A golf club head includes a face having a height ranging from 24 to 32 mm. The ratio W/H of the width W of a sole to the height H of the face is in the range from 1.5 to 2.2. The distance Y from a straight line along the central axis of a hosel to the end of a heel is in the range from 11 to 15 mm. The golf club head thus constructed is capable of hitting the ball over a sufficient distance in a good direction.

1. Field of the Invention
The present invention relates to a golf club head having a hollow structure, and more particularly to the head of a golf club for use as a fairway wood or a long iron.
2. Description of the Related Art
In recent years, hollow metallic golf club heads are mainly used as the heads of wood golf clubs such as drivers. A golf club with a hollow metallic head is advantageous in that it can deliver the ball over a larger distance in a more correct direction. With the hollow metallic head, its crown and side can be thin-walled to give much weight to at least a portion of the sole, and the center of gravity can be lowered and positioned rearwardly away from the face without causing an increase in the overall weight of the head. The lowered and rearwardly positioned center of gravity is effective to prevent the ball from going upwardly due to an excessive back spin, but to allow the ball to follow an ideal trajectory for traveling a sufficient distance. Because of the hollow structure, the club head has a relatively large moment of inertia and hence can hit the ball in a good direction.
There is known a wood club head having a face whose height is reduced for a low center of gravity. Specifically, since a golf club head with a low center of gravity is ideal for hitting the ball at a sweet spot for a fairway shot, many fairway wood club heads have a face with a reduced height. Golf club heads having a face with a reduced height can have its center of gravity lowered by positioning a sweet spot, which is at the foot of a perpendicular from the center of gravity of the head to the face, near the center of the face. If the center of gravity of a golf club head having a face with a large height is to be lowered, then the sweep spot is largely displaced downwardly on the face, resulting in a poor vertical balance of the head.
Wood golf club heads that have been available heretofore are preferable if they can hit the ball over a large distance in a good direction, have a sole whose area of contact with ground is small when hitting the ball, and allow the golf club user to perform a smooth transition from the downswing phase to the follow-through phase. Particularly, it is important for fairway wood golf clubs to have a sole configuration with a small area of contact with ground because they are used almost exclusively to hit the ball from a fairway or a rough area unlike drivers that are used to make a tee shot. It is therefore customary for fairway wood golf clubs to have a slanted or curved sole.
Though metallic wood golf club heads, particularly fairway wood golf club heads, are capable of hitting the ball over a large distance with the lowered center of gravity and allowing the golf player to perform a smooth transition action from the downswing phase to the follow-through phase with the shaped sole, they have much to be improved and should desirably be stabler with respect to the directivity of the shot.
The directivity of the shot is better as the club head has a larger moment of inertia. If the club head does not easily turn back when hitting the ball, then the hit ball will travel in a wrong direction. Conventional fairway wood golf clubs are problematic in that their head does not turn back well because the face tends to be in an open position with respect to the ball when hitting the ball.
It is a general object of the present invention to provide a golf club head which is capable of hitting the ball over a long distance in a good direction.
Another object of the present invention is to provide a golf club head which prevents the ball from going upwardly.
Still another object of the present invention is to provide a golf club head which allows the golf club user to perform a smooth transition from the downswing phase to the follow-through phase.
Yet another object of the present invention is to provide a golf club head which can easily turn back when hitting the ball.
According to the present invention, a golf club head of hollow structure has a head body having a heel, a toe, and a face extending between the heel and the toe, a sole connected to the head body and extending rearwardly from the face, and a hosel extending from the head body, the face having a height H ranging from 24 to 32 mm, the sole having a width W, the ratio W/H of the width W to the height H being in the range from 1.5 to 2.2, and the distance Y from a straight line along the central axis of the hosel to the end of the heel being in the range from 11 to 15 mm.
Since the height H and the ratio W/H of the width W to the height H are specified and the position of the hosel with respect to the face is also specified as described above, the golf club head can turn back well when hitting the ball and make the ball stable in its direction of travel.
The sole is curved to reduce its area of contact with ground for allowing the golf club user to perform a smooth transition from the downswing phase to the follow-through phase. The height of the face is reduced to lower the center of gravity of the golf club head for delivering the ball over a sufficient distance in a stable direction.
The sole is partly increased in thickness to provide a concentrated-weight portion which is located in an appropriate position and has appropriate width and weight. The concentrated-weight portion of the sole makes the golf club head capable of hitting the ball over a long distance in a good direction.
The head body has a height H ranging from 24 to 32 mm along the face. In order for the face to hit the ball on ground at its sweet spot that is positioned near the center of the face, the height H is about 33 mm or less. If the height H is smaller than 24 mm, however, the area of the face that is effective to hit the ball is too narrow.
The face has a length L ranging from 80 to 100 mm. If the length L were in excess of 100 mm, then since the shape of the face would be too different from the conventional shapes, the golf club user would tend to produce a wrong shot. If the length L were smaller than 80 mm, then the moment of inertia of the golf club head would be so reduced that the golf club user would fail to hit the ball in a good direction.
The ratio W/H ranges from 1.5 to 2.2, preferably from 1.7 to 2.0. The ratio W/H is set to a relatively small value in order to reduce the width W of the sole. However, if the ratio W/H were less than 1.5, then the golf club head would not turn back sufficiently when hitting the ball, and would not hit the ball in a stable direction. If the ratio W/H exceeded 2.2, then the golf club head would turn back excessively and might make unstable the direction of travel of the ball which has been hit.
The distance Y is in the range from 11 to 15 mm, preferably from 12 to 15 mm. The distance Y thus selected positions a shaft mounted in the hosel closely to the center of gravity of the golf club head, making stable the direction of travel of the ball which has been hit. If the distance Y were less than 11 mm or equal to or greater than 16 mm, then the ball would be hit in an unstable direction.
The golf club head may have a volume of at most 170 cc, and a lie angle xcex1 ranging from 56 to 60xc2x0. If the height H and the length L and the relationship between the width W and the height H are specified as described above, then the volume of the golf club head which is 170 cc or less is appropriate. If the lie angle xcex1 were less than 56xc2x0, then since a relatively long shaft is mounted on the golf club head, the face of the golf club head would be liable to be in an open position when hitting the ball. If the lie angle xcex1 were in excess of 60xc2x0, then since a relatively short shaft is mounted on the golf club head, the golf club head would be apt to fail to deliver the ball over a long distance.
The hosel may have a shaft receiving hole defined therein and open at the sole. The shaft receiving hole is also referred to as a through bore, which is known as easily making low the center of gravity of the golf club head. In-as-much as the hosel is relatively spaced apart from the end of the heel, the through bore defined in the hosel is effective to make the golf club head heavier at the heel, so that the golf club head can turn back easily when hitting ball.
The sole extends from the toe to the heel and has a radius R of curvature of at most 110 mm. However, it is not necessary for the sole have a curved surface having a single radius of curvature, but may have a curved surface having different radii of curvature. The radius R of curvature is preferably in the range from 60 to 100 mm, and more preferably in the range from 70 to 90 mm. If the radius R of curvature were too small, then the size of the golf club head would be too small, and the moment of inertia thereof would be too small, making poor the directivity of the ball which has been hit. If the radius R of curvature were larger than 110 mm, then the size of the golf club head would be too large, and the sole would have too a large area of contact with ground, so that the ability of the golf club head to make a smooth transition from the downswing phase to the follow-through phase would be reduced.
The concentrated-weight portion which has an increased wall thickness and is located at a rear position spaced from the face. The concentrated-weight portion has a width Z which is at most xc2xd, preferably in the range from ⅕ to xc2xd, of the width W of the sole, and a weight ranging from 40 to 100 g, preferably from 50 to 80 g. The concentrated-weight portion thus constructed allows the golf club head to have its center of gravity effectively lowered and positioned rearwardly without losing an adequate weight balance. If the width Z of the concentrated-weight portion were more than xc2xd of the width W of the sole, or the weight of the concentrated-weight portion were less than 40 g, then it would be difficult to lower and position rearwardly the center of gravity of the golf club head. The concentrated-weight portion may be positioned in an entire rear region of the sole at maximum.
The above and other objects, features, and advantages of the present invention will become more apparent from the following description when taken in conjunction with the accompanying drawings in which a preferred embodiment of the present invention is shown by way of illustrative example.


A method of die-necking the open end of a can body to form a reduced diameter neck having a smooth profile comprising first forming a reduced diameter control neck at the open end of the sidewall of the can body, and then totally reforming the control neck and the adjacent portion of the sidewall to form a second reduced diameter neck. The diameter of the second neck is less than the diameter of the control neck, and the axial length of the second neck is substantially greater than the axial length of the control neck.

This invention relates generally to a method of necking-in the open end of a cylindrical container and, more specifically, to a method of die-necking the open end of a container including a plurality of die-necking steps which form a smooth neck configuration on the open end of the can.
In recent years it has become commonplace in the beer and beverage industry to use two piece cans formed of thin sheet aluminum and consisting of a first cylindrical can body having an integral bottom end panel and an upper open end which, after filling, is closed by attaching a separate end cap onto the mouth of the open end of the can body. Because of the thickness of the metal used in forming the end cap, the cost of the cap is a very significant portion of the overall cost of the can. Consequently, a long standing cost reduction trend in the aluminum can industry has been to decrease the diameter of the mouth of the can by making a neck that is smaller than the diameter of the cylindrical can body in order to use a smaller end cap and thereby save on the cost of the metal for the end cap. For example, the outside diameter of the cylindrical body of a twelve ounce or sixteen ounce can is commonly 2-11/16 inches (a 211 diameter) and the open end of the can may be necked down to a diameter of 2-6/16 inches (a 206 diameter), with the continuing trend in the industry towards even smaller diameters, for example a diameter of 2-4/16 inches (a 204 diameter).
In the past, various processes including triple necking or quad necking operations have been employed to produce a stepped or ribbed neck having a reduced diameter of desired size. In addition, prior U.S. Pat. No. 3,029,507, 4,173,883, 4,403,493, 4,527,412, and 4,774,839 disclose various processes employing a plurality of die necking steps attempting to form smooth walled necks. However, as the diameter of the neck becomes smaller and smaller, it has become more difficult to provide a smooth neck profile free of wrinkles or pleats.
Also, a foreign subsidiary of the assignee of this invention for some time has employed a die-necking process in which the reduced diameter neck is formed by a plurality of die necking steps. The first step produces a reduced diameter neck corresponding in axial length to the desired axial length of the finished neck and each successive die necking step then reduces the diameter of the neck further while reforming by actual die contact only a portion of the length of the neck formed in the preceding step. This method is similar to the operations described in the above-noted patents
In die-necking processes the first necking step is the most critical and it is in that step where wrinkles or pleats are most commonly formed which produce scrap containers. Saunders U.S. Pat. Nos. 3,964,413 and 3,995,572 propose to avoid wrinkling problems by providing die-necking methods in which the first step forms a strengthening hoop at the peripheral edge of the can and a subsequent die necking step or steps form the final full length neck. However, the hoop formed in each of these systems is not totally reformed by die contact in the subsequent step and the final configuration of the neck remains directly dependent on the configuration of the hoop.
The invention described herein is directed to the elimination of the wrinkling or pleating problems associated with prior, multiple step, die-necking operations, particularly those associated with producing smooth walled 206, 204, and smaller diameter necks.


Formulations, kits and methods for bone or cartilage repair, including treatment of osteogenic defects, including formulations of synthetic heparin-binding growth factor analogs, non-ionic polymers, gelling agents and calcium-containing agents.

1. Field of the Invention (Technical Field)
The present invention relates to formulations, methods and kits for the delivery and administration of synthetic heparin-binding growth factor analogs, particularly for use in tissue repair, including bone and cartilage repair.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-à-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
The use of various bone filler agents and compositions is well known. Among materials used are various calcium-containing compounds and compositions including demineralized bone matrix (DBM). Limited research has been conducted using compositions which include growth factors, including recombinantly-produced growth factors, such as recombinantly produced bone morphogenic protein-2 (BMP-2).
The role of other growth factors in tissue repair, such as transforming growth factor-alpha (TGF-α) or transforming growth factor-beta (TGF-β), has been studied. In particular, TGF-β is known to accelerate the wound repair process. TGF-β1 has been proposed as a likely candidate for stimulating cartilage repair as it affects chondrocytes by enhancing matrix production, cell proliferation, and osteochondrogenic differentiation. There are at least three isoforms of TGF-β in man, TGF-β1, TGF-β2, TGF-β3. TGF-β exists in at least five isoforms, known TGF-β1, TGF-β2, TGF-β3, TGF-β4 and TGF-β5, that are not related to TGF-α. Their amino acid sequences display homologies on the order of 70-80 percent. TGF-β1 is the prevalent form and is found almost ubiquitously while the other isoforms are expressed in a more limited spectrum of cells and tissues.
TGF-beta is the prototype of a family of proteins known as the TGF-beta superfamily. This family includes inhibins, Activin A, MIS (Mullerian activating substance) and BMPs (Bone morphogenic proteins). Burt, Evolutionary grouping of the transforming growth factor-beta superfamily. Biochem. Biophys. Res. Commun. 184:590-5 (1992).
Some 23 fibroblast growth factors identified to date (FGFs 1-23). Peptides from natural HBGFs that bind heparin-binding growth factor receptors have been identified. See for example Ray et al., Proc. Natl. Acad. Sci. USA 94:7047-7052 (1997). FGFs useful in prevention or therapy of a wide range of diseases and disorders may be purified from natural sources or produced by recombinant DNA methods; however, such preparations are expensive and generally difficult to prepare.
However, there are no known formulations, methods or kits designed to provide components that augment or activate growth factors, such as FGF-2, BMP-2 or TGF-β, which may be present endogenously, such as produced by the individual being treatment, or which may be exogenous, such as derived from natural material or produced by recombinant means. There are further no known formulations, methods or kits that employ the synthetic heparin-binding growth factor analogs disclosed herein. It is against this background that the invention is made.

Formulations and methods for delivery of growth factor analogs

BioSurface Engineering Technologies, Inc.


To keep operation of a control circuit for a line sensor reading operation always the same regardless of variations and differences between readers, simplify the control circuit, and avoid complicated processes such as setting various software process parameters for canceling differences between the readers. A line shaped, two-wavelength transmitting LED array and a line shaped light emitting/photodetecting part comprising a photodetector array and a two-wavelength reflecting LED array are disposed in opposition each other such that a read medium passes between the two-wavelength LED array for transmitting light and the light emitting/photodetecting part, and the two-wavelength LED array for tranmitting light and two-wavelength LED array for reflecting light emit light of different wavelengths. An storage time control circuit is disposed in a signal processing circuit of the photodetector array; and a control means is provided for controlling light emission with the two-wavelength transmitting LED array and two-wavelength reflecting LED array, controlling reading with the photodetectors, and controlling the storage time control circuit. Variations in wavelength detection sensitivity and light quantity with different scanned media are adjusted by means of the storage time of the storage time control circuit.

1. Field of the Invention
The present inventions relate to an image reading apparatus for controlling the storage time of the reading means for banknote (bank bill) identification for each of the multiple wavelength light sources in an image reading apparatus using a multiple wavelength light source, and to a control method for the image reading apparatus.
2. Description of the Related Art
The prior art includes a banknote identification apparatus using an accumulation time control circuit as taught in Japanese Patent Publication (kokoku) No.8-12709. This banknote identification apparatus has a light emitting means for emitting two colors (two wavelengths) of light, a detection circuit for detecting the emission ratio of light from the light emitting means, and four photodetection circuits for detecting light reflected from the banknote. The absolute light quantity is controlled to a constant level and photodetection from the banknote is corrected based on the emission ratio of the two wavelengths of light to identify the banknote.
A problem with the above-noted conventional apparatus is that the banknote cannot be identified with good precision because of variation not only in the light quantity at the light emitting side, but also introduced by the photodetection elements and photodetection signal processing circuit. This is because the photodetector receives the two wavelengths to be detected mixed together, uses a filter to separate the wavelengths at the photodetection side, and instead of being a photodetector that receives reflected light from the actual medium, the photodetector corrects the actual detected light quantity using the detected light quantity of another photodetector.
The technology of a banknote identification apparatus such as described above typically uses light sources of multiple different wavelengths to read transmitted or reflected light as a means of detecting wrinkles and subtle soiling in the watermark of worn or soiled banknote. A problem in this case is that the sensitivity of the photodetection sensor varies according to the wavelength of the light source, and error based on the sensitivity difference results. Furthermore, depending upon whether the banknote being identified is over the sensor or not, the detected light quantity differs significantly when the detecting light passed through the banknote, and high gain is therefore required when reading the banknote. It is also necessary to switch the gain level, and error in conjunction with the degree of amplification occurs.
The present invention was conceived to resolve the above-mentioned problems. An object of the present invention is to provide an image reading apparatus using a multiple wavelength light source, and a control method therefor, whereby image reading operation (including the line sensor scanning operation and variations in the sensor system) can be always the same regardless of variations and differences between image readers, the control circuit can be simplified, and complicated processes such as setting various software process parameters for absorbing differences between the image readers can be avoided. A further object of the present invention is to eliminate error occurring in conjunction with sensitivity differences if the sensitivity of the photodetection sensor differs according to the wavelength of the light source.
The present invention relates to an image reading apparatus using a multiple wavelength light source and achieves the above noted object of the present invention by disposing a line shaped, a two-wavelength transmitting LED array and a line shaped light emitting/photodetecting part comprising a photodetector array and a two-wavelength reflecting LED array disposed in opposition such that a scanned medium passes between the two-wavelength transmitting LED array and light emitting/photodetecting part, said two-wavelength transmitting LED array and two-wavelength reflecting LED array emitting light of different wavelengths; an accumulation time control circuit disposed in a signal processing circuit of the photodetector array; and a control means for controlling light emission by the two-wavelength transmitting LED array and two-wavelength reflecting LED array, controlling scanning by the photodetectors, and controlling the accumulation time control circuit; wherein variations in wavelength detection sensitivity and light quantity with different read media are adjusted by means of the accumulation time of the accumulation time control circuit.
The above object is further achieved by disposing a line shaped, a two-wavelength transmitting LED array and a line shaped light emitting/photodetecting part comprising a photodetector array and a two-wavelength reflecting LED array disposed in opposition such that a read medium passes between the two-wavelength transmitting LED array and light emitting/photodetecting part, and a signal processing circuit for controlling an accumulation time of the photodetector array when the two-wavelength transmitting LED array and two-wavelength reflecting LED array emit light of different wavelengths.
In addition, the present invention relates to a control method for an image reading apparatus having a line shaped, a two-wavelength transmitting LED array and a line shaped light emitting/photodetecting part comprising a photodetector array and a two-wavelength reflecting LED array disposed in opposition such that a read medium passes between the two-wavelength transmitting LED array and light emitting/photodetecting part, and a signal processing circuit for controlling an accumulation time of the photodetector array when the two-wavelength transmitting LED array and two-wavelength reflecting LED array emit light of different wavelengths, and achieves the above object: by determining an accumulation time when there is no read medium after an automatic adjustment for correcting a rank indicative of the light emission efficiency class of the two-wavelength transmitting LED array, placing a white reference medium in the medium path, automatically adjusting a rank indicative of the light emission efficiency class of the two-wavelength reflecting LED array, determining the transmission/reflection accumulation time when a read medium is present is, and calculating a correction coefficient; by setting an accumulation time when there is no read medium and turning off the two-wavelength transmitting LED array and two-wavelength reflecting LED array to determine a dark output correction level when there is no read medium present, determining a dark output correction level, then turning on the two-wavelength transmitting LED array and two-wavelength reflecting LED array to determine a light emitting level, setting an accumulation time when there is a read medium present and turning off the two-wavelength transmitting LED array and two-wavelength reflecting LED array to determine a dark output correction level when a scanned medium is present, and determining a dark-output correction level and calculating a correction coefficient.

Image reading apparatus having multiple wavelength light sources and control method for the same


The present invention relates to an inhaler for administering medicaments (38) from blister packs (5), which has a housing with a mouthpiece (1) on one side, an air inlet opening (32) on the opposite side and, between them on the inside, a duct (7) which connects the mouthpiece (1) and the air inlet opening (32), it being possible for at least one blister strip (5) to be inserted into the housing so that the covering foil (35) of the inserted blister strip (5) adjoins the duct (7). The housing has means for pressing out the individual cavities (31) of the blister strip (5), which means contain at least one plunger (10) with a curved plunger surface, which corresponds to the shape of the blister cavities (31), for engagement on the blister cavity.

The invention relates to an inhaler for administering medicaments from blister packs, in which the blister cavities are emptied by means of a pressing-out aid.
Inhalers for administering medicaments to patients in a solid form distributed finely in an air flow, so-called powder inhalers, are used nowadays in great numbers and many embodiments in inhalation therapy. They partially replace the previously customary suspension inhalers, in which the aerosol is produced by means of a halogenated hydrocarbon as propellent gas, and whose use is no longer desirable for reasons of environmental protection. Most of the previously known powder inhalers use a device of a technically relatively complex design, with which a patient gives himself inhalable powder portions (doses) by inhalation.
One possibility of predosing medicaments is the packaging of appropriate portions in so-called "blister packs", which are also used, for example, for packaging tablets with the possibility of hygienic individual removal. EP-B-211 595, GB-A-2,129,691 and GB-A-2,142,246 disclose powder inhalers which release the medicament from blister packs in which it is enclosed in a solid, finely distributed form. A disc-shaped blister pack is inserted into the powder inhalers described in EP-B-211,595 and GB-A-2,129,691, the powder portion is released by a plunger when the inhaler is used, and the blister disc is replaced by a new one when it has been completely emptied. GB-A-2,142,246 relates to an inhaler into which a blister pack comprising a single chamber is inserted and is opened for use with a kind of mandrel.
An inhaler which is easy to handle and is inexpensive is described in the subsequently published DE-A-44 00 084. The inhaler comprises a housing which forms an elongate interior, is sealed off relative to the outside, and has a mouthpiece on a narrow side and an air inlet opening on the opposite side, regions with blister cavities being arranged at least on one main surface of the housing. In one embodiment, the housing comprises an open structure into which one or more strips can be introduced, for example by pushing them or inserting them into a structure which can be pivoted open. In all these embodiments of the inhalers, the user has to press the individual cavities of the blister pack open with his fingers, i.e. exert pressure on the outwardly curved dome so that the thin covering foil tears open and the medicament can drop into the interior of the housing. The disadvantage with these inhalers is that the powder in the blister cavities is mechanically loaded and compressed when the latter are pressed open by the finger, and thus can no longer be finely distributed, or can only be insufficiently distributed, in the inhalation flow.
All these powder inhalers have the disadvantage that they are extremely cumbersome, i.e. the device volume is relatively large in relation to the proportioned dose quantity used. Depending on the volume and number of parts per device, carrying a known powder inhaler can be inconvenient for the patient. Moreover, with the different, often complicated functioning principles, there is the risk that the devices may not be handled properly, or possibly cannot be handled at all, in an emergency (e.g. in an acute asthma attack) or in the case of little technical understanding on the part of the patient.

Inhaler for administering medicaments from blister packs


Disclosed are a full ice level sensing apparatus and method in which a full ice level of ice cubes in an ice bank is sensed by means of upward and downward movements of an elevating member, thereby minimizing an operational area of the elevating member required to sense the full ice level and increasing an effective volume of a freezing chamber. The full ice level sensing apparatus includes an elevating member disposed so as to rectilinearly move up and down into the ice bank, elevating means for rectilinearly moving the elevating member upward and downward, and sensing means for sensing whether or not the ice bank is at the full ice level based on the position of the elevating member.

1. Field of the Invention
The present invention relates to a full ice level sensing apparatus and method for a refrigerator, and more particularly to a full ice level sensing apparatus and method in which a full ice level of ice cubes in an ice bank is sensed by means of the upward and downward movements of an elevating member.
2. Description of the Related Art
Generally, refrigerators maintain a freezing chamber or a refrigerating chamber at a low temperature using a refrigerating cycle device, which comprises a compressor, a condenser, an expansion unit and an evaporator, by means of a refrigerant.
FIG. 1 is a perspective view of a conventional refrigerator, in which a freezing chamber door and a refrigerating chamber door are opened.
As shown in FIG. 1, the conventional refrigerator comprises a barrier 1 for dividing the inside of the refrigerator into a freezing chamber (F) and a refrigerating chamber (R), a main body 2 provided with a refrigerating cycle device for cooling the freezing chamber (F) and the refrigerating chamber (R) at a low temperature, a freezing chamber door 4 rotatably connected to the main body 2 for opening and closing the freezing chamber (F), and a refrigerating chamber door 6 rotatably connected to the main body 2 for opening and closing the refrigerating chamber (R).
The refrigerating cycle device includes a compressor for compressing a refrigerant in a low-temperature and low-pressure state to a high-temperature and high-pressure state, a condenser for condensing the refrigerant in the high-pressure state compressed by the compressor by emitting heat to outdoor air, an expansion unit for decompressing the refrigerant condensed by the condenser, and an evaporator for evaporating the refrigerant expanded by the expansion unit by absorbing heat from the freezing chamber (F) or the refrigerating chamber (R).
Recently, an automatic ice-making device for making ice by means of cool air in the freezing chamber (F) and then for exhausting the ice is installed in the refrigerator.
The automatic ice-making device includes an ice-maker 8 installed at an upper portion of the inside of the freezing chamber (F) for freezing water supplied thereto by means of cool air in the freezing chamber (F), an ice bank 9 installed in the freezing chamber (F) for containing ice cubes made by the ice-maker 8, a dispenser 10 installed at the freezing chamber door 4 for exhausting the ice cubes without opening the freezing chamber door 4, and an ice chute 11 for guiding the ice cubes contained in the ice bank 9 to drop down to the dispenser 10.
FIG. 2 is a perspective view illustrating the ice-maker and the ice bank for the conventional refrigerator. FIG. 3 is a schematic view of a controller of the ice-maker for the conventional refrigerator.
The ice-maker 8 includes an ice-maker mold 12 for containing water to be frozen and freezing the water into ice cubes having a designated shape, a water supply unit 13 for supplying the water into the ice-maker mold 12, a slider 14 for guiding the ice cubes into the ice bank 9, and a heater for separating the ice cubes from the ice-maker mold 12.
Here, the ice-maker mold 12 is connected to the freezing chamber of the refrigerator by a connection unit 12a.
The ice-maker 8 further includes an ice-making controller 16, and an ejector 17 axially connected to a motor of the ice-making controller 16 for exhausting the ice cubes made by the ice-maker mold 12 to the ice bank 10.
The ice-maker mold 12 has an approximately semi-cylindrical shape, and includes a plurality of partition plates 12a spaced from each other by designated intervals for allowing the plural ice cubes to be divisionally made.
Further, the ejector 17 includes a shaft 17a traversing the ice-maker mold 12, and a plurality of ejector pins 17b installed at the side wall of the shaft 17a.
Here, each of the ejector pins 17b is positioned between the partition plates 12b of the ice-maker mold 12.
The ejector pins 17a serve as means for exhausting the made ice cubes to the ice bank 10.
The ice cubes transferred by the ejector pins 17a are put on the slider 14, and are then dropped to the ice bank 9 along the surface of the slider 14.
Further, the heater is attached to the bottom of the ice-maker mold 12, and serves to increase the temperature of the ice-maker mold 12 so as to separate the ice cubes from the ice-maker mold 12 by melting the ice cubes at portions thereof adhered to the surface of the ice-maker mold 12. The ejector 17 transfers the separated ice cubes.
Before the ice cubes are separated from the ice-maker mold 12, a sensing lever 18 determines whether or not the ice bank 10 positioned below the ice-maker mold 12 is fully filled with the ice cubes (hereinafter, referred to as "at a full ice level").
Here, the sensing lever 18 is designed such that both ends of the sensing lever 18 are rotatably attached to both sides of the ice-maker 8 and the sensing lever 18 is outwardly bent at designated portions.
The ice-making controller 16 includes a control panel 21, a magnet 22 rotated by the rotation of the sensing lever 18, a hall sensor 23 for sensing a magnetic field generated from the magnet 22 when the rotation of the sensing lever 18 is limited by the amount of the ice cubes at the full ice level, a motor 24 for generating a driving force for rotating the sensing lever 18 and the ejector 17, a driving gear 25 axially connected to a shaft of the motor 24, a driven gear 26 interdigitated with the driving gear 25 and provided with a rotary shaft 26a connected to the shaft 17a of the ejector 17, a cam 27 protruded from the rotary shaft 26a of the driven gear 26, and an arm lever 28 geared with the cam 27 for rotating the sensing lever 18.
Here, the magnet 22 is installed at an extension portion 18a of the sensing lever 18.
The rotary frequency of the cam 27 is transmitted to the arm lever 28 for vertically moving the sensing lever 18.
The hall sensor 23 is installed on the control panel 21, and is positioned such that the variation in the magnetic field generated by the movement of the magnet 22 is sensed by the hall sensor 23.
That is, the hall sensor 23 senses the magnetic field through the variation in the rotary position of the magnet 22 generated by the rotation of the sensing lever 18, thereby determining whether or not the ice bank 9 is at the full ice level.
Since the sensing lever 18 of the above-described full ice level sensing apparatus is outwardly bent at designated portions and is rotated so as to sense the full ice level, the sensing level 18 requires a large area for operation, thereby reducing an effective volume of the freezing chamber (F).

Full ice level sensing apparatus and method


Provided is a robot cleaner. The artificial intelligence robot cleaner includes a traveling driving unit configured to allow the artificial intelligence robot cleaner to travel in an indoor space of a home, a cleaning unit configured to remove pollutants, a sensor configured to acquire data that is used to identify a plurality of members, and a processor configured to control the traveling driving unit and the cleaning unit so as to determine one or more subordinate spaces corresponding to each of the plurality of members among a plurality of subordinate spaces by using the data and a map of the indoor space, determine a return time of some or all of the plurality of members, determine a cleaning priority of the plurality of subordinate spaces based on the return time, and perform cleaning according to the cleaning priority.

The present disclosure relates to an artificial intelligence robot cleaner that is capable of changing an order of cleaning according to a return time of a member.
Artificial intelligence is a field of computer engineering and information technology involving studying how computers can think, learn and self-develop in ways similar to human intelligence, and means that computers can emulate intelligent actions of humans.
In addition, artificial intelligence does not exist by itself but is directly or indirectly associated with the other fields of computer science. In particular, many attempts have been made to introduce elements of artificial intelligence into various fields of information technology.
Meanwhile, techniques for recognizing and learning surrounding situations by using artificial intelligence, providing information desired by the user in a desired form, or performing a desired operation or function are being actively studied.
Also, electronic devices that provide various operations and functions may be called artificial intelligence devices.
The current robot cleaner only sets a moving path and travels along the set moving path, but does not consider whether a member exists in the indoor space.
Also, the member existing in the indoor space may feel uncomfortable due to movement or noise of the robot cleaner when the robot cleaner performs cleaning around the member. Also, from the perspective of the robot cleaner, if a person exists around the robot cleaner while the robot cleaner performs cleaning, movement of the person may be sensed to cause an error.


A horizontally traveling water screen for filtering debris from a wide flowing stream. The water screen, which may be realized by a foraminous modular plastic conveyor belt, is formed in an endless loop trained between drive and idle sprockets rotatable on generally vertical shafts. The upstream face of the water screen is oriented transverse to the flow and advances horizontally across the stream to drag debris to a cleaning and discharge station. Horizontally spaced hold down tabs extending outward of the inner surface of the loop hook onto and ride along a horizontal guide attached to a support frame for the water screen to prevent the screen from sagging.

The invention relates generally to traveling water screens and, more particularly, to water screens that travel in a generally horizontal direction across a flowing stream of water.
Water is diverted from rivers, lakes, and other bodies of water for municipal, irrigation, and industrial purposes. Fish or water screens serve as filters to prevent fish or debris from entering a water diversion. These screens range in size from a few square feet to several thousand and come in many shapes.
Rotary drum screens consist of a screen mesh wrapped around a cylinder rotating on a generally horizontal axis. The top of the cylindrical screen is above the surface of the water. Debris is carried over the screen as it rotates and is washed off on the downstream side. Because of their fixed diameters, rotary drum screens are restricted in how deep they can be submerged and do not accommodate varying water levels. If the water level is too high, fish and debris are carried over the top of the rotary drum. If the water level drops too low, the screen clogs and water flow is restricted.
Fixed plate screens are also widely used. These stationary plate screens consist of fixed perforated metal sheets or wedge wire panels, usually oriented vertically in a flowing stream of water. Although the fixed plate screens are themselves simple, they require an external cleaning system to prevent clogging. External cleaning systems for plate screens are high maintenance and often not effective. And, if the cleaning system fails, the clogged screen can collapse. External brush cleaners, which are often used, can injure or kill fish.
Another kind of frequently used screen is a vertical traveling screen, which consists of a vertically advancing mesh driven by rotating shaft-mounted sprockets. The axes of the shafts are oriented generally horizontally. The screen may be inclined in the direction of water flow to aid in debris removal. To screen wide diversions, several side-by-side vertical traveling screens have to be used because individual wide vertical traveling screens are expensive to build, support, and drive.
Thus, there is a need for a water screen that is easy to clean and useful in filtering debris from wide diversions.


The present invention is directed to a sheet-form environment purifying material comprising particles of metal and/or metal oxide consisting essentially of at least one member being selected from the group consisting of manganese, copper, zinc, iron, vanadium, nickel, titanium, palladium, platinum, manganese oxide, copper oxide, zinc oxide, iron oxide, vanadium oxide, nickel oxide, titanium oxide, palladium oxide, and platinum oxide, adsorbent particles consisting essentially of at least one member selected from the group consisting of activated carbon, zeolite, silica gel, sepiolite, activated alumina and activated clay, thermoplastic resin particles being selected from ultrahigh-molecular weight polyethylene, polyethylene, polycarbonate, polyamide acrylonitrile-butadiene-styrene resins, polyimide, polyvinyl chloride, cellulose acetate, polysulfone, polystyrene phthalate and polypropylene, and an air-permeable sheet of fibrous. The metal and/or metal oxide particles and the adsorbent particles are respectively bound to the thermoplastic resin particles while retaining their inherent surface areas and performances without being covered by the thermoplastic resin layers, and the thermoplastic resin particles are joined to the fibrous substrate. The present invention is also directed to a process for making the environment purifying material which comprises the steps of mixing all the particles and heating the mixture at a temperature not lower than the melting point of the thermoplastic resin and not higher than the thermal decomposition temperature thereof. The environment purifying material of the present invention is useful as deodorizers and harmful gas removers.

Methods by which harmful substances, rank odors and so forth, contained in gases such as air and exhaust gases are adsorbed and decomposed to make the gases pure are known to include a method in which they are caused to chemically react with chemicals such as acid, alkali and aluminum sulfate to remove them, a method in which they are adsorbed on adsorbents such as activated carbon and zeolite to remove them, a method in which they are masked with aromatics, and a method in which they are oxidized or burnt using catalytic particles of metals or metal oxides. Methods by which substances causing rank odors, pollution, turbidity and so forth, contained in water such as river water, pond water and waste water are adsorbed and decomposed to make the water pure are also known to include a method in which they are adsorbed on adsorbents such as activated carbon and zeolite, a method in which they are oxidized and decomposed using chemicals such as ozone, and a method in which they are decomposed by microorganisms.
As methods for producing porous structural materials containing adsorbent particles such as activated carbon and zeolite or particles of metals or metal oxides having a reactivity as catalyst (catalytic activity), the following methods are conventionally known.
One of them is a method in which particles such as particles of metals or metal oxides are mixed and the mixture is press-molded (a method called press molding). For example, Japanese Patent Application Laid-open (KOKAI) No. 50-30795 discloses a method in which 40 parts by weight of manganese dioxide, 20 parts by weight of cupric oxide and 40 parts by weight of gamma alumina are mixed and the mixture is formed into tablets.
Another method is a method in which a porous carrier or a porous structural material is impregnated with an aqueous solution of salts of metals such as manganese and copper, followed by baking (a method called baking or sintering). Materials used in such a method include, for example, a deodorizer comprising A-type zeolite incorporated with manganese oxide and copper oxide (Japanese Patent Application Laid-open (KOKAI) No. 1-151938), and a deodorizer comprising a honeycomb porous carrier supported with manganese dioxide and cupric oxide (Japanese Patent Application Laid-open (KOKAI) No. 4-156854).
Other methods are also known to include a method in which the adsorbent particles such as activated carbon and zeolite and/or particles of metals or metal oxides are mixed together with a binder and the mixture obtained is extruded by means of an extruder into stated shapes, followed by heating and activation to obtain porous particulate products (a method of extrusion molding with a binder), and a method in which the particles of metal oxides or the like are kneaded into a foamable thermoplastic resin, followed by heating to blow the resin into foams, which are used as deodorizing porous structural materials (a method of foaming), and so forth.
Methods for producing sheet-like deodorizers are also known to include a method in which a deodorizer powder and a thermoplastic resin powder are sprayed onto a substrate sheet made of paper or the like, followed by heating to bring them into an integral form (Japanese Patent Application Laid-open (KOKAI) No. 61-119269), and a method in which a mixture of a deodorizing powder for gas treatment and a thermoplastic resin powder is held between two layers of sheets at least one of which is an air-permeable sheet, followed by contact bonding to bring them into an integral form (Japanese Patent Application Laid-open (KOKAI) No. 5-49850), and so forth.
In the case when deodorizing porous structural materials are produced by the above pressure molding, the particles of metals or metal oxides are so closely packed that the molded products have a low specific surface area and a poor air permeability. There is another problem that particles that tend to collapse, as in the case of activated carbon and zeolite, cannot be molded.
In the case when they are produced by baking, there is a problem that oxide layers formed and impurities formed at the time of baking because of the binder used may block up the micropores of porous carriers, resulting in a decrease in specific surface area of the porous structural materials. In the case when they are produced by sintering, it is difficult to cause metal or metal oxide particles to join to the surface of activated carbon.
In the case when they are produced by extrusion molding with a binder or foaming, particles of the deodorizer powder are covered with the binder or the foamable resin, and hence odor components cannot come into direct contact with the deodorizer powder, to cause a problem that the performance inherent in the deodorizer powder cannot be exhibited.


Food packaging-use formed articles including at least one layer of a 3 to 90 microns thickness which comprises a composition consisting of polyvinyl alcohol resin having a degree of saponification of 60 to 95 mole % (A) and a compound elected from a group of alkylene glycol polymer, etc. falling within the range of from 3 weight parts of (B) to 100 weight parts of (A) to the saturated solubility of (B) in (A) and having a carbon dioxide/oxygen solubility ratio (SCO.sub.2 /SO.sub.2) of 30 or higher.. Furthermore, a resin composition consisting of the aforementioned (A), (B) and a saponified ethylene/vinylacetate copolymer resin (C) wherein the blending ratio of (B) is within the range of from 3 weight parts of (B) to 100 weight parts of (A) to the saturated solubility of (B) in (A), and the blending ratio of (C) being 20 to 50 weight parts of (C) to 100 weight parts of an aggregate of (A) and (C), and food packaging-use melt extruded articles containing at least one layer comprising the aforementioned composition.

1. Technical Field of the Invention
The present invention relates to a resin composition and formed articles obtained therefrom such as films, and furthermore relates to the application of said formed articles and the like to food packaging use. More particularly, the present invention relates to formed articles such as films excellent in the selective gas permeability obtained from a composition comprising polyvinyl alcohol resin (hereinafter abbreviated as "PVA") and specific compounds, and, furthermore, to the application of the aforementioned formed articles to food packaging use.
2. Description of the Prior Art
In the food packaging industry, technological innovation has been achieved in the recent years so remarkably that today's food packaging operations always call for optimal performances to be imparted by each kind of stock material for a given kind of food to be packaged.
Taking the cheese product, which is a kind of fermented foodstuff, for example, wax-coated packaging material has been conventionally used for packaging the natural cheese, whereas plastic materials have also been adopted for the purpose of improving the appearance, increasing the eatable portion and furthermore, for the manufacturing cost reduction's sake. Natural cheese being added with live bacteria to permit the ripening process to progress therein, the bacteria generate carbon dioxide not only during the ripening step, but throughout the later stages of physical distribution. Since such cheese packaged with the ordinary kind of plastic bag swells up with generated carbon dioxide gas, the introduction of such packaging material as will readily transmit carbon dioxide has been awaited. On the other hand, since oxygen has adverse effects such that oxygen accelerates growth of molds on the cheese and also oxidizes the fat content of the cheese, the trade concerned has been desirous of having a packaging material which suppresses transmission of oxygen. For foodstuff other than cheese, e.g. coffee bean, packaging materials that readily permits permeation of carbon dioxide, but considerably restrains permeation of oxygen have been desired.
Although it is desirable that plastic packaging materials intended for use on cheese product, coffee bean, etc. have higher gas transmission rate (hereinafter abbreviated as "GTR") to carbon dioxide and lower GTR to oxygen, such plastic packaging materials that have high GTR to carbon dioxide, almost without any exception, will have high GTR to oxygen.
Therefore, such packaging materials that have low oxygen GTR and have large carbon dioxide GTR to oxygen GTR, namely, high carbon dioxide/oxygen GTR ratio have been wanted.
There is described in the patent gazette of Published Patent Sho 44-2576 a process for producing a PVA film insoluble in cold water and soluble in warm water of 40 Deg. C. or higher, which is obtained by extruding a specific PVA added with a plasticizer, as a separation membrane. It is described in the same gazette that while glycerin is used as the plasticizer, polyethylene glycol can be also used. The film thus obtained, however, is used as the unit package material for detergent and agricultural chemical and as laundry bags. It is not used as a food packaging material for which selective gas permeability is particularly required.
Besides, there is described in the patent gazette of Published Patent Sho 54-15029 (U.S. Pat. No. 4,073,733) a process for producing a web possessing gas permeability by coagulating polyethylene glycol-containing PVA in a liquid phase, although the web thereby obtained is used for separation of urea and vitamin, and is not utilized as a food packaging material, for which selective gas permeability is required, similarly to the case described in Patent Publication Sho 44-2576.

Resin composition and food packaging materials formed therefrom


The proposed model is a Variational Autoencoder having a learnable prior that is parametrized with a Tensor Train (VAE-TTLP). The VAE-TTLP can be used to generate new objects, such as molecules, that have specific properties and that can have specific biological activity (when a molecule). The VAE-TTLP can be trained in a way with the Tensor Train so that the provided data may omit one or more properties of the object, and still result in an object with a desired property.

Deep neural networks (DNNs) are computer system architectures that have recently been created for complex data processing and artificial intelligence (AI). DNNs are machine learning models that employ more than one hidden layer of nonlinear computational units to predict outputs for a set of received inputs. DNNs can be provided in various configurations for various purposes, and continue to be developed to improve performance and predictive ability.
It would be advantageous to have a computer method for generating an object that satisfies a condition, where some conditions may be known and where some conditions may not be known using one or more DNNs.

Subset conditioning using variational autoencoder with a learnable tensor train induced prior


A method and apparatus allows an information provider to broadcast a graphical interactive information system application to a user even using a low-bandwidth transport such as the VBI. A compact protocol encapsulates graphical information using definitions of graphical objects and resources. A scripting and command language is also highly compact. A reception component receives the compact protocol and displays and operates a complete graphical interactive information system application.

Interactive information systems allow an information provider to broadcast information to a user, and in some cases allow a user to send a response to a response collector. The user may receive the information on a wide variety of devices, such as a pager, cellular telephone, personal digital assistant or a television. An interactive information system on which the user receives the information using a television is called an interactive television system.
An interactive television system can enhance the television viewing experience. An interactive television system allows an information provider to broadcast information to users for viewing on their television systems, and defines how the user is allowed to control the time, order, type of information displayed, or other aspects. An interactive television system may allow the user to send to a response collector responses to the information received, or new information.
Some interactive television systems provide a textual user interface, displaying formatted textual information to the user. However unlike graphical interactive information systems, text-based systems do not allow the information provider to control and present a wide variety of graphical information and formatting that are commonly used with graphical user interfaces. A graphical interactive information system uses a graphical user interface to display a variety of graphical information and allows the user to control the operation of the system based upon the graphical display. Text-based systems are more difficult to use and limit the appeal of the interactive television system in much the same way that text-based computer operating systems limited the appeal of computer systems prior to the introduction of graphical user interfaces.
One such attempt (Lappington, U.S. Pat. No. 5,343,239) inserts textual data in a binary format into unused lines in the Vertical Blanking Interval, or VBI, of the conventional television transmission for decoding by a set-top device and transmission to, and display on, a handheld remote control device. The VBI is a portion of the television picture which is broadcast, but not typically seen by the television viewer, and readily allows for insertion of data, such as closed captioning text. However, the limited data capacity of the VBI has thus far prevented the use of graphical user interfaces, because the VBI does not have the data capacity required to send the large amount of data to date required for a graphical user interface. For example, Lappington does not disclose a graphical user interface.
One interactive television system (Fascenda et al., U.S. Pat. No. 4,592,546) does not use the VBI at all, instead sending information to the user via an FM subcarrier channel. Such a system has the drawback of requiring a large initial user investment in equipment required to receive the information. Additionally, Fascenda does not suggest the transmission of graphical user interface information.
To circumvent the limited capacity of the available data transport mechanisms, a functionally-limited graphical-like interactive television system has been developed (Young, U.S. Pat. No. 5,353,121). Young suggests a system which allows an information provider to send a sequence of text over the VBI to a set of predefined overlays. The result appears to be a more graphical display than Lappington, because boxes surround each section of the text. Although Young does not disclose how the size of the box is determined, which party controls the size of the box, or how the box is displayed on the screen, nevertheless, the mere control of the width of a box surrounding text, without more, is not a graphical user interface of the type set forth in the illustrated embodiments of the present invention. In addition, Young does not allow the information provider to design new overlays, and thus is limited to the overlays which have been predefined. This restriction limits the type and format of the data which can be displayed to data fitting into one of the predefined overlays existing in the user-device used to render the display.
None of these devices allows an information provider to broadcast a true graphical user interface to an interactive information system. Nor do these devices solve the additional problems inherent in the reception and display of a graphical user interface.
One inherent problem is the reluctance of many users to significantly invest in separate reception or display equipment required to display and operate a graphical interactive information system. For example, many potential users of a graphical interactive television system will not pay the cost of receiving the graphical interactive information over an FM channel because of the cost of the additional tuner equipment required by such an approach. Conventional set top cable television decoder boxes can provide a desirable reception platform for interactive television systems because they are relatively cheap, contain much of the necessary interface and reception equipment, and are accepted in most homes. However, the use of such devices would be acceptable if only inexpensive, compact modifications were required to display and operate a graphical interactive information system.
Another problem is the lack of standards among reception and display equipment vendors. For example, conventional set-top cable decoder boxes might be used as a platform as described above. However, a variety of set-top equipment exists yielding a variety of capabilities. Each vendor promotes a system that will use the vendor's equipment capabilities to the fullest extent possible. Vendors typically would not accept a system which was designed only for the most basic equipment, nor would they likely accept a system which only operated with the most feature-rich equipment.
Another problem is the requirement for interactive television systems that such a system work rapidly enough to operate in conjunction with existing broadcast television shows. For example, graphical interactive television system applications which operate in conjunction with existing television game show programs must be transmitted to display the graphical user interface quickly. Furthermore, there must be a mechanism to make modifications to the user interface quickly, to allow large amounts of information to be updated rapidly.

Compact graphical interactive information system


Disclosed is an inverse quantization method that reverse-quantizes multiple quantized values as a set, obtaining a set of multiple inverse quantized values, said method being characterized in that the range of potential inverse quantized values for each quantized value is obtained using at least a signal other than that of the aforementioned quantized value, and in that the set of preliminary inverse quantized values for which the total variation norm is the minimum within the range of potential values for each inverse quantized value is obtained as the aforementioned set of reverse-quantized values.

The related video inverse quantization technology will be explained by making a reference to FIG. 1. However, an attention should be paid to the fact that a quantizer E1001 is shown for a purpose of indicating an input/output relation with an element calculator E1002 for performing a video inverse quantization, namely to the fact that the video inverse quantization technology can be configured only of the element calculator E1002.
Further, it is assumed that one piece of a video frame having a gray scale with m vertical pixels and n horizontal pixels is a video signal vector x. However, the prior arts and the present invention are applicable for color video signals as well, as apparent from the explanation that will be later made. Further, the prior arts and the present invention are applicable even though the aforementioned video signal vector x is a sub-region of the video frame. Additionally, in this paper, "a set of a plurality of elements" and "an aggregation of a plurality of elements" are referred to as "a vector".
The quantizer E1001 quantizes each elementxi,j(0≦i≦m−1,0≦j≦n−1)of the video signal vector x, and calculates a quantized value qi,j. Upon assuming the quantizer of E1001 to be a linear quantizer of which a quantization width is Qs,qi,j=floor(xi,j/Qs+0.5)  (1)is yielded. Where function floor( ), which is a floor function, is a function for returning a maximum integer, out of input values, being real number values. Hereafter, it is assumed that a set (an aggregation) of the aforementioned quantized values qi,j is a quantized value vector q.
The element calculator E1002 calculates an inverse-quantized value{circumflex over (x)}i,j by employing the aforementioned quantized value qi,j, and each element yi,j of another video signal vector y (auxiliary information y) having a correlation with the video signal vector x. Upon assuming a half-open interval corresponding to the aforementioned quantized value qi,j to be[Qi,j−,Qi,j+)(however,Qi,j−=Qs·qi,j−Qs/2,Qi,j+=Qs·qi,j+Qs/2)and a conditional provability density function corresponding to the aforementioned correlation to be fX|Y(x|y), the element calculator E1002 calculates each element (each inverse-quantized value){circumflex over (x)}i,j for which the minimum mean square error of the inverse-quantized video signal vector{circumflex over (x)},being the video signal vector that has been inverse-quantized, becomes minimized with the following conditional expectation value (FIG. 2).{circumflex over (x)}i,j=EX|y[x|xε[Qi,j−,Qi,j+),yi,j]=∫Qi,j−Qi,j+x·fX|y(x|yi,j)dx  (2)
Additionally, as a matter of fact, the approximate calculations (Non-patent literature 1, 2, and 3) that are replaced with the numerical expression (2) are utilized for the reason that a complete form of "conditional provability distribution fX|y is unknown", and that "the calculation of the numerical expression (2) requires integral calculation". For example, the Non-patent Literature 1 proposes to utilize the following numerical expression (2)′ instead of the numerical expression (2).
                                          x            ^                                i            ,            j                          =                  {                                                                                Q                                          i                      ,                      j                                        -                                    ,                                                            y                                              i                        ,                        j                                                              <                                          Q                                              i                        ,                        j                                            -                                                                                y                                          i                      ,                      j                                                        ,                                                            Q                                              i                        ,                        j                                            -                                        ≤                                          y                                              i                        ,                        j                                                              <                                          Q                                              i                        ,                        j                                            +                                                                                Q                                          i                      ,                      j                                        +                                    ,                                                            Q                                              i                        ,                        j                                            +                                        ≤                                          y                                              i                        ,                        j                                                                                (          2          )                '
So long as the approximate calculations is exact, calculating the inverse-quantized values by utilizing the aforementioned auxiliary information y makes it possible to reduce the mean square error of the inverse-quantized video signal vector{circumflex over (x)}all the more as compared with the case of calculating the inverse-quantized values by simply inverse-quantizing the video signal vector.
The aforementioned video inverse quantization of the element calculator E1002 enables the inverse-quantized video signal vector{circumflex over (x)}of which the mean square error is smaller to be calculated.
Above, the explanation of the related arts is finished.

Inverse quantization method, inverse quantization device, and program


An efficient method of calculating maximum current limits for library gates in which a current limit includes the impact of self-heating effects associated with the maximum current. A maximum current solution is obtained in a self-consistent fashion, providing a way of determining the self-consistent solution in a rapid fashion without extensive numerical calculations or simulations. The present method provides a practical approach for characterizing a large library of gates for use in CMOS designs.

In modern CMOS designs, as devices have scaled into a regime with channel lengths below 50 nm, the heat generated by the switching of digital logic gates or by their leakage, can no longer be efficiently dissipated through the substrate. Recent developments in silicon technology have exacerbated this issue, while at the same time, interconnect reliability is becoming increasingly subject to electromigration stress in advanced technology nodes due to a breakdown in the classical scaling of such devices. One development has been the use of silicon-on-insulator (SOI) technologies for high-performance CMOS designs. In such technologies, the buried oxide acts as a thermal insulator or barrier between the devices, which dissipate power as they are switched at high frequency, especially when driving heavy loads, and the substrate, acting a heat sink.
Another more recent development has been the introduction of multigate "finFET" technologies, which even when built on a bulk substrate, can result in significant self-heating due to the higher density of active channel width per unit area of silicon, and the high-resistance thermal path to the substrate (either through the fin itself, which is very narrow, or through the field oxide, which has a high thermal resistance). Therefore, self-heating has become a design concern for high-performance circuitry, and is expected to become increasingly important as technology scales to even smaller dimensions.
In the current art, in CMOS digital design methodology frameworks, the circuit temperature is specified as a chip level design parameter, usually matching the modeled substrate temperature for the chip. This is a reasonable assumption for older bulk planar technologies, where the device is fabricated in the bulk silicon itself, with a good thermal connection to the substrate. However it breaks down for SOI technologies, where there is a high-resistance thermal barrier between the device and the substrate. It also breaks down for finFET technologies, where there also is a poor thermal connection to the silicon substrate. In these situations, self-heating can become non-negligible even within regular CMOS logic gates, with high switching factors and/or high output loads. This device-level heating heats up the wires above the hot devices, reducing the electromigration lifetime of the wires, so that any internal logic gate connections, carrying DC current, will suffer a reduced lifetime. Now, in such technologies, thermal modeling techniques have been used to look at specific circuits and specific device heating scenarios. But these thermal modeling techniques require a significant number of computations and calculations for even very simple geometries, as described for example by Shrivastava et al., in IEEE Trans on Electron Devices, vol. 59, page 1353 (2012). No tools or methods currently exist for incorporating the device-self-heating effects, and the impact on electromigration into a digital CMOS design methodology capable of handling designs with hundreds of millions of logic gates. Accordingly, the current state-of-the-art CMOS design methodologies either just ignore any logic-gate self-heating, or apply blanket assumptions to all gates. This can be very pessimistic, if the worst-case temperature increase has to be assumed to apply to all gates, or very optimistic, if the temperature is set at some average value for every gate independent of the actual self-heating that is present.
The basic problem here is that, in conventional design methodologies, the maximum-current limits that are set, based on electromigration statistics for metal lines, do not take into account the device self-heating which would be associated with the generation of that current. Furthermore, it is not easy to do this in a self-consistent way, since the current limit due to electromigration is a complicated, non-linear function of the temperature of the wire. Furthermore, the thermal resistance of a library cell is very difficult to calculate, and can require detailed modeling with a 3D thermal analysis tool, taking into account the details of the structure of the gate, its wiring, the properties of all the different layers and materials making up the devices, and the details of the boundary conditions around the library cell.
It should be noted that Joule self-heating of wires is a well-known phenomenon, and various tools and methodologies have been developed to model the heating, and to guard against it. Furthermore, methods for EM analysis including self-heating treat only self-heating of wires (Joule heating), but not of the devices. Also such methodology is focused on rules designed to avoid any self-heating, not on including those effects in the analysis. The prior art treats self-heating of wires on methods to model, or avoid, wire self-heating, i.e., Joule heating. Other work focuses on self-heating effects on the delay of the gate, and is not applicable to the problem of setting current limits for electromigration robustness.
Referring to FIG. 1, a prior art library characterization flow is shown, covering an aspects of defining the maximum current (limited by electromigration) for each library cell.
Still referring to FIG. 1, starting with 100, a library cell is selected for analysis. Next, in 103, a maximum current, I0 is calculated based on a conventional electromigration analysis of the cell, including as inputs the detailed geometries of the wires, an assumed temperature, and the reliability specifications (electromigration equations, allowed failure rate and the total number of hours of use). The final result is assigned to the cell in question, in 106, and then if there are more library cells to be processed (107) another cell is chosen for analysis. Otherwise, the process terminates (108). In the present analysis, a worst-case temperature can be chosen in 103, in order to guard against the worst-case self-heating that could be encountered in a design application. However, it would be pessimistic to apply it to all cells, since many of the cells would see much less self-heating than the worst-case situation. On another hand, if an "average" temperature is selected, the design can end up with severe reliability exposures since some gates can experience higher temperatures becoming subjected to wear out.

Method for an efficient modeling of the impact of device-level self-heating on electromigration limited current specifications


The present invention relates to a cell for producing a secreted protein comprising a polynucleotide comprising a nucleic acid sequence encoding a fast cycling cdc42 mutant and a polynucleotide comprising a nucleic acid sequence encoding a secreted protein. It also relates to a method for producing said cell and to a method for producing a secreted protein using said cell.

Many of the current recombinant therapeutic proteins are complex biopharmaceuticals that require manufacturing processes based on eukaryotic cell culture technology. While prokaryotic systems are also suited to produce certain recombinant therapeutic proteins at large scale, many of the more complex biopharmaceuticals are produced in eukaryotic cells, since these cells are able to support correct folding, processing and post-translational modification.
Any increase in volumetric productivity in eukaryotic cell culture has a direct impact on costs for these complex biopharmaceuticals and is, thus, desirable both from a commercial and healthcare socioeconomic view. The yield of any biopharmaceutical production process depends on the cumulative amount of protein product which the producing cells secrete per unit time when grown under regulated process conditions.
Several avenues have been pursued to boost production yields from mammalian cell culture with great success resulting in 10-20 fold yield increase over the past decade. Mammalian cell based production systems start to match with lower prokaryotic systems in volumetric yields while they still lag behind in fermenter occupancy times. Media and fed-batch process design allowed maintaining highest viable cell densities and have contributed significantly to this success.
The producer cell itself offers potential for improvement. All steps involved in the expression and secretion of heterologous proteins such as transcription, RNA transport, translation, post-translational modification and protein transport are tightly regulated and have a strong impact on the specific productivity. This complex pattern of features also including growth properties, low sensitivity to apoptosis and specific nutrient requirements provides the basis for the selection of existing cell lines for large scale production of biopharmaceuticals. While the cell lines were selected for serum and growth factor independence as well as suspension growth using genetic and epigenetic flexibility, molecular optimization focused on transcription first.
In contrast to artificial transcription factors or polymerases that did not provide a large benefit, protection from gene inactivation is considered essential. Promoter regions from housekeeping genes equipped for continuous expression or individual elements isolated from those promoters such as ubiquitous chromatin opening elements (UCOEs) and scaffold/matrix-associated regions (S/MARs) alter the chromatin structure of promoter regions, allowing free access by the polymerase II complex thereby reducing the number of clones to be screened and causing expression stability.
Nutrient depletion, waste byproduct accumulation, extended exposure to impeller shear forces and other factors that occur during fermentation constitute apoptotic stimuli which can decrease cell viability. Therefore, anti-apoptotic genes of the bcl-2 family (Kaufmann and Fussenegger, 2003) were intensively investigated. Since the integral of viable cell density (IVCD) is one of the factors that impact the overall volumetric productivity in mammalian cell culture, it is desirable to keep cell viability at a high level over the duration of upstream processing. Production processes with cell lines that overexpressed anti-apoptotic genes showed prolonged cell culture viability and occasionally increased product yields (Chiang and Sisk, 2005).
Another bottleneck for high-yield production of heterologous proteins in eukaryotic cells is the secretory transport machinery of the producer cell line. The expression and secretion of heterologous proteins in non-polarized eukaryotic cells is a complex regulated multi-step process with multiple actuating variables. In a first step, the gene encoding the secreted protein is transcribed into mRNA which is then exported into the cytosol. mRNAs encoding proteins destined for secretion into the extracellular space or to the plasma membrane are recognized by the signal recognition particle and transported to ribosomes located on the outer membrane of the rough endoplasmic reticulum. There, the nascent proteins are co-translationally imported into the luminal space of the endoplasmic reticulum where certain sorting mechanisms apply. From there, they are packed in lipid vesicles and transported to the proximal cisternae of the Golgi apparatus and finally they are packaged into vesicles emerging from the distal trans-Golgi network (TGN) which are then transported to the plasma membrane where they are released into the culture medium. The entire secretion process is not straightforward but highly regulated on various levels. Known checkpoints and feedback loops of the secretion pathway include the Calnexin/Calreticulin System, the Unfolded protein response and ER overload response.
As a logical consequence of this complexity, the elimination of one bottleneck at early process stages is likely to lead to the creation of other bottlenecks either further downstream in the process chain or even in other crucial parallel sidelines of the secretion process. There is evidence in the literature that widening of the transcription and translation bottleneck is only effective up to a certain threshold. The specific productivity of a producer cell line has been reported to correlate linearly with the level of product gene transcription until a certain threshold mRNA-level is reached (Barnes et al., 2007). Further enhancement of transcriptional activity to mRNA levels beyond this threshold does not cause further titer increment. Rather, productivity even goes down as translation from the excess mRNA causes an overload of the protein synthesis, folding or transport machinery which in turn results in an intracellular accumulation of the protein product and concurrent triggering of the ER-Overload- and Unfolded Protein Response. As one of its consequences, the alpha subunit of the polypeptide chain initiation factor eIF2 is phosphorylated. The phosphorylated eIF2α inhibits the guanine nucleotide exchange factor eIF2β and prevents its recycling during protein synthesis. As a result, the overall rate of protein synthesis is diminished.
Specific differentiated cells such as plasma cells show very high protein secretion rates. This capacity is acquired during the terminal differentiation of B cells and has been associated with the expression of a splice form of the transcription factor XBP (Iwakoshi et al., 2003). XBP-1 regulates this differentiation process by binding to ER stress responsive elements (ERSE) within the promoters of a wide spectrum of secretory pathway genes. The XBP-1 mediated differentiation process results in a physical expansion of the ER, increased mitochondrial mass and function, larger cell size and enhanced total protein synthesis (Shaffer et al., 2004). This complex functional change is associated with cell cycle arrest.
Almost all cell types involved in high-level protein secretion (pancreatic beta cells, leydig cells, glandular cells, etc.) are terminally differentiated, are not able to proliferate and have a limited life-span before ultimately undergoing programmed cell death (Chen-Kiang, 2003). Unsurprisingly, attempts to increase protein secretion by overexpressing XBP-1 in non-plasma cells, especially production cell lines such as CHO-K1 cells, were only successful in increasing protein secretion to a limited extent (Tigges and Fussenegger, 2006). A high proliferation rate during early process phases and high cell viability remain critical for modern fed-batch production processes.
This general paradigm holds true for other factors upstream of XBP-1 capable of enhancing the secretory capacity such as ATF6 and IRE1α. Higher cell specific productivity due to enhanced secretion needs to compensate for lower viable cell mass and shorter process duration before higher yields are feasible. Moreover, expression of growth inhibitory genes is difficult to maintain and process robustness may suffer.
Molecular chaperones such as binding protein BiP/GRP78 and protein disulfide isomerase (PDI) are downstream effectors of XPB. BiP associates with the antibody heavy chain before its displacement by the light chain and plays a major role in its folding. Both BiP/GRP78 and protein disulfide isomerase (PDI) have been considered for secretion enhancement but were not yet successful in improving upstream yield. In contrast to what could be expected, BiP overexpression in mammalian cells has been shown to reduce rather than to increase the secretion of proteins with which BiP associates with (Domer and Kaufman, 1994). Likewise, PDI overexpression in CHO cells reduced the expression of a TNFR:FC fusion protein (Davis et al., 2000), whereas the specific production rate of an antibody could be increased by 40% (Borth et al., 2005).
Thus, there are different bottlenecks within the protein secretion machinery which are not yet overcome.
Further, the fact that an increase of the protein folding capacity of a cell creates a protein production bottle neck further downstream, is supported by a report describing ER to cis-Golgi transport problems for IFN-gamma production in a CHO cell line (Hooker et al., 1999). Other additional bottlenecks are expected further downstream in the cellular secretion machinery.
All of the above-described examples show that multiple bottlenecks, for example, within the protein production machinery and/or protein secretion machinery, exist which have to be overcome in order to optimize the preparation of secreted proteins in cells.
Thus, there is a need for protein producing cells comprising a regulator protein having an effect on multiple levels of cellular function. Said effect on multiple levels of cellular function should result in an enhancement of protein production and/or protein secretion, particularly in large-scale industrial protein production processes, e.g. industrial fed batch processes. There is also a need for a method for producing proteins (e.g. therapeutic proteins) using said cells.
Systems biology approaches, in particular comparative transcriptome and proteome analysis of high and low expressing cells, may identify molecular targets that help to overcome productivity bottlenecks. However, the combined expression of multiple regulators in a well adjusted and stable fashion is rather complex and may not be practical in all cases. On the other hand, the expression of individual high level regulators is an approach that allows to affect multiple pathways simultaneously. Nevertheless, the pleiotropic effects of such active high level regulator proteins and their mutants makes it difficult to predict how their expression within the cellular context will affect upstream product yield in industrial fed batch processes.
Many approaches for yield-enhancement by cell line engineering have focused on single enzymes and regulator proteins in the past. Only few attempts have been made to investigate the potential of regulator proteins that are known for their pleiotropic effects on multiple levels of cellular function. To some extent, the lack of research in this field may have resulted from the contradictive findings as reported in the literature and as described above.
One protein family that contains known high level regulators with pleiotropic effector functions is the GTPase superfamily.
The superfamily of small GTP binding proteins contains more than 100 members that can be divided into five groups, namely into the Ras, Rho, Rab, Sar/Arf and Ran group, based on structural and functional differences. Whereas regulation of gene expression has initially been associated only with the Ras proteins and vesicular transport with the Sar/Arf proteins, the Rho proteins were thought to control the organization of the cytoskeleton (Takai et al., 2001). It has later been shown that besides actin organization the three major members of the Rho family, namely Rho, cdc42 and Rac, are involved in processes of cell cycle progression, transcription, cell-cell adhesion, cell motility, vesicle shuttling, secretion, endocytosis, phagocytosis, mitogenesis, and/or apoptosis. This pleiotropic activity makes the Rho GTPases to interesting candidates as general regulators of cellular processes. However, only part of the natural responses will have the technically desired direction. For example, cell cycle promotion may induce proapoptotic signals, while differentiation may lead to ER expansion and enhanced secretory capacity.
Rho GTPases exist in an inactive GDP-bound and an active GTP-bound form. In their active conformation they can interact with a large number of effectors regulating multiple signal transduction pathways. Activation of Rho GTPases is mediated by guanine nucleotide exchange factors (GEFs) which catalyze the replacement of GDP by GTP. Only a fraction of the more than 80 GEFs known to date have been characterized in detail, but it is clear that many GEFs can activate more than one Rho GTPase (Schmidt and Hall, 2002). The activity of the Rho proteins, including cdc42, depends on their GTPase cycle. Said proteins are active in their GTP-bound form and inactive in their GDP-bound form. Three types of regulatory proteins control said GTPase cycle: (i) the Guanine nucleotide exchange factors (GEFs), (ii) the GTPase activating proteins (GAPs), and (iii) the Guanine nucleotide dissociation inhibitors (GDIs). The complexity of the functional network of Rho GTPases may provide an explanation for the seemingly contradictive effects of Rho GTPase overexpression that has been reported in the literature.
The GEF proteins that control Rho GTPases are tightly regulated themselves by inhibitory domains or inhibitor proteins and are activated upon dephosphorylation. Members of the dbl family of oncogenes that are overexpressed in a variety of cancer types represent guanine nucleotide exchange factors (GEFs) for cdc42 that help to maintain cdc42 in its activated state. This may led to the assumption that permanently active (GTP-bound) cdc42 could activate cell growth, and other functions attributed to cdc42. While heterologous overexpression of a tightly regulated protein is expected to have little functional impact, overexpression of a permanently activated regulator protein maintained in its activated state would be desirable. For cdc42, the permanently active mutants cdc42Q61L and cdc42V12 have been isolated. These mutants were shown to have positive effects on total secretion rates of p75, while LDLR secretion was inhibited in MDCK cells (Müsch et al., EMBO J. 2001 May 1; 20(9): 2171-2179). Efficient movement of correctly folded proteins from the ER to the Golgi is considered as an essential step in the production of secreted proteins. Contrary to expectations, it was found that expression of a permanently active GTPase-defective Cdc42 mutant led to growth inhibition or apoptosis. Moreover, the same constitutively active mutant cdc42Q61L was shown to block the ER to Golgi transport of VSVG (Wu 2000 Nature).
To resolve the scientifically contradictory results and to obtain cdc42s which are more active than the natural cdc42s, fast cycling cdc42 mutants such as cdc42F28L (R. Lin et al., A novel Cdc42Hs mutant induces cellular transformation. Curr. Biol. 7 (1997), pp. 794-797) or cdc42D118N (S. Tu et al., Antiapoptotic Cdc42 mutants are potent activators of cellular transformation. Biochemistry 41 (2002), pp. 12350-12358) have been generated. These mutants can undergo spontaneous GTP-GDP exchange while maintaining full GTPase activity. These mutants are no longer dependent on induction by dbl. Said mutants are self-activating mutants. The fast cycling cdc42 mutants such as cdc42F28L do not block trafficking as the permanently active cdc42 mutants (Wu 2000 Nature), but cause moderate acceleration. The cdc42F28L mutant, for example, survived in NIH 3T3 fibroblasts and allowed anchorage independent growth and increased growth rates in media with reduced serum (Tu et al., 2002). However, increased growth rates may contradict a high productivity as it is generally accepted that fast replication does not allow to build up the membrane systems required for efficient secretion and folding.
Cdc42 appears as one of the very broad and heterogeneous regulators of cellular activity. Nevertheless, as discussed above, the natural, permanently active and inactive forms of cdc42 have demonstrated features incompatible with a production cell. So far, cdc42 mediated active actin reorganization, fast cycling of vesicles and/or induction of anchorage independence has/have not been linked with increased productivity of non-adherent cells.
In a screen under industrial protein production process relevant conditions, the inventors of the present invention surprisingly found that fast cycling cdc42 mutants exert a net beneficial effect on protein yields obtained in non-adherent cell cultures. Said fast cycling cdc42 mutants directly boost productivity of non-adherent cell cultures, e.g. in a bioreactor setting. In particular, the fast cycling cdc42 mutants accelerate trafficking of proteins from the ER to the Golgi. As mentioned above, efficient movement of correctly folded proteins from the ER to the Golgi is considered as an essential step in the production of secreted proteins.
The inventors of the present invention further found that the beneficial effect of the fast cycling cdc42 mutants on protein yields is independent of the order in which the heterologous genes are introduced into the non-adherent cells. For example, said effect is achieved when (i) a high producer cell clone expressing the protein of interest is subsequently transfected with a nucleic acid sequence encoding a fast cycling cdc42 mutant, (ii) a naïve non-adherent cell is modified with a fast cycling cdc42 mutant to create a superior starter cell that is subsequently transfected with a nucleic acid sequence encoding the protein of interest or (iii) a naïve non-adherent cell is transfected simultaneously with a nucleic acid sequence encoding a fast cycling cdc42 mutant and with a nucleic acid sequence encoding the protein of interest.

Enhancement of protein production yield mediated by a fast shuttling CDC42 GTPase