A baculovirus/insect cell expression system in which both .alpha. and .beta. subunit of human IL-5 receptor can be over-expressed together in Sf9 cells has been developed. This system is able to express the human high-affinity IL-5 receptors at a very high level and finds use in a screening assay for IL-5 receptor-based antagonists. A preferred embodiment of the screening assay involves the use of peanut agglutinin as lectin in a scintillation proximity assay.

Human interleukin 5 (IL-5) is a lineage-specific cytokine released mainly from activated T cells. Sanderson, 1992, Blood 79:3101-3109. Takatsu et al., 1988, Immunol. Rev. 102:107-135. A number of studies have demonstrated that IL-5 is responsible for the differentiation, proliferation and maturation of eosinophils from their progenitors in the bone marrow. Saito et al., 1988, Proc. Natl. Acad. Sci. USA 85:2288-2392. Lopez et al., 1988, J. Exp. Med. 167:219-224. Clutterbuck and Sanderson, 1988, Blood 71:646-658. Clutterbuck et al., 1989, Blood 73:1504-1512. Ema et al., 1990, Blood 76:1956-1961.
IL-5, Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) exhibit similar functions on eosinophils in vitro. Clutterbuck et al., 1989, Blood 73:1504-1512. Ema et al., 1990, Blood 76:1956-1961. However, whereas the action of human IL-5 is restricted to eosinophil and closely related basophil lineages (Sanderson, 1992 Blood 79:3101-3109), IL-3 and GM-CSF also have activities on other hematopoietic lineages. Miyajima et al., 1993, Blood 82:1960-1974.
IL-5 mediates its activity through a cell membrane receptor complex. This complex has been characterized physicochemically in both the murine and human systems. Mita et al., 1989, Proc. Natl. Acad. Sci. USA. 86:2311-2315. Plaelinck et al., 1990, J. Exp. Med. 172:623-691. Two receptor proteins, with molecular masses closely resembling those of murine IL-5 receptor .alpha.- and .beta.-chains (mIL-5R.alpha. and mIL-5R.beta.) are involved in the binding of human IL-5 (hIL-5). The .alpha.-chain (60 kd component) corresponds to the low affinity IL-5 binding site (K.sub.d =10.sup.-9 M). The .beta.-chain (130 kd component) associates with the .alpha.-chain to form the high affinity binding site (K.sub.d =2.5.times.10.sup.-10 M). Tavernier et al., 1991, Cell 66:1175-1184. Miyajima et al., 1993, Blood 82:1960-1974. High affinity human IL-5 receptors (hIL-5R) have been found in eosinophils and their related cell lines. Migita et al., 1991, Cell. Immunol. 133:484-497; Ingley and Young, 1991, Blood 78:339-344.
The cDNAs encoding the human .alpha.-chain component (hIL-5R.alpha.) and the human .beta.-chain component (hIL-5.beta.) have been cloned and characterized. Tavernier et al., 1991, Cell, 66:1175-1184. Murata et al., 1992, J. Exp. Med. 175:341-351. Hayashida et al., 1990, Proc. Natl. Acad. Sci. USA 87:9655-9659. The .alpha. subunit is responsible for IL-5 binding specificity and is distinct from the IL-3R.alpha. subunit and the GM-CSFR.alpha. subunit. Consistent with the studies of receptor binding assays, Northern blot experiments also have demonstrated that the expression of IL-5R.alpha. mRNA is restricted to eosinophils and their related cell lines. The .beta. subunit is shared by IL-3R and GM-CSFR and is essential for both the formation of high-affinity receptor complexes and signal transduction. Miyajima et al., 1993, Blood 82:1960-1974. Nucleotide sequencing and binding experiments show that the .beta. receptor component is identical to the .beta.-chain component of human GM-CSFR. Tavernier et al., 1991, Cell 66:1175-1184. Takaki et al, 1993, J. Exp. Med. 177:1523-1529. The cell type specific expression of the IL-5R.alpha. chain appears to be a required and crucial factor for the specific roles of IL-5 to these cells. Miyajima et al., 1993, Blood 82:1960-1974.
The process of eosinophilopoiesis is increased in certain disease states. Eosinophilia is characteristic of most parasitic infections as well as other disorders including dermatoses, allergies, polyarteritis nodosa and neoplastic diseases. Bronchial eosinophilia is a cardinal feature of chronic asthma. Multiple lines of evidence indicate that overexpression of IL-5 plays a crucial role in a number of eosinophil-related diseases. Owen et al., 1989, J. Exp. Med. 170:343-348. Owen et al., 1990, Proc. Natl. Acad. Sci. USA 87:8647-8651.
A central and specific role of IL-5 in controlling eosinophil functions in vivo was suggested by studies that mice bearing an IL-5 transgene produce a specific eosinophilia. Vaux et al., 1990, Int. Immunol. 2:965-970. Dent et al., 1990, J. Exp. Med. 172:1425-1431. Limaye et al., 1990, J. Exp. Med. 172:399-402. Moreover, antibodies specific to IL-5 inhibit eosinophil production induced by parasites and pathological stimuli. Coffman et al., 1989, Science 245:308-310. Gulbenkian et al., 1992, Am. Rev. Respir. Dis. 146:263-265. Ohnishi et al., 1993, Am. Rev. Respir. Dis. 147:901-907. A selective enhancement of IL-5 production was demonstrated in human helminth-infected patients with eosinophilia and in eosinophilic mice infected with Toxocara canis. Limaye et al., 1990, J. Exp. Med. 172:399-402 and Yamaguchi et al. 1990, Exp. Hematol. 18:1152-1157, respectively.
There is a need in the art to find therapeutic compounds useful in the treatment of chronic asthma and other IL-5-based disorders and disease states with demonstrated eosinophilia. There thus is a need for an expression system capable of expressing high affinity IL-5R at high levels and methods that can be used to identify receptor-based IL-5 antagonists potentially useful as therapeutic agents.

Baculovirus expression system for human interleukin 5 receptor and method of screening for interleukin 5 antagonists


A composition and a method for treatment of urinary tract dysfunction and, particularly, non-bacterial cystitis and, even more particularly, non-bacterial chronic interstitial cystitis. The composition primarily relies upon the use of a bioflavonoid and, particularly, that bioflavonoid known as quercetin. The quercetin is mixed with a proteolytic digestive enzyme protease, such as bromelin and papain, as the primary active ingredients. However, the composition may optionally and beneficially include other cystitis affecting agents, such as cranberry, as well as some other active and non-active ingredients.

1. Field of the Invention
The invention primarily relates to a composition and method for the treatment of non-bacterial cystitis and, more particularly, to a composition and method for treating non-bacterial chronic interstitial cystitis syndromes using bioflavonoids in a treatment composition and in a treatment method.
2. Brief Description of the Related Art
Interstitial cystitis represents a non-specific group of urinary tract and, particularly, bladder related problems and is often characterized by pain, which may actually adopt the form of phantom symptomatic pain. Interstitial cystitis is generally a pervasive inflammatory condition of the bladder and can be disabling to a sufferer. The symptoms usually suffered are bladder pain and frequent micturition. (urination). Interstitial cystitis is one of the conditions in which very few of the available therapies are effective.
At present, the cause for this condition is not fully known. As a result, there is frequently no known cure for non-bacterial interstitial cystitis, although there are several therapies of varying effectiveness, and usually of limited effectiveness. These therapies are generally designed to address the issues of pain and discomfort as well as the other symptoms arising from this condition, but are not specific to any effective cure or permanent treatment therefor.
Subjects having chronic interstitial cystitis refractory to conventional therapies often present frustration to a urologist attempting to treat that condition. For patients who do not respond to antibiotic therapy, but have negative fluid cultures, the etiology is unclear. It is recognized that a certain percentage of these patients probably have persistent bacterial infections.
There is still a great deal of controversy concerning the pathophysiology and the treatment which may be appropriate therefor. At present, prolonged antibiotic therapy is common for both the bacterial and the non-bacterial cystitis. However, where microbial therapy has shown itself to be relatively ineffective, other therapies have used alpha-blockers, anti-inflammatory agents and muscles relaxants. Nevertheless, these therapies have only met with variable success. There has been some use of dimethyl sulfoxide in a 50% solution (known as Rimso 50) as an attempt to relieve some of the symptoms of this condition. However, this composition is introduced intervesically, usually by means of a catheter and therefore not an effective home use treatment.
Beyond the therapies which attempt to elevate this condition, anti-pain medication, including various tricylic medications have been employed. Biofeedback for pain control has been also employed. Even surgery has been used as a mode of treatment, but the patient frustration with this type of treatment is relatively high.
The existence of chronic interstitial cystitis syndromes are therefore well known and are common disorders in women, particularly as age progresses. However, very few of the available therapies are effective for treatment of this condition, as aforesaid. There has been some evidence that bioflavonoids in general have improved the symptoms of this disorder in cases where tried. The use of the bioflavonoids has been well tolerated in tests and does provide some slight symptomatic improvement.
There have been some tests with patients using the bioflavonoid quercetin, alone. The symptomatic response of these patients taking quercetin has been significant. However, few patients ever became completely asymptomatic. Severe urinary symptoms in particular were least likely to improve with the quercetin alone. However, pain was controlled.
Today, the available modes of treatment are relatively ineffective or have only limited effectiveness. Thus, there has been a need for some therapy to treat chronic non-bacterial interstitial cystitis.

This patent is subject to a terminal disclaimer.

Composition and method for treating non-bacterial cystitis


A new mutation has been found in the BRCA2 gene. The mutation is a twobase pair deletion of nucleotide 6495 at nucleotides 6495 of the published cDNA sequence of BRCA2. A process for identifying a sequence variation in a BRCA2 polynucleotide sequence is disclosed. The identification process includes allele specific sequence-based techniques assays of known sequence variations. The methods can be used for efficient and accurate detection of a mutation in a test BRCA2 gene sample.

This invention relates to a gene which predisposes individuals to breast and ovarian cancer. More specifically, this invention relates to a specific mutation in the BRCA2 gene. In addition, it also relates to a method for detecting the presence of the mutation.
BRCA2, located on chromosome 13q 12-q13, consists of over 70 kb of genomic DNA. The coding sequence produces a protein of 3,418 amino acids. Although most of the exons are small, exons 10 and 11 represent approximately 60% of the entire coding region. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer.
The location of one or more mutations in the BRCA2 gene provides a promising approach to reducing the high incidence and mortality associated with breast and ovarian cancer through the early detection of women at high risk. These women, once identified, can be targeted for more aggressive prevention programs. Screening is carried out by a variety of methods which include karyotyping, probe binding and DNA sequencing. In such cases where one or only a few known mutations are responsible for the disease, methods for detecting the mutations are targeted to the site within the gene at which they are known to occur.
There is a need in the art to identify mutations in the BRCA2 gene. Identification of mutations of the BRCA2 gene and protein would allow more widespread diagnostic screening for hereditary breast and ovarian cancer than is currently possible.
The present invention is based on the discovery of a two base pair deletion of nucleotide 6495 of the published BRCA2 cDNA sequence which is associated with susceptibility to and development of breast and ovarian cancer.
It is an object of the invention to provide a method for determining a predisposition or higher susceptibility to breast and ovarian cancer.
It is another object of the invention to provide primers for detecting and amplifying a region of DNA which contains the 6495delGC mutation.
The present invention is based on the discovery of a two base pair deletion of nucleotide 6495 of the published BRCA2 cDNA sequence. This deletion mutation is referred to as 6495delGC. The BRCA2 gene is a tumor suppressor gene associated with breast and ovarian cancer.
The 6495delGC interrupts the normal reading frame of the BRCA2 transcript, resulting in the appearance of an in-frame terminator TAG at codon position 2090. This mutation is, therefore, predicted to result in a truncated, and most likely, non-functional protein.
Useful DNA molecules according to the invention are those which will specifically hybridize to BRCA2 sequences in the region of the 6495delGC mutation. Typically these are 17 to 20 nucleotides in length and have the nucleotide sequence corresponding to the region of the 6495delGC mutation at nucleotides 6495 of the BRCA2 cDNA sequence. Such molecules can be labeled, according to any technique known in the art, such as with radiolabels, fluorescent labels, enzymatic labels, sequence tags, etc. According to another aspect of the invention, the DNA molecules contain the 6495delGC mutation. Such molecules can be used as allele-specific oligonucleotide probes to track a particular mutation through a family.
Blood samples can be tested to determine whether the BRCA2 gene contains the 6495delGC mutation. In one embodiment of the invention a pair of isolated oligonucleotide primers are provided.
BRCA2-11F: 5xe2x80x2-TAC AGC AAG TGG AAA GC-3xe2x80x2(SEQ ID NO: 1), and BRCA2-11-R: 5xe2x80x2-AAG TTT CAG TTT TAC CAA T-3xe2x80x2(SEQ ID NO:2). The designation BRCA2-11 refers to a sequence in exon 11 of the BRCA2 gene. F and R refer to forward and reverse. The oligonucleotide primers are useful in direct amplification of a target polynucleotide prior to sequencing. These unique BRCA2 exon 11 oligonucleotide primers were designed and produced at Oncormed based upon identification of the 6495delGC mutation.
In another embodiment of the invention a pair of isolated allele specific oligonucleotides are provided.
5xe2x80x2-GAA CTG AGC ATA GTC TT-3xe2x80x2(SEQ ID NO:3), and
5xe2x80x2-GAA CTG AAT AGT CTT CA-3xe2x80x2(SEQ ID NO:4).
The allele specific oligonucleotides are useful in diagnosis of a subject at risk of having breast or ovarian cancer. The allele specific oligonucleotides hybridize with a target polynucleotide sequence containing the 6495delGC mutation. 5xe2x80x2-GAA CTG AGC ATA GTC TT-3xe2x80x2(SEQ ID NO:3) hybridizes preferentially to the wildtype sequence and is useful as a control sequence. 5xe2x80x2-GAA CTG AAT AGT CTT CA-3xe2x80x2(SEQ ID NO:4) is designed to hybridize preferentially to the mutant sequence.
The term xe2x80x9csubstantially complementary toxe2x80x9d or xe2x80x9csubstantially the sequencexe2x80x9d refers to (e.g., SEQ ID NO:3 and SEQ ID NO:4) sequences which hybridize to the sequences provided under stringent conditions and/or sequences having sufficient homology with SEQ ID NO:3 and SEQ ID NO:4, such that the allele specific oligonucleotides of the invention hybridize to the sequence. The term xe2x80x9cisolatedxe2x80x9d as used herein includes oligonucleotides substantially free of other nucleic acids, proteins, lipids, carbohydrates or other materials with which they may be associated. Such association being either in cellular material or in a synthesis medium. A xe2x80x9ctarget polynucleotidexe2x80x9d refers to the nucleic acid sequence of interest e.g., the BRCA2 encoding polynucleotide. Other primers which can be used for primer hybridization will be known or readily ascertainable to those of skill in the art.
The primers of the invention embrace oligonucleotides of sufficient length and appropriate sequence so as to provide initiation of polymerization on a significant number of nucleic acids in the polymorphic locus. Specifically, the term xe2x80x9cprimerxe2x80x9d as used herein refers to a sequence comprising two or more deoxyribonucleotides or ribonucleotides, preferably more than three, and more preferably more than eight and most preferably at least 20 nucleotides of the BRCA2 gene wherein said DNA sequence contains the 6495delGC mutation relative to BRCA2 contained in SEQ ID NO""s:3 and 4. Environmental conditions conducive to synthesis include the presence of nucleoside triphosphates and an agent for polymerization, such as DNA polymerase, and a suitable temperature and pH. The primer is preferably single stranded for maximum efficiency in amplification, but may be double stranded. If double stranded, the primer is first treated to separate its strands before being used to prepare extension products. The primer must be sufficiently long to prime the synthesis of extension products in the presence of the inducing agent for polymerization. The exact length of the primer will depend on many factors, including temperature, buffer, and nucleotide composition. The oligonucleotide primer typically contains 12-20 or more nucleotides, although it may contain fewer nucleotides.
Primers of the invention are designed to be xe2x80x9csubstantiallyxe2x80x9d complementary to each strand of the genomic locus to be amplified. This means that the primers must be sufficiently complementary to hybridize with their respective strands under conditions which allow the agent for polymerization to perform. In other words, the primers should have sufficient complementarity with the 5xe2x80x2 and 3xe2x80x2 sequences flanking the mutation to hybridize therewith and permit amplification of the genomic locus.
Oligonucleotide primers of the invention are employed in the amplification process which is an enzymatic chain reaction that produces exponential quantities of polymorphic locus relative to the number of reaction steps involved. Typically, one primer is complementary to the negative (xe2x88x92) strand of the polymorphic locus and the other is complementary to the positive (+) strand. Annealing the primers to denatured nucleic acid followed by extension with an enzyme, such as the large fragment of DNA polymerase I (Klenow) and nucleotides, results in newly synthesized + and xe2x88x92 strands containing the target polymorphic locus sequence. Because these newly synthesized sequences are also templates, repeated cycles of denaturing, primer annealing, and extension results in exponential production of the region (i.e., the target polymorphic locus sequence) defined by the primers. The product of the chain reaction is a discreet nucleic acid duplex with termini corresponding to the ends of the specific primers employed.
The oligonucleotide primers of the invention may be prepared using any suitable method, such as conventional phosphotriester and phosphodiester methods or automated embodiments thereof. In one such automated embodiment, diethylphosphoramidites are used as starting materials and may be synthesized as described by Beaucage, et. al., Tetrahedron Letters, 22:1859-1862 (1981). One method for synthesizing oligonucleotides on a modified solid support is described in U.S. Pat. No. 4,458,066.
Any nucleic acid specimen, in purified or nonpurified form, can be utilized as the starting nucleic acid or acids, providing it contains, or is suspected of containing, the specific nucleic acid sequence containing the polymorphic locus. Thus, the process may amplify, for example, DNA or RNA, including messenger RNA, wherein DNA or RNA may be single stranded or double stranded. In the event that RNA is to be used as a template, enzymes, and/or conditions optimal for reverse transcribing the template to DNA would be utilized. In addition, a DNA-RNA hybrid which contains one strand of each may be utilized. A mixture of nucleic acids may also be employed, or the nucleic acids produced in a previous amplification reaction herein, using the same or different primers may be so utilized. The specific nucleic acid sequence to be amplified, i.e., the polymorphic locus, may be a fraction of a larger molecule or can be present initially as a discrete molecule, so that the specific sequence constitutes the entire nucleic acid. It is not necessary that the sequence to be amplified be present initially in a pure form; it may be a minor fraction of a complex mixture, such as contained in whole human DNA.
DNA utilized herein may be extracted from a body sample, such as blood, tissue material and the like by a variety of techniques such as that described by Maniatis, et. al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, N.Y., pp. 280-281 (1982). If the extracted sample is impure, it may be treated before amplification with an amount of a reagent effective to open the cells, or animal cell membranes of the sample, and to expose and/or separate the strand(s) of the nucleic acid(s). This lysing and nucleic acid denaturing step to expose and separate the strands will allow amplification to occur much more readily.
The deoxyribonucleotide triphosphates dATP, dCTP, dGTP, and dTTP are added to the synthesis mixture, either separately or together with the primers, in adequate amounts and the resulting solution is heated to about 90xc2x0-100xc2x0 C. from about 1 to 10 minutes, preferably from 1 to 4 minutes. After this heating period, the solution is allowed to cool, which is preferable for the primer hybridization. To the cooled mixture is added an appropriate agent for effecting the primer extension reaction (called herein xe2x80x9cagent for polymerizationxe2x80x9d), and the reaction is allowed to occur under conditions known in the art. The agent for polymerization may also be added together with the other reagents if it is heat stable. This synthesis (or amplification) reaction may occur at room temperature up to a temperature above which the agent for polymerization no longer functions. Thus, for example, if DNA polymerase is used as the agent, the temperature is generally no greater than about 40xc2x0 C. Most conveniently the reaction occurs at room temperature.
The agent for polymerization may be any compound or system which will function to accomplish the synthesis of primer extension products, including enzymes. Suitable enzymes for this purpose include, for example, E. coli DNA polymerase I, Klenow fragment of E. coli DNA polymerase, polymerase muteins, reverse transcriptase, other enzymes, including heat-stable enzymes (i.e., those enzymes which perform primer extension after being subjected to temperatures sufficiently elevated to cause denaturation), such as Taq polymerase. Suitable enzyme will facilitate combination of the nucleotides in the proper manner to form the primer extension products which are complementary to each polymorphic locus nucleic acid strand. Generally, the synthesis will be initiated at the 3xe2x80x2 end of each primer and proceed in the 5xe2x80x2 direction along the template strand, until synthesis terminates, producing molecules of different lengths.
The newly synthesized strand and its complementary nucleic acid strand will form a double-stranded molecule under hybridizing conditions described above and this hybrid is used in subsequent steps of the process. In the next step, the newly synthesized double-stranded molecule is subjected to denaturing conditions using any of the procedures described above to provide single-stranded molecules.
The steps of denaturing, annealing, and extension product synthesis can be repeated as often as needed to amplify the target polymorphic locus nucleic acid sequence to the extent necessary for detection. The amount of the specific nucleic acid sequence produced will accumulate in an exponential fashion. PCR. A Practical Approach, ILR Press, Eds. M. J. McPherson, P. Quirke, and G. R. Taylor (1992).
The amplification products may be detected by analyzing it by Southern blots without using radioactive probes. In such a process, for example, a small sample of DNA containing a very low level of the nucleic acid sequence of the polymorphic locus is amplified, and analyzed via a Southern blotting technique or similarly, using dot blot analysis. The use of non-radioactive probes or labels is facilitated by the high level of the amplified signal. Alternatively, probes used to detect the amplified products can be directly or indirectly detectably labeled, for example, with a radioisotope, a fluorescent compound, a bioluminescent compound, a chemiluminescent compound, a metal chelator or an enzyme. Those of ordinary skill in the art will know of other suitable labels for binding to the probe, or will be able to ascertain such, using routine experimentation.
Sequences amplified by the methods of the invention can be further evaluated, detected, cloned, sequenced, and the like, either in solution or after binding to a solid support, by any method usually applied to the detection of a specific DNA sequence such as PCR, oligomer restriction (Saiki, et. al., Bio/Technology, 3:1008-1012, 1985), allele-specific oligonucleotide (ASO) probe analysis (Conner, et. al., Proc. Nat. Acad. Sci. U.S.A., 80:278, 1983), oligonucleotide ligation assays (OLAS) (Landgren, et. al., Science, 241:1007, 1988), and the like. Molecular techniques for DNA analysis have been reviewed (Landgren, et. al., Science, 242:229-237, 1988).
Preferably, the method of amplifying is by PCR, as described herein and as is commonly used by those of ordinary skill in the art. Alternative methods of amplification have been described and can also be employed as long as the BRCA2 locus amplified by PCR using primers of the invention is similarly amplified by the alternative means. Such alternative amplification systems include but are not limited to self-sustained sequence replication, which begins with a short sequence of RNA of interest and a T7 promoter. Reverse transcriptase copies the RNA into cDNA and degrades the RNA, followed by reverse transcriptase polymerizing a second strand of DNA. Another nucleic acid amplification technique is nucleic acid sequence-based amplification (NASBA) which uses reverse transcription and T7 RNA polymerase and incorporates two primers to target its cycling scheme. NASBA can begin with either DNA or RNA and finish with either, and amplifies to 108 copies within 60 to 90 minutes. Alternatively, nucleic acid can be amplified by ligation activated transcription (LAT). LAT works from a single-stranded template with a single primer that is partially single-stranded and partially double-stranded. Amplification is initiated by ligating a cDNA to the promoter olignucleotide and within a few hours, amplification is 108 to 109 fold. The QB replicase system can be utilized by attaching an RNA sequence called MDV-1 to RNA complementary to a DNA sequence of interest. Upon mixing with a sample, the hybrid RNA finds its complement among the specimen""s mRNAs and binds, activating the replicase to copy the tagalong sequence of interest. Another nucleic acid amplification technique, ligase chain reaction (LCR), works by using two differently labeled halves of a sequence of interest which are covalently bonded by ligase in the presence of the contiguous sequence in a sample, forming a new target. The repair chain reaction (RCR) nucleic acid amplification technique uses two complementary and target-specific oligonucleotide probe pairs, thermostable polymerase and ligase, and DNA nucleotides to geometrically amplify targeted sequences. A 2-base gap separates the oligonucleotide probe pairs, and the RCR fills and joins the gap, mimicking normal DNA repair. Nucleic acid amplification by strand displacement activation (SDA) utilizes a short primer containing a recognition site for hincII with short overhang on the 5xe2x80x2 end which binds to target DNA. A DNA polymerase fills in the part of the primer opposite the overhang with sulfur-containing adenine analogs. HincII is added but only cuts the unmodified DNA strand. A DNA polymerase that lacks 5xe2x80x2 exonuclease activity enters at the cite of the nick and begins to polymerize, displacing the initial primer strand downstream and building a new one which serves as more primer. SDA produces greater than 107-fold amplification in 2 hours at 37xc2x0 C. Unlike PCR and LCR, SDA does not require instrumented Temperature cycling. Another amplification system useful in the method of the invention is the QB Replicase System. Although PCR is the preferred method of amplification of the invention, these other methods can also be used to amplify the BRCA2 locus as described in the method of the invention.
In another embodiment of the invention a method is provided for diagnosing a subject having a predisposition or higher susceptibility to (at risk of) breast or ovarian cancer comprising sequencing a target nucleic acid of a sample from a subject by dideoxy sequencing following amplification of the target nucleic acid.
In another embodiment of the invention a method is provided for diagnosing a subject having a predisposition or higher susceptibility to (at risk of) breast or ovarian cancer, comprising contacting a target nucleic acid of a sample from a subject with a reagent that detects the presence of the 6495delGC mutation and detecting the mutation.
In another embodiment of the invention a method is provided for characterizing a tumor. One method comprises sequencing the target nucleic acid isolated from the tumor to determine if the 6495delGC has occured. Sanger, F., et. al., J Mol. Biol. 142:1617 (1980).
Another method comprises contacting a target nucleic acid of a sample from a subject with a reagent that detects the presence of the 6495delGC mutation and detecting the mutation. A number of hybridization methods are well known to those skilled in the art. Many of them are useful in carrying out the invention.
The materials for use in the method of the invention are ideally suited for the preparation of a diagnostic kit. Such a kit may comprise a carrier means being compartmentalized to receive in close confinement one or more container means such as vials, tubes, and the like, each of the container means comprising one of the separate elements to be used in the method. For example, one of the container means may comprise means for amplifying BRCA2 DNA, said means comprising the necessary enzyme(s) and oligonucleotide primers for amplifying said target DNA from the subject. The oligonucleotide primers include primers having a sequence:
BRCA-2-11F: 5xe2x80x2-TAC AGC AAG TGG AAA GC-3xe2x80x2(SEQ ID NO:1) or
5xe2x80x2-AAG TTT CAG TTT TAC CAA T-3xe2x80x2(SEQ ID NO:2)
or primer sequences substantially complementary or substantially homologous thereto. The target flanking 5xe2x80x2 and 3xe2x80x2 polynucleotide sequence has substantially the sequence selected from the group consisting of:
5xe2x80x2-GAA CTG AGC ATA GTC TT-3xe2x80x2(SEQ ID NO: 3), and
5xe2x80x2-GAA CTG AAT AGT CTT CA-3xe2x80x2(SEQ ID NO:4)
and sequences substantially complementary or homologous thereto. Other oligonucleotide primers for amplifying BRCA2 will be known or readily ascertainable to those of skill in the art.
The following definitions are provided for the purpose of understanding this invention.
xe2x80x9cCoding sequencexe2x80x9d or xe2x80x9cDNA coding sequencexe2x80x9d refers to those portions of a gene which, taken together, code for a peptide (protein), or which nucleic acid itself has function.
xe2x80x9cPrimerxe2x80x9d as used herein refers to a sequence comprising about 20 or more nucleotides of a gene used to initiate DNA synthesis via the PCR.

A xe2x80x9ctarget polynucleotidexe2x80x9d refers to the nucleic acid sequence of interest e.g., the BRCA2 encoding polynucleotide.
xe2x80x9cConsensusxe2x80x9d means the most commonly occurring in the population.
xe2x80x9cSubstantially complementary toxe2x80x9d refers to probe or primer sequences which hybridize to the sequences provided under stringent conditions and/or sequences having sufficient homology with test polynucleotide sequences, such that the allele specific oligonucleotide probe or primers hybridize to the test polynucleotide sequences to which they are complimentary.
xe2x80x9cIsolatedxe2x80x9d as used herein refers to substantially free of other nucleic acids, proteins, lipids, carbohydrates or other materials with which they may be associated. Such association is typically either in cellular material or in a synthesis medium.
xe2x80x9cSequence variationxe2x80x9d as used herein refers to any difference in nucleotide sequence between two different oligonucleotide or polynucleotide sequences.
xe2x80x9cPolymorphismxe2x80x9d as used herein refers to a sequence variation in a gene which is not associated with pathology.
xe2x80x9cMutationxe2x80x9d as used herein refers to an altered genetic sequence which results in the gene coding for a non-functioning protein or a protein with substantially reduced or altered function. Generally, a deleterious mutation is associated with pathology or the potential for pathology. The mutations identified herein result in a premature stop codon.
xe2x80x9cPre-determined sequence variationxe2x80x9d as used herein refers to a nucleotide sequence that is designed to be different than the corresponding sequence in a reference nucleotide sequence. A predetermined sequence variation can be a known mutation in a gene.
xe2x80x9cAllele specific detection assayxe2x80x9d as used herein refers to an assay to detect the presence or absence of a pre-determined sequence variation in a test polynucleotide or oligonucleotide by annealing the test polynucleotide or oligonucleotide with a polynucleotide or oligonucleotide of pre-determined sequence such that differential DNA sequence based techniques or DNA amplification methods discriminate between normal and mutant.
xe2x80x9cSequence variation locating assayxe2x80x9d as used herein refers to an assay that detects a sequence variation in a test polynucleotide or oligonucleotide and localizes the position of the sequence variation to a sub-region of the test polynucleotide, without necessarily determining the precise base change or position of the sequence variation.
xe2x80x9cTargeted confirmatory sequencingxe2x80x9d as used herein refers to sequencing a polynucleotide in the region wherein a sequence variation has been located by a sequence variation locating assay in order to determine the precise base change and/or position of the sequence variation.
The invention in several of its embodiments includes:
Detection of Pre-determined Sequence Variations
Stage I analysis is used to determine the presence or absence of a pre-determined nucleotide sequence variation; preferably a known mutation or set of known mutations in the test gene. In accordance with the invention, such pre-determined sequence variations are detected by allele specific hybridization, a sequence-dependent-based technique which permits discrimination between normal and mutant alleles. An allele specific assay is dependent on the differential ability of mismatched nucleotide sequences (e.g., normal:mutant) to hybridize with each other, as compared with matching (e.g., normal:normal or mutant:mutant) sequences.
Detection of Pre-determined Sequence Variations Using Allele Specific Hybridization
A variety of methods well-known in the art can be used for detection of pre-determined sequence variations by allele specific hybridization. Preferably, the test gene is probed with allele specific oligonucleotides (ASOs); and each ASO contains the sequence of a known mutation. ASO analysis detects specific sequence variations in a target polynucleotide fragment by testing the ability of a specific oligonucleotide probe to hybridize to the target polynucleotide fragment. Preferably, the oligonucleotide contains the mutant sequence (or its complement). The presence of a sequence variation in the target sequence is indicated by hybridization between the oligonucleotide probe and the target fragment under conditions in which an oligonucleotide probe containing a normal sequence does not hybridize to the target fragment. A lack of hybridization between the sequence variant (e.g., mutant) oligonucleotide probe and the target polynucleotide fragment indicates the absence of the specific sequence variation (e.g., mutation) in the target fragment. In a preferred embodiment the test samples are probed in a standard dot blot format. Each region within the test gene that contains the sequence corresponding to the ASO is individually applied to a solid surface, for example, as an individual dot on a membrane. Each individual region can be produced, for example, as a separate PCR amplification product using methods well-known in the art (see, for example, the experimental embodiment set forth in Mullis, K. B., 1987, U.S. Pat. No. 4,683,202). The use of such a dot blot format is described in detail in one of the examples below, detailing the Stage I analysis of the human BRCA2 gene to detect the presence or absence of eight different known mutations using eight corresponding ASOS.
Membrane-based formats that can be used as alternatives to the dot blot format for performing ASO analysis include, but are not limited to, reverse dot blot, (multiplex amplification assay), and multiplex allele-specific diagnostic assay (MASDA).
In a reverse dot blot format, oligonucleotide or polynucleotide probes having known sequences are immobilized on the solid surface, and are subsequently hybridized with the labeled test polynucleotide sample.
In a multiplex format, individual samples contain multiple target sequences within the test gene, instead of just a single target sequence. For example, multiple PCR products each containing at least one of the ASO target sequences are applied within the same sample dot. Multiple PCR products can be produced simultaneously in a single amplification reaction using the methods of Caskey et. al., U.S. Pat. No. 5,582,989. The same blot, therefore, can be probed by each ASO whose corresponding sequence is represented in the sample dots.
A MASDA format expands the level of complexity of the multiplex format by using multiple ASOs to probe each blot (containing dots with multiple target sequences). This procedure is described in detail in U.S. Pat. No. 5,589,330 by A. P. Shuber, and in Michalowsky et. al., American Journal of Human Genetics 59(4):A272, poster 1573 (October 1996), each of which is incorporated herein by reference in its entirety. First, hybridization between the multiple ASO probe and immobilized sample is detected. This method relies on the prediction that the presence of a mutation among the multiple target sequences in a given dot is sufficiently rare that any positive hybridization signal results from a single ASO within the probe mixture hybridizing with the corresponding mutant target. The hybridizing ASO is then identified by isolating it from the site of hybridization and determining its nucleotide sequence.
Suitable materials that can be used in the dot blot, reverse dot blot, multiplex, and MASDA formats are well-known in the art and include, but are not limited to nylon and nitrocellulose membranes.
When the target sequences are produced by PCR amplification, the starting material can be chromosomal DNA in which case the DNA is directly amplified. Alternatively, the starting material can be mRNA, in which case. the mRNA is first reversed transcribed into cDNA and then amplified according to the well known technique of RT-PCR (see, for example, U.S. Pat. No. 5,561,058 by Gelfand et. al.).
The methods described above are suitable for moderate screening of a limited number of sequence variations. However, with the need in molecular diagnosis for rapid, cost effective large scale screening, technologies have developed that integrate the basic concept of ASO, but far exceed the capacity for mutation detection and sample number. These alternative methods to the ones described above include, but are not limited to, large scale chip array sequence-based techniques. The use of large scale arrays allows for the rapid analysis of many sequence variants. A review of the differences in the application and development of chip arrays is covered by Southern, E. M., Trends In Genetics, 12:110-115 (March 1996) and Cheng et. al., Molecular Diagnosis, 1:183-200 (September 1996). Several approaches exist involving the manufacture of chip arrays. Differences include, but not restricted to: type of solid support to attach the immobilized oligonucleotides, labeling techniques for identification of variants and changes in the sequence-based techniques of the target polynucleotide to the probe.
A promising methodology for large-scale analysis on xe2x80x98DNA chipsxe2x80x99 is described in detail in Hacia et. al., Nature Genetics 14:441-447 (1996), which is hereby incorporated by reference in its entirety. As described in Hacia et. al., high density arrays of over 96,000 oligonucleotides, each 20 nucleotides in length, are immobilized to a single glass or silicon chip using light directed chemical synthesis. Contingent on the number and design of the oligonucleotide probe, potentially every base in a sequence can be interrogated for alterations. Oligonucleotides applied to the chip, therefore, can contain sequence variations that are not yet known to occur in the population, or they can be limited to mutations that are known to occur in the population.
Prior to hybridization with oligo probes on the chip, the test sample is isolated, amplified and labeled (e.g. fluorescent markers) by means well known to those skilled in the art. The test polynucleotide sample is then hybridized to the immobilized oligonucleotides. The intensity of sequence-based techniques of the target polynucleotide to the immobilized probe is quantitated and compared to a reference sequence. The resulting genetic information can be used in molecular diagnosis.
A common, but not limiting, utility of the xe2x80x98DNA chipxe2x80x99 in molecular diagnosis is screening for known mutations. However, this may impose a limitation to the technique by only looking at mutations that have been described in the field. The present invention allows allele specific hybridization analysis be performed with a far greater number of mutations than previously available. Thus, the efficiency and comprehensiveness of large scale ASO analysis will be broadened, reducing the need for cumbersome end-to-end sequence analysis, not only with known mutations but in a comprehensive manner all mutations which might occur as predicted by the principles accepted, and the cost and time associated with these cumbersome tests will be decreased.

Susceptibility mutation 6495delGC of BRCA2


An ink set includes a cyan ink composition containing C.I. pigment blue 15:6 as a pigment; a magenta ink composition containing a quinacridone pigment selected from the group consisting of C.I. pigment violet 19, C.I. pigment red 122, C.I. pigment red 202, and C.I. pigment red 209, or a quinacridone solid solution pigment formed of at least two selected from the above group; and a yellow ink composition containing a pigment selected from the group consisting of C.I. pigment yellow 74, C.I. pigment yellow 213, and C.I. pigment yellow 185.

1. Technical Field
The present invention relates to an ink set having a wide color reproduction range (gamut), in particular, an ink set having a wide color reproduction range of a blue region in a dark portion and being excellent in color reproduction in other color regions. Furthermore, the invention relates to a recording method using the ink set and a recording apparatus therefor.
2. Related Art
As a color model, a CIE/L*a*b* color system is known. According to the CIE/L*a*b* color system, any color (spectrum) in a visible light region that can be observed by human beings is able to be expressed by chromaticity coordinates.
In three parameters (L*, a*, and b*) of the CIE/L*a*b* color system, L* denotes luminance (brightness) of a color, and a* and b* denote chromaticity representing hue and saturation, respectively. Here, L*=0 means black, and L*=100 means white; a* means the position of a color between red and green, wherein a negative value represents green, and a positive value represents red; and b* means the position of a color between yellow and blue, wherein a negative value represents blue, and a positive value represents yellow. Since the L*a*b* color model is three-dimensional, a color space is expressed by a three-dimensional space, wherein the luminance is shown on the vertical axis.
However, the L*a*b* color model is only an index for conceptually explaining a color space, and the color reproduction range thereof has limitation. That is, for example, in the case that an image is formed on a recording medium using a pigment-based ink or ink set, there is a color that cannot be reproduced by the colors of the L*a*b* color model.
At the same time, ink compositions containing various pigments having high chromogenicity have been proposed. JP-A-2006-282810 discloses that an ink having high chromogenicity and being excellent in ink reliability such as ejection stability, storage stability, and clogging can be obtained by an ink composition containing a quinacridone solid solution pigment, a polyether-modified polydimethylsiloxane compound, and water. JP-A-2007-186641 discloses that an ink excellent in ink reliability such as printing quality, ejection stability, storage stability, and clogging can be realized by an ink composition containing a water-insoluble vinyl polymer, water, and a surface-treated pigment (yellow, magenta, or cyan) that is composed of a solid solution pigment formed of specific two or more pigments and has a hydrophilic dispersing group bonded to the surface thereof.
Incidentally, the color reproduction of a blue region in a dark portion, particularly, a region where the L* value is 20 or less, has limitation. That is, since it is difficult to exhibit chromaticity and saturation when the luminance is low, a color having an L* value of 20 or less and an a* value of 30 or more or a b* value of −75 or less in the CIE/L*a*b* color system, for example, a color of (L*, a*, b*)=(19.4, 30.0, −72.6) or (L*, a*, b*)=(19.4, 37.6, −76.8), cannot be reproduced on an image recording medium with liquid droplets (ink). On the other hand, in an ink set, it is common to reproduce a color in a blue region by mixing a cyan ink composition and a magenta ink composition, a color in a red region by mixing a yellow ink composition and a magenta ink composition, and a color in a green region by mixing a yellow ink composition and a cyan ink composition. Therefore, when the color reproduction in a blue region is extended, it is necessary to simultaneously maintain the color reproduction ranges in other color regions, for example, considering the green region reproduced by a cyan ink composition and a yellow ink composition and the red region reproduced by a yellow ink composition and a magenta ink composition.
Accordingly, the present inventors have conducted intensive studies for extending the color reproduction range of a dark blue region and have proposed in a previous application (Japanese Patent Application No. 2008-215056) that an ink set composed of a combination of an cyan ink composition containing C.I. pigment blue 15:6 or C.I. pigment blue 60 as the pigment and a magenta ink composition containing a quinacridone-based pigment can extend the color reproduction range of a blue region in a dark portion with an L* value of 20 or less, in particular, that an ink set composed of a combination of an cyan ink composition containing C.I. pigment blue 15:6 as the pigment and a magenta ink composition containing a quinacridone solid solution pigment can produce a color having an L* value of 20 or less, an a* value of 30 or more, and a b* value of −75 or less. Such a color could not been reproduced with known ink sets.
However, this time, the inventors have found that C.I. pigment blue 60 contained in the cyan ink composition for extending the color reproduction range of a blue region in a dark portion largely reduces the chromogenicity of a green region.

Ink set, recording method, and recording apparatus


A method for inkjet varnishing a substrate includes the steps of jetting a micro-pattern of a varnish having a viscosity of less than 30 mPa·s at 45° C. and at a shear rate of 30 s−1 to a portion of the substrate by one or more printheads having nozzles with a nozzle diameter of no more than 30 μm, and at least partially curing the micro-pattern within 500 milliseconds after jetting to provide a micro-roughness to the portion of the substrate.

1. Field of the Invention
The present invention relates to methods for applying a varnish by inkjet printing to a substrate, e.g. to a printed image.
2. Description of the Related Art
A varnish is a transparent liquid applied to a surface for producing a glossy appearance. A varnish may also be designed to produce satin or semi-gloss sheens by the addition of "flatting" agents. These flatting agents, also often called matting agents, are particulate substances for scattering incident light rays on the varnished surface. The matting agent particles stand out from the varnish layer, invisible to the human eye. This requires the matting agent particles to have an average particle size of several microns to tens of microns. Such large particle sizes make reliable inkjet printing of a mat varnish impossible since the nozzles of an inkjet printhead generally have a nozzle diameter of about 30 μm or less. The major advantage of inkjet printing is that it allows variable data printing.
US 2006230965 (HEIDELBERGER DRUCKMASCHINEN) discloses an offset printing method wherein a transparent glossy varnish is coated on the entire printed surface of a print using a varnishing unit. In addition a mat varnish containing a high content of silicate matting agent can also be applied if a mat finish is desired. Even if large particle size of matting agents in a varnish would be feasible by inkjet, the use of two varnishes, a glossy and a mat varnish, for controlling the gloss of a print would make an inkjet printer more complex and expensive.
US 2010166975 (MGI) discloses in claims 12 and 13 an inkjet ink including an additive with a granulometry less than 50 μm, wherein the additive includes a flatting agent for obtaining a mat or satin varnish, and/or, flakes for obtaining a flaked varnish, and wherein the inkjet ink has a granulometry suited for passing through a nozzle when ink is deposited by an ink-jet on a printed substrate. There is no practical example disclosed of a mat varnish. However flatting agents having a particle size up to 50 μm implicitly require nozzles diameters in the inkjet print head for reliable inkjet printing being much larger than 50 μm, thereby also drastically reducing the print resolution of the mat varnish and the capability of controlling the gloss of a specific part of a printed image.
US 2006021535 (HEIDELBERGER DRUCKMASCHINEN) discloses a method for radiation curable printing and aftertreating a print, wherein the aftertreatment involves adjusting the level of gloss of the print by applying to the print particles matting the surface of the ink. The particles having a diameter of more than 5 μm are applied using a powdering device having powder nozzles.
Problems with gloss homogenity may be observed when the printing speed increases, such as e.g. in single pass inkjet printing. EP 1930169 A (AGFA GRAPHICS) discloses a UV-curable inkjet printing method using a first set of printing passes during which partial curing takes place, followed by a second set of passes during which no partial curing takes place for improving the gloss homogeneity.
Another method to produce a stripe-free, smooth and highly glossy surface is by using a fast flowing UV varnish. US 2006198964 (HEIDELBERGER DRUCKMASCHINEN) discloses a method for inkjet varnishing of a print, which comprises ejecting varnish drops by an inkjet printer onto a surface of the print, wherein the varnish drops are ejected in a screen pattern. In this way, the required amount of varnish is smaller than when a varnish layer is applied over the complete surface of the print. The screen may be an FM- or an AM-screen. This allows preventing disturbing line structures. Depending on the flow characteristics of the varnish that is applied, a glossy or a matt result may be obtained. To obtain a high gloss level, a UV varnish that has a low viscosity, and that thus flows easily, is used, while a UV varnish that has a high viscosity is used to obtain a matte surface. However, again two varnishes are required for controlling the gloss, including a varnish of higher viscosity which limits the printing speed. In industrial ink jet systems, there is a constant demand for increased printing speeds in combination with high image quality. The new print heads, designed for increasing printing speed, only operate with very low viscous inkjet inks and varnishes.
EP 2228230 A (XEROX) discloses a method of controlling gloss of an image through micro-patterning a radiation curable ink and/or overcoat, i.e. a varnish, by non-uniformly curing the ink and/or overcoat followed by flood curing. The non-uniformly curing of the ink and/or overcoat is achieved by applying radiation through a mesh mask, or by laser curing by means of rastering a continuous wave or pulsed laser. Including such curing means makes the inkjet printer more complex and expensive. The micro-pattern is imparted to the radiation curable ink and/or overcoat by providing micro-roughness to one or more portions of the radiation curable ink and/or overcoat. At least one gellant must be present in the overcoat which results in a solid-like overcoat composition that below 50° C. has a viscosity of about 103 to 107 mPa·s. This not only increases the energy consumption of the inkjet printer but also put some limitations on the type of substrates that can be printed upon due to their thermal sensitivity.
US 2010/0194837 A1 (RICOH) discloses an image recording method includes ejecting an ink to form an image on the surface of a recording layer of a recording medium; and then applying a glossiness imparting liquid on the surface of the recording medium.
GB 2423520 A (SUN CHEMICAL) discloses a sprayable energy-curable coating composition comprising an epoxide monomer or oligomer, a cationic photoinitiator, and a cyclic carbonate, wherein the cyclic carbonate is present in an amount of at least 7 wt. % based on the composition. The sprayable energy-curable coating composition is used as a varnisch formulation;
Micro-roughness refers to surfaces marked by irregularities and/or protuberances imperceptible to normal and unaided human sight and touch, which surfaces are capable of diffuse reflection of light.
Micro-patterning refers to an irregular (e.g. random) or regular patterning of one or more surfaces characterized by micro-roughness.
There is still a need for an improved method of inkjet varnishing a print which is capable of controlling the gloss of a print by using a single varnish of low viscosity that can be printed at high resolution, speed and reliability without the need of any flatting agents.


A TPMS that uses a unique signature, such as RSSI signal levels and statistics or Doppler shift information, to identify the location of where the TPMS signal is being transmitted from. The TPMS includes a separate transmitter unit provided in each tire, where each transmitter unit transmits TPMS signals including an ID code identifying the tire and the pressure in the tire. The TPMS also includes a receiver unit that receives the TPMS signals from each of the transmitter units, where the receiver unit stores an average or other classification of the signature over time to identify the location of the transmitter unit for a particular ID code. The receiver unit compares the new received TPMS signals to the classified signals to identify whether the ID code indicates that the position of the tire has changed.

1. Field of the Invention
This invention relates generally to a tire pressure monitoring system (TPMS) that monitors the pressure and temperature of each tire on a vehicle and, more particularly, to a TPMS that monitors the pressure and temperature of each tire on a vehicle and uses a received signal strength indicator (RSSI) or Doppler shift information available from the received signal to identify which tire is transmitting the signal that is received by a receiver.
2. Discussion of the Related Art
All new vehicles manufactured and sold in the United States are required to have a tire pressure monitoring system (TPMS) that monitors the pressure and temperature of the tires on the vehicle. Typically, the TPMS is an active system that includes its own power source, such as a battery, and a processor for processing data. The TPMS includes a suitable pressure sensor that measures the pressure within each tire and a suitable temperature sensor that measures the temperature within the tire. Sensor signals from the pressure and temperature sensors are sent to the processor in each tire, which conditions and encodes the data and the encoded signals are then modulated onto a carrier wave to be transmitted by an antenna as a TPMS signal. The TPMS signals transmitted from each tire are received by a receiver at a suitable location within the vehicle, where the received data is demodulated, decoded and used to determine whether a warning signal should be given that the tire pressure is too high or too low, or the tire is too hot.
In one known TPMS, sometimes referred to as a low-line system, each tire transmits the TPMS signal including the pressure and temperature information to a single receiver located at a desirable position on the vehicle, where the TPMS signal includes an identification (ID) code that identifies the tire. During manufacture of the vehicle the TPMS algorithm is programmed so that the receiver knows the location of the tire for a particular ID code, i.e., right-front, left-front, right-rear or left rear. If the vehicle owner rotates the tires or replaces one of the tires with the spare tire, the particular tire or tires are now not in their original location, but the receiver will process the TPMS signals thinking that the tires are in their original position. In this situation, if a warning signal is given that a particular tire is under inflated, the vehicle operator may provide air to the wrong tire, possibly over inflating it.
Currently, on these types of systems, it is necessary for the vehicle owner to take the vehicle to a dealer or service center to retrain the TPMS to identify the new location of the tires on the vehicle if the original location of the tires is changed. Particularly, a technician will put the TPMS into a learn mode through a diagnostic interface on the vehicle, and position a tool including a magnet near the valve stem of each tire, which causes the processor in that tire to transmit its ID code to be received by the receiver. While in the learn mode, the technician will cause the processors in each tire to send the TPMS signal in a certain order so that the receiver relearns the location of which tire is associated with which ID code. Currently, with this type of system, there does not exist a technique where the vehicle owner can readily cause the TPMS to relearn the position of the tires if they are changed.

Low line TPMS: sensor association using RSSI and doppler signatures with a single or multiple ECUs


A device for sensing ammonia (NH.sub.3) and nitrogen oxide (NO.sub.x) gases comprising: a sensor for detecting said ammonia and said nitrogen oxide gases, said sensor including a substrate and a layer consisting of cuprate material for detection of said ammonia and said nitrogen oxide gases, wherein said layer of cuprate material is selected from the group consisting of Y:Ba:Cu:O (YBCO) and Bi:Sr:Ca:Cu:O (BSCCO); a sensor holder for supporting said sensor; a perforated cap positioned over said sensor, said perforated cap having openings for passage of said ammonia and said nitrogen oxide gases to said sensor; a detection circuit communicating with said sensor for measuring output from said sensor; and a display or recording device connected to said detection circuit for displaying or recording a concentration of said ammonia and said nitrogen oxide gases based on the output from said sensor.

The extensive pollution problems in modem industrialized societies are adversly affecting our health and environment. Ever increasing industrialisation and number of automobiles make it absolutely necessary to constantly monitor and control air pollution in the environment. In many industries gases have become increasingly important as raw materials. Therefore, it has become very important to develop highly sensitive gas sensors and systems to prevent accidents and air pollution due to gas leakage. As a result, new and powerful research areas have emerged in our battle for awareness and environmental and health monitoring. The research and development of solid state gas sensor is one such area. Such sensors should allow continuous monitoring of the concentration of particular gases in the environment in a quantitative and selective manner.
Solid state gas sensors use an appropriate material, either in bulk form or in thick or thin film form as gas sensing element. The working principle for gas detection of these sensors is based on change in i) work function; ii) resistance iii) dielectric constant and or iv) mass of the sensing element due to adsorption of a gas. The resultant change in any one of these properties is measured to determine the presence and percentage of the gas in the ambient. Most of conventional sensors employ bulk or thick films of a gas sensing material.
However, in recent sensors, thin films are used as modern thin film preparation techniques give better control on gas sensing properties of a material.
Hitherto known gas sensors based on thin films of materials are of three kinds. First, metal oxides such as SnO.sub.2, ZnO, Ga.sub.2 O.sub.3 etc. (Taguchi: UK Patent 1280809, Mosely: Sensors & Actuators, B 6, 1992). Second, catalytic metals like Pd and Pt (I. Lundstrom et. al: Appl. Phys. Letts. 26, 1975, Sh. Kaihatsu: JP 1213563 A) and third, a special class of organic materials such as Phthalozyanine, Polypyrol u. a. (P. M. Burr et.al: Thin-Solid Films, 151, 1987, M. Josowicz: "Organic semiconductors as chemical sensor materials", Habilitation Universitat der Bundeswehr Munchen). The working principle for gas detection of most of these sensors is based on change in work function of the thin films, due to adsorption of a gas which in turn produces electrical signal. This signal is measured for qualitative and quantitative detection of a particular gas under test in the ambient. However, for the first type of sensors i.e. metal oxide based gas sensors, energy is needed for chemo-physical reactions on the sensing layer. This is achieved by heating the sensitive layer. Therefore, operating temperature of metal oxides based sensors is few hundred degree celsius e.g. from 300.degree. C. to 1000.degree. C. Reference may be made to (i) UK Patent 1280809--A. Mandelis (ii) C. Christofides: A Series of monographs on Analytical Chemistry and its Applications, ed. J. D. Winefordner, Vol. 125, John Wiely & Sons, INC. N.Y. 1993, Chapters 1 to 3 & Refs. there in, and (iii) M. Fleischer et. al. Sensor & Actuators B 25-27, 1995. The sensitivity, selectivity and dynamic response of these metal-oxide based sensors are temperature dependent and this necessitates them to operate at elevated temperatures. To realize these sensors, a heater is provided to heat the sensing film. Generally a thin film heater is fabricated on the back side of the sensing film and electrical power is supplied to it to achieve the desired temperature. Additionally, a temperature sensor is also required to be incorporated with the gas sensor to control the power to regulate the temperature of the sensor. Therefore, a heater and a temperature sensor are integral components of a gas sensing system based on metal-oxide sensors. In this way, heating requirement of the sensor makes fabrication technology and design of the sensing system very complex. It also necessitates thermal isolation between the sensor and the measurement circuit. Further, sensitivity of these sensors is critically dependent on film structure and its preparation technique (Peschke, M. et.al, sensors & Actuators B1, 21, 1990, Peschke, Ph. D. Thesis, 1990, Universitat der Bundeswehr Munchen, A. Mendelis and C. Christofides: Ref. above). The high temperature requirement of these sensors precludes their applications to battery operating equipments. Although application of catalytic metals films like Pt and Pd in FET or CCFET (Capacitive controlled FET) gas sensors has demonstrated room temperature operation (I. Lundstrom et. al, Sensors & Actuators Al, 1981 and Gergintschew, Z., Kornetzky, P., Schipanski, D., Patentschrift DE 433875 At.) but such ammonia gas sensors suffer from a drawback of their cross-sensitivity to hydrogen and hydrocarbon based gases. In addition to poor selectivity, metal film sensors also exhibited ageing effects (K. Dohos et.al Sensors & Actuators 4, 1983). Thus, despite of possibility of room temperature operation, these sensors have not yet became popular due to selectivity problem. For some special applications, the organic materials films are highly sensitive and selective but life time of organic film sensors is limited. Additionally organic materials films are not compatible to micro-electronic fabrication technologies and therefore, are not suitable for large scale production. In brief, the gas sensors known to date either can operate at elevated temperatures or suffer from selectivity problem.

Device useful for sensing ammonia and nitrogen oxides(s) gases at room temperature

Council of Scientific and Industrial Research


A construction tool has a tape measure. A handle is coupled to the tape measure. The handle allows a user of any size or shape hand to comfortably and easily use the tape measure.

In the construction industry, many different tools are used. In general, the construction worker will carry a number of these different tools on a tool belt which is coupled to the waist of the worker. One tool a construction worker may carry is a tape measure device. Tape measure devices typically comprise a flexible tape resiliently coiled within a housing. The tape is normally printed with incremental measuring marks for measuring distances. In use, the flexible tape is uncoiled and extended from the housing and placed on a surface to be measured. Distances can then be marked with a separate marking tool, such as a pencil, directly onto the surface measured.
Present tape measure devices have several problems. First, present tape measure devices fail to take into account the hand size of the user. Most tape measure devices are rather large and bulky in size. Because of the large size of these devices, these types of tape measure devices are difficult to handle. Furthermore, because of the large and bulky nature of these types of tape measure devices, it is difficult to use the locking switch which locks and releases the flexible tape. In present tape measure devices, the locking switch is positioned in the front of the tape measure device. For a person with small hands, it is difficult to use a large tape measure device and push the locking switch positioned in the front of the tape measure device. A further problem with current tape measure devices is that it is difficult to read the markings on the tape measure when used in confined or poorly lit areas.
Another device commonly used by construction workers is a chalk line marking device. A chalk line-marking device employs a chalk line that is wound up around a spool housed within a case. During use, the chalk line is extended and held taut near the surface to be marked. Typically, this requires two workers—one to hold the end of the chalk line and one to hold the case. The line is then grasped and released by one of the workers so that it snaps back toward the surface, thereby depositing a chalk line. Alternatively, one worker may devise a way to secure one end of the line using a weight or the like. In any event, the procedure is inconvenient. A handle is attached to the spool to allow the line to be wound back into the case after use.
The problem with present chalk line marking devices is that these devices are awkward and bulky in design. Construction workers are forced to use certain awkward hand positions in order to effectively hold and use present chalk line marking devices. Furthermore, present chalk line marking devices takes up additional space on an individual's tool belt. Space on the tool belt is required not only for the chalk line marking device, but also for bottles of chalk dust to be used in the chalk line marking device.
Therefore, a need existed to provide a device to overcome the above problem. The device must be less bulky and easier to handle then current construction tools. The device must further save space on a tool belt of a user.

Tape measure having a handle and a removable chalk line marker and method therefor


The invention provides an enclosure assembly configured to enhance accessibility to a drive unit of an agricultural applicator. The enclosure assembly generally includes a first panel and a second panel pivotally connected to the enclosure assembly and moveable between closed and open positions. In the closed position, the first panel is positioned in general alignment with the second panel. The enclosure assembly also accommodates an exhaust outlet extending upward from the drive unit. The forward end of the first panel includes a first cutout portion and the rearward end of the second panel includes a second cutout portion each configured in the closed position to receive the exhaust outlet. From the closed position, the first panel pivots in a rearward direction and the second panel pivots in a forward direction, relative to the forward direction of travel, to access the drive unit.

Numerous types of agricultural applicators are available today. These can include a pull type unit or a self-propelled unit. A certain known agricultural applicator is also referred to a "floater." The floater is a large vehicle that uses large, oversized floatation tires to carry the vehicle across firm to muddy agricultural environments. The chassis assembly of the floater generally includes three or more floatation tires. One particular chassis assembly includes a pair of rear floatation tires and a pair of front floatation tires. The chassis assembly is configured to support one or more bulk storage tanks or bins of product for application in an agricultural environment, usually before planting in the spring or after harvest in the fall. The types of agricultural products e.g., fertilizer, herbicide, pesticide, nutrients, etc. can vary. The floater can also be utilized to tow various agricultural implements. The oversized-tired agricultural applicators are generally desired for their ability to maneuver heavy loads over extremely rough and difficult agricultural terrain with minimal soil compaction.
However, these floater-type of agricultural applicators have drawbacks. For example, certain known floater-type agricultural applicators include an enclosure for a drive unit mounted toward a rearward end of the chassis assembly and behind a cab relative to a forward direction of travel of the agricultural applicator. A raised platform or walkway is provided from the cab to the drive unit enclosure. The drive unit enclosure typically includes a single-piece hood operable to open and provide access to the drive unit. The single piece hood generally does not provide adequate access to routine service points (e.g., air filter, oil level dipstick, engine valve backlash, etc.) of the drive unit. In addition, the single-piece hood generally extends the length of the drive unit and therefore is too heavy and cumbersome for a single person to move between a closed position and an open position.
U.S. Publication No. US 2003/0051931 to Johansson et al. discloses an engine housing for a motor mounted on a forward vehicle section. The engine housing includes a vertically aligned door and grille extending the height of the forward vehicle section. The door is pivotally attached about a lower horizontal end by a hinge arrangement disposed adjacent to the lower end of the motor. The inside of the door includes a pair of girders and steps mounted thereon operable in an open position to provide a ladder for accessing the motor. The door further includes a pair of locking devices mounted on each side of the hood and a structure of steps mounted on the hood. As with other known enclosures, the Johansson et al. vertical door and the structure of steps mounted thereon is heavy and cumbersome for a single person to move when accessing or servicing the motor.
U.S. Pat. No. 6,508,323 to Burgo discloses a hood for an earthmoving machine. The hood includes a front panel and a pair of side panels that extend the longitudinal length of the drive unit relative to a forward direction of travel of the machine. Again, the Burgo hood does not provide ready access to routine service points (e.g., air filter, oil level dipstick, engine valve backlash, etc.) of the drive unit, and the hood is of a length that is heavy and cumbersome to move between an open and closed positions.
Thus, there is a need for an enclosure for a drive unit configured to enhance ease of access to routine service points of the drive unit, and that is operable for a single person to readily move between an open and closed positions.


A foldable SIM card connector includes a body, a cover pivotally assembled with the body and a plurality of terminals received in the body. A rear portion of the body defines a beam, a rejecting portion and a pair of stop arms. A rear portion of the cover forms a resisting board, a pair of stop boards and a pair of stop edges. While the cover is opened to a certain angle, the resisting board is located below and pressed against the beam of the body. The stop board is located behind and presses against the rejecting portion of the body. Besides, the stop arm contacts the stop edge of the cover. These mechanisms avoid the cover pressing the edge of the fixing cavity of the mobile phone, and further prevent the cover from being propped up and falling off.

1. Field of the Invention
The present invention relates to a foldable subscriber identity module (SIM) card connector, and particularly to a foldable SIM card connector with mechanisms to avoid the falling off of the cover.
2. The Related Art
A foldable subscriber identity module (SIM) card connector is commonly used in electric devices such as mobile phone. A SIM card usually includes a terminal module to communicate with an identifying device. Accordingly, the SIM card connector includes a receiving cavity to receive the SIM card and a plurality of terminals to couple with the terminal module of the SIM card. While the SIM card is inserted into the receiving cavity of the SIM card connector, the terminals of the SIM card connector communicate with the terminal module of the SIM card to achieve the communication between the SIM card connector and the SIM card.
A traditional foldable SIM card connector includes a body, a cover, and a plurality of terminals received in the body. The cover defines a receiving cavity to receive the SIM card. One end of the terminal connects with the SIM card. The other end of the terminal connects with an external printed circuit board (PCB). The body defines a pair of pivoting holes. Coupling with the pivoting holes, the cover defines a pair of pivots. The pivots of the cover are pivotally fixed in the pivoting holes of the body. The cover can be closed and opened around the pivots.
However, the foldable SIM card is usually fixed in a fixing cavity defined on an inside surface of the mobile phone. While the foldable SIM card is closed, the top surface of the cover and the inside surface of the mobile phone are seated on the same plane. This means that, while the cover is opened to a certain angle, the edge of the fixing cavity becomes a fulcrum to the cover. While the cover is opened surpass this certain angle, the pivots of the cover are easily propped up and moved out of the pivoting cavities of the body which leading to the cover falling off the body.


The present invention discloses processes for oligomerizing a monomer containing internal olefins using a solid acid catalyst. Illustrative monomers can contain at least 50 wt. % C6 to C24 internal olefins.

The present invention relates generally to processes for oligomerizing olefins using a solid acid catalyst. In certain oligomerization processes, the solid acid catalyst can experience rapid catalyst deactivation, leading to relatively short catalyst lifetimes. It would be beneficial to develop oligomerization processes where catalyst lifetimes prior to deactivation are significantly improved. Accordingly, it is to this end that the present invention is directed.


System that automatically captures, processes, archives, reports on and distributes data for any computerized equipment at a facility. A single data repository is provided so any authorized user connected to the company/facility network can query secure data. Once data is collected it is batched or grouped according to user-defined rules. A batch is given a distinct number to identify the data. Data is automatically analyzed in near real-time utilizing user-defined modeling code. This code can be simple or complex as needed to compare the batch data against an ideal model. Users can view or trend data and access reports including adding electronic signatures. Additional process information such as standard operating procedures and cycle descriptions may be uploaded and attached to a batch. Any action a user performs that creates, modifies or deletes data in the data repository is audited.

The present invention was created as a solution to the problems commonly associated with batching, analyzing and viewing data from computerized and process control systems used in the manufacture of pharmaceutical products. Users were required to manually retrieve the data they wished to analyze and then perform complex, time-consuming and error-prone analyzation on that data. Often, different departments required different analyzation reports, further adding to an already complex situation. In some cases, quality issues were not found until weeks later, causing entire product lines to be scratched, and increasing costs.
The present invention consists of modules that allow for the customized batching, analyzation and viewing of data. By linking desktops with critical manufacturing and quality information from across an entire operation, many benefits can be achieved. Users can instantly discern the quality disposition of a batch or process run within seconds. Batch quality can be improved by automatic comparison of process data against recipe requirements, quality attributes and equipment specifications. Available in near real-time, analysis creates department-specific reports for each process and generate run summary data, useful for comparing and analyzing the critical process parameters in a given cycle for a specific piece of equipment over time. Department-specific reports allow each individual unit within the organization the ability to look at the same information, but displayed against the criteria specific to their individual needs. Slowly decaying equipment performance can be found in a matter of minutes by performing statistical analysis on historical data.

Method of batching and analyzing of data from computerized process and control systems


A memory stores data in a first-in-first-out order and associatively matches an incoming datum with the stored data. The stored data includes a first datum and a second datum stored following the first datum. The memory includes a data storage cell which comprises a memory cell coupled to a bit line and a word line. The memory cell stores the first datum. The memory cell can be accessed through the bit line and the word line for read and write operation. The memory cell includes a first half and a second half connected to each other. An exclusive NOR gate circuit is coupled to an output of the memory cell and the bit line for associatively comparing the first datum stored in the memory cell with an incoming datum along the bit line. The exclusive NOR gate circuit outputs a match signal when the incoming datum matches the first datum. A transistor circuit is coupled to the memory cell for disconnecting the first half from the second half under the control of a control signal coupled to the transistor circuit such that the first half retains the first datum and the second half is freed to receive the second datum through a pass transistor. When the transistor circuit connects the first half and the second half into the memory cell under the control of the control signal, the memory cell then stores the second datum. The data storage cell preserves the first-in-first-out order of the memory when the first datum is taken out of the data storage cell. The associative memory formed by a plurality of the data storage cells is also described.

In the field of supercomputer development, efforts have been made to develop various types of high speed computers that can deliver extremely high levels of performance. One type of such high speed computers employ a data flow concept and are therefore referred to as data flow computers.
Data flow computers have architectures that are completely different from the architectures of conventional control flow computers. In a data flow computer the sequence in which instructions are executed (i.e., instruction sequencing) is solely based upon the availability of data. In other words, an instruction is enabled or executed when all of its operands are available. This is in contrast to a typical control flow computer in which instructions are executed when "pointed to" by the contents of a centralized program counter. The flow of control travels from one instruction to the "next" instruction as directed by the program counter in the control flow computer. In a data flow computer, however, the flow of control is exactly the path that the data travels.
Another aspect of the data flow computer is that there is no concept of storage or memory for variables in the data flow computer although some form of storage is still provided. The elimination of the storage prevents the use of shared variables. This restriction thus keeps the instruction sequencing tied solely to data dependency and independent of any time ordering.
Various models have been developed for data flow computers. One prior model of data flow computer employed a tagged token data-flow architecture ("TTDA"). In a prior tagged token data flow TTDA computer, data is carried in the form of a token. Each token is tagged with an identifier that indicates its logical ordering. Instruction sequencing is determined by associatively matching data-bearing tokens in a waiting-matching unit. In the prior TTDA computer, a waiting-matching unit (i.e., W-M unit) is provided in each of a plurality of processing elements (i.e., PEs). The W-M unit is an associative memory with a controller. The W-M unit matches tokens with identical tags and stores tokens whose mates have not yet arrived. When an incoming token arrives at a W-M unit of a PE, the tag of the token is associatively compared with all the previously unmatched tokens stored in the W-M unit. If the tag of the incoming token matches the tag of a stored token, the stored token is extracted from the associative memory and the data portions of both matching tokens are delivered to an arithmetic logic unit ("ALU"). The storage location in the associative memory for the matching stored token is then free to store another incoming token. If a match does not occur for the incoming token, the token is then stored in the W-M unit.
The W-M unit typically needs to have relatively large storage capacity. This is due to the fact that a token stored in the W-M unit is removed only when matched to an incoming token. If the W-M unit becomes completely filled with unmatched tokens, the computer will immediately deadlock.
The speed of the W-M unit should typically match the computation speed of the ALU in order not to cause the ALU to wait for matched token pairs. Since the most often executed arithmetic instructions typically require two operands, the speed of the W-M unit is required to be twice of that of the ALU.
FIG. 1 illustrates a prior content addressable and reentrant memory (CARM) cell 10 used in the associative memory of a prior waiting-matching unit of a data flow computer. Typically, the associative memory of the prior W-M unit includes a plurality of such CARM cells arranged in an array. The unmatched tokens are stored initially in an ordered sequence. Once a match occurs, the matched token is fetched out and its memory location is freed to store a next unmatched incoming token. This action destroys the time ordering of the stored tokens. The associative memory is content addressable.
In FIG. 1, transistors 11 through 16 form a random access memory (RAM) cell 25. Transistors 11 and 12 are P-channel transistors and transistors 13-16 are N-channel transistors. Transistors 17 through 20 form a CMOS exclusive NOR gate circuit 27. RAM cell 25 is coupled to a word line 28 and bit lines 24 and 26. Bit lines 24 and 26 are driven in a complementary fashion. Exclusive NOR gate circuit 27 is coupled to a sense line 22 and to RAM cell 25. Exclusive NOR gate circuit 27 is used to perform the bit-wise associative comparison.
During a typical read or write operation, CARM cell 10 operates as a typical RAM cell. Word line 28 is asserted and bit lines 24 and 26 are sensed or driven to read or write RAM cell 25.
During an associative comparison, sense line 22 is charged to the power supply Vdd potential. Bit lines 24 and 26 are driven from a data register (not shown) by a bit of a data as in a write operation. Word line 28 is, however, kept at logical low voltage, thus turning off transistors 15 and 16. This preserves the content stored in cell 25 during the associative comparison. If the content stored in cell 25 does not match the bit information driven on bit lines 24 and 26, either transistors 17 and 19 or transistors 18 and 20 of exclusive NOR gate circuit 27 conduct to discharge sense line 22 to ground. If a match occurs, sense line 22 maintains the Vdd voltage.
When a match occurs for all cells along word line 28 driven by all bits of a data stored in the data register, sense line 22 maintains the Vdd voltage. This indicates a match between the data in the data register and the data word along word line 28. The address of the matching data word is then applied to external circuitry.
Disadvantages are however, associated with the W-M unit of a data flow computer employing the prior CARM cells. One disadvantage associated is that the prior associative memory comprising the CARM cells does not maintain the FIFO logic ordering of the stored tokens upon a successful associative comparison operation. When an incoming token is associatively matched with a stored token in the prior associative memory, the stored token is fetched out for execution with the incoming token and the location is freed to store other incoming tokens that have not found their mates in the associative memory. When an unmatched incoming token is stored in that location, the FIFO ordering of the stored tokens is therefore destroyed.
In order to maintain the FIFO ordering of the remaining stored tokens in the W-M unit, the prior associative memory would need to reorganize the remaining stored tokens after each successful associative matching operation. This would involve the operation of shifting the next succeeding younger token into the freed memory location. The same shifting process repeats until there is no freed memory location between two stored tokens. This takes a large amount of time when the storage capacity of the associative memory is relatively large, which in turn slows the speed performance of the W-M unit.
Another disadvantage of the prior associative memory is its need to output the address of the matched data values, not the data values associated with the matched token. This necessitates another random access memory be used to hold the data values. This typically incurs further delays in receiving the matched data values because of the additional access time of the second memory and of delays caused by device input and output buffers.

Data flow computer with an articulated first-in-first-out content addressable memory


The invention provides a recording apparatus capable of preventing deterioration of printing quality likely to be caused by ink ribbon creases. The recording apparatus uses a replaceable ink ribbon cartridge which has an ink ribbon wound on a take-up spindle and a feed spindle. A take-up spindle support section rotatably supports the take-up spindle when the ink ribbon cartridge is mounted in a specific position. The recording apparatus is further provided with a displaceable retaining member displaceable between a first position, for holding the take-up spindle between the take-up spindle support section and the retaining member to restrict the displacement of the take-up spindle, and a second position, for permitting movement of the take-up spindle into the take-up spindle support section.

1. Field of Invention
The invention relates to a recording apparatus for printing by the use of an ink ribbon cartridge mounted with a replaceable wide ink ribbon.
2. Description of Related Art
When a thermal printer is used to print on ordinary paper, generally a ribbon cartridge is used because of easy handling. When the thermal printer is a line printer, it is necessary to use a wide ink ribbon.
The wide ink ribbon, when used, is likely to crease. A crease in the ink ribbon adversely affects printing quality, and therefore it is desirable to prevent crease occurrence. To ensure this, it becomes necessary to provide a proper amount of tension to the ink ribbon between the press roller for pressing the recording paper and the ink ribbon to the recording surface of the print head and the take-up spindle of the ink ribbon. In earlier embodiments during development if such a tension was applied, however, the take-up spindle rose, resulting in a creased ink ribbon.
That is, the take-up spindle of the ink ribbon was provided on the ribbon cartridge side, and was supported by the take-up spindle support section on the casing body side when the ink ribbon cartridge was mounted in a specific position in the casing body. In this case, however, it was necessary to allow the take-up spindle to advance into the take-up spindle support section on the casing body side. Such a structure can not preclude the rise of the take-up spindle. The rise of the take-up spindle, even if as little as about 0.2 mm, resulted in serious damage to the printing quality, particularly when the take-up spindle is made of paper and a synthetic resin to reduce manufacturing costs, the take-up spindle, being light in weight, presents a serious problem.
However, in this earlier laboratory prototype recording apparatus, no special measures were adopted to prevent the rise of the take-up spindle and a sufficient tension to restrain the rise of the take-up spindle was applied to the ink ribbon. The structure can not fully restrain the occurrence of ink ribbon crease, resulting in a deteriorated printing quality.

Ink ribbon cartridge retention device for a recording apparatus


A small motor holding device in an individual Stalling receiver is designed, in which, even when the casing is shocked, the small motor is scarcely shocked, and vibration informing of the reception of a calling signal is transmitted positively to the casing, and which can be assembled with high work efficiency. A small motor is held in a motor holder of elastic material. The motor holder is coupled to a printed circuit board with the engaging section of the motor holder engaged with the engaging/receiving section of the printed circuit board. The motor holder is detachably press-fitted in a holding frame which is fixedly formed on the inner surface of a casing.

This invention relates to a small motor holding device in an individual calling receiver.
When an individual calling receiver receives a calling signal, it produces a sound to inform the bearer of the reception of the calling signal. However, the production of the sound may bother people around the receiver. In order to overcome this difficulty, an individual calling receiver has been proposed which produces vibration instead of sound. The receiver which produces vibration is designed as follows: An eccentric weight is mounted on the rotary shaft of a small motor. That is, upon reception of a calling signal, the small motor is turned to vibrate. The vibration is transmitted to the casing to inform the bearer of the reception of the calling signal.
Heretofore, in an individual calling receiver of this type, a small motor is inserted into a holder of elastic material such as rubber, and the holder is set on a printed circuit board, and is fixedly held with the inner surfaces of the upper and lower casings, or a small motor is directly mounted on a printed circuit board to vibrate the casing through the printed circuit board.
However, the individual calling receiver in which the small motor is directly mounted on the printed circuit board suffers from the following difficulties: For instance when it is dropped; that is, the casing holding the printed circuit board is shocked, the motor body is liable to be shocked. Hence, the motor is liable to be deteriorated in performance, so that the vibration is unstable.
In the individual calling receiver in which the small motor is inserted into the holder of rubber, and the holder is set on the printed circuit board, and is fixedly held with the inner surfaces of the upper and lower casings, the small motor is held by the upper and lower surfaces only. Hence, it is rather difficult to transmit the vibration positively to the casing. If it is tried to insert the motor into the casing together with the printed circuit board, since the rubber holder is held unstable, the assembling work of the receiver is low in efficiency.

Small motor holding device in individual calling receiver

Matsushita Electric Industrial Co., Ltd.