The invention concerns a method for the modulation of tissue-remodeling processes, by contacting the tissue to be remodeled with a compound comprising a sequence derived from certain regions of TGF-xcex2 super family Ser/Thr/kinase receptors.

The present invention concerns methods and compounds for changing (modulating) tissue-remodeling processes.
The eukaryotic protein kinase superfamily is composed of enzymes which specifically phosphorylate serine, threonine or tyrosine residues of intracellular proteins. These enzymes are important in mediating signal transduction in multicellular organisms and are involved in a wide variety of cellular events. A few examples include: cellular proliferation, cellular differentiation, oncogenesis, immune responses, and inflammatory responses.
Enhanced protein kinase activity can lead to persistent stimulation by secreted growth factors and other growth inducing factors which, in turn, can lead to proliferative diseases such as cancer, to nonmalignant proliferative diseases such as arteriosclerosis, psoriasis and to inflammatory responses such as septic shock. Decreased function can also lead to disease. For example, a decrease in the activity of insulin receptor kinase is a cause of various types of diabetes.
Thus, agents which can modulate (increase or decrease) the activity of protein kinases have great potential for the treatment of a wide variety of diseases and conditions such as cancer, autoimmune disorders, and inflammation.
PKs are known to have homologous xe2x80x9ccatalytic domainsxe2x80x9d which are responsible to the phosphorylation activity. Based on a comparison of a large number of protein kinases, it is now known that the kinase domain of protein kinases can be divided into twelve subdomains. These are regions that are generally uninterrupted by large amino acid insertions and contain characteristic patterns of conserved residues (Hanks and Hunter, xe2x80x9cThe Eukaryotic Protein Kinase Superfamilyxe2x80x9d, in Hardie and Hanks ed., The Protein Kinase Facts Book, Volume I, Academic Press, Chapter 2, 1995). These subdomains are referred to as Subdomain I through Subdomain XII.
Due to the high degree of homology found in the subdomains of different protein kinases, the amino acid sequences of the domains of different PKs can be aligned. Frequently, the alignment is carried out with reference to the prototypical protein kinase PKA-Cxcex1, as known in the art. Currently, the catalytic domains of a large number of protein kinases have been aligned and tables showing these alignments are available from various published sources, such as, for example, in the article by Hanks and Quinn in Methods of Enzymology 200: 38-62 (1991) or in the PKR Web Site: www.sdsc.edu/kinases.
U.S. Pat. No. 6,174,993, International Application WO 98/53051 (corresponding to pending U.S. Application 08/861,153), International Application WO 00/118895 (corresponding to U.S. Ser. No. 09/161,094, now abandoned), U.S. applications Ser. No. 09/458,491, now abandoned (corresponding to WO 01/42280), and U.S. Ser. No. 09/734,520, now abandoned (corresponding to WO 02/48336) (all incorporated herein by reference) concern small, previously undisclosed, regions of various protein kinases with high substrate specificity. Short peptides derived from these regions were found to modulate kinase activities, as determined by the modulation of cellular activity in various in vivo and in vitro models. Without wishing to be bound by theory it is assumed that the short peptides disclosed in these applications, mimic some region of the catalytic domain of the kinase, bind to other cellular components with which the kinase interacts (such as the substrates of the kinase, other kinases, other phosphatases) and thus modulate kinase activity either by mimicking the kinase activity, or alternatively by inhibiting the interaction of the kinase and the cellular components thus inhibiting kinase-mediated signaling.
U.S. Pat. No. 6,174,993 and WO 98/53051 disclose a domain termed the HJ-loop. The xe2x80x9cHJ-loopxe2x80x9d referred to therein is found within the kinase domain of protein kinases between the middle of Subdomain IX and the middle of Subdomain X. Because of the high degree of homology found in the subdomains of different protein kinases, the amino acid sequences of the domains of different ser/thr protein kinases can be aligned. Thus, the HJ-loop of protein kinases can be defined by reference to the amino acid sequence of a prototypical protein kinase, for example PKA-Cxcex1, and can be said to correspond to a contiguous sequence of about twenty amino acid residues found between about amino acid 229 and 248 of PKA-Cxcex1.
A second definition of the HJ loop of protein kinases, which is complementary to the definition provided in the proceeding paragraph, can be made by reference to the secondary structure of the kinase domain of protein kinases. The kinase domain of protein kinases has been found to contain at least nine alpha helices, referred to as helix A through helix I, nine beta sheets, referred to as b1 through b9 (Tabor et al., Phil. Trans. R. Soc. Lond. B340: 315 (1993), Mohammadi et al., Cell 86:577 (1996) and Hubbard et al., Nature 372:746 (1994)). The HJ loop is a contiguous sequence of about twenty amino acids beginning within the F helix about five amino acids residues from the N-terminus of the F helix and extending about five amino acid residues into the G helix. It is noteworthy that the HJ-loop of the TGF-xcex2/ILK family of protein kinases contains an insertion of about 12 to 15 extra amino acids as compared to other ser/thr or tyrosine (tyr) protein kinases.
WO 02/48336 discloses a region termed the xe2x80x9cA-regionxe2x80x9d. The xe2x80x9cA-regionxe2x80x9d referred to herein is found within the kinase domain of PKs in Subdomain III and Subdomain IV. With respect to the amino acid sequence of the prototypical protein kinase PKA-Cxcex1 the A region can be said to correspond to a contiguous sequence of about eighteen amino acid residues found between about amino acids 92 and 109 of PKA-Cxcex1. In some PKs, extra amino acids can be present in this region and the size of the A-region can, therefore, include more than 18 amino acids in length.
With respect to the secondary structure of protein kinases, the A region is a contiguous sequence of about five to twenty amino acids beginning at the middle of the xcex1C helix (hereby xcex1C) and ending at the beginning of the b4 beta sheet.
WO 01/42280 discloses a region termed B4-B5 region. The xe2x80x9cB4-5 regionxe2x80x9d referred to herein is found within the kinase domain of PKs in Subdomain IV and the beginning of Subdomain V. With respect to the amino acid sequence of the prototypical protein kinase PKA-Cxcex1, the B4-5 region can be said to correspond to a contiguous sequence representing the amino acid residues found between about amino acids 106 and 114 of PKA-Cxcex1.
In some PKs, extra amino acids might be inserted in this region and the size of the B4-5 region can, therefore, include more than 9 amino acids in length.
A second definition of the B4-5 region of a PK, which is complementary to the definition provided in the preceding paragraph, can be made by reference to the three dimensional structure of the kinase domain of PKs. The kinase domain of PKs has been found to contain at least nine alpha helices, referred to as helix A through helix I and nine beta sheets, referred to as b1 through b9 (Tabor et al., Phil. Trans. R. Soc. Lond., B340: 315 (1993), Mohammadi et al., Cell, 86:577 (1996) and Hubbard et al., Nature 372:746 (1994). The B4-5 region is a contiguous sequence of about five to twenty five amino acids beginning at the end of the b4 beta sheet and into the b5 beta sheet.
WO 00/18895 discloses a region termed the xe2x80x9cxcex1D regionxe2x80x9d. The xe2x80x9cxcex1D regionxe2x80x9d referred to herein is found within the kinase domain of PKs in Subdomain V and the beginning of Subdomain VI. The xe2x80x9cxcex1D regionxe2x80x9d of a PK can be defined by reference to the amino acid sequence of a prototypical protein kinase, for example PKA-Cxcex1 and can be said to correspond to a contiguous sequence of about twenty amino acid residues found between about amino acid 120 and 139 of PKA-Cxcex1.
In relation to the secondary structure of the kinase domain of PKs, the xcex1D region is a contiguous sequence of about fifteen to forty amino acids beginning at the end of the b5 beta sheet and extending through the D helix and the following loop to the beginning of helix E.
The three dimensional structure of a number of kinases has been determined. A classical view of this structure is given in Knighton et al., Science 253, 407-414 (1991).
The superfamily of transforming growth factor beta (TGF-xcex2), which include TGF-xcex2, activins, and bone morphogenetic proteins (BMPs), are secreted agents that regulate a plurality of cellular responses such as proliferation, differentiation, migration and apoptosis.
TGF-xcex2 superfamily signaling has been implicated in a multitude of disorders and in various human diseases, including: cancer, fibrosis and autoimmune diseases. TGF-xcex2 superfamily members transduce their signals across the plasma membranes by inducing the formation of heteromeric complexes of specific type I and type II serine/threonine kinase receptors, which in turn activate a particular subset of SMAD proteins (some of them being inhibitory and some being excitatory). The SMAD molecule compounds relay the signals into the nucleus where they direct transcriptional responses in concert with other proteins.
TGF-xcex2 superfamily was found to be involved in embryogenesis-related physiological functions such as: regulation of growth, cell-faith specification, differentiation and apoptosis; in postnatal mechanisms including inhibition of cell growth (epithelial, vascular endothelial, hematopoietic cells and lymphocytes), induction of synthesis of IgA in B-lymphocytes, in control of wound healing processes and remodeling; in BMP-dependent responses including induction: of fibroblasts, osteoblasts in the process of cartilage and bone formation, respectively, involvement in bone genesis and spermatogenesis.
Malfunction connected with TGF-xcex2 has been linked to several clinical disorders including cancer, fibrosis, bone diseases, diabetic nephropathy, primary pulmonary hypertension, as well as chronic vascular diseases such as artheriosclerosis and hypertension.
There have been attempts to try and modify the process of bone healing by changing the concentrations of the TGF-xcex2 ligands. For example, various attempts have been made to increase the rate of bone healing by locally administrating to the fracture and of various TGF-xcex2 and BMP ligands, as well as by application of other growth factors. However, to date the results of these attempts have not been successful.
The present invention is based on the discovery that administration to the tissue of various compounds, which comprise peptides, having either a sequence appearing in one of four specific regions of TGF-xcex2 superfamily serine/threonine kinase receptor, or a variant of said sequence, resulted in a marked alteration of tissue remodeling processes in the tissue to which the compound was administered.
Without wishing to be bound by theory, it is assumed that the peptide part of the compound, mimics a region in the kinase that interacts with other cellular components such as the substrates of the kinase; phosphatases or other kinases which regulate the level of phosphorylation of the TGF-xcex2 kinase. The peptide part of the compound thus interrupts the interaction of the native kinase with the other cellular components (for example the substrates). Where the interaction between the kinase and the cellular component is an xe2x80x9conxe2x80x9d reaction, i.e., having a net result of the increase of physiological property such as increased transcription (for example interaction of the TGF-xcex2 kinase with an excitatory SMAD), the effect of the interruption of the xe2x80x9conxe2x80x9d reaction is inhibition of the property, for example inhibition of collagen synthesis. Where the interaction between the kinase and the cellular component is an xe2x80x9coffxe2x80x9d reaction, i.e., has a net result of decrease of physiological property, for example, decrease of transcription (such as interaction of TGFxcex2 with inhibitory SMAD), the interruption of the xe2x80x9coffxe2x80x9d reaction results in increased physiological property such as increased transcription leading to increased bone healing.
Thus, the present invention concerns a method for the modulation of tissue-remodeling comprising: contacting the tissue to be remodeled with an effective amount of a compound comprising a sequence selected from:
(a) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 super family Ser/Thr kinase receptor, in positions of the receptor corresponding to positions 249 to 279 of TGF-xcex2I receptor (HJ loop);
(b) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 super family Ser/Thr kinase receptor, in positions of the receptor corresponding to positions 119 to 139 of TGF-xcex2I receptor (xcex1D region);
(c) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 super family Ser/Thr kinase receptor, in positions of the receptor corresponding to positions 104 to 115 of TGF-xcex2I receptor (B4-B5 region);
(d) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 super family Ser/Thr kinase receptor, in positions of the receptor corresponding to positions 89 to 103 of TGF-xcex2I receptor (A-region);
(e) a variant of a sequence according to any one of (a) to (d) wherein up to 40% of the amino acid of the native sequence have been replaced with a naturally or non-naturally occurring amino acid or with a peptidomimetic organic moiety; and/or up to 40% of the amino acids have their side chains chemically modified; and/or up to 20% of the amino acids have been deleted; provided that at least 50% of the amino acids in the parent sequence of (a) to (d) are maintained unaltered in the variant, and provided that the variant maintains the biological activity of the parent sequences of (a) to (d);
(f) a sequence of any one of (a) to (e) wherein at least one of the amino acids is replaced by the corresponding D-amino acid;
(g) a sequence of any one of (a) to (f) wherein at least one of the peptidic backbones has been altered to a non-naturally occurring peptidic backbone;
(h) a sequence being the sequence of any one of (a) to (g) in reverse order; and
(i) a combination of two o r more of the sequences of (a) to (h)
The term xe2x80x9ctissue-remodelingxe2x80x9d, in the context of the present invention, refers to a wide variety of cellular and tissue-related processes which are characterized by a generation of new cells or tissues and/or degeneration of existing cells or tissues, or characterized by a change in the ratio between generation and degeneration of cells or extracellular matrix, which leads to a change in the entire tissue manifested by: increased tissue growth, decreased tissue growth, prevention of tissue formation, enhanced tissue healing, change in the proportion of various cell types in the tissue, change in the level of extracellular matrix in the tissue, etc. In particular, this term refers to, but is not limited to, bone remodeling (and in particular bone healing); skin-remodeling including in particular skin healing and prevention of scar formation in the skin; change of amount collagen deposition and in particular decrease of fibrosis formation, resulting in decreased scarring, and improved wound healing after surgery or injury, as well as decrease of post-surgery adhesions; change of cell proliferation and myogenic differentiation. This term includes, but is not limited to, skin remodeling, skin healing, scar formation, prevention of alopecia, improved hair growth, inhibition of fibrosis, modulation cell migration (including neuronal crest cell migration), modulating cell proliferation, modulating adipose tissue proliferation, and modulating myogenic differentiation.
The term xe2x80x9cmodulationxe2x80x9d refers to a change (increase or decrease) in the level of tissue-remodeling, as compared to the level of tissue-remodeling in the absence of the compound of the invention or in the presence of a control compound. The change should be statistically significant. The change of level can be determined in accordance with each tissue remodeling phenomena, for example, modulation of bone healing (which is a tissue remodeling process) can be determined by decrease in the time required until complete bone healing, by measurement of the size of callous formation, by determination of the amount of the normal bone produced in a set period of time, etc. Modulation in connection with fibrosis may be carried out by comparing the size of fibrous tissue in a test as compared to control, by comparing the amount of collagen deposition in test vs. control, etc.
Modulation of an individual""s tissue-remodeling refers to, for example, an inhibition of alopecia, enhancement of bone growth, prevention of fibrosis and scar formation, prevention of adipose cell proliferation, prevention of excess fibrosis formation in a plurality of diseases such as pulmonary fibrosis, chronic renal disease, scleroderma, liver cirrhosis, keloid formation, post-surgical adhesions and the like.
As will be explained later in detail, while direct assessment of tissue remodeling has to be carried out in tissue or in vivo, a good indication of tissue remodeling processes and modulation of said processes can be achieved by assessing the level of TGF-xcex2-associated signal transduction in cells (for example by determination of TGF-xcex2-dependent proliferation of fibroblasts) or in cell-free assays (such as by determination of the level of phosphorylation of the TGF-xcex2-kinase substrates).
The term xe2x80x9ccompound (comprising sequence)xe2x80x9d refers to a compound that includes therewithin any of the sequences of (a) to (i) as defined above. The compound may be composed mainly from amino acid residues, and in that case the amino acid component of the compound should comprise no more than a total of about 35 amino acids. Where the compound is mainly an amino acid compound, it may consist of any one of the amino acid sequences of (a) to (h), a combination of two or more, preferably of three most preferably of two, of the sequences of (a) to (h) linked to each other (either directly or via a spacer moiety) to give the combination of (i). The compound may further comprise any one of the amino acid sequences, or combinations as described above (in (a) to (i) above), together with additional amino acids or amino acid sequences. The additional amino acids may be sequences from other regions of the TGF-xcex2-kinase, sequences that are present in the kinase vicinity of the regions, N-terminal or C-terminal to the sequences of (a) to (d), or sequences which are not present in the TGF-xcex2-kinase but were included in the compound in order to improve various physiological properties, such as penetration into cells (sequences which enhance penetration through membranes or barriers); decrease degradation or clearance; decrease repulsion by various cellular pumps; improve immunogenic activities; improve various modes of administration (such as attachment of various sequences which allow penetration through various barriers, blood brain barrier, through the gut, etc.); increase specificity; increase affinity; decrease toxicity; and the like. A specific example is the addition of the amino acid Gly to the N-terminal of the sequence.
The compound may also comprise non-amino acid moieties, such as, for example, hydrophobic moieties (various linear, branched, cyclic, polycyclic or heterocyclic hydrocarbons and hydrocarbon derivatives) attached to the peptides of (a) to (i) to improve penetration, various protecting groups, especially where the compound is linear, attached to the compound""s terminals to decrease degradation; chemical groups present in the compound to improve penetration or decrease toxic side effects; or various spacers, placed, for example, between one or more of the above amino acid sequences, so as to spatially position them in a suitable orientation in respect of each other. The compound of the invention may be linear or cyclic, and cyclization may take place by any means known in the art. Where the compound is composed predominantly of amino acids/amino acid sequences, cyclization may be N- to C-terminal, N-terminal to side chain and N-terminal to backbone, C-terminal to side chain, C-terminal to backbone, side chain to backbone and side chain to side chain, as well as backbone to backbone cyclization. Cyclization of the compound may also take place through the non-amino acid organic moieties.
The association between the amino acid sequence component of the compound and other components of the compound may be by covalent linking, by non-covalent complexion, for example, by complexion to a hydrophobic polymer, which can be degraded or cleaved producing a compound capable of sustained release; by entrapping the amino acid part of the compound in liposomes or micelles to produce the final compound of the invention. The association may be by the entrapment of the amino acid sequence within the other component (liposome, micelle) or the impregnation of the amino acid sequence within a polymer to give the final compound of the invention.
Preferably the compounds comprise an amino acid sequence of (a) to (i) above in association with (in the meaning described above) a moiety for transport across cellular membranes.
The term xe2x80x9cmoiety for transport across cellular membranesxe2x80x9d refers to a chemical entity, or a composition of matter (comprising several entities) that causes the transport of members associated (see above) with it through phospholipidic membranes. One example of such moieties are hydrophobic moieties such as linear, branched, cyclic, polycyclic or heterocyclic substituted or non-substituted hydrocarbons. Another example of such a moiety are short peptides that cause transport of compounds attached to them into the cell by gradient derived, active, or facilitated transport. Other examples of other non-peptidic moieties known to be transported through membranes, such as glycosylated steroid derivatives, are well known in the art. Yet another example are moieties that are endocytosed by cellular receptors such as ligands of the EGF and tranferrin receptors. The moiety for the transport across membranes may be a polymer, liposome or micelle containing, entrapping or incorporating the amino acid sequence therein. In the above examples, the compound of the invention is the polymer, liposome, micelle, etc., impregnated with the amino acid sequence.
The term xe2x80x9ca sequence which is a continuous stretch of at least 5 amino acids present . . . xe2x80x9d refers to any continuous stretch of at least 5 amino acids, which are present in a longer amino acid sequence described by reference to positions of TGF-xcex2I (see below). For example, if in a specific TGF-xcex2 Ser/Thr kinase receptor, the positions corresponding to amino acid residues X to Y of TGF-xcex2I are amino acid residues 200 to 219 of that specific kinase, the continuous stretch of at least 5 amino acids may be from amino acid at position 200 to 204, from 201 to 205, from 216 to 220, from 210 to 214, etc. The continuous sequence may also be of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 amino acids, obtained from each of these positions.
The term xe2x80x9cTGF-xcex2 superfamily Ser/Thr kinase receptorxe2x80x9d (hereinafter xe2x80x9cTGF-xcex2 kinasexe2x80x9d) refers to both Type I receptors (ALK 1-7) as well as Type II receptors (ACTR-II, ACTR-IIb, TGF-B-II, BMPR-II, and AMHRII), and includes receptors which are activated by all of the ligands of the superfamily, examples of the ligands being TGF-xcex2, BMP""s, as activins/inhibins, AMH, and GDF. In one specific example, the TGF-xcex2 superfamily Ser/Thr kinase receptors are selected from ALK1, ALK2, ALK3, ALK4, ALK5, ALK6, TGF-B-II, activin RII, BMPRII and ILK.
The term xe2x80x9csequence corresponding to positions . . . to . . . of TGF-xcex2Ixe2x80x9d refers to a sequence that matches the sequence appearing in the native TGF-xcex2I receptor 1 when the sequence of the catalytic unit of the specific kinase is aligned with the sequence of the catalytic unit of TGF-xcex2I. TGF-xcex2I is identified as in the chain-D crystal structure of the cytoplasmic domain of TGF-xcex2 receptor in complex with Fkbp12 (gi 5542077 in the NCBI database, in the PDB entry). The positions of the TGF-xcex2I receptor 1 kinase beginning in a certain position and ending in another position are indicated in the definition (a) to (d) above. For determining the beginning and end positions of the specific kinase used, the sequence of the catalytic unit of the specific kinase should be aligned with the sequence of the catalytic unit of TGF-xcex2I in pair-wise or multiple alignment manner. Alignment may be carried out using any state of the art software such as ClustAl(trademark) (version W or X).
FIG. 12 shows the alignment results of various kinases of the TGF superfamily Ser/Thr kinase receptor, in the above four regions, with TGF-xcex2I. Of course where the kinase is TGFxcex21 itself the positions are given, and there is no need for alignment.
The term xe2x80x9cwherein up to 40% of amino acids of the native sequence have been replaced with a naturally or non-naturally occurring amino acid or with a peptidomimetic organic moietyxe2x80x9d in accordance with the present invention, concerns an amino acid sequence, which shares at least 60% of its amino acid with the native sequence as described in (a), (b), (c) or (d) above, but some of the amino acids were replaced either by other naturally occurring amino acids, (both conservative and non-conservative substitutions), by non-naturally occurring amino acids (both conservative and non-conservative substitutions), or with organic moieties which serve either as true peptidomimetics (i.e., having the same steric and electrochemical properties as the replaced amino acid), or merely serve as spacers in lieu of an amino acid, so as to keep the spatial relations between the amino acid spanning this replaced amino acid. Guidelines for the determination of the replacements and substitutions are given in the detailed description part of the specification. Preferably no more than 30%, 25% or 20% of the amino acids are replaced.
The term xe2x80x9cwherein up to 40% of the amino acids have their side chains chemically modifiedxe2x80x9d refers to a variant which has the same type of amino acid residue, but to its side chain a functional group has been added. For example, the side chain may be phosphorylated, glycosylated, fatty acylated, acylated, iodinated or carboxyacylated. Other examples of chemical substitutions are known in the art and given below.
The term xe2x80x9cup to 20% of the amino have been deletedxe2x80x9d refer to an amino acid sequence which maintains at least 80% of its amino acids. Preferably no more than 10% of the amino acids are deleted and more preferably none of the amino acids are deleted.
The term xe2x80x9cprovided that at least 50% of the amino acids in the parent protein are maintained unaltered in the variantsxe2x80x9d, the up to 40% substitution, up to 40% chemical modification and up to 20% deletions are combinatorial, i.e., the same variant may have substitutions, chemical modifications and deletions so long as at least 50% of the native amino acids are identical to those of the native sequence both as regards the amino acid and its position. In addition, the properties of the parent sequence, in modulating tissue remodeling (for example as determined by TGF-xcex2 associated signal transduction), have to be maintained in the variant, typically at the same or at a higher level.
When calculating 40% (or 35, 30, 25, 20%) replacements, or 20% (or 10%) deletions from sequences, the number of actual amino acids should be rounded mathematically, so that 40% of an 11-mer sequence (4.4) is four amino acids and 40% of a 12-mer sequence (4.8) is five amino acids.
Typically xe2x80x9cessential amino acidsxe2x80x9d are maintained or replaced by conservative substitutions while non-essential amino acids may be maintained, deleted or replaced by conservative or non-conservative replacements. Generally, essential amino acids are determined by various Structure-Activity-Relationship (SAR) techniques (for example amino acids when replaced by Ala cause loss of activity) are replaced by conservative substitution while non-essential amino acids c an b e deleted or replaced by any type of substitution. Guidelines for the determination of the deletions, replacements and substitutions are given in the Detailed Description part of the specification.
The term xe2x80x9cregionxe2x80x9d refers to a sequence in a specific location in the specific member of the TGF-xcex2 superfamily Ser/Thr kinase receptor which corresponds to the positions selected from: 249 to 279 of TGF-xcex2I (termed: HJ loop); positions 119 to 139 (termed: xcex1D loop); positions 104 to 115 (termed: B4-B5 region); and positions 89 to 103 (termed: A-loop).
The term xe2x80x9ccorresponding D-amino acidxe2x80x9d refers to the replacement of the naturally occurring L-configuration of the natural amino acid residue by the D-configuration of the same residue.
The term xe2x80x9cat least one peptidic backbone has been altered to a non-naturally occurring peptidic backbonexe2x80x9d means that the bond between the N- of one amino acid residue to the C- of the next has been altered to non-naturally occurring bonds, for example, by reduction (to xe2x80x94CH2xe2x80x94NHxe2x80x94), alkylation (methylation) on the nitrogen atom, or the bonds have been replaced by amidic bonds, urea bonds, or sulfonamide bonds, etheric bonds (xe2x80x94CH2xe2x80x94Oxe2x80x94), thioetheric bonds (xe2x80x94CH2xe2x80x94Sxe2x80x94), or to xe2x80x94CSxe2x80x94NHxe2x80x94. The side chain of the residue may be shifted to the backbone nitrogen to obtain N-alkylated-Gly (a peptidoid).
The term xe2x80x9cin reverse orderxe2x80x9d refers to the fact that the sequence of (a) to (f) may have the order of the amino acids as it appears in the native TGF-xcex2 kinase from N- to the C-direction, or may have the reversed order (as read in the C- to N-direction). For example, if a subsequence of the A-region of TGFxcex2 receptor is QTVML (residues 1-5 of SEQ ID NO:53) a sequence in a reverse order is LMVTQ (SEQ ID NO:60). It has been found that many times sequences having such a reverse order can have the same properties, in small peptides, as the xe2x80x9ccorrectxe2x80x9d order, probably due to the fact that the side chains, and not the peptidic backbones, are those responsible for interaction with other cellular components. Particularly preferred are what is termed xe2x80x9cretro inversoxe2x80x9d peptidesxe2x80x94i.e., peptides that have both a reverse order as explained above, and in addition each and every single one of the amino acids has been replaced by the non-naturally occurring D-amino acid counterpart, so that the net end result, as regards the positioning of the side chains (the combination of reverse order and the change from L to D), is zero change. Such retro-inverso peptides, while having similar binding properties to the native peptide, were found to be resistant to degradation.
The present invention further concerns a method for the modulation of tissue-remodeling in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound comprising a sequence selected from:
(a) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 superfamily Ser/Thr kinase receptor, in positions of the kinase corresponding to positions 249 to 279 of TGF-xcex2 Receptor 1) (HJ loop);
(b) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 superfamily Ser/Thr kinase receptor, in positions of the kinase corresponding to positions 119 to 139of TGF-xcex2 Receptor 1 (xcex1D region);
(c) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 superfamily Ser/Thr kinase receptor, in positions of the kinase corresponding to positions 104 to 115 of TGF-xcex2 Receptor 1 (B4-B5 region);
(d) a sequence which is a continuous stretch of at least five amino acids present in a native TGF-xcex2 superfamily Ser/Thr kinase receptor, in positions of the kinase corresponding to positions 89 to 103 of TGFxcex2 TGF-xcex2 Receptor 1 (A-region);
(e) a variant of a sequence according to any one of (a) to (d) wherein up to 40% of the amino acid of the native sequence have been replaced with a naturally or non-naturally occurring amino acid or with a peptidomimetic organic moiety; and/or up to 40% of the amino acids have their side chains chemically modified; and/or up to 20% of the amino acids have been deleted; provided that at least 50% of the amino acids in the parent sequence of (a) to (d) are maintained unaltered in the variant, and provided that the variant maintains the biological activity of the parent sequences of (a) to (d);
(f) a sequence of any one of (a) to (e) wherein at least one of the amino acids is replaced by the corresponding D-amino acid;
(g) a sequence of any one of (a) to (f) wherein at least one of the peptidic backbones has been altered to a non-naturally occurring peptidic backbone;
(h) a sequence being the sequence of any one of (a) to (g) in reverse order; and
(i) a combination of two or more of the sequences of (a) to (h).
The term xe2x80x9csubjectxe2x80x9d in the meaning of the present invention concerns a human, but can also include animals for veterinary purposes.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d is the quantity of compound which results in an improved clinical outcome as a result of the treatment compared with a typical clinical outcome in the absence of the treatment. An xe2x80x9cimproved clinical outcomexe2x80x9d results in an individual with the disease experiencing fewer symptoms or complications of the disease, including a longer life expectancy, as a result of the treatment as well as the prevention of the disease before it occurs. With respect to bones, an xe2x80x9cimproved clinical outcomexe2x80x9d includes, but is not limited, to a shorter time period until bone healing is achieved; or to the healing of bone in cases where normal bone healing does not take place such as where a large bone section is missing (xe2x80x9cnon-unionxe2x80x9d). With respect to post-surgical fibrosis or scarring, the term refers to smaller amount fibrosis or scarring or prevention of the formation of either one before they are expected to occur, such as prevention of scarring or fibrosis after surgery. With respect to alopecia it concerns elimination or decrease in the amount of hair-loss in general and in particular following chemotherapeutic or radiotherapeutic treatment. The amount of compounds of the invention administered to the individual will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs as well as on the mode of administration. In the case of tissue remodeling, many applications are local to the tissue, the amounts used when locally administered may be smaller than in systemic administration. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Typically, a therapeutically effective amount of the compound can range from about 1 mg per day to about 1000 mg per day for an adult. Preferably, the dosage ranges from about 1 mg per day to about 100 mg per day.
The method for therapeutic treatment, by way of tissue remodeling may be used for improving bone healing (including improvement in rate of healing, achievement of healing in cases where a large bone segment xe2x80x9cnon-unionxe2x80x9d is missing, augmentation of various bones, increasing the probability of obtaining healthy bones); decreasing fibrosis (as determined by decreased scarring, decreased adhesion, decreased deposition of collagen and extracellular matrix in various diseases and post-operational and injury including injury to the skin and connective tissue), decreased alopecia and the like.
The present invention also concerns methods for obtaining the above compounds which can be used in a method for modulation of tissue remodeling. Thus the present invention concerns a method for obtaining a compound for the modulation of tissue-remodeling the method comprising:
(i) providing a plurality of candidate compounds comprising the sequences as defined above;
(ii) assaying the candidate compounds obtained in (i) in a test assay and determining the level of tissue-remodeling;
(iii) selecting those compounds which modulate tissue-remodeling as compared to the tissue-remodeling in the same test assay in the absence of the candidate compounds, thereby obtaining compounds being capable of modulating tissue modulating activities.
Assays for determining tissue-modeling activity will be specified in more detail hereinafter below. However, many of these assays require testing in vivo, or in tissue cultures, and thus are rather expensive and complicated for initial screening purposes. Therefore, many times it is preferable to conduct initial screening in a cellular, or cell-free system, which is used to determine the level of TGF-xcex2 superfamily Ser/Thr kinase receptor signal transduction pathways. Examples of such systems are assays for determination of the number of cells, which proliferation is dependent on this pathway, measurement of collagen deposition by cells, determination of level of phosphorylation of the substrate of the TGF-xcex2 kinase in intact cells or in cell free systems and the like. Compounds which are capable of modulating a TGF-xcex2 associated signal transduction have a high probably of also being active in tissue remodeling, however, this activity still has to be verified in a more relevant physiological assays.
Typically, modulation of the level of TGF-xcex2 associated signal transduction refers to a change in the level of phosphorylation of at least one the TGF-xcex2 substrate (which may be the direct or indirect substrate.
It should be appreciated that for the purpose of modulation, it is best to choose a compound comprising sequences derived from the same member of the TGF-xcex2 superfamily Ser/Thr kinase receptor as the one known (for example, in literature or from clinical information) to be involved in the modulation of the specific tissue of interest.
It should be appreciated that some of compounds comprising the sequences of (a) to (i) above, have better tissue remodeling modulating activities than others, and the selection of the compounds which are active in the tissue remodeling process should be done according to the method as indicated above.
Preferably, the determination of the sequence to be included in the candidate compound for modulating tissue remodeling should be carried out with the following steps:
(i) determining which specific member of the TGF-xcex2 superfamily Ser/Thr kinase receptor is involved in the remodeling of the tissue to be modulated, and determining the sequence of the specific member from a database of amino acid sequences;
(ii) aligning the sequence of the catalytic unit of the member obtained in (i) with the sequence of the catalytic unit of TGF-xcex2I receptor, and determining the sequence of the specific member in four regions corresponding, in the alignment, to the following, positions of TGF-xcex2I: 249 to 279 (HJ-loop), 119 to 139(xcex1D region), 104 to 115 (B4-B5 region), 89 to 103 (A-region);
(iii) determining a continuous stretch of at least 5 amino acids of any of the four regions of (ii) above, that is sorter than the length of the entire region and has modeling activities of the tissue-remodeling or TGF-xcex2kinase associated signal transduction, by: synthesizing a plurality of subsequences (optionally partially overlapping subsequences) of 5-10 mer from any of the above four regions; testing those sequences in a test assay for determining tissue-remodeling or TGF-xcex2-associated signal transduction modulating activities, and selecting those sequences that have tissue remodeling or TGF-xcex2-associated signal transduction modulating activities;
(iv) determining in the sequences of (ii) or in the sequences selected in (iii) above, essential and non-essential amino acids by: preparing a plurality of modified sequences wherein in each modified sequence a single and different position in the native sequence has been replaced with a test amino acid (preferably with Ala); testing those modified sequences in a test assay to determine tissue-remodeling or TGF-xcex2-associated signal transduction modulating activities; those amino acids which when replaced caused a statistically significant change in tissue-remodeling TGF-xcex2-associated signal transduction modulating activity being essential amino acids, and those amino acids which when replaced, did not cause a statistically significant change in tissue remodeling/TGF-xcex2-associated signal transduction modulating activity, being non-essential amino acids;
(v) preparing a plurality of compounds comprising sequences selected from:
(1) the sequences of (ii);
(2) the sequences selected in (iii);
(3) the sequences of (ii) or the selected sequence of (iii), wherein at least one of the essential amino acids has been replaced by a conservatively substituted naturally or non-naturally occurring amino acid, or a conservative peptidomimetic organic moiety; and/or at least one of the non-essential amino acids has been deleted, or substituted (conservatively or non-conservatively) by naturally or non-naturally occurring amino acids or a peptidomimetic;
(4) the sequences of (1) to (3) in a reverse order;
(5) the sequence of (4) wherein all the amino acids have been replaced by their D-counterpart residues;
said compounds of (v) being candidate compounds for modulating tissue remodeling.
Conceptually, the first step is deciding which specific member of the TGF-xcex2 superfamily Ser/Thr kinase receptor is involved in the tissue-remodeling which is to be modulated. This can be done for example by carrying out a literature search, and determining which kinase is known to be involved in the processes of tissue remodeling that is to be modulated.
Once this specific kinase is identified, its sequence can be obtained from amino acid sequence databases and it is possible to locate the above four regions, simply by aligning the sequence of the catalytic unit of the specific kinase chosen, as present in the database, with the TGF-xcex2 Receptor I catalytic subunit, and by this finding the specific sequences of the four regions. Although the sequences of the region are not very long (12-31 amino acids long), it is of course desirable to find the shorter subsequence of at least 5 continuous amino acids present within this full region, and use this shorter sequence in the compound of the invention. Finding this short subsequence is a routine procedure, which can be achieved by several possible manners, such as by synthesizing sequences of 5-10 mer having partially overlapping, or adjacent sequences, and optionally optimizing the chosen sequence (if rather longer sequences such as, for example, 8-10 mer are used) by sequentially deleting from one or both of its terminal amino acids until the optimal shorter sequence (not necessarily the shortest but a combination of length and activity should be considered) sequence still having tissue-remodeling modulating activities is obtained.
After obtaining shorter subsequence which still has tissue-remodeling properties (as may be determined both by a tissue-remodeling assay or in an indicative assay such as modulation of TGF-xcex2-kinase associated signal transduction), it is necessary to find which amino acids either in the sequence of the full region but preferably in the sequence of the shorter subsequence are essential (crucial for the modulating activity) and which are non-essential. This can be done by routine procedure, wherein a plurality of sequences are prepared, wherein in each sequence a single (and different) amino acid has been replaced, as compared to the native sequence by a xe2x80x9ctest amino acidsxe2x80x9dxe2x80x94 usually the amino acid residue Alanine (a procedure known as: xe2x80x9cAla-scanxe2x80x9d). Each of the plurality of sequences is again tested for its tissue-remodeling/TGF-xcex2-associated signal transduction modulating activities. Amino acids which when replaced cause lost, or substantial decrease in the modulating activity of the full sequence is considered as xe2x80x9cessential amino acidsxe2x80x9d. Amino acids which when replaced do not caused a change of modulating activity of the sequence are referred to as xe2x80x9cnon-essentialxe2x80x9d amino acids (the loss or decrease should be determined by statistically significant manners).
Finally, as a last step, a plurality of sequences is prepared which may comprise either the full native sequence of any of the regions, short subsequence of at least 5 amino acids as appearing in any of the regions, sequences wherein at least one essential amino acid has been replaced by conservative substitution by a naturally, non-naturally occurring amino acid or by a peptidomimetic organic moiety; and/or an amino acid sequence wherein at least one amino acid (present in a non-essential position) has been deleted, or an amino acid in a non-essential position has been replaced by conservative or non-conservative substitution by a naturally occurring, non-naturally occurring, or organic peptidomimetic moiety.
For example, 1, 2, 3, 4, 5, 6, 7, 8, amino acids may be replaced in the sequence used in the compound of the invention as compared with the native sequence present in the kinase. The total combination of replacements, deletions, etc. should be such that the resulting variant host where at least 50% of the amino acids of the native sequence are present unaltered.
A notable exception to the above is the use of retro-inverso amino acids (in reverse order as compared to the native sequence), where when the peptide is in the reversed order, all of its amino acids are replaced with their D-counterparts.
When preparing the compound, it is possible to proceed by one of two strategies: by one strategy it is possible to test (for tissue remodeling or TGF-xcex2-associated signal transduction modulating activities) a full compoundxe2x80x94i.e., a compound comprising both a candidate sequence, and for example, non-amino acid moieties such as hydrophobic moieties present in one of its terminals. This strategy is generally used where the test assay is intact cells or in-vivo where the issue of penetration through membranes, addressed by addition of a hydrophobic moiety, is crucial.
Alternatively, it is possible to first optimize the sequence alone (preferably by testing it in a cell-free system for TGF-xcex2-signaling dependent phosphorylation) so as to first find the best sequence possible, and then add to the optimal sequence other moieties, such as hydrophobic moieties, etc. to improve other properties of the compound as a whole such as for improving the penetration into cells, resistance to degradation, etc.
The present invention also concerns compounds for modulation of tissue-remodeling obtained by any of the above methods.
The present invention further concerns pharmaceutical compositions comprising the above compounds as active ingredients. The pharmaceutical composition may contain one species of compounds of the invention or a combination of several species of the invention.
The pharmaceutical compositions of the invention should be used for treatment of conditions or disorders wherein a therapeutically beneficial effect can be evident through the modulation of tissue remodeling.

Yissum Research Development Company of the Hebrew University of Jerusalem


A method for forming contact studs to connect the substrate component devices to the overlying wiring patterns is disclosed herein. The contact studs are formed by a combination of blanket depositing an adhesive and reactive layer into the contact opening. Onto said adhesive and reactive layer is deposited a seed layer and said contact stud is completed by filling the contact opening with a third metal layer. Preferably, the adhesive and reactive layer is a transition metal and the seen and fillter layers are refractory metals.

1. Field of the Invention
In general, this invention relates to a method for producing multi-level, co-planar, metal/insulator interconnection layers for high performance semiconductor chips and more particularly to a method for making contact studs for interconnecting the metallization layers at different levels in said semiconductor chips.
2. Description of Related Art
A semiconductor chip consists of an array of devices whose contacts are interconnected by patterns of metal wires. In VLSI chips these metal patterns are multi-layered and separated by layers of an insulating material. Interconnections between the layers of metal wiring patterns are made by holes (or via-holes), which are etched through the insulator. Typical chip designs consist of one, two or three wiring levels.
The forming of an interconnection metallurgy system for integrated circuit devices has conventionally been done by blanket depositing a metal layer, forming a photoresist layer on the metal layer, exposing the resist to the desired metallurgy pattern, developing the resist, and subsequently etching the exposed portions of the underlying metal layer to thereby form the interconnection wiring. The wiring pattern was subsequently covered by an insulating layer, planarized and then another metallurgy pattern was then formed on said insulating layer. Contact between layers was made through via holes, until the desired interconnection wiring diagram was complete.
Interconnection of the multi-level wiring structure to the device contacts on the substrate was typically made by the incorporation of an access wiring layer.
In an effort to further reduce device processing time and reduce size, access wiring layers were replaced by via studs or vertical wires, known in the art as studs. Studs were now able to be placed directly on top of the device contacts to make interconnection with the above multi-level wiring system.
Studs are known to be formed by using what is termed an "expendable mask method" or "lift-off method", which was initially described and claimed in U.S. Pat. No. 2,559,389. Improvements to the basic lift-off method have been made, as for example in commonly assigned U.S. Pat. Nos. 3,849,136 filed Aug. 31, 1973 and 3,873,361 filed Nov. 29, 1973. However, the lift-off technique for forming stud metallurgy does not totally overcome the problems of: uniform deposition of stud metallurgy, planarity problems associated with achieving uniform stud height, high aspect ratio stud depositions, and electromigration tendencies of the preferred stud metallurgies.
An example of the problems associated with stud formation can be seen from the use of lift-off with aluminum as the stud metal. The aluminum must be deposited by evaporation; however, evaporation of aluminum is known to create problems of voids and irregularities in its formation.
Another problem associated with stud formation is the structural irregularities which are known to be created by the nature of the master-slice processing. For example, as master-slice processing causes variation in depth of contacts, the height of the deposited studs becomes variable such that the aluminum studs must be ion etched back to form a planar surface. (See, for example, U.S. Pat. No. 4,541,169.).
While there have been many techniques proposed for achieving planarity of studs, these techniques have all been based on the use of Ion Etch back with lift-off, (For example, U.S. Pat. Nos. 4,410,622; 4,470,874, and 4,541,169) wherein the results have not achieved consistent planarity and the methods have been limited to larger line widths and studs.
Moreover, with aluminum as a stud metal, there are added problems in terms of contact alloying/penetration, electromigration, and silicon particle formation. Silicon will form particles and thin films in the contact holes which results in the aluminum being isolated from the substrate surface. Moreover, with the ever-continuing reduction of dimensions in the device multi-level interconnection system, limits as to insulation and electromigration tolerances in using aluminum are encountered.
Electromigration problems associated with aluminum deposited on silicon type substrates have been proposed to be cured by use of tungsten films as diffusion barriers (M. L. Green and R. A. Levy, Technical Proceedings, SEMICON/EAST 85, Semiconductor Equipment and Materials Institute Meeting, September, 1985, pp. 57-63). However, defects "wormholes" originating at the tungsten/silicon interface and problems with preferential erosion of N+ implanted silicon versus P+ implanted silicon from LPCVD tungsten deposition have taught against the solitary use of LPCVD tungsten as the contact stud filler metallurgy.
In a more recent publication (U. Fritsch, G. Higelin, G. Enders and W. Muller; Technical Proceedings, V-MIC Conference Meeting; June 13, 14, 1988, pp. 69-75), the authors propose one possible solution to the defects associated with deposition of CVD tungsten in CMOS devices. Therein, the authors propose first depositing a titanium/titanium nitride diffusion barrier by sputtering followed by a CVD tungsten layer. However, this structure does not create a seed layer which matches the atomic structure of the CVD refractory metal which is to follow. Therefore, there can be interface problems between the CVD refractory fill metal and the titanium nitride layer such as mechanical separation and/or electrical resistance.
It is therefore an object of the present invention to produce a method for producing a multi-level co-planar metal and insulation interconnection system for VLSI semiconductor devices.
It is a further object of the present invention to produce planar studs for contacting the substrate to the first level of interconnection wiring.
It is a still further object of the present invention to produce interconnect studs, incapable of being produced with liftoff tolerances (i.e., stud widths of less than 1.5 .mu.m).
It is another object of the present invention to produce substrate contact studs of a non-reactive metal for void free deposition with low electromigration characteristics.
It is still another object of the present invention to provide a substrate contact stud structure useable with different component contacts.

Contact stud structure for semiconductor devices

International Business Machines Corporation


A container for collecting, transporting, storing, delivering and dispensing fluid. The container has a hollow tube with an outer circumference diameter and is configured to receive a plunger. A collection adaptor and a dispensing adaptor provide interchangeable coupling of a variable volume container such as a syringe with a collection device such as a breast pump and a dispensing device such as a nipple. The container also has a circumferential seal assembly secured at one end of the hollow tube. The seal assembly outer diameter is substantially similar to the hollow tube outer diameter.

Maintaining aseptic integrity is of great importance in many fluid collection and dispensing applications. For example, in the delivery of breast milk or formula to premature infants who are unable to feed regularly, freshness and prevention of contamination are critical. The delivery of enteral fluids is often controlled by regulations and medical standards of practice.
In addition to proper collection and dispensing of biological fluids, such as breast milk or formula, it is also desirable to provide for the containment, mixing and delivery of pharmaceutical or nutritional supplements. Various consumer and/or professional applications would benefit from improved systems and methods for fluid collection and delivery.
It is to the provision of improved systems and methods for fluid collection and delivery that the present invention is primarily directed.

This patent is subject to a terminal disclaimer.


A suspension mounting arrangement for a suspended layer in a semiconductor accelerometer, the layer being suspended above and spaced apart from a substrate. The arrangement includes a common anchor point associated with the substrate; first and second anchor points associated with the suspended layer; a first flexible serpentine arm coupled between the first anchor point and the common anchor point; and a second flexible serpentine arm coupled between the second anchor point and the common anchor point. The first and second flexible serpentine arms are symmetrically configured with respect to one another.

The invention relates in general to a suspension arrangement for a semiconductor accelerometer, and more specifically to such an arrangement which provides complete symmetry to the entire device.
Surface micromachining is an IC-compatible technology in which a thin film microstructure material (typically polysilicon) is deposited and patterned on a sacrificial spacer layer (typically silicon dioxide), and the spacer is subsequently removed to release the free-standing microstructures. This technology has been used by Analog Devices, Inc. to fabricate integrated accelerometers. The devices typically include a moving mass and fixed cantilever electrodes that are interdigitated within electrodes associated with the moving mass. When the structure experiences an acceleration in the sensitive axis the capacitance between the fixed and moving fingers is changed, and a measurable signal results. Suspension tethers are designed to resist motion in the non-sensitive in-plane axis.
Due to the very small scale dimensions of the elements of a semiconductor accelerometer, particularly the moving mass, several problems can occur. Since the materials used, e.g., polysilicon, result in a uniform stress gradient through the thickness of elements such as the mass, the elements tend to bow or warp. In addition the tensile stress of the mass tends to cause shrinkage. If portions of the mass are too low, thus closer to the substrate surface, there is the possibility of contact and sticking. If the mass contacts or sticks to the underlying substrate, the acceleration measurements become inaccurate. Also, the bowing or warping of elements can result in the electrode fingers not aligning well, thus affecting measurement performance. In all, such problems can be optimized by trimming the responses, however, such techniques are time consuming and expensive.

Suspension arrangement for semiconductor accelerometer


A disk drive includes a housing, an actuator arm rotatably mounted in the housing, a suspension fixed at a base end portion thereof to a front end portion of the actuator arm, a head slider mounted on a front end portion of the suspension and having an electromagnetic transducer, and a head IC mounted on the suspension in adjacent relationship with the head slider. The disk drive further includes a radiating flexible printed circuit sheet mounted on the suspension and the actuator arm, the radiating flexible printed circuit sheet having a first end portion fixed to the suspension and thermally connected to the head IC and a second end portion fixed to the actuator arm.

1. Field of the Invention
The present invention relates to a disk drive, and more particularly to a head assembly for use in a disk drive.
2. Description of the Related Art
In recent years, a magnetic disk drive as a kind of external storage for a computer has been desired to have a small size and a large storage capacity. A method for increasing the storage capacity of a magnetic disk drive is to increase the number of magnetic disks mounted on a spindle motor, and accordingly the spacing of the magnetic disks mounted tends to be decreased in a recent magnetic disk drive. A contact start stop (CSS) type flying magnetic head slider is widely used in a recent magnetic disk drive. The CSS type flying magnetic head slider comes into contact with a magnetic disk in stopping the operation of the magnetic disk drive, while flying a microscopic height from the surface of the magnetic disk by the action of an air flow produced over the surface of the magnetic disk rotating at a high speed in recording/reproducing information.
The CSS type flying magnetic head slider includes an electromagnetic transducer (magnetic head element) for reading/writing information from/to the magnetic disk. The magnetic head slider is supported by a suspension. When the rotation of the magnetic disk is stopped, the magnetic head slider including the electromagnetic transducer comes into contact with the disk surface, whereas when the magnetic disk is in rotation, the electromagnetic transducer included in the magnetic head slider supported to the suspension is moved above the disk surface to a desired track, thereby recording/reproducing information with the electromagnetic transducer.
A portable personal computer such as a notebook personal computer is often carried, and it is therefore required to have high shock resistance. Accordingly, such a personal computer generally employs a load/unload type magnetic disk drive designed so that a head slider is unloaded from the surface of a magnetic disk when the computer is powered off or put into a sleep mode and that the head slider is loaded to the surface of the magnetic disk when the computer is operated. That is, in the load/unload type magnetic disc drive, when the computer is powered off or put into a sleep mode, a horn portion formed at the front end of the head slider is seated on a ramp (inclined portion) of a ramp member provided near the outer circumference of the magnetic disk to retract the head slider flying a microscopic height above the disk surface from the magnetic disk. Accordingly, even when the computer receives shock, it is possible to avoid the possibility that the head slider may collide with the magnetic disk to damage it.
Both in the CSS type magnetic disk drive and in the load/unload type magnetic disk drive, data writing to the magnetic disk and data reading from the magnetic disk are performed by using a read/write head integrated circuit (head IC) mounted on a main printed circuit board provided in the magnetic disk drive. In writing data, a write signal is supplied from the head IC through a relay flexible printed circuit sheet (relay FPC) to the magnetic head element, and the data is written onto the magnetic disk by the magnetic head element according to the write signal. In reading data, a very small electrical signal read by the magnetic head element is supplied through the relay FPC to the head IC incorporating a preamplifier, and this signal is amplified in the head IC.
Thus, the data recorded on the magnetic disk is read by the magnetic head element (electromagnetic transducer). However, since the head IC is mounted on the main printed circuit board in the prior art, the distance between the magnetic head element and the head IC is large, so that a data transfer rate is low. It is considered that the data transfer rate can be increased by mounting the head IC on the suspension in adjacent relationship with the magnetic head slider. However, in the case of simply mounting the head IC on the suspension, the temperature of the head IC becomes high because it is a highly heating element. As a result, the reliability of the head IC is reduced to cause a difficulty in practical use.
It is therefore an object of the present invention to provide a disk drive which can sufficiently radiate the heat generated from a head IC mounted on a suspension.
It is another object of the present invention to provide a head assembly which can efficiently radiate the heat generated from a head IC mounted on a suspension.
In accordance with an aspect of the present invention, there is provided a disk drive comprising a housing; an actuator arm rotatably mounted in the housing; a suspension fixed at a base end portion thereof to a front end portion of the actuator arm; a head slider mounted on a front end portion of the suspension and having an electromagnetic transducer; a head IC mounted on the suspension; and a radiating flexible printed circuit sheet mounted on the suspension and the actuator arm, the radiating flexible printed circuit sheet having a first end portion fixed to the suspension and thermally connected to the head IC and a second end portion fixed to the actuator arm.
The suspension has a first printed wiring pattern for connecting the electromagnetic transducer and the head IC and a second printed wiring pattern for connecting the head IC to an external circuit. Preferably, the head IC is connected through metal bumps to the first and second printed wiring patterns. Preferably, the radiating flexible printed circuit sheet comprises an insulating layer formed of polyimide or the like and a copper foil embedded in the insulating layer. The disk drive further comprises a relay flexible printed circuit sheet bonded to a side surface of the actuator arm, and the second printed wiring pattern is connected to the relay flexible printed circuit sheet.
With the above structure of the disk drive according to the present invention, the heat generated from the head IC mounted on the suspension can be efficiently transferred through the radiating flexible printed circuit sheet to the actuator arm, thereby preventing a temperature rise of the head IC to a given temperature or higher.
In accordance with another aspect of the present invention, there is provided a head assembly comprising a suspension; a head slider mounted on a front end portion of the suspension and having an electromagnetic transducer; a head IC mounted on the suspension; and a radiating flexible printed circuit sheet mounted on the suspension, the radiating flexible printed circuit sheet having a first end portion fixed to the suspension and thermally connected to the head IC and a second end portion extending beyond a base end portion of the suspension.
Preferably, the suspension has a first printed wiring pattern for connecting the electromagnetic transducer and the head IC and a second printed wiring pattern for connecting the head IC to an external circuit.
The above and other objects, features and advantages of the present invention and the manner of realizing them will become more apparent, and the invention itself will best be understood from a study of the following description and appended claims with reference to the attached drawings showing some preferred embodiments of the invention.

Head assembly having a head IC heat radiating element


The present invention relates to an ear-cleansing agent for companion animals and a method of manufacturing the same. More particularly, the present invention relates to an ear-cleansing agent for companion animals, which includes distilled Chamaecyparis obtusa water extracted from Chamaecyparis obtusa trees so as to enable antibacterial action, deodorization, and exfoliation and which does not include a surfactant so that the skin is not irritated even when the ear-cleansing agent is not washed away using water, and a method of manufacturing the same.

Companion animals are animals that are raised at home for a person to emotionally depend thereon. In the past, the term "pet" was often used to indicate that such an animal is cute and pleasing to persons. However, such animals have come to be called companion animals with growing awareness that animals are not toys but companions living together with persons. Examples of companion animals include mammals such as hamsters, birds such as parrots and canaries, fish such as goldfishes and tropical fishes, and reptiles such as iguanas and chameleons, in addition to dogs and cats.
In recent years, particularly, increasing numbers of dogs and cats have been living together in the same space as humans. Accordingly, the importance of hygiene and cleanliness has increased, and there is increasing need for the development of cleansing agents for companion animals only, which do not irritate the skin of companion animals.

Ear-cleansing agent for companion animals and method of manufacturing the same


Techniques are disclosed for increasing the throughput of a multiplexed electrical bus by exploiting available pipeline stages of a computer or other system. For example, a method for increasing a throughput of an electrical bus that connects at least two devices in a system comprises introducing at least one signal hold stage in a signal-receiving one of the two devices, such that a maximum frequency at which the two devices are operated is not limited by a number of cycles of an operating frequency of the electrical bus needed for a signal to propagate from a signal-transmitting one of the two devices to the signal-receiving one of the two devices. Preferably, the signal hold stage introduced in the signal-receiving one of the two devices is a pipeline stage re-allocated from the signal-transmitting one of the two devices.

Existing systems such as computer systems are known to employ relatively wide electrical buses for carrying address, data and various control signals to and from a multitude of devices. For example, these electrical buses serve to couple two or more integrated circuits (chips) in a computer or other system. There can be thousands of signals traversing between chips. Wiring massive amounts of signal connections across various chips and printed circuit boards can cause system cost to significantly escalate.
To limit this wiring or cabling cost, and also the number of chip inputs/outputs (I/O), it has become common practice to multiplex signals across electrical buses. As is known, multiplexing is a signal processing method by which multiple signals are combined into one signal over a shared medium, e.g., wire. Multiplexing reduces the number of wires or cables that need to be routed.

Increasing throughput of multiplexed electrical bus in pipe-lined architecture

International Business Machines Corporation


Sliding doors of showcases are normally locked by safety locks, the installation of which must, however, be very precise when a play of the sliding door in rest position is to be avoided. By the new device a safe locking of a showcase is also to be achieved without having to pay attention to an especially precise installation. The sliding door (4) is held in the closed position and rest position, respectively, by permanent magnets (7) provided at the showcase, the magnetic force of which can be neutralized by an electric coil and direct current flowing therethrough. As the installation of the permanent magnets must not be so precise, such a showcase can be built up also outside a workshop, for instance on the building site. Furthermore, in this way the safe closure of sliding doors can be achieved when at positions where known locking means are difficult to reach.

The invention relates to a device for locking a sliding door of a showcase having a face construction.
Showcases used for exhibition purposes have an opening at least at one side allowing access to the interior of the showcase and being in a condition to be closed frequently by a sliding door. For securing the sliding door in the closed position or in the rest position safety locks are used in order to protect the often valuable comtents against unauthorized access. The mounting of the safety locks must be very precise so that there is no play when the sliding door is in the closed position. Hence the mounting is very time-consuming and makes the building of such as showcase very expensive. Often the locks are difficult to get it.

Device for locking a sliding door of a showcase having a frame construction


An electronic salt meter including a sensor rod, salt meter body and receiving components to measure a temperature and salinity. The electronic salt meter includes a first and sensor electrode and a temperature sensor to detect a temperature of the measurement object. A measurement monitoring unit detects whether the first and second sensor electrodes are electrically connected to each other. A salinity measurement unit applies an AC power to the first and second sensor electrodes to measure salinity of the measurement object. A temperature measurement unit applies a power to the temperature sensor to measure the temperature of the measurement object. A thermal equilibrium detection unit stores the temperature value previously measured, and when the temperature variation is less than a predetermined threshold, it is determined as a thermal equilibrium state. A room-temperature salinity conversion unit converts the salinity value into a salinity value at room temperature.

1. Field of the Invention
The present invention relates to an electronic salt meter, and more particularly, to an electronic salt meter in which a temperature sensor quickly reaches thermal equilibrium with a measurement object to quickly and accurately measure a temperature, and a power is automatically turned on when measured to improve use convenience by removing various buttons.
2. Description of the Related Art
Recently, as attention regarding well-being and health has increased, the interest in a salt meter for measuring salinity contained in foods is increasing because salty foods are discovered as one of main factors causing a high blood pressure.
A conductivity method, which uses a conductivity difference depending on an amount of salinity contained in an object to be measured (hereinafter, referred to as a measurement object) and a reflectometer method, which uses a light refraction difference depending on the amount of salinity contained in the measurement object are widely known as a method for measuring salinity of a measurement object such as foods or sea water.
The conductivity method is a method in which conductivity due to ionized salinity (electrolyte) melting in the measurement object is measured using current flowing between two electrodes. Here, the salinity has an influence on a temperature. Typically, it is known that the salinity is changed by about 2% as the temperature is changed by about 1° C.
Thus, it is important that the temperature is precisely measured to precisely measure the salinity. Also, for avoiding user's confusion, the salinity of the measurement object is unified as salinity (unit, %, or ppt) at room temperature (25° C.), and then, the unified salinity is displayed. Thus, it is necessary that salinity measured at different temperatures is converted into salinity at room temperature.


A modulation apparatus comprising a first modulating section that outputs a first modulated signal having a fixed amplitude and a set phase; a second modulating section that outputs a second modulated signal having the fixed amplitude and a set phase; an adding section that outputs the output signal as the sum of the first and second modulated signals; a calculating section that calculates two phases to be set respectively in the first and second modulating sections, based on designated amplitude and phase; an allocating section that allocates, for the first and second modulated signals, the two phases calculated by the calculating section such that the first and second modulated signals are each connected more smoothly; and a setting section that sets the phase allocated for the first modulated signal in the first modulating section and sets the phase allocated for the second modulated signal in the second modulating section.

1. Technical Field
The present invention relates to a modulation apparatus, a phase setting method, and a test apparatus.
2. Related Art
A conventional LINC circuit is known that outputs a modulated signal, as shown in Non-Patent Documents 1 to 5, for example. The LINC circuit uses two IQ modulators to generate two modulated signals with different phases and fixed amplitudes, and outputs the desired amplitude and phase signals by adding together the two modulated signals generated by the two IQ modulators. This type of LINC circuit can output a signal with a high amplitude and low distortion, regardless of the linearity of the amplifier at the output stage.
Non-Patent Document 1: Lars Sundström, "Spectral Sensitivity of LINC Transmitters to Quadrature Modulator Misalignments", IEEE TRANSACTIONS ON VEHICULAR TECHNOLOGY, VOL. 49, NO. 4, JULY 2000
Non-Patent Document 2: Fernando J. Casadevall, and Antonio Valdovinos, "Performance Analysis of QAM Modulations Applied to the LINC Transmitter", IEEE TRANSACTIONS ON VEHICULAR TECHNOLOGY, VOL. 42, NO. 4, NOVEMBER 1993
Non-Patent Document 3: Gwenael Poitau, Ahmed Birafane and Ammar Kouki, "Experimental Characterization of LINC Outphasing Combiners' Efficiency and Linearity", IEEE Radio and Wireless Conference, 2004
Non-Patent Document 4: Young Yun Woo, Jaehyok Yi, Youngoo Yang, and Bumman Kim, "SDR Transmitter Based on LINC Amplifier with Bias Control", Microwave Symposium Digest, 2003 IEEE MTT-S International
Non-Patent Document 5: Xuejun Zhang, Lawrence E. Larson, and Peter Asbeck, "Design of Linear RF Outphasing Power Amplifiers", (USA), Artech House, 2003
In a LINC circuit, the control section calculates two phases based on the phase and amplitude designated from the outside, and sets the two calculated phases in the two IQ modulators. Regardless of which of the two IQ modulators the two calculated phases are set in, the amplitude and phase of the output signal from the LINC circuit are theoretically the same. However, if the frequency bands of the modulated signals output from the IQ modulators are wide, the distortion of the output signal is increased by the hardware.
Furthermore, when the amplitude of the output signal is zero, two modulated signals differing by 180° should be output. However, the frequency band widens if the phases of the two modulated signals are not set appropriately, and this increases the distortion in the output signal due to the hardware.
If the phases for the two IQ modulators are set to achieve band-limiting, the distortion in the modulated signals due to the hardware is decreased. However, the error of the phases set for the two IQ modulators increases. On the other hand, if the phases for the two IQ modulators are not set to achieve band-limiting, the phases of the two IQ modulators can be set in the usual manner but the distortion of the output signal increases.

Modulation apparatus, phase setting method and test apparatus


An infant seat (10) is disclosed for use with a vehicle seat (12) and seat belt (14) to restrain and protect an infant in the event the vehicle undergoes a sudden change in velocity. The seat (10) includes a foldable frame (16), preferably formed from a single sheet of material, and including a plurality of living hinges that flexibly join the various sections of the frame. A pair of arms (18 and 20) are included to lock the frame in an open position and include slots designed to engage the seat belt.

Modern vehicles include many safety features. For example, vehicles are typically designed to restrain and protect adult passengers in the event the vehicle undergoes a sudden change in velocity. To that end, the vehicle includes a seat, rigidly secured to the frame of the vehicle, and, for example, a seat belt and shoulder harness that cooperatively restrain the passenger relative to the seat. Unfortunately, conventional arrangements are often ergonomically unsuited for use with infants.
A relatively wide variety of infant seats have been developed to address the limitations of conventional vehicle seats. Many such infant seats have a rigid molded body covered by a cushion or pad. The infant seat is secured to the vehicle seat by the vehicle seat belt and a separate shoulder harness assembly is used to restrain the infant in the infant seat.
Conventional infant seats of this type, however, exhibit a number of shortcomings. For example, these seats are relatively bulky and awkward to transport and store. While not a problem when the infant seat is intended for semipermanent use in a particular vehicle, these factors are undesirable if the infant seat is to be used only occasionally or in a variety of different vehicles. Another disadvantage of conventional infant seats employing rigid molded bodies is that they tend to be relatively expensive to manufacture.
As an alternative, several different types of foldable infant seats have also been developed. For example, U.S. Pat. No. 5,002,338 (Gisser) discloses a child restraint device including a support structure defined by a base, a flap, and wings, joined by various hinges that allow the device to be opened and closed. The restraint device is attached to the vehicle seat by a special strap and a harness secures the infant in the device. Like the infant seats described above, however, the Gisser restraint device appears to be relatively expensive and difficult to manufacture. Also, the Gisser device is not freestanding and requires an additional strap for attachment to the vehicle seat.
Another folding infant support device is disclosed in U.S. Pat. No. 3,054,637 (Pambello). The Pambello device includes a seat and leg supporting member and a back and head supporting member, joined by an adjustable positioning assembly that allows their relative angular orientation to be controlled. Straps are provided to restrain an infant in the device and to carry the device. Special brackets are required to attach the device to a vehicle seat. As will be appreciated, the Pambello device is not particularly compact, appears to be relatively expensive and difficult to manufacture, and, due to the bracket arrangement required, is not easily adapted for use with alternative vehicle seats.
In U.S. Pat. No. 4,900,087 (Crisp), a child seat that is built into an automobile seat is disclosed. The child seat is bolted to the automobile seat and includes hinged seat panels that fold out to support the child. Straps are employed to restrain the child in the seat. Like the Gisser and Pambello devices, the Crisp seat appears to be relatively difficult and expensive to manufacture. In addition, although the Crisp seat can be unbolted from the vehicle seat, it is inconvenient to remove the seat for use elsewhere. Further, the Crisp seat is not designed for use with conventional vehicle seats.
A number of foldable seats have also been developed that appear unsuitable for use in restraining and protecting an infant in the event a vehicle undergoes a sudden change in velocity. These seats are typically simple and inexpensive but do not appear to have the structural strength required to protect the infant. Examples of such seats are disclosed in U.S. Pat. No. 4,775,188 (Fuchs et al.) and U.S. Pat. No. 2,960,149 (Throssel).
In view of the preceding observations, it would be desirable to provide a seat that is relatively inexpensive, simple to manufacture, easily attached to a variety of different vehicle seats, readily transported and stored, freestanding, and able to adequately restrain and protect an infant in the event of a sudden change in vehicle velocity.


A bend sensor for use in wirelessly sensing an amount of bend of a joint or other monitored object. The sensor includes a radio frequency (RF) antenna and an integrated circuit linked to the antenna. The integrated circuit or chip is passive and responds to, or is powered by, a read signal received by the antenna to transmit a reflected signal via the antenna such as to an RFID reader. The sensor also includes a transducer linked to the integrated circuit. The transducer defines reflecting impedance, which modulates amplitude and phase of the reflected signal. The transducer has impedance varying with deformation or bend. In one example, the transducer includes an upper conductor, and the amount of the deformation is defined by a bend radius of the upper conductor. The read signal may be at 5 GHz or higher such with the antenna and the transducer being microwave structures.

1. Field of the Description
The present invention relates, in general, to methods and systems for sensing the bend of an object such as a human joint (e.g., curling of a person's finger), and, more particularly, to a wireless backscatter bend sensor and systems and methods for processing signals or data from the bend sensor to quantify bend of an object upon which the bend sensor is mounted or attached.
2. Relevant Background
There are numerous settings where it is desirable to sense motion of objects such as whether or not an object is bent and, if so, to what degree is the object bent. For example, it may be desirable to sense the motion of a hand or of fingers of the hand for use in motion capture systems and for use in human computer interaction devices. In other cases, a bend sensor may be used to sense bend in applications requiring monitoring the health or status of a structure.
More specifically, in theme parks and other environments, it would be useful to provide visitors of the park with gloves that can be used to interact with robotic characters, interactive displays, and so on to obtain a user-controlled and immersive entertainment experience. If a bend sensor (or sensors) was imbedded in each finger of the glove, it would be possible to sense when and to what extent the fingers were bent, e.g., wiggle your fingers and a nearby robotic character also wiggles its fingers or otherwise responds to the visitor or glove user's control input. The bend sensing ability would allow the visitors/users to manipulate objects in the nearby environment that may otherwise appear inanimate, thereby creating a unique and exciting experience.
For this exemplary and many other uses, the bend sensor would preferably meet a number of design goals or criteria. First, it may be preferred that the bend sensors be inexpensive so that a park or other facility operator can distribute the sensors without charge or at relatively low fees to the users. The goal of an inexpensive bend sensor may also be furthered by eliminating or limiting the amount of conventional electronics typically provided with sensors such as analog-to-digital converters, amplifiers, and the like. Second, the bend sensor may be designed to have low power consumption and even be passive in some cases (e.g., not require a battery or other bulky and costly power source). Third, the use of the bend sensor may be adapted or configured such that the resolution and/or the degrees of freedom may be relatively low, which will also further the first and/or second goals of lower costs and low power consumption by simplifying the sensor design. Fourth, it typically is preferable that communications between the sensor and processor/controller be wireless such that the user is free to move about their environment.
Previous bend sensors have typically not met one or more of these goals with many bend sensors being costly, requiring significant amounts of power (e.g., an onboard battery), providing high resolution and degrees of freedom (adding to complexity of the design and output signal processing), and using a wired or direct communication link between the sensors and the processor/controller. With regard to hand joints, gloves have been designed and produced to sense the angle of hand joints or bend of fingers. These gloves are often referred to as data gloves and may utilize fiber optics linked to a processor or sensors relying on piezoresistive materials, such as conductive elastomers, conductive ink, sliding resistors, and conductive fluid. In other cases, such as for use with robotic devices, numerous strain gauges may be provided on or near joints. Each of these solutions to monitoring or sensing bend or motion may be expensive to design and manufacture, thereby limiting their use in many situations where cost is a significant parameter.
Hence, there remains a need for a bend sensor that meets the demand for a wireless sensor that can be implemented at low cost. Preferably, such a sensor would be passive or semi-passive and not require an onboard power source or a charge pump. The sensor, in some cases, may also be relatively low resolution with its output or sensing signals leading to less complex processing to determine sensed bending or movement of a monitored joint or other object.

Backscatter RFID sensor with a bend transducer


A method and system for managing tokens in an electronic gaming environment includes managing computer-readable tokens that may be issued by an issuer and transferred to an original recipient of the issued tokens, and thereafter, to one or more players of electronic casino games and/or to electronic gaming devices at which the players intend to play the casino games. The issued tokens may not be redeemable by the issuer, but may be redeemable by the original recipient of the issued tokens or an intermediary device of a hierarchy of devices including the original recipient and the electronic gaming devices. The players may play single-player and/or multi-player games. Tokens wagered during a single-player game may be cancelled if the wager is lost. Tokens wagered during a multi-player game may not be cancelled, but instead transferred to the winner of the multi-player game.

In traditional online casinos, poker rooms and sportsbooks, a player is first required to register and to create an account on a gaming server of the casino, poker room or sportsbook. The player is then required to pre-fund the account by purchasing credit that can be consumed by the player in wagering and game play activities. The gaming server stores, at all times, a credit balance corresponding to the player's account, which decreases in accordance with wagers made by the player and increases in accordance with any winnings paid out to the player. Such pre-funding is usually made by means of a credit card, debit card, e-wallet, check or wire transfer.
When playing a game at the online casino, or participating in a multi-player poker game at the online poker room, the player may make any wager that is permitted for the particular game being played. The player's wagers are usually denominated in integral units of credit and there must be sufficient credit in the player's account to cover any wager that is made by the player.
The gaming server stores data relating to the type and size of each player's wager in a database on an associated storage device, such as a magnetic or optical disk.
In an online multiplayer poker room, the operator of the poker room levies a commission (or "rake") on the cumulative amount of all player wagers in a multi-player poker game in order to derive revenue. The risk associated with game play is carried by the participating players who risk losing any wagers. It will be appreciated that the operator's rake can only be determined in arrears, once all of the players in the multi-player poker game have finished wagering.
The operator of an online casino, on the other hand, carries the risk associated with game play and is required to pay out all player wins. Traditionally, the revenue of an online casino is a function of a "gross win" derived by the casino over a particular period, which is the sum of all wagers made by players during the period less the sum of all winnings achieved by the players during the same period. As is the case in a multi-player poker game, the revenue of an online casino can only be established in arrears, at the end of the period in question.
The traditional model of requiring the player to first register with an online casino or poker room to create a credit account on a gaming server, and to pre-fund the credit account by means of a payment instrument is unnecessarily restrictive, particularly in jurisdictions where usage of such payment instruments is not widespread.
There is thus a desire for an alternative on-line gaming model in which a player is able to commence online game play without first requiring the player to perform a registration step followed by pre-funding of a player credit account.

Token management system and method of operation thereof


Disclosed herein are techniques and equipment for saving game history data and package identification information for software packages used to provide a game cycle on a wager gaming machine. The game cycle may later be re-created using the game history data and software packages. For scenarios where some or all of the software packages used are no longer present on the gaming machine at the time of re-creation, the package identification information may be referenced to determine which software packages are missing and need to be provided to enable full game cycle re-creation.

Entities offering wager gaming may wish to track a gaming machine's play history and to recover or re-create aspects of past-played games based on the tracked play history. For example, a wager gaming machine offering video slot machine play may save a screen capture of each game play provided by the wager gaming machine. The screen captures may later be referenced to determine what game outcome was displayed on the gaming machine for various game plays. Some gaming machines may save multiple screen captures during a game play to capture various stages of play during the game play, such as initial wager, additional wagers, initial draws, additional draws, etc.

Recovery of graphical game history after game software package has been removed from electronic gaming machine


A vibration damping device is equipped with a mass body disposed spaced apart from a rotational center axis of a rotary shaft by a certain distance, and a rolling bearing that rotatably supports the mass body with respect to the rotary shaft and holds a support posture of the mass body with respect to the rotational center axis of the rotary shaft constant.

1. Field of the Invention
The invention relates to a vibration damping device and a power transmission device, and more particularly, to a vibration damping device that damps vibrations of a rotary shaft in a translational direction other than a rotational direction thereof using an inertial mass (mass body), and a power transmission device fitted with the vibration damping device.
2. Description of the Related Art
As a vibration damping device that exerts a vibration damping effect in the vicinity of a resonance frequency of a vibration system, a dynamic vibration absorber composed of an inertial mass and an elastic body is often employed. For example, there is known a vibration damping device with an inertial mass and an elastic body whose rigidities are so tuned as to exert a vibration damping effect at the time of bending resonance or torsional resonance of a rotary shaft in a power transmission path of a vehicle.
In such a damper device, however, the rigidity of the elastic body changes due to a change in the temperature of an environment in which the damper device is used, and the rotational speed of the rotary shaft is likely to fluctuate due to a shift of the center of gravity of the inertial mass. In some cases, therefore, it is difficult to obtain a stable vibration damping effect.
Thus, there is a damper weight obtained by, for example, mounting an automatic aligning bearing on a rotary shaft and providing an outer race thereof with a mass (e.g., see Japanese Patent Application Publication No. 10-306844 (JP-A-10-306844)).
However, in the vibration damping device according to the related art as described above, the inertial mass body is rockable on a plane including a rotational center axis of the rotary shaft. Therefore, there is a problem in that bending vibrations of the rotary shaft cannot be effectively damped.
Further, among various noises/vibrations of a rear-wheel-drive vehicle, there is a whining noise on a vehicle interior side resulting from the resonance of a rotation input portion of a rear differential device as a phenomenon with a high degree of difficulty which causes troubles in ensuring the performance. As a measure against this whining noise, it is conceivable to fit the rotation input portion of the rear differential device with a torsional damper so as to suppress a compelling force causing resonance of the rotation input portion. However, the torsional damper is more costly than a mass damper. Besides, in the torsional damper, a resonance frequency exerting a vibration damping effect for torsional resonance is often greatly different from a resonance frequency exerting a vibration damping effect for bending resonance. It is very difficult to achieve both the vibration damping effects for torsional resonance and bending resonance, whose resonance frequencies are greatly different from each other, within a limited installation space, namely, the input portion of the differential device. Thus, in the case where torsional resonance is sufficiently damped at a certain frequency to attempt a reduction in the level of vibrations, the vibration level of bending resonance may worsen at other frequencies.
In addition, the torsional damper achieves a vibration damping effect by adding a new vibration system to existing torsional vibrations and hence changing the compliance characteristic of the torsional vibrations. For structural reasons, however, an inertial mass acts in a rotational direction of the existing torsional vibrations. Therefore, the peak level of the torsional vibrations tend to decrease, and a mesh point dynamic rigidity (compelling force) emerging as an inverse of compliance tends to worsen. Furthermore, around a target frequency, there always emerges a frequency lowering the level of vibrations because of the formation of a trough in the compliance characteristic. The mesh point dynamic rigidity is likely to worsen in that respect as well. As described above, the torsional damper has both an effect of reducing the level of vibrations for a compelling force and an adverse influence accompanied thereby. In some cases, therefore, a sufficient vibration damping effect as expected cannot be exerted even when the characteristic of the damper is adjusted.

Vibration damping device and power transmission device