A database evaluation system provides for intuitive end user analysis and exploration of large databases of information through real time fuzzy logic evaluation of utility preferences and nearest neighbor exploration. The system provides for domain modeling of various types of information domains using attribute mappings to database fields, and utility value weightings, allowing multiple different domain models to be coupled with a same database of information. User interaction with the evaluation system is through an interactive key generator interface providing immediate, iterative visual feedback as to which candidate items in the database match the user's partial query. A proximity searcher user interface provides for nearest neighbor navigation and allows the user to determine which items in the database are closest to a given item along each independent attribute of the items, and selectively navigate through such nearest neighbors. A fractal proximity searcher simultaneously displays multiple levels of nearest neighbors for user selected attributes.

A. Field of Invention
The present invention relates to database systems for evaluation of items according to user preferences, and more particularly to database systems using domain specific knowledge and utility functions to identify items meeting user defined criteria.
B. Background of Invention
The proliferation of computers and of the exploding use of the Internet have brought with them the increasing availability of computerized databases of products, information, and services from which users, such as consumers or professionals, evaluate and purchase such items. However, the ever increasing availability of such databases to more and diverse types of users has resulted in a widening gap between the existing and the user required skills for using these databases.
There exists sophisticated tools for database mining, analysis and the subsequent generation of information from the extracted data, but none of these tools allow users to quickly and efficiently perform a frequently desired task of finding in the database the item most suited to the user's objective and subjective preferences.
A typical activity involving this type of database access is online shopping: for example, a shopper is not interested in purchasing all of the VCRs that match her criteria, but only the one that gets closest to some "ideal VCR" defined by the user's own objective and subjective criteria (e.g., low cost, high performance, reliable, etc.). Conversely, even if no items match the shopper's search criteria, she might still be interested in purchasing the item that is `closest` or most similar to the her criteria. Current database access tools do not meet the following needs of such users for the following reasons.
First, conventional databases will often return empty search result sets where no matches found are found to the set of specific criteria input by a user; alternatively, they may return too many matches where very few critieria are specified. In either case, the user is unable to identify which items are most similar to her overall criteria, and must reformulate her search criteria.
Second, compound queries where multiple attributes are specified and which result in empty projections do not tell which criterion or group of criteria were responsible for reducing the number of matches to zero. Conversely, when too many matches are found, conventional tools provide no indication of the sensitivity of the database to each criterion. Thus, the user is unable to modify her criteria to eliminate such criteria, but must proceed by trial and error.
Third, shoppers compare items not on the basis of a single criterion, but using the concept of similarity given all or most critieria. For example, a car buyer who has identified a first car as a suitable item, may be looking for a less expensive car which implicitly would not only have a lower price tag, but simultaneously retain all other desirable features of the first car as much as possible. However, current database tools have the ability to evaluate items only along one dimension (e.g., price) without regard for the overall similarity of items along multiple dimensions, and thus are not suitable for this buyer to identify such a similar alternative car with similar features to the first car.
Fourth, many domains (automobiles, computers, financial instruments) are very complex and require significant expertise to understand at the database level ("variable valve timing", "256K cache", "0.14 negative market correlation"). The typical consumer does not have sufficient expertise to evalute different items with respect to such technical data, but does know various high level critieria that are important to their decision making. The complexity of the underlying domain makes it difficult for a shopper to formulate a query that reflects his fuzzy needs and desires, resulting in a mismatch between the results the database provides and the user's actual needs.
Finally, many shoppers are unable to describe what they are looking for with defined search criteria, but they can identify which items do not satisfy their requirements when such items are presented to them. With conventional tools, such shoppers are unable to deconstruct the domain into its constituent components and define useful search criteria which can then be used to select items from the database for further evaluation.
Accordingly, it is desirable to provide a database system that supports analysis and evaluation of the similarity of items in the database with respect to multiple critieria.

Supporting intuitive decision in complex multi-attributive domains using fuzzy, hierarchical expert models


A combination of materials comprised of an inner or core material and an outer material layer or coating on one or both sides of the core material whereby this combination of materials is to be used in conjunction with sheet metal forming equipment such as press brake and punch press machines to protect the sheet metal and equipment tooling during the sheet metal forming process as well as improve the quality of the finished sheet metal product.

Sheet metal shops process sheet metal by bending and piercing the sheet metal with press brakes, punch presses, and other similar sheet metal forming machines. Typically, press brakes are hydraulic devices that utilize metal dies and metal punching tools which are shaped in such a way that when the press brake compresses the die and punch with the sheet metal in between, a particular bend or curve is formed in the sheet metal. Punch press machines, on the other hand, punch holes of various sizes and shapes in the sheet metal. To accomplish this, turret assemblies containing punching tools are positioned above the sheet metal with dies positioned below the sheet metal. With tremendous pressure, the punch press forces the punching tool downward through the sheet metal and into the die. In addition, sophisticated punch press machines have the capability to slide and rotate the sheet metal at very high speed while operating dozens of turret assemblies simultaneously.
Because both sheet metal forming methods involve metal-on-metal contact and because there is relative movement between the sheet metal and the machine surfaces and tools, it is not uncommon for the machines to scratch, gouge, or otherwise mar the surface of the sheet metal. Precoated, plated and painted sheet metal is especially susceptible to damage. With punch press machines, the punching tools and dies wear quickly, causing an increase in the clearance between the two, further resulting in rough and distorted edges around the sheet metal holes. If the application calls for highly precise holes and visually perfect bends, scratches, gouges, and rough edges are simply unacceptable. Sometimes the sheet metal machine shop is forced to deburr or smooth rough edges which adds a costly and time consuming step to the sheet metal forming process.
In recognition of this problem, some sheet metal machine shops have begun placing protective material such as paper, cloth, and plastic between the sheet metal and the sheet metal machines. Some shops coat the sheet metal with polyvinylchloride (PVC) or polyurethane film. Others coat the machine surfaces and machine tools. These materials alone have not completely eliminated the problem, and in some cases, it has actually caused additional problems.
Transference of the protective material texture is just one of the problems. Most materials have some grain or pattern associated with the surface of the material. This is especially true with woven and fibrous materials. As mentioned, press brake and press punch machines exert extremely high levels of pressure on the sheet metal. This pressure can actually transfer the grain or pattern of the protective material to the sheet metal surface. Furthermore, press brake and press punch machines are capable of moving the sheet metal around at very high speed and the use of plastic, cloth, or paper products can impede this movement. Film coatings alone, on the other hand, generally provide little protection for either the sheet metal or the tools. This is especially true when the sheet metal is harder than the tools. Typically, the tools will wear quickly and, as mentioned above, cause rough, distorted, and imprecise edges or bends. Finally, with regard to punch press machines, there are so many punching operation per minute that it is very inconvenient and time consuming to continually place and replace pieces of protective material over the appropriated sections of sheet metal.

Material for protecting sheet metal during the sheet metal forming process


A road surface detecting apparatus comprises a camera sensor 11 for taking images of a region in front of a vehicle, and an electronic control unit (ECU) configured to: calculate, based on a taken image, parallax information including a parallax of each pixel composing the taken image; extract a pixel corresponding to a road surface from the taken image; acquire, based on information of the extracted pixel, information-indicating-a-road-surface; calculate, based on the information-indicating-a-road-surface, a road surface gradient formula by approximating a gradient of the road surface by a quadratic function; determine whether or not an absolute value of a coefficient of a quadratic term of this formula is greater than a coefficient threshold; and invalidate the information-indicating-a-road-surface when the absolute value is determined to be greater than the threshold.

Collision avoidance control has been conventionally performed as one embodiment of driving support, the collision avoidance control being a control for avoiding a collision with an obstacle existing in front of a vehicle or for reducing an impact due to the collision. The collision avoidance control is a control to perform at least one of following controls, that is, a warning control for raising a warning to a driver, an automatic braking control for automatically applying a braking force on the vehicle, and an automatic steering control for automatically changing a steered angle of a steered wheel of the vehicle. Each of these controls is performed when there exists an obstacle in front of the vehicle with a possibility of colliding with the vehicle.
In a case when the automatic steering control which is one of the collision avoidance control is to be performed, an avoidance route for avoiding a collision with an obstacle is set in advance, and the vehicle is controlled so as to travel along this avoidance route. If an avoidance route is set within a region inappropriate as a road surface on which a vehicle travels, the automatic steering control will not be conducted in a proper manner. Therefore, it has been desired to develop an apparatus for a vehicle capable of detecting a road surface suitable for traveling with a high accuracy.
For example, a road surface detecting apparatus disclosed in the Japanese Patent Application Laid-Open (kokai) No. 2016-206776 (hereinafter, referred to as a "prior art apparatus"), estimates, based on a parallax image acquired by a taken image in front of a vehicle, whether or not each of parallax points composing this parallax image is a parallax point corresponding to a road surface (Hereinafter, such a parallax point may be referred to as a "road surface parallax point".). Thereafter, the prior art apparatus estimates, based on a vehicle speed, a yaw rate, and the like, a travelling expected route on which the vehicle is expected to travel and weights each of the road surface parallax points, depending on a distance thereof to the travelling expected route.
More specifically, as a distance from a certain road surface parallax point to a travelling expected route becomes close, this parallax point is more heavily weighted. The prior art apparatus detects a road surface based on weighted road surface parallax points. It should be noted that in the Japanese Patent Application Laid-Open (kokai) No. 2016-206776, a road surface parallax point and a travelling expected route are expressed as a "road surface candidate point" and a "progress locus", respectively.
A region close to a travelling expected route has a higher probability of being a road than a region far from the travelling expected route. Thus, it is described in the Japanese Patent Application Laid-Open (kokai) No. 2016-206776 that by more heavily weighting road surface parallax points close to a travelling expected route compared to road surface parallax points far from the travelling expected route, the parallax points close to the travelling expected route are able to have a relatively large influence on a detection of a road surface, and thus a road surface can be detected with a high accuracy.


A lightfast colorant and a lightfast ink composition include a lightfast colorant that is derived by covalently binding a benzophenone derivative and a conventional colorant and that imparts effective lightfastness and long-term storage stability to an ink composition that is prepared with the same.

1. Field of the Invention
The present invention relates to a lightfast colorant and a lightfast ink composition including the same, and more particularly, to a lightfast colorant that is derived by chemically binding a benzophenone derivative to the molecular structure of a conventional colorant, and a lightfast ink composition containing the same.
2. Description of the Related Art
Ink-jet printing, which is a kind of non-impact printing, has the advantages of low noise generation, compared to impact printing, and easy color printing realization, compared to laser beam printing.
There are two types of non-impact printing: continuous ink-jet printing and drop-on-demand (DOD) printing. In continuous ink-jet printing, while ink is continuously discharged, a change in an electromagnetic field is induced to control a direction in which the ink is jetted. DOD printing, in which micro droplets of ink are jetted, includes thermal-bubble ink-jet printing and piezoelectric ink-jet printing. In thermal-bubble ink-jet printing, ink is discharged by a pressure generated by the swelling of bubbles that are generated as the ink is heated. In piezoelectric ink-jet printing, ink is discharged by a pressure generated by using a piezoelectric plate that may be mechanically deformable by electricity.
Recently, a dot-size of ink-jet printers utilized has become smaller, and there has been an increasing need for high-resolution, high-quality prints. Smaller dot-size ink-jet printers require a head having smaller nozzle orifices. However, smaller nozzle orifices are susceptible to being clogged by precipitates, and thus affect the size of ink droplets and the performance of the printer. It is obvious that the composition of the ink affects the clogging of the nozzle orifices. For this reason, a wetting agent is commonly added to the ink-jet ink compositions.
An ink composition for ink-jet printing contains a colorant, a solvent, and an additive. A dye or a pigment may be used as the colorant. However, using a dye as the colorant is limited because it causes a print to have poor lightfast and water-fast properties. When using a pigment as the colorant, a resulting print is more lightfast and water-fast than a print prepared using a dye, but is still susceptible to color change or discoloration when exposed to ultraviolet (UV) light. An additional lightfastness enhancer may be used. However, negative side effects, for example, the clogging of the nozzle orifices by agglomerated ink, the formation of a heterogeneous ink composition, and the like, occur when the lightfastness enhancer is used.
As an example, EP 1006161 A1 discloses an ink composition in which a colorant covered with a polymer that includes UV-absorbing and/or lightfast sites is dispersed. The ink composition that includes such a colorant coated with a UV-absorbing polymer is unstable due to poor dispersion stability of the polymer-coated colorant particles and the weak binding force between the colorant and the polymer.

Lightfast colorant and lightfast ink composition including the same


An ignition control device for an engine provided with ignition plugs for each cylinder. The ignition control device includes a sensor that detects a signal that determines whether the engine is in an idling state or not, and an ignition control unit that determines whether the engine is in the idling state on the basis of a signal from the sensor and controls the ignition plugs to be simultaneously ignited if the engine is in the idling state, and controls part of the ignition plugs to be ignited if the engine is in a state other than the idling state.

1. Field of the Invention
The present invention relates to an ignition control device for an engine provided with a plurality of ignition plugs for each cylinder.
2. Description of the Related Art
Heretofore, there has been proposed an engine provided with two ignition plugs for each cylinder (refer to Patent Document 1 (Japanese Patent Laid-Open No. 4-112069)). In such an engine, when the engine runs at low speed, one ignition plug is ignited, and when the engine runs at high speed, two ignition plugs are simultaneously ignited to increase a combustion speed at each cylinder. As a result, combustion pressure is increased to thereby improve an engine output.
Unfortunately, in a case where one ignition plug is ignited when an engine runs at low speed, for example, the amount of non-combustion gas may increase. Thus, a secondary air supply device for supplying a part of intake air as secondary air to an exhaust pipe, or a fuel injection device that adjusts fuel injection quantity is operated to reduce the amount of non-combustion gas. However, such a device may not sufficiently clean up exhaust gas.
Furthermore, when an engine runs at high speed, a combustion speed of a gaseous mixture in a combustion chamber increases as an intake air speed increases. At the time, if two ignition plugs are simultaneously ignited, the combustion speed may be excessively increased to cause a noise such as a piston hammering sound to be increased.
Further, when an engine runs at high speed, a combustion speed of a gaseous mixture in a combustion chamber increases as an intake air speed increases. At the time. If two ignition plugs are simultaneously ignited, the combustion speed may be excessively increased to cause a noise such as a piston hammering sound to be increased. In addition, at the time, if two ignition plugs are simultaneously ignited, the combustion speed may be excessively increased to cause a noise such as a piston hammering sound to be increased.


The invention provides compounds of Formula I and derivatives thereof, pharmaceutical compositions comprising a compound of Formula I, and methods of treatment utilizing such compounds and compositions:

Mammalian interleukin-1β. (IL-1β) plays an important role in various pathologic processes, including chronic and acute inflammation and autoimmune diseases. IL-1β is synthesized as a cell associated precursor polypeptide (pro-IL-1β) that is unable to bind IL-1 receptors and is biologically inactive. By inhibiting conversion of precursor IL-1β to mature IL-1β, the activity of interleukin-1 can be inhibited.
Interleukin-1β converting enzyme (ICE) is a protease responsible for the activation of interleukin-1β (IL-1β). ICE is a substrate-specific cysteine protease that cleaves the inactive prointerleukin-1 to produce the mature IL-1. The genes that encode for ICE and CPP32 are members of the mammalian ICE/Ced-3 family of genes which presently includes at least twelve members: ICE, CPP32/Yama/Apopain, mICE2, ICE4, ICH1, TX/ICH-2, MCH2, MCH3, MCH4, FLICE/MACH/MCH5, ICE-LAP6 and ICErel III. The proteolytic activity of this family of cysteine proteases, whose active site (a cysteine residue) is essential for ICE-mediated apoptosis, appears critical in mediating cell death (Miura et al., Cell 75:653–660 (1993)). This gene family has recently been named caspases (Alnernri et al., Cell, 87:171 (1996), and Thornberry et al., J. Biol. Chem. 272:17907–17911 (1997)) and divided into three groups according to its known functions.
Agents that modulate IL-1β activity have been shown to have beneficial in vivo effects. For example, compounds that are interleukin-1 receptor antagonists have been shown to inhibit ischemic and excitotoxic damage in rat brains (e.g., Relton et al. (1992) Brain Research Bulletin (1992) 29:243–246). Additionally, ICE inhibitors were shown to reduce inflammation and pyrexia in rats (Elford et al. (1995) British Journal of Pharmacology 115:601–606).
In addition to its effects on IL-1β, ICE has been shown to place a role in the production of the inflammatory mediator interferon-gamma (Ghayur et al. (1997) Nature 386:619–623). ICE processes the inactive proform of interferon-gamma (IGIF; interleukin-18) to active IGIF, a protein that induces production of interferon-gamma by T-cells and natural killer cells. Interferon-gamma has been implicated in the pathogenesis of diseases such as inflammatory disorders and septic shock. Therefore, inhibitors of caspase-1 would be expected to have beneficial effects in such disease states.
Many potent caspase inhibitors have been prepared based on the peptide substrate structures of caspases. However, the need exists for improved caspase-1 inhibitors. These inhibitors thus can be employed as therapeutic agents to treat disease states in which regulated cell death and the cytokine activity of IL-1 or IGIF play a role. Accordingly, it is an object of the present invention to provide methods and compositions useful in the inhibition of caspase-1.

Caspase-1 inhibitors and methods for their use

Abstract: wherein:        R1 is chosen from optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;        L is a linker;        R2 is chosen from optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; and

Abstract: or single stereoisomers, mixtures of stereoisomers, or the pharmaceutically acceptable salts, amides, or esters thereof.


An optical fiber cable includes: a core comprising gathered optical fibers; an inner sheath housing the core; a wire body embedded in the inner sheath; tension members embedded in the inner sheath, wherein the core is interposed between the tension members; a reinforcing sheet that covers the inner sheath; and an outer sheath that covers the reinforcing sheet, wherein in the inner sheath, ti<Ti and to<To are satisfied, where a thickness of a radially inner portion between the core and the wire body is ti, a thickness of a radially inner portion between the core and each of the tension members is Ti, a thickness of a radially outer portion between the wire body and the reinforcing sheet is to, a thickness of a radially outer portion between each of the tension members and the reinforcing sheet is To.

An optical fiber cable installed, laid, or embedded (hereinafter simply referred to as "installed") in a mountain or a forest may be bitten by a wild animal such as a mouse, a squirrel, or a woodpecker, or be hit by a flying object such as a bullet used in hunting. In such a case, an optical fiber inside the optical fiber cable may be damaged. In order to prevent such damage, the optical fiber cable disclosed in PTL 1 is protected by covering the optical fiber with a reinforcing sheet.
In an optical fiber cable having a reinforcing sheet, when disassembling or connecting the optical fiber after installation, the operation of cutting the reinforcing sheet or the like and drawing out the optical fiber from the inside (hereinafter referred to as "draw-out-operation") is complicated, and the operation time is prolonged. In addition, there is a case where the optical fiber is unexpectedly cut when cutting the reinforcing sheet.
On the other hand, an optical fiber cable of PTL 2 is provided with a core formed by assembling a plurality of optical fibers, an inner sheath accommodating the core therein, a rip cord disposed inside the inner sheath, a reinforcing sheet covering the inner sheath, and an outer sheath covering the reinforcing sheet. In this configuration, after removing the outer sheath and the reinforcing sheet with a tool such as a blade, the inner sheath is torn by the tool and the rip cord is drawn out. Since the inner sheath, a metal tape, and the outer sheath are torn by the rip cord, it is possible to shorten the draw-out-operation time while preventing unexpected cutting of the optical fiber.

NIPPON TELEGRAPH AND TELEPHONE CORPORATION


Techniques are disclosed for dynamic access and instrumentation of model specific registers (MSRs). A virtual machine monitor (VMM) can provide a kernel application program interface (API) that can be utilized to access and instrument an MSR. A method may include receiving, by the VMM, an MSR instrumentation command that identifies an MSR to instrument and causing instrumentation of the MSR identified in the MSR instrumentation command. Instrumentation of the identified MSR can be caused by configuring or manipulating a virtual machine control structure (VMCS) of a guest virtual machine (VM). The MSR instrumentation command may be an MSR instrumentation request command, an MSR remove request command, an MSR value set request command, or an MSR value fetch request command. In some cases, the VMM may be a Type-I hypervisor.

Hardware virtualization is the abstraction of computing resources from the software that uses them. Virtualization is performed on a given hardware platform by a host control program (i.e., a virtual machine monitor (VMM) or so-called hypervisor), which creates an abstraction layer between the underlying hardware and the software. Once a hypervisor is in place, it provides a simulated computing environment, commonly known as a virtual machine (VM), for its guest software. In typical applications, multiple VMs execute simultaneously on the same physical machine, sharing the hardware resources among them, thus reducing investment and operating costs. However, each VM run its own operating system and software applications and, thus, is logically separated from every other VM.
Virtual machine introspection provides capabilities to monitor the run-time state of a VM. For example, introspection may be used to observe the execution of a VM's operating system. Introspection involves obtaining information regarding the state of a VM executing on a computer, such as memory usage and processor state, without accessing the VM itself. Thus, introspection is useful for a variety of applications, including malware detection and analysis, software debugging, and forensic memory analysis, to name a few examples.

Model specific register (MSR) instrumentation


An autonomously operated automated food dispenser provides sustenance to one or more animals at prescribed intervals. The dispenser is portable and suitable for use for animals in space vehicle life support systems. A micro-controller controls operation of the outlet valve of a food reservoir that contains a food paste maintained under pressure by a pressurized gas source. Predetermined volume of food paste are extruded through the outlet upon the micro-controller's command. The food cannister is characterized by a novel two part assembly and houses a rolling diaphragm. Pressurized gas is applied to the bottom of the diaphragm, allowing the diaphragm to roll against the food paste, when the outlet valve is opened.

The viability of long-term human habitation of space requires study of the physiological and behavioral effects of the space environment on the human body. While some effects are known from flight studies performed with astronaut subjects, many effects cannot be studied without subjecting astronauts to discomfort or danger. For this reason, studies of the effects of the space environment are routinely performed using animals such as rodents and birds as subjects.
Experimental animals are housed in habitats that provide all life support requirements including food and water. Habitats often have science accommodations provisions for measuring the amount of food and water ingested by the animals, permitting study of the relationship of ingestion to various physiological and behavioral effects. However, it has proven difficult to meter water delivery in space, and a significant amount is spilled. It is even harder to meter ingestion of dry food because of high and variable amounts of wastage of the crumbs.
Habitats may have separated dry food and liquid water delivery systems, or a paste providing both food and water may be delivered from a single system. Paste diets offer to space research the advantages of a single delivery system for both food and water, less waste of both food and water, better control of delivery, better contamination control, and more accurate quantification of food ingestion. However, no satisfactory automated dispenser for paste diets is available.
One paste feeding apparatus for rodents previously developed by NASA is a ground unit that periodically fills a trough for group feeding of animals. This ground unit is not readily adaptable to space vehicle implementation, since it is too bulky, the fluid dynamics of trough filling in micro gravity are not known, and the trough design leaves a large surface area of paste exposed to contamination and to drying, which reduces the ratio of water to food ingested by the animal. In addition, there is no provision to monitor the quantity of food ingested.
A second device, also never deployed in space, is pie-shaped with pie slice-shaped compartments filled with food paste. An opening in the cover that is moved to expose a three day supply of food at one time. This device has the same drawbacks as designs based on troughs.
The Russian Space Agency (RSA) is understood to have tried a series of paste feeder devices based on the trough concept that are generally reputed to be unsuccessful and fraught with severe contamination problems. The designs have evolved to improve bioisolation, and recently the RSA flew a device with several external bladders filled with clean paste that are periodically squeezed by cosmonauts to deliver to the specimens aliquots of food. This device does not provide automatic delivery or quantification of ingestion, and if large aliquots are delivered to minimize crew involvement then uneaten food sits for extended periods and is subject to contamination.
Accordingly, an object of the present invention is to provide a food dispensing system that is suitable for autonomous unattended operation in space vehicles.
Another object of the invention is to provide an automated food dispenser that dispenses individual food servings for each animal individually only at prescribed mealtimes or, alternatively, on demand, and in a prescribed quantity.
A further object of the invention is to store sterilized food in bulk for long periods and to dispense uncontaminated food throughout that period in precisely measured amounts.
An additional object of the invention is to provide an automated food delivery system that is portable, is of simple construction and that permits quick and easy change in schedules and quantities of food and water dispensed.
And an ancillary object is to provide an automated dispenser that can be easily expanded to include dispensing of a variety of consumable substances, including food, medicine and water.
To meet the principal objectives the present invention uses food that has been powdered or minced and mixed with water to form a paste. Paste food provides the most convenient and flexible means of providing the full nutritional needs, including water, of humans and animals. Paste is easily sterilized within its packaging container by irradiation, and then stored for extended durations without danger of microbial spoilage. Many persons have seen news film footage showing astronauts squeezing paste foods from tubes directly into their mouths.
A regimen of food paste offers clear advantages over solid food for animal experimental subjects. Typically less than half the food and water storage volume is required. Food consumption is more accurately determined because there is less waste. Paste can be dispensed to an accuracy of .+-.0.10 gram food per day and .+-.0.3 ml water per day. Food is stored in a reservoir separately from the animal cage, providing bioisolation of the food from animal wastes. The animal's requirements for both food and water can be met by paste composed of the proper ratio of food to water, reducing the number of delivery systems by half and decreasing dispenser cost, volume and complexity of delivery mechanisms.
The need for reliable automated food dispensers for space applications is clear, but terrestrial applications are also applicable to the care and feeding of pet animals. Pet owners who must be absent from home must board their animals with a kennel or veterinarian, have neighbors attend their animal's needs, or travel with their pets, all of which stress the animal. With the effective and reliable automated food dispenser the animal can be regularly fed in its familiar home surroundings, greatly reducing the amount of attention required of neighbors.


A body-implantable device for controlling the size of a fluid flow passageway within the body, typically for use in a Fenestrated Fontan operation. A housing is provided and secured within the body, typically to the artificial septum sutured into place in the Fontan operation. A flow passageway extends through the housing. An antenna is responsive to electromagnetic signals emitted from outside the body and conveyed through the body without wires to the antenna. Means are provided for varying the cross-section of the flow passageway in a manner responsive to signals received by the antenna.

This invention relates to a body implantable device which controls the size of a fluid flow passageway within the body, controllable from outside of the body without any direct physical connection to a control unit outside of the body.
In surgery, there may be a need for controlling, for example, the cross-sectional area of the pulmonary artery in a pulmonary arterial banding procedure. There also is a need to control the size of an atrial fenestration in the Fontan operation. Both of the above procedures are well known.
Referring to the latter procedure, the Fontan operation is performed for physiologic correction of a congenital heart condition where there is only one pumping chamber. The principle of the procedure is that blood is propelled from the right upper chamber to the lungs without the need for the pumping action of the right lower chamber or ventricle.
To accomplish this, a right atrium is isolated through the use of a septation patch made of a synthetic material such as GORETEX PTFE sheeting. Then, the isolated right atrium is connected to the pulmonary artery. In this way, the blood flows from the body to the right atrium and directly to the pulmonary arteries. The blood then passes to the left atrium, and from there is pumped into the body.
The blood flow from the right atrium to the pulmonary arteries, leading to the lungs, is totally passive in this instance, and depends on the kinetic energy supplied by the left side of the heart. As a result, there is a mild degree of blood backup on the right side of the circulation. This causes relative blood stagnation and higher systemic venous pressure, leading to undesirable extravasation of fluids from the vascular system. To counteract this, a fenestration or aperture has been provided to the synthetic septation patch applied to the heart in this operation.
The major determinants of the eventual systemic venous pressure following the Fontan operation include the pulmonary vascular resistance, the left side filling pressure, which depends on the compliance and capacity of the left heart chambers, and the degree of mechanical obstruction to pulmonary arterial blood flow or pulmonary venous return. In most cases, these determinants are abnormal in the immediate postoperative period, and tend to improve with time.
The clinical results of the Fontan procedure are critically dependent on the early and late systemic venous pressure. Markedly elevated venous pressure following surgery leads to significant extravasation of fluids from the vascular system. This results in hypotension, low cardiac output and impaired organ functions. Thus, it is important to have the capacity to intervene in the early-post operative period to assist in causing these determinants to return to normal levels to obtain the best results with the Fontan operation.
The fenestration referred to above serves as an intentional atrial septal defect or hole between the upper two chambers, to reduce pressure on the right side of the circulation for minimization of post operative complications. It is usually desirable to subsequently close this hole when the different hemodynamic parameters immediately after operation return to normal later on in the postoperative period. Such an approach is presently called the Fenestrated Fontan operation, and has yielded excellent results with markedly improved outcome of the most critically sick patients.
There are currently two clinical approaches presently practiced for fenestration in the Fontan operation. One of these approaches comprises leaving a calibrated fenestration opening in the inner atrial patch that is emplaced by the surgeon. Cardiac catheterization is performed before discharge, and a trial occlusion of the fenestration by a balloon is performed. If the patient tolerates the occlusion, the fenestration is closed with an umbrella-like device emplaced by catheter, which hooks to the edge of the fenestration and occludes the opening on an essentially permanent basis.
One problem with this approach is that the size of the fenestration or hole is not adjustable. Thus, if the hole is too big or too small, nothing can be done to adjust its size after the patient is off the cardiopulmonary bypass machine. Also, this procedure requires repeat cardiac catheterization, which of course would be desirably avoided. Also, the umbrella device used in the procedure was withdrawn from the market by the Food and Drug Administration because of breakage in a very small number of instances. Finally, once the fenestration is closed, there is no way to reopen it short of major surgery.
The other approach of Fenestrated Fontan utilizes a similar hole between the upper two chambers in the artificial septum, but uses a "purse string suture" around the hole, with one end of the string lying subcutaneously, outside of the heart. As a disadvantage of this approach, while the hole size can be adjusted by tightening or loosening the string, the adjustments are usually gross and imprecise, and require an incision of the skin and subcutaneous tissue. This, in turn, can lead to a higher instance of infection, especially if it is done on a repeated basis. Hence, this approach is close to an all or nothing situation because the fine adjustments are made only with difficulty and luck.

Body-implantable device for controlling the size of a fluid passageway


The present invention relates to plant cells and plants which synthesize an increased amount of glucosaminoglycans, and to methods for preparing such plants, and also to methods for preparing glucosaminoglycans with the aid of these plant cells or plants. Here, plant cells or genetically modified plants according to the invention have glucosaminoglycan synthase activity and additionally an increased glucosamine 6-phosphate acetyltransferase activity and an increased UDP-N-acetyl-glucosamine pyrophosphorylase activity compared to wild-type plant cells or wild-type plants. The present invention furthermore relates to compositions comprising plant cells having an increased glucosaminoglycan synthesis.

(i) Field of the Invention
The present invention relates to plant cells and plants which synthesize an increased amount of glucosaminoglycans, and to methods for preparing such plants, and also to methods for preparing glucosaminoglycans with the aid of these plant cells or plants. Here, plant cells or genetically modified plants according to the invention have glucosaminoglycan synthase activity and additionally an increased glucosamine 6-phosphate acetyltransferase activity and an increased UDP-N-acetyl-glucosamine pyrophosphorylase activity compared to wild-type plant cells or wild-type plants. The present invention furthermore relates to compositions comprising plant cells having an increased glucosaminoglycan synthesis.
(ii) Description of the Related Art
Proteoglycans, a class of glycoproteins, are inter alia an essential component of cartilage and have, attached to a core protein, glucosaminoglycans composed of repetitive disaccharide units. The repetitive disaccharide units for their part are, via a characteristic carbohydrate binding sequence, attached covalently to the core protein. Depending on the composition of the disaccharide units, a distinction is made inter alia between the glucosaminoglycans heparan/heparin sulfate, keratan sulfate and chondroitin/dermatan sulfate whose disaccharide units each contain a molecule which is glucosamine or a glucosamine derivative.
Hyaluronan, a further glucosaminoglycan, also has a derivative of glucosamine acetyl-glucosamine) as one of the components of its disaccharide unit, but, in nature, is not attached to proteins. Except for hyaluronan, the glucosaminoglycans mentioned are naturally sulfated polymers. In these substances, sulfate groups are introduced at various atoms or substituents of the disaccharide units so that the substances mentioned are not uniform polymers but groups of polymers summarized under the respective generic term. The individual molecules of the polymer groups in question may differ both in the degree of sulfatation and in the position of the monomers having sulfate groups.
Hyaluronan is a naturally occurring unbranched, linear mucopolysaccharide (glucosaminoglycan) which is constructed of alternating molecules of glucuronic acid (GlcA) and N-acetyl-glucosamine (GlcNAc). The basic building block of hyaluronan consists of the disaccharide glucuronic acid-beta-1,3-N-acetyl-glucosamine. In hyaluronan, these repeating units are attached to one another via beta-1,4 linkages. In pharmacy, use is frequently made of the term hyaluronic acid. Since hyaluronan is in most cases present as a polyanion and not as the free acid, hereinbelow, the term hyaluronan is preferably used, but each term is to be understood as embracing both molecular forms.
Hyaluronan has unusual physical chemical properties, such as, for example, properties of polyelectrolytes, viscoelastic properties, a high capacity to bind water, properties of gel formation, which, in addition to further properties of hyaluronan, are described in a review article by Lapcik et al. (1998, Chemical Reviews 98(8), 2663-2684).
Hyaluronan is a component of extracellular connective tissue and bodily fluids of vertebrates. In humans, hyaluronic acid is synthesized by the cell membrane of all body cells, especially mesenchymal cells, and ubiquitously present in the body with a particularly high concentration in the connective tissues, the extracellular matrix, the umbilical cord, the joint fluid, the cartilaginous tissue, the skin and the vitreous body of the eye (Bernhard Gebauer, 1998, Inaugural-Dissertation, Virchow-Klinikum Medizinische Fakultät Charité der Humboldt Universität zu Berlin; Fraser et al., 1997, Journal of Internal Medicine 242, 27-33).
Recently, hyaluronan was also found in animal non-vertebrate organisms (molluscs) (Volpi and Maccari, 2003, Biochimie 85, 619-625).
Furthermore, some human pathogenic gram-positive bacteria (Streptococcus group A and C) and gram-negative bacteria (Pasteurella) synthesize hyaluronan as exopolysaccharides which protect these bacteria against attack by the immune system of their host, since hyaluronan is a non-immunogenic substance.
Viruses which infect single-cell green algae of the genus Chlorella, some of which are present as endosymbionts in Paramecium species, bestow upon the single-cell green algae the ability to synthesize hyaluronan after infection by the virus (Graves et al., 1999, Virology 257, 15-23). However, the ability to synthesize hyaluronan is not a feature which characterizes the algae in question. The ability of the algae to synthesize hyaluronan is mediated by an infection with a virus whose genome has a sequence coding for hyaluronan synthase (DeAngelis, 1997, Science 278, 1800-1803).
The catalysis of the hyaluronan synthesis is effected by a single membrane-integrated or membrane-associated enzyme, hyaluronan synthase.
The mechanism of the transfer of synthesized hyaluronan molecules across the cytoplasma membrane into the medium surrounding the cell has not yet been fully elucidated. Earlier hypotheses assumed that transport across the cell membrane was effected by hyaluronan synthase itself. However, more recent results indicate that the transport of hyaluronan molecules across the cytoplasma membrane takes place by energy-dependent transport via transport proteins responsible for this action. Thus, Streptococcus strains were generated by mutation in which the synthesis of an active transport protein was inhibited. These strains synthesized less hyaluronan than corresponding wild-type bacteria strains (Ouskova et al., 2004, Glycobiology 14(10), 931-938). In human fibroblasts, it was possible to demonstrate, with the aid of agents specifically inhibiting known transport proteins, that it is possible to reduce both the amount of hyaluronan produced and the activity of hyaluronan synthases (Prehm and Schumacher, 2004, Biochemical Pharmacology 68, 1401-1410). In which amount, if at all, transport proteins capable of transporting hyaluronan are present in plants is not known.
The unusual properties of hyaluronan offer a wealth of possibilities for application in various fields, such as, for example, pharmacy, the cosmetics industry, in the production of food and feed, in technical applications (for example as lubricants), etc. The most important applications where hyaluronan is currently being used are in the medicinal and cosmetics field (see, for example, Lapcik et al., 1998, Chemical Reviews 98(8), 2663-2684, Goa and Benfield, 1994, Drugs 47(3), 536-566).
In the medical field, hyaluronan-containing products are currently used for the intraarticular treatment of arthrosis and in ophthalmics used for eye surgery. Hyaluronan is also used for treating joint disorders in racehorses. In addition, hyaluronan is a component of some rhinologics which, for example in the form of eye drops and nasalia, serve to moisten dry mucous membranes. Hyaluronan-containing solutions for injection are used as analgesics and antirheumatics. Patches comprising hyaluronan or derivatized hyaluronan are employed in wound healing. As dermatics, hyaluronan-containing gel implants are used for correcting skin deformations in plastic surgery.
For pharmacological applications, preference is given to using hyaluronan having a high molecular weight.
In cosmetic medicine, hyaluronan preparations are among the most suitable skin filler materials. By injecting hyaluronan, for a limited period of time, it is possible to smooth wrinkles or to increase the volume of lips.
In cosmetic products, in particular in skin creams and lotions, hyaluronan is frequently used as moisturizer by virtue of its high water-binding capacity.
Furthermore, hyaluronan-containing preparations are sold as so-called nutraceuticals (food supplements) which can also be used in animals (for example dogs, horses) for the prophylaxis and alleviation of arthrosis.
Hyaluronan used for commercial purposes is currently isolated from animal tissues (cockscombs) or prepared fermentatively using bacterial cultures.
U.S. Pat. No. 4,141,973 describes a process for isolating hyaluronan from cockscombs or alternatively from umbilical cords. In addition to hyaluronan, animal tissues (for example cockscombs, umbilical cords) also contain further mucopolysaccharides related to hyaluronan, such as chondrotin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate and heparin. Furthermore, animal organisms contain proteins (hyaladherins) which bind specifically to hyaluronan and which are required for the most different functions in the organism, such as, for example, the degradation of hyaluronan in the liver, the function of hyaluronan as lead structure for cell migration, the regulation of endocytosis, the anchoring of hyaluronan on the cell surface or the formation of hyaluronan networks (Turley, 1991, Adv Drug Delivery Rev 7, 257 ff.; Laurent and Fraser, 1992, FASEB J. 6, 183 ff.; Stamenkovic and Aruffo, 1993, Methods Enzymol. 245, 195 if; Knudson and Knudson, 1993, FASEB 7, 1233 ff.).
The Streptococcus strains used for the bacterial production of hyaluronan are exclusively bacteria pathogenic to humans. During cultivation, too, these bacteria produce (pyrogenic) exotoxins and hemolysins (streptolysin, in particular alpha- and beta-hemolysin) Kilian, M.: Streptococcus and Enterococcus. In: Medical Microbiology. Greenwood, D.; Slack, R C A; Peutherer, J. F. (Eds.). Chapter 16. Churchill Livingstone, Edinburgh, UK: pp. 174-188, 2002, ISBN 0443070776) which are released into the culture medium. This renders purification and isolation of the hyaluronan prepared with the aid of Streptococcus strains more difficult. In particular for pharmaceutical application, the presence of exotoxins and hemolysins in the preparation is a problem.
U.S. Pat. No. 4,801,539 describes the preparation of hyaluronan by fermentation of a mutagenized bacterial strain (Streptococcus zooedemicus). The mutagenized bacteria strain used no longer synthesizes beta-hemolysin. The yield achieved was 3.6 g of hyaluronan per liter of culture.
EP 0694616 describes a method for cultivating Streptococcus zooedemicus or Streptococcus equi, where, under the culture conditions employed, no streptolysin, but increased amounts of hyaluronan are synthesized. The yield achieved was 3.5 g of hyaluronan per liter of culture.
During cultivation, Streptococcus strains release the enzyme hyaluronidase into the culture medium, as a consequence of which, in this production system, too, the molecular weight is reduced during purification. The use of hyaluronidase-negative Streptococcus strains or of methods for the production of hyaluronan where the production of hyaluronidase during cultivation is inhibited are described in U.S. Pat. No. 4,782,046. The yield achieved was up to 2.5 g of hyaluronan per liter of culture, and the maximum mean molecular weight achieved was 3.8×106 Da, at a molecular weight distribution of from 2.4×106 to 4.0×106.
US 20030175902 and WO 03 054163 describe the preparation of hyaluronan with the aid of heterologous expression of a hyaluronan synthase from Streptococcus equisimilis in Bacillus subtilis. To achieve the production of sufficient amounts of hyaluronan, in addition to heterologous expression of a hyaluronan synthase, simultaneous expression of a UDP-glucose dehydrogenase in the Bacillus cells is also required. US 20030175902 and WO 03 054163 do not state the absolute amount of hyaluronan obtained in the production with the aid of Bacillus subtilis. The maximum mean molecular weight achieved was about 4.2×106. However, this mean molecular weight was only achieved for the recombinant Bacillus strain where a gene coding for the hyaluronan synthase gene from Streptococcus equisimilis and the gene coding for the UDP-glucose dehydrogenase from Bacillus subtilis were integrated into the Bacillus subtilis genome under the control of the amyQ promoter, where at the same time the Bacillus subtilis-endogenous cxpY gene (which codes for a cytochrome P450 oxidase) was inactivated. Chien and Lee (2007, Biotechnol. Prog. Online publication, ASAP Article 10.1021/bp070036w, S8756-7938(07)00036-7) describe various recombinant Baciullus subtilis strains. One strain, which had been transformed with a nucleic acid sequence coding for a hyaluronan synthase and a nucleic acid sequence coding for a UDP-glucose dehydrogenase, synthesized at most 1.14 g/l of hyaluronan. A strain which, in addition to the nucleic acid sequences just mentioned, had been transformed with a nucleic acid sequence coding for Vitreoscilla hemoglobin synthesized 1.8 g/l hyaluronan.
WO 06 032538 describes transgenic plants transformed with nucleic acid molecules coding for hyaluronan synthases. The synthesis of hyaluronan in the plants in question was demonstrated unambiguously.
WO 05 012529 describes the production of transgenic tobacco plants which were transformed using nucleic acid molecules coding for hyaluronan synthases from Chlorella-infecting viruses. In WO 05 012529, use was made, on the one hand, of nucleic acid sequences coding for hyaluronan synthase of the Chlorella virus strain CVH1 and, on the other hand, of the Chlorella virus strain CVKA1 for transforming tobacco plants. The synthesis of hyaluronan could only be demonstrated for a plant transformed with a nucleic acid coding for a hyaluronan synthase isolated from the Chlorella virus strain CVKA1. For tobacco plants transformed with a nucleic acid sequence coding for a hyaluronan synthase isolated from the Chlorella virus strain CVH1, it was not possible to detect hyaluronan synthesis in the corresponding transgenic plants. The amount of hyaluronan synthesized by the only hyaluronan-producing transgenic tobacco plant in WO 05 012529 is stated as being about 4.2 μg of hyaluronan per ml of measured volume which, taking into account the description for carrying out the experiment in question, corresponds approximately to an amount of at most 12 μg of hyaluronan produced per gram of fresh weight of plant material.
WO 2007 039314 describes transgenic plants having the activity of a hyaluronan synthase and additionally an increased glutamine:fructose 6-phosphate amidotransferase (GFAT) activity. These plants synthesize an increased amount of hyaluronan compared to plants having only the activity of a hyaluronan synthase. The maximum amount of hyaluronan synthesized by these tobacco plants is about 0.03% per gram of fresh weight of plant material used for the measurement (see FIG. 5 in WO 2007 039316).
WO 2007 039316 describes transgenic plants having the activity of a hyaluronan synthase and additionally an increased glutamine:fructose 6-phosphate amidotransferase (GFAT) activity and an increased UDP-Glucose dehydrogenase (UDP-Glc-DH) activity compared to wild-type plants. These plants synthesize an increased amount of hyaluronan compared to plants having the activity of a hyaluronan synthase and at the same time the activity of a protein having the activity of a GFAT. The maximum amount of hyaluronan synthesized by these tobacco plants is 0.2% per gram of fresh weight of plant material used for the measurement (see FIG. 6 in WO 2007 039316).
Furthermore, WO 2007 039316 contains a list of proteins which can be expressed in plants cells to increase further the amount of synthesized hyaluronan in plant cells. The proteins proposed in WO 2007 039316 are a random list of enzymes which, in various organisms, are involved in the synthesis of UDP-GlcNAc. The proteins listed in WO 2007 039316 have various enzymatic functions. WO 2007 039316 gives no indication whether and which of the enzymes listed may indeed increase the hyaluronan content when expressed in transgenic plants.
The synthesis of the disaccharide chain of the chondroitin/dermatan ([beta-1,4)]-[glucuronic acid-beta-1,4-N-acetyl-galactosamine]) is catalyzed by a chondroitin synthase starting from UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetyl-galactosamine (UDP-GalNAc), an epimer of UDP-N-acetyl-glucosamine (UDP-GlcNAc) (Kitagawa et al., 2001, J Biol Chem 276(42), 38721-38726). By an epimerase, the glucuronic acid molecules of the chondroitin can be converted into iduronic acid. If more than 10% of the glucuronic acid molecules are present as iduronic acid, the polymer is referred to as dermatan. The introduction of the sulfate groups at various positions of the disaccharide chain of the chondroitin or the dermatan is then catalyzed by other enzymes, resulting in the formation of chondroitin/dermatan sulfate. Here, the degree of sulfatation may differ from molecule to molecule.
For some time, chondroitin sulfate has been discussed as a potential active compound for the treatment of osteoarthritis (Clegg et al., 2006, The New England Journal of Medicine 354(8), 795-808).
The synthesis of the disaccharide chain of the heparin/heparan (heparosans) ([alpha-1,4]-[glucuronic acid-beta-1,4-glucosamine], or [alpha-1,4]-[iduronic acid-alpha-1,4-glucosamine]n) is catalyzed by a heparin/heparosan synthase starting from UDP-GlcA and UDP-GlcNAc (DeAngelis and White, 2004, J. Bacteriology 186(24), 8529-8532). The glucuronic acid molecules of the heparosan can be converted by an epimerase into iduronic acid. The introduction of the sulfate groups at various positions of the disaccharide chain of the heparosan is then catalyzed by other enzymes, resulting in the formation of heparin or heparan sulfate. Heparin sulfate has a considerably higher substitution by sulfate groups than heparan sulfate. Heparin sulfate has about 90% iduronic acid molecules, whereas in heparan sulfate the glucuronic acid molecules predominate (Gallagher et al., 1992, Int. J. Biochem 24, 553-560). As in the case of chondroitin/dermatan sulfate, in the case of heparin/heparan sulfate, too, the degree of sulfatation may differ from molecule to molecule.
Heparin sulfate is used inter alia as an anticoagulant, for example for preventing and treating thromboses.
Currently, chondroitin/dermatan sulfat and heparin/heparan sulfate are prepared by isolation from animal tissue. Chondroitin sulfate is isolated mainly from bovine cartillage or shark cartillage, heparin/heparan sulfate is isolated from porcine intestine or bovine lungs. Since the disaccharide chains of chondroitin/dermatan sulfate and heparin/heparan sulfate have no uniform sulfatation pattern, it is difficult to obtain a uniform specific product. Accordingly, the product is always a mixture of molecules having various degrees of sulfatation.
As already described, glucosaminoglycans, such as, for example, chondroitin sulfate or heparin/heparan sulfate are currently isolated from animal tissues. In addition to the desired substances, these tissues also contain other glucosaminoglycans. The separation of the individual glucosaminoglycans, if possible at all, is difficult and expensive. Furthermore, the potential contamination of animal tissues by pathogenic microorganisms and/or by other substance such as, for example, BSE or the bird flu pathogen, which may lead to diseases in man, poses a problem when using glucosaminoglycans isolated from animal tissue. In patients, the use of medicinal preparations contaminated by animal proteins can result in unwanted immunological reactions of the body (for hyaluronan preparations see, for example, U.S. Pat. No. 4,141,973), in particular if the patient is allergic to animal proteins.
In addition, substances prepared from animal raw materials are unacceptable for some ways of life such as, for example, vegans or for koscher food preparation.
A further problem in the isolation of glucosaminoglycans from animal tissues consists in effect that frequently the molecular weight of glucosaminoglycans is reduced during purification since animal tissues also contain glucosaminoglycan-degrading enzymes.
The amounts (yields) of glucosaminoglycans which can be obtained in satisfactory quality and purity from animal tissues are low (for example hyaluronan from cockscomb: 0.079% w/w, EP 0144019, U.S. Pat. No. 4,782,046), which means that large amounts of animal tissues have to be processed.
The production of glucosaminoglycans by fermentation of bacteria strains is associated with high costs, since the bacteria have to be fermented in sealed sterile containers under expensive controlled culture conditions (see, for example, for hyaluronan, U.S. Pat. No. 4,897,349). Furthermore, the amount of glucosaminoglycans which can be produced by fermentation of bacteria strains is limited by the production facilities present in each case. Here, it also has to be taken into account that fermenters, as a consequence of physical laws, cannot be built for excessively large culture volumes. Particular mention may be made here of homogeneous mixing of the substances fed in from the outside (for example essential nutrient sources for bacteria, reagents for regulating the pH, oxygen) with the culture medium required for efficient production, which, in large fermenters, can be ensured only with great technical expenditure, if at all.
Plants do not naturally produce glucosaminoglycans such as, for example, hyaluronan, heparan/heparin sulfate, keratan sulfate or chondroitin/dermatan sulfate. Naturally occurring plants themselves do not have any nucleic acids in their genome which code for proteins catalyzing the synthesis of glucosaminoglycans, and, although a large number of plant carbohydrates have been described and characterized, it has hitherto not been possible to detect any of the glucosaminoglycans mentioned in non-infected natural plant cells (Graves et al., 1999, Virology 257, 15-23).
WO 98 35047 (U.S. Pat. No. 6,444,878) describes a metabolic path for the synthesis of GlcNAc in plant cells where glucosamine is converted via a plurality of successive enzymatically catalyzed reaction steps with formation of the metabolites GlcNAc, N-acetyl-glucosamine 6-phosphate and N-acetyl-glucosamine 1-phosphate into UDP-GlcNAc. In higher concentrations, glucosamine 6-phosphate is toxic for plant cells (WO 98 35047).
An alternative metabolic path described for plants comprises the reaction of fructose 6-phosphate and glutamine giving glucosamine 6-phosphate which is subsequently converted by a number of successive enzymatically catalyzed reaction steps with formation of the metabolites glucosamine 1-phosphate and N-acetyl-glucosamine 1-phosphate into UDP-GlcNAc (Mayer et al., 1968, Plant Physiol. 43, 1097-1107).
To date, it is still not clear which protein activities have to be modified in the metabolic path for the synthesis of UDP-GlcNAc in the plant for the plants to synthesize increased amounts of glucosaminoglycans.

Plants which synthesize increased amounts of glucosaminoglycans


Porous materials suitable for a variety of uses including waterproof/breathable fabrics, air filters, liquid filters, liquid/liquid separation membranes, vascular grafts, mechanical seals, etc. which comprises an intimate combination of about 50 to 99.9 wt % polytetrafluoroethylene polymer and about 0.1 to 50 wt % of a fluorinated organic polymer which is liquid under ambient conditions, such as the perfluoroether fluids, wherein the material has a microstructure characterized by nodes interconnected by fibrils.

Polytetrafluoroethylene is a unique compound commonly employed when one or more of the associated characteristics of chemical inertness, water repellency, and/or electrical insulating value are desired.
Polytetrafluoroethylene can be processed to form a highly porous breathable material which continues to retain the characteristics of chemical inertness, water repellency, and electrical insulating value. Briefly, such porous materials are generally produced by heating and expanding (stretching) a paste-formed body of the polytetrafluoroethylene.
Expanded porous polytetrafluoroethylene films may be used alone or laminated to an assortment of substrates to produce a variety of products including specifically, but not exclusively, sealing thread, breathable/water-repellant fabrics, air filters, liquid filters, vascular grafts (U.S. Pat. Nos. 3,953,566, 3,962,153, 4,208,745, 4,234,535, 4,321,711 4,332,035, 4,550,447, 4,647,416, 4,742,480, and 4,955,899), and numerous others.
Expanded porous polytetrafluoroethylene films have commanded wide acceptance since their introduction because of their unique combination of properties. However, efforts continue in an attempt to improve upon these properties and thereby increase the potential uses of expanded porous films of polytetrafluoroethylene. One area of concentrated research has been with respect to efforts to increase the radiation resistance of the films, which are notoriously susceptible to degradation by radiation.
Efforts to improve upon the properties and/or uses of porous polytetrafluoroethylene materials by blending an additional component into the polytetrafluoroethylene prior to expansion have met with limited success. In fact, common wisdom in the art advises against incorporation of a matrix interactive component into the polytetrafluoroethylene prior to expansion, except in trace amounts, as a high degree of crystallinity is thought to be necessary to achieve proper expansion of polytetrafluoroethylene and the addition of a matrix interactive component tends to adversely affect the crystallinity.
A singular success in this area is described in U.S. Pat. No. 4,764,560, wherein incorporation of a silicone elastomer into polytetrafluoroethylene resin prior to expansion, followed by polymerization of the silicone elastomer, produces a porous silicone/polytetrafluoroethylene interpenetrating polymeric network having enhanced properties.
Because of the exceptional potential for further unique uses of polytetrafluoroethylene-containing materials, research continues in an effort to improve upon the properties and/or uses of the material.

Porous products manufactured from polytetrafluoroethylene treated with a perfluoroether fluid and methods of manufacturing such products


Embodiments of the present invention are directed to Web-Services-based data backup and data-archiving applications that provide remote data backup and data archiving to private individuals, small businesses, and other organizations that need reliable, secure, geographically remote, and cost-effective data backup, data archiving, and backed-up and archived-data retrieval. In one embodiment of the present invention, a private or small-business client contracts with a service provider for data-backup and data-archiving services. The service provider, in turn, contracts with a remote data-storage facility to provide secure, reliable data backup and data archiving to the personal or small-business client. A client-side application is downloaded to the client computer and configured to allow the client to store locally encrypted data at the remote, data-storage facilities. Neither the service provider nor the data-storage facility can decrypt or otherwise access the information stored by the client.

Only 30 years ago, the vast majority of private individuals, small businesses, and even medium-sized businesses carried out word processing tasks on electronic typewriters and stored personal and business-related data on hand-written and typed papers and forms that were manually filed in indexed folders within filing cabinets. During the late 1970's and 1980's, mini-computer-based word-processing systems, and, subsequently, personal computers became widely available, and electronic data storage relatively quickly replaced hand-written and typed pages stored in filing cabinets. However, in many cases, electronic data was stored on floppy disks that were, in turn, indexed and physically stored in filing-cabinet-like enclosures, since the small capacity and lack of robustness of early mass-storage devices and computer systems limited their usefulness for storing data backups and archived data. Data backups and archived data need to be reliably stored for relatively long periods of time. Often, backed-up and archived data may never again be needed, but, in those cases in which backed-up or archived data needs to be retrieved for subsequent use, an ability to retrieve the backed-up or archived data may result in serious and, in certain cases, even fatal consequences for business organizations.
With the continued improvement of personal computers and business computing systems, and increased price performance of computers, data backups and data archives are currently most commonly stored in mass-storage devices accessible by networked computer systems. FIG. 1 illustrates options for data backup and data archiving in a small-business environment. In general, an employee or small-business owner carries out most data-related tasks on the employee's or business owner's personal computer 102. Personal computers are commonly purchased with multiple disk drives that allow for redundant data backup, including full disk mirroring, and redundant data archiving within a single computer system. However, small businesses generally employ networked systems of personal computers and one or more servers 104 with higher-capacity and more highly available and fault-tolerant data-storage subsystems. In such environments, the employee or business owner primarily using PC 102 can access, via a network, other PCs 106 and 108 or the centralized server 104 for storing backup data and for archiving data, in addition to any local backup and archiving within the employees or business owner's own PC 102. Similarly, home users may have multiple disk drives on their PCs, and often have networked, multiple-PC systems that allow for storing backup data and archiving data over two or more networked computers. Additionally, data can be backed up and archived, in the small system shown in FIG. 1, on writeable CDs or DVDs, magnetic tapes, or other types of physical storage media, and the CDs, DVDs, or tapes may be stored in remote locations. Again, however, such practices depend on regularly conducted backups and archiving, on managing remotely stored information, and other manual tasks that are often forgotten or put off.
Unfortunately, current trends and developments in personal and business computing are conspiring to make data backup and data archiving in small computer systems, such as the small computer system shown in FIG. 1, inefficient and dangerous. As applications and computer systems on which applications run continue to become larger and more capable, the amount of electronic data that is routinely generated and that that needs to be backed up and archived by personal and small-business users is increasing rapidly. Furthermore, as more activities and tasks become automated as a result of the increasing price performance in computer systems and the increasing availability of a wide variety of application programs, more types of electronic data are being generated by home and small-business computer users, much of which may need to be backed up and archived. New regulations and statutes require small business to maintain reliably backed-up data for relatively long periods of time. For example, certain new statues require electronic, reliable storage of medical records, and other new statutes require reliable, electronic storage of email and other securities-related information in companies dealing with securities transactions. These statutes and regulations contribute enormous added data-backup and data-archiving overhead. Data backup and data archiving require continuous diligence and technical understanding on the part of home users and small businesses. Home users and small businesses often lack the technical expertise, time, and vigilance required to effectively back up and archive data in ways that guarantee that backed-up and archived data is not lost or does not end up being unrecoverable for a variety of different reasons. Although progress has been made by computer vendors, operating-systems vendors, and other hardware, software, and service providers, efficient, user-friendly data backup and data archiving may require interfacing many different components with one another, and the many interfaces may be neither stable over time nor easy to set up and manage. Reliable data backup and data archiving require data to be stored in two or more geographically remote locations, to prevent catastrophic data loss at a single site. For example, even when data is backed up and archived in triply or quadruply redundant fashion within a small business, a fire, flood, or earthquake can easily result in all redundantly stored data being lost or unrecoverably damaged. Backing up and archiving data to geographically remote data-storage facilities is often beyond the technical and economic capabilities of home users and small businesses. Finally, even were a home user or small business able to create and manage a reliable and effective data backup and archiving system, it is exceedingly difficult for home users and small businesses to secure backed-up and archived data from inadvertent or malicious, unauthorized access. Such data is commonly accessed by hackers, business competitors, and fraudulent groups and organizations. For all of these reasons, home users, small businesses, and even medium-sized businesses and larger organizations have all recognized the need for user-friendly, reliable, and cost-efficient data backup and data storage services.


An improved architecture for a digital video processor that processes subvideo data to be superimposed on a main video image during a display image scanning process. The improved digital video processor divides and partitions the execution of subvideo data between a programable CPU and a dedicated hardware processor. The CPU is used to process the simpler, less time critical, nonpixel data, and the more complex, more time critical pixel data is processed in real time using a dedicated hardware processor operating under the control of the CPU. The improved digital video processor is adaptable to process subvideo data being supplied in different data formats.

There are many circumstances in which a television screen display is required to superimpose one video image on top of another video image. In the past, such superimposed images were generally created at the source of the video signal as part of the programming. Today, there are more and more applications where it is desirable to be able to create superimposed video images both from the program source, and interactively based on a user input. Almost all televisions manufactured today are capable of interfacing with different sources of programmed materials providing a video input signal for display on the television screen, for example, a VCR, a digital versatile or video disk ("DVD") player, cable, DSS, etc. Further, some of those sources provide digital audio and video input signals in accordance with the Moving Picture Expert Group MPEG-2 audio/video digital compression standard. Thus, contemporary televisions preferably have the capability of processing digital input signals and providing digital signals representing the desired images. Most often, those digital signals are converted to analog signals for use by known analog television display units.
Further, most televisions manufactured today and/or their plug compatible program sources have user interactive capabilities that utilize menus of possible actions superimposed on the screen simultaneously with the display of program material. Using such superimposed menu displays, a user may choose to have captions or subtitles displayed on the screen. In other applications, the displayed menus may be used to provide desired adjustments or settings, for example, audio and video levels, game time, degree of difficulty, etc., which are unique to the user. Those settings are often displayed in the form of linear scales that change in response to a user input pushing a button.
When program sources provide information in digital form, the information is provided in a data packet. Preferably, the audio and main video data are provided in respective data packets in an "MPEG-2" format. However, the information relating to subvideo or superimposed video may be provided in a data packet in any one of several formats. For example, the superimposed video may be provided in a Subpicture format that is defined in the known Digital Video Display ("DVD") standard. The Subpicture format includes a header block, a pixel data block, and a command data block. Generally, the header is used to identify the general nature of the data. For example, the header may be used to identify the format of the data, whether the pixel data is compressed, if a command structure is used, how the data is to be read, etc. In the Subpicture format, the pixel data represents color and contrast information and is compressed using known compression techniques, for example, run length compression. The command data in the Subpicture format identifies the location and size of the subpicture, the location and size of highlight areas within the subpicture, and the location and size of one or more smaller areas within the subpicture that may have unique color and contrast values, etc.
In other applications, the superimposed video data associated with the main video may be in other formats. For example, an on-screen display format for a DVB/STB system presents the subvideo data in a format that generally includes only a header block and an uncompressed pixel data block. In addition, although invisible to the viewer, subvideo data can also be utilized during the vertical blanking interval ("VBI") between display fields or frames of a complete video image. In further applications, the subvideo data may also be provided in proprietary formats, such as a DSS format used with digital satellite transmissions; or the subvideo data may be in the form of raw pixel data that can be directly converted to analog signals for use by the display unit.
In the past, it was commercially feasible to market televisions that were designed to be compatible with only a single format, for example, the on-screen display format for superimposed video information. However, with the recent development and standardization of the digital Subpicture format defined by the DVD standard, there is a need for televisions to provide the capability of recognizing and processing different formats for superimposed video data.

Digital video processor with subvideo processor


A method and apparatus for use in a vertical form, fill and seal machine to protect the longitudinal back seal. A pair of clamps retains the plastic film against the forming tube on either side of the back seal and on either side of a sealing platen if the platen is used for forming the back seal. The clamps extend for at least the length of the platen, and the clamps are operated together in unison.

This invention relates to vertical form, fill and seal machines, and in particular to a method and apparatus for protecting the back seal formed by the vertical form, fill and seal machine as product to be packaged is inserted.
For years, vertical form, fill and seal machines have been used to package various products by forming plastic film around a forming tube, making a back seal in plastic film while it is on the forming tube in order to form the plastic into a generally cylindrical shape, and then inserting product to be packaged by dropping it down the forming tube into partially formed packages before they are finally sealed. Once product is inserted, subsequent operations occur to add end seals which complete the package. Such an apparatus is disclosed in U.S. Pat. No. 4,288,965, the disclosure of which is incorporated herein by reference.
In the typical vertical form, fill and seal machine, when product is inserted down the forming tube, the plastic package is already sealed at its bottom end. Thus, as products fall within the forming tube, some back air pressure is built as products fall down the forming tube, such that back pressure being exerted within the partially-formed package against both the lateral bottom seal in the package and the longitudinal back seal for the package.
When small products are packaged, creation of back pressure is not a problem, since displaced air simply exhausts up the forming tube around the product as it is being dropped into the partially-formed package. However, when the size of the product increases, the back pressure increases and problems can occur. When a large product that nearly equals the diameter of the forming tube is inserted, the product acts like a piston with gravity drawing the product down the forming tube and air in the forming tube being compressed as the product moves downwardly. This can create two detrimental effects. First, the creation of back pressure can retard the velocity of the product, thus limiting the through put of the vertical form, fill and seal machine. Second, increased pressure in the partially-formed package can place excessive strain on both the lateral end seal and the longitudinal back seal of the partially-formed package.
The creation of back pressure is much like the action of a typical shock absorber. The greater the amount of air that can bypass the falling product, the faster the product will fall through the forming tube. Thus, the shape and size of the product being inserted has a considerable affect on the time that it takes the product to drop into the partially-formed package. If the time that the product takes to drop into the partially-formed package varies, this can result in product being trapped in either the final end seal being formed or a stager, if a stager is used to accommodate the weight of the product being inserted. Variability is particularly difficult to control, and product jams are a very undesirable result.
Various means have been developed in the past to try to relieve undesirable back pressure. One method previously utilized was to add vent tubes to the inside of the forming tube in order to exhaust air more efficiently than to simply rely on exhausting air bypassing any gaps between the product and the forming tube. Another possible way to alleviate the problem is to add vent holes to the plastic film, but this typically is unacceptable when a fully sealed package is desired.
Back pressure is not an entirely undesirable effect, since it cushions a product as it drops down the forming tube to help ensure less impact when entering the partially-formed package or impinging upon a stager which is utilized to absorb the impact of the descending product. However, back pressure is undesirable if it affects the quality of either the lateral end seal or the longitudinal back seal of the package.
Generally, when a heavy product, such as a bag filled with liquid, is being inserted down the forming tube, a stager is utilized to absorb the energy of the falling product. Utilization of a stager also greatly reduces the affect of back pressure on the lateral end seal, which is located below the stager. Also, in general, the integrity of the end seal is not a serious concern since typically the sealing pressure for the lateral end seal is higher thus allowing a lower sealing temperature and increased dwell time for the sealing jaws as compared to the platen with lower pressure, higher sealing temperature, and shortened dwell time used for the longitudinal back seal. Also, with the stager protecting the end seal, the back seal is typically the area where problems of integrity of the seal occur. Protecting the back seal is the primary object of the present invention.

Back seal support for vertical form, fill and seal machine


A three-dimensional array of memory elements that reversibly change a level of electrical conductance in response to a voltage difference being applied across them. The memory elements can be set to a low resistance state and reset to a high resistance state during standard operation by biasing appropriate voltages on the word lines and bit lines. Prior to standard operation, the memory elements undergo a forming operation, during which current through the bit lines is limited. A forming voltage is applied to the memory elements during forming with a polarity such that a higher voltage is applied to anodes and a lower voltage to cathodes.

Field of the Invention
The present invention relates to technology for non-volatile storage.
Description of the Related Art
One example of non-volatile memory uses variable resistance memory elements that may be set to either low a low resistance state or a high resistance state, and can remain in that state until subsequently re-set to the initial condition. The variable resistance memory elements are individually connected between two conductors (typically bit and word lines). The state of such a memory element is typically changed by proper voltages being placed on the intersecting conductors.
Some variable resistance memory elements may be in the high resistance state when first fabricated. The term "FORMING" is sometimes used to describe putting the variable resistance memory elements into a lower resistance state for the first time. After FORMING, the variable resistance memory elements may RESET to the high resistance state and SET again to a low resistance state.
One theory that is used to explain the FORMING mechanism, as well as the switching mechanism to RESET and SET the variable resistance memory elements, is that one or more conductive filaments are formed by the application of a voltage to the variable resistance memory elements. One example of a variable resistance memory element includes a metal oxide as the variable (reversible) resistance material. In response to a suitable voltage, a conductive filament may be formed in the metal oxide such that there is one or more conductive paths from the top electrode to the bottom electrode of the variable resistance memory element. The conductive filament lowers the resistance of the variable resistance memory element. Application of another voltage may rupture the conductive filaments, thereby increasing the resistance of the variable resistance memory element. Application of still another voltage may repair the rupture in the conductive filament, thereby decreasing the resistance of the variable resistance memory element once again. The initial formation of the conductive filament is referred to as "FORMING," the rupture of the filament is referred to as RESETTING and the repair of the rupture of the filament is referred to as SETTING. The variable resistance memory element may then be repeatedly switched between states by repeatedly RESETTING and SETTING the variable resistance memory element. The RESETTING process puts the variable resistance memory element in the high resistance state and the SETTING process puts the variable resistance memory element in the low resistance state. Data values are assigned to the high resistance state and the low resistance state.
The FORMING process may impact the ability of the variable resistance memory element to exhibit proper switching behavior. For example, the variable resistance memory element should switch between the high resistance state and the low resistance state in response to appropriate voltages, which may be referred to as "switching within the intended window."
Current FORMING operations often use a high voltage, which can result in high transient currents. These transient currents make it difficult to manage the FORMING process and sometimes may result in damaging one or more portions of the memory device. Surge currents are very difficult to control when a resistive memory layer is being formed, especially at higher operational voltage. The resistance changes quickly, often in less than 1 ns. Array lines driving the variable resistance memory elements have capacitance and a high voltage. This capacitive energy C*V discharges through the suddenly low resistance path of the variable resistance memory element producing currents that can reach 100 micro amps (or even the mA level) and cause the low resistance state to be even lower than desired, or stresses the variable resistance memory element so that it cannot not cycle as many times as desired.

Low forming voltage non-volatile storage device


Seamless pipes excellent in quality features with high productivity is made by a by carrying out piercing-rolling using a piercer provided with a pair of inclined rolls. The piercing-rolling is carried out under conditions such that the plug tip draft (TDFT) or the root of the product of the plug tip draft (TDFT) are controlled along with the number of billet revolutions (N), namely (TDFT×N)0.5. In addition, positions of the inclined rolls are controlled in connection with the gorge draft (GDFT) indicating the ratio of the roll gap (Rg) which is minimal in the gorge section between the inclined rolls to the billet outside diameter (Bd). The piercing-rolling is carried out using a plug having a particular shape.

Among various technologies known in the art for the manufacture of seamless steel pipes, the most efficient methods suited for mass production are those manufacturing methods which are based on a rolling technique (the so-called Mannesmann process) comprising piercing billets using a pair of inclined rolls and a piercing plug.
In piercing by the rolling technique, a heated billet is transferred to a piercing machine (piercer), pushed by a pusher and gripped by a pair of inclined rolls. Thereafter, the billet advances while the rolls rotate it. On that occasion, a rotary forging effect (Mannesmann effect) is exerted on the central portion of the billet during the period until the billet arrives at the tip of the piercing plug disposed along the pass line between the rolls and, as a result, that central portion becomes fragile. Then, the billet undergoes piercing-rolling by the pair of inclined rolls and the plug to form a hollow raw pipe (hereinafter also referred to as "raw pipe" for short). The hollow raw pipe is further processed in the subsequent steps, including elongation rolling, to give a seamless pipe having a predetermined size.
The piercing-rolling mentioned above is also applied to billets made of, for example, a continuously casting material having center segregations and/or porosity or of a stainless steel species poor in hot deformability. On that occasion, the rotary forging effect and additional shear deformation cause formation of leaf-like, fin-like or lap-like flaws or defects on the inner surface of the hollow raw pipe (such defects are collectively referred to as "inner surface defects"). For preventing this, the plug tip draft is generally reduced to thereby suppress the rotary forging effect as far as possible and prevent the formation of such inner surface defects. However, the reduction in plug tip draft tends to allow the occurrence of misrolling such as a gripping failure.
The plug tip draft is defined by the following formula:(Bd−d1)/Bd, namely 1−(d1/Bd)
Therefore, to reduce the plug tip draft means that when the billet diameter (Bd) is constant, d1 (gap between the rolls at the plug tip position) is increased or that the plug is shifted forward to the billet side to shift the tip thereof in the direction toward the smaller roll diameter side (cf. FIG. 1).
Patent Documents 1 and 2 describe methods of manufacturing seamless pipes one feature of which is to employ a plug tip draft of not lower than 95% or not lower than 97%. However, while these documents define the plug tip draft as "gap between the rolls at the plug tip position/billet diameter", the above-cited "not lower than 95%" and "not lower than 97%" should properly be described as "not lower than 0.95" and "not lower than 0.97", respectively. And, these plug tip draft ranges correspond to "not higher than 0.05" and "not higher than 0.03", respectively, according to the original definition given above.
[Patent Document 1] Japan Patent Unexamined Publication No. 2001-162307 (Application No. H11-346513)
[Patent Document 2] Japan Patent Unexamined Publication No. 2001-162306 (Application No. H11-346514)
Another difficulty arising from such reduction in plug tip draft consists in a decrease in piercing efficiency. The piercing efficiency is the percentage of the longitudinal advancement velocity of the raw pipe to the longitudinal direction component of the roll gorge peripheral velocity and is defined as follows:η=(VH/VR sin θ)×100(%)where η is the piercing efficiency (%), VH is the longitudinal velocity of the raw pipe (m/s) and VR is the roll gorge peripheral velocity (m/s).
FIG. 4 shows the results of tests carried out for piercing efficiency investigations using plugs of the same shape under the conditions shown in Table 1. As shown, the piercing efficiency decreases with the increase in plug tip draft and, in particular, the decrease in piercing efficiency is remarkable when the plug tip draft is 0.04 or lower.
[Table 1]
TABLE 1Billet material and sizeS45C, SUS304, diameter: 70 mmHollow raw pipe sizediameter: 75 mm, wall thickness: 8 to 9 mmRoll gorge diameter410 mmToe angle γ15°Feed angle β10°Plug tip draft TDFT0 to 0.05Maximum plug diameter 58 mmDistance from plug tip to115 mmmaximum diameter site
A reduction in piercing efficiency means a decrease in the longitudinal velocity of the raw pipe (above-mentioned VH) or, in other words, a decrease in the longitudinal velocity of the billet and means that the time during which the rotary forging effect is exercised on the billet is prolonged (the number of times of roll forging at the predetermined position of the billet is increased). Thus, with steel species having defects at the central portion, for example continuously casting materials, an excessive rotary forging effect even if the plug tip draft is set at a low level causes inner surface defects.
Furthermore, as a result of a decrease in piercing efficiency, the metal flow of the rolling target material is restrained in the axial direction and is facilitated in the circumferential direction. Then, the additional shear deformation in the circumferential direction increases, and the defects produced in front of the plug are further intensified by that shear deformation and, as a result, they remain on the raw pipe as large-size inner surface defects. In addition, the time required for piercing is prolonged by the decrease in piercing efficiency, so that a further problem arises, namely the thermal load on the plug increases and the life of the plug is shortened.
The methods described in the above-cited Patent Documents 1 and 2 both consist in combining a reduced roll circumferential velocity with pushing in by means of a pusher. According to these methods, piercing is carried out at a low plug tip draft even in the piercing of the middle portion of the billet, so that cracking due to the rotary forging effect in front of the plug can indeed be suppressed. However, under certain conditions of setting of the rolls and according to the shape of the plug, the slip in piercing the middle and subsequent portions of the billet increases and, as a result, the piercing efficiency may be decreased thereby, although the problem of gripping failure can be solved.
If the piercing efficiency in piercing the middle and subsequent portions of the billet is decreased, as mentioned above, the velocity, in the direction of rolling, of the entry side billet is decreased even in the steady rolling region, the number of billet revolutions (number of times of contacting between the roll pair and the rolling target material during the period from gripping of the billet by the rolls to the arrival of the billet at the plug tip) increases. Therefore, the number of times of the billet experiencing the rotary forging effect increases and, even if the plug tip draft is lower, cracks will be caused in the vicinity of the billet center by the excessive rotary forging effect and thus remain as inner surface defects in the raw pipe.