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Linear polyesters consisting essentially of residues of a bisphenol and dicarboxylic acids are important engineering thermoplastics especially noted for their excellent performance at high temperatures.
The transesterification reaction by a bisphenol and a diaryl ester of a dicarboxylic acid, preferentially in the presence of a small effective amount of a catalyst to prepare a thermoplastic linear polyester has been disclosed for example by British Pat. No. 924,697 assigned to Imperial Chemical Industries, Ltd. published Apr. 24, 1963.
The reaction, which is generally carried out in bulk, i.e. without solvent or diluent, with the reactants in molten condition generally employs temperatures in the range of above about 100.degree. to about 400.degree. or higher, e.g. above about 160.degree. to about 350.degree. C. for bisphenol A-isophthalate-terephthalate polyesters.
Since the reaction is reversible, provision is made for removal of the monohydroxy aromatic compound, e.g. phenol, displaced from the diaryl ester reactant during transesterification when a diphenyl ester is employed as the diaryl ester reactant, to cause the reaction to proceed to completion.
Monohydroxy aromatic compound removal is generally facilitated by gradually raising the temperature of the reaction mass from the minimum temperature required for onset of transesterification to about 300.degree.-400.degree. C. while gradually reducing the reaction pressure from about atmospheric pressure to about 0.1 mm or lower of mercury.
The viscosity of the polyester products is generally exceptionally high causing the viscosity of the reaction mass, as completion of the reaction is approached, to approach values above about 1.times.10.sup.6 to above about 10.times.10.sup.6 centipoises at reaction conditions, i.e. the range of viscosities of such polyesters as measured at shear rate of about 24 sec..sup.-1 and at about 320.degree. C.
Because of the above indicated wide variance in conditions, e.g. temperature and pressure, employed in the reaction and because of the necessity for wide variance in kind and degree of agitation, occasioned by the aforementioned viscosity increase during the reaction, the prior art has generally carried out the reaction in two stages, namely, a moderate temperature prepolymerization stage, to prepare a polyester oligomer prepolymer and a subsequent polymerization stage wherein said oligomer and the reactants are condensed to provide the polyester product.
The prepolymerization stage is carried out at about 100.degree. to about 350.degree. C. under moderate agitation conditions to prepare a low molecular weight polyester, i.e. prepolymer or oligomer, of relatively low molecular weight, corresponding to an intrinsic viscosity of less than about 0.1 to about 0.3 dl/g.
The polymerization stage is carried out at temperatures ranging to about 400.degree. C. employing extreme agitation conditions.
Because of difficulties in handling the aforementioned high viscosities of the molten reaction mass encountered in the transesterification reaction only batchwise mode or semi-continuous mode (wherein prepolymerization is batchwise and polymerization is continuous) have been suggested for preparation of these polyesters by transesterification.
Batchwise transesterification is in general not commercially attractive for production of large scale quantities of the polyester and generally provides an undesirably wide variance of product characteristics and properties from batch to batch of product.
In batchwise transesterification processes it is generally impossible to vary substantially the product molecular weight distribution, as measured by the product's polydispersity (which is further discussed below) by change of reaction conditions.
K. Eise et al., German Preliminary Application No. 2,232,877, published Jan. 17, 1974, disclose a semi-continuous transesterification polymerization of the polyester wherein the prepolymerization stage to prepare the oligomer (referred to as precondensate in the patent) is carried out batchwise and the subsequent polymerization stage is carried out continuously employing a vented extruder reactor, i.e. an extruder having provision for removal of vapors of the phenolic side product of the reaction.
Use of the extruder in accordance with the Eise et al. patent, generally has the disadvantage that the reaction mass in the extrusion reaction vessel is in the form of a thick mass, e.g. of greater than about 20 mm. thickness, principally adhering to the screw element of the extruder.
The residence time of the reaction mass in an extruder is relatively long compared to a thin film reactor giving rise to an undesirably long thermal history to the polyester. Such a long thermal history leads to a product of greater coloration which in the case of extreme product discoloration makes the product unacceptable for many uses. Under normal operations, the rate of new face exposure is limited, thus limiting the rate at which phenol can be eliminated from the system. As a result, relatively costly expenditures of energy are necessary to remove the phenolic side product to maintain a satisfactory rate of transesterification.
As an additional alternative to overcome the aforementioned difficulties in preparation of the polyester by transesterification especially the difficulties arising from the aforementioned high melt viscosity of the bisphenol-dicarboxylic acid polyester, the prior art (for example in U.S. Pat. No. 3,399,170, F. Blachke et al., assigned to Chemiche Werke Witten A.G., issued Aug. 27, 1968) has proposed modification of the structure of the polyester by introducing residues in minor proportion of alkylene and cycloalkylene glycols e.g. ethylene glycol, polybutylene glycol, into the polyester. Such structural modification of the polyester, while lowering the melt viscosity of the polyester thereby tending to overcome the aforementioned process difficulties, results in a modified polyester product which does not possess the high temperature performance characteristics of the unmodified bisphenoldicarboxylic acid polyesters of this invention.
According to technology developed by Teijin Co., Ltd., with respect to solid state polymerization, molecular weight build-up does occur in this method, but the method is limited to materials that do crystallize. | {
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I. Field of the Invention
This invention relates generally to implantable medical devices of the type including a pulse generator for stimulating tissue structures via medical leads and more particularly to a device for monitoring the force applied to a proximal terminal of the medical lead by a lead terminal lock mechanism in the implantable device.
II. Discussion of the Prior Art
Implantable medical devices, such as cardiac rhythm management devices and neural stimulators typically comprise a pulse generator contained within a hermetically sealed housing and which provides electrical stimulating pulses to target tissue through a medical lead. The medical lead comprises an elongated flexible plastic lead body having one or more electrodes at a distal end thereof and a terminal pin at a proximal end. The proximal terminal may include one or more electrical contacts that are insulated from one another and connected by elongated conductors extending through the lead body and connected to the distal electrodes.
Affixed to the housing of the pulse generator is a header, typically formed from an insulating plastic, and having a longitudinally extending bore into which the proximal terminal of the medical lead may be inserted. Disposed in the longitudinal bore are one or more contacts for mating with the contact on the lead's proximal terminal. The header contacts are connected by feed through wires, which extend through hermetic seals into the interior of the housing where they connect to the electronic circuitry comprising the pulse generator.
To prevent the lead's proximal terminal from moving within the lead receiving bore of the header, a lead lock is generally provided. One form of lead lock typically comprises a metal or plastic block captured in the lead receiving bore of the header, where the block includes a bore coaxially aligned with the lead receiving bore in the header. A transverse threaded bore is formed that intersects with the longitudinal bore in the block. A setscrew is fitted into the threaded bore and is intended to be tightened against a proximal end portion of the medical lead's terminal pin when inserted into the header to thereby prevent longitudinally directed forces on the lead from pulling the terminal pin free from the pulse generator's header.
It may happen, however, that an implanting physician may fail to adequately advance the setscrew with a sufficient force to hold the lead terminal in place. Such an event can result in a failure of the tissue stimulating device to properly function and, of course, is to be avoided.
A need, therefore, exists for a way of indicating whether a lead lock mechanism in the header of an implantable tissue stimulating device has been engaged so as to positively lock the proximal terminal of a medical lead in place. The present invention meets that need. | {
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Automation for the assembly of optoelectronic or photonics devices is an important way to reduce the manufacturing cost of these products. In one such manufacturing process, an optical axis of an optoelectronic device (for example, a light emitting device, photodetector or optical waveguide) is aligned with an optical axis of an optical fiber, and the aligned parts are then mechanically coupled. If the optical coupling efficiency is low, problems like a high loss of optical energy, a short transmission distance and a low signal-to-noise ratio may result.
Thus, high-precision alignment techniques are adopted in the assembly of these products to ensure high performance of the products. Both active and passive alignment techniques have been developed to address the requirement of high coupling efficiency. There are advantages and disadvantages associated with each of these techniques. Generally speaking, passive alignment techniques are faster but ultimately, the precision achieved using these techniques can hardly be less than one micron. In addition, the initial cost for making submounts for performing passive alignment is high. In comparison, with current motion control technology, active alignment techniques can achieve sub-micron accuracy and no passive alignment submount is needed. Unfortunately, most of the active alignment techniques are very time-consuming and therefore also very expensive for manufacturers.
Single-mode pigtailed laser diode devices are among the most common optoelectronic components which are produced in large quantities. A process for manufacturing these devices includes an alignment and coupling process as described above. Despite the simple structure of this device, its manufacturing cost is quite high due to the fact that it may incur a long assembly process time to align a single-mode fiber with a laser diode source actively in order to obtain a product with reasonably high coupling output. As a matter of fact, some manufacturers still rely on manual or semi-automated systems to perform this active alignment in their production lines. In order to reduce the manufacturing cost of this kind of products, a fully-automated system with a short assembly process cycle and high processing yield is needed.
Various techniques have been developed to speed up the active alignment process and to reduce the time needed for obtaining a high coupling efficiency from a laser diode source to a single-mode optical fiber. In U.S. Pat. No. 6,325,551 entitled “Method and Apparatus for Optically Aligning Fibers with Optical Devices”, an active alignment technique makes use of a positioning system with a high frequency closed loop optical feedback of a modulated signal to and from a light emitting device under assembly. The technique as described in this US patent imposes some complications on the electronic design and motion control for the system design.
Another prior art is described in U.S. Pat. No. 5,666,450, which describes an infrared position sensitive device (PSD) using InGaAs sensing elements to perform a so-called ‘dark search’ or ‘rough search’ of a laser spot before conducting a fine alignment search. This process seeks to reduce the overall alignment process time by dividing the two searches. However, a lot of the process time is still spent on the fine alignment process. The implementation of the technique as described in this US patent is also not easy since the high resolution InGaAs infrared two-dimensional PSD used with the apparatus is very expensive and is not readily available commercially.
The current invention has been especially developed to address the need of assembly automation and the reduction of the alignment process time for these fiber pigtailed devices, although it is also suitable for the coupling of other optoelectronic devices. | {
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Image editing computer applications perform various image enhancement operations on static or video images. Such image enhancement operations generally involve adjusting images so that the results are more suitable for display or further image analysis. Image enhancement can involve removing noise, sharpening an image or portions of an image, or brightening an image or portions of an image. Image enhancement may take an input image and adjust the individual pixel values (color characteristics) using one or more transformation functions to produce an output image with desired improvements. Image enhancement may add or remove noise from an image, remove unwanted elements, selectively change colors, change image orientation, distort or transform the shape of an image, correct images for lens distortions, make the image lighter or darker, change contrast, apply filters, merge images, change color depth, change contrast and brightness, etc. For example, an image editor can be used to increase the resolution of an images, decrease a level of noise present in the image, and/or decrease an amount of blurring of the image.
Existing image editing computer applications generally enhance images by determining patch updates for multiple patches of the image and then aggregating those patch updates to determine how to update the pixel values of the images. Existing patch aggregation techniques compute pixel update values on a patch-by-patch basis. Such patch-based aggregation techniques cannot be executed in parallel because doing so could result in conflicts when patches attempt to access the same pixel data at the same time. For example, if a given pixel is associated with two patches, executing patch aggregation processes for each of the patches at the same time impermissibly update that pixel at the same time. | {
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The semiconductor integrated circuit (IC) industry has produced a wide variety of digital devices to address issues in a number of different areas. In some of these digital devices, a clock tree is used for distributing a common clock signal to various components in order to synchronize the operation of the various components. Differences in the arrival time of the clock signals at two or more of the various components components of the IC results in errors affecting IC performance, in some instances. | {
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1. Field of the Invention
The present invention relates generally to solar cells, and more particularly but not exclusively to solar cell fabrication processes and structures.
2. Description of the Background Art
Solar cells are well known devices for converting solar radiation to electrical energy. They may be fabricated on a semiconductor wafer using semiconductor processing technology. A solar cell includes P-type and N-type diffusion regions. Solar radiation impinging on the solar cell creates electrons and holes that migrate to the diffusion regions, thereby creating voltage differentials between the diffusion regions. In a backside contact solar cell, both the diffusion regions and the metal contact fingers coupled to them are on the backside of the solar cell. The contact fingers allow an external electrical circuit to be coupled to and be powered by the solar cell.
Efficiency is an important characteristic of a solar cell as it is directly related to the solar cell's capability to generate power. Accordingly, techniques for improving the efficiency of solar cells are generally desirable. In addition, it is desirable to cut the cost of fabricating solar cells to make them competitive against other energy sources. | {
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Shutter devices are known to be arranged between the front grille and the radiator of a vehicle. Said shutter devices control the passage of air from the front grille to the radiator, which is responsible for dissipating the heat from the engine of a vehicle according to the cooling needs of said engine.
Shutter devices allow reducing vehicle fuel consumption by optimizing the aerodynamics of the vehicle when the cooling needs of the engine allow it.
Shutter devices are known to comprise a frame and a plurality of flaps coupled in a pivoting manner to said frame and positioned so as to obtain the airflow required for cooling the radiator of the engine. These shutter devices also comprise an actuator and a transmission part for transmitting the movement of the actuator to the flaps.
In addition, shutter devices are known to allow the sequential opening of different flap groups. Being able to open one flap group while another flap group remains closed is advantageous in some situations. For example, when the engine is turned off it may be of interest to keep some flaps closed to keep the engine hot, but it may be of interest to open some of them so that the engine does not overheat.
Shutter devices are known to allow the sequential opening of different flap groups using one actuator for each flap group, such that the opening of said groups can be controlled independently.
Shutter devices are also known to allow the sequential opening of different flap groups with a single actuator. For example, patent document DE102011055394A1 discloses a shutter device comprising a plurality of flaps and an actuator coupled to a wheel. The lower flap is coupled to said wheel by means of a first lever whereas the rest of the flaps are coupled to said wheel by means of a second lever. The wheel comprises a first guiding groove in which an end of the first lever is arranged and a second guiding groove in which an end of the second lever is arranged. Since said grooves follow different paths, the movement transmitted by the levers to their respective flaps is different, and a sequential opening is therefore achieved. | {
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(1) Field of the Invention
This invention relates to cotton gins, and more particularly to a cotton gin rib with a tungsten carbide insert attached at the ginning point.
(2) Description of the Related Art
Commercially, cotton is ginned by snagging locks of cotton upon the teeth of a rotating saw and pulling the lint between the ribs of the saw while preventing the seed from passing between the ribs.
It is known that the ribs wear because of the movement of the cotton fibers, seed, and other material upon the rib at this point.
McLean, in his U.S. Pat. No. 1,999,845; states that the rib could be hardened at the point of wear. It is assumed that this statement means case hardening. Also, Headly, U.S. Pat. Nos. 3,369,275; Nayfa 3,694,857; and Nayfa 4,463,479 disclose placing rollers at the ginning point. | {
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Leukemias encompass hematological malignancies, characterized by the clonal expansion of hematopoietic cells exhibiting abnormal proliferation, blocked differentiation, and reduced apoptosis. Leukemias are generally categorized into multiples types, such as acute or chronic, or myeloid or lymphoid, depending on the rate of disease progression and hematopoietic lineage, with further classification into subtypes based on the stage of differentiation blockage.
Chronic myelogenous leukemia (CML) is also known as chronic myeloid leukemia, chronic myelocytic leukemia, or chronic granulocytic leukemia. The majority of patients diagnosed with CML have a characteristic chromosomal abnormality called the Philadelphia chromosome which results in the formation of the BCR-ABL fusion protein. CML generally progresses through three phases characterized by the number of immature leukemic cells in the blood and bone marrow of the patient. Traditional therapies for CML include chemotherapy, bone marrow transplantation, and interferon therapy, although targeted therapies are under development.
Acute myelogenous leukemia (AML), also known as acute myeloid leukemia, acute myelocytic leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia, is characterized by abnormal proliferation of myeloid cells. The development of AML is thought to be mediated by two major mechanisms: increased self-renewal and a block in differentiation of the leukemia cells (Gilliland et al. 2004), in contrast to differentiation in normal hematopoiesis, which is mediated by lineage specific transcription factors (e.g. CEBPα, PU-1) directing the hematopoietic stem cells to differentiate into progenitor cells and finally to mature blood cells (Koschmieder et al. 2005). AML blasts, reflecting the immature, accumulating leukemia cells, can display a block in differentiation at any maturation level.
Standard treatment of AML to date includes intensive chemotherapy and bone marrow transplantation (Hiddemann et al. 2005). The overall long-term survival rate for AML patients is between 20-30%, depending on the treatment regime and study (Buechner et al. 2005). As chemotherapy is not a targeted therapy, AML patients often suffer from side-effects and relapse of the disease. The current standard chemotherapy for AML is a 30 year old treatment regime with cytarabine and an anthracycline, which is cytotoxic and has other deleterious side effects. Despite emerging novel targeted therapies like FLT3 inhibitors and anti-CD33 antibodies, only the introduction of all-trans-retinoic-acid (ATRA) for acute promyelocytic leukemia (also known as APL or AML M3) has provided a differentiating treatment for leukemia cells. The use of ATRA combined with chemotherapy has increased long term survival to 80-90% in APL patients (Kuchenbauer et al. 2005). However, many AML patients are resistant to exogenous differentiating agents, including ATRA (Hiddemann et al. 2004).
Micro RNAs (miRNAs) are generally 21-24 nucleotide (nt) long RNA molecules and are thought to be important posttranscriptional regulators of mRNAs (Bartel 2004). mRNAs are initially transcribed as longer RNA molecules called primary-miRNAs (pri-miRNAs), but undergo a multistep maturation process involving cleavage through Drosha (nuclear) and Dicer (cytoplasmic) (Kim 2005). The resulting double stranded RNA molecule, consisting of the mature miRNA strand and its partially complementary strand counterpart miRNA star (miRNA*), enters a protein complex named RNA induced silencing complex (RISC) that uses the strand with the mature miRNA sequence as template for degradation of the specific, complementary mRNA (Kim 2005). The mature miRNA is characterized by a “seed region”, generally comprising the bases 2-7 of the 5′ end (Lewis et al. 2005). The seed region is thought to primarily define the specificity of a miRNA towards the 3′UTR of its target mRNAs and has been used for computational target predictions (Lewis et al. 2005). For each miRNA a few hundred target mRNAs are predicted, whereas relatively few targets have been experimentally validated to date. Recent deep sequencing approaches led to changes in the current miRNA databases and implicate miRNA* as an active miRNA molecule (Ruby et al. 2006). Furthermore, in some miRNA stemloops, such as mir-302b, both the 5′ and the 3′ stemloop sequences are annotated as mature miRNAs, suggesting that both miRNA strands can have functional properties.
In general, miRNAs are closely related to siRNAs, which are double-stranded RNA molecules that are also processed by Dicer. In contrast to primitive organisms like C. elegans, endogenous siRNAs rarely occur in mammals and consequently do not play a physiological role (Aravin and Tuschl 2005).
A connection between miRNAs and hematopoiesis was made when it was demonstrated that certain miRNAs are expressed within specific hematopoietic lineages and that their expression levels regulate hematopoietic differentiation (Chen et al. 2004). MicroRNA profiling in chronic lymphatic leukaemia and other lymphomas suggests that miRNA expression changes during pathogenesis and implied that miRNAs may play a functional role in hematopoietic disorders. Overexpression of miR-155 and the miR-17-19b cluster was implicated in promoting the development of lymphomas, suggesting that miRNAs can act as oncogenes (Costinean et al. 2006; He et al. 2005).
Relatively little is known about the role of miRNAs in leukemias of myeloid origin. A study correlating the expression levels of 5 miRNAs with the genome-wide mRNA expression profiles of the same leukemias suggested that miR-181a correlates strongly with the AML morphological sub-type and with the expression of genes previously identified through sequence analysis as potential interaction targets (Debernadi et al. 2007). Another study suggested that expression of miR-223 induces granulocytic differentiation in an acute promyelocyte leukemia (APL) model and is controlled by a regulatory circuitry involving miR-223 and two transcriptional factors, NFI-A and CEBPalpha (Fazi et al. 2005). It has been also reported that miR-223 expression underlies a highly conserved transcriptional mechanism involving the myeloid transcription factors PU-1 and CEBPalpha (Fukao et al. 2007). | {
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1. Technical Field
This invention pertains in part to the art of visual communication of symbols and pictures by means of a modulated array of discrete light producing elements which array is smaller in number than the number of elements in the visual scene to be communicated. Also, this invention pertains in part to the art of tachistoscopy wherein visual images are flashed for brief intervals in the field of view of an observer or test subject. And in addition, this invention pertains to the art of creating a visual illusion, wherein the observer perceives images as originating from locations where there is no apparent source.
2. Background Art
Signs, data displays and pictoral displays using discrete light producing elements in an n.times.m array and modulated in intensity to form letters and pictures that are stationary or that move are well known.
A switching light source such as light emitting diodes, cathode ray tube phosphors, and gas discharge tubes permitted the invention of synthetic n.times.m arrays wherein a smaller number of light sources are made to move by mechanical means or to apparently move by mechanical and optical means, or by electromagnetic deflector means, and so to produce light in successive segments from n.times.m locations, the motion/apparent motion and modulating means being done quickly and repetetively so that the well known persistance characteristic of the eye causes the observer to see a complete, steady and constant image, provided he fixes his gaze on the area where the synthetic display is being generated, and provided the scanning means is synchronised to the light modulating means. See for example U.S. Pat. No. 4,099,172, Montanari et al.
The present invention departs from the prior art in that means for moving the light producing elements are omitted from the display device. Instead, the array is fixed in space and modulated in a manner attuned to characteristic scanning motions of the human eye, so that the information is perceived for a short interval after the observers eyes are in motion relative to the array during which interval the eye is normally unreceptive to visual information. This technique achieves an unusual illusory effect of producing a momentary perceptible image in a space dissociated from the actual array of light producing elements.
Although the present invention is simpler than the prior art in that scanning means are obviated and therefore smaller sizes can be achieved; the resultant visual effect is sufficiently different, having new and different applications, so that it is in a class apart from the prior art. | {
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Voice over Internet Protocol (VoIP) represents a variety of different transmission technologies that are used to provide voice communications over Internet Protocol (IP) networks, such as the Internet or similar packet-switched networks. In a general VoIP-based example, a microphone converts sound into analog electrical signals. The analog signals are then converted to a digital form. If desired, compression techniques (e.g., audio codecs that encode speech) are used to reduce bandwidth requirements. The resulting data is formatted into Internet protocol (IP) packets for transmission over the Internet. The process is reversed at the receiving end eventually producing sound from a speaker.
The connection and disconnection processes that are implemented between two VoIP endpoint devices are sometimes referred to as set-up and tear-down, respectively. This set-up and tear-down of calls is implemented according to rules defined by various VoIP (and or video-based) session control protocols, such as, H.323, Session Initiation Protocol (SIP), Real-time Transport Protocol (RTP), and/or IP Multimedia Subsystem (IMS).
The growth of Voice-over-IP (VoIP) devices, services and products presents a number of issues. Call routing is an important consideration in terms of costs for VoIP capable devices. Other issues include call quality factors such as packet loss, packet delay, and packet jitter.
Another expanding area relates to Video-over-IP (VioIP) devices, services and products. Although the data requirements are at least partially different relative to VoIP, similar issues with quality and user experience arise with video transmissions. For instance, packet loss can cause intermittent freezing of a video stream as well as artifacts. Such aspects can be considerably frustrating to a viewer and even render the video stream unintelligible. | {
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The invention relates generally to a system for forming x-rays, and more particularly to a system configured to direct electron beams at a plurality of discrete spots on a target to form x-rays.
X-ray scanning has been used in medical diagnostics, industrial imaging, and security related applications. Commercially available x-ray sources typically utilize conventional thermionic emitters, which are helical coils made of tungsten wire and operated at high temperatures. Each thermionic emitter is configured to emit a beam of electrons to a single focal spot on a target. To obtain a total current of 10 to 20 mA with an electron beam size of 10 mm2, helical coils formed of a metallic wire having a work function of 4.5 eV must be heated to about 2600 K. Due to its robust nature, tungsten wire has been the electron emitter of choice.
There are disadvantages to the use of conventional thermionic filament emitters. Such filament emitters lack a uniform emission profile necessary for proper beam steering and focusing. Further, a higher electron beam current will cause a reduction in the lifetime of such filament emitters. Additionally, such filament emitters require high quiescent power consumption, which leads to the need for larger, more complex cooling architectures, a larger system envelope, and greater cost. | {
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Plasma tools used for semiconductor processes such as chemical vapor deposition (CVD), etching, reactive ion etching and so forth typically employ either inductive coupling or capacitive coupling to strike and maintain a plasma. One advantage of inductively coupled plasmas over capacitively coupled plasmas is that the inductively coupled plasma is generated with a much smaller bias voltage on the substrate, reducing the likelihood of damage thereto. In addition, inductively coupled plasmas have a higher ion density thereby providing higher deposition rates and mean free paths, while operating at a much lower pressure than capacitively coupled plasmas. These advantages allow in situ sputtering and/or ion directionality during processing.
More recently, high density plasma (HDP) CVD processes have been used to provide a combination of chemical reactions and physical sputtering. HDP-CVD processes promote the disassociation of the reactant gases by the application of radio frequency (RF) energy to the reaction zone proximate the substrate surface thereby creating a plasma of highly reactive ionic species. The relatively non-reactive ionic constituents, i.e., Ar, are given high momentum (e field) used to dislodge deposited film material selectively from specific areas along the profile of the film based on a sputter yield curve. The high reactivity of the released ionic species reduces the energy required for a chemical reaction to take place, thus lowering the required temperature for these processes.
The goal in most HDP-CVD processes is to deposit a film of uniform thickness across the surface of a substrate, while also providing good gap fill between lines and other features formed on the substrate. Deposition uniformity and gap via fill are very sensitive to source configuration, gas flow changes, source radio frequency generator power, bias radio frequency generator power, gas nozzle design, including symmetry in distribution of nozzles, the number of nozzles, the height the nozzles are disposed above the substrate support and the lateral position of the nozzles relative to the substrate support. These variables change as processes performed within the tool change and as process gases change.
One problem encountered in semiconductor fabrication is generation and maintenance of plasma density uniformity above the substrate. Plasma uniformity is dependent upon magnetic and electric fields generated in the tool as well as gas flow into and out of the tool. As substrate sizes increase, i.e., to 300 mm, uniformity over a larger area becomes even more difficult achieve.
Another problem which affects deposition uniformity is uneven gas distribution over the substrate surface. Typically, a gas plenum is provided around the perimeter of a processing region and a plurality of nozzles extend radially inwardly to provide gases to the substrate surface. In some applications, the gases tend to be unevenly distributed across the substrate surface, with more gas provided towards the edge of the substrate and less gas provided towards the center of the substrate. In addition, reactant gases are typically mixed in the gas injection system prior to their introduction into the chamber. In these instances, material tends to deposit within the gas injection system itself, thereby clogging some gas injectors further heightening non-uniform gas distribution.
Still another problem encountered is maintaining a uniform temperature across the substrate surface. As a substrate is processed, there exists a significant heat load due to plasma radiation and ion bombardment exposed to the substrate surface. If a temperature gradient exists across the substrate surface, the deposition of the film can proceed in a non-uniform manner. Therefore, it is important to precisely control the temperature of the substrate.
Another problem is deposition of material on the tool itself. During processing, deposition material deposits throughout the tool, on the substrate support member, and on the gas distribution components. Over time, such material build up can flake off into the chamber resulting in particle contamination on the substrate which can compromise the integrity of the devices being fabricated. Thus, the tool must be periodically cleaned. A favored method of cleaning is to introduce cleaning gases into the chamber to react with the deposited material to form a product which can be exhausted from the chamber. Typically, a cleaning gas, such as a fluorinated gas, is introduced into the chamber and a plasma is struck in the chamber. The resultant excited products react with the deposition material to form gas phase byproducts which are then exhausted from the chamber. One problem with this process is that cleaning is typically localized in regions adjacent to the plasma. In order to enhance cleaning of all exposed chamber surfaces, the time period in which the cleaning process is performed is increased, thereby decreasing throughput, and/or the cleaning process is performed using high temperatures, thereby effectively over cleaning some of the chamber surfaces and increasing the cost of consumables and/or maintenance intervals.
Therefore, there is a need for a process tool which provides more uniform conditions for forming thin CVD films on a substrate, including enhanced cleaning features and high throughput, in a more manufacturing worthy way. | {
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In the above-described technical field, patent literature 1 discloses a technique of determining a bone cutting position from an inverted image of an unaffected bone and an image of a target bone. Patent literature 2 discloses a technique of generating a prosthetic artificial bone model based on a determined bone cutting position. Non-patent literature 1 shows software that generates 3D bone surface model (STL: Stereo Lithography) data from DICOM (Digital Imaging and Communication in Medicine) data that is a standard format of a medical image of CT (Computed Tomography)/MRI (Magnetic Resonance Imaging) or the like. Non-patent literature 2 shows software that simulates bone and joint surgery in advance using 3D bone surface model (STL) data. | {
"pile_set_name": "USPTO Backgrounds"
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Cameras face a fundamental trade-off between spatial resolution and temporal resolution. For example, many digital still cameras can capture images with high spatial resolution, while many high-speed video cameras suffer from low spatial resolution. This limitation is due in many instances to hardware factors such as readout and analog-to-digital (A/D) conversion time of image sensors. Although it is possible to increase the readout throughput by introducing parallel A/D convertors and frame buffers, doing so often requires more transistors per pixel, which lowers the fill factor, and increases the cost, for such image sensors. As a compromise; many current camera manufacturers implement a “thin-out” mode, which directly trades-off the spatial resolution for higher temporal resolution, thereby degrading the image quality.
Accordingly, new mechanisms for providing improved temporal resolution without sacrificing spatial resolution are desirable. | {
"pile_set_name": "USPTO Backgrounds"
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1. Technical Field
The present disclosure relates to an adhesive air guiding device, and a motherboard with the adhesive air guiding device.
2. Description of Related Art
Typically, a fan is mounted in a computer chassis to direct air from outside into the chassis, for forming airflow in a direction to cool a plurality of electronic components on a motherboard mounted on the chassis. However, most of the electronic components each have a sidewall perpendicular to the direction of the airflow, which will block the airflow and affect heat dissipation of the electronic components. | {
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Many elderly people live alone. The elderly also are at risk from disease and illness. Among other symptoms, a person may begin walking slower as their health declines or when they become ill. Similarly, a person recovering from an illness may begin walking faster as their health improves. Thus, a person's walking speed may be used as an indicator of health.
A system for identifying the walking speed of person in his living space is disclosed in U.S. Pat. No. 7,535,368.
The disclosed system comprises a plurality of sensors disposed in various rooms of a home. The sensors provide signals representative of motion and/or the location of the person within the home. The system also includes a unit receiving the sensor signals. The unit derives the location of the person on the basis of the sensor signals. The unit establishes a travel time for a path traveled by the person through the structure based on the established locations and stores the travel time. The unit measures the time traveled by the person through his home along a path defined by a number of sensor locations. The unit identifies a change in the person's walking speed by identifying changes in the travel time for the path traveled by the person.
The system may alert a caregiver to inform them of the change in walking speed identified by the system.
It is important that the reliability of the determined changing in walking speed is high, so that the caregiver can trust the information about the walking speed changings and false alerts are prevented. | {
"pile_set_name": "USPTO Backgrounds"
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Patent Document 1 describes compounds (I) and (II), which are useful as anti-HIV drugs and shown by formulae:
This document describes the following reaction formula as a method of producing compound (I).
Furthermore, Patent Documents 2 to 6 describe the following reaction formula as an improved method of producing compound (I).
However, the above production methods of these documents are not satisfactory for the industrial manufacturing method because of the followings:
these reaction processes for obtaining compound (I) include 16 or 11 steps, respectively, and are very long,
the total yield is low, thus being inefficient,
a high toxic and harmful reaction is used.
an expensive reagent is used,
an environmentally harmful reagent is used.
Therefore, the development of a method for more efficient industrial mass-production of compound (I), compound (II) and their derivatives has been desired.
Non-Patent Documents 1 and 2 describe a method of producing pyrane-4-one and pyridine 4-one. Patent Document 7 and Non-Patent Document 3 describe a method of producing enaminone derivatives. However, a method of producing pyronediester and pyridonediester of the present invention is not described in these documents. Furthermore, a method of manufacturing compounds having HIV-integrase inhibitory activity by using the production method of the present invention is not disclosed. Patent Document 8 is an international patent application by the present applicant. Though this document describes the method of producing pyronediester and pyridonediester identical to the present invention, compounds having HIV-integrase inhibitory activity and anti-HIV drugs are not described therein. | {
"pile_set_name": "USPTO Backgrounds"
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In the current cellphone market, more and more functions are introduced into different types of cellphones, such as the personal digital assistant (PDA), the smart phone, the clam shell phone, the bar type phone, the flip type phone and so on. No matter how the form of cellphones varies, the basic amount of input component, i.e. the keys, is always the same. As the functions of the cellphone become more and more complicated, it would be a serious problem if the amount of keys is insufficient to meet these functions. Because the amount of keys is unchangeable, the operation of the keys for different functions would be complex and troublesome.
In addition, the size of cellphones tends to be miniaturized in the future. However, with so many functions in one cellphone, it has become an important issue for cellphone manufacturers to provide the user with a more convenient operation, by means of more convenient hot keys or more keys to meet so many functions. However, it is certain that there will be more and more functions introduced into the cellphone, and it is difficult for the cellphone to be equipped with so many keys thereon due to its limited space.
From the above description, it is known that how to develop an input component with more operational functions has become a major problem waited to be solved. In order to overcome the drawbacks in the prior art, an improved input component is provided. The particular design in the present invention not only solves the problems described above, but also is easy to be implemented. Thus, the invention has the utility for the industry. | {
"pile_set_name": "USPTO Backgrounds"
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Previously, many types of shower water conservation devices have been used to provide an effective means for saving water when showering. Typically, when a person is ready to shower, the hot water valve is turned on and the person waits until the shower water is hot. The person then adjusts the water mixture until the desired water temperature is achieved. The reason for the wait is that in many cases the water heater is located some distance from the shower and the water in the pipes leading to the shower has been standing, thus causing the water to cool down and to reach equilibrium with the prevailing ambient temperature. Obviously, the initial cooled water is wasted because it is drained into the sewer system.
A search of the prior art did not disclose any patents that possess the novelty of the instant invention, however the following U.S. patents are considered related:
Patent NumberInventorIssue DateU.S. Pat. No. 4,224,700BloysSep. 30, 1980U.S. Pat. No. 4,854,498StaytonAug. 8, 1989U.S. Pat. No. 4,854,499NewmanAug. 8, 1989U.S. Pat. No. 5,277,218SanchezJan. 11, 1994U.S. Pat. No. 5,285,537HanksFeb. 15, 1994U.S. Pat. No. 5,689,543Duke et al.Nov. 25, 1997
U.S. Pat. No. 4,224,700 discloses a water conservation shower device that incorporates a stopper for insertion into the shower drain which includes a water pump attached to a shower head. Water accumulated in the bottom of the shower is re-circulated and reapplied through the shower head.
U.S. Pat. No. 4,854,498 discloses a shower temperature control system that includes a mixing valve which is connected between the hot and cold sources of water and a shower head. A gear motor shaft is connected to the mixing valve and controls the blend using a temperature sensor positioned in the shower plumbing.
U.S. Pat. No. 4,854,499 discloses a temperature sensitive shower diverter valve for diverting shower water used between the water source and the shower head.
U.S. Pat. No. 5,277,218 discloses a water delivery conduit operative through a valve member which directs water from a shower conduit to a storage tank. The storage tank permits selective use of water from a primary conduit or from the delivery conduit for the utilization of water therefrom.
U.S. Pat. No. 5,285,537 discloses an apparatus that includes a pickup head mounted to a shower drain, which is operative through a storage tank for pressurized flow to an auxiliary shower head.
U.S. Pat. No. 5,689,543 discloses a water conservation system for a shower. The system utilizes a foot operated control valve piped to a T-spigot that is connected to the shower head, thereby reducing the water flow by usage only when required.
For background purposes and as indicative of the art to which the invention is related reference may be made to the remaining patents located in the search:
Patent NumberInventorIssue DateU.S. Pat. No. 4,554,688Puccerella26 Nov. 1985U.S. Pat. No. 5,692,675Arlie 2 Dec. 1997U.S. Pat. No. 5,862,544Placencia26 Jan. 1999U.S. Pat. No. 7,024,706Hess11 Apr. 2006 | {
"pile_set_name": "USPTO Backgrounds"
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Cleaning solutions used where items, such as dishes or clothing, are washed or rinsed in a standing volume of water accumulates soils from the items and often results in a reddish-brown hue after several items are washed or rinsed. The perception is that such reddish-brown water is “dirty” and unfit for further use. Conventional dyes have been in an attempt to mask such reddish-brown water, but this has lead to less than acceptable results for consumers and impacting on other aesthetic aspects of the cleaning product.
Chelating agents have been used in cleaning products. However these types of chelating agents do not impact the aesthetic aspect of the color of the washing or rinsing volume of water utilized and these types of chelating agents do not change color upon complexation. Rather known chelating agents remove ions from the volume of water that impact the cleaning of the cleaning product. Therefore there exists a need to have a cleaning product having acceptable aesthetic aspects that is able to mask the reddish-brown water color after items are washed or rinsed in a standing volume of water. | {
"pile_set_name": "USPTO Backgrounds"
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1. Technical Field
The present invention relates to computer aided design, and more particularly to systems and methods for fast and accurate integrated circuit design tools.
2. Description of the Related Art
Fast and accurate circuit simulations and analysis are required to capture rapidly-changing device features, intrinsic device fluctuation, and random mismatch among adjacent devices in integrated circuits. Numerical device simulations (i.e., technology computer aided design (TCAD) based on drift-diffusion or hydrodynamic transport with partial differential equations are physically accurate tools. However, simulation run-time is significantly extended due to complex computations and computational overhead. Furthermore, to achieve and understand “statistical” distributions is very challenging in TCAD-aided analysis and for design for manufacturability (DfM) applications.
For circuit functionality at the macroscopic level, conventional statistical methods are typically based on threshold voltage (Vt), channel length (L), and channel width (W) distributions. These parameters include the use of standard deviations for Vt, L, and W. Thus, the application of conventional statistical methods is limited to critical circuits such as SRAM and eDRAM circuits (e.g., in mixed-mode simulations). However, a domain not adequately addressed thus far is the device or process functionality at the microscopic level. Statistical analyses should address device or process functionality and yield using different-level parameters beyond the macroscopic level of conventional circuit analysis tools. | {
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1. Field of the Invention The present invention relates to a structure of an optical connector and an aligning method for obtaining coincidence between the optical axes of optical fibers to be coupled to each other.
2. Description of the Related Art Referring first to FIGS. 3 to 6, a description will be made hereinbelow of a structure of a prior optical connector assembly made by the present assignee of this application.
FIG. 3 is a cross-sectional view showing the optical connector assembly, FIG. 4 is an illustration useful for explaining a fitting structure of a tube base fixed to a ferrule body and an optical connector housing, FIG. 5A is a perspective view showing the optical connector housing cut vertically, FIG. 5B is a perspective view showing the tube base fixed to the ferrule body, and FIGS. 6A and 6B are perspective views showing the optical connector housing and a key.
As shown in FIG. 5B, a tube base 2 has a cylindrical configuration and a portion 2d of an inner diameter of a hollow section 2c is formed to have a dimension slightly smaller than an outer diameter of a ferrule body 1. Further, a plurality of notch portions 2a and a plurality of fitting portions 2b are formed on an outer circumferential portion of the tube base 2.
The ferrule body 1 is fitted in the aforesaid inner-diameter portion 2d under pressure.
The ferrule body 1 has, at its central portion, an elongated small hole 1a for accepting and holding an optical fiber, and a clad portion of the optical fiber is inserted into this small hole 1a and fixed through an adhesive thereonto.
As shown in FIG. 5A, the optical connector housing 3 has a hollow section 3c having an inner diameter larger than the outer diameter of the tube base 2 and further has, in its bottom surface, a through hole 3a larger than the outer diameter of the ferrule body 1. In addition, on an inner circumferential surface of the hollow section 3c, one or more projecting portions 3b to be fitted in the notch portions 2a made in the outer circumferential portion of the tube base 2 are formed connectively with the through hole 3a. Moreover, a screw thread 3e is made in an inner circumferential surface of the hollow section 3c. Further, as shown in FIG. 6B, a circumferential groove 3d is made in an outer circumferential portion of the optical connector housing 3, and a key 4 with a tongue portion 4a shown in FIG. 6A is fixedly fitted over the circumferential groove 3d.
A holder 6 to be screwed into the optical connector housing 3 has a hollow section 6a with an inner diameter larger than an outer diameter of an optical fiber sheath 11 and further has, at its end portion, a coupling hole 6d with an inner diameter larger than an outer diameter of a spring 5, with a step portion 6c being formed between the coupling hole 6d and the hollow section 6a. A screw thread 6e is made on an outer circumferential portion of the holder 6.
In assembling, the ferrule body 1 is inserted into the optical connector housing 3 in a direction indicated by an arrow 13 in FIG. 5B, and the notch portions 2a of the tube base 2, fixed to the ferrule body 1, are engaged with the projecting portions 3b formed on a case section bottom surface. Whereupon, as shown in FIG. 4, an optical fiber end surface 1b of the ferrule body 1 protrudes from the through hole 3a in the case section bottom surface to the exterior of the optical connector housing 3.
As shown in FIG. 3, over the outer circumferential portion of the tube base 2 there is fitted the spring 5 having an outer diameter smaller than an inner diameter of the coupling hole 6d of the holder 6. One end portion of the spring 5 is placed against rear end surfaces 2e of the projecting portions 2b of the tube base 2, and in a manner that the screw thread 3e of the optical connector housing 3 is engaged with the screw thread 6e of the holder 6, the other end portion of the spring 5 hits against the step portion 6c of the holder 6.
Furthermore, a housing cover 10 having a screw thread 10b in its inner circumferential portion is set on the optical connector housing 3, thereby completing the optical connector assembly.
Secondly, using an adapter housing, a description will be made hereinbelow of a coupling structure of the aforesaid optical connector assembly. FIG. 7A is a side elevational view showing an adapter housing, FIG. 7B is a cross-sectional view thereof, FIG. 8A is a perspective view showing the adapter housing vertically cut, FIG. 8B is a perspective view showing a sleeve, FIG. 9 is a front elevational view available for describing the coupling structure of the optical connector assembly based upon the adapter housing, and FIG. 10 is an illustration for describing a method of making the coincidence between the axes of end surfaces of ferrule bodies within the adapter housing.
As shown in FIGS. 7A, 7B, 8A and 8B, an adapter housing 8 has, at its both end portions, circular tube grooves 8a each accepting the tip portion of the optical connector housing 3 and further has coupling grooves 8b each accepting the tongue portion 4a of the key 4. Further, it has, on its outer circumferential portion, screws thread 8c each engaged with the housing cover 10. In addition, it accepts, in its interior, a cylindrical sleeve (made of a metal or a zirconia ceramic) 9 having a cut section 9a at its central portion.
For the connection of the optical connector assembly, as shown in FIG. 9, the ferrule bodies 1 of the optical connector assemblies are respectively inserted from both sides into the adapter housing 8. The ferrule body 1 enters the sleeve 9, and the tongue portion 4a of the key 4 is fitted in the coupling groove 8b. In this case, the exit side end surfaces 1b of the ferrule bodies 1 are placed into contact with each other. Further, the screws thread 10b of the housing covers 10 are respectively tightly engaged with the screws thread 8c of the adapter housing 8, thus completing the connection.
At this time, a gap occurs because of a difference between the center of the small hole 1a being at the central portion of the ferrule body 1 and the center of the outer diameter of the ferrule body 1 or a difference between the inner diameter of the small hole 1a and the outer diameter of the clad of the optical fiber, whereupon an axial slippage E occurs between the center of a core portion 1d and the center of the outer diameter of the ferrule body 1 as shown in FIG. 10. Owing to this axial slippage E, if the ferrule bodies 1 are aligned with each other on the basis of their outer diameters through the use of the sleeve 9 housed in the adapter housing 8, the difference in position between the centers of the core portions 1d of the optical fibers being in opposed relation to each other comes to a maximum in the case that the slippage occurs in the opposite directions. Therefore, the positional difference F between the core portions 1d of the optical fibers being in opposed relation to each other becomes a maximum of 2E, so that the optical loss increases at the connecting point.
For eliminating this problem, in the prior art, the axial slippage E directions of the two optical connector assemblies to be joined to each other are coincided with each other with reference to the keys 4 of the optical connector housings 3 to be connected to each other, thereby minimizing the positional difference F between the core portions. In this way, the aligning work is done to reduce the optical loss at the connecting point.
In the case of the prior optical connector assemblies, after the assembling the ferrule body 1 protruding from the optical connector housing 3 can not freely rotate with respect to the key 4 of the optical connector housing 3 because the notch portions 2a made on the fixed tube base 2 are engaged with the projecting portions 3b made on the inner circumferential surface of the optical connector housing 3. Accordingly, for achieving the minimum optical loss, the key 4 of the optical connector housing 3 is made as a separate detachable part, and detached from the assembly and again attached thereto in a state where its attaching position is changed in the rotating direction. For a proper connection, this work is repeatedly done.
However, in the case of this aligning method, in addition to taking a long time, the abrasion powders of the optical connector housings and the keys generated when detaching the key sections stick to the optical fiber end surfaces of the ferrule bodies, which are cut and damaged to deteriorate their optical characteristics.
Another aligning method has been as follows.
The exit side end surface 1b of the ferrule body 1 for fixing the tube base 2 is polished before being built in the optical connector housing 3. The sleeve 9 is used without being accommodated in the adapter housing 8, and the ferrule bodies being in the opposed relation to each other are connected to each other, and they are rotated while measuring the optical loss, thereby taking the optimal position. In addition, they are inserted into the optical connector housing 3 in a state with keeping this condition, and the spring 5 is inserted thereinto and then the optical connector housing 3 is sealed with the holder 6. The alignment is accomplished by this method.
However, according to this aligning method, since the ferrule body is directly inserted into the sleeve not accommodated in the adapter housing, difficulty is encountered to straightly apply the pressing force in the direction of the axis of the ferrule body. For this reason, the sleeve receives a bending force and, hence, deforms, which produces a positional difference between the center positions of the fibers being in an opposed condition. This causes difficulty of sure alignment.
In addition, for the production of connectors with optical fibers laid for optical connector connections, it is necessary that the abrasion, alignment and assembling of optical connectors are done at the laying place or that the ferrule body sections of the optical connectors polished at a factory or the like are conveyed in a state of being not built in the spring, the optical connector housings and holders and the assembling and alignment are made at the laying place. | {
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Infants and other incontinent individuals wear absorbent articles such as diapers to receive and contain urine and other body exudates. Absorbent articles function both to contain discharged materials and to isolate the materials from the body of the wearer and from the wearer's garments and bed clothing. Disposable absorbent articles having many different basic designs are known to the art. For example, U.S. Pat. No. Re. 26,152, entitled “Disposable Diaper” issued to Duncan and Baker on Jan. 31, 1967 describes a conventional disposable diaper which has achieved worldwide acceptance and commercial success. Further, U.S. Pat. No. 5,246,433 entitled “Elasticized Disposable Training Pant And Method of Making The Same” issued to Hasse et al. on Sep. 21, 1993 discloses a unitary disposable absorbent article that can be used as a training pant.
In the market today, the consumer has a number of different basic diaper designs to choose from depending on the desired options, comfort and cost, including conventional diapers, belted diapers, and “pull-on” type diapers or training pants. However, many of the absorbent articles on the market today are capable of fitting only a small range of wearer sizes and therefore, the consumer must continually monitor the size of the wearer to determine which diaper will comfortably and effectively fit the wearer. Further, most commercially available diapers are limited in that they can only effectively be used in one of the above-mentioned configurations without any of the benefits attributable to any of the other diaper types. Thus, the consumer must purchase different diapers depending on the desired characteristics for the intended use.
Conventional diaper designs are generally the least expensive type of absorbent article to produce and are generally acceptable for use on babies and persons who are sick or otherwise confined to a bed. A conventional diaper is fitted to the wearer by first placing a portion of the diaper under the wearer (generally, the back portion of the diaper is placed under the buttocks and rear waist of the wearer) and then pulling the remainder of the diaper through the wearer's legs. The rear portion of the diaper is then attached to the front portion of the diaper on each side of the wearer. However, such conventional configurations tend to be very difficult to use when the wearer refuses to remain still throughout the period of application. Further, adult wearers and children in their toilet training stage often find the conventional type absorbent articles difficult to put on themselves without assistance.
The “pull-on” design absorbent article is often used in training pants and incontinence briefs. The “pull-on” design allows the wearer to pull the absorbent article on as pants and does not require any of the fastening steps of the conventional or belted type absorbent article designs. Although this feature is desirable for many adult users and children in their toilet training stage, the “pull-on” design is impractical for many users, especially those bed ridden and small children unable to dress themselves. Pull-on absorbent articles generally lack any features that allow the diaper to be put on, removed or checked for soiling without removal of the diaper and the wearer's outer clothing. Further, such articles often lack features that allow for convenient, sanitary disposal of the article.
The present invention combines the benefits of a conventional diaper with those of a “pull-on” type diaper. Further, the diaper of the present invention can comfortably and effectively fit a large range of wearer sizes. These unique characteristics are provided by the inventive coordination of special ear panels and fastening elements. The ear panels and fastening elements work together to solve the problems encountered in earlier attempts to provide some of the features of the present invention. For example, the present invention can be fitted to a wide range of wearers in the conventional configuration and provide excellent containment and comfort characteristics due to the ability of the ear panels to provide a snug fit when fitted to small wearers as well as a snug comfortable fit to much larger wearers. The refastenable fastening system provides a strong closure that can withstand the dynamic forces created by the motions of the wearer; the forces generally being different depending on the size and age of the wearer. Further, structural design of the diaper provides the user with the opportunity to use the diaper as a pull-on. The unique ear panels provide the necessary stretch to effectively accommodate a large range of wearers as well as the stretch needed to provide for easy application as a pull up diaper. Again, the fastening system complements the ear panels to provide a strong closure, yet still provides a means for removing the pull-on by opening the closures rather than pulling the diaper down over the hips of the wearer. This makes the removal of a soiled diaper a much quicker and cleaner without the need to remove the wearer's clothing. Furthermore, the refastenable fastening system provides a pull-on user with the ability to check for soiling of the diaper by opening one or more of the closures rather than removing the diaper completely. Also, the absorbent article of the present invention can easily be configured with a disposal feature (often the fastening system) which provides a convenient, sanitary means for disposing of the soiled article.
In the past, diapers designs attempting to provide the benefits described above have been generally unable to solve the problems associated with providing a diaper that effectively and comfortably fits a large range of wearer sizes as well as provides at least two ways in which the diaper may be constructed and fit to the wearer. In attempting to fit a large range of wearers, previous diaper designs (both conventional and pull-on) have generally been loose and ineffective containing the waste of small wearers while being extremely tight, uncomfortable and unable to withstand the dynamic forces produced by large wearers. Further, many pull-on designs lacked any means for checking the diaper for soiling without removal of the diaper and often the wearer's clothing. Likewise, pull-on designs generally lack any means for removing a soiled diaper without having to tear one or more elements (generally seams) of the diaper which can renders the diaper useless if checked for soiling. Also, pull-on diapers generally lack any means for convenient disposal.
Therefore, it would be beneficial to provide an absorbent article having a refastenable fastening system and stretchable ear panels designed to allow the absorbent article to be fitted to the wearer in a conventional or “pull-on” configuration.
It is also would be beneficial to provide an absorbent article that will effectively and comfortably fit a large range of wearer sizes in either a conventional or a pull-on configuration.
It is still would be beneficial to provide a diaper that can be fitted to a wearer or removed as a pull-on or a conventional diaper.
These and other objects of the present invention will be more readily apparent when considered in reference to the following description and when taken in conjunction with the accompanying drawings. | {
"pile_set_name": "USPTO Backgrounds"
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Tubular prostheses are used in body lumens to perform various functions. For example, a tubular stent may be used to maintain the opening of an esophagus that has been restricted by a tumor or a blood vessel restricted by plaque. Tubular grafts are used to substitute for or reinforce a weakened lumen, such as the aorta or other blood vessel that has been weakened by an aneurysm. In this latter technique, a graft of a knitted dacron may be used to advantage since the textured nature of the textile can induce blood clotting along the graft to contribute to the patency of the lumen formed by the graft.
Tubular prostheses for purposes such as the above may be positioned in the body lumen during a surgical procedure or may be delivered into the body by a catheter that supports the prosthesis in a compact form during percutaneous insertion and transport through body passageways to a desired site. Upon reaching the site, the prosthesis is expanded so that it engages the walls of the lumen. After this operation, the catheter is removed, leaving the device in the body.
The expansion technique may involve forcing the prosthesis to expand radially outwardly, for example, by inflation of a balloon carried by the catheter. Knitted, balloon expandable stents are discussed for example in Strecker U.S. Pat. No. 4,922,905, the entire content of which we hereby incorporate by reference. In another technique, the prosthesis is formed of an elastic material that can be arranged and held in a compact form for insertion and allowed to expand when in position by its own internal elastic restoring force. Knitted self-expanding stents are described in Strecker PCT EP 91/02194 and in Anderson U.S. Ser. No. 07/773,847, filed Oct. 9, 1991, the entire contents of both applications being incorporated herein by reference. | {
"pile_set_name": "USPTO Backgrounds"
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Pelvic health for men and women is a medical area of increasing importance, at least in part due to an aging population. Examples of common pelvic ailments include incontinence (e.g., fecal and urinary), pelvic tissue prolapse (e.g., female vaginal prolapse), and conditions of the pelvic floor.
Urinary incontinence can further be classified as including different types, such as stress urinary incontinence (SUI), urge urinary incontinence, mixed urinary incontinence, among others. Other pelvic floor disorders include cystocele, rectocele, enterocele, and prolapse such as anal, uterine and vaginal vault prolapse. A cystocele is a hernia of the bladder, usually into the vagina and introitus. Pelvic disorders such as these can result from weakness or damage to normal pelvic support systems.
Urinary incontinence can be characterized by the loss or diminution in the ability to maintain the urethral sphincter closed as the bladder fills with urine. Male or female stress urinary incontinence (SUI) generally occurs when the patient is physically stressed.
In its severest forms, vaginal vault prolapse can result in the distension of the vaginal apex outside of the vagina. An enterocele is a vaginal hernia in which the peritoneal sac containing a portion of the small bowel extends into the rectovaginal space. Vaginal vault prolapse and enterocele represent challenging forms of pelvic disorders for surgeons. These procedures often involve lengthy surgical procedure times.
Urinary incontinence can be characterized by the loss or diminution in the ability to maintain the urethral sphincter closed as the bladder fills with urine. Male or female stress urinary incontinence (SUI) occurs when the patient is physically stressed.
There is a desire to obtain a minimally invasive yet highly effective supportive implant that can be used to treat conditions that include incontinence, pelvic organ prolapse, and others. Moreover, there is ongoing desire to identify methods and implantable supportive implants that are able to be placed efficiently and effectively within a patient in a manner that provides effective or optimal support, and that can be placed with certain efficacy. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a spread illuminating apparatus, and more particularly to a spread illuminating apparatus used with a liquid crystal display.
2. Description of the Related Art
A liquid crystal display (hereinafter referred to as LCD), which is small in power consumption, low in profile, and light in weight, is heavily used in electric products such as a personal computer (hereinafter referred to as PC), a cellular phone, and the like, and is increasingly demanded.
Since a liquid crystal of the LCD does not emit light by itself, the LCD requires an illuminating means to radiate light on the liquid crystal when used in a place where sunlight or interior lighting is not fully available.
A PC, particularly notebook-type PC, and a cellular phone are required to be lower in profile and smaller in power consumption, and the requirements are fulfilled by a spread illuminating apparatus of side light type.
A conventional spread illuminating apparatus of side light type is shown in FIG. 13. In FIG. 13, a spread illuminating apparatus 1′ generally comprises a light conductive plate 2 made of a light transmissible material, and a bar-like lamp 5 disposed along and close to an end face 8 of the light conductive plate 2. Light emitted from the light lamp 5 is introduced into the light conductive plate 2 and directed to an LCD (not shown) disposed under the light conductive plate 2.
The lamp 5 comprises a light conductive bar 3 made of a light transmissible material, and two spot-like light sources 4, 4 (for example, light emitting diodes) disposed facing respective end faces 6, 7 of the light conductive bar 3. The light conductive bar 3 has an optical path conversion means 12 formed on a side face thereof opposite to a side face 9 facing the end face 8 of the light conductive plate 2. The optical path conversion means 12 comprises, for example, a plurality of grooves shaped triangular in section, and is adapted to guide light, which is emitted from the light source 4 into the light conductive bar 3, toward the end face 8 of the light conductive plate 2 in a substantially uniform manner. The light conductive bar 3 is disposed with its side face 9 facing the end face 8 of the light conductive plate 2 with a predetermined distance therebetween.
The light conductive bar 3 has a light reflection member (frame) 13 substantially U shaped in section and disposed therearound. The light reflection member 13 covers the longitudinal faces of the light conductive bar 3 except the side face 9 facing the light conductive plate 2.
The light conductive plate 2 has a light reflection pattern 19 formed on its upper face 15, and has a plain surface on its lower face 26. The light reflection pattern 19 has a stair-like configuration in section, comprising a plurality of small surfaces 17 having its longitudinal direction parallel to the length of the light conductive bar 3, and a plurality of large surfaces 18 each present between two adjacent small surfaces 17. The light reflection pattern 19 is adapted to guide light, which is emitted from the lamp 5 into the light conductive plate 2, toward the LCD (not shown) disposed under the light conductive plate 2. The light reflection pattern 19 may alternatively comprise a plurality of grooves, and a plurality of flat portions present between two adjacent grooves.
In the front-lighting system where an illuminating apparatus using the light reflection pattern 19 is disposed over the front face of a reflection type LCD element, when light reflected at the reflection type LCD element passes through the light reflection pattern 19, an interference fringe (moire pattern) appears, which is formed by the striping generated due to a difference in light outgoing efficiency resulting from a difference in refractive index between at the small surface 17 and at the large surface 18, and by the arrangement of the mosaic pattern (cell boundary) of crystal cells constituting pixels of the LCD, and which is detrimental to the observation of the image on the display. The moire pattern is closely related with the configuration of the light reflection pattern 19, specifically, the dimensions and inclinations of the small surfaces 17 and the large surfaces 18, or the like.
Also, there appears a light and dark striping of another kind different from the above described moire pattern. The light and dark striping is peculiar to the front-lighting system, and is characterized in that its location and striping interval change according to the position of the observer's eye. It has become apparent that the light and dark striping is generated by reflected light due to Fresnel reflection at the lower face of the light conductive plate opposite to the face provided with the light reflection pattern, that is, reflected light caused by the difference in refractive index between the light conductive plate and the air. It has been known that this reflected light has an adverse influence on the contrast characteristics of the display device, and the light conductive plate normally has non-reflective coating applied to its lower face for improving contrast.
The current non-reflective coating suppresses light reflection significantly but not down to 0% across the visible display area, normally allowing some 0.2% of light incident thereon to be reflected. This slight amount of reflected light generates the light and dark striping. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The invention relates to the field of integrated circuit devices and more particularly to improved scaleable transistor devices for us in high performance circuits.
2. Description of Related Art
Shallow and/or lightly doped source/drain junction structures are widely used in modern metal oxide field effect transistors (MOFETs). The shallow and/or lightly doped junction improves the hot electron reliability and reduces short channel effects, such as punch-through, Drain-Induced-Barrier-Lowering, and threshold voltage roll-off. In general, a reduction in the short channel effects also yields better gate control.
One shortcoming of the shallow and/or lightly doped source/drain junction structures is that such structures tend to increase the parasitic resistance of the junctions. An increased parasitic resistance tends to reduce the resistor drive current.
What is needed is a transistor device and a method of forming a transistor device that offers the benefits of shallow and/or lightly doped junction structures without the parasitic resistance shortcoming seen with these structures. | {
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At present, the prior art provides some approaches for trying to meet the previously described needs. For example a first approach may be identified as Static Bit-mapping. Briefly, memory locations under failure are identified by reading the data stored in these memory locations, and by comparing this data with the expected values.
More particularly, this type of bitmapping allows downloading of the read data in a sequential way and comparing them with the expected values through an exclusive OR (EX-OR) operation at all the times that a memory location is accessed, and also if the read datum is equivalent to the expected one. In this case, the scanning BIST algorithm interrupts the scanning of the volatile memory while an external pin of the device is serially provided with the data compared in the EX-OR for comparison with the expected values.
This approach may be able to identify only static failures since the sequential access to the memory locations does not occur at the nominal working frequency, but is interrupted by the serial downloads. A second approach is Bitmapping on error. This second approach may be considered as a first in, first out (FIFO) structure for identifying the failure state.
According to this type of bitmapping, the read data may be serially downloaded only in case of a failure. Typically, there is a structure of FIFO registers with N stages to collect, at the same memory working speed and the nominal frequency, the failure states, and thus prevent the execution of the BIST algorithm of the RAM devices from being interrupted in case of consecutive multiple errors. The single stage of the FIFO structure is serially downloaded.
This architecture has the advantage of executing a bitmapping at the nominal frequency in case of consecutive failures and if the FIFO structure is not filled, i.e. in case an overflow in the FIFO structure does not occur. However, there are several drawbacks which limit the application of this diagnosis method.
For example, in case of filling of the FIFO structure, the failures detected are mixed (static/dynamic). In fact, when an overflow occurs, the sequential access to the memory is suspended until at least one register or stage of the FIFO structure is freed. Moreover, the tester should dynamically synchronize the download of the data since the failures are not deterministic, just like the flow of the data being output. Thus, it may be difficult to define the depth of the FIFO structure since a high number of registers or stages increases the occupied area even if it improves the possibility of executing a diagnosis at the same working speed of the memory device. In other words, if the FIFO structure is full, it may be impossible to detect failures of dynamic transitions.
The technical problem is that of providing a shared diagnosis method of the BIST algorithm for random access volatile memory devices having such features as to allow a dynamic bitmapping, overcoming, at the same time, the limits of the approaches already provided by the prior art. | {
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Embodiments of the invention relate to processes for producing synthesis gas (“syngas”), a mixture primarily comprised of CO and H2. In particular, embodiments of the invention relate to processes for producing synthesis gas through steam reforming. Hydrogen production, as a component of synthesis gas production, is typically performed through catalytic steam reforming. The general reaction for catalytic steam reforming is as follows:
C x H y O z + ( x - z ) H 2 O → catalyst x CO + ( x - z + y 2 ) H 2
Synthesis gas (including hydrogen) can be produced from methane containing feedstocks by steam methane reforming (SMR), an endothermic reaction carried out either in heat exchange reactors, or by other means where substantial heat may be transferred to the reacting fluid, such as in the case of autothermal reforming (ATR), where a portion of the feedstock is combusted inside the reactor to provide heat for steam reforming either subsequently or in the same location as the combustion. Synthesis gas can also be produced from methane containing feedstocks by CO2 (“dry”) reforming, catalytic or thermal partial oxidation (CPOx or POx, respectively) and other processes known in the art. If hydrocarbon or alcohol feedstocks enriched, either naturally or by purposeful addition, in compounds with two or more carbon atoms per molecule (C2+ hydrocarbons) are used for hydrogen, or synthesis gas, generation, the risk of catalyst deactivation by carbon deposition in the hydrogen or synthesis gas generation reactor is greatly increased. As used herein, “enriched in compounds with two or more carbon atoms per molecule” generally means having greater than 5% C2+ hydrocarbons.
In order to minimize the risk of carbon deposition, existing hydrogen and synthesis gas production processes typically employ at least one adiabatic catalytic reactor prior to the synthesis gas generation reactor. These adiabatic reactors are referred to as pre-reformers.
In existing hydrogen and synthesis gas production processes employing pre-reformers and steam methane reformers, the hydrocarbon feedstock is mixed with 1 to 5% hydrogen by volume, then is subjected to a hydrodesulphurization (HDS) pre-treatment step to remove sulphur. The feedstock hydrocarbons are then mixed with superheated steam in a ratio determined by the average molecular weight of the feedstock molecules. Natural gas or other feedstocks where the average carbon number is less than two are processed with a molar steam to carbon ratio between 3:1 and 5:1. Higher molecular weight feedstocks are often processed with steam to carbon ratios as much as twice as high, between about 6:1 and 10:1. These high steam flowrates are used to suppress carbon formation, and enhance the steam reforming reaction. High steam to carbon ratios disadvantageously increase energy usage in the synthesis gas and/or hydrogen production process.
Existing hydrogen and synthesis gas production processes employing air, oxygen-enriched air, or pure oxygen feedstocks also typically mix the hydrocarbon feedstock with 1 to 5% hydrogen by volume and then conduct hydrodesulphurization to remove sulphur. Steam addition rates, expressed as a molar steam to carbon ratio, in these processes, especially when targeting production of synthesis gas with H2/CO ratios in the 2.0-2.5 range, are much lower than those employed in steam methane reforming, typically in the range of 0.5-1.0, although processes employing ratios as low as 0.2-0.4 (and lower) are known.
Because the reaction rates for steam reforming are low at the pre-reforming feed temperatures of 400° C. to 500° C., pre-reforming catalysts are prepared with very high metal loadings, above 10% by weight, and high metal surface areas. These high metal surface areas present several challenges. First, they are subject to rapid sintering and reduction of activity if feedstock temperature is not controlled very closely. Second, they present substantial safety risk due to their pyrophoric reaction with oxygen, especially when nickel metal is used, thus necessitating great care in handling the catalysts during reduction and subsequent operation. Further, even at the elevated steam to carbon ratios employed in existing steam methane reformer based hydrogen or synthesis gas production processes using pre-reformers for C2+ feedstocks, deactivation by carbon deposition remains a problem. At the much lower steam to carbon ratios typically employed in autothermal reforming or catalytic partial oxidation, deactivation by carbon deposition is especially problematic. Typically, volatile alkali or alkali-silicate promoters are added to suppress carbon deposition. Such promoters are very effective, but disadvantageously reduce catalyst reaction rate, necessitating larger pre-reforming reactors. Further, the promoters tend to volatilize and subsequently deposit on downstream catalysts and equipment. This causes deactivation of downstream catalysts and potential corrosion damage to equipment, both of which may lead to serious operation problems such as hot banding of reformer tubes, carbon deposition and eventual tube failure. Further, the protective effects of the alkali promoters are lost after they are volatilized, such that eventual pre-reformer catalyst failure is assured in such existing pre-reformers. Upon failure, the highly-reactive catalyst must be safely removed from the pre-reformer reactor and replaced.
There is a need for an improved hydrogen and synthesis gas production method that can process feedstocks containing 20% or more of molecules having at least two carbon atoms each without being deactivated by carbon deposition and without requiring the addition of excessive amounts of steam (S/C ratios of 6 to 10:1, or higher). | {
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Computers have become increasingly central to business, finance and other important aspects of our lives. It is now more important than ever to protect computers from "bad" or harmful computer programs. Unfortunately, since many of our most critical business, financial and governmental tasks now rely heavily on computers, dishonest people have a great incentive to use increasingly sophisticated and ingenious computer attacks.
Imagine, for example, if a dishonest customer of a major bank could reprogram the bank's computer so it adds to instead of subtracts from the customer's account--or diverts a penny to the customer's account from anyone else's bank deposit in excess of $10,000. If successful, such attacks would not only allow dishonest people to steal, but could also undermine society's confidence in the integrity and reliability of the banking system.
Terrorists can also try to attack us through our computers. We cannot afford to have harmful computer programs destroy the computers driving the greater San Francisco metropolitan air traffic controller network, the New York Stock Exchange, the life support systems of a major hospital, or the Northern Virginia metropolitan area fire and paramedic emergency dispatch service.
There are many different kinds of "bad" computer programs, which in general are termed "Trojan horses"--programs that cause a computer to act in a manner not intended by its operator, named after the famous wooden horse of Troy that delivered an attacking army disguised as an attractive gift. One of the most notorious kinds is so-called "computer viruses"--"diseases" that a computer can "catch" from another computer. A computer virus is a computer program that instructs the computer to do harmful or spurious things instead of useful things--and can also replicate itself to spread from one computer to another. Since the computer does whatever its instructions tell it to do, it will carry out the bad intent of a malicious human programmer who wrote the computer virus program--unless the computer is protected from the computer virus program. Special "anti-virus" protection software exists, but it unfortunately is only partially effective--for example, because new viruses can escape detection until they become widely known and recognized, and because sophisticated viruses can escape detection by masquerading as tasks the computer is supposed to be performing.
Computer security risks of all sorts--including the risks from computer viruses--have increased dramatically as computers have become increasingly connected to one another over the Internet and by other means. Increased computer connectivity provides increased capabilities, but also creates a host of computer security problems that haven't been fully solved. For example, electronic networks are an obvious path for spreading computer viruses. In October 1988, a university student used the Internet (a network of computer networks connected to millions of computers worldwide) to infect thousands of university and business computers with a self-replicating "worm" virus that took over the infected computers and caused them to execute the computer virus instead of performing the tasks they were supposed to perform. This computer virus outbreak (which resulted in a criminal prosecution) caused widespread panic throughout the electronic community.
Computer viruses are by no means the only computer security risk made even more significant by increased computer connectivity. For example, a significant percentage of the online electronic community has recently become committed to a new "portable" computer language called Java.TM. developed by Sun Microsystems of Mountain View, Calif. Java was designed to allow computers to interactively and dynamically download computer program code fragments (called "applets") over an electronic network such as the internet, and execute the downloaded code fragments locally. Java's "download and execute" capability is valuable because it allows certain tasks to be performed locally on local equipment using local resources. For example, a user's computer could run a particularly computationally or data-intensive routine--relieving the provider's computer from having to run the task and/or eliminating the need to transmit large amounts of data over the communications path.
While Java's "download and execute" capability has great potential, it raises significant computer security concerns. For example, Java applets could be written to damage hardware, software or information on the recipient computer, make the computer unstable by depleting its resources, and/or access confidential information on the computer and send it to someone else without first getting the computer owner's permission. People have expended lots of time and effort trying to solve Java's security problems. To alleviate some of these concerns, Sun Microsystems has developed a Java interpreter providing certain built-in security features such as:
a Java verifier that will not let an applet execute until the verifier verifies the applet doesn't violate certain rules, PA1 a Java class loader that treats applets originating remotely differently from those originating locally, PA1 a Java security manager that controls access to resources such as files and network access, and PA1 promised to come soon--the use of digital signatures for authenticating applets. PA1 the owner may wish to "turn off" payment mechanisms necessary to ensure that people delivering content and other value receive adequate compensation; or PA1 the owner may wish to defeat other electronic controls preventing him or her from performing certain tasks (for example, copying content without authorization); or PA1 the owner may wish to access someone else's confidential information embodied within electronic controls present in the owner's protected processing environment; or PA1 the owner may wish to change the identity of a payment recipient indicated within controls such that they receive payments themselves, or to interfere with commerce; or PA1 the owner may wish to defeat the mechanism(s) that disable some or all functions when budget has been exhausted, or audit trails have not been delivered. PA1 Encrypting and authenticating load modules whenever they are shared between protected processing environments via a communications path outside of a tamper-resistant barrier and/or passed between different virtual distribution environment participants; PA1 Using digital signatures to determine if load module executable content is intact and was created by a trusted source (i.e., one with a correct certificate for creating load modules); PA1 Strictly controlling initiation of load module execution by use of encryption keys, digital signatures and/or tags; PA1 Carefully controlling the process of creating, replacing, updating or deleting load modules; and PA1 Maintaining shared secrets (e.g., cryptographic keys) within a tamper resistant enclosure that the owner of the electronic appliance cannot easily tamper with.
Numerous security flaws have been found despite these techniques. Moreover, a philosophy underlying this overall security design is that a user will have no incentive to compromise the security of her own locally installed Java interpreter--and that any such compromise is inconsequential from a system security standpoint because only the user's own computer (and its contents) are at risk. This philosophy--which is typical of many security system designs--is seriously flawed in many useful electronic commerce contexts for reasons described below in connection with the above-referenced Ginter et al. patent specification.
The Ginter et al. specification describes a "virtual distribution environment" comprehensively providing overall systems and wide arrays of methods, techniques, structures and arrangements that enable secure, efficient electronic commerce and rights management, including on the Internet or other "Information Super Highway."
The Ginter et al. patent disclosure describes, among other things, techniques for providing a secure, tamper resistant execution spaces within a "protected processing environment" for computer programs and data. The protected processing environment described in Ginter et al. may be hardware-based, software-based, or a hybrid. It can execute computer code the Ginter et al. disclosure refers to as "load modules." See, for example, Ginter et al. FIG. 23 and corresponding text. These load modules--which can be transmitted from remote locations within secure cryptographic wrappers or "containers"--are used to perform the basic operations of the "virtual distribution environment." Load modules may contain algorithms, data, cryptographic keys, shared secrets, and/or other information that permits a load module to interact with other system components (e.g., other load modules and/or computer programs operating in the same or different protected processing environment). For a load module to operate and interact as intended, it must execute without unauthorized modification and its contents may need to be protected from disclosure.
Unlike many other computer security scenarios, there may be a significant incentive for an owner of a Ginter et al. type protected processing environment to attack his or her own protected processing environment. For example:
Security experts can often be heard to say that to competently do their job, they must "think like an attacker." For example, a successful home security system installer must try to put herself in the place of a burglar trying to break in. Only by anticipating how a burglar might try to break into a house can the installer successfully defend the house against burglary. Similarly, computer security experts must try to anticipate the sorts of attacks that might be brought against a presumably secure computer system.
From this "think like an attacker" viewpoint, introducing a bogus load module is one of the strongest possible forms of attack (by a protected processing environment user or anyone else) on the virtual distribution environment disclosed in the Ginter et al. patent specification. Because load modules have access to internal protected data structures within protected processing environments and also (at least to an extent) control the results brought about by those protected processing environments, bogus load modules can (putting aside for the moment additional possible local protections such as addressing and/or ring protection and also putting aside system level fraud and other security related checks) perform almost any action possible in the virtual distribution environment without being subject to intended electronic controls. Especially likely attacks may range from straightforward changes to protected data (for example, adding budget, billing for nothing instead of the desired amount, etc.) to wholesale compromise (for example, using a load module to expose a protected processing environment's cryptographic keys). For at least these reasons, the methods for validating the origin and soundness of a load module are critically important.
The Ginter et al. patent specification discloses important techniques for securing protected processing environments against inauthentic load modules introduced by the computer owner, user, or any other party, including for example:
Although the Ginter et al. patent specification comprehensively solves a host of load module (and other) security related problems, any computer system--no matter how secure--can be "cracked" if enough time, money and effort is devoted to the project. Therefore, even a very secure system such as that disclosed in Ginter et al. can be improved to provide even greater security and protection against attack.
The present invention provides improved techniques for protecting secure computation and/or execution spaces (as one important but non-limiting example, the protected processing environments as disclosed in Ginter et al) from unauthorized (and potentially harmful) load modules or other "executables" or associated data. In one particular preferred embodiment, these techniques build upon, enhance and/or extend in certain respects, the load module security techniques, arrangements and systems provided in the Ginter et al. specification.
In accordance with one aspect provided by the present invention, one or more trusted verifying authorities validate load modules or other executables by analyzing and/or testing them. A verifying authority digitally "signs" and "certifies" those load modules or other executables it has verified (using a public key based digital signature and/or certificate based thereon, for example).
Protected execution spaces such as protected processing environments can be programmed or otherwise conditioned to accept only those load modules or other executables bearing a digital signature/certificate of an accredited (or particular) verifying authority. Tamper resistant barriers may be used to protect this programming or other conditioning. The assurance levels described below are a measure or assessment of the effectiveness with which this programming or other conditioning is protected.
A web of trust may stand behind a verifying authority. For example, a verifying authority may be an independent organization that can be trusted by all electronic value chain participants not to collaborate with any particular participant to the disadvantage of other participants. A given load module or other executable may be independently certified by any number of authorized verifying authority participants. If a load module or other executable is signed, for example, by five different verifying authority participants, a user will have (potentially) a higher likelihood of finding one that they trust. General commercial users may insist on several different certifiers, and government users, large corporations, and international trading partners may each have their own unique "web of trust" requirements. This "web of trust" prevents value chain participants from conspiring to defraud other value chain participants.
In accordance with another aspect provided by this invention, each load module or other executable has specifications associated with it describing the executable, its operations, content, and functions. Such specifications could be represented by any combination of specifications, formal mathematical descriptions that can be verified in an automated or other well-defined manner, or any other forms of description that can be processed, verified, and/or tested in an automated or other well-defined manner. The load module or other executable is preferably constructed using a programming language (e.g., languages such as Java and Python) and/or design/implementation methodology (e.g., Gypsy, FDM) that can facilitate automated analysis, validation, verification, inspection, and/or testing.
A verifying authority analyzes, validates, verifies, inspects, and/or tests the load module or other executable, and compares its results with the specifications associated with the load module or other executable. A verifying authority may digitally sign or certify only those load modules or other executables having proper specifications--and may include the specifications as part of the material being signed or certified.
A verifying authority may instead, or in addition, selectively be given the responsibility for analyzing the load module and generating a specification for it. Such a specification could be reviewed by the load module's originator and/or any potential users of the load module.
A verifying authority may selectively be given the authority to generate an additional specification for the load module, for example by translating a formal mathematical specification to other kinds of specifications. This authority could be granted, for example, by a load module originator wishing to have a more accessible, but verified (certified), description of the load module for purposes of informing other potential users of the load module.
Additionally, a verifying authority may selectively be empowered to modify the specifications to make it accurate--but may refuse to sign or certify load modules or other executables that are harmful or dangerous irrespective of the accuracy of their associated specifications. The specifications may in some instances be viewable by ultimate users or other value chain participants--providing a high degree of assurance that load modules or other executables are not subverting the system and/or the legitimate interest of any participant in an electronic value chain the system supports.
In accordance with another aspect provided by the present invention, an execution environment protects itself by deciding--based on digital signatures, for example--which load modules or other executables it is willing to execute. A digital signature allows the execution environment to test both the authenticity and the integrity of the load module or other executables, as well permitting a user of such executables to determine their correctness with respect to their associated specifications or other description of their behavior, if such descriptions are included in the verification process.
A hierarchy of assurance levels may be provided for different protected processing environment security levels. Load modules or other executables can be provided with digital signatures associated with particular assurance levels. Appliances assigned to particular assurance levels can protect themselves from executing load modules or other executables associated with different assurance levels. Different digital signatures and/or certificates may be used to distinguish between load modules or other executables intended for different assurance levels. This strict assurance level hierarchy provides a framework to help ensure that a more trusted environment can protect itself from load modules or other executables exposed to environments with different work factors (e.g., less trusted or tamper resistant environments). This can be used to provide a high degree of security compartmentalization that helps protect the remainder of the system should parts of the system become compromised.
For example, protected processing environments or other secure execution spaces that are more impervious to tampering (such as those providing a higher degree of physical security) may use an assurance level that isolates it from protected processing environments or other secure execution spaces that are relatively more susceptible to tampering (such as those constructed solely by software executing on a general purpose digital computer in a nonsecure location).
A verifying authority may digitally sign load modules or other executables with a digital signature that indicates or implies assurance level. A verifying authority can use digital signature techniques to distinguish between assurance levels. As one example, each different digital signature may be encrypted using a different verification key and/or fundamentally different encryption, one-way hash and/or other techniques. A protected processing environment or other secure execution space protects itself by executing only those load modules or other executables that have been digitally signed for its corresponding assurance level.
The present invention may use a verifying authority and the digital signatures it provides to compartmentalize the different electronic appliances depending on their level of security (e.g., work factor or relative tamper resistance). In particular, a verifying authority and the digital signatures it provides isolate appliances with significantly different work factors--preventing the security of high work factor appliances from collapsing into the security of low work factor appliances due to free exchange of load modules or other executables.
Encryption can be used in combination with the assurance level scheme discussed above to ensure that load modules or other executables can be executed only in specific environments or types of environments. The secure way to ensure that a load module or other executable can't execute in a particular environment is to ensure that the environment doesn't have the key(s) necessary to decrypt it. Encryption can rely on multiple public keys and/or algorithms to transport basic key(s). Such encryption protects the load module or other executable from disclosure to environments (or assurance levels of environments) other than the one it is intended to execute in.
In accordance with another aspect provided by this invention, a verifying authority can digitally sign a load module or other executable with several different digital signatures and/or signature schemes. A protected processing environment or other secure execution space may require a load module or other executable to present multiple digital signatures before accepting it. An attacker would have to "break" each (all) of the several digital signatures and/or signature schemes to create an unauthorized load module or other executable that would be accepted by the protected processing environment or other secure execution space. Different protected processing environments (secure execution spaces) might examine different subsets of the multiple digital signatures--so that compromising one protected processing environment (secure execution space) will not compromise all of them. As an optimization, a protected processing environment or other secure execution space might verify only one of the several digital signatures (for example, chosen at random each time an executable is used)--thereby speeding up the digital signature verification while still maintaining a high degree of security. | {
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1. Technical Field
The present disclosure relates to a hub, and particularly, to an optical fiber hub.
2. Description of Related Art
Optical fiber connectors have been widely used as bus interfaces for installing and expending conventional USB hosts and USB function device. For instance, the USB host can be a computer, the USB function device can be a computer peripheral, such as a keyboard, a mouse, a printer, a cameral, or a projector. However, the USB host is generally communicated with the USB function device through a single optical fiber connector. This fails to satisfy requirements of simultaneously transmitting signals between an USB host and a plurality of USB function devices. Therefore, it is desired to provide an optical fiber hub capable of connecting a plurality of downstream peripherals to a single upstream host to overcome at least one of the aforementioned shortcomings. | {
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1. Field of the Invention
The present invention generally relates to technological field of devices detecting acceleration devices and detecting acceleration methods, as well as neutral control devices employing these acceleration devices or methods. More specifically, the present invention relates to correcting an error in a detected acceleration of a vehicle.
2. Background Information
In conventional acceleration detection devices, a zero point correction of an acceleration sensor is carried out by averaging detected acceleration values each time that the vehicle stops, and adding or subtracting this average value (drift from the zero point of the acceleration sensor) to or from the current detected acceleration value (see for example, Japanese Laid-Open Patent Application No. 7-159438). Thus, the zero point correction aids in eliminating the effect of a sloping road on the acceleration sensor.
In view of the above, it will be apparent to those skilled in the art from this disclosure that there exists a need for correcting the drift error or the like of a vehicle acceleration sensor. This invention addresses this need in the art as well as other needs, which will become apparent to those skilled in the art from this disclosure. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field
The following description relates to wireless communication and, more particularly, to an apparatus and method for performing handover in a multiple component carrier system.
2. Discussion of the Background
Cellular communication is a concept that has been introduced to overcome the restriction of a service area and the restriction of frequency and subscriber capacity. Cellular communication includes a method for providing coverage by changing a single high-output base station into a plurality of low-output base stations. That is, a mobile communication service area is divided into several small cells, different frequencies are allocated to neighboring cells, and the same frequency band is used by two cells which are sufficiently spaced apart from each other, thus not having interference therebetween, so that the frequency can be spatially reused.
Handover refers to a function in which, if a user equipment exits a current communication service area (hereinafter referred to as a ‘serving cell’) and moves to a neighboring communication service area (hereinafter referred to as a ‘neighbor cell’), the user equipment is tuned with a new traffic channel of the neighbor cell, thus continuously maintaining a traffic state. A user equipment communicating with a specific base station (hereinafter referred to as a ‘source base station (BS)’ is linked to another neighbor base station (hereinafter referred to as a ‘target BS’) through handover if the intensity of a signal in the source base station becomes weak. When handover is performed, a problem, such as call disconnection occurring when a user equipment moves from one cell to a neighbor cell, can be solved.
In general, a wireless communication system uses one bandwidth for data transmission. For example, the 2nd generation wireless communication system uses a bandwidth of 200 KHz to 1.25 MHz, and the 3rd generation wireless communication system uses a bandwidth of 5 MHz to 10 MHz. In order to support an increasing transmission capacity, the bandwidth of a recent 3GPP LTE or 802.16m has extended to 20 MHz or higher. To increase the bandwidth may be considered indispensable so as to increase the transmission capacity, but to support a high bandwidth even when the quality of service required is low may generate great power consumption.
In order to solve such problem, there has emerged a multiple component carrier system in which a component carrier having one bandwidth and the center frequency are defined, and data is transmitted or received through a plurality of component carriers using a wide band. That is, a narrow band and a wide band are supported at the same time by using one or more component carriers. For example, if one component carrier corresponds to a bandwidth of 5 MHz, a bandwidth of a maximum 20 MHz can be supported by using four component carriers.
However, in a handover in a base station using a single component carrier, the base station only performs the handover by taking only a single cell, measured and reported by a user equipment, into consideration. In case of a multiple component carrier system, however, the handover procedure must be performed by taking multiple component carriers into consideration. To this end, a target base station has to configure component carriers necessary for a user equipment through the handover procedure and has to provide a quality of service to the degree that a source base station provided the quality of service to the user equipment. In this case, it is difficult to configure an adequate level of component carriers or appropriate component carriers because the target base station may not accurately determine the quality of service was provided to the user equipment before the handover. Accordingly, there is a need for an apparatus and method for performing handover by taking multiple component carriers into consideration. | {
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The present invention relates to data processing and more particularly to management of a data storage cache where cache control employs dual stacks.
Memory systems in computers generally have two layers: a slow, inexpensive layer for mass storage (main memory) and a fast, more expensive layer (cache) for current use. Main memory is typically implemented in the form of disk storage while cache memory is typically implemented in semiconductor technology.
Cache management is an important aspect of every computer system. The goal is always to cache or store in the fast, more expensive layer of memory those items which will be frequently used in the future but only those items. Choosing which items to store in cache memory is done on the basis of item use history. A primary characteristic of cache performance is hit ratio, the frequency with which memory requests are satisfied using items already stored in the cache. It is well-known that some stored data is accessed more frequently than other stored data. If frequently used main memory, typically disk sectors, can be quickly and accurately identified, the data in such sectors can be moved to cache storage to improve the hit ratio and accelerate data retrieval, thereby boosting overall system performance.
While much of the following discussion is in the context of movement of stored data from main memory to cache memory in computer memory systems, it should be understood that caching techniques can also be useful where tables of calculated values must be constructed and maintained to support other computer processes. An example is a routing table used for making routing decisions in TCP/IP networks. By using caching techniques to build a small routing table containing only frequently used information, it may be possible to boost the overall performance of a router system.
Depending upon the application, cache control can be implemented using either of at least two techniques. According to the first technique, each location in a cache memory is used to store both a data unit to be made available to a computer system and a small, unambiguous label that functions as a pointer to that data unit. According to the second technique, only the labels are stored in the cache control element with the labels serving as pointers or addresses to data units stored in a separate cache memory unit. The first technique may be favored for applications in which the size of the data units is limited since the first technique avoids the need to address a separate cache memory. The second technique may be favored where large data units need to be accommodated. While the following description may refer only to the existence of labels or entries in cache stacks, it should be understood that the description is intended to cover cache systems implemented using either of the two techniques described.
Presently cache maintenance problems are commonly solved with a cache replacement algorithm known as Least Recently Used (LRU). In a computer memory system using LRU for cache management, the cache is refreshed each time a memory request is generated. Initially, all entries in the cache have a default value assumed here to be zero. When a new request can be satisfied using an entry already stored in the cache, the entry is retrieved from the cache without going to main memory. The entry is moved to the top of the cache stack and other entries in the stack are pushed down one position in the stack without changing their relative order.
When a request cannot be satisfied with cached entries, the entry is retrieved from main memory, sent to the requesting system and also written into the position at the top of the stack. Existing stack entries are pushed down one position with the stack entry previously at the bottom of the stack being discarded.
Discussions of LRU, related cache algorithms and their performance can be found at page 378 of Computer Architecture: a Quantitative Approach, 2nd edition, by J. Hennessy and D. Patterson, published in San Francisco by Morgan Kaufinan in 1990, and in R. Bachrach and Ran El-Yaniv, Online list accessing algorithms and their applications: recent empirical evidence, Proceedings of the Eight Annual ACM-SIAM Symposium on Discrete Algorithms, (1997) Vol. 8, pages 53-62.
The present invention is an improvement over known LRU algorithms which is believed to provide a higher hit ratio and thus an improvement in overall system performance under typical operating conditions.
The invention makes use of a cache storage control having two stacks. The first stack, which may be referred to as a preliminary stack, and the second stack, which may be referred to as the real stack, are preferably but not necessarily the same size; that is, have the same number of storage locations. When a new label request is received, both stacks are checked to determine whether a label already exists in the stacks. If the requested label is found in either stack, it is retrieved from the stack in which it is found and processed to recover the associated data unit. A conventional LRU algorithm of the type discussed above is used to refresh both the first and the second stacks. If the requested label is not found in either stack, the second stack is tested to determine if the bottom stack position is empty. If the bottom position is empty, the requested label (retrieved from a primary data source in a separate operation) is written to the top position of the second stack and all prior stack entries are pushed down one stack location. If the bottom position of the stack is not empty, all existing stack entries at and below a predetermined insertion point are shifted down one position with the label previously at the bottom the stack being discarded. The requested label is then written into the predetermined insertion point in the second stack. | {
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The present invention relates to an image forming apparatus such as a laser printer.
As an image forming apparatus such a laser printer, an upright-type image forming apparatus is generally known. For example, Japanese Laid-open Patent Application No. 2003-302889 discloses such an upright-type image forming apparatus, in which a paper feed tray (recording sheet storage unit) for storing papers as recording sheets and a paper output tray (recording sheet receiving unit) are arranged back and forth with these trays positioned upright.
In this image forming apparatus, the paper feed tray is arranged higher than the paper output tray, so that a paper conveyance passage extending from a lower part of the paper feed tray to a lower part of the paper output tray for conveying a paper is bent to form an L-shaped configuration. An image forming unit which forms an image on a paper is positioned intermediate of this paper conveyance passage at an extension extending downward from the lower part of the paper feed tray.
More specifically, the image forming unit includes a developer unit equipped with a toner cartridge and a developing roller, and a fixing device for thermally fixing developer that is transferred on a paper. The image forming unit is arranged such that the fixing device is positioned below the developer unit on the paper conveyance passage. Further, in this image forming apparatus, the toner cartridge is arranged between the paper output tray and the paper feed tray.
However, in this image forming apparatus, because the fixing device is positioned below the developer unit, heat generated at the fixing device rises to the developer unit. This may cause the developer unit to be heated disadvantageously, and as a result heat deterioration of the developer may occur. Further, because this image forming apparatus is configured such that the toner cartridge is arranged between the paper output tray and the paper feed tray, the size of the whole apparatus becomes disadvantageously large in a horizontal direction.
In view of the foregoing drawbacks of the prior art, the present invention seeks to provide an upright-type image forming apparatus which can restrict an increase in the size of the apparatus in the horizontal direction as well as heat deterioration of the developer. | {
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Computing devices may include memory modules. When in use, the memory modules may generate excessive heat, which may adversely affect the memory modules and/or other components of the computing device. A memory module cooler may be used to cool the memory modules. | {
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As show in FIG. 1, with the reduction of the cost of LED, the LED used as a back light source is widely used in the field of LCDs because of the characteristics of high efficiency, energy saving and long service life. However, the high-brightness LED(s) has certain heat dissipation problem; particularly in the gradually compact back light module, the temperature will continuously rise because of narrow space and difficulty in heat dissipation; and the overhigh LED temperature will have an influence on the optical taste and the display effect of the overall back light module and will reduce the LED service life. | {
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The present invention relates to a frequency conversion circuit.
A frequency conversion circuit is an essential circuit in a receiver. In a frequency conversion circuit, the non-linear characteristic of an active element such as a transistor is utilized to convert two signals of other frequencies.
An example of a frequency conversion circuit is shown in FIG. 1. Two signals A and B respectively having different frequencies f.sub.A and f.sub.B are applied respectively through d.c. blocking capacitors C.sub.1 and C.sub.2 to the base of a bipolar transistor Q.sub.1, which is a non-linear characteristic active element. An output signal C having a desired frequency f.sub.C is provided at the collector load of the transistor, specifically, a collector tuning circuit composed of a capacitor C.sub.3 and a transformer T.sub.1. A power source E.sub.1 and a resistor R.sub.1 provide base bias for the transistor Q.sub.1.
The input and output characteristic of the transistor Q.sub.1 can be represented by the following equation: EQU v.sub.o =a.sub.1 v.sub.i +a.sub.2 v.sub.i.sup.2 +a.sub.3 v.sub.i.sup.3 +(1)
where a.sub.1, a.sub.2, a.sub.3, . . . are constants, v.sub.i is the input signal, and v.sub.o is the output signal.
The case where a desired signal of frequency f.sub.d1 and interference signals of frequencies f.sub.1 and f.sub.2 which are close to f.sub.d1, as shown in FIG. 2, are applied to the transistor circuit having the above-described construction will be considered. If it is assumed that the frequencies of the interference signals are: f.sub.1 =f.sub.d1 +.DELTA.f and f.sub.2 =f.sub.d1 +2.DELTA.f, respectively, then signals having frequencies mf.sub.1 .+-.nf.sub.2 (where m and n are integers) are outputted. For m=2 and n=1, the following equation can be written: EQU 2f.sub.1 -f.sub.2 =2(f.sub.d1 +.DELTA.f)-(f.sub.d1 +2.multidot..DELTA.f)=f.sub.d1. (2)
That is, because of the non-linear characteristic operation of the transistor, an interference signal having the same frequency f.sub.d1 as that of the desired signal is produced from the two interference signals f.sub.1 and f.sub.2.
If m=-1 and n=2, the following equation can be written: EQU 2f.sub.2 -f.sub.1 =f.sub.d1 +3.multidot..DELTA.f=f.sub.d2. (3)
Thus, in receiving the second desired signal f.sub.d2, an interference signal having the same frequency as that of the desired signal is produced. The production of intermodulation (IM) interference signals in the cases of m=2, n=1 and m=-1, n=2 is attributed to the odd order terms of equation (1).
In the circuit of FIG. 1, the collector tuning circuit (C.sub.3 and T.sub.1) operates to select one of the signal frequencies f.sub.A +f.sub.B corresponding to the second order term in equation (1).
The circuit of FIG. 1 is disadvantageous in that, upon reception of the above-described interference signals f.sub.1 and f.sub.2, the desired signal f.sub.d1 =f.sub.A .+-.f.sub.B is subjected to IM (intermodulation) interference. In the conventional circuit, as long as the transistor Q.sub.1 has an input and output characteristic including the aforementioned odd order terms, the occurrence of IM (intermodulation) interference is unavoidable. | {
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This case relates generally to a carrier and a method of use of that carrier. More specifically, this case relates to a carrier for a cuvette used in a medical diagnostic analyzer and a method of using such a carrier.
Medical diagnostic analyzers are machines that process a sample and determine an element of the sample. For example, a medical diagnostic analyzer may process a human blood sample and may determine an amount of cholesterol in that human blood sample.
To do this, the sample may be added to a container, such as a reaction vessel, a cuvette and the like, on the medical diagnostic analyzer. The medical diagnostic analyzer may add other things, such as reagents, etc., to the sample in the container and "look" at the container to determine the element of interest.
Some medical diagnostic analyzers can process a number, such as 250, of samples in a given time period, such as 1 hour. If one container is used for each sample processed, then the medical diagnostic analyzer needs a suitable supply of containers to do the desired processing.
In some cases, a supply of containers are loaded onto the medical diagnostic analyzer. Because the containers may be relatively small, loading of the containers onto the medical diagnostic analyzer may require some effort and time. Also, because the containers are looked at to determine the element of interest in the sample, it is desirable to keep the containers relatively clean, e.g. free of finger prints, etc. Accordingly, it is desirable to provide a carrier that may facilitate loading of containers onto an medical diagnostic analyzer, transport of containers, etc. | {
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At present, the way of fixing the hand-held showerhead is achieved by a separate fixed bracket into which a hose connector of the hand-held showerhead connected to a hose is plugged downwards. Although the above way is simple, the user experience is still not user-friendly enough, and it is very inconvenience especially for users such as the elderly and children in use. To be specific, the hand-held showerhead is originally arranged in a very high fixed bracket, and when the hand-held showerhead is taken off, since it is connected to the fixed bracket at the hose connector, i.e. the plug-in position is at the hose connector which is loose and cannot serve as a force application point, the height of the position where the hand-held showerhead is held must exceed the plug-in position, and then the showerhead can only be taken off from the fixed bracket by lifting the handle of the showerhead up. The whole taking-off process is not user-friendly enough and it is inconvenient in use. Especially in Europe and America, when a hand-held showerhead is plugged into the fixed bracket, the existing method is also used for assembling, the position for fixing the showerhead is arranged below the hand-held showerhead, and both fixing and taking the showerhead can be achieved when the positions of the user's hand exceed the fixed position (plug-in position), so the user experience is insufficient and still needs to be further improved. | {
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In an interconnected computer network, the devices communicate through transactions. A transaction comprises one or more packets and conveys some meaningful information. For example, a CPU in a multiprocessor network may respond to a snoop request with a "snoop response" transaction. Generally, a packet consists of a fixed number of transfers or cycles in the interconnect structure. Different transactions may require different number of packets. A transaction may comprise one or more packets forming the header, followed by zero or more packets forming the accompanying data. The header packet(s) may comprise information such as the source node identifier, the destination node identifier, the address bits, the transaction identifier, length of the transaction, flow-control information. Note that different terms are sometimes used but have the same meaning, for example, it is common to use the terms address cycle and data cycle for the header packet and the data packet, respectively.
The raw bandwidth of an interconnect structure is determined by the number of wires and the frequency at which data is transferred. For example, the raw bandwidth available in a 39-bit wide bus, operating at 100 MHz, is 3900 Mbits/sec. The usable bandwidth would be less due to ECC and header packet overheads. The usable bandwidth will depend on the efficiency of the underlying protocol.
The prior art approach to improving the bandwidth relies on expanding the interconnect width and/or increasing the frequency of operation. This approach yields better bandwidth via wider interconnect andp/or faster data transfer. Thus, the improvement in usable bandwidth is solely due to the improvement in the raw bandwidth. The ratio of the usable bandwidth to the raw bandwidth remains unchanged. However, increasing the raw bandwidth is expensive in terms of manufacturing costs. Moreover, the increase in raw bandwidth may lead to electrical problems in the system interconnect interface. Note that technological limitations will restrict the amount with which the raw bandwidth can be increased.
Encoding schemes such as Hoffman encoding may be able to achieve more bandwidth by encoding the most frequently occurring patterns with less number of bits. However, Hoffman encoding require that these bit patterns be known before their actual use, so that the most used bit patterns are assigned the smallest number of bits. For example, assume that a system uses 4 bits in a pattern, and 1111 is the most common pattern. Using Hoffman coding, this pattern will be assigned 0. The next most common pattern will be assigned 10, the next will be assigned 110, then 1110, etc. Thus, Hoffman coding uses variable lengths of bit patterns to indicate the same width of data transfer. Note that some bit patterns are represented by a single bit and others, particularly, the least used patterns will be represented by more than 4 bits.
In typical systems, it is not possible to identify patterns that are more likely to occur than others, because computer systems exhibit a locality of reference that changes over time with regards to addresses and data patterns. Thus, in a computer system one may not be able to predict which addresses are more likely to be accessed than others, since this depends on the application, and space the address patterns change as the program executes. In other words, if a particular page or address is accessed, then most likely a nearby address will be accessed next. Hoffman codes are static and cannot change over time. Moreover, Hoffman encoding requires more bits for the patterns that are "less likely", as a result one may end up in degraded performance.
Therefore, there is a need in the art for a mechanism which will improve the ratio of usable bandwidth to the raw bandwidth and thereby increase the bandwidth without having to increase the frequency or the number of wires. | {
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1. Field of the Invention
The present invention relates to interface circuits converting send data into a pair of differential voltage signals and outputting the pair of differential voltage signals in sending data, and converting the pair of differential voltage signals received into a former data and outputting the former data in receiving data.
2. Description of Related Art
Recently, serial communications have been spread one of them includes a receiver which needs predetermined receiving sensitivity. For example, in USB specification which is one of the serial communications, as shown in FIG. 5, in the case where a differential voltage of a differential voltage signal is equal to or more than 150 mV and equal to or lower than −150 mV, it is specified that the signals are received as normal signals. In the case where a differential voltage of a differential voltage signal which is input signal is from −100 mV to 100 mV, the signal is cut off because it is squelch condition. As just described, because USB specification requires a high receiving sensitivity, it is desired to confirm a receiving sensitivity accurately and easily.
Here, Japanese Unexamined Patent Application Publication No. 2005-267124 (Yoshimoto) describes a transceiver interface which can estimate a sensitivity of a receiver (receiver for reception). As shown in FIG. 6, a transceiver interface 250 of the prior art realizes a data transfer of serial bus specification by converting send data into a pair of differential voltage signals and outputting it in sending data, and converting the received pair of differential voltage signals into a former data and outputting it in receiving data.
The transceiver interface 250 includes a reference voltage generation circuit 211. The reference voltage generation circuit 211 receives a power supply voltage VDD and a ground power supply voltage VSS and then generates a reference voltage signal. Further the transceiver interface 250 includes an inverter 212 and a pair of current driven drivers 213, 214. The send data is converted into the pair of differential voltage signals by the inverter 212 and a pair of current driven drivers 213, 214. The voltage level of the pair of differential voltage signals is determined by the reference voltage and a termination resistor as described below. The transceiver interface 250 further includes a receiver 215. The receiver 215 converts the pair of differential voltage signals which is received data into the former data.
The transceiver interface 250 further includes a sending data input terminal 201, a power supply input terminal 202, a ground supply input terminal 203, a received data output terminal REC 204, and differential voltage signal input and output terminals DP205, DM206. The differential voltage signal input and output terminals DP205, DM206 are connected to serial cable and input and output a pair of a differential voltage signals.
The transceiver interface 250 can input a voltage signal which is input from an external device and has arbitrary voltage level to the pair of current driven drivers 213, 214. In this way, the reference voltage generation circuit 211 has a first switch circuit (not shown) and a second switch circuit 216. The second switch circuit 216 is connected to a signal input terminal AAP and inputs the voltage signal which has arbitrary voltage level from an external device to the pair of current driven drivers 213, 214. The reference voltage generation circuit 211 is controlled by the first switch circuit so as to input the reference voltage signal to the pair of current driven drivers 213, 214 at normal timing and to shut off supply of the reference voltage signal at test timing.
A switch circuit switches a voltage signal which is input to the pair of current driven drivers 213, 214 to the reference voltage signal from the reference voltage generation circuit 211 or a voltage signal from the signal input terminal AAP207 based on a control signal from a first control terminal 208 connected to the switch circuit which has the second switch circuit 216 and the first switch circuit.
FIG. 7 is a view showing a specific example of the current driven driver. A reference voltage signal which is generated by a reference voltage generating circuit 251 is input to an input terminal 241 of a current driven driver 220. The current driven driver 220 includes send data input terminal 242 to which send data is inputted and a differential voltage signal output terminal 243 to which a reference voltage signal is input. The differential voltage signal output terminal 243 is connected to a differential voltage signal input and output terminal DP205. The current driven driver 220 corresponds to a current driven driver 213. Note, a current driven driver connected to a differential voltage signal input and output terminal DM has a same constitution and operation as above described, therefore the explanation is omitted.
The current driven driver 220 has an operational amplifier 221, P channel transistors 222-225, and N channel transistors 226-228 and transistors 222 and 223, 224 and 225, and 226 and 227 of those transistors configure current mirrors.
A constant current I3 is determined by a voltage level Vref input to a reference voltage input terminal 241 and a current mirror ratio and a driver flowing the constant current I3 is configured. When a signal level of send data is H, the transistor is turned on by terminating a differential voltage signal output terminal 243 with external resistors 230, 231. Then the constant current I3 flows in the external resistors 230, 231 and the voltage level of the differential voltage signal output terminal 243 is determined. That is, if a current flowing in the transistor 225 is I3, and resistances of the resistors 231, 232 are Rs1, Rs2, a voltage of the differential output voltage signal terminal 243 is Vdp=I3((1/Rs1)+(1/Rs2)). On the other hand, when a signal level of send data is L, since transistor 228 is turned off, the constant current I3 does not flow and a voltage level of the differential voltage signal output terminal 243 becomes GND. Thus, the voltage level of the differential voltage signals is determined by the voltage level input to the reference voltage input terminal 241 and resistances of the external resistances 230, 231.
In this prior art, at the sensitivity test of the receiver for itself, the differential voltage signal terminals DP205, DM206 of FIG. 6 are connected to the external resistance. When the signal input terminal AAP is enabled by the control terminal 208, and a voltage signal input from the signal input terminal AAP207 is input to a pair of the current driven drivers 213, 214, a constant current which is proportional to a voltage level which is input is output from the pair of the current driven drivers 213, 214 according to the signal level of the send data. The constant current is flowed in the external resistance, and the voltage level of the differential voltage signal terminals DP205, DM206 are determined, and then a potential difference between the differential voltage signal terminals DP205 and DM206 are generated. The differential signal of the potential is performed whether or not the receiver receives the signal.
Therefore, the sensitivity test of the receiver for itself is performed by inputting an arbitrary voltage level from an external device by using the signal input terminal AAP207 and generating a voltage level corresponding to the arbitrary voltage level in the differential voltage signal terminals DP205 and PM206.
However, according to the transceiver interface 250 of the prior art, there is a problem that an own power supply unit is needed since an arbitrary voltage level is supplied from an external device. Recently, with multi-functionalization by SOC (System On Chip), LSI gets to have many power supplies. Therefore it is not realistic to use a dedicated power supply unit in test. Further there is another problem that a test accuracy becomes low by an external effect such as an accuracy of a voltage supply source or a voltage drop with supplying a power supply from an external device. | {
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This disclosure relates to bit processing.
Some bit processing involves so-called bit-level permutation instructions or operations in which bits of an input ordered bit array (such as an input word) are permuted to form an output ordered bit array according to values of control bits such as so-called sieve bits.
In previously proposed systems, the sieve needs to be analysed to determine how much each data bit must be shifted by (and in which direction) and an n-bit datapath comprising the equivalent of n n-to-1 multiplexers is needed to perform the shifting. Control circuitry in a previously proposed arrangement can be complicated and can lack flexibility, in that it is dedicated to a particular permutation operation. | {
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This invention relates to a switching circuit for connecting an AC source to a load, and particularly to a solid state AC relay circuit which triggers an active switch element such as a triac when the value of the AC voltage to be controlled is substantially zero.
Relay devices generally respond to an input signal and close a switch in a path of main current flow. Where the path of main current flow conducts alternating current between a source and a load, it is desirable to sense the incoming signal and to close the switch during or near the next succeeding passage of the source voltage through zero. This avoids the transient problems that might otherwise occur if the switch were closed at an instant when the AC voltage being controlled had a substantial value.
The most convenient switch available for turning alternating current on and off is a so-called triac, a thyristor that breaks down when a voltage is applied in either direction across the two main electrodes and a correspondingly poled voltage is connected to a gate or control electrode. Conduction continues until the voltage at the main electrodes is removed or reversed. In constrast to a silicon controlled rectifier, conduction may occur in either direction.
In order to switch on the triac at or near the zero passage of the voltage, complicated circuits which draw large current have been used in past devices to avoid applying the input signal until the zero passage time occurs in the next alternating current cycle. For example, the circuit disclosed in U.S. Pat. No. 3,648,075 utilizes two diode bridges, an SCR, four transistors, three capacitors, a transformer, and additional circuitry. Such an arrangement is comparatively complex and draws a substantial amount of current to energize these components.
An object of the invention is to avoid these difficulties.
Another object of the invention is to improve devices at this time. | {
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The present invention relates generally to valves used in oilfield and, more particularly, to seal assemblies for valves and methods of sealing valves.
Various types of valves are used in oilfield well exploration, drilling, and production equipment. Valves are coupled to a pipeline and are typically used to shut off or turn on the flow of a fluid, such as a liquid, gas or both. Valves are typically either unidirectional or bi-directional. In a unidirectional valve, the valve has to be placed only in one unique way in a pipeline so as to match the pressure direction. In a bi-directional valve, either side of the valve can be used as the upstream side, which allows the valve to be placed in a pipeline without any specific side facing the direction of pressure. Valve sealing components are usually symmetrical for ease of installation and maintenance and to achieve bi-directionality.
A gate valve is a type of valve that includes a substantially rectangular-shaped gate that is moved by an operator in and out of the valve body to control the fluid. The operator may be manual or may be actuated hydraulically, pneumatically or electrically, for example. A gate valve also includes an annular or ring-shaped seat member that seals against the gate. Depending on gate valve design, one seat member may be disposed on either side of the gate, or alternatively, additional seat members may be disposed adjacent the seat member, which members are involved in the sealing of the valve. The additional seat members seal the passage between the seat member and body pocket.
A valve body pocket generally houses the seal assembly. A valve seal assembly generally includes sealing members such as the seat member adjacent the valve engaging member and other associated seat members which may be referred to as a body bushing or pocket insert, as examples. A seal assembly also generally includes at least one seal ring, which provide a seal between the various seat members, valve body pocket and the gate. Expanding gate valves utilize expanding gate assembly structures comprising a gate element and segment, which are adapted to expand transversely of one another against the sealing rings.
Another type of valve design is a plug valve, where a cylindrical plug having a bore in the center thereof is used to either block fluid flow, or to allow fluid to pass through the valve by rotating the plug. When the plug bore is aligned in parallel with the valve bore, the valve is open and fluid flows through the plug. When the plug bore is aligned perpendicular to the valve bore, the valve is closed and fluid is blocked from flowing through the plug.
Gate valves are classified as either downstream or upstream sealing. For downstream sealing gate valve designs, the sealing is done at the downstream side of the valve. The downstream side of the valve is the side farthest from the pressure source. Therefore, a valve having a downstream sealing design seals on the side of the valve farthest from the pressure source. In contrast, a valve having an upstream sealing design seals on the side of the valve closest to the pressure source.
Various types of seal assemblies have been devised for such valves. With many of these, such as where the seats are press-fit into seat pockets in the valve body, the seats must be installed or removed for repair purposes using special tools and associated costly procedures.
Embodiments of the present invention achieve technical advantages as a valve seal assembly having an improved seal arrangement. Two seal members include a seat member adjacent a valve engaging member, and a pocket insert adjacent the seat member. The pocket insert fits fixedly within the valve body. A seal ring is disposed between the seat member and pocket insert, and two U-shaped seal rings are disposed between the pocket insert and the valve body.
Disclosed is a preferred embodiment for a valve sealing assembly for sealing a valve engaging member to a valve body. The sealing assembly includes a first annular seat member adapted to fixedly sealingly fit within the first annular valve body pocket, the first seat member having a substantially L-shaped cross-section, the L-shaped cross-section having a bottom and a side. A first annular groove is disposed within the first seat member L-shaped cross-section bottom, a second annular groove is disposed within the first seat member bottom, the second annular groove positioned concentrically with the first annular groove, and a first seal ring is disposed between the first seat member and the first valve body pocket within the first seat member first groove. A second seal ring is disposed between the first seat member and the first valve body pocket within the first seat member second groove, a second annular seat member is adapted to sealingly fit within the first seat member, the second seat member including an annular groove disposed over the first seat member L-shaped bottom, the second seat member being adapted to sealingly couple to the valve engaging member first face, and a third seal ring is disposed between the second seat member and the first seat member within the second seat member groove.
Also disclosed is a valve sealing assembly for sealing a valve engaging member to a valve body, the sealing assembly including a first annular seat member adapted to sealingly fit within one of the annular valve body pockets, the first seat member having a substantially L-shaped cross-section, the first seat member having an annular groove along the side exterior. At least one seal ring is disposed between the first seat member and the valve body pocket, and a second annular seat member is adapted to sealingly fit within the first seat member, the second seat member being adapted to sealingly couple to the valve engaging member. A first retainer ring is adapted to fit within the first seat member groove, wherein the first retainer ring is adapted to retain the first seat member within the valve body pocket, and at least one seal ring disposed between the first seat member and the second seat member.
Further disclosed is a valve sealing assembly for sealing a valve engaging member to a valve body, the sealing assembly including a first annular seat member adapted to sealingly fit within one of the annular valve body pockets, the first seat member having a substantially L-shaped cross-section, and at least one seal ring disposed between the first seat member and the valve body pocket. A second annular seat member is adapted to sealingly fit within the first seat member, the second seat member being adapted to sealingly couple to the valve engaging member and including an annular groove along the exterior. A first retainer ring is adapted to fit within the second seat member groove, wherein the second retainer ring is adapted to retain the second seat member within the first seat member, and at least one seal ring is disposed between the first seat member and the second seat member.
Also disclosed are methods of sealing a valve engaging member to a valve body about a borehole and a method of retaining a seat member within a valve.
Advantages of embodiments of the invention include providing an improved seal assembly for a valve engaging member. Embodiments of the seal assembly allow fluid to enter the valve cavity from the pipeline bore during pressure applications, and allow the pressure in the valve cavity to bleed with the pipeline bore. Pressure is not trapped in the valve body cavity when the valve engaging member is in the fully closed or open position. Well bore fluid is not passed between the seating element and the body pocket, which prevents erosion and corrosion of the body pocket. The pocket insert is fixed within the valve body pocket and is a sacrificial component, which provides a labor and cost savings by avoiding the repair of valve body pockets. Equilibrium is achieved inside the valve engaging member sealing assembly, preventing damage to the sealing mechanism and components. A support ring disposed within each U-shaped seal prevents the collapse of the U-shaped seals with exposure to pressure. The built-in lip prevents debris from entering the space between two seat members with a built-in lip. This prevents valve failure and prevents damage to seals and seat members. The retainer rings hold the pocket insert within a valve body pocket, or a seat member within a pocket insert, even when the valve bore is in the vertical position. This improves the ease of servicing and repairing the valve, for workmen no longer have to remove the valve and place it horizontally on the ground to repair it. | {
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Regional monitoring systems, such as fire alarm systems, have a variety of components which are scattered through the region being monitored. These include ambient condition detectors such as smoke detectors, flame detectors, thermal detectors or gas detectors which are often monitored at or near a ceiling of part of the region being monitored. Other types of devices such as pull-stations, sensors for doors or windows or the like or other building monitoring sensors may be dispersed throughout the region being monitored at various locations including on the walls, adjacent to doors or windows or the like. Such devices are usually coupled by either a wired or wireless medium to a common or central control unit or panel.
The common control unit or panel might not be located in that part of the region being monitored. Instead, it might be installed, for example, in a lower level of a multi-level building along with other building control functions. This location might be substantially displaced from some or all of the devices of the system. In some installations, the control unit might be in RF communication with an installed system, or in communication via a computer network.
It has been recognized that because of the physical displacement of the various devices, servicing, maintenance or installation activities often require interaction between the personnel out in the region carrying out the activity and the personnel at or near the control unit. This communication, in known systems, is often carried out using a separate wireless communication system, such as RF walkie talkies.
Other systems which are installed in the region, such as security systems, often require feedback from personnel traveling through the region. Representative of these are security personnel or guard check in stations which are distributed throughout the region for purposes of tracking progress of security personnel on their rounds. Historically, this has resulted in installation of a completely separate set of equipment to carry out this function.
It would be desirable to be able to improve communication efficiency between the field personnel in the region being monitored and the control room for the region. Further, it would be desirable if such functionality could be incorporated into systems which are to be installed in the region, either initially or as after the fact upgrades to take advantage of existing communication capabilities of regional monitoring systems. Preferably, also such functionality could be incorporated without substantially increasing system costs or installation complexity. | {
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1. Field of the Invention
The invention relates to belt tensioning devices and arrangements, and in particular to hydraulically actuated belt tensioning devices for use with the endless drive belts of the drive systems for vehicle accessories. More particularly, the invention relates to a belt tensioner having an improved self-contained hydraulic fluid supply and pump assembly operated by an idler pulley mounted thereon and driven by the endless belt to maintain a predetermined constant tensioning force on the endless drive belt regardless of the engine operating condition by pivotal movement of one of the vehicle accessories.
2. Description of the Priot Art
There is the trend today in the automobile industry to operate the various vehicle accessories, such as the power steering pump, oil and air pumps, air conditioning and alternator, by a single endless belt driven by a pulley connected to the engine crankshaft. This system is referred to as a "serpentine" drive belt system. To insure optimum operating efficiency for these various accessories, it is necessary that the drive belt be maintained at a predetermined tension to assure efficient performance of the accessories as well as satisfactory service life for the belt. Due to the relatively greater length for the single drive belt which replaces the heretofore plurality of smaller belts, there is a greater tendency for the belt to stretch, which will affect the operating characteristics of the driven accessories. Therefore, it is desirable that an automatic belt tensioning device be used for these endless belts to provide reliable service over an extended period of time and to maintain a constant amount of tension thereon regardless of the amount of belt stretch without requiring any maintenance or manual adjustment.
Numerous devices have been proposed and used to accomplish this purpose. One type of tensioner uses a bushing formed of an elastomeric material which is placed in compression by some mechanical means for continuously exerting a tensioning force on the belt. Examples of these constructions are shown in U.S. Pat. Nos. 3,975,965 and 4,144,772. These tensioner constructions, which use an elastomeric material, have the disadvantages in that the high load rate which they exert on the belt results in the rapid loss of tensioning as the belt stretches, and this load rate limits the stroke of the belt-engaged idler pulley to a shorter distance than desired. Also, sudden acceleration and deceleration of the drive belt can cause a whipping action to occur which creates a time lag before full damping is achieved.
Numerous other types of belt tensioning devices use springs for applying and/or maintaining the entire tensioning force on a belt-engaging idler pulley or chain-engaging sprocket. Some examples of these types of constructions are shown in U.S. Pat. Nos. 2,703,019, 2,893,255, 3,413,866, 3,631,734, 3,768,324, 3,812,733, 3,924,483 and 3,965,768. Some of these various spring-actuated devices use the biasing force of the spring in combination with hydraulic actuated members for regulating the amount of tensioning force applied to the belt, depending on whether the engine is running or shut off.
U.S. Pat. No. 2,051,488 shows a chain tensioning device in which a hydraulic cylinder is actuated when the engine is running to reduce the tensioning pressure which is exerted on the drive chain by a biasing spring. This hydraulic cylinder applies a counter force to the biasing action of the spring when the engine is running in order to decrease the tensioning force on the chain, whereupon the full biasing force of the spring is exerted on the chain when the engine is off and the hydraulic cylinder inactive. U.S. Pat. No. 3,142,193 discloses another belt tensioner using a hydraulically actuated bellcrank and belt-engaging pulley in which a spring biases the pulley into tensioning engagement with the belt until the engine is operating, whereupon the hydraulic actuated piston imparts a greater tensioning force to the pulley through the bellcrank. When the engine stops, the piston retracts and the spring maintains a lesser tensioning force on the belt. U.S. Pat. No. 4,077,272 discloses another belt tensioner using both a spring and a hydraulic member to achieve the desired tensioning characteristics. In this device, when the engine is running, hydraulic oil from the engine lubricating system forces a piston back into its cylinder to overcome an internally mounted first spring so that only a second spring acts on the belt tensioning pulley when the engine is operating. When the engine is off, both springs act on the belt tensioning pulley. U.S. Pat. No. 3,132,596 shows a belt tensioner using a hydrostatic snubber controlled by the power steering pump of the vehicle, whereupon the snubber is forced outwardly in direct relationship to the output pressure of the power steering pump. This mechanism does not maintain a constant pressure on the belt when the vehicle engine is both on and off, and will apply different forces in relationship to the engine speed.
Many of these devices are believed to perform satisfactorily for their intended purpose. However, the use of springs for effecting the entire tensioning force on a drive belt or chain, either for applying or retracting a tensioning member therefrom, presents problems. The operating characteristics of these springs will change over the life of the spring and even in response to changes in ambient temperature. Also, as the drive belt stretches, the spring's biasing effect changes, making it difficult to maintain a constant tensioning force on the drive belt. Likewise, the springs may become rusted and corroded and break during the life of the vehicle, presenting mechanical maintenance problems for the vehicle owner.
Many of these problems are believed to be eliminated by the improved hydraulic belt tensioner constructions shown in a copending application of Nolte V. Sproul, Ser. No. 058,362, filed July 18, 1979, and my copending application, Ser. No. 060,903, filed July 28, 1979, both assigned to the same assignee as is the present application. These improved belt tensioners are operated by hydraulic pressure exerted by fluid from the vehicle engine, such as the relatively low fluid pressure of the engine's oil lubricating system or the high fluid pressure developed by the power steering pump of the vehicle.
However, some vehicle manufacturers prefer not to use the hydraulic fluid which is used for other purposes in the engine, such as lubricating or power steering, for the operation of the belt tensioner. This presents a possible problem situation in that if a serious leak occurs, it could affect the other operations of the vehicle and possibly damage or ruin an engine if not detected soon enough.
Accordingly, it is desirable to provide a belt tensioning device and arrangement which eliminates the use of springs for controlling the entire belt tensioning force, which device will maintain a nearly constant predetermined tension on the belt throughout the belt life and regardless of whether the engine is on or off or being driven at high or low speeds, and which device uses a source of hydraulic fluid completely independent of the vehicle hydraulic system for operation thereof.
There is no known belt tensioning device or arrangement of which I am aware which imparts and maintains a nearly constant predetermined tensioning force on an endless accessory drive belt by a hydraulic piston which is actuated by hydraulic fluid from a self-contained fluid supply reservoir completely independent of the vehicle hydraulic fluid system, and which maintains this constant pressure on the belt whether the engine is on or off or operating at various speeds, and which prevents belt whip and achieves a highly efficient damping effect. | {
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The present invention relates to a combination heat radiator and, more particularly, to an improved combination heat radiator capable of increasing contact area with an electronic heat-emitting device and being bent to match the shape of an optoelectronic heat-emitting device.
Along with continual progress of scientific technology, operational speeds of electronic tools (e.g., host computers, personal digital assistants, etc.) become faster and faster. Heat generated therein becomes more and more accordingly. In order to effectively radiate heat out of the system so that each device therein can operate under permissible temperatures, heat-radiating systems have become indispensable accessories in today""s electronic tools.
FIG. 1 shows a prior art heat radiator 10, which comprises a plurality of bent structures formed by punching metallic material like aluminum or copper. The heat radiator 10 can be glued with an electronic heat-emitting device (not shown) to help the electronic heat-emitting device effectively radiate heat out of the system, hence letting the electronic heat-emitting device operate under permissible temperatures.
However, because a plurality of grooves 101 are spaced on the above heat radiator 10, the contact area with the electronic heat-emitting device is reduced, thus decreasing heat-radiating effect of the heat radiator 10.
FIG. 2 shows another prior art heat radiator 11, which comprises a plurality of U-shaped plate bodies 111 formed by punching metallic material like aluminum or copper and then assembled with lumpy retaining elements 112. The heat radiator 11 can be glued with an electronic heat-emitting device (not shown) to help the electronic heat-emitting device effectively radiate heat out of the system, hence letting the electronic heat-emitting device operate under permissible temperatures.
Although the above heat radiator 11 can increase the contact area with an electronic heat-emitting device, because the lumpy retaining elements 112 are retained with one another, the whole heat radiator 11 cannot be bent. Because today""s electronic heat-emitting devices (e.g., hot tubes) are diversified, usage of the heat radiator 11 is reduced because it cannot be bent.
Accordingly, the above heat radiators have inconvenience and drawbacks in practical use. The present invention aims to resolve the problems in the prior art.
The primary object of the present invention is to provide a combination heat radiator capable of increasing contact area with an electronic heat-emitting device and providing better heat-radiating effect for the electronic heat-emitting device. Moreover, the combination heat radiator can be bent according to the shape of an electronic heat-emitting device to greatly enhance the heat-radiating efficiency and effectively reduce the production cost.
To achieve the above object, the present invention provides a combination heat radiator, which is a plate body formed by cutting thermal conductive material like aluminum, copper, or graphite. A plurality of spaced openings are formed by punching one side of the plate body. A connection portion is disposed on the other side of the plate body. Remaining materials of the plurality of openings are bent upwards to form a plurality of heat-radiating fins. The connection portion can be conveniently bent by a user to match the shape of different optoelectronic heat-emitting devices. The openings of the plate body are staggered with openings of another plate body to facilitate engagement of the two plate bodies. Complete heat-radiating fins are thus formed. The complete heat-radiating fins can be joined with an optoelectronic heat-emitting device by using thermal conductive glue. Thereby, the applicability of the heat-radiating fins can be enhanced, and expenses for developing different heat-radiating fins can be effectively reduced to greatly lower the production cost.
The various objects and advantages of the present invention will be more readily understood from the following detailed description when read in conjunction with the appended drawing, in which: | {
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Diesel pollution control devices include catalytic converters and diesel particulate filters or traps. The pollution control devices typically comprise a metal housing or casing with a pollution control element securely mounted within the casing by a resilient and flexible mounting mat. Pollution control devices are universally employed on motor vehicles to control atmospheric pollution. Two types of devices are currently in widespread use: catalytic converters and diesel particulate filters or traps. Catalytic converters contain a catalyst, which is typically coated on a monolithic structure mounted within a metallic housing. The monolithic structures are typically ceramic, although metal monoliths have also been used. The catalyst oxidizes carbon monoxide and hydrocarbons and reduces the oxides of nitrogen in automobile exhaust gases to control atmospheric pollution.
Diesel particulate filters or traps are typically wall flow filters, which have honeycombed, monolithic structures typically made from porous crystalline ceramic materials. Alternate cells of the honeycombed structure are typically plugged such that exhaust gas enters in one cell and is forced through the porous wall to an adjacent cell where it can exit the structure. In this way, the small soot particles that are present in diesel exhaust gas are collected.
The monoliths and in particular the ceramic pollution control monoliths, used in pollution control devices are fragile and susceptible to vibration or shock damage and breakage. They have a coefficient of thermal expansion generally an order of magnitude less than the metal housing which contains them. This means that as the pollution control device is heated the gap between the inside peripheral wall of the housing and the outer wall of the monolith increases. Even though the metallic housing undergoes a smaller temperature change due to the insulating effect of the mat, the higher coefficient of thermal expansion of the metallic housing causes the housing to expand to a larger peripheral size faster than the expansion of the monolithic element. Such thermal cycling occurs hundreds of times during the life and use of the pollution control device.
To avoid damage to the ceramic monoliths from for example road shock and vibrations, to compensate for the thermal expansion difference, and to prevent exhaust gases from passing between the monolith and metal housing (thereby bypassing the catalyst), mounting mats are disposed between the ceramic monolith and the metal housing. These mats must exert sufficient pressure to hold the monolith in place over the desired temperature range but not so much pressure as to damage the ceramic monolith.
Many of the mounting mats described in the art have been developed for mounting catalytic converters for treatment of exhaust from gasoline engines which typically operate at high temperature. Known mounting mats include intumescent sheet materials comprised of ceramic fibers, intumescent materials and organic and/or inorganic binders. Intumescent sheet materials useful for mounting a catalytic converter in a housing are described in, for example, U.S. Pat. No. 3,916,057 (Hatch et al.), U.S. Pat. No. 4,305,992 (Langer et al.) U.S. Pat. No. 5,151,253 (Merry et al.) U.S. Pat. No. 5,250,269 (Langer) and U.S. Pat. No. 5,736,109 (Howorth et al.). In recent years, non-intumescent mats comprised of polycrystalline ceramic fibers and binder have been used especially for the so-called ultra thin-wall monoliths, which have significantly lower strength due to their extremely thin cell walls. Examples of non-intumescent mats are described in, for example, U.S. Pat. No. 4,011,651 (Bradbury et al.), U.S. Pat. No. 4,929,429 (Merry), U.S. Pat. No. 5,028,397 (Merry), U.S. Pat. No. 5,996,228 (Shoji et al.), and U.S. Pat. No. 5,580,532 (Robinson et al.). Polycrystalline fibers are much more expensive than normal, melt formed ceramic fibers and, therefore, mats using these fibers are only used where absolutely necessary as, for example, with ultra thin-wall monoliths.
U.S. Pat. No. 5,290,522 describes a catalytic converter having a non-woven, mounting mat comprising at least 60% by weight shot-free high strength magnesium aluminosilicate glass fibers having a diameter greater than 5 micrometers. The mounting mats taught in this reference are primarily intended for use in high temperature applications as can be seen from the test data in the examples where the mats are subjected to exhaust gas temperatures of more than 700° C.
U.S. Pat. No. 5,380,580 describes a flexible non-woven mat comprising shot-free ceramic oxide fibers selected from the group consisting of (a) aluminosilicate fibers comprising aluminum oxide in the range from 60 to about 85% by weight and silicon oxide in the range of 40 to about 15% by weight silicon oxide, based on the total weight of said aluminosilicate-based fibers, said aluminosilicate-based fibers being at least 20% by weight crystalline (b) crystalline quartz fibers and (c) mixtures of (a) and (b), and wherein the combined weight of said aluminosilicate-based fibers and said crystalline quartz fibers is at least 50% by weight of the total weight of said non-woven mat. The flexible non-woven mat can additionally comprise high strength fibers selected from the group consisting of silicon carbide fibers, silicon nitride fibers, carbon fibers, silicon nitride fibers, glass fibers, stainless steel fibers, brass fibers, fugitive fibers, and mixtures thereof.
Diesel Oxidation Catalysts (DOC's) are used on modern diesel engines to oxidize the soluble organic fraction (SOF) of the diesel particulate emitted. Because of extremely low exhaust gas temperature, mounting of DOC's with conventional mounting materials has been problematic. The exhaust gas of modern diesel engines such as turbo-charged direct injection (TDI) engines may never exceed 300° C. This temperature is below the temperature needed to expand most intumescent mats. The expansion is needed to develop and maintain appropriate pressure within the catalytic converter. Additionally, this temperature is too low to burn out the organic binder contained in intumescent mat materials. At these temperatures the binder only softens, which acts to interfere with the resiliency of the ceramic fibers. As a result, field failures have occurred with DOC's when using conventional intumescent mounting mats. To overcome these difficulties, the converters are sometimes heat treated prior to installation to expand the vermiculite and burn out the binder. This is expensive and time consuming. Auxiliary wire mesh “L” seals have also been employed to augment the holding force of intumescent mats at low temperature, but also add cost and complexity to assembly. Most non-intumescent mats while performing somewhat better still contain an organic binder, which significantly reduces the resiliency of the fibers in the 200-300° C. temperature range. This is expected to be true for other diesel exhaust pollution control devices, as well, including lean NOx catalysts, Continuous regenerating traps (CRT's) and NOx traps.
U.S. Pat. No. 6,231,818 attempts to overcome the present difficulties of mounting low-temperature, diesel catalysts by using non-intumescent mats comprised of amorphous, inorganic fibers. Although it is taught in this patent that the mat can be organic binder free, it appears that several of the mats used in the examples require the use of substantial amounts of binders. Moreover, it was found that the mounting mats disclosed in this U.S. patent, still do not adequately perform for treatment of exhaust from diesel engines, in particular TDI engines.
It was thus desirable to find an alternative mounting mat for mounting a diesel pollution control monolith in the metallic casing of a pollution control device for the treatment of exhaust from a diesel engine. In particular, it was a desire to obtain such improved mounting mats that can be manufactured in an easy and convenient way at an affordable cost. Additionally, it was a desire to find mounting mats that show good to excellent performance in at least one or more of the following tests Real Condition Fixture Test (RCFT), Cyclical Compression Test, and Hot Vibration Test. Desirably, the mounting mat is also more acceptable in terms of health, safety and environmental aspects. | {
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Garages and garage doors are well known in the prior art. A typical homeowner uses a residential garage to store vehicles, yard tools, etc. A garage door is typically opened to move items into or out of the garage, after which, the garage door is closed. It is sometimes desirable to leave the garage door open to allow light or fresh air into the garage. However, a resulting problem is that insects or animals can get into the garage. Accordingly, what is needed is a combination garage door and roll-up curtain system that allows a flexible curtain to be lowered when the garage door is in a raised position. | {
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Vertical grinding mills are widely used in industrial process applications in the reduction and/or pulverization of ore, rock, minerals and other input materials for subsequent processing in mining applications, as well as for example, in the manufacture of fertilizers, cement, glass and ceramics. Conventionally, vertical grinding mills are provided with a grinding tank which is adapted to receive both a volume of solution and the material to be ground or pulverized as either part of a batch or continuous process. An impeller assembly is provided with a mixing or grinding blade which is positioned in a lower region of the grinding tank. When rotated, the mixing blade effects the mixing and physical abrasion of the solution and input material to form a slurry in which fine reduced particles of the infed material is contained in suspension, and which then flows or is pumped from the grinding tank for further processing.
To better effect pulverization, it is furthermore known to introduce into the bottom of the grinding tank, a quantity of hardened metal balls. When introduced, the cascading movement of such balls, combined with the rotary agitation of the mixing blade, achieves more effective and uniform material pulverization and grinding.
The applicant has appreciated that conventional vertical grinding mills, and in particular ball mills, continue to suffer the disadvantage that the input material may reside within lower regions of the grinding tank for insufficient time to achieve the desired materials size reduction/pulverization. In particular, where slurries are formed having higher input materials to grinding solution ratios, coarser ground materials of a pebble size or greater may tend to flow with the slurry outwardly from the grinding tank prematurely. The inclusion of coarser materials in the output slurry has the potential to adversely affect subsequent manufacturing steps. This may be of greatest importance where the relative amount of ground material to solution is more critical for the production of final products, as for example, where vertical mills are used as part of a lime slaking process in the production of slaked lime for pollution control applications. | {
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One view of the internet is the connection of clients, such as personal computers, tablets, smart phones, servers, digital photo-frames, and many other types of devices to publicly-accessible data-centers hosted in server farms. However, this picture represents a small portion of the overall usage of the globally-connected network. A very large number of connected resources currently exist, but are not publicly accessible. Examples include corporate networks, private organizational control and monitoring networks spanning the globe, and peer to peer relays designed for anonymity.
The Internet of Things (IoT) may bring Internet connectivity to as many as 50 billion devices by 2020. For organizations, IoT devices may provide opportunities for monitoring, tracking, or controlling other devices and items, including further IoT devices, other home and industrial devices, items in manufacturing and food production chains, and the like. Further, the emergence of IoT networks has served as a catalyst for profound change in the evolution of the internet. In the future, the internet is likely to evolve from a primarily human-oriented utility to an infrastructure where humans may eventually be minority actors in an interconnected world of devices.
The same numbers are used throughout the disclosure and the figures to reference like components and features. Numbers in the 100 series refer to features originally found in FIG. 1; numbers in the 200 series refer to features originally found in FIG. 2; and so on. | {
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The rapid growth in the semiconductor electronics industry over a wide range of applications, has led to some associated packaging, handling, and operating considerations for electronic devices. One consideration for many electronic devices is that static electricity be controlled in some fashion. For example, because electronic components are becoming smaller and smaller, and operating on smaller power and current levels, the generation of static electricity, which would be considered no more than a nuisance in other circumstances (e.g., getting a shock after walking on a synthetic carpet), can become a significant problem with electronic components and devices. For example, static electricity can affect the memory or performance characteristics of small integrated circuits or "chips." From a physical standpoint, static electricity, which has the tendency to cause small objects to be attracted to one another, can cause handling problems when the small delicate parts used in many electronic applications are being physically handled. Static electricity can affect memory or programming aspects of a chip either temporarily or permanently and can interfere with the operation of electronic devices, or their memory components, in a number of ways including loss of data on magnetic media, equipment damage, and even fire hazards.
Accordingly, control of static electricity, whether by shielding, grounding, or some other technique is a necessary consideration in the manufacture and use of electronic devices.
One application for which static electricity must be controlled is the handling during manufacture of semiconductor chips as they are being assembled into larger circuits and electronic devices. One such handling technique is set forth in copending application Ser. No. 08/252,177, U.S. Pat. No. 5,447,784, filed Jun. 2, 1994, for "STATIC DISSIPATIVE COVER TAPE" which is assigned to the assignee of the present invention. As set forth therein, in order to be conveniently packaged for automated or robotic handling and assembly, integrated circuits are often packaged in longitudinal strip packages which consist of molded pockets covered with an adhesive tape that completes the package. The adhesive tape is removed and the pocketed carrier advanced by mechanical devices. Because the chips are sensitive to static electricity, the packaging tape must likewise be either antistatic or static dissipating in character.
As generally used in this field, the terms "antistatic" and "static dissipating" both refer to the same property: conductivity. The term "static dissipating" generally refers to a higher conductivity than does the term "antistatic." For example, antistatic is often used to characterize resistivities of 10.sup.9 to 10.sup.14 ohms per square, while static dissipative is used to characterize resistivities of 10.sup.5 to 10.sup.9 ohms per square. It will be understood that these terms are thus used descriptively rather than in any absolute or unreasonably limiting sense.
One way to make a cover tape--or indeed any similar surface--static dissipating or antistatic in character is to coat it with a composition that will both adhere to the tape and provide the necessary conductivity properties. Conductive coatings can be formed of a number of different materials, all of which have various advantages and disadvantages. For example, a thin metal coating will be conductive and therefore antistatic or static dissipating, but metal coatings can be expensive and difficult to apply. Furthermore, when metals are applied in amounts sufficient to provide the necessary conductivity, they may make the surface opaque, or otherwise change its appearance, a factor which is undesirable in many circumstances.
Other conductive materials such as carbon black are appropriate in different circumstances, but as with metals, carbon black (as indicated by its common name) is generally unsuitable for antistatic or static dissipating applications where the color or transparency of a given substrate are of importance to the finished product.
Additional choices for conductive materials include monoacyl glycerides, monoalkyl phosphates, and various metallocenes. Some of these exhibit solubility problems, however, or tend to decompose at lower temperatures than are generally convenient for use in certain circumstances.
Yet another category of antistatic compositions includes the quaternary ammonium salts; i.e., organic nitrogen compounds that include a central nitrogen atom joined to four organic groups (the cation) and a negatively charged acid radical (the anion). Lewis, HAWLEY'S CONDENSED CHEMICAL DICTIONARY, 12th Ed. (1993) p. 986. These salt compositions are well-known, predictable in their antistatic characteristics, and soluble in water and in certain organic solvents. They tend, however, to be quite sensitive to relative humidity and in particular their conductive properties tend to fade or disappear at lower relative humidities; i.e., relative humidities of about 20% or less. Therefore, they are either undesirable or simply unusable for particular applications.
Therefore, there exists the need for compositions that can produce antistatic or static dissipating properties on substrates that can be easily coated on those substrates, will adhere to them properly, and will provide antistatic properties even under varying conditions of relative humidity. | {
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1. Field of the Invention
The present invention relates to a safety relief valve assembly for a fluid displacement apparatus and, more particularly, to a safety relief valve assembly for a refrigerant compressor used in an automotive air conditioning system.
2. Description of the Related Art
Many safety relief valves for refrigerant compressor applications are well known in the prior art. For example, Japanese Utility Publication No. H04-84976 discloses a safety relief valve device generally used in a refrigerant compressor for an automotive air conditioning system. The refrigerant compressor is provided with a safety relief valve device which automatically prevents excessive pressure build up in the compressor. The safety relief valve, which is mounted on the compressor housing, opens and closes in response to the pressure in the compressor if the pressure in the compressor or the cooling circuit abnormally increases.
When the safety relief valve operates, refrigerant gas including lubricating oil is emitted in the engine compartment of the vehicle. If the emission strikes a high temperature component of the engine, such as an exhaust manifold, smoke along with offensive odors and sometimes even fire result.
One attempt to resolve this problem was derived by the assignee of this application. Though not prior art, this attempt is indicative of the prior shortcomings of earlier solutions. Referring to FIGS. 1-3, relief valve assembly 10 includes valve mechanism 11 mounted on one end of a refrigerant compressor 100 and a cover member 18 attached to valve body 11a of valve mechanism 11. Valve mechanism 11 includes valve packing 15, valve member 14 surrounding valve packing 15, nut 13 disposed on the edge of valve body 11a, cap member 12 and spring 16 disposed between valve member 14 and cap member 12. Cap member 12 includes an opening 12a formed at the center radial axis thereof. Spring 16 biases valve member 14 and valve packing 15 toward the open end of passage 11b formed in the center of valve body 11a.
Cover member 18 comprises a hexagonal plate portion 18a, a connecting portion 18b perpendicularly extending from one end of hexagonal plate portion 18b, arm portion 18c extending from connecting portion 18b and a ring portion 18d extending from one end of arm portion 18c. Cover member 18 is secured to valve mechanism 11 such that arm portion 18c and ring portion 18d respectively hold nut 13 and valve body 11a, and hexagonal plate portion 18a faces opening 12a of cap member 12.
Cover member 18 is manufactured by blanking a plane plate and bending hexagonal plate portion 18a towards arm portion 18c at a 90.degree. angle as shown in FIG. 3. Cover member 18 is provided with connecting portion 18b which eases the bending of hexagonal plate portion 18a. Gap G (FIG. 1) is created between hexagonal plate portion 18a and arm portion 18c.
When the pressure in the cooling circuit and the compressor exceeds predetermined design pressures, the high pressure refrigerant gas causes valve member 14 and valve packing 15 to move away from the valve seat by overcoming the restoring force of coil spring 16. Refrigerant gas is then emitted in the direction of the longitudinal axis of valve body 11a through opening 12a of cap member 12. Thus, the refrigerant gas strikes and is directed along hexagonal plate portion 18a toward an area other than the high temperature components of the engine, for instance below compressor 100. When the pressure in the cooling circuit and the compressor decreases, valve member 14 and valve packing 15 return to the valve seat under the influence of the restoring force of coil spring 16.
Even in this configuration, however, it has been experienced that some of the refrigerant gas comes into contact with the high temperature components of the engine due to the presence of gap G. Thus, the problem has not been totally solved, and there remains the possibility of causing smoke or an offensive odor or even fire from the engine compartment of the vehicle.
These and other drawbacks are sought to be overcome by the invention of the referred embodiments. | {
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Drill chucks are used in conjunction with power drills for releasably engaging a drill bit. Conventional drill chucks also require a special tool for tightening and loosening the drill chuck onto the drill bit. Recently, drill chucks have been designed to be tightened by hand wherein a user can rotate a chuck sleeve of the drill chuck to cause the jaws of the drill chuck to engage and disengage a drill bit. The user of the drill must rotate the adjustable chuck sleeve with one hand while holding a drill bit inside the jaw members until the drill bit is locked in place. More recently, so-called self-locking drill chucks have been developed in which a drill bit can be inserted and with the chuck being disposed in a “chuck” mode, the operation of the drill will cause the chuck to be tightened or loosened, depending on the rotational direction of the drill. Currently, chuck devices that are capable of being tightened or loosened by operation of the drill are activated by adjusting the sleeve on the chuck between a drill mode position and chuck mode position. | {
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Alzheimer's disease (AD), the most common cause of dementia, is estimated to affect 5% of those over 65 years of age and 40% of those over 80 years of age, or a total of approximately 20 million people worldwide. The neuropathological characteristics of AD include: .beta.-amyloid plaques that are diagnostic when associated with dystrophic neurites; neurofibrillary tangles; loss of neurons and synapses; and proliferation of glial cells. The last few years have seen substantial progress in unravelling the genetic influences in AD. A small proportion of AD cases are inherited as an autosomal dominant trait and are attributable to point mutations in genes encoding .beta.-amyloid precursor protein (.beta.APP),.sup.1 presenilin 1,.sup.2 or presenilin 2..sup.3 A major genetic risk factor for the much more common sporadic AD is possession of the apolipoprotein E (APOE) e4 allele..sup.4 However possession of APOE e4 is neither necessary nor sufficient for the development of AD, leaving scope for other potential genetic or environmental influences.
Interleukin-1 (IL-1) is a potent pro-inflammatory cytokine that is markedly overexpressed in Alzheimer brain, predominantly in microglia,.sup.5 suggesting a role for inflammatory processes in AD pathogenesis..sup.6 This idea has received support from epidemiological studies showing that use of anti-inflammatory agents, in particular non-steroidal anti-inflammatory drugs, is associated with delayed onset or slowed progression of disease..sup.7 IL-1 has two structurally distinct forms, IL-1a and IL-1.beta., encoded by separate genes (IL-1 and IL-1B, respectively) located in a cluster on the long arm of chromosome 2 that also includes the IL-1 receptor antagonist gene..sup.8 Common polymorphisms have been described in both genes and there is evidence that they have functional significance. A polymorphism of the IL-1B gene (+3953), for instance, introduces a Taq1 restriction site resulting in two alleles, designated allele 1 and allele 2..sup.9 Homozygosity for allele 2 of IL-1B is associated with a fourfold increase in production of IL-1.beta. compared to homozygosity for allele 1..sup.9 A polymorphism in the 5' regulatory region of the IL-1 gene (a C to T transition at position -889 relative to the start site of transcription) again results in two alleles, also designated allele 1 and allele 2..sup.10 Both of these IL-1 polymorphisms have been associated with inflammatory diseases. For instance, IL-1 allele 2 has been associated with juvenile rheumatoid arthritis..sup.10
Genetic testing is now possible (see U.S. Pat. Nos. 4,582,788, 5,110,920 and 5,686,246) for diseases associated with or caused by one to two genes, once the genes are identified, to determine the risk of a person carrying a given gene for the disease (see for example U.S. Pat. Nos. 4,801,531, 4,666,828, 5,268,267 and 5,686,246). These patents are hereby incorporated by reference into this disclosure.
Many altered physiological functions induce or are caused by inflammatory and other immune mechanisms (see U.S. Pat. No. 5,328,829, column 1, for a review). Due to the commonality of the immune response in almost all disease states, research on inflammatory markers as genetic markers has had very limited success at differentiating predisposition to diseases. U.S. Pat. No. 5,686,246, is a notable exception, in that the inventors correlated IL-1a and IL-1b mutations with the susceptibility to severe periodontal disease.
Association of a single cytokine polymorphism and disease states have been found as, for example, in Systemic Lupus Erythematosus, Ulcerative Colitis and Juvenile rheumatoid arthritis (Mansfield et al., 1994; Verjans et al., 1992; Blakemore et al., 1994; McGuire et al., 1994; McDowell et al., 1995).
Therefore, it was an objective of the present invention to determine if genetic factors that are associated with inflammatory and other immune responses correlate with Alzheimer's disease. If so, it would be useful to identify the genetic factors and thereby identify persons who are susceptible to Alzheimer's disease for the purpose of providing prophylactic treatment. | {
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1. Field of the Invention
This invention relates to a magnification-changeable finder optical system, and particularly to a Keplerian zoom finder optical system suitable for use in a compact camera.
2. Related Background Art
In recent years, in lens shutter type compact cameras, zoom lenses having a great zoom ratio have been required as photo-taking objective lenses, and with it, zoom finders having a great magnification change ratio have become necessary also in camera finders.
As zoom finders of this kind, there are Japanese Laid-Open Patent Application No. 2-109009 which has been proposed by the applicant and already laid open, etc., and basically, these are such that the objective lens of a Keplerian telescope optical system in which a real image formed by the objective lens is enlarged and observed through an eyepiece is made into zoom, whereby the finder magnification is made continuously changeable.
The zoom finder disclosed in the above-mentioned Japanese Laid-Open Patent Application No. 2-109009 has a magnification change ratio (zoom ratio) of the order of 2.3 times and a field (angle of field) of the order of 55 degrees at the wide angle end and has an excellent optical performance.
This zoom finder, however, can hardly be said to be sufficient in respect of wide angle and high magnification change, and further, an attempt to endow this zoom finder with a great magnification change ratio has resulted in the possibility of making the finder optical system bulky. | {
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This invention relates to a connector assembly terminating a shielded cable and, more particularly, to an improved grounding bracket for use in such an assembly which engages the shield of the cable and provides continuity of that shield with a shield of a complementary mating connector assembly.
Local area networks interconnecting computers in a workplace are becoming more prevalent. One of the factors limiting the speed with which the computers can communicate over the network is the type of transmission medium connecting the computers to the network. For reasons of economy, twisted pair shielded cable has been developed that provides a sufficiently high data transfer rate. One such proposed type of cable is known as Category 7 twisted pair cable. Category 7 cable includes four pairs of individually insulated wires which are twisted together with a very tightly controlled twist specification. Each twisted pair is covered with its own individual conductive shield. All of the pairs are then bundled together and covered with a common shield. Typically, both the individual shields and the common shield are grounded. The common shield is covered with an outer plastic protective jacket.
When two such cables are connected together, or when connections are made from computers or network hubs to a cable, in order to insure good shielding qualities, especially at high frequencies, it is necessary to have good quality connections between the cable shields and the connectors, and also between mating connectors.
It would therefore be desirable to have a grounding bracket for a shielded cable connector which results in the aforedescribed good quality shield connections. | {
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Wireless local area networks (WLANs) are gaining in popularity, and new wireless applications are being developed. The original WLAN standards, such as “Bluetooth” and IEEE 802.11, were designed to enable communications at 1-2 Mbps in a band around 2.4 GHz. More recently, IEEE working groups have defined the 802.11a, 802.11b and 802.11g extensions to the original standard, in order to enable higher data rates. The 802.11a standard, for example, envisions data rates up to 54 Mbps over short distances in a 5 GHz band, while 802.11b defines data rates up to 22 Mbps in the 2.4 GHz band. In the context of the present patent application and in the claims, the term “802.11” is used to refer collectively to the original IEEE 802.11 standard and all its variants and extensions, unless specifically noted otherwise.
The theoretical capability of new WLAN technologies to offer enormous communication bandwidth to mobile users is severely hampered by the practical limitations of wireless communications. Indoor propagation of radio frequencies is not isotropic, because radio waves are influenced by building layout and furnishings. Therefore, even when wireless access points are carefully positioned throughout a building, some “black holes” generally remain—areas with little or no radio reception. Furthermore, 802.11 wireless links can operate at full speed only under conditions of high signal/noise ratio. Signal strength scales inversely with the distance of the mobile station from its access point, and therefore so does communication speed. A single mobile station with poor reception due to distance or radio propagation problems can slow down WLAN access for all other users in its basic service set (BSS—the group of mobile stations communicating with the same access point).
The natural response to these practical difficulties would be to distribute a greater number of access points within the area to be served. If a receiver receives signals simultaneously from two sources of similar strength on the same frequency channel, however, it is generally unable to decipher either signal. The 802.11 standard provides a mechanism for collision avoidance based on clear channel assessment (CCA), which requires a station to refrain from transmitting when it senses other transmissions on its frequency channel. In practice, this mechanism is of limited utility and can place a heavy burden on different BSSs operating on the same frequency channel.
Therefore, in high data-rate 802.11 WLANs known in the art, access points in mutual proximity must use different frequency channels. Theoretically, the 802.11b and 802.11g standards define 14 frequency channels in the 2.4 GHz band, but because of bandwidth and regulatory limitations, WLANs operating according to these standards in the United States actually have only three different frequency channels from which to choose. (In other countries, such as Spain, France and Japan, only one channel is available.) As a result, in complex, indoor environments, it becomes practically impossible to distribute wireless access points closely enough to give strong signals throughout the environment without substantial overlap in the coverage areas of different access points operating on the same frequency channel.
Access points in a WLAN system are typically interconnected by a wired LAN to communicate with a hub. The LAN serves as a distribution system (DS) for exchanging data between the access points and the hub. This arrangement enables the mobile stations to send and receive data through the access points to and from external networks, such as the Internet, via an access line connected to the hub.
Most commonly, the LAN used as a DS is an Ethernet LAN, operating in accordance with the Carrier Sense Multiple Access with Collision Detection (CSMA/CD) method of media access control (MAC) defined in IEEE Standard 802.3 (2000 Edition), which is incorporated herein by reference. The terms “Ethernet,” “CSMA/CD” and “802.3” are used in the art interchangeably to refer to LANs of this type. Ethernet LANs are typically capable of carrying data at high speeds—greater than the aggregate speed of wireless communications between the access points and mobile stations. For example, a 100BASE-T Ethernet LAN is capable of carrying data over twisted pair cabling at 100 Mb/s. Message latency on the LAN is relatively high, however, generally on the order of milliseconds, due mainly to collision avoidance mechanisms specified by the 802.3 standard and the lack of a fragmentation mechanism at the 802.3 MAC layer. Another factor contributing to latency in Ethernet LANs is that the minimum frame size permitted by the standard is 64 bytes (plus 8 more bytes for the frame preamble and start frame delimiter), while the maximum frame size is more than 1500 bytes. | {
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Electronic vapour provision devices are typically cigarette-sized and function by allowing a user to inhale a nicotine vapour from a liquid store by applying a suction force to a mouthpiece. Some electronic vapour provision devices have an airflow sensor that activates when a user applies the suction force and causes a heater coil to heat up and vaporise the liquid. Electronic vapour provision devices include electronic cigarettes. | {
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There is known to be some game machines each having a lottery mechanism. For example, there is known to be a game machine having a physical lottery mechanism for a bingo game, where a ball is discharged to a roulette wheel having a plurality of pockets, to each of which a numeral is assigned, and when the ball enters one of the pockets, the numeral is selected (for example, patent literature 1). | {
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1. Field of the Invention
The present invention relates to self-hydrating membrane electrode assemblies (MEAs), including MEAs that have been magnetically modified, and to methods of manufacture of the same. The present invention further relates to fuel cells that require only a self-hydrating MEA and a source of fuel.
2. Background of the Related Art
A fuel cell is a device that converts the energy of a chemical reaction into electricity. It differs from a battery primarily in that the fuel and oxidant are stored external to the cell, which can therefore generate power only as long as the fuel and oxidant are supplied. Moreover, unlike secondary batteries, fuel cells do not undergo charge/discharge cycles.
A fuel cell produces an electromotive force by bringing the fuel and oxidant into contact with two suitable, but different, electrodes separated by an electrolyte. A fuel, such as hydrogen gas for example, is introduced at a first electrode, where it reacts electrochemically in the presence of the electrolyte to produce electrons and protons in the first electrode.
These electrons are then circulated from the first electrode to a second electrode through an electrical circuit connecting the electrodes. Protons pass through the electrolyte to the second electrode.
At the same time as the fuel is introduced to the first electrode, an oxidant, such as oxygen gas or air, is introduced to the second electrode, where it reacts electrochemically in presence of the electrolyte to consume the electrons that have circulated through the electrical circuit and the protons that have passed through the electrolyte.
The first electrode is therefore an oxidizing electrode, while the second electrode is a reducing electrode. Thus, in the case of H2/O2 and H2/air cells, the respective half-cell reactions at the two electrodes are:H2→2H++2e−; and (1)½O2+2H++2e−→H2O. (2)
The electrical circuit connecting the two electrodes withdraws electrical current from the cell and thus receives electrical power. The overall fuel cell reaction produces electrical energy according to the sum of the separate half-cell reactions above. In addition to electrical energy, water is formed at the cathode as a byproduct of the reaction as well as some heat energy.
For many practical applications, fuel cells are usually not operated as single units due, at least in part, to the relatively low electrical energy produced by individual cells. Rather, fuel cells may be connected in a series, stacked one on top of the other, or placed side by side.
A series of fuel cells (referred to as a “fuel cell stack”) is normally enclosed in a housing. The fuel and oxidant are directed with manifolds to the electrodes, and the required cooling (to dissipate the heat energy) may be provided by the reactants or by a cooling medium.
Also within most common fuel cell stacks are current collectors, cell-to-cell seals, insulations, piping, and/or instrumentation. The combination of the fuel cell stack, housing, and associated hardware is known as a “fuel cell module.”
Fuel cells may be classified by the type of electrolyte (e.g., liquid or solid) that they contain. Fuel cells using electrolytes such as the solid polymer membranes referred to as “proton exchange membranes” or “polymer electrolyte membranes” (PEMs) operate best when the PEM is kept moist with water (PEMs transfer protons more efficiently when wet than when dry). The PEM therefore generally requires constant humidification during operation of the fuel cell.
This humidification has been achieved by adding water to the reactant gases (e.g. hydrogen and oxygen or air) that pass by the membrane on each side of the MEA. The accessories required for humidification, however, add instrumentation and weight to the fuel cell as well as increasing mechanical complexity and reducing output due to parasitic power loss (the energy required to heat water for humidification can consume 15% or more of power output).
The PEM used in solid polymer fuel cells acts both as the electrolyte as well as a barrier that prevents the mixing of the reactant gases, a potentially disastrous situation. Examples of suitable membrane materials are the polymeric perfluorocarbon ionomers generally containing a basic unit of fluorinated carbon chain and one or more sulphonic acid groups. There may be variations in the molecular configurations and/or molecular weights of this membrane. One such membrane commonly used as a fuel cell PEM is sold by E. I. DuPont de Nemours under the trademark “NAFION” (tetrafluoroethylene-perfluoro-3,6-dioxa-4-methyl-7-octenesulfonic acid copolymer). Typically, best fuel cell performance is obtained using these membranes if the fuel cells are operated under fully hydrated, i.e. essentially water-saturated, conditions. Thus, the PEM must be continuously humidified during fuel cell operation.
There have been other attempts to provide the necessary humifidication to a fuel cell PEM, or eliminate the need therefore entirely For example, U.S. Pat. No. 5,318,863 to Dhar discloses solid polymer fuel cells which operate at near ambient temperature and pressure without humidification. One such fuel cell employs very thin electrodes having a slightly oversize solid PEM between and in contact with them. The PEM has either a low gram equivalent weight or has a higher gram equivalent weight but is very thin so as to permit proton transfer at reduced internal electrolyte resistance. This decreased internal electrolyte resistance is intended to permit operation of the fuel cell at mild conditions without humidification. The use of very thin membranes can permit easier conductivity of water due to the shorter transport path length, but such membranes do not exhibit long term stability and frequently permit H2 crossover (which bleeds power). U.S. Pat. No. 5,242,764, also to Dhar, discloses a fuel cell which employs a solid PEM having a central hole between and in contact with the electrodes.
All of the above described fuel cells and MEAs, however, suffer from one or more problems and/or disadvantages that limit their applicability and/or commercial potential. Most state-of-the-art fuel cells use MEAs that typically require substantial hardware to sustain fuel cell operation. This includes hardware to pressurize, humidify and/or heat the fuel cell. This hardware introduces moving parts that substantially complicate the system and dramatically increase the weight and cost, as well as increasing mechanical noise, thermal signature and complexity.
Accordingly, there remains a need in the art for a fuel cell that runs without added pressurization, humidification and/or heat, and therefore without any of the extraneous hardware of prior fuel cells. | {
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1. Field of the Invention
The present invention relates to an image forming apparatus including a double-sided printing function.
2. Description of the Related Art
In recent years, image forming apparatuses such as a multifunction printer (MFP) including functions of a printer, a copying machine, FAX, and the like have been in widespread use. The image forming apparatuses generally include almost all functions necessary to complete office work, are compact, do not take up too much space, and are also excellent in terms of costs. Thus, the widespread use of these image forming apparatuses is expected to increase.
In addition, some image forming apparatuses include the double-sided printing function which forms an image on one side of a printing sheet and thereafter forms an image on the reverse side of the printing sheet (for example, see PTL 1). In the double-sided printing, an image is also formed on the reverse side by forming an image on one side of the printing sheet in an image forming section and then feeding and reversing the sheet to a double-sided sheet passing path to feed the sheet again into the image forming section. | {
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The present invention relates to a throttle actuator for controlling the amount of gas suctioned into an engine and, more particularly, to an electronically controlled throttle actuator in which control operation is made more precise and flexible so as to favorably ensure safe driving even when a failure occurs in the control mechanism or in a control device.
In a conventional electronically controlled throttle actuator, opening of a throttle valve is adjusted by operation of an accelerator pedal transmitted by means of an accelerator cable, which operation is supplemented by operation of an electronically controlled motor, as disclosed, e.g. in Japanese Patent Laid-Open No. 62-186022.
In the throttle actuator disclosed in Japanese Patent Laid-Open No. 62-186022, the throttle operation is performed mainly with the accelerator pedal. Normally, the motor is kept at a position such that no torque is transmitted from the motor to a throttle shaft. When needed, the motor is rotated to a position such that torque is transmitted to the throttle shaft, and then the motor controls the opening of the throttle valve. Thus, there are unsatisfactory features: response delay is likely during the initiation of the throttle control; a minute angle adjustment of the opening is not easy to perform; and at initiation of torque conduction from the motor to the throttle shaft, an impact caused by the inertia force of the motor transmits to the driver through the accelerator pedal. | {
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Squalene and botryococcene are related by their putative biosynthetic origins from the condensation of two farnesyl diphosphate (FPP) molecules, and are known to be synthesized byrace B, a fresh water green algae (Okada. et al., (1995). Journal Of Applied Phycology 555-559; Metzger and Largeau (2005). Applied Microbiology and Biotechnology 486-496.) Botryococcene is further modified in and becomes methylated with 1, 2, 3 or 4 additional methyl substituents catalyzed by a special triterpene methyl transferase. Botryococene and its methylated derivatives have attracted significant attention because these molecules are thought to be the progenitors to current oil shale deposits (Summons et al., (2002) Organic Geochemistry 99-109; Walters et al., (2005) Aapg Bulletin 1239-1 244.) and because they are considered promising renewable, alternative biofuels (Banerjee et al., (2002). Critical Reviews in Biotechnology 245-279.) For example, Hillen et al. (1982) Biotechnology And Bioengineering 193-205) previously reported on the catalytic cracking of methylated botryococcenes and squalene derivatives, and observed an overall conversion of 97% of the oil to combustible fuels under standard cracking conditions. Overall, 67% of the oil was converted to gasoline grade fuel, 15% to aviation turbine fuel, and 15% to diesel fuel with a residual of only 3%. Hence, catalytic hydrolysis (as performed in standard petroleum refineries) of these highly branched, poly-unsaturated triterpenes results in the generation of hydrocarbon fractions that are chemically equivalent to those derived from current petroleum deposits and are of direct utility as fuels for internal combustion engines, as well as feedstocks for chemical manufacturing (Banerjee et al., (2002)).
Up to this time, these energy-rich triterpene oils have only been available from cultures of a rather slow growing green algae that does not lend itself to large-scale or fermentation type culturing conditions (Casadevall et al., (1985). Biotechnology and Bioengineering 286-295). | {
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3.1. Overview
Circulating cholesterol is carried by plasma lipoproteins—complex particles of lipid and protein composition that transport lipids in the blood. Four major classes of lipoprotein particles circulate in plasma and are involved in the fat-transport system: chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). Chylomicrons constitute a short-lived product of intestinal fat absorption. VLDL and, particularly, LDL are responsible for the delivery of cholesterol from the liver (where it is synthesized or obtained from dietary sources) to extrahepatic tissues, including the arterial walls. HDL, by contrast, mediates reverse cholesterol transport (RCT), the removal of cholesterol lipids, in particular from extrahepatic tissues to the liver, where it is stored, catabolized, eliminated or recycled. HDL also plays a beneficial role in inflammation, transporting oxidized lipids and interleukin, which may in turn reduce inflammation in blood vessel walls.
Lipoprotein particles have a hydrophobic core comprised of cholesterol (normally in the form of a cholesteryl ester) and triglycerides. The core is surrounded by a surface coat comprising phospholipids, unesterified cholesterol and apolipoproteins. Apolipoproteins mediate lipid transport, and some may interact with enzymes involved in lipid metabolism. At least ten apolipoproteins have been identified, including: ApoA-I, ApoA-II, ApoA-IV, ApoA-V, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoJ and ApoH. Other proteins such as LCAT (lecithin:cholesterol acyltransferase), CETP (cholesteryl ester transfer protein), PLTP (phospholipid transfer protein) and PON (paraoxonase) are also found associated with lipoproteins.
Cardiovascular diseases such as coronary heart disease, coronary artery disease and atherosclerosis are linked overwhelmingly to elevated serum cholesterol levels. For example, atherosclerosis is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence supports the theory that lipids deposited in atherosclerotic lesions are derived primarily from plasma LDLs; thus, LDLs have popularly become known as “bad” cholesterol. In contrast, HDL serum levels correlate inversely with coronary heart disease. Indeed, high serum levels of HDLs are regarded as a negative risk factor. It is hypothesized that high levels of plasma HDLs are not only protective against coronary artery disease, but may actually induce regression of atherosclerotic plaque (see, e.g., Badimon et al., 1992, Circulation 86 (Suppl. III):86-94; Dansky and Fisher, 1999, Circulation 100:1762-63; Tangirala et al., 1999, Circulation 100(17):1816-22; Fan et al., 1999, Atherosclerosis 147(1):139-45; Deckert et al., 1999, Circulation 100(11):1230-35; Boisvert et al., 1999, Arterioscler. Thromb. Vasc. Biol. 19(3):525-30; Benoit et al., 1999, Circulation 99(1):105-10; Holvoet et al., 1998, J. Clin. Invest. 102(2):379-85; Duverger et al., 1996, Circulation 94(4):713-17; Miyazaki et al., 1995, Arterioscler. Thromb. Vasc. Biol. 15(11):1882-88; Mezdour et al., 1995, Atherosclerosis 113(2):237-46; Liu et al., 1994, J. Lipid Res. 35(12):2263-67; Plump et al., 1994, Proc. Nat. Acad. Sci. USA 91(20):9607-11; Paszty et al., 1994, J. Clin. Invest. 94(2):899-903; She et al, 1992, Chin. Med. J. (Engl). 105(5):369-73; Rubin et al., 1991, Nature 353(6341):265-67; She et al., 1990, Ann. NY Acad. Sci. 598:339-51; Ran, 1989, Chung Hua Ping Li Hsueh Tsa Chih (also translated as: Zhonghua Bing Li Xue Za Zhi) 18(4):257-61; Quezado et al., 1995, J. Pharmacol. Exp. Ther. 272(2):604-11; Duverger et al., 1996, Arterioscler. Thromb. Vasc. Biol. 16(12):1424-29; Kopfler et al., 1994, Circulation; 90(3):1319-27; Miller et al., 1985, Nature 314(6006):109-11; Ha et al., 1992, Biochim. Biophys. Acta 1125(2):223-29; Beitz et al., 1992, Prostaglandins Leukot. Essent. Fatty Acids 47(2):149-52). As a consequence, HDLs have popularly become known as “good” cholesterol, (see, e.g., Zhang, et al., 2003 Circulation 108:661-663).
The “protective” role of HDL has been confirmed in a number of studies (e.g., Miller et al., 1977, Lancet 1(8019):965-68; Whayne et al., 1981, Atherosclerosis 39:411-19). In these studies, the elevated levels of LDL appear to be associated with increased cardiovascular risk, whereas high HDL levels seem to confer cardiovascular protection. In vivo studies have further demonstrated the protective role of HDL, showing that HDL infusions into rabbits may hinder the development of cholesterol induced arterial lesions (Badimon et al., 1989, Lab. Invest. 60:455-61) and/or induce their regression (Badimon et al., 1990, J. Clin. Invest. 85:1234-41).
3.2. Reverse Cholesterol Transport, HDL and Apolipoprotein A-I
The reverse cholesterol transport (RCT) pathway functions to eliminate cholesterol from most extrahepatic tissues and is crucial to maintaining the structure and function of most cells in the body. RCT consists mainly of three steps: (a) cholesterol efflux, i.e., the initial removal of cholesterol from various pools of peripheral cells; (b) cholesterol esterification by the action of lecithin:cholesterol acyltransferase (LCAT), preventing a re-entry of effluxed cholesterol into cells; and (c) uptake of HDL-cholesterol and cholesteryl esters to liver cells for hydrolysis, then recycling, storage, excretion in bile or catabolism to bile acids.
LCAT, the key enzyme in RCT, is produced by the liver and circulates in plasma associated with the HDL fraction. LCAT converts cell-derived cholesterol to cholesteryl esters, which are sequestered in HDL destined for removal (see Jonas 2000, Biochim. Biophys. Acta 1529(1-3):245-56). Cholesteryl ester transfer protein CETP) and phospholipid transfer protein (PLTP) contribute to further remodeling of the circulating HDL population. CETP moves cholesteryl esters made by LCAT to other lipoproteins, particularly ApoB-comprising lipoproteins, such as VLDL and LDL. PLTP supplies lecithin to HDL. HDL triglycerides are catabolized by the extracellular hepatic triglyceride lipase, and lipoprotein cholesterol is removed by the liver via several mechanisms.
The functional characteristics of HDL particles are mainly determined by their major apolipoprotein components such as ApoA-I and ApoA-II. Minor amounts of ApoC-I, ApoC-II, ApoC-III, ApoD, ApoA-IV, ApoE, and ApoJ have also been observed associated with HDL. HDL exists in a wide variety of different sizes and different mixtures of the above-mentioned constituents, depending on the status of remodeling during the metabolic RCT cascade or pathway.
Each HDL particle usually comprises at least 1 molecule, and usually two to 4 molecules, of ApoA-I. HDL particles may also comprise only ApoE (gamma-LpE particles), which are known to also be responsible for cholesterol efflux, as described by Prof. Gerd Assmann (see, e.g., von Eckardstein et al., 1994, Curr Opin Lipidol. 5(6):404-16). ApoA-I is synthesized by the liver and small intestine as preproApolipoprotein A-I, which is secreted as proApolipoprotein A-I (proApoA-I) and rapidly cleaved to generate the plasma form of ApoA-I, a single polypeptide chain of 243 amino acids (Brewer et al., 1978, Biochem. Biophys. Res. Commun. 80:623-30). PreproApoA-I that is injected experimentally directly into the bloodstream is also cleaved into the plasma form of ApoA-I (Klon et al., 2000, Biophys. J. 79(3):1679-85; Segrest et al., 2000, Curr. Opin. Lipidol. 11(2):105-15; Segrest et al., 1999, J. Biol. Chem. 274 (45):31755-58).
ApoA-I comprises 6 to 8 different 22-amino acid alpha-helices or functional repeats spaced by a linker moiety that is frequently proline. The repeat units exist in amphipathic helical conformation (Segrest et al., 1974, FEBS Lett. 38: 247-53) and confer the main biological activities of ApoA-I, i.e., lipid binding and lecithin cholesterol acyl transferase (LCAT) activation.
ApoA-I forms three types of stable complexes with lipids: small, lipid-poor complexes referred to as pre-beta-1 HDL; flattened discoidal particles comprising polar lipids (phospholipid and cholesterol) referred to as pre-beta-2 HDL; and spherical particles, comprising both polar and nonpolar lipids, referred to as spherical or mature HDL (HDL3 and HDL2). Most HDL in the circulating population comprises both ApoA-I and ApoA-H (the “AI/AII-HDL fraction”). However, the fraction of HDL comprising only ApoA-I (the “AI-HDL fraction”) appears to be more effective in RCT. Certain epidemiologic studies support the hypothesis that the ApoA-I-HDL fraction is anti-atherogenic (Parra et al., 1992, Arterioscler. Thromb. 12:701-07; Decossin et al., 1997, Eur. J. Clin. Invest. 27:299-307).
HDL particles are made of several populations of particles that have different sizes, lipid composition and apolipoprotein composition. They can be separated according to their properties, including their hydrated density, apolipoprotein composition and charge characteristics. For example, the pre-beta-HDL fraction is characterized by a lower surface charge than mature alpha-HDL. Because of this charge difference, pre-beta-HDL and mature alpha-HDL have different electrophoretic mobilities in agarose gel (David et al., 1994, J. Biol. Chem. 269(12):8959-8965).
The metabolism of pre-beta-HDL and mature alpha-HDL also differs. Pre-beta-HDL has two metabolic fates: either removal from plasma and catabolism by the kidney or remodeling to medium-sized HDL that are preferentially degraded by the liver (Lee et al., 2004, J. Lipid Res. 45(4):716-728).
Although the mechanism for cholesterol transfer from the cell surface (i.e., cholesterol efflux) is unknown, it is believed that the lipid-poor complex, pre-beta-1 HDL, is the preferred acceptor for cholesterol transferred from peripheral tissue involved in RCT (see Davidson et al., 1994, J. Biol. Chem. 269:22975-82; Bielicki et al., 1992, J. Lipid Res. 33:1699-1709; Rothblat et al., 1992, J. Lipid Res. 33:1091-97; and Kawano et al., 1993, Biochemistry 32:5025-28; Kawano et al., 1997, Biochemistry 36:9816-25). During this process of cholesterol recruitment from the cell surface, pre-beta-1 HDL is rapidly converted to pre-beta-2 HDL. PLTP may increase the rate of pre-beta-2 HDL disc formation, but data indicating a role for PLTP in RCT are lacking. LCAT reacts preferentially with discoidal, small (pre-beta) and spherical (i.e., mature) HDL, transferring the 2-acyl group of lecithin or other phospholipids to the free hydroxyl residue of cholesterol to generate cholesteryl esters (retained in the HDL) and lysolecithin. The LCAT reaction requires ApoA-I as an activator; i.e., ApoA-I is the natural cofactor for LCAT. The conversion of cholesterol sequestered in the HDL to its ester prevents re-entry of cholesterol into the cell, the net result being that cholesterol is removed from the cell.
Cholesteryl esters in the mature HDL particles in the ApoAI-HDL fraction (i.e., comprising ApoA-I and no ApoA-II) are removed by the liver and processed into bile more effectively than those derived from HDL comprising both ApoA-I and ApoA-II (the AI/AII-HDL fraction). This may be owed, in part, to the more effective binding of ApoAI-HDL to the hepatocyte membrane. The existence of an HDL receptor has been hypothesized, and a scavenger receptor, class B, type I (SR-BI) has been identified as an HDL receptor (Acton et al., 1996, Science 271:518-20; Xu et al., 1997, Lipid Res. 38:1289-98). SR-BI is expressed most abundantly in steroidogenic tissues (e.g., the adrenals), and in the liver (Landschulz et al., 1996, J. Clin. Invest. 98:984-95; Rigotti et al., 1996, J. Biol. Chem. 271:33545-49). For a review of HDL receptors, see Broutin et al., 1988, Anal. Biol. Chem. 46:16-23.
Initial lipidation by ATP-binding cassette transporter AI appears to be critical for plasma HDL formation and for the ability of pre-beta-HDL particles to effect cholesterol efflux (Lee and Parks, 2005, Curr. Opin. Lipidol. 16(1):19-25). According to these authors, this initial lipidation enables pre-beta-HDL to function more efficiently as a cholesterol acceptor and prevents ApoA-I from rapidly associating with pre-existing plasma HDL particles, resulting in greater availability of pre-beta-HDL particles for cholesterol efflux.
CETP may also play a role in RCT. Changes in CETP activity or its acceptors, VLDL and LDL, play a role in “remodeling” the HDL population. For example, in the absence of CETP, the HDLs become enlarged particles that are not cleared. (For reviews of RCT and HDLs, see Fielding and Fielding, 1995, J. Lipid Res. 36:211-28; Barrans et al., 1996, Biochem. Biophys. Acta 1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol. 17(6):1053-59).
HDL also plays a role in the reverse transport of other lipids and apolar molecules, and in detoxification, i.e., the transport of lipids from cells, organs, and tissues to the liver for catabolism and excretion. Such lipids include sphingomyelin (SM), oxidized lipids, and lysophophatidylcholine. For example, Robins and Fasulo (1997, J. Clin. Invest. 99:380-84) have shown that HDLs stimulate the transport of plant sterol by the liver into bile secretions.
The major component of HDL, ApoA-I, can associate with SM in vitro. When ApoA-I is reconstituted in vitro with bovine brain SM (BBSM), a maximum rate of reconstitution occurs at 28° C., the temperature approximating the phase transition temperature for BBSM (Swaney, 1983, J. Biol. Chem. 258(2), 1254-59). At BBSM:ApoA-I ratios of 7.5:1 or less (wt/wt), a single reconstituted homogeneous HDL particle is formed that comprises three ApoA-I molecules per particle and that has a BBSM:ApoA-I molar ratio of 360:1. It appears in the electron microscope as a discoidal complex similar to that obtained by recombination of ApoA-I with phosphatidylcholine at elevated ratios of phospholipid protein. At BBSM:ApoA-I ratios of 15:1 (wt/wt), however, larger-diameter discoidal complexes form that have a higher phospholipid:protein molar ratio (535:1). These complexes are significantly larger, more stable, and more resistant to denaturation than ApoA-I complexes formed with phosphatidylcholine.
Sphingomyelin (SM) is elevated in early cholesterol acceptors (pre-beta-HDL and gamma-migrating ApoE-comprising lipoprotein), suggesting that SM might enhance the ability of these particles to promote cholesterol efflux (Dass and Jessup, 2000, J. Pharm. Pharmacol. 52:731-61; Huang et al., 1994, Proc. Natl. Acad. Sci. USA 91:1834-38; Fielding and Fielding 1995, J. Lipid Res. 36:211-28).
3.3. Protective Mechanism of HDL and ApoA-I
Studies of the protective mechanism(s) of HDL have focused on Apolipoprotein A-I (ApoA-I), the major component of HDL. High plasma levels of ApoA-I are associated with absence or reduction of coronary lesions (Maciejko et al., 1983, N. Engl. J. Med. 309:385-89; Sedlis et al., 1986, Circulation 73:978-84).
The infusion of ApoA-I or of HDL in experimental animals exerts significant biochemical changes, as well as reduces the extent and severity of atherosclerotic lesions. After an initial report by Maciejko and Mao (1982, Arteriosclerosis 2:407a), Badimon et al., (1989, Lab. Invest. 60:455-61; 1989, J. Clin. Invest. 85:1234-41) found that they could significantly reduce the extent of atherosclerotic lesions (reduction of 45%) and their cholesterol ester content (reduction of 58.5%) in cholesterol-fed rabbits, by infusing HDL (d=1.063-1.325 g/ml). They also found that the infusions of HDL led to a close to a 50% regression of established lesions. Esper et al. (1987, Arteriosclerosis 7:523a) have shown that infusions of HDL can markedly change the plasma lipoprotein composition of Watanabe rabbits with inherited hypercholesterolemia, which develop early arterial lesions. In these rabbits, HDL infusions can more than double the ratio between the protective HDL and the atherogenic LDL.
The potential of HDL to prevent arterial disease in animal models has been further underscored by the observation that ApoA-I can exert a fibrinolytic activity in vitro (Saku et al., 1985, Thromb. Res. 39:1-8). Ronneberger (1987, Xth Int. Congr. Pharmacol., Sydney, 990) demonstrated that ApoA-I can increase fibrinolysis in beagle dogs and in Cynomologous monkeys. A similar activity can be noted in vitro on human plasma. Ronneberger was able to confirm a reduction of lipid deposition and arterial plaque formation in ApoA-I treated animals.
In vitro studies indicate that complexes of ApoA-I and lecithin can promote the efflux of free cholesterol from cultured arterial smooth muscle cells (Stein et al., 1975, Biochem. Biophys. Acta, 380:106-18). By this mechanism, HDL can also reduce the proliferation of these cells (Yoshida et al., 1984, Exp. Mol. Pathol. 41:258-66).
Infusion therapy with HDL comprising ApoA-I or ApoA-I mimetic peptides has also been shown to regulate plasma HDL levels by the ABC1 transporter, leading to efficacy in the treatment of cardiovascular disease (see, e.g., Brewer et al., 2004, Arterioscler. Thromb. Vasc. Biol. 24:1755-1760).
Two naturally occurring human polymorphism of ApoA-I have been isolated in which an arginine residue is substituted with cysteine. In Apolipoprotein A-IMilano (ApoA-IM), this substitution occurs at residue 173, whereas in Apolipoprotein A-IParis (ApoA-IP), this substitution occurs at residue 151 (Franceschini et al., 1980, J. Clin. Invest. 66:892-900; Weisgraber et al., 1983, J. Biol. Chem. 258:2508-13; Bruckert et al., 1997, Atherosclerosis 128:121-28; Daum et al., 1999, J. Mol. Med. 77:614-22; Klon et al., 2000, Biophys. J. 79(3):1679-85). Yet a further naturally occurring human polymorphism of ApoA-I has been isolated, in which a leucine is substituted with an arginine at position 144. This polymorphism has been termed Apolipoprotein A-I Zaragoza (ApoA-IZ) and is associated with severe hypoalphalipoproteinemia and an enhanced effect of high density lipoprotein (HDL) reverse cholesterol transport (Recalde et al., 2001, Atherosclerosis 154(3):613-623; Fiddyment et al., 2011, Protein Expr. Purif. 80(1):110-116).
Reconstituted HDL particles comprising disulfide-linked homodimers of either ApoA-IM or ApoA-IP are similar to reconstituted HDL particles comprising wild-type ApoA-I in their ability to clear dimyristoylphosphatidylcholine (DMPC) emulsions and their ability to promote cholesterol efflux (Calabresi et al., 1997b, Biochemistry 36:12428-33; Franceschini et al., 1999, Arterioscler. Thromb. Vasc. Biol. 19:1257-62; Daum et al., 1999, J. Mol. Med. 77:614-22). In both mutations, heterozygous individuals have decreased levels of HDL but paradoxically, are at a reduced risk for atherosclerosis (Franceschini et al., 1980, J. Clin. Invest. 66:892-900; Weisgraber et al., 1983, J. Biol. Chem. 258:2508-13; Bruckert et al., 1997, Atherosclerosis 128:121-28). Reconstituted HDL particles comprising either variant are capable of LCAT activation, although with decreased efficiency when compared with reconstituted HDL particles comprising wild-type ApoA-I (Calabresi et al., 1997, Biochem. Biophys. Res. Commun. 232:345-49; Daum et al., 1999, J. Mol. Med. 77:614-22).
The ApoA-IM mutation is transmitted as an autosomal dominant trait; eight generations of carriers within a family have been identified (Gualandri et al., 1984, Am. J. Hum. Genet. 37:1083-97). The status of an ApoA-IM carrier individual is characterized by a remarkable reduction in HDL-cholesterol level. In spite of this, carrier individuals do not apparently show any increased risk of arterial disease. Indeed, by examination of genealogical records, it appears that these subjects may be “protected” from atherosclerosis (Sirtori et al., 2001, Circulation, 103: 1949-1954; Roma et al., 1993, J. Clin. Invest. 91(4):1445-520).
The mechanism of the possible protective effect of ApoA-IM in carriers of the mutation seems to be linked to a modification in the structure of the mutant ApoA-IM, with loss of one alpha-helix and an increased exposure of hydrophobic residues (Franceschini et al., 1985, J. Biol. Chem. 260:1632-35). The loss of the tight structure of the multiple alpha-helices leads to an increased flexibility of the molecule, which associates more readily with lipids, compared to normal ApoA-I. Moreover, lipoprotein complexes are more susceptible to denaturation, thus suggesting that lipid delivery is also improved in the case of the mutant.
Bielicki, et al. (1997, Arterioscler. Thromb. Vase. Biol. 17 (9):1637-43) has demonstrated that ApoA-IM has a limited capacity to recruit membrane cholesterol compared with wild-type ApoA-I. In addition, nascent HDL formed by the association of ApoA-IM with membrane lipids was predominantly 7.4-nm particles rather than larger 9- and 11-nm complexes formed by wild-type ApoA-I. These observations indicate that the Arg173→Cys173 substitution in the ApoA-I primary sequence interfered with the normal process of cellular cholesterol recruitment and nascent HDL assembly. The mutation is apparently associated with a decreased efficiency for cholesterol removal from cells. Its antiatherogenic properties may therefore be unrelated to RCT.
The most striking structural change attributed to the Arg173→Cys173 substitution is the dimerization of ApoA-IM (Bielicki et al., 1997, Arterioscler. Thromb. Vasc. Biol. 17 (9):1637-43). ApoA-IM can form homodimers with itself and heterodimers with ApoA-II. Studies of blood fractions comprising a mixture of apolipoproteins indicate that the presence of dimers and complexes in the circulation may be responsible for an increased elimination half-life of apolipoproteins. Such an increased elimination half-life has been observed in clinical studies of carriers of the mutation (Gregg et al., 1988, NATO ARW on Human Apolipoprotein Mutants: From Gene Structure to Phenotypic Expression, Limone S G). Other studies indicate that ApoA-IM dimers (ApoA-IM/ApoA-IM) act as an inhibiting factor in the interconversion of HDL particles in vitro (Franceschini et al., 1990, J. Biol. Chem. 265:12224-31).
3.4. Current Treatments for Dyslipidemia and Related Disorders
Dyslipidemic disorders are diseases associated with elevated serum cholesterol and triglyceride levels and lowered serum HDL:LDL ratios, and include hyperlipidemia, especially hypercholesterolemia, coronary heart disease, coronary artery disease, vascular and perivascular diseases, and cardiovascular diseases such as atherosclerosis. Syndromes associated with atherosclerosis such as transient ischemic attack or intermittent claudication, caused by arterial insufficiency, are also included. A number of treatments are currently available for lowering the elevated serum cholesterol and triglycerides associated with dyslipidemic disorders. However, each has its own drawbacks and limitations in terms of efficacy, side-effects and qualifying patient population.
Bile-acid-binding resins are a class of drugs that interrupt the recycling of bile acids from the intestine to the liver; e.g., cholestyramine (Questran Light®, Bristol-Myers Squibb), colestipol hydrochloride (Colestid®, The Upjohn Company), and colesevelam hydrochloride (Welchol®, Daiichi-Sankyo Company). When taken orally, these positively-charged resins bind to the negatively charged bile acids in the intestine. Because the resins cannot be absorbed from the intestine, they are excreted carrying the bile acids with them. The use of such resins at best, however, only lowers serum cholesterol levels by about 20%, and is associated with gastrointestinal side-effects, including constipation and certain vitamin deficiencies. Moreover, since the resins bind other drugs, other oral medications must be taken at least one hour before or four to six hours subsequent to ingestion of the resin; thus, complicating heart patient's drug regimens.
Statins are cholesterol lowering agents that block cholesterol synthesis by inhibiting HMGCoA reductase, the key enzyme involved in the cholesterol biosynthetic pathway. Statins, e.g., lovastatin (Mevacor®), simvastatin (Zocor®), pravastatin (Pravachol®), fluvastatin (Lescol®) and atorvastatin (Lipitor®), are sometimes used in combination with bile-acid-binding resins. Statins significantly reduce serum cholesterol and LDL-serum levels, and slow progression of coronary atherosclerosis. However, serum HDL cholesterol levels are only moderately increased. The mechanism of the LDL lowering effect may involve both reduction of VLDL concentration and induction of cellular expression of LDL-receptor, leading to reduced production and/or increased catabolism of LDLs. Side effects, including liver and kidney dysfunction are associated with the use of these drugs (The Physicians Desk Reference, 56th Ed., 2002, Medical Economics).
Niacin (nicotinic acid) is a water soluble vitamin B-complex used as a dietary supplement and antihyperlipidemic agent. Niacin diminishes production of VLDL and is effective at lowering LDL. In some cases, it is used in combination with bile-acid binding resins. Niacin can increase HDL when used at adequate doses, however, its usefulness is limited by serious side effects when used at such high doses. Niaspan® is a form of extended-release niacin that produces fewer side effects than pure niacin. Niacin/Lovastatin (Nicostatin®) is a formulation containing both niacin and lovastatin and combines the benefits of each drug.
Fibrates are a class of lipid-lowering drugs used to treat various forms of hyperlipidemia (i.e., elevated serum triglycerides) that may also be associated with hypercholesterolemia. Fibrates appear to reduce the VLDL fraction and modestly increase HDL, however the effect of these drugs on serum cholesterol is variable. In the United States, fibrates such as clofibrate (Atromid-S®), fenofibrate (Tricor®) and bezafibrate (Bezalip®) have been approved for use as antilipidemic drugs, but have not received approval as hypercholesterolemia agents. For example, clofibrate is an antilipidemic agent that acts (via an unknown mechanism) to lower serum triglycerides by reducing the VLDL fraction. Although serum cholesterol may be reduced in certain patient subpopulations, the biochemical response to the drug is variable, and is not always possible to predict which patients will obtain favorable results. Atromid-S® has not been shown to be effective for prevention of coronary heart disease. The chemically and pharmacologically related drug, gemfibrozil (Lopid®) is a lipid regulating agent that moderately decreases serum triglycerides and VLDL cholesterol, and moderately increases HDL cholesterol—the HDL2 and HDL3 subfractions as well as both ApoA-I and A-II (i.e., the AI/AMT-HDL fraction). However, the lipid response is heterogeneous, especially among different patient populations. Moreover, while prevention of coronary heart disease was observed in male patients between 40-55 without history or symptoms of existing coronary heart disease, it is not clear to what extent these findings can be extrapolated to other patient populations (e.g., women, older and younger males). Indeed, no efficacy was observed in patients with established coronary heart disease. Serious side-effects are associated with the use of fibrates including toxicity such as malignancy (especially gastrointestinal cancer), gallbladder disease and an increased incidence in non-coronary mortality.
Oral estrogen replacement therapy may be considered for moderate hypercholesterolemia in post-menopausal women. However, increases in HDL may be accompanied with an increase in triglycerides. Estrogen treatment is, of course, limited to a specific patient population (postmenopausal women) and is associated with serious side effects including induction of malignant neoplasms, gall bladder disease, thromboembolic disease, hepatic adenoma, elevated blood pressure, glucose intolerance, and hypercalcemia.
Other agents useful for the treatment of hyperlipidemia include ezetimibe (Zetia®; Merck), which blocks or inhibits cholesterol absorption. However, inhibitors of ezetimibe have been shown to exhibit certain toxicities.
HDL, as well as recombinant forms of ApoA-I complexed with phospholipids can serve as sinks/scavengers for apolar or amphipathic molecules, e.g., cholesterol and derivatives (oxysterols, oxidized sterols, plant sterols, etc.), cholesterol esters, phospholipids and derivatives (oxidized phospholipids), triglycerides, oxidation products, and lipopolysaccharides (LPS) (see, e.g., Casas et al., 1995, J. Surg. Res. Nov 59(5):544-52). HDL can also serve as also a scavenger for TNF-alpha and other lymphokines. HDL can also serve as a carrier for human serum paraoxonases, e.g., PON-1, -2, -3. Paraoxonase, an esterase associated with HDL, is important for protecting cell components against oxidation. Oxidation of LDL, which occurs during oxidative stress, appears directly linked to development of atherosclerosis (Aviram, 2000, Free Radic. Res. 33 Suppl:S85-97). Paraoxonase appears to play a role in susceptibility to atherosclerosis and cardiovascular disease (Aviram, 1999, Mol. Med. Today 5(9):381-86). Human serum paraoxonase (PON-1) is bound to high-density lipoproteins (HDLs). Its activity is inversely related to atherosclerosis. PON-1 hydrolyzes organophosphates and may protect against atherosclerosis by inhibition of the oxidation of HDL and low-density lipoprotein (LDL) (Aviram, 1999, Mol. Med. Today 5(9):381-86). Experimental studies suggest that this protection is associated with the ability of PON-1 to hydrolyze specific lipid peroxides in oxidized lipoproteins. Interventions that preserve or enhance PON-1 activity may help to delay the onset of atherosclerosis and coronary heart disease.
HDL further has a role as an antithrombotic agent and fibrinogen reducer, and as an agent in hemorrhagic shock (Cockerill et al., WO 01/13939, published Mar. 1, 2001). HDL, and ApoA-I in particular, has been show to facilitate an exchange of lipopolysaccharide produced by sepsis into lipid particles comprising ApoA-I, resulting in the functional neutralization of the lipopolysaccharide (Wright et al., WO9534289, published Dec. 21, 1995; Wright et al., U.S. Pat. No. 5,928,624 issued Jul. 27, 1999; Wright et al., U.S. Pat. No. 5,932,536, issued Aug. 3, 1999).
There are a variety of methods available for making lipoprotein complexes in vitro. U.S. Pat. Nos. 6,287,590 and 6,455,088 disclose a method entailing co-lyophilization of apolipoprotein and lipid solutions in organic solvent (or solvent mixtures) and formation of charged lipoprotein complexes during hydration of the lyophilized powder. Lipoprotein complexes can also be formed by a detergent dialysis method; e.g., a mixture of a lipid, a lipoprotein and a detergent such as cholate is dialyzed and reconstituted to form a complex (see, e.g., Jonas et al., 1986, Methods Enzymol. 128:553-82). Example 1 of U.S. publication 2004/0067873 discloses a cholate dispersion method, in which a lipid dispersion is combined with cholate under conditions for forming micelles, and these in turn are incubated with an apoliprotein solution to form complexes. Ultimately, the cholate, which is toxic, has to be removed, e.g., by dialysis, ultrafiltration or adsorption absorption onto an affinity bead or resin. U.S. Pat. No. 6,306,433 discloses lipoprotein complex formation by subjecting a fluid mixture of a protein and lipid to high pressure homogenization. However, proteins that are sensitive to high shear forces can lose activity when exposed to high pressure homogenization.
Thus, currently available manufacturing methods result in wastage of starting materials, such as protein degradation, and/or require purification of the resulting product, such as removal of a toxic agent, and thus are inefficient and costly. Additionally, preparations of lipoprotein complexes can be heterogeneous, containing a mixture of complexes varying in size and in composition. See, e.g., U.S. Pat. No. 5,876,968. Accordingly, there is a need to develop new methods for production of lipoprotein complexes that are efficient and yield more homogeneous complexes, preferably having a high degree of purity. Such processes could allow more economical production on a large scale while generating a more uniform pharmaceutically acceptable product with fewer risks of side effects due to contaminants.
Moreover, the therapeutic use of ApoA-I, ApoA-IM, ApoA-IP and other variants, as well as reconstituted HDL, is presently limited, however, by the large amount of apolipoprotein required for therapeutic administration and by the cost of protein production, considering the low overall yield of production and the occurrence of protein degradation in cultures of recombinantly expressed proteins. (See, e.g., Mallory et al., 1987, J. Biol. Chem. 262(9):4241-4247; Schmidt et al., 1997, Protein Expression & Purification 10:226-236). It has been suggested by early clinical trials that the dose range is between 1.5-4 g of protein per infusion for treatment of cardiovascular diseases. The number of infusions required for a full treatment is unknown. (See, e.g., Eriksson et al., 1999, Circulation 100(6):594-98; Carlson, 1995, Nutr. Metab. Cardiovasc. Dis. 5:85-91; Nanjee et al., 2000, Arterioscler. Thromb. Vasc. Biol. 20(9):2148-55; Nanjee et al., 1999, Arterioscler. Thromb. Vasc. Biol. 19(4):979-89; Nanjee et al., 1996, Arterioscler. Thromb. Vasc. Biol. 16(9):1203-14).
Recombinant human ApoA-I has been expressed in heterologous hosts, however, the yield of mature protein has been insufficient for large-scale therapeutic applications, especially when coupled to purification methods that further reduce yields and result in impure product.
Weinberg et al., 1988, J. Lipid Research 29:819-824, describes the separation of apolipoproteins A-I, A-II and A-IV and their isoforms purified from human plasma by reverse phase high pressure liquid chromatography.
WO 2009/025754 describes protein separation and purification of alpha-1-antitrypsin and ApoA-I from human plasma.
Hunter et al., 2009, Biotechnol. Prog. 25(2):446-453, describes large-scale purification of the ApoA-I Milano variant that is recombinantly expressed in E. coli.
Caparon et al., 2009, Biotechnol. And Bioeng. 105(2):239-249 describes the expression and purification of ApoA-I Milano from an E. coli host which was genetically engineered to delete two host cell proteins in order to reduce the levels of these proteins in the purified apolipoprotein product.
U.S. Pat. No. 6,090,921 describes purification of ApoA-I or apolipoprotein E (ApoE) from a fraction of human plasma containing ApoA-I and ApoE using anion-exchange chromatography.
Brewer et al., 1986, Meth. Enzymol. 128:223-246 describes the isolation and characterization of apolipoproteins from human blood using chromatographic techniques.
Weisweiler et al., 1987, Clinica Chimica Acta 169:249-254 describes isolation of ApoA-I and ApoA-II from human HDL using fast-protein liquid chromatography.
deSilva et al., 1990, J. Biol. Chem. 265(24):14292-14297 describes the purification of apolipoprotein J by immunoaffinity chromatography and reverse phase high performance liquid chromatography.
Lipoproteins and lipoprotein complexes are currently being developed for clinical use, with clinical studies using different lipoprotein-based agents establishing the feasibility of lipoprotein therapy (Tardif, 2010, Journal of Clinical Lipidology 4:399-404). One study evaluated autologous delipidated HDL (Waksman et al., 2010, J. Am. Coll. Cardiol. 55:2727-2735). Another study evaluated ETC-216, a complex of recombinant ApoA-IM and palmitoyl-oleoyl-PC(POPC) (Nissen et al., 2003, JAMA 290:2292-2300). CSL-111 is a reconstituted human ApoA-I purified from plasma complexed with soybean phosphatidylcholine (SBPC) (Tardif et al., 2007, JAMA 297:1675-1682). Current exploratory drugs have shown efficacy in reducing the atherosclerotic plaque but the effect was accompanied by secondary effects such as increase in transaminases or formation of ApoA-I antibodies (Nanjee et al., 1999, Arterioscler. Vase. Throm. Biol. 19:979-89; Nissen et al., 2003, JAMA 290:2292-2300; Spieker et al., 2002, Circulation 105:1399-1402; Nieuwdorp et al., 2004, Diabetologia 51:1081-4; Drew et al., 2009, Circulation 119, 2103-11; Shaw et al., 2008, Circ. Res. 103:1084-91; Tardiff et al., 2007, JAMA 297:1675-1682; Waksman, 2008, Circulation 118:S 371; Cho, U.S. Pat. No. 7,273,849 B2, issued Sep. 25, 2007). For example, the ERASE clinical trial (Tardiff et al., 2007, JAMA 297:1675-1682) utilized two doses of CSL-111: 40 mg/kg and 80 mg/kg of ApoA-I. The 80 mg/kg dose group had to be stopped due to liver toxicity (as shown by serious transaminase elevation). Even in the 40 mg/kg dose group several patient experience transaminase elevation.
The need therefore exists for safer drugs that are more efficacious in lowering serum cholesterol, increasing HDL serum levels, preventing and/or treating dyslipidemia and/or diseases, conditions and/or disorders associated with dyslipidemia. There is a need in the art for lipoprotein formulations that are not associated with liver toxicity, and preferably induce only minimal (or no) increase in triglycerides, LDL-triglycerides, or VLDL-triglycerides, as well as for robust production methods that can be used to reliably make these lipoprotein formulations on a commercial scale. | {
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As a charged particle beam apparatus capable of performing high-vacuum exhaust and low-vacuum exhaust, for example, there is a low-vacuum scanning electron microscope including a vacuum exhaust system disclosed in the following patent literature.
JP-A-2007-141633 (PTL 1) discloses a vacuum exhaust system that is capable of performing high-vacuum exhaust and low-vacuum exhaust of an electron gun chamber using minimum pumps and that has a configuration including a first pump (a turbo molecular pump) performing high-vacuum exhaust of the electron gun chamber and a second pump (an oil rotary pump) performing back pressure exhaust of the first pump and low-vacuum exhaust of a sample chamber as well.
JP-A-2011-034744 (PTL 2) discloses an exhaust system that includes a plurality of intermediate chambers through which electron rays pass between an electron gun chamber and a sample chamber, includes valves in openings between the plurality of intermediate chambers, and performs exhaust so that pressures of the intermediate chamber closer to the sample chamber than the value and the sample chamber are higher than pressures of the intermediate chamber closer to the electron source than the valve and the electron gun chamber in order to achieve an improvement in a throughput from sample exchange to observation since it is general to expose the sample chamber, the intermediate chambers, and the electron gun chamber to the atmosphere at the time of exchanging a sample in the low-vacuum scanning electron microscope of PTL 1 or the like. | {
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A digital speaker is known that generates sound on the basis of a digital signal (for example, see Patent Literature 1). The digital speaker can achieve high sound quality due to a lack of deterioration of sound quality by an analog system from audio amps and the like during transmission to the speaker. Further, for small-sized equipment such as mobile phones, the use of a digital terminal as a terminal for the output of sound is preferred from the standpoint of equipment design due to the digital terminal being smaller than an analog terminal (so-called pin jack), and thus demand is increasing for digital speakers, which generate sound on the basis of a digital signal output from the digital terminal.
A digital speaker requires an array of separate sound generating devices for each bit of the inputted digital signal. However, due to speaker units using a permanent magnet and voice coil often being utilized conventionally as each of the sound generating devices, a problem occurs due to mutual induction between coils. Further, differences between the individual coils also cause a problem of decreased sound quality. Also miniaturization is difficult due to the requirement that the number of speakers matches the bit count.
Further, Patent Literature 2 discloses a digital speaker in which the number of electrodes arranged on one piezoelectric element is the same as the bit count. Either the voltage applied to each electrode differs in accordance with the corresponding bit, or the surface area of each of the electrodes corresponds to the bit. However, Patent Literature 2 does not disclose a circuit applying a voltage to each of the electrodes, and enablement cannot be realized using the disclosed configuration. In particular, how voltage is applied to a central portion of the piezoelectric element is unclear. Further, the voltage of each bit is applied separately to the central portion and circumferential portion of the piezoelectric element, and thus frequency characteristics of each bit in the piezoelectric element are not uniform. | {
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This invention relates generally to a liquid crystal display device, and more particularly, to a liquid crystal display device having a reflector and which provides a display with improved brightness.
Super twisted nematic (STN) liquid crystal display devices including a uniaxial anisotropic member (an oriented high molecular weight polymer sheet) between the polarizers of the device have been proposed to improve the display contrast. An example of such a liquid crystal display device 10 with a uniaxial optically anisotropic member 12 is shown in FIG. 1. Device 10 includes a twisted nematic liquid crystal display cell 13 with an upper linear polarizer 11 and a lower polarizer 14 on the outer surfaces of cell 13 and optically anisotropic layer 12. Display cell 13 includes an upper substrate 15 and lower substrate 16 with transparent electrodes 17 and 18 disposed on the inner surfaces and a twisted nematic liquid crystal material 19 therebetween. A spacer 22 holds substrates 15 and 16 apart and liquid crystal material 19 therebetween. Liquid crystal material 19 is twist oriented by rubbing the interior surfaces of substrates 15 and 16. Device 10 would normally be back lit.
FIG. 2 shows the relationship between the axes of these elements. In FIG. 2, R15 and R16 designate the rubbing directions of upper substrate 15 and lower substrate 16. Angle T2 designates the direction and angle of twist of the liquid crystal molecules in material 19 from upper substrate 15 to lower substrate 16. P11 and P14 designate the directions of the axes of polarization of upper polarizer 11 and lower polarizer 14, respectfully. A line A-A' identifies the direction of observation of device 10. .THETA..sub.45 is the angle between direction of observation A-A' and rubbing direction R15 of upper substrate 15 and .THETA..sub.46 is the angle between direction of observation A-A' and rubbing direction R16 of lower substrate 16. .THETA..sub.45 and .THETA..sub.46 are approximately equal to each other. Device 10 is described in detail in applicant's U.S. Pat. No. 4,844,569, the contents of which are incorporated herein by reference.
In device 10, the retardation value of optically anisotropic member 12 and the relationship between the axes are set for use in an STN display mode in order to improve the contrast and allow for a black-and-white display. While this arrangement has improved contrast and achieved nearly a full black and white display compared to ordinary STN devices, viewing angle characteristics were not considered.
FIG. 11 is an alternative embodiment of a STN liquid crystal device including a phase difference plate between two polarizing plates to improve the contrast of the liquid crystal device, but including a reflector, rather than being intended to be back lit.
In a preferred embodiment of the instant invention, the STN liquid crystal material 145 of FIG. 11 is selected so that the liquid crystal molecules are homogeneously aligned so as to provide a helical structure having a twist angle of 180.degree. to 270.degree. and so that the layer of STN liquid crystal material has positive dielectric anisotropy. In FIG. 11, the STN liquid crystal material 145 is sealed between the gap defined by glass substrates 143 and 147. Upper and lower polarizing plates 141 and 148 are respectively disposed on the upper surface of the phase difference plate 142 and the lower surface of the lower glass substrate 147. Phase difference plate 142 is an optically anisotropic member. In addition reflector 149, which is formed of a high reflectance material, for example aluminum, is provided on the lower surface of lower polarizing plate 148.
In the past, because these phase difference plates are costly, the most efficient method for cutting them from stock is usually used. This most efficient cutting method is to have the direction of the optical axis of the phase difference plate to be either coincident with or perpendicular to the direction in which the device is normally viewed (observation direction) when the plate is cut from stock. As used herein, the observation direction is a direction in the plane of the display screen defined by the liquid crystal display cell formed by the substrates and liquid crystal material. The rubbing directions and the directions of the absorption axes of the set of polarizing plates are then conventionally determined by taking into consideration the colors and contrasts.
The conventional liquid crystal display devices which, utilize a phase difference plate having the optical axis coincident with or perpendicular to the direction in which the device is normally viewed, and a reflector, have an unfavorably low display brightness.
Accordingly, it is desirable to provide a liquid crystal display device with a reflector which has increased brightness by choosing the direction of the optical axis of the phase difference plate. | {
"pile_set_name": "USPTO Backgrounds"
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Many activities require secure electronic communications. To facilitate secure electronic communications, an encryption/decryption system may be implemented on an electronic assembly or printed circuit board assembly that is included in equipment connected to a communications network. Such an electronic assembly is an enticing target for malefactors since it may contain codes or keys to decrypt intercepted messages, or to encode fraudulent messages. To prevent this, an electronic assembly may be mounted in an enclosure, which is then wrapped in a security sensor and encapsulated with polyurethane resin. A security sensor may be, in one or more embodiments, a web or sheet of insulating material with circuit elements, such as closely-spaced, conductive lines fabricated on it. The circuit elements are disrupted if the sensor is torn, and the tear can be sensed in order to generate an alarm signal. The alarm signal may be conveyed to a monitor circuit in order to reveal an attack on the integrity of the assembly. The alarm signal may also trigger an erasure of encryption/decryption keys stored within the electronic assembly. | {
"pile_set_name": "USPTO Backgrounds"
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One common step that may be performed frequently during fabrication of modern semiconductor devices is the formation of a thin film on a semiconductor substrate by chemical reaction of gases. Such deposition processes are referred to generally as chemical vapor deposition (“CVD”) and include both thermal CVD processes and plasma-enhanced CVD (“PECVD”) process. In conventional thermal CVD processes, reactive gases are supplied to the substrate surface, where heat-induced chemical reactions take place to form the desired film. In a conventional plasma process, a controlled plasma is formed to decompose and/or energize reactive species to produce the desired film.
Any of these CVD techniques may be used to deposit conductive or insulative films during the fabrication of integrated circuits. One important physical property of CVD insulative films includes the film's ability to fill gaps completely between adjacent structures without leaving voids; this property is referred to as the film's gapfill capability. Gaps that may require filling by CVD insulative layers, such as silicon oxide based layers, include spaces between adjacent raised structures such as transistor gates, conductive lines, etched trenches, stacked capacitors or the like.
As semiconductor device geometries have decreased in size over the years, the ratio of the height of such gaps to their width, the so-called “aspect ratio,” has increased dramatically. Gaps having a combination of high aspect ratio and a small width present a particular challenge for semiconductor manufacturers to fill completely. In short, the challenge usually is to prevent the deposited film from growing in a manner that closes off the gap before it is filled. Failure to fill the gap completely results in the formation of voids in the deposited layer, which may adversely affect device operation. The semiconductor industry has accordingly been searching aggressively for techniques that may improve gapfill capabilities, particularly with high-aspect-ratio small-width gaps.
High-aspect-ratio gaps are difficult to fill using conventional CVD methods, causing some integrated-circuit manufacturers to turn to the use high-density-plasma CVD (“HDP-CVD”) techniques. The use of an HDP-CVD technique results in the formation of a plasma that has a density approximately two orders of magnitude greater than the density of a conventional, capacitively coupled plasma. Examples of HDP-CVD systems include inductively coupled plasma (“ICP”) systems and electron-cyclotron-resonance (“ECR”) systems, among others. There are a number of advantages of plasma-deposition processes in gapfill applications that are thus enhanced in the case of HDP-CVD deposition processes. For example, the high reactivity of the species in any plasma deposition process reduces the energy required for a chemical reaction to take place, thereby allowing the temperature of the process to be reduced compared with conventional thermal CVD processes; the temperatures of HDP-CVD processes may advantageously be even lower than with PECVD processes because the species reactivity is even higher. Similarly, HDP-CVD systems generally operate at lower pressure ranges than low-density plasma systems. The low chamber pressure provides active species having a long mean-free-path and reduced angular distribution. These factors contribute to a significant number of constituents from the plasma reaching even the deepest portions of closely spaced gaps, providing a film with improved gapfill capabilities.
Another factor that allows films deposited by HDP-CVD techniques to have improved gapfill characteristics is the occurrence of sputtering, promoted by the plasma's high density, simultaneous with film deposition. The sputtering component of HDP deposition slows deposition on certain features, such as the corners of raised surfaces, thereby contributing to the increased gapfill ability of HDP deposited films. Some HDP-CVD processes introduce an inert element that further promotes the sputtering effect, with the choice of inert element often depending on its atomic or molecular weight, a parameter that is generally correlated with the size of the sputtering effect. In addition, the sputtering effect may be further promoted by applying an electric bias with an electrode in the substrate support pedestal to use electrical attraction of the plasma species.
It was initially thought that the simultaneous deposition and etching provided by HDP-CVD processes would allow gaps to be filled in almost any application. Semiconductor manufacturers have discovered, however, that there is a practical limit to the aspect ratio of gaps that HDP-CVD deposition techniques are able to fill. The challenge of filling gaps with HDP-CVD is illustrated schematically with the cross-sectional views shown in FIGS. 1A and 1B. FIG. 1A shows a vertical cross section of a substrate 10, such as may be provided with a semiconductor wafer, having adjacent raised features 20, which may be adjacent metal lines, trench walls, or a variety of other structures. Adjacent features 20 define gaps 14 that are to be filled with dielectric material, with the sidewalls 16 of the gaps being defined by the surfaces of the features 20. As the deposition proceeds, dielectric material 18 accumulates on the surfaces of the features 20, as well as on the substrate 10, and forms overhangs 22 at the comers 24 of the features 20. As deposition of the dielectric material 18 continues, the overhangs 22 typically grow faster than the gap 14 in a characteristic breadloafing fashion. Eventually, the overhangs 22 grow together to form the dielectric film 26 shown in FIG. 1B, preventing deposition into an interior void 28.
In one commonly used process, an HDP-CVD process is used to deposit a silicon oxide film using a process gas that includes monosilane SiH4, molecular oxygen O2, and argon Ar. While such a process has been successfully used to fill certain narrow-width, high-aspect-ratio gaps for many applications, improved and/or alternative techniques are desired. | {
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1. Field of the Invention
This invention relates to data processing.
2. Description of the Prior Art
Some electronic data processing devices employ a processing core which can operate in accordance with a number of possible operating modes or states. In a simple example, the processing core may operate in either an "internal operation" mode or a "memory access" mode, depending on the particular processing task which has to be performed at any time.
It has been proposed to use a synchronous state machine to control the transition between the various operating states of such a processing core. Synchronous state machines are logic circuits which generally comprise both combinational logic and clocked registers, with a degree of feedback so that signals generated in response to a clocking pulse are passed back as inputs to a part of the circuit for use at the next clocking pulse. These circuits have a number of permitted output "states", represented by the logic levels of one or more output signals, and various permitted transitions between the output states. Because of the use of feedback, the circuit will move in a permitted transition from one state to another in response to particular sets of input signals. The transitions between states all take place in response to the clocking signal; for this reason such circuits are referred to as synchronous state machines.
In the simple example described above, a state machine may control synchronous transitions between the two possible operating states of the processing core. This can be achieved by supplying various inputs to the state machine representing the current and next tasks to be performed by the core and other current operating features of the data processing device. The output of the state machine is then connected as a control input to the processing core.
For example, when a memory access is required, the state machine would generate an output state controlling the core to assume the "memory access" mode. When the required memory address has been accessed, the state machine's output might revert back to an output controlling the core to assume the "internal operation" mode. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to a technique for reducing flicker of image shot with a video camera caused by luminance fluctuation of an illuminating light source.
2. Description of the Related Art
The frequency of commercial electrical power is standardized at either 50 Hz or 60 Hz depending on geographical region. Depending on the type of lighting equipment, the luminance of a lighting equipment which uses such commercial electrical power fluctuates at a frequency equal to the frequency of commercial electrical power (commercial power frequency) or a twice of the commercial power frequency. For example, in regions of 50 Hz commercial power frequency, the luminance of an incandescent lamp fluctuates at 100 Hz, while the luminance of a fluorescent lamp without an inverter fluctuates at 100 Hz or 50 Hz.
Meanwhile, the number of frames per second (frame rate) in a video camera and a video monitor is standardized for the television system. For example, in the case of the NTSC television system, the frame rate is standardized to be 60 frames per second (FPS).
For example, in the case of using a video camera with a frame rate of 60 FPS in a region of 50 Hz commercial power frequency to shoot video image of a subject illuminated by fluorescent light, the brightness fluctuation of individual frames, a phenomenon known as flicker, occurs resulting from the lightness fluctuation of the subject caused by the luminance fluctuation of the lighting equipment causes. Typically, the video camera is equipped with flicker reduction means for reducing such flicker. In an example of such flicker reduction means, the shutter speed is set to 1/00 second in order to reduce variation of light amount entering into the imaging elements of the video camera.
However, in such flicker reduction means provided to a video camera, flicker reduction processing is fixed for each model of the video camera. For this reason, it may sometimes occur that, flicker is not sufficiently reduced with a certain video camera under the conditions of the illuminating light source, while the picture quality of the video image output from a different video camera may degrade due to an excessive flicker reduction. | {
"pile_set_name": "USPTO Backgrounds"
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(1) Field of the Invention
The present invention relates to the growth of thin films, in particular to a method and apparatus for measuring and controlling accurately the optical thickness of a thin film during growth and to devices produced thereby.
(2) Description of the Art
Thin film technology is increasingly relevant to a wide range of scientific and industrial fields including semiconductors, optics and telecommunications. One particular application of thin-film technology is in the field of fibre-optic telecommunications, where multi-layer thin-film optical filters are routinely used for wavelength division multiplexing (WDM). Wavelength division multiplexing (WDM) employs multiple optical signal channels simultaneously within a single optical fibre, each optical signal channel using light of a different wavelength. In wavelength division multiplexing, the thin-film optical filters are used to separate out (demultiplex) signals at the receiver.
The above filters effectively govern how much information can be passed down an optical fibre and there is an ever-present requirement to improve the data capacity of such WDM telecommunications systems by reducing the spacing between adjacent signal channels, thereby increasing the number of channels available. Conventional dense wavelength division multiplexing (DWDM) communications systems typically employ over one hundred optical signal channels, evenly spaced at 100 GHz intervals, in the range 186700 GHz to 197100 GHz according to the International Telecommunications Union (ITU) set of standardised frequencies [EXFO Electro-Optical Engineering Inc, Quebec City, Canada, Guide to WDM technology and testing, 2000, pp 15].
In an attempt to increase data capacity, the telecommunications industry is now proposing that the channel spacing be further reduced from 100 GHz to 50 GHz. However, such a proposal is not without attendant disadvantages and the reduced channel spacing of 50 GHz places onerous tolerance requirements on the multi-layer thin-film optical filters that are used to demultiplex the signals at the optical-fibre receiver. Consequently, the optical thickness of the individual thin films layers that comprise such a multi-layer filter have to be measured and controlled as precisely as possible during the growth process.
A conventional method for measuring and controlling the optical thickness of a thin-film during growth is to use a quartz-crystal monitor inserted into the growth chamber along with the optical filter substrate [Macleod, H. A. Thin-film optical filters. Bristol: Institute of Physics Publishing (IoP), 2001, chapter 11.3.2]
A quartz-crystal monitor is a quartz crystal that is induced to oscillate at a given frequency. The quartz-crystal monitor is placed in the growth chamber so that it is exposed to the same thin film growth as the substrate. In this way, the mass and hence natural frequency of oscillation of the quartz-crystal changes as material is deposited onto the crystal. The change in mass can be translated to physical thickness if the density of the material being deposited is known. However, in order for the optical quarter-wave thickness to be calculated, the refractive index of the thin film at the design wavelength must also be known. These material parameters may depend on the growth process parameters, so may not be known to sufficient accuracy prior to the growth. At present, there is no satisfactory way of measuring the refractive index of the thin-film during deposition.
Optical monitoring systems may also be used to measure and subsequently control the thin-film thickness during growth. Optical monitoring systems typically consist of some sort of light source illuminating a test substrate which may or may not be one of the filters in the production batch, and a detector analysing the reflected or transmitted light [Macleod, H. A. Thin-film optical filters. Bristol: Institute of Physics Publishing (IoP), 2001, chapter 11.3.2]
For example, when a DWDM filter is being grown, a laser, whose wavelength is set to be at the design wavelength of the filter, is transmitted through the substrate. The variation in laser light intensity is then measured as the filter grows and the position of the first peak (or trough) in the transmission characteristic is looked for. Growth must be stopped before the first peak (or trough) is passed. This method is sometimes referred to as a laser turning point method. This method is an improvement over the quartz-crystal monitor since no physical parameters of the thin film material are required. However, laser turning point methods suffer several disadvantages. Firstly, terminating the growth process at the first peak (or trough) is difficult to achieve accurately since the intensity of the transmitted laser light can only normally be measured to an accuracy of +/−5% and the rate of change in intensity is very low.
Also, there is no possibility with this method of checking that the true turning point has been reached.
The accuracy of such an optical monitoring system may be improved by simulating the desired optical filter characteristic prior to growth. Typically, a broadband source is used to illuminate the filter and the broadband transmission characteristic is monitored as the filter grows. Deposition is terminated when the difference between the measured transmission characteristic and the simulated transmission characteristic satisfies a pre-determined error criterion.
A hybrid monitoring system utilising a quartz crystal monitor and an optical turning point technique in combination may also improve the accuracy with which the thickness of the individual thin-films layers may be monitored.
Despite any improvements that may be derived from combining the above monitoring techniques, all of the aforementioned methods have another inherent drawback; namely the methods are real-time monitoring techniques which only provide an indication of when the design characteristic of the thin-film has been achieved. Furthermore, any latency between the monitoring system providing an indication that the desired thin-film thickness has been achieved and the cessation of the growth process may lead to unacceptable inaccuracies in the thin-film thickness, leading to a degradation in the performance of the thin-film. Alternatively, the above methods will have to stop the growth process early if there is a significant time to termination of growth after any stop command is given. | {
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Current developments in integrated circuits have made possible the design of commercial television receivers in which signal processing is performed digitally. In such receivers broadcast TV signals are typically processed through a conventional tuner and IF section and then converted to digital format for further processing. Desirably, the analog-to-digital converter (ADC) should perform the conversion to 8-bit accuracy in order to provide adequate resolution during processing and display of the received signal. However, currently available 8-bit ADC's capable of operating at the video bandwidth either dissipate excessive power or are too large to be produced with acceptable yields, especially when they are to be utilized in relatively low cost mass produced television receivers. One solution to these difficulties has been to digitize the analog signal with 7-bit accuracy while dithering the input signal by one-half LSB at the horizontal line scanning rate. The dither tends to increase the accuracy but introduces other artifacts which can degrade the processed signal. | {
"pile_set_name": "USPTO Backgrounds"
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Field of the Disclosure
The present disclosure generally relates to methods and apparatus for removing organic matter from a body location and, more particularly, to methods and apparatus for removing organic matter from a root canal system of a tooth.
Description of the Related Art
In conventional root canal procedures, an opening is drilled through the crown of a diseased tooth, and endodontic files are inserted into the root canal system to open the canal and remove organic material therein. The root canal is then filled with solid matter such as gutta percha, and the tooth is restored. However, this procedure will not remove all organic material from all canal spaces. The action of the file during the process of opening the canal creates a smear layer of dentinal filings and diseased organic material on the dentinal walls, which is extremely difficult to remove. The organic material and necrotic tissue that remain in the canal spaces after completion of the procedure often result in post-procedure complications such as infections. | {
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Electrical connectors are used in a variety of applications wherein an electrical cable, including a plurality of conductors, is terminated to a plurality of terminals in the connector housing. Once the cable is terminated to the housing, there is a tendency to grab onto or hold the connector by means of the cable itself, or even to disconnect the connector by pulling on the cable. Such actions can cause the conductors of the cable to be pulled out of their respective terminals or actually pull the terminals out of the connector housing. Consequently, electrical connectors often have some form of strain relief means for clamping onto the cable so that forces from the cable are transmitted to the strain relief means and, in turn, to the connector housing rather than being transmitted to the terminals terminated to the conductors of the cable.
A typical application of such a system is in automotive assembly line operations wherein bundled wire assemblies are managed as single bundled units. A bundled wire unit may be terminated to a connector to define a wiring harness. The managing and handling of this wiring harness during assembly is often manual and done by way of grabbing the bundle of wires. Therefore, the connectors terminated to the wire bundles are provided with strain reliefs to ensure that when the wires are pulled or handled, the resulting tensile forces are transmitted from the wires through the strain relief means to the housing and not to the terminals.
Known strain relief members have been molded integrally with the connector housing or cover to reduce the number of components associated with the connector assembly. However, integrally molded strain relief members have presented various problems. For instance, one problem associated with integrally molded strain relief members is due to the fact that in some applications, such as in automotive assembly applications, the wire bundles are held to the strain relief members by cable wraps, tape, cable ties or the like. If a particular wire or terminal must be reworked within the connector housing, the entire wire bundle must be unwrapped and untaped from the strain relief member in order to access the particular wire or terminal. After reworking, the entire wire bundle must be reassembled and retaped to the integral strain relief member of the housing. This procedure can be costly in terms of time and labor.
Another problem associated with integrally molded strain relief members is that connector designs often are developed for particular customer applications which have specific configurations that route the wire bundles. While the connector itself may mate with a complementary connector in a given orientation, the wire bundles may have to exit the connector in a particular direction. These varying configurations require that the integral strain relief member be molded in a particular shape or configuration to ensure the customized routing of the wire bundle. These varying configurations and applications necessitate different strain relief and housing designs for each different orientation or location of the strain relief. This is very costly in terms of mold expenses, design time and inventory requirements. Even if a separate strain relief member is provided independent of the connector housing, various design specifications require the strain relief member to be positioned at different locations on the housing and a multiplicity of different housing configurations and resulting mold and inventory costs are incurred.
The present invention is directed to solving these various problems in an electrical connector having a strain relief system for an electrical cable. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field
The present disclosure relates generally to aircraft and, in particular, to a method and system for depicting flight plan information. Still more particularly, the present disclosure provides a method and system for graphically depicting important information about current flight plan status during flight.
2. Background
Aircraft flight management systems rely on flight plans for route and destination information. These flight plans are pre-defined and preloaded before a flight into the flight management system. The flight management system is often implemented in a flight deck computer of the aircraft or an electronic flight bag. A flight plan will include a required time of arrival for the aircraft at waypoints along the route and the destination.
During flight, an aircraft may encounter a number of conditions that affect the travel time of the aircraft. For example, wind conditions may affect the speed of an aircraft. When a condition affects the travel time of the aircraft, a required time of arrival at a particular waypoint or destination may no longer be met by the aircraft. This results in air traffic delays that are often not realized until the aircraft has reached its destination.
Current flight plans primarily rely on defined airways and navigation waypoints, but air traffic management is moving towards a “free flight” mode that is not limited to fixed airways. To ensure sufficient separation between aircraft in this environment flight plans will become four dimensional (4D) paths. Timing along the route is not as important as arrival time at a destination waypoint with traditional flight paths, but a 4D flight plan requires accurate timing all along the flight path to maintain airspace separation. Current systems are not designed to readily provide situational awareness of actual flight path as compared to a 4D flight plan. It is also important to update 4D flight plans during flight and quickly provide updated situational information to pilots.
Therefore, it would be advantageous to have a method and apparatus that addresses one or more of the issues discussed above. | {
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Ultra thin films having a thickness of less than 3 .mu.m, particularly less than 1 .mu.m, are required for the production of capacitors used in microelectronics. But, such films are difficult to produce on a large production scale.
Several processes for the production of ultra thin films have been described in the relevant literature. These processes generally utilize the following process steps: producing a thin film together with or on a base film, peeling the thin film off the base film, and then rolling up the thin film.
In British Patent Specification No. 1,190,698, the single films are joined together or adhered by pressure and/or heat. In this process, however, creases in the films are caused by slight thickness variations in the single films. These creases are formed repeatedly and are ironed into the film during the laminating process. The resulting creased thin films are useless for their intended purpose.
In U.S. Pat. Nos. 4,017,227 and 4,076,785, a device for casting two sheets next to each other and then joining those sheets before stretching in transverse direction is described. In this method, however, the supporting function of the base layer is missing and the splitting of the thin film is frequently observed.
In U.S. Pat. Nos. 4,708,905 and 4,756,064, coextruded laminated films, where the individual layers are made of different polymers, are stretched and then delaminated. Problems result from this process because each polymer has a different flow velocity and the velocities cannot be coordinated exactly. Regulating a uniform thickness profile across the film width creates the greatest problem, since allocating thickness distribution of the base film and the coating film is difficult. Additionally, the different polymer layers are subject to casual fluctuations during coextrusion. | {
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The invention relates to an apparatus for recording and reproducing signals on a magnetic tape accommodated in a cassette by means of a scanning device comprising at least one rotatable magnetic head moving along a circular path for scanning the magnetic tape in order to record and reproduce the signals, the apparatus comprising a cassette holder, which is movable between a loading position and an operating position for cooperation with the magnetic tape, into which holder in the loading position thereof the magnetic tape in the cassette can be inserted in an initial position and by means of which holder by its movement into the operating position the magnetic tape can be brought in an intermediate position, and a tape-threading device, which is adapted to cooperate with the magnetic tape and is movable between a thread-out position and a thread-in position, which tape-threading device in its thread-out position is engageable behind the magnetic tape which has been brought into its intermediate position and by means of which upon engagement as a result of the movement of said threading device to the thread-in position the magnetic tape can be arranged along a scanning path in which the magnetic tape is wrapped at least partly around the scanning device and can be scanned by the magnetic head, and a head-cleaning device which is movable between a rest position and a cleaning position, which cleaning device is urged to its rest position by a spring means and comprises an actuating member by means of which, as a result of the actuation of an afore-mentioned device for cooperation with the magnetic tape, the head-cleaning device is movable from its rest position into its cleaning position against the force of the spring means, in which cleaning position it has been moved towards the path of the magnetic head and cleans the magnetic head moving past it.
Such apparatuses are commercially available in different versions. Such an apparatus of the type defined in the opening paragraph is known from, for example, the Japanese Patent Application filed under number 63-111.223 and published under number 1-282.716 on Nov. 14, 1989. In this prior-art apparatus the construction is such that the actuating member of the head-cleaning device projects into the path of movement of a part of the tape-threading device which has been provided for cooperation with the magnetic tape and is consequently controlled by this part of the tape-threading device. Such a tape-threading device is a mechanically comparatively vulnerable assembly of such an apparatus, which should be subjected only to minimal mechanical loads. Moreover, with the prior-art apparatus it is not unlikely that in the event of a defect of the head-cleaning device this device may impair the threading operation of the threading device, which may result in undesirable tape damage. | {
"pile_set_name": "USPTO Backgrounds"
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1. Technical Field
The present disclosure relates to material handling systems and more particularly to devices and methods for transporting rolling racks using a lift truck such as a forklift, pallet jack or a pallet truck.
2. Background Art
Lift trucks such as pallet trucks, pallet jacks and forklifts are known in the art for moving materials. Such devices generally include a moveable base having one or more arms extending outwardly from the base. The arms are vertically moveable for lifting and lowering materials. When the arms are in a raised position, the base may be moved by an operator, either manually or with the use of a motor, thereby transporting material that is supported by the arms.
One problem associated with conventional forklifts, pallet jacks and pallet trucks is encountered when trying to transport rolling racks. Rolling racks generally include racks or shelves that have roller wheels on the bottom. The wheels allow the racks to be easily moved along the ground. In many applications, such as in a warehouse or in a container truck, it is desirable to move multiple rolling racks at once. Such racks may be empty or may be pre-loaded with other types of materials. It is generally inefficient to roll individual rolling racks over great distances. Others have attempted to load rolling racks on pallets or other types of rack holding platforms for transport using forklifts or pallet trucks. However, rolling racks have a tendency to roll off of such conventional pallets and platforms, complicating the transport process.
What is needed then are improvements in the devices and methods for transporting rolling racks using lift trucks such as forklifts, pallet jacks and pallet trucks. | {
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The present invention relates generally to providing a vertebral distractor for adjusting, particularly increasing, the distance between two vertebrae along the spinal axis when performing spinal procedures, particularly in the anterior cervical region, in conjunction with systems that use and generate images during medical and surgical procedures, which images assist in executing the procedures and indicate the relative position of various body parts and surgical instruments.
Vertebral distractors are known and are tools used during a spinal procedure, such as an anterior cervical procedure. Generally, the tool is used to increase the distance between two vertebral elements, such as vertebrae in a patient""s neck for the removal of damaged bone and/or the insertion of a bone graft into the damaged area. In particular, a vertebral distractor has two arms mounted in parallel on a shaft. The arms are movable in relation to each other.
To remove damaged bone and/or insert a bone graft, the arms of the vertebral distractor are engaged with or attached to different cervical vertebrae in the neck area. Certain vertebral distractors have arms with sharpened ends for gripping or otherwise engaging the vertebrae. The vertebrae are then pulled apart in a generally axial direction by manually increasing the distance between the arms of the distractor. While the vertebrae are distracted, the tension in the connecting soft tissues provides interbody rigidity. While the vertebrae remain distracted, surgical procedures can be performed, such as for example, damaged bone can be removed and new bone can be inserted.
During an anterior cervical spinal procedure, the vertebral distractor is positioned on either side of the throat area. In some cases, more than one vertebral distractor is used and is positioned such that there is a distractor on each side of the throat. This allows for more even distraction of the vertebrae. In positioning the vertebral distractor and engaging with or attaching it to the vertebrae of the patient, and, further, in completing the anterior cervical spinal surgery, the surgeon may have limited visual ability to determine the exact position of the vertebral distractor or the vertebrae with which the arms of the distractor are engaged.
Computer assisted image guided surgical navigation systems have been described that include indications of the relative positions of medical instruments and body parts used in medical or surgical procedures. For example, U.S. Pat. No. 5,383,454 to Bucholz; PCT Application No. PCT/US94/04530 (Publication No. WO 94/24933) to Bucholz; and PCT Application No. PCT/US95/12894 (Publication No. WO 96/11624) to Bucholz et al., the entire disclosures of which are incorporated herein by reference, disclose systems for use during a medical or surgical procedure using scans generated by a scanner prior to the procedure. Surgical navigation systems typically include tracking element such as for example an LED or reflector array on the body part and the medical instruments, a digitizer to track the positions of the body part and the instruments, and a display for the position of an instrument used in a medical procedure relative to a body part.
Accordingly, the present invention is directed to a vertebral distractor and a system for using a vertebral distractor in performing anterior surgery, particularly cervical spinal surgery. More specifically, an object of the present invention is directed to an apparatus for distraction or maintaining the relative position of at least two vertebrae in the cervical spinal area in conjunction with an image guided surgery system.
To achieve this object and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, the invention includes a vertebral distractor for use in performing anterior cervical spinal surgery. The vertebral distractor is used in conjunction with a computer controlled surgical navigation system employing a position sensing unit to track positions of the vertebral distractor in three dimensional space relative to a known reference point. The vertebral distractor comprises a shaft having first and second arms attached to the shaft movable with respect to each other. The first and second arms are engageable with the vertebrae, such as by gripping or pinning. Moreover, the second arm is movable with relation to the first arm as the arms are engaged with the vertebrae for adjusting the distance between the vertebrae. At least one tracking array is attached to the shaft for tracking the location of the vertebral distractor as it is used to increase the distance between the vertebrae. One preferred tracking array includes tracking elements such as at least three LEDs.
Moreover, the preferred first and second arms each have extensions located at the distal end for engaging the vertebrae in the cervical spinal region. It is further preferred that the extensions be pins, although other means for gripping known in the art can be used as well.
In yet another aspect, the invention includes a method for adjusting the distance between two vertebrae using the vertebral distractor described above. The method comprises the steps of engaging the vertebral distractor having at least one tracking array which has tracking elements with the vertebrae and then increasing the distance between the vertebrae by moving the second arm away from the first arm. A surgical navigation system with a computer controller and a position sensing unit is employed to communicate with the tracking elements of the tracking array on the vertebral distractor thereby creating a reference point for the vertebral distractor. Further, the location of each individual vertebrae element can be registered by contacting the vertebrae with a trackable instrument such as a registration probe. In a preferred embodiment the optically tracked instrument is a digitizer probe.
Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in this description.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. | {
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One of the most widely used types of machines for the manufacture of glassware is the so-called I.S. machine, which machine comprises a plurality of identical sections arranged side by side, the sections operating continuously out of time with each other to produce glassware. The I.S. machine has developed over the last sixty years from the original machine of this type described in U.S. Pat. No. 1,911,119--Ingle.
While during this period of sixty years there have been many improvements in I.S. machines, e.g. increased number of sections, increased numbers of moulds in each section, electronic control mechanisms replacing mechanical controls, the basic mechanical structure of the I.S. machine has remained unaltered.
Among the features which are common to almost all existing I.S. machines are the following;
1. The various mechanisms of the machine are integrated into a machine frame, and access to repair such mechanism is difficult. PA1 2. The various mechanisms are generally pneumatically operated, and a complex array of piping is necessary to provide the required supplies of compressed air. This piping is very time consuming (and thus expensive) not only to assemble in manufacture but also to repair. PA1 3. If any substantial repair is necessary to a section, the whole I.S. machine (i.e. all the sections) has to be shut down while the repair is carried out. PA1 4. The various sections are mounted side by side in a machine frame, having upright frame members which support ancillary mechanisms, for example gob distributors. Air supplies to the various sections are provided from piping leading from these upright frame members. Consequently there is a risk of different pneumatic conditions obtaining in sections remote from the upright frame members and those close to them, a risk which increases with the number of sections in the machine which is now frequently 12 or more.
EP 184394 describes a fluid operated individual section glassware forming machine. The intention is that the machine should be capable of adaptation for either pneumatic or hydraulic operation, and to avoid the proliferation of pipes which would result, the machine is so constructed that fluid under pressure to operate the various mechanism of the machine is provided through passageways formed in the plates providing the framework of the section. While the possibility of utilizing these passages for pneumatic operation is mentioned, it is not described; the description is of use of the passageway for hydraulic fluid while conventional pipe work is used for pneumatic operation. Consequently no indication is given of elimination of pipe work for pneumatic operation between the conventional valve block, used in such pneumatic operation, and the passageways. Particular problems would seem likely to arise in this respect as the initial part of the passageways are in a base plate of the section.
Further EP 184394 envisages the use in the machine of conventional mechanisms, that is to say mechanisms which are integrated into the machine frame and which are therefore not easily accessible for repair or replacement.
It is one of the objects of the present invention to provide a glassware forming machine comprising a pneumatically operated mechanism which is readily removed from a frame of the machine for replacement or repair. | {
"pile_set_name": "USPTO Backgrounds"
} |
Cloud storage systems are file hosting services that allow users to upload and synchronize files to one or more storage devices, and to subsequently access the files from a web browser or the user's local device. Performing searches for files within a cloud storage system implicates several privacy concerns, as documents, document indexes and metadata are accessible as cleartext to the cloud storage system service provider. Although various technologies and approaches have evolved to address these privacy concerns, these solutions have relied on providing documents in cleartext to the cloud storage system. As a result, if the cloud storage system is breached, all users using the service to store data are potentially at risk.
It is with respect to these and other general considerations that the aspects disclosed herein have been made. Also, although relatively specific problems may be discussed, it should be understood that the examples should not be limited to solving the specific problems identified in the background or elsewhere in this disclosure. | {
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Aspects of the present invention relate to an information service incorporating virtual objects, and more particularly to the interactions users and virtual objects in the information service.
The Internet enables a variety of information services, by which a user can use his computer or other electronic devices to interact with other remote users. Such well-known information services include online transaction platforms, online social networking platforms, and online gaming platforms.
Another popular type of information service available through the Internet is that of a “virtual world” which provides transactions, social networking, and gaming together. In this type of service, a user can select an “avatar” and can change the appearance or even the gender of the avatar at any time. Using the avatar as his or her proxy, the user can travel around the virtual world, chat with other users/avatars, or join a community to participate in activities in the virtual world.
Through the avatar, a user also can interact with virtual objects implemented in the virtual world. For example, an avatar can buy or sell a virtual object or even try on a virtual item of clothing. By performing actions on a virtual object, one or more computers implementing the “virtual world” may alter selected characteristics associated with that virtual object based on a programmed functions associated with the virtual object, and render the virtual object in the “virtual world” according to its altered state. For example, if a first user “sells” a virtual object to a second user, ownership data associated with the virtual object may be altered to transfer ownership from the first user to the second user. | {
"pile_set_name": "USPTO Backgrounds"
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The new Salvia cultivar is a product of a planned breeding program conducted by the inventor, Michael Uchneat in Bellefonte, Pa. The objective of the breeding program was to produce new Salvia splendens varieties with large, upright plant habits in a range of flower colors and persistent calyces. The self-pollination resulting in this new variety was made during June of 2013.
The parent variety is an unpatented, proprietary, Salvia splendens referred to as ‘28744-1’. This parent variety was self-pollinated and the resulting seed collected. Seed collected from this self-pollination was grown out, with the result of a variety of flower colors and plant sizes observed among the seedling population. The new variety was identified as a potentially interesting selection, from this seedling population in August 2014, at a greenhouse in Bellefonte, Pa.
Asexual reproduction of the new cultivar ‘SGRRE04-1’ by vegetative cuttings was first performed during August of 2014, at a research greenhouse in Bellefonte, Pa. Subsequent propagation has shown that the unique features of this cultivar are stable and reproduced true to type on successive generations. | {
"pile_set_name": "USPTO Backgrounds"
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1. Technical Field
The present invention generally relates to a lens shutter type of auto-focus camera, and more particularly to a zoom lens type of camera in which a zoom lens system is used as a taking or photographing optical system, and in which a finder optical system and an electronic flash device (i.e., a strobe) are associated with the zooming operation of the zoom lens system. In other words, the finder optical system and the strobe move in coordinated fashion with zooming movement of the lens.
This application is related to the commonly assigned application filed on even date herewith, application Ser. No. 143,946, entitled "Zoom Lens Drive System for lens shutter type of Camera", filed on Jan. 7, 1988, now U.S. Pat. No. 4,936,664, the disclosure of which is expressly incorporated by reference herein.
2. Background Art
Generally, in conventional lens shutter (i.e., between the lens shutter) types of auto focus cameras, it is impossible to vary the focal length of the photographic optical system. Other lens shutter types of auto focus cameras comprise a two focal length system, in which a lens is provided for varying the focal length and can be selectively inserted in the photographing optical system. In such a system, two focal lengths are provided; however, it is possible to use only the two focal lengths provided, e.g., a wide angle and a telephoto range for the zoom lens, or, e.g., a standard range and a telephoto range for the zoom lens. While taking advantage of such dual focal lengths, it is impossible to cover the range of focal lengths between the two extreme focal lengths, or between a wide angle and a medium telephoto focal length. Under such circumstances, taking pictures with the use of a zoom lens has heretofore only been possible by using a single lens reflex camera.
However, single lens reflex cameras are more expensive and heavier than lens shutter type cameras, and, accordingly, it is not easy for a photographer who is unfamiliar with cameras to freely use such single lens reflex cameras. Because of the heavy weight and relatively large size of such single lens reflex cameras, female photographers and travelers who are desirous of reducing the weight and the amount of baggage carried tend to hesitate to use such a single lens reflex (hereinafter SLR) camera, even if they appreciate the high quality pictures which are generally taken by such cameras.
Accordingly, users who would otherwise hesitate to use single lens reflex cameras which are relatively bulky and heavy, as noted above, have only two alternate choices: (a) a relatively small, light lens shutter type of automatic camera which has heretofore not been capable of controlling the focal length of the photographing optical system; or (b) a dual focal length type of auto focus camera in which only two extreme focal lengths can be used.
In view of such circumstances, one primary object of the present invention is to provide a small, light, compact lens shutter type of camera with a zoom lens in which focusing control and electronic flash or strobe control can be automatically effected.
Another object of the present invention is to provide a lens shutter type of auto-focus camera which has an additional macro (i.e., close-up) function with which an extremely large, detailed image can be taken; and in which a finder optical system and an electronic flash device are adapted to be coordinated with zooming operation of the zoom lens in the macro mode as well as in normal operation (e.g., in wide angle, telephoto or standard operation).
Yet another object of the present invention is to provide a movable macro compensating optical element which is used in the distance measuring apparatus or range finder in order to extend the optical base length from its value in the normal photographic mode, and to enable substantially the same area on the position detecting sensor to receive light when measuring the distance of a subject.
Still another object of the present invention is to provide a camera having a field of view with minimum parallax in the macro mode.
Another object of the present invention is to reduce parallax in a lens shutter type camera by providing a prism selectively movable into the path of a finder optical system in order to deflect the field of view downwardly and rightwardly to the axis of the photographing optical system when the camera is in its macro photographing mode.
Still a further object of the present invention is to move a strobe lamp assembly along an optical axis thereof in coordination with movement of a zoom lens.
Yet another object of the present invention is to provide a distance measuring device used in an auto-focus lens shutter type of camera in which an optical wedge is selectively inserted to extend the optical base length between the light emitter and the light receiver comprising the distance measuring device.
Still another object is to provide a finder optical system in which it is necessary to move only a single lens to vary the field of view.
Another object is to provide a lens shutter type camera with a light intercepting assembly which minimizes light from entering a photographic optical assembly lens system.
Still a further object of the present invention is to provide a lens shutter type of camera which includes a strobe assembly whose illumination angle varies in accordance with the position of a movable zoom lens assembly.
Yet another object of the present invention is to provide a lens shutter type camera in which a flexible printed circuit board is guided in its movement along one side of a cam ring and zoom lens, and which includes strucure for minimizing internal reflections from the FPC board into the interior of a photographing optical assembly. | {
"pile_set_name": "USPTO Backgrounds"
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The spine is critical in human physiology for mobility, support, and balance. The spine protects the nerves of the spinal cord, which convey commands from the brain to the rest of the body, and convey sensory information from the nerves below the neck to the brain. Even minor spinal injuries can be debilitating to the patient, and major spinal injuries can be catastrophic. The loss of the ability to bear weight or permit flexibility can immobilize the patient. Even in less severe cases, small irregularities in the spine can put pressure on the nerves connected to the spinal cord, causing devastating pain and loss of coordination.
Surgical procedures on the spine often include the immobilization of two or more vertebrae. Immobilizing the vertebrae may be accomplished in many ways (e.g. fixation plates and pedicle screw systems). One of the most common methods for achieving the desired immobilization is through the application of bone anchors (most often introduced into the pedicles associated with the respective vertebrae to be fixed) that are then connected by rigid rods locked to each pedicle screw. These pedicle screw systems are very effective. However, vertebrae of pediatric patients can be small, making the use of pedicle screws challenging, and the vertebrae of trauma patients, or patients having decreased vertebrae strength, may not have sufficient bone structure with which to use pedicle screw systems. Therefore, a need continues to exist for new bone fixation devices that can be used as alternatives to pedicle screws. | {
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In general, the present invention relates to the packaging of food products, particularly foods such as, for example, meat or fish, which may release blood or other liquids.
In particular, the invention relates to a tray comprising a sheet of substantially open-cell, low-density polystyrene having the capacity to absorb liquids, particularly aqueous liquids, and to a method of producing it.
In the packaging of foods which may release blood, such as meat or fish, there is a problem in providing packages which can isolate and hide the blood released by the food, since it has been found that is presence and visibility inside the package renders the latter unattractive to the purchaser.
Amongst the solutions proposed for this problem in the prior art, the simplest consists of the provision of a tray provided with a pad or layer of absorbent material, generally paper. Solutions of this type are described, for example, in patent applications EP-A-O 182 139, GB-A-1 168 925, EP-A-0 544 562, in patent FR 2 688 474, and in utility model DE 9013898.8.
The absorbent layer may simply be fixed to the internal surface of a tray of plastics material or interposed between two sheets of plastics material, of which that which is in contact with the food has holes through which the liquid released by the food is conveyed towards the interposed absorbent layer.
The trays mentioned above have the disadvantage of being made of materials of different kinds, that is, expanded plastics, generally polystyrene, and paper or similar hydrophilic materials, which are difficult to separate from one another so that there is little or no chance of their being recycled. Moreover, owing to the presence of the paper, the production cost of these trays is considerably greater than that of conventional non-absorbent trays.
Trays made of a single material, generally expanded polystyrene, which can isolate the liquid exuded from the food, causing it to descend by gravity into a space formed between two sheets of the aforesaid plastics material by passing through holes formed in the sheet on which the food is placed are also known. Examples of these trays are given in patent applications EP-A-0 574 819 and WO 94/00366.
Trays of the type described above have the disadvantage of necessarily having quite large holes in order to allow the blood to descend by the gravity and, for this reason, leave the blood which has collected in the space easily visible. Moreover, the blood can easily return the sheet which is in contact with the food as a result of the inversion or simply the inclination of the tray.
The technical problem upon which the present invention is based is that of providing a tray which is made solely of plastics material and which itself has the capacity to absorb liquids, particularly aqueous liquids, released by foods, thus preventing the problems set out above with reference to the trays of the prior art.
A partial solution to the aforementioned technical problem was offered in patent application EP 0 090 507, which describe a xe2x80x9cfast foodxe2x80x9d container produced from a composite structure constituted by two superimposed sheets of which one is a normal sheet of closed-cell expanded plastics material and the other is a sheet of substantially open-cell plastics material which has the ability to absorb condensed steam coming from the foods present in the container.
The sheet of substantially open-cell plastics material constitutes the inner layer of the container which is in direct contact with the food.
The aforesaid open-cell sheet has a high density (150-450 g/l), however, and its ability to absorb water is not adequate for the purposes of the present invention.
The open-cell sheet produced according to the method of the aforementioned patent application also has an irregular surface which impairs the appearance of the tray to a certain extent.
According to application EP 0 090 507, the open-cell sheet is produced, by the mixing of polystyrene with an excess of a chemical nucleating and expanding agent such as sodium bicarbonate/citric acid, in an extruder having a single mixing chamber and a single screw, the molten mixture being brought to a temperature of 196-204xc2x0 C. immediately before extrusion.
The technical problem set out above is solved, according to the present invention, by a method of producing substantially open-cell polystyrene sheet, comprising the steps of:
forming a mixture comprising from 30 to 95% of polystyrene incorporating an aliphatic hydrocarbon with 4-6 carbon atoms, from 0 from 65% of polystyrene, and from 0.2 to 10% of a nucelating agent,
mixing the mixture obtained and melting it by heating inside an extruder,
bringing the mixture to a temperature of 130-150xc2x0 C. in the final portion of the extruder,
extruding the mixture in a lower-pressure atmosphere to produce an expanded sheet.
Simply xe2x80x9cpolystyrenexe2x80x9d means polystyrene as such, that is, not incorporating hydrocarbons.
The percentage is given herein should be understood as the weight relative to the total weight of the mixture if not specified otherwise.
In order to increase the absorption capacity of the sheet, a quantity of from 5 to 10% by weight of the aforesaid nucleating agent, relative to the total weight of the mixture, is preferably used.
The aforesaid mixture preferably has a content of from 1 to 7% by weight, relative to the weight of the mixture, of aliphatic hydrocarbon with 4-6 carbon atoms and the hydrocarbon is preferably pentane.
The density of the final expanded sheet can be modified by variation of the percentage of polystyrene and, in particular, increases with increases in the aforesaid percentage.
Moreover, there are various types of polystyrene incorporating aliphatic hydrocarbons with 4-6 carbon atoms on the market, which incorporate different quantities of hydrocarbon; the density of the sheets produced from these products decreases as the hydrocarbon content increases.
The aforesaid nucleating agent is preferably selected from the group comprising sodium bicarbonate, citric acid, talc, sodium carbonate, Hydrocerol(copyright) and gypsum. This nucleating agent need not necessarily have chemical expanding properties, whereas this constituted an essential condition in the method according to EP-A-0 090 507.
The aliphatic hydrocarbon with 4-6 carbon atoms is preferably constituted by pentane.
In order to give the sheet according to the invention a better capacity to absorb aqueous liquids, a quantity of at least one surfactant variable from 0.2 to 10%, and preferably from 1 to 4% of the total weight of the mixture is added to the starting mixture.
The at least one surfactant may be selected from the anionic, cationic and non-ionic surfactants in common use, and is preferably a salt of a sulphonic acid of formula Rxe2x80x94SO3H or of a sulphuric ester of formula Rxe2x80x94OSO3H, in which R is selected from the group comprising alkyl and alkylaryl, with an alkali metal or an alkaline-earth metal.
A surfactant which has been found particularly useful for the purposes of the present invention is the aliphatic sulphonate marketed by the firm NOVACROME with the name HOSTASTAT SYSTEM E 3904(copyright).
It is advantageous, in order further to increase the capacity of the sheet to absorb aqueous liquids, to add a quantity of up to 30%, preferably from 10% to 20%, of the mixture, of a shock-resistant polystyrene, preferably a dispersion of polybutadiene in polystyrene such as, for example, ENICHEM""s product EDISTIR SR 550(copyright).
In comparison with the closest prior art (EP-A-0 090 507), the present method has the advantage of providing a substantially open-cell sheet with a considerably lower density, for a given percentage of open cells, which can therefore absorb a larger volume of liquid for a given weight.
Moreover, the method according to the present invention is carried out at a lower temperature than the aforementioned method of the prior art (130-150xc2x0 C. instead of 196-204xc2x0 C.): this has the favourable consequence of a considerable energy saving, an improvement in the aesthetic characteristics of the skin, and better workability of the sheet.
The density of the expanded sheet can easily be adjusted upon the basis of the quantity of polystyrene resin incorporating pentane included in the starting mixture and can be reduced to values of 50 g/l when the polystyrene resin used in the starting mixture is constituted exclusively by polystyrene resin incorporating aliphatic hydrocarbon with 4-6 carbon atoms.
The present invention also relates to a polystyrene tray comprising a base and side walls, made from a sheet of substantially open-cell expanded polystyrene covered integrally on both of its surfaces by a film made of plastics material which defines the inner surface and the outer surface of the tray, respectively, holes with diameters of from 0.1-1.5 mm extending through the inner surface into the thickness of the sheet, wherein the expanded polystyrene sheet has a density less than or equal to 140 g/l and a capacity to absorb aqueous liquids greater than or equal to 4 g/dm2 per mm of thickness and is obtainable by the method described above.
The aforementioned plastics material of which the film is made is preferably selected from the group comprising polystyrene, polyethylene, polypropylene and copolymers thereof.
The film is advantageously opacified to prevent the liquid held in the underlying absorbent sheet from being visible. Opacification can be achieved by the incorporation, in the plastics material, of titanium dioxide or coloured lacquers constituted, for example, by dyes adsorbed on aluminum hydroxide, which generally incorporates small percentages of basic aluminium sulphate.
The high absorption capacity of the expanded sheet according to the present invention is due to its very high percentage of open cells and to the creation of countless receptacles as a result of the rupture of a certain percentage of cells, and also of the so-called xe2x80x9cribsxe2x80x9d, as can be seen from FIG. 1 which is an electron-microscope photograph of a cross-section of the sheet, enlarged 100 times, showing countless frayed and torn portions both of the cell membranes and of the xe2x80x9cribsxe2x80x9d.
The high absorbtion capacity of the sheet is inevitably accompanied by inadequate mechanical strength which causes problems with its use as the sole starting material for producing packaging trays.
In order to produce trays having adequate mechanical strength, it is therefore necessary to couple the sheet, on both of its surface, with a film made of plastics material, for example, polystyrene, before the thermoforming of the tray is carried out.
This coupling can be achieved by hot lamination or by means of adhesives, or by any other method conventionally used for this purpose.
The coupling of the sheet of substantially open-cell, expanded polystyrene with the film made of plastics material produces a sheet with a sandwich structure. Holes with diameters of 0.1-1.5 mm are formed in one of the surfaces of the sheet, extending into the intermediate layer constituted by the expanded sheet and, finally, trays are formed therefrom by thermoforming.
Alternatively, the holes may be formed in the base of the tray produced by the thermoforming of the sheet having a sandwich structure.
The trays thus obtained have an optimal appearance since the surface film of plastics material has a smooth surface without streaks or corrugations.
Moreover, the water-repellency of the sheet prevents the blood exuded from the food from wetting the inner surface of the tray creating unpleasant marks, and facilitates its penetration into the underlying absorbent layer through the holes.
By virtue of its low density and hence low weight, the open-cell expanded polystyrene sheet produced by the method described above can also be used as an absorbent layer in place of the paper layers or pads used in trays of the prior art.
In this case, in fact, the absorbent layer is required solely to have a good capacity to absorb aqueous liquids since the mechanical strength of the tray depends solely upon the mechanical properties of the plastics material of which the tray supporting the absorbent layer is made.
The use of the substantially open-cell expanded sheet produced by the method described above as an absorbent pad for conventional polystyrene trays also solves the problem connected with the difficulty in recycling the materials and a considerable reduction in costs is achieved.
To facilitate the absorption of liquids, the absorbent pad formed with the expanded sheet may advantageously have holes with diameters of 0.1-1.5 mm.
These holes may be formed, for example, by the perforation of the expanded sheet using a needle roller machine.
The surface of the pad which is to be in contact with the food may advantageously be covered with a film of opacified plastics material in order to mask from view the liquid held in the pad.
The use of a pad of this type in the production of a tray according to patent FR 2 688 474 is particularly advantageous.
The advantages of the tray according to the invention will become clear from the detailed description of some embodiments thereof, given below by way of non-limiting example with reference to the appended drawings, in which: | {
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The present invention relates to a reader device (hereinafter termed "laser scanner" for the sake of brevity) for reading characters with different reflectance values, such as for example bar codes.
The use is known of two or more lasers, suitable to be focused at different distances, inside a single scanner, so as to increase the depth of field for the reading distance in bar code readers. An example of this technique is described in European Patent Application published on Apr. 15, 1992 under Serial No. 0480348.
In the known system, the lasers related to the various distances are activated sequentially and alternately, one for each scanning operation, and if one scan is found to contain the code, all subsequent scans are performed by the same laser, until the code remains present; once this situation ends, scanning resumes with cyclic alternation of the lasers.
Another known method entails the activation of the laser related to the reading distance by measuring, by means of a barrier of photocells external to the scanner, the height of the object that bears the code to be read.
These systems have drawbacks: in the first case, the actual scan rate is equal to the real scan rate divided by the number of lasers being scanned; the second method requires the use of external photocells and is furthermore effective only if the objects on which the code is placed have a regular shape. A defect of both systems is that only one focusing is possible during an individual scan. In other words, it is not possible to simultaneously read two codes that are aligned but located on planes that are at different distances from the scanner. | {
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This invention relates to pharmaceutically useful compounds which inhibit cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds of the invention are potent inhibitors of type 5 cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterase (cGMP PDE5) and are selective over other phosphodiesterases, including PDE6. The compounds of the invention therefore have utility in a variety of therapeutic areas.
The compounds of the invention are of value for the curative or prophylactic treatment of mammalian sexual disorders. In particular, the compounds are of value in the treatment of mammalian sexual dysfunctions such as male erectile dysfunction (MED), impotence, female sexual dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic dysfunction (FSOD) as well as sexual dysfunction due to spinal cord injury or selective serotonin re-uptake inhibitor (SSRI) induced sexual dysfunction but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated. Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, diseases and conditions of the eye such as glaucoma, optic neuropathy, macular degeneration, elevated intra-occular pressure, retinal or arterial occulsion and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Further medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated, and for which treatment with compounds of the present invention may be useful, include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy, neuropathy including autonomic and peripheral neuropathy and in particular diabetic neuropathy and symptoms thereof (e.g. gastroparesis), peripheral diabetic neuropathy, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure, haemorrhoids, hypoxic vasoconstriction, hypoxic vasoconstriction, diabetes, type 2 diabetes mellitus, the insulin resistance syndrome, insulin resistance, impaired glucose tolerance, as well as the stabilisation of blood pressure during haemodialysis.
Particularly preferred sexual disorders include MED and FSD.
According to the present invention, there is provided compounds of general formula I:
or a pharmaceutically or veterinarily acceptable salt and/or solvate, polymorph or pro-drug thereof, wherein
Y represents C or N, with N being in at least one, but not more than two, of the positions marked by Y;
X represents CH or N;
R1, R2 and R3 where present and attached to nitrogen independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R1, R2 and R3 where present and attached to carbon independently represent H, halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6(O)OR6 OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1 and R2 are present they may optionally be connected via a Cxe2x80x94C, Cxe2x80x94N or Cxe2x80x94O bond;
wherein when R2 and R3 are present they may optionally be connected via a Cxe2x80x94C, Cxe2x80x94N or Cxe2x80x94O bond;
R4 represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R5 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2 and R3, where present, or R4 or R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl and C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl and C1-C6 alkylaryl group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R6 represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R7 and R8 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17; or
R7 and R8 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12. C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R9 and R10 independently represent H, C(O)R6, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17; or
R9 and R10 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R11 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R12 represents H or C1-C6 alkyl;
R13 and R14 independently represent H or C1-C6 alkyl; or
R13 and R14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R15 and R16 independently represent H, C(O)R12, SO2R17 or C1-C6alkyl; or
R15 and R16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R17 represents C1-C6 alkyl;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof and with the proviso that when R5 is Het, said Het is C-linked to the sulphur atom of the SO2 group in general formula I
which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
According to the present invention compounds of the general formula (I) R1, R2 and R3 are only present where valency allows that this can be accommodated without Y being charged.
Preferred compounds of general formula I can be represented by general formulae IA, IB, IC, ID and IE:
Thus according to a preferred aspect of the present invention there are provided compounds of general formulae 1A, 1B, 1C, 1D and 1E wherein:
X represents CH or N;
R1, R2 and R3 where present and attached to nitrogen independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R1, R2 and R3 where present and attached to carbon independently represent H, halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R11, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1 and R2 are present they may optionally be connected via a Cxe2x80x94C, Cxe2x80x94N or Cxe2x80x94O bond;
wherein when R2 and R3 are present they may optionally be connected via a Cxe2x80x94C, Cxe2x80x94N or Cxe2x80x94O bond;
R4 represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R5 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R, R2 and R3, where present, or R4 or R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl and C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl and C1-C6 alkylaryl group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R6 represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R7 and R8 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17; or
R7 and R8 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R9 and R10 independently represent H, C(O)R6, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17; or
R9 and R10 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R11 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R12 represents H or C1-C6 alkyl;
R13 and R14 independently represent H or C1-C6 alkyl; or
R13 and R14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R15 and R16 independently represent H, C(O)R12, SO2R17 or C1-C6 alkyl; or
R15 and R16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R17 represents C1-C6 alkyl;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof wherein when R5 is Het then said Het is C-linked to the sulphur atom of the SO2 group in general formula I and
with the proviso that R3 does not represent H in formula IE where X is CH;
with the proviso that in formula 1A or 1 D when X is N, R5 does not represent C1-C6 alkyl, optionally substituted and/or terminated with one or more substituents selected from halo, OR17, NR12R17 or NR17C(O)R17.
The term xe2x80x9carylxe2x80x9d, when used herein, represents C1-C11 aryl groups which include phenyl and naphthyl groups.
The term xe2x80x9cHetxe2x80x9d, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The ring systems may be monocyclic, bicyclic or fused. The term thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl imidazopyridinyl and piperazinyl. Substitution at Het may be at a carbon atom of the Het ring or, where appropriate, at one or more of the heteroatoms.
xe2x80x9cHetxe2x80x9d groups may also be in the form of an N-oxide.
The heterocyclic ring that R7 and R8, R9 and R10, R13 and R14 or R15 and R16 (together with the nitrogen atom to which they are bound) may represent may be any heterocyclic ring that contains at least one nitrogen atom, and which ring forms a stable structure when attached to the remainder of the molecule via the essential nitrogen atom (which, for the avoidance of doubt, is the atom to which R7 and R8, R9 and R10, R13 and R14 or R15 and R16 are attached respectively). In this respect, heterocyclic rings that R7 and R8, R9 and R10, R13 and R14 or R15 and R16 (together with the nitrogen atom to which they are bound) may represent include four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain at least one nitrogen atom and optionally contain one or more further heteroatoms selected from nitrogen, oxygen and sulfur, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The term thus includes groups such as azetidinyl, pyrrolidinyl, imidazolyl, indolyl, triazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrazolyl and piperazinyl.
The term xe2x80x9cC1-C6 alkylxe2x80x9d (which includes the alkyl part of alkylHet and alkylaryl groups), when used herein, includes methyl, ethyl, propyl, butyl, pentyl and hexyl groups. Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated or be cyclic, acyclic or part cyclic/acyclic. Preferred C1-C6 alkyl groups for use herein are C1-C3 alkyl groups. The term xe2x80x9cC1-C6 alkylenexe2x80x9d, when used herein, includes C1-C6 groups which can be bonded at two places on the group and is otherwise defined in the same way as xe2x80x9cC1-C6 alkylxe2x80x9d. The term xe2x80x9cacylxe2x80x9d includes C(O)xe2x80x94(C1-C6)alkyl.
In the terms xe2x80x9cC1-C6 alkylHetxe2x80x9d and xe2x80x9cC1-C6 alkylarylxe2x80x9d, xe2x80x9cHetxe2x80x9d and xe2x80x9carylxe2x80x9d are as defined hereinbefore. Substituted C1-C6 alkylHet and C1-C6 alkylaryl may have substituents on the ring and/or on the alkyl chain.
Halo groups with which the above-mentioned groups may be substituted or terminated include fluoro, chloro, bromo and iodo.
The pharmaceutically or veterinarily acceptable salts of the compounds of the invention which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids. Examples include the HCl, HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts. For a review on suitable pharmaceutical salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
The pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof.
Also included within the scope of the compound and various salts of the invention are polymorphs thereof.
Compounds of formula I which contain one or more asymmetric carbon atoms exist in two or more stereoisomeric forms. Where a compound of formula I contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compounds of formula I and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of compounds of formula I or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula I may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
All stereoisomers are included within the scope of the invention.
A preferred group of compounds according to a further aspect of the invention, are compounds of formulae IA, IB, IC, ID and IE as hereinbefore defined, wherein:
X represents CH or N;
R1, R2 and R3, where present, independently represent C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl optionally substituted and/or terminated with one or more substituents selected from halo, OR6, C(O)OR6 and NR9R10;
R4 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl optionally substituted and/or terminated with one or more substituents selected from halo and OR6;
R5 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl (these groups are all optionally substituted and/or terminated with one or more substituents selected from halo, OR6, C(O)OR6 and NR9R10);
wherein R6, R9 and R10 are as hereinbefore defined;
with the proviso that when R5 is Het, said Het is C-linked to the sulphur atom of the SO2 group in general formula I; and
with the proviso that R3 does not represent H in formula IE when X is CH; and
with the proviso that in formula 1A or 1D when X is N, R5 does not represent C1-C6 alkyl, optionally substituted and/or terminated with one or more substituents selected from halo, OR17, NR12R17 or NR17C(O)R17.
A more preferred group of compounds according to a further aspect of the invention, are compounds of formulae IA, IB, and ID as hereinbefore defined, wherein:
X represents CH or N, and wherein X is preferably CH;
R1, R2 and R3, where present, independently represent C1-C6 alkyl, Het or C1-C6 alkylHet optionally substituted and/or terminated with one or more substituents selected from OR6, C1-C6 alkyl and NR9R10;
R4 represents C1-C6 alkyl, C1-C6 alkylHet, optionally substituted and/or terminated with OR6;
R5 represents C1-C6 alkyl optionally substituted and/or terminated with one or more substituents selected from halo, OR6, C(O)OR6 and NR9R10;
wherein R6, R9 and R10 are as hereinbefore defined
with the proviso that in formula 1A or 1D when X is N, R5 does not represent C1-C6 alkyl, optionally substituted and/or terminated with one or more substituents selected from halo, OR17, NR12R17 or NR17C(O)R17.
A more preferred group of compounds herein are compounds of general formulae IA and ID which can be represented by the general formula IG:
wherein general formula IG represents formula IA and ID depending upon whether RG is R1 or R2 as defined hereinbefore.
Thus according to a preferred aspect the present invention provides compounds of general formula IG wherein:
X represents CH or N, and wherein X is preferably CH;
RG is R1 or R2;
R1, R2 and R3, where present, independently represent C1-C6 alkyl, Het or C1-C6 alkylHet optionally substituted and/or terminated with one or more substituents selected from OR6, C1-C6 alkyl and NR9R10;
R4 represents C1-C6 alkyl, C1-C6 alkylHet, optionally substituted and/or terminated with OR6;
R5 represents C1-C6 alkyl optionally substituted and/or terminated with one or more substituents selected from halo, OR6, C(O)OR6 and NR9R10;
wherein R6, R9 and R10 are as hereinbefore defined
with the proviso that when X is N, R5 does not represent C1-C6 alkyl, optionally substituted and/or terminated with one or more substituents selected from halo, OR17, NR12R17 or NR17C(O)R17.
A preferred group of compounds of general formula IG include those wherein:
X represents CH;
RG is R1 and represents C1-C3 alkyl or C1-C3 alkylHet wherein said C1-C3 alkyl group is optionally substituted and/or terminated with one or more substituents selected from halo, OR6, C(O)OR6 and NR9R10 and wherein said C1-C3 alkylHet group is optionally substituted and/or terminated with one or more substituents selected from halo, C1-C6 alkyl, OR6, C(O)OR6 and NR9R10;
R3 represents C1-C6 alkyl optionally substituted and/or terminated with one or more substituents selected from halo and OR6;
R4 represents C1-C6 alkyl or C1-C6 alkylHet optionally substituted and/or terminated with one or more substituents selected from halo and OR6;
R5 represents C1-C6 alkyl optionally substituted and/or terminated with one or more substituents selected from halo and OR6;
A further preferred group of compounds of general formula IG include those wherein:
X represents CH;
RG represents R1 which represents methyl, ethyl or C1-C3 alkylHet wherein said C1-C3 alkylHet group is optionally substituted and/or terminated with one or more substituents selected from halo, C1-C6 alkyl, OR6, C(O)OR6 and NR9R10 and wherein R1 is preferably C1-C3 alkylHet optionally substituted and/or terminated with one or more substituents selected from C1-C6 alkyl and OR6 and wherein said Het group is a C-linked 5 or 6 membered saturated or unsaturated heterocyclic group containing at least one nitrogen atom and optionally including oxygen or sulphur atoms and wherein said Het is more preferably a C-linked 5 or 6-membered heterocyclic group containing one or two nitrogen atoms;
R3 represents C2-C4 alkyl, and is preferably ethyl, n-propyl or iso-propyl and is most preferably ethyl;
R4 represents C2-C4 alkyl optionally substituted and/or terminated with one or more substituents selected from halo and OR6 and wherein when said is C2-C4 alkyl group is preferably propyl;
R5 represents C1-C4 alkyl and wherein R5 is preferably C1-C3 alkyl, more preferably methyl or ethyl, most preferably methyl;
wherein R6, R9 and R10 are independently selected from methyl or ethyl groups.
An alternative preferred group of compounds herein are compounds of general formulae IG wherein:
X represents CH;
RG represents R2 and is C1-C6 alkyl, Het or C1-C3 alkylHet wherein said C1-C6 alkyl, Het or C1-C3 alkylHet groups are optionally substituted and/or terminated with one or more substituents selected from halo, C1-C6 alkyl, OR6, C(O)OR6 and NR9R10 and wherein when R2 represents C1-C6 alkyl, said alkyl group may be straight chain, branched chain or part or wholly cyclic;
R3, R4 and R5 independently represent C1-C6 alkyl optionally substituted and/or terminated with one or more substituents selected from halo and OR6;
An additional alternative preferred group of compounds of general formula IG include those wherein:
X represents CH;
RG represents R2 and is C1-C5 alkyl, Het or alkylHet wherein the Het groups of said Het or alkyl Het is a C-linked Het group which is optionally substitued and/or terminated with one or more substituents selected from halo, C1-C6 alkyl, OR6, C(O)OR6 and NR9R10, wherein when RG is alkyl Het, then said alkylHet group is preferably a 5 or 6-membered saturated or unsaturated heterocyclic group containing at least one nitrogen atom and optionally including oxygen or sulphur atoms and is preferably a pyrrolidinyl or an imidazolyl group and wherein when RG is Het, then said Het group is a 4 or 5-membered heterocyclic group containing one or two nitrogen atoms and is preferably an azetidinyl group wherein the N can be optionally substituted as described hereinbefore and wherein when RG is C1-C5 alkyl said alkyl is preferably cyclopropylmethyl;
R3 represents C2-C4 alkyl, and is preferably ethyl, n-propyl or iso-propyl and is most preferably ethyl;
R4 represents C2-C4 alkyl and is preferably propyl or butyl
R5 represents C1-C4 alkyl and wherein R5 is preferably C1-C3 alkyl and is more preferably methyl or ethyl, most preferably methyl;
wherein R6, R9 and R10 are independently selected from methyl or ethyl groups.
An alternative additional groups of compounds preferred herein are compounds of general formula IG wherein:
X is CH;
when RG is R1, RG represents C1-C3 alkyl or RG represents C1-C6 alkylHet, preferably C1-C3 pyridyl or pyrazolyl and wherein when RG is R1 then RG is more preferably C1-C3 alkyl, most preferably methyl; or
when RG is R2, RG represents C1-C6 alkylHet, wherein said Het is C-linked and is preferably C1-C3 imidazolyl or pyrazolyl or RG represents Het wherein said Het is C-linked and is preferably an optionally N-substitued azetidinyl group or RG represents C1-C5 alkyl and is preferably cyclopropylmethyl or methoxyethyl and wherein when RG R1 then RG is more preferably C1-C3 imidazolyl or C1-C3 pyrazolyl or cyclopropylmethyl;
R3 is C1-C6 alkyl, preferably C1-C4 alkyl and more preferably ethyl or propyl;
R4 is C1-C6 alkyl, preferably n-butyl, t-butyl, n-propyl, ethyl and more preferably ethyl when RG is R1 and more preferably propyl or t-butyl when RG is R2;
R5 is C1-C3 alkyl and is preferably methyl.
Preferred compounds of general formulae IA, IB or ID herein include the following:
5-[2-Ethoxy-5-(methylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-Butoxy-5-(methylsulfonyl)phenyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-1-(2-pyridinylmethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-Butoxy-5-(methylsulfonyl)phenyl]-3-ethyl-1-(2-pyridinylmethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-1-[(1-methyl-1H-imidazol-2-yl)methyl]-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-Butoxy-5-(methylsulfonyl)phenyl]-3-ethyl-2-[2-(4-morpholinyl)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-2-[(1-methyl-1H-imidazol-2-yl)methyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-2-[2-(4-morpholinyl)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[5-(methylsulfonyl)-2-propoxyphenyl]-1-(2-pyridinylmethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
2-(Cyclopropylmethyl)-3-ethyl-5-[5-(methylsulfonyl)-2-propoxyphenyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-1-{[(2S)-1-methylpyrrolidinyl]methyl}-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-2-{[(2R)-1-methylpyrrolidinyl]methyl}-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-2-(3-pyridazinylmethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-1-(3-pyridazinylmethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-2-(2-pyridinylmethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-1-{[(2S)-1-methylpyrrolidinyl]methyl}-5-[5-(methylsulfonyl)-2-propoxyphenyl]-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[2-Butoxy-5-(methylsulfonyl)phenyl]-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-1-(1-isopropyl-3-azetidinyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-2-(1-methyl-4-piperidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[2-isobutoxy-5-(methylsulfonyl)phenyl]-2-(1-isopropyl-4-piperidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
1-[2-(Diisopropylamino)ethyl]-3-ethyl-5-[5-(methylsulfonyl)-2-propoxyphenyl]-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
2-[2-(Diisopropylamino)ethyl]-3-ethyl-5-[5-(methylsulfonyl)-2-propoxyphenyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-5-[5-(ethylsulfonyl)-2-propoxyphenyl]-1-{[(2S)-1-methylpyrrolidinyl]methyl}-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-Ethyl-1-{[(2S)-1-methylpiperidinyl]methyl}-5-[5-(methylsulfonyl)-2-propoxyphenyl]-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or
5-Allyl-2-[2-butoxy-5-(methylsulfonyl)phenyl]-7-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
and pharmaceutically acceptable salts, solvates, pro-drugs or polymorphs thereof.
Also included within the scope of the invention are radiolabelled derivatives of compounds of formulae I, IA, IB, IC, ID and IE which are suitable for biological studies.
The present invention additionally provides compounds of general formula I:
or a pharmaceutically or veterinarily acceptable salt and/or solvate, polymorph or pro-drug thereof, wherein
Y represents C or N, with N being in at least one, but not more than two, of the positions marked by Y;
X represents CH or N;
R1, R2 and R3 where present and attached to nitrogen independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R1, R2 and R3 where present and attached to carbon independently represent H, halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1 and R2 are present they may optionally be connected via a Cxe2x80x94C, Cxe2x80x94N or Cxe2x80x94O bond;
wherein when R2 and R3 are present they may optionally be connected via a Cxe2x80x94C, Cxe2x80x94N or Cxe2x80x94O bond;
R4 represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R5 represents represent C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2 and R3, where present, or R4 or R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl and C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl and C1-C6 alkylaryl group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)N R7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R6 represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R7 and R8 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12 C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17; or
R7 and R8 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R9 and R10 independently represent H, C(O)R6, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15 R6, NR15 R16, SO2NR15R16, SO2R17; or
R9 and R10 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R11 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl which latter five substituent groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
R12 represents H or C1-C6 alkyl;
R13 and R14 independently represent H or C1-C6 alkyl; or
R13 and R14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R15 and R16 independently represent H, C(O)R12, SO2R17 or C1-C6 alkyl; or
R15 and R16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R17 represents C1-C6 alkyl;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof.
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention:
1. Compounds of formulae IA, IC, ID and IE may be prepared by cyclisation of corresponding compounds of formulae IIA, IIC, IID and IIE, respectively:
xe2x80x83wherein R1, R2, R3, R4, R5 and X are as defined previously for compounds of formulae IA, IC, ID and IE.
This cyclisation may be accomplished under basic, neutral or acidic conditions using known methods for pyrimidone ring formation. Preferably, the cyclisation is performed under basic conditions using an alkali metal salt of an alcohol or amine, such as sodium ethoxide, potassium tert-butoxide, cesium carbonate or potassium bis(trimethylsilyl)amide, in the presence of a suitable alcohol as solvent, for example at reflux temperature (or, if performed in a sealed vessel, at greater than reflux temperature). The skilled person will appreciate that, when an alcohol is selected as solvent, an appropriate alcohol of formula R4OH may be used if it is intended to mitigate alkoxide exchange at the 2-position of either the pyridin-3-yl or phenyl substituent. Conversely, a sterically hindered alcohol (e.g. 3-methyl-3-pentanol) may be used to avoid exchange at the 2-position of either the pyridin-3-yl or phenyl substituent. Optionally, an equivalent of an additive (e.g. R4OAc) may be added to act as a hydroxide scavenger.
Compounds of formulae IIA, IIC, IID and IIE may be prepared by reaction of corresponding compounds of formulae IIIA, IIIC, IIID and IIIE, respectively:
wherein R1, R2 and R3 are as defined previously for compounds of formulae IIA, IIC, IID and IIE, with a compound of formula IV or a carboxylic acid derivative thereof:
wherein R4, R5 and X are as defined previously for compounds of formulae IIA, IIC, IID and IIE.
This coupling reaction may be achieved by conventional amide bond forming techniques which are well known to those skilled in the art. For example, an acyl halide (e.g. chloride) derivative of a compound of formula IV may be reacted with a compound of formula IIIA, IIIC, IIID or IIIE in the presence of an excess of a tertiary amine, such as triethylamine or pyridine, optionally in the presence of a suitable catalyst, such as 4-dimethylaminopyridine, in a suitable solvent such as dichloromethane or THF, at a temperature of about 0xc2x0 C. to room temperature.
A variety of other amino acid coupling methodologies may be used to couple the compounds of formulae IIIA, IIIC, IIID or IIIE with the compound of formula IV. For example, the acid of formula IV or a suitable salt thereof (e.g. sodium salt) may be activated with an appropriate activating reagent, e.g. a carbodiimide, such as 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride optionally in the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst such as 4-dimethylaminopyridine; a halotrisaminophosphonium salt such as bromo-tris(pyrrolidinyl)phosphonium hexafluorophosphate; a suitable pyridinium salt such as 2-chloro-1-methyl pyridinium chloride; or another suitable coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl-uronium hexafluorophosphate (HATU). Either type of coupling reaction may be conducted in a suitable solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide, optionally in the presence of a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (for example when either the compound of formula IIIA, IIIC, IIID or IIIE, or the activating agent is presented in the form of an acid addition salt), at from about 0xc2x0 C. to about room temperature. Preferably, from about 1 to 2 molecular equivalents of the activating reagent and from 1 to 3 molecular equivalents of any tertiary amine present may be employed.
Alternatively, the carboxylic acid function of IV may be activated using an excess of a reagent such as N,Nxe2x80x2-carbonyldiimidazole in an appropriate solvent, e.g. ethyl acetate, dichloromethane or butan-2-one, at from about room temperature to about 80xc2x0 C., followed by reaction of the intermediate imidazolide with either a compound of the formula IIIA, IIIC, IIID or IIIE at from about 20xc2x0 C. to about 90xc2x0 C.
In a further variation, a compound of formula IA, IC, ID or IE, as defined previously, may be formed in a one-pot procedure by coupling a compound of formula IIA, IIIC, IIID or IIIE with the acyl chloride or a lower alkyl ester derivative of formula IV and by cyclising the resultant intermediate compound of formula IIA, IIC, IID or IIE, using the methods as described previously. When using an acyl chloride derivative of formula IV, a suitable solvent (e.g. pyridine) may serve as both an acid scavenger and as the solvent for the in-situ coupling and cyclisation reaction.
Compounds of formula IV, where X is CH and R5 is Me, may be prepared from compounds of formula V:
wherein R4 is as defined previously for compounds of formula IV, and Rpis a protecting group for a carboxylic acid (preferably a lower alkyl group such as methyl, ethyl or t-butyl), by using standard methods for deprotection.
Compounds of formula V may be prepared by the alkylation of compounds of formula VI:
wherein Rp is as defined previously for compounds of formula V, by reaction with a compound of formula R4-L, wherein R4 is as defined previously for compounds of formula V, and L is a leaving group, such as halo, preferably chloro, bromo or iodo, for example at between room and reflux temperature in a suitable solvent (e.g. acetonitrile) in the presence of a suitable base (e.g. cesium carbonate).
Compounds of formula VI may be prepared from compound VII using standard conditions for protecting carboxylic acids.
Alternatively, compounds of formula IV may be prepared from compounds of formula VIII:
wherein R4, R5 and X are as defined previously for compounds of formula IV, by reaction with an oxidant (e.g. meta chloroperbenzoic acid (mCPBA)), for example at between 0xc2x0 C. and room temperature in a suitable solvent (e.g. dichloromethane).
Compounds of formula VII may be prepared from compounds of formula IX by first forming an intermediate diazonium salt, for example by the action of sodium nitrite in a mixture of concentrated hydrochloric acid and glacial acetic acid at from about xe2x88x9225xc2x0 C. to about 0xc2x0 C., followed by reaction with R5SSR5 and a copper salt, preferably CuBr2, for example at between 0xc2x0 C. and room temperature:
wherein R4, R5 and X are as defined previously for compounds of formula VIII.
Compounds of formula IX may be prepared by reducing compounds of formula X:
wherein R4 and X are as defined previously for compounds of formula IX, for example with hydrogen at 60 psi in a suitable solvent (e.g. R4OH) at between room temperature and 60xc2x0 C. in the presence of an appropriate catalyst (e.g. 10% palladium on carbon).
Alternatively, compounds of formula VIII may be prepared from compounds of formula XI:
wherein R4, R5 and X are as defined previously for compounds of formula VII, and RP is a protecting group for a carboxylic acid (preferably a lower alkyl group such as methyl, ethyl or t-butyl), by using standard methods for deprotection.
Compounds of formula XI may be prepared from compounds of formula XII:
wherein R4, X and RP are as defined previously for compounds of formula XI, by reaction with thiourea (1.1 equivalents) and a nickel (0) catalyst, generated in situ from bis(triethylphosphine)nickel(II) chloride (0.05 equivalents) and sodium cyanoborohydride (0.075 equivalents), in a suitable solvent (e.g. N,N-dimethylformamide) at between room temperature and 80xc2x0 C., followed by addition of R5-L (wherein R5 is as defined previously for compounds of formula XI and L is a leaving group such as halo, preferably chloro, bromo or iodo) and a suitable base (e.g. calcium oxide).
Compounds of formula XII, where X is N, may be prepared from compounds of formula XIII:
wherein R4 and RP are as defined previously for compounds of formula XII, by reaction with N-iodosuccinimide (1 to 2 equivalents) in a 4:1 mixture of trifluoroacetic acid and trifluoroacetic anhydride at between room and reflux temperature.
Alternatively, compounds of formula IV may be prepared from compounds of formula XIV:
wherein R4, R5 and X are as defined previously for compounds of formula IV, and RP is a protecting group for a carboxylic acid (preferably a lower alkyl group such as methyl, ethyl or t-butyl), by using standard methods for deprotection.
Compounds of formula XIV may be prepared from compounds of formula XV:
wherein R4, X and RP are as defined previously for compounds of formula XIV, by reaction with sodium sulphite (2 equivalents) and sodium bicarbonate (2 equivalents) in water at room temperature, followed by reaction with sodium carbonate (2 equivalents) and R5-L (wherein R5 is as defined previously for compounds of formula XIV and L is a leaving group such as halo, preferably chloro, bromo or iodo) in aqueous alcohol (preferably R4OH) at between room and reflux temperature.
2. Compounds of formulae IA, IC, ID and IE, where X is CH, may alternatively be prepared by deprotecting corresponding compounds of formulae XVIA, XVIC, XVID and XVIE respectively:
xe2x80x83wherein R1, R2, R3, R4 and R5 are as defined previously for compounds of formulae IA, IC, ID and IE, and RP is a protecting group (e.g. methyl), for example by reaction with 6M HCl at between room temperature and 70xc2x0 C.
Compounds of formulae XVIA, XVIC, XVID and XVIE may be prepared by alkylating corresponding compounds of formulae XVIIA, XVIIC, XVIID and XVIIE (the skilled person will appreciate that XVIIA and XVIID are different tautomeric forms of the same compound) respectively:
wherein R1, R2, R3, R4, R5 and RP are as defined previously for compounds of formulae XVIA, XVIC, XVID and XVIE, by reaction with compounds of formulae R1-L, R3-L, R2-L and R3-L respectively, wherein R1, R2 and R3 are as defined previously for compounds of formulae XVIA, XVIC, XVID and XVIE, and L is a leaving group, such as halo, preferably chloro, bromo or iodo, or an alkyl or aryl sulphonate, preferably methane sulphonate or p-toluene sulphonate, for example at between room and reflux temperature in a suitable solvent (e.g. N,N-dimethylformamide) in the presence of a suitable base (e.g. potassium carbonate).
Compounds of formulae XVIIA, XVIIC, XVIID and XVIIE may be prepared by reacting corresponding compounds of formulae XVIIIA, XVIIIC, XVIIID and XVIIIE (the skilled person will appreciate that XVIIIA and XVIIID are different tautomeric forms of the same compound) respectively:
wherein R1, R2, R3, R4 and R5 are as defined previously for compounds of formulae XVIIA, XVIIC, XVIID and XVIIE, with RP-OH, wherein RP is as defined previously for compounds of formulae XVIIA, XVIIC, XVIID and XVIIE, for example at between room and reflux temperature in the presence of a suitable base (e.g. potassium tert-butoxide).
Compounds of formulae XVIIIA, XVIIIC, XVIIID and XVIIIE may be prepared by reacting corresponding compounds of formulae XIXA, XIXC, XIXD and XIXE (the skilled person will appreciate that XIXA and XIXD are different tautomeric forms of the same compound) respectively:
wherein R1, R R3, R4 and R5 are as defined previously for compounds of formulae XVIIIA, XVIIIC, XVIIID and XVIIIE, with a chlorinating agent (e.g. POCl3) at between room and reflux temperature, optionally in a suitable solvent and optionally in the presence of 1 to 2 equivalents of an additive (e.g. N,N-dimethylformamide or N,N-dimethylaniline). The skilled person will recognise that although the above structures have been given discreet formulae descriptors (XIXA, XIXC, XIXD and XIXE) for clarity, they are in fact a subset of formulae IA, IC, ID and IE wherein R1, R3, R2 and R3 are hydrogen respectively.
Compounds of formulae XIXA, XIXC, XIXD and XIXE may be prepared by cyclisation of corresponding compounds of formulae XXA, XXC, XXD and XXE (the skilled person will appreciate that XXA and XXD are different tautomeric forms of the same compound) respectively:
wherein R1, R2, R3, R4 and R5 are as defined previously for compounds of formulae XIXA, XIXC, XIXD and XIXE, using the same conditions described for the preparation of IA, IC, ID and IE in process 1. The skilled person will recognise that although the above structures have been given discreet formulae descriptors (XXA, XXC, XXD and XXE) for clarity, they are in fact a subset of formulae IIA, IIC, IID and IIE wherein R1, R3, R2 and R3 are hydrogen respectively.
Compounds of formulae XXA, XXC, XXD and XXE may be prepared by reaction of corresponding compounds of formulae XXIA, XXIC, XXID and XXIE respectively:
wherein R1, R2 and R3 are as defined previously for compounds of formulae XXA, XXC, XXD and XXE, with a compound of formula IV or a carboxylic acid derivative thereof, using the same conditions described for the preparation of IIA, IIC, IID and IIE in process 1. The skilled person will recognise that although the above structures have been given discreet formulae descriptors (XXIA, XXIC, XXID and XXIE) for clarity, they are in fact a subset of formulae IIIA, IIIC, IIID and IIIE wherein R1, R3, R2 and R3 are hydrogen respectively.
3. Compounds of formulae IIA, IIC, IID and IIE, in which R1, R2 and R3, when attached to nitrogen, do not represent hydrogen, may alternatively be prepared by reacting corresponding compounds of formulae XXA, XXC, XXD and XXE (the skilled person will appreciate that XXA and XXD are different tautomeric forms of the same compound), with compounds of formulae R1-L, R3-L, R2-L and R3-L respectively, wherein R1, R2 and R3 are as defined previously for compounds of formulae IIA, IIC, IID and IIE, and L is a leaving group, such as halo, preferably chloro, bromo or iodo, or an alkyl or aryl sulphonate, preferably methane sulphonate or p-toluene sulphonate, for example at between room and reflux temperature in a suitable solvent (e.g. N,N-dimethylformamide) in the presence of a suitable base (e.g. cesium carbonate).
4. Compounds of formulae IA, IC, ID and IE, in which R1, R2 and R3, when attached to nitrogen, do not represent hydrogen, may alternatively be prepared by reacting corresponding compounds of formulae XIXA, XIXC, XIXD and XIXE (the skilled person will appreciate that XIXA and XIXD are different tautomeric forms of the same compound), with compounds of formulae R1-L, R3-L, R2-L and R3-L respectively, wherein R1, R2 and R3 are as defined previously for compounds of formulae IA, IC, ID and IE, and L is a leaving group, such as halo, preferably chloro, bromo or iodo, or an alkyl or aryl sulphonate, preferably methane sulphonate or p-toluene sulphonate, for example at between room and reflux temperature in a suitable solvent (e.g. N,N-dimethylformamide) in the presence of a suitable base (e.g. cesium carbonate).
5. Compounds of formulae IA, IC, ID and IE, in which R1, R2 and R3, when attached to carbon, represent either cyano, C(O)R6, C(O)OR6, C(O)NR9R10, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl (which latter five groups are all optionally substituted and/or terminated as detailed in the definition of R1, R2 and R3) may alternatively be prepared by reacting corresponding compounds of formulae XXIIA, XXIIC, XXIID and XXIIE respectively:
xe2x80x83wherein X, R4, R5, R6, R9 and R10 are as defined previously for compounds of formulae IA, IC, ID and IE, and Hal represents Cl, Br or I (preferably Br or I), with R3-FG, R1-FG, R3-FG and R2-FG respectively, wherein R1, R2 and R3 are as defined previously for compounds of formulae IA, IC, ID and IE, and FG represents the appropriate functional group (obvious to those skilled in the art) required to utilise the following coupling conditions:
(a) so-called xe2x80x9cSuzukixe2x80x9d conditions (e.g. 1.2 equivalents of a boronic acid, 2 equivalents of K2CO3 and 0.1 equivalents of Pd(PPh3)4, at reflux temperature in a 4:1 mixture of dioxane and water);
(b) so-called xe2x80x9cStillexe2x80x9d conditions (e.g. 1.5 equivalents of a stannane, 10 equivalents of LiCl, 0.15 equivalents of Cul, and 0.1 equivalents of Pd(PPh3)4, at reflux temperature in dioxane);
(c) so-called xe2x80x9cHeckxe2x80x9d conditions (e.g. 2 equivalents of an alkene [such as butyl vinyl ether to prepare C(O)R8 containing compounds], 1.7 equivalents of Et3N and catalytic amounts of Pd(OAc)2 and P(o-tol)3, in MeCN at between room and reflux temperature);
(d) so-called xe2x80x9cSonogashiraxe2x80x9d conditions (e.g. 1.5 to 5 equivalents of a terminal alkyne and 0.03 equivalents of Pd(PPh3)2Cl2/Cul, in Et3N and MeCN at between room temperature and 60xc2x0 C. [alternatively followed by hydrolysis conditions (e.g. 0.3 equivalents HgSO4, H2SO4 in acetone at reflux temperature) to prepare C(O)R8 containing compounds]).
(e) Carbonylation conditions (e.g. palladium(II) acetate combined with 1,2-bis(diphenylphosphino)-propane (DPPP) under an atmosphere of carbon monoxide (e.g. at a pressure of around 70 psi) in the presence of an excess of a nucleophile (e.g. alcohol or amine), an excess of a tertiary amine base (e.g. Et3N), and optionally in the presence of a suitable solvent (e.g. dimethylsulfoxide).
The skilled person will recognise that although the above structures have been given discreet formulae descriptors (XXIIA, XXIIC, XXIID and XXIIE) for clarity, they are in fact a subset of formulae IA, IC, ID and IE wherein R3, R1, R3 and R2 are Hal respectively.
Compounds of formulae XXIIA, XXIIC, XXIID and XXIIE may be prepared by reaction of corresponding compounds of formulae XXIIIA, XXIIIC, XXIIID and XXIIIE respectively:
wherein X, R1, R2, R3, R4 and R5 are as defined previously for compounds of formulae XXIIA, XXIIC, XXIID and XXIIE, with the appropriate halogen (e.g. bromination can be achieved by reacting with 1.5 to 2.0 equivalents of bromine and 1.5 to 2.0 equivalents of sodium acetate in acetic acid at between room and reflux temperature). The skilled person will recognise that although the above structures have been given discreet formulae descriptors (XXIIIA, XXIIIC, XXIIID and XXIIIE) for clarity, they are in fact a subset of formulae IA, IC, ID and IE wherein R3, R1, R3 and R2 are H respectively.
Compounds of formulae XXIIIA, XXIIIC, XXIIID and XXIIIE may be prepared by analogous conditions to those described for the preparation of corresponding compounds of formulae IA, IC, ID and IE in process 1.
6. Compounds of formula XIXE may alternatively be prepared by reaction of a compound of formula XXIVE:
xe2x80x83wherein R4 and R5 are as defined previously for compounds of formula XIXE, with a compound of formula XXVE:
R2xe2x80x94CHOxe2x80x83xe2x80x83XXVE
xe2x80x83wherein R2 is as defined previously for compounds of formula XIXE, for example at between room and reflux temperature, optionally in the presence of a suitable mild oxidant (e.g. sodium metabisulfite), and optionally in an appropriate organic solvent (e.g. N,N-dimethylacetamide).
Compounds of formula XIXE may alternatively be prepared by reaction of compounds of formula XXIVE, as hereinbefore defined, with a compound of formula XXVIE:
R2xe2x80x94C(O)OHxe2x80x83xe2x80x83XXVIE
wherein R2 is as defined previously for compounds of formula XIXE, or a suitable carboxylic acid derivative thereof (e.g. an acid halide or an ortho ester), for example at between room and reflux temperature, optionally in the presence of a suitable solvent (e.g. N,N-dimethyl formamide) and/or an appropriate base.
7. Compounds of formula IB may be prepared by cyclisation of compounds of formula XXVIIB:
xe2x80x83wherein R1, R3, R4, R5 and X are as defined previously for compounds of formula IB, for example under conditions known to those skilled in the art. Such conditions include reaction, at between room and reflux temperature, in the presence of a suitable (Lewis acidic) dehydrating agent (e.g. phosphorous oxychloride) and an appropriate solvent (e.g. 1,2-dichloroethane), or as otherwise described in the art.
Compounds of formula XXVIIB may be prepared by the reaction of compounds of formula XXVIIIB:
wherein R17 represents C1-C6 alkyl, and R1 and R3 are as defined previously for compounds of formula XXVIIB, with compounds of formula XXIXB:
or a suitable acid addition salt thereof (e.g. an hydrogen chloride salt), wherein R4, R5 and X are as defined previously for compounds of formula XXVIIB, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at between room and reflux temperature in a suitable solvent (e.g. ethanol, ether, 1,4-dioxane or N,N-dimethylformamide).
Compounds of formula XXVIIIB may be prepared via standard techniques, for example by decarboxylation of compounds of formula XXXB:
wherein R1, R3 and R17 are as defined previously for compounds of formula XXVIIIB, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at elevated temperature (e.g. reflux temperature) in the presence of a suitable solvent (e.g. methanol or ethanol) and optionally in the presence of a suitable base (e.g. sodium hydrogencarbonate).
Compounds of formula XXXB may be prepared by reaction of compounds of formula XXXIB:
wherein R1 and R3 are as defined previously for compounds of formula XXXB, with a compound of formula XXXIIB:
wherein R17 is as defined previously for compounds of formula XXXB and L is as hereinbefore defined, for example under conditions known to those skilled in the art. Such conditions include reaction, at between room and reflux temperature, in the presence of a suitable organic solvent (e.g. THF or ether), an appropriate base (e.g. pyridine, sodium hydride, potassium tert-butoxide, lithium diisopropyl-amide, piperidine or triethylamine) optionally in the presence of a suitable catalyst (e.g. 4-(dimethylamino)pyridine), and optionally with the prior conversion of XXXIB into a 1,3-oxazol-5(4H)-one with excess XXXIIB (Dakin-West reaction).
Compounds of formula XXVIIIB may alternatively be prepared by reaction of a corresponding compound of formula XXXIIIB:
wherein R1, R3 and R17 are as defined previously for compounds of formula XXVIIIB, with ozone in a stream of oxygen, followed by reduction of the resulting ozonide, for example, for both steps, under conditions known to those skilled in the art. Conditions for the ozonation include, for example, reaction at sub-ambient temperature (e.g. xe2x88x9270xc2x0 C.) in the presence of a suitable solvent (e.g. dichloromethane). Conditions for reduction of the intermediate ozonide include, for example, reaction at sub-ambient temperature (e.g. xe2x88x9270xc2x0 C.) with a suitable reducing agent (e.g. dimethyl sulfide), followed by treatment (at the same temperature) with an appropriate base (e.g. pyridine).
Compounds of formula XXXIIIB may be prepared by reaction of a corresponding compound of formula XXXIVB:
wherein L2 represents a suitable leaving group (e.g. xe2x80x94N(CH3)OCH3 or halo) and R1 and R3 are as defined for compounds of formula XXXIIIB, with a compound of formula XXXVB:
wherein M represents H or a suitable metal-containing moiety (e.g. Na, Li, Mg(II) halide, or a cuprate) and R17 is as defined previously for compounds of formula XXXIIIB, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction of a compound of formula XXXIVB at between xe2x88x9280xc2x0 C. and room temperature in the presence of a suitable solvent (e.g. THF) with a mixture formed by reacting, at sub-ambient temperature (e.g. xe2x88x9278xc2x0 C.), a compound of formula XXXVB in which M represents H (e.g. ethyl vinyl ether), a suitable organolithium reagent (e.g. tert-butyllithium), an appropriate solvent (e.g. THF) and, optionally, a source of a suitable metal salt (e.g. MgBr2 diethyl etherate).
Compounds of formula XXXIVB may be prepared from corresponding compounds of formula XXXIB, as hereinbefore defined, under conditions known to those skilled in the art.
Compounds of formula XXVIIIB may alternatively be prepared by reaction of corresponding compounds of formula XXXVIB:
wherein R1, R3 and R17 are as previously defined for compounds of formula XXVIIIB, with an oxidising agent (e.g. Dess-Martin periodinane) at between xe2x88x9278xc2x0 C. and reflux temperature in a suitable solvent (e.g. DCM).
Compounds of formula XXXVIB may be prepared by the reaction of compounds of formula XXXVIIB:
wherein R1 and R3 are as previously defined for compounds of formula XXXVIB, with HCl(g) in R17OH, wherein R17 is as previously defined for compounds of formula XXXVIB, at between xe2x88x9210xc2x0 C. and 20xc2x0 C., followed by reaction with aqueous base (e.g. 10% Na2CO3 soln.) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXXVIIB may be prepared by the reaction of compounds of formula XXXVIIIB:
wherein R1 and R3 are as previously defined for compounds of formula XXXVIIB, with a source of cyanide (e.g. acetone cyanohydrin) in a suitable solvent (e.g. DCM), optionally in the presence of a base (e.g. Et3N), at between 0xc2x0 C. and reflux temperature.
Compounds of formula XXXVIIIB may be prepared by the reaction of compounds of formula XXXIXB:
wherein R1 and R3 are as previously defined for compounds of formula XXXVIIIB, with a source of hydride (e.g. LiAlH4) in a suitable solvent (e.g. THF) at between xe2x88x9278xc2x0 C. and 20xc2x0 C.
Compounds of formula XXXIXB may be prepared from compounds of formula XXXIB using conditions known to those skilled in the art.
Compounds of formula XXIXB may be prepared via standard techniques, for example by a reaction of a corresponding compound of formula XXXXB:
or an acid addition salt thereof (e.g. a hydrogen chloride salt), wherein R4, R5 and X are as defined previously for compounds of formula XXIXB, with hydrazine, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at between xe2x88x9210xc2x0 C. and room temperature in the presence of a suitable solvent (e.g. a lower alkyl (e.g. C1-3) alcohol), or as otherwise described in the prior art.
Compounds of formula XXXXB may be prepared from compounds of formula XXXXIB, which in turn can be prepared from compounds of formula XXXXIIB, which in turn can be prepared from compounds of formula IV or a carboxylic acid derivative thereof, wherein R4 and R5 and X are as defined previously for compounds of formula XXXXB, under conditions known to those skilled in the art.
Compounds of formula XXIXB may alternatively be prepared by the reaction of compounds of formula XXXXIIIB:
wherein R4 and R5 are as defined previously for compounds of formula XXIXB, with hydrazine in a suitable solvent (e.g. THF) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXXXIIIB may be prepared by the reaction of compounds of formula XXXXIVB:
wherein R4 and R5 are as defined previously for compounds of formula XXXXIIIB, with a methylating agent (e.g. iodomethane) in a suitable solvent (e.g. acetone) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXXXIVB may be prepared by the reaction of compounds of formula XXXXIIB with Lawesson""s reagent in a suitable solvent (e.g. toluene) at between 20xc2x0 C. and reflux temperature.
Compounds of formulae IIIA, IIIC, IIID, IIIE, VII, X, XII (where X represents CH), XII, XV, XXIA, XXIC, XXID, XXIE, XXIVE, XXVE, XXVIE, XXXIB, XXXIIB and XXXVB and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described hereinbefore, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions. For example, compounds of formula XXIVE may be prepared by, or by analogy with, methods described in U.S. Pat. No. 4,039,544.
Substituents on the aryl and Het groups in the above-mentioned compounds may be introduced, and interconverted, using techniques which are known to those skilled in the art.
Further standard substituent or functional group interconversions and transformations that may be performed on compounds of formulae I, IA, IB, IC, ID, IE and their precursors include procedures described hereinafter. In this respect:
(i) alkoxycarbonyl may be hydrolysed to carboxy under acidic or basic conditions;
(ii) amino may be alkylated (either by reaction with an alkylating agent or by reductive alkylation) to give alkylamino or dialkylamino;
(iii) amino may be acylated to give acylamino or sulfonated to give sulfonylamino.
In addition, certain acyclic groups may be converted to certain heterocyclic groups using reagents and conditions known to those skilled in the art, for example as described in Comprehensive Heterocyclic Chemistry II, edited by A R Katritsky, C W Rees and EFV Scriven, 1st Edition, Elsevier Science Ltd., Volumes 1-11 (1996).
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the course of carrying out the above processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), alkyl (e.g. methyl or methoxyethyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are known to those skilled in the art.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J W F McOmie, Plenum Press (1973), xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991) and xe2x80x9cProtecting Groupsxe2x80x9d by Philip J. Kocienski, Thieme, 1994.
Persons skilled in the art will also appreciate that, in order to obtain compounds of formulae I, IA, IB, IC, ID and IE, in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
Pharmaceutically acceptable acid addition salts of the compounds of formulae I, IA, IB, IC, ID and IE which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt may then be isolated either by filtration of by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formulae I, IA, IB, IC, ID and IE with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The present invention also includes all suitable isotopic variations of a compound of formulae I, IA, IB, IC, ID or IE or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of formulae 1, IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of formulae I, IA, IB, IC, ID or IE, and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 170, 180, 31p, 32p, 35S, 18F and 36Cl, respectively. Certain isotopic variations of the compounds of formulae I, IA, IB, IC, ID or IE, and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of formulae I, IA, IB, IC, ID or IE, and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formulae I, IA, IB, IC, ID and IE, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formulae I, IA, IB, IC, ID and IE may act as prodrugs of other compounds of formulae I, IA, IB, IC, ID and IE respectively.
All protected derivatives, and prodrugs, of compounds of formulae I, IA, IB, IC, ID and IE are included within the scope of the invention.
The present invention additionally comprises the combination of a cGMP PDE5 inhibitor compound of the general formulae I, IA, IB, IC, ID or IE, wherein said combination can be administered by sequential, simultaneous or joint administration of a compound of the general formulae I, IA, IB, IC, ID or IE, with:
(1) one or more naturally occurring or synthetic prostaglandins or esters thereof. Suitable prostaglandins for use herein include compounds such as alprostadil, prostaglandin E1, prostaglandin E0, 13, 14-dihydroprostaglandin E1, prostaglandin E2, eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in U.S. Pat. No. 6,037,346 issued on Mar. 14, 2000 and incorporated herein by reference, PGE0, PGE1, PGA1, PGB1, PGF1 xcex1, 19-hydroxy PGA1, 19-hydroxy-PGB1, PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3xcex1, carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprost and moxisylate; and/or
(2) one or more xcex1-adrenergic receptor antagonist compounds also known as xcex1-adrenoceptors or xcex1-receptors or xcex1 blockers. Suitable compounds for use herein include: the xcex1-adrenergic receptors as described in PCT application WO99/30697 published on Jun. 14, 1998, the disclosures of which relating to a-adrenergic receptors are incorporated herein by reference and include, selective xcex11-adrenoceptors or xcex12-adrenoceptors and non-selective adrenoceptors, suitable xcex11-adrenoceptors include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolfa alkaloids, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abanoquil and prazosin; xcex12-blockers from U.S. Pat. No. 6,037,346 [Mar. 14, 2000] dibenarnine, tolazoline, trimazosin and dibenarnine; xcex1-adrenergic receptors as described in U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000 each of which is incorporated herein by reference; xcex12-Adrenoceptors include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine; and/or
(3) one or more NO-donor (NO-agonist) compounds. Suitable NO-donor compounds for use herein include organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl brinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3-morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine (SNAP) S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso-N-cysteine, diazenium diolates,(NONOates), 1,5-pentanedinitrate, L-arginene, ginseng, zizphi fructus, molsidomine, Re-2047, nitrosylated maxisylyte derivatives such as NMI-678-11 and NMI-937 as described in published PCT application WO 0012075; and/or
(4) one or more potassium channel openers. Suitable potassium channel openers for use herein include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCl2; and/or
(5) one or more dopaminergic agents, preferably apomorphine or a selective D2, D3 or D2/D3 agonist such as pramipexol and ropirinol (as claimed in WO 0023056), L-Dopa or carbi dopa, PNU 95666 (as claimed in WO 0040226); and/or
(6) one or more vasodilator agents. Suitable vasodilator agents for use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, halo peridol, Rec 15/2739, trazodone; and/or
(7) one or more thromboxane A2 agonists; and/or
(8) one or more ergot alkoloids; Suitable ergot alkaloids are described in U.S. Pat. No. 6,037,346 issued on Mar. 14, 2000 and include acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride, terguride; and/or
(9) one or more compounds which modulate the action of atrial natruretic factor (also known as atrial naturetic peptide), B and C type naturetic factors such as inhibitors or neutral endopeptidase; and/or
(10) one or more compounds which inhibit angiotensin-converting enzyme such as enapril, and one or more combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat; and/or
(11) one or more angiotensin receptor antagonists such as losartan; and/or
(12) one or more substrates for NO-synthase, such as L-arginine; and/or
(13) one or more calcium channel blockers such as amlodipine; and/or
(14) one or more antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme; and/or
(15) one or more cholesterol lowering agents such as statins (e.g. atorvastatin/Lipitorxe2x80x94trade mark) and fibrates; and/or
(16) one or more antiplatelet and antithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors; and/or
(17) one or more insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide; and/or
(18) one or more COX 2 inhibitors; and/or
(19) pregabalene; and/or
(20) gabapentene; and/or
(21) one or more acetylcholinesterase inhibitors such as donezipil; and/or
(22) one or more steroidal anti-inflammatory agents; and/or
(23) one or more estrogen agonists and/or estrogen antagonists, preferably raloxifene or lasofoxifene, (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof (compound A below) the preparation of which is detailed in WO 96/21656.
(24) one or more one or more of a further PDE inhibitor, more particularly a PDE 2, 4, 7 or 8 inhibitor, preferably PDE2 inhibitor, said inhibitors preferably having an IC50 against the respective enzyme of less than 100 nM: and/or
(25) one or more of an NPY (neuropeptide Y) inhibitor, more particularly NPY1 or NPY5 inhibitor, preferably NPY1 inhibitor, preferably said NPY inhibitors (including NPY Y1 and NPY Y5) having an IC50 of less than 100 nM, more preferably less than 50 nM, suitable NPY and in particular NPY1 inhibitor compounds are described in EP-A-1097718; and/or
(26) one or more of vasoactive intestinal peptide (VIP), VIP mimetic, more particularly mediated by one or more of the VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide), one or more of a VIP receptor agonist or a VIP analogue (eg Ro-125-1553) or a VIP fragment, one or more of a xcex1-adrenoceptor antagonist with VIP combination (eg Invicorp, Aviptadil); and/or
(27) one or more of a melanocortin receptor agonist or modulator or melanocortin ehancer, such as melanotan II, PT-14, PT-141 or compounds claimed in WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, WO-09954358; and/or
(28) one or more of a serotonin receptor agonist, antagonist or modulator, more particularly agonists, antagonists or modulators for 5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993; and/or
(29) one or more of a modulator of transporters for noradrenaline, dopamine and/or serotonin, such as bupropion, GW-320659; and/or
(30) one or more of a purinergic receptor agonist and/or modulator; and/or
(31) one or more of a neurokinin (NK) receptor antagonist, including those described in WO-09964008; and/or
(32) one or more of an opioid receptor agonist, antagonist or modulator, preferably agonists for the ORL-1 receptor; and/or
(33) one or more of an agonist or modulator for oxytocin/vasopressin receptors, preferably a selective oxytocin agonist or modulator; and/or
(34) one or more modulators of cannabinoid receptors; and/or
(35) one or more of an NEP inhibitor, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC 3.4.24.11, more preferably a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11, which has an IC50 of less than 100 nM (e.g. ompatrilat, sampatrilat) suitable NEP inhibitor compounds are described in EP-A-1097719; and/or
(36) one or more compounds which inhibit angiotensin-converting enzyme such as enalapril, and one or more combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat; and/or
(37) one or more tricyclic antidepressants, e.g. amitriptiline; and/or
(38) one or more non-steroidal anti-inflammatory agents; and/or
(39) one or more angiotensin-converting enzyme (ACE) inhibitors, e.g. quinapril; and/or
(40) one or more anti-depressants (such as clomipramine and SSRls (such as paroxetine and sertaline).
wherein said combination can be in the form of co-administration, simultaneous administration, concurrent administration, or stepwise administration.
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals, including humans. They are therefore indicated as pharmaceuticals, as well as for use as animal medicaments.
In particular, compounds of the invention have been found to be potent and selective inhibitors of cGMP PDE5, for example as demonstrated in the tests described below, and are thus useful in the treatment of medical conditions in humans and other animals, in which cGMP PDE5 is indicated, and in which inhibition of cGMP PDE5 is desirable.
By the term xe2x80x9ctreatmentxe2x80x9d, we include both therapeutic (curative), palliative or prophylactic treatment.
Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which cGMP PDE5 is indicated. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which inhibition of cGMP PDE5 is desirable.
The compounds of the invention are expected to be useful for the curative, palliative or prophylactic treatment of mammalian sexual disorders or any of the other conditions or disorders detailed hereinbefore. In particular, the compounds are of value in the treatment of mammalian sexual dysfunctions such as male erectile dysfunction (MED), impotence, female sexual dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic dysfunction (FSOD) as well as sexual dysfunction due to spinal cord injury or selective serotonin re-uptake inhibitor (SSRI) induced sexual dysfunction but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated. Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, diseases and conditions of the eye such as glaucoma, optic neuropathy, macular degeneration, elevated intra-occular pressure, retinal or arterial occulsion and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Further medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated, and for which treatment with compounds of the present invention may be useful include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy, peripheral diabetic neuropathy, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, diabetes mellitus, the insulin resistance syndrome, anal fissure, haemorrhoids, hypoxic vasoconstriction as well as the stabilisation of blood pressure during haemodialysis.
Particularly preferred conditions include MED and FSD.
Thus, the invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in an animal (e.g. a mammal, including a human being), which comprises administering a therapeutically effective amount of a compound of the invention to an animal in need of such treatment.
The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with any other drugs useful in the inhibition of cGMP-PDEs, such as cGMP-PDE5.
The compounds of the invention, their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity can be administered alone but, in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the invention or salts or solvates thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, controlled-release such as modified-, dual-, sustained-, or pulsatile delivery applications. The compounds of the invention may also be administered via intracavernosal injection. The compounds of the invention may also be administered via fast dispersing or fast dissolving dosages forms.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients maybe present both within the dosage form i.e. within the matrix, and/or on the dosage form i.e. upon the surface or coating.
Fast dispersing or dissolving dosage formulations (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
The compounds of the invention can also be administered parenterally, for example, intracavernosally, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention or salts or solvates thereof will usually be from 10 to 500 mg (in single or divided doses).
Thus, for example, tablets or capsules of the compounds of the invention or salts or solvates thereof may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will also appreciate that, in the treatment of certain conditions (including MED and FSD), compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
In general a tablet formulation could typically contain between about 0.01 mg and 500 mg of a compound according to the present invention (or a salt thereof) whilst tablet fill weights may range from 50 mg to 1000 mg. An example formulation for a 10 mg tablet is illustrated:
Such tablets can be manufactured by standard processes, for example, direct compression or a wet or dry granulation process. The tablet cores may be coated with appropriate overcoats.
The compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark] or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 1 to 50 mg of a compound of the invention for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
The compounds of the invention may also be formulated for delivery via an atomiser. Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
Alternatively, the compounds of the invention or salts or solvates thereof can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention or salts or solvates thereof may also be dermally administered. The compounds of the invention or salts or solvates thereof may also be transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.
For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the invention or salts or solvates thereof can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
Generally, in humans, oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example in MED, avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration. A preferred oral dosing regimen in MED for a typical man is from 25 to 250 mg of compound when required. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, sublingually or buccally.
For veterinary use, a compound of the invention, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or pro-drug thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Thus, according to a further aspect of the invention there is provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.
In addition to the fact that compounds of the invention inhibit cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs) and in particular, are potent and selective inhibitors of cGMP PDE5, compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
Preferably the compounds of the invention are orally bioavailable. Oral bioavailablity refers to the proportion of an orally administered drug that reaches the systemic circulation. The factors that determine oral bioavailability of a drug are dissolution, membrane permeability and metabolic stability. Typically, a screening cascade of firstly in vitro and then in vivo techniques is used to determine oral bioavailablity.
Dissolution, the solubilisation of the drug by the aqueous contents of the gastro-intestinal tract (GIT), can be predicted from in vitro solubility experiments conducted at appropriate pH to mimic the GIT. Preferably the compounds of the invention have a minimum solubility of 50 mcg/ml. Solubility can be determined by standard procedures known in the art such as described in Adv. Drug Deliv. Rev. 23, 3-25, 1997.
Membrane permeability refers to the passage of the compound through the cells of the GIT. Lipophilicity is a key property in predicting this and is defined by in vitro Log D7.4 measurements using organic solvents and buffer. Preferably the compounds of the invention have a Log D7.4 of xe2x88x922 to +4, more preferably xe2x88x921 to +2. The log D can be determined by standard procedures known in the art such as described in J. Pharm. Pharmacol. 1990, 42:144.
Cell monolayer assays such as caco-2 add substantially to prediction of favourable membrane permeability in the presence of efflux transporters such as p-glycoprotein, so-called caco-2 flux. Preferably, compounds of the invention have a caco-2 flux of greater than 2xc3x9710xe2x88x926 cmsxe2x88x921, more preferably greater than 5xc3x9710xe2x88x926 cmsxe2x88x921. The caco flux value can be determined by standard procedures known in the art such as described in J. Pharm. Sci, 1990, 79, 595-600
Metabolic stability addresses the ability of the GIT or the liver to metabolise compounds during the absorption process: the first pass effect. Assay systems such as microsomes, hepatocytes etc. are predictive of metabolic liability. Preferably the compounds of the Examples show metabolic stablity in the assay system that is commensurate with an hepatic extraction of less then 0.5. Examples of assay systems and data manipulation are described in Curr. Opin. Drug Disc. Devel., 201, 4, 36-44, Drug Met. Disp., 2000, 28, 1518-1523
Because of the interplay of the above processes further support that a drug will be orally bioavailable in humans can be gained by in vivo experiments in animals. Absolute bioavailability is determined in these studies by administering the compound separately or in mixtures by the oral route. For absolute determinations (% absorbed) the intravenous route is also employed. Examples of the assessment of oral bioavailability in animals can be found in Drug Met. Disp., 2001, 29, 82-87; J. Med Chem, 1997, 40, 827-829, Drug Met. Disp., 1999, 27, 221-226
The biological activities of the compounds of the present invention were determined by the following test methods.
The compounds of the present invention are potent and selective cGMP PDE5 inhibitors. In vitro PDE inhibitory activities against cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) and cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) phosphodiesterases were determined by measurement of their IC50 values (the concentration of compound required for 50% inhibition of enzyme activity).
The required PDE enzymes were isolated from a variety of sources, including human corpus cavernosum, human platelets, human cardiac ventricle, human skeletal muscle and human and canine retina, essentially by the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10, 311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpus cavernosum tissue or human platelets; the cGMP-stimulated PDE (PDE2) was obtained from human corpus cavernosum or human platelets; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from recombinant clone or human skeletal muscle; and the photoreceptor PDE (PDE6) from canine or human retina. Phosphodiesterases 7-11 were generated from full length human recombinant clones transfected into SF9 cells.
Assays were performed either using a modification of the xe2x80x9cbatchxe2x80x9d method of W. J. Thompson et al. (Biochem., 1979, 18, 5228) or using a scintillation proximity assay for the direct detection of AMP/GMP using a modification of the protocol described by Amersham pic under product code TRKQ7090/7100. In summary, the effect of PDE inhibitors was investigated by assaying a fixed amount of enzyme in the presence of varying inhibitor concentrations and low substrate, (cGMP or cAMP in a 3:1 ratio unlabelled to [3H]-labeled at a conc xcx9cxc2xd Km) such that IC50 ≅Ki. The final assay volume was made up to 102 xcexcl with assay buffer [20 mM Tris-HCl pH 7.4, 5 mM MgCl2, 1 mg/ml bovine serum albumin]. Reactions were initiated with enzyme, incubated for 30-60 min at 30xc2x0 C. to give less than 30% substrate turnover and terminated with 50 xcexcl yttrium silicate SPA beads (containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 3, 9 and 11). Plates were resealed and shaken for 20 min, after which the beads were allowed to settle for 30 min in the dark and then counted on a TopCount plate reader (Packard, Meriden, Conn.). Radioactivity units were converted to % activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC50 values obtained using the xe2x80x98Fit Curvexe2x80x99 Microsoft Excel extension or inhouse equivalent. Results from these tests show that the compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE5.
This can be assessed in vitro by determining the capacity of a compound of the invention to enhance sodium nitroprusside-induced relaxation of pre-contracted rabbit corpus cavernosum tissue strips, as described by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118 (suppl.), abstract 153P).
This can be assessed by screening the compounds of the invention in anaesthetised dogs to determine their capacity, after i.v. administration, to enhance the pressure rises in the corpora cavernosa of the penis induced by intracavernosal injection of sodium nitroprusside, using a method based on that described by Trigo-Rocha et al. (Neurourol. and Urodyn., 1994, 13, 71).
Compounds of the invention can be tested at varying i.v and p.o. doses in animals such as mouse and dog, observing for any untoward effects.
In vitro metabolism experiments were carried out in the hepatic microsomal fractions from man. Transplant-quality human liver tissue was obtained from the International Institute for the Advancement of Medicine (Exton, Pa., USA). Microsomes were prepared according to the method described in Biochemical Pharmacology, 1966, 48, 2147-2156 and stored at xe2x88x9280xc2x0 C. The concentrations of protein and cytochrome P450 were determined by standard methods described in Journal of Biological Chemistry, 1951, 193, 265-275 and Journal of Biological Chemistry, 1964, 239, 2370-2378.
Microsomal incubations (1.5 ml) were prepared containing 0.5 xcexcM cytochrome P450, 200 mM phosphate buffer (pH 7.4), 0.1 M MgCl2, 0.1 M isocitric acid, 1 unit/ml isocitrate dehydrogenase and 20 mM xcex2-NADP. Compounds under study were added after a 5 min preincubation at 37xc2x0 C. to give an initial substrate concentration of 1 xcexcM. The mixture was incubated at 37xc2x0 C. and samples (100 xcexcl) were removed for analysis for up to 60 min. Metabolism in samples was terminated by the addition of NaOH (0.1 M) containing an internal standard (chosen to have similar physicochemical properties to compounds under study), followed by extraction into ethyl acetate (2 ml). The extracts were evaporated to dryness and analysed by LC-MS/MS (Hewlett Packard HP1100 binary pump, Hypersil HS100 C18, 5 cm by 4.6 mm internal diameter, 5 xcexcm column using a mobile phase of 2 mM ammonium acetate in 90:10 methanol/water, aqueous portion adjusted to pH 4 with glacial acetic acid, and a flowrate of 1 ml/min). The mass spectrometer was a Sciex API 2000 with TurbolonSpray interface using a positive ion multiple reaction monitoring (MRM) detection mode. Nitrogen was used as curtain, nebuliser, TurbolonSpray and collision gases, and the TurbolonSpray temperature was 100xc2x0 C. Typical voltages were as follows: IS=5.2 kV; RNG=380 V; Q0=xe2x88x9210 V; IQ1=xe2x88x9211 V; ST=xe2x88x9215;RO1=xe2x88x9211 V; MU=gain adjusted as per Sciex user manual. Collision energy was 55 eV for high MRM, OR=65 V. Dwell time was 200 msec with a 50 msec pause. Data was acquired using MSExpress v 1.1 and processed using Macquan 1.5 (PE Sciex)). Disappearance rate constants (k) in human microsomal preparations were determined by linear regression of the log ratio (compound under study/internal standard) versus time. The in vitro human microsomal half-lives were determined according to the equation t{fraction (1/12)}=In 2/k. Results from these studies show that the compounds of the present invention have human liver microsome (HLM) half-lives greater than the HLM half-lives of known compounds of the art.
Thus a particular advantage of the compounds of the invention is that they have longer in vitro microsomal half-lives than compounds of the art. Such improved in vitro microsomal half-lives are indicative of reduced clearance in vivo.
Preferred compounds of the present invention, such as those of Examples 1-22, 24-26 and 28-29 have IC50 values of less than about 30 nM for the PDE5 enzyme. More preferred compounds, such as those of Examples 1-3,5,7-19, 24-25 and 28-29 have IC50 values of less than about 10 nM for the PDE5 enzyme.
Especially preferred herein are compounds which have an IC50 value of less than about 30 nM, and more preferably less than 10 nM for the PDE5 enzyme and especially less than 5 nM for the PDE5 enzyme in combination with selectivity of greater than 10-fold, more preferably greater than 50-fold, more preferably greater than 100-fold and most preferably greater than 200-fold selectivity for the PDE5 enzyme versus the PDE6 enzyme.
An especially preferred subset of the compounds described in the previous paragraph are compounds with human liver microsome (HLM) half-lives greater than about 30 minutes, more preferably greater than 60 minutes, and most preferably greater than 120 minutesxe2x80x94when measured according to the methods detailed hereinbefore. Preferred compounds herein having HLM half-lifes greater than or equal to about 30 minutes include the compounds of examples 1, 2, 9, 11, 12, 14, 18 and 19.
Those skilled in the art will recognise that an increase in HLM half-life is predictive of reduced clearance in man for compounds cleared predominantly by cytochrome P450 mediated metabolism. | {
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1. Field of the Invention
This invention relates to novel tetrahydrocarbyl phosphonium phenoxide salts and the preparation of new epoxy-containing materials by a process employing these and other salts as catalysts. In one preferred embodiment, this invention pertains to a process for making a linear, polymeric material having a molecular weight of at least about 100,000 from the advancement reaction of an epoxy resin with a polyhydric phenol (specifically bisphenol A) in the presence of a tetrahydrocarbyl phosphonium bisphenoxide salt.
This invention also relates to precatalyzed epoxy resins and precatalyzed polyhydric phenolic compositions comprising, respectively, an epoxy resin having an average of more than one vicinal epoxide group per molecule or a polyhydric phenol, each composition containing a tetrahydrocarbyl phosphonium phenoxide salt catalyst for promoting the reaction between an epoxide and a phenolic hydroxyl group.
2. Prior Art
It is well-known in the art to produce hydroxyl-containing ethers by reacting a vicinal epoxide with a compound bearing phenolic hydroxyls in the presence of such catalysts as tertiary amines, quaternary ammonium halides, phosphonium halides and the like. See, for example: U.S. Pat. Nos. 2,216,099; 2,633,458; 2,658,855; 3,377,406; 3,477,990; 3,547,881; 3,547,885; 3,694,407; 3,738,862; 3,948,855; and 4,048,141. Canadian Pat. No. 893,191, German Pat. DT Nos. 2,206,218 and 2,335,199 and the text, Handbook of Epoxy Resins by H. Lee and K. Neville, McGraw-Hill (1967), Epoxy Resins-Chemistry and Technology, Edited by C. Maynard and Y. Tanaka, Marcel-Dekker, Inc. (1973) are also of interest. It is also taught in U.S. Pat. No. 4,048,141 that certain phosphonium catalysts promote the reaction between vicinal epoxides and phenols and/or carboxylic acids or anhydrides.
The prior art catalysts for promoting reactions of epoxides with phenols have generally been deficient in one or more aspects. In many instances, the catalysts react with the epoxy reactant and thus preclude the marketing of a blend comprising an epoxy resin and a catalyst, a so-called "precatalyzed epoxy resin". Blends comprising a polyhydric phenol and a catalyst (i.e., a precatalyzed polyhydric phenol) have likewise been avoided due to possible adverse reactions of the two components. Many prior art catalysts exhibit a lack of selectivity in that they simultaneously promote the reaction of an epoxy resin with both the phenolic hydroxyl group(s) on the reactant and the aliphatic hydroxyl group(s) on the product, which produces branched or cross-linked polymers rather than the desired linear polymers. In still other instances, the reaction rate is unsatisfactory and/or the product is highly colored or contaminated with corrosive anions (e.g., chloride). Moreover, vinyl ester resins made from the catalyzed reaction products of epoxy resins and polyhydric phenols in the presence of most prior art catalysts require undesirably long cure times because of the presence of relatively high concentrations of phenolic hydroxyl groups.
The prior art catalysts, to a greater or lesser degree, produce at best linear or substantially linear polymers of relatively limited molecular weights. For example, the advancement reaction of 4,4'-isopropylidenediphenol (i.e., bisphenol A) with a diglycidyl ether of bisphenol A in the presence of a triphenyl ethyl phosphonium acetate salt-acetic acid complex even when followed by further reaction with tetrabromobisphenol A produces a linear polymer with a maximum weight average molecular weight of about 60,000 as determined by gel permeation chromatography. These deficiencies have now been remedied by the subject invention. | {
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Technical Field
The present invention generally relates to an apparatus, system, and method of controlling display, and a display control program stored in a non-transitory recording medium.
Description of the Related Art
Recently, communication tools are employed, which display a large-size image to attract the user's attention. While display of the large-size image has been attractive, the user has been still using a remote controller to send an instruction to change display content of the large-size image. | {
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Pill containers, also known as pill boxes, are cases for housing medications such as pills, tablets, or capsules. Such cases can be used to store and dispense pills such as in a pharmacy or may be made compact to function as personal pill containers used by consumers not only to store and dispense pills but also to carry pills such as in a purse, pocket, or the like.
Personal pill containers allow users to pack limited individualized dosages of one or more medications, and thus enable convenient short-term carry. Since the number or amount of dosages held in such personal pill containers is normally limited, the user must periodically refill the container typically from standard pill containers supplied by the pharmacist. Such small, pocket-sized pill containers, which have been used for years, allow the user to pre-fill the container with medication to be dispensed for that day, and to conveniently carry it with them. These personal pill containers have been found to enhance the ease and regularity of administration by reminding the user of the proper time for dispensing of pills in a more consistent manner. In addition, their small size and compact profile make them especially convenient for individuals needing to take medications at scheduled intervals.
Personal pill containers are typically fabricated to include multiple compartments, which are generally individually accessible by the user through a corresponding closure. Each compartment is adapted to receive and retain a single grouping or dose of one or more medications to be taken at a particular time, which may be individually identified by indicia printed on the closure. In this manner, the personal pill containers can be implemented to enable users to take their medication at the appointed times. While traditional personal pill containers facilitate the prompting of use and transportation of medications, such containers have been found to be inadequate when the user is required to take more than one kind of medication at different time intervals during the day. In such an instance, the user often may not be able to distinguish the different medications, and thus, may erroneously take the medications at improper times.
Accordingly, there is a need for pill containers, which are capable of accommodating one or more dosable ingestible products typically in the form of pill medications which may be administered at same or different time intervals and/or groupings during the day, while maintaining ease of use and storage and carry convenience.
The pill containers may be made compact so that they can function as personal pill containers and therefore be convenient to carry by the user. | {
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1. Technical Field
This disclosure relates generally to the field of electrical circuit breakers and more particularly to a mechanical interlock feature that engages upon circuit breaker tripping.
2. Description of the Related Art
In general, circuit breakers are employed to selectively engage a branch circuit to an electrical power supply. This function occurs by engaging and disengaging a pair of operating contacts for each phase of the circuit breaker. The circuit breaker provides protection against persistent overcurrent conditions and against the very high currents produced by short circuits. Typically, one of each pair of the operating contacts are supported by a pivoting contact arm while the other operating contact is substantially stationary. The contact arm is pivoted by an operating mechanism such that the movable contact supported by the contact arm can be engaged and disengaged from the stationary contact.
There are several ways by which the operating mechanism for the circuit breaker can disengage the operating contacts: the circuit breaker operating handle can be used to activate the operating mechanism; or a tripping mechanism, responsive to unacceptable levels of current carried by the circuit breaker, can be used to activate the operating mechanism; or auxiliary devices can be used to trip the circuit breaker thereby move the movable contact. For many circuit breakers, the operating handle is coupled to the operating mechanism such that when the tripping mechanism activates the operating mechanism to separate the contacts, the operating handle moves to a fault or tripped position.
When an overload condition occurs, the trip bar is rotated away allowing the trip bar latch to disengage the auxiliary latch. With the auxiliary latch free, the cradle is able to pivot thereby disengaging the breaker contacts. This sequence of event is referred to as the breaker tripping. In order for the breaker to be safely reset, the auxiliary latch must be held open until the cradle is first reset. According to the prior art, a variety of heavy springs and dampers are used to keep the auxiliary latch from resetting prematurely. In addition a push to trip button could be used to trip the mechanism again.
The disadvantage of the prior art systems are that there is no guarantee that the auxiliary latch will not reset after the breaker is tripped. In addition, using some type of damper will add extra cost to the mechanism. Using a heavier torsion spring could make the auxiliary latch rebound thereby allowing itself to reset with the trip bar latch. The cradle could not be reset in this case as it would strike the top of the auxiliary latch.
Accordingly, there is a need for a secure feature that will prevent the auxiliary latch from resetting prematurely. | {
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1. Field of the Invention
The present invention relates to a variable stroke engine including: a connecting rod connected at one end to a piston through a piston pin; a subsidiary arm turnably connected at one end to the other end of the connecting rod and connected to a crankshaft through a crankpin; and a control rod connected at one end to the subsidiary arm at a position displaced from a connection position of the connecting rod; a support position of the other end of the control rod being cable of being displaced in a plane perpendicular to an axis of the crankshaft.
2. Description of the Related Art
Such an engine is conventionally known, for example, from Japanese Patent Application Laid-open No. 9-228858, U.S. Pat. No. 4,517,931 and the like, wherein the stroke of a piston in an expansion stroke is made larger than that in a compression stroke, whereby a larger expansion work is carried out in the same amount of an intake air-fuel mixture to enhance the cycle thermal efficiency.
In the above-described conventionally known engine, the stroke of the piston in the expansion stroke is made larger than that in the compression stroke irrespective of the engine load, thereby enhancing the cycle thermal efficiency. However, when the engine load is low, it is desirable that the operation of the engine is carried out while putting a high value on a reduction in fuel consumption.
The present invention has been accomplished with such circumstance in view, and it is an object of the present invention to provide a variable stroke engine, wherein a reduction in fuel consumption can be achieved irrespective of the level of the engine load, while putting a high value on a reduction in fuel consumption in a state in which the engine load is low.
To achieve the above object, the present invention provides a variable stroke engine including: a connecting rod connected at one end to a piston through a piston pin; a subsidiary arm turnably connected at one end to the other end of the connecting rod and connected to a crankshaft through a crankpin; and a control rod connected at one end to the subsidiary arm at a position displaced from a connection position of the connecting rod; a support position of the other end of the control rod being cable of being displaced in a plane perpendicular to an axis of the crankshaft, wherein the engine further includes a switchover means capable of switching over: a state in which a high expansion ratio is provided such that the stroke of the piston in an expansion stroke is larger than that in a compression stroke when an engine load is high; and a state in which a constant compression ratio is provided when the engine load is low.
With such arrangement of the invention, when the engine load is high, the high expansion ratio is provided, and when the engine load is low, the constant compression ratio is provided. Thus, it is possible to provide a reduction in fuel consumption irrespective of the engine load, while enabling the fuel consumption to be further reduced in the state in which the engine load is low. | {
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1. Field of the Invention
This invention relates generally to the field of orthopedic devices. More specifically, it relates to an orthopedic device allowing support for assisting in the stabilization and proper healing of ulcerative or pre-ulcerative conditions, post-operative off-loading of forefoot, wounds on the foot, or other conditions of the foot, especially for diabetic patients.
2. Brief Description of the Related Art
The human foot contains more than 26 bones, 33 joints, and more than a hundred muscle, tendons and ligaments. A foot is generally split up into three separate areas; hindfoot, midfoot, and forefoot. The hindfoot contains the talus (or ankle bone) and the calcaneus (or heal bone). Midfoot consists of five bones; the cuboid, navicular, and three cuneiform bones. Together the bones of the midfoot form the arches of the foot. Finally, the forefoot is composed of five toes and the corresponding five proximal long bones forming the metatarsus. Four of the toes are comprised of three phalange bones and the fifth toe (the big toe) has two phalange bones.
Wounds to the foot can be somewhat common injuries. Wounds can either be internal or external and can be caused by varying factors. For example, external wounds can be produced from external trauma, lacerations or burns. Some of these wounds can be deliberate, such as an incision for surgery. Other wounds can be unintentional, such as cuts. Finally, there are wounds caused by friction/pressure, such as foot ulcers. In fact, excessive pressure is a leading cause of ulcers in diabetic patients.
Every type of wound has the potential to cause additional complications to the affected foot. One major complication that physicians commonly have to address is infection. There are many different types of foot infections that vary in levels of complexity. To prevent injuries from getting worse, it is essential that physicians and patients have access to areas where a wound exists in order to properly care and treat the foot. It is also imperative that the area where the foot is wounded does not receive additional force that may aggravate existing issues or cause new problems.
Patients with diabetes are faced with especially difficult challenges when it comes to foot wounds. One such problem is called neuropathy or polyneuropathy, which is damage to the nerves caused by high blood sugar levels. Individuals with neuropathy or polyneuropathy suffer from a loss of feeling in the plantar surface, or bottom of the foot, which may extend from the toes up the foot to the heel and eventually up the leg. Because of this loss of protective sensation, a sense of when something is harmful to the foot, diabetic patients are especially susceptible for developing pressure ulcers.
Diabetes may also lead to many different vascular diseases, such as peripheral arterial disease (PAD). PAD occurs when narrowed arteries reduce blood flow to limbs. This reduced blood flow results in extremities, usually feet and legs, receiving insufficient blood flow to function properly. Symptoms include painful cramping after activities, such as climbing stairs, leg numbness or weakness, and sores on toes and feet that don't heal.
Diabetes patients experience varying degrees of vascular diseases and neuropathy. 60-70% of diabetics have mild to severe forms of nerve damage. In extreme cases, patients have little to no feeling in their feet. Lack of sensitivity combined with increased pressure and poor circulation often cause wounds to form and or increase in severity. For example, when a wound develops, patients may be unaware of the wound, resulting in the patient continuing to apply external factors that further aggravate the wounds. Further aggravation of the wound can potentially lead to additional tissue damage, ulcers, even infection, and often amputation. The most common complication leading to hospitalization in diabetic patients is foot ulcers.
Diabetes affects approximately 8.3% of people in the United States (about 26 million people), including approximately 7 million undiagnosed people. In 2010, 1.9 million new cases of diabetes were diagnosed in individuals twenty years of age and older. It is estimated that diabetes affects 250 million people worldwide. 1 in 4 patients with diabetes develop foot ulcers with over 50% requiring hospitalization.
Once infection sets in, amputation may be the only option for the patient's survival. Over 80% of lower limb, non-traumatic amputations occur in patients with diabetes. Approximately 1 in 5 foot ulcers will require amputation. Every year more than 82,000 amputations are performed on diabetics in the United States. Worldwide someone loses a limb to diabetes every 20 seconds. For diabetic patients the 5 year mortality rate after a limb amputation is 68%, second only to lung cancer. According to the Centers for Disease Control and Prevention, diabetes contributed to a total of 231,404 deaths in 2007.
Diabetes has national economic detriments, in addition to the physical complications. The Centers for Disease Control and Prevention estimated the total direct medical costs to be $116 billion in 2007. Indirect costs were estimated to be $58 billion in 2007. These staggering numbers necessitate the creation of ways to reduce, heal and prevent foot wounds, both in diabetic patients and in the general population.
Currently, there are several different types of shoes (for example, U.S. application number 20040031169, published 2004 and U.S. Pat. No. 5,566,479, granted 1996), boots (for example, U.S. Pat. No. 5,078,128, granted 1992, 5,329,705, granted July 1994, U.S. Pat. No. 5,378,223, granted January 1995, U.S. Pat. No. 5,464,385, granted November 1995, and 5,761,834, granted June 1998), and orthotic inserts (for example, U.S. App. No. 20040103561, published June 2004 and U.S. App. No. 20040194352) that attempt to reduce foot wound injuries, heal existing wounds and prevent future injury. While each specific embodiment has its own advantages and disadvantages, they all share common disadvantages. One such disadvantage is that there are still times when pressure and/or friction are applied to the wound site. Each embodiment also requires a patient to physically remove the device in order to gain access to the wound site. Finally, each embodiment generally lacks adaptability to change as the wound site changes. There are also significant stability issues with prior art designs.
Another widely established method, called the total contact cast (TCC), has widely been used for off-loading planter ulcers. Developed in the 1950s, the application and removal takes a number of time consuming steps. A patient must endure two applications, inner and outer, of plaster. Once the plaster is applied the patient has to wait for up to a 24-hour period before they can apply any weight to the TCC. Removal of the cast is also a time consuming process that must occur at least once a week. While the TCC is applied, the patient and the physician do not have access to the wound site. Additionally, the TCC cannot adapt to the changing circumstances of the wound without going through the tedious removal and application of the cast. Finally, the cast has the potential to cause additional ulcers or wounds in new locations because of its inability to adjust the pressure applied to the foot and leg.
Shoes, such as the DARCO® Ortho-Wedge, promote healing by shifting the weight from the forefoot to the midfoot and heel. Generally used with VELCRO®, these shoes allow for easy removal and application but still lack the ability for easy access while the shoe is on. Another disadvantage associated with these shoes is that they can't adapt as the wound adapts. In addition, the shoes can be highly unstable for patients with reduced sensitivity in their feet, such as diabetic patients. This lack of stability can cause a patient to fall, trip or otherwise put themselves at greater risk to receive additional injuries or wounds.
The prior art lacks a device that offloads the pressure from a patient's forefoot, but maintains stability while in use. Prior art also lacks adaptability as the wound changes. Finally, there is a need for a shoe that allows access to the affected area while in use.
However, in view of the art considered as a whole at the time the present invention was made, it was not obvious to those of ordinary skill in the field of this invention how the shortcomings of the prior art could be overcome. | {
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} |
With the widespread use of graphical interfaces in computer based applications, more flexibility is available in determining how information is entered by a user and displayed. "Computer forms" are the typical user interface that is used for entering and displaying information. Similar to paper forms, computer forms provide a two dimensional view of information Computer forms, however, also provide the capability for three dimensional viewing of information. Computer forms may consist of several text, graphics, control items, and other objects which simplify and organize the display of information and facilitate data entry. Examples of computer forms include e-mail messages, purchase orders, invoices, database entry forms, and financial tracking forms.
Designers of user interfaces are challenged by the requirement of creating generic, easily understandable, user interfaces that appeal to potential users. The success of a product in the market may relate to the "friendliness" of the user interface. Therefore, user interface designers try to meet the use requirements of the widest range of potential users. In an attempt to appeal to the widest range of potential users, some designers have integrated "user customizable" computer forms into their products. With this capability, users can tailor the appearance of a computer form to meet their individual requirements.
With a promising array of potential uses, user customizable forms are a valuable asset to a product The process of creating a form, however, can be difficult. Users must carefully align objects inserted onto the computer form, insert and align meaningful labels near the objects to indicate their purpose, and insure that the objects are large enough to display the required information. The construction of a typical computer form can consume a significant amount of the user's time. Therefore, it is desirable to provide a system that reduces the complexity and expedites the process of creating computer forms.
Many of the operations involved in creating computer forms are predictable. One such predictable operation is identifying the location to place an object on the computer form. Computer forms are generally created in a top down approach which means that objects appearing at the top of the form are entered first. In many applications, when an object is entered onto a form or into a window, the object is either placed at a generic location (such as the center of the form) or at a location selected by a pointing device such as a mouse pointer. Using this approach, an object must be inserted onto a form, moved to a desired location and then aligned with other objects. By automatically performing these operations, the process of creating a computer form can be simplified. Therefore, there is a need to provide a system that automates the process of identifying a location to place an object on a computer form.
Another predictable operation is determining the size of an object that has been placed on a computer form. Generally, the size of an object within a computer form may depend on the type or use of the object. For instance, a mail message computer form may contain one object which holds the name of the recipient, another for the subject of the mail message, and yet another for the text of the mail message. The name of the recipient and the subject of the message could conform to one object type while the text may conform to another object type. In previous solutions, the designer of the computer form would be required to place each of these objects and then adjust their size accordingly. This process again adds time and complexity to creating a computer form. Therefore, there also is a need to provide a system that automates the process of determining and adjusting the size of an object placed onto a computer form.
Another predictable operation is aligning objects that are placed onto a computer form. For aesthetic appearances, it is desirable for an array, consisting of a column or row of objects, to have their borders aligned with each other and to be uniformly spaced apart. As the number of objects in a computer form increases, this task can become tedious and time consuming. Because a typical user may desire to arrange objects in an aesthetically pleasing manner, the task of aligning and spacing the objects should be automated. Therefore, there also is a need to provide a system that automates the process of aligning and spacing objects that are placed onto a computer form.
Another predictable operation is attaching labels to objects that have been placed onto a computer form. Typically, a user is required to insert an object onto a computer form, insert a label to identify the object, align the object and the label, and then link the object and the label together. For complex computer forms, these operations can require a significant amount of time. Therefore, there is also a need to provide a system which automatically inserts, aligns, and links a label with an object when an object is inserted onto a computer form.
In some circumstances, a common computer form may be used by many different users. Depending on the specific uses, some users may want to modify certain aspects of the common computer form. Rather than having to create a new form, it is desirable to be able to modify a pre-existing form. For instance, a common e-mail computer form may include objects such as the recipients name, the senders name, the date the e-mail is sent, and a message box. If particular users desire to add a priority indicator at the top of the e-mail computer form, they must move each of the objects in order to create space for this additional object. The users then must insure that the moved objects and any labels associated with them are aligned and uniformly spaced. Similar operations must be performed if a user desires to rearrange the order of the objects on a computer form. Therefore, there is also a need to provide a system which automatically moves, aligns, and spaces previously-placed objects in a computer form when a new object inserted. Likewise, there is also a need for a system which automatically adjusts previously-placed objects on a computer form when one of the objects are moved.
Although uncommon, a user may desire to place objects on a computer form without having them aligned. Furthermore, a user may desire to create a computer form in a manner other than a top down approach. If the system for creating the forms automatically places and aligns the objects as they are entered onto the form or moved, this may frustrate the designer. Therefore, there is a desire to provide a system which automates the process of creating computer forms, yet allows a user to override the automatic alignment and positioning features of the system.
In view of the foregoing, there is a need for a system to provide automatic capabilities in creating user customizable computer forms. There is also a need to automate predictable operations involved in creating a custom computer form in order to reduce the time required and complexity involved in creating custom computer forms. | {
"pile_set_name": "USPTO Backgrounds"
} |
1. Field
One or more embodiments of the present invention relate to a thin film transistor (TFT) and a method of manufacturing the TFT.
2. Description of the Related Art
Recently, as the degree of integration in semiconductor devices has increased, the size of transistors has been reduced, improving an operating speed and reducing the size of the semiconductor devices. Such a reduction in the size of transistors may facilitate a reduction in a channel length of the transistors and an increase in switching speed of the transistors. However, the reduction in the channel length may generate a short-channel effect. The short-channel effect may include variation in a threshold voltage, excessive drain current leakage, a punch through, and drain induced barrier lowering (DIBL). | {
"pile_set_name": "USPTO Backgrounds"
} |
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