavelength bands. For instance, the pulse oximetry article from a uni-erlangen web site stated that four LEDs, at 630, 680, 730 and 780 nm, each with 10 nm bandwidths, can determine the four common species of hemoglobin. The article further calculated that the detection of nine wavelengths in the range of 600 to 850 nm would provide greater accuracy in assessing these four forms of hemoglobin, oxyhemoglobin (O2Hb), reduced hemoglobin (HHb), methemoglobin (MetHb), and carboxyhemoglobin (COHb). As used in the present invention, the term "pulse oximeter" or "oximeter" is meant to include all designs and types of pulse oximeters, including current and later developed models that transmit and detect at more than two wavelengths associated with absorption differences of these hemoglobin species.
At present, peripheral vascular resistance can only be measured invasively, or non-invasively by skilled technicians using Doppler flow devices. The use of Doppler and Doppler waveform analysis is now a standard investigation technique for obtaining measurements in blood flow resistance patients with possible circulatory disorders. For example, Dougherty and Lowry (J. Med. Eng. Technol., 1992: 16:123–128) combined a reflectance oximeter and a laser Doppler flowmeter to continuously measure both blood oxygen saturation and perfusion.
A number of patents have been issued directed to monitors, sensors and probes for use in pulse oximetry procedures. For instance, U.S. Pat. No. 6,334,065, issued on Dec. 25, 2001 to Al-Ali, et al., discloses a stereo pulse oximeter that provides for simultaneous, non-invasive oxygen status and photoplethysmograph measurements at both single and multiple sites. The invention is directed to the detection of neonatal heart abnormalities, particularly related to defects of heart-associated vessels, and specifically directed to Persistent Pulmonary Hypertension in Neonates (PHHN), Patent Ductus Arteriosis (PDA), and Aortic Coarctation. All of these conditions result in a flow of differentially oxygenated blood to different peripheral extremities. For instance, in PHHN and PDA, the blood that flows to the right hand is unaffected by the abnormal shunt that results in less oxygenated blood flowing to other areas. Thus, comparison of oxygen saturation values between a pulse oximeter sensor at the right hand and at, for instance, a foot site, is stated to detect or confirm the diagnosis of such neonatal heart abnormalities. Continuous monitoring with such pulse oximetry also is proposed, to provide feedback on the effectiveness of treatments or surgery to deal with these neonatal cardio/cardiopulmonary conditions. U.S. Pat. No. 6,334,065 does not address the use of two probes for detection, confirmation, or monitoring of perfusion- and resistance-related conditions in the patient. Such conditions would not be expected in a neonatal patient, and are instead more likely found in aging patients and in patients with certain accident conditions unrelated to neonatal heart and heart-associated vessel anomalies.
U.S. Pat. No. 6,263,223 was issued on Jul. 17, 2001 to Shepard et al., and teaches a method for taking reflectance oximeter readings within the nasal cavity and oral cavity and down through the posterior pharynx. Whereas the conventional transillumination pulse oximeter probe detects the light not absorbed or scattered as it crosses a vascularized tissue covered by skin (i.e., the LEDs and photodetector are separated by the tissue), a reflectance oximeter probe detects light by backscattering of light that traverses vascularized tissue not bounded by skin and is reflected back to a detector positioned on the same side of the tissue as the LEDs (e.g., on tissue in the mouth). The method includes inserting a reflectance pulse oximeter sensor into a cavity within a subject's skull and contacting a capillary bed disposed in the cavity with the reflectance pulse oximeter sensor. The method uses standard pulse oximeter sensor probes placed over capillary beds close to a buccal surface, posterior soft palate, hard palate or proximal posterior pharynx, including the tongue, nares or cheek. Reflectance pulse oximetry at these sites determines arterial oxygen saturation. One major problem with this device is that it does not permit cross-site comparisons of oxygen saturation values between several tissue sites. In addition, the pulse oximeter device used in this invention is an elongated tube that is inserted far into the nasal or oral cavity down into the pharynx, which is a highly invasive procedure.
U.S. Pat. No. 4,928,691, issued on May 29, 1990 to Nicolson et al., and currently withdrawn, discloses a non-invasive, electro-optical sensor probe and a method for its use. The sensor is enabled to measure light extinction during transillumination of a portion of blood-perfused tissue and to calculate the oxygen saturation and pulse rate from changes in absorption of the light detected. The sensor probe is placed at a central site such as the tongue, cheek, gum or lip of the patient and provides continuous assessment of arterial oxygen saturation and pulse rate. The sensor is malleable and extremely flexible, and is stated to conform to the structure of the skin and underlying tissue. U.S. Pat. No. 4,928,691 states that measurement at the preferred central sites provide accurate oxygen saturation and pulse readings for "patients with lowered or inconsistent peripheral perfusion." Critically, the probes according to U.S. Pat. No. 4,928,691 are highly flexible, leading to a high likelihood that upon typical movement of the patient there would be mal-alignment between the light source(s) and sensor, resulting in skewed, non-usable, or unreliable signals and results. Also, there is no teaching or suggestion to compare oxygen saturation values between several tissue sites to identify, characterize, or monitor peripheral perfusion conditions in such patients.
U.S. Pat. No. 5,218,962 was issued on Jun. 15, 1993 to Mannheimer et al., teaches a pulse oximetry system which monitors oxygen saturation and pulse rates by sensing the blood characteristics at two or more peripheral sites. The device includes one or more pulse oximetry probes which passes light through unique regions of tissue and a sensor which detects the amount of light passing through the tissue, and an instrument that independently calculates oxygen saturation level within each region. The difference in values represents how much the oxygen saturation of the first region of tissue differs from the oxygen saturation of the second region of tissue. When the difference between the two values is below a set threshold, the '962 patent attributes this to a sufficiently high probability that the value is true, and displays an oxygen saturation value that is a function of the two independent values. Where there is a difference greater than a set threshold, no oxygen saturation value is displayed. Thus, the '962 patent attributes substantial differences between two sites to be due to error, rather than to an indication of a problem with peripheral perfusion and/or resistance.
U.S. Pat. No. 5,335,659, issued on Aug. 9, 1994 to Pologe, teaches a nasal septum probe for photoplethysmographic measurements that clips onto a patient's nasal septum. Pulse oximetry is one of the stated applications for the apparatus. Structurally, the apparatus disclosed and claimed in the '659 patent has a body, or housing, from which two probe arms extend, these arms being sized to enter the nostrils of a nose. One arm bears at least two light sources, and the other arm bears at least one light detector. The probe apparatus securely grasps the nasal septum in such a way that there is contact on both sides of the nasal septum at the same time with both the light sources and the light detector. In all embodiments, the light sources and the light detector actually protrude from the main body of the respective probe arm, and are positioned to exert pressure upon and indent the tissue of the nasal septum. In some embodiments and all claims, a supply of gas is also provided from a source through a support means and to the nasal septum. However, the '659 patent does not disclose a nasal pulse oximeter probe that does not need to press into the tissue of the nasal septum in order to obtain reliable pulse oximetry data, nor a probe that includes an angle, or bend, to reach a desired highly vascular plexus on the septum.
U.S. Pat. No. 6,144,867, issued on Nov. 7, 2000 to Walker, teaches a flexible pulse oximeter sensor assembly capable of doubling over to surround a body part, such as an ear lobe, and comprised of a flexible base having a hole passing through it, a post preferably having a sharp tip, and a grommet. In use the sensor assembly wraps around a body part, and the post, or pin, passes through the body part to secure the probe to the body part. The grommet frames the hole and engages and holds the post. The patent discloses that body parts other than the ear lobe that may be pierced by the post (and, presumably, therefore suitable as a site for use of the sensor) include the webbing between the fingers and toes, the tongue, the nose, eyebrows, cheek/lip, breast nipples, and the foreskin.
WIPO Application No. WO0021435A1, to Barnett et al., was published Apr. 20, 2000. This publication teaches a non-invasive spectrophotometric examination and monitoring of blood metabolites in multiple tissue regions on an ongoing and instantaneous basis. The method includes attaching multiple sensors to a patient and coupling each sensor to a control and processing station enabled to analyze signals conveyed thereto. The control and processing station visually displays the data from multiple sites for direct mutual comparison of oxygen saturation values from multiple sites. A key aspect of the invention is the use of a "near" and a "far" (or "deep") detector at each detection site. Based on the positioning of the light-generating devices and the near and far sensors, the far sensor receives absorption signals from deeper inside the brain tissue. In a basic configuration, the "near" sensor, or detector, principally receives light from the source whose mean path length is primarily confined to the layers of skin, tissue, and skull, while the "far" detector which receives light sprectra that have followed a longer mean path length and traversed a substantial amount of brain tissue in addition to the bone and tissue traversed by the "near" detector. Other configurations indicate receptors receive signals from sources across the entire brain cross-section. This is stated to provide information about, by calculation differences, the condition of the deeper tissue, in particular the brain. The method is directed to compare oxygen saturation values for cerebral tissue, such as comparing the two hemispheres during surgery. The WO0021435A1 invention distinguishes itself from standard pulse oximetry of arteries close to the surface of the body, and focuses primarily on analysis of deeper tissues and organs. The application does not teach a method to measure "surface" peripheral or central tissue sites for development of information regarding perfusion status.
WIPO Application No. WO0154575A1, to Chen et al., was published on Aug. 2, 2001. This publication teaches a non-invasive apparatus and method for monitoring the blood pressure of a subject. A monitor is used for continuous, non-invasive blood pressure monitoring. The method includes using sensors to detect a first blood pressure pulse signal at a first location on patient and detecting a second blood pressure pulse signal at a second location on the patient; measuring a time difference between corresponding points on the first and second blood pressure pulse signals; and, computing an estimated blood pressure from the time difference. The first and second sensors are placed at locations such as a finger, toe, wrist, earlobe, ankle, nose, lip, or any other part of the body where blood vessels are close to the surface of the skin of a patient where a blood pressure pulse wave can be readily detected by the sensors, and/or where a pressure pulse wave from the patient's heart takes a different amount of time to propagate to the first location than to the second location.
In one regard, a superior monitor system would be able to provide real-time continuous measurements of signals that would be analyzed to provide arterial oxygen saturation, blood pressure, and pulse rate. A superior monitor system would utilize at least two pulse oximeter probes, one of which is placed at a highly perfused central tissue, such as the lip, tongue, nares, cheek, and a second probe placed at a typically less perfused areas such as a finger or toe. Also, in some situations, a peripheral probe may be placed at sites in or distal from areas that may be or are affected by disease- or accident-related diminished blood perfusion to tissues.
An additional aspect of a superior oximeter system provides both an inflow means of oxygen or oxygen-rich gas to a patient in need thereof, and an integral or adjoining pulse oximeter probe. This aspect is in conjunction with the above-described two pulse oximeter probe system, or in a system that only has one oximeter probe. In either case, one pulse oximeter probe, positioned at the nose or mouth, detects the levels of oxygenation saturation of blood in the patient, and detection of low or lowering oxygenation saturation levels results in one or more of: setting off a local or remote alarm or message; increasing the flow of oxygen or oxygen-rich gas to said patient. Likewise, detection of higher or increasing oxygenation levels results in one or more of: setting off a local or remote alarm or message; decreasing the flow of oxygen or oxygen-rich gas to said patient. Preferably, the pulse oximeter probe at the nose or mouth is integral with the delivery means of the oxygen or oxygen-rich gas. Preferably, the control of oxygenation levels is by signaling to (manually or automatically) adjust a valving mechanism that controls output flow from a source of auxiliary of oxygen or oxygen-rich gas. By such feedback mechanism the quantity of oxygen or oxygen-rich gas is conserved, and the needs of such patient are more closely attuned to the fluctuations in oxygen demand during activities at varying levels of exertion during a period of time.
As to references that pertain to the combining of a pulse oximeter with a system to control the inflow of oxygen or other oxygen-rich gas to a patient in need thereof, the following U.S. patents, and references contained therein, are considered to reflect the state of the current art: U.S. Pat. Nos. 4,889,116; 5,315,990; 5,365,922; 5,388,575; 6,371,114; and 6,512,938. None of these references are specifically directed to a combined, preferably integral combined pulse oximeter sensor/nasal cannula, which, when combined with an oximeter, or with an oximeter that controls the inflow of such oxygen or other oxygen-rich gas to the patient, provide the advantages disclosed and claimed herein.
All patents, patent applications and publications (scientific, lay or otherwise) discussed or cited herein are incorporated by reference to the same extent as if each individual patent, patent application or publication was specifically and individually set forth in its entirety.

Specially configured lip/cheek pulse oximeter/photoplethysmography probes, selectively with sampler for capnography, and covering sleeves for same

University of Florida Research Foundation, Inc.


Described herein is a novel member of the prostanoid receptor family, a guinea pig prostaglandin D2 receptor. Described are the receptor, the nucleic acid that encodes it, and various uses for both.

Prostanoids, including prostaglandin (PG), prostacyclin and thromboxane (TX), are important mediators of central and peripheral physiological effects. Prostaglandin D2 (PGD2) is formed in a variety of tissues including brain, spleen, lung, bone marrow, stomach, skin and also in mast cells (Lewis et al., 1982). PGD2 has been implicated in many physiological events both in the central nervous system and in the peripheral tissues. In the central nervous system, PGD2 has been shown to affect the induction of sleep, body temperature, olfactory function, hormone release and nociception. Peripherally, PGD2 is the major cyclooxygenase product of arachidonic acid produced from mast cells following immunological challenge. Local allergen challenge in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis has been shown to result in rapid elevation of PGD2 levels in nasal and bronchial lavage fluids, tears and skin chamber fluids. Activated mast cells, a major source of PGD2, are one of the key players in driving the allergic response in conditions such as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases (Brightling et al., 2003). Likewise, PGD2 has many inflammatory actions, such as increasing vascular permeability in the conjunctiva and skin, increasing nasal airway resistance, airway narrowing and eosinophil infiltration into the conjunctiva and trachea. Therefore, PGD2 is considered one of the key players in driving inflammatory reactions.
Early efforts have focused on identifying distinct receptors for the five naturally occurring bioactive prostanoids, PGD2, PGE2, PGF2α, PGI2 and TXA2, resulting in the classification of five basic types of prostanoid receptors: DP, EP, FP, prostacyclin (IP) and thomboxane (TP) receptors, respectively (Coleman et al., 1994). Many of the actions of prostaglandin D2 are mediated through its action on the D-type prostaglandin receptor (DP), a G protein-coupled receptor. While originally thought that each prostanoid acted preferentially on individual receptors, researchers studying prostanoid biology have begun to appreciate the promiscuity of these ligands to interact with members of the different receptor families. Thus, it is becoming ever more clear that to understand prostanoid signaling one must elucidate the biological consequence of prostanoid receptor activation.
The DP receptor is of particular interest because it is found in both central and peripheral cells suggesting its involvement in mediating varied biological pathways and, consequently, its potential therapeutic importance in many disease states. DP receptors have been identified in the brain and PGD2 has effects on sleep induction, body temperature, olfactory function, and hormone release (Negishi, et al., 1993; Wright et al., 1999 and references within). DP receptors have also been localized to discrete and distinct cell populations of the spinal cord. This observation may explain the discordant effects of hyperalgesia and allodynia (discomfort from innocuous tactile stimuli) induced by PGD2. DP receptors are also present in the gastrointestinal tract and have been implicated in the contractile response of the GI tract (Wright et al., 1999; Ito et al., 1989). Additionally, DP receptor ligands have been shown to induce mucous secretion and cell proliferation of intestinal cells. Glycogenesis in the liver may also be regulated by DP receptors (Ito et al., 1989). DP receptors are found in the eye and agonists reduce intraoccular pressure suggesting a role in glaucoma. Platelets contain the DP receptor and PGD2 has been shown to inhibit platelet aggregation supporting a role for the DP receptor in modulating blood disorders such as thrombosis (Armstrong, 1996). Thus, the varied expression of the DP receptor in different organs and tissues suggests the DP receptor may be an attractive target for different therapeutic areas.
Of particular interest, the DP receptor has been implicated in various inflammatory disorders including but not limited to asthma, allergic rhinitis, airway hyperactivity, allergic dermatitis, allergic conjunctivitis and chronic obstructive pulmonary disease. This is supported by the observation that PGD2 is the major prostanoid released by immunochallenged mast cells (Roberts, et al., 1980). In asthma, the respiratory epithelium has long been recognized as a key source of inflammatory cytokines and chemokines that drive the progression of the disease (Holgate et al., 2000). In an experimental murine model of asthma, the DP receptor is dramatically upregulated on airway epithelium on antigen challenge (Matsuoka et al., 2000). Conversely, in knockout mice lacking the DP receptor, there is a marked reduction in airway hyperreactivity and chronic inflammation (Matsuoka et al., 2000); two of the cardinal features of human asthma. Similarly, DP receptor antagonists have been shown to reduce airway inflammation in a guinea pig experimental asthma model (Arimura et al., 2001). The DP receptor is also thought to be involved in human allergic rhinitis, a frequent allergic disease that is characterized by the symptoms of sneezing, itching, rhinorea and nasal congestion. Local administration of PGD2 to the nose causes a dose dependent increase in nasal congestion (Doyle et al. 1990). DP antagonists have been shown to be effective at alleviating the symptoms of allergic rhinitis in multiple species, and more specifically, have been shown to inhibit the antigen-induced nasal congestion, the most manifest symptom of allergic rhinitis. DP antagonists are also effective in experimental models of allergic conjunctivitis and allergic dermatitis (Arimura et al., 2001). Thus, DP antagonists could therefore be useful in the treatment of a variety of PGD2-mediated disorders including, but not limited to, bronchial asthma, Chronic obstructive pulmonary disease (COPD), allergic rhinitis, allergic dermatitis, allergic conjunctivitis, systemic mastocytosis and ischemic reperfusion injury.
Thus far, the DP receptor has been cloned from human (Boie et al., 1995), rat (Wright et al., 1999) and mouse (Hirata et al., 1994). These DP receptors share 73-90% homology at the amino acid level between human, mouse and rat and, in each case, activation of the recombinant receptors leads to accumulation of intracellular cAMP. It is generally observed between G protein coupled receptors that compounds often show varying potencies from one orthologue receptor to another.
Disclosed here, for the first time, is a DP receptor from the guinea pig. The present invention provides several advantages over that which is currently known in the art. Species differences between mouse, rat, human and guinea pig can now be more fully determined and characterized. The low expression levels of the DP receptor in native tissues makes it difficult to assess a compound's activity as a modulator, effector, agonist or antagonist of the receptor. The present invention now provides the opportunity to examine the receptor in an isolated and purified condition providing the ability to test compounds and then to bridge in vitro studies to the same species in vivo. Because of its larger size, the guinea pig is a preferred animal model to smaller rodents, for instance, providing more surface area with regard to dermatology and gastrointestinal studies. More importantly, the guinea pig is the most usable small animal model for some allergy models such as nasal congestion and is more responsive to airway hyperactivity manipulations. Although the guinea pig represents an ideal preclinical model for the evaluation of DP receptor modulators in multiple disease models, as outlined above, the cloning of the guinea DP receptor has not previously been reported and hence it is difficult to predict the affinity of a compound against this orthologue.

Nucleic acid molecules encoding prostaglandin receptor proteins


An upper end of a carton includes first and second panels that are in an overlapping relationship with respect to one another. The first panel includes an opening for being in communication with the carton's interior. A flexible, elongate closure tab extends through a slot so that the closure tab is interposed between the first and second panels. The closure tab can be slid between the first and second panels, between open and closed configurations. In the closed configuration, the closure tab at least substantially obstructs the opening. In the open configuration, the opening is not substantially obstructed by the closure tab. A projection is engaged by the closure tab for discouraging the closure tab from being completely pulled out of the slot during the open configuration.

The present invention generally relates to containers with sliding tabs for controlling dispensing.
It is known for a carton to have a tab that can be slid between portions of the carton and relative to an opening, for opening and closing the opening and thereby controlling dispensing from the carton. For example, U.S. Pat. No. 4,094,456 discloses such a carton. A problem that can be encountered with such a carton is that the tab can be slid too far outwardly, such that the tab has to be reinserted.
For the foregoing other reasons, there is a desire for improvements.

Carton with slidable tab for controlling dispensing


To support a shell case having a different shape by support mechanisms in a shell lock seaming machine, the support mechanisms are disposed on both the sides of the opening edges of the shell case and a plurality of support members are provided with each of the support mechanisms, the plurality of support members being locked to the inner surface of both the opening edges of the shell case, wherein the plurality of support members can advance and retreat in the axial direction of the shell case as well as at least one of the plurality of support members is movable in a direction perpendicular to the axial center of the shell case.

1. Field of the Invention
The present invention relates to a shell lock seaming machine, and more specifically, to a shell lock seaming machine for winding a sheet member around the outer periphery of a shell case.
2. Description of the Related Art
Conventionally, there have been used shell lock seaming machines which employ a so-called over-winding method by which a sheet member is wound around the outer periphery of a shell case used as a silencer to reduce the noise created by an internal combustion engine in order to enhance the noise insulating properties of the silencer and make the silencer look more attractive.
The over-winding method will be schematically described with reference to FIG. 11A to FIG. 11F. First, a metal sheet member 100 shown in FIG. 11A is wound to a cylindrical shape as shown in FIG. 11B and both the ends thereof are coupled with each other by a lock seam 101; flanges 103, as shown in FIG. 11, are formed to both the opening edges of the shell case 102; contents 104 composed of barrier plates, end plates and the like to which an inner pipe is fixed are inserted from one of the opening edges as shown in FIG. 11D; thereafter, a sheet member 105 is fed below the shell case 102 and bent along the lower half of the shell case 102 by moving a pair of presser plates 106 upward as well as both the ends of the sheet member 105 are raised as shown in FIG. 11E; and then both the ends of the sheet member 105 are coupled with each other by a lock seam 107 as shown in FIG. 11F to thereby form a double-walled shell case.
At the above step at which the sheet member 105 is wound around the outer periphery of the shell case 102, there has been conventionally employed, as shown in FIG. 12A and FIG. 12B, a mechanism for supporting the shell case 102 which is arranged such that a pair of mandrels 108, 109 are disposed in confrontation with each other, the shell case 102 is located between the mandrels 108, 109 by a robot or the like as shown in FIG. 12A, thereafter both the mandrels 108, 109 are inserted into the shell case 102 from both the opening edges thereof to thereby support the shell case 102 as shown in FIG. 12B (for example, JP-A-06-269884).
The outer peripheral shape of the conventional mandrels 108, 109 is exclusive to the shape of both the opening edges of the shell case 102 to be processed. Thus, when a shell case having a different opening diameter is supported, the above mandrels must be replaced with mandrels whose shape corresponds to the different opening diameter. As a result, to make silencers having various types of sections, pairs of mandrels as many as the number of the sections must be prepared and a setup process for the mandrels is required.
Accordingly, the cost of mandrels and a setup cost therefor are incurred in this arrangement, and the efficiency of the operation is lowered due to the time consumed by the setup.
An object of the present invention is to provide a shell lock seaming machine which has a shell case support mechanism capable of supporting shell cases having various types of sections without the need of setup to thereby increase productivity when many types of shell cases are made by mixture.


In a method of filling a liquid crystal display panel with liquid crystal and a liquid crystal filling system using the method, a seal line and spacers are formed on a color filter substrate. A first volume defined by the seal line and a second volumes defined by the spacers are obtained. An amount of liquid crystal to be supplied into a region enclosed by the seal line is precisely calculated based on the first and second volumes. Shortage of the liquid crystal supplied into the LCD panel and overflow of the liquid crystal can be avoided. Accordingly, the steps for supplying the liquid crystal into the LCD panel may be reduced, and simultaneously peripheral regions of the LCD panel be prevented from being contaminated by the liquid crystal while the liquid crystal is filled into the LCD panel.

1. Field of the Invention
The present invention relates to a method of filling a liquid crystal display panel with liquid crystal and a liquid crystal filling system for performing the same.
2. Description of the Related Art
Generally, liquid crystal is interposed between a TFT substrate and a color filter substrate of a liquid crystal display panel.
The liquid crystal is affected by an electric field formed between the TFT substrate and the color filter substrate. In detail, the liquid crystal varies the transmissivity of the light supplied from an external light source depending on the electric field applied thereto, so that full-color images required by users can be displayed.
The TFT substrate and the color filter substrate have a cell gap for receiving the liquid crystal.
Since the cell gap has a size of a few micrometers (μm), a special method is required to uniformly supply liquid crystal over the entire area of the cell gap.
In order to fill the liquid crystal into the cell gap, firstly, a part of a liquid crystal display panel having the cell gap is firstly immersed into the liquid crystal contained in a barrel. Then, since vacuum pressure is formed in the cell gap, the liquid crystal is sucked into the cell gap.
The above method of filling liquid crystal using vacuum pressure has an advantage that the liquid crystal can be completely filled in the cell gap having the size of a few micrometers (μm), such that no empty area remains in the cell gap. However, an excessive amount of liquid crystal may be supplied into the cell gap.
For this reason, the above method of filling liquid crystal using vacuum pressure requires additional processes such as a pressing process for discharging excessively injected amount of liquid crystal, a liquid crystal sealing process for sealing an inlet and an outlet, through which the liquid crystal is respectively injected and discharged, with sealing materials, and a cleaning process for cleaning the liquid crystal remaining on an outer surface of the liquid crystal display panel.
Besides the liquid crystal filling method using vacuum-pressure, a second liquid crystal filling method has been recently developed.
According to the second liquid crystal filling method, first, the liquid crystal is dropped onto the color filter substrate. Then, the TFT substrate is bonded to the color filter substrate such that the liquid crystal is filled between the TFT substrate and the color filter substrate.
The second liquid crystal filling method may fill the liquid crystal between the TFT substrate and the color filter substrate in a relatively simple manner compared with the liquid crystal filling method using vacuum-pressure. However, according to the second liquid crystal filling method, bubbles are generated inside the liquid crystal display panel or the liquid crystal overflows the liquid crystal display panel.
For example, when an excessive amount of liquid crystal is supplied into the color filter substrate, the excessive amount of liquid crystal overflows outside of the liquid crystal display panel. On the contrary, when the liquid crystal is insufficiently supplied into the color filter substrate, a bubble area is formed inside the liquid crystal display panel. Since liquid crystal does not exist in the bubble area, image may not be displayed in the bubble area.
Accordingly, in the second liquid crystal filling method, it is important to determine a precise amount of liquid crystal to be supplied into the liquid crystal display panel.
The amount of liquid crystal supplied into the liquid crystal display panel is determined depending on a volume of spacers and an internal volume defined by a region enclosed by a seal line formed on the color filter substrate.
However, the internal volume and the volume of the spacers used for determining the amount of liquid crystal to be supplied may be varied depending on the liquid crystal filling process.
Especially, the volume of the spacers remarkably varies depending on substrates because of differences in the prosess of forming spacers.
The spacers are randomly attached to the region enclosed by the seal line of the color filter substrate by means of a spacer disperser. Since a random number of spacers are attached to the region enclosed by the seal line, measuring the total volume of the spacers is difficult.
For this reason, it is difficult to precisely calculate the total volume of the spacers. Therefore, the amount of liquid crystal to be supplied may not be precisely calculated.
On the other hand, the spacers may be formed through a process of patterning a photoresist film. In this case, a predetermined number of spacers are attached to predetermined positions on the substrate, so that the total volume of the spacers can be roughly calculated.
However, since a height of the photoresist film has a deviation depending on the positions on the substrate, the volume of the spacers may slightly vary depending on the positions of the spacer on the substrate. Therefore, it is difficult to precisely calculate the total volume of the spacers and the amount of liquid crystal to be supplied.

This patent is subject to a terminal disclaimer.

Method of filling liquid crystal display panel with liquid crystal and liquid crystal filling system performing the same


A motor includes a rotation shaft, a commutator, power supply brushes, and a brush holder. The brush holder includes an opposing portion that faces an end face of the commutator in an axial direction, a bearing holder, and a diffusion stopper. The diffusion stopper is arranged in a portion of the opposing portion located toward the outer side in the radial direction from the bearing holder and limits the diffusion of abrasion powder of the power supply brushes. The diffusion stopper is projected toward the commutator in the axial direction or recessed in the axial direction.

The present invention relates to a motor.
An armature of a conventional motor includes a rotation shaft and an armature core and a commutator, which are fixed to the rotation shaft. An armature coil is wound around the armature core. Power is supplied to the armature through a power supply brush that is in slidable contact with the commutator. Japanese Laid-Open Patent Publication No. 2012-178965 describes an example of a motor including an armature coil, which is accommodated in a yoke housing, and a power supply brush, which is held by a brush holder attached to an open end of the yoke housing. Further, a commutator is arranged in a recess of the brush holder. A speed reduction unit that reduces the rotation speed of the rotation shaft and outputs the reduced speed is coupled to the opening of the yoke housing.
In the motor including the power supply brush described above, when the power supply brush is in slidable contact with the outer circumferential surface of the commutator that rotates integrally with the rotation shaft, the power supply brush wears and produces abrasion powder. When the abrasion powder diffuses and deposits in the motor, the abrasion power may form a conductive line between the power supply brush and the rotation shaft and between the power supply brush and the armature core. This may cause an insulation defect.