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Three-dimensional (3D) printing refers to processes that create 3D objects based upon digital 3D object models and a materials dispenser. In 3D printing, a dispenser moves in at least 2-dimensions and dispenses material according to a determined print pattern. To build a 3D object, a platform that holds the object being printed is adjusted such that the dispenser is able to apply many layers of material, and printing many layers of material, one layer at a time, may print a 3D object.
A conventionally known 3D printing process is the UV ink-jet process. It is a three-stage process of applying a material, printing a UV-curable liquid, and finally hardened using a UV source. These steps are repeated layer-by-layer. In conventional 3D printing, disclosed in U.S. Pat. Nos. 6,375,874 and 6,416,850, generally an inkjet type print head delivers a liquid or a colloidal binder material to layers of a powdered build material. The printing technique involves applying a layer of a powdered build material to a surface typically using a roller. After the build material is applied to the surface, the print head delivers the liquid binder to predetermined areas of the layer of material. The binder infiltrates the material and reacts with the powder, causing the layer to solidify in the printed areas by, for example, activating an adhesive in the powder. The binder also penetrates into the underlying layers, producing interlayer bonding. After the first cross-sectional portion is formed, the previous steps are repeated, building successive cross-sectional portions until the final object is formed.
The oldest and the best-known laser-based 3D printing process is stereolithography (SLA). In this process, a liquid composition of a radiation-curable polymer is hardened layer-by-layer by using a laser. A similar process is Selective Laser Sintering (SLS) in which a thermoplastic or a sinterable metal is sintered selectively layer-by-layer by a laser to form the 3D object.
U.S. Pat. No. 5,121,329 describes the fused deposition modeling (FDM) process for the production of three-dimensional objects using an extrusion-based, digital manufacturing system. There are also other known processes that are substantially analogous with slight differences, for example fused filament fabrication (FFF), melt extrusion manufacturing (MEM) or selective deposition modeling (SDM).
In the FDM method, two different polymer filaments are melted in a nozzle and are printed selectively. One of the materials involves a support material, which is needed only at locations above which an overhanging part of the 3D object is printed and requires support during the subsequent printing procedure. The support material can be removed subsequently, e.g. via dissolution in acids, bases or water. The other material (the build material) forms the actual 3D object. Here again, the print is generally achieved layer-by-layer.
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Guanine nucleotide-binding proteins (G proteins) are believed to alternate between an inactive guanosine diphosphate (GDP) state and an active guanosine triphosphate (GTP) bound state. These two states have been linked to the release of a secondary messenger within a cell. The released secondary messenger can function to regulate downstream cell processes.
Secondary messengers include signaling molecules that are rapidly generated/released. These molecules produce cellular responses by activating effector proteins within the cell. Example cellular signaling systems include the phosphoinositol system, the cyclic adenosine monophosphate (cAMP) system, and the arachidonic acid system.
Changes between the different states of the G proteins can be triggered as a result of proteins called G protein-coupled receptors (GPCRs), G protein-linked receptors (GPLR), seven transmembrane domain receptors (7TM receptors) or heptahelical receptors. This protein family includes a variety of transmembrane receptors. These receptors respond to external stimuli (e.g., light, neurotransmitters, odors or hormones) by activating signal transduction pathways internal to the cell. Specifically, ligands bind and activate the transduction pathways thereby causing the G proteins to alternate states. GPCR-related activity is associated with many diseases, and thus, GPCRs are the target of many pharmaceuticals and treatments.
It is believed that over 30% of all drugs on the market target G-protein coupled receptors (GPCRs) and that many of those drugs relate to the production or inhibition of the secondary messenger cAMP. There is an abundance of pathological processes that directly involve cAMP, including neurophysiological, endocrinological, cardiac, metabolic, and immune diseases. In the study of complex mammalian behaviors, technological limitations have prevented spatiotemporally precise control over intracellular signaling processes. Current chemical-based methods for modulating secondary messenger levels, such as cAMP levels, operate relatively slowly and present problems to study activity on the fast timescales that the body uses in connection with certain tissue, such as in nervous or cardiac tissue. These chemical-methods often lack the speed to probe these fast timescales (e.g., while screening for novel therapeutics).
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The present invention relates to the analysis of life science data. More particularly, the present invention relates to computer based interpretation of biological sequences. Even more particularly, the present invention relates to a client/server or Internet based computer tool and method for identification of potential protein, DNA or RNA sites of interest based upon the underlying amino acid or DNA or RNA nucleic acid sequence characteristics.
Currently, life scientists and molecular biologists are working with a wide variety of manual and automated tools to determine particular characteristics regarding molecular biology data. While automated protein sequencing tools presently generate large volumes of protein amino acid sequence data, tools for easily handling and interpreting the new data have yet to become commonplace. Scientists have been attempting to manage their molecular biology data in a wide variety of ways, from expensive, dedicated and proprietary computer systems to manually reviewing data placed into common word processors or text editors not optimized for handling large amounts of life science information.
The challenge of the first approach lies primarily in its limited accessibility by the average life scientist. Dedicated proprietary computer systems for sequencing and interpretation of molecular biology information often cost far beyond what the budgets of small research operations will permit. Other drawbacks exist in addition to acquisition price, such as closed and user unfriendly proprietary system architecture which does not facilitate cross-platform sharing of molecular biology sequence information. Often researchers using state of the art proprietary systems purchased at great expense will encounter difficulty sharing molecular biology data with other researchers on different computer systems in the same lab, let alone with colleagues in another institution or country.
The difficulty encountered at the other end of the spectrum is just as common, if not more so. Researchers not able to gain access to high cost dedicated molecular biology computer systems may resort to utilizing the most rudimentary of toolsets to interpret their genetic sequence or corresponding protein data. Manually screening through volumes of protein sequence data using basic text editors and word processors is not unheard of, despite the fact that these tools are not optimized for or never designed to handle genetic data in any form. In addition, despite the high degree of sophistication the average life scientist may have with respect to his or her particular field, often a commensurate computer ability is not present in the average life science user. User interfaces currently designed for state of the art molecular biology computer systems can be so user unfriendly that a life scientist may actually prefer to work with a simple and easy to use text editor instead of an inflexible proprietary system. As for the problem of collaborative work on related sequence data, neither approach facilitates remote access to lab generated or public domain sequence library information.
In the end, a technologically robust and user friendly system for remotely interpreting and managing life science data is truly needed. Such a system would aid not only the research process itself, but would speed the end product of the research as well. An improved and broadly accessible tool for interpreting life science data would not simply aid research in and of itself, but bring about discoveries in an accelerated manner. Data brought closer to understanding by the life scientist consequently means accelerated medical breakthroughs, improved drug therapies, and better understood systematic models of disease and regulatory processes.
By combining a powerful biological sequence site scoring tool with remote computer access functionality, a web-based tool for the identification of molecular biology sequence sites is hereby disclosed. An example of the present system and method functionality is provided using the identification of Caspase cleavage sites as a working example. Scoring as applied to potential protein modifications sites is based on amino acid sequence characterization, and is easily modifiable to be utilized by nucleic acid sequences.
Disclosed is an objective, quantitative method and apparatus for searching and evaluating biological sequence data relative to a selected functional characteristic, such as enzyme cleavage site, binding site, secondary structure, or potential modification site. Software is used to scan known target sequences of amino acids, DNA or RNA base pairs, searching for sequence regions exhibiting composition characteristics derived from scoring matrices provided by user input. Characteristics may include number of residues, presence of specific residues, or specific sequences of residues. Sequence regions exhibiting characteristics similar to the predetermined characteristics are identified, flagged and quantitatively scored for closeness of fit to the group of all predetermined characteristics, including quantitative scoring for mandatory characteristics and exclusionary characteristics. Scoring takes place based upon one or more scoring matrices which detail the individual predetermined characteristics and their respective quantitative scores. The scoring matrices can be used to predict the relative functional effect of individual biological sequences within a potential sequence site and help interpret combinations of sequences relative to the specific functional characteristic of interest. The invention further provides the user with the ability to select threshold cutoff values to be used by the software for evaluation of scoring matrix results, thereby assisting the user in the site location identification process, and providing the user the ability to evaluate the effect of substitutions of characteristics.
To practice the claimed invention on a particular protein amino acid sequence cleavage site, one or more scoring matrices are developed. These scoring matrices are derived by comparing the cleavage sites from known protein targets and determining the frequency of amino acid content at each position. A score for each possible amino acid is then set for each position based on this frequency. For example, a particular cleavage site in a protein may contain 5 amino acids. If it were found that Aspartic acid occurred 50% of the time at the first position and Leucine 50% of the time at this position, then each of these amino acids would have a score of 0.5 and the remaining amino acids would have a score of 0 at this position. To ensure the return of particular results, such as when particular amino acids must be present (weighted score greater than or equal to 1) or must not be present (negative weighted score), scores outside of the anticipated frequency range can also be inserted. Thus, for each of the five positions in a protein cleavage site a score for each of the 20 amino acids is created, this information is stored in the scoring matrix. Each possible cleavage site in a target protein is assigned a cumulative score based on this matrix. All possible cleavage sites can be listed, sorted by this score. A threshold can be set such that only scores above a certain level of identity are returned when queried. This search can be performed on a single protein or on large public protein databases, residing anywhere from the initial client computer, the central server computer, or remotely on public databases accessible via the Internet. The data searched can be resident on the server undertaking the analysis, or remotely retrieved from public or private sequence databases. In addition, the results returned can be sent to a single remote client computer, or to a plurality of remote systems. Due to the pervasive nature of the Internet, it is an intended consequence of the claimed invention that multi-user collaboration is made possible under the client/server computer model, with data sets and stored queries are easily shared among users.
In the working example of Caspases, the Caspases are a family of proteases that are known to play a key role in the regulation of programmed cell death (apoptosis). These proteins have a high degree of substrate specificity and Caspase cleavage of specific key regulatory proteins is thought to play an integral role in cell death. This specificity is achieved by recognition of specific amino acid patterns in target proteins, for example, the amino acid sequence DEADG (aspartic acid, glutamic acid, alanine, aspartic acid and glycine) in Retinoblastoma protein (pRb) is recognized and cleaved by Caspase 3 during apoptosis. The aspartic acid in the 4th position is absolutely required for all Caspase cleavage, while the other 4 amino acids determine whether the sequence is cleaved by Caspases and if so by which Caspase. Thus, while aspartic acid residues are required for a Caspase cleavage site, the surrounding amino acids will determine whether Caspases can cleave the protein at that particular aspartic acid. Additionally, those surrounding amino acids can determine which Caspase acts on that site. Recently, it has become clear that Caspases can also regulate other cellular processes such as proliferation and differentiation. Thus, Caspases are critical regulators of cell fate and may play roles in the pathogenesis of diseases such as cancer, autoimmune disease, AIDS and Alzheimer""s Disease. The identification of Caspase substrates may therefore provide insight into the regulatory pathways involved in these diseases, and advances in characterizing potential Caspase cleavage sites would clearly advance medical discoveries in these areas.
The claimed invention as applied to this working example scans a protein""s amino acid sequence for potential cleavage sites and scores them using user-defined scoring matrices based on the consensus sites for several different proteases. In the working example of Caspases, the evaluated Caspase variants are Caspase 3, Caspase 6 and Caspase 8 respectively. These scoring matrices are derived by comparing the cleavage sites from known Caspase targets and determining the frequency of amino acid content at each position. A score for each possible amino acid is then set for each position based on this frequency. A score can also reflect particular user defined characteristics as well. For example, Caspase cleavage sites contain 5 amino acids. If it were found that Aspartic acid occurred 50% of the time at the first position and Leucine 50% of the time at this position, then each of these amino acids would have a score of 0.5 and the remaining amino acids would have a score of 0 at this position. For event determinative characteristics, a required amino acid at a particular position can be assigned a frequency score greater than one to guarantee inclusion of this indicator in the returned results. Also, amino acids requiring exclusion at a particular position can be assigned a score less than zero to ensure that potential sites including this amino acid at this position are not returned. Thus, for each of the five positions in a Caspase site a score for each of the 20 amino acids is created, this information is stored in the scoring matrix. Each possible cleavage site in a target protein is assigned a cumulative score based on this matrix. For Caspase cleavage, every aspartic acid is considered to be a potential cleavage site and is in fact required at the fourth sequence location, and is consequently assigned a value of xe2x80x982xe2x80x99 at the fourth position to guarantee inclusion in results returned. All possible cleavage sites can be listed, sorted by this score. A threshold can be set such that only scores above a certain level of identity are returned. This search can be performed on a single protein or on large public protein databases, located either on the client computer, central server computer, or remote public database accessible through the Internet. In the following tables, the exemplary scoring values for amino acids in Caspase cleavage sites are presented as Caspase 3, Caspase 6 and Caspase 8 tables, followed by the union table Caspaseall.
Table of Caspase 3 cleavage site scoring, length of site is 5, 4 is position of required amino acid D (Aspartic Acid)
Table of Caspase 6 cleavage site scoring, length of site is 5, 4 is position of required amino acid D (Aspartic Acid)
Table of Caspase 8 cleavage site scoring, length of site is 5, 4 is position of required amino acid D (Aspartic Acid)
Table of Caspaseall cleavage site scoring, length of site is 5, 4 is position of required amino acid D (Aspartic Acid)
Summary of cleavage table and explanation. Once the scoring matrices have been developed (examples provided as Tables 1-4 above), sequence analysis can take place. In reviewing a particular protein sequence through the working model of potential Caspase cleavage sites, the presence of Aspartic acid at the fourth position is required. Consequently, in each of the detailed scoring tables, a value higher than one (2 in this working example) is assigned to Aspartic acid at the fourth position to account for its mandatory inclusion in any returned sequence. In addition, mandatory sequence information can be placed in a header to a given matrix which describes the length of the site followed by the location of the required amino acid. This would be xe2x80x985 4xe2x80x99 according to the Caspase working example, since the cleavage site is five amino acids long, with the required amino acid at the fourth position. A consequence of Caspase cleavage sites requiring an Aspartic acid at the fourth position is that sequence scoring may be optimized based upon this characteristic. While this optimization characteristic is clearly available when searching for Caspase cleavage sites, the presence of an absolutely required sequence can be used to similarly optimize sequence searches according to the following method. Since the Aspartic acid is required for a cleavage site, there is little benefit to scoring sequence data until an Aspartic acid is found. Since it is clearly easier for a computer to scan for a particular amino acid instead of reading sets of five amino acids and performing scoring calculations based upon a selected matrix, the present embodiment of the claimed invention reads through the sequences until an Aspartic acid is found. Scoring only then takes place based upon the sequences surrounding the Aspartic acid. Since Aspartic acid is required for the fourth sequence position in the cleavage site, scoring then takes place on the three amino acids prior to the Aspartic acid, as well as on the amino acid after the Aspartic acid. Throughput is thus optimized above and beyond that which would have been obtained if each and every amino acid in a protein had been scored.
In parallel with or subsequent to development of the scoring matrices, the threshold for returning results must be decided upon. This cutoff threshold will determine the specificity of potential characterization sites which will be returned. In the Caspase model, a threshold value of 4 was selected. This means that sequences scored with a particular matrix must have a value of greater than four to be returned in a search as a putative Caspase cleavage site. Applying the Caspase 3 scoring table to the known Caspase cleavage site of DEVDG listed in FIG. 3, this site would return a score of 4.667, which is well above the threshold cutoff value, and is in fact the highest score possible according to this scoring table. The value of 4.667 was arrived at based upon adding 1 for Aspartic Acid (which is required for Caspase 3 cleavage, hence the score of 1) at the first position added with 0.397 for Glutamic Acid at the second position added with 0.270 for Valine at the third position added with 2 for Aspartic Acid at the fourth position (the required amino acid in this example) added with 1 for Glycine at the fifth position (which is one of three possible required amino acids at this position). If a particular amino acid sequence did not have Aspartic Acid at the fourth position, the score would drop by two, since all other amino acids have a score of zero at the fourth position and would fall below the threshold cutoff score of four and not be returned. Similarly, if a particular amino acid sequence was expressly not desired at a particular sequence position, assigning that amino acid a negative score such as negative one would similarly select against a result containing that amino acid at the specified position. In the working example described, substituting phenylalanine for valine at the third position would drop the score by 1.270, since the value contributed by having valine at the third position would not be added, and phenylalanine has a score of negative one for the third position. Consequently, the five sequence value would become 3.397 and would be excluded as a potential Caspase 3 cleavage site since it is less than the threshold cutoff value of 4.
For the web-based implementation of the described tool and method, a programming language such as the Perl programming language may be used, in conjunction with Apache (open source web server software) and MySQL (an open source relational database) running under the Linux operating system. Key components can be implemented using a module written in the C programming language. Obviously, this tool and method can easily be extended to search for any user-defined protein motif in a protein. For example, to search for potential phosphorylation sites, a scoring matrix reflecting a user-defined phosphorylation consensus sequence would be substituted for the Caspase cleavage specific scoring matrixes used in the example presented. Minor modifications to the user interface would allow the user to select from all matrices available (e.g. Pull down menu). Similarly, other public or private protein databases could be substituted or added to those shown. Though protein databases are used in this example, the method could be extended to nucleotide databases provided these nucleotide sequences were translated into the appropriate amino acid sequence using a standard codon table prior to application of this method.
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1. Field of the Invention
This invention relates to recording and storing signals and, in particular, to recording and storing signals from multiple sources.
2. Description of Related Art
Currently, there exists a large number of analog and digital signals available for home use. Analog signals include conventional television signals that are typically sent directly to a home television receiver via cable, satellite, or terrestrial transmissions using analog standards such as NTSC, PAL, and SECAM. Other analog signals include RF signals, audio signals, and data streams. More recently, signals (both video and audio) are also being transmitted digitally, which have been encoded according to the MPEG (Moving Pictures Experts Group) standard.
Home networking allows these signals from multiple sources to be connected to and output from a single source, such as a television (monitor and speakers), so that consumers can receive a variety of entertainment and information on their television sets. However, not all signals are standardized in a common format, i.e., they are transmitted with different formats, thereby requiring different types of receivers or devices to receive and process the various signals to an appropriate output format. These devices can include set-top boxes (STBs), video cassette recorders (VCRs), satellite dishes, and cable boxes for receiving signals from transmission methods such as direct satellite service (DSS), microwave broadcast, cellular television (xe2x80x9cwireless cablexe2x80x9d), and television delivered via digital telephone phone lines. Further, as home television systems become more advanced and the number of signal sources that such systems can receive increases, situations may arise where signals from two or more sources are desired during simultaneous or overlapping time periods.
In these cases, different recording and storage devices are required for each signal source. For example, an analog video cassette recorder (VCR) can be used for recording analog video/audio signals, a tape, CD, MD, or solid state memory can be used for storing analog/digital audio and data, and a memory card and hard disk drive (HDD) can be used for storing and retrieving digital video, audio, and data. Thus, separate and differently formatted recording devices are needed to store and record one or more of the different signals simultaneously for later retrieval. As the number of different signal sources continues to increase, the number of separate recording and storage devices will also increase, thereby increasing both the size and cost of the home networking system.
Therefore, it is desirable to provide a system for simultaneously recording and storing signals from multiple sources that overcomes the disadvantages discussed above associated with conventional systems.
In accordance with an aspect of the invention, a system and method are provided which allows simultaneous signals from various sources to be processed and stored for later retrieval and playback. Analog signals and digital signals of various formats are input to a source interface. The source interface routes selected signals, via a selector device such as a remote control, to appropriate devices for processing. Analog signals are routed to an analog tuner/demodulator to demodulate the RF signals down to IF signals. The IF signals are then transmitted to a decoder for converting the IF signals to a common analog format, such as NTSC, PAL, RGB, or YUV. The analog signals are then digitized using an analog-to-digital converter. The sampling rate or frequency can be selected by the user or automatically selected based on the quality of the analog signals and the quality of the output display device. Once the analog signals have been converted to digital signals, the digital signals are sent to an encoder for time-compression (e.g., MPEG encoding) to reduce the bit rates. After encoding, the digital signals are stored in a buffer.
Digital signals already in the desired format (e.g., MPEG) are routed to a demultiplexer to separate the digital stream into individual data streams, such as video and audio. These digital streams are also stored in the buffer. Digital signals in a format different than the desired format are first converted to the desired format by a converter before being transmitted to the buffer. Once all the signals from the various sources are in a common desired digital format (e.g., MPEG), the signal streams are sent to a packetizer for processing each signal stream into packets for identification and later retrieval. Once the signals have been packetized, they are sent to a formatter, which multiplexes the signals onto a single digital transport stream. The transport stream can then be stored in a digital storage device to be accessed at a later time. Thus, signals transmitted simultaneously or during overlapping time periods from different sources can be stored and retrieved by accessing specific packets within the stored transport stream. This eliminates the need for multiple decoders to receive and decode the incoming information.
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1. Field of the Invention
The outer ear serves to gather sound waves. In addition there is also a tube or canal called the meatus that carries the sound waves to the ear drum. The canal which is about an inch and one eighth long, must be kept clean of wax to insure that the sound reaches the drum.
2. Description of the Prior Art
Most people have common problems in cleaning their ears, specially cleaning the ears for others, for instance, children. The danger of inserting the cotton swab too deep into the ear canal, can be quiet serious, where people can hurt themselves and cause damage to their hearing. In any cotton swabs box there's a clear caution reminder: DO NOT ENTER EAR CANAL.
Another serious problem caused many times by cleaning with cotton swabs is hearing loss and infection as a result of the wax compressed towards the ear drum. This invention eliminates those problems.
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The present invention relates generally to wireless data communications. More particularly, the present invention relates to providing feedback describing the condition of an Orthogonal Frequency Division Modulation (OFDM) channel.
Conventional OFDM-based Multiple Input, Multiple Output (MIMO) wireless data communication systems employ a feedback mechanism that provides information describing the condition of the OFDM channel so that transmitters on the channel can maximize the bandwidth of the channel. Each packet transmitted over the channel includes a preamble, a signal field, and a payload. Receivers use the preamble to synchronize with the transmitter, perform channel estimation, and adjust gain settings. The signal field specifies the data rate of the data packet that follows, the number of antennas used, and additional information to assist the receiver in decoding the data packet.
Each receiver on the channel measures the channel while receiving the preamble of each packet. The signal field includes a channel condition request bit that, when set, requests a channel condition report from the receiver. When the receiver receives a packet with the channel condition request bit set, the receiver transmits a channel condition report based on the most recent channel condition measurement taken by the receiver.
The receiver does not know in advance when it will receive a channel condition request. And by the time the receiver processes the signal field in a packet to determine whether the channel condition request bit in the signal field is set, the preamble portion of the packet has already passed through the receiver, and so cannot be measured. Therefore this scheme requires that the measurement circuit that measures the channel condition be constantly active (that is, powered). Therefore the measurement circuit constantly consumes power, which constitutes a significant battery drain for a mobile receiver.
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1. Field of the Invention
The present invention relates to a portable vacuum cleaner capable of drawing in both dust and water.
2. Description of the Prior Art
U.S. Pat. No. 4,542,557 (corresponding to Unexamined Japanese Patent Publication SHO No. 60-188124) and U.S. Pat. No. 4,536,914, for example, disclose portable vacuum cleaners for cleaning by drawing in dust as mixed with water. These conventional cleaners comprise a cleaner main body having a fan motor incorporated therein, a dust case attached to the front side of the main body and integral with a suction nozzle, and means housed in the dust case for separating water and dust from the air drawn in. To prevent the water drawn in from reversely flowing out through the suction nozzle, the suction nozzle includes an extension in the form of a tube under the upper wall of the dust case and having a rear end opening close to the front side of the main body. However, these conventional cleaners have a disadvantage in that when the main body of the cleaner is stood upright, with the nozzle upward and the handle downward, water which is collected in the dust case flows into the main body of the cleaner via a through hole formed in the partition wall.
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The present disclosure relates to a display panel capable of performing multi view display which allows different two-dimensional images (planar images) to be visually recognized from respective perspectives, or performing three-dimensional display which allows a three-dimensional image (stereoscopic image) to be visually recognized from a particular perspective, and a display including the display panel. In addition, the present disclosure relates to an electronic device including the above-mentioned display.
In recent years, displays capable of performing multi view display or three-dimensional display have come into practical use. As one of such displays, for example, a display panel in which a barrier layer is provided on a display region is known. As one of such a barrier layer, for example, a barrier layer that is provided with a plurality of light-transmissive slits partitioned by light blocking regions is disclosed in Japanese Unexamined Patent Application Publication No. Hei 9-281440. In addition, for example, a barrier liquid crystal in which a light blocking region is generated when a voltage is applied to a liquid crystal is disclosed in Japanese Unexamined Patent Application Publication No. Hei 8-106070.
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Generally, to amplify DNA (Deoxyribose Nucleic Acid) using the PCR process, it is necessary to cycle a specially constituted liquid reaction mixture through several different temperature incubation periods. The reaction mixture is comprised of various components including the DNA to be amplified and at least two primers sufficiently complementary to the sample DNA to be able to create extension products of the DNA being amplified. A key to PCR is the concept of thermal cycling: alternating steps of melting DNA, annealing short primers to the resulting single strands, and extending those primers to make new copies of double-stranded DNA. In thermal cycling the PCR reaction mixture is repeatedly cycled from high temperatures of around 90° C. for melting the DNA, to lower temperatures of approximately 40° C. to 70° C. for primer annealing and extension. Generally, it is desirable to change the sample temperature to the next temperature in the cycle as rapidly as possible. The chemical reaction has an optimum temperature for each of its stages. Thus, less time spent at non optimum temperature means achieving better chemical results. Also a minimum time for holding the reaction mixture at each incubation temperature is required after each said incubation temperature is reached. These minimum incubation times establish the minimum time it takes to complete a cycle. As such, any transition time between sample incubation temperatures is time added to this minimum cycle time. Since the number of cycles is fairly large, this additional time unnecessarily heightens the total time needed to complete the amplification.
In some previous automated PCR instruments, sample tubes are inserted into sample wells on a thermal block assembly. To perform the PCR process, the temperature of the thermal block assembly is cycled according to prescribed temperatures and times specified by the user in a PCR protocol file. The cycling is controlled by a computing system and associated electronics. As the thermal block assembly changes temperature, the samples in the various tubes experience similar changes in temperature. However, in these previous instruments differences in sample temperature are generated by thermal non-uniformity (TNU) from place to place within the thermal block assembly. Temperature gradients exist within the material of the block, causing some samples to have different temperatures than others at particular times in the cycle. Because the chemical reaction of the mixture has an optimum temperature for each or its stages, achieving that actual temperature is critical for good analytical results. A large TNU can cause the yield of the PCR process to differ from sample vial to sample vial.
As such, the analysis of TNU is an important attribute for characterizing the performance of a thermal block assembly, which may be used in various bioanalysis instrumentation. The TNU is typically measured in a sample block portion of a thermal block assembly, and is typically expressed as either the difference or the average difference between the hottest well and the coolest position on the sample block portion engaging a sample or samples. The industry standard, set in comparison with gel data, a difference of about 1.0° C., or an average difference of 0.5° C. Historically, the focus on reducing TNU has been focused on the sample block. For example, it has been observed that the edges of the sample block are typically cooler than the center. One approach that has been taken to counteract such edge effects is to provide various perimeter and edge heaters around the sample block to offset the observed thermal gradient from the center to the edges.
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1. Field of the Invention
The present invention relates to an optical pickup head for optically recording, reproducing, or erasing information on or from an optical or magneto-optical medium such as an optical disk or an optical card.
2. Description of the Prior Art
An optical memory technology using an optical disk having pit-pattern has been expanding its utilization field as a high-density and large-capacity recording medium, so as to be used as a digital audio disk, a video disk, a floppy disk, and further a data file.
For such an optical memory technology, it is important to accurately carry out the recording on or reproducing from the optical disk through optical beam squeezed in a thin beam with high reliability. This mechanism largely depends on its optical system in reliability.
An optical head generally serves as an essential part of the optical system. Basic functions of the optical head are roughly categorized into a convergence for forming a diffraction-limited small spot, a focusing servo and tracking control in the optical system, and pit signal (information signal) detection.
These functions are embodied by various combinations of optical systems and photo-electrical conversion detecting systems on the basis of their purposes and uses. Especially, an optical pickup head apparatus using hologram has been recently introduced in order to reduce the size of optical pickup head apparatus itself and manufacture it thin.
As an example of prior art, FIGS. 24 and 25 show a constitution of an optical pickup head disclosed by J. C. LEHUREAU, J. Y. BEGUIN and J. COLINEAU; "Polarizing Grating Beamsplitter Using a Liquid Crystal Cell", Proc. Int. Symp. on Optical Memory, 1989 Japanese Journal of Applied Physics, Vol. 28 (1989) Supplement 28-3, pp. 201-203.
In FIG. 24, a reference numeral 2 denotes a radiation light source; for example, a semiconductor laser. A linearly polarized light beam 3 (a laser beam) emitted from this light source 2 passes through a liquid crystal hologram 172 and, in turn, is converted into a circular polarized beam by means of a quarter wavelength plate 15. Then, the circular polarized beam enters into an objective lens 4 and converges onto an information medium 5.
After reflection at the information medium 5, the rotational direction of the circular polarized beam is reversed. Then the light beam 3 travels the same light path in an opposite direction, and enters again into the quarter wavelength plate 15. In the quarter wavelength plate 15, the light beam 3 becomes a linearly polarized beam with a polarized direction rotated 90 degrees from its initial direction.
Subsequently, the light beam 3 enters into the liquid crystal hologram 172, and from which a +1-order diffraction light beam 66 inters into a photodetector unit 7. By calculating outputs of the photodetector unit 7, servo signals (i.e. focus error signals and tracking error signals) and information signals can be obtained.
As shown in FIG. 25, the liquid crystal hologram 172 consists of a pair of transparent substrates (glasses) 9 and 9, a polyimide 23 for forming a brazed hologram, a liquid crystal 17, and a pair of transparent electrodes 16 and 16.
An agent for orientating liquid crystal molecules and a sealing material are often used for the liquid crystal hologram 172 but are not related to the present invention. Therefore, they are not shown in the drawing. The liquid crystal 17 includes elliptic liquid crystal molecules 17a having a refractive index n.sub.s in its minor-axis direction and a refractive index n.sub.l in its major-axis direction. In this case, the refractive index n.sub.s is selected to be substantially the same as a refractive index n.sub.p of the polyimide 23 and the refractive index n.sub.l is largely different from the refractive index n.sub.p.
When a light beam 3 being linearly polarized in the minor axis direction (i.e. direction 1) of the liquid crystal 17 oriented in this liquid crystal hologram 172 is entered into the liquid crystal hologram 172, no diffraction is generated since the polyimide 23 and the liquid crystal 17 have substantially the same refractive index (n.sub.s .apprxeq.n.sub.p).
On the contrary, when a light beam 3 being linearly polarized in a different direction (i.e. direction 2) normal to the above-described polarized direction is entered into the liquid crystal hologram 172, a diffraction is generated due to a refractive index difference between the liquid crystal 17 and the polyimide 23 (n.sub.l .noteq.n.sub.p). Furthermore, since the polyimide 23 is brazed as shown in FIG. 25, +1-order diffraction light beam becomes strong.
By utilizing above-described property of such a liquid crystal hologram 172, if the light beam 3 is emitted in FIG. 24 so that a polarized direction of the light beam 3 becomes parallel with the direction 1, no diffraction occurs in a light beam path (forward light beam path) leading from the radiation light source 2 to the information medium 5 but the diffraction efficiency of the +1-order diffraction light beam becomes high in its opposite light beam path (backward light beam path) leading from the information medium 5 to the radiation light source 2.
Accordingly it is concluded that the efficiency of use of light beam in the forward and backward light beam paths is high. Hereupon, the efficiency of use of light beam in the forward and backward light beam paths is defined in general by multiplying the light quantity (0-order diffraction light quantity) passing through the hologram 172 in the forward light beam path and the +1-order diffraction light quantity emitted from the hologram in the backward light beam path.
According to this prior art, a focusing error (FE) signal is sensed by Foucault method or by astigmatic method. However, in the case where the Foucault method is adopted, a mechanical knife edge 22 shown in FIG. 24 must be additionally installed. On the other hand, in the case where the astigmatic method is adopted, a cylindrical lens must be additionally installed. In any case, there was a problem that the number of parts increased and therefore it resulted in cost up.
One method for solving above-described problem is to give a curvature on a hologram curve of the liquid crystal hologram 172. However, as is mentioned in the above-introduced reference paper, it is known that manufacturing a brazed hologram to have a curvature on its hologram pattern has been quite difficult.
Furthermore, this prior art mentions that the liquid crystal hologram can be generally used as a substitution for one polarized beamsplitter in an optical pickup head apparatus for a magneto-optical disk requiring more than two polarized beamsplitters. However, this is only effective in reducing a size of one component, and does not result in a sufficient overall reduction in size of optical pickup head apparatus.
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Machines, such as turbine engines, may develop noises during operation. These noises may spread into the environment of the machine through one or more ducts defining flow passages for the machine, which, for example, feed fresh air to a compressor or discharge exhaust gases from the turbine engine. In order to reduce the noise emission into the environment, it is a conventional practice to arrange a silencer in the ducts.
The silencer includes a number of baffles made of noise absorbing material that are positioned inside the duct. Conventionally, the baffles are individually connected to an inner surface of the duct. This results in an inflexible and expensive duct design. Further, the assembling/welding of each baffle into the duct is a difficult and expensive task. Furthermore, the baffles once assembled and/or mounted, are difficult to access for maintenance, thereby resulting in an extended downtime of the turbomachine. Moreover, upgrading the duct and/or the silencer to comply with new noise requirements may necessitate a new duct or a redesigned and rebuilt duct.
US Patent publication no. 2015/0076097 relates to a baffle plate assembly for installation in a rack structure. The baffle plate assembly directscooling air from a front side of the rack structure to a cooling air inlet and blocks heated air from below or behind the baffle plate assembly from entering the cooling air inlet. The baffle plate assembly includes a baffle plate defining a first surface plane, a pair of side plates, and a pair of mounting brackets. The side plates extend along the baffle plate while the mounting brackets are attached to the side plates. Further, the baffle plate first surface plane forms an oblique angle with respect to a plane defined by a first plate member of the mounting brackets.
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Ions are commonly implanted into a substrate in ion implantation processes to produce semiconductor devices. These ion implantations may be achieved in a number of different ways. For example, a beam-line ion implantation system may be used to perform the ion implantation process. In the beam-line ion implantation system, an ion source is used to generate ions, which are manipulated in a beam-like state, and then directed toward the wafer. As the ions strike the wafer, they dope a particular region of the wafer. The configuration of doped regions defines their functionality, and through the use of conductive interconnects, these wafers can be transformed into complex circuits.
In another example, a plasma containing ions may be generated near the substrate. A voltage is then applied to the substrate to attract ions toward the substrate. This technique is known as plasma doping (“PLAD”) or plasma immersion ion implantation (“PIII”) process. FIG. 1 shows an exemplary plasma doping system 100. The plasma doping system 100 includes a process chamber 102 defining an enclosed volume 103. Within the volume 103 of the process chamber 102, a platen 134 and a workpiece 138, which is supported by the platen 134, may be positioned.
A gas source 104 provides a dopant gas to the interior volume 103 of the process chamber 102 through the mass flow controller 106. A gas baffle 170 is positioned in the process chamber 102 to deflect the flow of gas from the gas source 104.
The process chamber 102 may also have a chamber top 118 having a dielectric section extending in a generally horizontal direction and another dielectric section extending in a generally vertical direction.
The plasma doping system may further include a plasma source 101 configured to generate a plasma 140 within the process chamber 102. The source 101 may include a RF power source 150 to supply RF power to either one or both of the planar antenna 126 and the helical antenna 146 to generate the plasma 140. The RF source 150 may be coupled to the antennas 126, 146 by an impedance matching network 152 that matches the output impedance of the RF source 150 to the impedance of the RF antennas 126, 146 in order to maximize the power transferred from the RF source 150 to the RF antennas 126, 146.
The plasma doping system 100 also may include a bias power supply 148 electrically coupled to the platen 134. The bias power supply 148 may provide a continuous or a pulsed platen signal having pulse ON and OFF time periods to bias the workpiece 138. In the process, the ions may be accelerated toward the workpiece 138. The bias power supply 148 may be a DC or an RF power supply.
In operation, the gas source 104 supplies a dopant gas containing a desired dopant species to the chamber 102. To generate the plasma 140, the RF source 150 resonates RF currents in at least one of the RF antennas 126, 146 to produce an oscillating magnetic field. The oscillating magnetic field induces RF currents into the process chamber 102. The RF currents in the process chamber 102 excite and ionize the primary dopant gas to generate the plasma 140.
The bias power supply 148 provides a pulsed platen signal to bias the platen 134 and, hence, the workpiece 138 to accelerate ions from the plasma 140 toward the workpiece 138. The frequency of the pulsed platen signal and/or the duty cycle of the pulses may be selected to provide a desired dose rate.
The above technique is known to provide high implant throughput. However, the uniformity of the dose is difficult to control. In the beam-line ion implantation system, components such mass analyzer magnets, deceleration electrodes and other beam-line components may be used to manipulate ions into a uniform ion beam, and the workpiece may be uniformly implanted with ions in the uniform ion beam. Such components, however, are not available with a plasma doping system. To uniformly implant the workpiece in the plasma doping system, the plasma generated near the substrate should be uniform, as PLAD implant uniformity is closely related to plasma uniformity.
In a typical plasma based system, the generated plasma is typically non-uniform; the plasma density is typically higher in the center of the plasma than near the chamber walls, as shown in FIG. 4. As a result, implant profile on the workpiece shows a similar non-uniform profile—higher implant dose in the middle, and lower dose in the edges of the workpiece. Typically, RF power, gas flow and distribution, magnetic confinements, etc. may be adjusted to improve the plasma uniformity. However, such techniques may mitigate the plasma non-uniformity, but cannot change the generic non-uniform density profile shown in FIG. 4.
As such, systems and methods to improve the uniformity of the plasma in a plasma based system are needed.
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Computers and computing systems have impacted nearly every aspect of modern living. For example, computers are generally involved in work, recreation, healthcare, transportation, entertainment, household management, etc.
Mixed-reality computer systems, which include virtual-reality systems and augmented-reality systems, have recently received significant interest for their ability to create immersive experiences for users. Conventional augmented-reality systems create an augmented-reality scenario by visually presenting virtual objects in the real world. In contrast, conventional virtual-reality systems create a more immersive experience because a user's entire view is obstructed by a virtual world. As used herein, mixed-reality, augmented-reality, and virtual-reality systems are described and referenced interchangeably. Unless specifically stated or unless specifically required, as understood by one of skill in the art, the descriptions herein apply equally to any type of mixed-reality system, including augmented-reality systems, virtual-reality systems, and/or any other similar system capable of displaying virtual objects to a user.
Mixed-reality computer systems use one or more on-body devices (e.g., a head-mounted device, a handheld device, etc.). A head-mounted device provides a display, sometimes referred to as a head-mounted display (hereinafter “HMD”), that enables a user to view overlapping and/or integrated visual information in the user's ambient environment (i.e. the user's field of view). By way of example, a mixed-reality computer system may present visual information in the form of a simulated object on an actual table surface.
Continued advances in hardware capabilities and rendering technologies have greatly increased the realism of virtual objects displayed to a user within a mixed-reality environment. For example, in mixed-reality environments, virtual objects can be placed within the real world in such a way as to give the impression that the virtual object is part of the real world. As a user moves around within the real world, the mixed-reality environment automatically updates so that the user is provided with the proper perspective and view of the virtual object. This mixed-reality environment is often referred to as a computer-generated scene, or simply a “scene.”
Although HMDs provide a versatile interface, modern-day HMDs are limited in the amount of “field of view” that is presented to a user. To clarify, HMDs have a limited amount of realty (i.e. space) in which a scene may be displayed. Because of this constraint, the user's virtual experience is limited to only the region displayed on the HMD. For areas outside of that viewable region, a user sees either no virtual content (e.g., in an augmented-reality situation) or complete darkness (e.g., in a virtual-reality situation). It is commonly known that some users, when immersed in such an environment, can feel discomfort.
In an effort to combat these problems, mixed-reality system designers have introduced the use of a “sparse peripheral display.” As suggested by its name, a sparse peripheral display is a low-resolution display that is situated around an outer perimeter of a main display. As used herein, “sparse peripheral display” and “peripheral display” are described and referenced interchangeably. This sparse peripheral display is comprised of an array of low resolution “pixels” that provide only a generalized context for the scene. Notably, a pixel refers to any light-emitting source (e.g., a light emitting diode “LED”).
As alluded to in the above passages, immersing a user into a mixed-reality environment (i.e. a scene) creates many challenges and difficulties that extend beyond the mere presentation of that mixed-reality environment to the user. As suggested above, some mixed-reality computer systems utilize sparse peripheral displays. However, conventional mixed-reality computer systems are somewhat limited in their use of sparse peripheral displays. As a result, these displays place unnecessary burdens on the computer system's operations. Accordingly, there exists a strong need in the field to improve the manner in which sparse peripheral displays are used.
The subject matter claimed herein is not limited to embodiments that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is provided to illustrate only one exemplary technology area where some embodiments described herein may be practiced.
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This invention relates to a radiation thermometer and a radiation sensor with multiple sensor elements for detecting infrared radiation from differing regions, and to a method for determining a temperature by means of such a radiation thermometer or radiation sensor.
The art knows of radiation thermometers having just a single infrared sensor element disposed at the end of an optical waveguide. The waveguide ensures that only radiation from a predetermined solid angle range impinges on the sensor element. Thus, for example, the probe head of an infrared thermometer designed to take a patient""s temperature in the ear is dimensioned such that the sensor element exhibits a field of view only of the approximate size of the tympanic membrane. However, the field of view of the sensor element usually covers parts of both the tympanic membrane and the ear canal whose temperatures differ. Generally, therefore, not the tympanic temperature is taken, which is considered as being representative of the true body core temperature, but rather an intermediate value that lies between the tympanic and the ear canal temperature. Hence the accuracy of a temperature reading depends on the placement of the probe head in the ear canal, that is, on its distance to the tympanic membrane and on the angle it forms with the ear canal.
From WO 95/14913 an ear thermometer is known in which multiple sensor elements are arranged at the end of an optical waveguide so as to receive radiation from differing solid angle ranges. By corresponding evaluation of the signals supplied by the sensor elements, a temperature reading is obtainable which, while being relatively independent of the placement of the probe head in the ear, is likewise representative of an intermediate value which does not correspond to the true tympanic temperature.
The conventional infrared ear thermometers further have the disadvantage that the optical waveguide customarily employed, which is a small tube of a diameter of about 3 mm having its inner diameter gold plated, is very expensive, in addition to guiding heat from the ear into the interior of the probe head during a temperature measurement. Hence complex approaches are necessary to prevent corruption of the measurement result.
From EP 0 566 156 B1 an infrared sensor having two infrared sensitive elements is known, one being shielded against infrared radiation, the sensor being intended for use in a thermometer for measuring body temperature, and a method for manufacturing the sensor. By comparing the signals supplied by the two elements, a measurement signal is obtainable which is representative of the amount of incident infrared radiation and is largely free from electric noise and thermal disturbances. The infrared sensitive elements have their upper and undersides protected by coatings.
From JP-A-03-263001 an infrared sensor with a microlens is known, which is intended for use in an ear thermometer for taking a patient""s temperature, and a method for manufacturing the sensor. The microlens serves to focus the infrared radiation on the infrared sensor. It has a diameter of 1.44 mm, approximately.
The manufacture of the known infrared sensors is accomplished using the processes known from the manufacture of semi-conductors, involving the formation of a plurality of sensor elements on a substrate subsequently cut into individual sensors each having one element only which are then provided with an enclosure, etc.
From JP-A-03-248477 an infrared sensor having four identical infrared sensitive elements is known, which is intended for use in an ear thermometer for taking a patient""s temperature, and a method for manufacturing the sensor. The four elements are arranged on bridges extending across a recess in a substrate.
From JP-A-04-333292 a two-dimensional array of thermo-elements is known which is intended for an infrared image sensor.
From xe2x80x9cUncooled IR Focal Plane Arraysxe2x80x9d by Paul W. Kruse, SPIE, vol. 2552, pages 556-563, sensor arrays, that is, two-dimensional arrays of infrared sensor elements are known in which one sensor element is less than 0.1 mm long and wide.
It is an object of the present invention to provide a radiation thermometer of straightforward construction and a radiation sensor and a method of computing the temperature for a radiation thermometer which enables selective measurement of the temperature of objects filling only part of the field of view of the radiation thermometer.
This object is accomplished with a radiation thermometer having a radiation sensor with multiple infrared sensor elements and multiple optical elements, wherein a single optical element is associated with either only one sensor element or a group of sensors comprising multiple sensor elements. The optical elements operate to ensure that the sensor elements or sensor groups are able to receive only radiation that is emitted by a region defined within narrow limits. In this manner, the field of view of the radiation thermometer is split into a plurality of partial fields of view whose temperatures can be measured individually. For the purposes of an ear thermometer, a certain amount of overlap of the individual partial fields of view is tolerable.
Advantageous for use in an ear thermometer is an infrared multiple sensor, that is, an array of multiple sensor elements arranged on a common substrate, because with such a multiple sensor a sufficiently small thermometer probe head can be realized. The optical elements are preferably combined to form a single optical component (multiple optical system), advantageously forming an integrated optical component. In a particularly advantageous aspect, a radiation sensor of the present invention includes a multiple sensor and a multiple optical system which is arranged in close proximity to or on the surface of the multiple sensor. Radiation sensors of this type are known, for example, from U.S. Pat. No. 5,701,008, JP-A-57-142526, JP-A-1-47923 and DE 36 33 199 A1.
Preferably, however, the optical elements and the sensor elements are configured as an integrated electro-optical temperature sensor in which the optical elements, for example, are provided directly on the surface of the multiple sensor. Such a temperature sensor can be manufactured using the methods known from semiconductor manufacture. An electro-optical infrared sensor in which the individual sensor elements are heat sensitive capacitors is known from U.S. Pat. No. 5,631,467.
A method of the present invention for temperature determination by means of a radiation thermometer as, for example, an ear thermometer, that includes a radiation sensor comprising multiple sensor elements enables in particular the temperature to be taken in a patient""s ear, that is, the tympanic temperature to be measured, although the field of view of the radiation thermometer covers both parts of the tympanic membrane and parts of the ear canal. In such a case the sensor elements viewing the tympanic membrane will detect a higher temperature than the remaining sensor elements which view the ear canal. According to the present invention, the evaluation process uses only the temperature signals from those sensor elements that detect higher or significantly higher, or in other applications lower or significantly lower, temperatures than the remaining sensor elements.
In a particularly advantageous method, the process of temperature determination is preceded by a check to see whether the probe head of the thermometer is properly aligned in the ear canal. If it is not, that is, if the tympanic membrane is outside the field of view of the radiation sensor so that the probe head is directed at parts of the ear canal exclusively, all sensor elements will supply largely the same temperature values. Hence, when the evaluation of the temperature signals does not reveal a sufficiently appreciable temperature gradient within the field of view of the radiation sensor, the method of the present invention, rather than supplying a temperature measurement value, produces a corresponding error message or a request to repeat the measurement. In this embodiment of a thermometer of the present invention, it is necessary for the field of view of the radiation sensor to be greater than the diameter of the tympanic membrane so that also in cases where the probe head points directly at the tympanic membrane the surrounding ear canal is also covered, hence enabling the temperature gradient between the tympanic membrane and the ear canal to be identified.
A clinical thermometer operating according to the method of the present invention affords the advantage of obtaining excellent repeatability characteristics because the measured temperatures are largely independent of the respective placement of a probe head in the ear. According to the principle, namely, each measurement requires that only a single one or very few of a total of, for example, one hundred sensor elements view the tympanic membrane in order to be able to measure the tympanic temperature, that is, a potential fever condition, accurately.
Moreover, the structure of a radiation thermometer of the present invention is simplified in the use of a radiation sensor of the present invention because it obviates the need to provide as a waveguide a metal tube having its inside diameter gold plated as is otherwise customary, its functions being performed by the optical elements instead. Hence more possibilities are afforded in the design of the probe head of a radiation thermometer of the present invention because the radiation sensor may also be located directly at the end of the probe head, for example. Also, multiple radiation sensors arranged at relative inclinations may be provided at the end of the probe head in order to obtain a sufficiently wide field of view.
Embodiments of the present invention will be described in the following with reference to the accompanying drawing. Further embodiments are referred to in the description. In the drawing.
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Osteopontin (Oldberg et al. (1986) Proc. Natl. Acad. Sci. USA 83:8819; Oldberg et al. (1986) J. Biol. Chem. 263:19433-19436) also known as OPN (Wrana et al. (1989) Nucl. Acid Res. 17:3306), 2ar (Smith and Denhardt (1987). J. Cell Biochem. 34:10-22), transformation-associated secreted phosphoprotein (Senger et al. (1989) Anticancer Res. 48:1291), or early T-lymphocyte activation-1 (Patarca et al. (1991) Proc. Natl. Acad. Sci. USA 88:2736), is a multifunctional secreted glycoprotein which is expressed by a wide variety of cell types including bone (Oldberg et al. (1986) J. Biol. Chem., supra), smooth muscle cells (e.g., cells of the vascular system) (Giachelli et al. (1991) Biochem. Biophys. Res. Commun. 177: 867-873), activated T-lymphocytes (Patarca et al. (1989) J. Exp. Med. 170:145-161; Patarca et al. (1991) Proc. Natl. Acad. Sci. USA, supra), macrophages (Singh et al. (1990). J. Exp. Med 171:1931-1942), and carcinomas and sarcomas (Senger et al., supra). In other tissues, osteopontin is expressed during various developmental stages and circulating levels of the protein have been found to be elevated in individuals with autoimmune diseases. Osteopontin is also elevated in sera from patients with advanced metastatic cancer and cellular transformation may lead to enhanced osteopontin expression and increased metastatic activity.
The protein is involved in a range of cellular functions including cell adhesion and spreading, cell migration and homing, chemotaxis, and calcium homeostasis (e.g., calcification). Osteopontin is induced by oxidative stress, including ischemia/reperfusion, heat shock or starvation, and exerts antioxidant effects by down-regulation of inducible nitric oxide synthetase (conferring protection against killing by macrophages). Moreover, osteopontin has been found to inhibit apoptosis in various cell types and in response to a wide range of stimuli.
In mammals, osteopontin is known to play an important role in regulation of bone formation and/or bone remodeling, regulation of immune responses, mediation of inflammation (e.g., tissue inflammation) in specific disease and injury states, angiogenesis, and arterial wound healing. Osteopontin has also been shown to be secreted by malignant tumors and is believed to play an important role in metastasis formation. The protein is subject to a large number of post-translational modifications (e.g., phosphorylation) and, in fact, the considerable number of functions that have been attributed to this protein are believed to be differentially regulated by such post translational modifications.
Osteopontin binds to cells via integrin and non-integrin receptors. The presence of a Gly-Arg-Gly-Asp-Ser (GRGDS, SEQ ID NO:1) cell-surface receptor binding motif within the sequence of osteopontin is involved in cell attachment and spreading via xcex1vxcex23, xcex1vxcex21 and xcex1vxcex25 integrins (Oldberg et al., supra). Cleavage of osteopontin with thrombin enhances its cell attachment properties. A distinct receptor-ligand interaction between CD44 and osteopontin, has also been shown to play a role in mediating chemotaxis and/or cell or attachment. Multiple phosphorylated and nonphosphorylated forms of osteopontin are secreted by cells and are differentially stimulated by tumor promoters (Kubota et al. (1989) Biochem. Biophys. Res. Commun. 162: 1453-1459). In addition, differential attachment of osteoclasts to surfaces coated with osteopontin isolated from various tissues and to phosphorylated and nonphosphorylated osteopontin has been demonstrated.
Given the important role that osteopontin plays in cellular processes including cell spreading and chemotaxis as well as the important functions it has in diverse processes including arterial wound healing, immune response, bone development, tissue remodeling, and metastasis, there exists a need to identify peptides and develop compounds that mimic or inhibit many of the unique functions of osteopontin. In particular, there exists a need for identifying peptides and developing compounds which mimic the chemotactic activities of osteopontin as well as agents (e.g., antibodies, peptides and compounds) which are inhibitory for osteopontin-dependent chemotaxis.
The present invention is based, at least in part, on the discovery of or identification of the chemotactic regions of the naturally-occurring osteopontin protein. This discovery led to the development of chemotactic compounds and peptides derived from osteopontin. The discovery also led to the development of peptides which are inhibitory to chemotaxis. Accordingly, the compounds and peptides of the present invention can be used to induce and/or inhibit chemotaxis, either in vivo or in vitro. The compounds and peptides of the present invention can be used to treat conditions or diseases associated with chemotaxis. For example, the compounds and peptides of the present invention can be used to treat or inhibit tumor metastasis, inflammation, osteoporosis and autoimmune disease. Moreover, the compounds and peptides of the present invention have applications in angiogenesis, wound-healing and in the development of prosthetic devices.
The present invention pertains to osteopontin derived compounds and peptides. The compounds and peptides are capable of modulating (e.g., inducing or inhibiting) the chemotaxis of several cell types. Examples of cell types include, but are not limited to, endothelial cells, periosteal cells, tumor cells, macrophages and osteoprogenitor cells.
In one embodiment, the invention features purified osteopontin-derived chemotactic peptide (e.g., purified osteopontin-derived peptides having chemotactic activity). In another embodiment, the invention features purified chemotactic compounds having the following formula:
Qxe2x80x94Axe2x80x94X,
wherein Q and X are flanking moieties and are absent or present and A is a hydrophobic core constituent, forming a compound having chemotactic activity.
In another embodiment, the invention features chemotactic compounds which include a hydrophobic core constituent (A) having the following motif:
"psgr"xe2x80x94xcex1xe2x88x92xe2x80x94xcex6xe2x80x94xcex2+,
wherein "psgr" is a hydrophobic patch, xcex1xe2x88x92 is an acidic moiety, xcex6 is a bend-forming moiety, and xcex2+ is a basic moiety.
The invention also pertains to isolated nucleic acid molecules encoding the osteopontin derived peptides of the present invention which can be used to produce the peptides and also as a therapeutic agent. Likewise, the invention pertains to antibodies (e.g., monoclonal antibodies) which specifically react with osteopontin-derived peptides. These antibodies can be administered to a subject in the form of a therapeutic composition to modulate the chemotactic effect of the peptides of the invention, thus neutralizing the migration of various cell types in response to osteopontin.
In another aspect, the invention features a therapeutic composition which includes an chemotactic compound, chemotactic peptide, inhibitory compound or peptide and a pharmaceutically-acceptable carrier or diluent. The therapeutic composition can be used in the methods described herein.
In another aspect, the invention features a method for modulating tumor invasion or tumor metastasis in a subject. In one embodiment, the method includes administering to a subject (e.g., at a tumor site) a therapeutically effective amount of an inhibitory compound, or a chemotactic peptide antibody, such that tumor invasion or tumor metastasis is modulated. In another embodiment, the method includes administering to a subject (e.g., at a tumor site) a therapeutically effective amount of an inhibitory compound complexed to a carrier (e.g., an extracellular matrix molecule, for example, collagen, glycosamoniglycans, for example, hyaluronic acid, chondroitin sulfates and heparan sulfates), such that tumor metastasis is modulated (e.g., inhibited).
In another aspect, the invention features a method for modulating nitrous oxide production in a cell or subject. In one embodiment, the method includes contacting a cell with an effective amount of a chemotactic peptide of the present invention (or an effective amount of an inhibitory peptide), such that nitrous oxide production is modulated (e.g., stimulated or inhibited, respectively). In another embodiment, the method includes administering to a subject a therapeutically effective amount of an chemotactic peptide or inhibitory compound such that nitrous oxide production is modulated (e.g., stimulated or inhibited, respectively).
In another aspect, the invention features a method for activating apoptosis in a cell or subject. In one embodiment, the method includes contacting a cell with an effective amount of a chemotactic peptide of the present invention such that apoptosis of the cell is activated. In another embodiment, the method includes administering to a subject a therapeutically effective amount of a chemotactic peptide such that apoptosis is activated (e.g., apoptosis of a cell(s) within the subject).
In another aspect, the invention features a method for promoting wound healing (e.g., scarless wound healing) in a subject. The method includes administering to a subject a therapeutically effective amount of a composition comprising an chemotactic compound or peptide and a pharmaceutically-acceptable carrier or diluent such that wound healing is promoted.
In another aspect, the invention features a method for promoting cell migration (e.g., cellular chemotaxis) to a target site. In one embodiment, the method includes administering to a subject (e.g. at a target site) a therapeutically effective amount of a chemotactic compound or peptide such that migration (e.g., cellular chemotaxis) of a desired cell to the target site is promoted. In another embodiment, the method includes administering at the target site, a chemotactic peptide or compound adhered to a substrate (e.g., an extracellular matrix components, for example, collagen, or glycosamoniglycans, including hyaluronic acid, chondroitin sulfates and heparan sulfates). In yet another embodiment, the method Includes coating a physical material (e.g., plastic, polyvinyl surface, steel, glass, polymer, PGA, metals, for example, titanium) with a chemotactic peptide prior to introducing the material to a subject, such that cell migration (e.g., cellular chemotaxis) is promoted.
In another aspect, the invention features a method for promoting cell migration (e.g., cellular chemotaxis) to a target site. In one embodiment, the method includes administering to a subject (e.g., at a target site) a therapeutically effective amount of a chemotactic compound or peptide such that migration (e.g., cellular chemotaxis) of a desired cell to the target site is promoted. In another embodiment, the method includes administering at the target site, a chemotactic peptide or compound adhered to a substrate (e.g., an extracellular matrix components, for ex.ample, collagen, or glycosamoniglycans. including hyaluronic acid, chondroitin sulfates and heparan sulfates). In yet another embodiment, the method includes coating a physical material (e.g., plastic, polyvinyl surface, steel, glass, polymer, PGA, metals, for example, titanium) with a chemotactic peptide prior to introducing the material to a subject, such that cell migration (e.g., cellular chemotaxis) is promoted.
In another aspect, the invention features a method for inhibiting cell migration (e.g., cellular chemotaxis) at a target site. In one embodiment, the method includes administering to a subject (e.g., at the target site) a therapeutically effective amount of an inhibitory compound or peptide or antibody such that migration (e.g., cellular chemotaxis) of a cell to the target site is inhibited. In another embodiment, the method includes administering at the target site, an inhibitory peptide or compound adhered to a substrate (e.g., an extracellular matrix components, for example, collagen, or glycosamoniglycans, including hyaluronic acid, chondroitin sulfates and heparan sulfates). In yet another embodiment, the method includes coating a physical material (e.g., plastic, polyvinyl surface, steel, glass, polymer, PGA, metals, for example, titanium) with an inhibitory peptide or compound prior to introducing the material to a subject, such that cell migration (e.g., cellular chemotaxis) is inhibited.
The invention also features a prosthetic device. The prosthetic device contains or coated with a therapeutically effective amount of a chemotactic or inhibitory compound or peptide in or on the prosthetic device.
The invention also features physical materials (e.g., plastic, polyvinyl surface, steel, glass, polymer, PGA, metals, for example, titanium) containing or coated with a therapeutically effective amount of a chemotactic or inhibitory compound or peptide.
In another aspect, the invention features a method for treating the formation of atherosclerotic plaques. The method includes administering to a subject a therapeutically effective amount of a chemotactic compound or peptide such that formation of artherosclerotic plaques is prevented.
In another aspect, the invention also features a method for treating an angiogenic-associated disease. The method includes administering to a subject a therapeutically effective amount of an antibody specifically reactive with a chemotactic peptide, or an inhibitory compound or peptide such that treatment of angiogenic-associated disease occurs.
In yet another aspect, the invention features a method of inducing in vitro chemotaxis of a cell. The method includes exposing the cell to a chemotactic compound or peptide in an amount effective to induce chemotaxis, such that chemotaxis is induced. In yet another aspect, the invention features a method of inhibiting in vitro chemotaxis of a cell. The method includes exposing the cell to an inhibitory compound or peptide in an amount effective to inhibit chemotaxis, such that chemotaxis is inhibited.
The methods of the invention are particularly useful for modulating the migration of cells (e.g., cells the movement of which it is desirable to control) involved in wound healing (e.g., extracellular matrix cells (connective tissue cells) involved in wound healing) to thereby promote recovery from wounds. The methods of the invention are particularly useful for modulating the migration of neoplastic cells (e.g., carcinoma cells, for example, of breast, testis, ovary, lung, gastrointestinal tract) to thereby modulate (e.g., inhibit) spreading from one location to another.
Antibodies specifically reactive with the chemotactic peptides of the invention or inhibitory compounds and/or peptides can also be administered to a subject having a metastatic disease (e.g., cancer) to modulate tumor invasion or to prevent or inhibit metastasis of the disease by inhibiting the chemotactic activity of osteopontin. The peptides, compounds and antibodies can be administered to the subject in the form of a therapeutic composition which includes the peptide, compound or antibody and a pharmaceutically acceptable carrier or diluent.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
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This invention relates to an apparatus which allows the user of a wheelchair to exercise, and in particular to such an apparatus in which the wheelchair is easily secured to the apparatus and in which the wheelchair operates in a manner which is similar to actual wheelchair operation.
Most aerobic exercise apparatus, such as treadmills, stationary bicycles, stair step machines and the like do not accommodate people who do not have full use of their legs. While there are exercise apparatus which allow a wheelchair to be driven while held stationary, the prior art apparatus of this type have two shortcomings. First, when a wheelchair is driven in the apparatus it needs to be securely attached to the apparatus if the user is going to exercise vigorously. Many of the prior art wheelchair exercise devices do not allow the wheel chair to be securely attached to them. Furthermore, in those that do, the attachment mechanism is difficult and time consuming to use, particularly for someone in a wheelchair.
Second, when a wheelchair is driven its weight creates momentum which keeps it traveling at relevantly the same speed even though there are intervals where the driving wheels are not being rotated by the user due to the cycling manner in which a user""s arms push the driving wheel. The prior art wheelchair exercise apparatus do not do a good job of simulating this momentum.
The subject invention overcomes the foregoing shortcomings and limitations of the prior art wheelchair exercise apparatus by providing an attachment arm having a first arm section with a first joint on its outer end which is pivotally attached to the exercise apparatus and a second arm section with a second joint at its outer end which is pivotally attached to a clamp which can easily and quickly be attached to a frame element of the wheelchair. The inner ends of the first and second arm sections are rotatably connected together through the third joint. A clamp mechanism permits simultaneously fixing the first, second and third joints irrotatably by the activation of a single activation member.
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1. Technical Field
This disclosure relates generally to securing resources in a distributed computing environment, such as a transaction processing environment.
2. Background of the Related Art
Security systems associated with complex, multi-component computing environments are designed to permit selective and controlled access by active entities (such as users) to static entities (such as data sources).
A representative multi-component system of this type, wherein components work together cooperatively to form a larger system, is the IBM® HyperText Transfer Protocol (HTTP) and Web Services processing environment, which may be implemented using IBM mainframe computers, such as the IBM z196 family of computing machines. This environment typically includes IBM's WebSphere® Application Server (WAS) middleware platform software product, working in conjunction with one or more transaction processing products, such as IBM Customer Information Control System (CICS®) and/or IBM Information Management System (IMS), a message processing product, such as IBM WebSphere MQ, and a relational database, such as the IBM DB2® database. An objective of a multi-component environment is to provide a high performance transaction processing computing system or environment accessible to client end-users via Internet browsers using HTTP or other Web Services. In this environment, the client end-user making the HTTP or Web Services request communicates directly with the application server. Typically, to fulfill the transaction request from the distributed client end-user, the application server invokes the services of one or more other components in the environment. One of more of these components typically execute on an operating system, such as IBM z/OS® operating system, which is often referred to as a “mainframe” operating system platform.
In such an environment, the transaction processing, messaging, and database components typically are executing within a mainframe computer that includes a framework for managing security within the environment. The framework includes a security server. In a representative z/OS implementation, the security framework is provided by z/OS Security Server, which includes the IBM Resource Access Control Facility (RACF®) as its security engine. RACF allows an administrator to set rules for controlling access to resources by defining what is protected at what level and determining who can access protected resources. In a typical mainframe operating environment (e.g., z/OS), RACF is used to identify and verify users' authority to access data and to use system facilities.
The above-described products and technologies expose interfaces that can be used by permitted entities, such as system administrators, to monitor and manage resources that are being protected by the system.
In addition, relational database technologies such as described above support various encryption methods for data stored in the database tables. Thus, for example, IBM InfoSphere® Guardium® Data Encryption for DB2 and IMS Databases implement EDITPROC security, which uses an Integrated Cryptographic Services Facility (ICSF) to provide encryption at the table level of the database. Consequently, all application users, developers and DB2 system administrators (SYSADMs) can access sensitive data if they have DB2 security and RACF access to the table granted by the SYSADM. This facility, however, does not provide any masking of sensitive data. Alternatively, DB2 includes built-in encryption security, which uses ICSF and is implemented at the column level of the database. This approach, however, requires extensive application changes, and passwords have to be defined and maintained by the application owner's independently of the SYSADMs. Further, passwords have to be defined and used by applications to access data, and no masking of sensitive data is provided. Another known approach is to use an encryption method that uses a User Defined Function (UDF) to afford application users access to sensitive data, although no masking of sensitive data is provided in this approach either.
Currently, however, there are no clearly-defined lines between the roles needed to implement and use cryptographic technology in relational databases such as DB2 z. The lack of well-defined roles and a comprehensive security model causes administrative confusion. It is desirable to provide a more comprehensive security model that may be enforced across the entire relational database management system. This disclosure addresses this need.
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The present invention relates to a printing apparatus for printing marks such as letters and figures on printing webs such as papers.
There has been heretofore provided a so-called printer for printing letters, figures and the like on materials such as printing papers. In such a prior art printing machine, a printing drum is driven by a suitable motor to align in printing positions the letters and the like to be printed and then a hammer disposed on an opposite side to the printing drum is driven by solenoid means to hit the drum thereby completing the print on the printing papers positioned between the hammer and the drum.
However, the prior art printing apparatus requires the motor to rotate the printing drum and also the solenoid means having a large capacity enough to drive the hammer. Accordingly, the apparatus is disadvantageous in that the structure thereof is intricate with a large size and a large amount of an electrical power is required to drive the solenoid means.
In order to eliminate such defects, an improved printing apparatus has been proposed in U.S. patent application Ser. No. 147,655 filed on May 7, 1980 and entitled "Printing Apparatus." In this printing apparatus, a printing drum to which a rotational torque from a rotational drive means is normally applied is arranged so as to face to a printing web, and a lever swingable against the printing web suitably supported by a roller rotatably carries the printing drum, and a forcible stopping means serves to prevent the rotation of the printing drum around its own axis whereby the lever can be rotated toward the printing web. According to such a printing apparatus, it is essentially possible to control both the rotation of the printing drum and the printing operation by a single motor. The printing apparatus is, therefore, simple in construction and small in size. Moreover, a small capacity is required for the solenoid means since the solenoid means only serves to rotate a stop lever at a small angle. For this reason, energy consumption may be reduced.
However, such a printing apparatus has the following disadvantages due to the fact that the forcible stopping means includes a ratchet wheel provided to the printing drum and the ratchet teeth ride over the projected stop lever to thereby carry out the printing operation. That is, it is difficult to effectively apply the generated drive force in the printing web direction during the ride-over of the ratchet teeth.
More specifically, the load applied to the motor is increased, which shortens the service life of the motor. Since a large amount of brake force is required for the forcible stopping means, the mechanical strength of the forcible stopping means must be enhanced, which results in the engagement of the apparatus. Also, since the stroke of the printing drum cannot be elongated beyond the ratchet tooth height, it is difficult to adjust the impact timing of the printing drum against the printing web. Furthermore, since the printing drum is rotated around its own axis to carry out the printing, the printing displacement tends to take place. It is also impossible to enhance the printing speed more than a predetermined value. Therefore, a main object of the present invention is to overcome the above-noted defects.
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This invention relates to an apparatus and method for applying a resin coating or patch to threaded fasteners. More particularly, the invention relates to an apparatus and method for applying a resin coating or patch to different portions of the fastener, such as its external and internal threads. The invention also relates to a self-locking fastener having both external and internal threads with a resin coating thereon.
This invention is particularly suited for applying a resin coating or patch to threaded inserts, which are fasteners that have both external and internal threads. Threaded inserts are typically installed into a receiving member where its external threads engage the receiving member. A separate externally threaded fastener may be then, in turn, installed and engaged with the threaded fastener's internal threads.
As with other fasteners, certain applications require that the threaded insert be self-locking, and some applications require the self-locking feature on both the external and internal threads of the insert. This has been previously achieved by a technique in which a vertical or horizontal bore is first made in the threaded insert to receive a pellet or strip of resilient plastic. While this technique is effective, it unduly increases the threaded insert's cost due to the additional machining step required.
Various methods and apparatus are also disclosed in the prior art for economically applying resin locking patches or coatings to either the external or internal threads of fasteners. For example, U.S. Pat. Nos. 3,579,684 and 3,858,262 are directed to techniques in which a fastener is heated and heat fusible powdered resin is then sprayed on the external or internal threads. The resin then adheres to the heated threads forming a coating or patch. These methods, however, do not address the application of a patch or coating to both the external and internal threads of a fastener.
It would, therefore, be advantageous to provide an apparatus and method which applies a resin coating or patch to different portions of a threaded fastener, such as both the external and internal threads of a fastener. It would also be advantageous to provide an apparatus which reduces the manufacturing costs of producing a threaded insert which has a reusable self-locking resin coating or patch on both its external and internal threads. Moreover, it would be advantageous to provide a self-locking fastener having both external and internal threads with an applied locking patch of resilient resin material.
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1. Field of Invention
The present invention relates to context-aware systems, in particular to context-aware systems employing sensors of varying availability.
2. Discussion of Background
Context-awareness is a key technology for the next generation of smart devices. These devices will not only know where they are, by whom they are used, and what other devices are around them, they will have a broad knowledge about what a user's desires and needs are and will act accordingly. To implement that, the devices will therefore need to utilise numerous internal and external sensors for collecting enough information to derive context information reliably.
Context, as it is used in this specification is defined by Anind Dey in “Understanding and using context”, Personal and Ubiquitous computing, special issue on Situated Interaction and Ubiquitous Computing”, Vol. 5(1), 2001, page 4-7, as any information that can be used to characterise the situation of an entity. An entity is a person, place, or object that is considered relevant to the interaction between a user and an application, including the user and applications themselves. The entity for which context information is collected is furthermore addressed as focus entity.
Knowledge about a context can be used in various ways to make applications and devices much smarter by automatically incorporating this context information. Unfortunately, context is rather complex and therefore hard to handle. The complexity results from the multiplicity of different types of context potentially derived from numerous different sensors. A tourist, e.g., moving around in a foreign city is supplied by his context-aware device with an active map and additionally with information about the sights he or she is currently viewing. In this case, the context-aware device will need—among others—information about the current location of the tourist. For the tourist being outdoors, this information can be obtained by using a Global Positioning System (GPS) but indoors, this is no longer feasible because accessing GPS satellites is impossible from within buildings. Consequently, special indoor location systems are to be used for retrieving the position information indoors. Whenever a user moves into or out of a building, his or her context-aware device has to switch to another location defining system. Handling this take-over from the outdoor to the indoor location defining system and vice a versa is currently performed on the application side, which works quite well when there are only a few possible sources of information available.
As soon as a large number of different sources have to be considered, this approach becomes impracticable. The tourist of the above example might for instance not only be interested in his own position, but also wants to know if certain persons move in or out of a certain area, e.g. if his children are going to far away. For this, a system has to utilise a large number of location sensors of different types—indoor as well as outdoor—whereby the indoor location type might also differ from building to building and therefore from person to person. The context-aware device will have to deal with this, and might have to implement the access to different types of location sensors at the same time. The configuration of a context-aware device will become even more complicated, if not only location information is used, but a wide range of different information sources like for temperature, pressure or the like to create a more complex context structure.
Anind Dey discloses a Context Toolkit developed at the Georgia Institute of Technology in “Providing Architectural Support for Building Context-Aware Applications”, PhD theses, College of Computing, Georgia Institute of Technology, December 2000. The purpose of the context tool kit is to hide the process of gathering context information in the same way that X-window widgets hide the complexity of the X-windows system from an application developer. Widgets represent a certain kind of information like e.g. a location or an activity based on data provided by sensors. X-window widgets accumulate complex graphical user interface handling functionality into one component and are accessed via a uniform interface thereby hiding the details of an underlying sensor configuration. Context aggregators sum up a number of widgets to a more complex “meta-widget” providing access to more complex context information. Interpreters transform low-level context information like a location or an activity to a more abstract higher level information, like e.g. by deducing from the information that somebody is lying in a bed with a regular low pulse that this particular person is sleeping.
The Context Toolkit is the currently most popular context handling system. It is very easy to use and simplifies the implementation of context-aware applications by providing widgets and interpreters for frequently used context types. The Context Toolkit assumes that the sensor configurations are static, i.e. the application developer determines at design time which widgets, interpreters and aggregators are to be used. Because no reconfiguration of the system is supported, the inflexible structure yields the problem, that if a sensor fails the error is propagated up to the application level.
The European funded Youngster project (IST-2000-25034) develops technologies to create a new open active mobile multimedia environment that is accessible from anywhere by a wide range of devices and networks, and that supports context-aware features including location-awareness.
Within the project, a context system for a mobile platform is evaluated, proposing in principle that all requests from context clients, i.e. context-aware devices are passed to a local context service. This service tries to resolve the requests locally by either providing shortcuts to local context sources or by reusing existing connections to context servers. If a request cannot be resolved locally, it is passed to a remote context server for further processing. Context service and context server may reside on the same host. Context sources have direct access to sensors and transform the sensor data into a format that is understood by the context server. Context sources might also be located within the server accessing the sensors only remotely.
The term context client refers to an entity requesting context information, while the term context server refers to an entity providing context information. Context clients request context information from a context server by specifying the desired information, like e.g. location. The mapping of the desired information type to the available sensors is done via the context server.
A context server creates paths from a requested data type to the available sensors. If a request cannot be mapped directly to respective sensors, a data transformation via so called context interpreters is performed.
With the paths created, a context information originates from a sensor and is afterwards translated by a context source from a proprietary format into a Youngster internal format that is understood by appropriate context interpreters. The context interpreters themselves process data and are composed within a chain. In the end of the chain, data in the originally requested format are stored in a context attribute which itself is part of a bigger data structure, the aggregator. The context attribute specifies the format, the type and through the parent context aggregator also the focus entity of the stored data.
In the context system for mobile service platforms as proposed in the Youngster project, clients do not need to have knowledge about available sensors or how to put them to use, but can transfer this task completely to the context system. The mapping from the desired type and format for the requested context information to the available sensors is done by the server by automatically creating a so-called context path. The path can be implemented in form of a linear path or a more complex structure with sensor hierarchies utilising basic and abstract sensors. Abstract sensors collect data from different basic sensors and transform the data to a certain degree. The configuration of the context path shows a tree structure with the root node being a context attribute that can be accessed from a context client.
The path from a requested data type to the available sensors has to be set up manually, which means that e.g. for all desired types and formats of context attributes a chain of context interpreters and sources has to be created and connected manually. Another possibility is to have the context clients specify what context interpreters and context attributes to use and how to connect them according to rules defined by the client. Although the advantages of an automatic and on-demand creation of a context path, like keeping the constructions of context clients simple, providing flexibility both on the client as well as on the server side, and an ease of maintenance are very obvious, no mechanism for automatically creating a context path is presently available.
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1. Field of the Invention
This invention relates in general to magnetic sensors, and more particularly to a method and apparatus for enhancing thermal stability, improving biasing and reducing damage from electrostatic discharge in self-pinned abutted junction heads.
2. Description of Related Art
Magnetic recording is a key and invaluable segment of the information-processing industry. While the basic principles are one hundred years old for early tape devices, and over forty years old for magnetic hard disk drives, an influx of technical innovations continues to extend the storage capacity and performance of magnetic recording products. For hard disk drives, the areal density or density of written data bits on the magnetic medium has increased by a factor of more than two million since the first disk drive was applied to data storage. Areal density continues to grow due to improvements in magnet recording heads, media, drive electronics, and mechanics.
The use of a magnetoresistive (MR) and giant magnetoresistive (GMR) sensors to sense magnetically recorded data has been known for many years. The GMR sensor includes a spin-valve film that provides a high magnetoresistance ratio (MR ratio) as compared with a conventional MR head. The MR ratio is the percentage change in resistance as an external magnetic field is switched between high and low values.
It has also been known that due to spin-orbit coupling, some ferromagnetic materials used in forming a sensor display anisotropic resistivity, i.e. the resistivity being a function of an orientation between a current and a magnetic field. Hence, both traverse bias (i.e., the bias field is perpendicular to a preferred magnetization axis (easy axis—EA) and current direction) and longitudinal bias (i.e., the bias field is along the easy axis and current direction) of an MR structure must be provided to eliminate noise, such as Barkhausen noise, and to maintain the sensor in its most linear operating range.
In the search for new materials that will allow MR heads to be scaled to very small dimensions for increased areal densities and that will also maintain good signal amplitude, scientists have developed films, which exhibit the GMR effect. GMR heads are made up of four layers of thin material that combine into a single structure. A free layer is the sensing layer. The free layer is passed over the surface of the data bits to be read. It is free to rotate in response to the magnetic patterns on the disk. A pinned layer is a layer that is held in a fixed magnetic orientation by its proximity to an exchange layer. The exchange layer is a layer of antiferromagnetic material that fixes the pinned layer's magnetic orientation. A spacer, typically made from copper, is a nonmagnetic layer that separates the magnetization of the free and pinned layers. When the head passes over a magnetic field of one polarity, the electrons on the free layer turn to align with those on the pinned layer, creating a lower resistance in the head structure. When the head passes over a field of opposite polarity, the free layer electrons rotate so that they are not aligned with the electrons on the pinned layer. This causes an increase in the structure's resistance.
To avoid noise, a longitudinal bias field along the current direction of the free layer element is needed. There are two popular longitudinal bias schemes for GMR heads: exchange bias and hard bias. Exchange bias refers to the unidirectional pinning of a ferromagnetic layer by an adjacent antiferromagnet. Ferromagnetic films typically have a preferred magnetization axis, easy axis, and the spin direction preferably aligns along this axis. Hence, there are two equally stable easy spin directions (rotated by 180°) along this axis and it requires the same energy and the same external field to align the spins along either direction.
The ferromagnetic layer may be magnetically pinned or oriented in the fixed and unchanging direction by an adjacent anti-ferromagnetic layer (AFM), commonly referred to as the pinning layer, which pins the magnetic orientation of the ferromagnetic layer (i.e., the pinned layer) through anti-ferromagnetic exchange coupling by the application of a sense current field. Also, the ferromagnetic layer may be self-pinned, in which the magnetic moment of the pinned layer is pinned in a fabrication process, i.e.—the magnetic moment is set by the specific thickness and composition of the film. The self-pinned layer may be formed of a single layer of a single material or may be a composite layer structure of multiple materials. It is noteworthy that a self-pinned spin valve requires no additional external layers applied adjacent thereto to maintain a desired magnetic orientation and, therefore, is considered to be an improvement over the anti-ferromagnetically pinned layer.
In a hard bias scheme, such as abutted junction hard bias, two hard magnets abut at least the free layer along a longitudinal direction. The hard (bias) magnets include a hard magnetic layer such as CoPtCr and appropriate under-layer and/or overlayer for desirable magnetic and electrical properties. The hard magnets are electrically connected to the free layer allowing sense current (IS) to pass through. A magnetostatic field generated by the hard magnets serves the longitudinal bias field (Hl).
However, the longitudinal schemes discussed above are sensitive to electrostatic discharge (ESD) and high temperatures produced thereby. Electrostatic discharge can be manifest on giant magneto resistive (GMR) head either physically (e.g., melting of a sensor) or magnetically (e.g., degrading electrical characteristics of a sensor).
Damage to a sensor form ESD occurs in different levels. If the energy level is high enough, ESD will burn and/or melt GMR stripes resulting in bumps on an air-bearing surface (ABS). For example, high ESD energy absorbed at the two ends of an abutted junction of a MR sensor may form bumps, including fractured stripes between the bumps, on the sensor. Also, high ESD energy absorbed along stripes of GMR sensor can melt the sensor forming several micro metal balls. A low ESD energy level may only damage the magnetic structure of an MR sensor (usually call as “soft” ESD).
In addition, the central active area between MR leads and hard bias layers tends to operate at high temperatures. Hence, the added energy from ESD can physically damage the sensor and/or cause unpinning of a pinned layer.
An alternative longitudinal bias scheme is a lead-overlay (LOL) (i.e., overlay hard bias scheme), in which the leads define a trackwidth of a written track. A self-pinned LOL is less sensitive to ESD than the self-pinned abutted junction head, however the LOL head does not provide a desired narrow trackwidth, e.g., below 0.15 um. Therefore, the self-pinned abutted junction head is preferable from an areal density perspective.
It can be seen then that there is a need for a method and apparatus for enhancing thermal stability, improving biasing and reducing damage from electrostatic discharge in self-pinned abutted junction heads.
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1. Field of the Invention
The invention relates to a process for preparing vinyl acetate in a heterogeneously catalyzed, continuous gas-phase process by reaction of ethylene with acetic acid and oxygen, with utilization of the heat of reaction liberated during the process.
2. Description of the Related Art
Vinyl acetate is prepared in continuous processes with recirculation of the purified product stream. In a heterogeneously catalyzed gas-phase process, ethylene reacts with acetic acid and oxygen over fixed-bed or fluidized-bed catalysts which generally comprise palladium and alkali metal salts on a support material and can additionally be doped with gold, rhodium or cadmium.
The starting materials ethylene, oxygen and acetic acid are reacted in an exothermic reaction, generally at a pressure of from 1 to 30 bar (pressure values here and in the following in bar gauge) and a temperature of from 130° C. to 200° C. in a fixed-bed tube reactor or fluidized-bed reactor to form vinyl acetate:C2H4+CH3COOH+0.5O2=>CH3COOCH═CH2+H2O
The ethylene conversion is about 10%, the acetic acid conversion is from about 20 to 30% and the oxygen conversion is up to 90%.
In the preparation of vinyl acetate, a gas mixture consisting predominantly of ethylene, carbon dioxide, ethane, nitrogen and oxygen (recycle gas which generally contains from 60 to 70% by volume of ethylene) is circulated. The gas stream is admixed with the reactants acetic acid, ethylene and oxygen upstream of the fixed-bed tube reactor or fluidized-bed reactor and brought to the reaction temperature by means of heat exchangers operated by means of heating steam. The enrichment of the recycle gas with acetic acid is usually effected by means of an acetic acid saturator or acetic acid vaporizer heated by means of heating steam. After the reaction, the reaction products and unreacted acetic acid are condensed out from the recycle gas and passed to work-up. Product which does not condense out is scrubbed out in a scrubber operated using acetic acid.
The recycle gas or part thereof is freed of carbon dioxide formed before it is once again admixed with the starting materials.
The products vinyl acetate and water and also unreacted acetic acid which have been condensed out are separated from one another in a multistage, usually steam-heated, distillation process. The usual distillation steps are dewatering, azeotropic distillation, pure distillation, by-product removal, wastewater purification, residue work-up and low-boiler and high-boiler removal. The production plants for the work-up of the vinyl acetate can vary.
The reaction temperature in the fixed-bed tube reactor or fluidized-bed reactor of from 130° C. to 200° C. is set by means of evaporative water cooling at a pressure of from 1 to 10 bar. This forms steam, known as process-generated steam, having a temperature of from 120° C. to 185° C. and a pressure of from 1 to 10 bar, preferably from 2.5 to 5 bar. The steam can sometimes be somewhat superheated. In this case, the temperature is higher than the boiling point at the respective process-generated steam pressure. This process-generated steam can then be used for heating further process steps of the vinyl acetate preparation, for example for heating individual distillation columns for the fractionation of the product mixture. Such a procedure is described in JP-A 02-091044.
The reaction temperature is set via the operating pressure of the evaporative water cooling and the process-generated steam formed. The decrease in activity of a catalyst over the operating time is compensated by increasing the reaction temperature, i.e. the operating pressure of the evaporative water cooling and of the process-generated steam formed. The reaction temperature and thus the process-generated steam temperature thus vary over time, which leads to utilization problems with the process-generated steam. To spare the catalyst, to optimize the selectivity and to minimize carbon dioxide formation, the vinyl acetate reaction is operated for as long as possible at a low reaction temperature, corresponding to a low process-generated steam pressure.
A disadvantage here is that the process-generated steam can only be used for heating some of the pressure steps because of its low temperature and pressure level. These are, for example, the dewatering column, wastewater purification, the residue work-up which is usually operated under vacuum, a recycle gas heater and various acetic acid vaporizers and heaters. For the further process steps such as azeotropic distillation or pure distillation, external, higher-grade and often superheated heating steam has to be introduced, usually at a temperature of from 160° C. to 250° C. and a pressure of from 5 bar to 15 bar. A further disadvantage is that cooling of the process reactor in which the exothermic gas-phase reaction takes place produces more process-generated steam than can be consumed in the process steps of vinyl acetate preparation and purification because of the pressure and temperature level of the process-generated steam. It is usually possible to consume only from about 75 to 80% by weight of the process-generated steam formed for heating in process steps. The use of the process-generated steam for process steps depends strongly on the apparatus dimensions selected and the pressure level of the heating steam used for operation of the plant.
The remaining amount can either be condensed, which leads to a complete loss of the energy, or alternatively can be passed on to other operations in an integrated works. However, this is complicated in terms of organization and apparatus. In addition, low-pressure steam is mostly used for heating of selected product pipes or buildings, is therefore subject to fluctuations over the year and can therefore often not be completely utilized further.
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1. Field of the Invention
The present invention relates to a manufacturing method of a pattern formed body which has a surface property varied in a pattern form and is used in the manufacture of, for example, a color filter.
2. Description of the Related Art
Conventionally, various methods have been suggested as a manufacturing method of a plurality of pattern formed bodies in which designs, images, characters, circuits or other various patterns are formed on a base material. For example, there are also used lithographic printing, offset printing, a printing method of using a heat-mode recording material to produce a lithographic original master, and other methods. Moreover, there is known, for example, a manufacturing method of a pattern formed body by photolithography, comprising the step of radiating light patternwise to a photoresist layer coated on a base material, developing the photoresist, and then etching the photoresist, or the step of using a material having functionality as a photoresist, and exposing the photoresist to light to form a target pattern directly.
However, the above-mentioned printing methods have: a problem that at the time of manufacturing a highly precise pattern formed body, which is used in such as a color filter, only low location accuracy is attained; and other problems. Thus, it is difficult to use the methods. The above-mentioned photolithography has: a problem that it is necessary to dispose of waste liquid since a photoresist is used and the photoresist is required to be developed with a developing liquid and be etched after exposed to light; and other problems. When a material having functionality is used as the photoresist, there is caused a problem that this material is deteriorated with an alkali solution or the like that is used in development.
Thus, there is suggested a manufacturing method of a pattern formed body, comprising the step of radiating vacuum-ultraviolet light patternwise through a photomask to a pattern forming substrate having a base material and an organic molecule membrane formed on the base material and made of an organic material, thereby decomposing and removing the organic molecule membrane to form a pattern (see Japanese Patent Application Laid-Open (JP-A) No. 2001-324816). According to this method, a pattern formed body can be manufactured without using any photoresist; therefore, the pattern formed body can easily be manufactured without any developing solution or the like.
Such formation of a pattern by use of vacuum-ultraviolet light is attained by decomposition and removal of the organic molecule membrane by action of the vacuum-ultraviolet light. Specifically, when vacuum-ultraviolet light is radiated thereto, molecular bonds of an organic material of the organic molecule membrane are cleaved by action of the vacuum-ultraviolet light; or in the presence of oxygen, oxygen atom radicals generated by excitation of the oxygen act onto the organic material, so that the organic material of the organic molecule membrane becomes a decomposition product and then this product is volatilized and removed from the pattern forming substrate so as to form a pattern.
However, in the case of manufacturing pattern formed bodies continuously by radiation of vacuum-ultraviolet light through a photomask as described above, a decomposition product and so on which are generated on a used pattern forming substrate deposit onto the photomask. This foreign matter hinders the action of the above-mentioned oxygen atom radicals. Conversely, the foreign matter may contribute to a change in the property of the pattern forming substrate. Thus, there remains a problem that patterns having a uniform line width are not easily formed on the pattern forming substrate.
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The present invention relates to a priority execution control method capable of processing as quick as possible a processing request which should be preferentially processed among a plurality of processing requests output from an application program, and an apparatus therefor.
Queues are generally used to absorb the difference between the processing request occurrence frequency per unit time and the processing amount per unit time in an information processing system. As shown in FIG. 17A, a plurality of processing requests 1102 generated in time-series from a processing request source 1101 such as an application program are temporarily stored in a queue 1103.
After the processing requests 1102 are stored in the queue 1103, a processor 1104 reads out one processing request 1102 from the queue 1103 in accordance with a FIFO (First-In First-Out) method. The processor 1104 performs processing in accordance with the contents of the processing request 1102, and outputs a processing result 1105. If another processing request 1102 remains in the queue 1103 after one processing request 1102 is processed, the processor 1104 similarly reads out the processing request 1102 and performs processing.
In FIG. 17A, the processing requests 1102 are sequentially processed in the generation order, and a specific processing request cannot be processed in preference to other processing requests. To preferentially execute a specific processing request, not a single queue but two, priority and normal queues are generally used. As shown in FIG. 17B, processing requests 1102 generated by the processing request source 1101 such as an application program are distributed to a priority queue 1107 and normal queue 1108 by a distributor 1106 in accordance with the processing priority.
The processor 1104 reads out the processing requests 1102 from the priority queue 1107 and normal queue 1108 in accordance with a predetermined rule, processes the processing requests 1102, and outputs processing results 1105. Assume that the predetermined rule is a rule that when a processing request exists in the priority queue 1107, the processing request is read out from the priority queue 1107, and only when no processing request exists, a processing request is read out from the normal queue 1108. In this case, a high-priority processing request 1102 stored in the priority queue 1107 is processed in preference to a processing request 1102 stored in the normal queue 1108.
A conventional priority execution control method using two, priority and normal queues is disclosed in Japanese Patent Laid-Open No. 4-176236 (reference 1). Reference 1 discloses a facsimile apparatus in which transmission data to which either normal or priority transmission is designated is stored in a priority or normal queue in accordance with the designation, transmission data is read out from the priority or normal queue in accordance with a preset ratio between priority communication and normal communication, and the transmission data is transmitted.
A similar priority execution control method is also adopted when a specific packet (e.g., audio packet) is preferentially transmitted by distributing the packet to a priority or normal queue in accordance with head information of the packet for the purpose of QoS (Quality of Service) in the path control apparatus of a packet communication network.
As a method of improving the performance of an information processing system, parallel processing is proposed. However, there is no application of the parallel processing technique to the priority execution control method using two, priority and normal queues. However, parallel operation of the processor 1104 shown in FIG. 17B would be achieved by an arrangement as shown in FIG. 17C. In FIG. 17C, processors 1104A and 1104B have the same function as that of the processor 1104 shown in FIG. 17B. That is, the processors 1104A and 1104B read out processing requests 1102 from the priority queue 1107 and normal queue 1108 in accordance with a predetermined rule, process the processing requests 1102, and output processing results 1105. Since processing means for processing the processing request 1102 operate parallel to each other, the processing amount per unit time increases in the information processing system.
In the priority execution control method shown in FIG. 17B, the probability of extracting the processing request 1102 from the priority queue 1107 is set higher than the probability of extracting the processing request 1102 from the normal queue 1108. A high-priority processing request 1102 stored in the priority queue 1107 can be processed in preference to a processing request 1102 stored in the normal queue 1108.
The following problem, however, arises when the priority queue 1107 is free and the normal queue 1108 stores one or more processing requests 1102. That is, if a high-priority processing request is stored in the priority queue 1107 after the processor 1104 extracts one processing request 1102 from the normal queue 1108 and starts processing, the high-priority processing request is not processed as quick as possible.
In this case, the problem cannot be solved by applying a top priority rule that when a processing request exists in the priority queue 1107, the processing request is read out from the priority queue 1107, and only when no processing request exists, a processing request is read out from the normal queue 1108. This is because when a high-priority processing request is stored in the priority queue 1107, the processor 1104 has executed a processing request extracted from the normal queue 1108, and cannot extract the processing request from the priority queue 1107 unless the current processing ends.
The same problem also occurs in an arrangement in which processors are arranged parallel to each other, as shown in FIG. 17C. If a high-priority processing request is stored in the blank priority queue 1107 while the processors 1104A and 1104B process one processing request 1102 from the normal queue 1108, the high-priority processing request is not processed until either of the processors 1104A and 1104B ends the processing of the current processing request.
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It is known to provide a powered sliding door system for a vehicle such as an automotive vehicle to allow an occupant to enter and exit an occupant compartment through a door opening in a vehicle body of the automotive vehicle. The powered sliding door system typically includes a door extending longitudinally and mounted on tracks for sliding movement to open and close the door opening. The powered sliding door system includes a cable attached to the door and routed through the vehicle body via pulleys so that pulling a first end of the cable opens the door and pulling a second end of the cable closes the door. The powered sliding door system also includes an actuator assembly having first and second reels about which the ends of the cable are wrapped. The actuator assembly includes a motor that drives in one direction, rotating the first reel to open the door, and is reversible to rotate in an opposite direction, rotating the second reel to close the door.
The actuator assembly is typically mounted in a rear compartment of the vehicle body, which varies in depth, width and height. The actuator assembly has a motor mounted on the side that used a clutch and two relatively big gears to provide speed reduction to the actuator assembly. Further, the transmission assembly must provide ease of sliding door movement in both a power and manual mode of operation.
Although the above powered sliding door system has worked well, it is desirable to provide a universal transmission assembly for both right-hand and left-hand sliding doors of the automotive vehicle. It is also desirable to provide multiple stages for speed reduction of the actuator assembly. Therefore, there is a need in the art to provide a transmission assembly for a sliding power door system for an automotive vehicle.
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1. Field of the Invention
The present invention relates to apparatus for supporting a small child adapted to allow linear and rotational movement and more particularly pertains to supporting a child in a seat while allowing the child to walk and rotate within the seat with respect to the frame for entertainment and exercise of the child.
2. Description of the Prior Art
The use of child seats which allow for exercise and entertainment is known in the prior art. More specifically, child seats which allow for exercise and entertainment heretofore devised and utilized for the purpose of supporting a child in a seat so as the child may exercise and entertain itself are known to consist basically of familiar, expected, and obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which has been developed for the fulfillment of countless objectives and requirements.
By way of example, the prior art discloses in U.S. Pat. No. 5,050,504 to Mulcaster a baby walker with safety track feature.
U.S. Pat. No. 4,621,804 to Mueller discloses a therapeutic roller/walker.
U.S. Pat. No. 4,252,063 to Brooks, Jr. discloses a support walker for orthopedic patients.
U.S. Pat. No. 3,985,082 to Barac an electric walker.
U.S. Pat. No. 3,721,437 to Skaricic a walking trainer.
In this respect, the apparatus for supporting a small child adapted to allow linear and rotational movement according to the present invention substantially departs from the conventional concepts and designs of the prior art, and in doing so provides an apparatus primarily developed for the purpose of supporting a child in a seat while allowing the child to walk and rotate within the seat with respect to the frame for entertainment and exercise of the child.
Therefore, it can be appreciated that there exists a continuing need for new and improved apparatus for supporting a small child adapted to allow linear and rotational movement which can be used for supporting a child in a seat while allowing the child to walk and rotate within the seat with respect to the frame for entertainment and exercise of the child. In this regard, the present invention substantially fulfills this need.
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The present invention is directed generally to electrical connectors of a type providing protection from electromagnetic interference (EMI). More particularly, the invention is directed to a multiple contact filer connector capable of conducting high RF currents and a method of fabricating the same at greatly reduced manufacturing cost.
In numerous applications where long unshielded cable runs enter a shielded housing containing circuitry sensitive to extraneous signals picked up by the cable, it is necessary to provide electrical filter networks as an integral part of a connector to suppress transients and other undesired signals, such as EMI, which may otherwise exist on circuits interconnected by the connector. An illustrative prior art filter connector used in such applications is shown and described in Tuchto et al, U.S. Pat. No. 3,854,107, assigned to the same assignee as the present invention.
The filter connector illustrated in the aforementioned Tuchto et al patent includes a dielectric body supporting a plurality of filter contacts and a thin conductive foil ground plate. Each filter contact includes a filter network comprising multiple concentric filter elements coaxially mounted on a reduced diameter portion of the contact and an outer ground electrode. The filter contacts are dimensioned and configured to accommodate insertion and removal from the dielectric body with the ground electrodes contacting the thin foil ground plate through wiping action.
While multiple contact filter connectors of the foregoing variety have proven successful when used to conduct relatively low RF currents of approximately one-quarter ampere, they have not been suitable for conducting high RF currents of, for example, three or more amperes. Because the ground plates are thin, the heat generated by high current conduction cannot be adequately dissipated. As a result, the connectors overheat and, ultimately, fail.
In order to overcome this problem some prior art connectors employ a relatively wide metal ground plate. While such wide metal plates have sufficient mass and conductivity to dissipate the extreme heat generated by high RF current conduction, they are not flexible and, as a result, are not suitable for making low resistance wiping contact with the surface of the network filter ground electrodes. Hence, other means must be provided for establishing the required electrical connection between the ground plate and the network filter ground electrodes. In some prior art connectors the network ground electrode, and therefore the filter itself, is conductively bonded to the ground plate with a conductive adhesive, such as conductive epoxy. This approach, however, engenders other disadvantages. For example, each ground electrode must be individually bonded to the ground plate. Typically, a single connector may include as many as 120 network filters, and as a result, the manufacturing costs in fabricating such a connector in this manner is extremely high. In addition, after fabrication, should one of the network filters be found to be defective, in most cases, the entire connector must be discarded since replacement of the faulty network filter is usually not possible. Moreover, removal of the faulty network filter, if possible, would jeopardize the bond between the ground plate and the other network filters. One suggested solution to this problem is to test each individual network filter prior to its placement and bonding within the connector. But even this approach fails to provide a complete answer because there is always the possibility that one or more of these fragile filters might be damaged during network filter installation and bonding within the connector.
Another significant problem found in connectors having network filters bonded to the ground plate involves the transmission of forces to the contacts and filters during mating and unmating of the connector. These axial forces may be transmitted through the contact to the filter and, as a result, the bond between the network filter ground electrodes and the ground plate may be broken. When this occurs, even with respect to just one network filter, the entire connector usually must be discarded.
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The formation of a contact plug on a semiconductor device is well known in the art. A common process for forming a contact plug comprises applying a layer of silicon dioxide (SiO.sub.2) to a substrate surface of polysilicon, silicon (Si) or metal. A pattern is then formed on the SiO.sub.2 by a standard photoresist process, and a contact or hole is etched into the SiO.sub.2.
Tungsten hexafluoride (WF.sub.6) plus hydrogen (H.sub.2) is used in a chemical vapor deposition (CVD) process, as is well known in the art, to deposit tungsten (W) into the contact. For the CVD process to work, the H.sub.2 must be dissociated into atomic H which is reactive with the WF.sub.6. The combination of WF.sub.6 and atomic H creates W plus hydrogen fluoride (HF). The HF is volatile and, therefore, is rapidly removed as a gas while the W is deposited into the contact.
If the substrate comprises a metallic substance, the metal will provide a catalyst to initiate the disassociation for the H.sub.2. Thus, the W from WF.sub.6 is allowed to attach to the metallic surface and deposit in layers within the contact. The layers are formed generally horizontal from the bottom of the contact to the top of the contact. Horizontal layering is caused because W is selective to the SiO.sub.2, meaning it will not deposit on the SiO.sub.2 sidewalls. However, the layering process takes so long to completely fill the contact that while the layering is proceeding, the top surface of the SiO.sub.2 also being bombarded with the reaction products from the WF.sub.6 and the H.sub.2. Eventually, the SiO.sub.2 surface may become damaged or contaminated, allowing tungsten nucleation to begin where it is not wanted. This forms W bumps on the surface which may create intralevel shorts in subsequent patterned metal layers.
If the substrate is comprised of Si, or certain metal silicides, the Si does not dissociate the H.sub.2 as well as a metal does. Unfortunately, the WF.sub.6 will also react with Si to create silicon tetrafluoride (SiF.sub.4) which is a gas. The SiF.sub.4 creation removes Si from the surface upon which the contact plug is to be built. Thus, as W is deposited, Si is also removed vertically as well as horizontally from under the SiO.sub.2 (encroachment). The removal of the Si in both directions is undesirable as it may cause shorting of p/n junctions positioned near the contact.
Due to the layering effect of the W (W being selective to SiO.sub.2), the W deposition is a time consuming process. The longer the deposition takes, the more likelihood there is of W also being deposited on the surface of the SiO.sub.2. Thus, there is a need for a way to enhance nonselective W deposition in a contact on a substrate without damaging the surrounding surfaces.
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An estimated 187,600 new cases of cancer are expected in Canada in 2013 [1] with radiation therapy (RT) indicated as part of the patient's management in approximately 40 percent of cancer cases [2]. The delivery of RT for the treatment of cancer typically is a complicated process that requires both clinical and technical expertise in order to generate treatment plans that are safe and effective for the treatment of cancer.
For the RT process, patients are imaged with computed tomography (CT) imaging and optionally with multi-modality imaging (e.g. MR, PET) depending on the treatment site. Regions of interest (ROIs) i.e. targets (the locations radiation is directed to) and normal tissue structures (the locations radiation is minimized to) are delineated manually and/or semi-automatically on the acquired images (a). Treatment plans are generated manually, in which the direction of radiation beams and the clinical objectives of the treatment must be specified. An optimization algorithm is then used to generate the intensity and/or shape and/or modulation of radiation beams to achieve the treatment objectives (b). A dose distribution, a spatial representation of the radiation dose the patient will receive, can then be calculated. Therefore, the dose distribution (also referred to as a dose map) is directly connected with the anatomical imaging acquired from the RT process to relate the dose and spatial information specific to the patient.
In addition, the dose distribution is used to quantitatively evaluate the dose received by the delineated ROIs for assessing treatment plan quality and safety (c). The steps (a-c) are repeated until an acceptable plan is generated. Finally, the completed treatment plans are then reviewed by the multi-disciplinary RT team for quality, safety and compliance with established clinical protocols before the treatment plan will be delivered to the patient.
RT Quality Assurance
The RT treatment plan quality assurance (QA) process typically relies on the vigilance of the multi-disciplinary team to review and assimilate relatively complex data from different sources. Human vigilance has been found to be effective in the treatment plan QA process in about 80 percent of cases [3] and for preventing treatment incidents in about 98 percent of cases [4,5]. As a result, sub-optimal treatment plans, which have the potential to result in a significant detriment to the patient, may be used clinically. Several studies have shown treatment plans, which deviate from established QA guidelines, result in worse patient outcomes [6,7]. Therefore, the current RT process may require substantial multi-disciplinary QA resources to reduce the likelihood of errors and to ensure a high standard of patient care.
The multi-disciplinary RT team comprising radiation therapists, physicists and oncologists typically reviews each proposed treatment plan for clinical and technical merit. This review typically includes assessing safety (e.g., that the proposed plan does not exceed any normal tissue dose tolerances), deliverability (e.g., the dose calculated in the proposed treatment plan can be reproduced on the treatment unit), consistency in the transfer of data between databases (e.g., the parameters defining the proposed plan are the same parameters to actually treat the specific patient) and overall quality (e.g., the proposed plan is consistent with other plans for the given site and technique in terms of the dose prescription, the dose distribution, target coverage etc.) [8-19].
This process is typically largely manual and complex, as there may be numerous parameters that require human expert review. This has lead to an interest in automated QA methods in order to reduce the reliance on human vigilance [20-23]. Methods developed to date have shown promise only in a limited clinical scope.
RT Planning
Technical innovations in RT have improved the quality of treatment plans usually at the cost of increased complexity. However, treatment planning still remains a highly manual process, which requires users to delineate numerous regions of interest (ROIs) for treatment planning and set treatment objectives for an optimization engine to solve. For example, optimization objectives may specify the target ROI must receive >95% of the prescription dose to >95% of the target volume while a healthy organ must receive <100% of the prescription dose to 1 cc of the organ volume.
The process almost always involves multiple iterations, as changes to the objectives and the ROIs themselves are required to generate an acceptable treatment plan. To date, conventional automated treatment planning methods have focused on setting objectives and then optimizing those objectives to generate the dose distribution (also referred to as a dose map). Such a process still requires ROI delineation, beam placement, and manual adjustment of the objectives.
In addition, the variation in ROI delineation and treatment plan quality is well-established [24, 25]. The use of automation may help to improve consistency and add standardization to the process [26].
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A supplier who competes in a market with one or more competitors is faced with the challenge of continuously pricing their goods and services. If a supplier understands the market's responsiveness to price as well as the supplier's cost, a supplier can determine the optimal price that ensures meeting one or more of the following business objectives; a) Maximizing revenue, b) Maximizing Gross Profit, c) Maximizing Earnings Before Income Tax, d) Market share, e) Factory utilization, and more. In addition to determining the optimum price to meet the designated business objective, the supplier may desire a capability to automatically update the optimal price as the market changes, forecast the supplier's financial performance based on the new optimized price, as well as forecast the performance of the supplier's competitors.
Prior art has multiple limitations that not only prevent a supplier from making an initial useable estimate of the optimal price, but also from making an accurate update of the optimal price, and forecasting the financial performance of the supplier and its competitors. The limitations begin with inaccuracies and potentially incorrect assumptions associated with the demand or yield curve, which depicts the relationship between quantity and price. These inaccuracies are the result of one or more of the following problems; a) Limited span in sales order data in which to build the demand curve, b) Lack of statistically relevant sales order data, c) Lack of market relevant sales order data, d) Implicit assumption that the historical and future sales environments remain the same, e) Lack of a rapid method for assessing whether a new optimized price is required as a result of a shift in market demand or pricing, f) Lack of a method of rapidly updating the optimized price calculation.
The demand curve is typically constructed using the supplier's historical sales order data, which limits the extent and completeness of the demand curve. For example, if the supplier behaves as the “low price leader”, the sales order data can only be used to create a demand curve reflecting how the market responds to low pricing.
The demand curve should depict the market's responsiveness to all pricing scenarios, not just those scenarios, previously employed by the company. As a result of using a demand curve constructed using a limited span of sale order data, it is not likely that the optimum price can be determined.
Another challenge in constructing the demand curve is the lack of statistically relevant data. Frequently, there are pieces of sales data which conflict. An example is that one customer was willing to pay $2.23 each for 10,000 units. Another customer, in the identical customer group may demand 11,500 units for $2.23 each, a 15% difference in quantity. This situation is not unusual, especially for opaque markets where one buyer does not see what other buyers are paying and therefore facilitates a supplier charging different unit prices for the same goods or services. The current art attempts to resolve this situation through averaging algorithms and requires sufficient sale order data for statistical relevance. The challenge is that there is seldom-sufficient data to build a statistically relevant demand curve.
Yet another challenge with the current art is that even if the demand curve is statistically relevant, it is not market relevant. Statistical relevance can be assured through a large enough set of sales orders. However, collecting a large set of sales orders may necessitate waiting long periods of time to allow a sufficient number of orders to be accumulated for statistical relevance. During the long collection period, the market may have changed considerably in its responsiveness to pricing. So while the demand curve may have statistical relevance, it is meaningless because it is based on data too old for market relevance. As a consequence, determining an optimum price based on a data demand curve is unlikely.
In the current art, there is an implicit assumption that the historical sales and future sales environments are identical. For example, if the derived demand curve indicates that 10,000 units were sold when the price was $3.25, the expectation going forward is that the supplier will again sell 10,000 units at $3.25. The implicit assumption is that the overall economic environment, the supplier's approach to marketing, and selling methodology has remained the same. Rarely do the economic environment, the supplier's marketing, and selling methodologies remain intact for any length of time. As a consequence, the validity of the demand curve is questionable and its usefulness in doubt.
Without a representative demand curve, it is impossible to determine an optimum price that ensure meeting one or more of the following business objectives; a) Maximizing revenue, b) Maximizing Gross Profit, c) Maximizing Earnings Before Income Tax, d) Market share, e) Factory utilization, etc.
Even if prior art could overcome the aforementioned issues associated with the span of sales order data, statistical relevance, market relevance, and the accommodate changes in selling methodologies, prior art still must overcome the final issue of rapidly determining when market shifts in pricing and demand necessitate updating the demand curve. Without a method for rapidly determining when the demand curve is no longer representative of the market's responsiveness to price, a supplier will continue under the presumption that the current price is optimal when the market shifts have necessitated that a new optimal price is needed.
In accuracies and poor assumptions aside, once a demand curve is created, the supplier can make a determination of how to price their goods and services in order to satisfy certain business objectives. With an understanding of the relationship between quantity and price, an income statement, as well as additional metrics, can be constructed for each price through the following steps; a) Calculation of revenue by multiplying the price and quantity, b) Determination of the cost-of-goods by multiply the quantity and unit cost at that quantity, c) Calculation of gross profit by subtracting the cost-of-goods from the revenue, d) Determining the sales and general administration costs, e) Calculating the earnings before income tax by subtracting the sales and general administration costs from the gross profit, f) Calculation of market share by dividing the quantity by the total quantity sold by all suppliers, and e) Calculating factor utilization by dividing the units sold by the capacity of the factory for that product.
Once the income statement and additional metrics are calculated for each price, the optimum price can be selected to satisfy various business objects. For example, the supplier may wish to optimize pricing to maximize revenue. To identify the optimum price that maximizes revenue, the income statements are searched to identify where the revenue is maximized and the associated price extracted.
In addition to optimizations with one objective in mind, optimizations are possible that maximize the multiple business objectives. For example, the supplier may wish to optimize pricing to maximize revenue and gross profit. In this example, the income statements are searched for the price at which revenue is maximized and the price at which gross profit is maximized. The supplier then selects a price between the maximum gross profit and revenue price that represents the best tradeoff between these two business objectives.
While forecasting an income statement for a supplier using price optimization remains a challenge because of the limitation of prior in creating a demand curve, accurately modeling the financial performance of a supplier with optimization and their competitors is an even steeper challenge. If the optimized supplier lowers their price, sales volume is likely to increase with a corresponding reduction in sales for other suppliers. In the absences of an accurate relationship of price and quantity for any of the suppliers, it is challenging if not impossible to predict the financial performance of the suppliers.
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The device relates to microwave-assisted magnetic recording for data storage. More specifically the device relates to spin torque oscillators used to generate high-frequency magnetic fields for microwave-assisted magnetic recording.
Perpendicular spin torque oscillators have been used to generate AC magnetic fields at microwave frequencies in thin film magnetic recording media to assist magnetic recording process. A conventional spin torque oscillator typically consists of one polarization layer for spin polarizing the injected electron current (polarizing in terms of spin orientation), yielding a spin transfer torque within the oscillating layer (also called field-generating layer).
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This invention relates to a junction box assembly, such as an electrical connection box assembly mounted on a vehicle or the like.
In various assembly processes, such as automobile assembly processes, many cable connections must be made, e.g., within the electrical system of a vehicle. Connections are often made using connectors, such as plug-in-type connectors.
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1. Field Of The Invention
This invention relates to a translucent block and, more particularly, to a translucent block having a 45.degree. dihedral angle formed by the projected planes of the side faces of the translucent block which can be utilized with similar translucent blocks and blocks of other shapes to provide various column and wall structures. The invention also includes the method of forming such column and wall structures.
2. Description Of The Prior Art
The use of translucent block, such as glass block, for exterior and interior applications is well known. Using glass block for various wall structures offers various aesthetic and design features, as well as providing various functional characteristics and advantages over other materials which may be used for similar purposes. For example, glass block structures promote energy conservation through their insulating capability to reduce heat gain or loss and provide thermal efficiencies for energy conservation. Additionally, glass block structures can control light transmission and glare, as well as reduce surface condensation, and draft and noise transmission. Because of their construction, glass block structures offer security advantages as well as maintaining light transmission therethrough. Further, glass block structures have the added advantage of ease of maintenance and installation.
U.S. Pat. No. Des. 114,085 discloses a corner block configuration having arcuate walls and appears to be formed of two halves having different configurations. One of the halves also has raised linear portions as an exterior design. The angle formed by the side walls appears to be a wider angle than 45.degree..
U.S. Pat. No. 2,086,185 discloses an integrally blown hollow glass block of regular hexagonal form. This prior art patent also discloses a masonry structure or wall including the hexagonal glass block positioned with mortar in a configuration wherein the hexagonal sides would combine to form the exterior surface of the structure or wall.
U.S. Pat. No. 2,281,524 discloses glass building blocks molded in a single piece and using a socket in socket construction. The disclosed glass block is formed at a 90.degree. angle and has an open bottom.
U S. Pat. No. 4,537,001 discloses building elements with sides that have mathematical relations to each other
U.S. Pat. No. 4,636,413 discloses a glass block that has at least approximately the shape of a sector of a circular cylinder, the side faces forming the sector of the circular cylinder and having an axis defined by the side faces of the cylinder including an angle of 45.degree. or 90.degree.. The end wall opposite the 45.degree. or 90.degree. axis is an arcuate end wall.
U.S. Pat. No. 4,651,486 discloses a translucent block having a generally irregular hexagonal configuration which can be utilized with similar translucent blocks and blocks of other shapes to provide various column and wall structures. The method of forming such column and wall structures is also disclosed.
U.S. Pat. No. 4,719,735 discloses a translucent end cap for use with a translucent glass block. The end cap has top and bottom surfaces parallel to each other. The side surfaces are perpendicular to and joined to the top and bottom surfaces. A raised rear surface portion extends from the side surface to form a protrusion so that the end cap may be secured to an abutting side surface of a translucent glass block.
U.S. Pat. No. 4,852,321 discloses a translucent end block which may be secured to an exposed top or side abutting surface of a translucent block to provide a wall structure in which the exposed top or side surface of the wall structure does not require wood or similar coverings to form useable top or side surfaces.
Accordingly, there remains a need for a translucent block configuration which can be employed as a corner piece for joining translucent block walls at an angle of 45.degree. or larger angles by using a plurality of such blocks for corner sections or can be independently employed to form walls and columns of different configurations.
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Portable communication and computing devices such as smartphones, mobile phones, tablets etc. are compact devices which are powered from rechargeable battery sources. The compact dimensions and battery source put severe constraints on the maximum acceptable dimensions and power consumption of microphones and microphone amplification circuit utilized in such portable communication devices.
US 2011/0051954 A1 discloses a signal conditioner for a capacitive transducer. The signal conditioner includes a differential preamplifier which includes a non-inverting input connected to a microphone transducer output and a separate inverting input connected to the output of a feedback path. The feedback path includes a digital-to-analogue converter and extends from an output of an analogue-to-digital converter to the inverting input of the preamplifier.
However, there exists a continued need to improve the sound quality and robustness of microphone assemblies for example by accurately controlling the frequency response and reducing or eliminating overload distortion of signal processing circuits like microphone preamplifiers at high sound pressure levels. The overload and distortion problems are often caused by saturation and non-linearity of active amplification elements like transistors of the signal processing circuits.
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Pets are an increasing part of everyday life. As such, people are taking their pets with them in their vehicles more often. Transporting a pet or pets within a vehicle can be difficult if the pet or pets are not prevented from accessing certain areas of the vehicle at certain times. There is therefore a need for a means of containing pets into an area of the car which is safe for the pet and the occupants of the vehicle.
Currently, there are two main ways to curtail the movement of a pet within an area of a vehicle. The first type is a manually installed and adjusted barrier which may be erected and adjusted by hand. This provides a mechanical barrier between areas of a vehicle to restrict the animal's movement. The second type of restriction uses a harness and tether or other mechanical restraint to prevent the animal's movement. Some variations of this allow the user vary the length of the restraint tether to restrict the animal's movement based on a computerized identification tag.
While the described methods of restraining an animal within a vehicle's interior are generally effective, these both require fairly substantial user intervention in order to implement. Harnesses require that the user connect a wriggling animal to the proper restraint points, and the use of net barriers require an involved take-down procedure when not in use.
Currently, methods exist for detecting of occupants within vehicles using a variety of techniques, such as thermal, activation, weight, motion, etc. Utilizing these techniques, it is possible to detect the presence of an animal within a vehicle.
While the aforementioned examples have previously attempted to solve aspects of this problem, there has been no solution which allows for an easy, automatic, and adjustable way to contain a pet in a particular area of a vehicle.
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The invention relates to high throughput methods for identifying the function of sample nucleic acids and their products. The invention is exemplified by the use of the E1-complementing adenoviral packaging cell line PER.C6 in combination with an E1-deleted plasmid-based generation system to produce recombinant adenoviral vectors in a high throughput setting to functionate the product of a sample nucleic acid.
The ultimate goal of the Human Genome Project is to sequence the entire human genome. The expected outcome of this effort is a precise map of the 70,000-100,000 genes that are expressed in man. However, a fairly complete inventory of human coding sequences will most likely be publicly available sooner. Since the early 1980s, a large number of Expressed Sequence Tags (ESTs), which are partial DNA sequences read from the ends of complementary DNA (cDNA) molecules, have been obtained by both government and private research organizations. A hallmark of these endeavors, carried out by a collaboration between Washington University Genome Sequencing Center and members of the IMAGE (Integrated Molecular Analysis of Gene Expression) consortium (http:/www-bio.llnl.gov/bbrp/image/image.html), has been the rapid deposition of the sequences into the public domain and the concomitant availability of the sequence-tagged cDNA clones from several distributors (Marra, et al. (1998) Trends Genet. 14 (1):4-7). At present, the collection of cDNAs is believed to represent approximately 50,000 different human genes expressed in a variety of tissues including liver, brain, spleen, B-cells, kidney, muscle, heart, alimentary tract, retina, and hypothalamus, and the number is growing daily.
Recent initiatives like that of the Cancer Genome Anatomy project support an effort to obtain full-length sequences of clones in the Unigene set (a set of cDNA clones that is publicly available) by the year 1999. At the same time, commercial entities propose to validate 40,000 full-length cDNA clones by 1999. These individual clones will then be available to any interested party. The speed by which the coding sequences of novel genes are identified is in sharp contrast to the rate by which the function of these genes is elucidated. Assigning functions to the cDNAs in the databases, or functional genomics, is a major challenge in biotechnology today.
For decades, novel genes were identified as a result of research designed to explain a biological process or hereditary disease and the function of the gene preceded its identification. In functional genomics, coding sequences of genes are first cloned and sequenced and the sequences are then used to find functions. Although other organisms such as Drosophila, C. elegans, and Zebrafish are highly useful for the analysis of fundamental genes, animal model systems are inevitable for complex mammalian physiological traits (blood glucose, cardiovascular disease, inflammation). However, the slow rate of reproduction and the high housing costs of the animal models are a major limitation to high throughput functional analysis of genes. Although labor intensive efforts are made to establish libraries of mouse strains with chemically or genetically mutated genes in a search for phenotypes that allow the elucidation of gene function or that are related to human diseases, a systematic analysis of the complete spectrum of mammalian genes, be it human or animal, is a significant task.
In order to keep pace with the volume of sequence data, the field of functional genomics needs the ability to perform high throughput analysis of true gene function. Recently, a number of techniques have been developed that are designed to link tissue and cell specific gene expression to gene function. These include cDNA microarraying and gene chip technology and differential display messenger RNA (mRNA). Serial Analysis of Gene Expression (SAGE) or differential display of mRNA can identify genes that are expressed in tumor tissue but are absent in the respective normal or healthy tissue. In this way, potential genes with regulatory functions can be separated from the excess of ubiquitously expressed genes that have a less likely chance to be useful for small drug screening or gene therapy projects. Gene chip technology has the potential to allow the monitoring of gene expression through the measurement of mRNA expression levels in cells of a large number of genes in only a few hours. Cells cultured under a variety of conditions can be analyzed for their mRNA expression patterns and compared. Currently, DNA microarray chips with 40,000 non-redundant human genes are produced and are planned to be on the market in 1999 (Editorial (1998) Nat. Genet. 18(3):195-7.). However, these techniques are primarily designed for screening cancer cells and not for screening for specific gene functions.
Double or triple hybrid systems also are used to add functional data to the genomic databases. These techniques assay for protein-protein, protein-RNA, or protein-DNA interactions in yeast or mammalian cells (Brent and Finley (1997) Annu. Rev. Genet. 31:663-704). However, this technology does not provide a means to assay for a large number of other gene functions such as differentiation, motility, signal transduction, and enzyme and transport activity. Yeast expression systems have been developed which are used to screen for naturally secreted and membrane proteins of mammalian origin (Klein, et al. (1996) Proc. Natl. Acad. Sci. USA 93 (14):7108-13). This system also allows for collapsing of large libraries into libraries with certain characteristics that aid in the identification of specific genes and gene products. One disadvantage of this system is that genes encoding secreted proteins are primarily selected. A second disadvantage is that the library may be biased because the technology is based on yeast as a heterologous expression system and there will be gene products that are not appropriately folded.
Other current strategies include the creation of transgenic mice or knockout mice. A successful example of gene discovery by such an approach is the identification of the osteoprotegerin gene. DNA databases were screened to select ESTs with features suggesting that the cognate genes encoded secreted proteins. The biological functions of the genes were assessed by placing the corresponding full-length cDNAs under the control of a liver-specific promoter. Transgenic mice created with each of these constructs consequently have high plasma levels of the relevant protein. Subsequently, the transgenic animals were subjected to a battery of qualitative and quantitative phenotypic investigations. One of the genes that was transfected into mice produced mice with an increased bone density, which led subsequently to the discovery of a potent anti-osteoporosis factor (Simonet, et al. (1997) Cell. 89(2):309-19). The disadvantages of this method are that the method is costly and highly time consuming.
The challenge in functional genomics is to develop and refine all the above-described techniques and integrate their results with existing data in a well-developed database that provides for the development of a picture of how gene function constitutes cellular metabolism and a means for this knowledge to be put to use in the development of novel medicinal products. The current technologies have limitations and do not necessarily result in true functional data. Therefore, there is a need for a method that allows for direct measurement of the function of a single gene from a collection of genes (gene pools or individual clones) in a high throughput setting in appropriate in vitro assay systems and animal models.
The development of high throughput screens is discussed in Jayawickreme and Kost, (1997) Curr. Opin. Biotechnol. 8:629-634. A high throughput screen for rarely transcribed differentially expressed genes is described in von Stein et al., (1997) Nucleic Acids Res. 35: 2598-2602. High throughput genotyping is disclosed in Hall et al., (1996) Genome Res. 6:781-790. Methods for screening transdominant intracellular effector peptides and RNA molecules are disclosed in Nolan, WO97/27212 and WO/9727213.
The invention includes methods, and compositions for use therein, for directly, rapidly, and unambiguously measuring the function of sample nucleic acids of unknown function in a high throughput setting, using a plasmid-based E1-deleted adenoviral vector system and an E1-complementing host cell. The method includes constructing a set of adapter plasmids by inserting a set of cDNAs, DNAs, ESTs, genes, synthetic oligonucleotides, or a library of nucleic acids into E1-deleted adapter plasmids; cotransfecting an E1-complementing cell line with the set or library of adapter plasmids and at least one plasmid having sequences homologous to sequences in the set of adapter plasmids and which also includes all adenoviral genes not provided by the complementing cell line or adapter plasmids necessary for replication and packaging to produce a set or library of recombinant adenoviral vectors preferably in a miniaturized, high throughput setting. To identify and assign a function to product(s) encoded by the sample nucleic acids, a host is transduced in a high throughput setting with the recombinant adenoviral vectors, which express the product(s) of the sample nucleic acids and thereby alter a phenotype of a host. The altered phenotype is identified and used as the basis to assign a function to the product(s) encoded by the sample nucleic acids. The plasmid-based system is used to rapidly produce adenoviral vector libraries that are preferably replications competent adenovirus (xe2x80x9cRCAxe2x80x9d)-free for high throughput screening. Each step of the method can be performed in a multiwell format and automated to further increase the capacity of the system. This high throughput system facilitates expression analysis of a large number of sample nucleic acids from human and other organisms both in vitro and in vivo and is a significant improvement over other available techniques in the field.
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Moveable or roaming objects, including persons and animals, may be required, for various reasons, to be located by a third party or system, from a remote location. Examples for such needs may include persons in distress, particularly children, adults or handicapped people that require assistance, lost pets, stolen vehicles to be restored and transported assets to be tracked on their way.
A conventional technique for locating roaming objects from remote location(s), involves utilizing wireless devices that are attached to these objects, in advance, and a radio network capable of communicating with these wireless devices and transmitting signals from which their location may be interpreted by a remote receiver. The communication channels in such network may comprise wireless and wireline elements, and the components of the network/system may be terrestrial, extraterrestrial airborne and space-borne. In some cases, this wireless location network serves also for telecommunications (“telecom”) of generic information, such as voice, data or video signals.
One particular framework for wireless location is promoted by the U.S. Federal Communications Commission (FCC), in order to locate cellular handsets operated by people in emergency situations. This plan is known as the “E911” act, an augmentation to the “911” service (a service that is provided in the U.S.A.), designed to handle distress calls, either from fixed or from mobile phones. Currently, the 911 service is capable of locating fixed phones, while in the future it is planed to be capable of locating mobile phones as well, for the same purpose of emergency assistance. For further information, see: http://www.fcc.gov/e911/ and also CFR (Code of Federal Regulations) Title 47, Volume 2, Parts 20 to 39, [Revised as of Oct. 1, 1999] PART 20-COMMERCIAL MOBILE RADIO SERVICES—Sec. 20.18-911 Service.
Several methods are known in the art for wirelessly determining the location of roaming devices. One known group of methods is based on dedicated Telecom networks or dedicated segments of a Telecom network. These methods are usually referred to as “network based”, i.e., they employ a wide area array of antennas and transceivers coupled together, such that a roaming wireless device can be located whenever being contained within the area that is covered by said antennas. Such methods usually require minimal modifications in the communication devices the location of which is to be determined by this network.
The latter methods are further subdivided into “sub-methods”. One such sub-method measures the Angle of Arrival (AOA) of a signal emitted by a roaming wireless device, received at least at two of the network's antennas. Knowing the location of these antennas and the AOA of the received signal, the location of the roaming wireless device can be derived by trigonometric calculations.
Another sub-method measures the Time of Arrival (TOA) of a signal emitted by the roaming wireless device, received at least at three of the network's antennas. Knowing the location of these antennas and the TOA of the received signal, the location of the roaming wireless device can be derived. The TOA method is based on spherical radio navigation, i.e., the geometric locus of points having a same range from a fixed point is a sphere surface, the fixed point of which is its center. In case of TOA, the fixed points are the receiving network's antennas and the range is [TOA×C] for each receiving antenna, wherein “C” is the velocity of light or electromagnetic waves. The location of the roaming device is calculated as one of the two points, defined by the crossing sector of all three sphere surfaces (the crossing sector of two spherical surfaces is a circle, and this circle crosses a third sphere surface at two points). Sometimes, a fourth antenna is used to remove this ambiguity or to compensate for clock discrepancies.
The Global Positioning System (GPS), as described hereinafter, is based on a TOA method as well. In addition, if the roaming device is known to be essentially on the ground (e.g., mounted in a car), the earth globe, with proper topography, can be used as an additional reference “sphere” to refine the TOA calculations. This approach is especially useful for GPS navigating vessels, particularly in oceans, where the altitude is constant (i.e., is the sea level).
One useful variation of TOA is TDOA (Time Difference Of Arrival), where a difference in time of arrival of one transmitted signal is measured at two different receivers. This method was originally developed for radio navigation systems as LORAN-C and OMEGA, however slightly different—the time difference between two signals, transmitted synchronously from two remote sites, is measured at the LORAN-C or OMEGA receiver. Both variations of TDOA are based on hyperbolic radio navigation, i.e., the geometric locus of points that have a common difference in range from two fixed points is a hyperbola. In TDOA, as in TOA and GPS, time measurements provide range estimation (“pseudorange”), since [time×C=range]. In order to determine the actual location of a moveable device by TDOA, at least three reference antennas are required, to provide two hyperbolas that cross each other at one point, being the required actual location. For further information, see the book “AMERICAN PRACTICAL NAVIGATOR” by N. Bowditch, Pub. No. 9, volume 1, part eight (ELECTRONICS AND NAVIGATION), published by the DEFENSE MAPPING AGENCY HYDROGRAPHIC CENTER, USA DoD.
An exemplary system that utilizes TDOA and AOA methods for location determination is Sigma-5000 TDOA-AOA, which has been developed by “SigmaOne” (Rehovot science park, Israel). See also www.sigma-1.com/index_flash.htm. However, network-based methods for wireless location determination, require a dedicated infrastructure of antennas and transceivers, which is costly and takes substantial time to deploy.
Another known group of methods for wirelessly determining the location of roaming devices is based on self-location capabilities incorporated in the Telecom end unit (e.g., a wireless “handset” device). The unit location can be measured at the unit itself by utilizing corresponding sensors, embedded in the unit. Then, a signal representing this location is transmitted wirelessly over the network to a place where it is required. These methods are usually referred to as “handset based”.
One handset based sub-method uses a GPS receiver embedded in a mobile Telecom unit. A GPS receiver measures its position by processing signals received from navigation satellites, launched by the U.S. Department Of Defense (DOD). Signals from at least 4 satellites are required to reach the antenna of the GPS receiver, in order to allow calculating its location. GPS technology is based on a TOA method, however slightly different—multiple transmissions are received at a single receiver. Due to clock discrepancies between satellites and GPS receivers, at least four in-view satellites are required in order to determine a GPS position (only three are required if the altitude is known, as in case of ocean navigation).
The GPS geographic position is expressed in latitude and longitude coordinates, in addition to altitude above sea level. GPS uses the World Geodetic System defined in 1984 (“WGS-84”). Though there are about 100 different local grids in use by cartographers in different parts of the world, in addition to different map projections, WGS-84 coordinates can be converted to any other reference grid.
GPS receivers have two different versions, military (P code) and civilian (C/A code). After the removal of the intentional degradation—“Selective Availability” (S/A) from the GPS signals, a C/A code GPS receiver can typically achieve an accuracy of better than 50 meters (rms). This position, practically expressed in about 10 bytes, can easily be transmitted over the network, by the same Telecom unit that contains the GPS receiver, to a place where it is required. For further information one might reference the web site www.trimble.com/gps/.
Examples for such prior art technologies are products of “SiRF” (California, U.S.A.) Particularly, those following SiRF's handset-based SiRFstar TM architectures SiRFstarI and SiRFstarII. For further information one might reference the web site www.sirf.com/.
Other prior art systems introduce capabilities for short-range wireless connectivity in cellular handsets and mobile computers. This type of connectivity is normally required for forming wLANs (wireless Local Area Networks) or wPANs (wireless Personal Area Networks), while the primary cellular network is usually referred as wWAN (wireless Wide Area Network). Usually, wLANs support faster data rates and larger transmission distances than wPANs. The typical state of the art of a wLAN transmitter range is about 500 meters, while a wPAN transmitter range is typically 10-100 meters. One specific standard for wLANs is IEEE 802. 11. WPANs typically replace short communication cables, supporting wireless handset peripherals, such as a keyboard, screen/display, headset, speaker and microphone, or data communications between a cellular handset and a Personal Digital Assistance (PDA), e.g., for updating a telephone list. One of the standards for short-range wireless connectivity (wPAN) is “Bluetooth” (“BT”), originally defined by Ericsson, Sweden, which utilizes wireless digital connectivity over the 2.4 GHz unlicensed band, using frequency hopping spread spectrum modulation, at 721 Kbps (revision 1.1). No line of sight is required between a transmitter and a receiver and the typical communication range is 10-100 meters, depending on which transmission class, chosen from one of the three available classes of maximum RF power, is in use: 1 mw (class 3), 10 mw (class 2) or 100 mw (class 1). Several schemes of power saving, error correction, authentication and encryption are included in the BT standard. Each BT device is assigned a unique 48 bits ID. BT devices form ad hoc “piconets”, even among devices that have no previous coordination, with up to 8 peer devices, one of which is considered a master device. Basically, the unit that initiates the connection is defined as master of the piconet. However, these roles can be switched over. For further details, one might reference the web site www.Bluetooth.com.
Currently, state of the art of BT technology allows the implementation of almost a full BT digital radio, including RF and baseband circuitry, in a smaller than 10×10 mm chip size. For example, see Cambridge Silicon Radio (CSR) “bcO1” chip, Philips “PCD 87750” or Ericsson's “PBA 3131” radio chip.
Since BT chips are also low power consumers, typically 100 mw in active mode (receive or transmit—class 3) and about 1 mw in standby mode (“page scan” or “inquiry scan” or “park”), they fit battery operation, and particularly designed to be embedded in cellular handsets and portable computers.
Several models of BT-enabled cellular handsets have already been introduced to the market, as “Ericsson R520”, “Nokia 6310” and “Motorola Timeport 270c”.
U.S. Pat. No. 6,246,376 discloses a method for refining GPS positioning by data provided over a Bluetooth (BT) connection, or by the BT received signal. This method might be utilized, for example, for measuring azimuth. A cellular handset is utilized, which includes a GPS receiver, a BT radio and additional navigation circuitry, for example a “north-finder”/compass. Such handset calculates its position by GPS, while utilizing also the received BT data signal. However, handset-based wireless location devices are expensive, consume a considerable amount of power, are relatively big in size and radiate substantial RF power.
There is another group of known methods for wireless location, which is based on a combination of network and handset based capabilities. Such methods are usually referred to as “hybrid solutions”. For example, WO/0150151 discloses a way for locating cellular handsets that include a GPS receiver. The data received by the GPS receiver is enhanced, particularly when satellites are blocked, by providing positioning data by nearby Bluetooth base stations.
Many wireless location systems are deployed and expected to be further deployed in the future, particularly systems to locate cellular handsets over cellular networks. The urge for the deployment is driven by Federal and state regulations, as well as by the need for location based commercial services.
All the methods described above have not yet provided satisfactory solutions to the problem of wirelessly determining the location of small, inexpensive and low power roaming devices, over a wide area, without requiring a dedicated infrastructure.
It is an object of the present invention to provide a system and method for wirelessly determining the location of devices, by leveraging the location determining capability of conventional positioning systems, such as those used to locate cellular handsets, to determine the location of a different type of wireless devices, smaller and cheaper, by wirelessly linking between both types of devices.
It is another object of the present invention to provide a system and a method for wirelessly determining the location of devices, by utilizing existing and widespread active Telecom units (“communication devices”), such as mobile telephones, to be used as gateways or access points for a second tier of wireless devices, forming a large and dense mobile communication infrastructure for said wireless devices, over a wide area.
It is still another object of the present invention to provide a system and a method for wirelessly determining the location of devices, by utilizing the existing infrastructure of a communication network having positioning capabilities.
It is yet another object of the present invention to provide a system and method for wirelessly determining the location of roaming objects in an area covered by a Telecom network, by using location determining devices which are small, inexpensive and having low power consumption.
It is yet another object of the present invention to provide a system and method for wirelessly determining the location of roaming objects in an area covered by a Telecom network, by using location determining devices, which emit low RF radiation and reduce potential risk to their carriers.
It is yet another object of the present invention to provide a system and method for wirelessly determining the location of roaming objects in an area covered by a Telecom network, by using location determining devices which do not require human interface/intervention.
It is yet another object of the present invention to provide a system and method for wirelessly determining the location of roaming devices, in an area covered by a Telecom network, that minimizes the amount of data that should be transmitted over the Telecom network.
Other objects and advantages of the invention will become apparent as the description proceeds.
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1. Field of the Invention
This invention relates to a water intake screen installation having an endless belt strainer that is cleaned by a submerged backwash current.
2. Description of the Prior Art
U.S. Pat. No. 2,804,209, that issued Aug. 27, 1957, to Carlton et al, shows a traveling water screen unit that removes both refuse and fish from a flowing stream of water. Above the surface of the stream, refuse is dislodged from the screen and directed by a water spray into a disposal trough that conveys the refuse to a location where it is disposed of in a non-polluting manner. Another water spray flushes fish from holding pans into another trough whereby the fish are returned to the stream at a remote location.
Energy is required to lift refuse, water and aquatic life from a stream of water. Such refuse removed from the water must be disposed of in a non-polluting manner such as burning or burying. Aquatic life, that is removed with water from the stream in a holding pan, then flushed from the pan into a trough, and later returned by the trough to the stream at a remote location, is subjected to a hazardous journey. The impact force of flushing water sprays can injure aquatic life.
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1. Field of the Invention
This invention relates to a color image forming apparatus having a color process cartridge capable of being inserted into and withdrawn from an apparatus body, and discarded when it reaches the limit of use.
2. Description of the Prior Art
The conventional color image forming apparatuses using a transfer drum is disclosed in Japanese Patent Laid-Open No. 61-123257 In the apparatus disclosed in this laid-open publication, a color image is formed by reading a document, modulating a laser beam by a digital signal obtained and writing the information on an image retainer to form an electrostatic latent image thereon, developing this image by a rotary type color developing device, and transferring the toner images of various colors obtained to a transfer paper on a transfer drum sequentially to fix the same thereon Japanese Patent Laid-Open No. 58-72159 proposes a transfer drum type color image forming apparatus having a process cartridge in which an image retaining drum, a plurality of developing devices and a cleaning device are unitarily incorporated This laid-open publication includes a statement to the effect that the apparatus may also have an interchangeable black-and-white image forming process cartridge.
Since the image retaining drum, developing devices and cleaning device are incorporated in the cartridge as stated in Japanese Patent Laid-Open No. 58-72159, a user can prevent an unnatural copying operation which causes scatter of the quality of the images obtained, and the manufacturer can easily guarantee the quality of their products.
However, when it becomes necessary in the apparatus disclosed in this laid-open publication to carry out, for example, the inserting and withdrawing of the process cartridge, the remedying of a jam and the replacement of parts, the image retaining drum and transfer drum have to be separated from each other in the apparatus. This makes it difficult to smoothly carry out the above-mentioned operations, and the necessity of providing a space large enough to carry out the separation of these drums causes the dimensions of the apparatus to increase. Especially, the positioning of the image retaining drum and transfer drum which is done after the completion of the above-mentioned operations of inserting and withdrawing the process cartridge, remedying a jam and replacing parts tends to lack accuracy, so that the imperfect image transfer and the doubling of different color image portions occur.
A cartridge in which an image retaining drum and a transfer drum are arranged is discarded when it reaches the limit of use. In view of the manufacturing cost of the cartridge, it is desirable that the cartridge be discarded on the basis of the lifetime of the image retaining drum.
The lifetime of the image retaining drum is usually supposed to be 50000-80000 in terms of number of color copies taken, and, during the lifetime, a copying operation continues to be carried out by replacing the developing devices and supplementing the toner.
Besides these problems, the waste toner scraped off by a cleaning blade from the image retaining drum, which has been subjected to an image transfer operation, is deposited in the cleaning device every time a copy is taken, and the originally small cleaning chamber shortly becomes unable to hold such waste toner. To eliminate this inconvenience from a conventional apparatus of this kind, a method of transferring the waste toner accumulated in the cleaning chamber, by a screw conveyor to a toner recovery box provided in the apparatus body, or a method of withdrawing a waste toner recovery cylinder inserted in the cleaning chamber is employed to throw away such toner. However, in the case where the waste toner recovery box is used, the insertion and withdrawal of the cartridge become troublesome since it is necessary to transfer the waste toner to the outside of the cartridge by the screw conveyor. In the case where the waste toner recovery cylinder is used, much labor and much copying time are required since it is necessary to interrupt a copying operation every time the recovery cylinder is withdrawn and inserted.
For example, Japanese Patent Laid-Open No. 61-140357 proposes the techniques for recovering the waste toner from an image retaining drum into the hollow therein by a screw conveyor.
With the recent spread of copiers, the development of a light, popular miniaturized machine has been demanded. Accordingly, the miniaturization of the image retaining drum has also been studied, and an image retaining drum having a small diameter of not more than 100 mm has usually been used. Therefore, the substantial capacity of the waste toner-holding hollow in the image retaining drum is small, so that this drum has a practical problem.
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Spreadsheet applications are widely used in the business- and education sector. One reason for their ubiquitous use is that they provide end-users not skilled in any programming language with means to specify calculations of various levels of complexity.
A formula specified within a cell can be of arbitrary complexity. In order to specify highly complex calculations in a spreadsheet application, commonly a multitude of formulas contained in a multitude of cells referencing each other are specified by a user.
It is a common requirement to execute complex calculations within a spreadsheet application on multiple different sets of input parameters and to compare the results generated on said different input data sets in order to evaluate the impact of the input data values on the final result. A scientist may have developed a complex formula representing a scientific theory and may want to evaluate the impact of different input data values on the result generated by his model. An accountant may want to know the impact of a reduction of costs in one item of expense on the final result calculated. A family may want to document and monitor the monthly income and expenses of each family member with the help of formulas specified in a spreadsheet document. In any of those cases it is required that the complex calculation, once having been specified, can be reused on different sets of input parameter values.
A related and common requirement is to execute nested, e.g. recursive, functions. A typical example of executing a nested function is the calculation of the surrender value of a life insurance over multiple years, given a particular amount of annual savings and a particular interest rate as input parameters. The calculation may soon get even more complex, if one of the input parameters, e.g. the annual savings and/or the annual interest rate is not constant over time, as it is often the case in practice.
Despite the ubiquity of the usage of spreadsheet applications such as EXCEL for calculating results from different input parameter values, existing spreadsheet applications do not provide means for displaying multiple result values generated by the same spreadsheet-function on different sets of input parameter values at the same time. The means provided by existing spreadsheet applications for displaying and evaluating the impact of a particular input data value on the final result are not intuitive, difficult to maintain and/or not applicable for users not familiar with a programming language (i.e. the broad majority of all users of spreadsheet applications).
Reusing Complex Calculations—State of the Art:
The most widely used spreadsheet application program, Microsoft EXCEL, provides users with the option to specify complex calculations by specifying a multitude of formula cells referencing each other. Basically, EXCEL provides two options for reusing a complex calculation multiple times on different input data sets after said calculation has been specified: the ‘code-duplication’ option and the ‘scenario manager’ option.
A complex calculation is usually specified in EXCEL via a multitude of cells referencing each other and comprising formulas and/or data values. If a user chooses the ‘code duplication’ option to apply such a complex calculation on two or more different sets of input parameter values, he or she has to copy the totality of cells specifying the complex calculation, paste said copied cells into another section of the same worksheet or into another worksheet, and edit the data values used as input by the duplicated cells.
A further means provided by EXCEL for specifying and reusing complex spreadsheet-functions on two or more different input data sets is the ‘scenario-manager’: a scenario is a set of input parameter values which is used to calculate an output parameter value. The ‘scenario manager’ manages different sets of input parameter values, each set corresponding to and representing a separate scenario. With the help of the scenario manager, the user can create different sets of input parameter values which are all assigned to one particular spreadsheet-function, e.g. a summarization or a complex user-defined mathematical function. Each scenario comprises a result value having been calculated on the input parameter set of said scenario. By switching between different scenarios, a user can evaluate the impact of different sets of input parameter values on the calculation result. However, as the two or more specified scenarios are displayed by the scenario manager in mutual exclusion, the user is not able to see and compare the two or more results at the same time. In addition, the results generated by the scenario-manager cannot be reused by other spreadsheet-functions.
Some spreadsheet applications, such as EXCEL, provide the user with the possibility to specify functions by means of a programming language such as VBA (Visual Basic for Applications). A person with programming skills may also use a programming language to create functions which can be applied multiple times on different sets of input parameter values. In practice, however, the overwhelming majority of EXCEL users does not have programming skills and is forced to rely solely on the ‘copy-paste’ option and the ‘scenario manager’.
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The present invention relates to article laminating apparatuses.
Laminating apparatuses typically include a pair of feed rolls, which carry a supply of laminating material. The laminating material is fed from these feed rolls (the feed rolls may be mounted to the frame individually or in a cartridge) into a processing assembly in which a processing operation bonds the materials to one another and to respective sides of an article for lamination inserted into the processing assembly. Traditionally, one or both of the laminating materials have an adhesive on one side. The adhesive may be self-adhering or heat activated. In the case that the adhesive being used in the processing operation is self-adhering, the processing assembly need only compress the materials to each other and to the article to cause bonding. This is usually accomplished with nip, or bonding, rollers. However, in the case that the adhesive being used is a heat activating type, the processing assembly must add heat to the materials prior to or during compression in order to instill a sufficiently strong bond between the materials and the article.
Along with various types of adhesives, laminating materials may also have various thicknesses. In heat laminating, the processing operation with relatively thick laminating material may require a somewhat longer time period to perform, since the material must be heated for a longer duration than with thinner laminating material. Alternatively, the temperature of the heater could be increased so that less time is needed to activate the adhesive. Also, the pressure applied to the materials may vary with the material thickness and/or the types of adhesive used. As such, laminating apparatuses have been designed that are capable of varying the feed speed, pressure and/or the operating temperature at which it operates in order to accommodate laminating materials with different thicknesses. However, these machines require the user to know the laminating material thickness and/or adhesive type and manually set adjustments of the machine (i.e., feed rate, pressure and/or heating temperature) according to appropriate values.
To obviate the need for the user to know these characteristics and manually adjust settings of the machine, one aspect of the present invention provides a laminating apparatus for use with a cartridge having a detectable element indicative of a characteristic of the laminating materials in the cartridge (the term a characteristic encompasses one or more than one characteristic). The article laminating apparatus of the present invention provides a frame constructed and arranged to removably mount the cartridge thereto. An article processing assembly is carried on the frame such that, when the cartridge is removably mounted thereto, an article can be inserted into the article processing assembly in a feeding direction together with the laminating materials unwound from their respective feed rolls and disposed on opposing sides of the article. The article processing assembly includes cooperating pressure applying structures and one or more heating elements. A control system controls the article processing assembly to perform an article processing operation. In the article processing operation, a temperature of the one or more heating elements is elevated to enable the adhesive to adhere to the article inserted into the processing assembly and the cooperating pressure applying structures apply pressure to the laminating materials and the article to affect adhesive bonding therebetween.
The apparatus further comprises a detector operable to detect the detectable element on the cartridge. The detector is communicated to the control system and transmits a signal indicative of the characteristic of the laminating material based on the detectable element on the cartridge. The control system is operable to adjust at least one parameter of the article processing operation based on the signal indicative of the characteristic of the laminating materials.
The parameter(s) adjusted may include the temperature of the one or more heating elements, the feed rate at which the article and the laminating materials are advanced through the apparatus, the pressure applied by the cooperating pressure applying structures, or any other parameter of the processing operation. Of course, the term at least one parameter is intended to encompass any one of these parameters alone, or any combination of parameters of the operation.
Other related aspects of the invention are directed to a cartridge for use with such an apparatus, a system including a cartridge and an apparatus in combination, and a method of performing an article processing operation.
Another aspect of the present application relates to the construction of the heating device in a heat laminating apparatus. Conventionally, laminating apparatuses have generally utilized one of two distinct types of heat sources to heat heat-sensitive adhesive material. The first type is a platen-type heating element. Laminating apparatuses with platen-type heating elements usually have a pair of the heating elements that are positioned within the apparatus to heat the material as it leaves the feed rolls and prior to compression by the bonding rollers. The pair of heating elements are generally planar plates positioned in spaced relation to one another so that the material may be fed between them. The plates are heated by application of an electrical current. As such, the laminating material is heated by convection via the platen-type heating elements. Another type of commonly used heat source is a heated bonding roller. For this type of heat source, the bonding rollers themselves are heated and thereby serve to heat the laminating material by conduction while simultaneously compressing it.
This aspect of the present invention provides an article laminating apparatus that has an improved heating system, specifically combining the benefits of the two types described above. The apparatus is designed for use with a pair of feed rolls carrying a supply of laminating material to be unwound. At least one of the laminating materials includes a layer of adhesive provided thereon. The apparatus includes a frame constructed and arranged to enable the feed rolls to be mounted thereon. An article processing assembly is carried on the frame such that an article can be inserted into the article processing assembly in a feeding direction. The article processing assembly includes a pair of cooperating pressure applying structures and a pair of heating elements.
The heating elements have pressure applying structure heating portions positioned in heat transferring relation adjacent the respective pressure applying structures so as to transfer heat to the respective pressure applying structures. The heating elements also have laminating material heating portions positioned such that, when the laminating materials are unwound and fed between the pressure applying structures, the laminating material heating portions are positioned in heat transferring relation adjacent respective laminating materials. The laminating material heating portions generally extend adjacent a lengthwise portion of the respective laminating material extending between the pressure applying structures and the respective feed roll so as to transfer heat to the laminating material prior to advancing between the pressure applying structures.
The article processing assembly is constructed and arranged to perform an article processing operation wherein portions of the laminating materials are initially heated by the laminating material heating portions of the heating elements prior to advancement between the pressure applying structures. The article and laminating materials are further heated and simultaneously compressed between the pressure applying structures. The article laminating apparatus according to this aspect of the invention offers an improved heating capability, since the laminating materials are pre-heated (prior to advancement between the pressure applying structures) and then heated while having pressure applied thereto (while being advanced between the pressure applying structures). As such, the laminating materials have sufficient exposure time to the heating elements (e.g., are-thoroughly heated so as to fully and uniformly activate the adhesive), which ensures that the laminating materials uniformly adhere to the article and/or each other.
Yet another aspect of the invention relates to a cutter system for a heat laminator. It is generally known in the art to provide a cutter for cutting the laminating material after the processing operation is performed. Cutters have been in the form of a guillotine-type cutter and sliding cutters. Guillotine-type cutters are advantageous in that they may quickly cut the complete width of the laminating material and are simple to manually operate. Slide cutters usually ride on a track with a vertically disposed blade that may be moved laterally across the width of the laminating material to cut it. Either of these cutters may be adequate to cut the laminating material while the material is stationary (i.e., not being fed through the apparatus). However, it has been found that neither of these cutters are well-suited for cutting the laminating material without stopping the feed of the material. As such, these cutters are not well-suited for use in heat laminators because stopping the feeding material results in excessive heat being applied to the portion of the film adjacent the heating elements during stoppage. This excessive heat can deform the laminating materials, thus ruining its appearance.
U.S. Pat. No. 4,743,325 of Miyake discloses a cutting system for a laminator that is capable of cutting while the film is being fed through the laminator. The cutting system of Miyake uses a cutter mounted to a pair of movable block members. The block members are mounted to the laminator to move in a film feeding direction relative thereto. The cutter extends between the block members parallel to a widthwise direction of the film (perpendicular to the film feeding direction). To cut the film, the block members are moved in the film feeding direction at a rate of speed equal to a film feed rate through the laminator. The cutter is then moved between the block members (perpendicular to the film feeding direction) to cut the film. As such, the film may be cut straight across without stopping the feed of film through the laminator. However, the cutting system of Miyake requires significant space, since the entire cutting system is moved in the feeding direction. Further, two drive systems are required to move the block members in the feeding direction and to move the cutter between the block members, respectively. As such, the cutting system of Miyake is relatively complex and expensive to manufacture.
To avoid these limitations, this aspect of the present invention provides an article laminating apparatus with an improved cutting system. The apparatus is designed for use with a pair of feed rolls carrying a supply of laminating material to be unwound. At least one of the laminating materials includes a layer of adhesive provided thereon. The article laminating apparatus includes a frame constructed and arranged to enable the feed rolls to be mounted thereto. An article processing assembly is carried within the frame such that, when the feed rolls are removably mounted thereto, an article can be inserted into the article processing assembly together with the laminating materials unwound from their respective feed rolls and disposed on opposing sides of the article. The article processing assembly includes cooperating pressure applying structures and one or more heating elements. A control system controls the article processing assembly to perform an article processing operation. In the article processing operation, a temperature of the one or more heating elements is elevated to a level sufficient to enable the adhesive to adhere to the article inserted into the processing assembly. The cooperating pressure applying structures apply pressure to the laminating materials and the article to affect adhesive bonding therebetween.
The apparatus further includes a cutter system including a blade mounted on a guide structure for a cutting movement to enable the blade to cut transversely through the bonded materials discharged from the article processing assembly. The guide structure is oriented at an angle with respect to a feeding direction in which the article and laminating materials advance through the article processing apparatus such that the blade moves along a cutting path oriented at the angle. The angle and a velocity at which the blade moves along the cutting path are related such that a velocity component at which the blade moves in the feeding direction along the cutting path is substantially identical to a feed rate at which the article and the laminating materials are advanced through the apparatus in the feeding direction so that the laminating materials are cut generally perpendicularly with respect to the feeding direction.
Other aspects, features, and advantages of the present invention will become apparent from the following detailed description, the accompanying drawings, and the appended claims.
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The invention relates to an X-ray system and an ultrasound system which generate images or sequences of images and modify or optimize the operational behavior of individual system components. The invention also relates to a method of controlling such system components.
During a medical X-ray examination by means of a series of X-ray images, the physician is often confronted with the problem of having to adjust, in addition to carrying out the actual examination, also the operational behavior of individual components of the X-ray examination system in order to achieve an optimum quality of the X-ray images in the image regions of interest. Optimum adjustment of the X-rays is of particular importance. On the one hand, an increase of the radiation dose usually enhances the image quality, but on the other hand the object to be examined should be exposed to an as small as possible radiation dose only. The requirements imposed on the image quality as a result thereof are normally defined by the type of examination while minimizing at the same time the radiation dose for the object to be examined. Various possibilities are known for automatic control of the X-ray dose by the system. To this end, during operation the system usually extracts information from images or image regions in order to readjust the dose automatically on the basis thereof. When the X-ray dose is controlled on the basis of the complete image contents, such control often leads to unsatisfactory results because the control is adversely affected by changing image regions and image regions which are strongly overexposed or underexposed because of properties that are inherent of the system. Therefore, for example, the documents EP 0435528 and EP 0748148 disclose X-ray systems which extract information for dose control from predetermined image regions, that is, so-called regions of interest or ROI, instead of from the entire image.
These systems, however, have the drawback that the ROI is predetermined and hence static. This gives rise to the problem that the object region to be examined must be imaged in the image region of the ROI. If this is not the case, the dose will be controlled on the basis of incorrect image data. When a moving object is examined by means of series of images, the object is liable to leave the static ROI because of its motion, so that the dose control again operates on to basis of incorrect image data. In order to mitigate this problem, for example, the object or the system could be positioned anew, usually implying an unacceptable amount of additional work for the staff, or the ROI could be enlarged, be it at the expense of a degradation of control. For the adjustment of different system parameters it is necessary to use information from different ROIs.
The document JP 04002332 discloses an X-ray examination system for use during heart catheterizations; this system supports the physician in positioning a catheter on the basis of a rectangular image section which is taken from a larger image and which shows the tip of the catheter at the center and automatically follows the catheter during its motion. The selection and shifting of the rectangular section are carried out by means of a simple motion analysis in which two successive images are subtracted. Further aids, notably means for simplifying the operability of the system, are not made available to the physician. This system has the drawback that the images wherefrom the image section is taken must always be larger than the image section which contains the information of interest to the physician. Consequently, an unnecessarily large region of the patient is exposed to X-rays. Moreover, the image quality is not changed.
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Heated hotrunners, manifolds, nozzles, nozzle tips and gate areas that are used in injection molding systems serve to receive and route molten material, typically polymer or plastic, under condtions of high pressure and high temperature. A natural consequence of the use of such high temperatures under which the molten material is injected into the manifold or distribution system is that operating components of the system such as an actuator that are incidentally in thermal communication with or disposed in close proximity to such heated components are themselves subjected to such high temperatures.
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Cytokines are proteins which are produced during the effector phases of natural and specific immunity and serve to mediate and regulate immune and inflammatory responses. Cytokines, like other polypeptide hormones, initiate their action by binding to specific receptors on the surface of target cells. One of the most well known families of cytokines are the interleukins which mediate natural immunity. For a detailed description of the structure and function of the interleukins, see Abbas et al. Cellular and Molecular Immunology, W. B. Saunders Company, Philadelphia, pp. 225–243, 1991.
Leukemia inhibitory factor (LIF), named for its ability to inhibit proliferation of a myeloid leukemic cell line by inducing differentiation, is a member of a family of ligands that includes IL-6, oncostatin M, ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (Gearing, Adv. Immunol. 53:31–58, 1993; Pennica et al., J. Biol Chem. 270:10915–10922, 1995; Patterson, Proc. Natl. Acad. Sci. U.S.A. 91:7833–7835, 1994). Although these cytokines share only very limited sequence homology, they exert very similar effects on a variety of tissues. For example, several of these proteins, including LIF, can induce the same set of acute-phase response proteins in liver, support the self renewal of cultured embryonic stem cells, inhibit lipogenesis and enhance the survival of cultured motor neurons. LIF is produced by diverse cell populations, including macrophages, synoviocytes and chondrocytes. When applied to peripheral nerves in vivo, LIF is retrogradely transported and rescues damaged sensory neurons (Hendry et al., J. Neurosci. 12:3427–3434, 1992; Cheema et al., J. Neurosci. Res. 37:213–218, 1994). LIF also regulates the growth and differentiation of osteablasts and endothelial cells. The rising follicular fluid LIF level around the time of ovulation indicates that LIF may play a role in ovulatory events, early embryonic development and implantation (Senturk et al., Am. J. Reprod. Immunol. 39:144–151, 1998; Stewart, Annals N.Y. Acad. Sci. 157–165).
Neurotrophins and neurotrophic factors are proteins or peptides capable of affecting the survival, target innervation and/or function of neuronal cell populations (Barde, Neuron, 2:1525–1534, 1989). The efficacy of neurotrophins both in vivo and in vitro has been well documented. For example, ciliary neurotrophic factor (CNTF) promotes survival of chicken embryo ciliary ganglia in vitro and supports survival of cultured sympathetic, sensory and spinal motor neurons (Ip et al., J. Physiol. Paris, 85:123–130, 1991).
A major obstacle to the in vivo therapeutic use of peptides is their susceptibility to proteolytic degradation. Retro-inverso peptides are isomers of linear peptides in which the direction of the sequence is reversed (retro) and the chirality, D or L, of each amino acid is inverted (inverso). There are also partially modified retro-inverso isomers of linear peptides in which only some of the peptide bonds are reversed and the chirality of the amino acid residues in the reversed portion is inverted. The major advantage of such peptides is their enhanced activity in vivo due to improved resistance to proteolytic degradation (For review, see Chorev et al., Trends Biotech., 13:438–445, 1995). Although such retro-inverso analogs exhibit increased metabolic stability, their biological activity is often greatly compromised (Guichard et al., Proc. Natl. Acad. Sci U.S.A., 91:9765–9769, 1994). For example, Richman et al. (J. Peptide Protein Res., 25:648–662) determined that analogs of linear and cyclic leu-enkephalin modified at the Gly3—Phe4 amide bond had activities ranging from 6%–14% of native leu-enkephalin. Chorev et al., (ibid.) showed that retro-inversion of a peptide which inhibits binding of vitronectin to its receptor resulted in one peptide which was less potent than the parent isomer by a factor of 50,000, and another peptide which was 4,000 fold more potent than the parent cyclic peptide. Guichard et al. (TIBTECH 14, 1996), teach that retro-inverso (all-D-retro) antigenic mimicry may only occur with peptides in random coil, loop or cyclic conformations. In the case of “helical” peptide, adequate functional mimicry would be expected only if the helicity was, in fact, absent under the solvent conditions used for assessing antigenic mimicry.
There is a need for LIF-derived and neurotrophic peptides exhibiting increased metabolic stability while retaining biological activity. The present invention addresses this need.
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The present invention is generally directed to leading arm and trailing arm vehicle suspension system types. More specifically, the present invention is directed to suspension systems having a longitudinally extending beam connecting a fabricated hollow vehicle axle to a vehicle frame hanger.
Leading and trailing arm vehicle suspension systems are known. Such suspensions typically have a longitudinally extending beam or arm that is pivotally connected at a proximal end to a vehicle frame hanger and generally rigidly connected at a distal end to a vehicle axle, typically through an axle seat or other intermediate suspension component. The beam or arm typically provides a bending stiffness to control axle windup and longitudinal stiffness to control axle position. As used herein, the terms beam and arm may be used interchangeably but shall be construed to exhibit the characteristics expressed within this paragraph.
Leading arm vehicle suspension systems are those types of suspensions wherein the vehicle axle is positioned forward of the frame hanger. Such suspensions typically are used on front steering axles in vehicles. Trailing arm vehicle suspension systems are those types of suspensions wherein the vehicle axle is positioned rearward of the frame hanger. Such suspensions are typically used on rear drive axles in vehicles.
While prior leading and trailing arm vehicle suspension systems have been adequate for certain purposes, they have lacked some of the advantages obtainable with the embodiments of the present invention. Many of these advantages are clearly described herein and others shall be readily apparent to those skilled in the art.
One advantage achieved by the present invention is the use of a leading or trailing arm beam in a leading or trailing arm suspension system wherein the beam is attached directly to a fabricated vehicle axle having a hollow, box-like cross-section by a durable thru-bolt connection.
Another advantage achieved by the present invention is the use of such a beam constructed to permit rack and pinion mounting thereto and having rack and pinion attachment holes machined through the beam.
Another advantage achieved by the present invention is the use of such a beam constructed to permit transverse torque rod bracket mounting thereto and having a torque rod bracket attachment hole machined through the beam.
Another advantage achieved by the present invention is the use of such a beam constructed to include a transverse torque rod attachment included in the beam casting.
Another advantage achieved by the present invention is the use of such a beam constructed to permit shock absorber mounting thereto and having a shock absorber attachment hole machined through the beam.
Another advantage achieved by the present invention is the use of such a beam constructed to permit air spring mounting thereto and having an air spring attachment hole machined through the beam.
Another advantage achieved by the present invention is use of such a beam to reduce suspension system weight, part count, assembly time and assembly complexity.
Another advantage achieved by the present invention is the use of such a beam to reduce failure modes and improve product integrity.
Another advantage achieved by the present invention is the ability to tune roll stiffness of the suspension by optimizing the compliance of the beam and the bushings used to connect the beam to its associated vehicle frame hanger.
These and other advantages of the preferred forms of the invention will become apparent from the following description. It will be understood, however, that an apparatus could still appropriate the invention claimed herein without exhibiting each and every one of these advantages, including those gleaned from the following description. The appended claims, not any advantages recited or implied herein, define the subject matter of this invention. Any and all advantages are derived from the preferred forms of the invention, not necessarily the invention in general.
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Most tap water is considered unsatisfactory for drinking, by many people, for reasons of taste and/or health. For example, many people buy fluoride water for their growing children. People with cardiovascular disorders should drink water that is low in sodium. Other people just don't like the taste of tap water, while still others find it more convenient to use bottled water than to run a water line to the place of use. Such water is available commercially in, for example, 5-gallon glass bottles delivered to the user's location.
The conventional dispenser comprises an open top reservoir having a gravitational flow bottom output terminated by a tap. The open top of the reservoir receives the shoulder of an inverted supply bottle so that the mouth or neck of the supply bottle extends down into the reservoir. The water flows out of the bottle, filling the reservoir, until the opening of the bottle is below the water surface. Only when water is drained from the tap, lowering the water surface, will water again flow out of the bottle. When the supply bottle is empty, it can be readily removed as it is light because it is empty. The full bottle must be now lifted and inverted over the reservoir. When one considers that a 5-gallon filled water bottle weighs more than 50 pounds, the person lifting it must be relatively strong and healthy. Since people who had heart attacks especially need low sodium water, they find it impossible to lift the filled water bottle because of their weakened condition.
The bottled water industry has long recognized a need for a solution to the foregoing problem and, in the past, means have been devised for lifting water from the floor to the dispenser. Some of these means are taught in U.S. Pat. Nos. 3,653,413; 3,495,612; and others. These prior art means are either expensive and need new equipment, as disclosed in U.S. Pat. No. 3,495,612; or required a self-contained motor assembly, as taught in U.S. Pat. No. 3,653,413. This latter patent also requires the user to make sure that the mouth of the inverted bottle is plugged before one attempts to refill the bottle.
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It has already been proposed to introduce yarns into a yarn guide by means of a blowing nozzle (German Offenlegungsschrift 3,701,671).
The object on which the invention is based is to combine such a device with a yarn-changing device and so design it that it works in an operationally reliable way.
The set object is achieved, according to the invention, by means of a device of the type mentioned in the introduction, in that the yarn blowing-in nozzle of the device is formed in a nozzle head having inlet channels for a plurality of yarns and preceded by a yarn-proportioning part which for each of the plurality of yarns has a yarn-loop region located respectively between a front and a rear separately actuable yarn-clamping point and which is equipped with at least one yarn looper. Advantageously, a cutting-off device conventional on yarn-changing devices can be combined with the threading and yarn-changing device, and it can be arranged in the effective range of at least one yarn guide together with a yarn-clamping device for a yarn guided through the yarn guide and coming out of the yarn guide. The device can be arranged in a stationary manner, so that the yarn guides have to be fed to it for equipment or for the yarn change. However, the device together with its plurality of parts can also be made movable, so that it can be brought to the yarn guides.
The combined threading and yarn-changing device according to the invention allows an automatic equipment of the yarn guides and an automatic change of the yarns guided by them. On flat knitting machines, by means of the device designed according to the invention either the number of yarn guides used and to be controlled individually can be reduced, because a separate yarn guide no longer has to be provided for every colour or yarn type employed, or the device makes it possible to use a number of different yarns which exceeds the number of yarn guides to be employed on the machine.
The threading and yarn-changing device is so designed that a knitting machine does not have to be stopped in order to introduce a yarn into a yarn guide or to change the yarn. The high operating reliability required for this is achieved by means of a simple construction of the device, whereby the yarn-proportioning part can have a yarn looper common to all the yarns and in the form of a blowing-nozzle bar extending transversely relative to all the yarns and arranged above the plurality of yarn-loop regions. But a mechanically active yarn follow-up web lowerable into the plurality of yarn-loop regions arranged next to one another can also be provided as a yarn looper. By means of the blowing-nozzle bar or the yarn follow-up web, storage loops are formed in the yarn-proportioning device for each yarn to a length which is sufficient for a yarn to be introduced to be brought through the yarn guide into the additional clamping device or for it to be drawn back out of the yarn guide again into the nozzle head behind the blowing nozzle. The yarn-clamping points in front of and behind each of the yarn-loop regions of the yarn-proportioning device appropriately all arranged next to one another can advantageously each have a spring-loaded movable clamping jaw which is coupled to a pneumatic, hydraulic, electrical or mechanical adjusting member. The yarn-clamping points ensure either that a formed yarn loop remains protected as long as the respective yarn is not inserted, or that, to form the yarn loop, yarn can either be drawn off from a storage reel or be drawn back out of a yarn guide via the nozzle head, or else that an inserted yarn has a free run through the yarn-proportioning part.
An exemplary embodiment of a threading and yarn-changing device designed according to the invention is explained in more detail below by means of the accompanying drawing.
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This invention relates to the field of absorbent articles in general, and more particularly to absorbent articles that provide leakage protection and/or skin protection, as well as methods for using and preparing same, and novel compositions and composites for use in same.
Disposable absorbent articles typically include a moisture-impervious backing sheet, an absorbent pad, and a liner sheet that contacts the body of a person wearing the article. In addition, elasticized regions are provided around the edges of the article to secure the article about the waist and legs of a wearer. Diapers typically further comprise opposed front and rear waist portions defining a waist opening, a crotch portion disposed there between, and a pair of elastically contractible leg openings along the side edges of the crotch portion. Disposable diapers having elasticized margins for placement about the legs of a wearer are disclosed in U.S. Pat. Nos. 4,050,462 and 5,092,861. An absorbent article having elasticized side margins and waist band margins are shown in U.S. Pat. No. 4,300,562.
Despite previous advancements in the field of absorbent articles, persons of ordinary skill in the art continue their efforts to produce more comfortable garments which are better able to contain urinary and fecal excretions. For instance, problems with prior diaper designs include leakage of urinary or fecal material from the garment. Prolonged contact of liquid or semi-solid excreta with the skin of the wearer is also a continuing problem in the art. For example, the moisture vapor and heat generated by the bodily exuded trapped within a diaper may lead conditions adjacent to wearer""s skin which promotes skin irritation, infection, and the like. Although a plastic backsheet, as described above, is generally effective in precluding the passage of bodily exude outwardly, the backsheet is not efficient in preventing lateral leakage of liquids from the opposed side portions of the core sideward between the leg gathers of the backsheet and the wearer""s skin. One solution to this problem, the tightening of leg gathers, presents problems in terms of the comfort of the baby and further skin irritation. Various other approaches had been attempted to address the lateral leakage of liquids from absorbent articles.
For example, U.S. Pat. No. 6,114,596 to Nayak et al. discloses a breathable diaper, feminine hygiene, or like disposable sanitary product having a cloth-like outer surface and including a plurality of materials from the skin-facing side outwardly, a topsheet, a core, an optional barrier, and a backsheet. The disclosed topsheet is formed of liquid- and vapor-permeable hydrophilic material, and the core is formed of highly absorbent material disposed outwardly of the topsheet for absorbing liquid received through the topsheet. The disclosed core has an inter surface in liquid communication with the topsheet and an outer surface. The disclosed optional barrier is formed for a multi-layer non-woven material which is hydrophobic and vapor-prominentable for limiting the outward escape of liquid therethrough while enabling the outward escape of heat and water vapor therethrough. The disclosed barrier has a base disposed adjacent the core outer surface. The disclosed backsheet is formed of a multi-layer non-woven material which is hydrophobic and vapor permeable for limiting the outward escape of liquid therethrough while enabling the outward escape of heat and water vapor therethrough. This backsheet is disclosed as being disposed at least partially as an outer surface of the diaper.
U.S. Pat. No. 6,017,336 to Sauer discloses an absorbent article which includes a pair of compression resistant containment barriers which are configured to inhibit the lateral flow of fecal exudates along the surface of the absorbent article. The containment barriers are disclosed as being laterally spaced apart to provide a void space between the wearer""s back side and the surface of the absorbent article for containing body exudates. Each containment barrier is disclosed as defining a width to height ratio of at least about 0.5 and a compression resistance of at least about 50%. The absorbent article is disclosed as optionally including a containment dam which is located on the body facing surface of the absorbent article and which is configured to inhibit a longitudinal flow of fecal exudates along the surface of the absorbent article.
U.S. Pat. No. 5,597,906 to Roe, et al. discloses an absorbent article comprising a liquid pervious topsheet, a liquid pervious backsheet joined to at least a portion of the topsheet, an absorbent cord disposed between at least a portion of the topsheet and the backsheet, and a waste management element disposed in at least a portion of the crotch region. The waste management element preferably has an acceptance under pressure value of greater than about 0.50 grams of a viscous fluid bodily waste per square inch of the waste management element millijoule of energy input. The waste management element is also disclosed as having a storage under pressure values of at least about 0.70 grams of the viscous fluid bodily waste per square inch of the waste management element. The waste management element is also disclosed as optional having an Immobilization Under Compressed Inversion valve of greater than about 70% of the viscous fluid bodily waste accepted by the waste management element. The waste management is disclosed as being located anywhere in the article, including the crotch region.
U.S. Pat. No. 5,941,864 to Roe discloses a disposable absorbent article, such as a diaper having a first topsheet with apertures large enough for low-viscosity fecal material to pass through to a fecal material storage element. The fecal material storage element is disclosed as immobilizing the fecal material in position for dewatering, so that the liquid components of the fecal material are absorbed by the core and solid components of the fecal material are separated from the liquid components, to provide for easier-cleaning of the wearer when the soiled disposable absorbent article is removed.
U.S. Pat. No. 5,941,862 to Haynes et al. discloses absorbent structures comprising a first layer, a second layer juxtaposed in facing relation with said first layer, wherein at least one of the layers is fluid pervious. These structures are disclosed as having a continuous region between said first and second layers comprising hydrogel-forming polymer that is substantially uniformly distributed throughout the region. The continuous region is disclosed as at least partially surrounding multiple, spaced apart zones between said layers, which zones are substantially devoid of hydrogel-forming absorbent polymer. The first and second layers are disclosed as being bonded together such that said hydrogel-forming absorbent polymer is substantially immobilized when in dry state, an preferably at sites within plurality of the zones.
U.S. Pat. No. 5,558,655 to Jezzi et al. discloses in absorbent article, such as diaper, which comprises a composite structure of a xe2x80x9ctwo-dimensionalxe2x80x9d or very flat, apertured film or nonwoven layer, in combination with a. fluid transferring layer and a superabsorbent polymer-containing laminate, and a absorbent core below the laminate to achieve superior dryness. The superabsorbent poylmer-containing laminate is disclosed as containing airlaid fibrous components and superabsorbent polymers and as swelling to at least three times its dry caliper upon fluid introduction in order to achieve movement of the coverstock away from the absorbent core which permits the coverstock to remain relatively dry and avoids rewetting.
U.S. Pat. No. 6,040,251 to Caldwell discloses barrier webs at a certain desirable physical qualities such as water resistance, increased durability, improved barrier qualities and the like. Barrier webs are disclosed as comprising a web that has been treated with a curable shear thinned thixotropic polymer composition which is adapted to be substantially impermeable to liquids, permeable to gases and impermeable to microorganisms. Further, the barrier webs are disclosed as being either impermeable to all microorganisms or impermeable to microorganisms of certain sizes. Also disclosed are fabrics that are capable of either selectively binding certain microorganisms, particles, or molecules depending upon what binding partners are incorporated into the polymer before application to the fabric.
U.S. Pat. No. 5,945,175 to Yahiaoui et al discloses a coated porous substrate composed of a hydrophobic polymer which is substantially uniformly coated with a hydrophilic polymeric material. The substrate may be a sheet-like material, examples of which are forms, fibers, and fibrous webs. The fibrous webs are disclosed as desirably being nonwoven webs. The coating on the substrate is disclosed as being durable to an aqueous medium at a temperature in a range of from about 10xc2x0 C. to about 50xc2x0 C. and does not significantly suppress the surface tension of an aqueous medium-with which the coated substrate may come in contract. The hydrophobic polymer is disclosed as being a polyolefin, such as polyethylene or polypropylene. The hydrophilic polymeric material is disclosed as being a polysaccharide or a modified polysaccharide.
U.S. Pat. No. 6,117,121 to Faulks et al. discloses an absorbent article including an absorbent core located between a bodyside liner and an outer cover. The absorbent article is disclosed as having a leg cuff mounted to a base structure in the crotch portion thereof. The leg cuffs are disclosed as being partially stretched when attached to respective longitudinal side portions near the crotch portion of the absorbent article.
U.S. Pat. No. 6,107,539 to Palumbo et al. discloses disposable absorbent articles comprising a backsheet, a topsheet, a fluid acquisition/distribution region and at least one fluid storage region, said article having a total product acquisition performance of more than 3.75 ml/sec in the first gush and more than 0.5 ml/sec in the fourth gush and an in bag stack height of less than 9.9 mm, characterized in that said topsheet allows it to retain no more then 0.25 g of fluid as measured by the topsheet-on-acquisition-material-wetness test, and that said acquisition/distribution region has a drip capacity of at least 5.0 grams of fluid per gram of material.
U.S. Pat. No. 5,935,118 to Gryskiewicz et al. discloses an absorbent article that includes a garment shell and at least one liquid containment beam formed of an absorbent material. The liquid containment beam has an attachment edge bonded to the garment shell so that the containment beam can lie against the garment shell and also pivot about an axis defined by the attachment edge. For comfort during use, the containment beam desirably has a width to thickness ratio of at least about 3:1. In particular embodiments, the absorbent article includes pairs of inner and outer containment beams, with the inner containment beams adapted to lie against the garment shell and the outer containment beams adapted to lie against the inner containment beams.
U.S. Pat. No. 6,087,550 to Anderson-Fischer et al. relates to water responsive thermoplastic compositions and articles constructed thereof. This invention particularly relates to thermoplastic copolyester compositions useful for the manufacture of disposable articles such as disposable diapers and feminine napkins. More particularly, this invention relates to thermoplastic copolyester compositions that are useful as a raw material in the manufacture of nonwovens, barrier films or coatings, as well as for various improved hot melt adhesive compositions useful for incorporating hydrophilic features into disposable articles.
U.S. Pat. No. 6,120,783 to Roe et al. discloses web materials which have two or more skin care compositions disposed thereon. The skin care compositions are transferable to the wearer""s skin by normal contact and/or wearer motion and/or body heat. The skin care compositions disclosed in the present invention are selected to maintain and/or improve the skin health of the wearer upon transfer during use, for example, to provide a skin protective barrier or a therapeutic benefit; to minimize the abrasion between the cuffs and skin in the area where the cuffs contact the wearer""s skin, resulting in less skin irritation; to improve BM clean up on the skin, or to improve the barrier properties of the cuffs. Web materials of the present invention have a wide range of potential uses in both durable and disposable articles, but are particularly well suited for use in disposable absorbent articles such as disposable diapers, incontinent briefs, training pants, sanitary napkins, and the like.
U.S. Pat. No. 5,683,809 to Freeman et al. discloses protective articles such as diapers, having filmless hydrophobic barrier elements such as cuffs and backing sheets. The barrier cuffsxe2x80x94which can be, for instance, leg cuffs and waistbandsxe2x80x94and the backing sheets can be provided from fabrics having a fabric weight of at least 10 gsy.
U.S. Pat. No. 5,928,209 to Bodford et al. discloses a breathable diaper, feminine hygiene, or like disposable sanitary product construction includes a plurality of materials including, from the skin-facing side outwardly, a topsheet of liquid- and vapor-permeable hydrophilic material. A core of highly absorbent material is disposed outwardly of the topsheet for absorbing fluid received through the topsheet, the core having an inner surface in fluid communication with the topsheet. A backsheet is disposed at least partially as an outer surface of the construction and is formed of a pouch defined by two layers of a non-woven hydrophobic and vapor-permeable material, with absorbent or superabsorbent particles therebetween, so that the backsheet limits the outward escape of liquid therethrough while enabling the outward escape of heat and water vapor therethrough. Each backsheet layer is an at least two-layer spunbound-meltblown SM or an at least three-layer spunbond-meltblown-spunbond SMS.
U.S. Pat. No. 5,990,377 to Chen et al. discloses a dual-zoned, three-dimensional, resilient absorbent web is disclosed which is suitable as body-side liner for absorbent articles such as feminine pads, diapers and the like. When used as a liner in absorbent articles, the dual-zoned web combines the advantages of apertured films and soft, nonwoven cover layers in one structure while still being inherently hydrophilic. The liner comprises a web of wet-resilient, hydrophilic basesheet having a three-dimensional topography comprising elevated regions onto which hydrophobic matter is deposited or printed and a plurality of spaced apart depressed regions. In a preferred embodiment, the hydrophobic matter applied to the elevated regions of the basesheet comprises hydrophobic fibers in a contiguous nonwoven web which has been apertured or provided with slits or other openings, such that the apertures or openings overlay a portion of the depressed regions. The elevated hydrophobic regions enhance dry feel and promote fluid flow toward the lower hydrophilic regions, which comprise the exposed depressed regions of the basesheet. The basesheet is preferably in liquid communication with underlying absorbent material, most preferably a stabilized airlaid cellulosic material or compressed stabilized fluff such that the absorbent material can wick fluid out of the basesheet by capillary action. When soft, hydrophobic fibers are deposited on the elevated regions, the liner also has a soft, cloth-like feel in addition to a dry feel in use.
U.S. Pat. No. 6,120,488 to VanRijswijck et al. discloses an absorbent article, such as a diaper, containing cuffs and a topsheet with one or more skin care compositions disposed thereon. The skin care compositions are transferable to the wearer""s skin by normal contact and/or wearer motion and/or body heat. The skin care compositions disclosed in-the present invention are selected to maintain and/or improve the skin health of the wearer upon transfer during use, for example, to provide a skin protective barrier or a therapeutic benefit; to minimize the abrasion between the cuffs and skin in the area where the cuffs contact the wearer""s skin, resulting in less skin irritation; to improve BM clean up on the skin, or to improve the barrier properties of the cuffs.
U.S. Pat. No. 5,817,079 to Bergquist et al. discloses in absorbent products, such as sanitary napkins, discreet areas of dry fibrous materials such as fluidrepellent materials are precisely placed in various planes within the product so as to provide barriers to bodily fluid leakage from the product. In a preferred embodiment, hydrophobic fibers are placed around the periphery of a central absorbent area of an absorbent product to discourage and/or prevent side or end leakage from the product.
U.S. Pat. No. 5,830,201 to George et al. discloses a flushable diaper for use on the body of an infant or adult. An envelope has inner and outer walls which are secured together at their outer periphery to form an inner cavity. The outer wall is comprised of a hydrophobic outer layer together with a hydrophilic inner layer. The inner wall is comprised of a hydrophobic outer layer together with a hydrophilic inner layer. The inner and outer walls are separated by an interior cavity which contains one or more containers. The container is comprised of either a single layer or a laminated wall which forms a chamber that encloses a charge of water. The laminated wall is comprised a hydrophobic inner laminate and a hydrophilic outer laminate. When manually ruptured, the containers release water into the double walled envelope, which causes disintegration of the hydrophilic inner layers of the double walls, along with the hydrophobic outer layers. An absorbent member is carried on the inner wall of the envelope, and the absorbent member comprises a fluid pervious cover which encloses an inner body that is comprised of a material which is sufficiently hydrophilic to absorb urine and other fluids from the body while maintaining structural integrity of the inner body and to also absorb water in an effective amount to cause the inner body to disintegrate into small pieces.
U.S. Pat. No. 5,885,266 to Chihani et al. discloses an absorbent article such as a diaper, an incontinence guard or a sanitary napkin includes a liquid-permeable outer sheet, a liquid-impermeable bottom sheet and an absorbent body placed therebetween. The outer sheet and the absorbent body are at least partially joined together with a hydrophilic glue.
As is apparent from the foregoing, each of the prior references present a variety of means for controlling leakage in absorbent garments. However, all of these proposed means are deficient in terms of effectiveness and low product quality, mechanical complexity in design, and/or associated cost inefficiencies.
In view of the deficiencies of the various products and processes disclosed in the above discussed references, it is highly desirable to provide cost-efficient absorbent articles that display superior leak protection, as well as novel compositions and composites for use in said absorbent articles. Further, it is highly desirable to provide a cost-efficient process for producing absorbent articles having superior leak protection. Moreover, it is also highly desirable to provide cost-efficient absorbent articles, and methods for preparing such articles, that confer secondary benefits of skin wellness to the users of said articles, in addition to superior leak protection.
The present invention provides cost-efficient absorbent articles, and novel compositions and composites for use in same, that display unexpectedly superior leak protection. Further, the present invention provides a cost-efficient process for producing absorbent articles having superior leak protection. Moreover, the present invention provides cost-efficient absorbent articles, methods for preparing and using such articles, and novel compositions and composites for use in same, that confer secondary benefits of skin wellness to the users of said articles in addition to superior leak protection.
One embodiment of the present invention is an absorbent article comprising: a permeable topsheet; a substantially impermeable backsheet; an absorbent core disposed between said permeable topsheet and said substantially impermeable backsheet; and a hydrophobic composition selectively disposed between the skin-opposing surface of the substantially impermeable backsheet and the skin of a wearer of the absorbent article to contain leakage.
A further embodiment of the present invention is an absorbent article comprising: a permeable topsheet; a substantially impermeable backsheet; an absorbent core disposed between said permeable topsheet and said substantially impermeable backsheet; and a hydrophobic composition disposed between the skin-opposing surface of the substantially impermeable backsheet and the skin of a wearer of the absorbent article at a leak protection zone or plurality of leak protection zones; wherein said hydrophobic composition comprises a hydrophobic substance effective for skin protection, a substance effective for skin care, a substance effective for skin wellness, a substance effective for skin improvement, a substance perceived as having a skin wellness benefit or combinations thereof.
A still further embodiment of the present invention is an absorbent garment comprising: a front waist portion and a rear waist portion cooperating to form a waist opening; a crotch region formed between said front waist portion and said rear waist portion; a pair of leg openings on opposed sides of the crotch region; a permeable topsheet, a substantially impermeable backsheet and an absorbent core positioned between said topsheet and said backsheet; and a hydrophobic composition disposed on said permeable topsheet at a leak protection zone or plurality of leak protection zones.
An even further embodiment of the present invention is an absorbent article comprising: a permeable topsheet; a substantially impermeable backsheet; an absorbent core disposed between the permeable topsheet and the substantial impermeable backsheet; a tissue layer disposed between the absorbent core and the permeable topsheet; and a hydrophobic composition disposed on said tissue layer at a leak protection zone or plurality of leak protection zones.
Another embodiment of the present invention is a method for preparing an absorbent article comprising: identifying a leak protection zone or a plurality of leak protection zones; disposing a hydrophobic composition at one or more predetermined areas on a substrate; and forming an absorbent article comprising the substrate such that the one or more predetermined areas correspond to the leak protection zone or plurality of leak protection zones.
Yet another embodiment of the present invention is a method for preparing an absorbent article comprising: disposing a hydrophobic composition at predetermined areas on a tissue layer or a permeable topsheet; and forming said tissue layer or permeable topsheet into an absorbent core such that the predetermined areas correspond to a leak protection zone or a plurality of leak protection zones.
Still another embodiment of the present invention is a composition in an absorbent article for providing leak protection and/or skin wellness comprising: an effective amount of a hydrophobic substance selected from the group consisting of cocoa butter, petrolatum, dimethicone, a zinc oxide preparation, beeswax, lanolin, jojoba oil and combinations thereof effective in providing leak protection when selectively disposed at a leak protection zone or plurality of leak protection zones on said absorbent article.
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About 2% of the world population (123 million individuals) are chronically infected with the hepatitis C virus (HCV). Chronic infection puts these individuals at risk for the development of hepatitis, cirrhosis, liver failure and hepatocellular carcinoma making chronic hepatitic C the leading cause for liver transplantation worldwide. In the United States a seroprevalence rate of 1.8% has been reported and HCV is associated with more than half of an increasing number of newly diagnosed hepatocellular carcinomas.
Current therapy combining pegylated interferon-alpha with ribavirin achieves cure rates of just above 50% (Fried et al., 2002, N Engl J Med 347:975-82; Manns et al., 2001, Lancet 358:958-965). Several difficult to treat patient groups show decreased response rates or cannot tolerate therapy at all. These include patients that have failed to respond to standard therapy, African Americans, patients with HIV-coinfection or end-stage liver disease and patients after liver transplantation. Currently, HCV infection of the graft after liver transplantation is universal, usually leading to rapid fibrosis progression and subsequent graft failure. This accounts for the poor outcome of liver transplantation for HCV-induced cirrhosis compared to other indications (Forman et al., 2002, Gastroenterology 122:889-96). Targeting HCV cell entry in this setting holds promise as a therapy capable of blocking viral entry even for a short period of time might prevent graft re-infection and thus turn liver transplantation from a palliative into a curative procedure. Hopefully, a more complete understanding of early HCV life cycle events will identify promising targets for this purpose.
Recent technical developments have opened up exciting new possibilities for molecular studies of hepatitis C virus (HCV). In the past decade, molecular clones that are functional for chimpanzee infection, efficient cell culture systems for studying RNA replication (replicons), and retroviral pseudotypes harboring functional HCV glycoproteins (HCVpp) have been developed. More recently, derivatives of a genotype 2a isolate, JFH-1, have yielded relatively high titers of cell culture infectious particles (HCVcc). Importantly, HCVcc is infectious in chimpanzees and a murine-human xenograft model and viral production in animals (chHCVcc or muHCVcc) retaining infectivity in cultured cells has been shown. This creates a complete and valuable set of reagents to study HCV neutralization and entry.
The tetraspanin CD81 and scavenger receptor BI/II (SR-BI/II) are cell surface molecules that bind the HCV E2 glycoprotein and participate in HCV entry. However, expression of these two molecules, in conjunction with numerous other candidate entry factors, is insufficient to render cells fully permissive for HCV entry. Thus, there necessarily remains an additional, as yet unidentified HCV coreceptor.
HCV is a member of the family Flaviviridae, which also includes Pestiviruses and Flaviviruses. The HCV virion consists of an enveloped nucleocapsid containing the viral genome, a single, positive stranded RNA of approximately 9,600 nucleotides. Viral entry into the host cell is thought to require a tightly regulated interaction between the viral envelope proteins, E1 and E2, and host proteins at the cell surface. Moreover, it has been shown that host cell infection requires endosomal acidification suggesting that fusion of the viral envelope with cellular membranes is a pH triggered event. After cell entry the nucleocapsid is released into the cytosol and the viral RNA is translated through action of an internal ribosome entry site (IRES) present in the 5′ untranslated region (5′UTR). The HCV genome encodes a single long open reading frame giving rise to a viral polyprotein of over 3000 amino acids that then undergoes co- and post-translational proteolytic processing to generate the mature viral proteins: C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B (FIG. 1). The viral structural proteins, including core, the capsid protein E1, and E2, are encoded by the first third of the polyprotein. p7 (a putative ion channel) and nonstructural (NS) proteins, encoded by the C-terminal two-thirds of the polyprotein, are components of the HCV RNA replication complex. The replication of the viral genome through a negative strand RNA intermediate occurs.
Recently, pseudotyped retroviral particles were developed to study HCV entry. To generate HCVpp, 293T cells are transfected with expression vectors encoding (1) unmodified HCV E1E2, (2) the gag-pol proteins of either MLV or HIV and (3) a packaging competent (but gag-pol and env deficient) retroviral genome containing either a GFP or lacZ reporter gene. This results in the release of infectious HIV or MLV nucleocapsids surrounded by an envelope containing HCV glycoproteins (Bartosch, B., J. Dubuisson, and F. L. Cosset. 2003. Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. J Exp Med 197:633-642). Alternatively, a two vector system using an envelope deficient HIV genome with a luciferase reporter and an HCV-E1E2 expressing vector can be employed (Hsu, M., J. Zhang, M. Flint, C. Logvinoff, C. Cheng-Mayer, C. M. Rice, and J. A. McKeating. 2003. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc. Natl. Acad. Sci. USA 100:7271-76). These HCVpp systems take advantage of the ability of retroviruses to incorporate heterologous glycoproteins into their envelope. HCVpp can infect a number of liver derived human cell lines and their reporter genes allow convenient quantification of target cell infection, making HCVpp the first robust assay for the study of HCV glycoprotein mediated cell entry.
More has been elucidated in the life cycle of HCV via the development of HCVcc (FIG. 2). This was made possible through the discovery of a genotype 2a HCV isolate from a Japanese patient with acute fulminant hepatitis (JFH)-1, that is capable of efficient subgenomic RNA replication in multiple cell types without the need for adaptive mutations (Date, T. et al. 2004. J Biol. Chem. 279:22371-6; Kato, T. et al. 2003 Gastroenterology 125:1808-17; Kato, T. et al. 2005J. Virol 79:592-6). Surprisingly, when full length JFH-1 genome RNA was transfected into Huh-7 cells, viral particles, termed HCVcc, were released that were capable of infecting naïve cells. Efficient in vitro systems based on the JFH genome recapitulating the entire HCV life cycle have been developed. Virus produced from full length JFH-1 RNA exhibits characteristics predicted for an HCV virion: the infectivity of these particles is blocked by antibodies against E2 or CD81 and by purified soluble CD81; moreover, virion density is similar to that found in sera of infected individuals. Although JFH-1 initially yielded low titers, higher viral titers were obtained by using Huh-7.5 cells and derived sublines (Lindenbach, B. D, et al. 2005 Science 309:623-6; Zhong, J. P., et al. 2005 Proc Natl Acad Sci USA 102:9294-9), which are highly permissive for HCV replication (Blight et al. 2002. J. Virol. 76:13001-14) due to a defect in the RIG-I intrinsic immune response pathway (Sumpter et al. 2005. J Virol 79:2689-99). Virion production was further enhanced through the use of a chimeric genotype 2a full length genome, expressing the core through NS2 region of the HCJ6 HCV isolate cloned into the JFH-1 genome (J6/JFH) (FIG. 1B), which, unexpectedly, produced higher initial titers post transfection than the full length JFH-1 genome (Lindenbach, B. D., et al. 2005 Science 309:623-6). Very recently, cell culture grown HCVcc has been used to infect both chimpanzees and uPA-SCID mice transplanted with human hepatocytes (Lindenbach, B. D., et al. 2006 Proc. Natl. Acad. Sci. USA 103 In press). In both cases rising viral loads and an infection sustained for several weeks ensued, validating the usefulness of the HCVcc system. More importantly, virus recovered from HCVcc inoculated animals (ex vivo HCVcc; chHCVcc and muHCVcc for virus recovered from chimps and mice, respectively) was infectious in cell culture establishing the first robust ex vivo culture system. Virus recovered from infected animals displayed both altered biophysical properties and increased specific infectivity (ratio of infectious units to RNA copies) indicating that ex vivo HCVcc is of great use in elucidating the role of host factors in modulating HCV infection.
Using HCVpp, much has been learned about the mechanism of HCV cell entry. Evaluations of entry using the HCVcc system yield comparable results with regard to cell entry properties such as CD81 dependence, restriction to human hepatoma cell lines and neutralization by anti-E2 antibodies. Even with HCVcc available, HCVpp still offer certain advantages, most notably (1) the ability to investigate HCV glycoprotein dependent entry in cells non-permissive to HCV replication and (2) the availability of stringent controls in the form of pseudoparticles bearing glycoproteins from viruses other than HCV, such as VSV or MLV, and pseudoparticles devoid of glycoproteins (no envelope). Nonetheless, future studies are needed to elucidate possible mechanistic differences between the cell entry properties of HCVpp, HCVcc and ex vivo HCVcc.
HCVpp infectivity requires both E1 and E2 with their intact transmembrane domains (Bartosch, B. J., et al. 2003 J Exp Med 197:633-642; Hsu, M., et al. 2003 Proc. Natl. Acad. Sci. USA 100:7271-76). The structure of the infectious unit in vivo may be more complex through the above mentioned association between the virus and host serum factors including different lipoprotein species (VLDL, LDL, HDL) and immunoglobulins (Kono, Y., J et al. 2003 Med Virol 70:42-8; Monazahian, M., et al. 2000 Journal of Medical Virology 57:223-9; Thomssen, R., et al. 1992 Med. Microbiol. Immunol. 181:293-300; Thomssen, R., et al. 1993 Med. Microbiol. Immunol. 182:329-334). Such associations may explain the heterogeneous buoyant density observed for both plasma-derived HCV (1.03-1.2 g/ml) (Bradley, D., J. et al. 1991 Med. Virol. 34:206-208; Hijikata, M., J. et al. 1993 Virol. 67:1953-1958; Thomssen, R., et al. 1993 Med. Microbiol. Immunol. 182:329-334) and HCVcc (1.04-1.18 g/ml) (Lindenbach, B. D., et al. 2005 Science 309:623-6; Wakita, T., et al. 2005 Nat Med 11:791-6; Zhong, J., et al. 2005 Proc Natl Acad Sci USA 102:9294-9). The highest infectivity seems to be associated with fractions of low to medium density (1.11 g/ml and below) (Bradley, D., J. et al. 1991 Med. Virol. 34:206-208; Hijikata, M., J. et al. 1993 Virol. 67:1953-1958; Lindenbach, B. D., et al. 2005 Science 309:623-6) indicating that an interaction with plasma lipids may enhance virion infectivity.
Low pH induces conformational changes in E2 and the dissociation of E1E2 complexes indicating the involvement of a pH-triggered step in the entry process (Flint, M., et al. 1999 J. Virol 73:6782-6790; Op De Beeck, A., et al. 2004 J Virol 78:2994-3002). In keeping with this, HCVpp entry has been shown to be sensitive to endosomal acidification inhibitors such as ammonium chloride, bafilomycin and concanamycin, as is HCVcc entry, as shown herein. This pH dependence indicates that virus interaction with putative cell surface receptors is followed by endocytotic uptake of the particle rather than fusion at the plasma membrane and that endosomal low pH is required, in some embodiments, to initiate virus-cell membrane fusion. An endosomal route of entry has also been described for the related flaviviruses (Gollins, S. W., et al. 1985 J. Gen. Virol. 66:1969-1982; Gollins, S. W., et al 1986 J. Gen. Virol. 67:157-166) as well as more evolutionarily distant alphaviruses (Helenius, A., et al. 1980 J Cell Biol 84:404-20).
Currently, the minimal host cell factor requirement for HCV cell entry (i.e., the sequence of events beginning with attachment to the host cell and ending with cytoplasmic delivery of the nucleocapsid) is not known. Numerous molecules have been proposed to function as HCV (co-)receptors (i.e., cell surface molecules required for entry that bind virus). However, none of these have had a precise function in the entry process conclusively defined, nor has the temporal sequence of interactions required for entry been determined. Beyond (co-) receptors, additional molecules that perform other functions in the entry process (e.g., endosomal proteases) may be required. Finally, there may also be molecules that are not essential but rather facilitate HCV entry (facilitating factors).
There appears to be a requirement for CD81 for HCV cell entry. CD81, a member of the tetraspanin superfamily with four transmembrane domains and short cytosolic N- and C-terminal tails, was initially identified as a candidate HCV receptor based on its ability to bind sE2124 The HCV-CD81 interaction is thought to take place between the CD81 large-extracellular loop (LEL) between transmembrane domains 3 and 4 (Drummer et al., 2005, Biochem Biophys Res Commun 328:251-7; Drummer et al., 2002, J Virol 76:11143-7; Higginbottom et al., 2000, J Virol 74:3642-9) and a conformational epitope on E252. Several pieces of evidence strongly support CD81's role as an essential (co-)receptor for HCV: (1) The human hepatoma cell line HepG2 does not express CD81 and cannot be infected with HCVpp or HCVcc, but becomes infectable with both upon transduction with CD81 (Bartosch et al., 2003, J Biol Chem 278:41624-30; Lindenbach et al., 2005, Science 309:623-6; Zhang et al., 2004, J Virol 78:1448-55). This CD81 requirement in HepG2 cells is conserved across HCVpp bearing E1 and E2 from all known genotypes (Lavillette et al., 2005, Hepatology 41:265-74; McKeating et al., 2004, J Virol 78:8496-505). (2) Knockdown of CD81 expression using siRNA abrogates susceptibility to HCVpp166. (3) Antibodies against CD81, as well as soluble forms of the large extracellular loop of CD81, block HCVpp and HCVcc infection in a dose-dependent manner (Bartosch, B., et al. 2003 J Exp Med 197:633-642; Hsu, M., et al. 2003 Proc. Natl. Acad. Sci. USA 100:7271-76; Lindenbach, B. D., et al. 2005 Science 309:623-6; Wakita, T., et al. 2005 Nat Med 11:791-6; Zhong, J., et al. 2005 Proc Natl Acad Sci USA 102:9294-9). However, other factors besides CD81 must be required for entry since CD81 expression alone is insufficient to allow HCVpp entry (Bartosch, B., et al. 2003 J Exp Med 197:633-642; Hsu, M., et al. 2003 Proc. Natl. Acad. Sci. USA 100:7271-76; Zhang, J., et al. 2004 J Virol 78:1448-55) and the expression of CD81 in all human cell types except erythrocytes and platelets (Levy, S., et al. 1998 Annu. Rev. Immunol. 16:89-109) does not explain HCV's apparent liver tropism. The precise role of CD81 in the entry process is unclear; some evidence suggests it may function as a co-receptor, interacting with the virus only after binding of the virus to another receptor molecule has occurred (Cormier, E. G., et al. 2004 Proc Natl Acad Sci USA 101:7270-4).
Like CD81, scavenger receptor class B member I (SR-BI) was first proposed as an HCV entry factor because of its ability to bind sE2136. SR-BI is expressed at high levels in the liver and steroidogenic tissues with lower levels detectable in placenta, small intestine, monocytes/macrophages and other tissues. It mediates selective uptake of cholesterol esters from HDL into the cellular membrane (Acton, S., et al. 1996 Science 271:518-20; Rodrigueza, W. V., et al. 1999 J. Biol Chem 274:20344-50) and possibly also endocytosis of entire HDL particles (Silver, D. L., et al. 2001 J Biol Chem 276:25287-93). The role of SR-BI in HCV cell entry is less clear than that of CD81. No SR-BI negative cell line that becomes permissive to HCV infection when transfected with SR-BI has been reported. Antibodies and siRNA directed against SR-BI inhibit HCVpp infection (Bartosch et al., 2003, J Biol Chem 278:41624-30; Lavillette et al., 2005, Hepatology 41:265-74), but both effects are less striking than those obtained for CD81 and vary considerably between HCV genotypes (Lavillette et al., 2005, Hepatology 41:265-74) (and unpublished data). Recently, HCVpp infectivity was found to be enhanced significantly in the presence of HDL (Bartosch et al., 2005, J Virol 79:8217-29; Meunier et al., 2005, Proc Natl Acad Sci USA 102:4560-5; Voisset et al., 2005, J Biol Chem 280:7793-9). The enhancement depends on functional SR-BI on the target cell since both SR-BI siRNA and BLT-4, a drug that inhibits flux of cholesteryl esters from SR-BI bound HDL into the target cell membrane_(Nieland, T. J., et al. 2002 Proc Natl Acad Sci USA 99:15422-7), completely abrogate the enhancing effect of HDL. These treatments have no (BLT-4) or variable (siRNA) effects on infectivity in the absence of HDL (Bartosch, B., et al. 2005 J Virol 79:8217-29; Voisset, C., et al. 2005 J Biol Chem 280:7793-9). Finally, it was found that oxidized LDL, an LDL-derived product of atherosclerotic processes and a known SR-BI ligand, dramatically inhibits HCVpp and HCVcc infectivity (Hahn, T., et al. 2006 Hepatology In press). Based on these findings, it would appear that, in addition to CD81, SR-BI also has an important role in HCV entry. However, co-expression of CD81 and SR-BI is not sufficient to confer susceptibility to HCVpp (Bartosch, B., A., et al. J Biol Chem 278:41624-30; Hsu, M., J. et al. 2003. Proc. Natl. Acad. Sci. USA 100:7271-76), suggesting that additional factors are required.
The C-type lectins dendritic cell- and liver-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN and L-SIGN) binds E2 (Gardner et al., 2003, Proc Natl Acad Sci USA 100:4498-4503; Lozach et al., 2003, J Biol Chem 278:20358-66; Pohlmann et al., 2003, J Virol 77:4070-4080), HCVpp (Cormier et al., 2004, Proc Natl Acad Sci USA 101:14067-72; Lozach et al., 2004, J Biol Chem 279:32035-45) and several other viruses (Alvarez et al., 2002, J Virol 76:6841; Geijtenbeek et al., 2000, Cell 100:587-97; Halary et al., 2002, Immunity 17:653-64; Tassaneetrithep et al., 2003, J Exp Med 197:823-9). The interaction between HCVpp and a cell expressing DC- or L-SIGN does not result in infection; however, bound HCVpp can be transmitted to permissive cells in co-culture (Cormier et al., 2004, Proc Natl Acad Sci USA 101:14067-7; Lozach et al., 2004, J Biol Chem 279:32035-45), as is the case for HIV (Geijtenbeek et al., 2000, Cell 100:587-97). As L-SIGN and DC-SIGN are expressed on liver sinusoidal endothelial cells and DCs, respectively, a model where they capture and transmit HCV particles to susceptible hepatocytes is feasible but unproven. The association of HCV with lipoproteins (Monazahian et al., 2000, Med Microbiol Immunol (Berl) 188:177-84; Thomssen et al., 1992, Med. Microbiol. Immunol. 181:293-30) has led to the hypothesis that the low density lipoprotein receptor (LDL-R) may be involved in HCV entry. At least in the presence of plasma, LDL-R appears to mediate cell attachment and possibly cellular uptake of plasma derived HCV RNA (Agnello et al., 1999, Proc. Natl. Acad. Sci. USA 96:12766-12771; Monazahian et al., 1999, Journal of Medical Virology 57:223-9; Wunschmann et al., 2000, J Virol 74:10055-62). Whether this interaction results in productive infection, however, is uncertain, as HCVpp do not seem to require LDL-R for cell entry (Bartosch et al., 2003, J Exp Med 197:633-642; Hsu et al., 2003, Proc. Natl. Acad. Sci. USA 100:7271-76). Moreover, heparan sulfates (HS) (Barth, H., et al. 2003 J Biol Chem 278:41003-12) and asialoglycoprotein receptor (ASGP-R) (Saunier, B., et al. 2003 J Virol 77:546-59) have been suggested as HCV entry factors, but their roles have not been rigorously validated in an infection assay.
When HCVpp became available it was quickly noted that only a select group of cell lines, all of which were derived from human liver, could be infected (Bartosch et al., 2003, J Exp Med 197:633-642; Hsu et al., 2003, Proc. Natl. Acad. Sci. USA 100:7271-76; Zhang et al., 2004, Virol 78:1448-55). What precisely defines this narrow tropism is as yet unclear. So far, no set of molecules sufficient to permit HCVpp entry into a target cell has been defined. Indeed, several cell lines express CD81, SR-BI and LDL-R at levels comparable to permissive cells and still cannot be infected (Hsu, M., et al. 2003 Proc. Natl. Acad. Sci. USA 100:7271-76). Thus one or more additional factor(s) essential for HCV entry are still missing.
In 1998, Furuse and colleagues identified CLDN1 and Claudin 2 (CLDN2) as integral membrane proteins present in the tight junctions of mouse hepatocytes that were able to reconstitute de novo tight junction (TJ) strands when expressed in mouse fibroblasts (Furuse, M., et al. 1998 J Cell Biol 141:1539-50; Furuse, M., et al. 1998 J Cell Biol 143:391-401). Subsequently, several homologous gene products were identified bringing the claudin gene family up to 24 members (Van Itallie, C. M., and J. M. Anderson. 2005. Claudins and Epithelial Paracellular Transport. Annu. Rev Physiol. for review). Claudins are small (20-27 kD) molecules with a short cytoplasmic N- and C-terminal tails. Four membrane-spanning helices are separated by a larger (˜53aa) first and a smaller (˜24aa) second extracellular loop (EL1 and EL2, respectively) and a very short intracellular loop (FIG. 3).
Claudins are thought to be the major structural component of the TJ in epithelia where claudin family members and other TJ associated membrane proteins such as occludin, the junction-adhesion-molecule (JAM) and the coxsackie-adenovirus-receptor (CAR) associate laterally to form the TJ strand (Furuse, M. et al. 1999 J Cell Biol 147:891-903; Gonzalez-Mariscal, L. et al. 2003 Prog Biophys Mol Biol 81:1-44). TJ strands in the membrane of neighboring cells then interact across the intercellular space to form the actual TJ. The extracellular loops of the claudins are thought to be central to these intercellular contacts that narrow and largely obliterate the intercellular space, thus forming the barrier between the apical and the basolateral side of the epithelium (Furuse, M., et al. 1999 J Cell Biol 147:891-903). Despite their name, TJs do not completely seal off the paracellular pathway but allow selective flux of solutes based on size and charge. Paracellular pathway selectivity seems to be determined largely by the extracellular domains of the claudins present in a given tight junction (Colegio, O. R., et al. 2003 Am J Physiol Cell Physiol 284:C1346-54; Furuse, M., et al. 2001. J Cell Biol 153:263-72). Thus, the modular claudin composition of the tight junction may determine both the transepithelial electrical resistance and the paracellular pathway selectivity for certain solutes in epithelial tissues. Finally, through their intracellular C-terminus, claudins interact with PDZ-domain containing adaptor proteins, such as the TJ associated proteins zonula occludens (ZO)-1, -2 and -384.
CLDN1 is expressed in a number of epithelia, with the highest levels detected in the liver followed by kidney, skin and other tissues (Furuse, M., et al. 1998 J Cell Biol 141:1539-50; Su, A. I., et al. 2002 Proc Natl Acad Sci USA 99:4465-70). Claudin-1 knockout mice die in the neonatal period due to water loss through the skin (Furuse, M., et al. 2002 J Cell Biol 156:1099-111). However, loss of CLDN1 is tolerated in humans; individuals homozygous for a two nucleotide deletion in the Claudin-1 gene resulting in frame shift and a premature stop codon have been found in two inbred families of Moroccan descent (Hadj-Rabia, S., et al. 2004 Gastroenterology 127:1386-90). Affected patients exhibit scaling skin (ichthyosis) and liver disease due to neonatal sclerosing cholangitis. Moreover, several other members of the claudin family have been implicated in genetic and infectious diseases: Claudin-14 mutations cause recessive non-syndromic deafness (Wilcox, E. R., et al. 2001 Cell 104:165-72) and this phenotype was replicated in Claudin-14 knockout mice_(Ben-Yosef, T., et all. 2003 Hum Mol Genet. 12:2049-61). Defects in Claudin-16 (Paracellin) result in renal magnesium loss in humans (Simon, D. B., et al. 1999 Science 285:103-6). The C-terminus of the Clostridium perfringens enterotoxin (CPE), a major cause of food poisoning, binds specifically to Claudin-3 and -4 causing disruption of intestinal TJs while the N-terminus forms pores in the plasma membrane leading to further disruption of epithelial integrity (Fujita, K., et al. 2000 FEBS Lett 476:258-61; Hanna, P. C., et al. 1992 Infect Immun 60:2110-4; Sonoda, N., et al. 1999 J Cell Biol 147:195-204). As mentioned above and described in section C, we have evidence indicating that CLDN1 is a required entry factor for HCV. Interestingly, several other TJ molecules have been implicated in viral infection; CAR functions as a receptor for coxsackie- and adenoviruses (Bergelson, J. M., et al. 1997 Science 275:1320-3); JAM is an essential receptor for reoviruses (Barton, E. S., et al. 2001 Cell 104:441-51); and CLDN7 has been implicated in HIV entry into CD4 negative cells (Zheng, J., et al. 2005 Retrovirology 2:79). A recent elegant study expanded on this theme of TJ components in viral entry by showing that group B coxsackie virus initially engages a receptor, DAF, on the luminal surface of intestinal cells. DAF binding triggers signaling events that result in the migration of the virus-DAF complex to the TJ where an interaction with a co-receptor, CAR, occurs that then results in caveolin dependent uptake of the viral particle (Coyne, C. B., et al. 2006 Cell 124:119-31).
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The invention relates to a method for installing a seat cover, including at least one shaped spar, onto a seat body that includes at least one securing element whose base is positioned over at least one slot in the seat body into which the shaped spar may be secured.
A shaped spar that is combined with a covering material is known from the European Patent EP 403 815 B1. There are slots in the seat body into which recessed securing elements are arranged. The seat cover is connected to the seat body so that the shaped spar is pressed into the securing elements from above. In this manner, simple installation of the seat cover onto a seat body that consists, for example, of foam, is possible. It has been shown however, that pressing the shaped spar into the securing elements is difficult because of the elasticity of the seat cover. An automated installation of the seat cover onto the seat body is additionally made more difficult because the shaped spar is secured to the underside of the seat cover and therefore cannot be gripped by robot grippers or the like. When pressed from above, the seat cover material becomes a hindrance so that machine gripping without damaging the material is not possible. Even manual installation has the difficulty that the position of the shaped spar and the securing element located below it must be detected by xe2x80x9cfeelxe2x80x9d.
It is therefore a principal object of the present invention to provide a method for installing a seat cover provided with at least one shaped spar that allows automated seat cover installation.
This object, as well as other objects which will become apparent from the discussion that follows, are achieved, according to the present invention, by providing a method which includes at least the following steps:
(a) penetrating the seat body with a gripper jaw of a shaped spar gripper from the seat body underside into the slot;
(b) opening the gripper jaw assembly, gripping the shaped spar, and closing the gripper jaw assembly;
(c) applying tension by means of the gripper jaw assembly gripping the shaped spar toward the underside of the seat body until the shaped spar clicks or is secured in place in the securing element; and
(d) opening the gripper jaws of the shaped spar gripper and removing the shaped spar gripper from the seat body.
This method is a reversal of the customary installation procedure. While the shaped spar is pressed into the securing element from the upper side of the seat cover in accordance with the state of the art, the method according to the invention uses the opposite approach, namely pressing the seat body from below, gripping the shaped spar, and then pressing it into the securing element until it clicks or snaps into place.
The seat body is advantageously positioned on top of a seat body bracket. Particularly for seat bodies made of soft foam, the forces necessary to create the snap connection between the shaped spar and the securing element are distributed over a greater area so that the deformation of the seat body during installation is reduced, resulting in reduced return forces within the seat body.
Penetration of the seat body may be performed by a cutting tool in soft foam and similar materials that is preferably positioned on the tip of the shaped spar gripper. A single cut can allow the insertion of the shaped spar gripper.
It is especially advantageous if at least one access channel is included in the slot that extends from the base of the slot to the underside of the seat body and through which the shaped spar gripper may be passed. This access channel may be included in the seat body as a first step, for which techniques such as drilling or grinding, or melting and cutting in the case of thermo-plastic foam materials, are particularly suited.
A seat body can also be used in which at least one access channel is included at the time of manufacture that extends from the base of the slot to the underside of the seat body, and through which the shaped spar gripper may be fed.
At least one access channel should be positioned between each pair of securing elements in order to distribute the forces evenly to the shaped spars and securing elements, and thus to ensure that the shaped spar clicks into place in all the securing elements on the seat body.
The invention further relates to a seat cover installation device used to perform the method described above. Since the installation of seat covers has always been performed manually, it is a further object of the invention to provide an installation device by means of which the method according to the invention may be performed automatically in order to secure a seat cover to a seat body.
This object is achieved by a seat cover installation device with a seat body bracket and at least one shaped spar gripper which may be dislocated by a first actuation device with respect to the seat body bracket, and which includes a gripper jaw assembly with at least two gripper jaws that may be opened or closed by means of a second actuation device.
Gripper jaws and shaped spar grippers may be operated independently of each other using drive mechanisms such as pneumatic cylinders or stepper motors. It is therefore possible to reach through the seat body from beneath, grip the shaped spar hanging down from the positioned seat cover, and insert it into the securing elements. Since the shaped spar is freely accessible from below in the slot, it may be gripped positively, centered, and secured using force.
The object is also achieved by a seat cover installation device with at least one fixed, positioned shaped spar gripper and a seat body bracket that may dislocated with respect to the shaped spar gripper via a first actuation device, whereby the shaped spar gripper includes a gripper jaw assembly with at least two gripper jaws that may be opened or closed by means of a second actuation device.
For this, the entire seat body bracket is moveable with respect to the fixed, vertically-positioned shaped spar grippers. The weight of the seat body bracket is sufficient to overcome friction forces in the support and to cause a sinking so that the first actuation device needs only to operate in one direction. Thus, for example, simpler pneumatic cylinders with no double chamber may be used as an actuation device.
This device allows penetration of the seat body by the gripper device and automatic gripping of the shaped spar without requiring additional positioning. Based on the jaw-type formation, a broad aperture is provided in an open gripper jaw assembly so that it may grip, center, and surround a shaped spar not positioned precisely above the securing elements with no extra action required by the operator.
A shaped spar gripper with the following properties is particularly advantageous:
(a) The shaped spar gripper includes a guide tube into which a tension rod coupled with the gripper jaws is inserted, and which may be at least partially drawn into the gripper jaws; and
(b) The gripper jaws are connected via their supporting shanks using a coupling whereby the tension rod is connected to at least one of the supporting shanks and/or the coupling.
The tube-shaped formation with gripper jaws that may be integrated within the guide tube permits a compact design, and consequently requires only a small width of the access channel incorporated into the seat body.
For a full understanding of the present invention, reference should now be made to the following detailed description of the preferred embodiments of the invention as illustrated in the accompanying drawings.
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Patients who undergo hemodialysis or other procedures that remove solutes and fluid from the blood often die of cardiac complications. Many factors may contribute to such death, including stress placed on the heart due to the increased blood fluid volume in these patients. Increased fluid concentrations and inability to remove waste products from the blood, in some cases, can also contribute to electrolyte and pH imbalance that can affect cardiac contractility and efficiency. Further, rapid changes in fluid volume or pH or electrolyte concentration of the blood during hemodialysis or other fluid removal processes may place additional stress on the heart and may contribute to the high rate of morbidity for patients who undergo blood fluid removal procedures.
When a patient reaches a point where routine blood fluid removal procedures are prescribed, the patient undergoes periodic examinations that allow a healthcare provider to set various parameters of the blood fluid removal procedures, such as the profile of fluid removal, the composition of dialysate or replacement fluid employed, and the like. These examinations typically occur once a month in accordance with current standards of care.
Hemodialysis or similar procedures may occur three to four times a week. Thus, the patient may undergo 10 to 15 or more blood fluid removal sessions before the prescription or parameters are changed. It is possible, for example, that a prescription with regard to a dialysate electrolyte and pH buffer composition will not be appropriate for a patient several days or weeks after the prescription is set. Accordingly, it may be desirable to more frequently determine whether the electrolyte or pH concentration of a fluid used in blood fluid removal sessions is appropriate. In addition, it may be desirable to adjust the concentration or composition of the fluid during a blood fluid removal session in a manner that may improve patient health and reduce morbidity.
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Mechanical and chemical-mechanical planarizing processes (collectively “CMP”) are used in the manufacturing of microelectronic devices for forming a flat surface on semiconductor wafers, field emission displays and many other microelectronic substrates. FIG. 1 schematically illustrates a planarizing machine 10 with a platen or table 20, a carrier assembly 30 over the table 20, a polishing pad 40 on the table 20, and a planarizing fluid 44 on the polishing pad 40. The planarizing machine 10 may also have an under-pad 25 between the platen 20 and the polishing pad 40. In many planarizing machines, a drive assembly 26 rotates (arrow A) and/or reciprocates (arrow B) the platen 20 to move the polishing pad 40 during planarization.
The carrier assembly 30 controls and protects a substrate 12 during planarization. The carrier assembly 30 typically has a substrate holder 32 that holds the substrate 12 via suction, and a pad 34 in the substrate holder 32 that supports the backside of the substrate 12. A drive assembly 36 of the carrier assembly 30 typically rotates and/or translates the substrate holder 32 (arrows C1 and D, respectively). The substrate holder 32, however, may be a weighted, free-floating disk (not shown) that slides over the polishing pad 40.
The combination of the polishing pad 40 and the planarizing fluid 44 generally define a planarizing medium that mechanically and/or chemically-mechanically removes material from the surface of the substrate 12. The polishing pad 40 can be a conventional non-abrasive polishing pad without abrasive particles composed of a polymeric material (e.g., polyurethane), or it can be an abrasive polishing pad with abrasive particles fixedly bonded to a suspension material. In a typical application, the planarizing fluid 44 may be a CMP slurry with abrasive particles and chemicals for use with a conventional nonabrasive polishing pad. In other applications for use with an abrasive polishing pad, the planarizing fluid 44 is generally a “clean” chemical solution without abrasive particles.
To planarize the substrate 12 with the planarizing machine 10, the carrier assembly 30 presses the substrate 12 against a planarizing surface 42 of the polishing pad 40 in the presence of the planarizing fluid 44 (arrow C2). The platen 20 and/or the substrate holder 32 then move relative to one another to translate the substrate 12 across the planarizing surface 42. As a result, the abrasive particles and/or the chemicals in the planarizing medium remove material from the surface of the substrate 12.
CMP processes should consistently and accurately produce a uniformly planar surface on the substrate assembly to enable precise fabrication of circuits and photo-patterns. During the fabrication of transistors, contacts, interconnects, and other components, many substrate assemblies develop large “step heights” that create a highly topographic substrate surface. To enable the fabrication of integrated circuits with high densities of components, it is necessary to produce a planar substrate surface at several stages of processing the substrate assembly because non-planar substrate surfaces significantly increase the difficulty of forming sub-micron features or photo-patterns to within a tolerance of approximately 0.1 μm. Thus, CMP processes should typically transform a highly topographical substrate surface into a highly uniform, planar substrate surface (e.g., a “blanket surface”).
In the competitive semiconductor industry, it is also highly desirable to maximize the yield of operable devices as quickly as possible. One factor of CMP processing that affects the yield of operable devices is the ability to accurately stop CMP processing at a desired endpoint. In a typical CMP process, the desired endpoint is reached when the surface of the substrate is highly planar and/or when enough material has been removed from the substrate assembly to form discrete components of the integrated circuits (e.g., shallow-trench-isolation structures, contacts, damascene lines, etc.). Accurately endpointing CMP processing is important for maintaining a high yield because: (1) subsequent processing may not be possible if the surface is not sufficiently planar; and/or (2) the integrated circuits may not operate if the discrete components are not accurately formed. For example, if the substrate is “under-planarized,” shallow-trench-isolation structures may not be adequately isolated from one another. Conversely, if the substrate assembly is “over-polished,” “dishing” can occur in shallow-trench-isolation structures that can cause current-leakage paths or parasitic capacitance. Extreme cases of over-polishing can even destroy sections of the substrate assembly. Thus, it is highly desirable to stop CMP processing at the desired endpoint.
One drawback of CMP processing is that it is difficult to determine when the substrate surface is both planar and at the desired endpoint elevation in the substrate assembly. In one conventional method for determining the endpoint of CMP processing, the planarizing period of one substrate assembly in a run is estimated using the polishing rate of previous substrate assemblies in the run and the thickness of material that is to be removed from the particular substrate assembly. The estimated planarizing period for the particular substrate assembly, however, may not be accurate because the polishing rate may change from one substrate assembly to another. Thus, this method may not accurately planarize all of the substrate assemblies in a run to the desired endpoint.
In another method for determining the endpoint of CMP processing, the substrate assembly is removed from the pad and the substrate carrier, and then a measuring device measures a change in thickness of the substrate assembly. Removing the substrate assembly from the pad and substrate carrier, however, is time-consuming and may damage the substrate assembly. Thus, this method generally reduces the throughput and yield of CMP processing.
In still another method for determining the endpoint of CMP processing, a portion of the substrate assembly is moved beyond the edge of the pad, and an interferometer directs a beam of light directly onto the exposed portion of the substrate assembly to measure a change in thickness of a transparent layer. The substrate assembly, however, may not be in the same reference position each time it overhangs the pad. For example, because the edge of the pad is compressible, the substrate assembly may not be at the same elevation for each measurement. Thus, this method may inaccurately measure the change in thickness of the substrate assembly.
In yet another method for determining the endpoint of CMP processing, U.S. Pat. Nos. 5,036,015 and 5,069,002, which are herein incorporated by reference, disclose detecting the planar endpoint by sensing a change in friction between a wafer and the polishing medium. Such a change of friction may be produced by a different coefficient of friction at the wafer surface as one material (e.g., an oxide) is removed from the wafer to expose another material (e.g., a metal film). More specifically, U.S. Pat. Nos. 5,036,015 and 5,069,002 disclose detecting the change in friction by measuring the change in electrical current through the drive motor for the platen and/or substrate holder.
Although the endpoint detection technique disclosed in U.S. Pat. Nos. 5,036,015 and 5,069,002 is an improvement over the previous endpointing methods, the increase in current through the drive motors may not accurately indicate the endpoint of a substrate. The detection of a single change in friction at the interface between the different materials may only indicate that at least a portion of the substrate surface is at the level of the interface. Other portions of the substrate surface, however, may be above or below the interface level and/or the interface level itself may not be planar. The apparatus and methods disclosed in U.S. Pat. Nos. 5,036,015 and 5,069,002 may accordingly indicate that at least a portion of the substrate surface is at the endpoint elevation, but they do not necessarily indicate that the substrate surface is planar. Thus, the apparatus and methods of U.S. Pat. Nos. 5,036,015 and 5,069,002 may not indicate that the substrate surface is both planar and at the endpoint elevation.
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1. Field of the Invention
The present invention relates to a copper foil for an inner layer board of a very thin, fine pitched pattern multi-layer board and a process for producing the same. More particularly, it relates to a printed circuit inner-layer copper foil having low surface roughness with fine nodules formed on both surfaces of the foil thereby to make it possible to obtain fine pitched pattern circuits by etching and have high adhesion to a substrate and also to a process for producing the same.
2. Prior Art
Conventional multi-layer boards have been produced by bonding ordinary inner-layer copper foils (where mat (rough) surface roughness Rz is around 7.0 .mu.m and shiny (smooth) surface roughness is around 0.7 .mu.m) having nodules formed on their mat surface to substrates facing to the mat surface, preparing circuits by etching, subjecting the circuits to black oxide treatment, adhering substrates respectively to the outsides of the circuits under heat and pressure, adhering copper foils respectively to the outsides of these substrates under heat and pressure, and then etching the outer copper foils to form circuits thereby to prepare a four-layer printed circuit board. To prepare five- or more-layer printed circuit (multilayer) printed circuit boards, the above steps may be repeated in turn. Alternatively, a copper foil with nodules formed on both side thereof (where mat surface roughness Rz is around 8.5 .mu.m and shiny surface roughness Rz is around 1.6 .mu.m) is commercially available as a both surfaces-treated copper foil.
However, in the above-mentioned black oxide treatment, a haloing phenomenon tends to take place since the oxide film is solved in a hydrochloric acid solution. Thus, the insulating characteristics and the reliability of layer-to-layer interconnection will tend to be deteriorated. To overcome such defects, the black oxide treatment may be followed by a chemical reduction treatment. The black oxide treatment should be performed using a concentrated alkaline solution and, in addition, the reduction treatment should be performed whereby the production cost will increase.
On the other hand, since the conventional both surfaces-treated copper foil has copper nodules formed on both the surfaces thereof, the above-mentioned problem is not raised. However, since this treated copper foil is prepared from a conventional copper foil, its mat surface roughness is high. Thus, this treated copper foil is difficult for use in the preparation of fine pitched pattern circuits therein which are now in rapid progress. When the surface roughness of the copper foil at the interface with the substrate is high, the linearity of the foot-line of conductor will decrease after circuits are obtained by etching. Thus, if the conductor spacing is small in this case, a problem such as migration will be occured.
In addition, multi-layer construction and thin board construction have now been in progress. To reduce the thickness of each layer consisting of a copper foil and a substrate therefor, tile thickness of the substrate is also decreased. Further, the decrease of interlayer insulation due to the roughness of the mat surface of the copper foil is strongly sought to be prevented as far as possible.
Since the shiny surface roughness Rz of a conventional copper foil is as low as 0.5 to 1 .mu.m, the strength of adhesion of the copper foil to the substrate will be unable to be improved even if the nodule forming treatment is performed on said surface. When the size of the nodules is increased in an attempt to enhance the adhesion strength, the nodules themselves on the copper foil will raise a problem such as dropping off from the copper foil. In addition, there are apt to be raised secondary problems that the nodules will be left in a substrate after a circuit is prepared by etching or they will be crushed when pressed.
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1. Field of Invention
This invention relates to solar energy collection, specifically to a system and method of maximizing solar energy collection from a solar panel array.
2. Description of Prior Art
In recent years, concerns have been raised that high demand for electricity taxing the capacity of existing electricity generating plants. Furthermore, concerns regarding the availability and environmental safety of fossil and nuclear fuel are being raised. As a result of the above factors, the price of electricity has been on a path of steady increasing. It has become increasing common to seek for alternative energy sources. One such energy source is the sun. Solar panels have been available for many years for the purpose of converting the energy from sunlight into electricity. The collected energy is thereafter often stored in some sort of energy bank and used for heating homes, water suppliers, and powering various electrical devices. The collected energy in a form of DC (Direct Current) electricity may also be injected into a power grid after it is converted into AC (Alternative Current) electricity by an inverter.
In order for the solar panel to receive as much solar energy as possible for conversion into electricity, it is desirable to mount the solar panel on an adjustable support apparatus that allows for variably orienting the solar panel relative to the general position of the sun. Many existing devices generally provide for tilting and rotation of the panel. Tilting of the panel is generally provided by a pivotal connection at the bottom of the panel and a drive mechanism of some sort, with the panel bottom either directly hinged to a base of some sort or hingedly connected to a rigid non-extendable linkage. Several of these devices also provide for rotation of the panel. The rotation is usually provided by separately rotating the support apparatus such as a pole or a plate for the entire panel.
As the sun moves across the sky from sunrise to sunset, it is desirable that the orientation of the solar panel is changed accordingly by the pivoting and tilting mechanism of the support apparatus to maintain an optimized position for generating highest electricity from the sunlight.
A clock mechanism has been employed to control the orientation of the panel. To compensate for the compound movement of the sun, daily from horizon to horizon, and seasonally with a progressing season elevation, the clock mechanism must be elaborate and therefore expensive.
Sensors such as illumination detectors have also been employed to derive the position of the sun. U.S. Pat. No. 4,297,572 to Carlton disclosed a solar energy collector assembly including a solar panel mounted for movement along a predetermined tracking path in order to maintain a predetermined orientation with respect to the sun. The disclosed assembly also includes a specific solar tracking sensor. There are many problems associated with the use of illumination detectors in the tracking mechanism including shadowing of the detector by a cloud in the sky.
A solar panel array comprising a multiple solar panels connected together in series and/or in parallel has recently become more and more popular, in particularly, for use as a power generation plant. It is important that the array generates highest possible electrical power to speed up the return on investment (ROI). Low cost wireless communication network has been proposed to enhance the operation efficiency of the array.
In US patent publication 2008/0087321 by Schwartzman, a solar energy generator module is disclosed including a modular photovoltaic array, sensors, controller and communication means for monitoring and communicating a variety of physical parameters from each module to a centralized computer. The collected information can be utilized to monitor module health for maintenance purposes, and also be used as a position input for the primary servomechanism control algorithm.
In US patent publication 2009/0188488 by Kraft et al., an apparatus for networking solar tracking devices is disclosed. The system includes one or more solar tracking devices, each comprising a tracking controller. Tracking controllers form a wireless mesh communication network managed by a network manager. Tracking controller receives operation data from and sends monitor data to host computer.
The potential to increase the efficiency of the solar array by employing a low cost communication network connectable to the Internet, however, has not yet been fully explored. It is desirable to have an intelligent solar panel array which can maximize the generated electricity with acceptable cost.
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This invention relates to a method for filling an electrolyte solution into a lithium secondary battery; said method capable of filling electrolyte solution into a case and extracting an excessive electrolyte solution therefrom, and sealing easily a battery, thereby the simplification of fabrication process, the reduction in the production cost, and the improvement in compaction of energy density can be achieved, and a battery structure of the lithium secondary battery; said battery having a reduced current collection resistance from positive electrodes and negative electrodes, and a narrowed deviation in the fluctuation in the resistances among the tabs engaged in current collection as well, and having a simple structure as a battery so as to enable easier assembly of the battery and to effectuate the aforementioned method for filling an electrolyte solution into the case easily.
In recent years, the lithium secondary battery has been widely used as a power battery for handy electronic appliances such as personal handy phone systems, video tape recorders, notebook-type computers, or the like. Additionally, in the case of a lithium secondary battery, a single battery can generate a voltage of approximately 4 V, and this level of voltage is higher than that of conventional secondary batteries such as a lead battery, or the like, and its energy density is also high. Thus, much attention has been paid to it not only as a power source for the aforementioned handy electronic appliances, but also as a motor driving power source for an electric vehicle (EV) or a hybrid electric vehicle (HEV), of which penetration among the general public is being earnestly planned as a low-pollution vehicle due to the recent development in the environmental problems.
In a lithium secondary battery, in general, a lithium-transition metal compound oxide as a positive active material, a carbon material as a negative active material, and an organic electrolyte solution obtained by dissolving a Li-ion forming electrolyte in an organic solvent as an electrolyte solution are used. And, for an internal electrode body as a portion where battery reaction is carried out, various types are available.
For example, in a coin-shaped battery with a small capacity, a sandwiched-type internal electrode body in which a separator is sandwiched between a positive electrode and a negative electrode is used. Here, as the positive electrode and the negative electrode, those that are formed in a disk like shape, or in a coin like shape by subjecting positive material and negative material to press-forming processing or the like, respectively are suitably used.
As one example of preferable structures of internal electrode bodies to be used for a lithium secondary battery with a comparatively large capacity usable for an EV, or the like, as is shown in FIG. 18,there is given a wound-type internal electrode body 1 being formed by winding around the outer periphery of a hollow cylinder-shaped core 6 a positive electrode 2 having one or more tabs 5 for current collection and a negative electrode 3 having one or more tabs 5 for current collection, in such a manner that the positive electrode 2 and negative electrode 3 are not brought into direct contact with each other, by sandwiching a separator 4 between the positive electrode 2 and the negative electrode 3. Here, in general, the length of the core 6 is set equal to the width of the positive electrode 2 and that of the negative electrode 3. Incidentally, there is also proposed a battery using a laminate-type internal electrode body formed by laminating alternately via separators 4 a plurality of positive electrodes 2 and negative electrodes 3 having been prepared by cutting the above-mentioned positive and negative electrodes, respectively into those with small areas.
Now, in any case where any of the above-described structures is adopted as an internal electrode body, it is necessary to soak the internal electrode body in an electrolyte solution. Here, as an electrolyte solution, a non-aqueous electrolyte solution (hereinafter to be referred to as an xe2x80x9celectrolyte solutionxe2x80x9d), which is obtained by dissolving a lithium electrolyte in an organic solvent, is used. In the case of a coin-shaped battery, for example, there is employed such a technique that a predetermined quantity of an electrolyte solution is injected by using a metering pump, or the like, under a reduced atmosphere and the battery case is sealed so as to fill the case with the electrolyte solution, after the internal electrode body is mounted inside a battery case. In addition, even in the case where a wound-type internal electrode body is used, a similar technique is used as long as a small capacity battery such as a common 18650 (with a diameter of 18 mmxcfx86 and a length of 65 mm) cylinder-type battery is produced. In such a method, an excessive amount of electrolyte solution that is not actually required is liable to be filled therein,
Since electrolyte solution is generally expensive, the percentage of battery costs attributable to electrolyte solution is not small. Nevertheless, in the case of those batteries having a small capacity, the reasons why the aforementioned method for filling an electrolyte solution is adopted are considered that:
the space where excessive electrolyte solution (hereinafter to be referred to as a xe2x80x9cexcessive electrolyte solutionxe2x80x9d) is filled in is small in the absolute value, the cost for the electrolyte solution used for filling such a small space is considered not to be so high since the internal electrode body does not occupy much space in the interior of the battery in a small capacity battery;
a desired battery performance is obtainable if a minimum required quantity of an electrolyte solution is filled in a case since the area of reaction in the battery is small; and
an introduction of a step for recovering excessive electrolyte solution results in raising production costs unintentionally, etc.
On the contrary, in the case of a battery having a relatively large capacity (hereinafter to be referred to as a xe2x80x9clarge capacity batteryxe2x80x9d) to be applied to an EV, or the like, the size of a battery itself will necessarily become large. In such a case, the use of the wound-type internal electrode body 1 shown in FIG. 18 requires a larger space for housing the current collection tabs 5 at both ends or one end of the case for the battery. Additionally, since a hollow cylinder-shaped type core is generally used for the core 6, the absolute volume to be occupied by these spaces inside the case for the battery becomes large.
Accordingly, if an electrolyte solution is filled into a case for a large capacity battery by using a technique similar to that for the above-described small capacity battery, an expensive electrolyte solution is used not in an economic manner. This would bring about an increase in the production cost and a reduction in the energy density of the battery, as well. Furthermore, it is not preferable, from the viewpoint of durability, for metal members other than the internal electrode body, sealing members of the battery case, and the like, to be always in contact with the electrolyte solution since it causes often the leakage of the electrolyte solution, the corrosion of said members, or the like.
On the other hand, the electrolyte solution is required to fill in an amount sufficient to impregnate the internal electrode body properly even in the case of a large internal electrode body having a large battery area. And in the case where this is not fulfilled, not only the desired battery performance cannot be attained, but also the fluctuation in the performance of respective batteries will take place. Accordingly, in the case of a large capacity battery, it is preferable to impregnate the internal electrode body thoroughly in an excessive amount of an electrolyte solution under a reduced atmosphere, and thereafter the excessive electrolyte solution is removed.
Therefore, in a large capacity battery, if one wants to fill an electrolyte solution by employing a technique similar to that for a small capacity battery, the following steps would be given as an example:
as shown in FIG. 17, at first, a case for battery 65 with one end portion 61 having been sealed is disposed in a globe box or the like with the sealed end 61 being placed downward,
then an electrolyte solution transferred from another end portion 62 of the case which is open at the upper portion with a metering pump or the like is injected by using a nozzle 63 or the like after reducing the atmosphere of the globe box in such a manner that the electrolyte solution is injected intermittently until the liquid surface does not go down so as to subject the internal electrode body to the impregnation treatment with the electrolyte solution for a predetermined period of time,
the interior of the globe box or the like is purged with inert gas,
thereafter the excessive electrolyte solution is drained by putting the case for battery 65 upside down, and
finally the end portion 62 which has been left open is sealed.
However, in the case of such a method that an electrolyte solution is supplied from the upper portion of the case for the battery, the impregnation of an electrolyte solution starts mainly from the upper portion of the internal electrode body under a reduced atmosphere. Therefore, bubbles generated in the lower portion of the internal electrode body will hardly be liberated form the upper portion of the case for the battery. Accordingly, it will require holding the resultant for a long period of time under reduced atmosphere. In this case, if an organic solvent being highly volatile is solely used for an electrolyte solution, the evaporation of the solvent will bring about a problem in that the density of electrolyte fluctuates from product to product. In addition, in the case where a highly volatile organic solvent is mixed with one or more other non-volatile solvent or the like for use, the predominant evaporation of the volatile organic solvent causes the deviation in mixing ratio from product to product. This would bring about a problem in that the density of the electrolyte fluctuates from product to product. Anyhow, in any one of these cases, the full extent of exertion of the performance of electrolyte solution cannot be expected.
Moreover, in the case of a large capacity battery, due to a big shape of the battery itself, the sealing of an open end of the case for the battery within the globe box or the like would bring about various problems. That is, an enlargement of the globe box or the like is required since a sealing device should be installed within the globe box or the like. Furthermore, the enlargement of the globe box results in the decrease in the degree of the reduction of the interior pressure thereof, the enlargement of the vacuum pump, and the mass consumption of purge gas or the like. Thus, it is not realistic.
Therefore, the present inventors have extensively studied, in particular, the simplification of a method for filling an electrolyte solution in the production of a large capacity battery. As a result, they reached the present invention to be described later. Moreover, various studies have been made at the same time so as to find out not only a battery structure suitable for using the method of filling an electrolyte solution according to the present invention, but also a battery structure capable of improving the battery performance and productivity even in the case where the method for filling an electrolyte solution according to the present invention is not used.
One of the problems to be solved is the reduction in current collection resistance from the internal electrode body and the reduction in difference in current collection resistance of each tab. A tab is connected directly with an external terminal of the battery, that is, directly with an electrode terminal to extract current out from the battery, or is connected with an internal terminal thereof, that is, a terminal to which the tabs are intermediately connected collectively inside the battery. Accordingly, in the case where the tabs are connected with the internal terminal, it is necessary that the internal terminal is made conductive to the external terminal to form a current path between the tabs and the external terminal.
As a method for forming the conductive state between the tabs and the external terminal, there is proposed, for example, in JP-A-9-92338, a lithium secondary battery 27 in which a series of flexible leads (equivalent to xe2x80x9ctabsxe2x80x9d in meaning) 37 is sandwiched between the electrode terminal 38 and the hold-down hardware 33, forming a warping shape as shown in FIG. 16; said leads 37 being welded to the electrode terminal 38 by laser beam. In this lithium secondary battery 27, the electrode terminal 38 is attached to a cap (ceiling plate) 29 by using a nut 34, and the cap 29 is provided with not only electrolyte solution injection opening 32 which is to be sealed with a blank cap 30 but also a pressure release valve 26.
However, in case of the lithium secondary battery 27 disclosed in the JP-A-9-92338, the leads 37 may be sandwiched with the hold-down hardware 33 at any position of the outer periphery of the electrode terminal 38; as a corollary, the leads 37 disposed in the inner periphery of the internal electrode body 35 become long, and, on the contrary, the leads 37 disposed in the outer periphery become short. In this case, since the quantity of current flow in each lead 37 is different due to the difference in resistance of each lead 37, depending upon its length, there is a fear that the uniformity in the battery reaction cannot be maintained when used as a battery for an EV which requires the frequent flow of a large current.
In addition, since the leads 37 may be attached to any position of the outer periphery of the electrode terminals 38 with laser welding, and the structure at the end portion of the battery is complicated and various parts are installed therein, as shown in FIG. 16, thus the work efficiency (productivity) of the battery assembly is considered to be not necessarily good.
Moreover, a battery 27 disclosed in JP-A-9-92338 has the configuration at both ends, as shown in FIG. 16. It is stated in the laid-open invention that the injection of electrolyte solution is carried out by injecting electrolyte solution from one end of the injection opening 32 for electrolyte solution, while keeping the interior of the battery 27 under a reduced pressure by deaerating from the other end of the injection opening 32 for electrolyte solution, and this step should be repeated several times. However, it is not advantageous to assemble a battery with the repetition of such steps several times. Moreover, it is not advantageous to provide both ends with the injection openings 32 for electrolyte solution which eventually will be sealed since the leakage of the electrolyte solution and the decrease in air tightness are liable to occur.
Furthermore, the battery disclosed in JP-A-9-92338 has been proposed to prevent damage to leads 37 under severe vibrations when the battery is used as for the battery for an EV. Therefore, it proposes to use a flexible material for lead 37. At the same time, it refers to the reduction in internal resistance by virtue of a broadened welded portion between the leads 37 and the electrode terminals 38 formed by laser welding, however, it is quite silent about the reduction in fluctuation in the resistance among respective leads 37.
Another problem is how to secure the durability against vibration during driving since the durability is an essential requirement in the case of a battery for an EV. For example, when the internal electrode body vibrates or moves inside the battery case, there is a fear that the electrode active materials coated on the positive electrode and the negative electrode are peeled, thereby the battery capacity is reduced. Furthermore, it is not preferable since there is a fear of formation of a short circuit between the positive electrode and the negative electrode due to the peeled electrode active materials. Moreover, the end surface of the internal electrode body is apt to be deformed from an initial plain shape into a shape such as spiral waves or the like due to vibration, and such a deformation of the internal electrode becomes a cause of an unfavorable uneven battery reaction.
Therefore, there is proposed, in JP-A-9-92241, a battery 28 having such a structure that, as shown in FIG. 15, an electrode pole 25 having its lower surface covered with insulator collar 39 is inserted into a hollow portion of a cylindrical core 31 around which an electrode spiral body 36 (equivalent to the internal electrode body 1) is formed, and said electrode pole 25 is fixed to a cap 29 with a nut 34. In addition, there is proposed, in JP-A-1-175176, a battery structure in which an internal electrode body formed by inserting a bar-shaped insulating body into a portion formed by using a tentative core which was removed thereafter is housed in the battery case.
However, in the case of the electrode spiral body 36 proposed in JP-A-9-92241, the inner peripheral surface of the battery case 19 and the electrode pole 25 function only as a stopper so as to suppress the movement of the electrode spiral body 36 in the diameter direction. However, it does not suppress the movement in the diameter direction, and it has such a structure that the movement in the longitudinal direction of the electrode spiral body 36 takes places easily in the distance of the gap with the electrode pole 25. If the movement to the longitudinal direction of the electrode spiral body 36 takes place, the electrode spiral body 36 collides with the electrode pole 25, which would damage the leads 37 (equivalent to tabs 5) attached on the end surfaces of the electrode spiral body 36. Moreover, it is considered that it is liable to receive such damage that the electrode active material is peeled, etc. at the end portions of the electrode spiral body 36.
Furthermore, in case of the invention disclosed in JP-A-1-175176, it is not formed in such a structure that the movement in the longitudinal direction of the internal electrode body is suppressed. This is because the internal electrode body is fixed by pressure formed between a solid bar of an insulator inserted into the inner peripheral surface of the battery case, and the core of the internal electrode body. Thus, no positive attempt has been made hitherto so as to suppress the movement in the longitudinal direction since much attention has been given to the fixation of the internal electrode body in the diametrical direction.
The present invention has been made so as to solve problems of the prior art mentioned above. Thus, the present invention is aiming to minimize the amount of the excessive electrolyte solution to be filled inside the battery on the occasion of forming a comparatively large capacity battery. Moreover, the present invention is aiming to provide a simple method for filling an electrolyte solution, and provide a battery structure capable of operating said filling method easily. Furthermore, the present invention is aiming to attain improvement in the battery performance such as reduction in current collection resistance and improvement of anti-vibration performance.
That is, one of the aspects of the present invention is directed to a method for filling an electrolyte solution into a lithium secondary battery comprising an internal electrode body formed by winding a positive electrode, and a negative electrode, with a separator sandwiched therebetween around the outer periphery of a core, and an electrolyte solution to impregnate said internal electrode, which comprises the steps of:
inserting a tip of a nozzle for injecting said electrolyte solution in such a depth that at least it reaches a position on an end surface of said internal electrode body located on an opposite side through a through hole of said core and an electrolyte solution injection opening being provided in an extended position of said through hole on one end surface of the battery, or an electrolyte solution injection opening being integrally formed with an external terminal in an extended position of the through hole of the core on one end surface of the battery,
injecting the electrolyte solution until at least the internal electrode body is immersed, and
thereafter extracting an excessive electrolyte solution remaining inside the battery by using a nozzle for extraction of electrolyte solution.
The method for filling an electrolyte solution of the present invention is preferably used in a battery where the electrolyte solution injection opening is disposed in the center of one end surface of the battery and/or the core is disposed in the center of the battery. In addition, one nozzle may be used as a nozzle for injection of electrolyte solution and a nozzle for extraction of electrolyte solution as well. It is preferable to insert the tip of the nozzle for injection of electrolyte solution or that of the nozzle for extraction of electrolyte solution in such a manner that it reaches the other end of the battery to implement injection or extraction of electrolyte solution under this state. In this case, if a recessed portion is provided in the inner center of the other end of the battery, or if a recessed portion is provided by forming the center portion of the other end of the battery in a convex shape outward, an excessive electrolyte solution remaining in this recessed portion is easily extracted by a nozzle for extraction of electrolyte solution.
After extraction of the excessive electrolyte solution, the electrolyte solution injection opening is enclosed from outside with screwing or pressure fitting or filling with a sealing material to implement sealing of the battery easily. Moreover, the assembly work of the battery becomes preferably good, if the electrolyte solution is extracted and/or injected by using a pipe as a body member of the battery case after the battery is sealed by subjecting both ends of the pipe to caulking processing in order to occlude the ends of the pipe with the cap. The method for filling an electrolyte solution of the present invention is suitably applied to a battery having a capacity of 2 Ah or more.
Now, as a first embodiment of a battery structure according to the present invention, there is provided a battery structure of a lithium secondary battery comprising an internal electrode body formed by winding a positive electrode, and a negative electrode, with a separator sandwiched therebetween around the outer periphery of a core, and an electrolyte solution to impregnate said internal electrode body;
wherein an electrolyte solution injection opening is provided in an extended position of the through hole of the core on one end surface of the battery, or an electrolyte solution injection opening is integrally formed with an external terminal in an extended position of the through hole of the core on one end surface of the battery.
In this first battery structure, the electrolyte solution injection opening is preferably disposed in the center of one end surface of the battery and/or the core is preferably disposed in the center of the battery. In addition, it is preferable that the electrolyte solution injection opening preferably may be sealed from outside with screwing or pressure fitting or filling with a sealing material.
In addition, as a second battery structure according to the present invention, there is provided a battery structure of a lithium secondary battery comprising an internal electrode body formed by winding a positive electrode, and a negative electrode, with a separator sandwiched therebetween around the outer periphery of a core, and an electrolyte solution to impregnate said internal electrode body,
wherein the core is sandwiched between caps for sealing the end surfaces of the battery case, and is fixed.
And in this second battery structure, insulating materials or metal materials the surfaces of which are covered with insulating materials are preferably used as a core.
Moreover, as a third battery structure according to the present invention, there is provided a battery structure of a lithium secondary battery comprising an internal electrode body formed by winding a positive electrode, and a negative electrode, with a separator sandwiched therebetween around the outer periphery of a core, and an electrolyte solution to impregnate said internal electrode body,
wherein insulating members are disposed at both ends of the core to extend the length of the core, and the core as well as the insulating member are sandwiched between caps to seal the end surfaces of the battery case, and are fixed.
In these second and third battery structures where the core, and the like are sandwiched between caps, it is preferred to provide an electrolyte solution injection opening on one of the caps at the position extended from the hollow portion of the core or the insulating member. At this time, it is preferred that hole portions or slits are provided on the end portions of the core or the insulating members. It is also preferred to provide a recessed portion in the inner center portion of the end surface of a case for battery where the electrolyte solution injection opening is not formed. It is also preferred to provide a recessed portion by forming a convex shape outwardly on the center portion of the end surface. Incidentally, such an arrangement to provide a recessed portion is suitably applied to the first battery structure, too.
Next, as a fourth battery structure according to the present invention, there is also provided a battery structure of a lithium secondary battery comprising an internal electrode body formed by winding a positive electrode, and a negative electrode, with a separator sandwiched therebetween around the outer periphery of a core, and an electrolyte solution to impregnate said internal electrode body,
wherein one collective connection portion is provided in one internal terminal to connect a plurality of tabs together in one place, and the collective connection portion is positioned within an extended range in the axial direction of the core covering from the outer periphery of the core to the outer periphery of the internal electrode body.
In the case of the fourth battery structure, it is preferred to provide one collective connection portion capable of connecting a plurality of tabs together in one place in one internal terminal, said collective connection portion being positioned within a range which is extended, in the axial direction of the core, from the outer periphery of the core to the outer periphery of the internal electrode body. Moreover, it is also preferred to form this collective connection portion in such a structure that a plurality of tabs provided so as to be positioned on an approximately straight line within a range, in the direction of diameter, which is extended from the outer periphery of the core to the outer periphery of the internal electrode body are collectively connected with one internal terminal. The internal terminal is suitably disposed in the caps sealing the end portions of the battery.
Moreover, a plurality of internal terminals is preferably disposed for the positive electrode and the negative electrode, respectively. And the collective connection portions of the internal terminals are preferably placed in the extended position in the center direction of diameter from the outer periphery of the core to reach the outer periphery of the internal electrode body. The collective connection of tabs with the internal terminal is preferably formed by means of welding, or caulking, or an eyelet. The material for the internal terminal is preferably produced from aluminum, aluminum alloy, copper or copper alloy. Incidentally, if the caps sealing the end portions of the battery can act as a path for electric current, the battery structure will not become complicated and is preferable.
It is preferable to use commonly a battery case of which caps are employed as the end surfaces of the battery, in any of the above-mentioned first to fourth battery structures; said battery cases being preferably configured in such a manner that the caps are sandwiched between the end portions of the pipe, and the end portions of the pipe are sealed by caulking process. In addition, between an end portion of the internal electrode body and a cap, it is preferable to provide a necked portion in the inner periphery portion of the pipe so as to suppress the movement of the internal electrode body inside the battery. The battery structure of the present invention is suitably applied to a battery with battery capacity of 2 Ah and more, but there are no reasons to exclude application to a battery using a wound-type internal electrode body with a lower battery capacity. In addition, the battery structure of the present invention can be suitably applied to a battery to be used as a motor driving power source for an electric vehicle or a hybrid electric vehicle.
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WO03/094112 discloses a local color correction approach. An input image represented by a set of input pixel values is color corrected by locally modifying the input pixel values according to pixel neighborhoods to obtain an output image which has a set of output pixel values. Each set of output pixel values equals a non-linear combination of a set of input pixel values and its corresponding set of modified pixel values.
In one embodiment of this prior art, the input pixel values are low-pass filtered to obtain a tone mask which is an image which contains numerical values which are indicative of shadows, highlights, and midtones in the received digital image. For each one of the input component color values (usually red, green, and blue) of an input pixel, the corresponding output color values are obtained by applying an exponential function on the input color values. The masked values of the input component color values are used to vary the exponent of the corresponding exponential function. Thus, the output color values are obtained by applying a pixel-wise gamma correction, wherein each pixel has its own particular gamma value due to its particular masked value. These local gamma values are determined by the tonal properties of the pixel and its surrounding pixels. It is disclosed that other non-linear functions may be used to determine the output color values as a function of the input color values, such as sigmoidal or hyperbolical functions. In another embodiment, the sigmoidal functions are used for masked values representing middle gray, while the exponential functions are used for masked values, which represent black and white.
Although this approach increases the visibility of image content in the extreme ends of the dynamic range, it also increases the noise in these parts of the image content, and further tends to decrease the contrast of the image by increasing the brightness in dark parts of the image and by decreasing the brightness in bright parts of the image.
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1. Field of the Invention
The present invention relates to a method of producing a semiconductor device and, more particularly, to a method of producing a semiconductor device in which fine metallic wires, except for gold wire, are used for the purpose of wiring between electrodes of a semiconductor chip and external leads, with a higher reliability than that of semiconductor devices using gold wire bonding.
2. Description of the Related Art
FIGS. 1 and 2 are sectional views of semiconductor devices produced through known processes, particularly electrode structures of the device. Each semiconductor device 1, 1a has an Si substrate 11 on which is formed an SiO.sub.2 film 12 which in turn is overlaid by an Al film 13.
The Si substrate 11 is bonded to a die pad 14 of a lead frame by a bonding material such as an epoxy resin 16 or an Au-Si solder 17. A fine metallic wire 21, which is in this case a copper wire, was melted at its end in order to form a copper ball 22. The copper ball 22 is pressed against the Al film 13 by means of a capillary chip (not shown) in order to deform the ball plastically. Meanwhile, ultrasonic energy is applied together with heat energy to a temperature of 250.degree. to 400.degree. C., from the Si substrate 11, so that an intermetallic compound is formed between the Al film 13 and the copper ball 22. More specifically, the intermetallic compound phases 31, 32 and 33 are, respectively, the .theta. phase (CuAl.sub.2), .eta..sub.2 phase (CuAl.sub.2) and .gamma..sub.2 phase (Cu.sub.9 Al.sub.4) of the copper and aluminum. This semiconductor device is then sealed with ceramic having an empty room for the chip or molded with resin. It seems that the .theta. phase layer 31 shown in FIG. 1 a non-uniform alloy layer, the thickness of which fluctuates largely, whereas the .theta. phase 31, .eta..sub.2 phase 32 and .gamma..sub.2 phase 33 shown in FIG. 2 are uniform alloy layers with little fluctuation in thickness.
The intermetallic compound of the alloy layer can be identified by the alloy layer phase color: namely, by etching the Al layer 13 with phosphoric acid (H.sub.3 PO.sub.4), causing the copper ball 22 to color by treating the same with an aqueous solution of sodium hydroxide (NaOH), and identifying the .theta. phase layer 31 by a brown color at the bonding face.
FIG. 3 is a schematic illustration of the bonding face of the copper ball 22 shown in FIG. 1. In this case, the brown color (.theta. phase) 31 does not exist uniformly over the entire area and non brown colored portions where the .theta. phase is not formed are observed here and there.
FIG. 4 is a schematic illustration of the bonding face of the copper ball 22 shown in FIG. 2. The brown color (.theta. phase) is spread over the entire area, and the white and blue color .eta..sub.2 phase 32 or .gamma..sub.2 phase 33 exist in local areas.
Japanese Published Patent Application 62-265729 discloses a semiconductor device. Judging from the description in the specification, it is understood that the structure of this device is similar to those shown in FIGS. 2 and 4, i.e., the .theta. phase (CuAl.sub.2), .eta..sub.2 phase (CuAl) and .gamma..sub.2 phase (Cu.sub.9 Al.sub.4) exist in the alloy layer.
The known semiconductor device has an above bonding structure. Then it is sealed with ceramic having an empty room for the chip or molded with resin.
The reliability of the semiconductor device is evaluated by an accelerated reliability test. The empty ceramic seal package device has little problems. However, when the device is molded in epoxy resin, and especially during the high temperature (250.degree. C.) storage test, the reliability of this device is subject to fluctuations larger than that of the device in which gold wire is used. In addition, the device life during the high temperature storage test is substantially equivalent to the device using gold wire, thus the expectation that the device using copper wire can expand the operational margin in higher temperature region over the gold wire.
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Devices suitable for delivering very small volumes of fluid have been available for several decades. Osmotic pumps are of particular interest for delivering small amounts of drugs or other similar applications. These osmotic pumps typically utilize a driving force based on a concentration gradient across a semi-permeable membrane. Most current designs involve a variety of flexible housings and may include one or more chambers. Unfortunately, these pumps tend to have limited control over the flow rate. Specifically, the flexible housings and membranes can create fluctuations in flow rate which are unpredictable. Although this may be acceptable in some applications, fluctuations in flow rate can generally be unacceptable for applications requiring more precise flow rates. In addition, any changes in contours or surface area of the semi-permeable membrane can affect the flow rate of solvent across the membrane.
Furthermore, continuous precise delivery of fluids for extended periods of time can present a unique challenge to these types of devices. Most often, current technologies are limited to delivery times of several weeks to a couple of months. If used in a patient, this requires frequent replacement and can be inconvenient. Further, such short useful durations increase costs associated with replacement, maintenance, and materials.
As such, cost effective systems and devices that are capable of effectively delivering relatively small volumes of fluids over an extended period of time continue to be sought through ongoing research and development efforts.
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1. Field of the Invention
The present invention relates to a power transmission apparatus, and more specifically, to a power transmission apparatus that has an electromagnetic friction clutch and a method for tuning the power transmission apparatus.
2. Discussion of the Background
Japanese Laid-Open Patent Publication No. 11-153159 discloses a conventional power transmission apparatus. The power transmission apparatus includes inner and outer rotary members, which are coaxially arranged with and rotate relative to each other, an annular friction clutch, which is located between the inner rotary member and the outer rotary member, and an electromagnetic drive apparatus, which drives the friction clutch when energized by current supply.
The electromagnetic drive apparatus has an annular armature, which is arranged to face the friction clutch, and an annular electromagnet, which is arranged to face the friction clutch with part of the outer rotary member located in between. When the electromagnet is energized, the armature is attracted to the electromagnet and causes friction with the friction clutch. Thus, the inner and outer rotary members are coupled with each other via the friction clutch to transmit torque.
The electromagnet is supported by an annular electromagnet support formed on a yoke. The electromagnet support and the electromagnet are accommodated in an annular groove formed at part of the outer rotary member. Predetermined outer and inner clearances are located between the electromagnet support and the annular groove. More specifically, the outer circumferential surface of the electromagnet support is apart from one side of the annular groove by a predetermined first distance. The inner circumferential surface of the electromagnet support is apart from the other side of the annular groove by a predetermined second distance.
When exciting current is supplied to the electromagnet, a magnetic path that circulates the yoke, the outer clearance, part of the outer rotary member, the friction clutch, the armature, the friction clutch, part of the outer rotary member, the inner clearance, and the yoke is generated. The armature is attracted toward the electromagnet by the operation of the magnetic induction and depresses the friction clutch. Thus, the outer rotary member and the inner rotary member are coupled to each other to transmit torque.
In an assembling procedure of the power transmission apparatus, the inner rotary member, the armature, and the friction clutch are mounted inside the outer rotary member. The yoke to which the electromagnet is attached is assembled in the last process.
In the assembling procedure of the yoke, an operator selects one of yokes having several sizes and mounts the yoke to the outer rotary member. Then, a conduction test of the electromagnet is performed to measure the exciting current/transmission torque characteristic. If the characteristic is undesirable, the operator changes the yoke with other yoke having different size that provides satisfactory exciting current/transmission torque characteristic.
The exciting current/transmission torque characteristic refers to the relationship between the exciting current supplied to the electromagnet (electromagnetic coil) and the torque transmitted from the outer rotary member to the inner rotary member.
Each yoke is formed such that the outer clearance and the inner clearance will be equal. More specifically, the inner circumferential surface and the outer circumferential surface of each yoke are cut such that the first and the second distances will be equal. Therefore, the manufacturing process of the yokes of the conventional power transmission apparatus is troublesome. Also, the tuning variation of the exciting current/transmission torque characteristic is relatively large.
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A folding knife may generally include a lock mechanism to keep the blade of the knife in a locked position when open. This may be helpful to reduce the possibility of the blade accidentally closing on a user's hand during use. For example, U.S. Pat. No. 5,826,340 to Hull discloses a traditional lock mechanism for a folding knife.
The knife includes a lock bar that is pivotally connected to a handle, adjacent the blade. The lock bar includes one lock member, and the blade includes a lock member receiving recess. The lock member includes a bottom wall, and two sidewalls that extend upwardly therefrom. The lock member receiving recess is defined by a bottom wall, and a pair of opposing sidewalls that extend upwardly therefrom. When the blade is in an opened position, the opposing sidewalls of the lock member matingly engage the respective opposing sidewalls of the lock member receiving recess. In other words, when the blade is in the opened position, respective surfaces of the lock member and the lock member receiving recess are in contact with one another.
This type of lock mechanism may, however, be prone to accidental unlocking by the user. Another problem that may occur with this type of lock mechanism is lock failure when a force is applied to a distal portion of the blade.
Another type of folding knife is illustrated in U.S. Pat. No. 5,615,484 to Pittman. This type of folding knife includes a lock mechanism having a stop pin and a slide member that engages the stop pin. When the blade is in the opened position, the stop pin contacts a notch formed in the end of the blade. The stop pin also contacts a sidewall of the slide member when the blade is in the opened position, and the slide member is in an engaged position. To return the blade to the closed position, the slide member is disengaged from contact with the stop pin, allowing the blade to be freely closed. This type of lock mechanism may also be disadvantageous because it may be prone to accidental unlocking by the user.
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Unless otherwise stated, by “greater unsaturated hydrocarbons” herein we mean the hydrocarbons which contain triple bond and/or two double bonds.
The process for converting hydrocarbons at a high temperature such as steam-cracking or alternatively catalytic cracking, provide unsaturated hydrocarbons such as for example, ethylene, propylene, butadiene, butene; saturated alkanes such as ethane, propane, butane, as well as lighter compounds such as methane, hydrogen and carbon monoxide, and hydrocarbons boiling in the gasoline range. Thus, the gaseous monoolefinic hydrocarbons with two or more carbon atoms, obtained by these processes also contain a considerable amount of hydrocarbons of greater unsaturation degree, i.e. acetylenes and diolefins. In general, the mainly olefin-containing process stream from these processes contains 0.5%-5.3% of acetylenes and diolefins. Acetylenes and diolefins could reduce the activity of the polymerization catalyst and weaken the physical properties of the polymer. Therefore, only after reducing the contents of acetylenes and diolefins below a definite value, can this gaseous monoolefin be used as monomers useful for synthesizing polymers or copolymers.
At present, the economical and simple method commonly adopted in the prior art is converting these greater unsaturated hydrocarbons into the corresponding monoolefins by catalytically selective hydrogenation. The catalytically selective hydrogenation comprises three types: back-end selective hydrogenation, front-end selective hydrogenation and hydrogenation of the cracked gas. The gas from the outlet of the compressor, beside hydrogen, methane, C2 and C3-fractions, also contains C4 fraction (mainly butadiene) and some C5 diolefins. Because of the quick deactivation of the hydrogenation catalyst caused by the polymer formed from diolefin polymerization, and a large portion of the butadiene was lost on the hydrogenation, the process for selectively hydrogenating the cracked gas is scarcely employed industrially.
By “front-end hydrogenation” and “back-end hydrogenation” are meant the location of “acetylenes hydrogenation reactor” relative to “demethanizer”, the hydrogenation reactor located in front of the demethanizer means front hydrogenation, and behind that means back-end hydrogenation.
The removal of acetylenes by back-end hydrogenation is that, the top process stream of deethanizer (methane, hydrogen and carbon monoxide) and the carbon mono- and dioxide-free stream out of the methanation reactor (methane and hydrogen) are added respectively and quantitatively into the top process stream of deethanizer (C2 fraction only) to remove the acetylenes by selective hydrogenation. Because of hydrogenation sensitivity to excursions in concentrations of acetylene and carbon monoxide during the acetylene removal, the selectivity of C2 hydrogenation catalyst must be adjusted by carefully regulating the addition of hydrogen and carbon monoxide. Moreover, because of the purity of the ethylene product being influenced by the impurities (such as carbon monoxide, methane etc.) introduced along with the hydrogen, and fluctuated now and then, a rectifying section or a second demethanizer must be installed at the downstream ethylene column, to separate out the remaining hydrogen and methane.
The front-end hydrogenation process for acetylenes removal has been emerged since the fifties of the twentieth century. In recent years, because of the Palladium catalyst with promoter, which has high ethylene-selectivity, small amount of green oil formed and great space velocity, etc., has been successfully developed, the front hydrogenation process for acetylenes removal has been adopted in more and more ethylene plants. There exist two types of front-end hydrogenation process, i.e. front deethanizing front-end hydrogenation process, and front depropanizing front-end hydrogenation process. The former is that before passing into demethanizer, the acetylene is removed by selective hydrogenation of the top stream of the front deethanizer (methane, hydrogen, carbon monoxide and C2); and the latter is that before passing into demethanizer, the acetylene and partial propyne, propadiene are removed by selective hydrogenation of the top stream of the front depropanizer (methane, hydrogen, carbon monoxide, C2 and C3). The disadvantage of the front-end hydrogenation process is that a large amount of hydrogen in the process stream and the fluctuations in the carbon monoxide content, lead to the acetylenes being easy to leak from the outlet or the abnormal operation of the reactor. These abnormal phenomena were due to the temperature excursions caused by the sensitivity and activity of the fresh catalyst at the initial start up of the ethylene production plant. Moreover, the separation of hydrogen and methane is performed in the demethanizer system where the energy consumption is higher, so the higher the content of the hydrogen passes through the demethanizer, the higher the energy consumes.
A process for hydrogenation of acetylene in the mixed phase front end has been disclosed in CN 1098709A (May 12, 1994) hereby incorporated by reference. A mixed phase hydrogenation reactor is adopted in said patent application. Said reactor is located at the downstream side of the front depropanizer and at the upstream side of the further separation units such as demethanizer and deethanizer. The advantages of said patent application is: as concerns the mixed phase hydrogenation of acetylene, the front depropanizer upstream is able to provide liquid stream into the mixed phase hydrogenation reactor, said liquid stream is used to wash and cool said reactor, and able to reduce the number of the front-end hydrogenation units to fully hydrogenate the acetylenes. It has been found that said hydrogenation units are better able to tolerate excursions in carbon monoxide and acetylene concentrations and the abnormal phenomena of the depropanizer.
The disadvantages of said patent application are:
1. Because of the mixed phase hydrogenation reactor being located at the downstream side of the front depropanizer, the cooled and partially condensed stream rich in C3 and lighter components passing through the mixed phase hydrogenation reactor, said process can only hydrogenate the lower unsaturated hydrocarbons, but not be able to hydrogenate the greater unsaturated hydrocarbons such as butyne, butadiene etc, thus the amount of hydrogen consumed is limited and a large amount of remaining hydrogen passes into the cryogenic section where the energy consumption being higher. 2. In said patent application, because of the stream, before passing through the front depropanizer, being not hydrotreated, the alkynes and diolefins in the stream are easy to form equipment fouling, thus increase the energy consumption. 3. When said patent application being employed, a series of units must be attached to perform respectively the additional treatments of the separated C3 and higher components for acetylenes and diolefins removal, so the equipment cost and energy consumption of the production, taken as a whole, would be increased.
Therefore, there needs a process for hydrogenating the greater unsaturated hydrocarbon in the front end of the process stream of the olefin production plant, without the above-mentioned defects of the prior art.
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The invention relates to self-expanding stent delivery systems, which are used to implant a stent into a patient""s body lumen to maintain the patency thereof. The stent delivery system is useful in the treatment and repair of body lumens, including coronary arteries, renal arteries, carotid arteries, and other body lumens.
Stents are generally cylindrically-shaped devices which function to hold open and sometimes expand a segment of a blood vessel or other body lumen. They are particularly suitable for use to support and hold back a dissected arterial lining which can occlude the fluid passageway therethrough. Stents also are useful in maintaining the patency of a body lumen, such as a coronary artery, after a percutaneous transluminal coronary angioplasty (PTCA) procedure or an atherectomy procedure to open a stenosed area of the artery.
A variety of devices are known in the art for use as stents and have included coiled wires in a variety of patterns that are expanded after being placed intraluminally by a balloon catheter; helically wound coil springs manufactured from an expandable heat sensitive material such as nickel-titanium; and self-expanding stents inserted in a compressed state and shaped in a zig-zag pattern.
Typically, the aforementioned stents are delivered intraluminally through a percutaneous incision through the femoral or renal arteries. A stent is mounted on the distal end of an elongated catheter, typically on the balloon portion of a catheter, and the catheter and stent are advanced intraluminally to the site where the stent is to be implanted. Typically with expandable stents, the balloon portion of the catheter is inflated to expand the stent radially outwardly into contact with the arterial wall, whereupon the stent undergoes plastic deformation and remains in an expanded state to hold open and support the artery.
With respect to self-expanding stents, typically a retractably sheath is positioned over the self-expanding stent which is mounted on the distal end of the catheter. Once the catheter has been advanced intraluminally to the site where the stent is to be implanted, the sheath is withdrawn thereby allowing the self-expanding stent to expand radially outwardly into contact with the arterial wall, thereby holding open and supporting the artery.
One of the problems associated with the prior art stents and catheter-delivery systems, is to removably attach the stent to the catheter""s distal end or the balloon portion of the catheter so that the stent does not dislodge or move axially on the catheter or balloon.
What has been needed and heretofore unavailable is a reliable catheter-delivery system on which the stent can be mounted and removably attached so that it does not move axially on the catheter either during delivery and advancement through the vascular system, or during implanting of the stent. The present invention satisfies this need.
The present invention is directed to a self-expanding stent delivery system in which a self-expanding stent is removably attached to a catheter so that the stent remains in position on the catheter until it is implanted. Unlike prior art stents, which may have a tendency to dislodge or move axially on the catheter shaft when the sheath is withdrawn or when the catheter is advanced through a tortuous vasculature, the present invention provides means for removably attaching the stent to the catheter so that it cannot move axially on the catheter shaft.
A catheter assembly for removably attaching an intravascular stent is provided in which an elongated catheter has an inner member and an outer member extending along a longitudinal axis wherein the inner member and the outer member have a coaxial configuration and are dimensioned for relative axial movement. A self-expanding stent, having an open lattice structure, and being biased toward an open configuration, is mounted within the outer member. The inner member is slidably positioned within the lumen of the stent, and then the inner member is heated until it conforms and fills the open lattice structure of the stent with attachment projections.
The present invention includes an inner member that is naturally pliable and deformable or is heat-deformable and formed from a polymeric material which when heated will fill the open lattice structure of the stent with attachment projections. The inner member can be formed from polymeric materials including polyurethanes, polyethylenes, polyethylterpthalate, and nylons.
In another embodiment of the invention, an elastomeric sleeve is attached to the distal end of the inner member. This stent is mounted in the distal end of the outer member and is biased outwardly against the outer member. The inner member distal end and its sleeve are positioned within the stent, and the sleeve is heated until it fills and forms attachment projections in the open lattice structure of the stent.
The invention also relates to the method of mounting the self-expanding stent on the delivery catheter. The delivery catheter includes an outer member and an inner member having relative axial movement and control handles for providing relative axial movement between the members. The self-expanding stent is positioned within the inner lumen of the outer member and the control handles are manipulated to slide the inner member distal end within the inner lumen of the self-expanding stent. Thereafter, heat is applied to the inner member distal end so that it conforms and fills the open lattice structure of the self-expanding stent with attachment projections, thereby removably attaching the self-expanding stent to the inner member distal end and preventing axial movement of the stent. The self-expanding stent remains biased radially outwardly and is retained from expanding by the outer member.
The invention also includes a method of implanting a self-expanding stent utilizing the catheter-delivery system described above. Using the catheter-delivery system, the stent is advanced through a patient""s vascular system until it is positioned at the site where the stent is to be implanted. The control handles are manipulated to simultaneously move the inner member axially in a distal direction and the outer member axially in a proximal direction. As the stent is exposed and no longer retained by the outer member, it will deploy by self-expanding radially outwardly into contact with the body lumen. The stent will not move axially on the catheter shaft as the inner member and the outer member are moved axially relative to one another, since the stent is removably attached to the inner member by attachment projections. After the stent is deployed, the catheter-delivery system is withdrawn from the patient.
One feature of the present invention is to permit the physician to partially deploy the stent, and if it is improperly positioned, the outer member can be moved axially to recapture the partially deployed stent so that the stent can be repositioned in the proper location. For example, the control handles can be manipulated to simultaneously move the inner member axially in the distal direction and the outer member axially in a proximal direction to begin to deploy the stent. Thereafter, if it is determined that the stent is being implanted at the wrong location in an artery, the control handles can be manipulated to simultaneously move the inner member axially in a proximal direction and the outer member axially in a distal direction to recapture the partially deployed stent so that it can be repositioned in the proper location in the artery. The stent is then implanted as described above.
Other features and advantages of the present invention will become more apparent from the following detailed description of the invention, when taken in conjunction with the accompanying exemplary drawings.
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Card connector 100 shown in FIG. 6 is a conventional card connector disclosed in Japanese Patent Publication No. 7-244710. Card connector 100 has a header housing 110 including upper and lower housing members 111, 112 that accommodate two memory cards 150, a plurality of electrical pin contacts 120 which are mounted in the housing members 111, 112 and which electrically connect the two cards 150 to a circuit board (not shown), a guide frame 130 which connects the two housing members 111, 112 together and which guides the cards 150 into the housing members, and an ejection mechanism 140 which ejects the two cards 150 accommodated in the housing members 111, 112. The ejection mechanism 140 is equipped with two ejection levers 141 (only one is shown) which respectively eject the two cards 150 accommodated in the housing members 111, 112 by pivoting, and a single operating member 142 which can be connected with one or the other of the ejection levers 141 by switching therebetween.
In order to eject the respective cards 150 accommodated in the housing members 111, 112, the operating member 142 is switched to the side of the card 150 selected for ejection; afterward, the operating member 142 is pushed in the direction indicated by arrow A in FIG. 6, so that one of the ejection levers 141 is caused to pivot. A resilient member 143, which has an engaging projection that engages with a slot 144 in the guide frame 130, is located on the operating member 142, and the operating member 142 can be pushed until the engages projection (not shown) on the resilient member 143 engaging the opening rim of the slot 144.
However, in the case of the conventional card connector, no stop mechanism is provided in order to stop the pivoting of the ejection levers 141 themselves. As a result, after the cards 150 accommodated in the housing members 111, 112 have been ejected, the ejection levers 141 do not stop; instead, the end portions of the ejection levers 141 protrude a considerable distance from the header housing 110, so that there is a danger of interference when the next cards 150 are inserted.
Accordingly, the object of the present invention is to provide a card connector which allows the secure stopping of ejection levers in a header housing accommodating a plurality of cards.
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Power conversion systems supply power to a variety of electronic systems, such as telecom and/or data communication equipment.
Various types of power converter circuitry has been developed for converting electrical energy to one form or the other, such as from AC to DC, from DC to AC and DC to DC. Many types of power converters also utilize transformers to electrically isolate the input source and power control circuitry from the load or loads that are coupled at an output thereof. In most converter topologies, there may be only a weak or no correlation between an average output current and the peak or average current in the primary switch devices in the converter. Accordingly, in order to provide feedback associated with output power or output current, existing designs typically require direct access to the output. For instance, if no direct access is available to an output load current, it may be necessary to level shift or transfer load current information across the isolation barrier. This approach tends to significantly increase the cost and can add additional inefficiencies.
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The use of ventilators and breathing circuits to assist in patient breathing is well known in the art. The ventilator and breathing circuit provides mechanical assistance to patients who are having difficulty breathing on their own. During surgery and other medical procedures, the patient is often connected to a ventilator to provide respiratory gases to the patient. One disadvantage of such breathing circuits is that the delivered air does not have a humidity level and/or temperature appropriate for the patient's lungs.
To provide air with desired humidity and/or temperature to the patient, an HME unit can be fluidly connected to the breathing circuit. As a point of reference, HME is a generic term, and can include simple condenser humidifiers, hygroscopic condenser humidifiers, hydrophobic condenser humidifiers, etc.
In general terms, HME units consist of a housing that contains a layer of heat and moisture retaining media or material (“HM media”). The HM media has the capacity to retain moisture and heat from the air that is exhaled from the patient's lungs, and then transfer the captured moisture and heat to the ventilator-provided air of the inhaled breath. The HM media can be formed of foam, paper or other suitable materials that are untreated or treated, for example, with hygroscopic material.
While the HME unit addresses the heat and humidity concerns associated with ventilator-provided air in the breathing circuit, other drawbacks may exist. For example, it is fairly common to introduce aerosolized medication particles into the breathing circuit (e.g., via a nebulizer) for delivery to the patient's lungs. However, where an HME unit is present in the breathing circuit, the medication particles will not readily traverse the HM media and thus not be delivered to the patient.
In addition, the HM media can become clogged with the droplets of liquid medication, in some instances leading to an elevated resistance of the HME unit. One approach for addressing these concerns is to remove the HME unit from the breathing circuit when introducing aerosolized medication. This step is time consuming, subject to errors and can result in the loss of recruited lung volume when the circuit is depressurized.
Alternatively, various HME units have been suggested that incorporate intricate bypass structures/valves that selectively and completely isolate the HM media from the airflow path. For example, existing bypass-type HME units employ a bypass structure that is internal or through the HM media. While viable, these and other bypass-type HME units are difficult to operate (e.g., requiring a caregiver to rotate two frictionally fitting housing units relatively to each other) and/or are relatively complex and thus expensive.
In light of the above, a need exists for improved HME units having an HM media bypass feature that addresses one or more of the problems associated with conventional bypass-type HME units.
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Many modern vehicles include an on-board diagnostic (OBD) system. An OBD system receives data from sensors located in various areas of the vehicle and can trigger indicators (e.g., dashboard lights) to warn an operator of the vehicle of potentially dangerous or problematic conditions. While these indicators may notify an operator of the existence of a condition, they are often vague and fail to provide the operator with adequate information for addressing the condition. Typically, such indicators merely convey to the operator that they should service the vehicle. In such cases, in order to obtain additional information regarding the condition, the operator may be required to have the vehicle serviced by a qualified service provider (e.g., a dealer) with equipment capable of interpreting diagnostic codes generated by the OBD system.
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Heart disease is the leading cause of death in the United States. Almost 2,000 Americans die of heart disease every day. There are many different types of pathologies that affect the heart. One of the most common pathologies is mitral valve insufficiency. Mitral valve insufficiency occurs when the mitral valve is unable to completely close off fluid communication between the left atrium and the left ventricle during systole. In this situation, the mitral valve leaflets fail to completely coapt or come together to thereby prevent oxygenated blood from flowing in a retrograde fashion from the left ventricle back into the left atrium.
The most common method for repairing mitral valve insufficiency today is open-heart surgery. During open heart surgery, the chest of the patient is opened to create a large enough cavity for access to the heart. One common surgical procedure involves sewing an annuloplasty ring onto the mitral valve annulus from above via an incision into the left atrium of the heart. Various other procedures exist involving the use of suture material in and around the heart.
Minimally invasive surgery, and especially transluminal or percutaneous delivery of instruments into a patient, has become more and more common in various surgical applications. A promising new area of heart surgery involves catheter-based minimally invasive surgery. Catheter-based minimally invasive surgery for mitral valve repair, for example, should lessen the risks that are normally associated with open-heart surgery and will lessen trauma to the patient associated with opening the chest and cutting into the wall of the heart.
One of the problems with using minimally invasive surgery in general, and even more specifically in connection with the heart, is that traditional suture cutting devices are not suitable. For example, conventional hand held scissors-type suture cutters are not suitable for a catheter-based minimally invasive procedure. Accordingly, improved minimally invasive suture cutting devices and methods for cutting suture in a minimally invasive surgery are needed.
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Poly-lactide or polylactic acid (PLA) is a synthetic aliphatic polyester derived from renewal resources, such a corn, sugar beet and cassava, which can ultimately be degraded under composting conditions. Polymers such as PLA have received particular attention, notably for partly replacing certain articles and mouldings in polyvinyl chloride (PVC), which despite their good balance of properties have certain shortcomings.
Although attempts have been made to utilize PLA for various end-use applications, PLA is known to be brittle and exhibit low toughness, which can result in low impact strength products or articles. In addition, when damaged, PLA items exhibit an irreversible weakness due to the cicatrices.
Impact resistance of PLA can be modified by using existing polymeric impact modifiers; however, currently available polymeric impact modifiers always decrease transparency of PLA comprising material. Liquid plasticizer can be used at high content (>15%) to improve impact resistance of PLA, however during the life time of the PLA blend, there is migration and leaching of the plasticizer.
Impact modifiers such as rubber, poly(ethylene glycol) (PEG), and acrylonitrile-butadiene-styrene copolymer (ABS) have been tested. Nevertheless, the immiscibility between these impact modifying additives and the PLA matrix is a major drawback.
Commercially available BioStrength® 150 a methyl methacrylate-butadiene-styrene co-polymer (MBS) is one of the best currently available impact modifiers for PLA; however haze of the resulting PLA material increases from 5, for pure PLA to 95 when 15% w/w of BioStrength® 150 is added.
Plasticizers are additives that increase the fluidity of a material. Commonly used plasticizers, are tributyl citrate (TBC) and acetyl tributyl citrate (ATBC). However, when 15% TBC or ATBC are mixed with PLA, the present inventors observed a plasticizer migration after storage for a few days at room temperature in summer time (25-30° C.).
In turn, Grinsted plasticizer is said not to migrate, however the present inventors observed whitening of PLA-containing Grinsted plasticizer during storage. Additionally differential scanning calorimetry (DSC) showed beginning of crystallization on aged material. Therefore, it can be said that this material is not stable during longer period of time.
There is therefore a need to improve the compositions of the prior art. There is therefore a need to develop polymer compositions obtained from renewable resources having improved impact resistance and allowing objects to be manufactured by the usual techniques of plastics processing.
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The present invention relates to an ion beam apparatus adapted for us in an ion microprobe analyzer or in an ion implantor and, more particularly, to an improvement in an ion source for an ion beam apparatus.
In conventional secondary ion mass spectrometry, as disclosed in U.S. Pat. No. 3,840,743, gaseous component elements such as O.sub.2.sup.+, Ar.sup.+, Ne.sup.+, or the like, are generally used as primary ions.
FIG. 1 shows the principle of operation of a typical conventional secondary ion mass spectrometer. The secondary ion mass spectrometer consists mainly of a primary ion beam illumination system and a scanning ion microscope. The primary ion beam illumination system is intended for generation of an ion beam and for controlling the beam so that an ion beam of desired intensity and size may be applied to the desired portion of the specimen surface.
Usually, the primary ion beam illumination system consists of a gas-leakage controlling device 1, cathode 2, intermediate electrode 3, anode 4, extracting electrode 5, condenser lens 6, object lens aperture 7, objective lens 8, electrostatic deflector 9, power source 19 for the filament, arc discharge power supply 20, accelerating power supply 21, and a lens power supply 22.
Ion beam 10, emitted from an ion gun (constituted by members 1, 2, 3, 4, and 5), is focused on a specimen 11 by a lens system 6, 8. The primary ion beam can be applied to any desired portion on the specimen, or can even scan over the area of the specimen as in the case of television, by a suitable control of the electrostatic deflector 9 and a scanning generator 28. Numeral 23 denotes a secondary ion acceleration power supply.
The mass spectrometer is constituted by a secondary ion extracting electrode 12, electrostatic sector 13, .beta. slit 15, secondary ion detector 16, electrostatic power supply 24, magnetic sector field 14, and its power supply 25, amplifier 26 and a secondary ion pick-up device 27. In operation, the secondary ions 18 generated by primary ion bombardment, are separated according to their mass to charge ratio by the magnetic sector field 14, are detected by a detector, and are then read out by the pick-up device 27. These ions are utilized for brightness modulation of CRT 17, as necessary.
A scanning type ion microscope consists of an auxiliary apparatus such as the aforementioned primary ion beam illumination system and mass spectrometer, and a CRT.
The arrangement is such that the primary ion is caused to scan in synchronization with the electron beam of the CRT, and the secondary ions emitted from the specimen are separated in accordance with mass to charge ratio and picked up as a specific ion which is to be used as a brightness modulation signal for CRT, so as to provide the elemental map of the specimen surface.
Usually, in the apparatus as shown in FIG. 1, a duo-plasmatron type ion source is used as the ion gun, so that the primary ions are produced by an electric discharge. This means that the element to be picked up in the form of ions has to be in gaseous phase. Therefore, such an apparatus can be applied only to limited use.
Also, the ionization coefficient of the element under application of ions largely depends on the kind of elements. FIG. 2 shows ionization coefficients of various elements bombarded by electronegative (O.sup.-) ions, where O.sup.- or Ar.sup.+ ions are used, the ionization coefficient is extremely high for the elements such as Be, Mg, Al, Ca, In, and Be, but is quite low for elements such as S, As, Se, Cd, Te, Au, and Pt. Therefore, the sensitivity of the apparatus is much smaller for the analysis of elements such as As, Cd, Se, Te, or Au, than for these elements such as Be, Mg, or Al. This presents one of the problems inherent in the secondary ion mass spectrometer.
Meanwhile, also in the field of semiconductors, ions such as of B, As, Te, and the like, are used in a technique called ion injection. In this case, these ions are produced by ionizing a gaseous compound containing these elements, also by means of an electric discharge. Therefore, it is quite indispensable that the compound exists in the gaseous phase and, therefore, it is quite difficult to obtain solely the ion of the desired element.
The specification of U.S. Pat. No. 3,631,283 has been known as disclosing a method which makes use of a solid ion source.
According to this description, an evaporation source is provided in the ion source. The solid material is heated and evaporated into gaseous phase for ionization. This method, however, suffers from practical problems that only these elements or compounds having a low melting point and low vapour pressure can be treated by this method, that the ion beam is rendered unstable due to unstable evaporation, that the ion source is prone to be overheated to cause melting down of electrodes, and other members, and that the ion source is seriously contaminated.
A surface ionization type ion source for cesium, which functions in a manner substantially the same as that of the aforementioned method making use of solid resource, is disclosed in a document for conference of study on electronic devices (Document No. EDD-74-22, Feb. 26, 1974) published from Electric Society of Japan. Briefly, this apparatus has the following construction. Two tungsten heaters are disposed in a cylinder (inner diameter 16 mm, length 25 mm) made of nickel. Between these heaters, a mesh of tantalum is stretched. The portion closer to the ion extracting aperture is adapted to be heated to a high temperature by one heater, so as to ionize the cesium atom through the surface ionization, while the portion separated from the first mentioned portion by the tantalum mesh functions as a furnace for evaporating the cesium.
The temperatures of these portions can be controlled independently of each other, by respective heaters.
Namely, the ionization portion is heated to a temperature which is not so high but sufficient to avoid the evaporation deposition of cesium, while the furnace portion is heated to provide an optimum evaporation rate of cesium, and need not be heated to a high temperature.
The cesium ion extracted from the ionization portion through the aperture of 1 mm diameter is then focused by a lens and reaches the specimen surface.
The ion current which reaches the specimen surface depends mainly on the evaporation rate of cesium and, therefore, rapidly grows as the power supply to the heater of ion source is increased.
Although the increased ion current shortens the life, an ion current as large as several micron amperes can readily be obtained by this apparatus. As a loading material or filler, used is cesium carbonate, cesium sulfate, cesium chromate or the like.
This apparatus also relies upon heating for obtaining ion and, accordingly, suffers from the same problems as those pointed out in relation with the aforementioned apparatus.
FIG. 3 shows the relationship between the relative ionization coefficient and the atomic number of secondary ions, when Cs.sup.+ ions produced by this apparatus is used as the primary ion. From the comparison of FIGS. 2 and 3 with each other, it will be seen that S, As, Se, Cd, Te, and Au which all exhibit quite small ionization coefficients in FIG. 2, show extremely large ionization coefficients in FIG. 3 due to the bombardment by Cs.sup.+ ions.
Thus, the same element exhibits different ionization coefficients by the use of a different primary ion. This leads to the conclusion that the secondary ion analysis of high accuracy can be obtained by suitable different primary ions.
Recently, a proposal to improve the heat-resistant property and surface hardness of metal has been carried out by injecting ions into the metal surface. This also serves to increase the demand for a solid ion source. However, a solid ion source which can overcome the aforementioned problems sufficiently well has not been available up to now, so that the progress of this field of industry has been hindered.
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.
Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET). This cleavage is caused by an endothelin converting enzyme (ECE). Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro.
It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)). An. agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. 83 1762 (1989)). In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46-2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber after SAH has also been recently reported (S. Itoh, T. Sasaki, K. Ide, K. Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. , 195: 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic benefit in the indicated disease states.
Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease. For example, Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9, 201-207) have demonstrated that a similar agent prevents ischemia-reperfusion injury in kidney transplantation. Similar studies have suggested the use of endothelin antagonists in the treatment of angina, pulmonary hypertension, Raynaud""s disease, and migraine. (Ferro and Webb, Drugs 1996, 51, 12-27).
Abnormal levels of endothelin or endothelin receptors have also been associated with a number of disease states, including prostate cancer (Nelson et al, Nature Medicine 1995, 1, 944-949), suggesting a role of endothelin in the pathophysiology of these diseases.
Wu-Wong et al (Lfe Sciences 1996, 58, 1839-1847) have shown hat both endothelin and endothelin antagonists bind tightly to plasma proteins, e.g., serum albumin. This plasma protein binding can decrease the effectiveness with which the antagonists inhibit endothelin""s action. Thus, endothelin antagonists with reduced plasma protein binding may be more effective than highly bound congeners.
In accordance with the present invention there are compounds of the formula (I):
wherein
Z is xe2x80x94C(R18)(R19)xe2x80x94 or xe2x80x94C(O)xe2x80x94 wherein R18 and R19 are independently selected from hydrogen and loweralkyl;
n is 0 or 1;
R is xe2x80x94(CH2)mxe2x80x94W wherein m is an integer from 0 to 6 and W is
(a) xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group,
(b) xe2x80x94PO3H2,
(c) xe2x80x94P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl,
(d) xe2x80x94CN,
(e) xe2x80x94C(O)NHR17 wherein R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) xe2x80x94C(O)NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino,
(m) xe2x80x94S(O)2NHC(O)R16 wherein R16 is defined as above,
R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)Nxe2x80x94Rccxe2x80x94 wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
R3 is (a) R4xe2x80x94C(O)xe2x80x94R5xe2x80x94, R4xe2x80x94R5axe2x80x94, R4xe2x80x94C(O)xe2x80x94R5xe2x80x94N(R6)xe2x80x94, R6xe2x80x94S(O)2xe2x80x94R7xe2x80x94 or R26xe2x80x94S(O)xe2x80x94R27xe2x80x94
wherein R5 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) xe2x80x94N(R20)xe2x80x94R8xe2x80x94 or xe2x80x94R8axe2x80x94N(R20)xe2x80x94R8xe2x80x94 wherein R8 and R8a are independently selected from the group consisting of alkylene and alkenylene and R20 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cylcoalkyl or cycloalkylalkyl or (v) xe2x80x94Oxe2x80x94R9xe2x80x94 or xe2x80x94R9axe2x80x94Oxe2x80x94R9xe2x80x94 wherein R9 and R9a are independently selected from alkylene;
R5a is (i) alkylene or (ii) alkenylene;
R7 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) xe2x80x94N(R21)xe2x80x94R10xe2x80x94 or xe2x80x94R10axe2x80x94N(R21)xe2x80x94R10xe2x80x94 wherein R10 and R10a are independently selected from the group consisting of alkylene and alkenylene and R21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;
R4 and R6 are independently selected from the group consisting of
(i) (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from
(1) hydrogen,
(2) loweralkyl,
(3) haloalkyl,
(4) alkoxyalkyl,
(5) haloalkoxyalkyl,
(6) alkenyl,
(7) alkynyl,
(8) cycloalkyl,
(9) cycloalkylalkyl,
(10) aryl,
(11) heterocyclic,
(12) arylalkyl,
(13) (heterocyclic)alkyl,
(14) hydroxyalkyl,
(1 5) alkoxy,
(16) aminoalkyl,
(17) trialkylaminoalkyl,
(18) alkylaminoalkyl,
(19) dialkylaminoalkyl, and
(20) carboxyalky1,
(ii) loweralkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) cycloalkyl,
(vi) cycloalkylalkyl,
(vii) aryl,
(viii) arylalkyl,
(ix) heterocyclic,
(x) (heterocyclic)alkyl,
(xi) alkoxyalkyl,
(xii) hydroxyalkyl,
(xiii) haloalkyl,
(xiv) haloalkenyl,
(xv) haloalkoxyalkyl,
(xvi) haloalkoxy,
(xvii) alkoxyhaloalkyl,
(xviii) alkylaminoalkyl,
(xix) dialkylaminoalkyl,
(xx) alkoxy, and
xe2x80x83wherein z is 0-5 and R7a is alkylene;
R26 is (i) loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy-substituted haloalkyl; and
R27 is alkylene or alkenylene;
(b) R22xe2x80x94Oxe2x80x94C(O)xe2x80x94R23xe2x80x94 wherein R22 is a carboxy protecting group or heterocyclic and R23 is (i) a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) xe2x80x94N(R24)xe2x80x94R25xe2x80x94wherein R25 is alkylene and R24 is hydrogen or loweralkyl,
(c) loweralkyl,
(d) alkenyl,
(e) alkynyl,
(f) cycloalkyl,
(g) cycloalkylalkyl,
(h) aryl,
(i) arylalkyl,
(j) aryloxyalkyl,
(k) heterocyclic,
(l) (heterocyclic)alkyl,
(m) alkoxyalkyl,
(n) alkoxyalkoxyalkyl, or
(o) R13xe2x80x94C(O)xe2x80x94CH(R14)xe2x80x94
xe2x80x83wherein R13 is amino, alkylamino or dialkylamino and R14 is aryl or R15xe2x80x94C(O)xe2x80x94 wherein R15 is amino, alkylamino or dialkylamino;
or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention is a compound of formula (II)
wherein the substituents xe2x80x94R2, xe2x80x94R and xe2x80x94R1 exist in a trans,trans relationship and Z, n, R, R1, R2, and R3 are as defined above.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0 and Z is xe2x80x94CH2xe2x80x94.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 1 and Z is xe2x80x94CH2xe2x80x94.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94, R6xe2x80x94S(O)2xe2x80x94R7xe2x80x94 or R26xe2x80x94S(O)xe2x80x94R27xe2x80x94 wherein R4, R5, R6, R7, R26 and R27 are as defined above.
Another preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, and R3 is alkoxyalkyl or alkoxyalkoxyalkyl.
A more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined above and R5 is alkylene or R3 is R6xe2x80x94S(O)2xe2x80x94R7xe2x80x94 or R26xe2x80x94S(O)xe2x80x94R27xe2x80x94 wherein R7 is alkylene, R27 is alkylene and R6 and R26 are defined as above.
Another more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94 and R3 is R4xe2x80x94C(O)xe2x80x94N(R20)xe2x80x94R8xe2x80x94 or R6xe2x80x94S(O)2xe2x80x94N(R21)xe2x80x94R10xe2x80x94 wherein R8 and R10 are alkylene and R4, R6, R20 and R21 are defined as above.
An even more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is tetrazolyl or xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group or R is tetrazolyl or R is xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is xe2x80x94CH2xe2x80x94,
R1 and R2 are independently selected from (i) loweralkyl, (ii) cycloalkyl, (iii) substituted aryl wherein aryl is phenyl substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, halo, alkoxyalkoxy and carboxyalkoxy, (iv) substituted or unsubstituted heterocyclic, (v) alkenyl, (vi) heterocyclic (alkyl), (vii) arylalkyl, (viii) aryloxyalkyl, (ix) (N-alkanoyl-N-alkyl)aminoalkyl and (x) alkylsulfonylamidoalkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and R5 is alkylene; or R3 is R4xe2x80x94C(O)xe2x80x94N(R20)xe2x80x94R8xe2x80x94 or R6xe2x80x94S(O)2xe2x80x94N(R21)xe2x80x94R10xe2x80x94 wherein R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R8 and R10 are alkylene and R20 and R21 are loweralkyl; or R3 is R6xe2x80x94S(O)2xe2x80x94R7xe2x80x94 or R26xe2x80x94S(O)xe2x80x94R27xe2x80x94 wherein R6 is loweralkyl or haloalkyl, R7 is alkylene, R26 is loweralkyl and R27 is alkylene.
A yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is xe2x80x94CH2xe2x80x94, R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4xe2x80x94C(O)xe2x80x94N(R20)xe2x80x94R8xe2x80x94 or R6xe2x80x94S(O)2xe2x80x94N(R21)xe2x80x94R10xe2x80x94 wherein R8 and R10 are alkylene, R20 and R21 are loweralkyl, R4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is xe2x80x94CH2xe2x80x94, R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) heterocyclic (alkyl), (x) arylalkyl, (xi) aryloxyalkyl, (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is xe2x80x94CH2xe2x80x94, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) aryl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 is loweralkyl and R12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is xe2x80x94CH2xe2x80x94, R1 is (i) loweralkyl, (ii) alkenyl, (iii) heterocyclic (alkyl), (iv) aryloxyalkyl, (v) arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6xe2x80x94S(O)2xe2x80x94N(R21)xe2x80x94R10xe2x80x94 wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.
Another yet more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl, haloalkyl or aryl, Z is xe2x80x94CH2xe2x80x94, R1 is (i) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl or 1,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is alkoxycarbonyl or R6xe2x80x94S(O)2xe2x80x94N(R21)xe2x80x94R10xe2x80x94 wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.
Another yet more preferred embodiment of the invention is a=compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is xe2x80x94CH2xe2x80x94, R1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
A still more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is xe2x80x94CH2xe2x80x94, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) heterocyclic (alkyl), (v) aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-N-alkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
Another still more preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or xe2x80x94C(O)xe2x80x94NHS(O)2R16 wherein R16 is loweralkyl or haloalkyl, Z is xe2x80x94CH2xe2x80x94, R1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or alkoxyalkyl, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.
A most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, Z is xe2x80x94CH2xe2x80x94, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from loweralkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, Z is xe2x80x94CH2xe2x80x94, R1 is substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is 1,3-benzodioxolyl, 1,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R1l is loweralkyl and R12 is aryl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, Z is xe2x80x94CH2xe2x80x94, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxany(or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R6xe2x80x94S(O)2xe2x80x94N(R21)xe2x80x94R10xe2x80x94 wherein R10 is alkylene, R6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R21 is loweralkyl, haloalkyl or alkoxyalkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, Z is xe2x80x94CH2xe2x80x94, R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 is alkyl and R12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, R is xe2x80x94C(O)2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, Z is xe2x80x94CH2xe2x80x94, R1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R5 is alkylene and R4 is (R11)(R12)Nxe2x80x94 wherein R11 and R12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the proviso that one or R11 and R12 is alkyl.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is loweralkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is alkenyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is heterocyclic (alkyl), and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is aryloxyalkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is arylalkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is aryl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is (N-alkanoyl-N-alkyl)aminoalkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
Another most highly preferred embodiment of the invention is a compound of formula (I) or (II) wherein n is 0, Z is xe2x80x94CH2xe2x80x94, R1 is alkylsulfonylamidoalkyl, and R3 is R4xe2x80x94C(O)xe2x80x94R5xe2x80x94 wherein R4 is (R11)(R12)Nxe2x80x94 as defined therein and R5 is alkylene.
The present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II).
The invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
The compounds of the invention comprise two or more asymmetrically substituted carbon atoms. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms xe2x80x9cSxe2x80x9d and xe2x80x9cRxe2x80x9d configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
The term xe2x80x9ccarboxy protecting groupxe2x80x9d as used herein refers to a carboxylic acid protecting ester group employed lo block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in xe2x80x9cPro-drugs as Novel Delivery Systemsxe2x80x9d, Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of xe2x80x9cBioreversible Carriers in Drug Design: Theory and Applicationxe2x80x9d, edited by E. B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C1 to C8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl, 1-methyl-1-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (John Wiley and Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term xe2x80x9calkanoylxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (xe2x80x94C(O)xe2x80x94) group. Examples of alkanoyl include acetyl, propionyl and the like.
The term xe2x80x9calkanoylaminoxe2x80x9d as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term xe2x80x9calkanoylaminoalkylxe2x80x9d as used herein refers to R43xe2x80x94NHxe2x80x94R44xe2x80x94 wherein R43 is an alkanoyl group and R44 is an alkylene group.
The term xe2x80x9calkanoyloxyalkylxe2x80x9d as used herein refers to R30xe2x80x94Oxe2x80x94R31xe2x80x94 wherein R30 is an alkanoyl group and R31 is an alkylene group. Examples of alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
The term xe2x80x9calkenylenexe2x80x9d denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbonxe2x80x94carbon double bond. Examples of alkenylene include xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (xe2x80x94Oxe2x80x94) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to R41Oxe2x80x94 wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to R80Oxe2x80x94R81Oxe2x80x94 wherein R80 is loweralkyl as defined above and R81 is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term xe2x80x9calkoxyalkoxyalkylxe2x80x9d as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term xe2x80x9calkoxyarbonylalkenylxe2x80x9d as used herein refers to an alkoxycarbonyl group as previously defined appended to an alkenyl radical. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenyl, ethoxycarbonylethenyl and the like.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d as used herein refers to R34xe2x80x94C(O)xe2x80x94R35xe2x80x94 wherein R34 is an alkoxy group and R35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
The term xe2x80x9calkoxycarbonylaminoalkylxe2x80x9d as used herein refers to R38xe2x80x94C(O)xe2x80x94NHxe2x80x94R39xe2x80x94 wherein R38 is an alkoxy group and R39 is an alkylene group.
The term xe2x80x9calkoxycarbonyloxyalkylxe2x80x9d as used herein refers to R36xe2x80x94C(O)xe2x80x94Oxe2x80x94R37xe2x80x94 wherein R36 is an alkoxy group and R37 is an alkylene group.
The term xe2x80x9c(alkoxycarbonyl)thioalkoxyxe2x80x9d as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The term xe2x80x9calkoxyhaloalkylxe2x80x9d as used herein refers to a haloalkyl radical to which is appended an alkoxy group.
The terms xe2x80x9calkylxe2x80x9d and xe2x80x9cloweralkylxe2x80x9d as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term xe2x80x9c(N-alkanoyl-N-alkyl)aminoalkylxe2x80x9d as used herein refers to R85C(O)N(R86)R87xe2x80x94 wherein R85 is an alkanoyl as previously defined, R86 is loweralkyl, and R87 is alkylene.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to R51NHxe2x80x94 wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term xe2x80x9calkylaminoalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an alkylamino group.
The term xe2x80x9calkylaminocarbonylxe2x80x9d as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (xe2x80x94C(O)xe2x80x94) linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
The term xe2x80x9calkylaminocarbonylalkenylxe2x80x9d as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
The term xe2x80x9calkylaminocarbonylalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an alkylaminocarbonyl group.
The term xe2x80x9calkylaminocarbonylaminoalkylxe2x80x9d as used herein refers to R40xe2x80x94C(O)xe2x80x94NHxe2x80x94R41xe2x80x94 wherein R40 is an alkylamino group and R41 is an alkylene group.
The term xe2x80x9calkylenexe2x80x9d denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2C(CH3)2CH2xe2x80x94 and the like.
The term xe2x80x9calkylsulfonylamidoalkylxe2x80x9d as used herein refers R88S(O)2NHR89xe2x80x94 wherein R88 is loweralkyl and R89 is alkylene.
The term xe2x80x9calkylsulfonylaminoxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (xe2x80x94S(O)2xe2x80x94NHxe2x80x94) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
The term xe2x80x9calkynylxe2x80x9d as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbonxe2x80x94carbon triple bond. Examples of alkynyl include xe2x80x94Cxe2x89xa1Cxe2x80x94H, Hxe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, Hxe2x80x94Cxe2x89xa1Cxe2x80x94CH(CH3)xe2x80x94 and the like.
The term xe2x80x9calkynylenexe2x80x9d refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing from 2 to 15 carbon atoms and also containing a carbon-carbon triple bond. Examples of alkynylene include xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH(CH3)xe2x80x94 and the like.
The term xe2x80x9caminoalkylxe2x80x9d as used herein refers to a xe2x80x94NH2, alkylamino, or dialkylamino group appended to the parent molecular moiety through an alkylene.
The term xe2x80x9caminocarbonylxe2x80x9d as used herein refers to H2Nxe2x80x94C(O)xe2x80x94.
The term xe2x80x9caminocarbonylalkenylxe2x80x9d as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH2C(O)xe2x80x94) group.
The term xe2x80x9caminocarbonylalkoxyxe2x80x9d as used herein refers to H2Nxe2x80x94C(O)xe2x80x94 appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term xe2x80x9caminocarbonylalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (NH2C(O)xe2x80x94) group.
The term xe2x80x9ctrialkylaminoalkylxe2x80x9d as used herein refers to (R90)(R91)(R92)N(R93)xe2x80x94 wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene.
The term xe2x80x9caroyloxyalkylxe2x80x9d as used herein refers to R32xe2x80x94C(O)xe2x80x94Oxe2x80x94R33xe2x80x94 wherein R32 is an aryl group and R33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9carylalkenylxe2x80x9d as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to R42Oxe2x80x94 wherein R42 is an arylalkyl group, for example, benzyloxy, and the like.
The term xe2x80x9carylalkoxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
The term xe2x80x9carylalkylxe2x80x9d as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to R45Oxe2x80x94 wherein R45 is an aryl group, for example, phenoxy, and the like.
The term xe2x80x9carylalkylcarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R62C(O)Oxe2x80x94 wherein R62 is an arylalkyl group).
The term xe2x80x9caryloxyalkylxe2x80x9d refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
The term xe2x80x9ccarboxaldehydexe2x80x9d as used herein refers to a formaldehyde radical, xe2x80x94C(O)H.
The term xe2x80x9ccarboxyxe2x80x9d as used herein refers to a carboxylic acid radical, xe2x80x94C(O)OH.
The term xe2x80x9ccarboxyalkenylxe2x80x9d as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-1-ethenyl and the like.
The term xe2x80x9ccarboxyalkoxyxe2x80x9d as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.
The term xe2x80x9ccyanoalkoxyxe2x80x9d as used herein refers to an alkoxy radical as previously defined to which is appended a cyano (xe2x80x94CN) group. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
The term xe2x80x9ccycloalkanoyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e., R60xe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R60 is a cycloalkyl group).
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to R56R57Nxe2x80x94 wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
The term xe2x80x9cdialkylaminoalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a dialkylamino group.
The term xe2x80x9cdialkylaminocarbonylxe2x80x9d as used herein refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (xe2x80x94C(O)xe2x80x94) linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
The term xe2x80x9cdialkylaminocarbonylalkenylxe2x80x9d as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
The term xe2x80x9cdialkylaminocarbonylalkylxe2x80x9d as used herein refers to R50xe2x80x94C(O)xe2x80x94R51xe2x80x94 wherein R50 is a dialkylamino group and R51 is an alkylene group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to I, Br, Cl or F.
The term xe2x80x9chaloalkenylxe2x80x9d as used herein refers to an alkenyl radical to which is appended at least one halogen substituent.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
The term xe2x80x9chaloalkoxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a haloalkoxy group.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to a lower alkyl radical, as defined above, to which is appended at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl and the like.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
Heterocyclics also include compounds of the formula
where X* is xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94 and Y* is xe2x80x94C(O)xe2x80x94 or [xe2x80x94C(Rxe2x80x3)2xe2x80x94]v where Rxe2x80x3 is hydrogen or C1-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (xe2x95x90O), alkylimino (R*N=wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, xe2x80x94COOH, xe2x80x94SO3H, alkoxycarbonyl, nitro, cyano and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.
The term xe2x80x9c(heterocyclic)alkoxyxe2x80x9d as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
The term xe2x80x9c(heterocyclic)alkylxe2x80x9d as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
The term xe2x80x9cheterocycliccarbonyloxyalkylxe2x80x9d as used herein refers to R46xe2x80x94C(O)xe2x80x94Oxe2x80x94R47xe2x80x94 wherein R46 is a heterocyclic group and R47 is an alkylene group.
The term xe2x80x9chydroxyxe2x80x9d as used herein refers to xe2x80x94OH.
The term xe2x80x9chydroxyalkenylxe2x80x9d as used herein refers to an alkenyl radical to which is appended a hydroxy group.
The term xe2x80x9chydroxyalkoxyxe2x80x9d as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (xe2x80x94OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a hydroxy group.
The term xe2x80x9cleaving groupxe2x80x9d as used herein refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like).
The term xe2x80x9cmercaptoxe2x80x9d as used herein refers to xe2x80x94SH.
The terms xe2x80x9cmethylenedioxyxe2x80x9d and xe2x80x9cethylenedioxyxe2x80x9d refer to one or two carbon chains attached to the parent molecular moiety through two oxygen atoms. In the case of methylenedioxy, a fused 5 membered ring is formed. In the case of ethylenedioxy, a fused 6 membered ring is formed. Methylenedixoy substituted on a phenyl ring results in the formation of a benzodioxolyl radical.
Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl radical
The term xe2x80x9csubstantially purexe2x80x9d as used herein means 95% or more of the specified compound.
The term xe2x80x9ctetrazolylxe2x80x9d as used herein refers to a radical of the formula
or a tautomer thereof.
The term xe2x80x9ctetrazolylalkoxyxe2x80x9d as used herein refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like.
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to R70Sxe2x80x94 wherein R70 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
The term xe2x80x9cthioalkoxyalkoxyxe2x80x9d as used herein refers to R80Sxe2x80x94R81Oxe2x80x94 wherein R80 is loweralkyl as defined above and R81 is alkylene. Representative examples of alkoxyalkoxy groups include CH3SCH2Oxe2x80x94, EtSCH2Oxe2x80x94, t-BuSCH2Oxe2x80x94 and the like.
The term xe2x80x9cthioalkoxyalkoxyalkylxe2x80x9d as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include CH3SCH2CH2OCH2CH2xe2x80x94, CH3SCH2OCH2xe2x80x94, and the like.
The term xe2x80x9ctrans,transxe2x80x9d as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
The term xe2x80x9ctrans,cisxe2x80x9d as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
This definition encompasses both the case where R and R2 are cis and R and R1 are trans and the case where R2 and R are trans and R and R1 are cis.
The term xe2x80x9ccis,cisxe2x80x9d as used herein refers to the orientation of substituents (R1 and R2) relative to the central substituent R as shown
Preferred compounds of the invention are selected from the group consisting of:
trans-trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[3-(N-propyl-N-n-pentanesulfonylamino)propyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(4-Methoxymethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-(2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3,4-Dimethoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(4-Propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(3,4-Difluorophenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(4-methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(4-Methoxy-3-fluorophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfonyl)-amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(1,4-Benzodioxan-6-yl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(n-pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)-ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)-ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-(2-methoxyethyl)-N-(butanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[2-(N-propyl-N-(2-methylpropanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid;
trans,trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-Methylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxo-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Tetrahydro-2H-pyran)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,4-Trimethyl-3-pentenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2, -Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxo-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N(2 methyl-3-fluorophenyl)]amino carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid;
trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-dimethylpentyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2, -Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-y)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(4-Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
(2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)1-(2-(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2, -Dimethyl-2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2, -Dimethyl-2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxo 1,2-dihydro pyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyridin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2(-2-Oxopiperidin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopiperidin-1-yl)-ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-trimethylammoniobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(3,3-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(4,4-Dimethyl-2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N ,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyll-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-berizodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-propanesultamyl)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-(N,N-dibutylaminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(2,3-dihydro-benzofuran-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-oxazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Oxazol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl-]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(5-Methyloxazol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-((N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(5-Methyloxazol-2-yl) ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans, trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2,5-Dioxopyrrolidin-1-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-((N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl-3-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(propoxy)amino)carbonylmethyll-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxo-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l -[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-((N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; and
trans,trans-2-(2-(1,3-benzodioxol-4-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
or a pharmaceutically acceptable salt.
Most preferred compounds of the invention are selected from the group consisting of:
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)]aminocarbonylmethyl]-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-l -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1,3-Dioxol-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2,-Dimethyl-2-(1,3-dioxolan-2-yl)ethyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(2-pyridyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2,2 Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N-4-heptyl-N-(4-fluoro-3-methylphenyl))aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
trans,trans-2-(2-(1-pyrazolyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2R, 3R, 4S)-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-[((N-propyl-N-pentanesulfonyl)amino)ethyl]-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R ,4S)-2-(2,2-Dimethyl pent-(E)-3-enyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
(2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; and
(2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
Methods for preparing the compounds of the invention are shown in Schemes I-XV.
Scheme I illustrates the general procedure for preparing the compounds of the invention when n and m are 0, Z is xe2x80x94CH2xe2x80x94 and W is xe2x80x94CO2H. A xcex2-ketoester 1, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a base (for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product 3 is reduced (for example, hydrogenation using a Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4. Reduction of 4 (for example, sodium cyanoborohydride or catalytic hydrogenation and the like) in a protic solvent such as ethanol or methanol and the like gives the pyrrolidine compound 5 as a mixture of cis-cis, trans,trans and cis,trans products. Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans,trans and cis,trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is (1) acylated or sulfonylated with R3xe2x80x94X (R3 is R4xe2x80x94C(O)xe2x80x94 or R6xe2x80x94S(O)2xe2x80x94 and X is a leaving group such as a halide (Cl is preferred) or X taken together with R4xe2x80x94C(O)xe2x80x94 or R6xe2x80x94S(O)2xe2x80x94 forms an activated ester including esters or anhydrides derived from formic acid, acetic acid and the like, alkoxycarbonyl halides, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxamide, 2,4,5-trichlorophenol and the like) or (2) alkylated with R3xe2x80x94X where X is a leaving group (for example, X is a halide (for example, Cl, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as diisopropyl ethylamine or triethylamine and the like to give the N-derivatized pyrrolidine 6 which is still a mixture of trans,trans and cis,trans isomers. Hydrolysis of the ester 6 (for example, using a base such a sodium hydroxide in EtOH/H2O) selectively hydrolyzes the trans,trans ester to give a mixture of 7 and 8, which are readily separated.
Scheme II illustrates a general procedure for preparing the compounds of the invention when n is 1, m is 0, Z is xe2x80x94CH2xe2x80x94 and W is xe2x80x94CO2H. A substituted benzyl chloride 9 is reacted with a lithio dithiane 10 in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound 11 is formed using a base such as n-butyllithium and then reacted with R1xe2x80x94CH2xe2x80x94Xxe2x80x2 wherein Xxe2x80x2 is a leaving group such as a halide or sulfonate to give compound 12. The dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 13. Reaction of ketone 13 with benzyl amine and formaldehyde gives the keto piperidine compound 14. Treatment of compound 14 with an activated nitrile such as trimethylsilyl cyanide followed by a dehydrating agent such as phosphorous oxychloride provides the isomeric ene nitrites 15. Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile 16. Hydrolysis of the nitrile using hydrochloric acid in the presence of a carboxy protecting reagent (for example, an alkyl alcohol) affords ester 17 (where E is a carboxy protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 18. Compound 18 is further elaborated by the procedures described in Scheme I for compound 5 to give the final product compound 19.
Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is xe2x80x94C(O)xe2x80x94 and W is xe2x80x94CO2H. xcex2-Keto ester 20 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an xcex1-haloester 21 (where J is lower alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tert-butoxide or lithium diisopropylamide in an inert solvent such as THF or dimethoxyethane to give diester 22. Treating compound 22 with R3xe2x80x94NH2 and heating in acetic acid gives the cyclic compound 23. The double bond is reduced (for example, by catalytic hydrogenation using a palladium on carbon catalyst or sodium cyanoborohydride reduction) to give pyrrolidone 24. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration, followed by sodium hydroxide hydrolysis of the ester, affords the desired trans,trans carboxylic acid 25.
Scheme IV illustrates a general procedure for preparing the compounds of the invention when n is 0, m is 1, Z is xe2x80x94CH2xe2x80x94 and W is xe2x80x94CO2H. The trans,trans compound 7, prepared in Scheme I, is homologated by the Arndt-Eistert synthesis. The carboxy terminus is activated (for example, by making the acid chloride using thionyl chloride) to give compound 52, where L is a leaving group (in the case of an acid chloride, L is Cl). Compound 52 is treated with diazomethane to give the diato ketone 53. Rearrangement of compound 53 (for example, using water or an alcohol and silver oxide or silver benzoate and triethylamine, or heating or photolysis in the presence of water or an alcohol) affords the acetic acid compound 54 or an ester which may be hydrolyzed. Compounds where m is from 2 to 6 can be obtained by repetition of the above described process.
A preferred embodiment is shown in Schemes V and VI. A benzoyl acetate 26 is reacted with a nitro vinyl benzodioxolyl compound 27 using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in toluene to give compound 28. Catalytic hydrogenation using Raney nickel leads to reduction of the nitro group to an amine and subsequent cyclization to give the dihydropyrrole 29. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 30 as a mixture of cisxe2x80x94cis, trans,trans and cis,trans isomers. Chromatography separates out the cisxe2x80x94cis isomer, leaving a mixture of the trans,trans and cis,trans isomers (31).
Scheme VI illustrates the further elaboration of the trans,trans isomer. The mixture (31) of trans,trans and cis,trans pyrrolidines described in Scheme IV is reacted with N-propyl bromoacetamide in acetonitrile in the presence of ethyldiisopropylamine to give the alkylated pyrrolidine compound 32, still as a mixture of trans,trans and cis,trans isomers. Sodium hydroxide in ethanol-water hydrolyzes the ethyl ester of the trans,trans compound but leaves the ethyl ester of the cis,trans compound untouched, thus allowing separation of the trans,trans carboxylic acid 33 from the cis,trans ester 34.
Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxotyl methyl chloride 35 is reacted with lithio dithiane 36 to give the alkylated compound 37. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound 38. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 39. Treatment of 39 with benzylamine and formaldehyde gives the keto piperidine 40. Treatment of compound 40 with trimethylsilyl cyanide followed by phosphorous oxychloride gives the ene nitrile as a mixture of isomers 41. Sodium borohydride reduction of the double bond gives the piperidinyl nitrile 42. Hydrochloric acid hydrolysis in the presence of ethanol gives ethyl ester 43. The N-benzyl protecting group is removed by catalytic hydrogenation to give the free piperidine compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 31 resulting in the formation of the N-derivatized carboxylic acid 45.
A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 46 (wherein E is loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl a-bromoacetate 47 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 48. Treating compound 48 with ethoxypropylamine and heating in acetic acid gives the cyclic compound 49. The double bond is reduced by catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone 50. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide hydrolysis of the ester to afford the desired trans,trans carboxylic acid 51.
Scheme IX illustrates the preparation of compounds where n is 0, Z is xe2x80x94CH2xe2x80x94, and W is other than carboxylic acid. Compound 55, which can be prepared by the procedures described in Scheme IV, is converted (for example, using peptide coupling condition, e.g. N-methylmorpholine, EDCl and HOBt, in the presence of ammonia or other amide forming reactions) to give carboxamide 56. The carboxamide is dehydrated (for example, using phosphorus oxychloride in pyridine) to give nitrile 57. Nitrile 57 under standard tetrazole forming conditions (sodium azide and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58. Alternatively nitrile 57 is reacted with hydroxylamine hydrochloride in the presence of a base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, triethylamine, sodium methoxide or NaH) in a solvent such as DMF, DMSO, or dimethylacetamide to give amidoxime 59. The amidoxime 59 is allowed to react with a methyl or ethyl chloroformate in a conventional organic solvent (such as, chloroform, methylene chloride, dioxane, THF, acetonitrile or pyridine) in the presence of a base (for example, triethylamine, pyridine, potassium carbonate and sodium carbonate) to give an O-acyl compound. Heating of the O-acyl amidoxime in an inert solvent (such as benzene, toluene, xylene, dioxane, THF, dichloroethane, or chloroform and the like) results in cyclization to compound 60. Alternatively reacting the amidoxime 59 with thionyl chloride in an inert solvent (for example, chloroform, dichloromethane, dixoane and THF and the like) affords the oxathiadiazole 61.
Scheme X illustrates the preparation of compounds in which R3 is an acylmethylene group. A carboxylic acid 62 (where R4 is as previously defined herein) is treated with oxalyl chloride in a solution of methylene chloride containing a catalytic amount of N,N-dimethylformamide to give the acid chloride. Treatment of the acid chloride with excess ethereal diazomethane affords a diazoketone, and then treatment with anhydrous HCl in dioxane gives the xcex1-chloroketone 63. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the xcex1-chloroketone 63 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid 65.
Scheme XI illustrates the preparation of xe2x80x9creverse amides and sulfonamidesxe2x80x9d. The carboxy protected pyrrolidine 5, prepared in Scheme I, is reacted with a difunctionalized compound Xxe2x80x94R8xe2x80x94X where R8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 66. Treatment of 66 with an amine (R20NH2) affords secondary amine 67. This amine (67) can be reacted with an activated acyl compound (for example, R4xe2x80x94C(O)xe2x80x94Cl) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine 67 can be reacted with an activated sulfonyl compound (for example, R6xe2x80x94S(O)2xe2x80x94Cl) and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford sulfonamide 69.
Scheme XII illustrates a method for synthesizing pyrrolidines by an azomethine ylide type [3+2]-cycloaddition to an acrylate. General structures such as compound 70 are known to add to unsaturated esters such as 71 to provide pyrrolidines such as compound 72 (O. Tsuge, S. Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), O. Tsuge, S. Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 73 is reacted with acrylate 74 in the presence of trimethylsilyl triflate and tetrabutylammonium fluoride to give the desired pyrrolidine 75 as a mixture of isomers. This method can be modified to provide the N-acetamido derivatives directly by reacting 73 and74 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give compound 76.
Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 80, which can be further elaborated on the pyrrolidine nitrogen. Intermediate racemic pyrrolidine ester 77 (for example, prepared by the procedure described in Scheme V) is Boc-nitrogen protected (for example, by treatment with Boc2O) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 78. The carboxylic acid is converted to its (+)-cinchonine salt, which can be recrystallized (for example from ethyl acetate and hexane or chloroform and hexane) to afford the diastereomerically pure salt. This diastereomerically pure salt can be neutralized (for example, with sodium carbonate or citric acid) to afford enantiomerically pure carboxylic acid 79. The pyrrolidine nitrogen can be deprotected (for example, using trifluoroacetic acid) and the ester reformed by the use of ethanolic hydrochloric acid to give salt 80. Alternatively one can use ethanol HCl to cleave the protecting group and form the ester in one step. The pyrrolidine nitrogen can be further elaborated (for example, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 81. The use of (xe2x88x92)-cinchonine will give the opposite enantiomer.
Scheme XIV describes another procedure for preparation of pyrrolidines. Pyrrolidines may be synthesized by the use of an azomethine ylide cycloaddition to an acrylate derivative as described by Cottrell, I. F., et.al., J. Chem. Soc., Perkin Trans. 1, 5: 1091-97 (1991). Thus, the azomethine ylide precursor 82 (where R55 is hydrogen or methyl) is condensed with a substituted acrylate 83 (wherein R2 is as described herein and R56 is loweralkyl) under acidic conditions to afford the substituted pyrrolidine 84. The N-protecting group can be removed (for example, by hydrogenolysis of an N-benzyl group) to give 85, which can be alkylated under the conditions described above to provide the N-substituted pyrrolidine 86. Standard ester hydrolysis of 86 produces the desired pyrrolidine carboxylic acid 87.
A preferred process is shown in Scheme XV. Nitro vinyl compound (88) is reacted with beta-keto ester 89 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a temperature of from about 0xc2x0 C. to about 100xc2x0 C. for a period of time from about 15 minutes to overnight to give compound 90. Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound 90 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine 91b. The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like, and the hydrogenation is continued to give pyrrolidine compound 92 as the cis,cis-isomer. Epimerization at C-3 is effected by treatment of compound 92 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about xe2x88x9220xc2x0 C. to about 120xc2x0 C. to give the trans,trans compound 93. Compound 93 itself can optionally be resolved into enantiomers prior to reacting with Xxe2x80x94R3. The substantially pure (i.e., at least 95% of the desired isomer) optically active (+)-isomer of compound 93 is obtained by treatment of a mixture of the (+)-isomer and the (xe2x88x92)-isomer of 93 with S-(+)-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like. The (+)-isomer of 93 selectively crystallizes as the salt, leaving the (xe2x88x92)-isomer of 93 in solution. Alternatively, the substantially pure (i.e., at least 95% of the desired isomer) optically active (xe2x88x92)-isomer of compound 93 can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (xe2x88x92)-isomer of 93 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired (+)-isomer of compound 93 in solution.
Compound93 (racemic or optically active) is reacted with Xxe2x80x94R3 (where X is a leaving group (for example, a halide or a sulfonate) and R3 is as previously defined) using a base such as diisopropylethylamine, triethylamine, sodium bicarbonate or potassium carbonate and the like in an inert solvent such as acetonitrile, THF, toluene, DMF or ethanol and the like at a temperature of from about 0xc2x0 C. to about 100xc2x0 C. to give the intermediate ester 94. The ester can be isolated or converted in situ to the carboxylic acid (95) using hydrolysis conditions such as a base such as sodium hydroxide or lithium hydroxide or potassium hydroxide and the like in a solvent such as ethanol-water or THF-ethanol and the like.
A more detailed description of the preparation of some specific analogs is provided in Schemes XVI-XXI. Aliphatic xcex2-ketoesters (Scheme XVI) may be prepared by copper-catalyzed addition of a Grignard reagent (for example, propylmagnesium bromide) to an unsaturated ester, for example, ethyl 3,3-dimethylacrylate. The resultant ester is hydrolyzed, for example with sodium hydroxide in aqueous alcohol, and is homologated in stepwise fashion to the corresponding xcex2-ketoester, for example by activation using carbonyldiimidazole and condensation with magnesio-ethoxymalonate. Alternatively, olefinic xcex2-ketoesters may be prepared by Claisen rearangement of the corresponding allylic alcohols; hydrolysis and homologation as described above produce the desired xcex2-ketoester.
N-alkyl,O-alkyl bromohydroxamates are prepared according to Scheme XVII. N-Boc-O-allyl hydroxylamine is alkylated with and alkyl halide, for example using sodium hydride as base; the double bond is selectively reduced, for example using hydrogen and a palladium catalyst. After removal of the Boc protecting group, for example with TFA, the resultant amine is acylated, for example using bromoacetyl bromide.
The xcex2-ketoesters described in Scheme XVI may be converted to pyrrolidine derivatives as described in Scheme XVIII. Michael addition onto a nitrostyrene derivative can be catalyzed with base, for example DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under controlled pH. A mixture of isomers are generated, in which the transxe2x80x94trans is generally preferred.
Scheme XIX describes several strategies for resolving the racemic pyrrolidines described above. Treatment with a chiral acid, for example (S)-(+)-mandelic acid, may provide a crystalline derivative, which can be further enriched through recrystallization. The salt may be washed with base to extract the resolving agent and return the optically active pyrrolidine product. Alternatively, the amino ester can be N-protected (for example with Boc-anhydride) and hydrolyzed (for example with sodium hydroxide) to give the corresponding N-protected amino acid. Activation of the acid, for example as the pentafluorophenyl ester, followed by coupling with a chiral nonracemic oxazolidinone anion, provides the corresponding acyloxazolidinone diastereomers, which may be separated chromatographically. Alcoholysis of one acyloxazolidinone diastereomer, followed by cleavage of the N-protecting group, returns an optically enriched amino ester. A similar transformation may be accomplished through coupling of the protected amino acid with a chiral nonracemic amino alcohol. After chromatographic separation of the resultant diastereomers, the amide is cleaved and the protecting group is removed to provide optically enriched product.
Optically active amino esters prepared as described above may be alkylated (Scheme XX) with a variety of electrophiles, for example dibutyl bromoacetamide, N-butyl,N-alkoxy bromoacetamide, N-(4-heptyl)-N-(3-methyl-4-fluorophenyl) bromoacetamide, or N-(xcexa9-hydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, for example using sodium hydroxide in aqueous alcohol, provides the product.
For one particular class of electrophile, N-(xcexa9-hydroxyalkyl)-N-alkyl haloacetamides, further transformations of the alkylation product are possible (Scheme XXI). Activation (for example using methanesulfonyl chloride) of the alcohol, followed by displacement with halogen (for example, using lithium bromide) provides the corresponding halide. Displacement of halide with an amine, for example dimethylamine, provides the corresponding amino ester, which may be hydrolyzed as previously described to provide product.
Compounds which are useful as intermediates for the preparation of compounds of the invention are:
wherein n is 0 or 1;
m is 0 to 6;
W is (a) xe2x80x94C(O)2xe2x80x94G where G is hydrogen or a carboxy protecting group,
(b) xe2x80x94PO3H2,
(c) xe2x80x94P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) xe2x80x94CN,
(e) xe2x80x94C(O)NHR17 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) xe2x80x94C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) xe2x80x94S(O)2NHC(O)R16,
R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)Nxe2x80x94Rccxe2x80x94 wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof;
or a compound of the formula:
wherein n is 0 or 1;
m is 0 to 6;
W is (a) xe2x80x94C(O)2xe2x80x94G where G is hydrogen or a carboxy protecting group,
(b) xe2x80x94PO3H2,
(c) xe2x80x94P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) xe2x80x94CN,
(e) xe2x80x94C(O)NHR17 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) xe2x80x94C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) xe2x80x94S(O)2NHC(O)R16,
R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alklayminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)Nxe2x80x94Rccxe2x80x94 wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof.
Preferred intermediates include compounds of formula (III), (IV) and (V) wherein
m is zero or 1;
W is xe2x80x94CO2xe2x80x94G wherein G is hydrogen or a carboxy protecting group,
and R1 and R2 are as defined above; or
the substantially pure (+)- or (xe2x88x92)-isomer thereof.
Particularly preferred intermediates are compounds of formula (III), (IV) and (V) wherein
n and m are both 0;
W is xe2x80x94CO2xe2x80x94G wherein G is hydrogen or a carboxy protecting group;
and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or
the substantially pure (+)- or (xe2x88x92)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
wherein n is 0 or 1;
m is 0 to 6;
R5b is alkylene;
Q is a leaving group;
W is (a) xe2x80x94C(O)2xe2x80x94G where G is hydrogen or a carboxy protecting group,
(b) xe2x80x94PO3H2,
(c) xe2x80x94P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) xe2x80x94CN,
(e) xe2x80x94C(O)NHR17 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) xe2x80x94C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) xe2x80x94S(O)2NHC(O)R16,
R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkehyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)Nxe2x80x94Rccxe2x80x94 wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof;
or a compound of the formula:
wherein n is 0 or 1;
m is 0 to 6;
R5b is alkylene;
Q is a leaving group;
W is (a) xe2x80x94C(O)2xe2x80x94G where G is hydrogen or a carboxy protecting group,
(b) xe2x80x94PO3H2,
(c) xe2x80x94P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) xe2x80x94CN,
(e) xe2x80x94C(O)NHR17 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) xe2x80x94C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) xe2x80x94S(O)2NHC(O)R16,
R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)Nxe2x80x94Rccxe2x80x94 wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof.
Preferred intermediates include compounds of formula (VI), (VII) and (VIII) wherein
m is zero or 1;
R5b is alkylene;
Q is a leaving group;
W is xe2x80x94CO2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, and R1 and R2 are as defined above; or
the substantially pure (+)- or (xe2x88x92)-isomer thereof.
Particularly preferred intermediates are compounds of formula (VI), (VII) and (VIII) wherein
n and m are both 0;
R5b is alkylene;
Q is a leaving group;
W is xe2x80x94CO2xe2x80x94G wherein G is hydrogen or a carboxy protecting group; and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or
the substantially pure (+)- or (xe2x88x92)-isomer thereof.
Other compounds which are useful as intermediates for the preparation of compounds of the invention are:
wherein n is 0 or 1;
m is 0 to 6;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is (a) xe2x80x94C(O)2xe2x80x94G where G is hydrogen or a carboxy protecting group,
(b) xe2x80x94PO3H2,
(c) xe2x80x94P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) xe2x80x94CN,
(e) xe2x80x94C(O)NHR17 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) xe2x80x94C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) xe2x80x94S(O)2NHC(O)R16,
R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)arninoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)Nxe2x80x94Rccxe2x80x94 wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof;
or a compound of the formula:
wherein n is 0 or 1;
m is 0 to 6;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is (a) xe2x80x94C(O)2xe2x80x94G where G is hydrogen or a carboxy protecting group,
(b) xe2x80x94PO3H2,
(c) xe2x80x94P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,
(d) xe2x80x94CN,
(e) xe2x80x94C(O)NHR17 where R17 is loweralkyl,
(f) alkylaminocarbonyl,
(g) dialkylaminocarbonyl,
(h) tetrazolyl,
(i) hydroxy,
(j) alkoxy,
(k) sulfonamido,
(l) xe2x80x94C(O)NHS(O)2R16 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino,
(m) xe2x80x94S(O)2NHC(O)R16,
R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylaikenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)Nxe2x80x94Rccxe2x80x94 wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and Rcc is alkylene, with the proviso that one or both of R1 and R2 is other than hydrogen;
or a salt thereof.
Preferred intermediates include compounds of formula (IX), (X) and (XI) wherein
m is zero or 1;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is xe2x80x94CO2xe2x80x94G wherein G is hydrogen or a carboxy protecting group, and R1 and R2 are as defined above; or
the substantially pure (+)- or (xe2x88x92)-isomer thereof.
Particularly preferred intermediates are compounds of formula (IX), (X) and (XI) wherein
n and m are both 0;
R5b is alkylene;
R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;
W is xe2x80x94CO2xe2x80x94G wherein G is hydrogen or a carboxy protecting group; and R1 is (i) loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, (v) phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, (x) aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3-benzodioxolyl, 1,4-benzodioxanyl, 8-methoxy-1,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or
the substantially pure (+)- or (xe2x88x92)-isomer thereof.
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{
"pile_set_name": "USPTO Backgrounds"
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The invention relates to the general field of improving the performance of systems in which operation relies on using a digital model including at least one parameter that depends on a measurement taken by a sensor.
While taking a measurement, it happens frequently that such sensors suffer from a certain amount of inertia that is specific to each sensor and that depends in particular on the mass or on the size of the sensor. This inertia leads to an offset in time between the moment when the measurement is taken by the sensor and the moment when the sensor delivers signal in response to the measurement. This is also referred to as the “lag effect”.
In order to mitigate that drawback, it is known to model the inertia of the sensor by using a filter having as its parameter a time constant that models the response time of the sensor, in other words its inertia.
Such methods, in particular as described in Document U.S. Pat. No. 5,080,496 make use of unchanging charts and they are difficult to apply, in particular when the time constant of the sensor depends on the environment in which it is being used or when the time constant of the sensor is likely to vary considerably from one sensor to another.
Document WO 2010/067009 presents a method of correcting a measurement signal delivered by a temperature sensor that enables the lag effect introduced by the sensor to be compensated, regardless of the time constant of the sensor.
That method makes use of a digital model for the temperature measured by the sensor. Nevertheless, errors in the model can lead to variation in the temperature during a mechanical transient being overestimated or underestimated for the period until the temperature measurement converges and stabilizes.
The invention seeks in particular to mitigate that drawback.
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"pile_set_name": "USPTO Backgrounds"
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Generally, controlled climate chambers are used for the incubation of eggs. For example, the eggs are placed in the controlled climate chamber and climatic conditions are matched as well as possible to the optimum growth conditions for the embryos in the eggs. For example, the eggs may be subjected to a temperature progression. Such a temperature progression may start at a particular temperature (e.g., 100° Fahrenheit), which is then lowered because the eggs themselves start to produce heat. Such incubation of the eggs through hatch is generally performed according to an incubation profile that takes into consideration necessary temperature changes, as well as other climatic conditions (e.g., carbon dioxide (CO2) content, humidity, etc.). The incubation process is typically carried out in a particular controlled climate chamber at a single hatchery facility (e.g., the incubation process is tied to a single facility).
As indicated above, generally, in the hatchery, eggs are hatched in a climate controlled chamber. The environment in this chamber is controlled to optimize the hatching process. In this context, temperature, CO2 content, and humidity are some of the control variables controlled during the incubation process. The climate controlled chambers generally include large egg holding structures in which various trays holding eggs are placed. Such eggs during the incubation process may be held in a fixed position (e.g., using pallets of egg trays) or, eggs may be, for example, rotated during a part of the incubation process (e.g., incubator racks configured to hold the eggs such that the eggs can be moved to present the eggs in different positions relative to an air stream provided in the incubator). For example, in an exemplary and conventional incubation process for turkeys or ducks, incubation is completed in incubator racks and pallets for the first 25 days or so of an approximate 28 day incubation cycle. Thereafter, the eggs are transferred to hatch baskets for hatching. The eggs generally hatch approximately around the same time. For about the first day or so following hatch, the newly hatched poults can remain in a hatching chamber, living off the yolk, with little or no additional nutrients being introduced into the climate controlled chamber.
After the poults are hatched in a hatchery, they are generally transported as quickly as possible to a subsequent farm (e.g., for fattening, rearing, breeding, etc.). Such poults may be transported, for example, in an apparatus such as described in International Publication No. WO2005/070198 A1 entitled “Method for holding poikilothermic poultry, and device for holding poikilothermic poultry,” assigned to HatchTech Group B.V., published 4 Aug. 2005, which describes a transportable climate controlled container (e.g., in which the temperature controlled).
In other words, a generally standard or conventional production cycle for poultry is for the poults to be hatched at a hatchery and then transported from the hatchery to a further farm, such as a fattening farm, where the poultry grows and is fattened. Farms of this type are generally many different fauns located at a distance from one another. For example, in many cases, such farms may be located a great distance from each other and/or from the hatchery.
Sex separate rearing is also an important component in the raising of poultry (e.g., turkey production). In other words, poults of a single sex are reared separate from those of the other sex. Typically, depending on production, processing/marketing requirements, and cost relationships, separate sex rearing can be of great economic benefit to poultry producers (e.g., one gender is raised much differently than another to optimize the production process). Yet further, in many circumstances, farms that raise one sex of poultry are generally located a substantial distance from farms that raise the other sex and/or may also be located a substantial distance from a hatchery.
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{
"pile_set_name": "USPTO Backgrounds"
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The present invention relates to equipment for bending and pressing wood laminations into curved forms.
Curved wood forms have long been used in a variety of applications. Curves desired include cyma curves, arcs, circles, S-curves and other shapes. Production of wood members having a desired curved form has previously been achieved by utilizing wood which grew in that form, by cutting the form from stock large enough to accommodate the curve, by steam-bending techniques, and by glue laminating thin layers of wood which can easily be bent into the desired form prior to bonding the laminations together. Curved members formed of laminations are highly desirable in many applications because of the superior strength and stability of such members as compared to solid wood structures of the same size and shape, because very tight curves can be achieved and because curved shapes can be produced which are not possible using solid wood.
Production of large-scale, multi-lamination wood forms is difficult, however, because of the need for a means for bending the laminations to and holding them in precisely the correct shape and relationship for a sufficient period of time to permit the adhesive or glue being used to cure. This must normally be accomplished by applying substantial amounts of opposing pressure normal to and distributed over substantially all of both sides of a workpiece made up of multiple layers of wood and uncured adhesive or glue.
A variety of shop-built and commercial machinery has previously been used to fabricate such curved members, including the Casati Macchine ARC50 arch bending machine available from Casati Macchine at 20027 Rescaldina (MI), Italy; the Stegherr RP and RSP bending and laminating fixtures available from Stegherr Maschinenbau GmbH and Co. K.G., Donaustaufer Strabe 30-Postbox 120449, D-8400 Regensburg 12, West Germany; and the devices disclosed in U.S. Pat. Nos. 927,975, 1,561,613, 2,331,972, 2,399,348, 2,796,096 and 4,141,775.
While many of the prior art machines can be successfully used to produce curved wood members, much of the prior art equipment is prohibitively expensive, difficult to use or difficult to adapt rapidly to production of different sizes of curved members.
Despite the deficiencies of the prior art equipment and techniques available for fabricating "half-round top" window and door frames by glue lamination of thin wood layers, the demand for such windows, doors and other architectural structures having similar curves has expanded enormously with the growth in the popularity of post-modern architecture.
Consequently, there is a substantial need for a curve-forming laminating fixture which is sturdy, well-suited for use in high volume production, utilizes a minimum amount of shop floor space, and of substantial importance, which can accommodate a variety of frame sizes economically and easily.
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{
"pile_set_name": "USPTO Backgrounds"
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A light-emitting diode (LED) is a widely used semiconductor device whose main characteristic is that it will emit energy in the form of light, usually within the visible spectrum, when a current flows through the device. The basic mechanisms by which light-emitting diodes operate are well understood in this art and are set forth, for example, by Sze, Physics of Semiconductor Devices, 2d Edition (1981) at pages 681-703. Silicon carbide-based LEDs are described in U.S. Pat. Nos. 4,918,497 and 5,027,168, both of which are assigned to the assignee of the present invention and incorporated entirely herein by reference. Co-pending and commonly assigned application Ser. No. 08/081,668 filed Jun. 23, 1993 for "Blue Light-Emitting Diode with High External Quantum Efficiency" also sets forth exemplary information about such devices.
As is well known to those familiar with semiconductor devices, light-emitting diodes, and the interactions between light and matter, the wavelength of light (i.e., its color) that can be emitted by a given material from which a light-emitting diode is formed, is limited by the physical characteristics of that material, specifically its bandgap. The bandgap in a semiconductor material represents the amount of energy that separates a lower energy valence band and a higher energy conduction band in which carriers (electrons or holes) can reside in accordance with well-known principles of quantum mechanics. When electrons and holes travel across the bandgap and recombine, they will, under certain circumstances, emit energy in the form of light. Biasing a semiconductor p-n junction to produce a current flow is one way to obtain such recombinations and the visible light they emit. Because the wavelength of light is inversely proportional to its frequency, and its frequency is directly proportional to the corresponding energy transaction, certain wavelengths of light cannot be obtained in materials that have relatively narrow bandgaps. For example, blue light is generally considered to be that visible light which is emitted in the 400-500 nanometer (nm) portion of the visible spectrum. It will be understood that 400-500 nm is a somewhat arbitrary range, and that wavelengths close to 400 nm are also considered to be violet, and those close to 500 nm to be green. Such wavelengths require energy transactions of at least 2.6 electron volts (eV) which means that light-emitting diodes that will emit blue light must be formed of materials that have a bandgap of at least 2.6 eV. Such materials include, in certain circumstances, zinc selenide (ZeSe), gallium nitride (GAN), diamond, and silicon carbide (SiC).
The desirable theoretical characteristics of silicon carbide, and its potential as a source material for blue LEDs, have been well understood for a number of decades, dating back almost to the beginning of the semiconductor era. Nevertheless, the difficulties of working with silicon carbide have precluded most researchers from producing commercially successful devices from it. For example, the author of the article "Whatever Happened to Silicon Carbides?", IEEE Transactions on Industrial Electronics, Volume IE-29, No. 2, May, 1982, basically concluded that although silicon carbide was a theoretically interesting material, "I see no viable market for SiC semiconductor devices in the near future."
Silicon carbide has a number of attractive features from an electronic standpoint. It has a high saturated electron-drift velocity, a wide bandgap, a high thermal conductivity, a high breakdown electric field, and is "hard" to radiation. Silicon carbide presents difficulties, however, because it can crystalize in over 150 polytypes, many of which are separated by very small thermodynamic differences. As a result, and as well known to those familiar with crystal growth techniques of semiconductors and other materials, obtaining the necessary pure single crystals of silicon carbide, and the typical epitaxial or implanted layers that are generally desired or required in many semiconductor device structures, has long been a difficult task.
In recent years, however, the assignees of the present invention have made significant progress in taming the process difficulties presented by silicon carbide and in taking advantage of its desirable characteristics. These include success in the areas of sublimation growth of single crystals (e.g., U.S. Pat. No. 4,866,005); growth of epitaxial layers of silicon carbide on single crystals (U.S. Pat. Nos. 4,912,063 and 4,912,064); implantation and activation of dopants into silicon carbide (U.S. Pat. No. 5,087,576); and etching techniques for silicon carbide (U.S. Pat. Nos. 4,865,685 and 4,981,551).
Building upon these successes, the assignees of the present invention have produced the first commercially viable blue light-emitting diodes in significant commercial quantities at reasonable prices. Such LEDs are thoroughly described in U.S. Pat. Nos. 4,918,497 and 5,027,168 which, as noted above, are incorporated entirely herein by reference.
Because an LED is a diode structure (i.e., a p-n junction), commercial LEDs formed from silicon carbide generally include an n-type substrate and terminate in a p-type epitaxial layer, or alternatively, incorporate a p-type substrate and terminate in an n-type layer. The characteristics of silicon carbide, however, are such that the n-type of silicon carbide is somewhat easier to dope, is more transparent when doped, and, as is usually the case with n-type semiconductors, has a greater conductivity than p-type silicon carbide. Accordingly, the use of n-type silicon carbide layers wherever possible affords greater electrical conductivity (lower resistance) and optical transparency with resulting increases in light emission, efficiency, and current spreading for LED structures made therefrom.
To date, however, the art has lacked a technique for maximizing the use of n-type silicon carbide in p-n junction LEDs. For example, although the nature of n-type silicon carbide is such that it would be advantageous to use it for both a substrate and a top layer of an LED, the presence of a p-n junction between two n-type layers would essentially result in an n-p-n structure; i.e., a bipolar junction transistor. As is known to those of ordinary skill in this art, a transistor functions quite differently from an LED and thus such a structure has to date remained impractical and undesirable.
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{
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The present invention relates generally to the field of electronic cards and, more particularly, to the field of electronic inlays used in electronic cards and the method of making such electronic inlays.
Generally, electronic cards may be used as credit cards, bankcards, ID cards, telephone cards, security cards, smart cards, or similar devices. Electronic cards are generally constructed by assembling several layers of plastic sheets in a sandwich array. Further, electronic cards contain electronic components that enable the card to perform a number of functions.
European Patent 0 350 179 discloses a smart card wherein electronic circuitry is encapsulated in a layer of plastic material that is introduced between the card's two surface layers. The method disclosed further comprises abutting a high tensile strength holding member against a side of a mold, locating the smart card's electronic components with respect to that side and then injecting a reaction moldable polymeric material into the mold such that it encapsulates the electronic components.
European Patent Application 95400365.3 teaches a method for making contact-less smart cards. The method employs a rigid frame to position and fix an electronic module in a void space between an upper thermoplastic sheet and a lower thermoplastic sheet. After the frame is mechanically affixed to the lower thermoplastic sheet, the void space is filled with a polymerizable resin material.
U.S. Pat. No. 5,399,847 teaches a credit card that is comprised of three layers, namely, a first outer layer, a second outer layer and an intermediate layer. The intermediate layer is formed by injection of a thermoplastic binding material that encases the smart card's electronic elements (e.g., an IC chip and an antenna) in the intermediate layer material. The binding material is preferably made up of a blend of copolyamides or a glue having two or more chemically reactive components that harden upon contact with air. The outer layers of this smart card can be made up of various polymeric materials, such as polyvinyl chloride or polyurethane.
U.S. Pat. No. 5,417,905 teaches a method for manufacturing plastic credit cards wherein a mold tool comprised of two shells is closed to define a cavity for producing such cards. A label or image support is placed in each mold shell. The mold shells are then brought together and a thermoplastic material is injected into the mold to form the card. The inflowing plastic forces the labels or image supports against the respective mold faces.
U.S. Pat. No. 5,510,074 teaches a method of manufacturing smart cards having a card body with substantially parallel major sides, a support member with a graphic element on at least one side, and an electronic module comprising a contact array that is fixed to a chip. The manufacturing method generally comprises the steps of: (1) placing the support member in a mold that defines the volume and shape of the card; (2) holding the support member against a first main wall of the mold; (3) injecting a thermoplastic material into the volume defined by the hollow space in order to fill that portion of the volume that is not occupied by the support member; and (4) inserting an electronic module at an appropriate position in the thermoplastic material before the injected material has the opportunity to completely solidify.
U.S. Pat. No. 4,339,407 discloses an electronic circuit encapsulation device in the form of a carrier having walls that have a specific arrangement of lands, grooves and bosses in combination with specific orifices. The mold's wall sections hold a circuit assembly in a given alignment. The walls of the carrier are made of a slightly flexible material in order to facilitate insertion of the smart card's electronic circuitry. The carrier is capable of being inserted into an outer mold. This causes the carrier walls to move toward one another in order to hold the components securely in alignment during the injection of the thermoplastic material. The outside of the walls of the carrier has projections that serve to mate with detents on the walls of the mold in order to locate and fix the carrier within the mold. The mold also has holes to permit the escape of trapped gases.
U.S. Pat. No. 5,350,553 teaches a method of producing a decorative pattern on, and placing an electronic circuit in, a plastic card in an injection molding machine. The method comprises the steps of: (a) introducing and positioning a film (e.g., a film bearing a decorative pattern) over an open mold cavity in the injection molding machine; (b) closing the mold cavity so that the film is fixed and clamped in position therein; (c) inserting an electronic circuit chip through an aperture in the mold into the mold cavity in order to position the chip in the cavity; (d) injecting a thermoplastic support composition into the mold cavity to form a unified card; (e) removing any excess material; (f) opening the mold cavity; and (g) removing the card.
U.S. Pat. No. 4,961,893 teaches a smart card whose main feature is a support element that supports an integrated circuit chip. The support element is used for positioning the chip inside a mold cavity. The card body is formed by injecting a plastic material into the cavity so that the chip is entirely embedded in the plastic material. In some embodiments, the edge regions of the support are clamped between the load bearing surfaces of the respective molds. The support element may be a film that is peeled off the finished card or it may be a sheet that remains as an integral part of the card. If the support element is a peel-off film, then any graphics elements contained therein are transferred and remain visible on the card. If the support element remains as an integral part of the card, then such graphics elements are formed on a face thereof and, hence, are visible to the card user.
U.S. Pat. No. 5,498,388 teaches a smart card device that includes a card board having a through-opening. A semiconductor module is mounted onto this opening. A resin is injected into the opening so that a resin molding is formed under such condition that only an electrode terminal face for external connection of said semiconductor module is exposed. The card is completed by mounting a card board having a through-opening onto a lower mold of two opposing molding dies, mounting a semiconductor module onto the opening of said card board, tightening an upper die that has a gate leading onto a lower die and injecting a resin into the opening via the gate.
U.S. Pat. No. 5,423,705 teaches a disc having a disc body made of a thermoplastic injection molded material and a laminate layer that is integrally joined to a disc body. The laminate layer includes an outer clear lamina and an inner white and opaque lamina. An imaging material is sandwiched between these lamina.
U.S. Pat. No. 6,025,054 discloses a method for constructing a smart card using low shrinkage glue to hold the electronic devices in place during the devices immersion in thermosetting material that becomes the core layer of the smart card.
Generally, all of the above methods involve using specialized equipment for the assembly of printed overlays that are deposited over the electronics. In view of this drawback, there is a need for the ability to present an electronic inlay that can be self-contained and capable of shipment to card manufacturing companies for incorporation into a variety of different electronic cards. In addition, there is a need for the ability to make electronic inlays that are capable of being incorporated into electronic cards through the use of conventional card making equipment in which printed overlays and laminate can be applied to the electronic inlay.
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With the advance in recent years of microminiaturization in the manufacture of semiconductor devices and semiconductor chip mounting boards, there have beer increasing demands for higher resolving power in the exposure apparatus used to manufacture these items. To satisfy this demand, the wavelength of the light source of the apparatus must be shortened and/or the NA (numerical aperture) of the projection optical system of the apparatus must be increased. If the wavelength is shortened, the optical glasses that can withstand practical use is limited due to the absorption of light. Furthermore, when it comes to the short wavelengths of ultraviolet rays and X-rays, usable optical glasses are nonexistent. In this case, it is impossible to construct reduction projection optical systems that are dioptric or catadioptric.
A reduction catoptric projection optical system is disclosed in, for example, U.S. Pat. No. 5,815,310. The projection optical system disclosed therein includes two sets of reduction optical systems comprising reflective surfaces with a concave-convex-concave configuration, and forms an intermediate image between the two reduction optical systems. This projection optical system has the advantage that its six reflective surfaces increase the number of degrees of freedom for aberration correction. Further, a plane reflective mirror is not needed just for the return path, since the number of reflective surfaces is naturally even. In addition, since the reduction magnification of the entire optical system can be distributed among the reduction optical systems, it has the advantage that the burden of each reduction optical system can be lightened. Unfortunately, however, because the two reduction optical systems are joined by a pair of mirror pairs, the diameter of the mirror pairs unavoidably increases. This results in increased cost of the projection optical system.
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The present disclosure relates generally to an elastomeric bearing and, more particularly, to cylindrical bearings for rotor devices and systems.
Cylindrical elastomeric bearings are used in many applications. Cylindrical elastomeric bearings typically include alternating layers of elastomeric material and metallic or composite shims. These bearings often replace non-lubricated or self-lubricated bearings such as Teflon fabric lined bearings. Typical aerospace elastomeric bearing applications include spherical rod end bearings for pitch control rods and dampers, spherical blade retention bearings for fully articulated rotors, and cylindrical bearings for semi-articulated rotors and fluid-elastic damper seals. Some cylindrical elastomeric bearings are exposed to both axial and radial loads. Elastomer layers tend to bulge at the edges due to radial and bending moment loads going through the bearing. These shear stresses are a limitation on the size of the bearing and can require significant growth of a bearing size in order to achieve an adequate design. Accordingly, the industry is receptive to innovations that extend the life of cylindrical elastomeric bearings, particularly those that are exposed to both radial and axial loads.
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When initializing or booting a computer platform, there are two primary stages of system evolution. First, in the pre-boot environment, the system performs tasks such as preparing the hardware, discovering and/or checking the memory, initializing the chipset, and so on. These tasks may be performed by BIOS or firmware in order to prepare the system to boot a target. Typically, the target to be booted is an operating system (O/S). After the target is booted, the system is in a run-time environment controlled by the O/S.
In the case of a catastrophic failure, there is relatively little visibility into the cause of an error within the pre-boot environment. Within the pre-boot environment itself, errors may be detected using a Power-On Self Test (POST) card, or other debug techniques. However, debug techniques such as POST do not typically provide a comprehensive log of pre-boot data; they simply provide information about the point at which a critical error has occurred.
There is also no mechanism by which the operating system may be notified of other non-critical issues that are encountered during pre-boot. The operating system and programs which are running on the O/S must rely upon the integrity of the underlying operating system and platform in order to function correctly. The existence of a non-critical error in the pre-boot environment may lead to a critical error or failure in the run-time environment. The O/S has no visibility of certain hardware issues that occurred during the pre-boot which the firmware would be aware of. Some examples of hardware problems that may occur in the pre-boot environment which the O/S may not be aware of, and that a user may not be able to find in a dump file, include the existence of a bad microprocessor (CPU), problems with chipset timing, or a bad disk.
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A serial data communication interface comprises a data bus operating in accordance with a data communication protocol to transfer data serially, i.e., one bit at a time, from one device to another. A well known family of serial data communication interfaces, sometimes referred to as Serial Peripheral Interface or SPI, includes at least three signal lines: Data, Clock and Select. Although these signal lines are commonly referred to as Data, Clock and Select, alternative names, such as Enable instead of Select, are also used. Various types of serial data communication interfaces having so-called “4-wire,” “3-wire,” “2-wire” and even “1-wire” data buses are known, where the term “wire” is a colloquial reference to a signal line. In actuality, the signal line may be a wire, a printed circuit board trace, an optical fiber, or other such single-channel signal-carrying medium. The term “Serial Peripheral Interface” or “SPI” is commonly used to refer to a 3-wire interface having a bidirectional Data line along with the Clock and Select lines, although in some instances the term has been used to refer to a 4-wire interface having two unidirectional Data lines along with the Clock and Select lines. Some SPI busses also include a Reset line.
The SPI is commonly used in electronic systems in which a relatively complex digital subsystem, such as one having a microprocessor, controls aspects of the operation of a peripheral device or other subsystem that is more basic or otherwise different from the controlling digital subsystem. For example, some digital subsystems use a SPI to control another subsystem that primarily comprises analog circuitry, such as radio frequency (RF) circuitry. As illustrated in FIG. 1, a mobile telephone handset 10 commonly comprises an RF subsystem 12 that includes radio transceiver circuitry, a baseband subsystem 14 that includes a microprocessor or similar circuitry for controlling the overall functionality of the handset, and a user interface 16 that includes a microphone, speaker, display, keypad, etc. The RF subsystem 12 receives, downconverts, and demodulates RF signals received through an antenna 18 and provides the demodulated signal 20 in digital form to baseband subsystem 14. Conversely, RF subsystem 12 receives digital signals 22 from baseband subsystem 14, modulates and upconverts them to RF for transmission, and provides the RF signals to antenna 18. Baseband subsystem 14 can modify various operating parameters of RF subsystem 12, such as transmission power levels and modulation modes, by sending instructions to RF subsystem 12 via an SPI bus 24. Baseband subsystem 14 can send such instructions to RF subsystem 12 by performing write operations on SPI bus 24 under control of an SPI controller (not shown in FIG. 1) in baseband subsystem 14.
As illustrated in FIG. 2, the above-referenced SPI controller is commonly referred to as an SPI “master” controller 26 because it is common to control two or more devices or two or more blocks of circuitry within a device. For example, RF subsystem 12 can include two or more RF integrated circuit (IC) chips 28, 30, etc., each of which can be individually controlled by SPI master controller 26. Each of RF IC chips 28, 30, etc., includes a corresponding SPI slave controller 32, 34, etc., that responds to the read and write operations initiated by SPI master controller 26. Each of SPI slave controllers 32, 34, etc., has a unique device identifier associated with it that allows SPI master controller 26 to address it on SPI bus 24. Accordingly, SPI master controller 26 controls the state of the Select signal line and Clock signal line on SPI bus 24 and also controls the state of the Data signal line during write operations. During read operations, the one of SPI slave controllers 32, 34, etc., being read from controls the state of the Data signal line. As described in further detail below with regard to timing diagrams illustrating several SPI protocols, in a data write or data read operation successive data bits are sent in serial format on the Data signal line in synchronism with successive cycles of the Clock signal. In accordance with each of the SPI protocols described below, the Clock signal is activated or asserted during the write or read operation and deactivate or de-asserted when no write or read operation is occurring. Although not shown in FIGS. 1-2, each of SPI slave controllers 32, 34, etc., interfaces with other circuitry, such as the aforementioned controllable analog circuitry, in its respective RF IC chip 28, 30, etc.
Several types of well-known SPI protocols are illustrated by means of the timing diagrams of FIGS. 3-8. As illustrated in FIGS. 3-4, in accordance with one such protocol, a SPI master controller (not shown) of the type described above with regard to FIG. 2 can cause Select to transition from a low logic state or logic-“0” to a high logic state or logic-“1” to indicate a data transfer. The SPI master controller also activates the Clock signal. In some instances a SPI master controller may activate the Clock signal before transitioning the Select signal, and in other instances a SPI master controller may activate the Clock signal after transitioning the Select signal, as indicated by the initial Clock cycle shown in broken line. A SPI protocol in which a data transfer operation begins with Select transitioning from low to high can be referred to as an “active-high select” type of SPI protocol. As illustrated in FIG. 3, the SPI master controller causes the first bit on the Data signal line following the transition of Select from low to a high to be a “0” to indicate that the operation is a write operation. (The label “WbR,” which is equivalent to “ Write/Read” or “Write_bar/Read,” is used in FIG. 3 and similar drawing figures herein to indicate this Write/Read bit.) On each of the next “a” clock cycles following that “0” or write-indicating bit, the SPI master controller can send one address bit (“Aa-1” through “A0”). Then, on each of the next “d” clock cycles following the address bits, the SPI master controller can send one data bit (“Dd-1” through “D0”). Following the transfer of the last data bit D0, the SPI master controller 26 causes Select to transition from high back to low. The number “a” of address bits and the number “d” of data bits are typically fixed or predetermined. That is, during every write operation, the SPI master controller sends the same number “a” of address bits and the same number “d” of data bits as it does during every other write operation. In response to the address and data information, and in accordance with the timing of the transitions of Select and Clock, the one SPI slave controller identified by the address bits (or a portion of the address bits) writes the data to a register (not shown).
As illustrated in FIG. 4, the SPI master controller can cause the first bit on the Data signal line following the transition of Select from a low logic state to a high logic state to be a “1” to indicate that the operation is a read operation. On each of the next “a” clock cycles following that “1” or read-indicating bit, the SPI master controller can send one address bit (“Aa-1” through “A0”). Following the transfer of the last address bit A0, the SPI master controller causes Select to transition from high back to low. Then, after a delay of one or more clock cycles that is commonly referred to a “turn-around time” or “turn-around length,” the SPI slave controller identified by those address bits (or a portion thereof) can read data bits from a register or similar source and send one data bit (“Dd-1” through “D0”) to the SPI master controller on each of “d” clock cycles.
As illustrated in FIGS. 5-6, in accordance with another such protocol, another SPI master controller (not shown) that is generally of the type described above with regard to FIG. 2 can cause Select to transition from high to low to indicate a data transfer. A SPI protocol in which a data transfer operation begins with Select transitioning from high to low can be referred to as an “active-low select” type of SPI protocol.
As illustrated in FIG. 5, the SPI master controller causes the first bit on the Data signal line following the transition of Select from high to low to be a “0” to indicate that the operation is a write operation. On each of the next “a” clock cycles following that “0” or write-indicating bit, SPI master controller 26 can send one address bit (“Aa-1” through “A0”). Then, on each of the next “d” clock cycles following the address bits, the SPI master controller can send one data bit (“Dd-1” through “D0”). Following the transfer of the last data bit D0, the SPI master controller causes Select to transition from a low logic state back to a high logic state. As in the above-described active-high select protocol, the number “a” of address bits and number “d” of data bits are typically fixed or predetermined. In response to the address and data information, and in accordance with the timing of the transitions of Select and Clock, the SPI slave controller identified by the address bits (or a portion of the address bits) writes the data to a register.
As illustrated in FIG. 6, SPI master controller 26 can cause the first bit on the Data signal line following the transition of Select from high to low to be a “1” to indicate that the operation is a read operation. On each of the next “a” clock cycles following that “1” or read-indicating bit, the SPI master controller can send one address bit (“Aa-1” through “A0”). Following the transfer of the last address bit A0, the SPI master controller causes Select to transition from a low logic state back to a high logic state. Then, after a delay of one or more clock cycles (i.e., the turn-around time), the SPI slave controller identified by those address bits (or a portion thereof) can read data bits from a register or similar source and send one data bit (“Dd-1” through “D0”) to the SPI master controller on each of “d” clock cycles.
As illustrated in FIGS. 7-8, in accordance with still another such protocol, still another SPI master controller (not shown) that is generally of the type described above with regard to FIG. 2 can initiate a data transfer without using Select. One such protocol is commonly known as “Inter-Integrated Circuit or “I2C.” Because the I2C protocol does not use Select, the I2C protocol is sometimes referred to as a 2-wire protocol rather than a 3-wire protocol. Although I2C is sometimes described as a separate protocol from SPI, I2C is referred to herein along with the above-described active-high select and active-low select protocols as another type of SPI protocol.
As illustrated in FIG. 7, to indicate the beginning of a data transfer under the I2C protocol, the SPI master controller first causes Data to transition from high to low while Clock is high. Then, to indicate that the data transfer operation is a write operation the SPI master controller holds the Data signal line low (logic-“0”) during the next rising edge of Clock. On each of the next “a” clock cycles following that “0” or write-indicating bit, SPI master controller 26 can send one address bit (“Aa-1” through “A0”). Then, on each of the next “d” clock cycles following the address bits, the SPI master controller can send one data bit (“Dd-1” through “D0”). As in the other protocols described above, the number “a” of address bits and number “d” of data bits are typically fixed or predetermined. The SPI master controller can indicate the end of the data transfer by holding Clock high while causing Data to transition from low to high. In response to the address and data information, and in accordance with the timing of the transitions of Data and Clock, the SPI slave controller identified by the address bits (or a portion of the address bits) writes the data to a register.
As illustrated in FIG. 8, to indicate the beginning of a data transfer under the I2C protocol, the SPI master controller first causes Data to transition from high to low while Clock is high. Then, to indicate that the data transfer operation is a read operation the SPI master controller holds the Data signal line high (logic-“1”) during the next rising edge of Clock. On each of the next “a” clock cycles following that “1” or read-indicating bit, SPI master controller 26 can send one address bit (“Aa-1” through “A0”). Then, after a delay of one or more clock cycles (i.e., the turn-around time), the SPI slave controller identified by those address bits (or a portion thereof) can read data bits from a register or similar source and send one data bit (“Dd-1” through “D0”) to the SPI master controller on each of “d” clock cycles. The SPI master controller can indicate the end of the data transfer by holding Clock high while causing Data to transition from low to high.
In a system in which, for example, SPI slave controller 32 operates in accordance with a first one of the above-described SPI protocols but SPI slave controller 34 operates in accordance with a second one of the above-described SPI protocols, SPI master controller 26 must be capable of switching between the two protocols, i.e., using the first protocol to communicate data with SPI slave controller 32 and using the second protocol to communicate data with SPI slave controller 34. Providing a master controller 26 that operates in accordance with several different protocols can introduce a number of inefficiencies for system manufacturers. Also, providing an RF subsystem 12 that integrates multiple slave controllers operating in accordance with different protocols can be similarly inefficient. It is possible to signal a SPI slave controller circuitry to operate in accordance with a selected SPI protocol by supplying a protocol mode control signal to a mode select pin or similar input on an integrated circuit chip having such a protocol mode select feature. However, dedicating a pin to a protocol mode control signal is wasteful of input/output resources.
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Many, if not all, fire codes require certain types of buildings, structures and areas to be equipped with a safety system used to prevent the spread of fires. Such fire protection systems commonly utilize a network of sprinkler pipes for conducting a fire extinguishing medium, such as water, to a plurality of automatic sprinklers which may be arranged vertically, either in a pendent position or an upright position, or horizontally. Two common types of automatic sprinkler systems are the wet pipe type and the dry pipe type.
In wet pipe systems, the sprinkler pipes are filled with a fire extinguishing medium usually water, and connected to an ample supply of the fire extinguishing medium. Individual sprinkler heads are normally closed, but are designed to open, for instance by the melting of an alloy insert, when the ambient temperature reaches a predetermined value, commonly in the neighborhood of 135.degree.-165.degree. F.
If the system piping is subjected to freezing temperatures, for instance, in unheated buildings, such as warehouses, it may be necessary to employ a dry pipe system, rather than a wet pipe system, to prevent the fire extinguishing medium from freezing in the sprinkler pipes. In dry pipe systems, the sprinkler pipes contain a gas, such as air, rather than a fire extinguishing medium. An ample supply of the fire extinguishing medium is connected to the system by a dry pipe valve, which opens in response to the opening of individual sprinkler heads to permit the gas to escape from the sprinkler pipes and water to enter them and discharge from the sprinkler heads.
Dry automatic sprinklers are known which permit the concealment of dry pipe systems and the extension of sprinkler protection to unheated areas from wet pipe systems. Such sprinklers normally have a valve mechanism at the inlet of a nipple which connects an individual sprinkler head to a supply pipe. When the sprinklers are installed in the supply pipe, the valve mechanism extends into the supply pipe, sealing off the nipple until the sprinkler is activated.
Willms U.S. Pat. No. 3,584,689 discloses such a dry sprinkler which includes an outer tube, an inner tube and a cylindrical sealing chamber affixed to the end of the inner tube adjacent a supply pipe and forming a seal with a cap member in the outer tube. In the embodiment shown in FIGS. 1 and 2 of the Willms patent, the inner tube is urged away from an operative position by a compression spring. In the embodiment illustrated in FIG. 3, the inner tube is urged towards its operative position. However, the cylindrical sealing member of both embodiments remains fixed on the end of the inner tube when the valve is released, requiring water to flow axially between the inner and outer tubes and radially through ports in the sealing member and in the inner tube.
The construction of both embodiments of the dry sprinkler of the Willms patent creates two serious problems. First, forces resulting from fluid pressure in the supply pipe are transmitted to the sprinkler head through the sealing member, the inner tube and the compression spring. If excessive, these forces can cause premature activation of the sprinkler. Second, mixed axial and radial flow of fluid through the sprinkler increases the pressure drop experienced by the flowing fluid. Because flow rate descreases as the pressure drop increases, the inner diameter of the inner tube must be selected, i.e., increased, to compensate for the increase in pressure drop, in order to achieve or maintain a desired or required rate of flow through the sprinkler. Providing a larger diameter inner tube increases manufacturing costs, which are further increased by the provision of ports in the inner tube to permit the entry of fluid passing from the outer tube to the inner tube.
In another known type of dry sprinkler, which has been marketed successfully for many years by the assignee of this application and includes an inner tube, an outer tube and an inlet fitting for attaching the outer tube to a supply pipe, a plurality of sealing balls form a fluid-tight seal at the inlet end of the sprinkler. The sealing balls are held in their sealing positions in the inlet fitting by a ring of locking balls which are maintained in engagement with the outlet end of the inlet fitting and an adjacent sealing ball by the inner tube. Upon the collapse of a heat-responsive device located at the outlet end of the sprinkler, the inner tube moves longitudinally, permitting a generally longitudinal movement of the locking balls which, as a result of such movement, disengage the adjacent sealing ball to permit all of the balls to be ejected from the inlet fitting by fluid pressure in the supply pipe.
By this construction, forces resulting from the fluid pressure in the supply pipe are transmitted to the heat-responsive device through the sealing balls, locking balls, and inner tube, creating the possibility of premature activation. Moreover, if the inner tube expands at a greater rate than the outer tube or inlet fitting when the sprinkler is subjected to above ambient temperatures, the sprinkler can be activated prematurely by the exertion of the heat-responsive device of an additional load resulting from the unequal thermal expansion of the tubes and fitting.
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1. Field of the Invention
Apparatuses and methods consistent with the present invention relate to an image projecting apparatus, and more particularly, to an image projecting apparatus, which has a cooling structure to cool a plurality of heat generating units installed therein.
2. Description of the Related Art
In general, image projecting apparatuses are image display apparatuses, which display a projected image on a screen using light emitted from light sources. As small display devices, such as a transmission-type Liquid Crystal Display (LCD) and a Digital Micro-mirror Device (DMD), are used, image projecting apparatuses have been developed toward miniaturization and light-weight trends.
Here, ultra-high pressure halogen lamps are mainly used as light sources. However, research and development of the image projecting apparatuses toward miniaturization and light-weight trends using small light sources, such as Light Emitting Diodes (LEDs), have been continuously carried out.
If LEDs are used as light sources, a plurality of white LEDs emitting white light may be used, or a plurality of red LEDs, a plurality of green LEDs, and a plurality of blue LEDs may be used to emit white light. If the red LEDs, the green LEDs, and the blue LEDs are used, LED modules, which respectively include a plurality of LEDs respectively emitting red, green, and blue lights and are respectively connected to LED substrates supporting and driving the LEDs, are provided.
When an image projecting apparatus is operated, light sources emit light and generate heat simultaneously. If LEDs are used as the light sources, LED modules are separately installed according to colors of light, and thus heat is generated from several positions concurrently. Accordingly, a suitable cooling device has been required.
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1. Field of the Invention
The present invention relates to a network relay program, a network relay apparatus, a communication system, and a network relay method, whereby spoofing another terminal by faking a Media Access Control address (MAC address) of a terminal is prevented.
2. Description of the Related Art
In recent years, many major companies in particular have been introducing the IEEE (Institute of Electrical and Electronic Engineers) 802.1x authentication system, in order to improve security. IEEE802.1x is a protocol arranged to allow only an authenticated user (authorized user) to access a network. With IEEE802.1x, an authentication server and an authentication switch (authenticator) cooperate to authenticate a terminal (supplicant).
Note that as for a conventional technique relating to the present invention, there is an authentication method arranged to update an MAC address table of the access points of a wireless Local Area Network (LAN) (e.g., see Japanese Unexamined Patent Application Publication No. 2001-111544).
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A typical machining apparatus has a frame having a vertical front wall and defining a work station, an intake station, and an output station. Conveyors can move the workpieces into the intake station and out of the output station. The work station holds at least one tool. vertical and horizontal guides support respective vertical and horizontal slides. A workpiece holder/grab carried on one of the slides is rotatable about a vertical axis and movable between a position alignable with the working, intake, and output stations on movement of the horizontal slide along the horizontal guide. Thus one of the workpiece can be shifted from the intake station into the work station, machined by the tool in the work stations, and deposited after machining in the output station, all while being held in the workpiece holder/grab, which typically is a three- or four-point chuck.
Such an apparatus using the pick-up principle is known in numerous designs, for instance form De 10 2004 005 498. They all have in common that the workpiece spindle is can be moved on a slide along horizontal guides on the machine frame so as to removes an unmachined workpiece from a conveyor, transfers it to the work station and subsequently deposits them again on the same or a different conveyor. On the upper frame of this machine, a horizontal guide is provided for the horizontal slide on which the vertical slide with the workpiece holder/grab can be vertically moved. The horizontal guide on the upper frame extends on both sides laterally beyond the working station so that the workpiece carrier can be moved on the one side into a workpiece intake position and on the other side into a workpiece output position. This results necessarily in a widely extended machine frame.
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Conventionally, a casing of an electric junction box mounted on a car body accommodates a laminate composed of bus bars formed by punching a conductive metal plate into a predetermined configuration and insulating plates layered on the bus bars alternately and circuit components consisting of an insulating substrate on which an electric conductor of a copper foil or the like is printed in a required pattern to form a printed-circuit board. When one casing accommodates a plurality of circuit components layered one upon another, electric conductors of the circuit components are connected with one another through a relay connector.
An electric junction box 1 of this kind accommodating the relay connector is provided, as disclosed in Japanese Patent Application Laid-Open No. 2001-15952 (patent document 1). As shown in FIG. 9, the electric junction box 1 has the laminate 2 of bus bars and the printed-circuit board 3. The housing (relay connector) 4 accommodating the relay terminal (not shown) is projected from the insulating plate of the bus bar laminate 2. The bus bars of the bus bar laminate 2 are connected with the relay terminal from below, and one end 5a of the connection terminal 5 is connected with the relay terminal from above. The other end 5b of the connection terminal 5 is soldered to the electric conductor of the printed-circuit board 3. Thereby the bus bars of the bus bar laminate 2 and the electric conductor of the printed-circuit board 3 are connected with each other.
But the number of circuits has increased owing to a rapid increase of electric and electronic parts in recent years. Thus in forming a required circuit from two circuit components, the circuit is necessarily horizontally large. The relay connector connecting the circuit components with each other is also necessarily large. Thereby the electric junction box is horizontally large.
In a construction in which three circuit components 6, 7, and 8 are accommodated in the casing of the electric junction box, with the circuit components 6, 7, and 8 vertically spaced at certain intervals, and the circuit components 6, 7, and 8 are connected with one another, it is possible to make the circuit components compact. But as shown in FIG. 10, it is necessary to form a housing 4 on the circuit component 7 located at an intermediate position and the circuit component 8 located at a lower position. Thus when the housing is formed on the circuit components 7 and 8, the interval between the circuit components is necessarily large. Therefore the electric junction box is very large in a vertical direction.
Patent document 1: Japanese Patent Application Laid-Open No.2001-15952
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Field of the Invention
The present invention relates to a work vehicle.
Description of the Related Art
In a work vehicle such as a wheel loader or a hydraulic excavator, a configuration has been disclosed in which a console box is disposed to the side of the operator's seat, and an operating lever is provided to the console box (see 2012-127137, for example).
With the hydraulic excavator disclosed in 2012-127137, in a state in which a gate lock lever is disposed in a locked position, the console box is positioned on the front side, and in a state in which the gate lock lever is disposed in an open position, the console box is positioned on the rear side.
The operator gets in and out of the vehicle with the console box moved to the rear side.
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1. Field of the Invention
The present invention relates to heat sink assemblies, and more particularly to a heat sink assembly for rapidly removing heat from an electronic device such as a central processing unit (CPU).
2. Description of Prior Art
During operating of an electronic device such as a computer central processing unit (CPU), a large amount of heat is often produced. The heat must be quickly removed from the CPU to prevent it from becoming unstable or being damaged. Typically, a heat sink is attached to an outer surface of the CPU to facilitate removal of heat therefrom
A conventional heat sink is usually integrally formed by extrusion, and comprises a base and a plurality of fins extending integrally from the base. However, because the heat sink is formed by extrusion, a height of the fins is limited to a relatively low height. In many applications, the fins of the heat sink are not high enough to dissipate heat generated by the corresponding electronic device such as a high-speed central processing unit (CPU). Furthermore, even when extrusion provides fins that are sufficiently high, such fins are liable to sustain large leveraging forces when the heat sink is attached to other components. As a result, the risk of damage to the fins is increased, and it is inconvenient to attempt to attach the heat sink with extra care. In summary, limited height of fins and their susceptibility to damage are two common problems inherent in conventional extruded heat sinks.
An improved heat sink assembly is desired to overcome the above-described disadvantages of the related art.
Accordingly, an object of the present invention is to provide a heat sink assembly which cooperates with a computer enclosure to dissipate heat generated by a device such as a central processing unit (CPU) of the computer.
Another object of the present invention is to provide a heat sink assembly which has excellent heat dissipation efficiency.
In order to achieve the objects set out above, a heat sink assembly for dissipating heat generated by a CPU in accordance with a preferred embodiment of the present invention comprises a computer enclosure, a heat sink a container, a fan and a tube. The container is partly filled with liquid and mounted on the heat sink. The fan is mounted in the container and open to a top wall of the container. The enclosure encloses the heat sink, the container, the fan and the tube therein. A medial portion of the tube is attached to the enclosure, an end of the tube is inserted through one side of the container and engaged in a side of the fan, and an opposite end of the tube is engaged in an opposite side of the container. In operation, the heat sink absorbs heat from the CPU and transfers heat to the container. Liquid in the container changes into high temperature vapor, rises to the top wall, turns into high temperature liquid droplets, and falls down toward the liquid. A proportion of the high temperature liquid droplets are received in the fan, and impelled by the fan to enter the tube. The high temperature liquid droplets transfer heat to the enclosure at the medial portion of the tube, and change into low temperature liquid droplets that return to the container.
Other objects, advantages and novel features of the present invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings, in which:
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The present invention relates to a method and apparatus for the production of composite filter plugs or mouthpieces which can be united with sections of tobacco-containing rods to form therewith filter tipped cigarettes, cigars or cigarillos. More particularly, the invention relates to a method and means for manipulating rod-like filter elements or components of several types prior to and during draping into a web of cigarette paper, imitation cork or other suitable wrapping material to form a continuous filter rod which is thereupon subdivided into composite filter plugs each of which contains at least a portion of at least one filter element of each of several types of such filter elements.
U.S. Pat. No. 2,953,878 to Schur discloses an apparatus for making composite filter plugs wherein filter elements of several types are shuffled to form a series of groups of assorted coaxial filter elements which move sideways. Successive groups are thereupon moved lengthwise exclusively by mechanical means to form a continuous line of filter elements, and the line is wrapped into a continuous web to form a filter rod. The rod is severed at selected points to yield a file of discrete filter plugs each of which contains one or more filter elements of each type. The means for moving successive groups lengthwise comprises an endless chain having spaced-apart lugs each of which engages and pushes the last filter element of a group so that the group advances toward a wrapping station. A drawback of such apparatus and of such mode of making a continuous line of assorted filter elements is that the speed of the chain conveyor is limited and the output of the apparatus is quite low. This will be readily appreciated since the speed at which a group which moves sideways (at zero axial speed) is caused to change its direction of movement (from sidewise to axial or lengthwise) cannot be increased at will without unduly affecting the appearance and/or damaging the filter element which is engaged by a lug.
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Among the most important advances in modern medical practice has been the adoption of a variety of minimally invasive procedures. Examples of such minimally invasive procedures include angioplasty, endoscopy, laparoscopy, arthroscopy and the like. Minimally invasive surgical procedures such as these can be distinguished from conventional open surgical procedures. In these minimally invasive procedures, access to a target site within the body of a patient is achieved through a relatively small incision, into which a tubular device (including a tube of a device) is inserted or introduced. The tubular device maintains the patency of the incision, while permitting access to the target site via the interior (lumen) of the device.
The tubular device can be configured for surgical use itself, or can be incorporated into another device. One example of the former is a balloon catheter, wherein the tube is configured as a catheter shaft, and carries an inflatable balloon on the shaft. Balloon catheters are useful, e.g., for performing angioplasty and for the deployment of an expandable stent and/or graft for preventing stenosis (closure) of a body passage, such as a blood vessel. Other examples of the former include a diagnostic, infusion or drainage catheter, in which the tubular device is configured as a catheter for the delivery of a diagnostic or therapeutic fluid to the patient, or for the removal of a fluid from the patient. Examples of devices including apparatus in addition to the tube are endoscopes, laparoscopes, arthroscopes and the like, as well as guide catheters and introducer sheaths (percutaneous or otherwise), through which a guide wire or other surgical device may be introduced into the patient.
To enhance torqueability and pushability, some catheters have included a braided reinforcement in the wall of the catheter shaft. However, braided catheters are relatively susceptible to kinking during use. Once a catheter kinks, fluid cannot pass through the lumen of its shaft, and the catheter becomes essentially useless. In balloon catheters, this prevents inflation of the catheter balloon. In addition, in other catheters, such as diagnostic, infusion and drainage catheters, prevention of fluid flow similarly interferes with their satisfactory use. As a result, the initially introduced catheter must be removed, and another catheter must be introduced into the patient and once again advanced through the vascular system to the narrowed site. This wastes time and increases the potential for trauma to the patient. To prevent kinking, some catheters include a coil embedded in the wall of the catheter shaft, rather than a braid. Although the presence of a coil inhibits kinking of the catheter, catheters having an embedded coil are undesirably susceptible to necking, that is, an undesirable reduction in its outer and/or inner diameter. In addition, utilizing a coil instead of a braid does not provide a great a degree of torqueability.
U.S. Pat. No. 6,939,337, assigned to the assignee herein, discloses a tubular medical device that includes a coil, such as a flat wire coil, in a stressed radially expanded condition, and a braid that extends over at least part of the coil. A bonding layer, formed from a polymer such as nylon or polyurethane, is positioned over and contacts the coil, or both the coil and the braid. The polymeric bonding layer maintains the coil in the stressed radially expanded condition, and is bonded to an inner liner, such as PTFE. By providing both a coil and a braid, the tubular device achieves some advantages attainable from each of these reinforcements. For example, the coil enables the device to better resist collapse, necking and kinking during use. The braid provides the device with enhanced pushability, trackability and torqueability. The '337 patent is incorporated by reference herein in its entirety.
Although the device of the '337 patent represents an improvement over prior art devices, it is desired to make still further improvements to such tubular devices to enhance their utility to an even greater degree than presently available. For example, it may be advantageous to have a splittable catheter shaft wall to facilitate deployment of a tubular medical device within a body vessel. During complete deployment of a stent or graft, the physician must retract the sheath from the stent over its entire length. This can be difficult for longer stents, e.g., over 140 mm, especially self-expanding stents, as the force of retraction and length of retraction are greater, making it relatively cumbersome to retract and requiring both hands to overcome the friction force.
United States Patent Application Publication No. 2007/0244540A1 to Pryor, which describes a delivery system for delivery a self-expanding stent, provides one solution for this problem. The delivery system includes a sheath with a breakaway having less structural integrity than the remainder to the sheath such that the sheath preferentially splits at the breakaway upon contact with a keel. However, the specific construct of the sheath in Pryor's delivery system is not described, and incorporating a sheath with a breakaway having less structural integrity than the remainder to the sheath reduces trackability, pushability and torqueability, as well as increase the probability of necking or kinking along the breakaway, during use of the sheath.
Thus, it would be desirable to provide an arrangement of a coil and/or a braid in a tubular device possessing sufficient trackability, pushability and torqueability, as well as being highly resistant to collapse, necking or kinking, during use. It would also be desirable if the tubular device is capable of being split longitudinally along its wall.
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1. Field
The present invention relates to an electronic calculator suitable to learn a formula operation process and a computer-readable medium storing a control program thereof.
2. Description of the Related Art
Conventionally, there has been devised an electronic desk calculator suitable to learn the formula operation process.
In the electronic desk calculator, when an ENTER key is pressed while a formula as an operation object is displayed, operation processing is sequentially performed to only an operator that is selected from operators in the formula according to an operation priority each time the ENTER key is pressed. Each time the operation processing of the formula is performed according to the operation priority of the operator, a formula element to which the operation processing is performed is displayed while replaced with a solution of the formula element. Therefore, an operation progress situation can be confirmed on a step-by-step basis until operation result of the formula is derived.
In the conventional electronic desk calculator, each formula element to which the operation processing is performed according to the operation priority of each operator included in the formula is formula-displayed while replaced with a solution of the operation processing each time of the operation processing. Therefore, unfortunately it cannot be understood that the operation processing is performed to the provided formulas in what order, or not only contents of the original formula element replaced with the solution but also the original formula cannot be understood with the progress of operation processing although the solution can currently be confirmed.
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With the continuous development of network technology, telepresence conferences are becoming an important form of conference. Telepresence conferences are convened over a network by combining video, audio and interactive components, thereby overcoming inconvenience caused by region differences.
In addition to high quality of audio and video effect and a conference site closing to reality, the telepresence conference can provide a conference control strategy to control a series of functions of the conference such as silencing/muting, disabling/enabling a video, and locking/unlocking.
In implementing the present disclosure, it has been appreciated by the inventor that there is at least the following issues in the conventional technologies.
In the conventional technologies, a telepresence conference can only silence/mute a single participant, disable/enable a video for the single participant, and lock/unlock the whole conference. Therefore, a conference control strategy is single and media streams can not be distinguished effectively in a case that a Realtime Transport Protocol is multiplexed in a multi-stream conference.
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The related application identified above discloses a frequency domain equalizer for vestigial sideband (VSB) decoders implemented within a single integrated circuit multi-standard demodulator also including an orthogonal frequency division multiplexing (OFDM) decoder. Rather than a frequency domain implementation of a time domain finite impulse response (FIR) filter, which is computationally intensive, the frequency domain equalizer disclosed employs a least square cost function which is memory intensive in adaptive inverse channel estimation. As a result, the hardware required for adaptive inverse channel estimation may be mapped to the hardware employed for (memory intensive) OFDM decoding.
From simulation results, the performance of the frequency domain equalizer disclosed in the related application is expected to be at least as good as currently implemented VSB equalizers, and in some cases even better, particularly for noisy non-minimum phase channels (where decision feedback equalizers suffer from convergence to a local minims if the length of the forward taps is short), long delay dispersions and co-channel interference. In addition, performance of the frequency domain equalizer disclosed is hardly affected by the location of a spike initialization (the center tap).
Even though performance of the frequency domain equalizer is at least as good as if not better than the performance of a typical standard time domain decision feedback equalizer (DFE) under the circumstances described, use of the frequency domain equalizer alone may not be adequate to solve the equalization problem of vestigial sideband (VSB) modulation with eight discrete amplitude levels (8-VSB). The frequency domain equalizer behavior approximates a finite impulse response (FIR) Wiener solution, which could be inadequate for noise channels that have deep notches.
On the other hand, a decision feedback equalizer (discussed generally in J. Proakis, Digital Communications, Third Edition) would theoretically exhibit better performance in such a situation if the decisions fed back to the equalizer are reliable and the length of the filters is sufficiently long. With reliable decisions, such as with a high signal-to-noise ratio (SNR) signal or using trellis decisions, the decision feedback equalizer would perform better than the frequency domain equalizer disclosed in the related application for some channels.
There is, therefore, a need in the art for a frequency domain equalizer which retains the advantages of adaptive inverse channel estimation while also obtaining the benefits of the feedback portion of a decision feedback equalizer with reliable decisions and a sufficiently long filter.
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The present invention relates to an overload protection device. Overload protection devices which have been known hitherto are used in the most diverse devices in which there is a transmission of force and/or momentum between two components, for example in presses in which an interruption of the movement of the force and/or momentum-transmitting component, for example the ram, is brought about in order to protect the recipient of the force and/or momentum against an overload in the form of excessively high forces and/or momentums, for example an excessively high to compressive force.
A solution of this kind is known from document DE 102 29 276 A1. This document describes a press in which the piston rod is provided with an overload protection device which arrests the ram if an admissible pressing force is exceeded. For this purpose, there is disposed within the piston rod, a pressure element which acts upon a cavity and upon a fluid located therein, when a compressive movement occurs. If the pressure exceeds a predetermined value, the pressurised fluid opens a pressure-limiting valve which is connected to the cavity via a line. The fluid flowing out triggers the decoupling of a flywheel belonging to the press, and also the actuation of a brake on the driving apparatus, in a valve-controlled manner and, in this way, interrupts the driving of the ram.
One object of the present invention consists in providing a simple and reliable overload protection device which has a high speed of response. Furthermore, the intention is to provide a device for protecting against overloads, whose response level can be adjusted within a wide range of values and which can be reused as often as desired.
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Glycosylation in eukaryotes has been studied intensively for decades as the most common covalent post translational protein modification mechanism (Varki et al 2009). About 1-2% of the human transcriptome (about 250-500 glycogenes) is predicted to translate proteins which are responsible for glycosylation (Campbell and Yarema 2005). Glycosylation of cellular proteins plays many key biological functions such as protein folding, stability, intracellular and inter-cellular trafficking, cell-cell and cell matrix Interaction.
There are four distinct groups of Glycoproteins: N-linked, O-linked, glycosaminoglycans, and glycosylphosphatidylinositol-anchored proteins. N-linked glycosylation occurs through the side chain amide nitrogen of asparagine residues, while O-linked glycosylation uses the oxygen atom in the side chain of serine or threonine residues. N-linked glycosylation takes place in the amino acid sequence of Asn-X-Ser/Thr, where X can be any amino acid except proline and aspartic acid (Helenius and Aebi 2004).
Fucose (6-deoxy-L-galactose) is a monosaccharide that is present in many glycoproteins and glycolipids present in vertebrates, invertebrates, plants, and bacteria. Fucosylation is the process of transferring a fucose residue to various proteins and oligosaccharides. Fucosylation is regulated by several molecules, including fucosyltransferases, guanosine diphosphate (GDP)-fucose synthetic enzymes, and GDP-fucose transporter(s). A large number of fucosylated glycoproteins are secretary proteins or membrane proteins on the cell surface. A potent example of fucosylated glycoprotein is fucosylated alpha-fetoprotein (AFP), an important cancer biomarker (Simm, 1979).
There are 14.1 million new cancer cases, 8.2 million cancer deaths and 32.6 million people living with cancer (within 5 years of diagnosis) in 2014 worldwide. The high mortality rate of cancer serves as a reminder of the need for more effective therapies. The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, known as “Monoclonal Antibodies” or mAbs. A decade ago, there were only two mAbs on the market and currently there are around 30 FDA approved mAbs of diverse therapeutic modalities, like Adalimumab, Infliximab, Rituximab etc. mAbs are the fastest growing segment in pharmaceutical industry and this rapid expansion is set to continue. Now there are more than 100 monoclonal antibody-based biologic drugs in clinical trials. Many of these are in phase II and phase III trials and will be coming before the Regulatory agencies for approval. Improvement of monoclonal antibody therapeutics through technologies described here will pave the way of better clinical outcome for patients.
Human IgG1 antibody is a highly fucosylated glycoprotein. Two N-linked biantennary oligosaccharides consisting of core hepta-saccharide with variable addition of fucose, galactose, bisecting N-acetylglucosamine and sialic acid are present at Asn-297 of IgG1. Antibody glycosylation leads to unique biological functions known as “effector functions”—Antibody Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC). ADCC is a cell mediated immune system where immune cells (like natural killer cells) lyse the target cells identified through antibodies against cell surface antigens.
The effector function of IgG molecule is defined by the interaction of antibody Fc region with leukocyte receptors, known as FcγRs or interactions with complement components. The composition of the oligosaccharide structure is critically important for effector function through FcγR binding (Shields et al. 2002; Shinkawa et al. 2003; Niwa et al. 2004; Niwa, Shoji-Hosaka, et al. 2004; Yamane-Ohnuki et al. 2004;). Crystal structure analysis of human IgG1 revealed intricate interaction of the oligosaccharide chains with the CH2 domain (Harris et al. 1998; Radaev et al. 2001).
The efficiency of the ADCC mechanism is considerably dependent on the level of antibody fucosylation; the lower the fucosylation, the higher is the rate of ADCC. Therefore, loss of fucosylation has significant biological consequences. The loss could be due to non-functional fucosyltransferase enzymes, resulting in non-fucosylation of cellular proteins. The absence of fucose from the primary N-acetylglucosamine results in the IgG1 antibody having increased binding affinity for the FcγRIIIα receptor, with consequent increase of 50-100 times higher efficacy of ADCC (Shinkawa et al. 2003). Improvement of ADCC with non-fucosylated IgG is directly proportional to the increased affinity for FcγRIIIα—this allows the non-fucosylated IgG Fc to overcome the competition from high concentrations of fucosylated IgG in normal serum. Plausible rationale for the increased affinity of non-fucosylated IgG Fc for FcγRIIIa may be the reduction or absence of steric inhibition at the receptor-ligand interface (Harris, 1998; Radaev, 2001).
In mammalian expression system, the enzyme α1-6 fucosyltransferase encoded by the Fut8 gene is responsible for transferring fucose moiety from GDP-fucose to N-acetylglucosamine of N-glycan chain in proteins (Miyoshi, 1999). Disruption of this gene function through various means leads to production of non-fucosylated proteins including antibodies (Naoko Yamane-Ohnuki, 2004).
Non-fucosylated forms of therapeutic antibodies developed in mammalian platforms, where fucose biosynthesis is impaired, may have clinical advantage over the fucosylated forms due to the enhanced efficiency of ADCC towards target tumor cells.
Historically, gene knock out systems completely depended on homologous recombination (HR) mediated targeted mutation, deletion and/or insertion. The HR system, although very specific, is highly inefficient, as thousands of clones need to be screened to find one mutated clone. Moreover, deleting allelic variations would take even further time and much larger screening. Multiple technologies have evolved in the last decade to achieve targeted gene modification using a combination of a DNA sequence recognition domain and a nuclease domain. These systems are highly efficient at identifying specific sites of interest and then introducing DNA strand breaks. DNA double-strand break (DSB) at genomic target locus activates DNA repair, which is utilized for modifying genes. The DNA damage response is highly conserved in eukaryotic cells. The concept of DSB-based genome engineering is easily transferrable between highly diverse organisms. Creating double strand break increases the frequency of gene knock out at targeted loci by thousand folds through homologous recombination and non-homologous end joining mechanisms.
In comparison Zinc Finger Nuclease (ZFN) requires three bases at the DNA level for each zinc finger tandem array. Moreover, target site overlap and cross-talk between individual fingers in a zinc-finger array considerably complicate the production of sequence-specific ZFNs. Additionally, major drawback of ZFNs includes elaborate and time-consuming experimental selection process to identify the ZFN motifs for specific DNA sequence recognition.
There are methods in the prior art for disruption of Fut8 genomic loci. However, none of the methods target the specific location on the FUT8 genomic loci by the TALEN technology.
The present disclosure overcomes the disadvantages or limitations associated with methods of the prior art by using the TALEN technology to target a specific location on the FUT8 genomic loci, which results in complete disruption of the FUT8 gene and related function, providing a cell that produces non-fucosylated proteins.
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The present invention relates to a five valve manifold for use with a pressure sensing apparatus.
Prior art pertaining to the present invention is represented, for instance, by Canadian patent 990,102 (Bias); by Canadian patent 1,254,108 (Nimberger); by U.S. Pat. No. 3,450,157 (Hewson) and by U.S. Pat. No. 4,711,268 (Coleman).
Prior art and the present invention will be described with reference to the accompanying diagram drawings wherein:
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Semiconductor memory devices may be classified into volatile memory devices and non-volatile memory devices according to whether stored information is retained when power to the semiconductor memory devices is off. The volatile memory devices such as a dynamic random access memory (DRAM) may be refreshed by sensing stored data and recharging sensed data to memory cells through bit lines. As operational temperature of the semiconductor memory device becomes higher, leakage current in the memory cell increases, and thus data retention time and refresh period may decrease.
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The invention relates to a device for a hydraulic unit, in particular in anti-skid systems for vehicle brake systems.
Devices of this type are included in motor vehicle brake systems provided with anti-skid systems. The vehicle brake systems are mounted on the wheels of the vehicle and provided with brake pressure lines that lead to the hydraulic brake system. To generate brake pressure and hence braking action, a master brake cylinder is actuated with the aid of a foot pedal. In modern vehicles, anti-skid systems are additionally built in with which in anti-skid operation a braking pressure is likewise generated for an automatically adapted braking, which nevertheless prevents wheel locking. To this end, sensors are attached to the wheels to detect any danger of locking, or skidding, and via a control unit signals from the sensors act on a motor, a return pump and magnetic control valves, for example, and thus effect suitable pressure changes in the brake lines compared with the pressure of the master brake cylinder. In the process of pressure equalization at the master brake cylinder, pulsations are created that are perceptible to the driver at the foot pedal. The process produces irritating noises as well.
German Offenlegungsschrift 23 36 973 discloses a device of the above-mentioned type. In this known version of a radial piston fluid pump, a pump piston is forced with a drive side against an eccentric cam. The drive side of the pump piston is provided with a recess to receive a sliding body, which is defined in that it comprises an elastic plastic, that the height of the sliding body is greater than the depth of the recess, and that the sliding body is axially movable in the recess. This is intended to prevent the loud percussive noises that is produced by the pistons as they lift up from the cam race if the pilot pressure in such pumps fails. In the pumping strokes that occur, the sliding body is intended to elastically absorb the resultant impacts, both to prevent noise from being generated and to prevent undue strain on the cam race.
To prevent recoiling motion of the brake pedal, German Offenlegungsschrift 34 38 646 proposes a device for controlling the hydraulic pressure, which can prevent the brake pedal from recoiling when the vehicle is braked. Complete suppression of pedal feedback proves to be disadvantageous, however, if the feedback means is missing so that the driver does not learn that his ABS or anti-skid system has come into play.
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The development of plasmid vectors useful for recombinant DNA genetics among microorganisms is well known. The editorial in Science, Vol. 196, April, 1977, gives a good summary of DNA research. This editorial is accompanied by a number of supporting papers in the same issue of Science.
Similar DNA work is currently being done on industrially important microorganisms of the genus Streptomyces. [Bibb, M. J., Ward, J. M., and Hopwood, D. A. 1978. "Transformation of plasmid DNA into Streptomyces at high frequency". Nature 274, 398-400]. Through plasmid DNA's have been detected in several Streptomycetes [Huber, M. L. B. and Godfrey, O. 1978. "A general method for lysis of Streptomyces species". Can. J. Microbiol. 24, 631-632.] [Schrempf, H., Bujard, H., Hopwood, D. A. and Goebel, W. 1975. "Isolation of covalently closed circular deoxyribonucleic acid from Streptomyces coelicolor A3(2)". J. Bacteriol. 121, 416-421.][Umezawa, H. 1977. "Microbial secondary metabolities with potential use in cancer treatment (Plasmid involvement in biosynthesis and compounds)". Biomedicine 26, 236-249.], [Malik, V. S. 1977. Preparative Method for the isolation of super-coiled DNA from a chloramphenicol producing Streptomycete. J. Antibiotics 30, 897-899.], only one Streptomycete plasmid has been physically isolated and extensively characterized in the literature [Schrempf, supra]. The existence of other plasmids in the genus Streptomyces has been inferred from reported genetic data as follows:
(1) Akagawa, H., Okanishi, M. and Umezawa, H. 1975. "A plasmid involved in chloramphenicol production in Streptomyces venezuelae: Evidence from genetic mapping". J. Gen. Microbiol. 90, 336-346. PA1 (2) Freeman, R. F. and Hopwood, D. A. 1978. "Unstable naturally occurring resistance to antibiotics in Streptomyces". J. Gen. Microbiol. 106, 377-381. PA1 (3) Friend, E. J. Warren, M. and Hopwood, D. A. 1978. "Genetic evidence for a plasmid controlling fertility in an industrial strain of Streptomyces rimosus". J. Gen. Microbiol. 106, 201-206. PA1 (4) Hopwood, D. A. and Wright, H. M. 1973. "A plasmid of Streptomyces coelicolor carrying a chromosomal locus and its inter-specific transfer". J. Gen. Microbiol. 79, 331-342. PA1 (5) Hotta, K., Okami, Y. and Umezawa, H. 1977. "Elimination of the ability of a kanamycin-producing strain to biosynthesize deoxystreptamine moiety by acriflavine". J. Antibiotics 30, 1146-1149. PA1 (6) Kirby, R., Wright, L. F. and Hopwood, D. A. 1975. "Plasmid-determined antibiotic synthesis and resistance in Streptomyces coelicolor". Nature 254, 265-267. PA1 (7) Kirby, R. and Hopwood, D. A. 1977. "Genetic determination of methylenomycin synthesis by the SCPI plasmid of Streptomyces coelicolor A3(2)". J. Gen. Microbiol. 98, 239-252. PA1 (8) Okanishi. M., Ohta, T. and Umezawa, H. 1969. "Possible control of formation of aerial mycelium and antibiotic production in Streptomyces by episomic factors". J. Antibiotics 23, 45-47.
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There are a variety of situations in which automated processing of a number of data items is desirable. One specific example of such an application is product catalogs. Product catalogs, whether in the form of a paper catalog or an Internet “Web” site, frequently have numerous pictures which each depict a respective one of the various items that are available for sale. Many years ago, these pictures were prepared using optical negatives and photographs. Currently, however, the trend is to maintain and process these pictures in the form of computer files containing digital images.
A given paper or on-line catalog will usually include products from a variety of different manufacturers, and it is common for each manufacturer to provide its own digital images. There will typically be variation between the form of images provided by different manufacturers, for example in terms of characteristics such as the size, shape, resolution, tint, and so forth. It is even possible that the images from a single given manufacturer may have different forms. Accordingly, in order for the images throughout a catalog to have a generally similar appearance, the various images from various sources need to be processed to adjust characteristics such as size, shape, resolution, and/or tint, so as to bring them into general conformity with each other.
A further consideration is that a manufacturer's images do not represent a static situation, because manufacturers are constantly adding new products with new images, discontinuing existing products and associated images, and providing updated images for existing products. Moreover, there may be other reasons for adjusting images. For example, with respect to a paper or on-line catalog intended for use during the Christmas season, there may be a desire to put a festive frame around each image, such as a frame of holly leaves and berries. Moreover, stylistic changes in the images are often desirable.
The traditional approach for carrying out these various types of image processing tasks has involved manual adjustments effected on an image-by-image basis, through use of image processing software requiring extensive operator interaction. However, this is extremely time consuming and expensive. Many organizations currently employ a number of graphic artists to do this work, at great expense.
A less common approach has been the preparation of a hard-coded software routine to process images, written in line-by-line source code. However, these routines are time-consuming and expensive to generate, are likely to include errors or “bugs”, and have little flexibility because they cannot be modified quickly and cheaply. Moreover, they can only be prepared and executed by a skilled programmer, rather than by a graphic artist who is skilled in image processing but has limited computer skills. It is difficult to find persons who have both artistic and computer skills, and they command large salaries.
Thus, while these traditional approaches have been generally adequate for their intended purposes, they have not been satisfactory in all respects. In this regard, when preparing a program or other definition that will control the automated processing of multiple items of data, one difficulty relates to the issue of how to ensure that the processed data will be satisfactory. For example, in the case of image data, a variety of different operations may be needed for the image data, such as adjustment of color, adjustment of tint, blending of two or more images, and so forth. It is relatively difficult to accurately predict how a resulting image will appear after it has been subjected to all of these processing functions. Where automated data processing is being effected through hard-coded source code, it is extremely tedious and time consuming to go through an iterative process of writing source code, compiling the resulting code, processing test data with the compiled code, evaluating the result of the processing, rewriting portions of the source code, and then repeating this cycle until a suitable result is achieved.
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{
"pile_set_name": "USPTO Backgrounds"
}
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1. Field of the Invention
The present invention is broadly concerned with an improved flea trap designed for use in and around areas where flea infestation is a problem, such as homes, barns and livestock sheds. More particularly, it is concerned with such an improved flea trap, as well as a method of attracting fleas, which makes use of a light source operated to give effectively varying intensities over time and preferably presenting a relatively narrow visible light spectrum in order to greatly enhance the attraction and arrest (e.g., capture and/or destruction) of fleas.
2. Description of the Prior Art
A number of devices have been proposed in the past for the trapping of fleas. Such units may be used for the control or reduction of flea infestations in human or pet premises, and as a research tool for monitoring or surveying flea populations.
For example, U.S. Pat. No. 5,044,112 describes a flea trap including a visible light source adapted to be installed close to floor level and having a reflector above the light source to reflect light downwardly; a sticky capture surface is located below the light source in order to trap fleas attracted by the light source.
Despite the many attempts to provide truly useful flea traps, in general devices of this character have proven to be of limited effectiveness. Indeed, actual control testing of certain commercially available flea traps has demonstrated that they are capable of attracting and capturing only a small percentage of the available flea population.
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{
"pile_set_name": "USPTO Backgrounds"
}
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Nondirectional speakers which spreadly emit out a voice in a direction in which an emitter is oriented have been widely used. On the other hand, there have been provided ultra-directional speakers which provide high directivity using the principle of parametric speakers. An ultra-directional speaker generates a sound having frequencies within the range of human hearing by using distortion components which are generated when a strong ultrasonic wave propagates through the air, and concentrates the generated sound to a front side thereof and makes it propagate, thereby offering sounds having high directivity. Such a parametric speaker is disclosed by, for example, patent reference 1.
A robot equipped with audiovisual system is disclosed by, for example, patent reference 2. This moving object equipped with audiovisual system can carry out a real-time process of performing visual and sound tracking on a target. This system also has a technology for unifying several pieces of sensor information about a visual sensor, an audio sensor, a motor sensor, etc., and, even if any one of the plural pieces of sensor information is lost, continuing the tracking by complementing the lost piece of sensor information.
Patent reference 1: JP,2001-346288,A
Patent reference 2: JP,2002-264058,A
Since a speaker which is mounted in a related art moving object is a low-directional speaker, a voice generated by the related art speaker reaches an indefinite number of things which exist around the moving object. For this reason, a related art speaker cannot provide voice information for a specific limited region.
In general, a related art ultra-directional speaker emits a voice in directions which are limited only to a region having an angle of 20 degrees in a direction of the front of an emitter, and does not have a function of automatically changing the direction of the front of the emitter to a direction in which the voice is to be emitted.
Conventionally, the adjustment of the level of the voice generated by the emitter of the related art ultra-directional speaker is manually performed, and the related art ultra-directional speaker does not have any function of adjusting the voice level according to a position to which the related art ultra-directional speaker provides the sound.
In addition, a problem with a case where a low-directional speaker is applied to a talking device of a robot communications system is that it is difficult for the robot communications system to recognize a voice from another sound source while the talking device is making a voice. To be more specific, a robot's microphone is disposed closer to the robot's drive motor compared with other sound sources, such as a partner to which the robot is talking. As a result, even if the absolute power of noise caused by the drive motor is small compared with those of other sound sources, the power of the motor noise collected by the microphone becomes relatively large and has an influence on voice recognition.
In addition, since the low-directional speaker emits a voice so that the voice can reach a partner to which the robot is going to talk, the output power of the voice is set to be large than that of the motor noise. Since such a voice outputted by the robot becomes noise at the time of recognizing a voice from the partner, the signal-to-noise (S/N) ratio becomes small as a result and it is therefore difficult for the robot to perform voice recognition. For this reason, a related art robot with a low-directional speaker turns off a hearing function while it is talking with a partner, or recognizes a voice from the partner by receiving it via not-the robot's microphone, but the microphone of a head set or the like, which is placed in the vicinity of the partner's month.
The present invention is made in order to solve the above-mentioned problems, and it is therefore an object of the present invention to provide an ultra-directional sound system that can surely provide a voice to a moving target to which the voice is to be provided, and which can provide voice information having an optimal volume in a direction of the target to which the voice is to be provided.
It is another object of the present invention to provide a moving object equipped with ultra-directional speaker which constitutes a robot communications system which implements a simultaneous dialog function and a high-concealment whispering function.
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{
"pile_set_name": "USPTO Backgrounds"
}
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