Apparatus and method for optical- or optical-and-electrical stimulation of midbrain and/or brainstem tissue (e.g., auditory nerve pathways). Peripheral neural stimulation using infrared lasers has been demonstrated in several systems; however, optical stimulation of the central nervous system (CNS) has not been previously described. In some embodiments of the present invention, radiant energy exposure of the cochlear nucleus using a mid-wavelength infrared laser generates optically-evoked auditory brainstem responses (oABRs). In an experiment, the cochlear nuclei of adult male Sprague-Dawley rats were exposed using a suboccipital craniotomy approach. In one embodiment, different regions of left cochlear nucleus were acutely stimulated with a 200- or 400-micron-diameter optical fiber placed on the surface of the brainstem, using 50- to 750-microsecond pulses of 1849-nm to 1865-nm-wavelength radiation at a rate of 10 to 40 Hz and power levels ranging from 10% to 80% of 5 watts. oABRs were recorded during the period of optical stimulation.

As a convention used herein, a nerve will be defined as a collection of individual nerve fibers (i.e., axons) of individual nerve cells (neurons) that together form a set of nerve pathways (an integrated set of pathways for signal propagation within the nervous system). Subsets of the individual nerve fibers are each bundled into one of a plurality of fascicles that together form the nerve. Action potentials can occur in the axon portion of individual nerve cells. A series of individual nerve fibers that together form an integrated signal pathway starting at a sensory-receptor nerve ending and extending to the brain will be referred to as a sensory-nerve pathway, a series of individual nerve fibers that together form an integrated signal pathway starting at the brain and extending to a muscle cell will be referred to as a motor-nerve pathway. A sensory-nerve pathway that carries auditory signals will be referred to as an auditory-nerve pathway, and a sensory-nerve pathway that carries signals from the sense-of-balance organs (e.g., the vestibular organs of the inner ear, or perhaps the eyes) will be referred to as a sense-of-balance nerve pathway.
Within each fascicle of a nerve, there will typically be a plurality of sensory-nerve pathways and a plurality of motor-nerve pathways, wherein the number of sensory-nerve pathways will typically be about fifteen times as many as the number of motor-nerve pathways. As well, a series of individual nerve fibers may together form an integrated pathway starting at one of various internal organs and ending in the brain, with then other series of individual nerve fibers together forming an integrated pathway starting at the brain and extending to some internal end organ (such as the digestive tract, the heart, or blood vessels) as part of the autonomic nervous system; and a series of individual nerve fibers may together form an integrated pathway within the brain referred to as a tract. As used herein, a nerve bundle or fascicle refers to a collection of nerve fibers that subserve a like function (e.g., a fascicle may support a plurality of different motor-nerve pathways and thus motor-control signals needed for the muscles for a hand grasp, for example; similarly the same and/or a nearby fascicle may support a plurality of corresponding sensory-nerve pathways and thus sensory signals that provide the brain with feedback for the hand grasp).
Applying an electrical signal across or into a neuron (nerve cell), or a nerve bundle or nerve, is one way to stimulate a nerve action potential (NAP), either in a single neuron (nerve cell), or in a plurality of neurons within a nerve bundle, or within a nerve (the combined signals of NAPs in a nerve bundle or nerve are referred to as a compound nerve action potential (CNAP)). Applying an optical signal (e.g., a short relatively high-power pulse of infrared (IR) laser light, for example at a signal wavelength about 1.9 microns) is another way to stimulate a NAP.
U.S. patent application Ser. No. 12/018,185 filed Jan. 22, 2008, titled "Hybrid Optical-Electrical Probes" by Mark P. Bendett and James S. Webb, which is incorporated herein by reference in its entirety (and which issued as U.S. Pat. No. 7,883,536 on Feb. 8, 2011), describes an optical-signal vestibular-nerve stimulation device and method that provides different nerve stimulation signals to a plurality of different vestibular nerves, including at least some of the three semicircular canal nerves and the two otolith organ nerves. In some embodiments described in that patent application, balance conditions of the person are sensed by the implanted device, and based on the sensed balance conditions, varying infrared (IR) nerve-stimulation signals are sent to a plurality of the different vestibular nerves. Also described is a method that includes obtaining light from an optical source; transmitting the light through an optical fiber between a tissue of an animal and an optical transducer, and detecting electrical signals using conductors attached to the optical fiber. The application also describes an apparatus that includes an optical source, an optical transmission medium operatively coupled to the optical source and configured to transmit light from the optical source to respective nerves of each of one or more organs of an animal, an electrical amplifier, and an electrical transmission medium integral with the optical transmission medium and operatively coupled to the electrical amplifier, wherein the electrical transmission medium is configured to transmit an electrical signal from the respective nerves to the electrical amplifier.
One way to treat deafness in a person is to implant a cochlear-stimulation device (frequently called a cochlear implant) that senses sound in the environment (e.g., using a microphone) and then generates a combination of different electrical signals in different locations in the person's cochlear inner-ear structure. Because it is difficult to confine the electric field of each one of a large number of separate electrical signals, each intended for a particular one of a large number of separate nerves, e.g., among those nerves that extend in the bundle from the cochlea into the brain (it is possible to generate CNAP responses in perhaps only sixteen different nerve pathways (channels)), this conventional approach can provide only a crude representation of normal hearing.
U.S. Pat. No. 6,921,413 issued Jul. 24, 2005 to Mahadevan-Jansen et al., titled "Methods and devices for optical stimulation of neural tissues," and U.S. patent application Ser. No. 11/257,793 filed Oct. 24, 2005 by Webb et al., titled "Apparatus and method for Optical Stimulation of Nerves and Other Animal Tissue," are each incorporated herein by reference in their entirety. Both of these describe optical stimulation of nerves in general.
U.S. Patent Application Publication No. US 2006-0161227, of Walsh et al., titled "Apparatus and Methods for Optical Stimulation of the Auditory Nerve," is incorporated herein by reference in its entirety. This application describes a cochlear implant placed in a cochlea of a living subject for stimulating the auditory system of the living subject, where the auditory system comprises auditory neurons. In one embodiment, the cochlear implant includes a plurality of light sources {Li}, placeable distal to the cochlea, each light source being operable independently and adapted for generating an optical energy, Ei, wherein i=1, . . . , N, and N is the number of the light sources, and delivering means placeable in the cochlea and optically coupled to the plurality of light sources, {Li}, such that in operation, the optical energies {Ei} generated by the plurality of light sources {Li} are delivered to target sites, {Gi}, of auditory neurons, respectively, wherein the target sites G1 and GN of auditory neurons are substantially proximate to the apical end and the basal end of the cochlea, respectively.
U.S. Patent Application Publication No. US 2005 0004627 titled "Auditory midbrain implant" filed by Peter Gibson et al. on Aug. 26, 2004 is incorporated herein by reference. This application describes an electrode array that is implantable within the inferior colliculus of the midbrain and/or other appropriate regions of the brain of an implantee and adapted to provide electrical stimulation thereto. The electrode array an elongate member having a plurality of electrodes mounted thereon in a longitudinal array. A delivery cannula for delivering the electrode array comprised of two half-pipes is also described.
There is a need for efficacious apparatus and methods for optically, or optically and electrically, stimulating auditory nerve and/or brain tissue in a living animal in order to generate a nerve action potential (NAP) in one neuron (nerve cell), or in multiple neurons within a nerve bundle or nerve (where the combined individual NAPs form a compound nerve action potential, or CNAP), or similar physiological response in the animal. Optical or electrical-and-optical stimulation of neurons can provide more precision in terms of stimulating a particular nerve pathway than is possible using only electrical stimulation.

Optical stimulation of the brainstem and/or midbrain, including auditory areas


A data processor (200) has a pipelined execution unit (120). Whether a first instruction is one of a class of instructions wherein as a result of execution of the first instruction the contents of an operand register will be stored in a destination register is determined. A second instruction that references the destination register is received before a completion of execution of the first instruction. The second instruction is executed using the contents of the operand register without stalling the second instruction in the pipelined execution unit (120).

Some data processors use a technique known as pipelining for higher performance. Pipelining is a technique that breaks down the instruction processing task into smaller, modular sub-tasks each of which can be performed during a particular atomic period of time known as a pipeline cycle. By breaking down the task into these smaller cycles data processors can, for example, be fetching one instruction while executing another and while writing back the results of a third instruction into the register file. Thus even though individual instructions may take several cycles to complete, the overall throughput can approach one instruction per pipeline cycle.
Modern microprocessors have more sophisticated pipelines than this three-stage example. For example, a five-stage pipeline may include fetch, decode, operand access, execute, and writeback stages. The longer the pipeline, the more complicated the data processing instruction can be while still maintaining the throughput close to one instruction per cycle.
A problem arises, however, when certain sequences of instructions occur. A particular sequence of instructions may cause what is known as a pipeline dependency. One type of pipeline dependency, known as an operand dependency, occurs when one instruction cannot be executed until the result of execution of a previous instruction is available. For example, assume the instruction sequence:                ADD R2, R0, R1        ADD R3, R1, R2in which the first register is the destination of the result, and the second and third registers store the input operands. Since R2 is the destination register of the first ADD instruction, the execution of the second ADD instruction depends on the outcome of the first ADD instruction and cannot occur until the results of the first ADD instruction are known.
Another type of dependency is known as a load dependency. For example, assume the instruction sequence:                MOV R0, (R1)        ADD R3, R0, R2In this sequence, the first instruction loads register R0 with the contents of memory pointed to by the address stored in register R1. Obviously correct execution of the ADD instruction depends on the new value of register R0 being available.
Mike Johnson et al. in U.S. Pat. No. 4,734,852 disclose a method in which a bypass path can be used to forward the results of an earlier memory load operation to a subsequent instruction without having to first write it to the destination register in the register file and then read it from the register file. Thus the new register value is available much earlier and the pipeline stall time after a load dependency can be minimized.
However in some data processors which have deep execution pipelines it would require significant additional circuit area to add bypass paths from every pipeline stage that produces results to the input of the pipeline to forward intermediate results so that new instructions can issue earlier. This is especially true in floating point execution units in which the operand may be, for example, 64 bits long. Furthermore some results are simply not available until the instruction has reached the end of the pipeline.
Accordingly, it would be desirable to take advantage of additional opportunities for reducing the negative impact of dependencies without adding excessive circuit area. These and other desirable features and characteristics of the present invention will become apparent from the subsequent detailed description and the appended claims, taken in conjunction with the accompanying drawings and the foregoing technical field and background.

Method and data processor with reduced stalling due to operand dependencies


An invention is disclosed for classifying a graphic—e.g. as text or non-text. In embodiments, machine learning is used to generate a solution for classifying graphics of a graphic based on providing the machine learning system a plurality of graphics that are already classified. The way to determine a classification is then used by a remote presentation session server to classify tiles of frames to be transmitted to a client in a remote presentation session. The server encodes the tiles based on their classifications and transmits the encoded tiles to the client.

In a remote presentation session, a client computer and a server computer communicate across a communications network. The client sends the server locally-received input, such as mouse cursor movements and keyboard presses. In turn, the server receives this input and performs processing associated with it, such as executing an application in a user session. When the server performs processing that results in output, such as graphical output or sound, the server sends this output to the client for presentation. In this manner, applications appear to a user of the client to execute locally on the client when, they in fact, execute on the server.
The amount of graphical output generated by a remote presentation server (frequently referred to as a plurality of "frames") often taxes or exceeds the bandwidth available between the server and the client. In view of this, its common for the server to encode the graphical output in a way that compresses it before sending the encoded graphical output to the client. There are many problems with prior techniques for compressing graphical output in a remote presentation session, some of which are well known.

Image type classifier for improved remote presentation session compression


A multimode electronic measuring instrument is provided that includes a ratiometric mode of operation. During the ratiometric mode, a desired dimension is established as a stored reference dimension Xref. After the reference dimension is stored in memory, subsequent ratiometric measurement readouts will equal a current measurement distance Xcurr divided by the reference dimension Xref. A persistent number of decimal places used to the right of the decimal point as seen on a display is determined based on a current reference dimension Xref, an increment used for the least significant digit, and an internal measurement resolution of the multimode electronic measuring instrument.

Most electronic calipers, dividers, and the like that are currently in use provide measurements only in conventional length or angle units such as inches, millimeters, degrees, or radians. Furthermore, devices that provide such measurements, particularly in the case of commercially-available electronic calipers, have become near-commodities. Elements such as the user-controlled functions, the number and spacing of the buttons to activate the functions, and the dimensions of the electronic housing and the LCD display portion have settled into a narrow range of configurations. These configurations provide the manufacturability, economical, functionality, and ergonomic factors that are expected or required by a majority of manufacturers and users of electronic calipers. As such, manufacturers and users are reluctant to accept design variations that may have undesirable effects, such as increasing the user-controlled functional complexity, increasing the number of buttons or decreasing their ergonomic spacing, increasing the ergonomic dimensions of the electronic housing, or decreasing the ergonomic visibility of LCD display elements, etc., even to a moderate extent.
If such undesirable effects are taken into account and mitigated during the design of electronic calipers, however, additional features may be added and accepted in new designs. An example of such a feature on an electronic caliper may be found in commonly-assigned U.S. Pat. No. 7,246,032, to Feldman (hereinafter "the '032 Patent"), herein incorporated by reference in its entirety. The '032 Patent discloses an electronic caliper with a ratio-measuring mode. In the ratio-measuring mode, a ratio is determined from a reference measurement and a current measurement, such that the current measurement is divided by the reference measurement to display a ratio of the two measurements. Using an electronic caliper in this way allows a user to measure not only a ratio of dimensions of physical objects, but also a ratio on scaled drawings or other blueprint type plans, for example. As the caliper arms are moved, the current measurement changes and so, too, does the ratio displayed on the screen.

Display configuration for multimode electronic calipers having a ratiometric measurement mode


Apparatus and method for positioning a wireless device. In one embodiment, a method for indoor positioning includes determining a reference location of a wireless device, based on satellite positioning, as the device passes between areas of satellite positioning signal reception and satellite positioning signal non-reception. While in the areas of non-reception, signals transmitted by wireless local area network (WLAN) access points (APs) and parameters of motion of the device are measured. Positions of the device are estimated while in the areas of non-reception based on the reference location and the parameters of motion. A positioning grid for positioning is generated based on the signals measured by the wireless device at the estimated positions.

As mobile devices proliferate, the demand for services tailored to device location also increases. Location based services depend on positioning systems to determine device location. Satellite based positioning systems, such as the global positioning system (GPS), GLONASS, and Galileo can provide high accuracy, but require a clear line of sight between the satellites and the mobile device to provide a position determination. Consequently, satellite positioning systems are largely ineffective for indoor positioning. Satellite positioning also requires specialized receivers that may increase the cost of the mobile device.
As an alternative or an augmentation to satellite based positioning, wireless local area network (WLAN) based positioning systems have been developed. WLAN based positioning systems are suitable for indoor positioning and require minimal investment because they make use of existing infrastructure. Furthermore, many mobile wireless devices include support for communication via WLAN. Systems that provide improvements in indoor positioning are desirable.

Apparatus and method for indoor positioning


An embodiment is a semiconductor device comprising a receiver circuit comprising fin field effect transistors (FinFETs), a transceiver circuit comprising FinFETs, and a transmit bus electrically coupling the receiver circuit and the transceiver circuit, wherein the receiver circuit and the transceiver circuit each further comprises an electrostatic discharge protection circuit comprising planar transistors electrically coupled to the transmit bus. Other embodiments may further comprise a power clamp electrically coupling a first power bus and a first ground bus, a power clamp electrically coupling a second power bus and a second ground bus, or at least two diodes electrically cross-coupling the first ground bus and the second ground bus. Also, the planar transistors of the transceiver circuit and the receiver circuit may each comprise a planar PMOS transistor and a planar NMOS transistor.

Fin field effect transistors (FinFETs) continue to be used more often in semiconductor technology as the size of technology decreases. Unfortunately, FinFETs are generally more susceptible to device failures from electrostatic discharge (ESD) events because of their relatively small channel width. Therefore, a solution is needed to overcome this problem.
FinFETs are considered three-dimensional transistors because of their physical structure. The active area of the FinFET—the drain, channel, and source—protrude up from the surface of the semiconductor substrate upon which the FinFET is located, much like a rectangular box. Also, the gate structure wraps around the channel, usually on three sides but sometimes on two sides.
FinFETs are advantageous in smaller technologies because of their relatively higher drive current when compared to devices of similar size and because of their general ability to prevent short-channel effects. FinFETs generally have increased drive currents because the gate wraps around the channel such that the effective width of the channel is increased. The increased channel width allows for a greater drive current. Further, by having the gate wrap around the channel, the gate can suppress leakage current through the channel more easily, thus decreasing short channel effects.
The advantages of FinFETs have led to their use in smaller technologies, particularly 32 nm and smaller, but the trade-off for smaller size has led to an increased susceptibility of failure for FinFETs during ESD events. The active area width of a FinFET is much smaller than that of another device of corresponding technology size. The smaller width leads to increased current density in the FinFET when an ESD event occurs. For example, FinFETs typically have a maximum of 0.1 mA/μm before device breakdown occurs as compared to approximately 2 mA/μm for planar bulk MOSFETs or approximately 1.4 mA/μm for planar SOI MOSFETs. This increased current density may cause the dielectric gate oxide to breakdown between the active area and the gate causing a short between the gate and the active area. Thus, the FinFET may experience complete failure.
ESD events are generally categorized into three different modes, the Human Body Mode (HBM), the Machine Mode (MM), and the Charged Device Mode (CDM). In HBM, generally a person will have a charge stored on him or her. Then the person will touch a pin on a semiconductor package discharging the stored charged onto the semiconductor chip. Ideally, circuitry within the chip will conduct the current away from the internal devices on the chip and drain the current to ground. HBM is generally the lowest magnitude of voltage of the three modes, but usually the longest in duration. Similar to HBM, in MM, a machine, usually considered to be a metal machine, will have a charge stored on it. The machine will contact a pin of a semiconductor package discharging the stored charge. Again, internal circuitry should conduct the current away from components in the chip and to ground. MM is usually between HBM and CDM in magnitude of voltage and duration. In CDM, a charge will build up on the chip itself. The internal circuitry of the chip attempts to direct the current to some power bus such that the current can then be directed away from other internal devices of the chip and drained away to a pin on the package. CDM is typically the highest voltage magnitude with the shortest duration of discharge.
During this CDM discharge is when FinFETs are most susceptible to device failure because of the high voltage magnitude discharged during the ESD event. Thus, there is a need in the prior art for a device to protect FinFETs during CDM ESD events.

Taiwan Semiconductor Manufacturing Company, Ltd.


A container for stacked food products, such as potato chips, is provided. The container includes composite laminate that includes one or more layers of cardboard. The container has a non-circular shape. The container has a horizontal cross-section with end portions that have a constant radius along their length and side portions that have a changing radius along their length wherein the end portions and the side portions transition between each other continuously.

The subject disclosure is related to containers that store stacked food products, such as stacked potato chips. It is desired to construct the container with materials that are recyclable. A significant constraint for elongate containers for stacked food products is resistance to implosion, which is a design constraint for food products that are packaged at a relatively high altitude and low relative humidity, and then transported to locations with low altitude and high relative humidity. This specification discloses a design for a container for stacked food items that is made from recyclable materials and is strong enough for significant changes in differential pressure across the container, such as the reasonable worst case differential pressure due to the elevation, temperature, and humidity extremes that can be found in the United States.


A cable connector assembly for high frequency applications having reduced electromagnetic emissions. Aspects include providing physical spacing and electrical isolation between the signal conductors and a conductive housing. An isolative member provides reduced capacitive coupling. One embodiment includes spring preloading of the electrical connector relative to the housing. One embodiment includes a connector floating longitudinally within a conductive housing.

Electromagnetic interference affects the performance of electrical circuits. Reduction of sensitivity to EMI, as well as the reduction of radiated levels of EMI, is an important consideration in the design of electrical circuits and devices. With increasing power levels and frequency, radiated emissions also rises. Conversely, circuits operating with reduced power levels are particularly sensitive to undesirable radiation.
Designers often rely on gaskets and other shielding measures to reduce EMI radiated emissions. An area of particular interest concerns EMI emission suppression for high density interconnects. Density refers to the number of electrical connections in a given area of a connector. A typical high density connector has 100 pins in the space having dimensions of approximately 38 mm by 10 mm, or an area of 3.8 cm2. An example of an application calling for such a connector is the High Performance Parallel Interface-6400 (HIPPI-6400) protocol. HIPPI-6400 relates to high frequency, digital data transmissions at 6400 Mbit/s of data per direction.
Two types of emissions are common to electronic systems: common mode (CM) and differential mode (DM). Common mode emissions are referenced to earth ground and can be caused by current on the outer surface of a shielded component. This current can be caused by capacitive coupling between the internal current carrying components (signal connector pins, traces or wires) and the shielding components (cable shield or backshells). Because of poor bonding between the different parts of the shielding system or inadequate thickness of the shielding, this current may find its way to the outer surface of the shield and can cause radiated emissions. This radiation can result in failure of a system or component to meet applicable EMI compliance standards.
For the reasons stated above, and for other reasons stated below which will become apparent to those skilled in the art upon reading and understanding the present specification, there is a need in the art for a connector assembly to address the problem of undesirable EMI emissions without adversely effecting the electrical connection.

Electromagnetic interference cable backshell assembly for high-density interconnect


An operating means such as for example a crown, with an element rigid with the housing and with an operable element which is movable with respect to this. Between these two elements there is arranged a lip seal with an elastic lip, which bears on the element rigid with the housing and delimits the timepiece inner space to the surroundings. By way of the fact that the lip is led in the direction of the surroundings conically onto the element rigid with the housing and lies on this element with pretensioning, on the one hand with an inner space excess pressure it may release itself from the element rigid with the housing for the purpose of pressure compensation between the inner space and the surroundings and on the other hand with a surrounding excess pressure it is more strongly pressed on the element rigid with the housing for the purpose of sealing the inner space with respect to the surroundings.

The present invention relates to an operating means with a seal, for a timepiece, according to the introductory part of claim 1. For sealing operating organs of a timepiece usually O-rings are applied. Since these do not always seal the inside of the timepiece to a satisfactory degree, already for some time there has been undertaken a variety of efforts to develop seals with improved sealing properties, in that the cross sectional shape of the O-rings has been dropped.
From CH 562 468 a dust-tight crown for timepiecees is known, which comprises an elastically deformable sealing packing with an S-shaped bent cross sectional shape. Although this sealing packing in comparison to O-rings on the side of the inner space is formed out differently than on the side which faces the surroundings, this packing acts roughly equally in both directions, i.e. that on excess pressure in the timepiece inner space it has a similar sealing behaviour as with a excess pressure in the surroundings.
On the one hand a packing of such a shaping ensures that a formation of a considerable excess pressure in the inside of the timepiece cannot occur since it comprises a tapering packing part which in such a situation comes away from the wall of the bore.
If however the pressure of the surroundings of a timepiece equipped with such a crown increases, for example on diving, then this packing likewise only puts up a small resistance to the penetration of matter into the inside of the timepiece on account of the shaping of the mentioned packing part.
Furthermore this solution has the disadvantage that on placing back the winding axis, from the hand setting position into the basic position, particles of dirt from the tapering packing part may be co-transported into the inside of the timepiece. By way of the contamination of the sealing region the danger of penetration of water is also considerably larger.
Furthermore such a crown requires an exact length setting and assembly of the winding-up shaft.
With CH 453 221 there is shown an operating organ with an L-shaped seal which comprises a conical sealing surface which is in contact with the outer walling of a sleeve arranged in the timepiece housing. This sleeve is formed conically so that the placing of the crown onto the sleeve can be carried out simply. In the placed-on condition the sealing is deformed so far that the conical sealing surface blends into a cylindrical one and accordingly bears on the sleeve over the whole circumference with a close fit, and with a relatively large pretensioning. For the purpose of an additional increasing of the bearing force the sealing is designed in a manner such that it broadens towards the inside in the direction to the axis.
As a rule the solution implies a differing sealing behaviour in both directions, however it has the effect that it only prevents penetration of matter into the inside of the timepiece in a limited manner and that a rapid reduction of excess pressure in the timepiece is not possible.
According to CH 324 259 between a bore in the crown and the outer walling of the sleeve there is arranged a sealing ring with a V-shaped cross section in whose wedge-shaped annular groove there is arranged a metal ring which is axially impinged by a spring. By way of the spring pressure the two arms of the V-shaped sealing ring are radially expanded in order to produce a bearing force on the one hand with respect to the sleeve and on the other hand to the bore of the crown.
Also with this solution there may arise a considerable excess pressure on the inside of the timepiece.
Furthermore CH 304 789 shows sealing disks which in each case bear on an annulus-shaped surface in a deformed manner and under pretension.
Although with this solution a reduction in excess pressure in the timepiece is possible, narrow limits are set to the axial path of the winding-up shaft.
Moreover also an exact length setting of the winding-up shaft is required.

Operating means with a seal, for a timepiece


The invention provides novel polynucleotides and polypeptides associated with the incidence of PPAR-agonist induced edema. The invention also provides polynucleotide fragments corresponding to the genomic and/or coding regions of these polynucleotides which comprise at least one polymorphic locus per fragment. Allele-specific primers and probes which hybridize to these regions, and/or which comprise at least one polymorphic locus are also provided. The polynucleotides, primers, and probes of the present invention are useful in phenotype correlations, medicine, and genetic analysis. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing said polynucleotides and/or polypeptides. The invention further relates to diagnostic and therapeutic methods for applying these novel polynucleotides and polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders, particularly PPAR-agonist induced edema or related indications. The invention further relates to screening methods for identifying agonists of PPAR proteins with decreased risk of inducing peripheral edema in patients.

The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor nucleic acid sequences (Gusella, Ann. Rev. Biochem., 55:831-854 (1986). The variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form, or may be neutral. In some instances, a variant form confers a lethal disadvantage and is not transmitted to subsequent generations of the organism. In other instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. In many instances, both progenitor and variant form(s) survive and co-exist in a species population. The coexistence of multiple forms of a sequence gives rise to polymorphisms.
Several different types of polymorphism have been reported. A restriction fragment length polymorphism (RFLP) is a variation in DNA sequence that alters the length of a restriction fragment. The restriction fragment length polymorphism may create or delete a restriction site, thus changing the length of the restriction fragment. RFLPs have been widely used in human and animal genetic analyses. When a heritable trait can be linked to a particular RFLP, the presence of the RFLP in an individual can be used to predict the likelihood that the animal will also exhibit the trait.
Other polymorphisms take the form of short tandem repeats (STRs) that include tandem di-, tri- and tetra-nucleotide repeated motifs. These tandem repeats are also referred to as variable number tandem repeat (VNTR) polymorphisms. VNTRs have been used in identity and paternity analysis, and in a large number of genetic mapping studies.
Other polymorphisms take the form of single nucleotide variations between individuals of the same species. Such polymorphisms are far more frequent than RFLPs, STRs and VNTRs. Some single nucleotide polymorphisms (SNPs) occur in protein-coding nucleic acid sequences (coding sequence SNP (cSNP)), in which case, one of the polymorphic forms may give rise to the expression of a defective or otherwise variant protein and, potentially, a genetic disease. Examples of genes in which polymorphisms within coding sequences give rise to genetic disease include: globin (sickle cell anemia), apoE4 (Alzheimer's Disease), Factor V Leiden (thrombosis), and CFTR (cystic fibrosis). cSNPs can alter the codon sequence of the gene and therefore specify an alternative amino acid. Such changes are called "missense" when another amino acid is substituted, and "nonsense" when the alternative codon specifies a stop signal in protein translation. When the cSNP does not alter the amino acid specified the cSNP is called "silent".
Other single nucleotide polymorphisms occur in noncoding regions. Some of these polymorphisms may also result in defective protein expression (e.g., as a result of defective splicing). Other single nucleotide polymorphisms have no phenotypic effects. Single nucleotide polymorphisms can be used in the same manner as RFLPs and VNTRs, but offer several advantages.
Single nucleotide polymorphisms occur with greater frequency and are spaced more uniformly throughout the genome than other forms of polymorphism. The greater frequency and uniformity of single nucleotide polymorphisms means that there is a greater probability that such a polymorphism will be found in close proximity to a genetic locus of interest than would be the case for other polymorphisms. The different forms of characterized single nucleotide polymorphisms are often easier to distinguish than other types of polymorphism (e.g., by use of assays employing allele-specific hybridization probes or primers).
Only a small percentage of the total repository of polymorphisms in humans and other organisms has been identified. The limited number of polymorphisms identified to date is due to the large amount of work required for their detection by conventional methods. For example, a conventional approach to identifying polymorphisms might be to sequence the same stretch of DNA in a population of individuals by dideoxy sequencing. In this type of approach, the amount of work increases in proportion to both the length of sequence and the number of individuals in a population and becomes impractical for large stretches of DNA or large numbers of persons.
The renin-angiotensin-aldosterone system (RAAS) represents an endocrine system that plays a fundamental role in cardiovascular function by regulating extracellular fluid volume and sodium balance. Activation of RAAS is triggered with the release of renin from the kidney, resulting in proteolytic cleavage of angiotensinogen to angiotensin I (AT1). AT1 is converted to angiotensin II (AT2) by angiotensin-converting enzyme (ACE). Additional non-renin and non-ACE-dependent mechanisms also exist for the production of AT2 directly from angiotensinogen and from AT1. Binding of AT2 to the angiotensin II receptor type 1 (AT2R1) stimulates the production of the steroid hormone aldosterone which mediates its effects through the mineralocorticoid receptor (MLR), promoting renal sodium retention and potassium loss.
Dysregulation of RAAS is associated with a number of disease states including renal injury and most forms of hypertension. Modulation of RAAS has been achieved clinically with compounds that suppress AT2 and aldosterone production (e.g. ACE inhibitors, AT2R1 blockers) as well as compounds that suppress aldosterone action (e.g. MLR antagonists).
Thiazolidinediones (TZDs) are high affinity PPARγ ligands which induce the expression of genes involved in glucose homeostasis and insulin sensitivity. PPARγ is expressed primarily in adipose tissue, where much of its antidiabetic actions are believed to be manifested. However PPARγ plays a significant role in vascular tissues as well. Expression of PPARγ has been detected in endothelial cells as well as vascular smooth muscle cells. PPARγ also plays a role in macrophages where its induction results in anti-inflammatory responses via inhibition of iNOS, MMP9 and scavenger receptor A genes. PPARγ has also been shown to play significant anti-inflammatory roles in monocytes and in atherosclerotic plaques.
An observed, adverse event associated with PPARγ-agonist treatment is the development of dose-dependent peripheral edema. Although the underlying mechanism is currently unknown, PPAR-agonist induced edema is believed to arise through direct action on the kidney (Hollenberg N K, Am J Med 115(8A):111-115 (2003)). Several lines of evidence have implicated a role for PPARγ agonists in the modulation of RAAS. In vascular smooth muscle cells, treatment with PPARγ agonists was shown to antagonize the transcription of the AT2R1 receptor, resulting in both reduced AT2R1 mRNA and protein levels (Sugawara et al., Endocrinology 142:3125-3134 (2000); Takeda et al., Circulation 102:1834-1839 (2000)). Moreover, animal model studies have shown that treatment with TZDs, including pioglitazone and rosiglitazone, mitigated hypertension in AT2-infused rats, in part, via inhibition of AT2R1 and induction of angiotensin II receptor type 2 (Diep et al., Circulation 105:2296-2302 (2002)). As RAAS plays a fundamental role in fluid volume homeostasis, it is conceivable that modulation of other components of this system, by PPAR agonists, might contribute to agonist-induced edema mechanism of action.
The endothelins (ETs) constitute a family of three separate genes (ET-1, ET-2, ET-3) that encode tissue-specific precursor peptide products (Gianessi et al., 2001). All three ET isoforms are proteolytically processed to generate 21 amino acid vasoactive peptides. ET-1 is the predominant isoform that is secreted by vascular endothelial cells in response to endothelial cell activators such as thrombin, TNF-α and angiotensin II (Gianessi et al., 2001; Delerive et al., 1999).
Endothelin-1 (ET-1) plays a role in a number of biological processes including monocytic chemotaxis, induction of endothelial cell adhesion molecules as well as vascular tone maintenance (Gianessi et al., 2001; Delerive et al., 1999). ET-1 is the most potent vasoconstrictor known and, as such, plays a important role in blood pressure elevation in several animal models of hypertension (Schiffrin, 2001). ET-1 also participates in salt and water homeostasis via cross-talk with the Renin-Angiotensin-Aldosterone-System (RAAS) (Agapitov and Haynes (2002)
Elevated ET-1 secretion is associated with a number of clinical states including hypertension, atherosclerosis, heart failure and renal failure (Luscher and Barton, 2000). Hyperinsulinemia and/or insulin resistance is also associated with increased ET-1 secretion from vascular endothelial cells in vitro and in vivo (Satoh et al., 1999). ET-1 receptor antagonists possess hypotensive effects in animal models of hypertension (Luscher and Barton, 2000) and in patients with essential hypertension (Satoh et al., 1999). Taken together, these observations suggest that elevated ET-1 may play a role in type 2 diabetes-associated hypertension (Satoh et al., 1999).
Recent studies have shown that ET-1 secretion is suppressed by PPARα and -γ agonists in endothelial and vascular smooth muscle cells (Fukunaga et al., 2001; Delerive et al., 1999; Satoh et al., 1999). The underlying mechanism of action is through negative interference of PPARα and -γ with the Activator Protein-1 signaling pathway (Delerive et al., 1999), which regulates ET-1 transcriptional activity (Kawana et al., 1995). This inhibition may contribute to the hypotensive effect observed with PPAR-agonist treatment in diabetic patients (Satoh et al., 1999).
The roles described above for ET-1 in vascular tone maintenance, along with its involvement in numerous cardiovascular disease processes suggest ET-1 may potential be involved in PPAR-agonist induced edema mechanism of action.
Genetic polymorphisms in members of the renin-angiotensin-aldosterone system, in addition to other proteins described herein, may cause alterations in the level of renin or its related peptides, or may affect downstream signal transduction. Genetic polymorphisms in ET-1 may also cause alterations in the level of ET-1 or its related peptides, or may affect downstream signal transduction. Such polymorphisms may genetically predispose certain individuals to an increased risk of developing edema, particularly in response to PPAR-agonist induced therapy. Such polymorphisms are expected to show a significant difference in allele frequency between individuals treated with a high dose of a PPAR-agonist who do not exhibit edema and individuals treated with a PPAR-agonist who do exhibit edema. Genotypes of such polymorphisms can predict each individual's susceptibility to edema, and thus will be useful in identifying a group of high risk individuals that may be subject to modified PPAR-directed treatment regimens. Alternatively, the identification of such a group may preclude one or more individuals within said group from being administered an PPAR-directed agonist or antagonist.
Moreover, the present invention also provides, for the first time, strong supporting evidence that renin expression is specifically upregulated and endothelin-1 expression is specifically downregulated in response to PPAR-agonist treatment and thus serves as an effective predictive marker for PPAR-agonist efficacy in addition to aiding in the identification of individuals at risk of developing PPAR-agonist induced dose-dependent peripheral edema.
The β-adrenergic receptor family consists of three genes (β1, β2, β3) that encode membrane-bound G-protein coupled receptors (Dzimiri et al., 1999). All three receptor subtypes respond to extracellular signals by increasing intracellular cAMP levels via G-protein dependent adenylyl cyclase activation. Increased cAMP levels activate cAMP-dependent protein kinase A (PKA), which, in turn, phosphorylates a variety of target proteins to elicit cellular responses (Castellano and Bohm, 1997; Dzimiri et al., 1999)
In cardiac tissue, β-adrenergic signaling enhances overall cardiac output by increasing heart rate and contractility in response to catecholamine-induced receptor stimulation. These effects are brought about by PKA-dependent phosphorylation of target genes that are essential for cardiac function including L-type calcium channels, phospholambin-a, troponin I and myosin binding protein C. (Lohse et al., 2003; Bengtsson et al., 2001; Dzimiri, 1999). Together, these target proteins mediate their effects through the regulation of calcium activity (e.g. availability and sensitivity) in cardiomyocytes. Although both β1 and β2 contribute to these cardiac effects, most of the functional effects are mediated through β1 subtype (Lohse et al., 2003) β1 also mediates other cellular responses relevant to cardiac function including transient relaxation of blood vessels (Chruscinski et al., 2001) and activation of RAAS by enhancing renin secretion in the kidneys (Dzimiri et al., 1999).
The roles described above for β1-adrenergic receptor in regulating cardiac performance directly within cardiomyocytes as well as indirectly via actions on kidney function suggest that the β1-adrenergic receptor may be associated with the mechanism of action of PPAR-agonist induced edema.
Genetic polymorphisms in the β1-adrenergic receptor may cause alterations in the level of the β1-adrenergic receptor or its related peptides, or may affect downstream signal transduction. Such polymorphisms may genetically predispose certain individuals to an increased risk of developing edema, particularly in response to PPAR-agonist induced therapy. Such polymorphisms are expected to show a significant difference in allele frequency between healthy individuals and edema subjects. Genotypes of such polymorphisms can predict each individual's susceptibility to edema, and thus will be useful in identifying a group of high risk individuals that may be subject to modified PPAR-directed treatment regimens. Alternatively, the identification of such a group may preclude one or more individuals within said group from being administered an PPAR-directed agonist or antagonist.

Method of identifying a PPARgamma-agonist compound having a decreased likelihood of inducing dose-dependent peripheral edema


In the copy prevention apparatus and its method, it is discriminated whether an object is legally copied or not; a constant event is generated at or below a predetermined probability; and an abnormal operation is executed only if the two conditions of the object having been determined as an illegal copy, and the event having been generated, are satisfied. Therefore, even if the object is determined as an illegal copy, the abnormal operation is not always executed, but executed at or below a predetermined probability. Although the occurrence of the abnormal operation can be indicated to the user immediately, it is also preferable to keep the abnormal operation occurrence secret for a time and inform the user of the occurrence an appropriate time later.

1. Field of the Invention
the present invention relates to a copy prevention apparatus and a method of preventing intellectual property such as computer software or semiconductor circuits form being copied illegally.
2. Description of the Prior Art
In software on the market for personal computers, a special countermeasure against illegal copying has been conventionally provided for the memory medium. For example, copy program operation is disabled by inhibiting part of memory medium from being read by ordinary methods. Furthermore, even if software is copied without copying the inhibited part of the memory medium, when the inhibited part can be read normally at the start of software or when the erroneous phenomenon caused when the inhibited part is not read, is different from that determined by the original software, the program is stopped because the software itself determines that the program has been copied illegally.
Furthermore, in the case of semiconductor circuits such as microprocessors, unnecessary gates disabled by ion implantation have been conventionally provided by copy prevention, so that when the gates are copied, the circuit will not operate normally.
In the prior-art software copy prevention method, however, even if some countermeasure has been considered for the memory medium, since violators who copy software, compare the illegally copied software with the original, and improves the copying means by repeatedly analyzing the difference between the two until the copied software can operate normally, it has been difficult to prevent software from being illegally copied in this manner.
On the other hand, in the case of software, since the value of software cannot be recognized until the software is actually used, when the software is protected perfectly, there exists a problem in that the user must purchase software for which value is unknown at the risk of disuse.
Furthermore, in the case of semiconductor circuits, violators who want to copy the circuits can realize the circuits on bread boards as they are by repeatedly searching for the causes when the circuits do not operate normally.
As described above, in the prior-art software copy prevention method, new methods of removing the copy protection are always being sought and therefore a vicious and meaningless cycle of protection development and protection removal is repeated. On the other hand, there exists another problem in that the value of software is recognized only after the software has been tested. Therefore, there exists a strong need for providing a more perfect means for preventing intellectual property such as software or semiconductor circuits from being copied illegally.

Copy prevention apparatus and method therefor


Techniques are described for identifying patterns of memory cells in a memory array that are predictive of non-correctable errors (“corruption patterns”). The techniques described herein identify patterns of cell errors that are likely to generate errors that cannot be corrected by an error correction code (ECC). The identification of non-correctable cells is accomplished by identifying a pattern of cell errors storing bit values that deviate from corresponding expected values. The pattern of these memory cells and various combinations of the cells in the pattern are compared to patterns of cells that are known to be correctable using ECC. If the error pattern or one or more of the combinations of erroneous cells in the pattern are not associated with patterns that are correctable via ECC, the error pattern is identified as predictive of a likely uncorrectable error.

Dynamic random access memory (DRAM) is generally constructed from regular arrays of memory cells (e.g., deep trench capacitors), each of which stores a charge state that indicates a single bit of data that is either a "1" or a "0." A single DRAM device (i.e., an electronically packaged integrated circuit die) may include millions or billions of individual cells. The individual cells within each device may be arranged in a hierarchy of blocks of cells.
In some cases, the charge state stored in a memory cell is unintentionally switched from the stored (written) state to an erroneous state that is different from the stored state, thereby unintentionally creating an erroneous bit value in the cell. These so called "soft errors" may be caused by an encounter between a memory cell and a cosmically originating particle, naturally occurring radiation from the decay of materials used in the fabrication of electronic devices, among other causes. A processor in communication with a memory device may execute error correcting code (ECC) algorithms that use metadata stored in a memory device to identify errors in the corresponding stored data. For example, ECC algorithms may identify cells in a memory region that store a bit value different than the bit value originally written to that cell. Some errors are correctable in that various techniques may be used to restore the written value to the memory cell. Other errors are not correctable.
The approaches described in this section are approaches that could be pursued, but not necessarily approaches that have been previously conceived or pursued. Therefore, unless otherwise indicated, it should not be assumed that any of the approaches described in this section qualify as prior art merely by virtue of their inclusion in this section.

Identifying non-correctable errors using error pattern analysis


The present application discloses a verification platform for a system on chip and a verification method thereof, the method comprises: constructing a simulation verification environment for the system on chip; creating a bus function model unit, and binding the bus function model unit to the same interface at which a central processing unit being connected to the bus; creating an Universal Verification Methodology test instance, and performing the Universal Verification Methodology test instance by the bus function model unit to implement the system on chip test; creating a plurality of software test instances; and compiling the software test instances, and performing the compiled software test instances by the central processing unit to implement the system on chip test.

SoC (system on chip) technology refers to a technology for integrating all system techniques and corresponding components (such as one or more of: central processing unit(s), bus(es), memor(ies), IP (Intellectual Property) core module(s), Input/Output (I/O) peripheral(s), etc.) into a single chip to provide a system. SoC technology can effectively reduce product area, improve product performance, reduce product power consumption and improve product reliability, so it has been widely used. However, due to the high cost of the chip, in order to ensure the functionality and performance of the SoC chip, there is a need of a large amount adequate verification before chip taping out.
There are two verification methods for the SoC chip in the prior art. One method is to perform test through the CPU, which needs technicians to implement software code, CPU booting and other processes in the verification platform in advance, and then start the simulation. This verification method requires each verification engineer to have an in-depth understanding of the CPU, especially the assembly language. Moreover, it may take a certain amount of time for the development of software code, the CPU booting and other processes, so the start of verification is delayed. When the CPU executes the software code, it has to firstly run the same booting process before starting the test program, which affects the verification progress. The other method is to perform test through Universal Verification Methodology Cases, which cannot reuse software test program.

Verification platform for system on chip and verification method thereof

MONTAGE LZ TECHNOLOGIES (Chengdu) Co., Ltd.


A method of forming an organic semiconductor includes forming a thin film transistor (“TFT”) backplane; forming a pixel well over the TFT backplane using a photoresist; performing a first plasma etch of the pixel well; stripping the photoresist in the pixel well; performing a second plasma etch of the pixel well; performing a first wash of the pixel well; exposing the pixel well to ultraviolet light; performing a second wash of the pixel well; and forming an organic photodiode in the pixel well.

Organic semiconductors, including image sensor circuits, have many potential advantages over traditional amorphous silicon-based semiconductors. The chemicals used in the photodiode for the image sensor circuit can be tailored to be sensitive to different frequencies ranging from ultraviolet to infrared. The chemical films have lower stress and lower process temperatures; thus, working well with lower temperature applications, such as flexible substrates.
Manufacturing of individual organic photodiodes on a substrate to create photo sensing arrays remains a challenge. The thin film transistor ("TFT") backplane upon which the organic photodiode is deposited must be free of any organic or inorganic residue, such as residual photoresist, etch process compounds and must be very planar. This is especially important when making a photo sensitive array. If the surface is not free of any residue, then the organic chemical will not have sufficient electrical contact with the bottom electrode of the TFT backplane. This will cause non-repeatable performance from the photo sensing array from one process run to another. If the TFT backplane electrode is not planar, then the organic material may not completely cover the electrode and possible electrical shorts will result. Even if the organic material is able to cover the uneven electrode surface, performance of the organic material will be inconsistent and unrepeatable.
What is desired is an improved process of cleaning and optimizing the surface of the TFT backplane to ensure repeatable performance of an organic semiconductor.

Method of optimizing an interface for processing of an organic semiconductor


A processing executing apparatus includes: a display; a storage that stores group identifying information for identifying a first group of a plurality of groups; a communication device communicable with a server that stores user information corresponding to each of users and at least including group belonging information indicating which group each of the users belongs; and a controller. The controller executes: a first receiving processing in which the controller receives, from the server, user information including the group belonging information indicating the first group identified by the group identifying information stored in the storage; and a first display processing in which the controller controls the display to display at least one operation button for each user corresponding to the user information received in the first receiving processing. The at least one operation button is for instructing execution of at least one processing.

Technical Field
The following disclosure relates to a processing executing apparatus capable of executing at least one processing and a non-transitory storage medium storing a plurality of instructions readable by a computer of the processing executing apparatus.
Description of the Related Art
Many processing executing apparatuses have a shortcut function. The processing executing apparatus having the shortcut function stores shortcut information relating to a setting condition required for execution of various processings and controls a display to display an operation button related to the shortcut information, i. e., a shortcut icon. When the shortcut icon is operated, the processing executing apparatus executes a processing based on the shortcut information corresponding to the operated shortcut icon. Use of the shortcut function reduces the number of user operations. There is known a technique in which a user stores shortcut information customized for him or her into the processing executing apparatus.

Processing executing apparatus displaying operation buttons and non-transitory storage medium storing instructions readable by the processing executing apparatus displaying the same


In a general aspect, medical images are segmented by a medical image segmentation system. In some aspects, a medical image segmentation method includes obtaining a medical image comprising a series of images; obtaining a surrogate context based on a support set of images; identifying a query set of images; providing the surrogate context, the support set of images and the query set of images as inputs to a machine learning process; and segmenting the query set by operation of the machine learning process executed on a computer system, wherein executing the machine learning process produces segmentation information of the query set. The support set of images includes a first subset of the series of images and the query set of images includes a second subset of the series of images.

The following description relates to segmenting medical images.
Medical images are generated by many types of imaging platforms, for example, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) technologies, to name a few. Medical images are often segmented to identify anatomical features of an imaging subject.


A system for cooling a reductant injector in an emissions module is provided. The system includes an emissions module, coupled to an engine exhaust duct, and a cooling system fluidly coupled to the emissions module. The emissions module includes a reductant system and a selective catalytic reduction (SCR) module. The reductant system includes a reductant injector having a cooling passage. The cooling system includes a reservoir tank, a supply pump fluidly coupled to the reservoir tank, and a siphon tank fluidly coupled to the supply pump and the reductant injector cooling passage. The siphon tank is disposed proximate to the reductant injector, and a gravitational elevation of a base of the siphon tank is greater than a gravitational elevation of the reductant injector.

Exhaust aftertreatment systems are used to chemically convert or physically remove constituents from a combustion engine exhaust stream. Operation of such exhaust aftertreatment systems may benefit from the ability to inject a fluid into the exhaust stream. For example, some catalytic converters used for selective catalytic reduction (SCR) require injection of reductant into combustion exhaust upstream of the catalyst to effect the desired chemical species conversion. Similarly, regeneration of a diesel particulate filter (DPF) may benefit from upstream injection of a combustible fluid into the exhaust stream. In these cases, a fluid injector would be located upstream of each device.
The fluid injector may include a valve located between a pressurized fluid supply and an injector nozzle, where the injector nozzle is exposed to the exhaust stream. In such an injector, minimizing the distance from the injector valve to the injector nozzle tip may be advantageous with respect to injection spray characteristics and mechanical packaging considerations, but can result in detrimental overheating of the injector valve. Further, overheating of residual fluid within the injector can cause detrimental corrosion or boiling within the injector.
Flow of the fluid through the injector can transfer heat away from the injector. However, some system operating modes may require the injector valve to close for significant time durations, thereby stopping the flow of the fluid through the injector. Accordingly, cooling the injector with the fluid may not be sufficient across all operating modes for an exhaust aftertreatment system.
U.S. Pat. No. 7,877,990 discloses a metering device cooling system including a cooling circuit having a cooling device that transfers heat out of the cooling circuit, where at least a part of the cooling circuit is disposed below the cooling device and at least another part of the cooling circuit is disposed above a point where heat is added to the cooling circuit. However, the need for a cooling device adds undesirable complexity, and may require vehicle motion to drive sufficient heat transfer.
Accordingly, improved apparatus and methods for cooling injectors that are mounted on a combustion engine exhaust duct are desired.


System, method and computer program product for background compensation of a digital image containing at least one first object, the at least one first object having received at least one molecule comprising genetic information, and at least one second object, the at least one second object not having received a molecule comprising genetic information, the at least one molecule being configured to receive a fluorescent compound, the digital image being determined by an optical imaging system during emission of electromagnetic radiation by the fluorescent compound.

The present invention relates to systems and methods for background compensation of a digital image containing at least one first object and at least one second object. More particularly, the present invention relates to background compensation of a digital image being determined by an optical imaging system during emission of electromagnetic radiation by a fluorescent compound, preferably for DNA/RNA-sequencing, wherein autofluorescence effects play a role.
Biotechnology, medicine and related technical fields are based on the analysis of molecules. Electronic devices can analyse molecules with high precision and specificity. Especially in last years, automated electronic devices have been developed for analysing large numbers of samples by routine methods. For example, modern DNA sequencing apparatus are used for routine analysis of large numbers of DNA probes. Protein samples can be analysed by high throughput screening and related methods. Frequently, such electronic devices detect fluorescent signals emitted from the sample probes. This is possible when molecules, such as nucleic acids or proteins, have been labelled with fluorescent compounds such as dyes.
Commercially available sequencing apparatus are capable of sequencing large numbers of samples labelled with fluorescent dyes in parallel. Recently developed methods, referred to as "next-generation sequencing", NGS, have revolutionized sequencing. NGS allows the massively parallel sequencing of clonally amplified or single DNA molecules that are spatially separated in a flow cell or by generation of an oil-water emulsion. NGS allows thousands or even millions to billions of sequencing reactions to be performed simultaneously.
In NGS, sequencing is performed by repeated cycles of polymerase-mediated nucleotide extensions or, in one format, by iterative cycles of oligonucleotide ligation. As a massively parallel process, NGS generates hundreds of megabases to gigabases of nucleotide-sequence output in a single instrument run, depending on the platform. The inexpensive production of large volumes of sequence data is the primary advantage over conventional methods. NGS platforms and common applications/fields for NGS technologies are e.g. reviewed in Voelkerding et al, Clinical Chemistry 55:4 641-658, 2009 and Metzker, Nature Reviews/Genetics Volume 11, January 2010, pages 31-46.
In NGS, various oligonucleotides of interest are covalently attached to a support. Subsequently, a nucleotide labelled with a fluorescent dye is attached to the growing oligonucleotide chain with DNA polymerase. When the four nucleotides are labelled with different fluorescent dyes, fluorescent signals emitted from a probe can be detected and the type of nucleotide attached to the oligonucleotide can be identified. After detection, the fluorescent dye is cleaved off and the next synthesis cycle is carried out, in which a new labelled nucleotide is attached to the growing chain. By carrying out multiple cycles, the sequence of a growing oligonucleotide chain can be determined in a stepwise manner. The working steps are carried out in an automated sequencing apparatus.
US 2010/0323350 A1 and WO 2009/117119 A1 relate to methods and compositions for determining the identity of nucleic acids in nucleotide sequences using, for example, data obtained from sequencing by synthesis methods.
WO 2008/097455 A1 relates to an imaging system for exciting and measuring fluorescence on or in samples comprising fluorescent materials, e.g. fluorescent labels, dyes or pigments, in particular to detect fluorescent labels on nucleic acid. Moreover, a device is disclosed being configured such that fluorescent labels in a plurality of different DNA templates are simultaneously detected.
WO 2014/020137 A1 relates to a method for enriching target sequences from a sequencing library to provide a target enriched sequencing library, wherein the sequencing library is suitable for massive parallel sequencing and comprises a plurality of double-stranded nucleic acid molecules.
Fluorescent signals emitted from sample probes with labelled molecules are weak, but the signals have to be detected with high precision and specificity. Thus, precise optical equipment, especially cameras and scanning technology, is required for such processes.
In addition, extensive evaluation of the digital images captured by an optical imaging system of the sequencing apparatus is necessary for obtaining a precise and reliable result of the sequencing, e.g. in FASTQ.
The observed signal intensities, as determined from the optical imaging system, can be considered to be a sum of independent contributions, e.g. autofluorescence and fluorescence, signal intensity. Further, these intensities are additionally attenuated by a vignetting effect due to uneven illumination and the optical system. In conventional systems without background compensation, these effects lead to a decreased precision in the information obtained from the image, that is, in the precision of the base call in DNA/RNA-sequencing.
It is an object of the invention to provide a method and a system, which overcomes the above mentioned problems of the prior art. In particular, one object is to determine and remove the autofluorescence signal from each observed signal in order to allow a robust and reliable processing in subsequent processing steps.
This object is achieved with the features of the independent claims. The dependent claims relate to further aspects of the invention.
The method according to the present invention is computer-implemented. However, it is understood by the skilled person that there are also other ways of implementing the method according to the present invention.
In one aspect of the present invention a method for background compensation of a digital image containing at least one first object is provided. The at least one first object having received at least one molecule comprising genetic information, and at least one second object, the at least one second object not having received a molecule comprising genetic information. The at least one molecule is configured to receive a fluorescent compound. The digital image is determined by an optical imaging system during emission of electromagnetic radiation by the fluorescent compound. The method comprises the following steps, preferably in the following order:
a) determining first intensity values from the digital image for each object;
b) determining second intensity values from the digital image for the at least one second object within a plurality of predetermined areas;
c) computing median intensity values from the second intensity values for each of the plurality of predetermined areas;
d) interpolating the median intensity values to the size of the original digital image;
e) computing background compensated intensity values for each object by subtracting the interpolated median intensity values from the determined first intensity values.
The objects statuses are preferably determined beforehand and inputted into the method as known parameters. In addition, the object positions are preferably determined from a corresponding white-light image beforehand and might be inputted into the method as known parameters.
The at least one first object is preferably one live-bead having received at least one DNA strand and the at least one second object is preferably one blank-bead not having received a DNA strand. The DNA strand is preferably a single stranded DNA fragment. Such beads are commercially available e.g. from Thermo Fisher Scientific Inc., e.g. under the brand Dynabeads, see reference [1].
Preferably each DNA strand is configured to receive molecules, preferably nucleotides. The nucleotides preferably comprise a cleavable fluorescent compound and a cleavable cap. It is further preferred that the molecules are a plurality of four different molecules each having a fluorescent compound specific for each of the four different molecules.
Each of the plurality of cycles is preferably characterized in that one of the four molecules is attached to one of the DNA strands, wherein the cleavable cap ensures that only one molecule is attached to one DNA strand during one cycle.
It is preferred that for each cycle a plurality of pictures, preferably four, are taken, one for each of the four fluorescent compounds attached to the molecules. It is further preferred that the four fluorescent compounds have one of a main emission spectra in the red, blue, yellow or green spectral regime.
After each of the cycle, the cleavable cap and the fluorescent compound, e.g. a fluorescent dye, are removed so that another molecule can be attached to the DNA strand in the next cycle.
The optical imaging system preferably comprises of an illumination device, e.g. an LED, to activate the fluorescent compound(s) and a detection system, e.g. a CCD detector, to detect the emission spectra of the fluorescent compound(s).
Each of the predetermined areas preferably comprises a plurality of pixels of the original digital image. The predetermined areas correspond to the predetermined positions of the at least one second object. It is preferred that the size of the predetermined areas is approximately the size of the at least one second object, e.g. 2.8 pixel.
The method may further comprise arranging the computed median intensity values in a topological grid structure, preferably a median matrix, based on a position of the at least one second object within the plurality of predetermined areas.
The method might further comprise applying a region growing approach to the computed median intensity values of the plurality of predetermined areas. That is, the method might further comprise applying a region growing approach to the median matrix. A region growing approach might be advantageous to increase the stability of the method, because empty elements in a corresponding matrix representation might be filled.
In particular, empty elements in the median matrix may be present if one or more predetermined area(s) of the plurality of predetermined areas do not contain a second object, i.e. a blank bead. Thus, for that (those) predetermined area(s) no second intensity value is determined and therefore the respective element of the median matrix is empty.
Preferably, the method further comprises applying a median filter to the computed median intensity values of the plurality of predetermined areas. That is, the method further comprises applying a median filter to the median matrix.
It is also preferred that the method further comprises applying a Gaussian filter to the computed median intensity values of the plurality of predetermined areas. That is, the method further comprises applying a Gaussian filter to the median matrix.
Interpolating the median intensity values to the original digital image size preferably comprises a bilinear interpolation. That is, after the interpolation, there is a corresponding median intensity value for each pixel in the original digital image. Even though a bilinear interpolation is preferred, the person skilled in the art knows that other interpolation algorithms might be applied just as well.
The at least one object might be a bead preferably being configured to receive DNA and/or RNA. As already outlined above, the objects might be beads for receiving DNA/RNA strands, which then receive the molecules with their cleavable caps and cleavable fluorescent compounds, e.g. fluorescent dye.
According to a further aspect of the present invention, a computer program product is provided, wherein the computer program product comprises one or more computer readable media having computer executable instructions for performing the steps of the above described method.
According to yet another aspect of the present invention a system for background compensation of a digital image containing at least one first object is provided. The at least one first object having received at least one molecule comprising genetic information, and at least one second object, the at least one second object not having received a molecule comprising genetic information. The at least one molecule is configured to receive a fluorescent compound. The digital image is determined by an optical imaging system during emission of electromagnetic radiation by the fluorescent compound. The system is preferably configured to carry out the steps of any of the method steps described above. The system comprises an intensity determining unit configured to determine first intensity values from the digital image for each object and second intensity values for the at least one second object within a plurality of predetermined areas and a computation unit configured to compute median intensity values from the second intensity values for each of the plurality of predetermined areas and to compute an interpolation of the median intensity values to the original digital image size and to compute background compensated intensity for each object by subtracting the interpolated median intensity values from the determined first intensity values.
The computation unit might further be configured to arrange the computed median intensity values in a topological grid structure, preferably a median matrix, based on a position of the at least one second object within the plurality of predetermined areas.
The computation unit might further be configured to apply a region growing approach to the computed median intensity values of the plurality of predetermined areas. That is, the computation unit might further be configured to apply a region growing approach to the median matrix. As outlined above, the region growing approach might be applied in order to fill empty elements of a matrix representation of the median intensity values.
The computation unit is preferably further configured to apply a median filter to the computed median intensity values of the plurality of predetermined areas. That is, the computation unit is preferably further configured to apply a median filter to the median matrix.
The computation unit is can further be configured to apply a Gaussian filter to the computed median intensity values of the plurality of predetermined areas. That is, the computation unit is can further be configured to apply a Gaussian filter to the median matrix.
Computing of the interpolation might comprise a bilinear interpolation.
Thus, the present invention considers the challenging variance of the intensities by local processing and robust handling of outlier intensities, e.g. by the usage of the median.
FIG. 1 illustrates a system according to the present invention. The system comprises an intensity determining unit 100 and a computational unit 200 according to an exemplary embodiment of the present invention. The units are configured to execute one or more of the steps of the present invention. While the present invention is described using two independent units 100, 200, it is apparent that the independent units can also be part of one single "master" unit.
In a preferred embodiment of the present invention the intensity determining unit 100 is configured to determine first intensity values from the digital image for each object and second intensity values for the at least one second object within a plurality of predetermined areas.
The computation unit 200 is configured to compute median intensity values for each of the plurality of predetermined areas and to compute an interpolation of the median intensity values to the original digital image size and to compute background compensated intensity for each object by subtracting the median intensity values from the determined first intensity values.
The functionality of the intensity determining unit 100 and the computation unit 200 will be further described in terms of method steps in the following preferred embodiments of the present invention. It is obvious for a person skilled in the art that the following description of method steps gives rise to corresponding functions of the intensity determining unit 100 and the computation unit 200.
FIG. 2 illustrates a typical intensity level for a live-bead (first object) and a blank-bead (second object) with the presence of autofluorescence. The blank-bead intensity is shown on the left side of the graph and the live-bead intensity is shown on the right side of the graph (separated by the dashed line). As can be seen, the intensity level of the blank-bead is not zero, as should be the case in an "ideal" case. However, the presence of emitted fluorescent light leads to autofluorescence even at the position of blank-beads. At the position of the live-bead, the intensity level that stems from autofluorescence is added to the intensity value due to the emission of fluorescence light ("DNA" signal).
In accordance with the present invention it is assumed that the first objects (live-beads) and second objects (blank-beads) are classified beforehand, i.e. it is determined beforehand which objects have received DNA strands and which do not. In other words, the classification of the beads, whether they are able to receive nucleotides with a fluorescent compound or not is already known to the method and system of the present invention and might be inputted into the intensity determining unit and/or the computational unit 200.
In a first step of the exemplary embodiment, the determination of median intensity values based on a sub-tile approach is executed. For this, the bead intensities are sorted in a grid, depending on the bead positions and bead state by using only blank-beads. That is, the autofluorescence typically is extracted from blank-beads, which are not populated with DNA. Based on the bead-positions a spatial grid is formed in order to ensure local processing, which reduces the impact of the vignetting effect. Here, the typical spatial resolution which is mapped on one grid element is 64×64 pixels. That is, one grid for each blank-bead position. However, the computation time might be saved by only taking a predetermined number of grids into account.
Next a median matrix is calculated by computing the median intensity value for each grid-cell (sub-tile). The median is used in order to compensate for outliers, thus to improve the robustness. Here outliers can originate from misclassified beads, e.g. when live-beads have been erroneously classified as blank.
Subsequently, empty elements of the median matrix are filled by a region growing approach, if necessary.
A surface smoothing might be applied in order to eliminate possible extreme values in the resulting median matrix by applying a median filtering (3×3), which might be followed by applying a Gaussian filter.
As the image has been subdivided into a plurality of grids the matrix of median intensity values has to be upscaled to the original image size, e.g. by bilinear interpolation in order to allow the extraction of a median value for each bead. That is, the goal is to have a corresponding median value (autofluorescence) for pixel of the original digital image. Therefore, the median matrix (e.g. 52×39) is enlarged by bilinear interpolation to the original digital image size (e.g. 3296×2472 pixels).
Finally, the background correction for each bead intensity is performed by subtracting the corresponding median intensity value from the original intensity value. If computational power and time is not of the essence, the subtraction might be done for every pixel of the digital image. However, it is sufficient to only subtract the corresponding median intensity value from the original intensity value for each bead position as the bead positions.
The forgoing method steps of the preferred embodiment have been described as relating to DNA/RNA sequencing. However, as will be apparent to the person skilled in the art the present invention is not restricted to this field. It is clear that the solution of the present invention can be applied to numerous other technical fields, where fluorescent images are used and autofluorescence effects play a role. That is, the objects do not have to be beads as in this exemplary embodiment, but can also be any kind of fluorescent emitting objects in an image, wherein autofluorescence effects are present due to the fluorescent nature of the objects.
As the present invention may be embodied in several forms without departing from the scope or essential characteristics thereof, it should be understood that the above-described embodiments are not limited by any of the details of the foregoing descriptions, unless otherwise specified, but rather should be construed broadly within the scope as defined in the appended claims, and therefore all changes and modifications that fall within the present invention are therefore intended to be embraced by the appended claims.
Furthermore, in the claims the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single unit may fulfil the functions of several features recited in the claims. The terms "essentially", "about", "approximately" and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively.


A foreground statistic with respect to a distribution of image values in a foreground region and a background statistic with respect to a distribution of image values in a background region are calculated. Image values of a plurality of input images that are captured at different times are corrected based on the foreground statistics and the background statistics which are obtained by processing the input images.

1. Field of the Invention
The present invention relates to an image processing apparatus, an image processing method, and a non-transitory storage medium.
2. Description of the Related Art
In the medical field, there have recently been proposed various image processing technologies for making images captured and acquired under different conditions look substantially in the same manner for higher repeatability of image diagnosis.
Japanese Laid-Open Patent Publication No. 2004-097331 discloses a method of and an apparatus for generating feature quantities (e.g., a histogram) of a target area and normalizing the density distribution of an image based on the relationship between the generated feature quantities and reference feature quantities (hereinafter referred to as "reference data"). The publication states that the density distributions which are different depending on apparatus types or settings can be approximated to a method and apparatus.

Image processing apparatus, image processing method, and non-transitory storage medium


A method of managing resources dedicated to a content object in a content delivery network includes transcoding and storing the content object in one or more of a plurality of delivery formats, and associating a transcoding profile with the content object, the transcoding profile including records of the content object with respect to delivery of the content object to end users across the plurality of delivery formats. The method also includes periodically executing a process that determines, utilizing the transcoding profile, an elapsed time since a most recent delivery of the content object in a particular delivery format to one of the end users, and deletes a copy of the content object in the particular delivery format when the elapsed time exceeds a threshold.

Video and audio content that is provided over networks (e.g., the Internet) to a variety of end user systems typically must be transcoded into a variety of formats for compatibility with the end user systems. For example, mobile devices often require different video formats than laptop or desktop computers, and different video formats than each other. The need for transcoding introduces a variety of challenges for institutions such as content delivery networks, that store and provide large quantities of content, especially when such content is in high demand. However, indefinite storage of large quantities of transcoded content in multiple formats can consume a high amount of network storage resources.

Lazy transcoding and re-transcoding of media objects in an online video platform


Some embodiments include an apparatus having a well region extending into a semiconductor substrate. A first conductive element is over the well region, and a second conductive element is over the first conductive element. A hole extends through the first conductive element. A connecting element extends from the second conductive element to the well region, and passes through the hole.

Integrated arrangements may include multiple conductive levels over a semiconductor substrate. The conductive levels may be vertically stacked relative to one another such that some conductive levels are under other conductive levels. The conductive levels may comprise wiring or other conductive structures. It may be desired to form an interconnect which extends from a conductive structure of an upper conductive level, through one or more of the lower conductive levels, and to an underlying structure (for instance, a diffusion region associated with the semiconductor substrate). It can be difficult to form such interconnects. If the interconnects serpentine around conductive wiring within the lower conductive levels, the interconnects will be long and will have higher resistance (i.e., increased IR drop) than would shorter interconnects. If instead the interconnects are formed to directly pass through underlying conductive levels, the interconnects will advantageously be short and have desired low resistance. However, the wiring within the underlying conductive levels may end up serpentining around the interconnects and accordingly will be lengthened and have higher resistance than if the wiring were shorter.
It would be desirable to develop new integrated arrangements in which interconnects extend from a conductive structure of an upper conductive level, through one or more lower conductive levels, and to an underlying structure; while avoiding the problems discussed above.

Apparatuses having an interconnect extending from an upper conductive structure, through a hole in another conductive structure, and to an underlying structure


A sealing system for a flow channel includes a mandrel, a swellable element disposed about the mandrel, and a degradable polymeric element disposed on a surface of the swellable element and configured to delay swelling of the swellable element. The degradable polymeric element comprises one or more of the following: polyurethane; cured cyanate ester; an epoxy; polyimide; unsaturated polyester; or nylon.

Isolation of downhole environments depends on the deployment of a downhole tool that effectively seals the entirety of the borehole or a portion thereof, for example, an annulus between a casing wall and production tube. Swellable packers are particularly useful in that they are capable of generating a contact force against a nearby structure when exposed to one or more downhole fluids such as water, oil, or a combination thereof. Compared with mechanically setup packers and inflatable packers, fluid-swellable packers are easier to set up.
Oil swellable packers normally contain an elastomer such as EPDM that expands when exposed to hydrocarbon based fluids. EPDM rubber often swells rapidly in the oil or oil based fluids and can seal a borehole within one or two days at elevated temperatures. However, under certain circumstances, it is desirable to delay the swelling of the packers to allow the operator to have more time to carry out various completion operations. Such delayed swelling period can be a few days or weeks.
One possible solution is to dispose an outer layer on an EPDM elastomer core to regulate the amount of well fluids that can reach the elastomer core thus controlling the swelling rate of the core. While such proposed packers may have a delayed swelling rate, the outer layer can prevent the core from reaching its full expansion potential and adversely affect the formation of an effective seal. Thus, alternative sealing elements having controlled swelling are desired in the art.

Packers having controlled swelling and methods of manufacturing thereof