2 or more sets of initial setup data specifying different operation conditions are stored in a memory cell array comprising electrically-rewritable non-volatile memory cells arranged therein. A control circuit reads a set of initial setup data out of the 2 or more sets of initial setup data via an sense amplifier circuit based on the area information. The initial setup data is transferred to an initial setup data latch and stored therein.

1. Field of the Invention
The present invention relates to a non-volatile semiconductor memory device. More particularly, it relates to a non-volatile semiconductor memory device with an area storing initial setup data in a memory cell array.
2. Description of the Related Art
In recent years, an electrically-rewritable non-volatile semiconductor memory device (hereinafter "EEPROM") has become large in capacity. A non-volatile semiconductor memory device is beginning to be adopted as secondary memory storage instead of a hard disk drive.
Especially, a NAND type EEPROM, which is configured with NAND memory cells connected in series is suitable for high density integration. For this reason, it is widely used for a secondary memory device, a memory card and the like used in a portable terminal such as a cellular phone.
In a conventional EEPROM, initial setup data including parameters for controlling various operations are stored in a memory cell array.
This initial setup data includes fail address data for defective cell replacement, voltage setup data for write voltage or the like, voltage adjustment data for adjusting setup voltage in response to fluctuation of processes, and control parameters for various operations such as data write and data erase. This initial setup data is read from a memory cell array when a power supply is turned on, and are transferred into various setting registers. Thereafter, a memory performs operation of writing, reading erasing and the like, based on the initial setup data stored in these various setting registers (see JP 2001-176290).
However, such a conventional memory stores only one set of initial setup data in a memory cell array. There sometimes arises a need that a usage or a application of the memory device should be changed after initial setup data are programmed. In that case, the memory cell array must be initialized or erased, and initial setup data corresponding to the usage or the application to be needed must be programmed again.

Non-volatile semiconductor memory device


There is provided a manufacturing method of a magnetic recording medium that maintains a high level of perpendicular orientation of a perpendicular magnetic layer and enables to further increase high recording density, prepared such that at least on a non-magnetic substrate, there are laminated a soft magnetic base layer, an orientation control layer 11 that controls the orientation of the layer immediately thereabove, and a perpendicular magnetic layer with a magnetization easy axis thereof primarily oriented perpendicular to the non-magnetic substrate. The manufacturing method is characterized in that when configuring the perpendicular magnetic layer with two or more magnetic layers 12 to 14 and crystal-growing each layer so that the crystal grains that constitute the respective magnetic layers 12 to 14, together with the crystal grains that constitute the orientation control layer 11, form column-shaped crystals S1 to S3 in a consecutive manner in the thickness direction, lamination of the orientation control layer 11 is performed while the substrate is being cooled or immediately after the substrate has been cooled.

The recording density of a hard disk drive (HDD), which is a type of magnetic recording/reproducing apparatus, is increasing at an annual rate of 50% or higher, and this increasing trend is expected to continue. In response to this, magnetic heads and magnetic recording media that are suitable for high recording density are being developed.
A magnetic recording medium equipped in a magnetic recording/reproducing apparatus currently available on the market is a so-called perpendicular magnetic recording medium in which the magnetization easy axis in the magnetic film is primarily oriented perpendicular. In a perpendicular magnetic recording medium, even when its recording density is highly increased, diamagnetic field influence in a boundary region between recording bits is small and clear bit boundaries are formed, and therefore, an increase in noise can be suppressed. In addition, it has a small decrease in recording bit volumes when highly increasing recording density, and consequently is resistant to thermal fluctuation effects. For this reason, perpendicular magnetic recording media are receiving broad attention in recent years, and there has been proposed a structure of a medium that is suitable for perpendicular magnetic recording.
Moreover, in order to respond to the demand for further increasing the recording density of a magnetic recording medium, use of a single magnetic pole head, which has a superior ability to write into a perpendicular magnetic layer, is being considered. In order to adapt to such a single magnetic pole head, there has been proposed a magnetic recording medium that improves incoming/outgoing efficiency of magnetic flux between a single magnetic pole head and a magnetic recording medium by providing a layer called a backing layer composed of a soft magnetic material between a perpendicular magnetic layer that serves as a recording layer and a non-magnetic substrate.
However, in a magnetic recording/reproducing apparatus that uses the above-mentioned magnetic recording medium simply having a backing layer provided therein, recording/reproducing characteristics when recording and reproducing, resistance to thermal fluctuations, and recording resolution are not satisfactory, and consequently there has been a demand for a magnetic recording medium that excels in these characteristics.
In order to further increase recording density in the future, it is essential to: achieve high S/N ratio, which is a ratio of signal to noise (S/N ratio) in reproduction and is particularly important as a recording/reproducing characteristic; and improve thermal fluctuation resistance. However, these two items are in a conflicting relationship, in which if one of them is improved, then the other one will be insufficient, and therefore, achieving both of them at a high level is a significant problem.
In order to solve such a problem, there has been proposed a magnetic recording medium that is characterized in that three magnetic layers are AFC (anti-ferromagnetic coupling) bonded using a non-magnetic layer and the like, and thereby advantage of the reduction in composite Mrt and PW50 is taken without causing a reduction in S/N ratio (for example, refer to Patent Document 1).
Specifically, this Patent Document 1 discloses a magnetic recording medium that is characterized in that it has: a substrate; a first lower ferromagnetic layer that is provided on the substrate and has a residual magnetization Mr, a thickness t, and a product Mrt of residual magnetization times thickness; a ferromagnetic bonding layer that is provided on the first lower ferromagnetic layer; a second lower ferromagnetic layer that is provided on the ferromagnetic bonding layer and has an Mrt value; an anti-ferromagnetic bonding layer that is provided on the second lower ferromagnetic layer; and an upper ferromagnetic layer that is provided on the anti-ferromagnetic bonding layer and has an Mrt value greater than that of the total Mrt value of the first and second lower ferromagnetic layers.
Meanwhile, in order to improve the recording/reproducing characteristic and thermal fluctuation characteristic of a perpendicular magnetic recording medium, there has been proposed to use an orientation control layer and form multiple magnetic layers so as to prepare crystal grains of each magnetic layer into consecutive column-shaped crystals, thereby enhancing the perpendicular orientation of the magnetic layers (for example, refer to Patent Document 2).
Moreover, for example, use of Ru as the orientation control layer has been disclosed. The apex section of a column-shaped crystal of Ru has a dome-shaped convex section, and therefore Ru has an effect such that crystal grains of a magnetic layer and the like are grown on this convex section, isolated structure of the grown crystal grains is promoted, the crystal grains are isolated, and magnetic grains are grown into a column shape (for example, refer to Patent Document 3).

Manufacturing method of magnetic recording medium and magnetic recording/reproducing apparatus


An ecosystem can be used for processing user questions and commands received via a conversational interface in a hierarchical permissioning manner. The questions and commands which a user is permissioned to ask/issue are determined at user logon. The ecosystem may be configured to access and return appropriate answers from a variety of sources, but only for questions which the user is permissioned to ask. In addition, the ecosystem can be configured to execute commands which may be received by the user via the conversational interface, but only for the commands which the user is permissioned to issue.

Businesses around the world largely consume a large amount of data and companies typically have a multitude of systems that are utilized by their employees to retrieve, view, analyze, manipulate, and/or enter data. It is not uncommon for a single user to utilize anywhere between half a dozen and a dozen separate applications each day for these purposes. Moreover, in many cases, desired information is only available through a distributed network of different types of data sources, fees, or repositories. These are often located on remote sources accessible through the internet, each having its own particular protocol for data access and retrieval. For companies involved in the financial industry, an employee may need to retrieve information from and multiple disparate market data sources, various online trading platforms and exchanges, news feeds, and even weather, traffic data, and various historical records. As a result, users must manually hunt for data or access and/or input data on multiple systems in various formats. This reduces efficiency and can introduce other issues as well.
The need to utilize a multitude of systems for unique and at times similar data also has problems because the same data item may be referred to differently on different platforms. As a result, each user must know the appropriate key words for the platform. This is a particularly acute issue in the financial services industry where users can be forced to manually work with and remember multiple different codes to reference the same instrument on different systems. For example, on one platform a commodity may be referred to as "West Texas Intermediate" while on others the same commodity is WTI, TI, or even CL. Similar issues exist for more mundane data fields, such as the date format (e.g., Mar-17, Mar17, March 2017, March-17, H17, 2017-03, Red March, Blue March, etc.) The user workflow fragmentation resulting from multiple applications, interfaces and syntaxes creates organizational inefficiencies increasing workloads and distracting employees from their core responsibilities. Similar differences may exist between companies. For example, two different companies (or even different departments or employees) may internally refer to the same commodity using different terminology. Combined, these disparities introduce many inefficiencies and opportunities for error.
The issues above are further magnified when user input to a data query system is provided by audio input and is processed using a speech recognition system. While audio input systems allow for rapid user input without a keyboard, speech recognition systems are prone to transcriptions errors, particularly where the speaker may have an accent that the system is not trained specifically to address.
Accordingly, there is a need for an improved method and system for processing user input that will allow users at various companies to access a variety of data sources through a conversational interfaces and without the need for the user to specifically select the source from which the requested data will be retrieved.
There is a further need for a query based data access system that can efficiently process user input queries to identify the particular data source corresponding to the query, forward the query in the proper format to the source of the data, and then retrieve and present the results in an appropriate format.
While an organization may have access to a large number of data sources, it may restrict access to these based on a user's authority level. There is a further need for such a system to efficiently process user input queries in a manner that accounts for restrictions not only in which data sources a user may query but on which queries can be made for that source.

Ecosystem for providing responses to user queries entered via a conversational interface

Abstract: The ecosystem may include a computer system configured to receive a text query representing a question asked from the user, score the questions which the user is permissioned to ask, select a high-scoring question, use an API to receive information responsive to the high-scoring question, and output the answer to the user.


A system creates a graph of nodes connected by edges, the nodes including: i) a first node associated with a first value and a count of the first value, and ii) a second node associated with a second value and a count of the second value, the edges including an edge that connects the first and second nodes and is associated with a count of instances of the first value being stored with the second value. The system includes each node and each associated with clique count less than clique threshold in keys sets and deletes each node and each edge associated with clique count less than clique threshold. The system identifies triplet nodes connected by triplet edges. If estimated clique count for triplet values represented by triplet nodes is less than clique threshold, the system includes triplet values in keys set and identify triplet of nodes as analyzed.

The subject matter discussed in the background section should not be assumed to be prior art merely as a result of its mention in the background section. Similarly, a problem mentioned in the background section or associated with the subject matter of the background section should not be assumed to have been previously recognized in the prior art. The subject matter in the background section merely represents different approaches, which in and of themselves may also be inventions.
Companies are often overwhelmed with customer data. Examples of customer data fields include a name, a billing address, a shipping address, an email address, and a phone number. Managing customer data may become extremely complex and dynamic due to the many changes that individual customers go through over time. For example, a company's purchasing agent can change her family name upon marriage, change her email address, change her phone number, and change her employer within a relatively short period of time. In another example, a customer who is known by the name Robert can also use Rob, Robby, Bob, and Bobby as his given name. The use of customer data may create additional challenges, such as due to invalid email addresses, invalid phone numbers, invalid street addresses, names spelled wrong, incorrect employer information, and duplicate customer data records with inconsistent information. When these customer data fields are multiplied by the millions of customer data records which a company may have in its data sources, and the frequency of how often this customer data is incorrect or changes is also taken into consideration, the result is that many companies have a significant data management challenge.
Furthermore, the potential for customer data challenges may increase when customer data enters a company's customer data system from the company's multiple data sources. Examples of a company's data sources include the customer data from interactions conducted by the company's marketing, retail, and customer service departments. This customer data may be distributed for storage by different cloud storage providers, and/or these company departments may be organized as different tenants in a multi-tenant database.
A traditional approach to resolving these challenges is through the instantiation of a database system that functions as a master data management hub which stages, profiles, cleanses, enriches, matches, reconciles, and instantiates all customer related records to create a single master profile for each customer, and then provides access to these master profiles and their cross references to business applications. The master profile construction process involves using match keys to match specific fields of customer data records, followed by clustering sets of customer records for the same customers, and finally by merging the clusters to create master profiles. For example, a cluster contains 5 records for the same customer, comprised of 3 distinct given name field values, such as R., Robert, and Bob. The merging process determines which of these 3 values (or possibly some other value) should be listed as the given name in the customer's master profile.
A database system's process that determines whether any existing records sufficiently match any other existing database records could be an intensive process that matches multiple values between these records, thereby consuming a significant amount of system resources. The reason that such a matching process would be intensive is that any particular record would need to be matched against all of the records, which is possibly millions of records. Since this matching would need to be done for every record, the matching process could include millions multiplied by millions of potential matches. Consequently, a database system can initially identify any existing database records that match only one or two corresponding values stored by an existing record in a shallow matching process that consumes a relatively limited amount of system resources. Shallow matching takes a given record and narrows down records that potentially match the given record from the full set of records to a very small set of potentially matching records. Therefore, shallow matching of records is faster because index lookups narrows the potential match candidates. Non-candidate records are not matched at all by shallow matching or deep matching. Then the database system can apply an intensive multiple-value matching process to each of the relatively small number of shallow matching records in the existing database records, thereby collectively reducing system resource consumption.
The database system can use the generated master profiles to assist in responding to customer requests. For example, a customer makes a purchase via a company's retail cloud instance, and the customer enters some identifying information when filing a service request with the company's customer service cloud instance. The database system responds by automatically finding all that is known about this customer in their master profile, especially in the purchase record(s) of the relevant item, so as to enable the company's customer service department to process the service request more effectively.
A database system's process that determines whether newly received database records sufficiently match existing database records could be an intensive process that matches multiple values between these records, because the number of existing database records may be very large, even if there are only a few newly received records in any given time period, thereby consuming a significant amount of system resources. Consequently, a database system can initially identify any existing database records that match only one or two corresponding values stored by a newly received database record in a shallow matching process that consumes a relatively limited amount of system resources. Then the database system can apply an intensive multiple-value matching process to each of the relatively small number of shallow matching database records in the existing database records, thereby collectively reducing system resource consumption.
Therefore, the database system can create match keys from values stored by existing database records and/or by newly received database records, and then use the match keys to identify the existing database records that shallow match newly received database records. The design of match keys takes recall and performance into consideration. Recall is the percentage of actual matching records that are identified by a database system. To achieve the ideal of 100% recall, a database system may need to treat every existing record in the database as a candidate for matching every other existing database record or every newly received database record, which typically is not feasible, performance-wise. At the other extreme of the recall/performance spectrum, a database system can quickly search database records by using narrowly focused match keys, but narrowly focused match keys may fail to identify some matching database records.
There are some scenarios when match keys need to be composed of triplets of values. For example. a database of one million person profiles receives a new record in which the first name is John, the last name is Smith, the city is San Francisco, and no other fields include any data. Before adding this record to the database, the database system will need to search the database for all records that could identify a John Smith in the city of San Francisco to determine if the new record matches any existing records. However, using any match key which includes the values from at most two fields risks returning too many results, which would have to be pruned. There may be too many John Smiths, too many Johns in the city of San Francisco, or too many Smiths in the city of San Francisco.

Generating adaptive match keys based on estimating counts


A projector includes a lens driving unit that drives a lens unit including a projection lens; a reception unit that receives instruction information that is input; and a control unit that controls a lens shift by the lens driving unit based on lens shift instruction information with respect to the projection lens, which is received by the reception unit, in such a manner that zoom, which is performed by the lens driving unit based on zoom instruction information adjusting angle of view with respect to the projection lens, is performed in a predetermined state for a first image which is projecting in a state that a central position of the first image is different from a basis position of the zoom.

1. Technical Field
The present invention relates to a projector, and a control method thereof.
2. Related Art
For example, as described in JP-A-2006-5534, there is provided a projector having a zoom function and a lens shift function with respect to a projection lens.
In a situation in which a projector projects an image, when a zoom state is changed in a state where a lens shift is not performed, the size of an image is changed on the basis of the central position of the image. In contrast, when the zoom state is changed in a state where the lens shift is performed, a size of the image is changed on the basis of a position that is not the central position of the image. In this way, in a general projector, there is a difference in a variation of a zoom state depending on a state of whether or not a lens shift is performed. That is, in case that the central position of the image is different from the basis position of the zoom which adjusts the angle of view of the projector, there is a difference in a variation of a zoom state of the image compared with the case that the central position of the image matches the basis position of the zoom.
For example, in a case where a user performs the lens shift to avoid an obstacle, an image is magnified in all direction by a zoom indication, and therefore a part of the image overlaps with the obstacle. Therefore, there is a problem in that the lens shift has to be performed again.

Projector having control unit that controls lens shift during zoom by lens driving unit and control method thereof


Techniques are described for providing insurance coverage for a virtual wallet stored on a computing device. The virtual wallet has a value equal to a sum of assigned values of a plurality of virtual financial assets included in the virtual wallet. A user of the computing device purchases an insurance policy for the virtual wallet with an insured amount based on the value of the virtual wallet. The computing device is configured to send messages to an insurance server reporting an updated value of the virtual wallet based on changes to the assigned values of the virtual financial assets. The insurance server updates the insured amount of the insurance policy based on the updated value of the virtual wallet. Upon the virtual wallet being compromised, the insurance policy has an insured amount equal to the most recent updated value of the virtual wallet.

In general, a virtual wallet refers to an application running on a computing device that allows a user of the computing device to perform online transactions. A computing device configured to execute a virtual wallet application may be any of a wide range of devices, including laptop or desktop computers, tablet computers, so-called "smart" phones, "smart" pads, "smart" watches, or other personal digital appliances equipped for wired or wireless communication. In some examples, the virtual wallet may be used to purchase goods or services via either a website or a point-of-sale device configured to receive online payments.
A virtual wallet includes one or more virtual financial assets, which may correspond to any type of digitized asset that has a monetary value. Commonly, a virtual wallet includes one or more virtual credit accounts, virtual banking accounts, virtual currency accounts, or other liquid virtual assets that can be used to purchase goods and services. In some examples, a virtual wallet may also include non-liquid virtual assets, such as virtual stock and bond certificates; virtual ownership titles for real estate, automobiles, and other property; and virtual event tickets or other virtual documents having a monetary value. In other examples, a virtual wallet may include virtual identification documents.
In the above examples, the virtual wallet includes sensitive information that needs to be kept secure. Like all technology, however, virtual wallets have security risks. For example, a virtual wallet may be compromised if the virtual wallet is accessed by an unauthorized user, or if the computing device that stores the virtual wallet is lost, stolen, destroyed, or accessed by an authorized user. Unlike a stolen credit card, if the virtual wallet is compromised, there may be no way for a user to recover the virtual financial assets included in the virtual wallet.


An actuator system for controlling the external fins on a gun-launched projectile to control the flight path of the projectile. These actuator systems include an electric motor having a rotor and output shaft which is driven between travel limits that are less than 180 apart (less than 90 in either direction from a central rest position). Coupling from the motor shaft to the control shaft for the external fins is via a coupling between an eccentric ball on the motor shaft and an eccentric receptacle member on the fin shaft. As the angle of the motor shaft varies, the eccentric ball slides in a slot in the fin coupling member, causing the fin shaft angle to vary correspondingly. In another embodiment, the eccentric ball for controlling the fin shaft angle is mounted on a link arm that is coupled to the motor shaft, thereby permitting the motor to be mounted off the projectile axis and thus accommodating a shortened space in the projectile required for the actuator system and associated power supply.

1. Field of the Invention
The present invention generally relates to fin control systems for gun-launched projectiles and, more particularly, to the actuators and associated linkages for controlling the angle of the aerodynamic control fins which impart steering forces to the projectile during flight.
2. Description of the Related Art
Presently existing actuators for fin control on gun-launched projectiles are both complex and expensive. The requirement to withstand the acceleration forces, which typically range from 10,000 to 30,000 G""s, places very stringent demands on the actuators. Therefore, the designs are required to be extremely robust in order to withstand the loads induced by these accelerations.
It is an object of this invention to provide a simple but effective configuration which is simple in structure but which is also low cost to produce and extremely robust. It is particularly capable of withstanding extreme accelerations.
At present, existing actuators for fin control on gun-launched projectiles typically employ electric motors to drive the fins through a gear reduction system. These motors are either brush or brushless types that make several revolutions of the motor while moving the fin from one travel limit to the other. In the case of the brush type motors, there are substantial reliability issues with the brush systems due to the high acceleration loads and problems with corrosion resulting from long-term storage. The brushless types have reliability issues with rotor position sensing complexity.
There are typically two basic configurations of gun hardened projectile actuators: (1) the motor on the central axis, and (2) the motor off the central axis to allow the fins to be folded adjacent to the motor. The design of the present invention addresses both configurations. This design is applicable to projectiles in which the fins are stowed internally and extended to effect steering control after the projectile is fired. The design is also applicable in those configurations in which the fins are not folded because they are small or short enough to fit in the gun barrel. Also, it is appropriate for projectiles where a sabot is used to adapt a projectile with external fins to the dimensions of the gun barrel, wherein the sabot opens up and peels away after the projectile leaves the muzzle.
Systems of the present invention comprise as the motive element a limited rotation motor, the shaft of which rotates through less than half a revolution in driving the fin from one travel limit to another. These limited rotation motors lend themselves to low cost manufacturing techniques. There is no requirement for secondary electronics to sense the motor commutation steps. Cost is reduced by not having to commutate the motor over its rotation. Prior art systems utilizing brushless motors operating over several revolutions require Hall effect sensors or some other means of sensing rotor position to switch phases. A brush-type motor would require brushes and a commutator. Either approach introduces added cost over what is required in the design of the present invention.
Limited rotation motors of the type used herein may be either a moving magnet type or a variable reluctance type wherein the rotor reluctance is used to torque the motor in the external armature field. Because the variable reluctance approach does not use permanent magnets, it has a potential for lower cost. Either of these types of motors is relatively cheap to manufacture. Either can be machine wound automatically so very little handwork is required. Also, each design is very robust and can be hardened for gun launching. In either case the inherent simplicity of the design makes for high reliability. This design also provides benefits in the case where a more conventional motor of either brush or brushless type is used. This is because, among other reasons, as the loads increase with increase of fin angle, the reduction ratio between the motor and the output shaft increases. This reduces the power needed to provide the required torque at the output shaft.
The relatively low reduction ratio between the motor and the fin shaft of the instant design is well suited to rapidly rolling airframes, for example up to a 30 Hz roll rate. This is because rolling airframes require fin deflections that follow the projectile roll without significant phase error. This allows maneuvering in a single plane without inducing spiraling. Thus, it is a feature of the present invention design that it is well suited to applications with rolling airframes.
Furthermore, there is potential for energy conservation in these rolling airframe applications because the aerodynamic induced torque applied to the control fin can be used to decelerate and re-accelerate the motor, thus recovering some of the electrical energy that was input to the motor. The degree and effectiveness of this energy recovery depends on several factors, among which are the motor and mechanical drive characteristics, the electronic driver, and the battery or other power source.
The change in the reduction ratio between the motor and the fin shaft as the angle of the fin increases comes about because the ratio from motor to fin shaft varies as the sine of motor shaft position divided by the sine of the fin shaft position. Since the motor shaft angular displacement is a multiple of the displacement of the fin shaft, the effective ratio increases as a function of displacement. Thus, the maximum ratio occurs at the extremes of travel where the aerodynamic load is greatest. This feature permits minimization of the motor size because of the inherent torque increase for maximum load.
Comparison of the cost of the embodiments of the present invention with known prior art arrangements is extremely favorable for the present invention. The simplest way to look at cost is to compare part count and complexity. The simple ball and crank pin and eccentric slotted coupling for the fin shaft are much lower cost than any gear or screw drives. These features are also much lower cost than precision bearing bores for gears.
In brief, particular arrangements in accordance with the present invention comprise a brushless motor having an output shaft which is controlled to rotate less than 90xc2x0 from either side of a rest position. The end of the motor shaft has a crank arm that is offset by a prescribed distance with a ball end machined on the end of the crank. In an alternative arrangement, a ball is mounted to the motor shaft by an eccentric pin. As the motor rotates, the ball slides in a slot in the fin shaft which is perpendicular to the motor axis. The ball and slot are at a radius of about one-half the prescribed offset distance, resulting in a motor-to-fin ratio of about 6:1. This sliding ball-and-slot coupling of the motor shaft to the fin shaft is a major feature of the present invention, since it takes advantage of the limited rotation of the fin shaft to eliminate the need for any gears or screw drives. Contact is maintained with the ball in the shaft slot as the shaft moves through its arc by allowing the ball to slide axially by a limited amount in the slot. The ball-to-slot interface is a tight slip fit. This arrangement results in a very high overall efficiency of the drive coupling, on the order of 90%.
In one particular arrangement of the present invention, the motor is mounted along the center line of the projectile, and engages the fin shaft through a right-angle mounted eccentric coupler.
In an alternative embodiment of the present invention, the motor is displaced from the projectile axis. The motor shaft is coupled to the output shaft by a link arm which permits the motor to be folded back into the projectile interior space, which also includes the battery envelope, thereby allowing use of the same motor and electronics of the other embodiment while further reducing total package length. In all cases, the design of the present invention allows for a very compact actuator drive package.

Gun-launched rolling projectile actuator


A surgery dedicated ultrasound system is described. The system is used for imaging and/or guidance and/or controlling purposes. The surgeon uses and controls the system and accesses the information obtained and processed through the system while performing surgery.

The present invention relates to medical ultrasound systems and methods.
In conventional medical ultrasound devices, transducers mounted in a hand-held probe work both as a source of an ultrasound pulse and as a receiver of the echo. The received echoes are converted to electric signals which are then processed into visual and/or audio information.
Recent technological advances have improved the B-Mode image quality significantly. Colored images of blood flow are now routine clinical tools. Systems that provide static 3-D images and even real-time 3-D images have also entered the market.
Despite these advances, a surgery dedicated ultrasound system that does not interrupt or interfere with the surgical process but enables surgeons to detect and obtain information about anatomical and pathological surfaces and structures just before or during dissecting has not been provided. It would be particularly desirable if surgeons were capable of reorienting themselves easily and to reassess tissue types, borders, etc. during surgery. Also, it would be desirable to use medical ultrasound systems as a medical tool to perform faster and safer surgeries.
Accordingly, there is a need for an improved ultrasound system specifically designed for surgeon use during a surgery.
The present invention is directed to an ultrasound system especially suited for use during surgery. In one embodiment, the ultrasound system includes a wearable ultrasonic probe in combination with a display positioned within the sterile operating field and coupled via a processor to the probe. In a particular embodiment the probe, display and the processor of a completely wearable ultrasound system are worn on the hand of a surgeon. In other embodiments, the display is worn by the surgeon but is not positioned within the sterile operating field, or the display is carried by an articulated arm and is positioned near the surgical site. Also methods for using an ultrasound system during a surgery are disclosed. One embodiment includes placing a wearable ultrasonic probe of an ultrasound system onto a hand of a surgeon and using the ultrasound system during the surgery to provide display information to the surgeon while the surgeon""s head is positioned to view the surgical site.


It is disclosed a polyolefin blend having an exhibiting improved processability and mechanical properties comprising of a major amount of a high molecular weight or low melt flow polyolefin, and minor amounts of a high melt flow polyolefin and an ordinary melt flow polyolefin copolymer. The improvement in processability, optical, and mechanical properties is synergistic, and is particularly evident by the improvement in output rate and dart drop impact strength.

Polyolefin polymers are very well known in the art. Methods of manufacturing and/or processing polyolefins are likewise well known in the art. These methods of processing include but are not limited to blow molding, injection molding, pultrusion and pulforming, and extrusion. The problems associated with each of these processes are known, and seeking solutions to these problems, and/or improvements in processing conditions and equipment remains of interest to the art and industry.
For example, it is known that olefinic homopolymers such as high-density polyethylenes (HDPE) and polypropylenes generally have poor processability and poor impact properties. Because of the wide commercial uses of these polymers in various applications such as automotives, households, and. packaging, it is always desirable to discover new methods, additives, and/or equipment which enable these polymers to be better and more economically processed, and to improve the mechanical and other properties of these polymers and/or products made from the polymers.

Olefinic polymer blends for improving polyolefins


A system, methods and apparatus for rapidly and automatically orienting spherical objects, such as game balls, for subsequent downstream processing comprises a series of processing steps that can be performed at four separate, mechanically similar (or even identical) workstations. An imaging sub-system needs only one camera to image the spherical object and image the work process. The method of transposing the spherical object between work stations is simple, requiring an apparatus having only one degree of freedom to simultaneously convey and rotate spherical objects, and the system and method can automatically and rapidly determine the object's spatial orientation and change the orientation as required for downstream processing.

1. Field of the Invention
This invention relates to a system and method for automatically orienting a spherical object, particularly a game ball, based on an existing "reference" pattern or indicium on the surface of the spherical object so that additional processing, e.g., printing, inspecting, etc. can take place on the spherical object at a target point that has a predetermined positional relationship with respect to the existing reference pattern or indicium.
2. Description of Prior Art
A growing segment of the golf ball industry is the manufacturing of balls customized with corporate logos, country club emblems, personal names, etc. These balls are usually produced by taking a finished golf ball and adding the custom printing at a predetermined location relative to the existing trade name or indicium printed on the ball. This is most commonly done by manually orienting the ball and placing it into a printing machine. Some of the problems with this method are: 1) it is labor intensive and therefore expensive, 2) it requires a significant training period for a person to become proficient at it, 3) a person is subject to fatigue and must take frequent breaks, 4) the process requires a great deal of repetitive motion, which can be source of injury, and 5) the accuracy is not as good as the system described herein.
U.S. Pat. No. 5,632,205 to Gordon (1997) describes a method of automatically orienting a game ball. This method uses a single station to perform the entire orientation on a single ball at a time. Two conical wheels are used to support the ball and rotate it around two orthogonal axes depending on whether the wheels are rotated in the same or opposite directions. The third axis of rotation is achieved by making two moves using the first two axes. The limitations of this method are: 1) operating rates are low, due to the fact that it performs the orientation on only one ball at a time, 2) the amount of time it takes to orient the ball can vary significantly depending on the initial orientation of the ball, making it difficult to synchronize the ball-orienting apparatus with the printing apparatus, which is usually designed to run at a fixed cycle rate, and 3) the area sensor camera photographs only a limited area of the surface of the ball at one time, therefore more images need to be acquired and, hence more time to process such images.
U.S. Pat. No. 5,611,723 to Mitoma (1997) describes another method of automatically orienting a golf ball in two dimensions for the purpose of removing molding burrs and flash from the equator of the ball. The Mitoma method describes a sequential arrangement that allows a different ball to be at each station of the orientation process simultaneously. The limitations of this system are that it requires six stations and three cameras to orient the ball in only two dimensions. The individual stations are mechanically and spatially complex because their orthogonal arrangement requires such stations to be considerably different from one another. Additionally, the conveyance arm that transports the balls from one station to the next adjacent station requires two degrees of freedom, one to lift and place the balls and another to transport them, therefore operating rates are low.

Method and system for automatically orienting a spherical object


Methods and systems of manipulating data on an electronic device and a remote terminal are disclosed. The system includes at least one controller in an electronic device and a remote terminal, configured to initialize the electronic device and the remote terminal, detect a first input signal associated with a desired action, capture at least a portion of an external environment, detect a second input signal associated with the desired action, and perform the desired action on the electronic device and the remote terminal according to the first input signal and the second input signal. The system also includes at least one signal detection system in the electronic device and the remote terminal controlled by the at least one controller, at least one imaging and display system in the electronic device and the remote terminal generating an image output data in real-time.

Technical Field
The invention relates generally to a method and system of data manipulation between an electronic device and a remote terminal.
Related Art
Due to advancements in imaging technologies, camera systems have been utilized to capture various activities. However, when it comes to wearable electronic devices, such as cameras worn by a participant in an activity so that the hands are free to participate in the activity, these tend to be bulky and unaesthetic. Moreover, these wearable electronic devices may cause discomfort and may be controlled by activation systems that are not intuitive or prone to false triggers. Therefore, an effective method and system of data manipulation between an electronic device and a remote terminal that is both accurate, discreet, and intuitive is highly desirable.

Data manipulation on electronic device and remote terminal


The present invention relates to a method of broadcasting and receiving a neighboring base station advertisement message in a wideband wireless access system and a handover method using the same. In the present invention, a base station broadcasts a neighboring base station advertisement message including information that indicates that frequency overlay is supported in neighboring base stations to terminals. The terminal confirms whether frequency overlay is supported in the neighboring base stations included in the neighboring base station advertisement message, and can perform handover to a frequency overlay supporting base station as a destination base station. According to the present invention, when a non-frequency overlay communication system and a frequency overlay communication system are mixed with each other, it is possible to ensure that a frequency overlay supporting terminal performs handover from a base station of a frequency overlay communication system to a base station of another frequency overlay communication system.

A wideband wireless access system defines a terminal (MS), a base station (BS), and a router (ACR) to be compatible with an existing public IP network, and allows the terminal to have mobility, such that the terminal can use an IP-based network service during movement. An existing wideband wireless access system provides a structure in which one terminal enables communication with a base station through a frequency band that belongs to only one frequency assignment (FA).
Meanwhile, as an advanced type of the existing wideband wireless access system, an advanced wideband wireless access system has been suggested in which one terminal can communicate with a base station through a plurality of FAs. In this case, a function of allowing a terminal to communicate with a base station using a plurality of FAs is called a frequency overlay function. According to the advanced wideband wireless access system (hereinafter referred to as "frequency overlay communication system"), a connection structure between a base station and a public IP network is the same as that of the existing wideband wireless access system (hereinafter referred to as "non-frequency overlay communication system"), but a wireless access portion between the base station and the terminal is different from that of the non-frequency overlay communication system. That is, the base station and the terminal can communicate with each other through a plurality of frequency bands that are connected using two or more FAs. The frequency overlay communication system having the above-described structure has the following merits. If a wireless access method between a terminal and a base station and only a function of a MAC layer related to the wireless access method is slightly changed, it is possible to use a frequency band N times wider than that in the non-frequency overlay communication system (on the assumption that one terminal uses two FAs, a frequency band two times wider than that of the non-frequency overlay communication system can be used, and as a result, an available frequency band increases in proportion to the number of FAs used by the terminal). As a result, it is possible to increase a data transmission speed between the terminal and the base station by two times or more (generally, when the number of FAs used between the terminal and the base station is N, the transmission speed is increased N times faster than that of the non-frequency overlay communication system using one FA).
As this frequency overlay communication system is developed, a non-frequency overlay communication system and a frequency overlay communication system are mixed, which provides a mobile communication service to the terminal. As such, in a mobile communication system where a frequency overlay communication system and a non-frequency overlay communication system are mixed and a mobile communication service is provided, it is difficult to ensure that a terminal that is capable of performing a frequency overlay function (hereinafter referred to as "frequency overlay supporting terminal") performs handover to a base station that is capable of performing a frequency overlay function (hereinafter referred to as "frequency overlay supporting base station"). Accordingly, when a frequency overlay supporting terminal that performs communication with a frequency overlay supporting base station using two or more FAs performs handover to a base station under the control of a non-frequency overlay communication system (hereinafter referred to as "frequency overlay non-supporting base station"), the frequency overlay supporting terminal can perform communication using a plurality of FAs. However, since the base station that is subjected to handover is a frequency overlay non-supporting base station, the base station can perform communication using only one FA. Therefore, there is a technical limitation in that the merits of the frequency overlay communication system are not sufficiently available.
Meanwhile, even when a frequency overlay supporting terminal performs handover from a frequency overlay supporting base station to another frequency overlay supporting base station, if a base station to which the frequency overlay supporting terminal performs handover does not know information indicating whether a plurality of FAs that can be used by the frequency overlay supporting terminal can use only adjacent frequency bands or both adjacent frequency bands and non-adjacent frequency bands, the following problem occurs. The frequency overlay supporting terminal can perform communication using only one FA depending on whether FAs allocated by the frequency overlay supporting base station are adjacent to each other.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the invention and therefore it may contain information that does not form the prior art that is already known in this country to a person of ordinary skill in the art.

Method of broadcasting and receiving neighboring base station advertisement message in broadband wireless access system, and handover method using the same

Electronics and Telecommunications Research Institute


[PROBLEMS] To increase the rate of gas transfer in gas exchangers.

As a gas exchanger that removes gas components from a liquid or transfers gas components to make them dissolve in a liquid, those utilizing hollow fiber membranes are used. Hollow fiber membranes are used as a module in which multiple hollow fiber membranes are bundled and caps are provided on both ends. Such module is used in such a manner that a liquid is caused to flow through the hollow fiber membranes, and a gas contained in the liquid is removed by external aspiration, or a gas is caused to blend into the liquid in the hollow fiber membranes by pressurizing an external gas (see Japanese Patent No. 3370407 publication).
One exemplary total organic carbon measuring instrument for measuring total organic carbon in a sample water is equipped with an organic compound oxidative decomposing part for converting organic carbon into carbon dioxide; a carbon dioxide extracting part for extracting carbon dioxide generated in the organic compound oxidative decomposing part into pure water; and a detecting part for detecting conductivity of pure water in the carbon dioxide extracting part for quantifying the carbon dioxide extracted in the carbon dioxide extracting part.
In such a total organic carbon measuring instrument, for transferring carbon dioxide from a sample water having been subjected to oxidation process in the organic compound oxidative decomposing part into pure water, in the carbon dioxide extracting part, the sample water and the pure water are arranged with a gas permeable membrane or a porous membrane intervened therebetween so that carbon dioxide in the sample water is transferred into the pure water via the gas permeable membrane or the porous membrane.

Abstract: [MEANS FOR SOLVING PROBLEMS] A gas exchange chip comprises substrates (1,2); two flow channels (3,4) formed in the substrates (1,2) and each having an inlet port and an outlet port; and multiple grooves (9) interlinking the flow channels (3,4). The grooves (9) have the size of their sectional area predetermined and have at least a part of the internal surface thereof rendered hydrophobic so as to permit the transfer of gas component while inhibiting any liquid passage. A sample water containing carbon dioxide is caused to flow through one of the flow channels (3) while pure water is caused to flow through the other flow channel (4) to thereby transfer the carbon dioxide contained in the sample water into the pure water.


A method and a system for improving recall of speech data in a computer speech system can include a plurality of speech cache management steps including providing a speech cache, receiving a speech system input and identifying a speech event in the received speech system input, the speech event comprising speech data. Subsequently, the speech data can be compared to pre-determined speech cache entry criteria; and, if the speech data meets one of the pre-determined entry criteria, at least one entry can be added to the speech cache, the at least one entry corresponding to the speech data. Additionally, the speech data can be compared to pre-determined speech cache exit criteria; and, if the speech data meets one of the pre-determined exit criteria, at least one entry can be purged from the speech cache, the at least one entry corresponding to the speech data. The entry criteria can include frequently used speech data, recently used speech data, and important speech data. Similarly, the exit criteria can include least frequently used speech data associated with each entry in the speech cache, least recently used speech data associated with each entry in the speech cache and least important speed data associated with each entry in the speech cache.

(Not Applicable)
(Not Applicable)
1. Technical Field
This invention relates to the field of speech recognition software, and more particularly, to using a speech cache in conjunction with a speech recognition `application to improve system performance.
2. Description of the Related Art
Speech recognition is the process by which an acoustic signal received by microphone is converted to a set of text words by a computer. These recognized words may then be used in a variety of computer software applications for purposes such as document preparation, data entry, and command and control. Improvements to speech dictation systems provide an important way to enhance user productivity.
Some speech recognition applications cannot recognize a user spoken utterance identifying a word or a word phrase without the aid of attributes. This is particularly true of embedded speech recognition applications having limited vocabularies, such as the variety used in navigation systems in automobiles. Attributes provide the speech recognition system with supplemental information detailing the user spoken utterance. Oftentimes, for such a speech recognition system to recognize a user spoken utterance, the user must also issue a lengthy series of attributes. For example, if the user utters a phrase recognized as a speech command such as xe2x80x9chow farxe2x80x9d in conjunction with a speech object, xe2x80x9cRoller Coaster Worldxe2x80x9d, then the system may require attributes identifying the object within the speech command. In this case, to properly identify the object xe2x80x9cRoller Coaster Worldxe2x80x9d to the speech recognition system, attributes such as xe2x80x9cU.S.A.xe2x80x9d, xe2x80x9cFloridaxe2x80x9d, xe2x80x9cOrlandoxe2x80x9d, and xe2x80x9camusement park named Roller Coaster Worldxe2x80x9d may be necessary. Using attributes to specify a speech object within a speech command can be analogized to navigating through a system of computer directories to find a particular computer file.
Even more troublesome is the case when the user repeatedly issues the same speech command or issues a series of subsequent speech commands involving the same object. This situation commonly occurs in the case of a user driving to a distant location for vacation. Conventional systems do not store previously issued speech commands, objects, or attributes. Thus, each time the user issues a speech command regarding a previously identified object, the user must also provide the system with the previously mentioned attributes identifying the object. For example, each user command requesting information such as the distance or route to xe2x80x9cRoller Coaster Worldxe2x80x9d must be accompanied by the lengthy list of attributes identifying xe2x80x9cRoller Coaster Worldxe2x80x9d to the system. A significant amount of time and efficiency could be gained if speech recognition systems having a limited vocabulary could more efficiently recall previously used commands or objects.
The invention disclosed herein for improving system performance of speech systems in accordance with the inventive arrangements satisfies the long-felt need of the prior art by using a speech cache and speech cache logic in conjunction with the recognition system. Such speech systems can recall particular objects or speech commands from a speech cache, thereby eliminating the need for users to continually utter redundant attributes to the speech system in an effort to properly describe a speech object. Because speech systems frequently use a set of commands or objects, the cache is a cost effective method of enhancing memory systems using statistical means, without having to resort to the expense of making the whole memory system faster.
The invention concerns a method and a system for improving recall of speech data in a computer speech system. Significantly, the speech system can be an embedded computer speech system. The method of the invention involves a plurality of speech cache management steps including providing a speech cache; receiving a speech system input and identifying a speech event in the received speech system input, the speech event comprising speech data. Subsequently, the speech data can be compared to pre-determined speech cache entry criteria; and, if the speech data meets one of the pre-determined entry criteria, at least one entry can be added to the speech cache, the at least one entry corresponding to the speech data. Additionally, the speech data can be compared to pre-determined speech cache exit criteria; and, if the speech data meets one of the pre-determined exit criteria, at least one entry can be purged from the speech cache, the at least one entry corresponding to the speech data.
In the preferred embodiment, the entry criteria comprises frequently used speech data, recently used speech data, and important speech data. Similarly, the exit criteria can comprise least frequently used speech data associated with each entry in the speech cache, least recently used speech data associated with each entry in the speech cache and least important speed data associated with each entry in the speech cache.
The method of the invention can also include a speech cache filtering process. Specifically, an embodiment incorporating speech cache filtering can compare entries in the speech cache with filtering criteria; and, sort the entries according to the filtering criteria. The filtering criteria can comprise frequency of use of speech data associated with each entry in the speech cache, least recency of use of speech data associated with each entry in the speech cache, and importance of use of speech data associated with each entry in the speech cache.
In the preferred embodiment, the speech system input can be one of a system event and a speech event. To accommodate system events, the method of the invention can further establish a table of system events and corresponding speech cache commands. Responsive to receiving a system event, the received system event can be compared to the system events in the table. If the received system event matches a system event in the table, the speech cache command corresponding to the matching system event in the table can be performed. Notably, the corresponding speech cache commands can include purge commands and add commands.
In the preferred embodiment, the comparing step can comprise evaluating the speech system input against user-configurable rules for adding and deleting from the speech cache entries corresponding to the speech data, the rules based on frequency of use of the speech data, recency of use of the speech data and importance of use of the speech data. Similarly, the comparing step can comprise the step of evaluating the speech system input against system configured rules for adding and deleting from the speech cache entries corresponding to the speech data, the rules based on a pre-specified list of speech data. Significantly, comparisons performed against the system-specified entry and exit criteria can be overridden with the comparisons performed against the user-specified entry and exit criteria
In a preferred embodiment, the method of the invention can further include establishing a frequency counter for the speech data. Responsive to receiving a speech event, the frequency counter corresponding to the speech data can be incremented. Thus, the comparing step can comprise evaluating the speech system input against user-configurable rules for adding and deleting from the speech cache entries corresponding to the speech data, the rules based on frequency of use of the speech data. In that case, the frequency can be measured by the frequency counter established for the speech data. Moreover, the adding step cans be performed in response to a frequency indicated by the frequency counter exceeding a pre-determined threshold. Likewise, the deleting step can be performed in response to a frequency indicated by the frequency counter falling below a pre-determined threshold.
Advantageously, the method can further comprise the steps of sensing when the speech cache is full; and, responsive to sensing a full speech cache, purging entries from the speech cache according to pre-determined purging criteria. Notably, like the exit criteria, the purging criteria can include least frequently used speech data associated with each entry in the speech cache, least recently used speech data associated with each entry in the speech cache and least important speed data associated with each entry in the speech cache. The purging step can include the steps of: displaying a list of speech cache entries sorted according to the purging criteria; accepting confirmation from a user before purging entries in the speech cache selected for purging based on the purging criteria; and, in response to receiving the confirmation, purging the selected speech cache entries.
Finally, in an alternative embodiment of the present invention, the method can include the steps of associating expiration data with at least one entry in the speech cache; and purging the associated entries in the speech cache according to the expiration data. In the alternative embodiment, the associating step can comprise the steps of accepting user-specified expiration data; and, associating the user-specified expiration data with at least one user specified entry in the speech cache.
According to a second aspect, the invention can be a computer speech system for managing a speech cache. Significantly, the speech system can be adapted for use in a vehicle. Moreover, the speech system can be adapted for use in a vehicle navigation system. In the second aspect of the invention, the system can comprise: a speech enabled application where the speech enabled application is coupled to a speech recognition engine and the speech enabled application and the speech recognition engine are configured to process speech data. Also included is a speech cache for storing entries corresponding to the speech data and predetermined speech cache entry and exit criteria. The entry criteria specify rules for adding entries corresponding to the speech data to the speech cache. Similarly, the exit criteria specify rules for purging entries corresponding to the speech data from the speech cache. Finally, the system can include speech cache logic for comparing the speech data to the pre-determined entry and exit criteria. The speech cache logic can add to the speech cache at least one entry corresponding to speech data meeting the pre-determined entry criteria. Likewise, the speech cache logic can purge from the speech cache at least one entry corresponding to speech data meeting the pre-determined exit criteria.
In the preferred embodiment, the speech cache is a circular cache. Moreover, the entries in the speech cache comprise speech commands, speech objects, pointers to speech commands and pointers to speech objects. The entries can further comprise at least one entry having corresponding expiration data. In that instance, the speech cache logic can purge the at least one entry having corresponding expiration data according to the expiration data.
In the preferred embodiment, the speech cache logic is adapted to receive system events in the speech system. The speech cache logic can further include a table of system events and corresponding speech cache commands. The speech cache logic can be adapted to perform a speech cache command in response to receiving a corresponding system event. Notably, the pre-determined entry and exit criteria can include a speech cache command, frequency of use of the speech data, recency of use of the speech data and importance of use of the speech data. Moreover, the speech cache command can include an add command and a purge command.
The system can further include pre-determined purging criteria. Where the system includes purging criteria, the speech cache logic, in response to receiving the purge command, can purge entries in the speech cache according to the purging criteria. Like the pre-determined exit criteria, the pre-determined purging criteria can include frequency of use of the speech data corresponding to the entries in the speech cache, recency of use of the speech data corresponding to the entries in the speech cache and importance of use of the speech data corresponding to the entries in the speech cache. Finally, a system in accordance with the inventive arrangements which incorporates purging criteria can further include a display for displaying to a user a list of entries in the speech cache selected for purging based on the purging criteria. As such, the system can confirm the purge command before purging the selected entries.
The speech cache logic can further comprise filtering logic for sorting the entries in the cache according to pre-determined filtering criteria. Like the entry criteria, the filtering criteria can comprise frequency of use of the speech data corresponding to the entries, recency of use of the speech data corresponding to the entries and importance of use of the speech data corresponding to the entries. Notably, in the preferred embodiment, the speech cache logic can further comprise at least one incrementable frequency counter corresponding to particular speech data. In consequence, the frequency of use of the particular speech data can be indicated by the frequency counter. In the preferred embodiment, the frequency counter can be incremented in response to the speech cache logic receiving an instance of the particular speech data from the speech system.
According to a third aspect, the invention may comprise a machine readable storage, having stored thereon a computer program having a plurality of code sections executable by a machine for causing the machine to perform the above-described method of the invention.

International Business Machines Corporation


The present disclosure relates to a third generation tubulysin analogues and process of preparation thereof. The present disclosure also relates to a method of using these third generation tubulysin analogues for treatment of various diseases including cancer.

Cancer is known since ancient times and first reported by Egyptian and Greek physicians. Suffering from cancer has been observed in all age groups of global society, and the World Health Organization mark says one out of six deaths globally by cancer. Past 20 years, we have seen paradigm in the treatment of cancer. However, the current status of cancer treatment is very challenging because of the scarcity of FDA approved anticancer drugs, complex synthetic protocols, non-targeted drug delivery, development of drug resistance in cancers, and low bio-stability of the drug in the blood serum. The few FDA approved cancer therapies are very expensive which restrict its approachability to low economic patient group.
Currently available portfolio of anticancer drugs has its own drawbacks. These agents have shown side effects like hair and skin changes, anemia, bowel dysfunction, immune suppression, lung dysfunction, along with nausea, weight changes, and dietary issues. The nonspecific binding of anticancer drugs is responsible for these side effects. Targeting for cancer-specific cells can be achieved by conjugating the anticancer drugs with either monoclonal antibody or targeting ligand, which specifically binds with an antigen over-expressed over cancer cells. In cancer treatment, microRNAs (miRNAs) have received wide attention of researchers as they control the expression of the gene at the level of post-transcription. However, this approach has faced challenges because in vivo experimental models have reported low stability of RNA. This technique also encountered difficulties of targeted delivery along with the nonspecific binding of miRNAs. The miRNAs also affected by the first-pass metabolism.
Over the years, various researchers successfully targeted tubulysin derivatives to several cancer cell lines through this concept. Studies have suggested that cancer cells have at least two molecular pumps that expel out the cancer drug molecules. This leads to the condition of the multi-drug resistance of cancer cells against the treatment. This cellular response is accountable for the failure of a large number of chemotherapeutic agents available. In research, it has been identified that tubulysins do not get effluxed by these molecular pumps. So tubulysin derivatives have become potential drug candidates for the treatment of multidrug-resistant cancers.
The microtubule system has a very significant role in cellular events like maintenance of cellular morphology, control of intracellular transportation, regulation of mitotic spindle fiber formation, and cell division (Theg, D. E. Cytoplasmic microtubules in different animal cells. J. Cell. Biol. 1964, 23, 265-275). Significance of microtubule formation is further increased in the cancerous condition where frequent mitotic spindle formation is highly demanded for uncontrolled proliferation of cancer cells. Therefore, inhibition of microtubule formation emerges as a powerful tool to arrest or treat cancerous growth. Any event that disrupts microtubule assembly formation leads to mitotic arrest at metaphase of cell cycle and ultimately induces apoptosis of cells (Wilson, L. Action of drugs on microtubules. Life Sci. 1975, 17, 303-309). Microtubule dynamics is controlled by polymerization and de-polymerization of α- and β-tubulin proteins. Consequently, researchers have identified natural products or small molecules that block either polymerization or de-polymerization of tubulin protein and exhibit the cytotoxic effect intended to kill the cancer cells (Nogales, E.; Wolf, S. G.; Downing, K. H. Structure of the αβ tubulin dimer by electron crystallography. Nature, 1998, 391, 199-203). Recently, a family of natural products called tubulysins and their derivatives have emerged as an outstanding candidate for tubulin polymerization inhibitor. Höfle et al. (2000) first isolated tubulysin derivatives from two strains of Myxobacteria culture broths Angiococcus disciformis and Archangium gephyra (Sasse, F.; Steinmetz, H.; Heil, J.; Höfle, G.; Reichenbach, H. Tubulysins new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties. J. Antibiot (Tokyo). 2000, 53, 879-885). The natural tubulysin derivatives are termed as tubulysin A to I, U, V, and Z (FIG. 1). The structural composition of tubulysin family of natural products consists of four amino acid fragments. The first fragment is F-tubuphenylalanine or F-tubutyrosine, which is sequentially connected with F-tubuvaline, F-isoleucine, and N-methyl pipecolic acid. In few of the tubulysin derivatives, the amide linkage of tubuvaline and F-isoleucine is also functionalized. This family of natural products is the first generation of tubulysin antimitotic agents with several stereocenters.
Exhaustive literature search mentioned above concludes that the tubulysin derivatives are recognized as potent anticancer drugs with potency in nano to picomolar range to kill fast dividing cells. Isolation of natural tubulins is performed by the fermentation process. Conventionally used processes as such are extremely time consuming, expensive, laborious, often resulting in poor yields (0.5 mg to 4 mg per liter). Further, these methods also require multiple purification processes for isolation of a single derivative from the fermentation mixture, thereby making the whole process very cumbersome. The total synthesis of tubulysin derivatives by conventional processes is also challenging because fragments are complicated to synthesize, and epimerization occurs at various steps of synthesis. Moreover, these synthetic steps are inefficient and very intricate, with low yields
Multiple research groups have put their efforts to synthesize either fragments or complete tubulysin natural products or their derivatives. Among them, Hofle., G et al in Pure Appl. Chem. 2003, 75, 167-178; Domling (Tetrahedron Lett. 2003, 44, 8947-8950), Wipf (Org. Lett. 2004, 22, 4057-4060) and Friestad (Org. Lett. 2004, 6, 3249-3252) have reported the total synthesis of L-tubuvaline and L-tubuphenylalanine/L-tubutyrosine fragments of tubulysin. The biosynthetic precursor tubulysin, named pretubulysin, was identified by Muller's group in year 2004 and his group later explored the inhibitor for its tubulin depolymerization activity (Sandmann, A.; Chem. Biol. 2004, II, 1071-1079). After two years in 2006, Ellman's research group developed a total synthesis (16-steps) of tubulysin D with 13% overall yield. As research on tubulysin family progressed, various biological pathways were identified for its cytotoxic property (Peltier, H. M.; et al. J. Am. Chem. Soc. 2006, 128, 16018-16019). For the first time, Agarwal's research group in 2006 explored the antiangiogenic property of the tubulysin A.
Meanwhile, new synthetic derivatives of natural tubulysin were also explored to identify its structure activity correlation for cytotoxic activity. In year 2007, the Ellman's group reported ten analogues of tubulysin D by modifying different fragments. They suggested that the modifications in fragments are well tolerated. In the same year, Wipf's group reported a total asymmetric synthesis of N14-desacetoxytubulysin H in 20-steps with only 2.1% overall yield. This molecule later named as tubulysin M suggest that N,O-acetal fragment is not crucial for inhibitory activity. Further in 2008, Fecik's research group also developed new and simplified derivatives of tubulysin by modifying N-methyl pipecolinic acid and L-tubuphenylalanine residues. However, cytotoxic activities of these derivatives were found to be in the micromolar range not suitable for preclinical trials. In the same year, Ellman optimized the asymmetric total synthesis of tubulysin derivative with linear steps and 40% overall yield.
As tubulysin was established as potent cytotoxic agent, research groups put the efforts to target it by conjugating with targeting ligand and also developed various drug delivery systems. In 2008, Endocyte, Inc. USA successfully conjugated potent tubulysin derivative with folic acid to target the folate receptor positive cancers and thereby developed the first targeted therapy of tubulysin derivative. They have claimed the folate targeted antiproliferative activity of water-soluble folic acid conjugated tubulysin derivative by in vitro and in vivo models (Leamon, C. P.; Cancer Res. 2008, 68, 9839-9844). Later in year 2009, Schluep's group covalently attached the tubulysin A to linear, β-cyclodextrin based polymer through disulfide linker and evaluated its activity by in vitro and in vivo models. These prodrug constructs improved the therapeutic index of tubulysin derivatives but failed to show further clinical efficacy (Schluep, T.; Clin. Cancer Res. 2009, 15, 181-189). Further in year 2011, Ellman conjugated tubulysin analogue with dendrimer by acyl hydrazone linkage and developed a polymeric drug delivery system for tubulysin derivatives. This improved the stability, lowered the toxicity, and enhanced the water solubility for in vivo evaluation (Floyd W. C.; et al, Chem. Med. Chem. 2011, 6, 49-53).
Wessjohann's group, in year 2011, reported the second generation of tubulysin derivative named "Tubugis" by multicomponent reactions. In the new derivatives N,O-acetal ester moiety, which is sensitive for acidic and basic condition, is replaced by more stable retro-amide. The GI50 value for tubugis derivative is in the high picomolar range which is quite interesting (Pando, O.; et. al, J. Am. Chem. Soc. 2011, 133, 7692-7695).
In the year 2014, Dongen's groups developed antibody-drug conjugate using tubulysin derivative as drug. In this research, they have radiolabelled two tubulysin derivatives and conjugated with the anti-HER2 monoclonal antibody (mAh), named trastuzumab, and successfully analysed its potential for targeting tumour and consequently antitumor effects in nude mice (Cohen, R.; Cancer Res. 2014, 74, 5700-5710). In the same year, Steinmetz's group identified a new binding site which is different from vinca domain and consequently inhibits the longitudinal interactions of tubulin protein (Protaa, A. E.; et al, PNAS. 2014, 111, 13817-13821).
In the year 2015, Low's group developed another targeted therapy by conjugating the tubulysin B with cholecystokinin 2 receptor targeting ligand. Cholecystokinin 2 receptor is overexpressed in many lung, pancreas, liver, and GI tract cancers. They selectively delivered tubulysin B to Cholecystokinin 2 receptor-positive tumors (Wayua, C.; et al, Mol. Pharmaceutics. 2015, 12, 2477-2483).
Further, more synthetic derivatives based on second generation tubulysin, tubugi, were developed and evaluated by Kazmaier's group (2015) by modifying the acylal side chain. They reported that nonpolar side chains like allyl or propargyl groups are more tolerated, while polar side chains like amide are less tolerated for cytotoxic activity (Hoffmann, J.; et al Org. Biomol. Chem. 2015, 13, 6010-6020). In the same year, Ryu and Lee developed new derivatives of tubulysin where tubuvaline moiety was cyclized. They reported that the cyclization induced the structural rigidity, which drastically reduced the tubulin polymerization efficacy. They reported that the cyclization induced structural rigidity drastically reduced tubulin polymerization efficacy. They reported that the cyclization induced the structural rigidity, which drastically reduced the tubulin polymerization efficacy (Park Y.; et al Bioorgan. Med. Chem. 2015, 23, 6827-6843).
Toader's group (2016) modified the N-methyl pipecolic acid and tubuphenylalanine moieties with various different fragments and explained the relationship between the basicity of N-terminus of tubulysin derivative and its cytotoxicity (Toader, D.; et al J. Med Chem. 2016, 59, 10781-10787). In the same year, Nicolaou's group also synthesised several tubulysin derivatives by modifying all four fragments and evaluated its cytotoxic activity. They have summarized all the results as a structure-activity relationship and claimed that N-methyl-D-pipecolinic acid is essential for activity, whereas isoleucine domain can be modified by other lipophilic groups. Also, L-tubuvaline and L-tubuphenylalanine are much affected by modification for their cytotoxicity activity (Nicolaou, K. C.; et al J. Am. Chem. Soc. 2016, 138, 1698-1708).
A similar analysis was also performed by Wipf (2016), and he tabulated some of the tolerated and non-tolerated fragments for N-methyl-D-pipecolinic acid, tubuvaline, and tubuphenylalanine (Colombo, R.; et al, J. Org. Chem. 2016, 81, 10302-10320). Further, in the same year, Zhang's group provided the pharmacophoric details of tubulysin derivatives. They analyzed the crystal structure of microtubule with tubulysin M as a co-crystallised inhibitor. They claimed that tubulysin predominantly bound with the β subunit of tubulin and exhibited the cytotoxicity effect (Wang, Y.; Benz, F. W.; Wu, Y.; Wang, Q.; Chen, Y.; Chen, X.; Li, H.; Zhang, Y.; Zhang, R.; Yang, J. Structural insights into the pharmacophore of vinca domain inhibitors of microtubules, Mol. Pharmacol. 2016, 89, 233-242). Further in 2016, tubulysin based antibody-drug conjugate was optimised by Turney's (Turney, L. N.; et al, ACS Med. Chem. Lett. 2016, 7, 977-982) along with Leverett and Sukuru's group of Pfizer inc. USA (Leverett, C. A.; Sukuru, et al, ACS Med. Chem. Lett. 2016, 7, 999-1004). They designed tubulysin derivatives which might be the best candidates for antibody drug conjugation and having less liability for metabolism and with improved cytotoxicity.
In year 2017, Low's group developed tubulysin based therapy by selectively targeting cancer cells which overexpress carbonic anhydrase IX. They reported that the conjugate shown cytotoxicity in the range of mid-nanomolar and also good tumor selectivity in the in vivo models (Lv, P. C.; Roy, J.; Putt, K. S.; Low, P. S. Evaluation of Nonpeptidic Ligand Conjugates for the treatment of hypoxic and carbonic anhydrase IX-expressing cancers. Mol. Cancer. Ther. 2017, 16, 453-460). In the same year, Low's group developed one more therapy targeting neurokinin 1 receptor-expressing cancers like melanomas, gliomas neuroblastomas, pancreatic ductal carcinomas, retinoblastomas, invasive breast cancers and colon carcinomas. In this therapeutic construct, targeting ligand is connected to tubulysin B hydrazide through a hydrophilic linker. The IC50 of developed tubulysin based therapeutic agent was found to be 10 nM (Kanduluru, A. K.; Low, P. S. Development of a ligand-targeted therapeutic agent for neurokinin-1 receptor expressing cancers. Mol. Pharmaceutics. 2017, 14, 3859-3865). In same year, Pillow's group reported an approach to develop stable and bio-reversible antibody-tubulysin conjugate without loss of activity (Staben, et al, ACS Med Chem. Lett. 2017, 8, 1037-1041). Also, Parker's group from AstraZeneca reported the solid phase peptide synthesis-based development of antibody-tubulysin conjugate payload. They optimized the synthetic strategy and achieved overall yield from 0.01% to 2.4%.
In 2018, Endocyte performed preclinical and clinical (Phase I and II) evaluation of this targeted therapy. They reported that the treatment showed substantial anti-cancer activity against the animal model of FR-positive tumors, even in drug-resistant cases. In the same year, Nicolaou's group designed and synthesized various tubulysin-based derivatives, and some derivatives shown excellent cytotoxic potency in the range of pico-molar. In 2018, our research group also reported new strategy for the synthesis of L-tubuphenylalanine and epi-tubuphenylalanine fragments of tubulysin. In 2019, Endocyte targeted prostate cancer biomarker named prostate-specific membrane antigen (PSMA), by conjugating tubulysin B with a targeting ligand. Through in vitro and in vivo evaluation, they claimed that PSMA positive cancer could be treated by tubulysin based PSMA targeting conjugates, but the human clinical trials have a glitch due to possible instability of the tubulysin family of natural products in the serum.
In 2019, a new strategy for large scale synthesis of deacetoxytubuvaline fragment of pretubulysin and its highly lipophilic methyl-substituted thiazole and oxazole analogues for incorporation into pretubulysins was reported (Reddy, R. B.; Dudhe, P.; Chelvam, V. Synthesis of the deacetoxytubuvaline fragment of pretubulysin and its lipophilic analogues for enhanced permeability in cancer cell lines, Synlett. 2019, 30, 77-81). The strategy is mentioned in FIG. 2.
In an unpublished work, (Reddy, R. B.; Chelvam V) has also developed a convenient strategy for the practical and scalable synthesis of L-tubuvaline fragment of L-tubulysin natural products by asymmetric dihydroxylation of N-tosylhomoallylamine from commercially available L-valine. The synthetic strategy developed in our laboratory is depicted in FIG. 3. Though the strategy is simple and reduced the total number of linear steps, the preparation of thiazole in large quantities posed a big problem in industrial manufacturing sectors. Therefore, we resorted to a disruptive modification step to change the molecular structure of tubulysin totally to obtain third generation of tubulysin family of natural products. This can be performed by replacing sensitive, pharmacologically active moiety F-tubvaline fragment containing a chiral centre and thiazole moiety with another thiazole moiety without any chiral center, as shown in FIG. 3.
Thus, it is desired to address the above-mentioned disadvantages or other shortcomings or at least provide a useful alternative. The present disclosure herein solves the above problems by third-generation tubulysin derivatives, fragments of which are easy to synthesize by traditional solution-phase synthesis, and all the fragments are coupled by solid-phase peptide synthesis.

Third generation tubulysin analogues and process of preparation thereof


A system is provided to monitor a structure within an outer casing of a gas turbine engine. The system may comprise an optical fiber bundle, a fiber bundle palette and a camera palette assembly. The optical fiber bundle may have first and second ends. The first end is adapted to pass through a bore in the outer casing of the gas turbine engine so as to be positioned adjacent the structure within the gas turbine engine casing to be monitored. The fiber bundle palette is adapted to be located outside of the engine casing to receive the second end of the optical fiber bundle. The camera palette assembly comprises a fixture movable relative to the fiber bundle palette and a first camera mounted to the fixture. The first camera is adapted to be positioned adjacent to the second end of the optical fiber bundle so as to receive electromagnetic radiation received by the first end of and transmitted through the optical fiber bundle.

Thermal barrier coatings (TBCs) applied to turbine airfoils are well known in the art for protecting parts such as blades and vanes from elevated operating temperatures within a gas turbine engine. However, TBCs are subject to degradation over their service life, and need to be inspected periodically to assess the integrity of the coating. Further, inspection of cooling ducts/openings in turbine airfoils is needed.
Other components within a gas turbine engine also need to be periodically inspected, such as vanes and blades in a compressor of the gas turbine engine for cracks or surface damage. It is also necessary to inspect the locations where the compressor vanes are coupled to a vane carrier to make sure the vanes are properly seated. Inspection of other gas turbine engine components such as combustor baskets is also required.
In the past, inspection of gas turbine engine components has been performed by partially disassembling the turbine engine and performing visual inspections on individual components. In-situ visual inspections may be performed without engine disassembly by using a borescope inserted into the turbine engine, but such procedures are labor intensive, time consuming, and require that the gas turbine engine be shut down, and the rotating parts held stationary for the inspection. Other inspections techniques have also been proposed, such as those disclosed in U.S. Pat. No. 6,992,315 and Patent Application Publication Nos. U.S. 2006/0078193 A1 and U.S. 2006/0088793 A1, the entire disclosure of each of these published patent and applications is hereby incorporated by reference herein.
An improved system for monitoring components within a gas turbine engine is desired.

System to monitor a structure within an outer casing of a gas turbine engine