A joint of a patient is scanned using MRI apparatus, and images of the joint area are produced as a body part of the patient is moved into a particular position known to cause a problem in the joint. The patient may walk or run on a treadmill during the process, or the body part may be supported on a surface causing or allowing such movement.

1. Field of the Invention
This invention relates to forming images of joint structures, and, more particularly, to forming such images as body members connected to the joint structures are moved.
2. Summary of the Background Information
Magnetic resonance imaging (MRI), which is additionally called nuclear magnetic resonance imaging (NMRI), or magnetic resonance tomography (MRT), is a medical imaging technique used to visualize internal structures of the body, making use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body in a process known to create more detailed images of the human body than possible with X-rays. A conventional MRI scanner includes a large, powerful magnet, extending around a cavity in which the patient 108 lies, while a magnetic field formed by the magnet aligns the magnetization of certain atomic nuclei within the body, and while radio frequency magnetic fields are applied to systematically alter the alignment of this magnetization. This causes the nuclei within certain atoms in the body to produce a rotating magnetic field detectable by the scanner, which in turn causes information to be recorded for constructing an image of the scanned area of the body. Magnetic field gradients cause nuclei at different locations to process at different speeds, allowing spatial information to be recovered using Fourier analysis of the measured signal. By using gradients in different directions, two-dimensional images or three-dimensional volumes can be obtained in any arbitrary orientation. The resulting images display good contrast between the different soft tissues of the body, making the MRI process especially useful in imaging the brain, muscles, heart, and cancers compared with other medical imaging techniques such as computed tomography (CT) or X-rays. Furthermore, an important advantage for MRI arises from the fact that unlike CT scans or traditional X-rays, MRI does not expose the patient to ionizing radiation.
For some time it has been possible to make moving images of the heart and other organs from MRI scans, with such images being displayed, for example, on the Internet. However, in the past, such images were reconstructed after completion of the scanning process by combining images derived from a number of repetitive actions (such as a heart beat occurring while the subject holds his breath) into a motion picture sequence.
More recently, a process, known as "Real-time MRI," has been developed for making pictures of moving objects using MRI in real time, so that the images are displayed during the scanning. Because the generation of image data was based on a time-consuming process of data reconstruction from scanned data, in what is known as 'k-space," real-time MRI was formerly possible only with low image quality or low temporal resolution. In the past such images could only be formed at a rate of about one per second.
This limitation has now been eliminated, particularly through the use of an iterative reconstruction algorithm that alleviates problems caused by undersampling, and with radial FLASH MRI, in an improved process offering rapid and continuous data acquisition, motion robustness, and tolerance to undersampling. In particular, improved techniques integrates the data from multiple receive coils, in a process also known as parallel MRI, and exploits the redundancy in a sequence of images, reducing the effects of data undersampling by an order of magnitude, so that high-quality images may be obtained from of as little as 5 to 10% of the data required for a normal image reconstruction. For example, a temporal resolution of 20 to 30 milliseconds can now be achieved achieved, along with an in-plane resolution of 1.5 to 2.0 mm.
While, in principle this technique can be implemented with most current scanners, a practical limitation lies in the amount of computing power required to perform the real-time reconstruction of the images. Improvements in the algorithms used for image reconstruction and the use of parallel computer processors are significantly reducing time required to produce one minute of images displaying motion from one half hour.
The patent literature includes a number of examples of imaging apparatus and image data processing methods for increasing the speed at which images can be reconstructed and for increasing the resulting resolution of the images. For example, a magnetic resonance (MR) imaging apparatus and technique is described as exploiting spatial information inherent in a surface coil array to increase MR image acquisition speed, resolution and/or field of view. Partial signals arc acquired simultaneously in the component coils of the array and formed into two or more signals corresponding to orthogonal spatial representations. In a Fourier embodiment, lines of the k-space matrix required for image production are formed using a set of separate, preferably linear combinations of the component coil signals to substitute for spatial modulations normally produced by phase encoding gradients. The signal combining may proceed in a parallel or flow-through fashion, or as post-processing, which in either case reduces the need for time-consuming gradient switching and expensive fast magnet arrangements. In the post-processing approach, stored signals are combined after the fact to yield the full data matrix. In the flow-through approach, a plug-in unit consisting of a coil array with an on board processor outputs two or more sets of combined spatial signals for each spin conditioning cycle, each directly corresponding to a distinct line in k-space. This partially parallel imaging strategy, dubbed Simultaneous Acquisition of Spatial Harmonics (SMASH), is readily integrated with many existing fast imaging sequences, yielding multiplicative time savings without a significant sacrifice in spatial resolution or signal-to-noise ratio. An experimental system achieved two-fold improvement in image acquisition time with a prototype three-coil array, and larger factors are achievable with then coil arrangements.
In another example from the patent literature, a method of and system are described in which the method comprises acquiring a plurality of magnetic resonance signals from a receiver coil array placed about a subject in the MRI system, where the receiver coil array has a plurality of receiver elements arranged in rows and, during application of a readout gradient in a frequency encoding direction, shifting receiver frequencies by a selectable amount for each row of the array in order to shift a limited field of view in the frequency encoding direction.
In yet another example from the patent literature, an MRI system produces a three-dimensional. Image by acquiring NMR signals that fully sample a central region as a set of asymmetric radial sectors. The NMR signals are acquired with a plurality of receive channels and coils. An image is reconstructed using a homodyne reconstruction combined with SENSE nrocessine.
The patent literature further describes the use of a Halbach magnet array in place of the conventional, very large, horseshow magnet within MRI apparatus. In general, a Halbach magnet array is an arrangement of magnets that augments the magnetic field on one side of the arrangement while canceling the magnetic field, to nearly a zero level, on the other side.
FIG. 1 is a perspective view of MRI apparatus to described in prior art patent documents. The apparatus 10 includes a Halbach array 12 of magnetic structures 14 located at corners of a square, in which probe apparatus 17 is held to receive signals for processing. Each of the magnetic structures 14 includes a dipole magnet, generating a magnetic field extending transverse to its direction of elongation, indicated by arrow 16. Each of the magnetic structures 14 may include one or more permanent magnets, and may additionally or alternatively include one or more electromagnetic coils, which may be held within a tube filled, for example, with liquid helium to achieve superconductivity.
FIG. 2 is a schematic cross-sectional transverse view of the apparatus 10, taken in as indicated by section lines 2-2 in FIG. 1, with an arrow 18 showing a direction of the magnetic field extending transversely within each of the magnetic structures 14. Transverse magnetic fields 20 extend outward from each of the magnetic structures 14, with fields formed in the direction of arrow 22 a central region 24 surrounded by the magnetic structures 14 being strengthened, and with magnetic fields in a region 26 outside the Halbach array 12 being substantially reduced, as reflected in the increased distance between flux lines in the figure.
FIG. 3 is a schematic cross-sectional transverse view of the apparatus 10 showing the magnetic structures 14 oriented so the transverse magnetic fields within the magnetic structures 14 are oriented as shown by arrows 30 to produce a magnetic field in the direction of arrow 32 within the central region 24.
FIG. 4 is an elevation of a hand-held MRI probe 40, described in the patent literature, which includes a coil section 42 having an imaging coil It is noted that the lack of exposure to ionizing radiation during the MRI process makes it possible for an individual to remain with the patient during the process, and that the probe 40 can be held close to the tissues being scanned, with a resulting improvement in the quality of the images being produced.
d to allow a patient, as you described, show what was happening when he had a transient pain or discomfort. The main problem in making such pictures appears to be computer processing time to get the images ready for viewing, since it takes about a half hour to process about a minute of real time film, and limitations on the resolution of the images, which can be expected to limit the resolution of the images. The need for an open structure does not

Application and method for producing images of moving joints


An adjusting and interlocking unit for displaceable and pivotable doors and/or walls, which are guided to be movable at and/or in a roller rail via rollers, includes an upper part, attachable to the roller rail, a central part attachable to a movable carriage profile of a door respectively of a wall, and a lower part attachable to the door, respectively to the wall. A locking element allows for releasing or interlocking the doors and/or wall.

1. Field of the Invention
The invention relates to an arresting and an interlocking unit for displaceable and pivotable doors and/or walls, which are attached so as to be movable via rollers to/in a roller rail. Furthermore, the invention relates to a partition wall system, including a roller rail, two or more displaceable and pivotable doors and/or walls, which are guided to be movable via rollers at and/or in the roller rail, for each door or wall at least one movable carriage profile to which one or more rollers are attached, as well as an adjusting and interlocking unit for at least one of the doors or walls.
2. Description of the Related Art
A system composed of sliding walls, respectively sliding doors, includes fixedly mounted roller rails with corresponding rail branches which allow for displacing parts of or the entire unit disposed thereunder, in other words in particular one or more sliding leaves of the partition wall system, or to park them in a side position. This will always occur in the event a space, for example, needs to be separated or else if a space needs to be subdivided into several smaller spaces. Another application area of a partition wall system made from sliding walls, respectively sliding doors, is nowadays found more and more in the utilization of door wall elements in the area of restaurants and business premises. In this case, depending on the weather conditions, the entire door wall frontage can be removed or else only parts of the door frontage can be displaced or pivoted to the side.
Partition wall systems, respectively systems composed of sliding walls or sliding doors of this species, can be found in the documents DE 35 22 824 A1 as well as DE 31 48 464 A1. In order to be able to modify this type of installation fast and without major expenditure of forces, the partition wall elements, respectively the door wall elements, are equipped with so-called arresting devices, which are located at the upper end of an element and can be released or arrested by protracting, respectively retracting an interlocking device. However, this action becomes difficult, if, in case of high partition wall systems of more than 2 meters measured from above the ground, not every person will still be able to reach the interlocking device without the help of ladders or the like.
In currently known systems with displaceable and/or pivotable doors and/or walls, in particular in the area of horizontal sliding walls, respectively sliding doors, one element, respectively one swing/sliding leaf is currently secured by an arresting and interlocking unit, which includes two screws, wherein the screws are screwed by their thread into a corresponding counter-piece by a rotating movement. An arresting and interlocking unit of this species for displaceable and/or pivotable doors and/or walls is known for example from the document EP 0 562 073 B1. The arresting and interlocking unit consists of an upper part, a central part and a lower part, which are placed one below the other. The three parts are affixed to the outside of the door installation by fastening screws. In this case, respectively one screw for the arresting procedure and for the interlocking procedure is located in the unit. The screws are operated from the ground by an articulated handle, which, at its upper end, has a ball head hexagon socket screw wrench. Both the arresting screw and the interlocking screw can be screwed in or out by the ball head hexagon socket screw wrench.
If, for example a door, respectively a door wall element needs to be closed, the arresting screw, which is located in the central part of the unit, is screwed into the upper part of the unit by a rotating movement, which part is attached to the roller rail of the door wall system. Thereby, two parts of the unit, namely the upper and the lower parts, are connected to each other, and the door leaf cannot be laterally moved any more. In order to be able to secure the swung-out condition of the door leaf, so to say essentially vertically to the lateral displacement, the second interlocking screw, which is located in the lower part of the unit, can be screwed into the central part of the unit. The type of screw connection allows for arresting the entire door, respectively a door element. Upper, central and lower parts form one single unit.
Now, in case a swing/sliding leaf needs to be brought into a parking position, the arresting connection needs to be released correspondingly and the swing/sliding leaf can be displaced within the roller rail. In case only swinging of the swing/sliding leaf is desired, the connection of the arresting screw to the roller rail needs to be maintained. Furthermore, the arresting screw needs to be unscrewed from the central part, and the swing/sliding leaf, respectively the entire swing/sliding leaf frontage is not arrested in its pivoting range. Articulated handles are utilized for operating the screws. The potential of hazard when adjusting the arresting and interlocking devices is reduced to almost zero, in particular because no additional devices need to be used.
If, however, one of the screws is not properly screwed in, the thread of the corresponding screw is adversely affected. The circumstance may result in a complete deformation of the thread and thereby of the screw such that the corresponding screw cannot be screwed any more into the upper part or the central part. In particular on account of the order of operation, the ease of operation is not optimal. As a consequence, it is no longer possible to prevent a door or a wall from pivoting and/or from being displaced, such that the entire partition wall system becomes instable.

Arresting and interlocking unit for a partition wall system, as well as a partition wall system


A method of creating ultra tin body fully-depleted SOI MOSFETs in which the SOI thickness changes with gate-length variations thereby minimizing the threshold voltage variations that are typically caused by SOI thickness and gate-length variations is provided. The method of present invention uses a replacement gate process in which nitrogen is implanted to selectively retard oxidation during formation of a recessed channel. A self-limited chemical oxide removal (COR) processing step can be used to improve the control in the recessed channel step. If the channel is doped, the inventive method is designed such that the thickness of the SOI layer is increased with shorter channel length. If the channel is undoped or counter-doped, the inventive method is designed such that the thickness of the SOI layer is decreased with shorter channel length.

The present invention relates to semiconductor integrated circuit devices as well as their fabrication, and more particularly to ultra thin body, e.g., channel, fully-depleted silicon-on-insulator (SOI) metal oxide semiconductor field effect transistor (MOSFET) devices in which the threshold voltage variation of each device is controlled.
In semiconductor processing, silicon-on-insulator (SOI) technology is becoming increasingly important since it permits the formation of high-speed integrated circuits. In SOI technology, a buried insulating layer, especially a buried oxide, electrically isolates a top Si-containing layer from a bottom Si-containing substrate layer. The top Si-containing layer, which is oftentimes referred to in the art as the SOI layer, is generally the area in which active devices such as transistors are formed. Devices formed using SOI technology offer many advantages over the bulk counterparts including, for example, higher performance, absence of latch up, higher packing density and low voltage applications.
In the semiconductor industry, the SOI layer thickness has been scaled down in every SOI device technology generation. Current technology trends are for providing SOI devices that have ultra thin Si channels. Ultra thin Si channel devices, which are formed in the SOI layer, have demonstrated excellent scalibity. The term "ultra thin" is used throughout the present application to denote a channel region having a vertical thickness of less than about 20 nm.
It is also known that fully-depleted SOI MOSFET devices with doped channels typically have very large threshold voltage variations. The threshold voltage variations are effected by SOI thickness as well as well as the channel length variations that are a result of conventional device fabrication.
In conventional fully-depleted SOI devices, the silicon film thickness is usually less than or equal to half the depletion width of the bulk device. The surface potentials at the front and back interfaces are strongly coupled to each other and capacitively coupled to the front-gate and substrate through the front-gate dielectric and the buried oxide, respectively. Therefore, the potential throughout the silicon film, and hence the charge, is determined by the bias conditions on both the front-gate and the substrate. The large variation in threshold voltage mentioned above has prevented fully-depleted SOI MOSFETs to become mainstream manufacturable complementary metal oxide semiconductor (CMOS) technology. Because of the current trends in reducing the SOI thickness, partially depleted SOI devices are being pushed closer and closer to the fully-depleted mode.
SOI MOSFETs are often distinguished as partially depleted (PD) when the silicon film is thicker than the maximum gate depletion width, and fully developed (FD) when the silicon film is thin enough that the entire film is depleted before the threshold voltage condition is reached.
In the prior art, halo implantation can be used to create a device in which the channel-length is dependent upon the total charge doping concentration. A well-designed halo implant can create devices such that the channel doping is higher in short channel devices. As a result, the threshold voltage vs. gate length curve can be flatten out. Therefore, devices can be operated at much shorter channel lengths. This prior art method however cannot be extended any further because 1) the junction leakage current could be to high with high halo doping concentration; and 2) the doping fluctuation effect could dominate the threshold variations in narrow width devices.
In view of the prior art mentioned above, there is a need for providing a method of forming a fully-depleted SOI MOSFET device in which the threshold voltage variation with respect to SOI thickness and channel-length variations is minimized.

Ultra thin body fully-depleted SOI MOSFETs

International Business Machines Corporation


A device that estimates information from a signal includes a receiver for receiving an input signal and electronic processing circuitry. The electronic processing circuitry generates a matrix associated with the input signal and determines an approximation of an inverse of the matrix based on the adjoint of the matrix and a scaling factor associated with the determinant of the matrix. This approximation avoids possible mathematical difficulties that may be encountered in certain situations when a typical matrix inversion is calculated. The approximated inverse matrix is applied to the input signal to transform the input signal into an output signal. Information associated with the input signal is then determined based on the output signal.

Many signal processing applications use matrix-based calculations. One example is channel equalization in wireless communications. Example equalization techniques that use matrices include linear equalization techniques, such as generalized Rake (G-Rake) and chip equalization, frequency-domain linear equalization, linear turbo equalization, decision feedback equalization (DFE) that includes a linear, feedforward filter, and prefiltering, a form of partial linear equalization used, e.g., in GSM/EDGE, WiFi, WiMAX, and LTE. In addition to wireless systems, linear equalization techniques are used for wireline modems and magnetic recording. Another matrix-driven signal processing area is antenna array processing involving multiple receive antennas. Array processing and equalization are often performed together.
Consider the following example filter or weight computation taken from a linear equalization and array processing context, which is typical of the type of matrix-based calculations that modern signal processors must calculate. Received signal quantities, such as samples from different time delays and receive antennas or prefiltered quantities such as Rake-combined values, can be collected into a column vector x. This vector can often be modeled asx=hs+n, where s is a modulation symbol to be recovered, h is a channel response accounting for the effects of the transmitter, transmission medium, and receiver front-end, and n is a vector of noise and interference (impairment). A soft symbol estimate can be obtained by applying a filter or combining vector to the received vector x, givingŝ=wHxwhere superscript "H" denotes Hermitian transpose (conjugate transpose). The filter or weight computation involves solving a set of equations of the formRw=h,   (1)where R is a data or impairment covariance matrix, w is a vector of combining weights or filter coefficients, and h is a signal that represents a channel response associated with R. Equation (1) is typically solved one of two ways:
1) iteratively, using Gauss-Seidel, conjugate gradient, or other approaches, or
2) non-iteratively, by inverting R or using a factorization such as Cholesky factorization or QR decomposition.
The second approach is of interest here because it requires inverting the matrix R.
An inverted matrix computation also exists in some signal quality estimation computations, e.g., signal-to-interference-plus-noise ratio (SINR) or simply SIR. SINR may be estimated for a variety of applications including, in the example context of wireless communications, power control, rate adaptation, and as a metric for processing delay selection. If the weights w in equation (1) are used in a linear receiver, the signal quality can be estimated asSINR=hHR−1h=wHh=hHw   (2)Again, an inverted matrix R−1 must be calculated.
In addition to equalization and some signal quality determinations having to invert a matrix, linear multi-user detection techniques, such as linear minimum mean squared error (MMSE) and decorrelator detection, also involve inverting a matrix and applying the result to chip samples or despread symbols to demodulate the symbols transmitted. In this case, the matrix may consist of symbol waveform correlations or chip sample correlations.
The weights or filter coefficients are parameters combined with a received or other input signal in order to estimate some kind of information like received data symbols, SINR, position, direction-of-arrival, etc. Another parameter estimation application is channel estimation. Certain channel estimation techniques involve solving a set of equations or inverting a matrix. Examples include Wiener or MMSE channel estimation and recursive channel estimation, such as Kalman filtering and recursive least squares (RLS) filtering. With adaptive filtering, a matrix inverse is often updated recursively. A similar parameter estimation problem occurs in radar and sonar signal processing.
Signal processing applications like those examples described above that require inverting a matrix confront a numerical problem when the matrix R to be inverted is "ill-conditioned." An ill-conditioned matrix is one where the ratio of its largest eigenvalue to smallest eigenvalue is large. There are different possible approaches to address this problem. One is based on regularization where a small positive value is added to the diagonal of matrix R to improve the conditioning of R so that the matrix is easier to invert. A drawback with this approach is that the accuracy of the matrix calculation is affected, which potentially sacrifices some performance in the signal processing end result. Another approach is based on virtual noise where a second matrix Q is added to the matrix R. Matrix Q represents the covariance of an imaginary noise source (regularization can be viewed as a special case of virtual white noise). The difficulty is again selecting Q so that performance is not sacrificed. Noise corresponding to frequencies where there is no signal energy could be added, but that has limited application and efficacy. The third approach is based on singular value decomposition (SVD) equalization where the received signal is projected onto the major eigenvectors of its received covariance matrix. But this approach is complex, requiring calculation of eigenvalues and eigenvectors, and it also sacrifices performance.
What is needed is a simple and effective way to invert a matrix that can handle ill-conditioned numbers and still provide good performance across a wider variety of signal processing applications.

Signal processor for estimating signal parameters using an approximated inverse matrix


A CuInS2@ZnS nanomaterial synthesized with thiosalicylic acid and sodium citrate as dual-stabilizers is taken as a chemiluminescent luminophore, and Tris buffer containing both N2H4.H2O and H2O2 is taken as the triggering solution; introducing the H2O2 into the triggering solution can bring out greatly enhanced CL emission and obviously shortened CL process, enable the CuInS2@ZnS nanomaterial with strong flash-type and near-infrared CL; the luminophore of CuInS2@ZnS nanomaterial is synthesized by a one-pot method; compared with acridinium ester (a classical flash-type chemiluminescent substance), the CuInS2@ZnS nanomaterial is simple in synthesis method, mild in conditions and short in the required time, the synthesized CuInS2@ZnS nanomaterial is not easy to decompose under light, and the CL waveband is in the near-infrared region.

In recent years, inorganic nanomaterials have been applied widely in the field of electrochemiluminescence because of high quantum efficiency and adjustable band gap, such as CdSe quantum dots (Sens. Actuator B-Chem. 2016, 226, 444-449), CdTe quantum dots (Biosens. Bioelectron. 2019, 131, 178-184), CuInS2 nanomaterial (Anal. Chem. 2018, 90, 3563-3569) and Au cluster (Biosens. Bioelectron. 2021, 190, 113449). However, the reports on inorganic nanomaterials are very limited in the field of direct CL.
The previous patent documents of the inventor of the present invention disclose a method for preparing a CuInS2/ZnS nanomaterial with photoluminescence (PL) and CL characteristics (CN111944521A), and a general method for preparing a carboxylated CuInS2/ZnS nanomaterial with a CL characteristic (CN112940719A). In these documents, CL radiation can be generated in a near-infrared region by taking the CuInS2/ZnS nanomaterial as a chemiluminescent substance and hydrazine hydrate (N2H4.H2O) as a triggering reagent. However, if the above-mentioned liquid composition is applied to the field of CL immunoassay, the CL intensity of the liquid composition is far from enough, and the CL time is long, which is not good for rapid analysis.
As a typical flash-type CL representative, the acridinium ester CL liquid composition is CL generated from chemical reaction between acridinium ester and hydrogen peroxide, with high CL intensity and short CL time. However, the synthesis steps of acridinium ester are complicated, a synthesis period is long, and products are easy to decompose under light.
Therefore, it is of great significance to develop a flash-type CL liquid composition with photostability.

Flash-type chemiluminescence system based on CUINS2@ZNS nanomaterial


A digital feedback loop circuit achieves a resolution as good as the intrinsic resolution of the delay element of the circuit, notwithstanding the presence of a feedback counter/divider of integer value N that might otherwise be expected to multiply the minimum resolution by N. Output altering circuitry is used to alter the error feedback signal for M out of every N feedback cycles in such a way that the overall delay over N cycles can be controlled to within the resolution of the delay element. In one embodiment, the output altering circuitry includes a second counter whose maximum value is controllable and that outputs a signal whose value changes after its current maximum value has been reached. In another embodiment, the output altering circuitry includes a lookup table preloaded with sequences of output signals, with the sequence selected by a controller.

This invention relates to a digital phase-locked loop circuit or delay-locked loop circuit. More particularly, this invention relates to such a circuit having improved resolution.
Feedback loop circuits, including phase-locked loops (PLLs) and delay-locked loops (DLLs), are well known. In such circuits, an output signal is fed back to a detector (e.g., a phase-frequency detector in a PLL or a phase detector in a DLL) that also samples a reference signal. If the output does not bear the desired relationship to the reference signal, the detector generates a signal that causes the output signal generator (e.g., a variable frequency oscillator in a PLL or a variable delay line in a DLL) to vary its output to bring it closer to the desired relationship. This continues until the output signal locks to the reference signal. In a digital loop circuit, the signal generated by the detector is converted by a digital controller into a digital control word that conveys to the output signal generator the amount of delay required to achieve a signal lock.
For frequency synthesis, the feedback loop may include a feedback counter with an integer value N that has the effect of multiplying the output frequency of the signal by N. This is achieved by counting N cycles for each reference cycle. In the case of a digital loop circuit, assuming that the loop circuit (i.e., its delay element) has a certain intrinsic temporal resolution Δt, the effective resolution of the loop circuit becomes NΔt. This degrades the locking performance of the digital loop circuit or, alternatively, requires much higher precision components to achieve the same resolution.
It therefore would be desirable to be able to use a feedback counter for frequency synthesis in a digital loop circuit while maintaining the intrinsic resolution of the circuit.


An operating method applied to an out-of-order executive bus system includes: according to dependency constraints, linking requests using the bus system to form dependency request links having an order; and processing the order of the requests according to the dependency request links. In addition, a bus system is provided. The bus system includes a request queue and a dependency request link generator. The request queue receives and stores a newly received request including at least a link tag. The dependency request link generator generates N dependency request links according to dependency constraints of N link tags of the newly received request, where N is any positive integer. Each link tag of the newly received request is implemented to indicate a link relation with respect to an order of the newly received request and a plurality of unserved requests preceding the newly received request.

1. Field of the Invention
The invention relates to an operating method of an out-of-order executive bus system, and more particularly, to a method of forming dependency request links according to dependency constraints in the out-of-order executive bus system.
2. Description of the Prior Art
Traditional bus protocols are all serving requests using an in-order manner. For example, Advanced High performance Bus (AHB) serves requests sequentially according to each request's order. However, such an executive method comes along with a drawback. When dealing with a data transaction with a large data amount, many following transactions will be delayed. When the system becomes larger and more complicated, the in-order executive bus architecture will fail to meet the requirement. Hence, current large-scale systems tend to employ out-of-order executive bus systems, such as Advanced extensible Interface (AXI) and Open Core Protocol (OCP) bus systems. These out-of-order executive bus systems allow the master and the slave on the bus to have more space to process the requests transmitted via the bus. In out-of-order executive bus systems, data are not queued in order. For example, requests transmitted through a command channel and the write data corresponding to the requests transmitted through a write-data channel do not enter the slave in order. Therefore, identification information, such as the thread ID or tag ID, is usually used to deal with the requests which are out-of-order but related to one another. Nevertheless, when these thread/tag IDs are transmitted on the bus out of order, the related requests will not be served in order, and errors will easily happen.
U.S. Patent Publication No. 2007/0067549 (referred to as '549 patent hereinafter) has come up with a related solution that uses the conventional first-in first-out (FIFO) conception to avoid the occurrence of data hazards caused by outstanding write requests and a following read requests, '549 patent buffers related data of the outstanding writing request in a FIFO memory, and when the potential undesired data hazard caused by the following reading operation is detected, the reading operation is paused until the processing of the outstanding write request is done to thereby avoid the data hazard. However, some problems still exist in this conventional solution. For example, when the reading operation is paused, all the following reading operations are also paused, even though there will be no data hazards if those following actions are processed first. For this reason, employing the solution proposed by the '549 patent will decrease the overall performance of the system.

Out-of-order executive bus system and operating method thereof


An electric vehicle comprises an electric motor which generates driving power for driving a wheel; a battery case accommodating a battery storing DC power to be supplied to the electric motor, in a battery space in an interior of the battery case; and a plurality of electric components electrically connected to the battery and placed above the battery, wherein the plurality of electric components are placed in a plurality of layers, and arranged vertically to overlap with each other when viewed from above.

In recent years, an electric motorcycle which drives a wheel with driving power generated in an electric motor with electric power supplied from batteries has been developed. Patent Literature 1 discloses an electric motorcycle in which batteries are accommodated in a battery accommodating section placed below a seat, and an inverter is placed on a floor panel below the batteries.


A method of manufacturing a semiconductor device and device in which a sacrificial N shelf layer is grown on a P+ semiconductor substrate to contain the out-diffusion of dopant from the substrate. An N+ buffer layer is grown on the N shelf layer and an N- epitaxial layer is grown on the N+ buffer layer. The presence of the N shelf layer, which is consumed by the substrate dopant during further device fabrication, allows the integrated dopant level of the N+ buffer layer to be accurately controlled in the finished device.

The present invention relates to semiconductor devices, and more specifically to a method of fabricating a power semiconductor device and a semiconductor high voltage switch in which a sacrificial N shelf layer is grown on a P+semiconductor substrate to alleviate a change in integrated dopant level of an N+buffer layer atop the shelf layer due to out-diffusion of dopant from the substrate.
Semiconductor devices, such as high voltage switches (e.g., 600 to 1200 volt Insulated Gate Bipolar Transistors), are manufactured to meet predetermined specifications which are desirably narrowly defined (that is, there is little tolerance for variation in the finished devices.) However, device fabrication processing introduces variations which may cause some devices to fail to meet specifications, reducing device yield. By way of example, one such specification is the 1200V IGBT conductivity measurement, collector emitter saturation voltage V.sub.CE(SAT) (sometimes denoted V.sub.CE(ON)), which is desirably kept low--on the order of 2.0 to 3.0 volts--and tightly distributed about a desired voltage.
In some devices, such as high voltage switches, V.sub.CE(SAT) may vary unacceptably so as to cause low device yields, although it has been found that the severity of the V.sub.CE(SAT) variations may be controlled, at least in part, during the device manufacturing process. For example and with reference to FIG. 1, the manufacture of high voltage switches may include growing an N+ buffer layer 12 between a P+ substrate 14 and an N- epitaxial layer 16 (the structure shown is a portion of a switch, the remainder of the switch structure being unrelated to the present invention and known in the art.) It has been found that the V.sub.CE(SAT) variations get worse as the starting dopant level and thickness of the buffer layer 12 increase, especially after lifetime control is performed (integrated dopant level is a term also used in this regard, where integrated dopant level is the integral of the layer dopant level over layer thickness.) Irradiation or any other method of lifetime control of a semiconductor device during fabrication affects the variability of some of its characteristics. Irradiation is used to control carrier lifetime, typically occurs late in the device fabrication process, and inevitably causes some variability in device characteristics. The variability is amplified if the dopant level and thickness of buffer layer 12 also vary so as to cause the integrated dopant level to vary. Therefore it is desirable to control the buffer layer 12 integrated dopant level so that all devices have characteristics which are tightly distributed about desired levels.
As will be appreciated, the desired integrated dopant level of buffer layer 12 in the finished semiconductor device drives the selection of the starting dopant level, thickness and irradiation dose, and there are trade-offs which can be made to achieve the desired result. For example, the irradiation dose may be kept low and the starting dopant level and/or thickness increased commensurately. The starting dopant level and/or thickness is increased because during device fabrication (e.g., epitaxial growth, high temperature drives) dopant from substrate 14 out-diffuses into buffer layer 12 reducing its thickness and/or dopant level (that is, some of the N type region is overwhelmed by P type dopant.) In the prior art the starting dopant level and layer thickness thus are initially larger than needed to account for this shrinkage. It would be desirable to avoid the higher starting dopant level and increased buffer layer thickness (and attendant high integrated dopant level) while maintaining a low irradiation dose to make the process of epitaxial growth more manufacturable.
If the effect of the out-diffusion on the N+ buffer layer can be reduced (the out-diffusion itself cannot be stopped), the starting dopant level and buffer layer thickness (and irradiation dose) may be kept low. When these are kept low the V.sub.CE(SAT) variations may be controlled so that the specification for V.sub.CE(SAT) and other characteristics may be met more easily in the finished product.
By way of further background, semiconductor switches desirably have a fast turn-off capability, in some power devices several hundred nanoseconds. One of the factors determining turn-off speed is the doping level adjacent the PN junction 18 between substrate 14 and buffer layer 12. High doping levels in this area allow the switch to operate with acceptably fast turnoff speeds, while low doping levels adjacent PN junction 18 do not.
The prior art has not been able to mass produce such epitaxial-based and lifetime controlled semiconductor power switches which have V.sub.CE(SAT) S which are tightly distributed about a desired voltage, and which have fast turn-off speeds. The tight control of the integrated dopant level of N+ buffer layer 12 has been incompatible with the need to provide high dopant levels adjacent PN junction 18.
Accordingly, it is an object of the present invention to provide a novel method of manufacturing a semiconductor device which obviates the problems of the prior art.
It is another object of the present invention to provide a novel method of manufacturing a semiconductor device in which a sacrificial shelf layer is grown on a substrate to alleviate a reduction in integrated dopant level in a buffer layer atop the shelf layer due to out-diffusion of dopant from the substrate.
It is yet another object of the present invention to provide a novel method of reducing variability of V.sub.CE(SAT) in a semiconductor device caused during manufacture of the device by growing a shelf layer between a substrate and an overlying buffer layer, the shelf layer being provided with a dopant level less than a dopant level of the overlying buffer layer so that the shelf layer absorbs out-diffusion of dopant from the substrate during subsequent device processing with little change in the net N+ buffer integrated dopant level.
It is still another object of the present invention to provide a novel method of alleviating a reduction in the integrated dopant level of an N+ buffer layer by growing an N shelf layer between the N+ buffer layer and the substrate, and doping the shelf layer to a level one to two orders of magnitude less than the dopant level of the buffer layer and of the dopant level of the substrate.
It is a further object of the present invention to provide a novel method of manufacturing a semiconductor device in which a desired integrated dopant level is provided in a thinner N+ buffer layer than available in the prior art while preventing P+ substrate diffusion through the N+buffer layer.
These and many other objects and advantages of the present invention will be readily apparent to one skilled in the art to which the invention pertains from a perusal of the claims, the appended drawings, and the following detailed description of the preferred embodiments.

Method of forming power semiconductor devices with controllable integrated buffer


A screw with a heat exchange function is rotatably fit in a barrel, and includes a heat exchange medium chamber located at a center section in the radial direction, running along the lengthwise direction. The chamber stores a heat exchange medium supply pipe supplying a heat exchange medium. The heat exchange medium supply pipe is constituted by split pipes split into two or more sections in the lengthwise direction. Pipe connection joints connect the split pipes with each other while securing such degrees of freedom so that these split pipes can move by predetermined quantity in the lengthwise direction and the radial direction. The screw enables to stably supply a heat exchange medium for a long period without fatigue fracture of a heat exchange medium supply pipe even if the screw is bent during mixing and extrusion of a raw material.

1. Field of the Invention
The present invention relates to a screw, a mixer and an extruder which have a heat exchange function, and more particularly relates to a screw, a mixer and an extruder which have a heat exchange function enabling to supply a heat exchange medium without fatigue fracture of a heat exchange medium supply pipe even if the screw is bent and deformed during mixing and extrusion.
2. Description of the Related Art
In a mixer or an extruder which mixes or extrudes a raw material including thermoplastic resin such as resin and a rubber material, it is important for the quality of a product to adjust the temperature of the raw material being mixed or extruded, and to prevent the raw material from being over heated, attaching to a screw, and deteriorating. Hence, a medium communication hole (referred to as a heat exchange medium chamber hereinafter) is provided in the screw of the mixer and the extruder, and the screw is constituted such that the temperature is controlled by supplying a heat exchange medium such as liquid coolant into the heat exchange medium chamber.
In more detail, in the screw, there is formed the heat exchange medium chamber which is located at a center section in the radial direction, runs along the lengthwise direction, and has an opening on one shaft end. A heat exchange medium supply pipe is fit into the liquid coolant chamber through a rotary joint. In this case, the heat exchange medium supplied through the rotary joint flows through the heat exchange medium supply pipe, and flows out from an extreme end of the heat exchange medium supply pipe. The liquid coolant flowing out from the extreme end of the heat exchange medium supply pipe collides with a terminal end of the heat exchange medium chamber, and changes its direction toward a base end direction of the heat exchange medium supply pipe. The heat exchange medium then flows in a flow passage in a cylindrical shape formed between an outer periphery of the heat exchange medium supply pipe and an inner wall of the heat exchange medium chamber, and then flows out through the rotary joint.
There are two types of the heat exchange medium supply pipe which supplies the heat exchange medium into the heat exchange medium chamber of the screw of the mixer or the extruder. One type is constituted by one pipe, and the other type is constituted by connecting multiple pipes. Supports whose extreme end is in contact with the inner wall of the heat exchange medium chamber are provided at multiple locations in the lengthwise direction on the outer periphery of the heat exchange medium supply pipe of the former type. Namely, it is intended that the supports cause the center of the heat exchange medium supply pipe to coincide with the center in the radial direction of the heat exchange medium chamber. As for the heat exchange medium supply pipe of the latter type, multiple pipes are connected by threadedly attaching the pipes to pipe joints also serving as a support. The pipe joints also serving as the support cause the center of the heat exchange medium supply pipe to coincide with the center in the radial direction of the heat exchange medium chamber (for example, see Japanese Patent Publication No. 2778797).
Since the screw of the mixer or the extruder receives an offset load (bending force) from the raw material during the operation of the mixer or the extruder, the screw rotates while yielding. As a result, the highly rigid heat exchange medium supply pipe made of metal and the like is forcefully displaced repeatedly by the yield of the screw, and consequently, the heat exchange medium supply pipe may be fatigue-fractured. If the heat exchange medium supply pipe is fatigue-fractured, since cooling function (heat exchange function) provided for the screw decreases, it is impossible to adjust the temperature of the raw material being mixed or extruded, or to prevent the raw material which has melted, has being over heated, and has attached to the screw from deteriorating.
As a result, since it is necessary to stop the operation of the mixer or the extruder for maintenance, there has been such a problem to be solved that it is not possible to expect an increase of the productivity of a mixed material or extruded products due to the decrease of the availability of the mixer or the extruder in addition to a disadvantage in terms of the running cost of the mixer or the extruder.

Screw with heat exchange function, mixer and extruder


An AOTF control apparatus, which applies an RF signal to an AOTF to allow a selected light to pass through the AOTF, includes: a first calculating unit calculating a relationship between a frequency of the RF signal and a wavelength of the selected light based on a frequency of the RF signal that allows a reference light to pass through the AOTF; and a second calculating unit calculating a relationship between a power of the RF signal and an attenuation amount of the selected light based on an input/output power of the reference signal at the input/output of the AOTF.

1. Field of the Invention
The present invention relates to an acousto-optic tunable filter control apparatus for outputting an optical signal at an arbitrary wavelength from a wavelength division multiplexing (WDM) transmission signal obtained by multiplexing optical signals at different wavelengths, and an optical control method.
2. Description of the Related Art
Recently, demand for an optical communication technique capable of very long distance transmission and high capacity transmission rises following a rapid increase in the number of multimedia network users. To meet this demand, WDM that is a technique for multiplexing optical signals at different wavelengths and for transmitting signals in a plurality of channels to one optical fiber so as to increase a transmission capacity, in particular, is being used.
An optical communication network using the WDM needs to have an optical signal passing-through, splitting, and inserting function and an optical routing and cross connect function. In the former function, the optical communication network passes through, splits, and inserts an optical signal according to a need at each point on the network. In the latter function, the system selects an optical signal at a wavelength in a selected channel from the multiplexed optical signal, and outputs the selected optical signal to an optical transmission path. Accordingly, it is indispensable to do research and development according to a purpose of a user of an optical add-drop multiplexer (OADM) apparatus that passes through, splits, and inserts an optical signal. At present, as OADM apparatuses, a fixed-wavelength OADM apparatus capable of splitting and inserting an optical signal at a fixed wavelength and an arbitrary-wavelength OADM apparatus capable of splitting and inserting an optical signal at an arbitrary wavelength are provided.
As a device that realizes a necessary wavelength selecting function necessary for the OADM apparatus to perform a process for passing through and splitting an optical signal, attention is paid particularly to an acousto-optic tunable filter (hereinafter, "AOTF"). Since a selected wavelength is fixed, the AOTF operates to extract a light at the selected wavelength and can, therefore, select an arbitrary wavelength, differently from fiber grating.
FIG. 9 is an explanatory view of a configuration of the AOTF. As shown in FIG. 9, the AOTF is configured so that two optical waveguides 1-1 and 1-2 are formed on a lithium niobate (LiNbO3) substrate 1-7 that consists of a kind of ferroelectric crystal and that exhibits a piezoelectric action by titanium (Ti) diffusion. These optical waveguides 1-1 and 1-2 intersect each other at two positions, and waveguide polarization beam splitters (hereinafter, "PBS") 1-3 and 1-4 are provided at the respective intersecting positions.
A SAW guide 1-6 including a metal film is formed on the two optical waveguides 1-1 and 1-2. This SAW guide 1-6 includes an electrode (an inter digital transducer (hereinafter, "IDT")) 1-5 having interlocking comb tooth. If a radio frequency electric signal (hereinafter, "RF signal") output from an RF signal generator circuit 1-10 is applied to this IDT 1-5, a surface acoustic wave (hereinafter, "SAW") is generated. The SAW is propagated in the optical waveguides 1-1 and 1-2.
In FIG. 9, if lights at wavelengths λ1, λ2, and λ3 are input to a port 1 of the AOTF, an input light hybridized in polarization modes of a TE mode and a TM mode by the PBS 1-3 is split into a light in the TE mode and that in the TM mode. The respective lights are propagated in the optical waveguides 1-1 and 1-2. If the SAW is propagated in the SAW guide 1-6 by applying an RF signal f1 at a specific frequency, refractive indexes of the two optical waveguides 1-1 and 1-2 are cyclically changed at intersecting positions, at which the optical waveguides 1-1 and 1-2 intersect the SAW guide 1-6, respectively, by an acousto-optic (AO) effect.
Accordingly, out of the input lights, the polarization mode of the light at a specific wavelength interacting with a cyclic change in the refractive index of each of the optical waveguides 1-1 and 1-2 is rotated, whereby the TE mode and the TM mode are converted into each other. The TE mode is a guided mode in which no electric field component is present in a propagation direction, and the TM mode is a guided mode in which no magnetic field component is present in the propagation direction. A rotation amount is proportional to an action length by which the light in the TE mode or that in the TM mode interacts with the change in the refractive index and a power of an RF signal. The action length is adjusted by a distance between absorbers 1-8 that are formed on the optical waveguides 1-1 and 1-2 across the IDT 1-5 and that absorb the SAW.
Namely, by optimizing the action length and the power of the RF signal, a TM mode light is converted into a TE mode light in the optical waveguide 1-1. In addition, a TE mode light is converted into a TM mode light in the optical waveguide 1-2. A forward direction of the TE mode light or TM mode light thus obtained is changed by the PBS 1-4, and the light at the wavelength interacting with the cyclic change in the refractive index is selected as a split light. FIG. 9 shows that the RF signals f1 and f2 act on the optical signals at the wavelengths λ1 and λ2, respectively, and that the respective lights are selected as split lights.
As explained above, the AOTF can select and split a light at a wavelength according to a frequency of each RF signal. By changing the frequency of this RF signal, the AOTF can change the wavelength of the selected light. In addition, an output light emitted from a port 2 of the AOTF corresponds to optical signals (at wavelength of λ3) obtained by eliminating the lights at the wavelengths corresponding to the frequencies of the RF signals from the input lights incident on the port 1 of the AOTF. Therefore, the AOTF also includes a rejection function.
FIG. 10 is an explanatory view of a relationship between the RF signal and the AOTF output light. In a graph 1000 shown in FIG. 10, a horizontal axis indicates a power of the RF signal (dBm) and a vertical axis indicates a power of the AOTF output light (dBm). As evident from a characteristic curve 1001 shown in FIG. 10, if the RF signal power is changed, the AOTF output light power is changed. While the AOTF is the device that can operate to select a wavelength in response to the RF control signal, the AOTF can be used as a wavelength selection filter that includes a variable attenuation function by using this characteristic.
Techniques using the AOTF as an attenuator are already disclosed (in, for example, Japanese Patent Application Laid-open No. 2002-368317). FIGS. 11 and 12 are explanatory views of variable attenuators using conventional AOTFs, respectively. A variable attenuator 1100 shown in FIG. 11 includes a pump light source 1101, an erbium-doped fiber (EDF) 1102, an equalizer 1103, an AOTF 1104, an RF signal generator 1105, a monitor 1106, and an optical isolator 1107.
The variable attenuator 1100 demultiplexes an output light of the AOTF 1104 to lights at respective wavelengths by a coupler (not shown). Powers of demultiplexed output lights are detected by the monitor 1106. Based on this detection result, intensities (amplitudes) of frequencies f1 to f4 of RF signals applied to the AOTF 1104 are controlled so as to flatten the powers of the output lights at the respective wavelengths. By feedback-controlling the amplitudes of the RF signals based on the powers of the output lights at the respective wavelengths, intensities of SAWs generated according to the respective RF signals are changed. In addition, the powers of the output lights at the respective wavelengths selected by the AOTF 1104 are adjusted according to the intensities of the corresponding SAWs. Therefore, the powers of the output lights at the respective wavelengths are flattened, and the output lights at the respective wavelengths with the flattened power are output to an outside of the variable attenuator 1100.
A variable attenuator 1200 shown in FIG. 12 includes a database 1201 for controlling an RF signal applied to the AOTF 1104 in place of the monitor 1106 included in the variable attenuator 1100. This database 1201 records, as data, correction values of optical powers in all oscillation patterns obtained in advance by measurement or the like. The correction values recorded in the database are referred to according to the respective oscillation patterns, and the intensities of the RF signals applied to the AOTF 1104 are respectively controlled. It is thereby possible to flatten the powers of the output lights.
However, the conventional apparatus that includes the attenuation function similarly to that of the variable attenuator 1100, and that realizes the wavelength selecting function as the AOTF control apparatus has the following disadvantages. If the power of the light at the desired and selected wavelength in the WDM transmission signal input to the AOTF 1104 is high, the power of an initial output light before the light is attenuated by the AOTF 1104 can possibly be set high. If the power of the output light is set high, the optical power of the WDM transmission signal input to an apparatus connected in rear of the AOTF 1104, e.g., an optical receiver can possibly exceed an input power limit of the optical receiver while the variable attenuation function is acting. The light at the power exceeding the input power limit possibly cause damage and a deterioration in the optical receiver.
The power of the input light can be limited so as to prevent a light at an excessive power from being input to the apparatus connected in rear of the AOTF 1104 even before the variable attenuation function acts. However, this restriction makes it difficult to enable an attenuation width of the AOTF 1104 to effectively act. Besides, since the variable attenuation function of the variable attenuator 1100 has a fixed target value set for the powers of the output lights of the AOTF 1104, it is impossible to designate and set an arbitrary attenuation amount according to a user's purpose.
Furthermore, the database 1201 of the variable attenuator 1200 records, as the data, the correction values of the intensities of lights obtained in advance by the measurement or the like. The correction values recorded in the database 1201 are referred to according to the respective oscillation patterns. The intensities of the RF signals applied to the AOTF 1104 are controlled according to the respective correction values, and the powers of the output lights are adjusted by the variable attenuation function. However, the variable attenuator 1200 fails to include a function of compensating for a secular deterioration in the AOTF 1104. As a result, a long-time reliability of the variable attenuator 1200 is not ensured. Besides, since the attenuation characteristics are irregular according to the respective AOTFs, it is necessary to measure and set the values to be recorded in the database in advance for every AOTF. This increases the number of manufacturing steps and imposes a burden on the user. This results in an increase in manufacturing cost.

Acousto-optic tunable filter control apparatus automatically adjusting frequency and power of radio frequency signal


This invention relates to an expression vector wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen protein or peptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence all operatively linked. More particularly, it relates to the method of eliciting an immune response directed against an antigen in a mammal comprising the steps of introducing the expression vector into a cell, expressing the vector to produce an antigen under conditions wherein the antigen is secreted from the cell, endocytosing the secreted antigen into the cell, processing the antigen, and presenting fragments to a receptor to elicit a T-cell response. In addition, this invention relates to a vaccine and a method of use. The invention also relates to the method of identifying MHC-II restricted epitopes.

This invention relates to an expression vector and its use to elicit a complete immune response in a mammal. More particularly it relates the processing of an endogenous antigen as an exogenous antigen for presentation on MHC-II. This invention also relates to a vaccine and its method of use to immunize a mammal.
Inadequate antigen presentation in humans results in the failure of human immune system to control and clear many pathogenic infections and malignant cell growth. Successful therapeutic vaccines and immunotherapies for chronic infection and cancer rely on the development of new approaches for efficient antigen presentation to induce a vigorous immune. response which is capable of controlling and clearing the offensive antigens.
The ability of T cells to recognize an antigen is dependent on association of the antigen with either MHC Class I (MHC-I) or Class II (MCH-II) proteins. For example, cytotoxic T cells respond to an antigen in association with MHC-I proteins. Thus, a cytotoxic T cell that kills a virus-infected cell will not kill a cell infected with the same virus if the cell does not also express the appropriate MHC-I protein. Helper T cells recognize MHC-II proteins. Helper T cell activity depends in general on both the recognition of the antigen on antigen presenting cells and the presence on these cells of xe2x80x9cselfxe2x80x9d MHC-II proteins. This requirement to recognize an antigen in association with a self-MHC protein is called MHC restriction. MHC-I proteins are found on the surface of virtually all nucleated cells. MHC-II proteins are found on the surface of certain cells including macrophages, B cells, and dendritic cells of the spleen and Langerhans cells of the skin.
A crucial step in mounting an immune response in mammals, is the activation of CD4+ helper T-cells that recognize major histocompatibility complexes (MHC)-II restricted exogenous antigens. These antigens are captured and processed in the cellular endosomal pathway in antigen presenting cells, such as dendritic cells (DCs) (Zajac et al., 1998; Bona et al., 1998; Kalams et al., 1998; Mellman et al., 1998; Banchereau et al., 1998). In the endosome and lysosome, the antigen is processed into small antigenic peptides that are presented onto the MHC-II in the Golgi compartment to form an antigen-MHC-II complex. This complex is expressed on the cell surface, which expression induces the activation of CD4+ T cells.
Other crucial events in the induction of an effective immune response in an animal involve the activation of CD8+ T-cells and B cells. CD8+ cells are activated when the desired protein is routed through the cell in such a manner so as to be presented on the cell surface as processed proteins, which are complexed with MHC-I antigens. B cells can interact with the antigen via their surface immunoglobulins (IgM and IgD) without the need for MHC proteins. However, the activation of the CD4+ T-cells stimulates all arms of the immune system. Upon activation, CD4+ T-cells (helper T cells) produce interleukins. These interleukins help activate the other arms of the immune system. For example, helper T cells produce interleukin-4 (IL-4) and interleukin-5 (IL-5), which help B cells produce antibodies; interleukin-2 (IL-2), which activates CD4+ and CD8+ T-cells; and gamma interferon, which activates macrophages.
Since helper T-cells that recognize MHC-II restricted antigens play a central role in the activation and clonal expansion of cytotoxic T-cells, macrophages, natural killer cells and B cells, the initial event of activating the helper T cells in response to an antigen is crucial for the induction of an effective immune response directed against that antigen. Attempts to stimulate helper T-cell activation using a sequence derived from the lysosomal transmembrane proteins have been reported (Wu, 1995). However, these attempts did not result in the induction of effective immune responses with respect to CD8+ T-cells and B cells in the mammals being tested.
Thus, there is a long felt need in the art for efficient and directed means of eliciting an immune response for the treatment of diseases in mammals. The present invention satisfies this need.
An embodiment of the present invention is an expression vector comprising a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence all operatively linked.
In specific embodiments of the present invention, the polynucleotide promoter sequence is selected from the group consisting of a constitutive promoter, an inducible promoter and a tissue specific promoter.
In another specific embodiment of the present invention, the polynucleotide encoding a signal sequence is selected from the group consisting of a hepatitis B virus E antigen signal sequence, an immunoglobulin heavy chain leader sequence, and a cytokine leader sequence.
An embodiment of the present invention is an expression vector wherein the polynucleotide encoding an antigen comprises a polynucleotide sequence for at least one epitope, wherein said at least one epitope induces a B cell response in a mammal.
A further embodiment of the present invention is an expression vector wherein the polynucleotide encoding an antigen comprises a polynucleotide sequence for at least one epitope, wherein said at least one epitope induces a CD4+ T-cell response in a mammal.
Another embodiment of the present invention is an expression vector wherein the polynucleotide encoding an antigen comprises a polynucleotide sequence for at least one epitope, wherein said at least one epitope induces a CD8+ T-cell response in a mammal.
A specific embodiment of the present invention is an expression vector wherein the polynucleotide sequence encoding an antigen comprises a polynucleotide sequence for at least one epitope, wherein said at least one epitope induces a B cell response, a CD4+ T-cell response and a CD8+ T-cell response in a mammal into which said antigen is introduced.
A further specific embodiment of the present invention is an expression vector wherein the polynucleotide sequence encoding an antigen comprises a polynucleotide sequence for a plurality of epitopes, wherein said plurality of epitopes induces a B cell response, a CD4+ T-cell response and a CD8+ T-cell response in a mammal into which said antigen is introduced.
A further embodiment of the present invention is an expression vector wherein the polynucleotide encoding a cell binding element is a polynucleotide sequence of a ligand which binds to a cell surface receptor. In specific embodiments, the cell binding element sequence is selected from the group consisting of polynucleotide sequences which encode a Fc fragment, a toxin cell binding domain, a cytokine, a small peptide and an antibody. In specific embodiments, the polynucleotide encoding a cell binding element is a homologous polynucleotide sequence or a heterologous polynucleotide sequence.
An additional embodiment of the present invention is a transformed cell comprising an expression vector wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence all operatively linked.
Another specific embodiment of the present invention is a fusion protein wherein the fusion protein comprises a signal sequence, an antigen and a cell binding element. In specific embodiments, antigen presenting cells have been transduced with the fusion protein in vitro. In further embodiments, the fusion protein is administered directly to a mammal.
A specific embodiment of the present invention is a vaccine comprising an expression vector wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence all operatively linked. In specific embodiments, a vaccine comprises antigen presenting cells, wherein said antigen presenting cells are transduced in vitro with the expression vector. In further embodiments, a vaccine comprises antigen presenting cells, wherein said antigen presenting cells are transduced in vitro with the fusion protein.
Another specific embodiment of the present invention is an expression vector comprising at least a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen and a polynucleotide encoding a cell binding element.
A further embodiment of the present invention is a method to elicit an immune response directed against an antigen, comprising the steps of: introducing an expression vector into a cell, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked; and expressing said vector to produce an antigen under conditions wherein said antigen is secreted from the cell; said secreted antigen is endocytosed into the cell; said endocytosed antigen is processed inside the cell; and said processed antigen is presented to a cell surface protein, to elicit a T-cell mediated immune response. In specific embodiments, the antigen is secreted by a first cell and internalized by a second cell wherein the first and second cells are antigen presenting cells. In further embodiments, the first cells is a non-antigen presenting cell and the second cell is an antigen presenting cell.
Another specific embodiment of the present invention is a method to identify a polynucleotide sequence which encodes at least one MHC-II restricted epitope that is capable of activating CD4+ helper T-cells, said method comprising the steps of: introducing an expression vector into an antigen presenting cell to produce a transduced antigen presenting cell, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked; contacting said transduced antigen presenting cell with naive or primed T-cells; and assessing whether any naive T-cells or primed T-cells are activated upon contact with said transduced antigen presenting cell, wherein activation of any of said T-cells indicates that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells. In specific embodiments, the polynucleotide encoding a test polypeptide is selected from the group of cDNA libraries consisting of viral genomes, bacterial genomes, parasitic genomes and human genomes.
Another embodiment of the present invention is a method to identify a polynucleotide sequence which encodes at least one MHC-II restricted epitope that is capable of eliciting an immune response in vivo, said method comprising the steps of: introducing an expression vector into antigen presenting cells to produce transduced antigen presenting cells, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked; administering said transduced antigen presenting cells to a mammal via a parenteral route; collecting T-cells from splenocytes and co-culturing with dendritic cells; and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells. In specific embodiments, the polynucleotide encoding a test polypeptide is selected from the group of cDNA libraries consisting of viral genomes, bacterial genomes, parasitic genomes and human genomes.
A specific embodiment of the present invention is a method to identify a polynucleotide sequence which encodes at least one MHC-II restricted epitope that is capable of eliciting an immune response in vivo, said method comprising the steps of: administering to a mammal via parenteral route an expression vector, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked; administering said transduced antigen presenting cells to a mammal via a parenteral route; collecting T-cells from splenocytes and co-culturing with dendritic cells; and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells. In specific embodiments, the polynucleotide encoding a test polypeptide is selected from the group of cDNA libraries consisting of viral genomes, bacterial genomes, parasitic genomes and human genomes.
A specific embodiment of the present invention is a method of treating cancer comprising the steps of identifying a test polypeptide which encodes at least one MHC-II restricted epitope, wherein said polypeptide is identified under the conditions of transducing antigen presenting cells with an expression vector into antigen presenting cells to produce transduced antigen presenting cells, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells; and administering antigen presenting cells to a mammal via a parenteral route, wherein said antigen presenting cells are transduced with the test polypeptide.
Another specific embodiment of the present invention is a method of treating cancer comprising the steps of identifying a test polypeptide which encodes at least one MHC-II restricted epitope, wherein said polypeptide is identified under the conditions of transducing antigen presenting cells with an expression vector into antigen presenting cells to produce transduced antigen presenting cells, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells; and administering to a mammal via a parenteral route an expression vector, wherein said expression vector comprises at least the polynucleotide encoding the test polypeptide and a polynucleotide encoding a cell binding element said antigen presenting cells are transduced with the test polypeptide.
A further specific embodiment of the present invention is a method of treating a viral infection comprising the steps of identifying a test polypeptide which encodes at least one MHC-II restricted epitope, wherein said polypeptide is identified under the conditions of transducing antigen presenting cells with an expression vector into antigen presenting cells to produce transduced antigen presenting cells, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells; and administering antigen presenting cells to a mammal via a parenteral route, wherein said antigen presenting cells are transduced with the test polypeptide.
Another embodiment of the present invention is a method of treating a viral infection comprising the steps of identifying a test polypeptide which encodes at least one MHC-II restricted epitope, wherein said polypeptide is identified under the conditions of transducing antigen presenting cells with an expression vector into antigen presenting cells to produce transduced antigen presenting cells, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells; and administering to a mammal via a parenteral route an expression vector, wherein said expression vector comprises at least the polynucleotide encoding the test polypeptide and a polynucleotide encoding a cell binding element said antigen presenting cells are transduced with the test polypeptide.
Another embodiment of the present invention is a method of treating an autoimmune disease comprising the steps of identifying a test polypeptide which encodes at least one MHC-II restricted epitope, wherein said polypeptide is identified under the conditions of transducing antigen presenting cells with an expression vector into antigen presenting cells to produce transduced antigen presenting cells, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells; and administering antigen presenting cells to a mammal via a parenteral route, wherein said antigen presenting cells are transduced with the test polypeptide.
A specific embodiment of the present invention is a method of treating an autoimmune disease comprising the steps of identifying a test polypeptide which encodes at least one MHC-II restricted epitope, wherein said polypeptide is identified under the conditions of transducing antigen presenting cells with an expression vector into antigen presenting cells to produce transduced antigen presenting cells, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a test polypeptide, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and assessing activation of T-cells, wherein said activation of T-cells indicate that the polynucleotide encoding the test polypeptide is a gene or fragment thereof capable of activating CD4+ helper T-cells; and administering to a mammal via a parenteral route an expression vector, wherein said expression vector comprises at least the polynucleotide encoding the test polypeptide and a polynucleotide encoding a cell binding element said antigen presenting cells are transduced with the test polypeptide.
A further embodiment of the present invention is a method of producing a vaccine to immunize a mammal comprising the steps of: transducing antigen presenting cell by introducing an expression vector into a cell, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked; and expressing said vector to produce an antigen under conditions wherein said antigen is secreted from the cell. In specific embodiments, antigen presenting cells are transduced with the antigen in vitro or ex vivo prior to administering the antigen presenting cells to the mammal.
Another specific embodiment of the present invention is a method of inducing an immune response comprising the steps of co-administering to a mammal a cytokine expression vector and a retrogen expression vector, wherein the retrogen expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence all operatively linked.
A further embodiment of the present invention is a method of inducing an immune response comprising the steps of co-administering to a mammal one expression vector, wherein said expression vector comprises a polynucleotide sequence encoding a cytokine protein and a polynucleotide sequence encoding a fusion protein under transcriptional control of one promoter, wherein said fusion protein comprises an antigen and a cell binding element. In specific embodiments, the polynucleotide sequence encoding the cytokine protein and the polynucleotide sequence encoding the fusion protein are under separate transcriptional control, and wherein the polynucleotide sequence encoding the cytokine protein and the polynucleotide sequence encoding the fusion protein are in tandem in the one expression vector.
Another embodiment of the present invention is a method of inducing an immune response comprising the steps of co-administering to a mammal two different retrogen expression vectors, wherein a first retrogen expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a first antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence all operatively linked; and a second retrogen expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a second antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence all operatively.
Another specific embodiment of the present invention is a method of inducing an immune response comprising the steps of administering to a mammal one expression vector, wherein said expression vector comprises a polynucleotide sequence encoding a first fusion protein and a polynucleotide sequence encoding a second fusion protein under transcriptional control of one promoter, wherein said first fusion protein comprises a first antigen and a first cell binding element and said second fusion protein comprises a second antigen and a first cell binding element. In specific embodiments, the first and second antigens are different antigens and the cell binding elements is a Fc fragment. In further embodiments, the first and second antigens are different antigens and the first and second cell binding elements are different cell binding elements. An additional embodiment includes that the polynucleotide sequence encoding the first fusion protein and the polynucleotide sequence encoding the second fusion protein are under separate transcriptional control, and wherein the polynucleotide sequence encoding the first fusion protein and the polynucleotide sequence encoding the second fusion protein are in tandem in one expression vector.
A specific embodiment of the present invention is a method of simultaneously inducing both CD4+ and CD8+ T-cells comprising the steps of administering a fusion protein wherein the protein comprises both a MHC-I and MHC-II epitope fused to a cell binding element.
A further embodiment of the present invention is a method of producing a fusion protein comprising the steps of introducing an expression vector into a cell, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an antigen, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and expressing said vector to produce a fusion protein under conditions wherein said fusion protein is secreted from the cell. In specific embodiments, antigen presenting cells are transduced with the fusion protein in vitro.
A specific embodiment of the present invention is a method of secreting an intracellular protein comprising the steps of introducing an expression vector into a cell, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding an intracellular protein, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and expressing said vector to produce a fusion protein under conditions wherein said fusion protein is secreted from the cell. More specifically, the polynucleotide sequence encoding the intracellular protein is truncated or mutated to increase efficiency of secretion.
Another specific embodiment of the present invention is a method of secreting a membrane protein comprising the steps of introducing an expression vector into a cell, wherein said expression vector comprises a polynucleotide promoter sequence, a polynucleotide encoding a signal sequence, a polynucleotide encoding a membrane protein, a polynucleotide encoding a cell binding element, and a polynucleotide polyadenylation sequence, all operatively linked and expressing said vector to produce a fusion protein under conditions wherein said fusion protein is secreted from the cell. More specifically, the polynucleotide sequence encoding the membrane protein is truncated or mutated to increase efficiency of secretion.

Compositions and methods for identifying antigens which elicit an immune response

Wake Forest University School of Medicine


A knife assembly (10) particularly adapted for coupling with an extruder barrel (26) is provided having a knife shaft (16) supporting a knife unit (14), with the knife shaft (16) axially rotatable and axially shiftable through fore and aft limits. The assembly (10) may be adjusted during operation without interrupting the axially rotation of shaft (16), using adjustment mechanism (24) located in a safely remote position from knife unit (14). The preferred assembly (10) includes axial shift limiting structure (114, 116, 124) serving to limit the extent of fore and aft axial movement of shaft (16). The mechanism (24) allows fine adjustment of the position of knife unit (14) relative to the extruder barrel (26), and also permits monitoring of the wear of knife unit (14).

1. Field of the Invention
The present invention is broadly concerned with improved knife assemblies of the kind commonly used with extruders to cut extrudate on a continuous basis. More particularly the invention is concerned with such knife assemblies and corresponding methods wherein the knife assemblies include an adjustment mechanism allowing easy and safe axial adjustment of the cutting knives relative to an extruder die.
2. Description of the Prior Art
Extruder systems for the production of comestible and other products typically include an elongated extruder barrel with an internal, axially rotatable auger serving to subject materials to be processed to high levels of shear and temperature. The barrel is equipped with an endmost extrusion die which serves to shape the materials as they are extruded. It is also common to provide a rotating knife assembly adjacent the die end of such an extruder barrel, in order to cut the extrudate to desired lengths. Such cut products then fall by gravity onto a conveyor belt or other similar equipment to transport the product away from the system.
The conventional knife assemblies in use today are deficient in several respects. First of all, it can be difficult and even hazardous to change the axial position of the rotating knives during operation. Indeed, in many cases it is necessary to stop the knife assembly and thus the entire system in order to adjust the knife position. Some on-the-go knife adjustment mechanisms have been proposed, but these are generally very complex and costly. For example, hydraulic devices have been tried, but these are not really satisfactory. Furthermore, some prior knife adjustment mechanisms were of the rotating type, i.e., the adjustment components normally rotate at knife speed.
In addition, it is sometimes difficult to properly gauge and determine the extent of knife wear during operation of conventional knife assemblies. This is important in that over-worn knives become inefficient and damage to the knife assembly can occur if the blades are excessively worn.
There is accordingly the need in the art for an improved knife assembly of the type used in extruder systems and wherein the knife assembly may be adjusted during and without interfering with cutting operations, and which make use of non-rotating adjustment components which can be manually manipulated by the operator. Furthermore, there is a need for such a knife assembly which can monitor the extent of blade wear during operation.
The following references are indicative of the state of the art. U.S Pat. Nos. 2,594,894; 3,029,466; 3,196,487; 3,266,090; 3,337,913; 3,353,213; 3,564,650; 3,673,298; 4,151,241; 4,184,833; 4,249,879; 4,285,652; 4,529,370; 4,728,276; 5,059,103; 5,146,831; 5,360,585; 5,836,225; 6,332,765; 6,604,929; US Publication No. 2007/0172533; German Patents Nos. 3436394; 3437495; European Patent No. 001576881; Great Britain Patents Nos. 0016891; 0848596; Japanese Patent No. 54-072261; and Russian Patent No. 0514707.

Extruder cut-off knife assembly having remote adjustment mechanism


A gas cylinder dispensing valve having an internal flow path provided with a pressure regulator. An isolation valve is provided within the flow path between the pressure regulator and a gas inlet of the valve and a flow control valve is provided within the flow path between the pressure regulator and a gas outlet to discharge the gas. Both isolation valve and the flow control valve can be manipulated by a single control knob which when set in an off position closes the isolation valve. The control knob can be rotated from the off position to select discrete, calibrated flow rates or an auxiliary position in which gas may be dispensed at a regulated pressure from an auxiliary outlet port.

Industrial gases such as those obtained from the fractionation of air, can be delivered and utilized with the use of portable compressed gas cylinders. For instance, hospitals routinely use portable gas cylinders containing breathable compressed gases for patients during the course of their stay. The gas cylinder is normally connected to a pressure regulator to reduce the pressure of the gas and a flow meter to control the flow of the gas to the patient.
Gas cylinder dispensing valves have been introduced that incorporate a pressure regulator and a flow control valve within a valve body. The valve body is designed to be connected to a gas cylinder containing the breathable gas to be dispensed for patient uses. The primary problem with the use of such dispensing valves is the tendency of the valve to leak between its filling and usage. This is mostly due to temperature shrinkage of different materials utilized within the valves.
In order to overcome this problem, U.S. Pat. No. 5,996,625 provides a dispensing valve that incorporates an isolation valve that can be set to cut off the flow of the gas within the valve. The device illustrated in this patent incorporates an isolation valve set transversely to the axis of rotation of control knobs that are located at the top of the body of the valve. The isolation valve is not biased and is toggled between open and closed positions by force applied to opposite ends of the valve that protrude from the valve body. The isolation valve is activated by a control knob having a tubular member covering the valve and provided with an internal cam-like surface to contact opposite ends of the valve to toggle the isolation valve. A top portion of the control knob is recessed to contain a separate control knob to adjust a flow control valve and therefore the gas flow rate of the gas to be dispensed. Hence, setting the valve in open and closed positions and adjusting the flow rate requires two separate motions by manipulation of the two control knobs.
As will be discussed, the present invention provides a gas cylinder dispensing valve having both a flow control valve and an isolation valve that are both manipulated by a single control knob. This simplifies the setting of the valve. Moreover, the present invention allows the dispensing valve to be constructed in a manner that is straight forward and thus, far less complicated than prior art designs.