A manufacturing defect analyzer, for inspecting assembled printed circuit boards, including a light source, an optical receiver, a computer controller, and a memory. A plurality of key-points are specified for each component mounted to a printed circuit board. A data record characterizing each key-point is then stored in memory. Next, the defect analyzer measures the height of selected key-points relative to reference key-points for each component. Finally, the measured heights are compared with limit values, thereby determining whether each component is defectively attached to the printed circuit board. The data records facilitate inspection of printed circuit boards having components that are available in different package types.

This invention relates generally to the manufacture of printed circuit boards, and more specifically, to manufacturing defect analyzers.
Printed circuit boards are typically tested during the manufacturing process to determine whether the boards contain manufacturing defects. In this way, defective printed circuit boards are identified before being incorporated into electronic products, thereby minimizing the chance that the electronic products will fail prematurely in the field.
One method of testing printed circuit boards is known as card edge testing, which includes attaching a test device to input and output ports of a board under test (BUT), applying test signals to selected input ports, detecting response signals at selected output ports, and comparing the response signals to expected results. The applied test signals typically instruct the BUT to perform a series of predetermined functions. The detected response signals are then analyzed to determine whether the BUT performed the predetermined functions correctly.
However, card edge testing has certain limitations. In general, card edge testing is most useful for testing printed circuit boards that have a relatively small number of components, which are capable of performing only a limited number of functions. However, as the number of components mounted to printed circuit boards has increased, the number of functions that the boards perform has also increased. As a result, card edge testing no longer provides the fault coverage that many printed circuit board manufacturers require.
An improvement to card edge testing is in-circuit testing, which includes attaching a fixture, called a "bed-of-nails," to certain nodes on the BUT, applying test signals to selected nodes, and evaluating response signals detected at other selected nodes. The bed-of-nails fixture typically isolates a small number of components from the remaining components on the BUT. Functional testing is then performed on the isolated components. In-circuit testing is typically repeated until all of the components on the BUT have been tested. Board manufacturers have used in-circuit testing to test relatively large printed circuit boards with many components.
Nevertheless, in-circuit testing also has certain limitations. For example, both active and passive components must be spaced far enough apart on the BUT so that nodes are accessible to the bed-of-nails fixture. However, this spacing requirement cannot always be satisfied on densely populated printed circuit boards. It is particularly difficult to access the nodes on printed circuit boards that are designed using PCMCIA technology, which is typically used in the manufacture of boards for laptop computers.
Also, in-circuit testing generally does not provide complete fault coverage. For example, in-circuit testing cannot reliably detect missing by-pass capacitors, joints with insufficient amounts of solder, bent leads on semiconductor packages, or improperly aligned components.
Another method of verifying printed circuit boards is generally known as optical inspection. Originally, optical inspection was performed by human inspectors using either the naked eye or a microscope. At certain stages of the printed circuit board manufacturing process, human inspectors typically looked for missing components, extra components, improperly oriented components, tilted semiconductor packages, crooked leads, faulty solder joints, or solder bridges between closely-spaced leads. Further, by combining visual inspection with in-circuit testing, many board manufacturers have achieved nearly 100% fault coverage. However, as printed circuit boards became more complex, visual inspection of boards proved to be slow, inaccurate and expensive.
An improvement to visual inspection is automatic optical inspection (AOI), which generally uses an illumination device and a series of video cameras mounted in a fixture. A test computer typically controls movement of the fixture relative to the BUT, thereby allowing the cameras to scan and obtain images of a surface of the BUT. The test computer then digitizes the images for subsequent analysis. Because AOI devices are used to perform non-contact testing, they are generally unaffected by inaccessible nodes on densely populated printed circuit boards. Also, over the long term, AOI devices tend to be more accurate than human inspectors.
Nevertheless, AOI devices also have some disadvantages. For example, in a typical AOI device, video cameras capture light and color characteristics of the surfaces of the BUT, the components, and the solder joints within their respective fields of view. The AOI device then converts the captured light and color information into digitized image data, which is analyzed by the test computer. However, the surfaces of the BUT, the components, and the solder joints each have a relatively wide range of acceptable parameters relating to reflectivity, color, and texture. This means that in order to obtain accurate results, AOI devices must be programmed and operated by highly trained technical personnel. Even if highly trained personnel are used, AOI sometimes results in either the rejection of good boards or the acceptance of faulty boards.
Another limitation of AOI devices is that the characteristics of both the illuminators and the video cameras can vary from AOI device to AOI device. As a result, a test program written for one AOI device might not function properly on another AOI device. Finally, AOI devices are generally slow, thereby making them less adaptable to some high speed manufacturing processes.
Accordingly, it would be desirable to have a reliable way of detecting missing components, extra components, improperly oriented components, tilted semiconductor packages, bent leads, faulty solder joints, and solder bridges between closely-spaced leads on densely populated printed circuit boards. It would also be desirable to have a manufacturing defect analyzer that locates faults quickly, is easy to program and operate, and can run test programs developed for other defect analyzers without modification.

Method and apparatus for inspecting component placement and solder connection in printed circuit board manufacture


The present disclosure relates to a method of providing media to a user based on analysis of an image. The method comprises analysing the image to obtain image information about what is depicted therein. The method also comprises, based on said obtained image information, selecting a first plurality of media items comprising audio, from a media database, said media items of the first plurality being associated with that which is depicted in the image according to the image information. The method also comprises filtering the first plurality of media items based on metadata associated with the user to obtain a plurality of seed media items. The method also comprises providing at least one media item from the media database to the user based on the obtained seed media items.

A service provider for providing media to a user may suggest media items based on user history, e.g. based on what genre of songs, videos or other types of media items provided by the service provider the user usually listens to. The service provider may also suggest media items for an activity, e.g. running or meditation, based on metadata of the media items. For instance if the media items are included in a playlist for running.


A method of developing software comprises the steps of defining a plurality of component objects for receiving input data and producing output data, defining a plurality of connection objects for passing data between the component objects, and executing an initialization script to define a behavioral model for the system by defining relationships between the component objects and the connection objects. A software development system that performs the method is also provided.

Software development is a significant component of both the cost and schedule of the development of unmanned air vehicle systems. Three types of software are required to implement and validate an Unmanned Autonomous Vehicle (UAV) program: the Operational Flight Program (OFP), the Closed Loop Simulation (CLS) and the Test Environment. Unfortunately, very little software is reused from one UAV program to the next. Not only is the OFP often redeveloped from scratch, but also the CLS environment and the software testing environments are all "reinvented" on a program-by-program basis resulting in little consistency, lower quality, and higher costs.
OFP development strategy traditionally aims toward the implementation of a single instance of a large executable program that resides in a specific single target computer using cross-compilation tools. This preconception unnecessarily results in artificial obstacles in the software development process, such as the prerequisite delivery of specialized hardware and/or development tools before any practical software testing can be performed, with the additional possibility that undesirable and undetectable system timing dependencies may be embedded in OFP source code.
The current method for developing flight software places constraints on the software developers by requiring them to develop pieces of the OFP code from scratch on their desktop and then wait until the flight computers are ready on a hot bench before they can do verification and validation. Traditionally, the hot bench becomes a choke point for the schedule as many developers all vie for access to this precious resource. This requires a substantial investment in a hot bench, with a flight computer for each instance of the OFP. This in turn leads to schedule delays, cost overruns, and a lesser quality product as typically two shifts are run.
There is a need for a system for developing software more efficiently.

Remote component and connection architecture


The invention relates to a positioning apparatus, comprising a rotatable spindle, a sliding member, wherein a spindle counter segment of the sliding member is displaced along the spindle when the spindle rotates, a first guide for the sliding member, which interacts with a first guide counter segment of the sliding member and, in the process, leaves the sliding member with a linear mobility along the first guide axis and a pivotability about the first guide axis, and a second guide for the sliding member, which interacts with a second guide counter segment of the sliding member and, in the process, restricts the pivotability of the sliding member about the first guide axis.

An application of a positioning apparatus in an optical instrument (such as a telescopic sight or other observation or image recording devices) for adjusting an optical unit, e.g. linearly along an optical axis of the instrument, requires the ability to position the optical unit in a repeatable and highly precise manner and without play such that an image of an object to be observed or to be recorded can be focused as precisely as possible and within the shortest amount of time possible prior to, or during, the observation/image recording.
In order to realize e.g. zoom movements or focus adjusting movements of individual lenses or lens groups in optical devices, use is increasingly made of electromotive direct drives instead of cam tubes or mechanical gearboxes. Since the installation space in an optical device is relatively small, the size of the adjustment unit is an important performance criterion. Therefore, it is possible to use e.g. small drive motors which, although they have low torque, nevertheless realize great accuracies (e.g. ±10 μm) at relatively fast displacement movements (e.g. 20 mm/s) in all spatial positions.
U.S. Pat. No. 5,815,325 describes a zoom drive for a camcorder, in which use is made of a stepper motor with small dimensions. Here, the motor shaft is embodied directly as threaded spindle so as to avoid constraining and axial forces, and borne at the one end thereof on an arm. Here, the arm is fastened directly to the motor housing.
In order to receive the rotational movement emanating from the threaded spindle and convert this movement into a translational displacement of an optical element, use is made of a form element provided with a threaded plate made of plastic. The threaded plate made of plastic acts in a resilient manner on the threaded spindle by means of a leaf spring, which is likewise a constituent of the form element. This form element is connected to the guided sliding member, which carries the optical element, by means of a rotational shaft such that there is an adjustment movement of the sliding member in the direction of the optical axis as a result of the rotational movement of the spindle.
DE 10 160 587 A1 has disclosed a further positioning apparatus of this type, for adjusting zoom lenses or zoom lens systems in optical devices.
The positioning apparatus, to which the invention relates, can specifically be designed to adjust a focusing optical unit in a telescopic sight of a geodetic surveying device.
A known example of such a geodetic surveying device includes a theodolite, a tachymeter or a total station, which is also referred to as electronic tachymeter or computer tachymeter. By way of example, such a geodetic measuring apparatus of the prior art is described in the publication EP 1 686 350. Such devices have electrical sensor-based angle and distance measurement functions, which allow a direction and distance to a selected target to be determined. In the process, the angle and distance variables are established in the internal reference system of the device and may optionally still have to be linked to an external reference system for determining an absolute position.
Modern total stations comprise microprocessors for digital processing and storing of registered measurement data. The devices are generally produced with a compact and integrated design, wherein usually coaxial distance and angle measurement elements and computer, control and storage units are integrated in a device. Depending on the development stage of the total station, means are integrated for motorizing the targeting optical unit, for reflector-less path measurement, for automated target search and tracking and for remote control of the whole device. Furthermore, total stations known from the prior art comprise at least one wireless data interface for establishing a wireless connection to external peripheral components such as e.g. a data registration device which, in particular, can be embodied as remote control, portable data logger, field computer, notebook, small computer or PDA. By means of the data interface, it is possible to output measurement data, which was registered and stored by the total station, for the purposes of external further processing, to read externally registered measurement data into the total station for the purposes of storage and/or further processing, to input or output remote control signals for remotely controlling the total station or a further external component, in particular in mobile field use, and to upload control software into the total station.
For sighting or targeting a target point to be surveyed, generic surveying devices have a targeting appliance (such as a telescopic sight/telescope). In a simple embodiment variant, the sighting appliance is embodied e.g. as a pure direct-vision telescopic sight. Moreover, modern devices can have a camera integrated into the telescopic sight, for registering an image, wherein the registered image can, in particular, be displayed as live image on a display of the total station and/or a display of the peripheral device—like a data logger—employed for the remote control. Here, the optical unit of the sighting appliance can have a manual focus—e.g. a set screw for changing the focus position of the optical unit or comprise an autofocus, wherein the focus position is changed e.g. by motors. However, a manually operable focus by all means can also be embodied in a motorized manner. Automatic focusing appliances for telescopic sights of geodetic devices are known from e.g. DE 19710722, DE 19926706 or DE 19949580.
The optical system or the optical visual channel of the targeting appliance (telescopic sight) in particular contains an objective lens group, a focusing lens group and an eyepiece, which are arranged in this sequence starting from the object side. The position of the focusing lens group is set dependent on the object distance in such a way that an in-focus object image is produced on an optical element, arranged in the focusing plane, with a targeting marking (in particular reticle or graticule, or else a plate with a crosshair marking and line markings). This optical element with the image produced in this plane can then be observed through the eyepiece.
The coaxial camera (e.g. with a CCD or CMOS area sensor) provided in addition to, or in place of a direct vision channel can be arranged in a further image plane provided in the telescopic sight optical unit, for which purpose provision can be made for decoupling a partial light beam by means of a beam splitter such that the camera can be used to record an image (or a series of images or a video stream) through the objective.
Furthermore, an additional, separate transmission and reception channel branch can be provided for the coaxial electronic distance measurement. Moreover, conventional surveying devices have in the meantime been equipped with an automatic target recognition (ATR) function, for the purposes of which a further, separate ATR light source e.g. a multi-mode fiber output, which emits light at a further defined wavelength and a special ATR camera sensor are additionally integrated into the telescope.
In order to avoid distortions, color distortions or vignetting—i.e. a drop in brightness in edge regions of the observable visual field—very high demands are placed on the individual optical components. Accordingly, optical units coated in a specific and complicated manner are generally required for decoupling and coupling individual wavelengths, wherein the visual band should allow a representation with the highest possible color fidelity despite the coating.
The design of generic telescopic sights of geodetic devices is shown in the publications EP 1 081 459 or EP 1 662 278 in an exemplary manner.
The accuracy obtainable for surveying when targeting objects—through the telescopic sight via direct vision—depends strongly on the precision of the positioning and adjustment of the optical units installed in the telescopic sight. Movable optical units in particular (as represented by the focusing optical unit in such telescopic sights) can constitute a substantial factor for the accuracy that can be achieved with such surveying devices since any radial deflection of such a movable optical unit on the displacement path, which should in fact be as axial as possible, along the intended optical axis causes a change in the actual optical axis defined by the overall optical system. Since the intended optical axis then may no longer correspond sufficiently to the actual optical axis, the intended optical axis may in fact point past the target object—despite apparently "correct" sighting of the target object—such that incorrect solid angles are possibly read out for the target object.
By way of example, U.S. Pat. No. 7,793,424 has disclosed such a positioning apparatuses for adjusting focus lenses of focus lens systems in a telescopic sight of a geodetic surveying system.
Here, a sliding member carrying the focusing optical unit is guided by means of a first and second guide (namely a rod and a sliding surface) such that the mobility of the sliding member is, firstly, restricted by the rod to a linear mobility along the first guide axis and a pivotability about the first guide axis and, moreover, a stop for the pivotability is given by the sliding surface.
Here, a roller of the sliding member running on the sliding surface is pressed onto the sliding surface by a magnet apparatus or the magnet apparatus ensures that the roller is pressed against the sliding surface and kept in a pressed-on and contacting state.
To ensure displaceability of the sliding member, provision is made for a rotatable threaded spindle, which is driven by a motor (the driveshaft of which is connected to the spindle via a flexible coupling). A pickup with a counter thread is displaced in a translational manner on the spindle when the spindle performs rotational movement. Here, the pickup is connected to the sliding member in a special manner, namely by means of an elastic connection element which causes a torque tilting the pickup in relation to the spindle.
This arrangement is intended to ensure that there is as little play as possible (at least at special contact points of action) between the counter thread and the thread of the spindle and it is thereby intended to be able to reduce or avoid hysteresis in the translational movement of the pickup and of the sliding member when there is a change in direction of the rotational movement of the spindle. By way of example, disadvantages of this arrangement include the fixed tension of pickup and spindle, ensured by the torque acting on the pickup, and so—if the sliding member is already situated at a mechanical stop present for restricting the displacement path, and the spindle is nevertheless rotated further in the correspondingly wrong direction—there may be an irreversible mechanical defect on the spindle thread, on the counter thread of the pickup, on the adjustment path stop and/or on the guides.
A further disadvantage also lies in the complex complicated design and the required large number of components—each of which only ensuring precisely one single special function—of the positioning apparatus.
Furthermore, adjusting the focusing optical unit (i.e. that is to say aligning the focusing optical unit in such a way that the principal point of the optical unit sits precisely at the intended position thereof in the telescopic sight and moves precisely along the intended axis of the telescopic sight) within the telescopic sight is complicated in the positioning apparatus described in U.S. Pat. No. 7,793,424.

Positioning apparatus, in particular for adjusting lenses or lens system in optical devices


One or more secondary data structures are maintained containing mappings of logical flash memory addresses to physical flash memory addresses. Each secondary data structure has a predetermined capacity of mappings. A master data structure is also maintained containing a pointer to each of the one or more secondary data structures. Additional secondary data structures are allocated as needed to provide capacity for additional mappings. One or more counters associated with each of the one or more secondary data structures, respectively, provides an indication of when each of the one or more secondary data structures reaches the predetermined capacity of mappings.

Most modern file systems use a bitmap to explicitly track the free space left on a flash medium. Often this bit map is part of an allocation table maintained in a volatile memory device such some type of random access memory. The bitmap is a simple data structure whereby a single bit is used to indicate if a particular physical sector is free or not. As the user creates and deletes files, directories, and performs other file related tasks over the lifetime of the file system, the file system updates this bitmap accordingly. The problem with this approach is that it tends to require a tremendous amount of memory space and is slower than desired when attempts are made to access information from the bit map.

This patent is subject to a terminal disclaimer.

Dynamic data structures for tracking file system free space in a flash memory device


The invention concerns a carrier plate (2) holding an abrading element, for detachable mounting on a rotatably mounted abrading plate (1) driven during use, for abrading stone or concrete floors, which carrier plate (2) has sides (2a, 2b) which form an acute angle with each other. The sides (2a, 2b) have flanges (2a1, 2b1) which are formed for surrounding engagement with a shoulder (1a) arranged on the abrading plate (1) so that the carrier plate (2) can be fixed on the abrading plate (1) with an engagement based on form and friction.

A machine, preferably for abrading stone and concrete floors, is known for example from PCT/SE93/00865. The abrading element, fixed on a carrier plate which in turn is detachably mounted on the abrading plate, must be considered a consumable. Changing the abrading element is labour-intensive and time-consuming, and adversely affects the production time of the abrading machine.
Examples of known devices for detachable mounting of abrading elements on abrading discs are shown in DE-1 127 745, U.S. Pat. No. 1,470,957 and U.S. Pat. No. 5,076,023.

Carrier plate holding an abrading element and abrading plate


An adaptor for body fluid measurement of the present invention includes a puncture instrument holding section for detachably carrying a puncture instrument for protruding a puncture needle and a measuring instrument holding section for detachably carrying a measuring instrument for analyzing body fluid with a biosensor, the biosensor being attached to the measuring instrument and having a body fluid supply part to which body fluid is supplied. With use of the adaptor, the body fluid can be measured easily and speedily with the puncture instrument and the measuring instrument attached thereto, which are independent from each other. The present invention further provides a measuring instrument including a puncture instrument holding section.

To diagnosis and treatment of diseases, of very importance are analysis of body fluid such as blood and intercellular fluid of a human body, in particular, detection of the existence of a specific substance in the body fluid or measurement of the contents of substrates contained in the body fluid such as glucose, cholesterol and lactic acid. Here, as an example of the body fluid analysis, explanation is given of measurement of a glucose concentration in blood (hereinafter referred to as a "blood glucose level").
Self-control of the blood glucose level is important for treatment of diabetes. Therefore, a patient of diabetes needs to conduct frequent measurement of his/her blood glucose level to maintain the blood glucose level within a normal range. When the patient measures his/her blood glucose level by himself/herself, the blood glucose level measurement is performed by the following steps.
1) A disposable puncture needle is loaded in advance into a puncture instrument such as a lancet and a disposable biosensor is loaded into a measuring instrument.
2) The puncture instrument is held in a dominant hand and a tip of the puncture instrument is pressed against an arm or a finger of the other hand, and then a puncture needle is protruded to allow blood to ooze out.
3) A measuring instrument is held in the dominant hand in place of the puncture instrument.
4) A body fluid supply part of the biosensor loaded in the measuring instrument is brought into contact with a body part from which blood is allowed to ooze to supply the blood into the biosensor, then the measurement results are waited for.
In this way, the puncture instrument must be replaced with the measuring instrument during the measurement, which is troublesome. Further, if it takes a long time until the blood is supplied to the biosensor after the blood is allowed to ooze, the blood may be dried to deteriorate measurement accuracy.
Under the circumstances, there has been proposed an integrated measuring device in which the puncture instrument and the measuring instrument are united to allow blood collection and measurement. Such an integrated measurement device is sold by Dinabbott under the name of "Sof-Tact", for example.
However, regarding an integrated measuring device of this kind, the puncture needle is held in the device and hence it is difficult to know exactly where the puncture needle protrudes. Therefore, the position to be pricked by the puncture needle cannot be fine adjusted and an area where the blood is allowed to ooze is restricted to relatively large body parts such as arms, which makes blood collection difficult in small parts such as fingertips. There are also problems in that the blood supply to the biosensor cannot be visually checked and the device is large to cause inconvenience in carrying it.
The integrated measuring device conducts the measurement by a succession of operations. Therefore, if a problem occurs in the puncture operation or the blood supply to the sensor, both of the puncture needle and the sensor need to be replaced, which increases the cost. Further, in view of the infection via blood adhered thereto, it is impossible to share the measuring device among many patients at the bedside in an inpatient ward or a diagnosis field.
In view of the above, an object of the present invention is to provide an adaptor for measurement that allows a user to conduct easy and speedy measurement even if a puncture instrument and a measuring instrument are separated.
Further, an object of the present invention is to provide a body fluid measuring instrument attached with a puncture instrument that allows easy and speedy measurement.

Body fluid measuring adapter and body fluid measuring unit

Matsushita Electric Industrial Co., Ltd.


An infrared absorption film (first through third infrared absorption films) that constitutes a photoreceptor of a thermal-type infrared detection element comprises a laminate film in which a film composed of a novel SiCO material having high absorption on the short-wavelength end (approximately 8 to 10 μm) of the waveband (atmospheric window) from 8 to 14 μm is combined with a film composed of SiO, SiN, SiC, SiON, SiCN, or another material having high absorption on the long-wavelength end (approximately 10 to 14 μm) of the abovementioned waveband. Infrared rays on the short-wavelength end that could not be effectively utilized by the conventional thermal infrared detection element can thereby be absorbed by the SiCO membrane, infrared rays throughout the abovementioned waveband can be effectively utilized, and the sensitivity of the thermal infrared detection element can be enhanced.

1. Field of the Invention
The present invention relates to a thermal-type infrared detection element having an improved infrared absorption film that constitutes a photoreceptor.
2. Description of the Related Art
A thermal-type infrared detection element measures the temperature of an object from the change in resistance that occurs in a heat-sensitive resistor. This usually occurs when infrared rays emitted by a body are absorbed and converted to heat in an infrared absorption film, the temperature of a bolometer thin film or other heat-sensitive resistor that forms a diaphragm having a microbridge structure is increased, and the resistance of the resistor is changed.
More specifically, this type of thermal-type infrared detection element is composed of a photoreceptor and a beam for holding the photoreceptor in a suspended state above a circuit board. The photoreceptor is provided with a bolometer layer and an infrared absorption film for absorbing incident infrared rays and protecting the bolometer layer. The beam is provided with wiring for connecting the bolometer layer with a reading circuit formed in advance on the circuit board. When incident infrared rays are absorbed by the infrared absorption film, and the temperature of the photoreceptor is increased, the resistance of the bolometer layer changes, and this change in resistance is detected by the reading circuit and outputted as a temperature. A thermal-type infrared detection element having this type of structure is disclosed in JP-A 2002-71452 (pp. 5-8, FIG. 6), for example.
Increasing the change in resistance of the bolometer layer with respect to the change in temperature of the photoreceptor is of primary importance in increasing the sensitivity (S/N ratio) of the thermal-type infrared detection element described above. Therefore, a material having a large temperature coefficient of resistance (TCR: Temperature Coefficient Resistance) is used for the bolometer layer. Increasing the efficiency with which incident infrared rays are absorbed is the second most important factor. In order to achieve this object, an infrared reflection film is provided in a position facing the photoreceptor on the circuit board, and the gap between the photoreceptor and the infrared reflection film is set so that an optical resonance structure is formed. In order to also increase the absorption efficiency with respect to incident infrared rays, the infrared absorption film that constitutes a photoreceptor is endowed with a laminate structure made up of films composed of different materials.
Since the thermal-type infrared detection element thus configured detects infrared rays having wavelengths from 8 to 14 μm in the so-called atmospheric window, the infrared absorption film must be composed of a material that absorbs infrared rays having the abovementioned wavelengths. From a manufacturing standpoint, the infrared absorption film must also be composed of a material that is easily formed into a film, etched, or otherwise processed. Therefore, silicon oxide (SiO), silicon nitride (SiN), silicon carbide (SiC), silicon oxynitride (SiON), silicon carbonitride (SiCN), and the like have conventionally been used as materials that satisfy these conditions.
However, although these materials absorb infrared rays in the abovementioned waveband, since the absorption rate is high on the long-wavelength end (approximately 10 to 13 μm) of the abovementioned waveband, and is low on the short-wavelength end thereof (approximately 8 to 10 μm), infrared rays on the short-wavelength end of the abovementioned waveband are not effectively utilized.
More specifically, as shown in FIG. 1, SiC has maximum absorption of wavelengths near 13 μm; SiN, SiCN, and SiON have maximum absorption of wavelengths near 12 μm; and absorption is high for infrared rays on the long-wavelength end of the abovementioned waveband. However, absorption sharply declines on the short-wavelength end, and the absorption in the waveband of 8 to 12 μm for SiON and SiN is only about 20%. Since the absorption rate of SiO is at maximum near 10 μm, but is generally low compared to that of SiN, SiON, and SiC, infrared rays having wavelengths in the abovementioned range cannot be efficiently absorbed. Infrared rays on the short-wavelength end of the abovementioned waveband therefore cannot be effectively utilized even when infrared absorption films composed of these materials are combined in a laminate. This results in drawbacks whereby the sensitivity of the thermal-type infrared detection element cannot be adequately increased.
A method for increasing the thickness of the infrared absorption film is also considered as a way of increasing the absorption efficiency of infrared rays, but the heat capacity of the photoreceptor increases when the thickness of the infrared absorption film is increased, and the temperature change-with respect to the incident infrared rays decreases. Since an infrared absorption film is also formed in the beam, the beam increases in diameter, and the amount of heat discharged towards the circuit board increases. Therefore, the sensitivity of the thermal-type infrared detection element cannot be increased by this method.


A frequency divider circuit comprises a plurality of T flip-flops, a first transmission gate, a second transmission gate and an inverter. The plurality of T flip-flops is connected in series. The output of the inverter is connected to a clock input of a first T flip-flop. The first transmission gate connects a clock signal and the other clock input of the first T flip-flop and the input of the inverter. The second transmission gate connects the inverted signal of the clock signal and the output of the first transmission gate.

1. Field of the Invention
The present invention relates to a circuit, and more particularly, to a frequency divider circuit.
2. Description of the Related Art
When designing a circuit, there is usually a need for clock signals of periods different from that of the main clock signal. Power supporting circuits, for example, usually require clock signals of different periods for different channels of power outputs such that the total amount of power output is more uniformly distributed over time. However, it is not efficient to design corresponding clock generating circuits for every clock signal of a different period. Therefore, there is a need for a frequency divider circuit which divides the frequency of a clock signal to generate clock signals of different periods. The ratios of the periods of clock signals generated by an ordinary frequency divider circuit to the period of the original clock signal are usually exponents of 2, such as 2, 4 or 8. The applications of ordinary frequency divider circuits are thus limited.
U.S. Pat. No. 4,348,640 discloses a frequency divider circuit comprising three JK flip-flops and five logic gates, wherein the frequency divider circuit down-converts a clock signal into another signal with a period three times of the period of the original clock signal. However, the frequency divider circuit requires a lot of flip-flops and logic gates, and also requires a lot of effort to be adapted to generate signals of different periods.
U.S. Pat. No. 6,389,095 discloses a frequency divider circuit comprising two D flip-flops, an OR gate and a NOR gate, wherein the frequency divider circuit down-converts a clock signal into another signal with a period three times of the period of the original clock signal. Even though the frequency divider circuit reduces the number of the required transistors, it still requires an OR gate and a NOR gate. In CMOS manufacturing process, the frequency divider circuit requires at least 10 transistors, which does not meet the requirement for cost efficiency. In addition, the frequency divider circuit requires a lot of effort to be adapted to generate signals of different periods, and hence its usage is limited.
Accordingly, there is a need to design a frequency divider circuit with simple structure that can be easily adapted to generate signals of different periods to meet the requirement of modern circuit design.


A magnetic storage device that includes a housing, including a base, a cover, and an interior cavity. The magnetic storage device also includes an actuator controller, located in the interior cavity and configured to generate an actuator command signal. The magnetic storage device further includes an actuatable component, located in the interior cavity, and an actuator, located in the interior cavity and operable to actuate the actuatable component in response to the actuator command signal. The magnetic storage device also includes a vibration sensor, located in the interior cavity and configured to detect a vibration of the cover. The magnetic storage device further includes a sensor feedforward controller, located in the interior cavity and configured to generate a gain signal, based on the vibration of the cover detected by the vibration sensor, and to modify the actuator command signal proportional to the gain signal.

Magnetic storage devices, such as hard disk drives, include several actuatable components. Precisely controlling the position of some actuatable components of magnetic storage devices is important to the overall performance and reliability of the magnetic storage devices. However, certain factors, such as vibration of the magnetic storage devices can cause the actuatable components to experience position errors. Position errors occur when the actual position of the actuatable components is different than a desired or expected position of the actuatable components.
Conventional techniques for reducing position errors rely solely on feedback control. However, adequately compensating for certain types and magnitudes of vibrations using conventional feedback control techniques can be difficult.

Vibration sensor feedforward control for magnetic storage device


Data security and privacy are improved by a client providing a hashed version of collected data to a remote analysis service, and having the analysis service determine the relevancy of the data from the hashes before requesting the plaintext of the data. In one example, a browser plug-in obtains data which is divided into overlapping three-character sequences, and the sequences are hashed to produce a sequence of hashes. The sequence of hashes is sent by the plug-in to the remote service, which uses the hashes to determine if the associated data is relevant to the analysis performed by the remote service, without requiring access to the associated plaintext. After making the determination, the remote service may request that relevant data be provided to the service in plaintext form, while data that is not relevant need not be sent to the remote service.

Entities often collect significant amounts of user data for use to improve the user experience. This data is sometimes traceable to a particular user. Therefore, although this information is generally collected with the permission of the user, many users are concerned about controlling the use of data associated with them. Data misuse or loss can be a huge problem and can even result in fines or legal actions against the entity. Therefore, data privacy and security are important considerations when dealing with sensitive user-identifiable information.

Cryptographic data encoding method with enhanced data security


A slide door structure of an automobile which enables occupants to get in and out with ease even in a narrow parking space because the door of the automobile can be largely opened and capable of reducing the constraints on the design of the body of the automobile. Forward lower rail boards (11, 13) are positioned on the lower part of the body (1) at the front of a rear wheel house (5) when the slide doors (2, 3) are closed and, when the slide doors (2, 3) are opened, extracted from the front side of the rear wheel house (5) to the outside rear side of the body (1) by the rotation of a front link mechanism, and a rear lower rail board (12) is positioned on the lower part of the body (1) at the rear of the rear wheel house (5) when the slide doors (2, 3) are closed and, when the slide doors (2, 3) are opened, extracted from the rear side of the rear wheel house (5) to the outside front side of the body (1) by the rotation of a rear link mechanism.

1. Field of the Invention
The present invention relates to a slide door structure of an automobile, and more particularly to a slide door structure of an automobile which can slide and open both a front door and a rear door to a rear side of a vehicle body.
2. Description of the Related Art
A door of an automobile which open and closes to the right and left sides by a hinge mechanism is generally well-known. However, in the case of opening and closing the door mentioned above so as to get in and out of the vehicle, a space for which a passenger getting in and out can avoid any interference with the door so as to pass is necessary in a side of the vehicle. In the case that a sufficient width is not obtained even if the space is secured, it is necessary to pass through a narrow space in an unnatural posture, and many problems are generated for an aged person and a handicapped person. Further, in a road having a lot of traffic or the like, there is a risk that a person, a vehicle, a bicycle or the like comes into collision with the wide-open door and a great accident or the like is triggered, so that adequate care is necessary.
As one method for solving the problem mentioned above, there is a slide door. In the slide door, because the door is opened and closed by moving the door backward and forward, it is possible to completely leave open an opening portion in a side surface of the vehicle, which is different from the hinge type door, the slide door is user friendly and convenient in the case that the person comes in and out between inner and outer sides of a passenger room or the case that the person carries a load in and out. There is obtained an advantage that it is possible to get in and out of the vehicle parked in a narrow parking space without any difficulty, and the slide door is particularly convenient for the aged person and the handicapped person.
In this case, in the conventional slide door for the automobile, it is often the case that only one of the front door and the rear door is generally of the slide type, and it is often the case that the front door is of a type which must be moved forward to be opened, and the rear door is of a type which must be moved backward so as to be opened (for example, refer to patent document 1 and patent document 2).
However, in the case that only one door is of the slide type, it is not possible to completely make good use of the advantage of the slide type so as to obtain a wide opening, and there is left the problem that it is necessary to pay attention to open and close the other side door which is not of the slide type.
Further, a structure in which both the doors are slid backward and forward (for example, refer to patent document 3) becomes ungainly, and is better adapted to a particular intended use such as a camper or the like. However, there is generated a problem that a vehicle body design is not well thought out, in a passenger car.
Patent Document 1: Japanese Unexamined Patent Publication No. 2004-50877
Patent Document 2: Japanese Unexamined Patent Publication No. 2005-81878
Patent Document 3: Japanese Unexamined Patent Publication No. 2005-88811


In one embodiment, a method for providing voice quality assurance is provided. The method determines voice information for an end point in a voice communication system. The voice information may be from an ingress microphone. The method determines if the voice quality is considered degraded based on an analysis of the voice information. For example, the voice information may indicate that it is distorted, too loud, too soft, is subject to an external noise, etc. Feedback information is determined if the voice quality is considered degraded where the feedback information designed to improve voice quality at an ingress point for a user speaking. The feedback information is then outputted at the end point to the user using the end point.

Voice communication systems, such as traditional public switched telephone network (PSTN) telephone systems, cellular telephone systems, and land mobile radio systems, can experience voice degradation caused by microphone distortion. In a specific example, a push-to-talk (PTT) communication system may be used by emergency response personnel to communicate amongst each other. These users work in physically and emotionally stressful conditions, such as in burning buildings, volatile crime scenes, etc., and are often under personal threat or performing aerobic physical exertion. One consequence of the stressful use is that voices may be distorted to the point of unintelligibility because of actions by the users. For example, users may hold the microphone too close to the mouth, which may produce too much breath noise or too much acoustic pressure for a proper voice transmission. Further, users may speak too softly or too loudly because of the situation they are in, such as a user may not be able to speak loudly because they are in danger or the user may be excited and speak too loudly. This often results in distortion and other users listening to the speaker cannot understand what the speaker is saying. Often, the communications from the speaker may be critical and thus it is important that users understand the speaker.

Automated near-end distortion detection for voice communication systems


An integrated circuit die is disclosed including a temperature detection circuit and a memory configured to store calibration data. The temperature detection circuit is operatively coupled to the memory, and receives an input signal. The temperature detection circuit is configured to produce an output signal dependent upon the input signal and indicative of whether a temperature of the integrated circuit die is greater than a selected temperature. During a normal operating mode of the integrated circuit die the input signal comprises the calibration data. A system and methods for calibrating the temperature detection circuit are also described.

1. Field of the Invention
This invention relates generally to semiconductor electronics and, more particularly, to integrated circuits.
2. Description of the Related Art
A wafer fabrication process typically forms many identical integrated circuits upon each of several silicon wafers processed as a group (i.e., lot). Each integrated circuit is formed within a designated area of a wafer, and includes electronic devices electrically coupled by conductive traces called interconnect lines (i.e., interconnects). Interconnects are typically patterned from conductive layers formed on or above the surface of a silicon substrate. Following wafer fabrication, the individual integrated circuit dice are separated from the wafers, and each functional die is typically secured within a protective semiconductor device package.
Integrated circuits dissipate electrical power during operation, transforming electrical energy into heat energy. At the same time, several key operating parameters of an integrated circuit typically vary with temperature, and reliable device operation within specifications occurs only within a defined operating temperature range. For high performance devices, such as microprocessors, specified performance is only achieved when the temperature of the device is below a specified maximum operating temperature. Operation of the device at a temperature above the specified maximum operating temperature, may result in irreversible damage to the device. In addition, it has been established that the reliability of an integrated circuit decreases with increasing operating temperature. The heat energy produced by an integrated circuit during operation must thus be removed from the integrated circuit at a rate which ensures operational and reliability requirements are met.
The continued demand for higher performance microprocessors, aided by advances in integrated circuit fabrication and packaging technologies, has led to higher clock signal frequencies (i.e., increased clock signal speeds) and increased levels of integration. Despite shrinking device sizes, maximum microprocessor power dissipations continue to increase at exponential rates. As a result, it is becoming increasingly more difficult to operate high performance integrated circuits (e.g., microprocessors) such that maximum operating temperatures, specified by manufactures for the operational stability and reliability reasons described above, are not exceeded.
It would thus be beneficial to have an integrated circuit die including a temperature detection circuit, and a system and method for calibrating the temperature detection circuit. The temperature detection circuit may be, for example, used to keep a temperature of the die below a maximum operating temperature of the integrated circuit.

Integrated circuit die including a temperature detection circuit, and system and methods for calibrating the temperature detection circuit

International Business Machines Corporation


Disclosed is an all-optical frequency upconverter in a radio-over-fiber system that outputs upconverted optical radio frequency (RF) signals using an optical intermediate frequency signal and an optical local oscillation signal. The all-optical frequency upconverter includes a semiconductor optical amplifier that mixes the optical intermediate frequency signal with the optical local oscillation signal through four wave mixing, and an optical filter that filters a plurality of frequency component signals, which are generated through the four wave mixing, to extract optical RF signals. According to the invention the system configuration can be made simple, and wide LO and IF frequency bandwidths can be provided.

1. Technical Field
The present invention relates to an all-optical frequency upconversion method and an all-optical frequency upconverter in a radio-over-fiber system, and in particular, to all-optical frequency upconversion method and an all-optical frequency upconverter in a radio-over-fiber system that mix an optical IF (Intermediate Frequency) signal with an optical LO (Local Oscillation) signal to generate an optical RF (Radio Frequency) signal.
2. Background Art
Recently, in the fields of wireless communications, studies for improving speed and quality of broadband multimedia traffic are actively in progress. In a broadband multimedia service, for massive data transmission, the frequency of a radio signal is being increased up to the microwave or millimeter-wave band. As the frequency is increased, an electric transmission line, generally used for transmission of high-frequency electrical signals, experiences a high transmission loss. A radio-over-fiber (RoF) technology has been proposed so as to solve the problem arising from the high transmission loss of the electrical transmission line. According to the RoF technology, an optical RF signal containing a microwave or millimeter-wave radio signal is transmitted through an optical fiber, which has features including ultra-wide broadband and low transmission loss.
The RoF system has attracted much attention in the broadband wireless access fields, such as wireless backbone network, remote medical service, and multimedia broadcasting. With the RoF technology, a cost-effective broadband convergence network incorporating a high-speed optical communication network and a wireless communication network can be constructed.
FIG. 1 is a conceptual diagram showing a general RoF system.
Referring to FIG. 1, the RoF system includes a central station 10, a remote node 30, and a remote antenna station (RAS) 40.
Data (carried on an IF signal) from the high-speed backbone network is modulated by a modulator at the remote node 30 using an LO signal to produce an optical RF signal 31. The optical RF signal 31 is then transmitted to the RAS 40 through an optical fiber 32, which has features including ultra-wide broadband and low transmission loss. The RAS 40 converts the optical RF signal 31 into a radio signal and sends the converted radio signal through an antenna.
Methods for converting data into the optical RF signal 31 include one that uses an electro-optic modulator and the other that uses all-optical frequency converter.
The all-optical frequency conversion method is suitable for an ultra-wide broadband RoF system because the wavelength division multiplexing (WDM) system, which is capable of markedly improving the frequency utilization, can be used. The WDM system is a technology that multiplexes multiple channels on a single optical fiber by using different wavelengths. That is, the channels are allocated to different wavelengths spaced at an equal wavelength interval, then the signals are correspondingly carried on the channels, and subsequently the channels are optically multiplexed. Accordingly, different signals are transmitted through a single optical fiber.
The all-optical frequency conversion system reported previously uses XGM (Cross-Gain Modulation) or XPM (Cross-Phase Modulation) effect inherent in a semiconductor optical amplifier (SOA). The all-optical frequency conversion system employing the XGM or XPM effect of the SOA is advantageously applied to the WDM system due to its wide LO frequency bandwidth characteristics. However, it has a limited IF frequency bandwidth (usually limited to several GHz or less) arising from the carrier lifetime of the SOA.
The limited IF frequency bandwidth characteristics of the all-optical frequency conversion system employing the XGM or XPM effect of the SOA adversely affects application of the sub-carrier multiplexing (SCM) system, which is also capable of markedly increasing the data transmission capacity, to the RoF system, together with the WDM system.
Accordingly, for implementation of the millimeter-wave ultra-wide broadband RoF, there is a need for a novel all-optical frequency conversion system that is capable of simultaneously applying the WDM system and the SCM system, and has wide LO and IF frequency bandwidths.
There are reports on all-optical frequency conversion system that use four wave mixing (FWM) effect by a HNL-DSF (High-nonlinear dispersion shifted fiber) and a Raman pump ("Seamless Integration of an 8×2.5 Gb/s WDM-PON and Radio-Over-Fiber Using All-Optical Up-Conversion Based on Raman-Assisted FWM", IEEE Photon. Technol. Lett., vol. 17, pp. 1986-1988, September 2005, Jianjun Yu, Jinxing Gu, Xiang Liu, Zhensheng Jia, and Gee-Kung Chang). These all-optical frequency conversion systems utilizing the FWM have wider IF frequency bandwidth than the all-optical frequency conversion system utilizing the XGM or XPM effect of the SOA, and thus the WDM system and the SCM system can be simultaneously applied to increase the bandwidth of the RoF system. However, in the known all-optical frequency conversion system, which uses the FWM effect by the HNL-DSF and the Raman pump, a no-gain optical fiber is used to use the FWM effect. For this reason, the HNL-DSF and the Raman pump having good nonlinearity are used to increase the conversion efficiency in the no-gain optical fiber. As a result, the length of the optical fiber to be used reaches approximately 1 km, and the Raman pump needs to be provided, which causes the complexity of the overall system configuration.

All-optical frequency upconverter and all-optical frequency upconversion method in radio-over-fiber system

Gwangju Institute of Science and Technology


Data communication methods and systems are provided for use in an LTE-based vehicle-to-everything (V2X) communication. The method (300) includes: receiving (315), on the data interface and according to a predefined timing reference (TREF) a synchronization signal; determining (317) a timing synchronization according to the synchronization signal; and transmitting or receiving data according to the timing synchronization. Furthermore, the method may include receiving, on a data interface, a positioning signal; performing a coarse timing synchronization according to the positioning signal; and refining the coarse timing synchronization according to the synchronization signal. Data may be communication using a configurable V2X communication cycle comprising one or more first V2X-communication periods for event-triggered V2X message transmission and one or more second V2X-communication period s for periodic V2X application message transmission.

Background Art3GPP3rd Generation Partnership ProjectCAMCooperative Awareness MessageCAN-BusController Area Network BusD2DDevice to Device communicationDFND2D Frame numberDLDownLinkDSRCDedicated Short Range CommunicationGPSGlobal Position Systemhh:mm:sshour hour:minute minute:second second.HDOPHorizontal Dilution of PrecisionHEPEHorizontal Estimated Position ErrorI/OInputs/OutputsIFInterfaceITSIntelligent Transport SystemLTELong Term EvolutionMACMedium Access ControlMCSModulation and Coding SchemeNHTSANational Highway Traffic Safety AdministrationNTRPTime Resource Pattern numberOBU/OBEOn-board Unit/On-board EquipmentP25Project 25, suit of standard for digital radiocommunicationPC5Sidelink air interfacePHYPhysicalPMRPrivate Mobile RadioPRBPhysical Resource BlockProSeProximity-based Services or so called LTE D2Dor Sidelink communicationPSCCHPhysical Sidelink Control ChannelPSSCHPhysical Sidelink Shared ChannelRSU/RSERoad-side Unit/Road-side EquipmentRXReceiveSAScheduling AssignmentSFNSystem Frame numberSLSidelink communication or Device to DevicecommunicationTBSTransport Block SizeTRPTime Resource PatternTSTechnical SpecificationTXTransmitULUpLinkUSBUniversal Serial BusUTCCoordinated Universal TimeUuLTE Radio InterfaceV2HVehicle to home communicationV2HVehicle-to-HomeV2IVehicle to Infrastructure or Infrastructure to VehiclecommunicationV2NVehicle to Network communication using cellularcommunicationV2PVehicle to Pedestrian communicationV2PVehicle-to-PedestriansV2VVehicle to Vehicle communicationV2XVehicle to everything, a Collection of V2V, V2I, V2Pand V2HVANETVehicular Ad-Hoc NetworkVFNV2X Frame NumberWAVEWireless Access for Vehicular EnvironmentWiFiWireless FidelityYYYY-MM-DDYearYearYearYear-MonthMonth-DayDay
Vehicle-to-Everything (V2X) communication enables vehicles to communicate with other vehicles (i.e. Vehicle-to-Vehicle (V2V) communication), with infrastructure (i.e. Vehicle-to-Infrastructure (V2I), with wireless networks (i.e. Vehicle-to-Network (V2N) communication), with pedestrians (i.e. Vehicle-to-Pedestrian (V2P) communication), and even with the owner's home (i.e. Vehicle-to-Home (V2H)). Examples of infrastructure include roadside units such as traffic lights, toll gates and the like.
V2X communication can be used in a wide range of scenarios, including in accident prevention and safety, convenience, traffic efficiency and clean driving, and ultimately in relation to autonomous/self-driving vehicles. For example, in relate to accident prevention, it has been estimated that appropriate V2X systems can prevent over 80 percent of accidents for unimpaired drivers, by alerting the drivers to hidden dangers that can't be sensed by traditional on-board equipment such as sensors.
In relation to traffic efficiency, an appropriate V2X system in combination with a nationwide data collection and processing network, may facilitate environmental improvements, as well as improvements to public safety, mobility, productivity and convenience by providing optimised traffic routing, increased traffic flow, traffic control and incident management.
In V2V, data may be shared between V2X-equipped vehicles within a half-mile or 800 m radius of each other, which can be used to provide a driver with a global view of traffic and be alerted to the most common causes of accidents in time to take evasive action. In more advanced applications, an evasive action or a chain of evasive actions may be initiated by the receiving vehicle automatically.

Vehicle to everything (V2X) communication method and system


The invention includes compositions comprising selective AKR1C3 inhibitors. The invention also includes compositions comprising bifunctional AKR1C3 inhibitors and selective androgen receptor modulators. The invention further includes methods of treatment using the compositions of the invention.

Hormone-dependent malignancies of the prostate and breast are leading causes of cancer incidence and death in the Western world. For example, prostate cancer (PC) is the second most common cancer in American men and is responsible for about 11% of all cancer related deaths (Jemal et al., 2010, Cancer J. Clin. 60:277; Altekruse et al., Eds., SEER Cancer Statistics Review, 1975-2007; National Cancer Institute: Bethesda, Md., 2010).
Since the pioneering studies of Charles Huggins, hormonal ablative therapy of these diseases has become standard practice (Huggins & Hodges, 1941, Cancer Res. 1:293-397; Huggins, 1954, J. Natl. Cancer Inst. 15:1-25; Huggins & Yang, 1962, Science 137:257-62; Huggins, 1965, Cancer Res. 25:1163-67). Modern approaches include targeting steroid receptors in these tissues with androgen receptor antagonists (i.e., flutamide, also known as 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide; Trachtenberg et al., 2002, Can. J. Urol. 3:240-45) or estrogen receptor antagonists (i.e., tamoxifen, also known as (Z)-2-[4-(1,2-diphenyl-but-1-enyl)phenoxy]-N,N-dimethyl-ethanamine; MacGregor & Jordan, 1998, Pharmacol. Rev. 50:1551-96). With the realization that agents that antagonize androgen and estrogen receptors in one tissue may act as agonists in another tissue, the accepted term for these agents are selective androgen receptor modulators (SARMs) and selective estrogen receptor modulators (SERMs), respectively. SARMs that target prostate cancer need only act as an androgen receptor antagonist in the prostate.
Prostate cancer is initially dependent on testicular androgens and is thus responsive to androgen ablation with surgical or chemical castration. The drug of choice for chemical castration is the luteinizing hormone-releasing hormone (LH-RH) agonist leuprolide (p-Pro-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (SEQ ID NO:6); Leupron). Leuprolide inhibits the release of LH from the anterior pituitary and prevents Leydig cell testosterone biosynthesis. Supplementation of castration with blockade of androgen action in the prostate is common and may be achieved with an AR antagonist (bicalutamide, also known as N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide) or by inhibition of type 1 5α-reductase (SRDSA 1) and type 2 5α-reductase (SRD5A2) with dutasteride ((5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide). Bicalutamide is a relatively weak ligand for the AR and in castrate resistant prostate cancer (CRPC) this compound can even act as a weak agonist leading to the desire for better agents (Tran et al., 2009, Science 324:787-90).
In prostate cancer the therapeutic benefit of androgen deprivation therapy (ADT) is temporary and is often followed by recurrence of a more aggressive metastatic disease—CRPC. CRPC is characterized by elevated intratumoral androgen biosynthesis, increased androgen receptor (AR) signaling and expression of pro-survival genes despite castrate level circulating androgen concentrations (Knudsen & Scher, 2009, Clin. Cancer Res. 15:4792; Knudsen & Penning, 2010, Trends Endocrinol. Metab. 21:315; Locke et al., 2008, Cancer Res. 68:6407). The source of intratumoral androgens is likely dehydroepiandrosterone (DHEA) and/or 4-androstene-3,17-dione (Δ4-AD) from the adrenal, which is subsequently metabolized to testosterone and 5α-dihydrotestosterone (5α-DHT). The conversion of testosterone to 5α-DHT is catalyzed by 5α-reductase isoforms. While the use of 5α-reductase inhibitors in the treatment of CRPC is still under clinical investigation, chemoprevention trials of prostate cancer with both finasteride (a selective 5α-reductase type 2 inhibitor) and dutasteride (a combined 5α-reductase type 1 and type 2 inhibitor) have produced controversial outcomes (Andriole et al., 2010, N. Engl. J. Med. 362:1192-1202; Thompson et al., 2007, J. Clin. Oncol. 25:3076-81; Walsh, 2010, New Engl. J. Med. 362:1237-38).
Prostate tumor reappearance appears to be driven by adaptive intratumoral androgen synthesis that bypasses the effects of ADT (Attard et al., 2009, Cancer Res. 69:4937-40). This conclusion is supported by the success of the new drug abiraterone acetate ((3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol acetate; Johnson & Johnson) at arresting CRPC and reducing the size of bone metastases in ongoing phase II/III clinical trials (Attard et al., J. Clin. Oncol. 27:3742-48; Reid et al., 2010, J. Clin. Oncol. 28:1489-95). Approved by the FDA for the treatment of CRPC, abiraterone acetate is a steroidal P450 17α-hydroxylase/17,20-lyase (CYP17) inhibitor that blocks the conversion of pregnenolone to dehydroepiandrosterone (DHEA). It blocks this step in the adrenal, which is the major source of circulating DHEA, or in the prostate, if there is de novo steroidogenesis from cholesterol. One disadvantage is that CYP17 is high up in the steroidogenic pathway. Its inhibition in the adrenal diverts pregnenolone to form the mineralocorticoid desoxycorticosterone (DOC). In addition, CYP17 inhibition prevents the formation of cortisol, which feeds-back and inhibits the production of ACTH in the anterior pituitary. The combined effect is elevated DOC production and potentially life-threatening hypertension. Abiraterone is therefore co-administered with a glucocorticoid (hydrocortisone or prednisone) to suppress the hypothalamo-pituitary-adrenal axis. Chronic use of glucocorticoids can however lead to drug induced Cushing's syndrome, immunosuppression and osteoporosis. A second generation analog of abiraterone acetate is VN/124-1 or TOK-001, which is both a CYP17 inhibitor and an AR antagonist that targets the receptor for degradation (Vasaitis et al., 2008, Mol. Cancer Therap. 7:2348-57). VN/124-1 validates the concept that the androgen axes in CRPC may be effectively shut down by inhibiting local androgen biosynthesis and by blocking the AR.
Another approach to treatment has been to develop a more potent AR antagonist than bicalutamide, whose effects may be easily surmounted by intratumoral androgen synthesis, and acts as a weak androgen receptor agonist. MDV3100 (Medivation) also known as enzalutamide prevents both AR nuclear translocation and binding to DNA and is more potent than bicalutamide and does not exhibit agonist activity (Tran et al., 2009, Science 324:787-90). MDV3100 phase I/II clinical trials show that this agent reduces serum PSA, circulating tumor cells and causes radiographic stabilization of the disease (Scher et al., 2010, Lancet 375:1437-46). However, MDV3100 belongs to a class of anti-androgens that carry seizure risk, likely mediated via antagonism of the CNS-based GABAA receptor (Foster et al., 2010, Prostate 71:480-8). MDV3100 may ultimately be replaced by the use of its congener ARN-509 (Clegg et al., 2012, Cancer Res 72:1494-1503). MDV3100 has also been approved by the FDA for the clinical treatment of CRPC.
Steroid-target tissues produce steroid hormones locally (intracrine and paracrine formation) to maintain their growth (Labrie et al., 1995, Ann. Endocrinol. 56:23-29; Labrie et al., 2000, J. Mol. Endocrinol. 25:1-16). This is important in prostate and breast cancer, which are diseases of the aging male and female. In these individuals, the gonadal production of steroid hormones has been compromised (e.g. andropause and menopause). Enzymes important in the local production of androgens (e.g. type 2 5α-reductase) and estrogens (e.g. aromatase) have become the targets for inhibitor development to treat hormone dependent malignancies of the prostate and breast (Miller, 1996, Endocrine-Related Cancer 3:65-79; Gormley, 1996, Endocrine-Related Cancer 3:65-79). Effective agents include finasteride and exemestane (10,13-dimethyl-6-methylidene-7,8,9,10,11,12,13,14,15,16-decahydrocyclopenta[a]phenanthrene-3,17-dione), which are mechanism-based inactivators for type 2 5α-reductase and aromatase, respectively (Bull et al., 1996, J. Amer. Chem. Soc. 118:2359-65; Brodie et al., 1981, Steroids 38:693-702). One disadvantage to this approach is that aromatase inhibitors cause global decreases in active estrogens and can have unintended side effects (e.g. osteoporosis). Also such treatments can cause these malignancies to become refractory to hormone ablation.
The local levels of steroid hormones are also regulated by hydroxysteroid dehydrogenases (HSDs) (Penning, 1997, Endocrine Rev. 18:281-305). HSDs catalyze the NAD(P)(H) dependent oxidation or reduction of potent steroid hormones to their cognate inactive metabolites and vice-versa. For each steroid hormone there are pairs of HSDs that will either act as reductases or oxidases to modulate the potency of the hormone. For example, type 1 17β-HSD reduces E1 to E2 and is estrogenic, while type 2 and type 4 17β-HSD will oxidize E2 to E1 and attenuate estrogen action (Labrie et al., 2000, J. Mol. Endocrinol. 25:1-16; Labrie et al., 1997, Steroids 62:148-58; Labrie et al., 1995, Cell Biol. 14(10):849-61; Adamski et al., 1995, Biochem J. 311(Pt 2):437-43).
Aldo-keto reductases are a superfamily of 15 families of generally monomeric (37 kDa) cytosolic NAD(P)(H) dependent oxidoreductases that convert carbonyl groups to alcohols. Natural substrates for these enzymes include steroids, prostaglandins and lipid aldehydes (Hyndman et al., 2003, Chem-Biol. Inter. 143-144:621-31). All the HSDs in this superfamily are highly related in sequence (>67% identity) and comprise the AKR1 C family. The four human AKR1C isoforms (AKR1C1—SEQ ID NO:1; AKR1C2—SEQ ID NO:2; AKR1C3—SEQ ID NO:3; AKR1C4—SEQ ID NO:4) have been cloned and expressed, their enzymatic properties in vitro have been assigned, and their tissue specific expression patterns have been studied (Penning et al., 2000, Biochem. J. 351:67-77). Each of the four isoforms share >86% sequence identity but have different ratios of 3-, 17- and 20-ketosteroid reductase activities. AKR1C1 is a major 20α-HSD, AKR1C2 (type 3 3α-HSD and bile acid binding protein) is a major peripheral 3α-HSD, AKR1C3 is a peripheral 17β-HSD, and AKR 1 C4 (type 1 3αHSD/chlordecone reductase) is a hepatic specific 3α-HSD (Penning et al., 2000, Biochem. J. 351:67-77). These enzymes have the potential to regulate ligand occupancy of the PR, AR, and ER. This is referred to as the pre-receptor regulation of nuclear receptors (FIG. 1).
AKR1C3 catalyzes the NADPH dependent reduction of carbonyl moieties on substrates of importance to the pre-receptor regulation of signaling pathways involved in cell proliferation. The interconversion of a ketone group with a hydroxyl group on lipophilic ligands can drastically alter their affinity for their cognate receptors (FIG. 2). For example, AKR1C3 reduces the 17-position of Δ4-AD (a weak androgen) to form testosterone (a potent androgen) and of estrone (a weak estrogen) to form 17β-estradiol (a potent estrogen), leading to trans-activation of the androgen and estrogen receptors, respectively (Byrns et al., 2010, J. Steroid. Biochem. Mol. Biol. 118:177-87; Dufort et al., 1999, Endocrinology 140:568-74). Because of this activity, AKR1C3 is also known as type 5 17β-hydroxysteroid dehydrogenase. It can also act at the 20-position of progesterone and deoxycorticosterone, forming 20α-hydroxy metabolites with reduced affinities for the progesterone and mineralocorticoid receptors, respectively (Sharma et al., 2006, Mol. Cell. Endocrinol. 248:79-86). Finally, as prostaglandin (PG) F synthase, AKR1C3 catalyzes the stereo-specific reduction of PGH2 to PGF2α and of PGD2 to 9α,11β-PGF2 (Byrns et al., 2010, J. Steroid. Biochem. Mol. Biol. 118:177-87; Suzuki-Yamamoto et al., 1999, FEBS Lett. 462:335-40; Koda et al., 2004, Arch. Biochem. & Biophys. 424:128-36). In the absence of AKR1C3 activity, PGD2 spontaneously dehydrates and rearranges to form the PGJ2 prostanoids (Byrns et al., 2010, J. Steroid. Biochem. Mol. Biol. 118:177-87). The PGF2 isomers are pro-inflammatory and enhance proliferation, while the PGJ2 products, particularly 15-deoxy-Δ12,14-PGJ2 (15dPGJ2), are anti-inflammatory, promote differentiation, and are anti-neoplastic via several mechanisms (Jabbour et al., 2005, Endocrinology 146:4657-64; Ray et al., 2006, J. Immunol. 177:5068-76; Diers et al., 2010, Biochem. J. 430:69-78; Nakata et al., 2006, Mol. Cancer Therapeutics 1827-35; Butler et al., 2000, Cell Growth Differ. 11:49-61; Scher & Pillinger, 2009, J. Investig. Med. 57:703-08).
The products of reactions catalyzed by AKR1C3 promote tumor growth. It is therefore an important target for the prevention or treatment of both hormone-dependent and hormone-independent cancers. AKR1C3 likely contributes to the development of CRPC through the intratumoral formation of the active androgen testosterone (Penning et al., 2008, Mol. Cell. Endocrinol. 281:1-8). Transcript levels and measurement of testosterone: 5α-dihydrotestosterone (5α-DHT) ratios support the notion that there is a reprogramming of androgen dependence in castrate resistant disease that favors formation of testosterone by AKR1C3 (Montgomery et al., 2008, Cancer Res. 68:4447-54; Mostaghel et al., 2007, Cancer Res. 67:5033-41). Other studies have shown that there three pathways to the potent androgen 5α-DHT in prostate cancer, and AKR1C3 is required for each pathway. The first pathway known as the "classical pathway" involves the sequence: DHEA→Δ4-Aandrostene-3,17-dione (Δ4AD)→testosterone→5α-DHT. In this pathway AKR1C3 catalyzes the NADPH dependent reduction of Δ4-AD→testosterone. The second pathway is known as the "backdoor pathway" in which 5α-reduction occurs at the level of the pregnanes and by-passes DHEA and testosterone altogether (Auchus, 2004, Trends, Endocrinol. Metab. 15: 432-38). The critical conversions are: 5α-pregnane-3,20-dione (DHP)→allopregnanolone→androsterone→3α-androstanediol→5α-DHT. In this pathway, AKR1C3 catalyzes the NADPH dependent reduction of androsterone→3α-androstanediol. The third pathway known as the "alternative pathway" involves the sequence: DHEA→Δ4-AD→5α-androstane-3,17-dione→5α-DHT (Chang et al., 2011, Proc. Natl. Acad, sci. USA 108, 13728-33). In this pathway AKR1C3 catalyzes the NADPH dependent reduction of 5α-androstane-3,17-dione→5α-DHT. Thus AKR1C3 plays essential roles in the formation of the potent androgens that activate the AR, irrespective of the pathway responsible for their formation, FIG. 3.
In the breast, AKR1C3 catalyzes the reduction of Δ4-AD to testosterone, which can undergo aromatization to form 17β-estradiol. In addition, AKR1C3 also reduces estrone to 17β-estradiol. Consistent with these activities AKR1C3 has been shown to promote proliferation of MCF-7 hormone-dependent breast cancer cells (Byrns et al., 2010, J. Steroid. Biochem. Mol. Biol. 118:177-87).
In the endometrium, AKR1C3 could increase estrogen levels and decrease progesterone levels and thus promote endometrial cancer cell proliferation (Smuc & Rizner, 2009, Mol. Cell. Endocrinol. 301:74-82).
By increasing proliferative PGF2 isomers and decreasing anti-proliferative PGJ2 products, the prostaglandin F synthase activities of AKR1C3 have the potential to impact both hormone-dependent and hormone-independent cancers. In particular, prostaglandin metabolism by AKR1C3 has been shown to prevent differentiation of leukemia cells and AKR1C3 inhibition is being explored as a treatment for acute myelogenous leukemia (AML) (Khanim et al., 2009, PLoS One 4 e8147).
AKR1C3 is over-expressed across a wide variety of cancers, including those of prostate and breast, and its expression increases with tumor aggressiveness (Guise et al., Cancer Res. 70:1573-84; Lin et al., 2004, Steroids 69:795-801; Stanbrough et al., 2006, Cancer Res. 66:2815-25; Hofland et al., 2010, Cancer Res. 70:1256-64; Nakamura et al., 2005, Endocrine-Related Cancer 12:101-07; Jansson et al., 2006, Cancer Res. 66:11471-77).
AKR1C3-catalyzed reactions also play important roles in other physiological and pathological processes that may be targets for therapeutic intervention. Androgen production by AKR1C3 is likely involved in the development of benign prostatic hyperplasia (Ballinan et al., 2006, Mol. Endocrinol. 20:444-58). Increased estrogen and decreased progesterone receptor signaling due to increased AKR1C3 activity could contribute to endometriosis and dysmenorrhea (Smuc et al., 2009, Mol. Cell. Endocrinol. 301:59-64). PGF2 isomers formed by AKR1C3 stimulate smooth muscle contraction during parturition, while the AKR1C3 substrate progesterone prevents parturition, so AKR1C3 inhibitors may be useful as progestational agents (Breuiller-Fouche et al., Biol. Reprod. 83:155-62; Andersson et al., 2008, J. Clin. Endocrinol. Metab. 93:2366-74). Interestingly, indomethacin has proven effective at stopping premature parturition. This effect is thought to result from its inhibition of the prostaglandin G/H synthases (PGHS), but indomethacin also inhibits AKR1C3 in the same therapeutic dose range. Use of indomethacin for this purpose is limited due to side-effects in the fetus that likely stem from the inhibition of PGHS activities in developing organ systems (Loudon et al., 2003, Best Pract. Res. Clin. Obstet. Gynaecol. 17:731-44).
Because PGF2α is involved in preventing adipocyte differentiation and 15dPGJ2 promotes differentiation of adipocytes, inhibiting the prostaglandin F synthase activities of AKR1C3 may have beneficial effects in diabetes similar to those observed with PPARγ agonists (Reginato et al., 1998, J. Biol. Chem. 273:1855-58; Kliewer et al., 1995, Cell 83:813-19). AKR1C3 is also involved in the metabolism of other steroids as well as prostaglandins, suggesting that AKR1C3 may be used to treat other diseases. Currently, a non-selective AKR1C3 inhibitor, 6-medroxyprogesterone acetate, is used in early clinical trials to treat AML in Europe, based on a clearly defined role of AKR1C3 in regulating the differentiation of AML cells (Khanin et al., 2009, PLoS One e1847). A selective AKR1C3 could be a promising lead for the treatment of AML.
A specific inhibitor of AKR1C3 would be a valuable tool to better understand AKR1C3 and its contribution to normal physiology and disease. One challenge in the development of an AKR1C3 inhibitor is that three other closely related enzyme isoforms (AKR1C1, AKR1C2, and AKR1C4) are also involved in steroid hormone metabolism (Penning et al., 2000, Biochem. J. 351:67-77). AKR1C4 is liver specific, while AKR1C1 and AKR1C2 are widely expressed across tissue types, including prostate. Inhibition of these three isoforms, particularly AKR1C1 and AKR1C2, is not desirable in prostate cancer as they act primarily as 3-ketosteroid reductases towards androgens. For example, AKR1C1 reduces 5α-DHT to 3β-androstanediol (a pro-apoptotic ligand of estrogen receptor β) and AKR1C2 reduces 5α-DHT to 3α-androstanediol (a weak androgen). Inhibition of these activities would promote androgen dependent proliferative signaling in the prostate and would be counterproductive.
Twenty-two crystal structures of different AKR1C3 ternary complexes have been deposited into the Protein Data Bank (Table 1) (Qiu et al., 2007, J. Biol. Chem. 282:8368-79; Komoto et al., 2004, Biochemistry 43:2188-98; Lovering et al., 2004, Cancer Res. 64:1802-10; Qiu et al., 2004, Mol. Endocrinol. 18:1798-1807; Komoto et al., 2006, Biochemistry 45:1987-96; Bennett et al., 1997, Structure 5:799-812).
TABLE 1Available crystal structures of AKR1C3 in the Protein Data Bank.PDBIDLigandsReference1RYONADP+, PGD2Komoto et al., 2004,1RY8NADP+, rutinBiochemistry 43: 2188-981S1PNADP+, 2-methyl-2,4-pentanediol, acetate ionLovering et al., 2004,1S1RNADP+, 2-methyl-2,4-pentanediol, acetate ionCancer Res. 64: 1802-101S2ANADP+, indomethacin pH 6.0, unknown atom orion, dimethyl sulfoxide1S2CNADP+, flufenamic acid, dimethyl sulfoxide1XFONADP+, 4-androstene-3,17-dione, acetate ionQiu et al., 2004, Mol.Endocrinol. 18: 1798-18072F38NADP+, bimatoprostKomoto et al., 2006,Biochemistry 45: 1987-961ZQ5NADP+, EM1404, acetate ionQiu et al., 2007, J. Biol.2FGBNADP+, hexaethylene glycol, acetate ionChem. 282: 8368-793UWENADP+, 3-phenoxybenzoic acid, 1,2-ethanediolYusaatmadja et al, releasedMay 20123UG8NADP+, indomethacin pH 7.5, 1,2-ethandiolYusaatmadja et al, releasedMay 20123UGRNADP+, indomethacin pH 6.8, 1,2-ethanediolYusaatmadja et al, releasedMay 20123R58NADP+, Naproxen, 1,2-ethanediolYusaatmadja et al, releasedMay 2012UFYNADP+, R-Naproxen, 1,2-ethanediolYusaatmadja et al, releasedMay 2012R43NADP+, Mefenamic acid, 1,2-ethanediolYusaatmadja et al, releasedMay 20123R6INADP+, meclofenamic acid, 1,2-ethanediolYusaatmadja et al, releasedMay 20123R94NADP+, flurbiprofen, 1,2-ethanediolYusaatmadja et al, releasedMay 20123R8HNADP+, zomepirac, 1,2-ethanediolYusaatmadja et al, releasedMay 20123R8GNADP+, ibuprofen, 1,2-ethanediolYusaatmadja et al, releasedMay 20123R7MNADP+, sulindac, 1,2-ethanediolYusaatmadja et al, releasedMay 20124FAMNADP+ 3-(3,4-Dihydroisoquinolin-2(1H)-Turnbull et al., 2012ylsulfonyl)benzoic acids, 12-ethanediol
In the twenty two crystal structures of AKR1C3, the enzyme is complexed with the cofactor NADP+ and a second ligand. Close inspection of these structures reveals that the binding site for the second ligand is large and can be dissected into the following sub-sites: oxyanion site, steroid channel, and three sub-pockets named SP1, SP2, and SP3. One common feature of all twelve AKR1C3 structures is an occupied SP1 site (albeit to different degree), while the occupancy of other sites varies with different ligands. The occupancies of sub-sites in AKR1C3 by four inhibitors EM1404, bimatoprost, flufenamic acid, and indomethacin are depicted in FIG. 5. Understanding the binding interactions between ligands and their sub-pockets may aid inhibitor design and synthesis.
The oxyanion site refers to the conserved site that anchors the oxyanion intermediate formed during the enzyme reaction and consists of the catalytic residues Y55, H117 and NADP+ in all AKR1C enzymes (Bennett et al., 1997, Structure 5:799-812). This position is often found occupied by the oxygen atom of a carboxylic acid, ketone, or hydroxyl group of a ligand. Strong hydrogen bonding interactions form between the occupant and Y55 and H117 (2.6 Å and 2.8 Å, respectively). The positioning of the carbonyl group of a substrate at the oxyanion site is believed to be essential for productive binding since the anchoring brings the carbonyl group in proximity to the cofactor, allowing the reaction to proceed (Bennett et al., 1997, Structure 5:799-812; Jin & Penning, 2006, Steroids 71:380-91; Jin et al., 2001, Biochemistry 40:10161-68). Similarly, it is believed that the binding of the carboxylate or ketone group of an NSAID at the oxyanion site explains the general inhibition of AKR1C enzymes by NSAIDs. For example, the carboxylic acid moiety of flufenamic acid is anchored at the oxyanion site of AKR1C3, while the bridge carbonyl group of indomethacin at pH 6.0 binds via an unidentified atom to the oxyanion site of the enzyme (FIGS. 5C and 5D). At pH 7.0, indomethacin rotates so that its crabxylate is now tethered to the oxyanion site. Interestingly, the oxyanion site does not appear to significantly contribute to the binding of EM1404 and bimatoprost (FIGS. 5A and 5B) in AKR1C3, as the site was occupied by an acetate ion and a water molecule, respectively in the crystal structures of the AKR1C3.NADP+.EM1404 and AKR1C3.NADP+.bimatoprost complexes (Komoto et al., 2006, Biochemistry 45:1987-96).
The steroid channel refers to the elongated open channel that is also conserved in all AKR1C enzymes (Bennett et al., 1997, Structure 5:799-812). W227 and L/V54 are important gate keepers for the steroid channel and determine the positional and stereochemical specificities of the steroid transforming activity of AKR1C enzymes (Jin et al., 2001, Biochem. 40:10161-68). Interestingly, the steroid channel does not appear to be an important inhibitor binding site for AKR1C3. With the exception of EM1404, which has its steroid ring structure partially occupying the steroid channel, this channel is left empty by bimatoprost, flufenamic acid, and indomethacin (FIG. 5).
The SP1 sub-pocket is formed by residues S118, N167, F306, F311, and Y319 in AKR1C3, and is the only site that is occupied in all available crystal structures of this enzyme. As such, it accommodates the lactone moiety of EMI404 (FIG. 5A), the 12β-chain of PGD2, the 8α-chain of bimatoprost (FIG. 5B), or the —CF3 substituted B-ring of flufenamic acid (FIG. 5C). The p-chlorobenzoyl group of indomethacin also projects into this site, although in that structure a solvent molecule from the crystallization solution (dimethyl sulfoxide) was bound in the bottom of SP1 (FIG. 5D).
The SP2 sub-pocket refers to a pocket formed by residues W86, S129, W227 and F311 in AKR1C3. This pocket is where the 8α-chain of PGD2 and the 12β-chain of bimatoprost were bound (Komoto et al., 2004, Biochemistry 43:2188-98). It appears that this sub-pocket is only used by the two prostanoids.
The SP3 sub-pocket refers to a large pocket lined by residues Y24, E192, S217, S221, Q222, Y305, and F306 in AKR1C3. These residues surround the indole ring and the carboxylate group of the indomethacin molecule at pH 6.0. SP3 is not occupied by other ligands in AKR1C3.
The variety of AKR1C3 ligands in structure and size demonstrate the flexibility of the enzyme's ligand binding site. The key residues to AKR1C3's ability to accommodate different ligands are W227, F306, and F311. These residues can assume different conformations and result in "induced-fit" to various ligands. W227 controls the sizes of SP2 and the steroid channel. F306 lines the SP1 site for the AKR1C3-NADP+-flufenamic acid complex, but assumes a different rotamer conformation in the crystal of the AKR1C3-NADP+-indomethacin complex, thereby exposing the SP3 pocket. F311 forms part of SP1 for the binding of flufenamic acid, but lines SP2 for the binding of bimatoprost and PGD2.
Comparison of the ligand binding sites of AKR1C 1-4 reveals that there are considerable structural differences in sub-pockets between AKR1C3 and the other isoforms (Couture et al., 2003, J. Mol. Biol. 331:593-604). SP1 is significantly larger for AKR1C3. The difference in the size of SP1 is largely due to the shift in main chain positions of residues 305-311 between AKR1C3 and the other enzymes (FIG. 6A). As a result, residue 308 collapses inward and significantly reduces the size of SP1 for AKR1C1, AKR1C2 and AKR1C4. In AKR1C3 the side chain of S308 is not involved in ligand binding (>4 Å), but the corresponding residues of L308 in AKR1C2 and M308 in AKR1C4 would extend into SP1. In addition, different residues at positions 118 and 319 also reduce the size of SP1 in AKR1C ½ and AKR1C4. In AKR1C3, the side-chains of S118 and Y319 are >4 Å away from the ligand, whereas the corresponding residues of F118 (1.7 Å) and F319 (˜1 Å) in AKR1C2 would clash with a long ligand such as PGD2 or bimatoprost (Komoto et al., 2006, Biochem. 45:1987-96). Importantly, the serine residue at position 118 in AKR1C3 is capable of forming hydrogen-bonding interactions with a ligand, i.e., with the amide group of the 8α-chain of bimatoprost (Komoto et al., 2006, Biochem. 45:1987-96). In contrast, the corresponding residue for AKR1C1, AKR1C2 and AKR1C4 is a phenylalanine incapable of hydrogen bonding with a ligand.
No ligands have been observed to occupy the SP2 site in crystals of AKR1C1, AKR1C2, or AKR1C4. Comparison of the SP2 sites of these enzymes shows structural differences at position 129 and 311 that make the SP2 pocket shorter for AKR1C1, AKR1C2, and AKR1C4 than that for AKR1C3 (FIG. 6B). In addition, S129 of AKR1C3 can form hydrogen-bonding interactions with a ligand, i.e., with the carboxylate group of the 8α-chain of PGD2 or with the hydroxyl group on 12β-chain of bimatoprost (Komoto et al., 2006, Biochem. 45:1987-96). In contrast, the corresponding residues in other isoforms—I129 for AKR1C1 and AKR1C2 and L129 for AKR1C4—are incapable of hydrogen bonding with a ligand.
Structural differences at position 306 also cause the SP3 site of AKR1C3 to differ from those for the other enzymes (FIG. 6C). In the AKR1C3-NADP+-indomethacin complex at pH 6.0, the side chain of F306 assumes a conformation that points away from the ligand. However, the corresponding residues L306 of AKR1C1 and AKR1C2 and V306 of AKR1C4 have more rigid side chains that would clash with the indole ring of indomethacin.
Despite the availability of structural information, there has been no report to date of an AKR1C3 inhibitor that does not inhibit AKR1C1 and AKR1C2 and has good developmental properties. Such a selective inhibitor is needed to explore the role of AKR1C3 in normal and aberrant cell signaling. Such a selective compound may find use in treating CRPC through the inhibition of AKR1C3. There is thus a need in the art to identify novel inhibitors of AKR1C3 that show selectivity over AKR1C1 or AKR1C2. The present invention fulfills this need.

Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof

The Trustees of the University of Pennsylvania


Shown and described are a device and a method for securing closure films to pouring elements arranged on composite packages with a cyclic or phased conveying device for conveying the closure films, with a feed device, with a welding device, and with a transport device for transporting the composite packages. In order to allow closure films to be secured reliably and rapidly to pouring elements on the composite packages during the manufacturing process, the welding device is arranged above the transport device, the feed device exhibits at least one clamping device for taking up the closure films and is arranged so as to be movable between a take-up position and a welding position, and the take-up position is turned towards the phased conveying device and the welding position is turned towards the transport device.

1. Field of the Invention
The present invention relates to a device and a method for the securing of closure films on pouring elements arranged on composite packages, in particular on beverage packages.
2. Discussion of the Present Technology
Composite packages, especially for beverages, are today frequently provided with what are referred to as pouring elements, in order to allow for such packages to be opened and closed again. In order to ensure that the packages can be reliably closed again after being opened for the first time, use is often made for this purpose of screw closure elements in particular. The problem arises with screw closure elements, however, as with the other pouring elements used, that in the closed state they do not exhibit a very high degree of gas tightness. The result of this is that it is possible that gases may pass from the outside through the closure element into the interior of the package, and so impair the preservation of the content of the package. Under certain circumstances this may mean that the long storage life times desired by the manufacturers can no longer be guaranteed. Likewise, loss of quality and/or aroma of the filled product may be incurred by migration from the inside to the outside.
It has therefore proved necessary for the pouring openings of the pouring elements beneath the cover element to have a closure film drawn over them and in this way for them to be closed so as to be gas-tight. To this end, it is possible for a film to be sealed over the opening for the pouring element on the inside of the package, which is perforated the first time the package is opened. As an alternative to this, it is also possible for the pouring opening of the pouring element to be provided itself with a closure film, which seals the pouring opening. In the case of a screw closure, the cover element is only screwed on after this closure film has been applied. A pouring element of this type is known, for example, from EP 0 505 388 B1.
In particular in cases in which it is intended that the packages are to be filled under aseptic conditions, it is desirable for the closure film not to be applied to the pouring opening after the filling, but to be secured beforehand in the area of the pouring element and for the pouring opening to be closed tight with the closure film immediately after sterilization and filling. The result of this is that the side turned towards the package contents in particular will be sterilized together with the closure film.
The problem arises in this situation, however, that it is necessary for the closure film to be reliably secured before filling to the pouring element in such a way that, on the one hand, subsequent sealing of the pouring opening is possible without any difficulties and, on the other, the securing of the closure film does not unnecessarily impede or delay the manufacturing process of the packages. In addition to this, it is necessary for the filling of the package to be possible with the closure film already secured.

Device and method for fixing closing films to pouring elements arranged on composite packages


A new and distinct cultivar of Veronica prostrata plant characterized by a unique combination of gold foliage, violet-blue flowers, and sun tolerance.

The present invention relates to a new and distinct discovery of Veronica prostrata, of the family Scrophulariaceae, which originated as a naturally occurring gold seedling of Veronica prostrata (unpatented) found by the applicant, and is given the cultivar name xe2x80x98Aztec Goldxe2x80x99. The other Veronica prostrata seedlings from the sowing had the green foliage typical of the species, rather than the gold foliage that distinguishes this new cultivar.
This new Veronica prostrata variety has been reproduced only by asexual propagation (cuttings). Each of the progeny exhibits identical characteristics to the original plant.
This plant is characterized by the following:
1. Gold foliage.
2. Violet-blue flowers.
3. Tolerates full sun.
Asexual propagation by division and tissue culture as done in Canby, Oreg., shows that the foregoing characteristics and distinctions come true to form and are established and transmitted through succeeding propagations. The present invention has not been evaluated under all possible environmental conditions. The phenotype may vary with variations in environment without a change in the genotype of the plant.

Veronica prostrata plant named xe2x80x98Aztec Goldxe2x80x99