Apparatus for assembling microstructures onto a substrate through fluid transport. The apparatus includes a vessel that contains the substrate, a fluid, and microstructures. The substrate has at least one recessed region thereon. The microstructures being shaped blocks self-align into the recessed regions located on the substrate such that the microstructure becomes integral with the substrate. The apparatus also includes a pump that circulates the microstructures within the vessel at a rate where at least one of the microstructures is disposed into the recessed region.

The present invention relates to the field of electronic integrated circuits. The invention is illustrated in an example with regard to the manufacture of gallium arsenide microstructures onto a silicon substrate, but it will be recognized that the invention will have a wider range of applicability. Merely by way of example, the invention may be applied in the manufacture of devices containing silicon based electronic devices integrated with a gallium arsenide based microstructures (or devices) such as light emitting diodes (LED), lasers, tunneling transistors, Gunn oscillators, integrated circuits, solar collectors, liquid crystal displays (LCDs), and others.
Industry currently needs a cost effective, efficient, and practical method for assembling a higher cost microstructure onto a lower cost commercially available substrate. In particular, a material such as gallium arsenide possesses substantially better characteristics for some specific electronic and opto-electronic applications rather than materials such as silicon. However, in the fabrication of gallium arsenide devices, substantial regions of a gallium arsenide wafer are typically unused and wasted. Such unused regions generally create an inefficient use of precious die area. In addition, processing gallium arsenide typically requires special techniques, chemicals, and equipment, and is therefore costly.
Other applications such as very large scale integrated (VLSI) circuits may be better fabricated in silicon rather than gallium arsenide. In still further applications, it may be desirable to produce integrated circuits having characteristics of both types of materials. Accordingly, industry needs to develop an effective method of fabricating a gallium arsenide device integrated with a silicon based integrated circuit. The resulting structure of such method includes advantages of both gallium arsenide and silicon based devices.
Methods such as flip chip bonding, lift off methods, and others, generally require large areas of a substrate and are incompatible with a micron sized state-of-art microstructure. Such methods often create difficulty in positioning a particle onto a substrate. Accordingly, industry needs to develop an effective method of fabricating higher cost materials such as a gallium arsenide microstructure onto a lower cost substrate such as silicon.
Industry utilizes or has proposed several methods for fabricating individual electronic components (or generally microstructures) and assembling such structures onto a substrate. One approach is to grow gallium arsenide devices directly onto a silicon substrate. This approach becomes limiting because the lattice structure of gallium arsenide mismatches that of silicon. In addition, growing gallium arsenide onto silicon is inherently difficult and therefore costly. Accordingly, gallium arsenide can not efficiently be grown on a silicon substrate.
Another approach is described by Yando in U.S. Pat. No. 3,439,416. Yando describes components or structures placed, trapped, or vibrated on an array of magnets. Such magnets include magnetized layers alternating with non-magnetized layers to form a laminated structure. Components are matched onto the array of magnets forming an assembly thereof. However, severe limitations exist on the shape, size, and distribution of the components. Component width must match the spacing of the magnetic layers and the distribution of components are constrained by the parallel geometry of lamination. In addition, self-alignment of components requires the presence of the laminated structure. Furthermore, the structures disclosed by Yando typically possess millimeter sized dimensions and are therefore generally incompatible with micron sized integrated circuit structures. Accordingly, the method and structure disclosed by Yando is thereby too large and complicated to be effective for assembling a state-of-art microstructure or component onto a substrate.
Another approach involves mating physical features between a packaged surface mount device and substrate as described in U.S. Pat. No. 5,034,802, Liebes, Jr. et al. The assembly process described requires a human or robotics arm to physically pick, align, and attach a centimeter sized packaged surface mount device onto a substrate. Such process is limiting because of the need for the human or robotics arm. The human or robotics arm assembles each packaged device onto the substrate one-by-one and not simultaneously, thereby limiting the efficiency and effectiveness of the operation. Moreover, the method uses centimeter sized devices (or packed surface mount integrated circuits), and would have little applicability with micron sized integrated circuits in die form.
Another approach, such as the one described in U.S. Pat. No. 4,542,397, Biegelsen et al. involves a method of placing parallelogram shaped structures onto a substrate by mechanical vibration. Alternatively, the method may also employ pulsating air through apertures in the support surface (or substrate). A limitation to the method includes an apparatus capable of vibrating the structures, or an apparatus for pulsating air through the apertures. Moreover, the method described relies upon centimeter-sized dies and would have little applicability with state-of-art micron sized structures.
A further approach such as that described in U.S. Pat. No. 4,194,668 by Akyurek discloses an apparatus for aligning and soldering electrode pedestals onto solderable ohmic anode contacts. The anode contacts are portions of individual semiconductor chips located on a wafer. Assembling the structures requires techniques of sprinkling pedestals onto a mask and then electromagnetic shaking such pedestals for alignment. The method becomes limiting because of the need for a shaking apparatus for the electromagnetic shaking step. In addition, the method also requires a feed surface gently sloping to the mask for transferring electronic pedestals onto the mask. Moreover, the method is solely in context to electrode pedestals and silicon wafers, thereby limiting the use of such method to these structures.
Still another approach requires assembling integrated circuits onto a substrate through electrostatic forces as described in application Ser. No. 07/902,986 filed Jun. 23, 1992 by Cohn. The electrostatic forces vibrate particles such that the particles are arranged at a state of minimum potential energy. A limitation with such method includes providing an apparatus capable of vibrating particles with electrostatic forces. Moreover, the method of Cohn creates damage to a portion of the integrated circuits by mechanically vibrating them against each other and is also generally ineffective. Accordingly the method typically becomes incompatible with a state-of-art microstructure.
From the above it is seen that a method of assembling a microstructure onto a substrate that is compact, low cost, efficient, reliable, and requires little maintenance is desired.

Apparatus for fabricating self-assembling microstructures

The Regents of the University of California


When JPEG data is open on a personal computer 10, YCbCr to RGB conversion is carried out. The converted RGB data may include negative color values and color values of and over 256, which are outside of a 0 to 255 color value range in the sRGB color space generally used on the personal computer 10. The negative color values and the color values of and over 256 included in the RGB data are linearly compressed into color values in the 0 to 255 color value range, are subjected to image processing, and are then linearly expanded. This arrangement effectively reduces deterioration of the image processed RGB data relative to the original RGB data.

The present invention relates to an image processing apparatus that makes image data subjected to image processing. On existing operating systems, the sRGB color space or the standard color space for monitors is used to represent RGB data. When generally used JPEG data is open on a personal computer, for example, the JPEG data is immediately converted into RGB data. The conversion of the JPEG data into the RGB data may give color values outside the color range in the sRGB color space. These color values are not displayable in the sRGB color space and are thus clipped (cut off).
The prior art technique accordingly causes part of the color values in the original JPEG image data to be lost in the course of image processing. The processed image data is kept without restoration of the lost color values. This undesirably leads to deterioration of the JPEG data.


A dispenser is formed of a flexible plastic pouch which has a removable flap providing an opening adjacent the bottom of the pouch, and a mounting element adhesively attached adjacent the top of the pouch which provides selective mounting to diverse surfaces. The mounting element has opposed interengaged Velcro pads whereby when the pouch is adhesively mounted to a surface, the Velcro pads may be disengaged and the pouch removed and replaced with another pouch. A plurality of stacked reclosable ended separate plastic bags are disposed in a folded stack within the pouch. A portion of one outermost plastic bag is disposed in the bottom pouch opening so that the user by the thumb and forefinger pulls the one plastic bag portion causing the one plastic bag to frictionally engage and slide over the adjacent plastic bag and through the opening without tearing the pouch or dismounting the mounting element from the surface mount. After removal of one bag, the next immediately adjacent bag is then similarly positioned for removal. The removed plastic bag is immediately ready for filling. With removal of all the bags, the depleted pouch is detached and replaced with a full pouch by the Velcro pads engagement.

1. Field of the Invention
This invention relates to improvements in a dispenser for plastic bags or like articles.
2. Discussion of the Prior Art
In the art directed to dispensers for plastic bags, such constructions were generally constructed of rigid box-like containers wherein the plastic bags were separably inter-connected within the box. Such dispensers are disclosed in U.S. Pat. No. 4,712,684 to Boeckman, U.S. Pat. No. 4,805,800 to Nocek et al and U.S. Pat. No. 5,109,978 to Cawley. One attempt to make the plastic bags more readily removable from a box is disclosed in U.S. Pat. No. 4,512,276 to Herrington. In Herrington the plastic bags had to first be individually folded on parallel fold lines formed in each bag, and then assembled and stacked within the box. In another rigid walled construction bag dispenser, such as is disclosed in U.S. Pat. No. 5,267,423 to Nguyen, separate stacked bags were mounted on a roller bar for bag removal.
Another prior art approach was where there was no container or dispenser, and instead the plastic bags were detachably attached on a header with the user having to pull and separate the bag from the header usually at a perforated line, and open the bag during or after removal. Such prior art constructions are disclosed in U.S. Pat. No. 3,221,927 to Lowry, U.S. Pat. No. 4,290,467 to Schmidt, U.S. Pat. No. 4,846,586 to Bruno, U.S. Pat. No. 5,255,883 to Greenfield et al, U.S. Pat. No. 5,309,698 to Huseman and U.S. Pat. No. 5,419,437 to Huseman.
One attempt to provide mounting a plastic bag dispenser is disclosed in U.S. Pat. No. 4,216,863 to Seymour-Smith. The Seymour-Smith mounting construction required that the dispenser top portion be strengthened and provided with a through hole by which the dispenser was suspended vertically from a hook. The use of a punched hole in the top of the dispenser as the mounting element was undesirable in that excessive thermo-forming or dispenser strengthening was required to prevent tearing of the bag around the hole, and particularly so when the plastic bags slidingly frictionally engaged the pouch and other bag surfaces in removal. Still further, the location of the dispenser was limited by the presence and location of the hook and hook mount on the wall. Further it was both necessary and most inconvenient to obtain a hook suitably sized and mounted in order to use the Seymour-Smith bag dispenser. Users would also be incumbered in mounting the hook and then be constrained in the dispenser mount location by the hook mount location.
Now there is provided by the present invention an improved plastic bag dispenser which is selectively mounted to diverse vertical and horizontal surfaces, and wherein the dispenser when depleted of plastic bags can be detached from the selected surface mount and then readily replaced with a full dispenser on the same mounting element.
The art also desired a readily manufactured and assembled low cost flexible construction bag dispenser which could store and readily dispense a folded stack of bags without damage to the thin walled flexible plastic sheet construction dispenser. The present invention achieves these prior art goals as well.


In one embodiment, packet forwarding apparatus includes a data packet receiving interface, a data packet forwarding interface, and a configuration interface. The apparatus also includes circuitry that defines a plurality of data packet forwarding paths between the data packet receiving interface and the data packet forwarding interface. The circuitry defines at least one of the plurality of data packet forwarding paths in response to input received via the configuration interface, and the circuitry adaptively reconfigures at least one of the plurality of data packet forwarding paths i) in response to input received via the configuration interface, and ii) while data packets are being received by the packet forwarding apparatus.

It is often desirable to capture the data packets that are carried over a network. Captured data packets may then be, for example: analyzed to determine their presence and correctness; sorted for purposes such as call flow analysis; factored into various statistics; or examined to determine the content or completeness of their payloads.

Apparatus and methods for forwarding data packets captured from a network


Methods, apparatus, and systems are disclosed that adjust transient response in a multistage system. An example apparatus includes a first filter including an input configured to be coupled to an output of a master stage, an amplifier, the first input of the amplifier coupled to the input of the first filter, the second input of the amplifier coupled to the output of the first filter, a second filter, the input of the second filter coupled to the output of the amplifier, and a comparator, the first input of the comparator coupled to the input of the first filter circuit, the second input of the comparator coupled to the output of the amplifier, the third input of the comparator coupled to the output of the second filter, and the output of the comparator adapted to be coupled to a latch.

Power converters, power supply systems, and/or various power electronic devices (such as buck converters or buck-boost converters) operate in response to a pulse width modulated (PWM) signal generated. Some power converters, power supply systems, and/or various power electronic device applications operate in response to multiple PWM signals generated by multiple PWM signal generators generated by multiple stages, each of which generates a PWM signal.

Methods, apparatus, and systems to adjust transient response in a multistage system


An apparatus includes a container, a plurality of lights and a circuit. The container may comprise an outer shell comprising a material configured to protect contents of the apparatus and an inner surface. The outer shell may be configured to open to enable the contents to be placed on the inner surface. A cavity may be formed within the container when the outer shell is closed. The plurality of lights implemented on the inner surface may each be configured to adjust a characteristic of light output in response to a signal. The circuit may be configured to generate the signal in response to an input. The circuit may be implemented between the outer shell and the inner surface. A reactive material of the contents of the container may be configured to change appearance in response to the characteristic of light.

Some estimates indicate that at least 60% of people wear eyeglasses. Frames for eyeglasses come in many different styles and color combinations. However, purchasing eyeglasses can be very expensive. Since eyeglasses have a considerable cost, many eyeglass wearers only buy a single pair of eyeglasses.
Despite having many options for style, it can be prohibitively expensive for an eyeglass wearer to have more than one option. Conventional eyeglass frames lack the ability to change appearance based on the desire of the user. This inability to change style includes, but is not limited to, color, style and design. Eyeglasses wearers are effectively 'stuck' with the eyeglasses they first chose when they fill a lens prescription.
Similar issues exist with other types accessories (both wearable and non-wearable). Items such as earbuds, watches and smartphone cases might be available in multiple color options. However, buying multiple versions of the same product in order to have multiple options for colors can be prohibitively expensive, increases waste, and requires the product manufacturer to produce multiple different versions of the same product. Often times, accessories are only made available in a single color (i.e., black), because the market for other colors might not be as large. Both manufacturers and consumers can be limited to a fixed color/design. There is an inability to change the color/design of an accessory based on a desire of the user. The ability to change the appearance of the accessory may provide the consumer with enjoyment of the product.
It would be desirable to implement an apparatus for improving accessories.


A novelty combination feeding and watering device having feeding and drinking facilities incorporated within a design which resembles, proportionally, actual toilets found in the household.

The present invention relates generally to a novelty animal nourishment center. With more particularity, a preferred embodiment of the present invention relates to domesticated canine combination feeding and watering device which is proportionally shaped, in a general sense, to resemble an actual toilet apparatus commonly found in households today.
Conventional combination feeding and watering devices have been heretofore proposed but have not taken on the novelty form of an actual toilet apparatus. An example of such a conventional combination device is disclosed by Clugston in U.S. Pat. No. 4,192,256. Conventional devices such as that taught by Clugston have lacked novelty aspects which distinguish them from other competing devices. The fact that these conventional devices lack such a novelty aspect has prevented them from becoming popular as an amusing gift or as the subject of a practical joke. Further, a feeding and watering device which includes some sort of novelty aspect would no doubt quickly become a conversation piece when viewed by a homeowner's guests.
It therefore is an object of the present invention to provide a combination feeding and watering device which, as a novelty aspect, has the likeness of an actual toilet apparatus.

Novelty combination feeding and watering device


A system and method for a connection resource system is disclosed. According to an embodiment of the invention, a method includes establishing a first connection, the first connection being between one of one or more server applications and one of one or more external resources; and establishing a second connection, the second connection being between one of the one or more server applications and one of the one or more external resources; wherein the first connection and the second connection are established utilizing a single resource system.

A server may include multiple server applications. The applications may be comprised of program components of varying types and existing in different containers, each container providing life cycle management, security, deployment, and runtime services for the components. Each of such applications may in turn require connections with various external resources, with the resources being connected to the servers using varying connectors.
The connections of the applications and the external resources may be complex. Generally it is necessary that each connection between an application and a resource be negotiated and handled separately. Each of the relationships between an application and an external resource may require a separate resource manager for the establishment of the communications contract for the relationship.
Therefore, the establishment and elimination of connections for a server may be complex when multiple applications and resources are involved. Further, the separate negotiation and establishment of communications contracts may mean that possible sharing of resources among components is not addressed and that processes for enlisting and delisting resources are not handled efficiently.


A semiconductor strain sensor includes a silicon substrate, a strain resistive element and electrodes. The silicon substrate has a deformable portion which is deformed when stress is applied to it. The strain resistive element is formed on the deformable portion and has an at least a first layer and a second layer which form a heterojunction between them. The first layer is doped with impurities so that a two-dimensional carrier gas layer is formed in the second layer near the heterojunction. The two-dimensional carrier gas layer has carriers originating from the impurities. The electrodes electrically contact the two dimensional carrier gas layer. Change of resistance of the strain resistive element in accordance with the stress is detected through the electrodes.

1. Field of the Invention
The present invention relates to a semiconductor strain sensor for detecting acceleration, pressure or the like.
2. Description of the Related Art
When stress is applied to a semiconductor element, such as silicon, germanium, its resistivity changes. This phenomenon is called the piezoresistance effect. Both pressure sensors and acceleration sensors use the piezoresistance effect.
A conventional semiconductor strain sensor is disclosed in U.S. Pat. No. 4,967,597 and uses silicon for its piezoresistance effect. Silicon has many advantages over other materials--the piezoresistivity of silicon is large, it is mechanically strong, and many techniques for manufacturing devices using silicon have been established.
However, the practical piezoresistivity of silicon is limited at approximately 50.times.10.sup.-12 cm.sup.2 /dyn because it cannot self-compensate for temperature when its piezoresistivity is higher than that. Therefore, it has been difficult to use a silicon-based semiconductor strain sensor to detect a very low acceleration or pressure.
The technical report of the Institute of Electronics, Information and Communication engineers, ED88-18, P51-56 (1988) "Piezoresistance Effect in Selectively Doped Structure" by Kato et al., proposed a strain resistive element having a hetero structure of Al.sub.x G.sub.al-x A.sub.s /G.sub.a A.sub.s. The strain resistive element has a high sensitivity. However, this strain sensor uses G.sub.a A.sub.s structure on which the hetero structure is formed. Therefore, the strain sensor has not been practically used due to weak mechanical strength of G.sub.a A.sub.s.


A valve pin actuator is disclosed that includes a cylinder mounted to the clamping plate, a piston slidably mounted in the cylinder, and a valve pin assembly carried by the piston. A hydraulic or pneumatic circuit is provided for controlling the movement of the piston, and in turn translation of the valve pin between the seated and unseated positions. The valve pin assembly includes a first part removably secured to the piston so as to translate therewith, and a second part for receiving the valve pin and secured to said manifold. The actuator assembly enables removal of the clamping plate without removal of the valve pin assembly, and also adjusting of the valve pin without removal of the clamping plate. The assembly further provides a clearance between the piston and valve pin assembly, to accommodate expansion and movement of the manifold that would otherwise cause a side load to be exerted on the valve pin.

1. Field of the Invention
This invention relates in general to improvements in valve gate actuators used in injection molding systems. Although not limited to any particular field of use, the actuator of the present invention is in particular useful for the fabrication of large molded parts such as, for example, automotive bumper fascia.
2. Description of the Related Art
In hot runner systems used in injection molding, valve pins are used to open and close the gate to a cavity in the mold in which the molded part is formed. Typically, the valve pin is opened prior to the start of injection allowing plastic to flow into the cavity of the mold. The valve pin is maintained in the open position while the melt material is being packed in the cavity to form the molded part. At the end of packing, the pin is closed to eliminate any drooling from the hot runner nozzle and eliminate any vestige that would be left on the molded part by forming a smooth surface with inner surface of the mold cavity.
The valve pin is typically located in the center of the bore of the hot runner nozzle. In a multiple gate system that uses a plurality of nozzles, the nozzles typically will be connected to a heated manifold, which in turn receives the machine nozzle from the injection molding machine. The tip of the valve pin extends to the gate of the mold. From its tip, the valve pin extends through the hot runner nozzle, through a bore in the manifold, and is connected at one end to an actuator located above the manifold and attached to a top clamp plate. A valve pin cylinder in the actuator is usually actuated using either hydraulic or pneumatic pressure.
In hot runner systems, that there are two basic techniques for providing valve pin actuators. The first technique is to build the hydraulic actuator assembly into the top clamp plate. With this product, when performing maintenance on, or disassembling, the system, it is necessary to allow the manifold to cool, then remove the valve pin from the hot runner manifold prior to removal of the top clamp plate. This can require a significant amount of time. Since the valve pin is precision machined to fit at the gate, great care must be taken when replacing the valve pin. Molds for large automotive parts are very large, thus, ease of assembly and disassembly for maintenance of the hot runner is an important issue.
A further drawback of prior systems is the fact that the valve pin itself is typically mounted in the actuator in a relatively fixed position and is free to move only in one direction. The manifold will expand relative to the top clamp plate when heated. Thus, the valve pin actuator has to be positioned so that the pin can slip relative to the actuator in the expansion direction. If the alignment or predicted expansion direction is off, the pin sees a side load resulting from the expansion of the manifold, possibly resulting in binding of the pin in the valve pin bushing, or even pin breakage. Thus, prediction of the line of expansion is necessary along with precise alignment of the valve pin.
Another type of actuator has the entire hydraulic actuator assembly bolted to the hot runner manifold. This system includes through holes in the top clamp plate to provide clearance for the actuator assembly. There are several drawbacks associated with this system. For example, because the actuator cylinder is directly bolted to the heated manifold, the actuator cylinder needs water channels formed therein for cooling. Further, because it is bolted directly to the manifold, flexible water and hydraulic lines must be run to each valve gate actuator between the manifold and the top clamp plate. It can be cumbersome to position these lines, and they can get hot due to proximity to the manifold causing deterioration of hoses and fittings. Leakage can result. If hydraulic fluid contacts the hot manifold, hazards may result.
Accordingly, it is an object of the present invention to provide an improved valve pin actuator, particularly wherein the actuator itself can be at least partially disassembled without requiring removal of the valve pin.
Another object of the present invention is to provide a valve pin actuator in which the cylinder and piston along with the hydraulic fluid lines are retained within the top clamp plate, while the valve pin assembly itself stays with the hot runner system.
Still another object of the present invention is to provide an improved valve pin actuator wherein the actuator can be at least partially dissembled without the need to drain the hydraulic fluid lines, and without the need to remove the valve pin from the hot runner manifold.
A further object of the present invention is to provide an improved valve pin actuator that provides for a clearance between the actuator piston and actuator cap. This clearance allows for relative expansion between the hot runner manifold and the top clamp plate in any direction, without putting a significant side load force on the valve pin.
Still another object of the present invention is to provide an improved valve pin actuator that provides for a more simplified operating hydraulic circuit.


The curtain consists of a single, translucent, yet untransparent fabric sheet, hung to sliders carried by a track, the latter track anchored in horizontal position against a vertical wall above a window frame. A cord at the end of the track operates the sliders to both slide the curtain sheet lengthwisely of the track, to fold/unfold in accordeon like the curtain sheet for extending/retracting same, as well as tilt the sliders about their vertical axes, as with a vertical blind actuating mechanism. The drape has a wavy configuration, whereby as the sliders are pivoted by the control cord, the amount of light traversing the drapes will adjustably vary in a progressive fashion. Each slider includes a cardboard plate, lodged into a pocket made at the top edge portion of the drapes, and releasably engaged by a slider hook.

In U.S. Pat. No. 3,844,330 issued in 1974 to LouverDrape, Inc., there is disclosed a window covering system using conventional vertical blind hardware employed with vertically disposed louvers. The drape sheet has a generally wavy configuration, and is attached to the louvers so that as the louvers rotate about their vertical axes, each of the successive drape sheet sections progressively fold from a first position (FIG. 2), generally transverse to the window frame, to a second position, generally parallel to the window frame and edgewisely abutting against each other in successive pairs (see FIG. 3). A normal drape like effect is thus obtained, which further has the capability of varying the degree of opaqueness of the drape, i.e. the amount of light that can traverse the drape.
According to this 330' patent, the flexible drape sheet material is hung from the upper portion of each louver, and each louver is to extend the full height of the window frame, see column 2, lines 45-67 of this latter patent. It is further envisioned that these louvers be either plane, to achieve a minimum profile when perpendicularly disposed with respect to the window, or slightly curved, to provide increased bending and torsional rigidity.
According to the present inventor, it is not desirable to provide a louver extending the full height of the drapes, in that the opaqueness of the louver itself will interfere with that of the drape, and thus substantially reduce the light adjusting capability of the drape system.
Another pertinent reference is U.S. Pat. No. 3,851,699 issued in 1974 to Harry SHAPIRO. In this patent, vertical louvers 23 are anchored at their top edges to the top edges of a flexible drape 16, by rivets 24. The conventional hanger slides 26, carried along horizontal track 27, controls the orientation of the louvers 23 to which they are connected. The louvers extend for the full vertical length of the drapes. Clearly then, such an arrangement requires structural modifications to an existing vertical louver assembly - notably, the installation of rivet means 19, 24 on the slat 23 and on the drapes 19) before the louver assembly can be transformed into a louver type drape means.

Sheet curtain with vertical blind actuating mechanism


A new hardware description language (HDL) extension at the register-transfer level (RTL) for designating particular logic functions as fault tolerant and a method of implementing a fault redundant scheme for the fault tolerant logic functions. Code (20) is written in VHDL at the RTL and includes instructions for adding the operator “FT” to certain logic functions. Logic functions that include the FT operator are considered critical functions, i.e., fault tolerant. By including the FT operator, a logic synthesis tool is alerted to the functions that have been designated as fault tolerant. As a result, the preprogrammed logic synthesis tool causes the design of the IC to include a fault redundant scheme (30) for the logic functions that include the FT operator. Fault redundant scheme (30) includes three copies of the logic function, i.e., Copy A (32), Copy B (34), and Copy C (36), as well as a majority voter 38.

1. Field of the Invention
The present invention relates generally to selective fault protection for logic functions in an IC design, and more particularly to a new HDL extension at the RTL for designating particular logic functions as fault tolerant and a method of implementing a fault redundant scheme for those logic functions designated as fault tolerant.
2. Background of the Invention
For the design of integrated circuits (IC) technology on a very large scale, designers typically employ computer aided design (CAD) tools. Hardware description languages (HDLs) or other standard languages are typically used to describe ICs and facilitate the design and simulation of complex digital ICs. Common HDLs include the open languages, VHDL and Verilog. VHDL and Verilog are all-purpose HDLs that utilize abstract data types to define a hardware model at the gate level, the register-transfer level (RTL), or the behavioral level.
At the RTL, a description of the IC written in HDL is typically referred to as the RTL description or the RTL code. At the RTL, a description of the system specifying all registers (whether instantiated or inferred), and combinational logic in between them (using logical statements, etc.) is outlined. The RTL description or code specifies the clock-by-clock behavior of the system. The RTL description or code of an IC describes the circuit in terms of a plurality of digital registers, clocking circuits, and logic elements that are combined to implement the desired function of the circuit.
After creation of the RTL code, a designer uses a logic synthesis tool to map the IC design to a target technology, e.g., a field-programmable gate array (FPGA) or application specific integrated circuit (ASIC). Thereafter, each logic function, e.g., combinational logic block (CLB) for FPGAs, is assigned to a location on the chip and signals are routed with wires on the chip to appropriate other logic functions.
In many prior art ICs, even a single logic fault can cause improper operation resulting in data integrity errors or a system crash. Such a scenario can occur with either a soft error, i.e., temporary fault due to radiation, or a permanent fault. Prior art IC design methodology treats each of the logic functions in an IC design the same and fails to provide a way for providing fault protection to particular logic functions. In addition, providing additional fault protection to all of the logic functions in the IC typically increases the amount of area required by the IC and thus the overall size of the IC.

Method of selectively building redundant logic structures to improve fault tolerance

International Business Machines Corporation


A power management system includes an energy storage device and a control system coupled to the energy storage device. The control system is configured to execute a control routine to determine whether to charge or discharge the energy storage device using a target state of charge and a current state of charge of the energy storage device. The control system is configured to determine that an output signal, received from a power generator, is outside of a specified range. The control system is configured to modify the target state of charge of the energy storage device in response to determining that the output signal is outside of the specified range.

Renewable resources, such as wind and solar energy, are attractive alternatives to the use of fossil fuels for generating power due to their renewable nature and clean operation. However, unlike thermal power plants (e.g., coal fired or natural gas fired plants), generally, the amount of wind or solar energy available at any given time cannot be controlled or reliably predicted. Further, due to the inherent variability of these renewable energy sources, (e.g., wind gusts and/or directional changes, weather conditions, breaking clouds), the instantaneous power output of an associated power generator (e.g., a wind turbine) may vary significantly from one second to the next.
Introducing such variability into the grid may destabilize the grid. For example, a sudden increase in active power may result in a corresponding increase in grid frequency. These increases may result in protective relay tripping, thereby separating portions of the grid and potentially creating a load/generation imbalance in certain portions of the grid. In some cases, such an imbalance may result in a cascading power failure as the grid is further segmented and/or available generation resources trip off-line to prevent damage that may result from the imbalance.
Ramp rate limits help protect the grid from such an event by limiting the rate at which power injected into the grid increases or decreases. By limiting the rate of change in power of generation resources coupled to the grid, grid operators are provided with more time to respond to the change and maintain a load/generation balance.
For wind turbine applications, ramp rate limiting can be implemented by manipulating the wind turbine and/or its controls (e.g., yawing or tilting the plane of rotation, varying the blade pitch, using a passive/active stall mechanism, controlling the output of a variable-speed generator, etc.). However, intentionally reducing power output despite the availability of wind energy (i.e., curtailment) decreases the overall energy efficiency of the system. Similarly, preemptively reducing the power output of a wind turbine generator so that a sudden decrease in wind energy appears less abrupt also decreases the overall energy efficiency of the system.
In some applications, ramp rate limiting may be implemented, at least in part, by using an energy storage device to absorb excess power during a ramp up and/or to supplement power output during a ramp down. Generally, such energy storage devices have a fixed storage capacity. Having a fixed storage capacity typically limits a device's ability to mitigate the risk of exceeding a ramp rate limit (i.e., a ramp rate violation). For example, a system having a 50% state of charge may be able to avoid a ramp rate violation in either direction for finite, and approximately equal, periods of time, assuming equal, worst-case-rates of change and equal ramp rate limits.
In operation, such systems may implement a target state of charge (SOC) around which the storage device is managed. When the SOC of the device drops below this target or moves beyond this target, the energy storage device is controlled such that the SOC returns to the target SOC in preparation for the next event.
Using a target SOC near the center of an energy storage device's charge/discharge capacity increases the probability that the energy storage device will recover to such a level prior to a subsequent event. A centered target SOC also increases the probability that the energy storage device will be available to mitigate a ramp rate violation irrespective of whether the event is a ramp up event or a ramp down event. Such an implementation may improve the efficiency of a ramp-rate-limited power generation facility by minimizing the need to curtail power output for at least a corresponding period of time. The period of time may be increased by increasing the size of the energy storage device and/or by utilizing multiple energy storage devices to provide additional charge/discharge capacity. Outside that time period, other measures may be implemented to avoid a ramp rate violation, e.g., curtailment.

Power management systems with dynamic target state of charge


An apparatus for video summarization using sematic information is described herein. The apparatus includes a controller, a scoring mechanism, and a summarizer. The controller is to segment an incoming video stream into a plurality of activity segments, wherein each frame is associated with an activity. The scoring mechanism is to calculate a score for each frame of each activity, wherein the score is based on a plurality of objects in each frame. The summarizer is to summarize the activity segments based on the score for each frame.

Electronic devices typically include image capture mechanisms capable of capturing images, still shots, and video data. Electronic devices include, but are not limited to, mobile and wearable devices. Video data can be easily captured and shared for a variety of purposes. Video data is typically recorded and saved locally or shared online. Due to ease of capture, users can save and share a large number of videos. However, users are unwillingly to spend time and effort in going through the large amount of videos to locate a specific video or moment they want to watch or share. Additionally, the video data can consume a large amount of storage space.
The same numbers are used throughout the disclosure and the figures to reference like components and features. Numbers in the 100 series refer to features originally found in FIG. 1; numbers in the 200 series refer to features originally found in FIG. 2; and so on.

Video summarization using semantic information


A vertical GaN-based LED is made by growing an epitaxial LED structure on a silicon wafer. A silver layer is added and annealed to withstand >450° C. temperatures. A barrier layer (e.g., Ni/Ti) is provided that is effective for five minutes at >450° C. at preventing bond metal from diffusing into the silver. The resulting device wafer structure is then wafer bonded to a carrier wafer structure using a high temperature bond metal (e.g., AlGe) that melts at >380° C. After wafer bonding, the silicon is removed, gold-free electrodes (e.g., Al) are added, and the structure is singulated. High temperature solder (e.g., ZnAl) that is compatible with the electrode metal is used for die attach. Die attach occurs at >380° C. for ten seconds without melting the bond metal or otherwise damaging the device. The entire LED contains no gold, and consequently is manufacturable in a high-volume gold-free semiconductor fabrication facility.

A Light Emitting Diode (LED) is a solid state device that converts electrical energy to light. Light is emitted from an active layer of semiconductor materials sandwiched between oppositely doped layers when a voltage is applied across the doped layers. One type of LED device, referred to here as a blue LED device, involves gallium nitride (GaN) layers.
FIGS. 1-3 (Prior Art) illustrate a prior art process used to make such a prior art blue LED device. A buffer layer 50 is grown on a silicon substrate 52, and a template layer 51 is grown on the buffer layer. An epitaxial LED structure 53 including an n-type layer 54, an active layer 55, and a p-type layer 56 is grown on the template layer. A silver mirror layer 57 is formed over the epitaxial LED structure. A silver encapsulation layer 58 is formed over the silver layer 57. A barrier layer 59 is formed over the encapsulation layer 58. The resulting device wafer structure 60 is then wafer bonded to a carrier wafer structure 61 as illustrated in FIG. 1 to form a wafer bonded structure 66.
Carrier wafer structure 61 involves a conductive carrier 63, a sublayer 64 of gold, and a sublayer 65 of gold/tin as illustrated. Prior to wafer bonding, there is also a sublayer 62 of gold on the top of the device wafer structure 60. The gold sublayers and the gold/tin sublayer are together referred to as a wafer bonding layer.
Wafer bonding involves pressing the two wafer structures 60 and 61 together and raising the temperature such that the gold/tin sublayer 65 melts. After cooling, when the gold/tin sublayer resolidifies, the two wafer structures are bonded together to form the wafer bonded structure 66. If during the wafer bonding process any of gold or tin were to diffuse into the silver layer 57, then the reflectivity of the silver might be decreased and/or the resistance of the contact at the silver-to-p-layer interface might be increased. Barrier layer 59 is provided to prevent such unwanted diffusion. FIG. 1 shows the multi-layer structure of the barrier layer 59 in the prior art example of FIGS. 1-3. Barrier layer 59 includes multiple periods. Each period includes a platinum sublayer and a titanium-tungsten sublayer.
Silicon is opaque to the blue light emitted by the active layer. Silicon substrate 52 and buffer layer 50 are therefore removed from the bonded wafer structure, thereby forming the wafer bonded structure 66 illustrated in FIG. 2. The upper surface of structure 66 is then roughened, and an n-type metal electrode 67 is added to the top of the structure, and a p-type metal electrode 68 is added to the bottom of the structure. The wafer bonded structure with its electrodes is then singulated to form individual LED devices.
FIG. 3 (Prior Art) shows one of these LED devices as part of a white LED assembly 74. The LED device is attached to a first portion of metal 69 of a metal core Printed Circuit Board (PCB) 70 or other package in what is commonly referred to as "die attach". The LED device cannot be heated to too high a temperature during the die attach process or the gold/tin wafer bond material will melt and the LED device will come apart. Silver epoxy 71, that is applied and cures in a temperature environment that does not exceed 150° C., is therefore commonly used. The n-electrode 67 is typically connected via a wire bond 72 to a second portion of metal 73 of the metal core PCB 70 as illustrated in FIG. 3.

High temperature gold-free wafer bonding for light emitting diodes


The invention relates to compounds of general structure (1): Q-(L1)n-(L2)o-(L3)p-(L4)q-D (1), wherein Q is a click probe; D is a cytotoxin containing an enediyne moiety; L1, L2, L3 and L4 are each individually linkers that together link Q to D; n, o, p and q are each individually 0 or 1, provided that n+o+p+q=1, 2, 3 or 4, wherein D comprises a functional moiety (21):

The enediynes represent one of the most fascinating families of natural products for their unprecedented molecular architecture and extraordinary biological activities. Since the neocarzinostatin (NCS) chromophore structure was first unveiled in 1985, the enediyne family has grown steadily to 11 structurally characterized members and 4 additional members isolated in their cycloaromatized form known to date. Classified into two subcategories according to the size of the enediyne core structures, members of the 9-membered enediyne subcategory include NCS, C-1027, kedarcidin (KED), maduropeptin (MDP), N1999A2, the sporolides (SPO), the cyanosporasides (CYA and CYN), and the fijiolides, with the latter four isolated in cycloaromatized form. Members of the 10-membered enediyne subcategory include the calicheamicins (CAL), the esperamicins (ESP), dynemicin (DYN), namenamicin, shishijimicin, and uncialamycin (UCM).
The enediynes have had a profound impact on modern chemistry, biology, and medicine. All enediynes contain a unit consisting of two acetylenic groups conjugated to a double bond or an incipient double bond within the 9- or 10-membered carbocycle. As a consequence of this structural feature, the enediynes share a mode of action: electronic rearrangement of the enediyne carbocycle produces a transient benzenoid diradical. When positioned within the minor groove of DNA, the diradical abstracts hydrogen atoms from the deoxyribose backbone of duplex DNA; the DNA-centered radicals can then cause interstrand cross-links (ICLs) or react with molecular oxygen, leading ultimately to DNA double-strand breaks, or both. With their exquisite mode of action and their extraordinary cytotoxicity, the enediynes have been successfully translated into clinical drugs.
It is remarkable that, among the 11 enediynes known to date, two [NCS as poly(styrene-comaleic acid)-conjugated NCS (SMANCS) and calicheamicin as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin (Besponsa)] have been developed into marketed drugs, one (C-1027, also known as lidamycin) has been in phase II clinical trials, and several have been (esperamicin, dynemicin, kedarcidin) or still are (uncialamycin) in preclinical studies, representing an astonishing and remarkable success rate with the enediyne class of natural products.
Calicheamicin γ1I (also known as LL-E33288) was discovered in the early 1980s, when it was isolated from bacteria residing on a chalky rock from a site near a Texas highway. Calicheamicin γ1I was found to possess phenomenally high potency against tumor cells, which provided the impetus for its structure elucidation (see below), and consists of three domains: (1) an enediyne segment ("molecular warhead"), (2) a trisulfide moiety ("triggering device") and (3) an oligosaccharide chain ("recognition device").
Due to their unique mode of action and potency, several analogues of the calicheamicins have been tested in preclinical models as potential antitumor agents. Their development as single agent therapies has not been pursued, however, because of delayed toxicities that limit the therapeutic dose range for treatment. However, the potency of calicheamicins makes them ideal for antibody-targeted chemotherapy.
Antibody-targeted chemotherapy is known in the art, and consists of treatment of a cancer patient with a recombinant antibody covalently bound to a cytotoxic chemical via a synthetic linker (S. C. Alley et al, Curr. Opin. Chem. Biol. 2010, 14, 529-537). The main objective of an antibody-drug conjugate (ADC), also called immunotoxin, is to combine the high specificity of a monoclonal antibody for a tumor-associated antigen with the pharmacological potency of a "small" cytotoxic drug (typically 300 to 2,000 Da). Examples of ADCs include gemtuzumab ozogamicin (Mylotarg; anti-CD33 mAb conjugated to calicheamycin, Pfizer/Wyeth); brentuximab vedotin (SGN-35, Adcetris, a CD30-targeting ADC consisting of brentuximab, covalently linked to MMAE (monomethylauristatin E), Seattle Genetics); trastuzumab-DM1 conjugate (T-DM1). ADCs known from the prior art are commonly prepared by conjugation of the linker-toxin to the side chain of antibody amino acid lysine or cysteine, by acylation or alkylation, respectively. Some early generation ADCs were prepared by conjugation of a hydrazide derivative of the cytotoxic chemical to an oxidized glycan of the monoclonal antibody.
The first series of antibody conjugates of calicheamicin γ1I were based on attachment to the anti-MUC1 antibody CTM01 via a hydrazone linkage to the oxidized antibody glycan as a site of hydrolytic release (see for example Hinman et al. Cancer Res. 1993, 53, 3336-3342). In addition, the original trisulfide moiety is replaced by a dimethylated, stabilized disulfide, which likely prevents the premature release of calicheamicin by circulating reduced thiols (e.g. glutathione). Thirdly, comparison of the therapeutic efficacy of several calicheamicin conjugates against the MX-1 xenograft tumor implanted in nude mice indicated that the therapeutic window was highest for the N-acetylated derivative of the calicheamicin core.
Further work on conjugates of the same anti-MUC1 antibody by Hamann et al. (Bioconj. Chem. 2005, 16, 346-353) showed that the "amide conjugate" which lacks the hydrazone site of hydrolysis was equivalent or superior to the amide-linker ADC in all preclinical models examined, especially against resistant cell lines. On the basis of these findings, an amide-linked ADC with calicheamicin payload (CMB-401) was clinically evaluated for the treatment of recurrent platinum-sensitive epithelial ovarian carcinoma (EOC) but was discontinued after a phase II study did not meet its end-point (see for example Chan et al. Canc. Immunol. Immunother. 2003, 52, 243-248).
In contrast to the CMT01-conjugate, it was found by Hamann et al. (Bioconj. Chem. 2002, 13, 40-46) that ADCs based on the anti-CD33 murine antibody P67.6 showed a clear benefit for a hydrolytic release mechanism of the calicheamicin derivative, as afforded by the hydrazone conjugate, versus the non-cleavable amide conjugate, in terms of beneficial potency and selectivity in vitro, in vivo, and ex vivo. As a consequence, the P67.6-calicheamicin hydrazone conjugate was a priori selected for application in development of an ADC against acute myeloid leukemia (AML). However, it was later reported by the same authors (Hamann et al., Bioconj. Chem. 2002, 13, 47-58) that the humanized version of P67.6 was not suitable to make hydrazone conjugates because of unexpected sensitivity of the antibody to periodate oxidation. A series of bifunctional linkers was therefore developed, resulting in a new class of 'hybrid' conjugates, combining stable attachment of the calicheamicin to lysines but with the hydrazone incorporated in the linker as a site of hydrolytic release. The optimized conjugate chosen for clinical trials, CMA-676, was found to be significantly more potent and selective than the carbohydrate conjugate it replaced. In clinical trials, CMA-676 selectively inhibited leukemia colony formation by marrow cells from a significant proportion of AML patients and became the first antibody-targeted chemotherapeutic agent approved by the FDA in 2000, gemtuzumab ozogamicin (Mylotarg®), for older patients with CD33-positive AML who had experienced a relapse (Stasi, Expert Opin. Biol. Ther. 2008, 8, 527-540).
However, in a post-approval study it was found that gemtuzumab ozogamicin in combination with chemotherapy did not demonstrate improved survival but instead showed a higher rate of toxicity than chemotherapy alone, leading to a high number of early deaths and then the voluntary withdrawal of this ADC from the market by Pfizer in 2010. Nevertheless, Mylotarg® remained in clinical use under 'compassionate use' regulation, during which studies it was observed that a treatment regimen based on fractionated dosing outweighed the risks and afforded significant clinical benefit. Based on these observations, Mylotarg® was resubmitted to FDA to receive approval again on Sep. 1, 2017. Better then with the first approval, clinical indication this time included adults not only with refractory, but also with newly diagnosed acute CD33-positive AML.
Just two weeks earlier, on Aug. 17, 2017, FDA approved another ADC, Besponsa®, for treatment of adults with relapsed or refractory acute lymphoblastic leukemia (ALL). Besponsa® (inotuzomab ozogamicin) is composed of a CD22-targeting monoclonal antibody (G544) conjugated to identical linker-calicheamicin format as present in Mylotarg®.
An alternative cleavable linker to acid-sensitive hydrazone is disclosed in WO2016/172273, based on well-established dipeptide cathepsin-sensitive substrate. In addition, conjugation technology for attachment of calicheamicin to the monoclonal antibody is changed from amide bond (with lysine side-chains) to maleimide (with cysteine side-chains), and other mainstream conjugation technologies suggested. Also in WO2016/172273, N-acetylcalicheamicin γ1I (R═Ac) is used throughout as the calicheamicin derivative of choice, although unmodified calicheamicin γ1I (R═H) and a large number of other acylated derivatives at the N-ethyl sugar component are also claimed.
Lee et al. (J. Am. Chem. Soc. 1987, 109, 3464-3466 and J. Am. Chem. Soc. 1992, 114, 985-997), as part of their efforts to elucidate the structure of the calicheamicin antibiotics, were the first to report on the N-acetylated version of calicheamicin γ1I. Specifically, it was shown that treatment of a methanolic solution of calicheamicin γ1I with a large excess of acetic anhydride (varying from 50 to >100 equivalents) for 3-4 hours affords N-acetylcalicheamicin γ1I after concentration and purification. A similar procedure is disclosed in EP0392376, as well as two specific other acylated derivatives of calicheamicin γ1I, i.e. formyl- and N-monomethylsuccinyl calicheamicin γ1I. N-formylcalicheamicin γ1I was obtained by a similar procedure as N-acetylcalicheamicin γ1I, i.e. using large excess of highly reactive mixed anhydride of formic acid and acetic acid, properly characterized and subjected to in vitro evaluation studies. Synthesis of the N-monomethylsuccinylcalicheamicin γ1I derivative is described by stirring of methanolic solution of calicheamicin γ1I with 28 equivalents of the anhydride of succinic acid monomethyl ester for 3 days.
Next, concentration and trituration of a 'gummy precipitate' was followed by precipitation from a mixture of ethyl acetate/diethyl ether/hexane, to afford the crude N-monomethylsuccinylacetyl calicheamicin γ1I, which was not further analyzed or evaluated.
In a similar approach, it is demonstrated in EP0289030 that esperamicin, an enediyne antibiotic with a structure highly resembling calicheamicin, can be efficiently acetylated by stirring with 40 equivalents of acetic anhydride for 48 h or with 30 equivalents for 16 h at 30° C.
These examples demonstrate that acylation of enediyne antibiotics having an N-alkylsugar in their structure, and calicheamicins in particular, can be achieved by treatment with excess of a small and highly reactive anhydride reagent like acetic anhydride or formic/acetic mixed anhydride.
While until recently all calicheamicin-based ADCs were obtained by an exchange reaction of the trisulfide moiety, Bernt et al. (Bioconj. Chem. 2009, 20, 1587-1594) for the first time describe how a specific calicheamicin derivative, calicheamicin Θ, can be connected to an anti-CD19 antibody through the N-ethyl sugar at the other end of the molecule. To this end, a pyridiyldisulfide linker containing an N-hydroxysuccinimide ester (2 equivalents) and dimethylaminopyridine (not quantified) as catalyst in DMSO, is reacted with calicheamicin Θ by stirring for 6 h at 0° C. Without further purification, the resulting mixture is added to the sulfhydryl-modified anti-CD19 antibody in PBS buffer, to generate an ADC with average two (2) molecules of calicheamicin Θ per antibody, as determined by absorption spectroscopy (analytical method not specified). Consecutive in vitro cytotoxicity determination as well as an in vivo xenograft study suggest a beneficial therapeutic effect for the anti-CD19-calicheamicin Θ conjugate, however given the lack of analytical data on the ADC it cannot be concluded whether this effect is due to the anticipated conjugation through the N-ethyl sugar or through any of the free alcohol functions of calicheamicin Θ (5 in total), given the well-established procedure for the formation of an ester by treatment of an alcohol with an activated ester in the presence of DMAP. In addition, given the lack of experimental verification, it cannot be excluded that in vitro and in vivo response is the result of the combination of naked anti-CD19 and free calicheamicin Θ.
In WO2017172907, it is disclosed how calicheamicin γ1I can be connected through its N-ethylaminosugar to either cysteine or lysine side chains of a monoclonal antibody. To this end, calicheamicin γ1I is reacted with an active ester or carbonate, leading to an amide or carbamate derivative at the N-ethylaminosugar, which is then further modified to give a construct containing a specific cleavable linker (oligopeptide, Val-Cit-PABC or Val-Ala-PABC) and a reactive moiety at the other end (maleimide, ortho-bishaloalkylaromatic molecules or active esters), for conjugation to cysteine or lysine. Another optional modification of calicheamicin γ1I as described in WO2017172907 involves the exchange of the trisulfide moiety to a functionalized or isopropyl disulfide, by means of a well-known procedure involving treatment with excess of a mercaptan. By introduction of a mercaptan containing a hydrophilic group (further containing an alcohol group, a sulfonate group, or a carbohydrate group) it is suggested that the resulting ADCs display improved solubility in aqueous buffer and mitigate the issue of aggregation. In addition, a sterically hindered disulfide moiety instead of the natural trisulfide of calicheamicin improves stability of the payload in vivo. However, multiple synthetic steps are in all cases required to reach from calicheamicin γ1 to the reactive derivative suitable for conjugation with antibody.
The advantage of the extremely high potency of enediyne antibiotics offers a considerable potential for incorporation into antibody-drug conjugates and therefore a benefit for patients. However, the manufacturing and handling of these highly potent active ingredients also potentially poses occupational risk for workers, even at very low airborne concentrations. As a result, safe handling systems to protect a healthy workforce against the adverse effects of these materials are routinely used by (bio)pharmaceutical manufacturing companies, such as containment devices with transfer chambers and airlocks, and with careful monitoring of airborne drug concentration. One effective way to reduce the occupational risk of workers in pharmaceutical manufacturing is to reduce the number of synthetic steps with the highly potent ingredient.
Besides direct conjugation of toxic payload through acylation of lysine (as applied in Mylotarg, Besponsa and Kadcyla) or alkylation of cysteine (as applied in Adcetris), a promising alternative approach to prepare antibody-drug conjugates involves the generation or functionalization of a monoclonal antibody with a so-called click probe to undergo attachment of toxic payload by click reaction in the second step. Typically, the click reaction will involve a [3+2] or [4+2] cycloaddition between two functional groups, such as strained cycloalkyne groups, terminal alkyne groups, azido groups, tetrazine groups and strained cycloalkene groups.
A well-known click reaction is the 1,3-dipolar cycloaddition of an azide with an alkyne group to form a stable triazole. The 1,3-dipolar cycloaddition can be performed between an azide and a terminal acetylene group in the present of copper(I). Alternatively, the 1,3-dipolar cycloaddition of azide can be performed in the absence of copper(I) if a strained (hetero)cycloalkyne is employed, in particular a (hetero)cyclooctyne. Well-known examples of (hetero)cyclooctynes used for metal-free click chemistry are difluorinated cyclooctyne (DIFO), benzoannulated cyclooctyne (DIBO, DIBAC, BARAC and COMBO) or cyclooctyne fused with a cyclopropane ring (BCN). With these strained alkynes, 1,3-dipolar cycloaddition also takes place with other 1,3-dipoles such as nitrones, nitrile oxides and diazo compounds.
Another well-known class of click reactions involve the Diels-Alder cycloaddition of an electron-poor aromatic moiety (such as a tetrazine, a triazine or a 1,2-orthoquinone) with a strained alkene or strained alkyne. Most prominently, the cycloaddition of a tetrazine with a strained alkene is employed because of its exceptionally high reaction rate. Most common tetrazines in this regard are (functionalized) 3-phenyltetrazine, 3,6-diphenyltetrazine or 3,6-dipyridyltetrazines. Most common strained alkenes involve (functionalized) methylcyclopropene or trans-cyclooctene (TCO), as well as variants thereof.
In order to prepare an antibody-drug conjugate by means of a click chemistry reaction, one (or more) click chemistry probe(s) must be installed onto the monoclonal antibody and the mutually reactive probe onto the toxic payload. The latter molecule can be readily prepared by chemical procedures known in the art. Installment of a click probe onto a monoclonal antibody can be achieved in a variety of manners, as for example summarized in Aggerwal et al. (Bioconj. Chem. 2015, 26, 176-192), including (a) direct chemical conjugation, (b) genetic encoding of a particular amino acid (or peptide sequence) followed by installation of click probe through this particular amino acid (or peptide sequence), (c) genetic encoding or incorporation by auxotrophic organism of a non-natural amino acid already harboring a click probe and (d) direct enzymatic modification of the monoclonal antibody.
One of the oldest and most versatile methods for antibody modification is through lysine conjugation, due to solvent accessibility and the high abundance of these residues on a protein surface. In general, this is achieved through the formation of an amide bond between a lysine residue and activated esters, such as N-hydroxysuccinimide (NHS), pentafluorophenol, or 4-sulfotetrafluorophenyl esters. An alternatively chemical approach for antibody conjugation involves treatment of antibody with mild reducing agent such as TCEP, followed by alkylation of liberated thiol groups with a suitable electrophilic reagent such as a maleimide, 1,2-bisbromomaleimide, 1,2-bisbromopyridazinedione, 1,2-bisbromomethylbenzene or bissulfone reagents, as summarized in Dovgan et al. Bioconj. Chem. 2017, 28, 1452-1457. Obviously, either method of lysine acylation or cysteine alkylation is highly suitable for installation of a click probe onto the antibody if already present in the electrophilic reagent. For example, Dovgan et al. show how treatment of a monoclonal antibody with 4-azidobenzoyl fluoride leads to efficient acylation of lysine residues in a PBS buffer, suitable for installation of toxic payload by copper-free click conjugation with BCN-modified monomethylauristatin E (MMAE). Another example is provided by Maruani et al. (Nat. Communications 2015, DOI: 10.1038/ncomms7645) for installation of alkyne group onto monoclonal antibodies by partial reduction followed by treatment with a suitably functionalized 1,2-bisbromopyridazinedione.
In order to achieve better control of conjugation site, monoclonal antibodies can be genetically modified with a specific additional cysteine, which can be chemoselectively modified after recombinant expression (Junutula et al. Nat. Biotechnol. 2008, 26, 925-932). Alternatively, a designed peptide tag can be installed into the monoclonal antibody for enzymatic modification. The latter types of enzymatic tagging methods include for example biotin ligase, transglutaminase, and lipoic acid ligase, as summarized by Aggerwal et al. (Bioconj. Chem. 2015, 26, 176-192).
Methods for genetic encoding of non-natural amino acids by ribosomal incorporation into proteins are well-known in the art and provide an elegant solution to the problem of site-specific engineering of functionality into a protein. In the most widely used method for non-natural amino acid incorporation, a mutant protein encoded by a gene with the amber stop codon (TAG) at the site of the desired non-natural amino acid is expressed in cells, along with a corresponding orthogonal tRNA/aminoacyl-tRNA synthetase (aaRS) pair capable of installing the non-natural amino acid at the amber stop codon site. Genetic encoding has inter alia been employed for installation of azide, tetrazine, cyclooctyne, cyclopropene or trans-cyclooctene moieties onto proteins. Another method to introduce a non-natural amino acid into a protein involves the metabolic incorporation of a non-natural amino acid, for example azidohomoalanine, instead of a natural amino acid, by an auxotrophic organism.
The fourth method of modification of antibodies with a click probe involves the enzymatic modification at a specific site. For example, it has been shown by Dennler et al. (Bioconj. Chem. 2014, 25, 569-578) that enzymatic deglycosylation at N297 of trastuzumab liberates a specific glutamine residue (N295) for modification with transglutaminase, thereby enabling the installation of an azide moiety. A similar strategy was employed by van Geel et al. (Bioconj. Chem. 2015, 26, 2233-2242), involving trimming of antibody glycan with an endoglycosidase, thereby liberating the core N-acetylglucosamine for enzymatic installation of an azidosugar under the action of a glycosyl transferase.
Hydrophobic interaction chromatography (HIC) is a non-denaturing liquid chromatography method that separates proteins based on their affinity to a hydrophobic stationary phase. ADCs typically have a rightward shift of the major peak as compared to their corresponding naked mAb due to the hydrophobicity of the payload, and ADCs with a higher DAR therefore have a longer HIC retention time, reflecting greater hydrophobic character. It has been demonstrated that in order to interact with the HIC stationary phase, the linker-payload must be able to reach out into bulk solvent. Therefore, the HIC retention of ADCs may be a crude method of comparing the steric accessibility of the linker-payload toward metabolic enzymes (see for example Tumey et al., ACS Med. Chem. Lett. 2016, 7, 977-982). In addition, pharmacokinetics of ADCs are inversely correlated to ADC hydrophobicity, therefore ADCs with longer HIC retention times are cleared faster (see for example Lyon et al, Nat. Biotechn. 2015, 33, 733-736 and Tumey et al., AAPS J., 2017, 19, 1123-1135). As convenient measure to predict the pharmacokinetics of a given ADC is therefore by calculation of a HIC relative retention time (rrt), by dividing the absolute retention time of the ADC by the retention time of a mAb reference standard (unmodified antibody). Thus, small relative retention times (up to ˜1.3) reflect a relatively non-hydrophobic ADC with pharmacokinetics likely not significantly altered from the that of the naked antibody.
Another important ADC attribute is aggregation. The increase in susceptibility of ADCs to aggregation could directly affect thermal stability and serum half-life and therefore impact manufacturing, storage and in vivo performance (efficacy, toxicity, and immune reaction of patients). Therefore, it is essential to keep aggregation propensity level low.

Abstract: wherein R12═C1-3-alkyl, the wavy line indicates the connection to the remainder of the cytotoxin, and wherein D is conjugated to (L4)q by replacing the amine H atom, and to conjugates obtainable by reacting the compound according to the invention with a protein comprising a click probe F capable of reacting with click probe Q in a click reaction. The invention further relates to a bioconjugate according to general structure (2): Pr-[(L6)-Z-(L1)n-(L2)o-(L3)p-(L4)q-D]xx (2), wherein Z is a connecting group that is formed in a click reaction, L6 is a linker that links Z to Pr and Pr is a (glyco)protein.


A divider configured to be secured in the seats of automobiles for forming a physical barrier between passengers is disclosed herein. The divider can be used for children, pets, or adults. A rectangular prism shaped booster may be provided below the divider for raising the height of the divider. The profile of the divider is designed to fit securely against the back of a seat and the bottom of the seat. The curved front side of the divider allows the driver to view all passengers, maintain views out the windows, and still be an effective barrier without being so large as to be in the way. A notch is provided in the curved front side of the divider for receiving a seat belt or strap for securing the divider. The divider and the booster may have removable covers with pockets for holding items, such as water bottles, tissues, and wipes.

Passengers seated in the rear seat of an automobile may engage in fighting, or other behavior that may be distracting to the driver. There are many U.S. patents that attempt to solve this problem with a type of divider, for example, U.S. Pat. Nos. 1,239,166; 2,006,883: 4,118,812; 4,938,401; 5,123,707; 5,255,958; 5,518,293; 5,560,680; 5,054,837; 4,595,227.
However, none of the above prior patents address all of the necessary issues and concerns in one invention, for a safe, secure, effective divider for all ages. There is a need for a simple universal divider that is soft yet durable and strong, has multiple height options to fit various cars and individuals, can have multiple width options as needed to allow for the best functional divider that will fit in the space, while preventing the backseat passengers from seeing each other and touching each other, while also allowing the driver unobstructed view of the passengers and the road, can easily be attached securely in any car with either a lap belt or shoulder belt or if needed can attach with an additional accessory strap to the latch hooks included in many cars. The divider also has covers which could be made in various colors and patterns, and has various pockets to provide functional storage as well as loops to attach trash bags and other items.

Automobile seat divider—the backseat buddy


A sealed slide switch having a toggle mechanism with a handle extending through a housing into a cavity of a slide. An O-ring on the handle seals any opening between the base of the handle and the housing. A surface plate retains the slide of the switch on top of the housing. A plug in the bottom of the housing provides electrical connections between the toggle mechanism and an application circuit.

1. Field of the Invention
This patent relates generally to electrical switches and in particular to a sealed slide switch having a pivoting toggle type of operation.
2. Description of Related Art
Sealed switches are desired or often necessary for various applications where the switch needs to be sealed so that corrosives, dust, and other impurities in the atmosphere will not impair operation of the switch or shorten its useful life. Further, a sealed switch is required to protect a switch during certain component board processes such as wave soldering.
The sealing of slide switches has generally been accomplished by a secondary operation of installing a boot on the switch to protect it during various fabrication steps which otherwise would be damaging to the switch. Secondary operations add cost to these switches. Another approach is to provide a sealing means within the slide switch, but then the movement of the slide is not easy or smooth resulting in poor feel and inferior seal.
U.S. Pat. No. 4,191,387 issued Mar. 4, 1980 to Francis D. Kirchoff describes a water tight seal for toggle switches. The exterior of the switch housing is watertight by reason of a turn nut compressing an O-ring. The interior of the toggle switch handle housing is made watertight, while still permitting toggle motion, by an elongated seal of solid cross section engaging the outer face of a bulbous portion of the handle and a second elongated seal of solid cross section engaging the inner face of the bulbous portion.
U.S. Pat. No. 4,482,792 issued Nov. 13, 1984 to Leo Geremia describes a sealed toggle switch having an O-ring sealed in a groove of an upper surface of a base and extending around the periphery of the same. A lead actuator 50 includes an elongated ball portion and a ball which fits against a socket or bushing and is held against the O-ring to form a seal.
U.S. Pat. No. 4,731,511 issued Mar. 15, 1988 to Budd Steinhilber et al. describes a decorator wall plate and slide caps for positioning over a toggle-type electrical switch. A switch toggle lever protrudes through an opening in a wallplate and the slide member acts as a cam to exert force upon the switch toggle and move it from one position to another position. However, it does not disclose any sealing of the slide switches, and it does not have a method for accurate translation of the slide motion to the toggle motion.
U.S. Pat. No. 5,134,258 issued Jul. 28, 1992 to Melvin A. Carrodus describes a manually operated circuit breaker with sliding action for control and setting. A linkage member fits over a switch handle and is attached through a knurled pin to the handle. The linkage member slides right or left upon a flat surface of the housing. However, it does not disclose any sealing of the slide switch. Furthermore, in small switch configurations the use of a small pin to translate sliding motion to toggle motion results in a very fragile pin subject to breakage or damage when actuated.


A method of simulating noise generated by a tire using a computer, wherein waveforms of the sounds are determined, considering the phase, of which sounds originate from sources of sound, namely, a leading edge which is an edge of the load-supporting portion of the tread and first contacts the road surface when the tire rotates, and a trailing edge positioned opposite to the leading edge. The so-determined waveforms of the sound are integrated over the entire surface of the tread, after that, audible sound of the integrated waveforms is emitted from a headphone as tire-noise.

1. Field of the Invention
The present invention relates to a method of simulating tire tread noise and a simulator therefor. More specifically, the present invention relates to a method of simulating tire tread noise and a simulator of tire tread noise whereby tire noise with high fidelity can be generated.
2. Description of the Related Art
The method of simulating tire tread noise on which the present invention is based is disclosed in U.S. Pat. Nos. 4,727,501 and 4,788,651. In this method, a tread surface is represented as a large number of matrix elements on a coordinate system in order to distinguish between load-supporting portions (i.e. lugs) and grooves of the tread, to thereby determine a contour of a front edge of a contact portion (footprint) of the tread which comes into contact with the road surface, or a contour of a rear edge of this contact portion, in accordance with an equation. Then, the waveforms of sound generated from each of the matrix elements, which are sound sources, are determined and the waveforms of sound are integrated over the contours of the front edge or the rear edge of the footprint. Next the so-integrated value is further integrated along the direction of the circumference of the tire, and audible sound is generated on the basis of the integrated value, thereby simulating tire tread noise.
When the load-supporting portion of the tread comes into contact with the road surface and when the load-supporting portion which has contacted the road surface separates from the road surface, the contacting portion of the load-supporting portion which comes into contact with the road surface and another portion of the load-supporting portion which separates from the road surface are sources of vibration, and cause the tread rubber to vibrate. The vibration of the tread rubber is transmitted to the side walls of the tire and thus, tire tread noise is generated. This is understood by inventors of the present invention. However, in the conventional simulating method, the waveform of sound has been integrated along either the contour of the front edge or the contour of the rear edge of the footprint, by assuming that the entire surface of the load-supporting portion will be a source of sound, without specifying the actual portions thereof which constitute the sound source. As a result, there exists a problem that it is not possible to simulate the sound with high fidelity by such a technique since it is not possible to integrate sound generated from the actual source of sound, and also not possible to integrate sound, considering the phase of the sound.

Method of simulating tire tread noise and simulator therefor


The invention is in the field of virus vaccines for protecting animals against infection by parvovirus, their production and use. More in particular, the invention is related to a vaccine comprising an attenuated parvovirus comprising a capsid protein or fragment thereof derivable from another parvovirus. Surprisingly it was found that such a vaccine was capable of inducing higher titers of protecting antibodies against a challenge with the second type of parvovirus strains while maintaining good immunity against the first type of parvovirus. Recombinant virus strains also remained attenuated.

Parvovirus belongs to the family of single stranded DNA viruses. Parvoviruses can cause disease in some animals like cats, dogs and pigs. Because the viruses require actively dividing cells in order to replicate, the type of tissue infected varies with the age of the animal. The gastrointestinal tract and lymphatic system can be affected at any age, leading to vomiting, diarrhea and immunosuppression, but cerebellar hypoplasia is only seen in cats that were infected in the womb or at less than two weeks of age, and disease of the myocardium is seen in puppies infected between the ages of three and eight weeks.
Canine parvovirus is a particularly deadly disease among young puppies, about 80% fatal, causing gastrointestinal tract damage and dehydration as well as a cardiac syndrome in very young pups. It is spread by contact with an infected dog's feces. Symptoms include lethargy, severe diarrhea, fever, vomiting, loss of appetite, and dehydration. Porcine parvovirus causes a reproductive disease in swine known as SMEDI, which stands for stillbirth, mummification, embryonic death, and infertility. Feline panleukopenia is common in kittens and causes fever, low white blood cell count, diarrhea, and death. Infection of the cat fetus and kittens less than two weeks old causes cerebellar hypoplasia. Mink enteritis virus is similar in effect to feline panleukopenia, except that it does not cause cerebellar hypoplasia. A different parvovirus causes Aleutian Disease in minks and other mustelids, characterized by lymphadenopathy, splenomegaly, glomerulonephritis, anemia, and death. The most accurate diagnosis of parvovirus is by ELISA. Dogs, cats and swine can be vaccinated against parvovirus.
At the DNA level, canine, feline and porcine parvoviruses are known to have a highly homologous genome. Canine parvovirus (CPV2) is a virus which is responsible for an acute and sometimes fatal enteritis in dogs (Kelly, Aust. Vet. J. 54; 593, 1978; Appel et al., Vet. Rec. 105; 156-159, 1979). The virus, which first appeared around 1977, probably arose from a very closely related virus in cats, feline panleukopaenia virus (FPLV) through a small number of mutations in the single capsid protein; a species jump which may have involved intermediate passage in other carnivores such as mink or raccoons (Truyen et al., Virology 215, 186-189, 1996).
As early as 1979 the first variants of CPV2 appeared, termed CPV2a, and they were quickly followed by the appearance of CPV2b in 1984. (Parrish et al., Science 230, 1046-1048, 1985, and J. Virol. 65; 6544-6552, 1991).
The original type 2 virus has now disappeared from the field having been replaced by the 2a and 2b variants; although the relative proportions of these two types varies from country to country (Truyen et al., supra; Chinchkar et al., Arch. Virol. 151, 1881-1887, 2006; Pereira et al., Infect. Genet. Evol. 3, 399-409, 2007). The amino acid changes in the capsid protein (VP2), which characterise the shift from 2 to 2a and to 2b, are very limited. Substitutions at positions 87 (Met to Leu), 300 (Gly to Ala), 305 (Tyr to Asp) and 555 (Val to Ile) occurred in the evolution of 2 to 2a and 426 (Asn to Asp) and 555 (Ile to Val) in the emergence of 2b from 2a (Parrish et al., supra; Truyen et al., J. Virol. 69, 4702-4710, 1995). Recently, 2a strains lacking the Val to Ile substitution at position 555 have been reported (Wang et al., Virus Genes 31, 171-174, 2005; Martella et al., Virus Genes 33, 11-13, 2006). It appeared that a single amino acid change can differentiate the CPV2a and CPV2b VP2 sequences.
More recently strains have emerged in Italy in which the amino acid at position 426 (Asn in 2a and Asp in 2b) has become a glutamic acid (Glu) residue
(Buonavoglia et al., J. Gen. Virol. 82, 3021-3025, 2001; Martella et al., J. Clin. Microbiol. 42, 1333-1336, 2004). The fact that these Glu 426 variants, termed CPV2c viruses, are circulating and co-existing with other CPV types in Italy and other European countries (Decaro et al., J. Vet. Med. B. Infect. Dis. Vet. Public Health 53, 468-472, 2006) and have also been isolated in countries as geographically diverse as
Vietnam and Scotland (Nakamura et al., Arch Virol.149, 2261-2269, 2004, Spibey et al., Vet. Microbiol 128, 48-55, 2008) suggests that they have an advantage in at least a proportion of the dog population.
The relatively rapid evolution of canine parvovirus has resulted in the loss and then re-gaining of the feline host range (Truyen et al., 1996 supra), and this regained ability to replicate in cats may well account for the replacement of the original type 2 virus with the 2a, 2b and 2c variants. In the late 1970s and early 1980s both live and inactivated FPL vaccines were used to protect dogs against CPV disease due to the shared antigens which stimulated cross-protection, however the levels of protection they afforded was poor and duration of immunity was short. These vaccines were replaced by live attenuated CPV vaccines, which provided excellent protection and longer duration of immunity. Currently the live attenuated vaccines are derived from either CPV2b isolates or the original type 2 virus. Since the type 2 virus has been entirely replaced in the field by 2a, 2b and now 2c viruses there has been concern over the level of protection afforded by attenuated type 2 vaccines (Pratelli et al., Clin. Diag. Lab. Immunol. 8, 612-615, 2001; Truyen, Vet. Microbiol. 69, 47-50, 1999).
However, based on studies with available monoclonal antibodies each new antigenic variant has lost at least one neutralising epitope compared with the former variant (Strassheim et al., Virology 198, 175-184, 1994; Pereira et al., supra). Previously it has been demonstrated that the live attenuated CPV2 vaccine is able to protect dogs against 2a and 2b field challenges (Greenwood et al., Vet. Record. 136, 63-67, 1995) even though cross-neutralisation studies conducted in vitro using sera raised against the various antigenic types do show marked differences (Pratelli et al., supra).
Recently, it was shown that live attenuated type 2 vaccine (Nobivac-Intervet) was able to protect dogs from challenge with the most recent CPV variant, CPV2c (Spibey et al., Vet. Microbiol 128, 48-55, 2008).
Nevertheless there exists a need in the field for vaccines that improve the immunity of animals, in particular cats, dogs and pigs against infection with new types of parvoviruses. However, such vaccines are not available, in particular, vaccines specific for Canine parvovirus type 2c are not available.


The invention relates to an interventional system comprising an introduction element (4) like a catheter for being introduced into an object (9), for instance, a person. A moving unit (2) like a robot moves the introduction element within the object, wherein a tracking image generating unit (3) generates tracking images of the introduction element within the object and wherein a controller (8) controls the tracking image generating unit depending on movement parameters of the moving unit, which are indicative of the movement, such that the tracking images show the introduction element. This control can be performed very accurately based on the known real physical movement of the introduction element such that it is not necessary to, for instance, irradiate a relatively large area of the object for ensuring that the introduction element is really captured by the tracking images, thereby allowing for a reduced radiation dose applied to the object.

WO 2005/009243 A1 discloses an x-ray unit for generating images of a body, wherein the x-ray unit comprises an x-ray source, an automatically adjustable collimator for limiting, locally attenuating and/or filtering an x-ray beam, an x-ray detector and a data processing unit that is coupled to the collimator and the x-ray detector. The data processing unit is adapted to localize a region of interest inside the body on at least a first x-ray image of the body transmitted by the x-ray detector and to adjust the collimator such that subsequent x-ray images are concentrated on the region of interest.
If the x-ray unit is used for tracking a movement of a catheter tip within the body, i.e. if the region of interest is a moving region of interest defined by the moving catheter tip, and if this tracking is performed by acquiring a sequence of x-ray images, the x-ray source has to irradiate a relatively large region of the body, which corresponds to the largest distance the catheter tip can travel between consecutive x-ray images, in order to ensure that the catheter tip is really captured by the x-ray images and can therefore be tracked by using the x-ray unit. This relatively large irradiated region of the body results in a relatively large radiation dose applied to the body. Moreover, if the x-ray source is switched off for a short time and if the x-ray source is then switched on again, the location of the catheter tip is not known such that a relatively large part of the body has to be irradiated by the x-ray radiation, in order to find the moving catheter tip. Also this leads to a relatively large radiation dose.