Systems and methods are described to perform wireless communication. The device includes a pre-distortion circuit configured to pre-distort an input signal based on a parameter set including a plurality of coefficients and generate a pre-distorted signal, a power amplifier configured to amplify the pre-distorted signal and generate an output signal, and a parameter obtaining circuit configured to perform an iterative approximation operation based on the output signal and the pre-distorted signal, which change over time, according to an indirect training structure configured to minimize a difference between an intermediate signal obtained based on the output signal and the pre-distorted signal, and obtain the parameter set.

The inventive concept relates to a wireless communication device, and more particularly, to a device and method of compensating for the nonlinearity of a power amplifier.
Many people use wireless communication devices such as smartphones and tablet computers. Transmitters are used in wireless communication devices to transmit radio frequency (RF)-band signals.
A baseband signal, or original signal, may be generated prior to transmitting the RF-band signal. Due nonlinearity of the transmitter, the RF-band signal may be distorted while processing the baseband signal to produce the RF-band signal.
The nonlinearity of transmitter effects can reduce the quality of a signal, thereby distorting the RF-band signal. A reduced quality of signal causes disrupted wireless connections, dropped calls, and interruptions in data transfer. Therefore, there is a need in the art to reduce the distortion to the RF-band signal due to nonlinearity of transmitters in wireless communication devices.

Device and method of compensating for nonlinearity of power amplifier


A spinning reel includes a reel main body having a rod attachment portion, a handle shaft rotatably supported by the reel main body, a spool, a rotor, a rotor shaft, a pinion gear, a face gear, and a reciprocating mechanism. The face gear includes a disc portion and an annular ring portion axially extending from the disc portion. The annular ring portion includes gear teeth disposed on an axial surface of the annular ring portion. The pinion gear is disposed on the rotor shaft, and engages the face gear and is coupled to the rotor. The reciprocating mechanism includes a screw shaft which is rotated by the pinion gear. The distance between the axial center of the face gear and an attachment face of the rod attachment portion is set to be no more than 85 mm, and an outer diameter of the face gear is no less than 40% of this distance. An inner diameter of the face gear is no less than four times the distance between the axial center of the pinion gear and the axial center of the face gear.

1. Field of the Invention
The present invention relates to a spinning reel, and more particularly to a spinning reel having a screw shaft for reciprocating a spool disposed on the spinning reel.
2. Description of the Related Art
A spinning reel typically includes a reel main body, a rotor rotatably supported by the reel main body, and a spool supported by the reel main body. Fishing line is wound around the outer periphery of the spool.
The reel main body is equipped with a handle and a handle shaft, with a face gear fixed to the handle shaft. The face gear is meshed with a pinion gear, with an end portion of the pinion gear fixed to the rotor. An intermediate gear is fitted to an end portion of the screw shaft and is meshed with the pinion gear. An end portion of the pinion gear is supported by a bearing portion and is disposed within the circumference of the face gear. A slider is engaged with a spool shaft, and the screw shaft moves the slider along the screw shaft, thereby reciprocating the spool and the spool shaft.
The rotor includes a pair of bail supporting arm portions, with a bail and a line roller for guiding the fishing line around the outer periphery of the spool being disposed between both the bail supporting arm portions.
With this type of spinning reel, when the handle is rotated by the user, the rotor spins around the periphery of the spool and the spool reciprocates, thereby allowing the fishing line to be uniformly wound around the outer periphery of the spool.
The type of spool reciprocating mechanism described above allows the range of reciprocal motion of the spool to be increased without increasing the diameter of the face gear or the overall size of the reel body. However, when the diameter of the face gear is small, the gear ratio is such that operation of the handle is often not optimal. In other words, a spinning reel with a smaller face gear requires the user to apply more force to spin the rotor than a spinning reel with a larger face gear.
It is desirable for an end portion of the pinion gear to be supported by a ball bearing mechanism, so that the force needed to spin the rotor could be reduced. However a small face gear does not provide sufficient space for a ball bearing mechanism to be disposed at the end portion of the pinion gear adjacent to the face gear.

Spinning reel having a roller-type one-way clutch


A method for treating a subterranean formation penetrated by a wellbore that includes injecting an alkali silicate into the wellbore; injecting a solid micronized silicate-precipitating agent into the wellbore; and allowing the alkali silicate and the solid micronized silicate-precipitating agent to react to form a silicate gel is disclosed.

1. Field of the Invention
Embodiments disclosed herein relate generally to wellbore fluids that may include silicate-based additives for stabilizing an unconsolidated formation.
2. Background Art
Hydrocarbon fluids, such as oil and natural gas, and other desirable formation fluids are obtained from a subterranean geologic formation, i.e., a reservoir, by drilling a well that penetrates the formation zone that contains the desired fluid. Once a wellbore has been drilled, the well must be completed. A well "completion" involves the design, selection, and installation of equipment and materials in or around the wellbore for conveying, pumping, or controlling the production or injection of fluids. After the well has been completed, production of the formation fluids can begin.
When the subterranean formation is "soft" or poorly consolidated, small particulates (typically sand) present in the formation may dislodge and travel along with the produced fluid to the wellbore. Production of sand is highly undesirable as it tends to cause erosion of surface and subterranean equipment, and therefore, it must be removed from the produced fluids before they can be processed. In addition, the migrating sand can plug the flow channels in the formation, thereby necessitating other stimulation techniques, such as acid stimulation, to restore the well's performance.
Various types of unconsolidated formations include dune sands, alluvial deposits of sand and gravel, and unconsolidated marine deposits. The challenges in drilling and completing wells in these types of formations are to keep the borehole open and prevent caving, and to avoid reducing the hydraulic conductivity of the near-well formation by introducing irrecoverable mud or smearing clay at the well/aquifer interface during the drilling process. Drilling fluids for unconsolidated formations are typically water-based and generally include clean fresh water, water with clay additives, water with polymeric additives and water with a mixture of clay and polymeric additives.
One method of controlling loose sands in unconsolidated formations involves placing a filtration bed of gravel near the wellbore in order to present a physical barrier to the transport of unconsolidated formation fines with the production of hydrocarbons. Typically, such so-called "gravel packing operations" involve the pumping and placement of a quantity of a desired particulate into the unconsolidated formation adjacent the wellbore. Such packs are time consuming and expensive to install.
Another method used to control loose sands in unconsolidated formations involves consolidating or stabilizing the unconsolidated subterranean producing zones into hard permeable masses by pre-flushing the formation, applying a hardenable resin composition, applying a spacer fluid, applying an external catalyst to cause the resin to set, and applying an afterflush fluid to remove excess resin from the pore spaces of the zones. Such multiple-component applications, however, often result in uncertainty and create a risk for undesirable results. For example, when an insufficient amount of spacer fluid is used between the application of the hardenable resin and the application of the external catalyst the resin may come into contact with the external catalyst in the wellbore itself rather than in the unconsolidated subterranean producing zone. When resin is contacted with an external catalyst an exothermic reaction occurs that may result in rapid polymerization. The polymerization may damage the formation by plugging the pore channels, may halt pumping when the wellbore is plugged with solid material, or may even result in a downhole explosion as a result of the heat of polymerization. Also, using these conventional processes to treat long intervals of unconsolidated regions is not practical due to the difficulty in determining if the entire interval that has been treated with both the resin and the activation agent.
These techniques typically involve the injection of a consolidating fluid, such as a resin-based consolidating fluid, through the wellbore and into the formation surrounding the interval of interest. Resin-based consolidating fluids generally include an organic resin, a curing agent, a catalyst and an oil wetting agent. The resin system hardens in the formation, thereby consolidating it. Examples of such resin-based consolidating fluids and methods for using them are described in, for example, U.S. Pat. Nos. 4,291,766; 4,427,069; 4,669,543; 5,199,492; and 5,806,593. Resin-based consolidation systems may be complicated to apply, especially those involving multiple treatment stages, and the treatment results may be erratic. When the individual components of the consolidating fluid are pumped at different stages into the formation they may or may not come together in the right order, or in the right amounts, or they may not even come together at all. And, even when they do come together, good mixing of the components is not assured, helping to explain the erratic and unreliable results that operators have experienced using such multi-stage consolidating fluids.
In an effort to improve performance, other well treatments have been proposed which use inorganic systems, specifically the use of components which form silica gels, to modify the formation and thereby reduce the production of formation fines. For example, U.S. Pat. No. 3,593,796 describes a multi-stage process in which the following components are injected sequentially into the formation: (1) an aqueous solution containing a silicate adapted to wet the fine sand grain particles, (2) an aqueous solution of a silicate-precipitating agent capable of reacting with the silicate in solution (1) so as to form a solidifying material and therein to bind the fine sand grain particles, and (3) a solution containing an oil-wetting agent. This treatment is designed to immobilize the fine particles in the formation and prevent their migration when subjected to subsequent fluid flow. The patent states that aqueous solutions of alkaline earth metal salts (e.g., calcium chloride), acidic iron salts, and certain other metal salts can be used as the silicate-precipitating agent.
In another instance, U.S. Pat. No. 3,741,308 describes a method of converting an unconsolidated sand formation into a consolidated, permeable formation by flowing volumes of aqueous calcium hydroxide (or compounds which hydrolyze or react with each other to form calcium hydroxide) through the pores of the unconsolidated formation. The patent states that the calcium hydroxide solution could be formed by adding sodium hydroxide to a solution of calcium chloride. The patent also states that during the practice of the process the sand particles in the formation become coated with calcium silicates of unknown or indefinite composition, and proposes that the coating cements the individual grains together and increases the structural strength of the sand assemblage.
Yet another approach has been described in two companion cases (U.S. Pat. Nos. 5,088,555 and 5,101,901). In U.S. Pat. No. 5,088,555, a sand consolidation method was described involving sequential injections of (a) an aqueous solution of an alkali metal silicate and (b) certain organic solutions of a calcium salt (e.g., calcium chloride hydrate or chelated calcium) through perforations in the casing of a borehole. The components of these two solutions are said to react to form a calcium silicate cement with permeability retention characteristics in the formation interval being treated that prevents sand from being produced during the production of hydrocarbon fluids from the well.
However, the use of a silicate-precipitating agent that is in solution may give rise to short gellation times upon contact silicates. Accordingly, there exists a need for consolidation or stabilization methods which allow for longer and/or controllable gellation times.

Silicate-based wellbore fluid and methods for stabilizing unconsolidated formations


A personal eyeglass and head gear retainer system to protect the user thereof from the loss of such items. The system comprises, in combination, a conventional style head gear, preferably in the form of a baseball cap or a sun visor, where the head gear features a discontinuous peripheral rim, and conventional style eyeglasses, such as sunglasses. Included in the combination is a pair of flexible cords of a discrete length and joined together at an intermediate position along the lengths. A first end of each cord is secure to the peripheral rim of the head gear, and a second end is secured to a respective free end of the eyeglass ear supports.

The present invention is directed to a personal retainer system, such as for head gear and eyeglasses, that may be worn by a user on a windy day where one's hands may not be free to hold a fleeting cap or remove and hold eyeglasses. Such a system can be particularly valuable to a sport fisherman, or even a golfer whose hands are generally occupied with his/her chosen activity.
Eyeglass retainers, in the form of a chain worn about the neck and removably secured to the ear stems of eyeglasses, are quite common today. However, there are no known systems or devices that can perform the dual function of allowing one to remove and conveniently position the eyeglasses on one's chest, while also protecting against the loss of a cap, for example, that might occur on a windy day.
U.S. Pat. No. 5,778,448, to Maher, teaches an assembly for removably attaching sunglasses to the bil of a baseball cap. The assembly comprises a flexible main frame bridge which has hinges with teeth, a pair of clamps which grip the bill of the cap and which are adjustable by means of teeth interlocking with the teeth on the hinges, and a clamp which fits the main frame bridge and allows the sunglasses to be flipped up or down. While the assembly thereof appears to recognize the need for a user to have a sun protecting cap in combination with sunglasses, it does not provide an assembly to protect against losing same on a windy day.
The manner by which the system hereof provides such protection, particularly for a person whose hands are occupied, will become apparent to those skilled in the art from the following specification, especially when read in conjunction with the accompanying drawings.


A data feed server configured for tracking usage of a data feed includes a data feed server configured to respond to polls from client computers and transmit a data feed in response to a poll from a client computer. The data feed server is further configured to received usage data from a client computer that indicates usage of the data feed at the client computer. A client computer for accessing a data feed includes a client computer configured to communicate with at least one data feed server that publishes a data feed. The client computer selectively polls the data feed server for the data feed. The client computer is further configured to record usage data indicating usage of the data feed at the client computer and, in a subsequent polling of the data feed sever, report the usage data for the data feed to the data feed server. A method of determining usage of a data feed includes collecting information with a data server that indicates whether a data feed provided by the data server was accessed by a user at a client computer to which the data server had transmitted the data feed.

The present invention relates to a method, apparatus and software for collecting usage data for one or more data feeds. Specifically, the present invention relates a computer system comprising a set of client computers connected via a network to a server computer wherein the server computer and the client computers may be arranged in conjunction with software for providing data feeds from the server computer to any of the client computers over the network and wherein the usage data for one or more data feeds may be determined and logged.
Data feeds are a mechanism that enables data users or subscribers to receive periodically updated data from a data source or publisher. Data feeds enable a data publisher to disseminate regularly updated data to a large number of data subscribers in an efficient manner. The data may, for example, comprise news, message or financial data and be provided over a network such as the Internet. Data feed protocols commonly operate by the data subscriber or client periodically polling the data feed source for updates to a given data feed. A number of protocols exist for data feed services such as the Really Simple Syndication (RSS) protocol, the Atom Syndication Format (ATF) protocol, or the Resource Description Framework (RDF) Feeds protocol. Data feeds may also be implemented in other network protocols such as the Hypertext Transfer Protocol (HTTP).
Current data feed mechanisms enable subscribers to subscribe to a given feed anonymously. Furthermore, the same data feed subscriber may repeatedly poll the same data feed source regardless of whether or not the user has not viewed the data feed. Thus, it is difficult for a data feed publisher to determine usage statistics for a given data feed.

INTERNATIONAL BUSINESS MACHINES CORPORATION


An exercise balance board may have at least a platform for a user supported by a resilient, air-filled partial sphere. It contains features which allow users of any size or fitness level to properly exercise muscle groups. The balance board allows a user to exercise upper and lower muscle extremity groups either individually or simultaneously.

Exercise devices have been invented to address various situations. These devices share the general purpose of increasing strength, balance, or ability for a particular sport. Many of the devices incorporate a balance ball or half-ball of some sort, either with or without a board disposed on the ball, and with or without components that allow arm exercises. The devices are generally designed for average sized adults and are difficult to adjust to accommodate taller people, children or smaller than average adults. As far as the user's reach and ability to adjust the arm exercise portion of the devices, devices of this type currently on the market are not adjustable. They also may be limited in the types of exercises a user can do, and in the range of muscle groups that can be strengthened using the devices. Many of the more popular devices related to the current invention are not adjustable. The present invention has a unique feature in that it has a visual aid to allow a user to easily determine the level at which the balance ball component has been adjusted, and it allows a range of adjustments for arm exercises.
Examples of related art are described below:
U.S. Pat. No. 4,787,630 pertains to an exercise device including rotatably interconnected base and platform assemblies. The base assembly is adapted to rock back and forth on a floor or other horizontal surface and a person using the device stands, sits, kneels or lays on the platform assembly. The device is adjustable whereby the permitted range of movement can be widely varied. Ropes, springs, elastic cords or poles can be grasped by a person using the device for balance and for upper body exercise.
U.S. Pat. No. 7,112,168 pertains to balancing equipment that provides a selectively dynamic platform for an individual thereon. The weight and movement of the individual causes the platform to tilt in any direction, thereby attempting to throw off the balance of the individual, causing the individual to work on maintaining balance while on the dynamic platform. The dynamic nature of the platform can be adjusted to correspond to the balancing abilities of individuals. An adjustment mechanism increases or reduces the amount the platform is able to tilt, without requiring the raising or lowering of any component of the platform. An exercise mechanism can also be connected to the platform
U.S. Patent Application 2004/0087421 pertains to an exercise balance trainer that includes a hard board and a resilient ball body connected to the board. The ball body has a first curved wall with a first rim, a second curved wall with a second rim connected fixedly to the first rim so as to define an air-receiving chamber between the first and second curved walls, and an annular flange connected to the board and a junction of the first and second rims. The first and second rims have the same diameter. The first curved wall has a maximum height that is not greater than one-half of the diameter of the first rim. The second curved wall has a maximum height that is not greater than one-third of the diameter of the second rim.
U.S. Patent Application 2011/0143896 pertains to an exercise device, and more particularly a combination balance and stability training and resistance training exercise device, comprising a platform and a balance element. The exercise device can also comprise one or more resilient, elongate resistance training elements for resistance training. The exercise device can be provided with a stabilizing device. When removed from the stabilizing device, the exercise device can be used in a manner similar to a conventional balance board. When mounted on the stabilizing device, the exercise device is supported in a stable orientation for performing exercises requiring a stable and balanced support surface.
None of the art described above addresses all of the issues that the present invention does. This invention includes a rigid elongated platform, similar to a snowboard platform, which is joined to a resilient balancing element. The user stands on the rigid elongated platform and moves in the manner desired for the exercise desired. The resilient balancing element is approximately a half-sphere made of a material such as rubber and is preferably filled with air. The pressure and therefore the level of exercise difficulty can be adjusted by adjusting the air volume.
The present invention is unique in many aspects. It can be easily adjusted for use by a variety of users, both in body size and shape and in age or fitness level. The present invention includes an attachment for a specialized handle, so it may be used by a handicapped person or by someone whose hand is crippled with arthritis. The present invention also allows a user to perform isolation techniques to stabilize or challenge a particular muscle group. No other device in the related art can do this for therapeutic or home use. In addition, the present invention allows a user to attach an auxiliary board, such as a snowboard, to the device. Thus an athlete can use his own snowboard to practice with and hone his technique.
The present invention also includes flexible elements with handles that a user can grasp with his hands for added balance or arm exercises. There are multiple flexible elements disposed in varying distances from the user's core, such that a user can choose the ones most appropriate to his arm length, exercise type, etc.
When compared with other devices of the same nature, the present invention provides a user with a larger surface area on which to plant his feet; this allows a user to practice the correct stance for any sport or activity. For instance, if a basketball player wants to strengthen his knees and practice a pivot type of movement with his feet spread on the device, he would have ample room to do so. Other devices in the art don't allow for this because they're not long enough. In addition, the present invention includes an embodiment that allows for lengthening the device, so a tall person could easily use it. This also enables a user to attach an auxiliary device, as the rigid elongated platform allows ample room for this, and is easily extendable if necessary.
Another feature that adds to the uniqueness of the present invention is the visual indicator of difficulty levels. The outer surface of the resilient balancing element has a series of patterns disposed on it. The patterns run horizontally across the surface and indicate the level and distribution of pressure in it. Thus, if a novice user desires a lower pressure so the resiliency is lessened, he can easily see from the patterns how inflated the resilient balancing element is. This may encourage a reluctant user to use the device, as he can more easily discern the level of difficulty. Although the related art has features that are adjustable, they are more difficult to adjust and it isn't easy to determine at a glance the level of the adjustment.
The adjustable feature of the resilient balancing element also allows it to be suitable for use by children, the elderly or a very weak person; the resilient balancing element can be deflated to a very low pressure for maximum ease of use, and the flexible elements with handles can also be employed. As the person gains strength and balance, the pressure and thus difficulty level in the resilient balancing element may also be increased.
Another feature of one embodiment of the invention that is unique to this type of device is a stability skirt. The skirt provides reassurance and stability for a user trying to balance or move on the invention.
Other unique features include sensors on the invention that can read a user's physical parameters through his or her feet while the user is standing on the platform and doing exercises. This allows the trainer or user to make real-time adjustments based on real-time measurements such as heart rate, and also to measure parameters such as BMI, weight, and percent body fat. The ability of the board to vibrate through the use of integral or removable vibration devices adds a therapeutic element for people with diseases such Parkinson's and cystic fibrosis, and it aids in increasing muscle growth.
The presence of multiple flexible elements disposed at differing distances, both horizontally and vertically along the rigid elongated platform, allows the user to choose flexible elements that are in the proper position for his arm reach and exercise. This allows the user to perform upper extremity movements in proper biomechanical form. The flexible nature of the flexible elements also decreases stress on the user's joints.
One difference between the present invention and the related art is evident in the placement of the multiple flexible elements in relation to the rigid elongated platform. None of the related art described above allows for matching the position of the flexible elements to the user's arm reach; thus, exercises may be done at the wrong angle and may cause injury, or may fail to exercise the desired muscle group in the desired manner.
The present invention thus solves a number of issues that other devices in the field don't, as it is novel and unique to the field.

Agility and strength improvement apparatus


A thermoplastic cable and method of manufacture for use in an electrical system comprising a core which comprises a transmission medium, said transmission medium being an insulated metallic conductor or optical fiber, and a jacket which encloses the core and the jacket being co-extruded on the core and comprises an extruded inner layer and an extruded outer layer, with the inner layer being inseparable from and integrally formed with the outer layer.

Outdoor cables or cords are generally manufactured with a glossy jacket finish. However, due to a common user perception, such a finish is synonymous with low cost electrical and electronic products. Matte finishes, on the other hand, have a user perception of being synonymous with quality electrical and electronic products. These matte jacketed cables are typically used indoors as, for example, power supply cords. While these matte jacketed cables conform to consumer demands on appearance and are suitable for indoor use, they do not satisfy the minimum sunlight resistance and low temperature performance while maintaining tensile and elongation requirements of standards organizations, such as Underwriters Laboratories, Inc. (UL) or Canadian Standards Association (CSA), which are necessary for the outdoor usage of cables. Thus, current techniques and materials produce cables that exhibit either a glossy (high luster) appearance or a matte finish that fails to meet the necessary UL and CSA requirements for both indoor and outdoor use.


Provided are systems and methods for maximizing saturation of two different sets of actors performing different sets of dependent operations at different rates over different but overlapping periods of time in a non-conflicting manner. The systems and methods may include transferring a first set of ordered items from item storage to item cache locations at a first rate during a first period of time, and fulfilling orders at a faster second rate over a later second period of time by picking items from a first set of the item cache locations at the second rate, and by replacing items at a non-overlapping second set of the item cache locations at the first rate. The transferring is commenced before the picking to create a buffer that allows a first set of actors, operating at the first rate, to continually provide the dependencies needed for a second set of actors to operate at the faster second rate without conflict and with each set of actors operating at their respective maximum rates.

Order fulfillment in a warehouse or other site may involve at least two different sets of operations that are performed by two different sets of actors. The first set of operations may include retrieving different items of an order from storage locations within the site to a packing station. The second set of operations may include aggregating and/or packing the retrieved items of the order into a common container at the packing station.
Traditional workflows have resulted in inefficient usage of the actors performing the retrieval, packing, and/or other operations associated with order fulfillment. For instance, a first actor may travel across a site in order to retrieve and aggregate different items for a first order, and a second actor may travel much of the same path in order to retrieve and aggregate some of the same or different items for a second order. Similarly, the first actor may move to opposite ends of the site in order to retrieve the items of the first order, even though second and third actors may already be located at the opposite ends of the site and may be performed retrieval operations for different orders.
To prevent some of the inefficiencies described above, the retrieval and packing operations may be divided between different sets of actors. However, having one set of actors exclusively perform one set of operations and another set of actors exclusively perform another set of operations can lead to other inefficiencies. For instance, a first set of actors may complete operations at a faster rate than a second set of actors and the operations may include dependencies such that the first set of actors are left waiting for the second set of actors to complete their operations before the first set of actors can perform additional operations. As a specific example, a first actor may aggregate and pack items faster than one or more actors retrieve and deliver the items. In this example, the first actor operates in bursts rather than in a continuous manner because the first actor is dependent on the one or more other actors completing their operations first. Conversely, a first actor may retrieve and deliver a tote carrying multiple units of a particular item to a second actor, but the first actor may have to wait for the second actor to finish picking different items from another tote before the second actor can begin picking items from the tote delivered by the first actor. The first actor may wait until the second actors completes its picks from the tote before returning the tote to its storage location. In this case, the first actor may spend indeterminate amounts of time waiting in a queue because of the different rates at which the first and second sets of actors operate.
In the examples above, the inefficiencies stem unbalanced execution of dependent operations by different actors. The loss in efficiency results increased costs, lowered overall productivity, and unnecessary resource utilization.


Systems and methods for fueling (or charging) communication, for example between a hydrogen fueling station and a hydrogen powered vehicle (or an electric vehicle and charging station) may utilize near field communication as well as vehicle to infrastructure communication. Safety information, fueling or charging information, payment information, and other information may be transmitted, and the redundant nature of the communication permits fault recovery and improved process monitoring. In this manner, fueling and/or recharging is made safer, faster, and more efficient.

Typical approaches for fueling surface vehicles (e.g., automobiles) with gaseous hydrogen operate under safety standards set by SAE International, which standards include, for example SAE J2601 (Fueling Protocols for Light Duty Gaseous Hydrogen Surface Vehicles) and SAE J2799 (Hydrogen Surface Vehicle to Station Communications Hardware and Software). Under such standards, data concerning the fueling operation (e.g., temperature and pressure within and volume of a vehicle fuel tank) is typically provided to a hydrogen fueling station from a vehicle being fueled via a unidirectional communication approach utilizing an Infrared Data Association protocol (IrDA protocol). However, approaches using the IrDA protocol fail to satisfy meaningful risk classification levels on the station side under, for example, the Safety Integrity Level (SIL) or the Automotive Safety Integrity Level (ASIL) and should not, therefore, be relied upon in assessing risk for hydrogen fueling. Accordingly, improved communication systems and methods, for example for use in connection with fueling of hydrogen vehicles, remain desirable. Similarly, improved communication or safety approaches usable in connection with charging of electric vehicles remain desirable.

Communication systems and methods for hydrogen fueling and electric charging


A pet-play apparatus (20) for interactive use with a domestic cat or other pet (24) incorporates a lash (26) made of a strip of fake fur (56) formed into a tube (42) with a nap (58) of the fake fur (56) upon an external surface (60) of the tube (42), a crop (22) coupled to a first end (32) of the lash (26), a toy (28) detachably coupled to a second end (36) of the lash (26), and a sonic device (86) coupled to the crop (22) and configured to produce a prey-sound for the domestic cat or other pet (24) in the form of a chirp or squeak in response to a movement of the crop (22). A first attachment device (62) is affixed to the second end (36) of the lash (26) and incorporates a hook part (70) of a hook-and-loop fastener (88). A second attachment device (64) is affixed to the toy (28) and incorporates a loop part (72) of the hook-and-loop fastener (88), the hook and loop parts (70, 72) being detachably coupled to each other.

There are many pet-play apparatuses for interactive use between a pet and its owner utilizing a crop-lash-toy design approach. Pet-play apparatuses of this type stimulate the hunting and pouncing instincts and are most often used with small carnivorous pets, such as cats, ferrets, toy dogs, and the like.
Conventionally, such pet-play apparatuses are manufactured using string, twine, elastic cordage, monofilament line, picture wire, or other string-like materials as the lash. This poses several inherent dangers to the pet.
When a lash is formed of a string-like material, the pet may chew and ingest this material. Once ingested, this material can bind in the pet's intestines, resulting in intestinal distress, or even death. This is especially true of cats, which instinctively chew, sever, and ingest the lash.
Additionally, the chewing of some of these materials, especially monofilament line and picture wire, may chip or otherwise damage the pet's teeth, especially the carnassial teeth, may produce gomphiasis, and may lacerate the gingiva. All such conditions are injurious and/or unpleasant for the pet and potentially expensive for the owner.
Also, the pet may become entangled in the lash during play. This entanglement may cut off the flow of blood to a portion of the body or, if around the neck, may cut off the flow of air. A pet so entangled will typically panic, exacerbating the entanglement. If not freed, the pet may be strangled or risk permanent injury or death from loss of blood flow.
Many such pet-play apparatuses use an attachment device in the form of a clip, ring, or button to attach the lash to the suspended toy. This is especially true of those pet-play apparatuses where the toy is separable from the lash and may be used as an independent toy for solo use by the pet. In such an attachment device, the clip, ring, or button is often made of a hard plastic or metal.
Such devices may be bitten or chewed free or may simply break free during play. Furthermore, chewing of plastic devices may distort and break off pieces thereof, often leaving sharp edges and corners. Ingestion of these devices or portions thereof exposes the pet to several dangers. Choking may occur if the size, inflexibility, shape, and/or sharp edges of the object inhibit swallowing. Blockage, laceration, and/or perforation of the esophagus, stomach, or intestines may occur, especially if the object or object portion has sharp edges or points. Peritonitis may occur as a complication of perforation. Since many plastics and metals are either inherently toxic or produce toxic substances when exposed to acids (i.e., digestive fluids), poisoning is a distinct possibility. In addition, biting or chewing an attachment device formed of metal or hard plastic may chip or otherwise damage the pet's teeth, especially the laniary and carnassial teeth, may produce gomphiasis, and may lacerate the gingiva. All such conditions are unpleasant, injurious and/or possibly fatal to the pet. The correction of such conditions, where possible, is potentially expensive for the owner.
What is needed, therefore, is a pet-play apparatus of the crop-lash-toy type that is formed of materials that are not potentially injurious to the pet.
Many pets rapidly tire of the simple crop-lash-toy apparatus. It is therefore desirous that additional stimulation be provided. This additional stimulation extends the period of pet interest, thereby allowing for a more thorough workout for the pet and a marked increase in enjoyment for both the pet and the pet owner.
Also, pets often catch the toy of a conventional crop-lash-toy apparatus. When caught, the toy is subject to clawing and/or chewing, which markedly reduces the useful life of the toy. This is especially true of cats, as their natural instinct is to arrest movement of their prey through the use of their claws and teeth. It is therefore desirous that the toy be easily replaced without necessitating replacement of the entire apparatus.

This patent is subject to a terminal disclaimer.

Pet-play apparatus configured for interactive use


Expendable video camera cover for medical use comprises a sleeve-shaped cover means shaped such as to cover a video camera and its electrical cable, and rigid ring-shaped case means for holding the cover means therein. The case has a generally U-shaped cross-section with its outer and lateral sides closed and leaving a central hole open, and the cover means is contained in said case in a tightly packed state resulting from the cover means having, first, one of its ends fixedly attached to said case, and second, the rest of the cover means being gradually crushed against the outer and lateral sides of the case means such as to leave a central hole in the cover means in its packed state, and leaving the second end of the cover means free. A process for manufacturing a video camera cover comprises the steps of attaching one side of a sleeve-shaped cover means to a rigid case; inserting the rigid case with one end of the cover means attached thereon to a pole mounted on a base, so that the cover means can be inserted into the case; and gradually crushing said cover means into that case.

This invention relates to video camera covers, and more particularly to such covers which are sterile and include means for covering video cameras for medical use.
Heretofore, various devices and methods have been devised to sterilize the video cameras used in operation rooms or for other medical purposes. Medical equipment may be sterilized by the use of chemical or physical agents, for example using hot steam, gas or gamma rays sterilization. These means may not be appropriate for the delicate video camera.
A more convenient sterilization means uses expendable sterile covers wrapped around the medical equipment. The expendable cover or drape is used only once; it is removed and thrown away after use. Until now, it was difficult to cover the video camera and cable, since a long sleeve is required (about 250 cm or more). It takes time to unwrap the sleeve; handling the long sleeve during the covering process may be difficult. Moreover, special care has to be paid so that no part of the sleeve should touch any nonsterile surface, for then the sleeve is no more sterile and does not protect the patient or the medical staff. Sterile covers known in the art are folded to a bulky package, which is difficult to store and to handle.
For example, Adair Edwin, U.S. Pat. No. 5,433,221, details a windowed self-centering drape for a surgical camera. The drape includes a generally cylindrical body portion and a flexible and elastic distal end. The proximal end of the body portion may include either a roll fold or an accordion fold in order to reduce the size of the drape for storage prior to use.
Lemke Norbert, U.S. Pat. No. 5,419,313, details a microwave sterilizable and reusable endoscope which has an objective arranged at its distal end, the image of which a relay-lens system conveys to the proximal end of the endoscope a light guide at least partially surrounds the relay-lens system and the objective, and conveys illumination light of an illumination light source from a light-entry connection to the distal end. The light guide is provided with a hollow-cylinder made of a transparent and optically clear material which surrounds the objective and the relay-lens system. The light from the illumination light source can be coupled into the circular front face of the hollow cylinder.
Szabo Steve, U.S. Pat. No. 5,325,846, details an endoscopic draping apparatus and method which allows operating room personnel to easily and expeditiously drape an endoscope. The drape is preferably made of polyethylene or some other suitable plastic material. The cylindrical drape cartridge itself acts as a shroud and functions as a sterile barrier. The drape cartridge consists of an inner and outer polyethylene tube which retains the polyethylene drape within its walls. The proximal end of the cartridge is mechanically secured by detents and a chamfer that encase a corrugated pattern of the polyethylene drape. The inner tube acts as a mandrel, allowing the drape to be compressed in a manner that accommodates the various lengths of required draping while lessening the bulk of the draping system.
Lafferty et al, U.S. Pat. No. 5,301,657, detail a disposable sterile sleeve which is removably attachable to a video camera of an arthroscope. The sleeve comprises a flexible elongate tubular shroud and a rigid annular mounting collar. The shroud is open ended with the collar rotatably attached to one open end by a connector member providing independent rotation of the collar relative to the shroud. A pull tab is attached to the opposite open end of the shroud to facilitate extension of the shroud over the camera. The sleeve may be compacted for storage prior to use by tightly scrunching the shroud together, thereby folding it onto itself. To attach the sleeve to the camera, the video camera is inserted through the compacted shroud until it engages the collar. A male thread provided on the camera is threaded into a female thread provided on the collar and the shroud is then extended over the camera by pulling on the tab to draw out the folds in the shroud.
Dunn James, U.S. Pat. No. 5,274,500, details a surgical drape for an endoscopic video camera device which provides a sealed, sterile encasement of the camera and its associated transmission cable and which permits quick, easy interchanging of various endoscopic rod lenses without contamination of the camera head or cable or distortion of the camera image. More particularly, it is concerned with a drape having an opening for insertion of a camera and cable, a clear lens, and structure for constricting the drape around the camera and cable.
Adair Edwin, U.S. Pat. No. 5,251,613, details a videoscope which can easily be used by the doctor to examine the cervix and vagina for cancerous lesions or other abnormalities. The video camera unit can be removed from the speculum and inserted into a sterile sheath for reinsertion into the vagina for examination for lesions and areas covered by the speculum blade. It can also be inserted into the colon and other body passageways where lesions are suspected. The video camera unit can be removed from the sheath, resterilized or disinfected and reattached to a sterile speculum for use with another patient.
Hicks John, U.S. Pat. No. 5,198,894, details an endoscope having a sleeve-like drape secured in a retracted position at the proximal end of the endoscope. The proximal end of the endoscope is secured to a CCD camera, the drape is extended to telescope over and envelope the camera such that the resulting outer surface of the drape in its extended position remains sterile.
Kurtzer Stephen, U.S. Pat. No. 5,168,863, details an apparatus for providing a sterile operating environment for endoscopic diagnosis and/or surgery. A covering comprises a pair of generally orthogonally arranged component bags. Each of the component bags is of an accordian-like extendible type. The component bags are joined adjacent the open end of one bag and an aperture adjacent the open end of the other bag. The open end of the second bag is engaged either to a sterile endoscopic probe preferably of the disposable type or to a shield for enclosing the distal end of an endoscope. The entire apparatus is sterilized and configured so that the component bags can be extended along the camera and light guide cables of the endoscopic system so that resistant spores, bacteria and viruses cannot contaminate the open incision.
Disadvantages of these devices and methods include the difficulty in covering the video camera and the bulky package.


Embodiments of the invention include a method and apparatus for determining values for data reproduced or retrieved from data storage media such as in holographic memory systems. The method includes initially approximating the value of data members retrieved initially from the data storage medium of interest (e.g., by their intensity levels based on an absolute scale), using those approximations collectively to establish one or more threshold levels for defining ranges for the data values to be determined, and determining values for the retrieved data members by comparing the initial data value approximations of the retrieved data members to the established threshold levels. Alternatively, the threshold level(s) are set initially and adjusted iteratively based on the initial approximations of the individual data members until a final established threshold level is established. Advantageously, embodiments of the invention reduce data encoding overhead by using data members to establish comparative threshold levels for the determination of their intended values.

1. Field of the Invention
The invention relates to data value determination. More particularly, the invention relates to determining the values of data retrieved from data storage devices such as holographic memory devices and other data storage media.
2. Description of the Related Art
Accurate retrieval or reproduction of stored data from data storage media has been important to the development of data storage systems such as holographic memory systems. Typically, a holographic memory or data storage system involves three-dimensional storage of holographic representations (i.e., holograms) of data members as a pattern of varying refractive index and/or absorption imprinted in a storage medium such as a crystal of lithium niobate. Holographic memory systems are characterized by their high density storage potential and the potential speed with which the stored data is randomly accessed and transferred.
When stored data is to be recalled, detector arrays are used for reading the information emerging from the memory pages. Typically, the recalled holographic information is projected onto an imaging unit such as a charged coupled device (CCD) or a CMOS detector array such as an active pixel sensors (APS), which are sensitive to the emerging optical information. A decoding unit coupled to the imaging unit then determines the corresponding values of the data initially encoded and holographically stored.
However, reproduction of stored data in holographic storage devices is less than ideal due to effects often inherent in holographic memory systems. For example, the number of data members imprinted in the storage medium typically is inversely proportional to the diffraction efficiency and thus the reliability of the holograms stored therein to be reproduced upon read out. Other factors often affecting the quality of the stored data include time-dependent fluctuations in light intensity throughout the storage medium, physical and optical disturbance of the mechanical relationship between system components, thermal expansion and other temperature-induced variations throughout the system, and other noise introduced into the system.
Because of the often poor quality in retrieving or reproducing such data, the value of a data member often is represented by comparisons of multiple data members. For example, it is possible to employ some sort of differential encoding scheme, in which a particular data value sought to be retrieved results from the comparison of one data member to another. Alternatively, it is possible to use a reference encoding scheme, in which the value of a data member is compared to one or more known reference data member values. See, for example, U.S. Pat. No. 5,450,218 and U.S. Pat. No. 5,838,469 entitled "Apparatus And Method For Processing Data Stored In Page-Wise Memory", filed on even date herewith.
However, such encoding schemes require the use of more than one data member to represent the data value of a single data member. For example, in typical differential encoding schemes, a single data value is based on the value of a first data member relative to a second data member. In this manner, two data members are needed to represent a single data value or data bit. Therefore, roughly half of the data members stored and retrieved from the storage medium are not actual data values but are "overhead" necessary for implementation of the encoding scheme. As such, the theoretical maximum data storage efficiency for conventional differential encoding schemes approaches approximately 50%.
In conventional local reference encoding schemes, an individual data value is based on the value of a first data member relative to one or more reference data members. In this manner, for every n data values represented, reference encoding schemes typically require at least approximately n+1, n+2 or even more data members. Thus, the data storage efficiency approaches (n/(n+2))% or (n/(n+1))%. However, due to the inherent variations in holographic storage media discussed above, in practice n typically is kept small so that existing variations are somewhat consistent for both the reference data members and those data members being compared to the reference data members.
Therefore, although encoding schemes exist for improving data storage efficiencies among, e.g., holographic and other memory systems, a need still exists for reducing overhead among data members stored within and retrieved from data such storage media.

Comparator-based thresholding method for determining data values


A device that tests the chronometric precision of a watch movement or a watch includes a control device controlling a predefined cycle of motions passing through standard chronometric test positions, and a fine control device including a sequencer arranged to control the changes of chronometric test position of this movement, or respectively of this watch, in a multi-position sequence, after each measurement per position, and to start another multi-position sequence as soon as the preceding sequence finishes and which observes the predefined total duration of one cycle of several successive multi-position sequences. This sequencer is also arranged to manage the rate stabilisation durations, durations of measurement per position, and multi-position sequence durations.

Testing the chronometric precision of a timepiece, particularly a watch, or of its movement, is essential to check the quality of the product released to the user. This testing is governed by official certification standards, established by recognized laboratories or observatories, which are unavoidable for placing products on the market.
Current chronometer tests measure the properties of the watch in static positions. Conventionally, tests are carried out in six test positions: two horizontal positions known as 'HH' (dial up—A), 'HB' (dial down—B) and four vertical positions: 'VB' (pendant down—C), 'VG' (pendant left—D), 'VH' (pendant up—E), 'VD' (pendant right—F).
Various acoustic measurement protocols are known to those skilled in the art.
A first type of measurement, called 0/24 hours, illustrated in FIG. 1, consists in taking measurements at 24 hour intervals, the first series with a fully wound mainspring, the second series after 24 hours of unwinding, each time in the six standard positions, with an acoustic measuring device, allowing a parameter 'm', consisting of the rate or amplitude, to be measured.
In this 0/24 hour measurement, the object to be tested (the watch, or movement, or watch head), which will be referred to hereinafter as a 'movement', is placed on the measuring device. A typical measurement is performed as follows: in the first position, 30 seconds of rate stabilisation, 2 minutes of measurement, then a change of position and the measurement is repeated in the remaining positions. This measurement, which takes several minutes in total, is performed with the mainspring fully wound ('0 h') and after 24 hours of unwinding ('24 h'). The movement is left on the workbench for 24 hours to wait for the mainspring to unwind, or the spring is unwound manually by a watchmaker by a number of turns equivalent to 24 hours of operation. The total measurement duration is short, since it is completed in approximately two times twenty minutes. However, no information is provided as to chronometric precision between the two measurements (instantaneous measurement).
To overcome this drawback, one solution consists in taking a measurement over 24 hours in each position, with the mainspring rewound at each change of position, as seen in FIGS. 2 and 3. The movement is placed on a measuring device similar to the 0/24 hour measuring device. A typical measurement is performed as follows: 30 seconds of rate stabilisation, 24 hours of measurement, then a change of position, winding the mainspring, and the measurement is then repeated in the remaining positions. The total measurement duration is long and takes 6 days. The advantage of this measurement over 24 hours is that it provides detailed information about chronometric precision between '0 hour' and '24 hours'. The drawback is, of course, the measurement duration, which results in a large number of parts undergoing testing, linked also to a large measurement database. FIG. 3 shows the superposition of the six measurements made in six positions, reduced to a single theoretical 24-hour cycle.
EP Patent Application No EP 3136189A1 in the name of ROLEX discloses a method for measuring chronometric precision and more specifically concerns the positions in which the watch or watch head is positioned during measurement. Chronometric tests simulate the various positions of the watch during a typical user's day.
EP Patent Application No 10192725 in the name of The Swatch Group Research & Development Ltd describes the chronometric tests using optical methods.


The present invention addresses two previously unresolved problems simultaneously. First, the question concerning the amount of heparin applied to a stent is resolved. That is, the invention set forth herein will demonstrate that by varying the amount of heparin, the practitioner can actually more adequately determine whether in fact the patient will receive the correct dosage to address the problem, and at the right time in which to address the problem. Second, the problem of applying the heparin coating to a stent is addressed. There, specifically, the invention turns to the fashion in which to apply multiple layers of heparin coating to the stent, and to thereby variably adjust the dosage applied to the patient at the lesion site. The present invention does so by providing a method and device for coating a stent with multiple layers of heparin coating. By so doing, the heparin coating is absorbed by the body in a degree which varies with the amount of heparin applied. Thus, contrary to formerly popular belief, the present method allows for the significant adjustment of heparin therapy. And, the stent so coated allows for the variable application of such heparin therapy at the lesion site.

The use of stents to hold open the lumens of blood vessels has become quite widespread. The Palmaz-Schatz stent marketed by Johnson & Johnson Interventional Systems of Warren N.J. has become universally recognized as the premier device for holding open occluded blood vessels, including the occluded coronary arteries. Nonetheless, the use of these stents is limited to a certain degree. That is, it is not always possible to prevent thrombosis arising near the lesion site, and there is always the possibility of occlusion of the lumen in the days following stent implantation. It would be desirable to provide the patient with protection against such undesirable events. This therapy, it is believed, helps to prevent early thrombus. Also, it appears that the heparin treatment will help to reduce the occurrence and the degree of restenosis.
With this in mind, there is a need for technology which will enable the interventionalist to apply heparin or other therapy to the surface of an implanted device in optimum degrees, But, the theory about such treatment has heretofore been an all or nothing approach. Simply, the interventionist believed that the amount of heparin applied and the nature of its attachment would not matter. There could be no middle ground. As this mindset set in, there simply would be no attention paid to researching the way to apply varying amounts of heparin, and, for that matter, whether the varying amounts of heparin on the stent actually could matter.

Stent and method of varying amounts of heparin coated thereon to control treatment


A water gate locker comprises a locker body, a bracket, a fastener-seat, a press-bolt, a position-ring, a nut. A position-slice is extended from one side of the locker body and a turning-axle is extended downward from the bottom of the locker body, and a thread is provided at the front end of the turning-axle, and a hole, with the upper portion larger than the lower, is provided on the locker body, and is penetrated through by a press-bolt, a screw-hole is provided at each side of the bracket, and a protrudent-cylinder is protruded upward from the middle of bracket, and an axle-hole is penetrated through the protrudent-cylinder, and two fastener-portions are penetrated beside the axle-hole, and a runner in an arc form with smaller diameter is penetrated between the two fastener-portions, a screw-hole is provided at each side of the fastener-seat, and a position-plate is extended upward from a side of the fastener-seat, and a position-runner is provided on a suitable portion of the position-plate, the turning-axle of the locker body is fitted in the axle-hole of the protrudent-cylinder of the bracket, and the locker body is integrated with the bracket via a nut, and the bottom end of the press-bolt is protruded from the runner of the protrudent-cylinder, and then a position-ring is combined with the bottom end of the press-bolt. Accordingly, the water gate locker according to the present invention is formed.

1. Field of the Invention
The present invention relates to a water gate locker, particularly to a water gate locker, in which a positioning device is installed in the locker body, which facilitates achieving the position of the water gate by using said positioning device.
2. Description of the Prior Art
FIG. 1 shows the structural schematic diagram of a conventional water gate locker, which mainly comprises a locker 11, a position-seat 12, and a fastener-seat 13, wherein the locker 11 has an extended position-slice 111 at one side thereof, combined with a position-seat 12, and connected with the position-seat 12 each other by using a position-bolt 112; a position-runner 131 is provided on the fastener-seat 13; when the user want to close the water gate, the user only needs to turn the locker 11 90° to allow the position-slice 111 of the locker 11 to be locked in the position-runner 131 on the fastener-seat 13, and thus achieving the positioning of the water gate. Although this mechanism can maintain the water gate in desired position, the user may dash against the locker 11 during marching or performing anything else, which may cause the position-slice 111 of the locker 11 to be separated from the position-runner 131 of the fastener-seat 13, and thus the object of using the locker 11 to position the water gate cannot be achieved.
Thus it can be seen, the above-mentioned conventional water gate locker still has drawbacks, not designed well actually, and need improved urgently.
In view of disadvantages derived from the above-mentioned conventional water gate locker, the present inventor had devoted to improve and innovate, and, after studying intensively for years, developed successfully a water gate locker according to the invention.


Systems and methods provide an ability to split multiple email addresses having the same email domain across a plurality of email service providers. A first email server receives a forwarded email message from a second email server, the forwarded email message including an original domain and an intermediary domain, the intermediary domain added by the second email server. The first email server removes the intermediary domain from the recipient address and delivers the email message to a corresponding email account that is serviced by the first email server.

The Internet comprises a vast number of computers and computer networks that are interconnected through communication links. The interconnected computers exchange information using various services. In particular, a server computer system, referred to herein as an email server, web server, server device, server, or the like, may receive connections through the Internet from one or more remote client computer systems, and may send to or receive from the remote client computer system one or more email messages. Further, the email server may connect with various other email servers or other server types throughout the Internet to effect the delivery of email messages either through sending outgoing email messages, receiving incoming email messages, or propagating email messages along to other email servers.
When an outgoing email message is to be sent, an email server checks the email address domain in the recipient address (e.g., "example.com" in the example email address "firstname.lastname@example.com") and queries a Mail Exchange (MX) record at a Domain Name Service (DNS) server to determine where to send the email message having that particular address domain. The MX record contains message exchange information and points to an "A" record in the DNS server, the A record containing at least one proper Internet Protocol (IP) address of the recipient email server to which the email message is to be sent. The DNS server will respond with at least one of the IP addresses in the A record. The email server then sends the email message to the recipient email server located at that IP address. The recipient email server for that particular recipient domain (indicated by the MX record), and more specifically, the Mail Transfer Agent (MTA) of the recipient email server, is subsequently tasked with determining the particular username or email inbox to deliver the received email message. Notably, the MX record does not distinguish between individual usernames or specific addresses within a particular domain.
Though suitable for some purposes, such a process does not meet the needs of all applications and settings because the structure of the MX record within the DNS allows only for a domain-level determination of where to send an email message. In this process it is not possible to establish multiple email addresses utilizing a single email domain where the multiple email addresses are spread across different email service providers. For example, a first email address, (e.g., email@example.com) cannot be serviced by a first email service provider while a second email having the same domain (e.g., email@example.com) is serviced by a second email service provider. Thus, organizations and individuals are limited to utilizing a single email service provider to service all email address or usernames within their domain.

System and methods for multiple email services having a common domain


An endoscopic imaging system (10) employing an endoscope (20) and an endoscope guidance controller (30). In operation, endoscope (20) generates an endoscopic video (23) of an anatomical structure within an anatomical region. Endoscopic guidance controller (30), responsive to a registration between the endoscopic video (23) and a volume image (44) of the anatomical region, controls a user interaction (50) with a graphical user interface (31) including one or more interactive planar slices (32) of the volume image (44), and responsive to the user interaction (50) with the graphical user interface (31), endoscopic guidance controller (30) controls a positioning of the endoscope (20) relative to the anatomical structure derived from the interactive planar slices (32) of the volume image (44). A robotic endoscopic imaging system (11) incorporates a robot (23) in the endoscopic imaging system (10) whereby endoscope guidance controller (30) controls a positioning by robot (23) of the endoscope (20) relative to the anatomical structure.

Minimally invasive surgery is performed using elongated instruments inserted into the patient's body through small ports. The main visualization method during these procedures is endoscopic imaging. In robotic guided minimally invasive surgery, one or more of the instruments is held and controlled by a robotic device, particularly an endoscope.
To aid the minimally invasive surgery team, an image registration is accomplished between the visible endoscopic view and a preoperative three-dimensional ("3D") imaging of the anatomical region (e.g., a CT, a X-ray or a MRI modality). After a registration is completed between preoperative 3D imaging and the live endoscopic video feed, a transform between the preoperative imaging coordinate system and the endoscopic imaging coordinate system is known.
Once the registration is found, as known in the art, an overlay of diagnostically relevant feature(s) of anatomical structure(s) segmented from the preoperative 3D image of the anatomical region are superimposed onto the endoscopic video of the anatomical region to provide a visual aid to the surgical team. Normally, to be able to do this superimposition, a camera calibration matrix must be known, which requires a calibration procedure that is prone to errors and is not practical in a clinical setting. From the calibration, as known in the art, the surgical team guides the robotic system that holds an endoscope toward locations chosen on the overlaid anatomical structures within the endoscopic video, allowing the team to guide the endoscope even if the relevant anatomical feature(s) is(are) hidden in the endoscopic video. Alternative to calibration, as known in the art, movement of the robot may be guided using uncalibrated visual servoing with remote center of motion of the robot.
For the calibrated or uncalibrated endoscope, the robotic system may be guided directly from the preoperative 3D imaging as known in the art. For example, the surgical team selects a point on the preoperative 3D image of the anatomical region, and using the registration between the preoperative imaging coordinate system and the endoscopic imaging coordinate system, the highlighted point is transformed into the associated point on the live endoscope video. The robotic system then guides the endoscope towards that point as known in the art.
There are several issues that may arise with the aforementioned known guidance of an endoscope during a minimally invasive procedure.
First, feature(s) of an anatomical structure segmented from the preoperative 3D image by themselves may be difficult to navigate and orientate in order to select the desired viewing location of the anatomical structure (e.g. an arterial tree segment from a preoperative 3D image of a heart may be difficult to navigate and orientate in order to select the desired viewing location of the heart). Furthermore, if the segmentation of the anatomical feature(s) is insufficient, then the anatomical structure is even more difficult to navigate.
Second, the surgical team may be more accustomed to analyzing and navigating slices of the preoperative 3D image (e.g., axial, coronal and sagittal image slices) as opposed to the 3D volume itself.
Third, typical 3D visualization of a segmented preoperative image only enables the surgical team to see surface features on the segmented anatomical structure, and thus not allowing the surgical team to navigate the robotic system based on internal features of the anatomical structure illustrated within the preoperative 3D image.

Endoscope guidance from interactive planar slices of a volume image


Methylotrophic recombinant yeast strain producing human insulin precursor, the strain comprising, in its genome, a copy of a first DNA construction and a second DNA construction, wherein the constructions are capably of directing the expression and secretion of human insulin precursor of the formula B(1-30)-Y1-Y2-A(1-21), wherein Y1 is lysine or arginine; Y2 is lysine or arginine; B(1-30) is the B peptide of the human insulin; and B(1-21) is the A peptide of human insulin, and wherein the strain is yeast Pichia Pastoris. DNA constructions and method for obtaining the strain are also provided.

1. Field of the Invention
The present invention relates to the expression of human insulin in P. pastoris and, more particularly the invention is related to the field of DNA recombinant technology and to the production of insulin precursors in host microorganisms such as yeast. More precisely, the invention refers to a recombinant methylotrophic yeast strain for producing human insulin precursors. The invention also relates to DNA constructions and methods for obtaining the strains. The inventive strain comprises, in its genome, at least one copy of a first DNA construction and one copy of a second DNA construction, wherein said constructions are capable of expressing and secreting an insulin precursor.
2. Description of the Prior Art
It is well known that diabetes is usually treated with insulin injections, e.g. of human insulin. Insulin is an essential hormone in metabolism and is a protein consisting of two polypeptide chains, namely A chain and B chain. A chain comprises 21 amino acid residues and B chain comprises 30 amino acid residues, and both chains are covalently connected by disulfide bridges in the positions A7–B7 and A20–B19, and by an intra-chain disulfide bond connecting residues A6–A11.
Insulin is produced in the pancreas by the β cells of the Langerhans islets as preproinsulin. Preproinsulin consists of a prepropeptide having 24 amino acids acting as an export signal sequence followed by a peptide named proinsulin and containing 86 amino acid residues. Said preproinsulin may be represented by: prepeptide-B-C-A, wherein the C peptide is a connecting peptide comprising 31 amino acid residues and chains A and B are chains A and B of proinsulin.
When the preproinsulin chain is synthesized, the signal peptide directs synthesis towards the endoplasmic reticulum of the β cells and at that moment the signal peptide splits out, secreting the proinsulin into the endoplasmic reticulum.
Then, during packing of the insulin molecule within the secreting system of the β cells, the C peptide is cleaved, thus liberating the native insulin molecule, which is appropriately "folded". Cleavage of the C peptide is carried out through the action of enzymes acting upon the proinsulin dibasic sequences.
Presently it is known that the C peptide has an important function in the formation of the tertiary structure of the insulin molecule.
The production of insulin for treating diabetes has been a concern in the pharmaceutical industry for many years. Since the development of recombinant DNA techniques, a wide variety of methods for the production of insulin in microorganisms have been published.
Bacteria were the first host microorganisms employed in recombinant DNA techniques, particularly Escherichia coli (E. coli). In the first experiments using E. coli, strategies similar to those used in the production of synthetic insulin were employed. According to these methods, chains A and B were cloned and expressed independently in the host microorganisms, thus obtaining two polypeptides corresponding to chains A and B. The native insulin was then obtained by performing the steps of forming disulfide bonds between chains A and B and the respective intra-chain bridge in vitro. This oxidizing process was carried out as described by Chance, R. E. et al., in Diabetes Care 4:147; 1981; and Goedel, D. V. et al. in Proc. Natl. Acad. Sci. U.S.A. 76: 106–110, 1979. One of the biggest difficulties presented by this method was the random formation of disulfide bonds, which generated molecules with an incorrect tertiary structure. Through this method, the yield of native insulin with biological activity was extremely low, thus increasing production costs dramatically.
In view of the above difficulties, experts have introduced the idea of cloning the DNA sequence of proinsulin or its derivatives, where the C peptide is represented by fragments of different sizes. This idea is based on the fact that the presence of the C peptide or its derivatives produces a higher yield of correctly folded proinsulin after the oxidizing step as compared to the yield resulting from oxidizing chains A and B separately (Dteiner, D. F. et al. Proc. Acad. Sci. 60:622; 1968). Thus, it was observed that chain C which acts as a connecting peptide of chains B and A, allows for cysteine residues to be spatially favored for a correct oxidation. It was demonstrated that the proinsulin molecule formed in this manner could function as a precursor from which insulin could be obtained by in vitro removal of peptide C, using specific enzymes. (Kemmler, W. et al. J. Biol. Chem. 91: 246:6786; 1971). It was also demonstrated that if fragment C of these precursors was changed for a connecting peptide of a smaller size that maintains in vitro cleavable sites at both ends, and, if proper enzyme action was used, equivalent, and in some cases better results were obtained in the production of insulin. These precursors were named mini-proinsulins (Wollmer, A. et al. Hoppe-Seyler's, Z. Physiol. Chem. 355:1471–1476; 1974 and EPO Patent 195 691).
European Patent No. EP 0055945 discloses a process for producing and expressing proinsulin in E. coli and methods for producing human insulin. The production of proinsulin in E. Coli on a large or commercial scale is disclosed in U.S. Pat. No. 5,460,954. U.S. Pat. No. 4,431,740 discloses a DNA having a sequence encoding proinsulin, and another DNA encoding pre-proinsulin, and a microorganism such as E. coli transformed with such sequences.
However, the expression of heterologous proteins in E. coli, has a number of difficulties well known by those skilled in the art. Briefly, the following can be mentioned:
When an E. coli or any prokaryotic microorganism is used as a host for the expression of proteins from eukaryotes, the microorganism is incapable of forming the disulfide bonds which allow for the correct formation of a tertiary structure. As a consequence, when proteins such as human insulin are cloned and expressed in microorganisms, said proteins tend to aggregate forming inactive complexes or inclusion bodies.
Solubilization and purification of proinsulin from the inclusion bodies requires a large number of additional steps. One of these steps comprises dissolving the aggregates with reagents such as urea or guanidine chloride. Subsequently, it is necessary to submit the insulin precursor to an oxidizing agent by oxidative sulfitolysis, wherein the cysteine molecules of both chains adopt the SSO−3 form. Subsequently, the S-sulfonated groups are converted into sulphydryl groups (—SH—) in the presence of a thiolated agent (di-thiotreitol or 2-mercaptoethanol). Finally, these groups are oxidized in presence of oxygen for the formation of the sulfide bonds.
New methods for the recovery of proinsulin from the inclusion bodies are still the aim of several investigations, attempting to improve the yield and achieve a correct folding of the protein which is dramatically reduced by purification of the protein and causes the purification process to be extremely complex. (Chance, R. et al. Proceedings of the Seventh American Peptide Chemistry Symposium, pages 721–728; 1981; Pierce Chemical Company, Rockford, Ill.; Chan, S. J. et al. Proc. Natl. Acad. Sci. USA 78 (9): 5401–5405, 1981, and Frank, B. H. et al. Proceedings of the Seventh American Peptide Chemistry Symposium, pages 729–739; 1981; Pierce Chemical Company, Rockford, Ill.).
In addition, in E. coli or any other prokaryote organisms protein translation starts with a methionine residue. In order to remove the methionine from the amino terminal end the gene of interest is usually cloned as a fusion protein. The removal of insulin from the fusion peptide requires an additional step involving digestion of the peptide with specific proteases. Otherwise, the methionine residue must be removed with cyanogen bromide (CNBr).
European Patent No. 0 055 945 discloses a method and a vector to cleave a proinsulin analog having a smaller C peptide and wherein the methionine residue is removed by treatment with CNBr.
Other difficulties and drawbacks that may be found in the expression of heterologous proteins in prokaryotes is the decrease or reduction of protein stability under the action of cytoplasmic protease. U.S. Pat. No. 5,460,954 discloses a process for producing human proinsulin in E. coli which comprises a vector containing a sequence at the 5′ end of the proinsulin gene, encoding an amino acid sequence which prevents degradation by protease within the cell.
Many investigators are attempting to improve the methods for producing human insulin in E. coli through a simpler method and with better results. These methods for improving protein yield consist in replacing the C peptide by smaller sequences (Chang, Seung-Gu at al. Biochem. J. 329; 631–635, 1998).
Methods for expressing proinsulin in bacteria have also been developed, which combine different procedures such as the expression of a fusion protein comprising a polyhistidine tail in the N-terminal end, a methionine residue and the proprotein sequence of of human insulin, all included in an expression vector for bacteria (Cowley, Darrin J. et al. FEBS Letters, 402: 124–130, 1997).
By reason of the operative drawbacks and difficulties found in the expression of human insulin in prokaryotic hosts, many attempts have been made to obtain high levels of expression of human insulin in eukaryotic hosts such as yeast. Consequently, yeast has become one of the selected hosts for the expression of eukaryotic proteins. These microorganisms provide clear advantages as compared to bacteria in relation to the production of mammalian proteins. Yeast has secretion mechanisms that are similar to those of mammals and has the capacity of properly folding, proteolitically processing, glycosilating and secretingmammalian proteins.
When appropriate vectors are employed in the yeast for exporting the protein outside the cell, the process for recovering and purifying the proteins exported into the culture medium is simpler and has a better yield than the expression in cell cytoplasm. In addition, the secretion system provides an appropriate environment for the formation of the di-sulfide bonds that are necessary for protein folding (Smith, et al. 1985; Science 229:1219). On the other hand, cytoplasm is a reducing environment in which these bonds are not formed. Under these circumstances, production of any proteins requiring di-sulfide bonds for maintaining a correct tertiary structure, as is the case of insulin, will have better results when said proteins are secreted.
A yeast system used as host for the production of a large number of proteins is, for example, the yeast species Saccharomyces cerevisiae. The genetic structure of this yeast has been studied in detail by a number of investigation groups.
Several polypeptides such as insulin have been cloned and expressed in Saccharomyces cerevisiae. The expression of this propeptide may follow the secretory path or may be accumulated in the cytoplasm of the host microorganism. In the event of the accumulation, time consuming and complex purification processes must be employed, the processes requiring steps for the formation of di-sulfide bonds, as disclosed in European Patent No. 37255. In order to avoid these drawbacks and complicated steps, the proinsulin gene sequence is cloned subsequently to an additional DNA sequence named "leader" or signal peptide that originates the pre-proinsulin peptide. This peptide, once recognized and processed by the yeast, provides the secretion of proinsulin into the culture medium.
In addition to the foregoing, any precursors of the proinsulin type that are produced in Saccharomyces cerevisiae undergo a rapid enzymatic process either when expressed in the cytoplasm or when secreted into the medium. It has been demonstrated that human proinsulin is especially sensitive to enzymatic cuts in two dibasic sequences (Arg31–Arg32 and Lys64–Arg65). This causes the cleavage of the molecule before the formation of the di-sulfide bonds, thus resulting in the separate generation of peptides C, A and B.
It has been found that if, instead of proinsulin, shorter sequences are employed wherein the C peptide has been removed or, it is simply represented by shorter fragments having up to two amino acids of lysine, arginine type, a more stable molecule is obtained, which is not digestible by proteases, and capable of been processed in vitro to give a biologically active insulin molecule (Lars Thim et al. Proc. Natl. Acad. Sci. USA 83: 6766–67770; 1986).
European Patent No. 195 691 discloses several precursors, inter alia, those of type B-X-Y-A where B and A correspond to the B and A chains of human insulin, and where X and Y are represented by the amino acids lysine and arginine, these amino acids being digestible by the trypsine and carboxypeptidase B enzymes for their conversion into human insulin. However, while considerable amounts of A0Arg-desB(30) are produced as digestion sub-products, these sub-products do not have amino acid 30 of the B chain while an arginine residue remains connected to the A chain. The arginine residue can not be easily removed and this causes serious inconveniencies in the process of purifying the protein, also considerably diminishing product yields. Total yield of this precursor in Saccharomyces cerevisiae is remarkably low.
On the other hand, U.S. Pat. No. 4,916,212 discloses a simple chain proinsulin precursor, where said precursor is represented by the formula: B(1-29)—(Xn—Y)m—A(1-21), Xn is a peptidic chain of n amino acids, Y is lysine or arginine, n is an integer from 0 to 35, m is 0 or 1, B(1-29) is a B chain lacking the threonine at position 30, and A(1-21) is the A chain of human insulin. This US patent reveals that —Xn—Y— does not have two adjacent basic amino acids, such as lysine and arginine, because the digestion with trypsin produces byproducts that are difficult to separate during the purification steps. The products obtained from these genetic designs do not contain threonine at position 30 and, therefore, they must be subjected to an additional step consisting in the addition of this amino acid by the catalytic action of trypsin in the presence of Thr-Obu ester, as disclosed in U.S. Pat. No. 4,343,898 and Rose, K. et al. Biochem. J. 211:671–676, 1983.
In any case, in addition to all the modifications introduced into the insulin precursors, the expression of these peptides in Saccharomyces cerevisiae has resulted in low yields and scaling drawbacks in heterologous protein production. These problems are generally associated to low efficiency promoters and to the fact that the sequences of interest are cloned in autonomous replication plasmids. These plasmids do not remain uniformly distributed within the culture medium and they usually decrease as the number of copies increases. As a result of this, and after some duplication cycles, cells with 2, 3 or 0 copies of the plasmid used as vector are found in the culture (Chan, S. J. et al. Proc. Natl. Acad. Sci. USA 78 (9): 5401–5405. 1981).
An expression system in yeast, but not using Saccharomyces as a host, is the methylotrophic yeast system. These microorganisms may be very useful as hosts for the expression of heterologous proteins required to be produced in large volumes. Heterologous proteins that are expressed in methylotrophic yeast may be secreted with expression levels that are equivalent to those of E. coli and higher than those of Saccharomyces cerevisiae.
Mthylotrophic yeasts are unicellular microorganisms capable of growing in the presence of methanol as the only carbon source. This yeast can be kept without trouble in high cellular densities when grown in a high volume fermentor. In addition, this yeast is capable of producing many of the post-translated modifications undergone by the higher eukaryotic cells, such as proteolytic digestions, protein folding, di-sulfide bonds formation and glycosilation.
Pichia pastoris is one of the twelve species within the four yeast genera capable of metabolizing methanol as the only one carbon source (Cregg, J. M. et al. Bio/Technology 11:905–910, 1993). The remaining genera are represented by Candida, Hansenula and Torulopsis.
These yeasts share a large number of enzymes corresponding to the metabolic pathways of methanol (Veenhuis, M. et al. Adv. Microb. Physiol. 24:1–82, 1983). The first step of this metabolic pathway is the oxidation of methanol into formaldehyde, generating hydrogen peroxide by action of the alcohol oxidase enzyme (AOX).
The cell avoids hydrogen peroxide toxicity by carrying out this first metabolic reaction of methanol in a special organelle named peroxisome.
There are two genes in P. pastoris which encode alcohol oxidase enzymes I and II: AOX1 and AOX2 genes. The AOX2 gene is responsible of most alcohol oxidase activity in the cell (Cregg, J. M. et al. Mol. Cell. Biol. 9:1316–1323, 1989).
The expression of this gene is highly regulated and it is induced by methanol, with AOX1 representing a value close to 30% of the total soluble cell proteins. It is for this reason that the expression systems usually employed with Pichia pastoris include in their vectors the AOX1 gene promoter.
Thomas Kjeldsen et al. compared the expression of proinsulin and precursor peptides of (B1-29-Ala-Ala-Lys-A1-21) insulin in S. cereviciae and in P. pastoris. The products were secreted into the culture medium with the aid of an amino acid sequence that is fused to the leader (amino) end of the precursor. Several signal peptides were employed for determining the secretion efficiency of the insulin precursor such as the pre-pro-peptide αmating factor of Saccharomyces cerevisiae and synthetic derivatives thereof. These pre pro peptides have amino acid sequences useful as targets for the activity of specific proteases resulting in the release of the peptide into the culture medium. All the insulin peptides employed by these authors are secreted into the medium as a precursor lacking threonine at position 30 of the B chain. This product, recovered and purified from the culture medium, had to be submitted to an exhaustive process called transpeptidation. Transpeptidation consists in the addition of threonine and it is disclosed in U.S. Pat. No. 4,916,212 to Markussen et al. It adds a step to the purification process of the insulin molecule.
In the above described state of the art, it has been a concern of the inventors to find a solution to all of the above mentioned problems and drawbacks in the prior art.

Expression of a human insulin precursor in