The purpose of this study was to identify the periodontal regeneration factors in enamel protein shown to induce cementum- and osteo-promotive activities in vivo. The cementum regeneration (CR), a part of periodontal regeneration, was examined by using experimental cavities prepared in a buccal dehiscence dog model. The CR activity was found in the aggregate consisted of sheath proteins along with a small amount of amelogenins separated from newly formed secretory enamel. The sheath proteins were purified to be homogeneous, and examined for the alkaline phosphatase (ALP) inducing activity of human periodontal ligament (HPDL) cells. Application of 17 kDa sheath protein induced ALP activity in HPDL cells. Peptides synthesized from the sheath protein sequence also showed ALP inducing activity. The 17 kDa sheath protein has cell differentiation activity.

1. Field of the Invention
The present invention relates generally to the field of periodontal tissue regeneration, and particularly concerns the treatment of diseases related to periodontitis and periodontal disease. The invention provides 17 kDa sheath protein and its derived peptides, which have cementum regeneration promoting activity and are involved in periodontal regeneration and cytodifferentiation of periodontal ligament cells. Also disclosed are the methods for isolating other enamel matrix proteins, and various therapeutic methods using the compositions of the invention.
The invention provides a cementum regeneration promoting protein segment comprising an isolated, synthesized and recombinant sheath protein, polypeptide, or peptide. In certain embodiments of the present invention, the sheath protein is a porcine sheath protein. In other embodiments of the present invention the sheath protein is a human, murine, rat, bovine, sheep, monkey and every mammal sheath protein.
As used herein in the context of various of the instant compositions and methods, the term "protein" will be understood to mean a proteinaceous segment that is longer than about 150 contiguous amino acids and in most aspects comprises more than about 70% of the amino acids encoded by a gene. As used herein in the context of various of the instant compositions and methods, the term "polypeptide" will be understood to mean a proteinaceous segment that is longer than about 50 contiguous amino acids in length, and the term "peptide" will be understood to mean a proteinaceous segment that is between about 3 and about 50 contiguous amino acids in length. Thus sheath protein proteinaceous segment of varying overall length that retain signaling, regulatory and structural properties and functions are provided herein.
As used herein in the context of various of the instant compositions and methods, the term "sheath protein" or the term "sheathlin" will be understood to include wild-type, polymorphic and mutant versions of sheath protein or sheathlin sequences. Wild-type sequences are defined as the first identified sequence; polymorphic sequences are defined as naturally occurring variants of the wild type sequence that have no effect on the expression or function of the sheath protein or sheathlin proteins, polypeptides, or peptides or domain thereof; and mutant sequences are defined as changes in the wild-type sequence, either naturally occurring or introduced by the hand of man, that have an effect on either the expression and/or the function of the sheath protein or sheathlin proteins, polypeptides or peptides or domains thereof. The invention thus also includes the provision of DNA segments vectors, genes and coding sequence region that encode various forms of sheath protein or sheathlin proteins, polypeptides, peptides or any fusion protein, polypeptides or peptide thereof.
As used herein in the context of various of the instant compositions and methods, the term "cementum regeneration promoting protein" will be understood to include the proteins, polypeptides and peptides containing amino acid sequences shown a cementum regeneration promoting activity in sheath protein sequences. Wild-type sequences are defined as the first identified sequence; polymorphic sequences are defined as naturally occurring variants of the wild type sequence that have no effect on the expression or function of the sheath proteins, polypeptides, or peptides or domain thereof; and mutant sequences are defined as changes in the wild-type sequence, either naturally occurring or introduced by the hand of man, that have an effect on either the expression and/or the function of the sheath proteins, polypeptides or peptides or domains thereof. The invention thus also includes the provision of DNA segments vectors, genes and coding sequence region that encode various forms of sheath proteins, polypeptides, peptides or any fusion protein, polypeptides or peptide thereof.
The sheathlin (Hu et al., 1997a) is the parent protein of sheath protein (Uchida et al., 1995) which is named as it is accumulated to the enamel sheath of immature enamel to reveal honeycomb pattern on immunohistochemical detection. The sheath protein is firstly found to be 13 kDa˜17 kDa non-amelogenin protein in newly formed enamel of pig (Fukae and Tanabe, 1987a). The sheathlin is degraded at early stage of development into three peptides, 17 kDa sheath protein, 25 kDa acidic protein and Ca binding protein (Fuake and Tanabe, 1987b).
Various therapeutic methods using the compositions of the invention contains the application for not only periodontal ligament regeneration, cementum regeneration and alveolar bone regeneration against periodontal disease and periodontitis, but also implant of artificial material like tooth and replantation of extracted tooth.
2. Description of Related Art
The enamel matrix proteins (enamel matrix derivatives: EMD) are used for repairing the periodontal ligament of periodontitis as one of the periodontal regeneration remedy. It is well accepted that the enamel matrix proteins have the periodontal regeneration activity (Hammarström 1997, Hammarström et al., 1997). Nevertheless, the final periodontal regeneration which gratifies patient's desires is not always accomplished. In addition there is a risk of infection of E type or unknown virus, since the extract from porcine immature enamel matrix is used for the remedy for clinical treatment, although the risk is at present avoided by heating the enamel matrix proteins before preparing the remedy. Another risk is that immunity from EMD for repeat application to the same patient is not always denied, although clinical safety of EMD is reported (Zetterström et al., 1997). The biggest problem is at present scarce information about periodontal regeneration promoting factor, because the enamel matrix proteins are consisted of multi components.
Enamel Matrix Proteins
There are in the enamel matrix three enamel matrix proteins and two proteolytic enzymes. The cDNA and derived amino acid sequences of these proteins and proteinases have been revealed by previous studies. In addition, two growth factors are found to be in porcine secretory enamel matrix.
The structural proteins are amelogenin, (Fukae et al., 1983; Snead et al., 1985; Shimokawa et al., 1987), enemelin (Fukae et al., 1993; Fukae et al., 1996; Hu et al., 1997b), and sheathlin (ameloblastin/amelin) (Cerny et al., 1996; Krebsbach et al., 1996; Hu et al., 1997a). In the developing enamel matrix, enamel matrix serine proteinase (EMSP) (Fukae et al., 1977; Tanabe 1983; Tanabe et al., 1996; Simmer et al., 1998) and a novel metalloproteinase (enamelysin) (Bartlett et al., 1996; Fukae et al., 1998) are cloned and characterized. It is confirmed in porcine enamel matrix the existence of osteogenetic growth factors which are bone morphogenetic factor (BMP) and transforming growth factor (TGF)-β (Suzuki et al., 2005).
Therefore, the immature enamel matrices throughout several developing stages contain a lot of amelogenin, sheathlin and enamelin derivatives. If the purification of specific protein was performed from enamel matrix protein fraction, the purification is interrupted by the causes of a lot of amelogenin gene products and their derivatives, and their aggregation nature.
Amelogenin
Amelogenins are abundant throughout the developing enamel matrix, and have an aggregation nature in solution. They aggregate to form a precipitate in neutral pH at room temperature and reversibly change their phase into the solution at lower temperature. Protein chemical analyses suggest that apparent molecular weights of 25 kDa amelogenin, one of uncleaved amelogenin polypeptides (Fukae et al., 1980; Uchida et al., 1991) is most abundant in the porcine gene products along with 27, 18 and 6.5 kDa amelogenins produced by splicing of amelogenin mRNA (Yamakoshi et al., 1994; Hu et al., 1996; Ikawa et al., 2005).
In newly formed enamel porcine 25 kDa amelogenin is converted by the cleavage of C-terminal hydrophilic domain with the action of enamelysin into 20 kDa amelogenin, and then in advanced developmental secretory enamel the 20 kDa amelogenin is splitted out into two fragments of 6 kDa and 13 kDa amelogenins by the action of the other proteinase EMSP (KLK4). The 13 kDa amelogenin is soluble in neutral solution and disappears from the system to produce the space for crystal growth during the secretory stage enamel.
Sheathlin
Sheathlin has 65 kDa molecular mass and is the parent protein of sheath protein which is named for 13˜17 kDa non-amelogenin protein found firstly in porcine newly formed enamel matrix (Fukae and Tanabe 1987a; Uchida et al., 1991). Porcine sheathlin is degraded at once after its secretion from ameloblasts into three segments, 17 kDa sheath protein derived from N-terminal side, 29 kDa calcium binding protein derived from C-terminal side (Fukae and Tanabe 1987b; Murakami et al., 1997; Yamakoshi et al., 2001) and 25 kDa acidic protein derived from middle part of molecule. The sheath protein accumulates at once to in future prism sheath space (Uchida et al., 1991; Uchida et al., 1995) and is degraded into lower molecular weight of 15 kDa and 13 kDa sheath protein in advanced developing stage of secretory enamel.
Enamelin
Enamelin is a parent protein of 155 kDa with cleavage products having apparent molecular weights of 142, 89, 56, 45, 34, 32, and 25 kDa (Fukae et al., 1996; Hu et al., 1997b). In the newly formed enamel 89 kDa enamelin is mainly existed in alkaline soluble fraction. In advanced developing secretory enamel the 89 kDa enamelin is degradated into 32 kDa enamelin which is soluble in neutral solution and has affinities for fluorohydroxyapatite (Tanabe et al., 1990) and Ca ions (Yamakoshi et al., 2001).
Growth Factors
There is additional evidence that, besides enamel proteins, potent signaling molecules may be resident in enamel extracts. Recently, bone morphogenetic protein (BMP)-like activity was deduced to be in porcine enamel extracts using ST2 cells (a mouse bone marrow stromal cell line) by the action of noggin (Iwata et al., 2002), transforming growth factor beta (TGF-β)-like activity was identified using oral epithelial and fibroblastic cells (Kawase et al., 2001). The TGF-β-like activity in the enamel matrix protein increases the ALP activity of HPDL cells, promotes their cytodifferentiation, and finally induces mineralization (Nagano 2003). The relationship between the presence of these growth factor-like activities in enamel extracts and the induction of osteogenesis and cementogenesis during periodontal regeneration is unknown.
It is shown that the periodontal ligament (PDL) is regenerated in the experimental cavities of intrabony defects created on a buccal dehiscence model in monkeys after the application of porcine enamel matrix proteins (Hammarström 1997, Hammarström et al., 1997). The idea that enamel matrix proteins are involved in the formation of cementum is based on the fact that coronal acellular extrinsic fiber cementum is formed on enamel surface in a number of species (Hammarström 1997). Application of porcine enamel matrix in experimental cavities in the roots of incisors of monkeys induces formation of acellular cementum that is well attached to the dentin. It indicates the enamel matrix proteins have the potential to induce regeneration of the same type of cementum (Hammarström 1997, Hammarström et al., 1997). The enamel matrix derivatives stimulate the proliferation and differentiation of human PDL cells (Gestrelius et al., 1997) and enhance bone formation (Boyan et al., 2000). These show that enamel proteins have bioactivities such as the induction of osteogenesis and cementogenesis.
Based on these results, the enamel proteins, enamel matrix derivatives (EMD) which is commercially available as EMDOGAIN®, are used clinically for PDL regeneration of periodontitis (Heijl 1997, Heijl et al., 1997). This new treatment induces a noteworthy result which is not obtained up to that time as the effect of periodontal disease treatment. However, when the enamel proteins are used for the treatment of periodontitis, periodontal ligament regeneration is not always accomplished to the level of expected result. It indicates that the usage of enamel proteins for the treatment of periodontal disease leaves much room for improvement.
The problem remaining to be solved is the elucidation of the real form of bioactivities contained in the enamel proteins. The researchers developed the EMD expect that the bioactivities are due to the amelogenin family a major component in enamel matrix. However, this idea is denied by finding the existence of periodontal ligament in amelogenin-deficient mice (Gibson et al., 2001). In fact, the amelogenins and their derivatives separated by ammonium sulfate precipitation fractionation (Kanazashi et al., 2004) or gel filtration system (Kanazashi et al., 2006; Fukae et al., 2006) have no cementum regeneration activity by histological analyses using experimental defects created on buccal dehiscence model of dogs.
There is another approach to estimate the bioactivities such as osteoinductive activities, BMP-like activity (Iwata et al., 2002) and TGF-β-like activity (Kawase et al., 2001). The TGF-β-like activity in the enamel matrix protein increases the alkaline phosphatase (ALP) activity of human periodontal ligament (HPDL) cells, promotes their cell differentiation and finally induces the mineralization (Nagano 2003; Nagano et al., 2004). The existences of both BMP and TGF-β in porcine enamel proteins are confirmed by lucipherase reporter assays (Suzuki et al., 2005). However, it is unclear the function of these osteoinductive factors in periodontal regeneration in in vivo system, although these may contribute to the induction of osteogenesis and cementogenesis or both and biomineralization during periodontal regeneration.
It is not doubted that the EMD has the periodontal regeneration activity. However, it is too hard to separate the activity from the EMD since the EMD consists of multi components containing a lot of amelogenins and their derivatives which have aggregation nature. To avoid the obstruction by amelogenin aggregation, the usage of newly formed secretory enamel for separating the cementum regeneration promoting factor seems to be advantageous. Because it contains the smallest amount of amelogenin degradation products comparing to the other advanced developmental immature enamel. The 0.05M carbonate buffer (pH 10.8) which inhibits the aggregation of amelogenins is employed for the separation. Over 95% of whole proteins contained in immature enamel is solubilized briefly by homogenizing in this buffer (Fukae and Tanabe, 1998).
The management to avoid the degradation of periodontal regeneration activity is employed. There are at least four proteolytic activities detected in developing dental enamel matrix. They are two metalloproteinases, gelatinase and enamelysin (MMP-20) (Bartlett et al., 1996; Fukae et al., 1998), and two serine proteinases including EMSP (KLK4) (Fukae et al., 1977; Shimizu et al., 1979; Simmer et al., 1998). Enamel matrix serine proteinase and enamelysin were cloned characterized and involved in the degradation of amelogenins and non-amelogenin proteins during not only transition stage enamel but also secretory stage enamel (Tanabe et al., 1992; Tanabe et al., 1996; Fukae and Tanabe, 1998). EMSP and proEMSP found in the secretory enamel are extracted with only the neutral phosphate buffer. The extraction of neutral soluble fraction is needed to avoid the degradation of periodontal regeneration activity, since proEMSP is activated with metalloproteinases (Tanabe et al., 1996). The action of MMP-20 found in alkaline soluble fraction was inhibited by adding at once EDTA, the inhibitor of matrix metalloproteinase, after the extraction of alkaline soluble fraction.
Complete periodontal regeneration could be accomplished by first cementum regeneration (CR) along with burying of collagenous bundles and then periodontal ligament regeneration and alveolar bone regeneration, if it is reasoned by the analogy of root formation at tooth development. Therefore, the cementum regeneration is thought to be most important part in the periodontal regeneration processes. Nevertheless, since no marker protein is found in the cementum formation, the histological analysis on buccal dehiscence model of dogs are employed for cementum regeneration (CR) activity of fractionated enamel proteins. The CR capacity of individual protein fraction obtained at each separation or purification step is evaluated step by step by the regenerated cementum of eight weeks produced on the experimental intrabony defects created along the roots of the canine mandibular premolars.
When porcine enamel proteins are separated under the difference of developmental stage and examined for their CR activity, the CR activity is found in newly formed enamel rather than the advanced developmental secretory enamel. In newly formed secretory enamel, CR activity was detected in the alkaline soluble fraction, but not in the neutral soluble fraction. When the alkaline soluble fraction was separated into 4 fractions by Sephadex G-100 gel filtration, CR activity was found in the first eluted peak (fraction 1) containing the aggregate of sheath proteins along with a small amount of amelogenins and enamelins. The other peaks consisted of amelogenins and their derivatives had no CR activity.
When the fraction 1 was separated into enamelin fraction and aggregate fraction containing sheath proteins and amelogenins, the activity was found in the aggregate fraction. It is concluded the CR activity was in sheath proteins, because the amelogenin had no CR activity. And so sheath proteins were purified in dissociative condition and homogeneous protein fraction of each 13 kDa, 15 kDa and 17 kDa sheath protein was obtained. CR activity was found only in 17 kDa sheath protein. The 17 kDa sheath protein was split into 15 kDa sheath protein by the cleavage of C-terminal side peptide and the 13 kDa sheath protein was derived from the 15 kDa sheath protein by the cleavage of N-terminal side peptide. Therefore, CR activity was existed in the sequence of C-terminal side of 17 kDa sheath protein.
After CR activity was determined to be resided in the C-terminal peptide of 17 kDa sheath protein, to search the specific sequence having CR activity was examined by the detection of alkaline phosphatase inducing activity of human periodontal ligament (HPDL) cells, after application of purified enamel proteins or their peptides on cell culture system. The employment of cell culture system is handy method to link the detection of CR promoting activity, because the increase of ALP activity of HPDL cells shown their cytodifferentiation plays important function for acellular cementum formation, deduced from morphometric evaluation in the light microscope on ALP-deficient mice (Beertsen et al., 1999). In general, it is unclear whether the evaluation of ALP activity in HPDL cell culture system contributes to the induction of osteogenesis or cementogenesis. However, CR activity resided in the 17 kDa sheath protein was determined by the regenerated cementum of eight weeks produced on the experimental intrabony defects created on the canine mandibular premolars' roots. Therefore, the increase of ALP activity of HPDL cells in the cell culture system links strongly to the evaluation of CR promoting activity of 17 kDa sheath protein or peptides. It was characterized about HPDL cells on cell culture system that ALP activity of HPDL cells induced by adding 1α-25-dihydroxy-Vitamin D3 was increased by adding TGF-β, and decreased by adding BMP
The purified porcine three sheath proteins were examined their ALP inducing activity of HPDL cells in cell culture system. ALP inducing activity was found in 17 kDa sheath protein, but scarce activity was in 13 kDa and 15 kDa sheath proteins. It indicates the cytodifferentiation activity of HPDL cells is resided in the C-terminal side peptide of 17 kDa sheath protein. And so, based on the sequence of porcine or human sheath protein, the peptides were synthesized and examined their ALP inducing activity on the cell culture system. On human synthesized peptides, SEQ ID NO: 1 and SEQ ID NO: 2 were shown dose dependently to increase ALP inducing activity of HPDL cells. Since the activities of these peptides were not inhibited by TGF-β1 inhibitor, TGF-β1 receptor was not common receptor of these peptides.
As will be appreciated by persons skilled in the art, the invention also relates to protein sequences with deduced amino acid sequences of SEQ ID NO:1 to SEQ ID NO:34 which have preferably 5% or greater identity, more preferably 10% or greater identity, more preferably 15% or greater identity, more preferably 20% or greater identity, more preferably 25% or greater identity, more preferably 30% or greater identity, more preferably 35% or greater identity, more preferably 40% or greater identity, more preferably 45% or greater identity, more preferably 50% or greater identity, more preferably 55% or greater identity, more preferably 60% or greater identity, more preferably 65% or greater identity, more preferably 70% or greater identity, more preferably 75% or greater identity, more preferably 80% or greater identity, more preferably 85% or greater identity, more preferably 90% or greater identity, more preferably 95% or greater identity, more preferably 96% or greater identity, more preferably 97% or greater identity, more preferably 98% or greater identity, and more preferably 99% or greater identity.
The present invention further provides proteins that consist essentially of the amino acid sequences provided in SEQ ID NO:1 to SEQ ID NO: 34. A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues, for example from about 1 to about 100 or so additional residues, typically from 1 to about 20 additional residues in the final protein.
The present invention further provides proteins that comprise the amino acid sequences provided in SEQ ID NO: 1 to SEQ ID NO: 34. A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein can be only the peptide or have additional amino acid molecules, such as amino acid residues (contiguous encoded sequence) that are naturally associated with it or heterogeneous amino acid residues/peptide sequences. Such a protein can have a few additional amino acid residues or can comprise several hundred or more additional amino acids.
To determine the percent identity of two amino acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues at corresponding amino acid positions are then compared. When a position in the first sequence is occupied by the same amino acid residue as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid "identity" is equivalent to amino acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
Some embodiments of the present inventions are described with reference to the numbered paragraphs below:
1. A protein comprising: an isolated sheath protein that is one of a derivative produced by the action of proteinase from a sheathlin (ameloblastin/amelin), one of structural enamel proteins; and is derived from amino-terminal side of the sheathlin.
2. The protein of paragraph 1, where the isolated sheath protein is mammalian.
3. The protein of paragraph 2, where the isolated mammalian sheath protein is porcine.
4. The protein of paragraph 2, where the isolated mammalian sheath protein is human.
5. The protein of paragraph 1, where amino acid sequence of the isolated sheath protein is selected from the group consisting of SEQ ID NO: 10 and SEQ ID NO: 11.
6. A method of producing an effect comprising administering the protein of paragraph 5 to a mammal.
7. The method of paragraph 6, where the mammal is a Human.
8. A method of producing an effect comprising administering the protein of SEQ ID NO: 11 to a mammal.
9. The method of paragraph 8, where the mammal is a Human.
10. A polypeptide or peptide segment characterized as: comprising a sequence region of at least about 3 contiguous amino acids that have the same sequence as about 3 contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13; or comprising from 3 to about 1,000 amino acids in length that synthesizes the polypeptide segment selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13.
11. The polypeptide or peptide segment of paragraph 10, wherein the segment comprises a sequence region of at least 3 contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO:13.
12. The polypeptide or peptide segment of paragraph 10, wherein the segment is from about 3 to about 1,000 amino acids in length and synthesizes an amino acid segment of an artificial sequence comprising a sequence region of contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13.
13. The polypeptide or peptide segment of paragraph 10, wherein the segment is from about 3 to about 1,000 amino acids in length and biosynthesizes by a recombinant protein expression system to the amino acid segment of an artificial sequence comprising a sequence region of contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13.
14. A method of producing an effect comprising administering the protein of paragraph 10 to a mammal.
15. The method of paragraph 14, where the mammal is a Human.
16. A polypeptide or peptide segment characterized as: comprising a sequence region of at least about 3 contiguous amino acids that have the same sequence as about 3 contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 24 and SEQ ID NO: 25; or comprising from 3 to about 1,000 amino acids in length that synthesizes the polypeptide segment selected from the group consisting of SEQ ID NO: 24 and SEQ ID NO: 25.
17. The polypeptide or peptide segment of paragraph 16, wherein the segment comprises a sequence region of at least 3 contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 24 and SEQ ID NO: 25.
18 The polypeptide or peptide segment of paragraph 16, wherein the segment is from about 3 to about 1,000 amino acids in length and synthesizes an amino acid segment of an artificial sequence comprising a sequence region of contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 24 and SEQ ID NO: 25.
19. The polypeptide or peptide segment of paragraph 16, wherein the segment is from about 3 to about 1,000 amino acids in length and biosynthesizes by a recombinant protein expression system to the amino acid segment of an artificial sequence comprising a sequence region of contiguous amino acids of the sequence selected from the group consisting of SEQ ID NO: 24 and SEQ ID NO: 25.
20. A method of producing an effect comprising administering the protein of paragraph 16 to a mammal.
21. The method of paragraph 20, where the mammal is a Human.
22. A polypeptide or peptide segment characterized as: comprising a sequence region of at least about 3 contiguous amino acids that have the same sequence as about 3 contiguous amino acids of SEQ ID NO: 9; or comprising from 3 to about 1,000 amino acids in length that synthesizes the polypeptide segment of SEQ ID NO: 9.
23. The polypeptide or peptide segment of paragraph 22, wherein the segment comprises a sequence region of at least 3 contiguous amino acids from SEQ ID NO: 9.
24. The polypeptide or peptide segment of paragraph 22, wherein the segment is from about 3 to about 1,000 amino acids in length and synthesizes an amino acid segment of an artificial sequence comprising a sequence region of contiguous amino acids from SEQ ID NO: 9.
25. The polypeptide or peptide segment of paragraph 22, wherein the segment is from about 3 to about 1,000 amino acids in length and biosynthesizes by a recombinant protein expression system an amino acid segment of an artificial sequence comprising a sequence region of contiguous amino acids from SEQ ID NO: 9.
26. A method of producing an effect comprising administering the protein of paragraph 22 to a mammal.
27. The method of paragraph 26, where the mammal is a Human.
28. A polypeptide or peptide segment characterized as comprising a sequence region selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32.
29. A method of producing an effect comprising administering the polypeptide segment of paragraph 28 to a mammal.
30. The method of paragraph 28, where the mammal is a Human.
31. A composition comprising an isolated aggregate that comprises a sheath protein.
32. The composition of paragraph 31, where the isolated aggregate forms with sheath proteins and amelogenins in an alkaline solution.
33. The composition of paragraph 31, where the isolated aggregate resides in outer layer enamel, newly formed enamel, corresponding to approximately 30 μm thickness from the surface of secretory stage enamel of mammal.
34. The composition of paragraph 31, where the isolated aggregate is prepared from the outer layer enamel, newly formed enamel.
35. The composition of paragraph 31, where the isolated aggregate is separated using a method selected from the group consisting of gel filtration in alkaline solution, ion exchange chromatography, and ammonium sulfate fractionation.
36. A method of producing an effect comprising administering the protein of paragraph 31 to a mammal.
37. The method of paragraph 36, where the mammal is a Human.
38. A composition comprising isolated enamel proteins that comprise a sheath protein.
39. The composition of paragraph 38, where the isolated enamel proteins are prepared from the outer layer enamel, newly formed enamel, corresponding to approximately 30 μm thickness from the surface of secretory stage enamel of mammal.
40. The composition of paragraph 38, where the isolated enamel proteins are extracted by an alkaline solution after the extraction of neutral soluble proteins from the outer layer enamel, newly formed enamel.
41. A method of producing an effect comprising administering the protein of paragraph 38 to a mammal.
42. The method of paragraph 41, where the mammal is a Human.
This invention is not limited to specific polypeptides or peptides and the numerous modifications and variations therein will be apparent to those skilled in the art. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

Effect of porcine sheath proteins on the regeneration activity of periodontal ligament


A thermostat assembly for a combustion engine having at least one cylinder is disclosed. The assembly has a cylinder head configured to cap off the at least one cylinder, the cylinder head having a recess fluidly connected to a coolant passage of the combustion engine. The assembly also has a thermostat located completely within the recess.

An internal combustion engine generally includes one or more combustion chambers that house a combustion process to produce mechanical work and a flow of exhaust. Each combustion chamber is formed from a cylinder, the top surface of a piston, and the bottom surface of a cylinder head. Air or an air/fuel mixture is directed into the combustion chamber by way of intake ports disposed in the cylinder head, and the resulting exhaust flow is discharged from the combustion chamber by way of exhaust ports also disposed in the cylinder head. Valves are located within the ports of the cylinder head and seal against seats at the entrance of the ports to selectively allow and block the flow of air and exhaust.
Because of the proximity to the combustion process and/or due to friction within the engine, the cylinder head, cylinder liner, and other areas of the engine may be cooled in order to ensure proper and efficient operation of the engine. A cooling system is required to cool fluids directed into or out of the engine and generally includes a heat exchanger. An engine driven fan is disposed either in front of the engine/exchanger package to blow air across the exchanger and the engine, or between the engine and exchanger to blow air past the engine or suck air past the exchanger. In either configuration, a thermostat is located to selectively block the flow of coolant through the engine when the temperature of the engine is too low, and to allow the flow of coolant when the temperature of the engine exceeds a predetermined threshold. This thermostat is generally housed in its own dedicated housing, which can be mounted to the engine block or to the cylinder head. Before or after flowing through the engine, the coolant passes through the thermostat housing.
Although adequate for most situations, the separate thermostat housing can be problematic. Specifically, the separate housing consumes valuable space on the engine and is costly and time-consuming to produce and assemble. In addition, the separate housing introduces opportunities for leaks.
One attempt to solve the problems caused by having a separate thermostat housing is disclosed in U.S. Pat. No. 6,446,586 (the '586 patent) issued to Fukamachi on Sep. 10, 2002. The '586 patent discloses an adjoining engine block and a cylinder head, where both the engine block and the cylinder head have matching overhanging portions. A thermostat housing is fitted between the overhanging portion of the engine block and the overhanging portion of the cylinder head so that it projects from the engine body as little as possible. In this manner, the amount of space consumed by the separate thermostat housing may be minimized.
Although the thermostat housing arrangement of the '586 patent may minimize the amount of engine space consumed, it may still be a separate housing. Therefore, the thermostat housing may still be expensive to produce, time-consuming to assemble, and may provide leakage opportunities.
The present disclosure is directed to overcoming one or more of the shortcomings set forth above and/or other deficiencies in the art.

Thermostat assembly having integral cylinder head and thermostat housing


A computer system and processing method are provided for coupling multiple physical processing nodes together, wherein each physical processing node is characterized as having its own memory, by either at least one channel which is independent of and coupled to the multiple physical processing nodes or by at least one input/output (I/O) processor, again which is independent of and coupled to the multiple physical processing nodes. The at least one channel and/or the at least one I/O processor couple the multiple physical processing nodes to at least one shared input/output device. Sharing of the at least one channel and/or at least one I/O processor is practical by providing "indirect logical addressing" using logical address tables within the channel subsystem. The logical address tables associate an image identifier (Image.sub.-- ID) and processing node identifier (PN.sub.-- ID) concatenation with an indexed logical address for use in communicating I/O operation parameters across the at least one channel.

In a coupled systems complex with many physical processing nodes, for example, each comprising International Business Machines' System/390 parallel transaction server, the cost of input/output (I/O) connectivity between the different processors and their shared I/O devices is a significant component of the total computer system cost. Today, each processor has its own dedicated I/O subsystem structure, including its own channel subsystem with at least one channel connecting the processor to one or more of the shared I/O devices. Configuring enough channels, control unit adapters and (for IBM System/390-like systems) switches for full connectivity, results in using a much larger number of channels, control unit adapters, and switches than otherwise needed for performance and availability. A separate channel is required for each processing node, and switching (or multiple adapters at the control unit) is required to enable each processing node to communicate with a control unit connected to a desired input/output device.
In a conventional data processing system architecture, such as International Business Machines' Enterprise Systems Architecture/390, information is passed between main storage and input/output devices via a processor's dedicated channel subsystem. The channel subsystem uses one or more channel paths, each including a channel and one or more control units and serial links, as the communication links between its main storage and the input/output devices. The writing of data from main storage to input/output devices or the reading of data from input/output devices to main storage is accomplished by executing input/output operations. The execution of input/output operations is accomplished by the decoding and executing of channel command words by the channel subsystem and input/output devices.
As used herein, the phrase "physical processing node" comprises a processor having its own main storage or memory which is separate from and not accessible by other physical processing nodes in a computer system comprising a plurality of physical processing nodes. Conventionally, each physical processing node has its own channel subsystem and I/O processor(s) coupling its main storage to the shared I/O devices of the coupled systems complex.
There exists a need in the art for a computer system architecture and data processing approach which allow multiple physical processing nodes to obtain full connectivity to I/O devices using a smaller number of channels, control unit adapters, and switches, while still meeting performance and availability objectives.

Independent channel coupled to be shared by multiple physical processing nodes with each node characterized as having its own memory, CPU and operating system image

International Business Machines Corporation


A removable ironing board (2) enclosed in a piece of furniture (1). The ironing board (2) is mounted on extendible rails (19 and 20) so that the ironing surface (2) projects out of the enclosure (3) when in use. A panel (4) is attached to the ironing surface(2), and is movable to a position underneath the ironing surface (2) when the ironing surface (2) is extended. The ironing board (2) may be replaced with a differently shaped ironing surface, or removed from the piece of furniture and the enclosure (3) used to house a drawer.

This invention relates to an ironing board, and in particular an ironing board built into a piece of furniture. The ironing board has a cabinet face covering the enclosure used to store the ironing board, and rails to extend and retract the ironing board out of and into the enclosure.
Ironing boards that are foldable or telescoping and are incorporated into furniture have been described, and include: U.S. Pat. No. 5,444,928 issued on Aug. 29, 1995, to Sagel; U.S. Pat. No. 5,241,766 issued on Sep. 7, 1993, to Waltz et al.; and U.S. Pat. No. 3,641,947 issued on Feb. 15, 1972 to Finney. These ironing boards have a seam on the working surface where the ironing board is folded, thus potentially causing unwanted creases to be formed in the article of clothing or material being ironed.
Previous ironing boards that are stored in cabinet like enclosures and are not folded are known in the art and include: U.S. Pat. No. 5,452,531 issued on Sep. 26, 1995 to Graville et al.; U.S. Pat. No. 4,049,332 issued on Sep. 20, 1977 to Bourdeaux; U.S. Pat. No. 5,241,766 issued on Sep. 7, 1993 to Waltz et al.; and U.S. Pat. No. 2,227,786 issued on Jan. 7, 1941 to LaFee. Each of these ironing boards is incorporated into furniture in a relatively permanent way, and removal of the ironing board assembly cannot be accomplished without the use of tools.


A pressure sensor includes: a housing having a pressure introduction port; and a connector case integrated with the housing. The connector case includes: a protruding portion that protrudes in the pressure introduction port along with the introduction direction from one end of the connector case, and has a concavity hollowed in a direction perpendicular to the introduction direction; a sensor chip having a pressure gauge on one surface of the chip in the concavity; a terminal having one end inserted and molded in the connector case; and a bonding wire that electrically connects the sensor chip and the one end of the terminal. The connector case seals a connection portion between the bonding wire and the terminal, a connection portion between the boding wire and the sensor chip, and the bonding wire.

A pressure sensor in which even if a pressure medium is brought into direct contact with the pressure receiving plane of a pressure detection element or with a bonding wire connected to the pressure receiving plane, the pressure detection element is protected and an electric leak is prevented is proposed in the related art, for example, in a patent document 1.
Specifically, the patent document 1 proposes the pressure sensor including: a housing into which a pressure medium is introduced; a case mounted in the housing; a sensor chip as a pressure detection element which is mounted in the case and has a pressure receiving plane on which pressure from the pressure medium is received; a terminal mounted around the sensor chip of the case; and a bonding wire whose one end is electrically connected to the pressure receiving plane of the sensor chip and whose other end is electrically connected to the terminal.
In this pressure sensor, a middle portion between the one end and the other end of the boding wire is coated with a first coating material having electric insulation and resistance to the pressure medium. Moreover, the connection portion of the bonding wire and the sensor chip, the connection portion of the bonding wire and the terminal, and the pressure receiving plane of the sensor chip are coated with a second coating material having electric insulation and resistance to the pressure medium.
The sensor chip is mounted in the case in such a way that the pressure receiving plane is vertical to the direction in which the pressure medium is introduced. The bonding wire is extended in a direction vertical to the direction, in which the pressure medium is introduced, from the pressure receiving plane of the sensor chip and is connected to a terminal arranged on the same plane as the pressure receiving plane. Moreover, the housing and the case are sealed from each other via an O ring of a sealing part arranged so as to surround the sensor chip, the bonding wire, and the terminal.
The above-mentioned pressure sensor is constructed in such a way that the pressure medium is directly introduced to the pressure receiving plane of the sensor chip, but the bonding wire and the pressure receiving plane of the sensor chip are coated with the coating material. Hence, the sensor chip can be protected and an electric leak can be prevented.    [Patent Document] JP-2006-208088A
However, in the related art, the pressure receiving plane of the sensor chip is arranged vertically to the direction in which the pressure medium is introduced and hence the bonding wire needs to be extended on the same plane as the pressure receiving plane from the pressure receiving plane of the sensor chip, which results in enlarging the outside diameter of the case. In this case, the outside diameter needs to be increased in consideration of the arrangement of the O ring surrounding the terminal and the like. In this manner, the related art presents a problem that the outside diameter of the pressure sensor results in being enlarged.
Moreover, the first coating material with which the bonding wire is coated performs the function of protecting the boding wire from the pressure medium but the pressure of the pressure medium is directly applied to the bonding wire. That is, there is presented a problem that the bonding wire is broken by the pulsation of the pressure medium, which results in interrupting the electric connection of the sensor chip and the terminal.
Thus, it is required to reduce the size of a pressure sensor and to prevent the electric connection of a sensor chip and a terminal from being interrupted.
Further, a pressure sensor having its size reduced is proposed in the related art, for example, in a patent document 2. Specifically, the patent document 2 proposes a structure in which a resin case has a wiring board mounted on its one end portion and in which a sensor chip formed of a semiconductor substrate is flip-chip bonded to the one plane of the wiring board via bumps.
The wiring board is electrically connected to terminals inserted and molded in the case and is mounted on the case with the plane of the board directed in parallel to the radial direction of the pressure sensor. Moreover, a gage part for detecting pressure is formed in the central portion of a square pressure receiving plane of the sensor chip and the bumps are disposed on four corners of the pressure receiving plane. The sensor chip is flip-chip bonded to the wiring board via the bumps, whereby the sensor chip, the wiring board, the terminals are electrically connected to each other. With this, the sensor chip is disposed in parallel to the wiring board and hence the pressure receiving plane of the sensor chip is directed in parallel to the radial direction of the pressure sensor.
In this manner, the electric connection portions of the sensor chip are connected not by wire bonding but by flip-chip bonding requiring a smaller area, so that the size of the pressure sensor can be reduced.    [Patent Document 2] JP-2006-177925A Corresponding to U.S. Pat. No. 7,210,357
However, the related art described above presents the following problem: that is, when the pressure sensor receives ambient temperature and the temperature of a pressure medium, because the case made of resin, the bump made of metal, and the sensor chip made of semiconductor are different from each other in the coefficient of linear expansion, a thermal stress is caused by the expansion of the case made of resin having the largest coefficient of linear expansion and is transmitted to the sensor chip made of semiconductor having the smallest coefficient of linear expansion via the wiring board and the bumps.
As described above, since the bumps are disposed on the four corners of the pressure receiving plane, the thermal stress is directly transmitted to the gage part via paths in four directions. In other words, the gage part is distorted by the thermal stress in four directions. Thus, pressure including pressure produced by the distortion caused by the thermal stress is detected in the gage part. This reduces the accuracy of detecting the pressure.
Thus, it is required to provide a pressure sensor that can make it harder for thermal stress to be transmitted to a gage part and a method for manufacturing the pressure sensor.

Pressure sensor and method for manufacturing the same


Nanoparticle-amphiphilic polymer complexes for nucleic acid delivery and real-time imaging.

RNA interference (RNAi) is emerging as one of the most powerful technologies for sequence-specific suppression of genes and has potential applications ranging from functional gene analysis to therapeutics. Due to the relatively low immunogenic and oncologic effects, the development of non-viral delivery methods in vitro and in organisms is of considerable current interest. In recent years, a number of strategies have been developed based on liposomes, gold and silica nanoparticles (NPs), cationic and biodegradable polymers, and peptides. The delivery efficiency, however, remains low, especially under in vivo conditions. Another limitation shared by all the existing delivery technologies is the lack of an intrinsic signal for long term and real-time imaging of siRNA transport and release. Such imaging could provide important information on rational design of siRNA carriers. Currently, organic fluorophores are used to label siRNA or the delivery vehicles. However, the photobleaching problem associated with essentially all organic dyes prevents long-term tracking of siRNA-carrier complexes. Similarly, electron-dense gold NPs are visible under transmission electron microscope (TEM) and provide the highest imaging resolution in fixed cells, but they do not allow real-time imaging of live cells.
QDs have been used for siRNA delivery and imaging. However, these QD probes are either mixed with conventional siRNA delivery agents (Lipofectamine™) or external endosomal rupture compounds (e.g., chloroquine) for gene silencing activity, significantly limiting their potential applications in vivo. Therefore, development of multifunctional QDs with integrated functionalities of cell binding and internalization, endosome escape, siRNA protection against enzyme activities, siRNA unpackaging (siRNA-carrier dissociation), and siRNA tracking is of urgent need. Furthermore, packaging these functionalities into single nanoparticles also represents a significant technological challenge.
In one aspect, the present invention seeks to fulfill this need and provides further related advantages.
Combination of gene vectors such as liposome, cationic polymers and recombinant viruses with magnetic nanoparticles or microparticles allows rapid delivery of DNAs and RNAs into cells, a process also referred to as magnetofection. In addition to the magnetic force directed delivery, another key feature of magnetofection is that it is capable of reaching similar transfection efficiency at significantly reduced DNA and RNA concentrations. Protocols on how to transfect nucleic acids to both suspended and adherent cells (including primary neurons) using cationic liposomes and polymers associated with MNPs has been recently reported. Similarly, the combination of magnetic microspheres of various sizes with recombinant adeno-associated viral vectors for increased gene transduction efficiency and modified in vivo biodistribution has also been recently reported.
Despite these recent advances, a major drawback of the magnetofection carriers is that the fully assembled magnetic vectors are based on large aggregates of MNPs, nucleic acids, and cationic lyposomes (or polymers), often in the sub-μm to μm range. The aggregated MNPs are highly responsive to external magnetic fields compared with the original single MNPs. However, aggregated MNPs are associated with problems related to their size. That is, aggregated MNPs cannot be further developed into biomolecularly targeted and MRI traceable drug delivery vehicles because it is extremely difficult to control the aggregation process for compact and uniform nanoparticle clusters. This is indeed evidenced by the absence of magnetofection of siRNA in vivo, since the first reported data on siRNA magnetofection in 2003. Instead, the rational design of dispersed nanostructures with precisely tunable sizes, integrated targeting, imaging, and therapeutic functionalities, has become the most promising route for efficient siRNA delivery.
Recent advances in high-temperature non-hydrolytic nanoparticle synthesis has led to the development of highly monodisperse MNPs with size tunability ranging from a few nanometers to approximately 50 nm in diameter, which is suitable to many biomedical applications. For example, it has been demonstrated that magnetic resonance signals from MNPs of 4 to 12 nm vary drastically. Using the same MNP size range, MNPs response to magnetic fields have been shown to be highly size dependent, which opens new opportunities for simultaneous separation of complex mixtures. Similarly, in nanoparticle based siRNA delivery, the particle size is also one of the most important factors in that it affects the particle diffusion, in vivo biodistribution, plasma circulation time, and surface functionalities (e.g., curvature and number of ligands). Uniform MNPs can be routinely made with nanometer precision, which is difficult, if not impossible, to achieve with traditional aqueous-based synthetic approaches (used to make MNPs in essentially all the reported magnetotransfection studies). However, until now these monodisperse MNPs have been mainly used in bio-separation and in vivo MRI.
In another aspect, the present invention seeks to fulfill this need and provides further related advantages.

Nanoparticle-amphipol complexes for nucleic acid intracellular delivery and imaging


Approaches presented herein enable generation of a multi-dimensional tag metric in a cloud resource management environment. More specifically, a tagging namespace is provided for managing a resource in the cloud resource management environment. This namespace comprises at least two dimensions and a plurality of positions. A set of tags associated with the resource are received into the tagging namespace. A match of each tag of the set of tags to a position within the namespace into which that tag was received is verified and an alert is triggered in the case verification fails. Alternatively, in the case verification is successful, the tag-containing namespace is validated as a multi-dimensional tag metric.

The networked computing environment (e.g., cloud computing environment) is an enhancement to the predecessor grid environment, whereby multiple grids and other computation resources may be further enhanced by one or more additional abstraction layers (e.g., a cloud layer), thus making disparate devices appear to an end-consumer as a single pool of seamless resources. These resources may include such things as physical or logical computing engines, servers and devices, device memory, and storage devices, among others.
Providers in the networked computing environment often deliver services online via a remote server, which can be accessed via a web service and/or software, such as a web browser. Individual clients can run virtual machines (VMs) that utilize these services and store the data in the networked computing environment. This can allow a single physical server to host and/or run many VMs simultaneously.
In a cloud native environment, tags and labels are becoming increasingly more common for managing various types of resources. These tags and labels allow a user to group and organize cloud computing resources he or she wishes to use. While some cloud resources providers have tag/label naming rules specific to that provider, there are no uniform techniques to manage tags/labels. This generally results in users or the enterprises for which they work creating user or enterprise-specific tag-naming conventions and/or other tag policies in order to maintain consistency between tags. However, when these self-imposed naming conventions and policies are not strictly followed, such as when two users of an enterprise use even slightly differing naming conventions within the same resource pool, the cloud environment can be left susceptible, for example, to service interruptions and other failures.
Several endeavors into the field of resource tagging have been made, including, for example, the following.
U.S. Patent Application Publication 2012/0246157 discloses: "dynamically tagging metrics data" through a "virtualization infrastructure [ ] that can manage and reserve computer resources for the user during a future usage time period."
U.S. Pat. No. 9,934,269 discloses: "A resource groups service [that] allows customers and/or other users of the service provider network to view and access collections of computing resources that share common resource tags and/or other attributes."
U.S. Patent Application Publication 2016/0315943 discloses: techniques "to provide fine grained protection of resources in an access management environment."
U.S. Pat. No. 9,787,598 discloses: "monitoring and managing information technology (IT) resources" with "tags that correspond to conditions that alert the resource manager when to begin actively managing the IT resource."

Multi-dimensional tagging namespace for cloud resource management

International Business Machines Corporation


A matrix multiplication circuit comprises a memory storage device, processing circuitry, a parallel multiply circuit, and buffer circuits. The parallel multiply circuit simultaneously performs a count of multiplies in a parallel multiplication operation. The buffer circuits include prefetch buffer circuits each having a storage array dimension corresponding to the count of multiplies in the parallel multiplication operation. The processing circuitry loads a first prefetch buffer circuit with values from the first matrix; fetches a value of the second matrix and, in parallel with the fetch, preload the second prefetch buffer circuit with another value from the first matrix; initiates a parallel multiply of the fetched value of the second matrix and the values in the first prefetch buffer circuit; and stores partial product results of the parallel multiply, including adding a current partial product result to a previously stored partial product result.

Matrix multiplication is a fundamental operation in many algorithms. For example, matrix multiplication maybe used in an algorithm used by transceivers to determine spatial correlation of a wireless signal's spatial direction and the average received signal gain.
To multiply an M*N matrix with an N*P matrix (where M, N, and P are positive integers), M*N*P multiplications need to be performed. Most processors support only one or sometimes two multiplications per cycle. This means that matrix multiplication consumes significant processing time and in certain cases is inefficient. To counteract the significant amount of processing time required, hardware accelerators are used for matrix multiplication. A hardware accelerator for matrix multiplication may multiply some of the matrix elements simultaneously or in parallel. However, this results in needing multiple fetches from memory to perform one cycle of multiplication. Loading this increased amount of data from memory can lead to bottle necks in the input/output (IO) between the processor and the memory storing the matrices.

Parallel matrix multiplication technique optimized for memory fetches

Analog Devices International Unlimited Company


A child vehicle safety seat includes a frame securable to a vehicle seat such that a child seat mounted thereon is freely pivotable with respect to the frame to reduce the chances of head, neck and compression injuries normally experienced when the vehicle experiences a rapid deceleration or an abrupt stop. The child seat includes a mechanism for adjustment of sensitivity such that the child seat may act like a swing to provide a gentle rocking motion during normal movement of the vehicle or pivot only upon rapid deceleration of the vehicle. The frame is securely fastened to the vehicle seat via the vehicle seat belt and hooks which attach to the backrest and seat cushion of the vehicle seat. Locking devices eliminate slack in the vehicle seat belt to reduce movement of the frame with respect to the vehicle seat.

The use of child vehicle safety seats is now required by law in most states. Conventional child vehicle safety seats have proven highly effective in reducing injuries to children when used properly. Unfortunately, research has shown that the design of most child vehicle safety seats available in the marketplace is such that many parents find installation in the vehicle to be quite complicated. Child vehicle seats are, therefore, often improperly installed, such that the seat provides no added protection for the child and may actually intensify potential injury to the child in the event of an accident.
There are a number of drawbacks associated with conventional child vehicle safety seats. For example, conventional child vehicle safety seats are designed to remain in one fixed position on the vehicle seat. The child seat restraining devices prevent essentially all movement of the child's upper torso. Depending on the degree of deceleration, these restraining devices apply proportional resistance pressures to the very child they are trying to protect and, as a result, may cause not only surface contusions but also serious internal injury.
Even more serious than these compression injuries is the injury potential caused by a sudden snapping forward of the child's head and any portions of the body extending above the location of the restraining devices, such as a lap strap, being employed.
Another drawback of conventional child vehicle safety seats is that they are typically most effective when they are placed in the back seat of the vehicle such that the child faces the rear of the vehicle. However, when the child is placed in this fashion, the driver is unable to view the child and, consequently, may be inclined to repeatedly glance backward, thereby taking his eyes off the road and creating the potential for an accident. Further, older children typically prefer facing forward when seated in a vehicle. Although head straps could be used to reduce whiplash when the child is placed in a forward seated position, this would simply not be an acceptable solution to either the child or a majority of parents.
Placing a child in a conventional child car seat in the front seat of a vehicle also poses an additional hazard where the vehicle is equipped with an airbag, as are most of today's vehicles. In particular, studies have shown that airbag deployment can actually cause head and neck injuries to children and even death.
Another drawback of most conventional one piece child vehicle safety seat designs is that the only manner of securing them to the vehicle seat is by threading the auto seat belts through tunnel-like openings which tend to be obscure and make proper placement very difficult.
Most vehicle safety belts are designed to provide a considerable amount of slack upon impact or rapid deceleration. They cannot truly hold a child vehicle safety seat firmly in place against the vehicle seat.
There is, therefore, a need for a child vehicle safety seat which is easily installed and allows the child to be placed in a forward seated position with less risk of injury.


A tuning fork sensor system places a controlled bias on the proof-mass drive-axis electrodes to cancel the quadrature charge. Also, its charge amplifiers employ a field-effect transistor biased slightly into the triode region so that it behaves as a very large value resistor. In addition, it uses a phase-locked loop having a special loop filter in order to optimize performance by rejecting off-frequency drive feedthrough to the motor pick-off while resulting in very low phase wander for the demodulation references.

Tuning-fork rate sensors and specifically gyroscopes are known. They often have a pair of proof-masses intended to oscillate in anti-parallel fashion along a drive axis. Upon rotation of the sensor along an "inertially-sensitive axis," Coriolis acceleration is experienced by the masses, resulting in a small anti-parallel oscillation along this sense axis, called the sense mode oscillation. The sense-mode oscillation amplitude is proportional to inertial rate along the inertially-sensitive axis. The sense-mode oscillation amplitude can be detected by sensitive electronics to produce an inertial rate sensor.
In this vein, U.S. Pat. No. 5,911,156, to Ward, et al., concerns a MicroElectroMechanical system (MEMS) tuning-fork gyroscope (TFG) system that includes two proof-masses and split center and outer motor electrodes. This configuration allows for rejection of errors from mismatch in relative amplitude or phase. By applying excitations of equal and opposite potentials to each set of independent center and outer motor electrodes, each mass cancels the charge generated by its own motion, thereby reducing the in-phase bias errors and minimizing limitations on dynamic range.
U.S. Pat. No. 6,862,934, to Weinberg, et al., recognized the problem that steady state acceleration or gravitational inputs in a direction perpendicular to the plane of the substrate cause both proof-masses to move away from the substrate resulting in a scale factor error. Moreover, tuning fork gyroscopes exhibit bias errors because the motor comb drives impart forces on the proof-masses along the sensing axis. Lift force is caused by the asymmetry where the bottom of the drive combs faces a ground plane while the top sees free space. Nominally, both the left and right outer motors exert forces in opposite directions so that the tuning fork (antiparallel mode) proof-mass motion is excited. The solution was to add sense plates above as well as below the proof-masses thus increasing the scale factor and sensitivity of the gyroscope, and by applying selected voltages to each of the sense plates depending upon the size of the gaps between the sense plates and the proof-masses, thus making tight manufacturing tolerances less critical and decreasing the gyroscope's scale factor sensitivity to acceleration.

Method and system for control and readout of tuning fork gyroscope

THE CHARLES STARK DRAPER LABORATORY, INC.


A temperature detection module for detecting a temperature of a measurement target is provided. The temperature detection module includes a temperature sensor, and a holder for holding the temperature sensor such that movement is possible in a separation and contact direction in which the temperature sensor is separated from and brought into contact with the measurement target. The temperature sensor includes a sensor main body portion in which a temperature detection element is accommodated, and a spring portion that is integrally provided on the sensor main body portion. The spring portion is of a type that expands and contracts only in a single direction, and expands and contracts only in the separation and contact direction. The spring portion is attached to the holder and biases the temperature sensor such that a detection surface comes into contact with the measurement target.

Conventionally, the technique disclosed in JP 2011-60675A has been known as a temperature detection module including a temperature sensor. The temperature detection module is attached to a power storage element group having multiple power storage elements.
A temperature sensor is attached to the temperature detection module. In the temperature sensor, an elastic arm protrudes obliquely upward from a main body portion in which a thermistor is accommodated. The elastic arm can be elastically deformed, and biases the main body portion toward the power storage element.


Isolated nucleic acids encoding allergens of Canis familiaris, Can f I or Can f II, are disclosed. A cDNA encoding a peptide having a Can f I activity and a predicted molecular weight of about 19,200 daltons is also described. A cDNA encoding a peptide having Can f II activity and a predicted molecular weight of about 18,200 daltons is also disclosed. The nucleic acids can be used as probes to detect the presence of Can f I or Can f II nucleic acid in a sample or for the recombinant production of petides having a Can f I or Can f II activity. Peptides having a Can f I or Can f II activity can be used in compositions suitable for pharmaceutical administration or methods of diagnosing sensitivity to dog dander.

Approximately 10% of the population become hypersensitized (allergic) upon exposure to antigens from a variety of environmental sources. Those antigens that induce immediate and/or delayed types of hypersensitivity are known as allergens (King, T. P., (1976) Adv. Immunol., 23: 77-105. These include products of grasses, trees, weeds, animal dander, insects, food, drugs, and chemicals. Genetic predisposition of an individual is believed to play a role in the development of immediate allergenic responses (Young, R. P. et al., (1990) Clin. Sci., 79: 19a) such as atopy and anaphylaxis whose symptoms include hay fever, asthma, and hives.
The antibodies involved in atopic allergy belong primarily to the IgE class of immunoglobulins. IgE binds to basophils, mast cells and dendritic cells via a specific, high-affinity receptor Fc.epsilon.RI (Kinet, J. P., (1990) Curr. Opin. Immunol, 2: 499-505). Upon combination of an allergen acting as a ligand with its cognate receptor IgE, Fc.epsilon.RI bound to the IgE may be cross-linked on the cell surface, resulting in physiological manifestations of the IgE--allergen interaction. These physiological effects include the release of, among other substances, histamine, serotonin, heparin, chemotactic factor(s) for eosinophilic leukocytes and/or leukotrienes C4, D4, and E4, which cause prolonged constriction of bronchial smooth muscle cells (Hood, L. E. et al., Immunology (2nd ed.), The Benjamin/Cumming Publishing Co., Inc. (1984)). Hence, the ultimate consequence of the interaction of an allergen with IgE are allergic symptoms triggered by release of the aforementioned mediators. Such symptoms may be systemic or local in nature, depending on the route of entry of the antigen and the pattern of deposition of IgE on mast cells or basophils. Local manifestations generally occur on epithelial surfaces at the site of entry of the allergen. Systemic effects can induce anaphylaxis (anaphylactic shock) which results from IgE-basophil response to circulating (intravascular) antigen.
The pet dog (Canis familiaris) is kept in households the world over. In houses and public schools where dogs have been kept on a regular basis, dog dander allergens can be detected in dust samples (Wood, R. A. et al., (1988) Am Rev Respir. Dis., 137: 358-363, and Dybendal, T. et al., (1989) Allergy, 44: 401-411). The prevalence of allergy to dogs as assessed by skin prick test is approximately 15% (Haahtela, T. et al., (1981) Allergy, 36: 251-256, and de Groot, H. et al., (1991) J. Allergy Clin. Immunol, 87: 1056-1065). In one study, sensitivity to dog allergen(s) was detected in 40% of asthmatic children, even though dogs were not kept as pets in their homes (Vanto, T. and Koivikko, A., (1983) Acta Paediatr Scand., 72: 571-575).
Treatment of patients with dog allergy by administration of dog dander extracts has not proven to be as efficacious as treatment of cat allergic patients with cat dander extracts (Hedlin, G. et al.,(1991) J. Allergy Clin Immunol., 87: 955-964). As with any desensitization scheme involving injection of increasing doses of allergen(s), there are the drawbacks of potential anaphylaxis during treatment, and the possible necessity of continuing therapy over a period of several years to build up sufficient tolerance that results in significant diminution of clinical symptoms.
Dog hair and dander extracts are complex mixtures containing a number of allergenic proteins. (Loewenstein, H et al., (1982) Proceedings 11th International Congress of Allergology and Clinical Immunology, London, pp 545-548; Uchlin, T et al., (1984) Allergy, 39: 125-133; Yman, L. et al., (1984) Int. Arch. Allergy Appl. Immunol.U, 44: 358-368; Spitzauer, S. et al., (1993) Int. Arch. Allergy Immunol., 100: 60-67). Two allergens present in dog hair/dander have been purified using immunoaffinity chromatography. A major allergen from dog, Can f I (Nomenclature according to the criteria of the IUIS (Marsh, D. G. et al., (1988) Clin. Allergy, 18: 201-209; Ag13 according to original nomenclature), has been partially purified by two groups (Schou, C. et al., (1991) Clin. and Exp. Allergy, 21: 321-328 and de Groot et al., supra). Both groups, partially purified Can f I was established as an allergen by CRIE analysis (Ford A. W. et al., (1989) Clin. Exp. Allergy, 19: 183-190), and then rabbits or Balb/b mice were immunized to obtain polyclonal or monoclonal antibodies against the allergen, respectively. Immunoaffinity purified Can f I (.about.25 kD in molecular weight, with a minor component .about.18 kD) which elicited a high frequency of positive skin prick tests among dog allergic patients was able to deplete 50-70% of IgE binding to dog dander extracts in RAST (radioallergosorbent test) analysis. While de Groot et al. did not attempt to determine any amino acid sequence of Can f I, Schou et al. found the amino terminus of their immunoaffinity purified Can f I was blocked. Hence, no amino acid sequence of Can f I is presently in the public domain.
The presence of a second (minor) allergen in dog extract was detected by binding of IgE antibodies to dog dander/hair extracts by several groups (de Groot et al., supra, Schou, C. et al., supra and Spitzauer et al., (1993) Int. Arch. Allergy Immunol., 100: 60-67). The molecular weight of a minor allergen was reported to be 18 kD (Schou et al., supra), 19 kD (Spitzauer et al., supra) and 27 kd (de Groot et el., supra). It is difficult however to correlate these results since only one group (de Groot et al., supra) affinity purified an allergen designated Can f II (originally named Dog 2 allergen). Can f II was purified from dog dander extracts in a manner analogous to Can f I using monoclonal antibodies generated to a second allergen present in extracts (de Groot et al., supra). Molecular weight of Can f II reported by this group as .about.27 kD was later verified to be .about.24 kD (Aalberse, R. C. personal communication). Purified Can f II allergen was found to react with IgE of only 66% of dog allergic patients. In RAST analysis, Can f II allergen was able to compete with 23% of the IgE directed against dog dander extract. The amino acid sequence of Can f II has not been previously determined.
Many patients with sensitivity to dog dander allergens are treated currently by administration of small, gradually increasing doses of dog dander extracts. Use of these extracts has multiple drawbacks, including potential anaphylaxis during treatment and the necessity of continuing therapy, often for a period of several years to build up sufficient tolerance and significant diminution of clinical symptoms. The ability to substitute compositions of at least the major dog dander allergens, such as Can f I and Can f II, would overcome several of these drawbacks. Thus, a source of pure allergen that could be provided in quantity for use as a diagnostic or therapeutic reagent and therapeutic methods that would overcome the drawbacks associated with dog dander extracts are highly desirable.

Allergenic proteins and peptides from dog dander and use therefor


A recessed region containing a line portion and a bulge portion is formed in a hard mask layer. Self-assembling block copolymers containing two or more different polymeric block components that are immiscible with one another are applied within the recessed region and annealed. A cylindrical polymeric block centered at the bulge portion is removed selective to a polymeric block matrix surrounding the cylindrical polymeric block. A via cavity is formed by transferring the cavity formed by removal of the cylindrical polymeric block into a dielectric layer. The pattern in the hard mask layer is subsequently transferred into the dielectric layer to form a line cavity. A metal via and a metal line are formed by deposition and planarization of metal. The metal via is self-aligned to the metal line.

A dual damascene integration scheme is a process integration scheme employed in semiconductor manufacturing to form metal vias and metal lines with a single metal fill process and a single metal planarization process. Two lithographic masks are employed to pattern via holes and metal line cavities separately in a conventional dual damascene integration scheme. Variations in the conventional dual damascene integration scheme includes a via first dual damascene integration scheme, in which via cavities are formed prior to patterning of line cavities, and a line first dual damascene integration scheme, in which line cavities are formed prior to patterning of via cavities. The via cavities and the line cavities formed in a dielectric layer are filled by the metal fill process at the same time. Upon planarization of the metal layer, metal vias filling the via cavities and metal lines filling the line cavities are simultaneously formed.
Since the line cavities and the via cavities are formed in separate lithographic processes, it is necessary to control the overlay between the pattern for the via cavities and the pattern for the line cavities. For high performance semiconductor chips employing high density semiconductor devices and high density metal wiring, critical masks, i.e., lithographic masks having the smallest possible overlay tolerance in alignment with another level during the lithographic imaging process, need to be employed for patterning the via cavities and the line cavities to insure that sufficient overlap is present between the resulting metal vias and metal lines. Use of such critical masks increases manufacturing cost significantly since lithographic processing steps, and especially critical level lithographic processing steps, require expensive state-of-the-art lithographic equipment.
Further, even with such state-of-the-art lithographic equipment, overlay variations between two lithographic images are necessarily finite. With continual reduction in feature size and the limited capabilities of lithographic tools to scale overlay tolerance with the scaling of feature sizes of metal lines and metal vias, the overlay variations between the image of via cavities and line cavities may statistically result in a significant reduction in contact area between metal vias and metal lines and adversely affect yield, performance, and/or reliability of the metal interconnect structure.
In view of the above, there exists a need to provide a metal interconnect structure that may be manufactured with reduced processing cost through reduction in the number of lithographic steps employed to pattern via cavities and line cavities.
Further, there exists a need for a metal interconnect structure in which the overlay variation between a via cavity and a line cavity is reduced or eliminated so that yield, performance, and/or reliability of the metal interconnect structure is enhanced, and methods of manufacturing the same.

Dual damascene metal interconnect structure having a self-aligned via


A detonator for a hand grenade fuze comprises a detonator case; a slider that is transversely reciprocable in the detonator case from an unarmed position to an armed position, the slider including a longitudinal through-hole filled with a primary explosive; a spring that biases the slider to the unarmed position; an arming mechanism attached to the slider, the arming mechanism comprising a shape memory alloy; an explosive lead disposed below the slider; and a booster charge disposed below the explosive lead.

The invention relates in general to hand grenades and in particular to fuzes for hand grenades.
Grenades, such as the M67 fragmentation hand grenade, are widely used in the field by the US Army and US Marine Corps. The present fuze for the M67 hand grenade does not comply with the Insensitive Munitions (IM) requirements. This problem relates to the C70 Detonator used in the fuze. The detonator contains large quantities of lead-based primary explosives (lead azide, lead styphnate) as well as RDX. These explosives initiate the grenade under many of the IM test conditions. Safety issues, in combination with the environmental compliance requirements for use of lead compounds, make the manufacture of these detonators an unattractive investment for US-based manufacturers.
A need exists for a new hand grenade fuze. The new fuze must not impact the lethality of the present design (M67), while meeting the IM safety requirements. It also should reduce the item's total life-cycle cost, and the soldiers' and environment's exposure to lead.

The United States of America as represented by the Secretary of the Army


An ankle and foot orthosis brace for use in supporting and immobilization of a patient's ankle and foot. The brace is of a multiple part L-shaped configuration with a contoured leg support portion and a foot portion interconnected by an incrementally adjustable hinge assembly therebetween. A foot pad with apertured tabs extending therefrom is part of the foot portion with adjustable fabric fasteners extending from both the foot portions apertured tabs and the leg support portion secured to the brace to the patient's leg and foot.

1. Technical Field
The present invention relates to leg and foot brace devices that are secured to a patient's foot and leg. Such devices are used to maintain constant pressure against the foot, sole and ankle of the patient for therapeutic purposes.
2. Description of Prior Art
Prior art devices of this type provide for a variety of leg, ankle and foot stabilization utilizing two-part brace assemblies interconnected by free hinges of an elastomeric materials as seen in U.S. Pat. No. 5,496,263 that permit the tolocural articulation to move about a single axis.
U.S. Pat. No. 5,486,157 discloses a hinge at the apex of a contoured heel portion to provide free dorsiflexion and plantar flexion with a pivot point below the hinges for inversion, eversion, pronation, and supination of the foot.
Another orthotic brace is illustrated in U.S. Pat. No. 5,086,760 which provides support to an anatomical joint that connects the lower leg with the foot that is selectively adjustable for predetermining the extent or angular range of dorsiflexion/plantar flexion and inverse/eversion of the foot. Such orthotic joints are also seen in U.S. Pat. Nos. 5,542,774 and 5,611,773.
In U.S. Pat. No. 5,542,774 a joint is illustrated having an interchangeable cam follower of shock absorbent material for more comfortable and therapeutic use.
In U.S. Pat. No. 5,611,773 multiple adjustable insert pins for an ankle pivot cap that allow for pin adjustment by movement within a contoured pivot path by corresponding registration with a dorsiflexion limiting aperture or plantar flexion limiting apertures.
A foot brace can be seen in U.S. Pat. No. 4,934,355 having a heel cup flexible connector to a leg engagement portion. The flexible connection is formed by an elastomeric block therebetween.
Applicant's own prior art patents U.S. Pat. Nos. 5,088,479 and 5,593,383 disclose orthotic devices which are characterized by an adjustable foot portion interconnected to a leg portion by a semi-flexible heel member.
U.S. Pat. No. 5,593,383 introduces a foot pad with a securing apparatus to enhance and simplify usefulness.
U.S. Pat. No. 5,088,479 discloses a basic ankle and foot orthosis device having adjustable length and height for the leg and foot portion respectively.


The present disclosure relates to systems, methods, and non-transitory computer readable media for generating a predicted response to a digital survey question and identifying digital survey questions to remove from a digital survey. For example, the disclosed systems can reduce the number of digital survey questions distributed as part of a digital survey by identifying and removing similar digital survey questions. In addition, the disclosed systems can generate a predicted response to an unprovided digital survey question based on determining relationships between respondents. Further, based on respondent relationships, the disclosed systems can identify digital survey questions that a respondent is likely to answer and can provide the digital survey questions to a respondent device of the respondent.

Advancements in software and hardware platforms have led to a variety of improvements in systems that provide digital surveys to respondent devices and collect survey response information based on responses to digital survey questions. For example, digital survey systems are now able to provide digital survey questions of many different question types across various platforms of respondent device types. Despite these advances however, conventional digital survey systems continue to suffer from a number of disadvantages.
For example, conventional systems often generate inaccurate survey response information by providing digital surveys with too many digital survey questions. Empirical data suggests that the longer the digital survey the less time each respondent device spends on each digital survey question. Researchers have shown that digital surveys with 30 digital survey questions take respondent devices an average of 10 minutes to complete, giving an average time spent per digital survey question of 19 seconds. On the other hand, researchers have shown that a digital survey with 1 question takes respondent devices an average of 75 seconds to complete. Based on this research, long digital surveys can result in low-quality, inaccurate digital survey responses collected via the digital surveys. However, digital surveys that are too short can result in too few responses collected and the digital surveys can therefore be less informative.
Conventional digital survey systems are also inefficient. In particular, many conventional systems inefficiently utilize computer resources such as computing time and computing power. Indeed, in an attempt to collect actionable information, conventional systems often generate and provide digital surveys with large numbers of digital survey questions. By generating, providing, and collecting responses for such large numbers of digital survey questions, these conventional systems utilize excessive amounts of computing time and computing power processing the generation, transmittal, and analysis of the digital survey questions and the corresponding responses from potentially large numbers of respondent devices (e.g., 10,000 or more). Moreover, digital surveys with such large numbers of digital survey questions require onerous numbers of respondent interactions and response time on the part of respondents completing the digital survey via respondent devices.
Additionally, conventional digital survey systems are inflexible. More specifically, conventional systems often generate and distribute digital surveys with a fixed number of digital survey questions. Indeed, for a given digital survey, many conventional digital survey systems generate a uniform set of digital survey questions to provide to each respondent device across the board. Thus, these conventional systems cannot adapt digital surveys to accommodate individual preferences of respondents or time constraints of respondents that can often result in the collection of low-quality response information or no response information, as mentioned above.
Thus, there are several disadvantages with regard to conventional digital survey systems.

Generating and distributing digital surveys based on predicting survey responses to digital survey questions


A digital-data-transmission-line circuit for actively clamping transmission signal and signal-complement amplitudes so as to reduce pattern-related jitter at a receiver/analyzer. The circuit includes a pair of opposing diode devices, where each diode device is coupled across the pair of conducting wires that make up the transmission line. The diode devices clamp the difference in potential between the two transmission lines so that the signal amplitude seen at the receiver will not vary to significantly with the number of like pulses that are transmitted in succession. In this manner, the present invention reduces pattern-dependent jitter in the cross-over from HIGH to LOW as seen at the receiver. By means of the parasitic capacitance accompanying the diode devices, the circuit of the present invention additionally provides some high-frequency filtering and smoothing of the waveform of the received signal.

1. Field of the Invention
The present invention relates to clamping differential drivers. More particularly, the present invention relates to the field of digital data transmission. More particularly yet, the present invention relates to improving the consistency of digital data transmissions over long cables and especially to reducing pattern-dependent jitter when such cables are used. Still more particularly, the present invention is a clamping circuit for reducing pattern-dependent jitter in digital data transmission/reception by means of amplitude clamping and also for high-frequency filtering in such transmission/reception.
2. Description of the Prior Art
Digital data is typically transmitted between electronic devices such as telephones, facsimile machines, computers, and the like, by simple electric cables. Such a cable can be as simple as a pair of twisted wires, the impedance of which is about 50-100 ohms, an acceptable and accounted-for impedance. However, when such cables are used to transmit data over great distances (which can be defined as distances in excess of 30 meters) and/or when the rate of data transmission becomes high, the cable itself becomes an important component of the overall system, in that its increasing resistance can result in data errors being introduced at the receiving end of the cable, related to an increase in the ramping of bit patterns.
For present purposes, it is sufficient to think of the transmission cable as a single pair of wires connected to a transmitter which at any instant is imposing on one member of the pair a signal and on the other member of the pair a signal-complement. The signal is binary and at any time one wire will have imposed on it by the transmitter either a HIGH signal or a LOW signal, while the complement of that signal is imposed on the other member of the pair. Of course, either wire can conduct either signal. The two wires are typically connected to a differential receiver for subsequent processing.
Under ideal transmission/reception conditions, the signals imposed at the transmission end of the line will be exactly reproduced at the receiver. This will be achieved if the rise-time and fall-time (for LOW-to-HIGH and HIGH-to-LOW transitions, respectively) of the voltage on the cable is extremely well defined and consistent. Although this is physically impossible, given that the cable is a real physical entity with its own characteristic impedance leading to finite rise- and fall-times, it is sufficient as a practical matter that these times be short with respect to the duration of the individual pulses making up the digital signal.
As transmission lines become longer--with a concomitant increase in their rise--time-and signal rates higher--with a concomitant decrease in pulse-width--it becomes increasingly more challenging to ensure that the signal seen at the receiver bears a unique correlation to the signal imposed at the transmitter end of the cable. Although it is not necessary that there be exact identity between these two signals, it is necessary that the correlation does not depend on things such as a particular pattern of HIGHs and LOWs transmitted.
For definiteness, this discussion will address most transmission systems, with varying definitions of what constitutes HIGH and LOW, respectively. In particular, it will be directed to systems in which a "high" voltage level is identified generically as VOH, while a "low" ,voltage level is identified generically as VOL. The particular voltage levels and swings associated with VOH and VOL depend upon the particular transmission/reception circuitry associated with the transmissions. For example, in emitter coupled logic (ECL) systems and low voltage differential systems (LVDS), the swings between VOH and VOL are relatively small--on the order of 700 mV for example. On the other hand, for transistor-transistor logic (TTL) systems, the swings between VOH and VOL may be much greater--on the order of 2 V or more.
In order to have a reproducible transmission of data, there must be a correlation between the HIGH/LOW or LOW/HIGH "cross-over" , at the transmitter and the cross-over at the receiver. If that correspondence is not achieved, an incoming signal may not be translated properly and bits of information may be lost for failure to be read properly. Although the respective cross-overs at the two ends of the cable will not occur at precisely the same instant, it is important to ensure that any delay that exists remains constant and, in particular, not dependent on the pattern of HIGHs and LOWs imposed by the transmitter.
FIG. 1 depicts a simplified transmission/reception system in accord with the above discussion. It shows an incoming signal 5 giving rise at the input driver 6 to itself and to its complement prior to being imposed on the transmitter-ends of a signal line 8 and a signal-complement line 9, the receiver ends of which are connected to an input driver or translator 7, generally a differential driver. By this circuit arrangement, HIGH/LOW signal strings representing digitized information--such as voices, music, pictures, etc.--are delivered from one location to another. It is the transmission fidelity of these strings that is of interest here. The particular problem addressed is data loss arising from transition time jitter which in turn is due to HIGH-to-LOW transition-interval variation based on signal string pattern.
If the charge time of the transmission line is significant with respect to the pulse-width of the signal imposed on the line by the transmitter, then the amplitude of the HIGH pulse seen by the receiver will vary with signal pattern. To see this, consider first that the signal imposed by the transmitter consists of a simple string of pulses 01010101010101--the highest transmission frequency possible. When the rise time of the transmission line is greater than the pulse width, the voltage seen by the receiver during a single HIGH pulse will not reach the maximum VOH; indeed, the voltage at the receiver will still be rising when the HIGH-to-LOW transition is imposed. In the extreme case, the transmission cable may load down the transmitter so much that the voltage seen at the receiver may never reach an unambiguous HIGH level associated with the particular VOH of the particular transmission/reception system. This is not the situation being addressed here, but rather the situation where the voltage at the receiver reaches some level higher than a minimal VOH but lower than an ideal VOH during a time interval of one pulse-width. Thus, even though the voltage at the receiver does not reach the level imposed by the transmitter, it will be high enough to cause a LOW-to-HIGH transition at the receiver end. It can be seen that, up to a point, the more HIGH pulses are transmitted in succession the higher the voltage will reach at the receiver. This per se will not cause a problem, since anything above the minimal VOH will be read as HIGH. The problem comes from the fact that the higher the transmission-cable voltage is when a HIGH-to-LOW is imposed, the longer it will take for the voltage on the transmission line to fall to the cross-over voltage, that is, to the voltage where the receiver will make the transition to LOW. Thus, for example, the mid-string HIGH-to-LOW transition at the receiver will occur at a different time for the string 11110000 than it will for the string 01010000. Since generally the systems will be driven by an internal system clock, this means that, depending on the particular nature of the signal string being transmitted, the instant at which a particular HIGH-to-LOW transition occurs will deviate from the clock transition time by an amount depending on the preceding signal string. This shifting back and forth about the clock period is referred to as pattern-dependent jitter, something that may result in an indeterminant signal level, resulting in the dropping of a bit. While loss of a single bit is of minimal concern, it is undesirable to have unnecessarily high bit error rates in transmissions.
As far as is known, there is no prior art relating to the reduction of the pattern-dependent jitter described above. As is discussed below, the approach of the present invention to this reduction involves a diode-based clamping of the receiver-input voltage. In the general field of using diodes to clip amplifier input, for example for protection against electrostatic spikes, there is of course prior art. For example, U.S. Pat. No. 5,589,813 issued to Nielsen in 1996, describes the use of a pair of diodes essentially as electrostatic discharge (ESD) protection devices in a communications system. Nielsen thus provides a pathway for voltage transients that may or may not ever occur. This contrasts greatly with the use of diodes to address pattern-dependent jitter on transmission lines that otherwise would occur on a fairly regular basis. Moreover, Nielsen includes a capacitor in series with the diodes, which capacitor will cause an opening of the circuit including the diode pathways after there is a transition between HIGH and LOW signals, thus preventing further signal transfer through the open pathway.
What is needed is a circuit that actively clamps excess amplitude voltage signals particularly evident of pattern-dependent jitter. That is, what is needed is a circuit that limits the relative maximum amplitude between the complementary signals delivered by the differential pair of transmission lines. What is also needed is such a circuit that remains operative during signal transitions and during fixed patterns of either HIGH or LOW transmissions. Further, it is also preferred to have a circuit that provides some beneficial high-frequency filtering in addition to clamping. Still further, what is needed is such circuitry that is readily compatible with existing differential drivers and that is relatively simple to manufacture.