An apparatus and method in which illumination light and collected emitted light share a pathway and subsequently are physically separated. The optical configuration is designed such that at the point of separation, the illumination light is at has a smaller cross sectional area than the collected light. Collected light is directed away from the pathway of the illumination light and to detection optics. This configuration is adaptable to illumination and light collection across a broad wavelength spectrum. This configuration is adaptable to scanning in a limited depth of field to allow high throughput optical analysis of samples.

This invention relates to optical detection instruments more particularly optical detection systems that may illuminate, collect and detect light of a broad spectral range of wavelengths.
In chemical, biochemical and cellular analytical systems, imaging provides a powerful tool. The imaging may use fluorescence, luminescence (e.g. chemiluminescence) or radio labels in a large number of analytical procedures. This imaging allows very sensitive detection. The use of such labels is well characterized, for example as detection agents conjugated to probes or binding agents. Alternatively the label may be directly incorporated into a target of interest. The sensitivity of these labels allows detection of rare events and rapid sample analysis. Optical analysts may be applied to a number of different analytical applications including identification of compounds, assay of array of biomolecules (e.g. biopolymers) or assay of binding events (e.g. competitive binding).
The benefits of imaging technology have led to widespread application of this technology to research needs. One benefit of optical screening has been in increased throughput. The speed and sensitivity of optical scanning is adaptable to automated high throughput assays that are required for screening large numbers of samples against numerous interaction agents.
Developments in the fields of genomics, cytology and chemistry have produced challenges for the evaluation and analysis of large numbers of unique samples, compounds or biological isolates.
For example, in the field of genetics, the human genome project and other genome sequencing efforts have identified tens of thousands of unique oligonucleotide sequences. Screening of gene expression against these known sequences would provide information on gene expression and regulation. This information could be correlated with disease states or applied to evaluate response of cells to therapeutic treatment (e.g. for clinical evaluation of potential pharmaceutical evaluation, monitoring of response to therapy, etc.). Labeled mRNA or cDNA isolated from cells could be used in expression evaluations. Alternatively, genomic fragments may be screened against known sequences to determine homology between the screened DNA and known genes.
Clinical evaluation of DNA expression could require analysis of DNA from hundreds of thousands of individuals. This analysis could involve screening of nucleic acid isolations from hundreds of different cell types against tens of thousands of unique oligonucleotide sequences. The present need for throughput has motivated the development of multiplexed, automated, high throughput analysis of nucleic acid homology.
There is no single, standardized technology for nucleic acid analysis. In part this is a result of the differing throughput needs. The density of analytical arrays or the scale of separation analysis of DNA will depend on the amount of samples that are being analyzed. Gene expression analysis may be performed in wells on a multiwell plate, on a separation gel, on a chip substrate containing an array of reaction spots or using other formats. If a separation gel or chip substrate is used, the separation substrate may either be read directly or transferred to another substrate, (e.g. a transfer [blotting] membrane). Alternatively, an emitted signal from an assay of samples (e.g. chemiluminescent signal, radio signal) may be recorded on a storage device (e.g. a storage phosphor screen), which is subsequently analyzed. The samples of interest may be detected by detecting a signal associated with the sample.
In addition to the label and substrate variability, the sample size may vary. This may range from the relatively large target from a separation gel to a spot on a chip array, which may be orders of magnitude smaller. Presently, most automated analytical systems are limited in types of substrates and target densities that the system is able to analyze. The data from different analytical systems often must be subsequently combined to make a finalized evaluation of a biological sample or compound.
High throughput analysis ability is required to analyze sample nucleic acids using known sequences to study genetic variation, differential expression, etc. High throughput systems have taken advantage of automation to increase sample analytical rate. Optical analytical systems may further increase sample processing throughput by designing systems with multiplex capability. For example, the ability to distinguish multiple dyes at a single dye location allows a number of dyes, each associated with a unique probe or binding agent to be used in a single assay. The combination of markers may be used at a single target loci and distinguished by the analytical system by the unique dye emission wavelength profile. This further increases the information gained from each analytical scan and increases analytical throughput. However, this would only be possible in an analytical system in which the illumination and detection optics were adapted for use with a number of different emission profiles and could operate over a wide spectral range.
In a number of scanning fluorescent analytical instruments, the excitation light and the generated fluorescent emission share a pathway and must be optically separated. Some mechanism is needed to separate an excitation laser beam from a spectrally shifted collinear, counter propagating collected fluorescent light. Typical systems use a dichroic mirror to reflect wavelengths of the laser light and transmit wavelengths of the emission light. One example is seen in Baer et al. (U.S. Pat. No. 5,547,849). A laser produces coherent light that is directed onto a dichroic mirror. The mirror directs light of the wavelengths produced by the laser through an objective lens and onto a sample. The focused beam waist is directed onto a layer to be scanned. The emitted fluorescent light is collected by the objective lens and transmitted as a collimated retrobeam to the dichroic mirror. The mirror is selected to transmit the wavelengths of the collected fluorescent light to detection optics. An alternative system is seen in Kamentsky (U.S. Pat. No. 5,072,382). In this system a laser produces an illumination beam that is directed through a dichroic mirror and onto a focus lens. The focus lens focuses the illumination light onto a sample, exciting fluorescence. The lens collects excited fluorescent light, which is transmitted as a retrobeam to the dichroic mirror. Light of the fluorescent wavelengths is reflected by the mirror onto detection optics.
These arrangements allow the rapid scanning of a sample and detection of emitted light. However, these systems have several significant drawbacks. First, the coatings on dichroic mirrors may be angle sensitive when the coatings must filter or reflect multiple sets of wavelengths. A slight variation in angle can result a significant change in the wavelengths transmitted and reflected by the mirror coating. In such cases, the positioning of the mirror must be precise for proper functioning. Second, the coatings are designed to transmit and reflect specific spectral bands. This severely limits the illumination and emission wavelengths that may be used in the optical scanning system. Changing the excitation laser wavelength or the fluorescent dye (having an alternative emission profile) would require replacement of the dichroic mirror. For any one dichroic mirror, the system is locked into specific wavelength choices. Third, the coatings that are designed to transmit or reflect multiple excitation wavelengths must still be selected for specific wavelength bands. It is common that the excitation wavelength will encroach on an emission profile of a fluorescence dye. Since the dichroic mirror transmits only a selected range of wavelengths, some emission intensity outside of this range is lost. The separation of excitation and emission wavelengths may result in a substantial loss of the collected fluorescence due to the dichroic mirror not transmitting some emission light to the detectors.
Versatility in analyzing various analytical substrates is also important to maximize the utility of optical analytical systems. Presently, a number of different substrates are used to analyze bio-molecular samples. These include gels, microplates, membranes, arrays (disposed on plastic, glass or membranes) storage phosphor screens storing radiant energy images from various samples and other devices. At present, optical analytical systems are generally designed for analysis of a single type of device. The elements of an analytical device, such as the reading stage and the focusing optics are generally selected to be used with a single sample type. In many optical analytical systems fixed illumination optics determine an illumination geometry, limiting the range of targets sizes which may be illuminated by a single system. As applied this has meant that different analytical systems must be used for different analytical targets. An analytical system would have increased utility if the system were adaptable to a range of target sizes and target densities. This would allow a single analytical system to scan a number of different sample types and sample densities.
A number of different optical readers have been developed to provide technology to meet imaging needs. U.S. Pat. No. 6,043,506 describes an optical scanner in which optical fibers are fixed into a scan head for illumination and/or collection of light from a sample. The scan head is moved by a transfer gantry to scan the head in two dimensions over a sample surface. To ensure the scan head is operating within the desired parameters of the system, the scan head is moved to a separate calibration location prior to each scan. Although some control of the resolution of the scanning system is possible (e.g. by limiting the scanning geometry by finer graduated steps of the scan head), the fixed optics of the scan head provides a limit to the resolution of the scan system.
U.S. patents granted to Mathies et al. are also relevant to the field of the present invention. In U.S. Pat. No. 4,979,824, an optical analytical apparatus is described. This apparatus is based on a flow cytometry system and utilizes a spatial filter to define a small probe volume that allows for detection of individual fluorescent particles and molecules. Laser power and exposure time of the sample are selected to enhance signal-to-noise ratio. Real-time detection of photon bursts from fluorescent particles is used to distinguish the number, location or concentration of the particles from background energy.
In U.S. Pat. No. 5,091,652 to Mathies et al., a laser-excited fluorescent scanner is enclosed for scanning separated samples using a confocal microscope. Generally, the sample is separated on a slab gel by electrophoresis. The gel is subsequently optically analyzed. Alternatively, the sample may be analyzed on a membrane, filter paper, petri dish, or glass substrate. The confocal microscope directs an illumination laser beam into the sample with beam oriented so that background scattering is minimized by the polarization characteristics of the scattered light.
U.S. Pat. No. 5,274,240 also granted to Mathies et al. and a continuation-in-part of the above patent, teaches a capillary array scanner. This invention is primarily intended for fluorescence detection from a plurality of in-line capillary tubes containing samples that have been separated by capillary electrophoresis. The fluorescence detection assembly employs a confocal system to detect fluorescence from the interior volumes of each capillary tube.
U.S. Pat. No. 5,784,152 discloses an optical scanner for analyzing multiwell plates, gel plates, or u storage phosphor screens. The sample is illuminated with focused light that is xe2x80x9ctunedxe2x80x9d by filters to a selected illumination wavelength. The detection is also xe2x80x9ctunedxe2x80x9d by filters or other optical devices to allow for light detection at a selected wavelength. For both illumination and detection a bandpass filter is used as a primary wavelength selector. As with the prior referenced system, the system resolution is both fixed and fairly limited. The plate or gel is scanned by two-dimensional movement of the stage or illuminating light.
U.S. Pat. No. 5,591,981 discloses a method and apparatus that provides continuous tuning of excitation and/or emission in fluorescent imaging. For both illumination and detection, dispersive elements or filters are used to produce spectral shifts to transmit a selected wavelength range. A non-coherent, broad wavelength lamp is focused to illuminate the sample. The emitted light passes through a filter on a filter wheel and an interferometer. The light emission then passes onto a charge coupled diode detector. The detection system is tuned to different settings to allow individual, one-at-a-time detection of individual dyes.
In these optical systems, fixed sample scanning optics limit the system to relatively narrow ranges of detection resolution.
The scanning mechanism of the optical system impacts the throughput potential of the system. Movement of a scan head requires additional scan time, requires additional calibration and requires additional motor parts that increase system size. Transmission and collection of multiple wavelengths in optical fibers limits resolution. The optical transmission fiber diameter must be sufficient for multimode propagation if multiple wavelengths are transmitted through the fiber. Light may lose coherence when the light is propagated through multiple fibers. If the wavelengths are not aligned into various fibers (due to varying fiber length) the beam may lose Gaussian properties. In some systems, the use of long pass filters in conjunction with each detector limits each detector to detect a single wavelength intensity measurement.
It is an object of the invention to provide a reader for the optical analysis of a number of different substrates, including chip arrays, microplate wells, cells within microplate wells, gels and storage phosphor screens. It is a further object to allow the illumination and detection to be selectable across a number of wavelengths. It is a further object of the invention to be able to detect at a plurality of resolutions, including detection of discrete targets 1-100 um in width. It is a further object to enable detection of a greater number of dyes than detection channels used.
The objects are achieved with an optical analytical system that scans in a limited depth of field. The system allows illumination and detection at selectable wavelengths while also allowing for selectable resolution of detection. In this system, a selected set of one or more lasers provide excitation illumination. If multiple illumination sources are used, the beams may be optically combined into a single illumination beam or used individually. Separate optics split the illumination beam, diverting part of the beam into a beam detector that monitors beam output and power fluctuation. A selectable laser line filter is used with each laser to filter out wavelengths other than the selected laser wavelength.
The illumination beam may be directed through a zoom contractor/expander optic that shapes the beam spot. This multi-element lens is focused to shape the illumination beam, producing a beam spot of a selectable size at the targeted sample location. The beam spot size is selected to concentrate energy into a limited depth. This would allow optimized scanning of different density arrays. After passing through the beam expander/contractor optic, the beam is directed by a scanning optic that produces a beam scan in a first direction dimension. A galvo mirror, resonant scanner, rotating polygonal mirror, or acousto/optic scanner, or other scanning optic may be used to effect the beam scan. The focused scanned beam is directed onto the sample.
The emitted light is collected and sent to the detection optics. The objective acts as a wide angle light collector that collects light and transmits the light as a retrobeam to the detection optics. The excitation beam and emission light are separated using an optical element having a central optic, that directs the illumination light to the sample, surrounded by an annular optic that directs the collected emission light to the detection optics. This could be effected by a central broadly reflective mirror annularly surrounded by a transmissive material that allows collected emission light to pass to the detection optics. In another embodiment, a central hole in a broadly reflective mirror allows the illumination beam to pass through the illuminate the sample. The collected fluorescent light beam is radially much larger than the illumination beam. The collected retrobeam is reflected by the mirror onto detection optics.
In the present invention the beam focusing optics allow the system to be used to analyze a range of sample densities present on a number of different types of substrates. In one embodiment, the arrays are present on the bottom of multiwell plates. Autofocus mechanisms allow rapid focus onto the bottom of multiwell plates or other analytical substrates. Alternatively, storage phosphor screens may be scanned. The storage phosphor screen records the signal emitted from either a luminescent or radioactive label.


An image forming apparatus includes a color toner image forming device, a fixing device, a cooling device, a colorless toner image forming device, and a control device. The color toner image forming device forms a toner image on a recording medium with a color toner. The fixing device heats the toner image on the recording medium to fix the toner image on the recording medium. The cooling device cools the fixed toner image. The colorless toner image forming device forms a toner image on the recording medium with a colorless toner having a storage elastic modulus of 100 or less and a loss tangent of 10 or greater at a heating temperature of the fixing device. The control device controls cooling power of the cooling device based on whether or not the colorless toner image forming device forms the toner image.

1. Technical Field
Embodiments of this disclosure relate to an image forming apparatus, such as a copier, a printer, or a facsimile machine, equipped with a heat fixing device.
2. Related Art
In a typical electrophotographic image forming apparatus equipped with a heat fixing device, a toner image formed on a recording medium is subjected to heat and pressure via a fixing member to cause fusion or swelling in at least a part of a resin component of toner forming the toner image, thereby fixing the toner image on the recording medium. The heat fixing device is capable of providing a high fixed image quality at a high fixing speed, and thus is preferably used.
The image forming apparatus may include a cooling device that cools the toner on the recording medium heated by the heat fixing device.
In a commonly used image forming apparatus, toner images formed with toners of multiple colors, such as yellow, magenta, cyan, and black, (hereinafter referred to as process color toners) are superimposed on a recording medium and fixed thereon by a fixing device to obtain a color image.
With increasingly diversified image qualities in recent years, some image forming apparatuses employ a toner other than the process color toners to obtain high value-added prints unobtainable with normal process color toners. An example of the toner other than the process color toners is a colorless clear toner (also referred to as transparent toner, colorless toner, achromatic toner, or pigmentless toner). For example, some image forming apparatuses apply a high gloss clear toner over the entirety or a desired part of a color image print and fix the high gloss clear toner thereon with a fixing device, to thereby provide gloss to the entirety or the desired part of the print.

Image forming apparatus which includes a colorless toner image forming device


A three-dimensional morphological vessel model (20) can be obtained by assigning diameters (14,15) along the vessel derived from a two-dimensional morphological projection (10) at locations in the three-dimensional model defined by the temporal locations (21,22) of a trackable instrument (5). An apparatus (7), a system (1) and a method (100) for use of the system (1) in characterizing the vessel of a living being (2) by rendering a three-5 dimensional morphological vessel model (20) are presented.

A typical technique for identifying stenotic regions in a blood vessel is using angiography, whereas the functional impact of the stenosis is quantified with the fractional flow reserve (FFR) method. FFR is calculated from the ratio of pressures at the distal and proximal ends of the stenosis, measured with a sensor positioned at the tip of a wire. According to the FFR value the severity of the stenosis is established, specifically whether the stenosis limits blood flow within the vessel to an extent that treatment is required. Common treatment options include angioplasty, stenting or bypass.
Angiography, a fluoroscopy imaging technique in conjunction with radio-opaque contrast agents, can be used to visualize the vasculature of a patient.
U.S. Pat. No. 4,875,165 A describes a method for determination of three-dimensional structure in biplane angiography, including determining the distances of perpendicular lines from the focal spots of respective x-ray sources to respective image planes and defining the origin of each biplane image as the point of intersection with the perpendicular line thereto, obtaining two biplane digital images at arbitrary orientations with respect to an object, identifying at least eight points in both images which correspond to respective points in the object, determining the image coordinates of the eight identified object points in the respective biplane unknowns based on the image coordinates of the object points and based on the known focal spot to image plane distances for the two biplane images; solving the linear equations to yield the eight unknowns, which represent the fundamental geometric parameters of the biplane imaging system; using the fundamental parameters to calculate the three-dimensional positions of the object points identified in the biplane images; and determination of the three-dimensional positions of the vessel segments between the object points.
WO 2013001388 A1 discloses a method, and system for providing a live 3D image of a body lumen. The 3D shape of a flexible surgical tool in the body lumen is determined using optical shape sensing. An x-ray image is taken of the body lumen, with at least one of the body lumen and the surgical tool being radiopaque. The determined 3D surgical tool shape is registered to the x-ray image.


A system for the intelligent management of knowledge and delivery of content is provided. The system allows end users to access targeted fixes in connection with resolving problems with appliances, such as computers or other devices. The system further provides for the delivery of inventory information and information regarding attempts that have been made to fix problems with an appliance to technical support personnel. Technical support personnel may selectively access approved fixes or potential fixes through selections made from a tree of devices and/or problems or through the identification of key indicators. Technicians may also create fixes and made such fixes available to other technicians immediately.

The delivery of dynamically generated and intelligent content or knowledge (intelligent refers to the information being specifically targeted) to users of appliances, such as technical support, instructions or other information, is important to ensuring service quality and customer satisfaction. However, providing content or knowledge such as technical support is expensive and time-consuming. Furthermore, the process of obtaining technical support can be frustrating for end users, particularly where suggested fixes fail to correct the stated problem, where repeated contacts with technical support personnel are required, or where the end user is required to repeatedly explain their problem or questions to technical support personnel.
In a typical technical support solution, a technician may obtain information regarding the perceived problem being experienced by an end user each time technical support personnel are contacted. Furthermore, while such systems may enable technicians to take notes that can be viewed later by that technician or by other technicians, such notes are often incomplete, imprecise and disconnected. Therefore, identifying a problem being experienced by an end user and providing follow-up services typically require time-consuming and often repetitive queries directed to the end user or to the database regarding the problem appliance. In addition, technical support personnel have a limited body of information that they can draw from to provide end users with solutions. In particular, solutions generally consist of problem solving procedures that have been administered or created by other personnel and approved by yet another group for delivery to end users. This process can and often does lead to solutions taking weeks and/or months to be applied to real world systems for use by tech support personnel. Due to the creation of such solutions being so time-consuming, technical support personnel are often forced to work from adhoc tools or notes, and more often than not end up providing solutions to problems that are either out of date, or lack in consistency of delivery; this being especially true with regard to newly introduced systems, software or devices, or newly created or arising viruses, conflicts or other problems.
In order to assist technical support personnel in problem solving, systems may provide end users and/or the technicians with a knowledge base of information, for example consisting of frequently asked questions. However, knowledge bases are often difficult to search or require advanced understanding to use effectively, and often apply to slightly different situations or variances than those specifically addressed. Furthermore, although provision may be made for storing notes regarding solutions developed or applied by technicians in solving particular problems, such notes are generally not conveniently available to other technicians who would be assisting other end users during different and/or simultaneous time periods. As a result, knowledge gained by individual technical support personnel is often lost. In order to address this problem, technicians may be able to post solutions they have developed to administrators to be considered for inclusion in official solution procedures. However, because doing so typically requires review and editing, substantial amounts of time can elapse between development of the solution by a knowledge/programming engineer and the delivery and availability of that solution to support technicians.
In still other aspects, typical technical support systems require that technicians or end users access solutions based on correctly identifying a problem device or program. Accordingly, it may be difficult for the actual cause of problems to be identified, and solutions applied.

Collecting appliance problem information over network and providing remote technical support to deliver appliance fix information to an end user


A disclosed information processing system includes plural information processing apparatuses connected with a network. One of the plural information processing apparatuses includes: a first allocation unit to identify, for each subnetwork of plural subnetworks included in the network, one information processing apparatus from among information processing apparatuses included in the subnetwork, and assign to the identified one information processing apparatus, a first Reduce processing that is a processing to summarize results of a Map processing executed for data held in the information processing apparatuses included in the subnetwork; and a second allocation unit to allocate to any one of the plural information processing apparatuses, a second Reduce processing that is a processing to summarize results of the first Reduce processing executed for each subnetwork of the plural subnetworks.

In order to improve throughput when executing a large-scale MapReduce job over a wide area, it is extremely important that no delays in communication occur. Conventionally, the following technique was developed in order to suppress a drop in throughput due to delays in communication.
For example, in an Open Science Data Cloud (OSDC), it becomes possible to execute Hadoop over a wide area by connecting data centers using dedicated lines.
Moreover, in a wide area network, a processing for Transmission Control Protocol (TCP) is sometimes the cause of delays. Therefore, the use of a protocol called UDP-based Data Transfer Protocol (UDT) that is based on User Datagram Protocol (UDP) is proposed. Furthermore, in a technique that is called Sector/Sphere, UDT is employed as the core technique in order to achieve a distributed file system and parallel data processing.
In the technique that is called CloudBLAST, the throughput is improved by using a Wide Area Network (WAN) technique in the transport layer, which is called ViNe (Virtual Network).
However, there are cases in which the utilization of the techniques such as described above is not always suitable for a MapReduce job. For example, not only is the cost of techniques such as described above high, but flexibly analyzing data that is generated daily at data centers located around the world is difficult. Furthermore, when the transport-layer protocol other than TCP is used, there is a possibility that the existing firewall framework may not be usable, so there is a security problem.
Moreover, there is no conventional art that can improve the throughput in the MapReduce processing that is executed over a wide area.

Information processing system and control method thereof


A lock includes a shackle having a short first portion, a long second portion and a curved portion. The second portion has a groove defined in outside thereof. A body has a first hole and a second hole for receiving the first and second portions respectively. A passage is defined in outside of the body and perpendicularly communicates with the second hole. A positioning unit is located in the passage and has a securing member, a pin and a resilient member. The securing member has a path in which a narrowed section of the pin is inserted. The resilient member biases the pin which is engaged with the groove. When the pin is moved to compress the resilient member, the pin is removed from the groove and the narrowed section is located corresponding to the groove so that the second portion can be removed from the second hole.

The conventional padlock generally comprises a body with a core received in a space defined therein, and a shackle is connected to the body. The shackle includes a first portion, a second portion and a curved portion which is connected between the first and second portions, wherein the first portion is shorter than the second portion. A first hole for receiving the first portion, and a second hole for receiving the second portion is defined in the top of the body. A room is defined in the body and communicates with first hole. A threaded hole is defined from outside of the body and communicates with the second hole perpendicularly. The threaded hole has inner threads with which a bolt is threadedly connected. The bolt is a hexagonal bolt.
The core is located in the space and has a cam which is driven by a key, the cam is located corresponding to the room.
The second portion of the shackle has a groove and the first portion has a notch.
When the padlock is in locked status, the cam is located in the room and engaged with the notch so that the first portion cannot be removed from the first hole. When unlocking the padlock, the key is used to rotate the cam so that the cam is disengaged from the notch of the first portion of the shackle, and the first portion can be pulled out from the first hole. The bolt has one end thereof to seal the threaded hole and the other end of the bolt is engaged with the groove of the second portion, so that the second portion cannot be removed from the second hole. In other words, when replacing the shackle, the user has to remove the bolt from the body by using a specific tool to remove the hexagonal bolt. For safety concern, the bolt is designed to be connected to the threaded hole in only one direction, and cannot be removed in the opposite direction so that the bolt cannot be easily removed from the body and the replacement of the shackle becomes difficult.
The present invention intends to provide a lock whose shackle is easily replaced.


A plate spring includes holding section, first attached section, second attached section, first spring section connected between the holding section and the second attached section, and a second spring section connected between the first fixed portion and the second fixed portion. The holding section has a first edge, second edge opposite to the first edge, and a third edge. The first attached section is positioned adjacent to an intersection of the third edge and the second edge. The second attached section is positioned adjacent to an intersection of the third edge and the first edge. The first spring section has a wavy configuration and extends from an end of the first edge to the second attached section. The second spring section also has a wavy configuration and extends from an end of the second to the first attached section. The present disclosure also provides a voice coil motor.

1. Technical Field
The present disclosure relates to plate spring and a voice coil motor, and particularly, to a plate spring and a voice coil motor used in an anti-shake camera module.
2. Description of Related Art
Lens modules and image sensors are key components of camera modules. In normal use of a camera module, light rays coming from an object, transmit through the lens module along a predetermined path and fall on a central region of the image sensor. That is, an image plane of the object is precisely on the image sensor, and thus a clear image is obtained. However, inadvertent shaking of the camera module may occur during the time that an image is captured. When this happens, either or both of the lens module and the image sensor may move slightly relative to the object. In such case, the light rays from the object may not accurately fall on the image sensor. That is, the image plane of the object may not be precisely on the image sensor, resulting in a blurry image.
What is needed, therefore, is a plate spring and a voice coil motor used in a camera which can overcome the above shortcomings.


A hold-open for a refrigerator display case door having two slotted elongated members which are connected for linear sliding engaging on their respective inside surfaces. The inside surfaces of each elongated member is provided with a raised impediment which contact and ride over each other when the door is opened a sufficient amount, and thus place the door in a hold-open position.

1. Field of the Invention
This invention pertains in general to hardware for door opening, closing and holding open and in particular to devices for releasably holding open doors.
2. Description of Related Art
Devices for stopping the opening movement of a door hinged to a door frame and/or for holding doors open at a pre-determined position have application in many fields. For example, the automotive industry makes widespread use of such devices as evidenced by U.S. Pat. No. 3,710,417 to Berman, et al., and U.S. Pat. No. 2,893,050 to Hollanswoth.
Similarly, the cabinet making art frequently relies upon hinges which incorporate some means for stopping and/or holding a cabinet door at a predetermined open position. Examples of this art are to be found in, for example, the disclosure of Tuerk, in U.S. Pat. No. 313,457; Hoffman in U.S. Pat. No. 644,203; or to Gorgon, et al., in U.S. Pat. No. 3,262,149.
One field to which such devices are particularly applicable is that of hinged appliance doors, for example refrigerator doors and more particularly to refrigerator display units such as those which are found in supermarkets and self-service stores. In this latter field, it is desirable to have a large, typically doubleglazed door stopped and retained at an open position of about 90.degree. so that customers and/or stocking clerks can access the refrigerated contents of the case conveniently for selection for purchases or for stocking. These doors typically are hinged separately and may incorporate an automatic return mechanism separately. Thus, it is desirable to have a mechanism which will retain the door in the open position by a force of a predetermined amount slightly more than that exerted by the closing mechanism, which hold-open force can be easily overcome by the application of a small, external manual closing force.
The present invention is, therefore, the provision of a hold-open for a door hingeably attached to a door frame. It is a further object of the present invention to provide such a device that is simple, inexpensive to fabricate, and easy to install, but which is smooth and reliable in operation and able to withstand the rigors of hard use.


Surgical devices are disclosed herein that generally include an intracorporeal elbow joint to facilitate translational movement of an end effector while allowing a body portion of the surgical device and a trocar or working channel through which the device is inserted to be maintained in a fixed angular orientation relative to the patient. This allows a plurality of such devices to be used effectively with a single incision or access device. Such devices also generally provide end effector movement with six degrees of freedom, while maintaining a mechanical linkage between the user and the end effector and while mimicking and/or mirroring natural user movement. Various methods related to such devices are also disclosed.

Minimally invasive surgery (MIS) is often preferred over traditional open surgery due to the reduced post-operative recovery time and minimal scarring associated therewith. Laparoscopic surgery is one type of MIS procedure in which one or more small incisions are formed in the abdomen and a trocar is inserted through each incision to form a pathway that provides access to the abdominal cavity. The trocar is used to introduce various instruments and tools into the abdominal cavity, as well as to provide insufflation to elevate the abdominal wall above the organs. The instruments and tools can be used to engage and/or treat tissue in a number of ways to achieve a diagnostic or therapeutic effect. Endoscopic surgery is another type of MIS procedure in which elongate flexible shafts are introduced into the body through a natural orifice.
Conventional MIS devices include a handle, an elongate shaft, and an end effector at the distal end. Motion of the end effector is typically limited to four degrees of freedom: (1) rotation of the end effector about its longitudinal axis, which is achieved by rotating the entire device relative to the trocar, (2) in-out translational movement of the end effector, which is achieved by sliding the entire device longitudinally relative to the trocar, (3) up-down translational movement of the end effector, which is achieved by angling the device and trocar relative to the patient, and (4) left-right translational movement of the end effector, which is also achieved by angling the device and trocar relative to the patient. Some MIS devices also include a wrist joint proximal to the end effector which provides two additional degrees of freedom: (5) up-down pivot movement of the end effector and (6) left-right pivot movement of the end effector.
Conventional MIS devices suffer from a number of disadvantages. For example, the trocar angling that is required to achieve up-down translational movement and left-right translational movement of the end effector places a significant amount of strain on the incision in which the trocar is inserted, which can cause increased trauma and inadvertent release of insufflation gas. Moreover, this trocar angling makes it difficult if not impossible to operate effectively with two devices inserted into the same incision, or inserted into incisions that are in close proximity to each other, as the elongate shafts of the two devices interfere with one another when the devices are angled. Thus, in order to maintain optimum maneuverability, multiple incisions are used when multiple conventional MIS devices must be employed simultaneously, which further increases patient trauma and scarring.
By way of further example, controlling conventional MIS systems can be cumbersome, and motion error introduced by such devices makes end effector movement seem unnatural to the user. In addition, shear forces associated with conventional MIS instruments can be high, leading to increased user fatigue.
Various robotic systems have been developed to assist in MIS procedures. Robotic systems generally operate by translating user motion of a master device into control signals for driving a plurality of servos. The servos in turn selectively actuate a slave device to impart the desired motion thereto. One drawback with robotic systems, however, is the loss of a direct mechanical linkage between the user and the tissue or object being manipulated. With robotic systems, there can be no true force feedback given to the user. Another drawback is the high expense associated with such systems. Furthermore, robotic systems suffer from the same trocar angling requirements as conventional MIS devices.
Accordingly, there remains a need for improved methods and devices for controlling movement of an end effector assembly on a distal end of a surgical device.


To provide a compound, when the compound has both a high clearing point and a low crystallization temperature, having a wide temperature range of a liquid crystal phase and also an excellent solubility in other liquid crystal compounds, and further having general physical properties necessary for the compound, namely, stability to heat, light and so forth, a suitable optical anisotropy and a suitable dielectric anisotropy. A compound is represented by formula (1):

A liquid crystal display device typified by a liquid crystal display panel, a liquid crystal display module and so forth utilizes optical anisotropy, dielectric anisotropy and so forth of a liquid crystal compound. As an operating mode of the liquid crystal display device, various kinds of modes are known, such as a phase change (PC) mode, a twisted nematic (TN) mode, a super twisted nematic (STN) mode, a bistable twisted nematic (BTN) mode, an electrically controlled birefringence (ECB) mode, an optically compensated bend (OCB) mode, an in-plane switching (IPS) mode, a vertical alignment (VA) mode and a polymer sustained alignment (PSA) mode.
The liquid crystal display device is required to have capability of being driven in a temperature range from a high temperature to a low temperature. However, many cyclohexane rings are used in a compound in a composition that has been used so far, and compatibility of a compound having such a cyclohexane ring has been poor at a low temperature. Thus, a smectic phase or crystals easily precipitate, and therefore driving at a low temperature has not been easy, in particular. From such a background, development has been required for a liquid crystal compound having a high clearing point, a low crystallization temperature, an excellent compatibility and an excellent chemical stability.
For example, compound (A) as described below is reported (Patent literature No. 1, for example). However, the compound (A) has a significantly poor liquid crystallinity, and has not been sufficient as a liquid crystal compound constituting a liquid crystal composition having desired physical properties.

Moreover, compound (B) as described below is reported (Non-patent literature No. 1, for example). However, the compound (B) has a moiety having a problem in chemical stability, such as an ester group and a cyano group, and has not been sufficient as a liquid crystal compound constituting a liquid crystal composition used for a liquid crystal display device in which high reliability is required.

The prior arts are as described below. A further preferred liquid crystal compound, liquid crystal composition and liquid crystal display device are desired.

This patent is subject to a terminal disclaimer.

Cyclohexene-3,6-diyl compound, liquid crystal composition and liquid crystal display device

Abstract: wherein, for example, Ra and Rb are alkyl having 1 to 10 carbons; A1, A2, A3 and A4 are 1,4-phenylene; Z1, Z2, Z3 and Z4 are a single bond or alkylene having 1 to 4 carbons; and m, n, q and r are independently 0, 1, or 2, and a sum of m, n, q and r is 1, 2, 3 or 4.


A valve assembly includes a valve body that defines an internal flow passageway between an inlet and an outlet, and a valve seat disposed in the valve body with a sealing surface perpendicular to the flow passageway. The valve assembly further includes a clapper pivotally correlated to the valve seat having a closed configuration extending across the valve seat configured to substantially close off the flow passageway, and an open configuration configured to substantially allow fluid flow in the flow passageway from the inlet to the outlet through the valve body. An annular valve seat seal is disposed within an annular groove formed in a surface of the valve seat, where the annular valve seat seal is disposed at an interface between the valve seat and the clapper when the clapper is in the closed configuration.

Hydraulic fracturing is a process to obtain hydrocarbons such as natural gas and petroleum by injecting a fracking fluid or slurry at high pressure into a wellbore to create cracks in deep rock formations. The hydraulic fracturing process employs a variety of different types of equipment at the site of the well, including one or more positive displacement pumps, slurry blender, fracturing fluid tanks, high-pressure flow iron (pipe or conduit), wellhead, valves, charge pumps, and trailers upon which some equipment are carried. In these operations, clapper check valves are commonly used in fluid conduits to control the flow of fracking and/or gravel-packing fluids. A clapper style check valve (also called a clapper check valve or a clapper valve) permits fluid flow in one direction, but prevents, or at least reduces, fluid flow in a second direction, which is generally in the opposite direction. Any vibration caused by, for example, turbulence in the flow of fluid through the clapper valve, often produces significant wear to the internal components of the clapper valve. Moreover, the effectiveness of the clapper valve in preventing, or at least reducing, fluid flow in the second direction is often diminished as a result of improper alignment and/or excessive loading of the internal components of the clapper valve. Such issues typically cause premature deterioration of the clapper valve.

Clapper check valve with a valve seat seal member


A multi-tasking execution apparatus and a method for easily controlling applications running in a portable terminal are provided. The apparatus includes a display and a controller. The display displays an application-containing image in which at least one specific image representing at least one application running in a background is contained and arranged. The controller operatively displays at least one specific image representing at least one application running in the background, so as to be contained in the application-containing image, and controls the at least one application running in the background by controlling the specific image based on a specific gesture.

1. Field of the Invention
The present invention relates to an apparatus and method for performing multi-tasking in a portable terminal More particularly, the present invention relates to a multi-tasking execution apparatus and method capable of easily controlling applications that are running in a portable terminal.
2. Description of the Related Art
Many portable terminals still have a software platform supporting the single-tasking environment. However, these portable terminals supporting the single-tasking environment may lose competitiveness in the coming high-end smartphone market.
Recently, portable terminals capable of multi-tasking have led the new trend of the smartphone market. Such advanced portable terminals with a multi-tasking platform are expected to replace the existing portable terminals with a single-tasking platform, thereby making it possible for many users to perform multi-tasking on their own portable terminal.
To maximize the user convenience in the multi-tasking environment, there is a need for an appropriate interface that can inform users of the multi-tasking and facilitate switching between running applications.
When an application presently running on a screen is paused, the application simply disappears from the screen, so it is difficult for the user to determine whether the application has entered a background state or whether the application has been terminated.
To check a list of applications running in the background, a user must go through an annoying key input and its associated operation, though such a process for determining what applications are running in the background may be different depending on an Operating System (OS) or a platform on which a specific portable terminal operates. Further, inconveniently, the user may find it difficult to identify the applications presently running in the background, as the recently used programs (or applications) will be displayed together in the list of applications running in the background.
Therefore, a need exists for an apparatus and method for providing multi-tasking execution and for easily and intuitively controlling applications that are running in a portable terminal.
The above is presented as background information only to assist with an understanding of the present disclosure. No determination has been made, and no assertion is made, as to whether any of the above might be applicable as prior art with regard to the present invention.

Apparatus and method for performing multi-tasking in portable terminal


Properly inserted terminal fittings (40) are engaged and locked by locks (20) returned to their free states. A retainer (30) mounted into a housing (10) then enters deformation spaces (26) for the locks (20). The retainer (30) presses and deforms the locks (20) from their free states toward the terminal fittings (40). Thus, areas of engagement of the locks (20) and the terminal fittings (40) are increased. Additionally, the degree of the resilient deformation of the locks (20) in the inserting process of the terminal fittings (40) is low and resistance acting when the terminal fittings (40) are inserted is suppressed.

1. Field of the Invention
The invention relates to a connector for doubly locking terminal fittings.
2. Description of the Related Art
Japanese Unexamined Utility Model Publication No. 4-102576 discloses a connector that performs a function of doubly locking terminal fittings. This connector has a housing formed with cavities for receiving terminal fittings. Each terminal fitting is inserted into the cavity from behind and engages a resiliently deformable lock in the cavity. Forces exerted by the terminal fitting deform the lock. However, the lock resiliently returns to engage and lock the terminal fitting when the terminal fitting reaches a proper insertion position. A front retainer is assembled to the front of the housing in this state, and fasteners of the front retainer fit into deformation spaces for the locks to prevent the locks from deforming out of engagement with the terminal fittings. In this way, the locks directly fasten the terminal fittings and the front retainer indirectly fastens the terminal fittings by preventing the deformation of the locks.
A degree of deformation of the lock toward the deformation space in the above-described connector corresponds to an area of engagement of the lock with the terminal fitting. Accordingly, a larger degree of deformation of the locks may be provided to increase the area of engagement of the terminal fittings and the locks.
However, an increase in the degree of deformation of the lock in the inserting process of the terminal fitting results in an increase in the resilient restoring force that accumulates in the lock is increased. Friction between the lock and the terminal fitting increases accordingly. This leads to an increase in resistance against the insertion of the terminal fitting, and also to buckling of a wire if the inserting operation is performed by gripping the wire. As a result, smooth inserting operation of the terminal fitting is hindered.
The present invention was developed in view of the above problem and an object thereof is to improve the reliability of a terminal fitting locking function without reducing the insertion operability of a terminal fitting.
The invention relates to a connector with a housing formed with at least one cavity into which at least one terminal fitting is insertable. A lock is formed in each cavity and interferes with the terminal fitting in the process of inserting the terminal fitting into the cavity. The lock deforms during insertion of the terminal fitting into the cavity. However, the lock is restored resiliently to engage and lock the terminal fitting when the terminal fitting reaches or is close to a proper insertion position. The connector also includes a retainer to be assembled with the housing. The retainer presses and deforms the lock toward the corresponding terminal fitting when the retainer is fit into the deformation spaces. The area of engagement of the lock and the terminal fitting is increased by as much as the deformation of the lock caused by the retainer. Accordingly, the degree of the deformation of the lock during insertion of the terminal fittings is low and the resistance that acts when the terminal fitting is inserted is suppressed.
The lock preferably returns toward its free state and engages the terminal fitting to lock the terminal fitting when the terminal fitting reaches a proper insertion position. The lock preferably is pressed by the retainer and is deformed toward the corresponding terminal fittings from the free state when the retainer is fitted into the deformation space.
The retainer preferably enters the deformation space for the lock to prevent the lock from being deformed in a direction to be disengaged from the terminal fitting when the retainer is assembled with the housing.
The housing preferably has a plurality of cavities, and a wall forming a front end of each cavity preferably projects independently of the other cavities. The retainer may have engageable portions that engage and surround the walls forming the front ends of the cavities. Fittable portions are formed on the engageable portions of the retainer and fit into the deformation spaces.
The engageable portions of the retainer surround the walls forming the front ends of the cavities and make no loose movement with respect to the cavities or the terminal fittings inserted into the cavities. Thus, the fittable portions on the engageable portions can securely resiliently deform the locks toward the corresponding terminal fittings without loosely moving with respect to the cavities and/or the terminal fittings.
The fittable portions preferably are thrust into a space between the locks and a corresponding portion of the housing to deform the locks. Accordingly, the locks can be more deformed more reliably and with a greater force.
Each lock preferably is cantilevered forward and an extending end of each lock serves as a locking section engageable with the terminal fitting to lock the terminal fitting.
A lock could be formed with a catch for a disengagement jig, and the catch could extend from a locking section that engages with a terminal fitting. This catch could interfere with the outer surface of the terminal fitting to restrict a degree of resilient deformation of the lock when the lock is deformed from its free state. Contrary to this, the present preferred embodiment has locks that are cantilevered and the extending ends engage the terminal fittings. Thus, the locks have no part comparable to the catch that can interfere with the outer surfaces of the terminal fittings. Therefore, a large degree of deformation of the locks to engage the terminal fittings can be ensured.
Each lock preferably is cantilevered substantially forward and the retainer contacts the locks behind positions of engagement between the locks and the terminal fittings. Additionally, the housing and/or each terminal fitting preferably comprise a displacement preventing portion for preventing a locking section of the lock engageable with the terminal fitting from being displaced toward the corresponding terminal fitting.
A backward pulling force on a terminal fitting creates forces that could cause a lock to buckle so that a portion of the lock between its supporting point of resilient deformation and the position of engagement with the terminal fitting could bend toward the deformation space. However, the retainer of the subject invention contacts the lock from the side of the deformation space between the supporting position of resilient deformation and the position of engagement with the terminal fitting. Thus, the lock undergoes no buckling deformation and cannot bend toward the deformation space. Further, the extending end of the lock is prevented from a displacement in a direction away from the retainer and toward the terminal fitting. Therefore, the retainer is held in contact with the lock and a function of the retainer for preventing a buckling deformation cannot be degraded.
According to a further preferred embodiment, a movable surface substantially facing a side opposite from the deformation space is formed at a side of each lock. A sidewall forming the cavity and arranged along the side of the lock is formed with a receiving surface substantially facing the movable surface, and the movable surface is proximate to or substantially in contact with the receiving surface while the retainer resiliently deforms the locks toward the corresponding terminal fittings.
The cavities are exposed to outside via the clearances between the sidewalls and the sides of the locks. Thus, a leak or opening may occur between the terminal fittings inserted in the adjacent cavities. However, the movable surfaces of the locks come to be proximate to or in contact with the receiving surfaces of the sidewalls in the present invention. Thus, the clearances between the sidewalls and the locks are closed to prevent a leak.
The movable surface preferably is substantially parallel with or converging toward the receiving surfaces in the free unbiased state of the lock where it is not deformed.
The lock and/or the retainer preferably comprise at least one slanted guiding surface for guiding the lock into engagement with the terminal fitting.
The lock preferably has an inverted T-shaped cross section that is transversely symmetrical.
These and other objects, features and advantages of the present invention will become more apparent upon reading of the following detailed description of preferred embodiments and accompanying drawings. It should be understood that even though embodiments are separately described, single features thereof may be combined to additional embodiments.


The present invention provides a porous cooling block for cooling corium, comprising: a base part that includes a plurality of pores; a plurality of porous cooling blocks that include a channel part that communicates with some of the plurality of pores of the base part; a sacrificial part that covers the exposed upper surfaces of the porous cooling blocks; and a cooling-water supply unit that supplies cooling water to the porous cooling blocks. Corium is cooled by using steam or cooling water discharged from the porous cooling blocks. Therefore, the corium can be cooled and solidified in the shape of a porous form. Further, the cooling water is uniformly supplied to one surface formed by the cooling block on the whole, thereby easily cooling the corium.

Generally, a nuclear power plant (NPP) carries out a producing function of electric energy to be able to be used in practical living using nuclear energy by controlling a plenty of energy occurred by nuclear fission to be released slowly.
Here, though the possibility of occurrence is very low, corium of ultra-high temperature with radioactive feature may be released into a cavity of primary reactor containment under a nuclear reactor container by nuclear fuel of reactor core being molten and breakdown of nuclear reactor container when a severe accident occurs at a nuclear power plant. At this situation, the corium released is a radioactive material with ultra-high temperature higher than 2000K, and has a feature that heat is occurred endlessly. And when fail to cooling the released corium properly, the primary reactor containment of nuclear reactor constructed as a concrete structure may be damaged by the corium of ultra-high temperature and radioactive material may leak outside. In case that radioactive material being leaked from the primary reactor containment of nuclear reactor like this is released to soil or atmosphere, it may not only become a threat to a stability of the nuclear power plant facilities, of course become a pollution to the surrounding environment of the nuclear power plant, but also may cause a critical harmful influence to the health of ordinary general public.
Thus, recent nuclear power plant applies or develops a method for cooling and controlling properly the corium in the primary reactor containment of nuclear power plant in order not to leak the corium outside of the primary reactor containment of nuclear power plant. That is, a method of capable of cooling the corium with ease is required since the corium of high temperature released from a nuclear reactor container to a cavity pore of the primary reactor containment of nuclear power plant may melt and erode the floor concrete of the primary reactor containment of nuclear power plant if not cooled properly.
At this time, the cooling of released corium is divided upper portion cooling and lower portion cooling of the corium. Since a damage of floor concrete occurs by contact of lower portion of corium, a lower portion cooling of the corium is required. For this lower portion cooling of the corium, an indirect cooling method in which cooling is performed at a state a cooling-water and the corium are not in contact using a cooling container, a direct cooling method in which cooling is performed at a state a cooling-water and the corium are directly in contact, etc. may be applied.
Among this, the direct cooling method can get a more increased cooling efficiency than that of indirect cooling method since it cools directly the corium by contacting the corium and cooling-water, and has a merit of requiring less installation space. Thus, a development of a corium cooling apparatus is wanted with easy installation for application not only to a new nuclear power plant but also to a running nuclear power plant and capable of maximization of cooling efficiency.

Porous cooling block for cooling corium and corium cooling apparatus including same, and corium cooling method using same


The present invention provides a compound of formula (I):

The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.
Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif. 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et al., Science 1991, 253, 407-414; Hiles et al., Cell 1992, 70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al., EMBO J. 1994, 13, 2352-2361).
In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
PIM-1 is the protooncogene activated by murine leukemia virus (Provirus Integration site for Moloney murine leukemia virus) [Cuypers, H. T., et al., Cell 37, 141-150 (1984)]. The expression of the protoconcogene produces a non-transmembrane serine/threonine kinase of 313 residues, including a kinase domain consisting of 253 amino acid residues. Two isoforms are known through alternative initiation (p44 and p33) [Saris, C. J. M., et al., EMBO J., 10, 655-664 (1991)]. Two PIM-1 homologs have been described [Baytel, D., Biochim Biophys Acta 1442, 274-85 (1998); Feldman, J., et al., J Biol Chem 273, 16535-16543(1998)]. PIM-2 and PIM-3 are respectively 58% and 69% identical to Pim-1 at the amino acid level. PIM-1 is highly expressed in the liver and spleen during hematopoiesis, and expression is induced by cytokines such as GM-CSF, G-SCF, IL-3, IF-α, and IL-6 [Lilly, M., et al., Oncogene 7, 727-732 (1992); Sato, N., et al., EMBO J. 12, 4181-4189 (1993); Jaster, R., et al., Cell Signal 11, 331-335 (1999); Matikainen, S., et al., Blood 93, 1980-1991 (1999)].
PIM-1 has been implicated in lymphoma development. Induced expression of PIM-1 and the protooncogene c-myc synergize to increase the incidence of lymphomagenesis [Breuer M., et al., Nature 340, 61-63 (1989); van Lohuizen M., et al., Cell 65, 737-52 (1991)]. PIM-1 functions in cytokine signaling pathways and has been shown to play a role in T cell development [Schmidt, T., et al., EMBO J 17, 5349-5359 (1998); Jacobs, H., et al., JEM 190, 1059-1068 (1999)]. Signaling through gp130, a subunit common to receptors of the IL-6 cytokine family, activates the transcription factor STAT3 and can lead to the proliferation of hematopoietic cells [Hirano, T., et al., Oncogene 19, 2548-2556 (2000)]. A kinase-active PIM-1 appears to be essential for the gp130-mediated STAT3 proliferation signal. In cooperation with the c-myc PIM-1 can promote STAT3-mediated cell cycle progression and antiapoptosis [Shirogane, T., et al., Immunity 11, 709-719 (1999)]. PIM-1 also appears to be necessary for IL-3-stimulated growth in bone marrow-derived mast cells [Domen J., et al., Blood 82, 1445-52 (1993)] and survival of FDCP1 cells after IL-3 withdrawal [Lilly, M., et al., Oncogene 18, 4022-4031 (1999)].
Additionally, control of cell proliferation and survival by PIM-1 may be effected by means of its phosphorylation of the well established cell cycle regulators cdc25 [Mochizuki, T., et al., J Biol Chem 274, 18659-18666 (1999)] and/or p21(Cip1/WAF1)[Wang, Z., et al., Biochim Biophys Acta 1593, 45-55 (2002)] or phosphorylation of heterochromatin protein 1, a molecule involved in chromatin structure and transcriptional regulation [Koike N., et al., FEBS Lett 467,17-21 (2000)].
Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases consisting of a β-sheet rich amino-terminal lobe and a larger carboxy-terminal lobe which is largely α-helical. The CDKs display the 11 subdomains shared by all protein kinases and range in molecular mass from 33 to 44 kD. This family of kinases, which includes CDK1, CKD2, CDK4, and CDK6, requires phosphorylation at the residue corresponding to CDK-2 Thr160 in order to be fully active [Meijer, L., Drug Resistance Updates, 3, 83-88 (2000)].
Each CDK complex is formed from a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g., CDK1, CDK-2, CDK4, CDK5, and CDK6). Each different kinase/cyclin pair functions to regulate the different and specific phases of the cell cycle known as the G1, S, G2, and M phases [Nigg, E., Nature Reviews, 2, 21-32 (2001); Flatt, P., Pietenpol, J., Drug Metabolism Reviews, 32, 283-305 (2000)].
The CDKs have been implicated in cell proliferation disorders, particularly in cancer. Cell proliferation is a result of the direct or indirect deregulation of the cell division cycle and the CDKs play a critical role in the regulation of the various phases of this cycle. For example, the over-expression of cyclin D1 is commonly associated with numerous human cancers including breast, colon, hepatocellular carcinomas and gliomas [Flatt, P., Pietenpol, J., Drug Metabolism Reviews, 32, 283-305 (2000)]. The CDK-2/cyclin E complex plays a key role in the progression from the early G1 to S phases of the cell cycle and the overexpression of cyclin E has been associated with various solid tumors. Therefore, inhibitors of cyclins D1, E, or their associated CDKs are useful targets for cancer therapy [Kaubisch, A., Schwartz, G., The Cancer Journal, 6, 192-212 (2000)].
CDKs, especially CDK-2, also play a role in apoptosis and T-cell development. CDK-2 has been identified as a key regulator of thymocyte apoptosis [Williams, O., et al, European Journal of Immunology, 709-713 (2000)]. Stimulation of CDK-2 kinase activity is associated with the progression of apoptosis in thymocytes, in response to specific stimuli. Inhibition of CDK-2 kinase activity blocks this apoptosis resulting in the protection of thymocytes.
In addition to regulating the cell cycle and apoptosis, the CDKs are directly involved in the process of transcription. Numerous viruses require CDKs for their replication process. Examples where CDK inhibitors restrain viral replication include human cytomegakovirus, herpes virus, and varicella-zoster virus [Meijer, L., Drug Resistance Updates, 3, 83-88 (2000)].
Inhibition of CDK is also useful for the treatment of neurodegenerative disorders such as Alzheimer's disease. The appearance of Paired Helical Filaments (PHF), associated with Alzheimer's disease, is caused by the hyperphosphorylation of Tau protein by CDK5/p25 [Meijer, L., Drug Resistance Updates, 3, 83-88 (2000)].
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of α and β isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry & Biology 2000, 7, 793-803; and Kim and Kimmel, Curr. Opinion Genetics Dev., 2000 10, 508-514]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocyte hypertrophy [PCT Application Nos.: WO 99/65897 and WO 00/38675; and Haq et al., J. Cell Biol. 2000, 151, 117-130]. These diseases are associated with the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase, which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor β-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-myc, c-myb, CREB, and CEPBα. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation, and development.
In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS 1996, 93, 8455-8459; Cross et al., Biochem. J. 1994, 303, 21-26); Cohen, Biochem. Soc. Trans. 1993, 21, 555-567; and Massillon et al., Biochem J. 1994, 299, 123-128]. However, in a diabetic patient, where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long-term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [see, PCT Application: WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.
GSK-3 activity is also associated with Alzheimer's disease. This disease is characterized by the well-known β-amyloid peptide and the formation of intracellular neurofibrillary tangles. Aβ peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE2, followed by presenilin-dependent γ-secretase cleavage. It has been demonstrated that antibodies against β-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease (Hock et al., Neuron, 2003, 38, 547-554), and thus other β-amyloid-lowering strategies (e.g., the development of agents capable of inhibiting β-amyloid peptide) would be useful in the treatment of Alzherimer's disease and other psychotic and neurodegenerative disorders. Additionally, the neurofibrillary tangles contain hyperphosphorylated Tau protein, in which Tau is phosphorylated on abnormal sites, and thus agents capable of inhibiting the hyperphosphorylation of Tau protein would be useful in the treatment of Alzherimer's disease and other psychotic and neurodegenerative disorders.
GSK-3 is known to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 1994, 4, 1077-86; and Brownlees et al., Neuroreport 1997, 8, 3251-55]. Therefore, GSK-3 activity promotes generation of the neurofibrillary tangles and the progression of Alzheimer's disease. It has also been shown that GSK-3 facilitates APP processing and that a GSK-3 inhibitor (lithium) inhibits of the generation of Aβ peptides through the inhibition of GSK-3 (Phiel et al. Nature 2003, 423, 435-439). Thus, the development of inhibitors of GSK-3 would be useful for the reduction of the formation of amyloid plaques and neurofibrillary tangles, the pathological hallmarks of Alzheimer's Disease, and would also be useful for the treatment of other psychotic and neurodegenerative disorders.
Another substrate of GSK-3 is β-catenin, which is degraded after phosphorylation by GSK-3. Reduced levels of β-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature 1998, 395, 698-702; Takashima et al., PNAS 1993, 90, 7789-93; and Pei et al., J. Neuropathol. Exp 1997,56, 70-78].
GSK-3 activity is also associated with stroke [Wang et al., Brain Res 2000, 859, 381-5; Sasaki et al., Neurol Res 2001, 23, 588-92; Hashimoto et al., J. Biol. Chem 2002, 277, 32985-32991]. Another kinase family of particular interest is the Src family of kinases. These kinases are implicated in cancer, immune system dysfunction and bone remodeling diseases. For general reviews, see Thomas and Brugge, Annu. Rev. Cell Dev. Biol. (1997) 13, 513; Lawrence and Niu, Pharmacol. Ther. (1998) 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow) (2000) 65, 49; Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).
Members of the Src family include the following eight kinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, and Blk. These are nonreceptor protein kinases that range in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is comprised of six distinct functional domains: Src homology domain 4 (SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain (SH1), and a C-terminal regulatory region. Tatosyan et al. Biochemistry (Moscow) 65, 49-58 (2000).
Based on published studies, Src kinases are considered as potential therapeutic targets for various human diseases. Mice that are deficient in Src develop osteopetrosis, or bone build-up, because of depressed bone resorption by osteoclasts. This suggests that osteoporosis resulting from abnormally high bone resorption can be treated by inhibiting Src. Soriano et al., Cell, 69, 551 (1992) and Soriano et al., Cell, 64, 693 (1991).
Suppression of arthritic bone destruction has been achieved by the overexpression of CSK in rheumatoid synoviocytes and osteoclasts. Takayanagi et al., J. Clin. Invest., 104, 137 (1999). CSK, or C-terminal Src kinase, phosphorylates and thereby inhibits Src catalytic activity. This implies that Src inhibition may prevent joint destruction that is characteristic in patients suffering from rheumatoid arthritis. Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).
Src also plays a role in the replication of hepatitis B virus. The virally encoded transcription factor HBx activates Src in a step required for propagation of the virus. Klein et al., EMBO J., 18, 5019, (1999) and Klein et al., Mol. Cell. Biol., 17, 6427 (1997).
A number of studies have linked Src expression to cancers such as colon, breast, hepatic and pancreatic cancer, certain B-cell leukemias and lymphomas. Talamonti et al., J. Clin. Invest., 91, 53 (1993); Lutz et al., Biochem. Biophys. Res. 243, 503 (1998); Rosen et al., J. Biol. Chem., 261, 13754 (1986); Bolen et al., Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki et al., Hepatology, 27, 1257 (1998); Biscardi et al., Adv. Cancer Res., 76, 61 (1999); Lynch et al., Leukemia, 7, 1416 (1993). Furthermore, antisense Src expressed in ovarian and colon tumor cells has been shown to inhibit tumor growth. Wiener et al., Clin. Cancer Res., 5, 2164 (1999); Staley et al., Cell Growth Diff., 8, 269 (1997).
Other Src family kinases are also potential therapeutic targets. Lck plays a role in T-cell signaling. Mice that lack the Lck gene have a poor ability to develop thymocytes. The function of Lck as a positive activator of T-cell signaling suggests that Lck inhibitors may be useful for treating autoimmune disease such as rheumatoid arthritis. Molina et al., Nature, 357, 161 (1992). Hck, Fgr and Lyn have been identified as important mediators of integrin signaling in myeloid leukocytes. Lowell et al., J. Leukoc. Biol., 65, 313 (1999). Inhibition of these kinase mediators may therefore be useful for treating inflammation. Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).
Accordingly, there is a great need to develop inhibitors of PIM-1, CDK-2, SRC, and GSK-3 protein kinases that are useful in treating various diseases or conditions associated with PIM-1, CDK-2, SRC, or GSK-3 activation, particularly given the inadequate treatments currently available for the majority of these disorders.

Compositions useful as inhibitors of protein kinases

Abstract: or a pharmaceutically acceptable salt thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of PIM-1, CDK-2, GSK-3, and SRC mammalian protein kinases. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.


A new cultivar of Veronica, ‘Bicolor Explosion’, characterized by its compact, upright and strong plant habit, its flowers that are bi-colored purple and violet, its freely branching inflorescences, and its tolerance to powdery mildew.

The present invention relates to a new and distinct cultivar of Veronica of hybrid origin and will be referred to hereafter by its cultivar name, 'Bicolor Explosion'. 'Bicolor Explosion' represents a new herbaceous perennial grown for landscape use.
The new cultivar, 'Bicolor Explosion', was discovered by the Inventor in summer of 2010 as a naturally occurring branch mutation of Veronica 'Blue Explosion' (U.S. Plant Pat. No. 22,497) in a trial bed in Haarlem, The Netherlands.
Asexual propagation of the new cultivar was first accomplished by softwood cuttings by the Inventor in summer of 2010 in Haarlem, The Netherlands. Asexual propagation by division and softwood cuttings has determined that the characteristics of the new cultivar are stable and are reproduced true to type in successive generations.

A. VERSCHOOR HORTICULTURE IMPORT-EXPORT B.V


A fan outlet guide vane assembly (36) for a turbofan gas turbine engine (10) comprises a fan casing (32) and a plurality of circumferentially spaced radially extending fan outlet guide vanes (34). The fan outlet guide vanes (34) are secured at their radially outer ends to the fan casing (32). A plurality of panels (40) are secured to the fan casing (32). Each panel (40) is arranged between two adjacent fan outlet guide vanes (34) to define the flow path between the fan outlet guide vanes (34). Each panel (40) comprises a perforated skin (42) and a honeycomb structure (44) to form an acoustic treatment structure. The perforated skin (42) defines the flow path between the fan outlet guide vanes (34). The pressure equalization across the panels (40) minimises the possibility of the panels (40) being removed.

The present invention relates to a guide vane assembly for a gas turbine engine and in particular relates to a fan outlet guide vane assembly for a turbofan gas turbine engine.
A fan outlet guide vane of a gas turbine engine currently comprises a plurality of fan outlet guide vanes, a casing and a plurality of panels. The fan outlet guide vanes are circumferentially spaced, are secured at their radially outer ends to the casing and extend radially inwardly from the casing. The panels are secured to the casing. Each panel is arranged between two adjacent fan outlet guide vanes to define the flow path between the fan outlet guide vanes. The panels are secured to the casing by fasteners, for example nuts and radially extending bolts or by an adhesive bond and fasteners.
A problem with the current design is that there is a pressure difference between the radially inner faces and the radially outer faces of the panels, which tends to remove the panels from the casing. Additionally the fan outlet guide vane assembly provides no noise reduction features to minimise noise produced by the turbofan gas turbine engine.
Accordingly the present invention seeks to provide a novel guide vane assembly which reduces, preferably overcomes, the above mentioned problems.
Accordingly the present invention provides a guide vane assembly comprising a casing, a plurality of circumferentially spaced radially extending guide vanes, the guide vanes being secured at their radially outer ends to the casing, a plurality of panels being secured to the casing, each panel being arranged between two adjacent guide vanes to define the flow path between the guide vanes, at least one panel comprising a perforated skin and an acoustic treatment structure, the perforated skin defining the flow path between the guide vanes.
Preferably each panel comprises a perforated skin and an acoustic treatment structure, the perforated skin defining the flow path between the guide vanes.
Preferably the at least one panel is secured to the casing by fasteners or by an adhesive bond and fasteners.
Preferably the perforated skin of the at least one panel comprises a composite material. Preferably the at least one perforated skin comprises a
Preferably the acoustic treatment structure comprises a honeycomb structure. Preferably the honeycomb structure comprises a plurality of cells, each cell having eight sides or less.
Preferably the honeycomb structure comprises an aluminium honeycomb, a composite material honeycomb or other suitable honeycomb.
Preferably the guide vanes are secured to the casing by fasteners or by welded joints.
Preferably a flexible seal is arranged between the circumferential edges of the at least one panel and the two adjacent guide vanes to seal the gap between the circumferential edges of the at least one panel and the two adjacent guide vanes.
Preferably the guide vanes are fan outlet guide vanes and the casing is a fan casing.
The perforated skin and the acoustic treatment structure may be integral.
The perforated skin and the acoustic treatment may comprise a composite material or a metal.
The perforated skin and the acoustic treatment may comprise aluminium or glass fibre reinforced nylon.
The acoustic treatment may be provided with drainage apertures to allow water and/or lubricant to flow generally axially and to prevent water and/or lubricant flowing generally circumferentially between the panel and the casing between the two adjacent guide vanes.


In various aspects and embodiments, the invention provides microbial cells and methods for producing advanced glycosylation products from lower glycosylated intermediates. The microbial cell expresses one or more UDP-dependent glycosyl transferase enzymes in the cytoplasm, for glycosylation of the intermediates. When incubating the microbial strain with a plant extract or fraction thereof comprising the intermediates, these glycosylated intermediates are available for further glycosylation by the cell, and the advanced glycosylation products can be recovered from the media and/or microbial cells.

Glycosyltransferases of small molecules are encoded by a large multigene family in the plant kingdom. These enzymes transfer sugars from nucleotide sugars to a wide range of secondary metabolites, thereby altering the physical and chemical properties of the acceptor molecule. For example, steviol glycosides are a class of compounds found in the leaves of Stevia rebaudiana Bertoni, a perennial shrub of the Asteraceae (Compositae) family native to certain regions of South America. They are characterized structurally by a single base, steviol, differing by the presence of carbohydrate residues at positions C13 and C19. They accumulate in stevia leaves, composing approximately 10% to 20% of the total dry weight. On a dry weight basis, the four major glycosides found in the leaves of Stevia typically include stevioside (9.1%), rebaudioside A (3.8%), rebaudioside C (0.6-1.0%) and dulcoside A (0.3%). Other steviol glycosides are present at small or trace amounts, including rebaudioside B, D, E, F, G, H, I, J, K, L, M and O, dulcoside B, steviolbioside and rubusoside.
The minor glycosylation product rebaudioside M (RebM) is estimated to be about 200-350 times more potent than sucrose, and is described as possessing a clean, sweet taste with a slightly bitter or licorice aftertaste. Prakash I. et al., Development of Next Generation Stevia Sweetener: Rebaudioside M, Foods 3(1), 162-175 (2014). While RebM is of great interest to the global food industry, its low prevalence in stevia extract necessitates innovative processes for its synthesis.
There remains a need for economical methods for producing high value glycosides that are minor products of natural plant extract.

Production of steviol glycosides through whole cell biotransformation of steviol glycoside intermediates